Treatment of hepatocellular carcinoma

文档序号：1471265 发布日期：2020-02-21 浏览：27次中文

阅读说明：本技术 肝细胞癌的治疗 (Treatment of hepatocellular carcinoma ) 是由玉井俊行于 2018-05-15 设计创作，主要内容包括：本披露提供了用于用乐伐替尼或其药学上可接受的盐治疗肝细胞癌(例如，不可切除的HCC)的方法。本披露还涵盖乐伐替尼或其药学上可接受的盐的本文所述的剂量方案，用于在根据本文所述的任一种方法治疗肝细胞癌(例如，不可切除的肝细胞癌)中使用。还披露了特别有用的剂量和发生一个或多个不良事件时的剂量修改。(The present disclosure provides methods for treating hepatocellular carcinoma (e.g., unresectable HCC) with lenvatinib or a pharmaceutically acceptable salt thereof. The present disclosure also encompasses the dosage regimen described herein of lenvatinib, or a pharmaceutically acceptable salt thereof, for use in treating hepatocellular carcinoma (e.g., unresectable hepatocellular carcinoma) according to any of the methods described herein. Particularly useful dosages and modifications of dosages in the event of one or more adverse events are also disclosed.)

1. A method of treating unresectable hepatocellular carcinoma, the method comprising administering to a human subject having unresectable hepatocellular carcinoma a dosage regimen of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 12 mg/day when the body weight of the human subject is equal to or exceeds 60kg or (ii) 8 mg/day when the body weight of the human subject is less than 60 kg.

2. A method of treating unresectable hepatocellular carcinoma, the method comprising administering to a human subject having unresectable hepatocellular carcinoma and moderate liver damage classified as Child-Pugh class B according to the Child-Pugh classification a dosage regimen of 8 mg/day of lenvatinib or a pharmaceutically acceptable salt thereof.

3. A method of treating unresectable hepatocellular carcinoma, the method comprising administering to a human subject having unresectable hepatocellular carcinoma a first dosage regimen comprising a dose of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 12 mg/day when the body weight of the human subject is equal to or greater than 60kg or (ii) 8 mg/day when the body weight of the human subject is less than 60kg,

wherein the human subject exhibits the onset of a first grade 3 non-hematologic toxicity during treatment with the first dosage regimen, and the method further comprises:

(a) terminating administration of the first dosage regimen after the first grade 3 non-hematologic toxicity has occurred until the first grade 3 non-hematologic toxicity subsides to grade 0-1 or baseline, and administering to the human subject a second dosage regimen comprising the following doses of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 8 mg/day when the body weight of the human subject equals or exceeds 60kg or (ii) 4 mg/day when the body weight of the human subject is less than 60kg, wherein the human subject exhibits the onset of a second grade 3 non-hematologic toxicity during treatment with the second dosage regimen;

(b) terminating administration of the second dosage regimen after the second grade 3 non-hematologic toxicity has occurred until the second grade 3 non-hematologic toxicity subsides to grade 0-1 or baseline, and administering to the human subject a third dosage regimen comprising the following doses of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 4 mg/day when the body weight of the human subject equals or exceeds 60kg or (ii) 4mg every other day when the body weight of the human subject is less than 60kg, wherein the human subject exhibits the onset of a third grade 3 non-hematologic toxicity during treatment with the third dosage regimen; and is

(c) Terminating administration of the third dosage regimen after the third grade 3 non-hematologic toxicity has occurred until the third grade 3 non-hematologic toxicity subsides to grade 0-1 or baseline, and administering to the human subject every other day a fourth dosage regimen comprising lenvatinib at a dose of 4mg or a pharmaceutically acceptable salt thereof when the body weight of the human subject equals or exceeds 60 kg.

4. A method of treating unresectable hepatocellular carcinoma, the method comprising administering to a human subject having unresectable hepatocellular carcinoma and moderate liver damage classified as Child-Pugh class B according to the Child-Pugh classification a first dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 8 mg/day,

wherein the human subject exhibits the onset of a first grade 3 non-hematologic toxicity during treatment with the first dosage regimen, and the method further comprises:

(a) terminating administration of the first dosage regimen after the first grade 3 non-hematologic toxicity has occurred until the first grade 3 non-hematologic toxicity subsides to grade 0-1 or baseline, and administering to the human subject a second dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4 mg/day, wherein the human subject exhibits an occurrence of a second grade 3 non-hematologic toxicity during treatment with the second dosage regimen;

(b) terminating administration of the second dosage regimen after the occurrence of the second grade 3 non-hematologic toxicity until the second grade 3 non-hematologic toxicity subsides to grade 0-1 or baseline, and administering a third dosage regimen comprising a dose of 4mg of lenvatinib or a pharmaceutically acceptable salt thereof to the human subject every other day, wherein the human subject exhibits the occurrence of a third grade 3 non-hematologic toxicity during treatment with the third dosage regimen; and is

(c) Terminating administration of the third dosage regimen after the third grade 3 non-hematologic toxicity has occurred.

5. A method of treating unresectable hepatocellular carcinoma, the method comprising administering to a human subject having unresectable hepatocellular carcinoma a first dosage regimen comprising a dose of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 12 mg/day when the body weight of the human subject is equal to or greater than 60kg or (ii) 8 mg/day when the body weight of the human subject is less than 60kg,

wherein the human subject exhibits an onset of a first sustained and intolerable grade 2 or 3 non-hematologic toxicity during treatment with the first dosage regimen, and the method further comprises:

(a) terminating administration of the first dosage regimen after the first sustained and intolerant grade 2 or grade 3 non-hematologic toxicity has occurred until the first sustained and intolerant grade 2 or grade 3 non-hematologic toxicity subsides to grade 0-1 or baseline, and administering to the human subject a second dosage regimen comprising the following doses of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 8 mg/day when the body weight of the human subject equals or exceeds 60kg or (ii) 4 mg/day when the body weight of the human subject is less than 60kg, wherein the human subject exhibits the onset of a second sustained and intolerable grade 2 or grade 3 non-hematologic toxicity during treatment with the second dosage regimen;

(b) terminating administration of the second dosage regimen after the occurrence of the second sustained and intolerant grade 2 or grade 3 non-hematologic toxicity until the second sustained and intolerant grade 2 or grade 3 non-hematologic toxicity subsides to grade 0-1 or baseline, and administering to the human subject a third dosage regimen comprising the following dose of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 4 mg/day when the body weight of the human subject equals or exceeds 60kg or (ii) 4mg every other day when the body weight of the human subject is less than 60kg, wherein the human subject exhibits the onset of a third sustained and intolerable grade 2 or grade 3 non-hematologic toxicity during treatment with the third dosage regimen; and is

(c) Terminating administration of the third dosage regimen after the third sustained and intolerant grade 2 or grade 3 non-hematologic toxicity has occurred until the third sustained and intolerant grade 2 or grade 3 non-hematologic toxicity subsides to grade 0-1 or baseline, and administering to the human subject every other day a fourth dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4mg when the body weight of the human subject equals or exceeds 60 kg.

6. A method of treating unresectable hepatocellular carcinoma, the method comprising administering to a human subject having unresectable hepatocellular carcinoma and moderate liver damage classified as Child-Pugh class B according to the Child-Pugh classification a first dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 8 mg/day,

(a) terminating administration of the first dosage regimen after the occurrence of the first sustained and intolerant grade 2 or grade 3 non-hematological toxicity until the first sustained and intolerant grade 2 or grade 3 non-hematological toxicity subsides to grade 0-1 or baseline, and administering to the human subject a second dosage regimen comprising a dose of 4 mg/day lenvatinib or a pharmaceutically acceptable salt thereof, wherein the human subject exhibits the occurrence of a second sustained and intolerant grade 2 or grade 3 non-hematological toxicity during treatment with the second dosage regimen;

(b) terminating administration of the second dosage regimen after the occurrence of the second sustained and intolerant grade 2 or grade 3 non-hematological toxicity until the second sustained and intolerant grade 2 or grade 3 non-hematological toxicity subsides to grade 0-1 or baseline, and administering a third dosage regimen comprising a dose of 4mg of lenvatinib or a pharmaceutically acceptable salt thereof to the human subject every other day, wherein the human subject exhibits the occurrence of a third sustained and intolerant grade 2 or grade 3 non-hematological toxicity during treatment with the third dosage regimen; and is

(c) Terminating administration of the third dosage regimen after the third sustained and intolerable grade 2 or 3 non-hematologic toxicity has occurred.

7. A method of treating unresectable hepatocellular carcinoma, the method comprising administering to a human subject having unresectable hepatocellular carcinoma a first dosage regimen comprising a dose of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 12 mg/day when the body weight of the human subject is equal to or greater than 60kg or (ii) 8 mg/day when the body weight of the human subject is less than 60kg,

wherein the human subject exhibits a first persistent and intolerable grade 2 or 3 non-hematologic toxicity or non-life threatening grade 4 laboratory test abnormality during treatment with the first dose regimen, and the method further comprises:

(a) terminating administration of the first dosage regimen after the occurrence of the first sustained and intolerant grade 2 or grade 3 non-hematologic toxicity or non-life threatening grade 4 laboratory test abnormality until the first sustained and intolerant grade 2 or grade 3 non-hematologic toxicity or non-life threatening grade 4 laboratory test abnormality subsides to grade 0-1 or baseline, and administering to the human subject a second dosage regimen comprising a dose of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 8 mg/day when the body weight of the human subject equals or exceeds 60kg or (ii) 4 mg/day when the body weight of the human subject is less than 60kg, wherein the human subject exhibits a second sustained and intolerable grade 2 or 3 non-hematologic toxicity or occurrence of a non-life-threatening grade 4 laboratory test abnormality during treatment with the second dosage regimen;

(b) terminating administration of the second dosage regimen after the occurrence of the second persistent and intolerable grade 2 or 3 non-hematologic toxicity or non-life threatening grade 4 laboratory test abnormality until the second persistent and intolerable grade 2 or 3 non-hematologic toxicity or non-life threatening grade 4 laboratory test abnormality subsides to grade 0-1 or baseline, and administering to the human subject a third dosage regimen comprising a dose of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 4 mg/day when the body weight of the human subject equals or exceeds 60kg or (ii) 4mg every other day when the body weight of the human subject is less than 60kg, wherein the human subject exhibits the occurrence of a third sustained and intolerable grade 2 or 3 non-hematologic toxicity or non-life threatening grade 4 laboratory test abnormality during treatment with the third dosage regimen; and is

(c) Terminating administration of the third dosage regimen after the occurrence of the third persistent and intolerable grade 2 or 3 non-hematologic toxicity or non-life threatening grade 4 laboratory test abnormality until the third persistent and intolerable grade 2 or 3 non-hematologic toxicity or non-life threatening grade 4 laboratory test abnormality subsides to grade 0-1 or baseline, and administering to the human subject every other day a fourth dosage regimen comprising a dose of 4mg of lenvatinib or a pharmaceutically acceptable salt thereof when the body weight of the human subject equals or exceeds 60 kg.

8. A method of treating unresectable hepatocellular carcinoma, the method comprising administering to a human subject having unresectable hepatocellular carcinoma and moderate liver damage classified as Child-Pugh class B according to the Child-Pugh classification a first dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 8 mg/day,

(a) terminating administration of the first dosage regimen after the occurrence of the first persistent and intolerant grade 2 or grade 3 non-hematologic toxicity or non-life threatening grade 4 laboratory test abnormality until the first persistent and intolerant grade 2 or grade 3 non-hematologic toxicity or non-life threatening grade 4 laboratory test abnormality subsides to grade 0-1 or baseline, and administering to the human subject a second dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4 mg/day, wherein the human subject exhibits the occurrence of a second persistent and intolerant grade 2 or grade 3 non-hematologic toxicity or non-life threatening grade 4 laboratory test abnormality during treatment with the second dosage regimen;

(b) terminating administration of the second dosage regimen after the occurrence of the second persistent and intolerant grade 2 or grade 3 non-hematologic toxicity or non-life threatening grade 4 laboratory test abnormality until the second persistent and intolerant grade 2 or grade 3 non-hematologic toxicity or non-life threatening grade 4 laboratory test abnormality subsides to grade 0-1 or baseline, and administering to the human subject a third dosage regimen comprising a dose of 4mg of lenvatinib or a pharmaceutically acceptable salt thereof every other day, wherein the human subject exhibits the occurrence of a third persistent and intolerant grade 2 or grade 3 non-hematologic toxicity or non-life threatening grade 4 laboratory test abnormality during treatment with the third dosage regimen; and is

(c) Administration of the third dosage regimen is terminated after the third persistent and intolerable grade 2 or 3 non-hematologic toxicity or non-life threatening grade 4 laboratory test abnormality occurs.

9. The method of any one of claims 2-8, wherein the human subject exhibits an onset of grade 4 non-hematologic toxicity other than a non-life-threatening grade 4 laboratory test abnormality during treatment with the first, second, third, or fourth dosage regimen, and the method further comprises terminating administration of the dosage regimen after the onset of the grade 4 non-hematologic toxicity other than the non-life-threatening grade 4 laboratory test abnormality.

10. A method of treating unresectable hepatocellular carcinoma, the method comprising administering to a human subject having unresectable hepatocellular carcinoma a first dosage regimen comprising a dose of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 12 mg/day when the body weight of the human subject is equal to or greater than 60kg or (ii) 8 mg/day when the body weight of the human subject is less than 60kg,

wherein the human subject exhibits the onset of a first grade 3 hematologic toxicity or proteinuria during treatment with the first dosage regimen, and the method further comprises:

(a) terminating administration of the first dosage regimen after the first grade 3 hematological toxicity or proteinuria has occurred until the first grade 3 hematological toxicity or proteinuria has resolved to grade 0-2 or baseline, and administering to the human subject a second dosage regimen comprising a dose of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 12 mg/day when the body weight of the human subject equals or exceeds 60kg or (ii) 8 mg/day when the body weight of the human subject is less than 60kg, wherein the human subject exhibits a second grade 3 hematological toxicity or the occurrence of proteinuria during treatment with the second dosage regimen;

(b) terminating administration of the second dosage regimen after the occurrence of the second grade 3 hematological toxicity or proteinuria until the second grade 3 hematological toxicity or proteinuria resolves to grade 0-2 or baseline, and administering to the human subject a third dosage regimen comprising a dose of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 8 mg/day when the body weight of the human subject equals or exceeds 60kg or (ii) 4 mg/day when the body weight of the human subject is less than 60kg, wherein the human subject exhibits a third grade 3 hematological toxicity or the occurrence of proteinuria during treatment with the third dosage regimen;

(c) terminating administration of the third dosage regimen after the third grade 3 hematological toxicity or proteinuria has occurred until the third grade 3 hematological toxicity or proteinuria has resolved to grade 0-2 or baseline, and administering to the human subject a fourth dosage regimen comprising a dose of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 4 mg/day when the body weight of the human subject equals or exceeds 60kg or (ii) 4mg every other day when the body weight of the human subject is less than 60kg, wherein the human subject exhibits a fourth grade 3 hematological toxicity or the occurrence of proteinuria during treatment with the fourth dosage regimen; and is

(d) Terminating administration of the fourth dosage regimen after the occurrence of the fourth grade 3 hematological toxicity or proteinuria until the fourth grade 3 hematological toxicity or proteinuria subsides to grade 0-2 or baseline, and administering to the human subject every other day a fifth dosage regimen comprising lenvatinib at a dose of 4mg or a pharmaceutically acceptable salt thereof when the body weight of the human subject equals or exceeds 60 kg.

11. A method of treating unresectable hepatocellular carcinoma, the method comprising administering to a human subject having unresectable hepatocellular carcinoma and moderate liver damage classified as Child-Pugh class B according to the Child-Pugh classification a first dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 8 mg/day,

wherein the human subject exhibits the onset of a first grade 3 hematologic toxicity or proteinuria during treatment with the first dosage regimen, and the method further comprises:

(a) terminating administration of the first dosage regimen after the occurrence of the first grade 3 hematological toxicity or proteinuria until the first grade 3 hematological toxicity or proteinuria resolves to grade 0-2 or baseline, and administering to the human subject a second dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 8 mg/day, wherein the human subject exhibits the occurrence of a second grade 3 hematological toxicity or proteinuria during treatment with the second dosage regimen;

(b) terminating administration of the second dosage regimen after the occurrence of the second grade 3 hematological toxicity or proteinuria until the second grade 3 hematological toxicity or proteinuria resolves to grade 0-2 or baseline, and administering to the human subject a third dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4 mg/day, wherein the human subject exhibits the occurrence of a third grade 3 hematological toxicity or proteinuria during treatment with the third dosage regimen;

(c) terminating administration of the third dosage regimen after the occurrence of the third grade 3 hematological toxicity or proteinuria until the third grade 3 hematological toxicity or proteinuria subsides to grade 0-2 or baseline, and administering a fourth dosage regimen comprising a dose of 4mg of lenvatinib or a pharmaceutically acceptable salt thereof to the human subject every other day, wherein the human subject exhibits the occurrence of a fourth grade 3 hematological toxicity or proteinuria during treatment with the fourth dosage regimen; and is

(d) Administration of the fourth dosage regimen is terminated after the fourth grade 3 hematological toxicity or proteinuria has occurred.

12. A method of treating unresectable hepatocellular carcinoma, the method comprising administering to a human subject having unresectable hepatocellular carcinoma a first dosage regimen comprising a dose of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 12 mg/day when the body weight of the human subject is equal to or greater than 60kg or (ii) 8 mg/day when the body weight of the human subject is less than 60kg,

wherein the human subject exhibits the onset of a first grade 4 hematologic toxicity during treatment with the first dosage regimen, and the method further comprises:

(a) terminating administration of the first dosage regimen after the first grade 4 hematological toxicity has occurred until the first grade 4 hematological toxicity subsides to grade 0-2 or baseline, and administering to the human subject a second dosage regimen comprising the following dose of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 8 mg/day when the body weight of the human subject equals or exceeds 60kg or (ii) 4 mg/day when the body weight of the human subject is less than 60kg, wherein the human subject exhibits the onset of a second grade 4 hematologic toxicity during treatment with the second dosage regimen;

(b) terminating administration of the second dosage regimen after the second grade 4 hematological toxicity has occurred until the second grade 4 hematological toxicity subsides to grade 0-2 or baseline, and administering to the human subject a third dosage regimen comprising the following dose of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 4 mg/day when the body weight of the human subject equals or exceeds 60kg or (ii) 4mg every other day when the body weight of the human subject is less than 60kg, wherein the human subject exhibits the onset of a third grade 4 hematological toxicity during treatment with the third dosage regimen; and is

(c) Terminating administration of the third dosage regimen after the third grade 4 hematological toxicity has occurred until the third grade 4 hematological toxicity subsides to grade 0-2 or baseline, and administering to the human subject a fourth dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4mg every other day when the body weight of the human subject equals or exceeds 60 kg.

13. A method of treating unresectable hepatocellular carcinoma, the method comprising administering to a human subject having unresectable hepatocellular carcinoma and moderate liver damage classified as Child-Pugh class B according to the Child-Pugh classification a first dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 8 mg/day,

wherein the human subject exhibits the onset of a first grade 4 hematologic toxicity during treatment with the first dosage regimen, and the method further comprises:

(a) terminating administration of the first dosage regimen after the occurrence of the first grade 4 hematological toxicity until the first grade 4 hematological toxicity subsides to grade 0-2 or baseline, and administering to the human subject a second dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4 mg/day, wherein the human subject exhibits the occurrence of a second grade 4 hematological toxicity during treatment with the second dosage regimen;

(b) terminating administration of the second dosage regimen after the occurrence of the second grade 4 hematological toxicity until the second grade 4 hematological toxicity subsides to grade 0-2 or baseline, and administering a third dosage regimen comprising a dose of 4mg of lenvatinib or a pharmaceutically acceptable salt thereof to the human subject every other day, wherein the human subject exhibits an occurrence of a third grade 4 hematological toxicity during treatment with the third dosage regimen; and is

(c) Administration of the third dosage regimen is terminated after the third grade 4 hematological toxicity has occurred.

14. A method of treating unresectable hepatocellular carcinoma, the method comprising administering to a human subject having unresectable hepatocellular carcinoma a first dosage regimen comprising a dose of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 12 mg/day when the body weight of the human subject is equal to or greater than 60kg or (ii) 8 mg/day when the body weight of the human subject is less than 60kg,

(I) Wherein the human subject exhibits a first persistent and intolerable grade 2 or 3 non-hematologic toxicity or non-life threatening grade 4 laboratory test abnormality during treatment with the first dose regimen, and the method further comprises:

(II) wherein the human subject exhibits the onset of a first grade 3 hematologic toxicity or proteinuria during treatment with the first dosage regimen, and the method further comprises:

(III) wherein the human subject exhibits the onset of a first grade 4 hematologic toxicity during treatment with the first dosage regimen, and the method further comprises:

15. A method of treating unresectable hepatocellular carcinoma, the method comprising administering to a human subject having unresectable hepatocellular carcinoma and moderate liver damage classified as Child-Pugh class B according to the Child-Pugh classification a first dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 8 mg/day,

(I) wherein the human subject exhibits a first persistent and intolerable grade 2 or 3 non-hematologic toxicity or non-life threatening grade 4 laboratory test abnormality during treatment with the first dose regimen, and the method further comprises:

(II) wherein the human subject exhibits the onset of a first grade 3 hematologic toxicity or proteinuria during treatment with the first dosage regimen, and the method further comprises:

(b) terminating administration of the second dosage regimen after the occurrence of the second grade 3 hematological toxicity or proteinuria until the second grade 3 hematological toxicity or proteinuria resolves to grade 0-2 or baseline, and administering to the human subject a third dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4 mg/day, wherein the human subject exhibits the occurrence of a third grade 3 hematological toxicity or proteinuria during treatment with the third dosage regimen;

(d) Terminating administration of the fourth dosage regimen after the occurrence of the fourth grade 3 hematological toxicity or proteinuria; or

(III) wherein the human subject exhibits the onset of a first grade 4 hematologic toxicity during treatment with the first dosage regimen, and the method further comprises:

(c) Administration of the third dosage regimen is terminated after the third grade 4 hematological toxicity has occurred.

16. The method of any one of claims 10-15, wherein the human subject exhibits the onset of grade 4 non-hematologic toxicity other than a non-life-threatening grade 4 laboratory test abnormality during treatment with the first, second, third, fourth, or fifth dosage regimen, and the method further comprises terminating administration of the dosage regimen after the onset of the grade 4 non-hematologic toxicity other than the non-life-threatening grade 4 laboratory test abnormality.

17. A method of treating unresectable hepatocellular carcinoma, the method comprising administering to a human subject having unresectable hepatocellular carcinoma a first dosage regimen comprising a dose of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 12 mg/day when the body weight of the human subject is equal to or greater than 60kg or (ii) 8 mg/day when the body weight of the human subject is less than 60kg,

(I) wherein the human subject exhibits the occurrence of grade 3 hematological toxicity or proteinuria during treatment with the first dosage regimen, other than a clinically relevant laboratory test abnormality, and the method further comprises:

(a) terminating administration of the first dosage regimen after the occurrence of the grade 3 hematological toxicity or proteinuria other than the first non-clinically relevant laboratory test abnormality until the grade 3 hematological toxicity or proteinuria other than the first non-clinically relevant laboratory test abnormality subsides to grade 0-2 or baseline, and administering to the human subject a second dosage regimen comprising a dose of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 12 mg/day when the body weight of the human subject equals or exceeds 60kg or (ii) 8 mg/day when the body weight of the human subject is less than 60kg, wherein the human subject exhibits a second grade 3 hematological toxicity or occurrence of proteinuria during treatment with the second dosage regimen, except for clinically relevant laboratory test abnormalities;

(b) terminating administration of the second dosage regimen after the occurrence of grade 3 hematological toxicity or proteinuria other than the second non-clinically relevant laboratory test abnormality until the grade 3 hematological toxicity or proteinuria other than the second non-clinically relevant laboratory test abnormality subsides to grade 0-2 or baseline, and administering to the human subject a third dosage regimen comprising a dose of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 8 mg/day when the body weight of the human subject equals or exceeds 60kg or (ii) 4 mg/day when the body weight of the human subject is less than 60kg, wherein the human subject exhibits a third grade 3 hematological toxicity or the occurrence of proteinuria during treatment with the third dosage regimen, except for clinically relevant laboratory test abnormalities;

(c) terminating administration of the third dosage regimen after the third non-clinically relevant laboratory test abnormality in grade 3 hematological toxicity or proteinuria has occurred until the third non-clinically relevant laboratory test abnormality in grade 3 hematological toxicity or proteinuria has resolved to grade 0-2 or baseline, and administering to the human subject a fourth dosage regimen comprising a dose of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 4 mg/day when the body weight of the human subject equals or exceeds 60kg or (ii) 4mg every other day when the body weight of the human subject is less than 60kg, wherein the human subject exhibits a fourth grade 3 hematological toxicity or occurrence of proteinuria during treatment with the fourth dosage regimen, except for clinically relevant laboratory test abnormalities; and is

(d) Terminating administration of the fourth dosage regimen after the occurrence of the grade 3 hematological toxicity or proteinuria other than the abnormality in the fourth non-clinically relevant laboratory test until the grade 3 hematological toxicity or proteinuria other than the abnormality in the fourth non-clinically relevant laboratory test subsides to grade 0-2 or baseline, and administering to the human subject every other day a fifth dosage regimen comprising a dose of 4mg of lenvatinib or a pharmaceutically acceptable salt thereof, when the body weight of the human subject equals or exceeds 60 kg;

(II) wherein the human subject exhibits the onset of a first grade 4 hematologic toxicity during treatment with the first dosage regimen, and the method further comprises:

(a) after the first sustained and intolerant grade 2 non-hematologic toxicity has occurred and with or without interruption of the first dosage regimen, terminating administration of the first dosage regimen until the first sustained and intolerant grade 2 non-hematologic toxicity subsides to grade 0-1 or baseline, administering to the human subject a second dosage regimen comprising the following dose of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 8 mg/day when the body weight of the human subject equals or exceeds 60kg or (ii) 4 mg/day when the body weight of the human subject is less than 60kg, wherein the human subject exhibits a second sustained and intolerable occurrence of grade 2 non-hematologic toxicity during treatment with the second dosage regimen;

(b) after the second sustained and intolerant grade 2 non-hematologic toxicity has occurred and the first dosage regimen is terminated with or without interruption, until the first sustained and intolerant grade 2 non-hematologic toxicity subsides to grade 0-1 or baseline, administering to the human subject a third dosage regimen comprising the following dose of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 4 mg/day when the body weight of the human subject equals or exceeds 60kg or (ii) 4mg every other day when the body weight of the human subject is less than 60kg, wherein the human subject exhibits the onset of a third sustained and intolerable grade 2 non-hematologic toxicity during treatment with the third dosage regimen; and is

(c) Terminating administration of the third dosage regimen after the occurrence of the third sustained and intolerable grade 2 non-hematological toxicity and with or without interruption of the first dosage regimen until the first sustained and intolerable grade 2 non-hematological toxicity subsides to grade 0-1 or baseline, administering to the human subject every other day a fourth dosage regimen comprising a dose of 4mg of lenvatinib or a pharmaceutically acceptable salt thereof when the body weight of the human subject equals or exceeds 60 kg;

(IV) wherein the human subject exhibits the occurrence of grade 3 non-hematologic toxicity during treatment with the first dosage regimen, except for clinically relevant laboratory test abnormalities, and the method further comprises:

(a) terminating administration of the first dosage regimen after the occurrence of the grade 3 non-hematological toxicity other than the first non-clinically relevant laboratory test abnormality until the grade 3 non-hematological toxicity other than the first non-clinically relevant laboratory test abnormality subsides to grade 0-1 or baseline, and administering to the human subject a second dosage regimen comprising a dose of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 8 mg/day when the body weight of the human subject equals or exceeds 60kg or (ii) 4 mg/day when the body weight of the human subject is less than 60kg, wherein the human subject exhibits the occurrence of grade 3 non-hematologic toxicity during treatment with the second dosage regimen except for clinically relevant laboratory test abnormalities;

(b) terminating administration of the second dosage regimen after the occurrence of the grade 3 non-hematological toxicity other than the second non-clinically relevant laboratory test abnormality until the grade 3 non-hematological toxicity other than the second non-clinically relevant laboratory test abnormality subsides to grade 0-1 or baseline, and administering to the human subject a third dosage regimen comprising a dose of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 4 mg/day when the body weight of the human subject equals or exceeds 60kg or (ii) 4mg every other day when the body weight of the human subject is less than 60kg, wherein the human subject during treatment with the third dosage regimen displays the occurrence of grade 3 non-hematologic toxicity except for clinically relevant laboratory test abnormalities; and is

(c) Terminating administration of the third dosage regimen after the occurrence of the grade 3 non-hematological toxicity other than the third non-clinically relevant laboratory test abnormality until the grade 3 non-hematological toxicity other than the third non-clinically relevant laboratory test abnormality subsides to grade 0-1 or baseline, and administering to the human subject every other day a fourth dosage regimen comprising a dose of 4mg of varenib or a pharmaceutically acceptable salt thereof when the body weight of the human subject equals or exceeds 60 kg; or

(V) wherein the human subject, during treatment with the first, second, third, fourth or fifth dosage regimen, exhibits the onset of grade 4 non-hematologic toxicity other than a non-life threatening laboratory test abnormality, and the method further comprises terminating administration of the dosage regimen after the onset of grade 4 non-hematologic toxicity other than the non-life threatening laboratory test abnormality.

18. A method of treating unresectable hepatocellular carcinoma, the method comprising administering to a human subject having unresectable hepatocellular carcinoma and moderate liver damage classified as Child-Pugh class B according to the Child-Pugh classification a first dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 8 mg/day,

(a) terminating administration of the first dosage regimen after the occurrence of grade 3 hematological toxicity or proteinuria other than the first non-clinically relevant laboratory test abnormality until grade 3 hematological toxicity or proteinuria other than the first non-clinically relevant laboratory test abnormality subsides to grade 0-2 or baseline, and administering to the human subject a second dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 8 mg/day, wherein the human subject exhibits the occurrence of grade 3 hematological toxicity or proteinuria other than the second non-clinically relevant laboratory test abnormality during treatment with the second dosage regimen;

(b) terminating administration of the second dosage regimen after the occurrence of grade 3 hematological toxicity or proteinuria other than the second non-clinically relevant laboratory test abnormality until the grade 3 hematological toxicity or proteinuria other than the second non-clinically relevant laboratory test abnormality subsides to grade 0-2 or baseline, and administering to the human subject a third dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4 mg/day, wherein the human subject exhibits the occurrence of grade 3 hematological toxicity or proteinuria other than the third non-clinically relevant laboratory test abnormality during treatment with the third dosage regimen;

(c) terminating administration of the third dosage regimen after the occurrence of grade 3 hematological toxicity or proteinuria other than the third non-clinically relevant laboratory test abnormality until the grade 3 hematological toxicity or proteinuria other than the third non-clinically relevant laboratory test abnormality subsides to grade 0-2 or baseline, and administering a fourth dosage regimen comprising a dose of 4mg of lenvatinib or a pharmaceutically acceptable salt thereof to the human subject every other day, wherein the human subject exhibits the occurrence of grade 3 hematological toxicity or proteinuria other than the fourth non-clinically relevant laboratory test abnormality during treatment with the fourth dosage regimen; and is

(d) Terminating administration of the fourth dosage regimen after the occurrence of grade 3 hematological toxicity or proteinuria other than the abnormality of the fourth non-clinically relevant laboratory test;

(II) wherein the human subject exhibits the onset of a first grade 4 hematologic toxicity during treatment with the first dosage regimen, and the method further comprises:

(a) terminating administration of the first dosage regimen after the occurrence of the first sustained and intolerant grade 2 non-hematologic toxicity and with or without interruption of the first dosage regimen until the first sustained and intolerant grade 2 non-hematologic toxicity subsides to grade 0-1 or baseline, administering to the human subject a second dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4 mg/day, wherein the human subject exhibits the occurrence of a second sustained and intolerant grade 2 non-hematologic toxicity during treatment with the second dosage regimen;

(b) terminating administration of the second dosage regimen after the occurrence of the second sustained and intolerable grade 2 non-hematological toxicity and with or without interruption of the first dosage regimen until the first sustained and intolerable grade 2 non-hematological toxicity subsides to grade 0-1 or baseline, administering a third dosage regimen comprising a dose of 4mg of lenvatinib or a pharmaceutically acceptable salt thereof to the human subject every other day, wherein the human subject exhibits the occurrence of a third sustained and intolerable grade 2 non-hematological toxicity during treatment with the third dosage regimen; and is

(a) terminating administration of the first dosage regimen after the occurrence of grade 3 non-hematological toxicity other than the first non-clinically relevant laboratory test abnormality until grade 3 non-hematological toxicity other than the first non-clinically relevant laboratory test abnormality subsides to grade 0-1 or baseline, and administering to the human subject a second dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4 mg/day, wherein the human subject exhibits the occurrence of grade 3 non-hematological toxicity other than the second non-clinically relevant laboratory test abnormality during treatment with the second dosage regimen;

(b) terminating administration of the second dosage regimen after the occurrence of grade 3 non-hematological toxicity other than the second non-clinically relevant laboratory test abnormality until grade 3 non-hematological toxicity other than the second non-clinically relevant laboratory test abnormality subsides to grade 0-1 or baseline, and administering to the human subject every other day a third dosage regimen comprising a dose of 4mg of lenvatinib or a pharmaceutically acceptable salt thereof, wherein the human subject exhibits the occurrence of grade 3 non-hematological toxicity other than third non-clinically relevant laboratory test abnormality during treatment with the third dosage regimen; and is

(c) Terminating administration of the third dosage regimen after the occurrence of the third non-grade 3 non-hematologic toxicity other than a clinically relevant laboratory test abnormality; or

(V) wherein the human subject, during treatment with the first, second, third, or fourth dosage regimen, exhibits the onset of grade 4 non-hematologic toxicity other than a non-life threatening laboratory test abnormality, and the method further comprises terminating administration of the dosage regimen after the onset of grade 4 non-hematologic toxicity other than the non-life threatening laboratory test abnormality.

19. A method of treating unresectable hepatocellular carcinoma, the method comprising administering to a human subject having unresectable hepatocellular carcinoma a first dosage regimen comprising a dose of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 12 mg/day when the body weight of the human subject is equal to or greater than 60kg or (ii) 8 mg/day when the body weight of the human subject is less than 60kg,

(I) wherein the human subject exhibits an onset of grade 3 hematological toxicity or proteinuria during treatment with the first dosage regimen other than a clinically relevant laboratory test abnormality, and the method further comprises terminating administration of the first dosage regimen after the onset of the grade 3 hematological toxicity or proteinuria other than the first non-clinically relevant laboratory test abnormality until the grade 3 hematological toxicity or proteinuria other than the first non-clinically relevant laboratory test abnormality subsides to grade 0-2 or baseline, and administering to the human subject a second dosage regimen comprising a dose of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 12 mg/day when the body weight of the human subject is equal to or exceeds 60kg or (ii) 8 mg/day when the body weight of the human subject is less than 60 kg;

(II) wherein the human subject exhibits the onset of a first grade 4 hematological toxicity during treatment with the first dosage regimen, and the method further comprises terminating administration of the first dosage regimen after the onset of the first grade 4 hematological toxicity until the first grade 4 hematological toxicity subsides to grade 0-2 or baseline, and administering to the human subject a second dosage regimen comprising the following doses of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 8 mg/day when the body weight of the human subject is equal to or exceeds 60kg or (ii) 4 mg/day when the body weight of the human subject is less than 60 kg;

(III) wherein the human subject exhibits an onset of a first sustained and intolerable grade 2 non-hematologic toxicity during treatment with the first dosage regimen, and the method further comprises terminating administration of the first dosage regimen after the onset of the first sustained and intolerable grade 2 non-hematologic toxicity and with or without interruption of the first dosage regimen until the first sustained and intolerable grade 2 non-hematologic toxicity subsides to grade 0-1 or baseline, administering to the human subject a second dosage regimen comprising the following dose of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 8 mg/day when the body weight of the human subject is equal to or exceeds 60kg or (ii) 4 mg/day when the body weight of the human subject is less than 60 kg;

(IV) wherein the human subject, during treatment with the first dosage regimen, exhibits the onset of grade 3 non-hematologic toxicity other than a first non-clinically relevant laboratory test abnormality, and the method further comprises terminating administration of the first dosage regimen after the onset of the grade 3 non-hematologic toxicity other than the first non-clinically relevant laboratory test abnormality, until the grade 3 non-hematologic toxicity other than the first non-clinically relevant laboratory test abnormality subsides to grade 0-1 or baseline, and administering to the human subject a second dosage regimen comprising the following dose of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 8 mg/day when the body weight of the human subject is equal to or exceeds 60kg or (ii) 4 mg/day when the body weight of the human subject is less than 60 kg; or

(V) wherein the human subject, during treatment with the first dosage regimen, exhibits the onset of grade 4 non-hematologic toxicity other than a non-life threatening laboratory test abnormality, and the method further comprises terminating administration of the dosage regimen after the onset of the grade 4 non-hematologic toxicity other than the non-life threatening laboratory test abnormality.

20. A method of treating unresectable hepatocellular carcinoma, the method comprising administering to a human subject having unresectable hepatocellular carcinoma and moderate liver damage classified as Child-Pugh class B according to the Child-Pugh classification a first dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 8 mg/day,

(I) wherein the human subject exhibits an onset of grade 3 hematological toxicity or proteinuria during treatment with the first dosage regimen other than a first non-clinically relevant laboratory test abnormality, and the method further comprises terminating administration of the first dosage regimen after the onset of grade 3 hematological toxicity or proteinuria other than the first non-clinically relevant laboratory test abnormality until the grade 3 hematological toxicity or proteinuria other than the first non-clinically relevant laboratory test abnormality subsides to grade 0-2 or baseline, and administering to the human subject a second dosage regimen comprising valletinib or a pharmaceutically acceptable salt thereof at a dose of 8 mg/day;

(II) wherein the human subject exhibits the onset of a first grade 4 hematological toxicity during treatment with the first dosage regimen, and the method further comprises terminating administration of the first dosage regimen after the onset of the first grade 4 hematological toxicity until the first grade 4 hematological toxicity subsides to grade 0-2 or baseline, and administering to the human subject a second dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4 mg/day;

(III) wherein the human subject exhibits an onset of a first sustained and intolerable grade 2 non-hematologic toxicity during treatment with the first dosage regimen, and the method further comprises terminating administration of the first dosage regimen after the onset of the first sustained and intolerable grade 2 non-hematologic toxicity and with or without interruption of the first dosage regimen until the first sustained and intolerable grade 2 non-hematologic toxicity subsides to grade 0-1 or baseline, administering to the human subject a second dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4 mg/day;

(IV) wherein the human subject, during treatment with the first dosage regimen, exhibits the onset of grade 3 non-hematological toxicity other than a first non-clinically relevant laboratory test abnormality, and the method further comprises terminating administration of the first dosage regimen after the onset of grade 3 non-hematological toxicity other than the first non-clinically relevant laboratory test abnormality, until the grade 3 non-hematological toxicity other than the first non-clinically relevant laboratory test abnormality subsides to grade 0-1 or baseline, and administering to the human subject a second dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4 mg/day; or

21. The method of any one of claims 3-9 and 14-18, wherein medical management of each of the first, second, and third persistent and intolerable grade 2 or 3 non-hematologic toxic or non-life threatening grade 4 laboratory test abnormalities begins before terminating administration of the dosage regimen administered at the beginning of the grade 2 or 3 non-hematologic toxic or non-life threatening grade 4 laboratory test abnormality.

22. The method of any one of claims 10, 11, and 14-18, wherein medical management of each of the first, second, third, and fourth grade 3 hematological toxicity or proteinuria is initiated prior to terminating administration of the dosage regimen administered at the initiation of the grade 3 hematological toxicity or proteinuria.

23. The method of any one of claims 12-18, wherein medical management of each of the first, second, and third sustained and intolerable grade 4 hematological toxicities is initiated prior to terminating administration of the dosage regimen administered at the initiation of the grade 4 hematological toxicity.

24. The method of any one of claims 3-9 and 14-18, wherein the first persistent and intolerant grade 2 or grade 3 non-hematologic toxicity or non-life threatening grade 4 laboratory test abnormality is the same as the second and/or third persistent and intolerant grade 2 or grade 3 non-hematologic toxicity or non-life threatening grade 4 laboratory test abnormality.

25. The method of any one of claims 10, 11, and 14-18, wherein the first grade 3 hematological toxicity or proteinuria is the same as the second and/or third grade 3 hematological toxicity or proteinuria.

26. The method of any one of claims 12-18, wherein the first grade 4 hematological toxicity is the same as the second and/or third grade 4 hematological toxicity.

27. The method of any one of claims 3-9 and 14-20, wherein the grade 3 non-hematologic toxicity is selected from the group consisting of: grade 3 blood pressure, grade 3 diarrhea, grade 3 arthralgia, grade 3 myalgia, grade 3 appetite decrease, grade 3 fatigue, grade 3 weight decrease, grade 3 dysarthria, grade 3 nausea, grade 3 abdominal pain, grade 3 QT/QTc interval prolongation, grade 3 hypothyroidism, grade 3 vomiting, grade 3 constipation, grade 3 rash, and grade 3 palmoplantar loss erythema.

28. The method of any one of claims 5-9 and 14-20, wherein the grade 2 or 3 non-hematologic toxicity is selected from the group consisting of: level 3 blood pressure, level 2 blood pressure, level 3 diarrhea, level 2 diarrhea, level 3 appetite decrease, level 2 appetite decrease, level 3 arthralgia, level 2 arthralgia, level 3 myalgia, level 2 myalgia, level 3 fatigue, level 2 fatigue, level 3 weight decrease, level 2 alopecia, level 3 dysarthria, level 2 dysarthria, level 3 nausea, level 2 nausea, level 3 abdominal pain, level 2 abdominal pain, level 3 QT/QTc interval prolongation, level 2 QT/QTc interval prolongation, level 3 hypothyroidism, level 2 hypothyroidism, level 3 emesis, level 2 emesis, level 3 constipation, level 2 constipation, level 3 rash, level 2 rash, level 3 palmoplantar sensory loss erythema, and level 2 palmoplantar sensory loss erythema.

29. The method of any one of claims 7-9 and 14-20, wherein the level 4 laboratory inspection anomaly is selected from the group consisting of: increased aspartate aminotransferase level 4, increased alanine aminotransferase level 4, increased alkaline phosphatase level 4, hypokalemia level 4, hyponatremia level 4, hypoglycemia level 4, increased blood bilirubin level 4, and increased gamma glutamyl transferase level 4.

30. The method of any one of claims 10, 11 and 14-20, wherein the grade 3 hematological toxicity or proteinuria is selected from the group consisting of: grade 3 proteinuria, grade 3 thrombocytopenia (thrombocytopenia), grade 3 anemia, grade 3 leukopenia, grade 3 neutropenia, and grade 3 lymphopenia.

31. The method of any one of claims 12-20, wherein the grade 4 hematological toxicity is selected from the group consisting of: grade 4 thrombocytopenia (thrombocytopenia), grade 4 anemia, grade 4 leukopenia, grade 4 neutropenia, and grade 4 lymphopenia.

32. A method of treating unresectable hepatocellular carcinoma, the method comprising administering to a human subject having unresectable hepatocellular carcinoma:

a dosage regimen comprising the following doses of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 8 mg/day when the body weight of the human subject equals or exceeds 60kg or (ii) 4 mg/day when the body weight of the human subject is less than 60kg, wherein the human subject was previously treated with a previous dosage regimen comprising the following dose of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 12 mg/day when the body weight of the human subject equals or exceeds 60kg or (ii) 8 mg/day when the body weight of the human subject is less than 60kg, and wherein the human subject exhibits the onset of grade 3 non-hematologic toxicity during treatment with the prior dosage regimen;

a dosage regimen comprising the following doses of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 4 mg/day when the body weight of the human subject is equal to or exceeds 60kg or (ii) 4mg every other day when the body weight of the human subject is less than 60kg, wherein the human subject was previously treated with a previous dosage regimen comprising the following dose of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 8 mg/day when the body weight of the human subject equals or exceeds 60kg or (ii) 4 mg/day when the body weight of the human subject is less than 60kg, and wherein the human subject exhibits the onset of grade 3 non-hematologic toxicity during treatment with the prior dosage regimen; or

A dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4mg every other day, wherein the body weight of the human subject is equal to or exceeds 60kg, wherein the human subject was previously treated with a previous dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4 mg/day, and wherein the human subject exhibits the onset of grade 3 non-hematologic toxicity during treatment with the previous dosage regimen.

33. A method of treating unresectable hepatocellular carcinoma, the method comprising administering to a human subject having unresectable hepatocellular carcinoma and moderate liver damage classified as Child-Pugh class B according to the Child-Pugh classification:

a dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4 mg/day, wherein the human subject was previously treated with a previous dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 8 mg/day, and wherein the human subject exhibits the onset of grade 3 non-hematologic toxicity during treatment with the previous dosage regimen; or

A dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4mg every other day, wherein the human subject was previously treated with a previous dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4 mg/day, and wherein the human subject exhibits the onset of grade 3 non-hematologic toxicity during treatment with the previous dosage regimen.

34. A method of treating unresectable hepatocellular carcinoma, the method comprising administering to a human subject having unresectable hepatocellular carcinoma:

a dosage regimen comprising the following doses of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 8 mg/day when the body weight of the human subject equals or exceeds 60kg or (ii) 4 mg/day when the body weight of the human subject is less than 60kg, wherein the human subject was previously treated with a previous dosage regimen comprising the following dose of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 12 mg/day when the body weight of the human subject equals or exceeds 60kg or (ii) 8 mg/day when the body weight of the human subject is less than 60kg, and wherein the human subject exhibits the onset of sustained and intolerable grade 2 or grade 3 non-hematologic toxicity during treatment with the prior dosage regimen;

a dosage regimen comprising the following doses of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 4 mg/day when the body weight of the human subject is equal to or exceeds 60kg or (ii) 4mg every other day when the body weight of the human subject is less than 60kg, wherein the human subject was previously treated with a previous dosage regimen comprising the following dose of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 8 mg/day when the body weight of the human subject equals or exceeds 60kg or (ii) 4 mg/day when the body weight of the human subject is less than 60kg, and wherein the human subject exhibits the onset of sustained and intolerable grade 2 or grade 3 non-hematologic toxicity during treatment with the prior dosage regimen; or

A dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4mg every other day, wherein the body weight of the human subject is equal to or exceeds 60kg, wherein the human subject was previously treated with a previous dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4 mg/day, and wherein the human subject exhibits the onset of sustained and intolerable grade 2 or grade 3 non-hematologic toxicity during treatment with the previous dosage regimen.

35. A method of treating unresectable hepatocellular carcinoma, the method comprising administering to a human subject having unresectable hepatocellular carcinoma and moderate liver damage classified as Child-Pugh class B according to the Child-Pugh classification:

a dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4 mg/day, wherein the human subject was previously treated with a previous dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 8 mg/day, and wherein the human subject exhibits an onset of persistent and intolerable grade 2 or 3 non-hematologic toxicity during treatment with the previous dosage regimen; or

A dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4mg every other day, wherein the human subject was previously treated with a previous dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4 mg/day, and wherein the human subject exhibits the onset of persistent and intolerable grade 2 or 3 non-hematologic toxicity during treatment with the previous dosage regimen.

36. A method of treating unresectable hepatocellular carcinoma, the method comprising administering to a human subject having unresectable hepatocellular carcinoma:

a dosage regimen comprising the following doses of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 8 mg/day when the body weight of the human subject equals or exceeds 60kg or (ii) 4 mg/day when the body weight of the human subject is less than 60kg, wherein the human subject was previously treated with a previous dosage regimen comprising the following dose of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 12 mg/day when the body weight of the human subject equals or exceeds 60kg or (ii) 8 mg/day when the body weight of the human subject is less than 60kg, and wherein the human subject exhibits persistent and intolerable grade 2 or 3 non-hematologic toxicity or non-life-threatening grade 4 laboratory test abnormalities during treatment with the prior dosage regimen;

a dosage regimen comprising the following doses of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 4 mg/day when the body weight of the human subject is equal to or exceeds 60kg or (ii) 4mg every other day when the body weight of the human subject is less than 60kg, wherein the human subject was previously treated with a previous dosage regimen comprising the following dose of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 8 mg/day when the body weight of the human subject equals or exceeds 60kg or (ii) 4 mg/day when the body weight of the human subject is less than 60kg, and wherein the human subject exhibits persistent and intolerable grade 2 or 3 non-hematologic toxicity or non-life threatening grade 4 laboratory test abnormalities during treatment with the prior dosage regimen; or

A dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4mg every other day, wherein the body weight of the human subject equals or exceeds 60kg, wherein the human subject was previously treated with a previous dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4 mg/day, and wherein the human subject exhibits a persistent and intolerable grade 2 or 3 non-hematologic toxicity or non-life threatening grade 4 laboratory test for the occurrence of an abnormality during treatment with the previous dosage regimen.

37. A method of treating unresectable hepatocellular carcinoma, the method comprising administering to a human subject having unresectable hepatocellular carcinoma and moderate liver damage classified as Child-Pugh class B according to the Child-Pugh classification:

a dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4 mg/day, wherein the human subject was previously treated with a previous dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 8 mg/day, and wherein the human subject exhibits persistent and intolerant grade 2 or grade 3 non-hematologic toxicity or non-life threatening grade 4 laboratory test abnormalities during treatment with the previous dosage regimen; or

A dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4mg every other day, wherein the human subject was previously treated with a previous dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4 mg/day, and wherein the human subject exhibits persistent and intolerable grade 2 or 3 non-hematologic toxicity or non-life threatening grade 4 laboratory test abnormalities during treatment with the previous dosage regimen.

38. A method of treating unresectable hepatocellular carcinoma, the method comprising administering to a human subject having unresectable hepatocellular carcinoma:

a dosage regimen comprising the following doses of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 12 mg/day when the body weight of the human subject equals or exceeds 60kg or (ii) 8 mg/day when the body weight of the human subject is less than 60kg, wherein the human subject was previously treated with a previous dosage regimen comprising the following dose of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 12 mg/day when the body weight of the human subject equals or exceeds 60kg or (ii) 8 mg/day when the body weight of the human subject is less than 60kg, and wherein the human subject exhibits the occurrence of grade 3 hematological toxicity or proteinuria during treatment with the prior dosage regimen;

a dosage regimen comprising the following doses of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 8 mg/day when the body weight of the human subject equals or exceeds 60kg or (ii) 4 mg/day when the body weight of the human subject is less than 60kg, wherein the human subject was previously treated with a previous dosage regimen comprising the following dose of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 12 mg/day when the body weight of the human subject equals or exceeds 60kg or (ii) 8 mg/day when the body weight of the human subject is less than 60kg, and wherein the human subject exhibits the occurrence of grade 3 hematological toxicity or proteinuria during treatment with the prior dosage regimen;

a dosage regimen comprising the following doses of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 4 mg/day when the body weight of the human subject is equal to or exceeds 60kg or (ii) 4mg every other day when the body weight of the human subject is less than 60kg, wherein the human subject was previously treated with a previous dosage regimen comprising the following dose of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 8 mg/day when the body weight of the human subject equals or exceeds 60kg or (ii) 4 mg/day when the body weight of the human subject is less than 60kg, and wherein the human subject exhibits the occurrence of grade 3 hematological toxicity or proteinuria during treatment with the prior dosage regimen; or

A dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4mg every other day, wherein the body weight of the human subject is equal to or exceeds 60kg, wherein the human subject was previously treated with a previous dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4 mg/day, and wherein the human subject exhibits grade 3 hematologic toxicity or the occurrence of proteinuria during treatment with the previous dosage regimen.

39. A method of treating unresectable hepatocellular carcinoma, the method comprising administering to a human subject having unresectable hepatocellular carcinoma and moderate liver damage classified as Child-Pugh class B according to the Child-Pugh classification:

a dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 8 mg/day, wherein the human subject was previously treated with a previous dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 8 mg/day, and wherein the human subject exhibits the occurrence of grade 3 hematologic toxicity or proteinuria during treatment with the previous dosage regimen;

a dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4 mg/day, wherein the human subject was previously treated with a previous dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 8 mg/day, and wherein the human subject exhibits the occurrence of grade 3 hematologic toxicity or proteinuria during treatment with the previous dosage regimen; or

A dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4mg every other day, wherein the human subject was previously treated with a previous dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4 mg/day, and wherein the human subject exhibits a grade 3 hematologic toxicity or occurrence of proteinuria during treatment with the previous dosage regimen.

40. A method of treating unresectable hepatocellular carcinoma, the method comprising administering to a human subject having unresectable hepatocellular carcinoma:

a dosage regimen comprising the following doses of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 8 mg/day when the body weight of the human subject equals or exceeds 60kg or (ii) 4 mg/day when the body weight of the human subject is less than 60kg, wherein the human subject was previously treated with a previous dosage regimen comprising the following dose of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 12 mg/day when the body weight of the human subject equals or exceeds 60kg or (ii) 8 mg/day when the body weight of the human subject is less than 60kg, and wherein the human subject exhibits the onset of grade 4 hematological toxicity during treatment with the prior dosage regimen;

a dosage regimen comprising the following doses of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 4 mg/day when the body weight of the human subject is equal to or exceeds 60kg or (ii) 4mg every other day when the body weight of the human subject is less than 60kg, wherein the human subject was previously treated with a previous dosage regimen comprising the following dose of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 8 mg/day when the body weight of the human subject equals or exceeds 60kg or (ii) 4 mg/day when the body weight of the human subject is less than 60kg, and wherein the human subject exhibits the onset of grade 4 hematologic toxicity during treatment with the prior dosage regimen; or

A dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4mg every other day, wherein the body weight of the human subject is equal to or exceeds 60kg, wherein the human subject was previously treated with a previous dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4 mg/day, and wherein the human subject exhibits the onset of grade 4 hematologic toxicity during treatment with the previous dosage regimen.

41. A method of treating unresectable hepatocellular carcinoma, the method comprising administering to a human subject having unresectable hepatocellular carcinoma and moderate liver damage classified as Child-Pugh class B according to the Child-Pugh classification:

a dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4 mg/day, wherein the human subject was previously treated with a previous dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 8 mg/day, and wherein the human subject exhibits the onset of grade 4 hematologic toxicity during treatment with the previous dosage regimen; or

A dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4mg every other day, wherein the human subject was previously treated with a previous dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4 mg/day, and wherein the human subject exhibits the onset of grade 4 hematologic toxicity during treatment with the previous dosage regimen.

42. The method of claim 32 or 33, wherein the grade 3 non-hematologic toxicity is selected from the group consisting of: grade 3 blood pressure, grade 3 diarrhea, grade 3 arthralgia, grade 3 myalgia, grade 3 appetite decrease, grade 3 fatigue, grade 3 weight decrease, grade 3 dysarthria, grade 3 nausea, grade 3 abdominal pain, grade 3 QT/QTc interval prolongation, grade 3 hypothyroidism, grade 3 vomiting, grade 3 constipation, grade 3 rash, and grade 3 palmoplantar loss erythema.

43. The method of any one of claims 34-37, wherein the grade 2 or 3 non-hematologic toxicity is selected from the group consisting of: level 3 blood pressure, level 2 blood pressure, level 3 diarrhea, level 2 diarrhea, level 3 appetite decrease, level 2 appetite decrease, level 3 arthralgia, level 2 arthralgia, level 3 myalgia, level 2 myalgia, level 3 fatigue, level 2 fatigue, level 3 weight decrease, level 2 alopecia, level 3 dysarthria, level 2 dysarthria, level 3 nausea, level 2 nausea, level 3 abdominal pain, level 2 abdominal pain, level 3 QT/QTc interval prolongation, level 2 QT/QTc interval prolongation, level 3 hypothyroidism, level 2 hypothyroidism, level 3 emesis, level 2 emesis, level 3 constipation, level 2 constipation, level 3 rash, level 2 rash, level 3 palmoplantar sensory loss erythema, and level 2 palmoplantar sensory loss erythema.

44. The method of any one of claims 36 or 37, wherein the level 4 laboratory check abnormality is selected from the group consisting of: increased aspartate aminotransferase level 4, increased alanine aminotransferase level 4, increased alkaline phosphatase level 4, hypokalemia level 4, hyponatremia level 4, hypoglycemia level 4, increased blood bilirubin level 4, and increased gamma glutamyl transferase level 4.

45. The method of claim 38 or 39, wherein the grade 3 hematological toxicity or proteinuria is selected from the group consisting of: grade 3 proteinuria, grade 3 thrombocytopenia (thrombocytopenia), grade 3 anemia, grade 3 leukopenia, grade 3 neutropenia, and grade 3 lymphopenia.

46. The method of claim 40 or 41, wherein the grade 4 hematological toxicity is selected from the group consisting of: grade 4 thrombocytopenia (thrombocytopenia), grade 4 anemia, grade 4 leukopenia, grade 4 neutropenia, and grade 4 lymphopenia.

47. A method of treating unresectable hepatocellular carcinoma, the method comprising administering to a human subject having unresectable hepatocellular carcinoma a first dosage regimen comprising a dose of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 12 mg/day when the body weight of the human subject is equal to or greater than 60kg or (ii) 8 mg/day when the body weight of the human subject is less than 60kg,

(I) wherein the human subject exhibits a first sustained and intolerant grade 2 or grade 3 adverse reaction or grade 4 laboratory test abnormality during treatment with the first dosage regimen, and the method further comprises:

(a) terminating administration of the first dosage regimen after the occurrence of the first sustained and intolerant grade 2 or grade 3 adverse effect or grade 4 laboratory test abnormality until the first sustained and intolerant grade 2 or grade 3 adverse effect or grade 4 laboratory test abnormality subsides to grade 0-1 or baseline, and administering to the human subject a second dosage regimen comprising a dose of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 8 mg/day when the body weight of the human subject equals or exceeds 60kg or (ii) 4 mg/day when the body weight of the human subject is less than 60kg, wherein the human subject exhibits the occurrence of a second sustained and intolerable grade 2 or 3 adverse reaction or grade 4 laboratory test abnormality during treatment with the second dosage regimen;

(b) terminating administration of the second dosage regimen after the occurrence of the second sustained and intolerant grade 2 or grade 3 adverse effect or grade 4 laboratory test abnormality until the second sustained and intolerant grade 2 or grade 3 adverse effect or grade 4 laboratory test abnormality subsides to grade 0-1 or baseline, and administering to the human subject a third dosage regimen comprising a dose of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 4 mg/day when the body weight of the human subject equals or exceeds 60kg or (ii) 4mg every other day when the body weight of the human subject is less than 60kg, wherein the human subject exhibits the occurrence of a third sustained and intolerable grade 2 or 3 adverse reaction or grade 4 laboratory test abnormality during treatment with the third dosage regimen; and is

(c) Terminating administration of the third dosage regimen after the occurrence of the third sustained and intolerant grade 2 or grade 3 adverse effect or grade 4 laboratory test abnormality until the third sustained and intolerant grade 2 or grade 3 adverse effect or grade 4 laboratory test abnormality subsides to grade 0-1 or baseline, and administering to the human subject every other day a fourth dosage regimen comprising a dose of 4mg lenvatinib or a pharmaceutically acceptable salt thereof when the body weight of the human subject equals or exceeds 60 kg; or

(II) wherein the human subject exhibits an occurrence of a grade 4 adverse reaction other than a grade 4 laboratory test abnormality during treatment with the first, second, third, or fourth dosage regimen, and the method further comprises terminating administration of the dosage regimen after the occurrence of the grade 4 adverse reaction other than a grade 4 laboratory test abnormality;

provided that level 3 blood pressure, level 4 blood pressure, level 3 cardiac dysfunction, level 4 cardiac dysfunction, arterial thromboembolic events of any level, level 3 hepatotoxicity, level 4 hepatotoxicity, proteinuria of 2g or higher within 24 hours, level 3 renal failure or injury, level 4 renal failure or injury, gastrointestinal perforation of any level, level 3 fistula, level 4 fistula, prolongation of the QT/QTc interval of greater than 500ms, an increase of greater than 60ms relative to the prolongation of the QT baseline/QTc interval, and reversible rear leukoencephalopathy syndromes of any level are excluded from the persistent and intolerable level 2, level 3, or level 4 adverse reactions, or level 4 laboratory test abnormalities.

48. A method of treating unresectable hepatocellular carcinoma, the method comprising administering to a human subject having unresectable hepatocellular carcinoma and moderate liver damage classified as Child-Pugh class B according to the Child-Pugh classification a first dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 8 mg/day,

(a) terminating administration of the first dosage regimen after the occurrence of the first sustained and intolerant grade 2 or grade 3 adverse effect or grade 4 laboratory test abnormality until the first sustained and intolerant grade 2 or grade 3 adverse effect or grade 4 laboratory test abnormality subsides to grade 0-1 or baseline, and administering to the human subject a second dosage regimen comprising a dose of 4 mg/day lenvatinib or a pharmaceutically acceptable salt thereof, wherein the human subject exhibits the occurrence of a second sustained and intolerant grade 2 or grade 3 adverse effect or grade 4 laboratory test abnormality during treatment with the second dosage regimen;

(b) terminating administration of the second dosage regimen after the occurrence of the second sustained and intolerant grade 2 or grade 3 adverse effect or grade 4 laboratory test abnormality until the second sustained and intolerant grade 2 or grade 3 adverse effect or grade 4 laboratory test abnormality subsides to grade 0-1 or baseline, and administering a third dosage regimen comprising a dose of 4mg of lenvatinib or a pharmaceutically acceptable salt thereof to the human subject every other day, wherein the human subject exhibits the occurrence of a third sustained and intolerant grade 2 or grade 3 adverse effect or grade 4 laboratory test abnormality during treatment with the third dosage regimen; and is

(c) Terminating administration of the third dosage regimen after the occurrence of the third persistent and intolerable grade 2 or 3 adverse reaction or grade 4 laboratory test abnormality; or

(II) wherein the human subject exhibits the occurrence of a grade 4 adverse reaction other than a grade 4 laboratory test abnormality during treatment with the first, second, third or fourth dosage regimen and the method further comprises terminating administration of the dosage regimen after the occurrence of the grade 4 adverse reaction other than a grade 4 laboratory test abnormality;

provided that level 3 blood pressure, level 4 blood pressure, level 3 cardiac dysfunction, level 4 cardiac dysfunction, arterial thromboembolic events of any level, level 3 hepatotoxicity, level 4 hepatotoxicity, proteinuria of 2g or higher within 24 hours, level 3 renal failure or injury, level 4 renal failure or injury, gastrointestinal perforation of any level, level 3 fistula, level 4 fistula, prolongation of the QT/QTc interval of greater than 500ms, an increase of greater than 60ms relative to the prolongation of the QT baseline/QTc interval, and reversible rear leukoencephalopathy syndromes of any level are excluded from the persistent and intolerable level 2, level 3 or 4 adverse reactions or level 4 laboratory examinations abnormalities.

49. A method of treating unresectable hepatocellular carcinoma, the method comprising administering to a human subject having unresectable hepatocellular carcinoma a first dosage regimen comprising a dose of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 12 mg/day when the body weight of the human subject is equal to or greater than 60kg or (ii) 8 mg/day when the body weight of the human subject is less than 60kg,

(I) wherein the human subject exhibits an occurrence of a first sustained and intolerant grade 2 or grade 3 adverse effect or grade 4 laboratory test abnormality during treatment with the first dosage regimen, and the method further comprises terminating administration of the first dosage regimen after the occurrence of the first sustained and intolerant grade 2 or grade 3 adverse effect or grade 4 laboratory test abnormality until the first sustained and intolerant grade 2 or grade 3 adverse effect or grade 4 laboratory test abnormality subsides to grade 0-1 or baseline, and administering to the human subject a second dosage regimen comprising a dose of valcanib or a pharmaceutically acceptable salt thereof: (i) 8 mg/day when the body weight of the human subject is equal to or exceeds 60kg or (ii) 4 mg/day when the body weight of the human subject is less than 60 kg; or

(II) wherein the human subject exhibits an occurrence of a grade 4 adverse reaction other than a grade 4 laboratory test abnormality during treatment with the first dose regimen, and the method further comprises terminating administration of the dose regimen after the occurrence of the grade 4 adverse reaction other than a grade 4 laboratory test abnormality;

provided that level 3 blood pressure, level 4 blood pressure, level 3 cardiac dysfunction, level 4 cardiac dysfunction, arterial thromboembolic events of any level, level 3 hepatotoxicity, level 4 hepatotoxicity, proteinuria of 2g or higher within 24 hours, level 3 renal failure or injury, level 4 renal failure or injury, gastrointestinal perforation of any level, level 3 fistula, level 4 fistula, prolongation of the QT/QTc interval of greater than 500ms, an increase of greater than 60ms relative to the prolongation of the QT baseline/QTc interval, and reversible rear leukoencephalopathy syndromes of any level are excluded from the persistent and intolerable level 2, level 3 or 4 adverse reactions or level 4 laboratory examinations abnormalities.

50. A method of treating unresectable hepatocellular carcinoma, the method comprising administering to a human subject having unresectable hepatocellular carcinoma and moderate liver damage classified as Child-Pugh class B according to the Child-Pugh classification a first dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 8 mg/day,

(I) wherein the human subject exhibits an occurrence of a first sustained and intolerant grade 2 or grade 3 adverse effect or grade 4 laboratory test abnormality during treatment with the first dosage regimen, and the method further comprises terminating administration of the first dosage regimen after the occurrence of the first sustained and intolerant grade 2 or grade 3 adverse effect or grade 4 laboratory test abnormality until the first sustained and intolerant grade 2 or grade 3 adverse effect or grade 4 laboratory test abnormality subsides to grade 0-1 or baseline, and administering to the human subject a second dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4 mg/day; or

provided that level 3 blood pressure, level 4 blood pressure, level 3 cardiac dysfunction, level 4 cardiac dysfunction, arterial thromboembolic events of any level, level 3 hepatotoxicity, level 4 hepatotoxicity, proteinuria of 2g or higher within 24 hours, level 3 renal failure or injury, level 4 renal failure or injury, gastrointestinal perforation of any level, level 3 fistula, level 4 fistula, prolongation of the QT/QTc interval of greater than 500ms, an increase of greater than 60ms relative to the prolongation of the QT baseline/QTc interval, and reversible rear leukoencephalopathy syndromes of any level are excluded from the persistent and intolerable level 2, level 3 or 4 adverse reactions or level 4 laboratory examinations abnormalities.

51. A method of treating unresectable hepatocellular carcinoma, the method comprising administering to a human subject having unresectable hepatocellular carcinoma a first dosage regimen comprising a dose of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 12 mg/day when the body weight of the human subject is equal to or greater than 60kg or (ii) 8 mg/day when the body weight of the human subject is less than 60kg,

provided that hypertension, cardiac dysfunction, arterial thromboembolic events, hepatotoxicity, proteinuria, renal failure or injury, gastrointestinal perforation, fistulae, prolongation of QT/QTc interval, and reversible rear leukoencephalopathy syndromes are excluded from the persistent and intolerable grade 2, 3, or 4 adverse reactions or grade 4 laboratory test abnormalities.

52. A method of treating unresectable hepatocellular carcinoma, the method comprising administering to a human subject having unresectable hepatocellular carcinoma and moderate liver damage classified as Child-Pugh class B according to the Child-Pugh classification a first dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 8 mg/day,

(a) terminating administration of the first dosage regimen after the occurrence of the first sustained and intolerant grade 2 or grade 3 adverse effect or grade 4 laboratory test abnormality until the first sustained and intolerant grade 2 or grade 3 adverse effect or grade 4 laboratory test abnormality subsides to grade 0-1 or baseline, and administering to the human subject a second dosage regimen comprising a dose of 4 mg/day lenvatinib or a pharmaceutically acceptable salt thereof, wherein the human subject exhibits the occurrence of a second sustained and intolerant grade 2 or grade 3 adverse effect or grade 4 laboratory test abnormality during treatment with the second dosage regimen;

(b) terminating administration of the second dosage regimen after the occurrence of the second sustained and intolerant grade 2 or grade 3 adverse effect or grade 4 laboratory test abnormality until the second sustained and intolerant grade 2 or grade 3 adverse effect or grade 4 laboratory test abnormality subsides to grade 0-1 or baseline, and administering a third dosage regimen comprising a dose of 4mg of lenvatinib or a pharmaceutically acceptable salt thereof to the human subject every other day, wherein the human subject exhibits the occurrence of a third sustained and intolerant grade 2 or grade 3 adverse effect or grade 4 laboratory test abnormality during treatment with the third dosage regimen; and is

(c) Terminating administration of the third dosage regimen after the occurrence of the third persistent and intolerable grade 2 or 3 adverse reaction or grade 4 laboratory test abnormality; or

53. A method of treating unresectable hepatocellular carcinoma, the method comprising administering to a human subject having unresectable hepatocellular carcinoma a first dosage regimen comprising a dose of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 12 mg/day when the body weight of the human subject is equal to or greater than 60kg or (ii) 8 mg/day when the body weight of the human subject is less than 60kg,

54. A method of treating unresectable hepatocellular carcinoma, the method comprising administering to a human subject having unresectable hepatocellular carcinoma and moderate liver damage classified as Child-Pugh class B according to the Child-Pugh classification a first dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 8 mg/day,

(I) wherein the human subject exhibits an occurrence of a first sustained and intolerant grade 2 or grade 3 adverse effect or grade 4 laboratory test abnormality during treatment with the first dosage regimen, and the method further comprises terminating administration of the first dosage regimen after the occurrence of the first sustained and intolerant grade 2 or grade 3 adverse effect or grade 4 laboratory test abnormality until the first sustained and intolerant grade 2 or grade 3 adverse effect or grade 4 laboratory test abnormality subsides to grade 0-1 or baseline, and administering to the human subject a second dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4 mg/day; or

55. A method of treating unresectable hepatocellular carcinoma, the method comprising administering to a human subject having unresectable hepatocellular carcinoma a first dosage regimen comprising a dose of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 12 mg/day when the body weight of the human subject is equal to or greater than 60kg or (ii) 8 mg/day when the body weight of the human subject is less than 60kg,

wherein the human subject exhibits an incidence of level 3 hypertension during treatment with the first dosage regimen, and the method further comprises terminating administration of the first dosage regimen after the occurrence of the level 3 hypertension until the level 3 hypertension is controlled to be less than or equal to level 2, and administering to the human subject a second dosage regimen comprising the following dose of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 8 mg/day when the body weight of the human subject is equal to or exceeds 60kg or (ii) 4 mg/day when the body weight of the human subject is less than 60 kg.

56. A method of treating unresectable hepatocellular carcinoma, the method comprising administering to a human subject having unresectable hepatocellular carcinoma and moderate liver damage classified as Child-Pugh class B according to the Child-Pugh classification a first dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 8 mg/day,

wherein the human subject exhibits the onset of level 3 hypertension during treatment with the first dosage regimen, and the method further comprises terminating administration of the first dosage regimen after the onset of the level 3 hypertension until the level 3 hypertension is controlled to be less than or equal to level 2, and administering to the human subject a second dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4 mg/day.

57. A method of treating unresectable hepatocellular carcinoma, the method comprising administering to a human subject having unresectable hepatocellular carcinoma a first dosage regimen comprising a dose of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 12 mg/day when the body weight of the human subject is equal to or greater than 60kg or (ii) 8 mg/day when the body weight of the human subject is less than 60kg,

wherein the human subject exhibits an incidence of proteinuria of 2g or greater within 24 hours during treatment with the first dosage regimen, then the method further comprises terminating administration of the dosage regimen after 2g or greater of proteinuria within the 24 hours has occurred until the proteinuria is less than or equal to 2g proteinuria within 24 hours, and administering to the human subject a second dosage regimen comprising a dose of lenvatinib or a pharmaceutically acceptable salt thereof that is: (i) 8 mg/day when the body weight of the human subject is equal to or greater than 60kg or (ii) 4 mg/day when the body weight of the human subject is less than 60kg,

provided that the human subject exhibits the onset of nephrotic syndrome during treatment with the first dosage regimen, and the method further comprises terminating administration of the dosage regimen after the nephrotic syndrome has occurred.

58. A method of treating unresectable hepatocellular carcinoma, the method comprising administering to a human subject having unresectable hepatocellular carcinoma and moderate liver damage classified as Child-Pugh class B according to the Child-Pugh classification a first dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 8 mg/day,

wherein the human subject exhibits an incidence of proteinuria of 2g or greater within 24 hours during treatment with the first dosage regimen, and the method further comprises terminating administration of the dosage regimen after 2g or greater of proteinuria within the 24 hours has occurred until the proteinuria is less than or equal to 2g proteinuria within 24 hours, and administering to the human subject a second dosage regimen comprising valcanib or a pharmaceutically acceptable salt thereof at a dose of 4 mg/day,

59. A method of treating unresectable hepatocellular carcinoma, the method comprising administering to a human subject having unresectable hepatocellular carcinoma a first dosage regimen comprising a dose of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 12 mg/day when the body weight of the human subject is equal to or greater than 60kg or (ii) 8 mg/day when the body weight of the human subject is less than 60kg,

wherein the human subject exhibits a prolongation of the QT/QTc interval of greater than 500ms or an occurrence of an increase of greater than 60ms relative to the baseline QT/QTc interval prolongation during treatment with the first dosage regimen, and the method further comprises terminating administration of the dosage regimen after the prolongation of the QT/QTc interval of greater than 500ms or the increase of greater than 60ms relative to the baseline QT/QTc interval prolongation occurs until the QT/QTc interval prolongation is improved to less than or equal to 480ms or baseline, and administering to the human subject a second dosage regimen comprising the following dose of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 8 mg/day when the body weight of the human subject is equal to or exceeds 60kg or (ii) 4 mg/day when the body weight of the human subject is less than 60 kg.

60. A method of treating unresectable hepatocellular carcinoma, the method comprising administering to a human subject having unresectable hepatocellular carcinoma and moderate liver damage classified as Child-Pugh class B according to the Child-Pugh classification a first dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 8 mg/day,

wherein the human subject exhibits a prolongation of the QT/QTc interval of greater than 500ms or an occurrence of an increase of greater than 60ms of prolongation of the QT/QTc interval relative to the baseline QT/QTc interval during treatment with the first dosage regimen, and the method further comprises terminating administration of the dosage regimen after the prolongation of the QT/QTc interval of greater than 500ms or the increase of greater than 60ms of prolongation of the baseline QT/QTc interval occurs until the QT/QTc interval prolongation is improved to less than or equal to 480ms or baseline, and administering to the human subject a second dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4 mg/day.

61. The method of any one of claims 1 to 60, wherein the median overall survival is 13.6 months.

62. The method of any one of claims 1 to 60, wherein the median overall survival with a 95% confidence interval is between 12.1 months and 14.9 months.

63. The method of any one of claims 1 to 60, wherein the risk ratio for overall survival compared to Sorafenib at a twice daily dose of 400mg is 0.92.

64. The method of any one of claims 1 to 60, wherein the risk ratio of overall survival compared to sorafenib at a 400mg twice daily dose with a 95% confidence interval is between 0.79 and 1.06.

65. The method of any one of claims 1 to 60, wherein overall survival is from 12 to 15 months.

66. The method of any one of claims 1 to 60, wherein median progression-free survival is 7.3 months.

67. The method of any one of claims 1 to 60, wherein median progression-free survival with 95% confidence interval is between 5.6 and 7.5 months.

68. The method of any one of claims 1 to 60, wherein the risk ratio for progression-free survival compared to Sorafenib at a twice daily dose of 400mg is 0.64.

69. The method of any one of claims 1 to 60, wherein the risk ratio for progression-free survival compared to Sorafenib at a twice-daily dose of 400mg with a 95% confidence interval is between 0.55 and 0.75.

70. The method of any one of claims 1 to 60, wherein progression-free survival is from 5 to 8 months.

71. The method of any one of claims 1 to 60, wherein median time to progression is 7.3 months.

72. The method of any one of claims 1 to 60, wherein the median time to progression with 95% confidence interval is between 5.6 to 7.5 months.

73. The method of any one of claims 1 to 60, wherein the risk ratio of time to progression compared to a twice daily dose of 400mg of sorafenib is 0.65.

74. The method of any one of claims 1 to 60, wherein the risk ratio of time to progression with 95% confidence interval compared to a twice daily dose of 400mg sorafenib is between 0.56 and 0.77.

75. The method of any one of claims 1 to 60, wherein time of progression is shown in figure 6 (Kaplan-Meier curve of time of progression).

76. The method according to any one of claims 1-60, wherein the objective response rate is 19%.

77. The method according to any one of claims 1-60, wherein the odds ratio for objective response rate compared to sorafenib at a twice daily dose of 400mg is 3.13.

78. The method of any one of claims 1 to 60, wherein the odds ratio for objective response rate compared to sorafenib at a 400mg twice daily dose with a 95% confidence interval is between 2.15 and 4.56.

79. The method of any one of claims 1 to 60, wherein the method comprises achieving the results shown in Table 10 (therapeutic outcome in HCC).

80. The method of any one of claims 1 to 60, wherein the method comprises achieving the results (quality of life) shown in figure 15.

81. The method of any one of claims 1 to 80, wherein the human subject consists essentially of a subject with mild liver injury classified as Child-Pugh class A according to the Child-Pugh classification.

82. The method of any one of claims 1-81, wherein the human subject is classified as stage B or stage C based on the Barcelona Clinical Liver Cancer (BCLC) staging system.

83. The method of any one of claims 1-82, wherein lenvatinib or a pharmaceutically acceptable salt thereof is formulated as a capsule.

84. The method of any one of claims 1-83, wherein lenvatinib or a pharmaceutically acceptable salt thereof is administered orally to the human subject.

85. The method of any one of claims 1 to 84, wherein lenvatinib or a pharmaceutically acceptable salt thereof is lenvatinib mesylate.

[ technical field ]

The present application relates generally to methods of treating hepatocellular carcinoma.

[ background art ]

Hepatocellular carcinoma (HCC) is the second leading cause of cancer death worldwide and causes approximately 745,000 deaths each year. It often occurs in the context of chronic liver disease, particularly cirrhosis, which limits the feasibility of surgical resection. The oral multi-kinase inhibitor Sorafenib (Sorafenib), when used as a first-line treatment for HCC, extended overall survival, exhibiting a median improvement of 2.8 months compared to placebo (10.7 months versus 7.9 months; risk ratio [ HR ]: 0.69; P < 0.001), but with a low response rate of 2% (Llovet, N engl.j Med. [ new england medical journal ], 359: 378- > 390, 2008).

In the last 10 years, drug development of HCC was marked by four failed phase 3 trials (sunitinib, brivanib, rilifanib and erlotinib plus sorafenib) which did not exhibit non-inferiority in overall survival relative to sorafenib (Cheng, j.clin.oncol. [ journal of clinical oncology ], 31: 4067. sub. 4075, 2013; Johnson, j.clin.oncol. [ journal of clinical oncology ], 31: 36517. sub. 3524, 2013; Cainap, j.clin.oncol. [ journal of clinical oncology ], 33: 172. sub. 179, 2015) or superiority (Zhu, j.clin.oncol. [ journal of clinical oncology ], 559-66, Zhu, j.clin.oncol. (clinical oncology, 559-66). Thus, unresectable HCC represents a highly unmet medical need.

[ summary of the invention ]

The present disclosure relates, in part, to methods of treating a subject with HCC (e.g., advanced HCC, unresectable HCC (uHCC), or advanced uHCC) with lenvatinib (lenvatinib) or a pharmaceutically acceptable salt thereof. In some embodiments, lenvatinib or a pharmaceutically acceptable salt thereof is administered as a first line single agent to a patient with unresectable HCC. In some embodiments, the dose of lenvatinib or a pharmaceutically acceptable salt thereof is modified following the occurrence of one or more adverse events in the treated subject.

In a first aspect, the disclosure features a method of treating unresectable hepatocellular carcinoma. The method comprises administering to a human subject with unresectable hepatocellular carcinoma a dosage regimen of lenvatinib or a pharmaceutically acceptable salt thereof that is: (i) 12 mg/day when the body weight of the human subject is equal to or exceeds 60kg or (ii) 8 mg/day when the body weight of the human subject is less than 60 kg. In certain embodiments, the lenvatinib or a pharmaceutically acceptable salt thereof is administered orally. In certain embodiments, the lenvatinib or a pharmaceutically acceptable salt thereof is administered once daily. In certain embodiments, the lenvatinib or a pharmaceutically acceptable salt thereof is administered orally once daily.

In a second aspect, the disclosure features a method of treating unresectable hepatocellular carcinoma. The method comprises administering to a human subject having unresectable hepatocellular carcinoma and moderate liver damage classified as Child-Pugh class B according to the Child-Pugh classification a dosage regimen of 8 mg/day of lenvatinib or a pharmaceutically acceptable salt thereof. In certain embodiments, the lenvatinib or a pharmaceutically acceptable salt thereof is administered orally. In certain embodiments, the lenvatinib or a pharmaceutically acceptable salt thereof is administered once daily. In certain embodiments, the lenvatinib or a pharmaceutically acceptable salt thereof is administered orally once daily.

As used throughout this disclosure, a dosage regimen comprising a specified dose of lenvatinib or a pharmaceutically acceptable salt thereof means that lenvatinib or a pharmaceutically acceptable salt thereof is present in the dosage regimen at the specified dose. Although such dosage regimen may contain additional ingredients, lenvatinib or a pharmaceutically acceptable salt thereof is present only in the specific dosages listed. The dose of lenvatinib or a pharmaceutically acceptable salt thereof (e.g., 12mg, 8mg, or 4mg) as used herein refers to a dose of lenvatinib in free form.

In a third aspect, the present disclosure provides a method of treating unresectable hepatocellular carcinoma, the method comprising administering to a human subject having unresectable hepatocellular carcinoma a first dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at: (i) 12 mg/day when the body weight of the human subject is equal to or exceeds 60kg or (ii) 8 mg/day when the body weight of the human subject is less than 60 kg. In performing this method, the human subject exhibits the onset of a first grade 3 non-hematologic toxicity during treatment with the first dosage regimen. Then, the method further comprises terminating administration of the first dosage regimen after the first grade 3 non-hematologic toxicity has occurred until the first grade 3 non-hematologic toxicity subsides to grade 0-1 or baseline, and administering to the human subject a second dosage regimen comprising the following doses of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 8 mg/day when the body weight of the human subject is equal to or exceeds 60kg or (ii) 4 mg/day when the body weight of the human subject is less than 60 kg. In certain embodiments, the human subject exhibits the onset of a second grade 3 non-hematologic toxicity during treatment with the second dosage regimen. In such embodiments, the method further comprises terminating administration of the second dosage regimen after the occurrence of the second grade 3 non-hematological toxicity until the second grade 3 non-hematological toxicity subsides to grade 0-1 or baseline, and administering to the human subject a third dosage regimen comprising the following dose of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 4 mg/day when the body weight of the human subject is equal to or exceeds 60kg or (ii) 4mg every other day when the body weight of the human subject is less than 60 kg. In certain embodiments, the human subject exhibits the onset of third grade 3 non-hematologic toxicity during treatment with the third dosage regimen. In such embodiments, the method further comprises terminating administration of the third dosage regimen after the third grade 3 non-hematological toxicity has occurred until the third grade 3 non-hematological toxicity subsides to grade 0-1 or baseline, and administering to the human subject a fourth dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4mg every other day when the body weight of the human subject equals or exceeds 60 kg.

In a fourth aspect, the disclosure provides a method of treating unresectable hepatocellular carcinoma, the method comprising administering to a human subject having unresectable hepatocellular carcinoma and moderate liver damage classified as Child-Pugh class B according to the Child-Pugh classification a first dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 8 mg/day. In performing this method, the human subject exhibits the onset of a first grade 3 non-hematologic toxicity during treatment with the first dosage regimen. Then, the method further comprises terminating administration of the first dosage regimen after the first grade 3 non-hematologic toxicity has occurred until the first grade 3 non-hematologic toxicity subsides to grade 0-1 or baseline, and administering to the human subject a second dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4 mg/day. In certain embodiments, the human subject exhibits the onset of a second grade 3 non-hematologic toxicity during treatment with the second dosage regimen. In such embodiments, the method further comprises terminating administration of the second dosage regimen after the occurrence of the second grade 3 non-hematological toxicity until the second grade 3 non-hematological toxicity subsides to grade 0-1 or baseline, and administering to the human subject a third dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4mg every other day. In certain embodiments, the human subject exhibits the onset of third grade 3 non-hematologic toxicity during treatment with the third dosage regimen. In such embodiments, the method further comprises terminating administration of the third dosage regimen after the third grade 3 non-hematologic toxicity has occurred.

In a fifth aspect, the present disclosure provides a method of treating unresectable hepatocellular carcinoma, the method comprising administering to a human subject having unresectable hepatocellular carcinoma a first dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at: (i) 12 mg/day when the body weight of the human subject is equal to or exceeds 60kg or (ii) 8 mg/day when the body weight of the human subject is less than 60 kg. In carrying out this method, the human subject exhibits the onset of a first sustained and intolerable grade 2 or 3 non-hematologic toxicity during treatment with the first dosage regimen. Then, the method further comprises terminating administration of the first dosage regimen after the first sustained and intolerant grade 2 or grade 3 non-hematologic toxicity has occurred until the first sustained and intolerant grade 2 or grade 3 non-hematologic toxicity subsides to grade 0-1 or baseline, and administering to the human subject a second dosage regimen comprising the following dose of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 8 mg/day when the body weight of the human subject is equal to or exceeds 60kg or (ii) 4 mg/day when the body weight of the human subject is less than 60 kg. In certain embodiments, the human subject exhibits an onset of a second sustained and intolerable grade 2 or 3 non-hematologic toxicity during treatment with the second dosage regimen. In such embodiments, the method further comprises terminating administration of the second dosage regimen after the occurrence of the second sustained and intolerant grade 2 or grade 3 non-hematologic toxicity until the second sustained and intolerant grade 2 or grade 3 non-hematologic toxicity subsides to grade 0-1 or baseline, and administering to the human subject a third dosage regimen comprising the following dose of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 4 mg/day when the body weight of the human subject is equal to or exceeds 60kg or (ii) 4mg every other day when the body weight of the human subject is less than 60 kg. In certain embodiments, the human subject exhibits an onset of third sustained and intolerable grade 2 or 3 non-hematologic toxicity during treatment with the third dosage regimen. In such embodiments, the method further comprises terminating administration of the third dosage regimen after the third sustained and intolerant grade 2 or grade 3 non-hematological toxicity has occurred until the third sustained and intolerant grade 2 or grade 3 non-hematological toxicity subsides to grade 0-1 or baseline, and administering to the human subject a fourth dosage regimen comprising a dose of 4mg lenvatinib or a pharmaceutically acceptable salt thereof every other day when the body weight of the human subject equals or exceeds 60 kg.

In a sixth aspect, the present disclosure provides a method of treating unresectable hepatocellular carcinoma, the method comprising administering to a human subject having unresectable hepatocellular carcinoma and moderate liver damage classified as Child-Pugh class B according to the Child-Pugh classification a first dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 8 mg/day. In carrying out this method, the human subject exhibits the onset of a first sustained and intolerable grade 2 or 3 non-hematologic toxicity during treatment with the first dosage regimen. Then, the method further comprises terminating administration of the first dosage regimen after the first sustained and intolerant grade 2 or grade 3 non-hematologic toxicity has occurred until the first sustained and intolerant grade 2 or grade 3 non-hematologic toxicity subsides to grade 0-1 or baseline, and administering to the human subject a second dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4 mg/day. In certain embodiments, the human subject exhibits an onset of a second sustained and intolerable grade 2 or 3 non-hematologic toxicity during treatment with the second dosage regimen. In such embodiments, the method further comprises terminating administration of the second dosage regimen after the occurrence of the second sustained and intolerant grade 2 or grade 3 non-hematologic toxicity until the second sustained and intolerant grade 2 or grade 3 non-hematologic toxicity subsides to grade 0-1 or baseline, and administering a third dosage regimen comprising a dose of 4mg of lenvatinib or a pharmaceutically acceptable salt thereof to the human subject every other day. In certain embodiments, the human subject exhibits an onset of third sustained and intolerable grade 2 or 3 non-hematologic toxicity during treatment with the third dosage regimen. In such embodiments, the method further comprises terminating administration of the third dosage regimen after the third sustained and intolerable grade 2 or 3 non-hematologic toxicity has occurred.

In a seventh aspect, the present disclosure provides a method of treating unresectable hepatocellular carcinoma, the method comprising administering to a human subject having unresectable hepatocellular carcinoma a first dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at: (i) 12 mg/day when the body weight of the human subject is equal to or exceeds 60kg or (ii) 8 mg/day when the body weight of the human subject is less than 60 kg. In carrying out this method, the human subject exhibits a first sustained and intolerable grade 2 or 3 non-hematologic toxicity or occurrence of a non-life threatening grade 4 laboratory test abnormality during treatment with the first dose regimen. Then, the method further comprises terminating administration of the first dosage regimen after the occurrence of the first sustained and intolerant grade 2 or grade 3 non-hematologic toxicity or non-life threatening grade 4 laboratory test abnormality until the first sustained and intolerant grade 2 or grade 3 non-hematologic toxicity or non-life threatening grade 4 laboratory test abnormality subsides to grade 0-1 or baseline, and administering to the human subject a second dosage regimen comprising the following dose of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 8 mg/day when the body weight of the human subject is equal to or exceeds 60kg or (ii) 4 mg/day when the body weight of the human subject is less than 60 kg. In certain embodiments, the human subject exhibits the onset of a second persistent and intolerable grade 2 or 3 non-hematologic toxicity or non-life threatening grade 4 laboratory test abnormality during treatment with the second dosage regimen. In such embodiments, the method further comprises terminating administration of the second dosage regimen after the occurrence of the second sustained and intolerant grade 2 or grade 3 non-hematologic toxicity or non-life threatening grade 4 laboratory test abnormality until the second sustained and intolerant grade 2 or grade 3 non-hematologic toxicity or non-life threatening grade 4 laboratory test abnormality subsides to grade 0-1 or baseline, and administering to the human subject a third dosage regimen comprising the following doses of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 4 mg/day when the body weight of the human subject is equal to or exceeds 60kg or (ii) 4mg every other day when the body weight of the human subject is less than 60 kg. In certain embodiments, the human subject exhibits the onset of a third persistent and intolerable grade 2 or 3 non-hematologic toxicity or non-life threatening grade 4 laboratory test abnormality during treatment with the third dosage regimen. In such embodiments, the method further comprises terminating administration of the third dosage regimen after the occurrence of the third sustained and intolerable grade 2 or 3 non-hematologic toxicity or non-life threatening grade 4 laboratory test abnormality until the third sustained and intolerable grade 2 or 3 non-hematologic toxicity or non-life threatening grade 4 laboratory test abnormality subsides to grade 0-1 or baseline, and administering to the human subject every other day a fourth dosage regimen comprising a dose of 4mg of lenvatinib or a pharmaceutically acceptable salt thereof when the body weight of the human subject equals or exceeds 60 kg.

In an eighth aspect, the present disclosure provides a method of treating unresectable hepatocellular carcinoma, the method comprising administering to a human subject having unresectable hepatocellular carcinoma and moderate liver damage classified as Child-Pugh class B according to the Child-Pugh classification a first dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 8 mg/day. In carrying out this method, the human subject exhibits a first sustained and intolerable grade 2 or 3 non-hematologic toxicity or occurrence of a non-life threatening grade 4 laboratory test abnormality during treatment with the first dose regimen. Thus, the method further comprises terminating administration of the first dosage regimen after the occurrence of the first sustained and intolerant grade 2 or grade 3 non-hematologic toxicity or non-life threatening grade 4 laboratory test abnormality until the first sustained and intolerant grade 2 or grade 3 non-hematologic toxicity or non-life threatening grade 4 laboratory test abnormality subsides to grade 0-1 or baseline, and administering to the human subject a second dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4 mg/day. In certain embodiments, the human subject exhibits the onset of a second persistent and intolerable grade 2 or 3 non-hematologic toxicity or non-life threatening grade 4 laboratory test abnormality during treatment with the second dosage regimen. In such embodiments, the method further comprises terminating administration of the second dosage regimen after the occurrence of the second sustained and intolerant grade 2 or grade 3 non-hematologic toxicity or non-life threatening grade 4 laboratory test abnormality until the second sustained and intolerant grade 2 or grade 3 non-hematologic toxicity or non-life threatening grade 4 laboratory test abnormality subsides to grade 0-1 or baseline, and administering to the human subject a third dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4mg every other day. In certain embodiments, the human subject exhibits the onset of a third persistent and intolerable grade 2 or 3 non-hematologic toxicity or non-life threatening grade 4 laboratory test abnormality during treatment with the third dosage regimen. In such embodiments, the method further comprises terminating administration of the third dosage regimen after the occurrence of the third sustained and intolerable grade 2 or 3 non-hematologic toxicity or non-life threatening grade 4 laboratory test abnormality.

In some embodiments of the third through eighth aspects, the human subject does not exhibit the onset of a second persistent and intolerable grade 2 or 3 non-hematologic toxicity or non-life threatening grade 4 laboratory test abnormality after or during treatment with the second dosage regimen. In such embodiments, the method further comprises continuing to administer the second dosage regimen to the human subject (i.e., without decreasing the dose being administered in the second dosage regimen).

In some embodiments of the third through eighth aspects, the human subject does not exhibit the onset of a third persistent and intolerable grade 2 or 3 non-hematologic toxicity or non-life threatening grade 4 laboratory test abnormality after or during treatment with the third dosage regimen. In such embodiments, the method further comprises continuing to administer the third dosage regimen to the human subject (i.e., without decreasing the dose being administered in the third dosage regimen).

In certain embodiments, the human subject exhibits the occurrence of grade 4 non-hematologic toxicity during treatment with the dosage regimen described above except for life-threatening grade 4 laboratory test abnormalities. In such embodiments, the method further comprises terminating administration of the dosage regimen after the occurrence of the grade 4 non-hematologic toxicity other than the non-life-threatening grade 4 laboratory test abnormality.

In a ninth aspect, the present disclosure provides a method of treating unresectable hepatocellular carcinoma, the method comprising administering to a human subject having unresectable hepatocellular carcinoma a first dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at: (i) 12 mg/day when the body weight of the human subject is equal to or exceeds 60kg or (ii) 8 mg/day when the body weight of the human subject is less than 60 kg. In carrying out this method, the human subject exhibits the occurrence of a first grade 3 hematological toxicity or proteinuria during treatment with the first dosage regimen. Then, the method further comprises terminating administration of the first dosage regimen after the first grade 3 hematological toxicity or proteinuria has occurred until the first grade 3 hematological toxicity or proteinuria has resolved to grade 0-2 or baseline, and administering to the human subject a second dosage regimen comprising the following dose of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 12 mg/day when the body weight of the human subject is equal to or exceeds 60kg or (ii) 8 mg/day when the body weight of the human subject is less than 60 kg. In certain embodiments, the human subject exhibits the occurrence of a second grade 3 hematological toxicity or proteinuria during treatment with the second dosage regimen. In such embodiments, the method further comprises terminating administration of the second dosage regimen after the occurrence of the second grade 3 hematological toxicity or proteinuria until the second grade 3 hematological toxicity or proteinuria resolves to grade 0-2 or baseline, and administering to the human subject a third dosage regimen comprising the following dose of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 8 mg/day when the body weight of the human subject is equal to or exceeds 60kg or (ii) 4 mg/day when the body weight of the human subject is less than 60 kg. In certain embodiments, the human subject exhibits the occurrence of grade 3 hematological toxicity or proteinuria during treatment with the third dosage regimen. In such embodiments, the method further comprises terminating administration of the third dosage regimen after the occurrence of the third grade 3 hematological toxicity or proteinuria until the third grade 3 hematological toxicity or proteinuria resolves to grade 0-2 or baseline, and administering to the human subject a fourth dosage regimen comprising the following dose of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 4 mg/day when the body weight of the human subject is equal to or exceeds 60kg or (ii) 4mg every other day when the body weight of the human subject is less than 60 kg. In certain embodiments, the human subject exhibits the occurrence of fourth grade 3 hematological toxicity or proteinuria during treatment with the fourth dosage regimen. In such embodiments, the method further comprises terminating administration of the fourth dosage regimen after the occurrence of the fourth level 3 hematological toxicity or proteinuria until the fourth level 3 hematological toxicity or proteinuria subsides to a level 0-2 or baseline, and administering to the human subject a fifth dosage regimen comprising a dose of 4mg of lenvatinib or a pharmaceutically acceptable salt thereof every other day when the body weight of the human subject equals or exceeds 60 kg.

In a tenth aspect, the present disclosure provides a method of treating unresectable hepatocellular carcinoma, the method comprising administering to a human subject having unresectable hepatocellular carcinoma and moderate liver damage classified as Child-Pugh class B according to the Child-Pugh classification a first dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 8 mg/day. In carrying out this method, the human subject exhibits the occurrence of a first grade 3 hematological toxicity or proteinuria during treatment with the first dosage regimen. Thus, the method further comprises terminating administration of the first dosage regimen after the first grade 3 hematological toxicity or proteinuria has occurred until the first grade 3 hematological toxicity or proteinuria has resolved to grade 0-2 or baseline, and administering to the human subject a second dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 8 mg/day. In certain embodiments, the human subject exhibits the occurrence of a second grade 3 hematological toxicity or proteinuria during treatment with the second dosage regimen. In such embodiments, the method further comprises terminating administration of the second dosage regimen after the occurrence of the second grade 3 hematological toxicity or proteinuria until the second grade 3 hematological toxicity or proteinuria resolves to grade 0-2 or baseline, and administering to the human subject a third dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4 mg/day. In certain embodiments, the human subject exhibits the occurrence of grade 3 hematological toxicity or proteinuria during treatment with the third dosage regimen. In such embodiments, the method further comprises terminating administration of the third dosage regimen after the occurrence of the third grade 3 hematological toxicity or proteinuria until the third grade 3 hematological toxicity or proteinuria subsides to grade 0-2 or baseline, and administering to the human subject a fourth dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4mg every other day. In certain embodiments, the human subject exhibits the occurrence of fourth grade 3 hematological toxicity or proteinuria during treatment with the fourth dosage regimen. In such embodiments, the method further comprises terminating administration of the fourth dosage regimen after the fourth grade 3 hematological toxicity or proteinuria has occurred.

In some embodiments of the ninth or tenth aspect, the human subject does not exhibit the occurrence of grade 3 hematological toxicity or proteinuria after or during treatment with the second dosage regimen. In such embodiments, the method further comprises continuing to administer the second dosage regimen to the human subject (i.e., without decreasing the dose being administered in the second dosage regimen).

In some embodiments of the ninth or tenth aspect, the human subject does not exhibit the occurrence of grade 3 hematological toxicity or proteinuria after or during treatment with the third dosage regimen. In such embodiments, the method further comprises continuing to administer the third dosage regimen to the human subject (i.e., without decreasing the dose being administered in the third dosage regimen).

In some embodiments of the ninth or tenth aspect, the human subject does not exhibit the occurrence of grade 3 hematological toxicity or proteinuria after or during treatment with the fourth dosage regimen. In such embodiments, the method further comprises continuing to administer the fourth dosage regimen to the human subject (i.e., without decreasing the dose being administered in the fourth dosage regimen).

In an eleventh aspect, the present disclosure provides a method of treating unresectable hepatocellular carcinoma, the method comprising administering to a human subject having unresectable hepatocellular carcinoma a first dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of: (i) 12 mg/day when the body weight of the human subject is equal to or exceeds 60kg or (ii) 8 mg/day when the body weight of the human subject is less than 60 kg. In performing this method, the human subject exhibits the onset of a first grade 4 hematological toxicity during treatment with the first dosage regimen. Then, the method further comprises terminating administration of the first dosage regimen after the first grade 4 hematological toxicity has occurred until the first grade 4 hematological toxicity subsides to grade 0-2 or baseline, and administering to the human subject a second dosage regimen comprising the following doses of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 8 mg/day when the body weight of the human subject is equal to or exceeds 60kg or (ii) 4 mg/day when the body weight of the human subject is less than 60 kg. In certain embodiments, the human subject exhibits the onset of a second grade 4 hematological toxicity during treatment with the second dosage regimen. In such embodiments, the method further comprises terminating administration of the second dosage regimen after the occurrence of the second grade 4 hematological toxicity until the second grade 4 hematological toxicity subsides to grade 0-2 or baseline, and administering to the human subject a third dosage regimen comprising the following dose of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 4 mg/day when the body weight of the human subject is equal to or exceeds 60kg or (ii) 4mg every other day when the body weight of the human subject is less than 60 kg. In certain embodiments, the human subject exhibits the onset of third grade 4 hematological toxicity during treatment with the third dosage regimen. In such embodiments, the method further comprises terminating administration of the third dosage regimen after the occurrence of the third grade 4 hematological toxicity until the third grade 4 hematological toxicity subsides to grade 0-2 or baseline, and administering to the human subject a fourth dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4mg every other day when the body weight of the human subject equals or exceeds 60 kg.

In a twelfth aspect, the disclosure provides a method of treating unresectable hepatocellular carcinoma, the method comprising administering to a human subject having unresectable hepatocellular carcinoma and moderate liver damage classified as Child-Pugh class B according to the Child-Pugh classification a first dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 8 mg/day. In performing this method, the human subject exhibits the onset of a first grade 4 hematological toxicity during treatment with the first dosage regimen. Thus, the method further comprises terminating administration of the first dosage regimen after the first grade 4 hematological toxicity has occurred until the first grade 4 hematological toxicity subsides to grade 0-2 or baseline, and administering to the human subject a second dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4 mg/day. In certain embodiments, the human subject exhibits the onset of a second grade 4 hematological toxicity during treatment with the second dosage regimen. In such embodiments, the method further comprises terminating administration of the second dosage regimen after the occurrence of the second grade 4 hematological toxicity until the second grade 4 hematological toxicity subsides to grade 0-2 or baseline, and administering a third dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4mg to the human subject every other day. In certain embodiments, the human subject exhibits the onset of third grade 4 hematological toxicity during treatment with the third dosage regimen. In such embodiments, the method further comprises terminating administration of the third dosage regimen after the third grade 4 hematological toxicity has occurred.

In a thirteenth aspect, the disclosure features a method of treating unresectable hepatocellular carcinoma. The method comprises administering to a human subject having unresectable hepatocellular carcinoma a first dosage regimen comprising the following doses of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 12 mg/day when the body weight of the human subject is equal to or exceeds 60kg or (ii) 8 mg/day when the body weight of the human subject is less than 60 kg. If the human subject exhibits the occurrence of grade 3 hematological toxicity or proteinuria other than first non-clinically relevant laboratory test abnormalities during treatment with the first dosage regimen, the method further comprises terminating administration of the first dosage regimen after the occurrence of grade 3 hematological toxicity or proteinuria other than first non-clinically relevant laboratory test abnormalities until grade 3 hematological toxicity or proteinuria other than first non-clinically relevant laboratory test abnormalities subsides to grade 0-2 or baseline, and administering to the human subject a second dosage regimen comprising the following dose of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 12 mg/day when the body weight of the human subject is equal to or exceeds 60kg or (ii) 8 mg/day when the body weight of the human subject is less than 60 kg. If the human subject exhibits the onset of a first grade 4 hematological toxicity during treatment with the first dosage regimen, the method further comprises terminating administration of the first dosage regimen after the onset of the first grade 4 hematological toxicity until the first grade 4 hematological toxicity subsides to grade 0-2 or baseline, and administering to the human subject a second dosage regimen comprising the following dose of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 8 mg/day when the body weight of the human subject is equal to or exceeds 60kg or (ii) 4 mg/day when the body weight of the human subject is less than 60 kg. If the human subject exhibits the onset of a first sustained and intolerable grade 2 non-hematologic toxicity during treatment with the first dosage regimen, the method further comprises terminating administration of the first dosage regimen after the onset of the first sustained and intolerable grade 2 non-hematologic toxicity and with or without interruption of the first dosage regimen until the first sustained and intolerable grade 2 non-hematologic toxicity subsides to grade 0-1 or baseline, administering to the human subject a second dosage regimen comprising the following doses of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 8 mg/day when the body weight of the human subject is equal to or exceeds 60kg or (ii) 4 mg/day when the body weight of the human subject is less than 60 kg. If the human subject exhibits the onset of a first grade 3 non-hematologic toxicity other than a clinically relevant laboratory test abnormality during treatment with the first dosage regimen, the method further comprises terminating administration of the first dosage regimen after the onset of the first grade 3 non-hematologic toxicity other than a clinically relevant laboratory test abnormality occurs until the grade 3 non-hematologic toxicity other than the first non-clinically relevant laboratory test abnormality subsides to grade 0-1 or baseline, and administering to the human subject a second dosage regimen comprising the following doses of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 8 mg/day when the body weight of the human subject is equal to or exceeds 60kg or (ii) 4 mg/day when the body weight of the human subject is less than 60 kg. If the human subject exhibits the onset of grade 4 non-hematologic toxicity other than a non-life threatening laboratory test abnormality during treatment with the first dosage regimen, the method further comprises terminating administration of the dosage regimen after the onset of the grade 4 non-hematologic toxicity other than the non-life threatening laboratory test abnormality.

In a fourteenth aspect, the disclosure features a method of treating unresectable hepatocellular carcinoma. The method comprises administering to a human subject having unresectable hepatocellular carcinoma and moderate liver damage classified as Child-Pugh class B according to the Child-Pugh classification a first dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 8 mg/day. If the human subject exhibits the onset of grade 3 hematological toxicity or proteinuria other than the first non-clinically relevant laboratory test abnormality during treatment with the first dosage regimen, the method further comprises terminating administration of the first dosage regimen after the onset of grade 3 hematological toxicity or proteinuria other than the first non-clinically relevant laboratory test abnormality until the grade 3 hematological toxicity or proteinuria other than the first non-clinically relevant laboratory test abnormality subsides to grade 0-2 or baseline, and administering to the human subject a second dosage regimen comprising valletinib or a pharmaceutically acceptable salt thereof at a dose of 8 mg/day. If the human subject exhibits the onset of a first grade 4 hematological toxicity during treatment with the first dosage regimen, the method further comprises terminating administration of the first dosage regimen after the onset of the first grade 4 hematological toxicity until the first grade 4 hematological toxicity subsides to grade 0-2 or baseline, and administering to the human subject a second dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4 mg/day. If the human subject exhibits the onset of a first sustained and intolerable grade 2 non-hematological toxicity during treatment with the first dosage regimen, the method further comprises terminating administration of the first dosage regimen after the onset of the first sustained and intolerable grade 2 non-hematological toxicity and with or without interruption of the first dosage regimen until the first sustained and intolerable grade 2 non-hematological toxicity subsides to grade 0-1 or baseline, administering to the human subject a second dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4 mg/day. If the human subject exhibits the onset of grade 3 non-hematological toxicity other than the first non-clinically relevant laboratory test abnormality during treatment with the first dosage regimen, the method further comprises terminating administration of the first dosage regimen after the onset of grade 3 non-hematological toxicity other than the first non-clinically relevant laboratory test abnormality occurs until the grade 3 non-hematological toxicity other than the first non-clinically relevant laboratory test abnormality subsides to grade 0-1 or baseline, and administering to the human subject a second dosage regimen comprising 4 mg/day of lenvatinib or a pharmaceutically acceptable salt thereof. If the human subject exhibits the onset of grade 4 non-hematologic toxicity other than a non-life threatening laboratory test abnormality during treatment with the first dosage regimen, the method further comprises terminating administration of the dosage regimen after the onset of the grade 4 non-hematologic toxicity other than the non-life threatening laboratory test abnormality.

In some embodiments of the eleventh through fourteenth aspects, the human subject does not exhibit the onset of a second grade 4 hematological toxicity after or during treatment with the second dosage regimen. In such embodiments, the method further comprises continuing to administer the second dosage regimen to the human subject (i.e., without decreasing the dose being administered in the second dosage regimen).

In some embodiments of the eleventh through fourteenth aspects, the human subject does not exhibit the onset of third grade 4 hematological toxicity after or during treatment with the third dosage regimen. In such embodiments, the method further comprises continuing to administer the third dosage regimen to the human subject (i.e., without decreasing the dose being administered in the third dosage regimen).

In a fifteenth aspect, the disclosure features a method of treating unresectable hepatocellular carcinoma. In some cases, the method comprises administering to a human subject with unresectable hepatocellular carcinoma a dosage regimen comprising the following doses of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 8 mg/day when the body weight of the human subject equals or exceeds 60kg or (ii) 4 mg/day when the body weight of the human subject is less than 60kg, wherein the human subject was previously treated with a previous dosage regimen comprising the following dose of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 12 mg/day when the body weight of the human subject equals or exceeds 60kg or (ii) 8 mg/day when the body weight of the human subject is less than 60kg, and wherein the human subject exhibits the onset of grade 3 non-hematologic toxicity during treatment with the prior dosage regimen. In other cases, the method comprises administering to a human subject with unresectable hepatocellular carcinoma a dosage regimen comprising the following doses of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 4 mg/day when the body weight of the human subject is equal to or exceeds 60kg or (ii) 4mg every other day when the body weight of the human subject is less than 60kg, wherein the human subject was previously treated with a previous dosage regimen comprising the following dose of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 8 mg/day when the body weight of the human subject equals or exceeds 60kg or (ii) 4 mg/day when the body weight of the human subject is less than 60kg, and wherein the human subject exhibits the onset of grade 3 non-hematologic toxicity during treatment with the prior dosage regimen. In still other instances, the method comprises administering to a human subject with unresectable hepatocellular carcinoma, every other day, a dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4mg, wherein the human subject has a body weight equal to or exceeding 60kg, wherein the human subject was previously treated with a previous dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4 mg/day, and wherein the human subject exhibits the onset of grade 3 non-hematologic toxicity during treatment with the previous dosage regimen.

In a sixteenth aspect, the disclosure features a method of treating unresectable hepatocellular carcinoma. In some cases, the method comprises administering to a human subject with unresectable hepatocellular carcinoma and moderate liver damage classified as Child-Pugh class B according to the Child-Pugh classification a dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4 mg/day, wherein the human subject was previously treated with a previous dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 8 mg/day, and wherein the human subject exhibits the onset of grade 3 non-hematologic toxicity during treatment with the previous dosage regimen. In other instances, the method comprises administering a dosage regimen comprising a dose of 4mg of lenvatinib or a pharmaceutically acceptable salt thereof every other day to a human subject having unresectable hepatocellular carcinoma and moderate liver injury classified as Child-Pugh class B according to the Child-Pugh classification, wherein the human subject was previously treated with a previous dosage regimen comprising a dose of 4 mg/day of lenvatinib or a pharmaceutically acceptable salt thereof, and wherein the human subject exhibited an incidence of grade 3 non-hematologic toxicity during treatment with the previous dosage regimen.

In a seventeenth aspect, the disclosure features a method of treating unresectable hepatocellular carcinoma. In some cases, the method comprises administering to a human subject with unresectable hepatocellular carcinoma a dosage regimen comprising the following doses of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 8 mg/day when the body weight of the human subject equals or exceeds 60kg or (ii) 4 mg/day when the body weight of the human subject is less than 60kg, wherein the human subject was previously treated with a previous dosage regimen comprising the following dose of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 12 mg/day when the body weight of the human subject equals or exceeds 60kg or (ii) 8 mg/day when the body weight of the human subject is less than 60kg, and wherein the human subject exhibits the onset of sustained and intolerable grade 2 or grade 3 non-hematologic toxicity during treatment with the prior dosage regimen. In other cases, the method comprises administering to a human subject with unresectable hepatocellular carcinoma a dosage regimen comprising the following doses of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 4 mg/day when the body weight of the human subject is equal to or exceeds 60kg or (ii) 4mg every other day when the body weight of the human subject is less than 60kg, wherein the human subject was previously treated with a previous dosage regimen comprising the following dose of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 8 mg/day when the body weight of the human subject equals or exceeds 60kg or (ii) 4 mg/day when the body weight of the human subject is less than 60kg, and wherein the human subject exhibits the onset of sustained and intolerable grade 2 or grade 3 non-hematologic toxicity during treatment with the prior dosage regimen. In still other instances, the method comprises administering to a human subject with unresectable hepatocellular carcinoma, every other day, a dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4mg, wherein the human subject has a body weight equal to or exceeding 60kg, wherein the human subject was previously treated with a previous dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4 mg/day, and wherein the human subject exhibits the onset of persistent and intolerable grade 2 or grade 3 non-hematologic toxicity during treatment with the previous dosage regimen.

In an eighteenth aspect, the disclosure features a method of treating unresectable hepatocellular carcinoma. In some cases, the method comprises administering to a human subject with unresectable hepatocellular carcinoma and moderate liver damage classified as Child-Pugh class B according to the Child-Pugh classification a dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4 mg/day, wherein the human subject was previously treated with a previous dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 8 mg/day, and wherein the human subject exhibits an onset of persistent and intolerable grade 2 or grade 3 non-hematologic toxicity during treatment with the previous dosage regimen. In other cases, the method comprises administering every other day a dosage regimen comprising a dose of 4mg of lenvatinib or a pharmaceutically acceptable salt thereof to a human subject with unresectable hepatocellular carcinoma and moderate liver injury classified as Child-Pugh class B according to the Child-Pugh classification, wherein the human subject was previously treated with a previous dosage regimen comprising a dose of 4 mg/day of lenvatinib or a pharmaceutically acceptable salt thereof, and wherein the human subject exhibits an onset of persistent and intolerable grade 2 or grade 3 non-hematologic toxicity during treatment with the previous dosage regimen.

In a nineteenth aspect, the disclosure features a method of treating unresectable hepatocellular carcinoma. In some cases, the method comprises administering to a human subject with unresectable hepatocellular carcinoma a dosage regimen comprising the following doses of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 8 mg/day when the body weight of the human subject equals or exceeds 60kg or (ii) 4 mg/day when the body weight of the human subject is less than 60kg, wherein the human subject was previously treated with a previous dosage regimen comprising the following dose of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 12 mg/day when the body weight of the human subject equals or exceeds 60kg or (ii) 8 mg/day when the body weight of the human subject is less than 60kg, and wherein the human subject exhibits persistent and intolerable grade 2 or 3 non-hematologic toxicity or non-life threatening grade 4 laboratory test abnormalities during treatment with the prior dosage regimen. In other cases, the method comprises administering to a human subject with unresectable hepatocellular carcinoma a dosage regimen comprising the following doses of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 4 mg/day when the body weight of the human subject is equal to or exceeds 60kg or (ii) 4mg every other day when the body weight of the human subject is less than 60kg, wherein the human subject was previously treated with a previous dosage regimen comprising the following dose of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 8 mg/day when the body weight of the human subject equals or exceeds 60kg or (ii) 4 mg/day when the body weight of the human subject is less than 60kg, and wherein the human subject exhibits persistent and intolerable grade 2 or 3 non-hematologic toxicity or non-life threatening grade 4 laboratory test abnormalities during treatment with the prior dosage regimen. In certain instances, the method comprises administering to a human subject with unresectable hepatocellular carcinoma every other day a dosage regimen comprising a dose of 4mg of lenvatinib or a pharmaceutically acceptable salt thereof, wherein the human subject has a body weight equal to or exceeding 60kg, wherein the human subject was previously treated with a previous dosage regimen comprising a dose of 4 mg/day lenvatinib or a pharmaceutically acceptable salt thereof, and wherein the human subject exhibits persistent and intolerable grade 2 or 3 non-hematologic toxicity or non-life threatening grade 4 laboratory test for the occurrence of an abnormality during treatment with the previous dosage regimen.

In a twentieth aspect, the disclosure features a method of treating unresectable hepatocellular carcinoma. In some cases, the method comprises administering a dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4 mg/day to a human subject with unresectable hepatocellular carcinoma and moderate liver injury classified as Child-Pugh class B according to the Child-Pugh classification, wherein the human subject was previously treated with a previous dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 8 mg/day, and wherein the human subject is examined for the occurrence of abnormalities in a grade 2 or grade 3 non-hematologic toxicity or non-life threatening class 4 laboratory that appears persistent and intolerable during treatment with the previous dosage regimen. In other cases, the method comprises administering a dosage regimen comprising a dose of 4mg of lenvatinib or a pharmaceutically acceptable salt thereof every other day to a human subject with unresectable hepatocellular carcinoma and moderate liver injury classified as Child-Pugh class B according to the Child-Pugh classification, wherein the human subject was previously treated with a previous dosage regimen comprising a dose of 4 mg/day of lenvatinib or a pharmaceutically acceptable salt thereof, and wherein the human subject is examined for the occurrence of abnormalities in a grade 2 or grade 3 non-hematologic toxicity or non-life-threatening grade 4 laboratory that appears persistent and intolerable during treatment with the previous dosage regimen.

In a twenty-first aspect, the disclosure features a method of treating unresectable hepatocellular carcinoma. In some cases, the method comprises administering to a human subject with unresectable hepatocellular carcinoma a dosage regimen comprising the following doses of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 12 mg/day when the body weight of the human subject equals or exceeds 60kg or (ii) 8 mg/day when the body weight of the human subject is less than 60kg, wherein the human subject was previously treated with a previous dosage regimen comprising the following dose of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 12 mg/day when the body weight of the human subject equals or exceeds 60kg or (ii) 8 mg/day when the body weight of the human subject is less than 60kg, and wherein the human subject exhibits the occurrence of grade 3 hematological toxicity or proteinuria during treatment with the prior dosage regimen. In some cases, the method comprises administering to a human subject with unresectable hepatocellular carcinoma a dosage regimen comprising the following doses of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 8 mg/day when the body weight of the human subject equals or exceeds 60kg or (ii) 4 mg/day when the body weight of the human subject is less than 60kg, wherein the human subject was previously treated with a previous dosage regimen comprising the following dose of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 12 mg/day when the body weight of the human subject equals or exceeds 60kg or (ii) 8 mg/day when the body weight of the human subject is less than 60kg, and wherein the human subject exhibits the occurrence of grade 3 hematological toxicity or proteinuria during treatment with the prior dosage regimen. In certain instances, the method comprises administering to a human subject with unresectable hepatocellular carcinoma a dosage regimen comprising the following doses of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 4 mg/day when the body weight of the human subject is equal to or exceeds 60kg or (ii) 4mg every other day when the body weight of the human subject is less than 60kg, wherein the human subject was previously treated with a previous dosage regimen comprising the following dose of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 8 mg/day when the body weight of the human subject equals or exceeds 60kg or (ii) 4 mg/day when the body weight of the human subject is less than 60kg, and wherein the human subject exhibits the occurrence of grade 3 hematological toxicity or proteinuria during treatment with the prior dosage regimen. In other instances, the method comprises administering to a human subject with unresectable hepatocellular carcinoma a dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4mg every other day, wherein the human subject has a body weight equal to or greater than 60kg, wherein the human subject was previously treated with a previous dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4 mg/day, and wherein the human subject exhibits grade 3 hematologic toxicity or the occurrence of proteinuria during treatment with the previous dosage regimen.

In a twenty-second aspect, the disclosure features a method of treating unresectable hepatocellular carcinoma. In some cases, the method comprises administering to a human subject with unresectable hepatocellular carcinoma and moderate liver injury classified as Child-Pugh class B according to the Child-Pugh classification a dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 8 mg/day, wherein the human subject was previously treated with a previous dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 8 mg/day, and wherein the human subject exhibits grade 3 hematologic toxicity or the occurrence of proteinuria during treatment with the previous dosage regimen. In other instances, the method comprises administering to a human subject with unresectable hepatocellular carcinoma and moderate liver injury classified as Child-Pugh class B according to the Child-Pugh classification a dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4 mg/day, wherein the human subject was previously treated with a previous dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 8 mg/day, and wherein the human subject exhibits grade 3 hematologic toxicity or the occurrence of proteinuria during treatment with the previous dosage regimen. In still other instances, the method comprises administering every other day a dosage regimen comprising a dose of 4mg of lenvatinib or a pharmaceutically acceptable salt thereof to a human subject with unresectable hepatocellular carcinoma and moderate liver injury classified as Child-Pugh class B according to the Child-Pugh classification, wherein the human subject was previously treated with a previous dosage regimen comprising a dose of 4 mg/day of lenvatinib or a pharmaceutically acceptable salt thereof, and wherein the human subject exhibited grade 3 hematologic toxicity or the occurrence of proteinuria during treatment with the previous dosage regimen.

In a twenty-third aspect, the disclosure features a method of treating unresectable hepatocellular carcinoma. In some cases, the method comprises administering to a human subject with unresectable hepatocellular carcinoma a dosage regimen comprising the following doses of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 8 mg/day when the body weight of the human subject equals or exceeds 60kg or (ii) 4 mg/day when the body weight of the human subject is less than 60kg, wherein the human subject was previously treated with a previous dosage regimen comprising the following dose of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 12 mg/day when the body weight of the human subject equals or exceeds 60kg or (ii) 8 mg/day when the body weight of the human subject is less than 60kg, and wherein the human subject exhibits the onset of grade 4 hematologic toxicity during treatment with the prior dosage regimen. In other cases, the method comprises administering to a human subject with unresectable hepatocellular carcinoma a dosage regimen comprising the following doses of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 4 mg/day when the body weight of the human subject is equal to or exceeds 60kg or (ii) 4mg every other day when the body weight of the human subject is less than 60kg, wherein the human subject was previously treated with a previous dosage regimen comprising the following dose of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 8 mg/day when the body weight of the human subject equals or exceeds 60kg or (ii) 4 mg/day when the body weight of the human subject is less than 60kg, and wherein the human subject exhibits the onset of grade 4 hematologic toxicity during treatment with the prior dosage regimen. In still other instances, the method comprises administering to a human subject with unresectable hepatocellular carcinoma, every other day, a dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4mg, wherein the human subject has a body weight equal to or exceeding 60kg, wherein the human subject was previously treated with a previous dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4 mg/day, and wherein the human subject exhibits an occurrence of grade 4 non-hematologic toxicity during treatment with the previous dosage regimen.

In a twenty-fourth aspect, the disclosure features a method of treating unresectable hepatocellular carcinoma. In some cases, the method comprises administering to a human subject with unresectable hepatocellular carcinoma and moderate liver damage classified as Child-Pugh class B according to the Child-Pugh classification a dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4 mg/day, wherein the human subject was previously treated with a previous dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 8 mg/day, and wherein the human subject exhibited an occurrence of grade 4 hematologic toxicity during treatment with the previous dosage regimen. In some cases, the method comprises administering a dosage regimen comprising a dose of 4mg of lenvatinib or a pharmaceutically acceptable salt thereof every other day to a human subject having unresectable hepatocellular carcinoma and moderate liver injury classified as Child-Pugh class B according to the Child-Pugh classification, wherein the human subject was previously treated with a previous dosage regimen comprising a dose of 4 mg/day of lenvatinib or a pharmaceutically acceptable salt thereof, and wherein the human subject exhibited an occurrence of grade 4 hematologic toxicity during treatment with the previous dosage regimen.

In a twenty-fifth aspect, the disclosure features a method of treating unresectable hepatocellular carcinoma. The method comprises administering to a human subject having unresectable hepatocellular carcinoma a first dosage regimen comprising the following doses of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 12 mg/day when the body weight of the human subject is equal to or exceeds 60kg or (ii) 8 mg/day when the body weight of the human subject is less than 60 kg. The human subject exhibits a first sustained and intolerable grade 2 or 3 adverse reaction or grade 4 laboratory test abnormality occurrence during treatment with the first dose regimen. In some cases, the method further comprises terminating administration of the first dosage regimen after the occurrence of the first sustained and intolerant grade 2 or grade 3 adverse effect or grade 4 laboratory test abnormality until the first sustained and intolerant grade 2 or grade 3 adverse effect or grade 4 laboratory test abnormality subsides to grade 0-1 or baseline, and administering to the human subject a second dosage regimen comprising a dose of varenib or a pharmaceutically acceptable salt thereof that is: (i) 8 mg/day when the body weight of the human subject equals or exceeds 60kg or (ii) 4 mg/day when the body weight of the human subject is less than 60kg, wherein the human subject exhibits the occurrence of a second sustained and intolerable grade 2 or grade 3 adverse reaction or grade 4 laboratory test abnormality during treatment with the second dosage regimen. The method further comprises terminating administration of the second dosage regimen after the occurrence of the second sustained and intolerant grade 2 or grade 3 adverse effect or grade 4 laboratory test abnormality until the second sustained and intolerant grade 2 or grade 3 adverse effect or grade 4 laboratory test abnormality resolves to grade 0-1 or baseline, and administering to the human subject a third dosage regimen comprising the following dose of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 4 mg/day when the body weight of the human subject equals or exceeds 60kg or (ii) 4mg every other day when the body weight of the human subject is less than 60kg, wherein the human subject exhibits the occurrence of a third sustained and intolerable grade 2 or 3 adverse effect or grade 4 laboratory test abnormality during treatment with the third dosage regimen. The method further comprises terminating administration of the third dosage regimen after the occurrence of the third sustained and intolerant grade 2 or grade 3 adverse effect or grade 4 laboratory test abnormality until the third sustained and intolerant grade 2 or grade 3 adverse effect or grade 4 laboratory test abnormality subsides to grade 0-1 or baseline, and administering to the human subject every other day a fourth dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4mg when the body weight of the human subject equals or exceeds 60 kg. In the case where the human subject exhibits the occurrence of a grade 4 adverse reaction other than a grade 4 laboratory test abnormality during treatment with the first, second, third, or fourth dosage regimen, the method further comprises terminating administration of the dosage regimen after the occurrence of the grade 4 adverse reaction other than a grade 4 laboratory test abnormality. In the above aspects, level 3 blood pressure, level 4 blood pressure, level 3 cardiac dysfunction, level 4 cardiac dysfunction, arterial thromboembolic events of any level, level 3 hepatotoxicity, level 4 hepatotoxicity, proteinuria of 2g or higher within 24 hours, level 3 renal failure or injury, level 4 renal failure or injury, gastrointestinal perforation of any level, level 3 fistula, level 4 fistula, prolongation of the QT/QTc interval of greater than 500ms, an increase of greater than 60ms relative to baseline QT/QTc interval prolongation, and reversible posterior leukoencephalopathy syndromes of any level are excluded from the persistent and intolerable level 2, level 3 or level 4 adverse reactions or level 4 laboratory test abnormalities.

In a twenty-sixth aspect, the disclosure features a method of treating unresectable hepatocellular carcinoma. The method comprises administering to a human subject having unresectable hepatocellular carcinoma and moderate liver damage classified as Child-Pugh class B according to the Child-Pugh classification a first dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 8 mg/day. The human subject exhibits a first sustained and intolerable grade 2 or 3 adverse reaction or grade 4 laboratory test abnormality occurrence during treatment with the first dose regimen. In some cases, the method further comprises terminating administration of the first dosage regimen after the occurrence of the first sustained and intolerant grade 2 or grade 3 adverse effect or grade 4 laboratory test abnormality until the first sustained and intolerant grade 2 or grade 3 adverse effect or grade 4 laboratory test abnormality subsides to grade 0-1 or baseline, and administering to the human subject a second dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4 mg/day, wherein the human subject exhibits the occurrence of a second sustained and intolerant grade 2 or grade 3 adverse effect or grade 4 laboratory test abnormality during treatment with the second dosage regimen. The method further comprises terminating administration of the second dosage regimen after the occurrence of the second sustained and intolerant grade 2 or grade 3 adverse effect or grade 4 laboratory test abnormality until the second sustained and intolerant grade 2 or grade 3 adverse effect or grade 4 laboratory test abnormality subsides to grade 0-1 or baseline, and administering a third dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4mg to the human subject every other day, wherein the human subject exhibits the occurrence of a third sustained and intolerant grade 2 or grade 3 adverse effect or grade 4 laboratory test abnormality during treatment with the third dosage regimen. The method further comprises terminating administration of the third dosage regimen after the occurrence of the third persistent and intolerable grade 2 or 3 adverse reaction or grade 4 laboratory check abnormality. In the case where the human subject exhibits the occurrence of a grade 4 adverse reaction other than a grade 4 laboratory test abnormality during treatment with the first, second, third, or fourth dosage regimen, the method further comprises terminating administration of the dosage regimen after the occurrence of the grade 4 adverse reaction other than a grade 4 laboratory test abnormality. In the above aspects, level 3 blood pressure, level 4 blood pressure, level 3 cardiac dysfunction, level 4 cardiac dysfunction, arterial thromboembolic events of any level, level 3 hepatotoxicity, level 4 hepatotoxicity, proteinuria of 2g or higher within 24 hours, level 3 renal failure or injury, level 4 renal failure or injury, gastrointestinal perforation of any level, level 3 fistula, level 4 fistula, prolongation of the QT/QTc interval of greater than 500ms, an increase of greater than 60ms relative to baseline QT/QTc interval prolongation, and reversible posterior leukoencephalopathy syndromes of any level are excluded from the persistent and intolerable level 2, level 3 or level 4 adverse reactions or level 4 laboratory test abnormalities.

In a twenty-seventh aspect, the disclosure features a method of treating unresectable hepatocellular carcinoma. The method comprises administering to a human subject having unresectable hepatocellular carcinoma a first dosage regimen comprising the following doses of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 12 mg/day when the body weight of the human subject is equal to or exceeds 60kg or (ii) 8 mg/day when the body weight of the human subject is less than 60 kg. In cases where the human subject exhibits an occurrence of a first sustained and intolerant grade 2 or grade 3 adverse effect or grade 4 laboratory test abnormality during treatment with the first dosage regimen, the method further comprises terminating administration of the first dosage regimen after the occurrence of the first sustained and intolerant grade 2 or grade 3 adverse effect or grade 4 laboratory test abnormality until the first sustained and intolerant grade 2 or grade 3 adverse effect or grade 4 laboratory test abnormality subsides to grade 0-1 or baseline, and administering to the human subject a second dosage regimen comprising a dose of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 8 mg/day when the body weight of the human subject is equal to or exceeds 60kg or (ii) 4 mg/day when the body weight of the human subject is less than 60 kg. In the case where the human subject exhibits the occurrence of a grade 4 adverse reaction other than a grade 4 laboratory test abnormality during treatment with the first dosage regimen, the method further comprises terminating administration of the dosage regimen after the occurrence of the grade 4 adverse reaction other than a grade 4 laboratory test abnormality. In the above aspects, level 3 blood pressure, level 4 blood pressure, level 3 cardiac dysfunction, level 4 cardiac dysfunction, arterial thromboembolic events of any level, level 3 hepatotoxicity, level 4 hepatotoxicity, proteinuria of 2g or higher within 24 hours, level 3 renal failure or injury, level 4 renal failure or injury, gastrointestinal perforation of any level, level 3 fistula, level 4 fistula, prolongation of the QT/QTc interval of greater than 500ms, an increase of greater than 60ms relative to baseline QT/QTc interval prolongation, and reversible posterior leukoencephalopathy syndromes of any level are excluded from the persistent and intolerable level 2, level 3 or level 4 adverse reactions or level 4 laboratory test abnormalities.

In a twenty-eighth aspect, the disclosure features a method of treating unresectable hepatocellular carcinoma. The method comprises administering to a human subject having unresectable hepatocellular carcinoma and moderate liver damage classified as Child-Pugh class B according to the Child-Pugh classification a first dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 8 mg/day. In the case where the human subject exhibits an occurrence of a first sustained and intolerant grade 2 or grade 3 adverse effect or grade 4 laboratory test abnormality during treatment with the first dosage regimen, the method further comprises terminating administration of the first dosage regimen after the occurrence of the first sustained and intolerant grade 2 or grade 3 adverse effect or grade 4 laboratory test abnormality until the first sustained and intolerant grade 2 or grade 3 adverse effect or grade 4 laboratory test abnormality subsides to grade 0-1 or baseline, and administering to the human subject a second dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4 mg/day. In the case where the human subject exhibits the occurrence of a grade 4 adverse reaction other than a grade 4 laboratory test abnormality during treatment with the first dosage regimen, the method further comprises terminating administration of the dosage regimen after the occurrence of the grade 4 adverse reaction other than a grade 4 laboratory test abnormality. In the above aspects, level 3 blood pressure, level 4 blood pressure, level 3 cardiac dysfunction, level 4 cardiac dysfunction, arterial thromboembolic events of any level, level 3 hepatotoxicity, level 4 hepatotoxicity, proteinuria of 2g or higher within 24 hours, level 3 renal failure or injury, level 4 renal failure or injury, gastrointestinal perforation of any level, level 3 fistula, level 4 fistula, prolongation of the QT/QTc interval of greater than 500ms, an increase of greater than 60ms relative to baseline QT/QTc interval prolongation, and reversible posterior leukoencephalopathy syndromes of any level are excluded from the persistent and intolerable level 2, level 3 or level 4 adverse reactions or level 4 laboratory test abnormalities.

In a twenty-ninth aspect, the disclosure features a method of treating unresectable hepatocellular carcinoma. The method comprises administering to a human subject having unresectable hepatocellular carcinoma a first dosage regimen comprising the following doses of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 12 mg/day when the body weight of the human subject is equal to or exceeds 60kg or (ii) 8 mg/day when the body weight of the human subject is less than 60 kg. The human subject exhibits a first sustained and intolerable grade 2 or 3 adverse reaction or grade 4 laboratory test abnormality occurrence during treatment with the first dose regimen. In some cases, the method further comprises terminating administration of the first dosage regimen after the occurrence of the first sustained and intolerant grade 2 or grade 3 adverse effect or grade 4 laboratory test abnormality until the first sustained and intolerant grade 2 or grade 3 adverse effect or grade 4 laboratory test abnormality subsides to grade 0-1 or baseline, and administering to the human subject a second dosage regimen comprising a dose of varenib or a pharmaceutically acceptable salt thereof that is: (i) 8 mg/day when the body weight of the human subject equals or exceeds 60kg or (ii) 4 mg/day when the body weight of the human subject is less than 60kg, wherein the human subject exhibits the occurrence of a second sustained and intolerable grade 2 or grade 3 adverse reaction or grade 4 laboratory test abnormality during treatment with the second dosage regimen. The method further comprises terminating administration of the second dosage regimen after the occurrence of the second sustained and intolerant grade 2 or grade 3 adverse effect or grade 4 laboratory test abnormality until the second sustained and intolerant grade 2 or grade 3 adverse effect or grade 4 laboratory test abnormality resolves to grade 0-1 or baseline, and administering to the human subject a third dosage regimen comprising the following dose of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 4 mg/day when the body weight of the human subject equals or exceeds 60kg or (ii) 4mg every other day when the body weight of the human subject is less than 60kg, wherein the human subject exhibits the occurrence of a third sustained and intolerable grade 2 or 3 adverse effect or grade 4 laboratory test abnormality during treatment with the third dosage regimen. The method further comprises terminating administration of the third dosage regimen after the occurrence of the third sustained and intolerant grade 2 or grade 3 adverse effect or grade 4 laboratory test abnormality until the third sustained and intolerant grade 2 or grade 3 adverse effect or grade 4 laboratory test abnormality subsides to grade 0-1 or baseline, and administering to the human subject every other day a fourth dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4mg when the body weight of the human subject equals or exceeds 60 kg. In the case where the human subject exhibits the occurrence of a grade 4 adverse reaction other than a grade 4 laboratory test abnormality during treatment with the first, second, third, or fourth dosage regimen, the method further comprises terminating administration of the dosage regimen after the occurrence of the grade 4 adverse reaction other than a grade 4 laboratory test abnormality. In the above aspects, hypertension, cardiac dysfunction, arterial thromboembolic events, hepatotoxicity, proteinuria, renal failure or injury, gastrointestinal perforation, fistula, QT/QTc interval prolongation, and reversible posterior leukoencephalopathy syndromes are excluded from the persistent and intolerable grade 2, 3, or 4 adverse reactions or grade 4 laboratory test abnormalities.

In a thirtieth aspect, the disclosure features a method of treating unresectable hepatocellular carcinoma. The method comprises administering to a human subject having unresectable hepatocellular carcinoma and moderate liver damage classified as Child-Pugh class B according to the Child-Pugh classification a first dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 8 mg/day. The human subject exhibits a first sustained and intolerable grade 2 or 3 adverse reaction or grade 4 laboratory test abnormality occurrence during treatment with the first dose regimen. In some cases, the method further comprises terminating administration of the first dosage regimen after the occurrence of the first sustained and intolerant grade 2 or grade 3 adverse effect or grade 4 laboratory test abnormality until the first sustained and intolerant grade 2 or grade 3 adverse effect or grade 4 laboratory test abnormality subsides to grade 0-1 or baseline, and administering to the human subject a second dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4 mg/day, wherein the human subject exhibits the occurrence of a second sustained and intolerant grade 2 or grade 3 adverse effect or grade 4 laboratory test abnormality during treatment with the second dosage regimen. The method further comprises terminating administration of the second dosage regimen after the occurrence of the second sustained and intolerant grade 2 or grade 3 adverse effect or grade 4 laboratory test abnormality until the second sustained and intolerant grade 2 or grade 3 adverse effect or grade 4 laboratory test abnormality subsides to grade 0-1 or baseline, and administering a third dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4mg to the human subject every other day, wherein the human subject exhibits the occurrence of a third sustained and intolerant grade 2 or grade 3 adverse effect or grade 4 laboratory test abnormality during treatment with the third dosage regimen. The method further comprises terminating administration of the third dosage regimen after the occurrence of the third persistent and intolerable grade 2 or 3 adverse reaction or grade 4 laboratory check abnormality. In the case where the human subject exhibits the occurrence of a grade 4 adverse reaction other than a grade 4 laboratory test abnormality during treatment with the first, second, third, or fourth dosage regimen, the method further comprises terminating administration of the dosage regimen after the occurrence of the grade 4 adverse reaction other than a grade 4 laboratory test abnormality. In the above aspects, hypertension, cardiac dysfunction, arterial thromboembolic events, hepatotoxicity, proteinuria, renal failure or injury, gastrointestinal perforation, fistula, QT/QTc interval prolongation, and reversible posterior leukoencephalopathy syndromes are excluded from the persistent and intolerable grade 2, 3, or 4 adverse reactions or grade 4 laboratory test abnormalities.

In a thirty-first aspect, the disclosure features a method of treating unresectable hepatocellular carcinoma. The method comprises administering to a human subject having unresectable hepatocellular carcinoma a first dosage regimen comprising the following doses of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 12 mg/day when the body weight of the human subject is equal to or exceeds 60kg or (ii) 8 mg/day when the body weight of the human subject is less than 60 kg. In cases where the human subject exhibits an occurrence of a first sustained and intolerant grade 2 or grade 3 adverse effect or grade 4 laboratory test abnormality during treatment with the first dosage regimen, the method further comprises terminating administration of the first dosage regimen after the occurrence of the first sustained and intolerant grade 2 or grade 3 adverse effect or grade 4 laboratory test abnormality until the first sustained and intolerant grade 2 or grade 3 adverse effect or grade 4 laboratory test abnormality subsides to grade 0-1 or baseline, and administering to the human subject a second dosage regimen comprising a dose of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 8 mg/day when the body weight of the human subject is equal to or exceeds 60kg or (ii) 4 mg/day when the body weight of the human subject is less than 60 kg. In the case where the human subject exhibits the occurrence of a grade 4 adverse reaction other than a grade 4 laboratory test abnormality during treatment with the first dosage regimen, the method further comprises terminating administration of the dosage regimen after the occurrence of the grade 4 adverse reaction other than a grade 4 laboratory test abnormality. In the above aspects, hypertension, cardiac dysfunction, arterial thromboembolic events, hepatotoxicity, proteinuria, renal failure or injury, gastrointestinal perforation, fistula, QT/QTc interval prolongation, and reversible posterior leukoencephalopathy syndromes are excluded from the persistent and intolerable grade 2, 3, or 4 adverse reactions or grade 4 laboratory test abnormalities.

In a thirty-second aspect, the disclosure features a method of treating unresectable hepatocellular carcinoma. The method comprises administering to a human subject having unresectable hepatocellular carcinoma and moderate liver damage classified as Child-Pugh class B according to the Child-Pugh classification a first dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 8 mg/day. In the case where the human subject exhibits an occurrence of a first sustained and intolerant grade 2 or grade 3 adverse effect or grade 4 laboratory test abnormality during treatment with the first dosage regimen, the method further comprises terminating administration of the first dosage regimen after the occurrence of the first sustained and intolerant grade 2 or grade 3 adverse effect or grade 4 laboratory test abnormality until the first sustained and intolerant grade 2 or grade 3 adverse effect or grade 4 laboratory test abnormality subsides to grade 0-1 or baseline, and administering to the human subject a second dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4 mg/day. In the case where the human subject exhibits the occurrence of a grade 4 adverse reaction other than a grade 4 laboratory test abnormality during treatment with the first dosage regimen, the method further comprises terminating administration of the dosage regimen after the occurrence of the grade 4 adverse reaction other than a grade 4 laboratory test abnormality. In the above aspects, hypertension, cardiac dysfunction, arterial thromboembolic events, hepatotoxicity, proteinuria, renal failure or injury, gastrointestinal perforation, fistula, QT/QTc interval prolongation, and reversible posterior leukoencephalopathy syndromes are excluded from the persistent and intolerable grade 2, 3, or 4 adverse reactions or grade 4 laboratory test abnormalities.

In a thirty-third aspect, the disclosure features a method of treating unresectable hepatocellular carcinoma. The method comprises administering to a human subject having unresectable hepatocellular carcinoma a first dosage regimen comprising the following doses of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 12 mg/day when the body weight of the human subject is equal to or exceeds 60kg or (ii) 8 mg/day when the body weight of the human subject is less than 60 kg. If the human subject exhibits the onset of level 3 hypertension during treatment with the first dosage regimen, the method further comprises terminating administration of the first dosage regimen after the onset of the level 3 hypertension until the level 3 hypertension is controlled to be less than or equal to level 2, and administering to the human subject a second dosage regimen comprising the following dose of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 8 mg/day when the body weight of the human subject is equal to or exceeds 60kg or (ii) 4 mg/day when the body weight of the human subject is less than 60 kg.

In a thirty-fourth aspect, the disclosure features a method of treating unresectable hepatocellular carcinoma. The method comprises administering to a human subject having unresectable hepatocellular carcinoma and moderate liver damage classified as Child-Pugh class B according to the Child-Pugh classification a first dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 8 mg/day. If the human subject exhibits the onset of level 3 hypertension during treatment with the first dosage regimen, the method further comprises terminating administration of the first dosage regimen after the onset of the level 3 hypertension until the level 3 hypertension is controlled to be less than or equal to level 2, and administering to the human subject a second dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 4 mg/day.

In a thirty-fifth aspect, the disclosure features a method of treating unresectable hepatocellular carcinoma. The method comprises administering to a human subject having unresectable hepatocellular carcinoma a first dosage regimen comprising the following doses of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 12 mg/day when the body weight of the human subject is equal to or exceeds 60kg or (ii) 8 mg/day when the body weight of the human subject is less than 60 kg. If the human subject exhibits an incidence of proteinuria of 2g or greater within 24 hours during treatment with the first dosage regimen, the method further comprises terminating administration of the dosage regimen after 2g or greater of proteinuria within the 24 hours has occurred until the proteinuria is less than or equal to 2g proteinuria within 24 hours, and administering to the human subject a second dosage regimen comprising a dose of lenvatinib or a pharmaceutically acceptable salt thereof that is: (i) 8 mg/day when the body weight of the human subject is equal to or exceeds 60kg or (ii) 4 mg/day when the body weight of the human subject is less than 60 kg. In the above aspect, the human subject develops occurrence of nephrotic syndrome during treatment with the first dosage regimen, and the method further comprises terminating administration of the dosage regimen after occurrence of the nephrotic syndrome.

In a thirty-sixth aspect, the disclosure features a method of treating unresectable hepatocellular carcinoma. The method comprises administering to a human subject having unresectable hepatocellular carcinoma and moderate liver damage classified as Child-Pugh class B according to the Child-Pugh classification a first dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 8 mg/day. If the human subject exhibits an incidence of proteinuria of 2g or greater within 24 hours during treatment with the first dosage regimen, the method further comprises terminating administration of the dosage regimen after 2g or greater of proteinuria within the 24 hours has occurred until the proteinuria is less than or equal to 2g proteinuria within 24 hours, and administering to the human subject a second dosage regimen comprising valcanib or a pharmaceutically acceptable salt thereof at a dose of 4 mg/day. In the above aspect, the human subject develops occurrence of nephrotic syndrome during treatment with the first dosage regimen, and the method further comprises terminating administration of the dosage regimen after occurrence of the nephrotic syndrome.

In a thirty-seventh aspect, the disclosure features a method of treating unresectable hepatocellular carcinoma. The method comprises administering to a human subject having unresectable hepatocellular carcinoma a first dosage regimen comprising the following doses of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 12 mg/day when the body weight of the human subject is equal to or exceeds 60kg or (ii) 8 mg/day when the body weight of the human subject is less than 60 kg. If the human subject exhibits an onset of prolongation of the QT/QTc interval of greater than 500ms or an increase of greater than 60ms relative to the baseline QT/QTc interval prolongation during treatment with the first dosage regimen, the method further comprises terminating administration of the dosage regimen after the onset of the prolongation of the QT/QTc interval of greater than 500ms or the increase of greater than 60ms relative to the baseline QT/QTc interval prolongation until the QT/QTc interval prolongation is improved to less than or equal to 480ms or baseline, and administering to the human subject a second dosage regimen comprising the following dose of lenvatinib or a pharmaceutically acceptable salt thereof: (i) 8 mg/day when the body weight of the human subject is equal to or exceeds 60kg or (ii) 4 mg/day when the body weight of the human subject is less than 60 kg.

In a thirty-eighth aspect, the disclosure features a method of treating unresectable hepatocellular carcinoma. The method comprises administering to a human subject having unresectable hepatocellular carcinoma and moderate liver damage classified as Child-Pugh class B according to the Child-Pugh classification a first dosage regimen comprising lenvatinib or a pharmaceutically acceptable salt thereof at a dose of 8 mg/day. If the human subject exhibits an onset of prolongation of the QT/QTc interval of greater than 500ms or an increase of greater than 60ms relative to the baseline QT/QTc interval prolongation during treatment with the first dosage regimen, the method further comprises terminating administration of the dosage regimen after the onset of the prolongation of the QT/QTc interval of greater than 500ms or the increase of greater than 60ms relative to the baseline QT/QTc interval prolongation until the QT/QTc interval prolongation is improved to less than or equal to 480ms or baseline, and administering to the human subject a second dosage regimen comprising a dose of 4 mg/day of lenvatinib or a pharmaceutically acceptable salt thereof when the body weight of the human subject is less than 60 kg.

In some embodiments of the above aspects, the median overall survival is 13.6 months.

In some embodiments of the above aspects, the median overall survival with 95% confidence interval is between 12.1 months and 14.9 months.

In some embodiments of the above aspects, the risk ratio for overall survival compared to a twice daily dose of 400mg sorafenib is 0.92.

In some embodiments of the above aspects, the risk ratio for overall survival compared to sorafenib at a 400mg twice daily dose with a 95% confidence interval is between 0.79 and 1.06.

In some embodiments of the above aspects, the overall lifetime is shown in fig. 1 (Kaplan-Meier curve of overall lifetime).

In some embodiments of the above aspects, the median progression-free survival is 7.4 months.

In some embodiments of the above aspect, wherein the median progression-free survival with a 95% confidence interval is between 6.9 months and 8.8 months.

In some embodiments of the above aspects, the risk ratio for progression-free survival compared to a twice daily dose of 400mg sorafenib is 0.66.

In some embodiments of the above aspects, the risk ratio for progression-free survival compared to sorafenib at a twice daily dose of 400mg with a 95% confidence interval is between 0.57 and 0.77.

In some embodiments of the above aspects, the progression-free survival is shown in fig. 2 (Kaplan-Meier curve of progression-free survival).

In some embodiments of the above aspects, the median time to progression is 8.9 months.

In some embodiments of the above aspect, the median time to progression with a 95% confidence interval is between 7.4 months and 9.2 months.

In some embodiments of the above aspects, the risk ratio of time to progression compared to a twice daily dose of 400mg of sorafenib is 0.63.

In some embodiments of the above aspects, the risk ratio of time to progression with 95% confidence interval compared to sorafenib at a twice daily dose of 400mg is between 0.53 and 0.73.

In some embodiments of the above aspects, the time of progression is shown in fig. 6 (Kaplan-Meier curve of time of progression).

In some embodiments of the above aspects, the objective response rate is 24.1%.

In some embodiments of the above aspects, the odds ratio for the objective response rate compared to the twice daily dose of 400mg sorafenib is 3.13.

In some embodiments of the above aspects, the odds ratio for objective response rate compared to sorafenib at a 400mg twice daily dose with a 95% confidence interval is between 2.15 and 4.56.

In some embodiments of the above aspects, the method comprises achieving the results shown in table 2 or table 10 (therapeutic outcome in HCC).

In some embodiments of the above aspects, the method includes implementing the results (quality of life) shown in fig. 15.

In some embodiments of the above aspects, the human subject consists essentially of a subject having mild liver injury classified as Child-Pugh class A according to the Child-Pugh classification.

In some embodiments of the above aspects, the human subject is classified as stage B or stage C based on the Barcelona (Barcelona) clinical liver cancer (BCLC) staging system.

In some embodiments of the above aspects, the medical management of each of the first, second, and third persistent and intolerable grade 2 or 3 non-hematologic toxicity or non-life threatening grade 4 laboratory test abnormalities is initiated prior to terminating administration of the dosage regimen administered at the initiation of the grade 2 or 3 non-hematologic toxicity or non-life threatening grade 4 laboratory test abnormality.

In some embodiments of the above aspects, the medical management of each of the first, second, third, and fourth grade 3 hematological toxicity or proteinuria is initiated prior to terminating administration of the dosage regimen administered at the initiation of the grade 3 hematological toxicity or proteinuria.

In some embodiments of the above aspects, the medical management of each of the first, second, and third grade 4 hematological toxicities is initiated prior to terminating administration of the dosage regimen administered at the initiation of the grade 4 hematological toxicity.

In some embodiments of the above aspects, the first persistent and intolerant grade 2 or grade 3 non-hematologic toxicity or non-life threatening grade 4 laboratory test abnormality is the same as the second and/or third persistent and intolerant grade 2 or grade 3 non-hematologic toxicity or non-life threatening grade 4 laboratory test abnormality.

In some embodiments of the above aspects, the first grade 3 hematological toxicity or proteinuria is the same as the second and/or third grade 3 hematological toxicity or proteinuria.

In some embodiments of the above aspects, the first grade 4 hematological toxicity is the same as the second and/or third grade 4 hematological toxicity.

In some embodiments of any of the above aspects, the grade 3 non-hematologic toxicity is selected from the group consisting of: grade 3 blood pressure, grade 3 diarrhea, grade 3 appetite decline, grade 3 fatigue, grade 3 joint pain, grade 3 myalgia, grade 3 weight decline, grade 3 dysarthria, grade 3 nausea, grade 3 abdominal pain, grade 3 QT/QTc interval prolongation, grade 3 hypothyroidism, grade 3 vomiting, grade 3 constipation, grade 3 rash, and grade 3 palmar-plantaris sensorineural erythema.

In some embodiments of any of the above aspects, the grade 2 or 3 non-hematologic toxicity is selected from the group consisting of: level 3 blood pressure, level 2 blood pressure, level 3 diarrhea, level 2 diarrhea, level 3 appetite decrease, level 2 appetite decrease, level 3 fatigue, level 2 fatigue, level 3 arthralgia, level 2 arthralgia, level 3 myalgia, level 2 myalgia, level 3 weight decrease, level 2 alopecia, level 3 dysarthria, level 2 dysarthria, level 3 nausea, level 2 nausea, level 3 abdominal pain, level 2 abdominal pain, level 3 QT/QTc interval prolongation, level 2 QT/QTc interval prolongation, level 3 hypothyroidism, level 2 hypothyroidism, level 3 emesis, level 2 emesis, level 3 constipation, level 2 constipation, level 3 rash, level 2 rash, level 3 palmoplantar sensory loss erythema, and level 2 palmoplantar sensory loss erythema.

In some embodiments of any of the above aspects, the level 4 laboratory check exception is selected from the group consisting of: increased aspartate aminotransferase level 4, increased alanine aminotransferase level 4, increased alkaline phosphatase level 4, hypokalemia level 4, hyponatremia level 4, hypoglycemia level 4, increased blood bilirubin level 4, and increased gamma glutamyl transferase level 4.

In some embodiments of any of the above aspects, the grade 3 hematological toxicity or proteinuria is selected from the group consisting of: grade 3 proteinuria, grade 3 thrombocytopenia (thrombocytopenia), grade 3 anemia, grade 3 white blood cell count reduction, grade 3 neutropenia, and grade 3 lymphopenia.

In some embodiments of any of the above aspects, the grade 4 hematological toxicity is selected from the group consisting of: grade 4 thrombocytopenia (thrombocytopenia), grade 4 anemia, grade 4 leukopenia, grade 4 neutropenia, and grade 4 lymphopenia.

In some embodiments of the above aspects, the lenvatinib or the pharmaceutically acceptable salt thereof is formulated as a capsule.

In some embodiments of the above aspects, the lenvatinib or the pharmaceutically acceptable salt thereof is administered orally to the human subject.

In some embodiments of the above aspect, the lenvatinib or the pharmaceutically acceptable salt thereof is lenvatinib mesylate.

The present disclosure also encompasses a dosage regimen described herein of lenvatinib, or a pharmaceutically acceptable salt thereof, for use in treating hepatocellular carcinoma (e.g., unresectable hepatocellular carcinoma) according to any of the methods described herein.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the following description of exemplary methods and materials is provided. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present application, including definitions, will control. These materials, methods, and examples are illustrative only and not intended to be limiting.

Other features and advantages of the invention will be apparent from the following detailed description, and from the claims.

102页详细技术资料下载

上一篇：一种医用注射器针头装配设备

下一篇：经鼻给药用医药组合物

Treatment of hepatocellular carcinoma

相关技术

网友询问留言