阅读说明：本技术 用于治疗非小细胞肺癌的奧希替尼 (Hitinib for treating non-small cell lung cancer ) 是由 A.F.P.纳什 于 2019-02-11 设计创作，主要内容包括：本说明书涉及用于治疗患有局部晚期不可切除的表皮生长因子受体(EGFR)突变阳性非小细胞肺癌(III期)的患者的奧希替尼或其药学上可接受的盐,并且特别地涉及疾病在确定性铂基化放疗疗法之后还未进展的患者的治疗。(The present specification relates to cintinib, or a pharmaceutically acceptable salt thereof, for use in treating patients with locally advanced unresectable Epidermal Growth Factor Receptor (EGFR) mutation-positive non-small cell lung cancer (stage III), and in particular to the treatment of patients whose disease has not progressed following definitive platinum-based radiotherapy therapy.)

1. cintinib, or a pharmaceutically acceptable salt thereof, for use in treating patients with locally advanced unresectable EGFR mutation-positive NSCLC whose disease has not progressed following definitive platinum-based chemo-radiation therapy.

2. The compound for use according to claim 1, wherein the unresectable EGFR mutation positive NSCLC is considered curable by chemo-radiotherapy therapy.

3. The compound for use according to claim 1 or claim 2, wherein the chemo-radiotherapy therapy comprises a synchronized radiotherapy therapy.

4. The compound for use according to any preceding claim, wherein the chemo-radiotherapy therapy comprises sequential chemo-radiotherapy therapy.

5. A compound for use according to any preceding claim, wherein the chemo-radiotherapy therapy comprises platinum-based duplex chemotherapy.

6. A compound for use according to any preceding claim, wherein the chemo-radiotherapy treatment comprises a platinum-based agent selected from cisplatin or carboplatin.

7. A compound for use according to any preceding claim, wherein the chemo-radiotherapy treatment comprises a non-platinum based agent selected from etoposide, vinorelbine, vinblastine, pemetrexed, paclitaxel, docetaxel or gemcitabine.

8. The compound for use according to any preceding claim, wherein the EGFR mutation-positive NSCLC comprises activating mutations in EGFR selected from the group consisting of an exon 19 deletion or L858R substitution mutation.

9. A compound for use according to any preceding claim, wherein the cintinib or a pharmaceutically acceptable salt thereof is administered once daily.

10. The compound for use according to any preceding claim, wherein the cintinib, or a pharmaceutically acceptable salt thereof, is not administered to the patient prior to completion of the chemo-radiation therapy.

11. A compound for use according to any preceding claim, wherein the cintinib or a pharmaceutically acceptable salt thereof is in the form of a tablet.

12. A compound for use according to any preceding claim, wherein the cintinib or a pharmaceutically acceptable salt thereof is in the form of the mesylate salt.

13. A method of treating locally advanced stage III unresectable EGFR mutation positive NSCLC in a human patient, comprising administering cintinib, or a pharmaceutically acceptable salt thereof, to the patient, wherein the disease has not progressed following definitive platinizing radiotherapy therapy.

14. Use of cintinib, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating patients with locally advanced unresectable EGFR mutation-positive NSCLC whose disease has not progressed following definitive platinizing radiotherapy therapy.

Technical Field

The present specification describes cintinib, or a pharmaceutically acceptable salt thereof, for use in treating a patient having locally advanced unresectable Epidermal Growth Factor Receptor (EGFR) mutation positive non-small cell lung cancer (stage III). In particular, the present specification describes such treatment in patients whose disease has not progressed following definitive platinizing radiotherapy treatment.

Background

Primary lung cancer is the most common form of cancer following non-melanocytic skin cancers (accounting for 12.9% of all new cancers worldwide) and remains the leading cause of cancer-related death overall (accounting for 19.4% of all cancer deaths) (ann. Non-small cell lung cancer (NSCLC) accounts for approximately 80% to 85% of all lung cancers.

Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitors (TKIs), such as gefitinib, erlotinib, lapatinib and afatinib, typically prolong the progression-free survival of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors show one or more activating mutations in the EGFR gene. The most common EGFR activating mutations are the L858R substitution mutation and the exon 19 deletion. However, most of these patients develop tolerance to these EGFR-TKIs, usually within 9 to 13 months after treatment. An important mechanism for acquired tolerance is the T790M EGFR mutation in exon 20 of the EGFR gene. This acquired tolerance has led to the development of additional EGFR-TKIs, such as Hitinib (TAGRISSO)^TM) Citinib has been approved for the treatment of patients with metastatic EGFR T790M mutation-positive NSCLC who have progressed on or after receiving alternative EGFR-TKI therapy.

However, although EGFR-TKI significantly improves the prognosis of NSCLC patients in metastatic settings, these drugs do not represent the standard of care for patients with stage III unresectable NSCLC. It is estimated that in 2016, stage III NSCLC affects approximately 100,000 patients in G7 countries (usa, france, germany, italy, spain, uk, and japan), most (about 70%) of which have unresectable disease (Kantar Health Cancer Mpact [ khaki healthy Cancer Mpact ] 2016). The proportion of patients diagnosed with stage III disease was approximately 27% according to the US National Cancer Database of 813,032 patients diagnosed with NSCLC during 1998 to 2006 with available staging information (US National Cancer Database) (j.thorac. oncol. [ journal of breast oncology ] [2010], 29-33).

The current standard of care for patients with unresectable stage III NSCLC is treatment with chemo-radiotherapy for the purpose of healing. The same standard of care applies to both EGFR mutation positive patients and EGFR wild type patients. Synchronized radiotherapy (CCRT) is considered the standard of care for young patients with good behavioral status and minimal co-morbidities. Sequential chemo-radiotherapy (SCRT) is usually given to less robust patients. However, the difference in the level of efficacy is small.

For patients with no EGFR selection, improvements in the following were made with some improvement in the outcome of patients with unresectable disease: (i) staging of the tumor (leading to stage migration); (ii) planning and delivery of radiation therapy (e.g., Intensity Modulated Radiation Therapy (IMRT)); and (iii) management of toxicity associated with chemo-radiation therapy. The efficacy results associated with CCRT ranged from 20.6 to 28.7 months median Overall Survival (OS) (Lancet Oncol. [ Lancet Oncol ] [2015], Vol.16 (2), 187 & 199, J.Clin. Oncol. [ J.Clin. Oncol ] [2016], Vol.34 (9), 953 & 962, Ann. Oncol. [ annual Oncol ] [2017], Vol.28 (4), 777 & 783, J.Clin. Oncol. [ J.Clin. Oncol ] [2015], Vol.33 (24), 2660 & 2666, Ann. Oncol. [2015], Vol.26 (6), 1134 & 1142).

For patients with unresectable stage III EGFR mutation-positive NSCLC, the same standard of care for chemo-radiation therapy for cure was given. Median progression-free survival (PFS) after chemo-radiotherapy is similar or lower compared to patients with EGFR wild-type tumors. However, in this context, local regional control is superior, while distant metastasis control (distantcontrol) is inferior (J.radial.Res. [ J.radiotheraphy study ] [2016], Vol.57 (5), 449-. In patients with EGFR mutation-positive tumors, median overall survival is generally longer, which may be due in part to the administration of EGFR-TKI as the disease progresses. After chemo-radiation therapy, the standard of care is observation. Only patients with EGFR mutation-positive NSCLC would be expected to receive EGFR-TKI after disease progression.

Although definitive chemo-radiotherapy therapy is given as a cure-purpose treatment, unfortunately most patients relapse. Thus, there remains a substantial unmet medical need for patients with unresectable stage III NSCLC.

Although many previous clinical trials have investigated the use of first generation EGFR-TKIs (such as erlotinib, gefitinib and afatinib) for the treatment of stage III NSCLC, the results are ragged. These trials are typically small-scale and there is significant non-uniformity with respect to disease characteristics at baseline, the existing chemo-radiotherapy protocol employed, the timing of EGFR-TKI treatment and whether additional treatment strategies are allowed (such as surgery) (J Clin Oncol [ journal of clinical oncology ] [2008], volume 26 (15), 2450-, 8531; and Cancer Res Treat [ Cancer research and treatment ] [2017], Vol.49 (4), 981-.

No phase III trial has been reported to date investigating chemo-radiation treatment outcomes in patients with EGFR mutation-positive NSCLC. Current International Guidelines (Current International Guidelines) indicate that EGFR-TKI does not function in the management of stage III unresectable EGFR mutation-positive NSCLC. Patients in this setting clearly need alternative treatment options in view of the poor prognosis for these patients. We have found that use of cintinib in such patients following definitive platinizing radiotherapy treatment can result in an improved prognosis, for example an improvement in one or more of the following: improved progression-free survival (PFS), or improved duration of response (DoR), or improved Overall Survival (OS).

Disclosure of Invention

The present specification describes cintinib, or a pharmaceutically acceptable salt thereof, for use in treating patients with locally advanced unresectable EGFR mutation-positive NSCLC (stage III) whose disease has not progressed following definitive platinizing radiotherapy therapy.

This specification also describes such treatment, wherein cintinib is administered to the patient only after completion of the definitive platinizing radiotherapy therapy.

The present specification also describes such treatments, wherein the treatment results in one or more of the following: improved progression-free survival (PFS); improved duration of reaction (DoR); or improved Overall Survival (OS).

Detailed Description

In a first embodiment, cintinib, or a pharmaceutically acceptable salt thereof, is provided for the treatment of patients with locally advanced unresectable EGFR mutation-positive NSCLC (stage III) whose disease has not progressed following definitive platinizing radiotherapy therapy.

In another embodiment, there is provided a method of treating locally advanced unresectable EGFR mutation-positive NSCLC (stage III) in a human patient, the method comprising administering cintinib, or a pharmaceutically acceptable salt thereof, to the patient, wherein the disease has not progressed following definitive platinum-based radiotherapy therapy.

In another embodiment, there is provided the use of cintinib, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating patients with locally advanced unresectable EGFR mutation-positive NSCLC (stage III) whose disease has not progressed following definitive platinum-based radiotherapy therapy.

As used herein, the term "about" when referring to any given numerical value means within ± 10% of that value.

Locally advanced (stage III) unresectable NSCLC

Locally advanced (stage III) NSCLC represents a diverse patient cohort with a wide range of prognoses (see, e.g., the European Society of medicine Oncology) guidelines for locally advanced stage III non-small cell Lung Cancer (Annals of Oncology [ Ann. Rev. ]2015, Vol. 26, 1573. 1588, 2015), and the International Association of Lung Cancer (International Association for the Lung Cancer, IASLC)/International Association for International Cancer Control, 8 th edition, tumor/nodule/metastasis (TNM) staging (J.Thorac. Oncol. [ thoracic Oncology ] [2016], Vol. 11, 39-51)). In one aspect, patients with T3 and N1 diseases are generally considered resectable (i.e., visible tumors can be surgically removed). On the other hand, patients with T4 disease (i.e. disease affecting important central structures (septum, mediastinum, heart, great vessels, trachea, recurrent laryngeal nerves, esophagus, vertebral bodies and carina)) and/or patients with ipsilateral mediastinal node involvement (N2), ipsilateral distal node disease or contralateral node involvement (N3) are generally considered unresectable. Various combinations of stage T and nodal status determine whether to classify the disease as stage IIIA, IIIB or IIIC associated with progressively worse outcomes. Methods of classifying locally advanced NSCLC in a given patient as stage IIIA, IIIB or IIIC, and methods of assessing locally advanced NSCLC in a given patient as resectable or unresectable will be known to those skilled in the art.

Thus, in one embodiment, locally advanced unresectable NSCLC comprises unresectable NSCLC that is considered curable by chemo-radiotherapy therapy.

In another embodiment, the locally advanced unresectable NSCLC comprises locally advanced non-metastatic NSCLC.

In another embodiment, the locally advanced unresectable NSCLC comprises stage IIIC unresectable NSCLC.

In another embodiment, the locally advanced unresectable NSCLC comprises stage IIIB unresectable NSCLC.

In another embodiment, the locally advanced unresectable NSCLC comprises stage IIIA unresectable NSCLC.

In another embodiment, the locally advanced unresectable NSCLC comprises stage IIIB and stage IIIC unresectable NSCLC.

EGFR mutation-positive NSCLC and diagnostic methods

In 2004, it was reported that activating mutations in exons 18-21 of EGFR correlated with response to EGFR-TKI therapy in NSCLC (Science [ Science ] [2004], volume 304, 1497-1500; New England Journal of medicine [ New England Journal of medicine ] [2004], volume 350, 2129-2139). These mutations are estimated to be prevalent in approximately 10% -16% of NSCLC patients in the united states and europe and approximately 30% -50% of NSCLC patients in asia. The two most significant EGFR activating mutations were exon 19 deletion and missense mutation in exon 21. Exon 19 deletions account for approximately 45% of known EGFR mutations. Eleven different mutations were detected in exon 19 resulting in three to seven amino acid deletions and all centered on the consistently deleted codon for amino acids 747-749. The most significant exon 19 deletion is E746-A750. Missense mutations in exon 21 account for approximately 39% -45% of known EGFR mutations, with substitution mutation L858R accounting for approximately 39% of the total mutations in exon 21 (j.thorac. oncol. [ journal of breast oncology ] [2010], 1551-1558). The skilled artisan will recognize mutations in EGFR that are associated with improved response to EGFR-TKI therapy.

Thus, in one embodiment, an EGFR mutation-positive NSCLC comprises an activating mutation in EGFR. In another embodiment, the activating mutation in EGFR comprises an activating mutation in exons 18-21. In another embodiment, the activating mutation in EGFR comprises an exon 19 deletion or a missense mutation in exon 21. In another embodiment, the activating mutation in EGFR comprises an exon 19 deletion or L858R substitution mutation.

The skilled artisan will recognize that there are many methods for detecting EGFR activating mutations. These methods include tumor tissue-based diagnostic methods and plasma-based diagnostic methods. Typically, a patient-derived tumor tissue biopsy is first used to assess EGFR mutation status. If the tumor sampleUnavailable, or if the tumor sample is negative, plasma samples can be used to assess EGFR mutation status. A specific example of a suitable diagnostic method for detecting EGFR activating mutations, in particular detecting exon 19 deletion or L858R substitution mutations, is Cobas^TMEGFR mutation test v2 (roche molecular System).

Thus, in one embodiment, an EGFR mutation-positive NSCLC comprises an activating mutation in EGFR (such as an activating mutation in exons 18-21, e.g., an exon 19 deletion and a missense mutation in exon 21, e.g., an exon 19 deletion or an L858R substitution mutation), wherein the EGFR mutation status of the patient is determined using an appropriate diagnostic method. In another embodiment, tumor tissue samples are used to determine EGFR mutation status. In another embodiment, plasma samples are used to determine EGFR mutation status. In another embodiment, the diagnostic method uses Cobas^TMEGFR mutation test (v1 or v 2).

Definitive platinization radiotherapy

The current standard of care for patients with locally advanced unresectable NSCLC (stage III) is definitive chemo-radiotherapy therapy (CRT), i.e. CRT used for curative purposes rather than palliative purposes, in particular definitive platinization radiotherapy therapy.

Thus, in one embodiment, patients include patients with unresectable NSCLC whose disease is considered curable by chemo-radiation therapy.

The maximum radiotherapeutic dose that can be administered in CRT depends on the targeted tumor volume and the ability to minimize exposure to healthy tissue, especially to normal healthy organs. Improvements in radiation therapy, such as the introduction of three-dimensional conformal planning, four-dimensional planning CT scanning, Intensity Modulated Radiation Therapy (IMRT), and Image Guided Radiation Therapy (IGRT) techniques, improve targeting of tumor volumes, allowing higher radiation therapy doses. It is currently possible to safely administer a total radiation dose of up to about 100Gy (curr. Opin. Oncol. [ current oncology point of view ] [2011], Vol.23, 140-. The skilled person will recognize the appropriate total radiotherapy dose and the appropriate frequency of administration for any given NSCLC patient.

Many different chemotherapeutic agents are suitable for platinum-based CRT use. The standard of care is the administration of platinum-based duplex chemotherapy, in which a platinum-based agent (such as cisplatin or carboplatin) is administered in combination with a second chemotherapeutic agent group or additional chemotherapeutic agents. The second chemotherapeutic group or further chemotherapeutic may be a non-platinum based chemotherapeutic (such as etoposide, vinorelbine, pemetrexed, a taxane (such as paclitaxel or docetaxel), vinblastine, doxorubicin or gemcitabine). The skilled artisan will recognize the appropriate chemotherapy regimen for any given stage III unresectable NSCLC patient.

There are many options for sequencing radiation therapy and chemotherapy treatment in CRT. The treatment may be a sequential treatment, wherein CRT is provided during two separate phases, i.e. a first phase in which chemotherapy is administered, followed by a second phase in which radiation therapy is administered (sequential chemo-radiotherapy therapy or SCRT). The treatment may also be a synchronized treatment, wherein the radiation therapy and chemotherapy are administered (e.g., simultaneously (same day)) during a single phase (synchronized radiotherapy therapy or CCRT). Such simultaneous treatment may also include: (i) an additional phase preceding the synchronization phase, wherein chemotherapy is further administered during the induction phase; or (ii) an additional phase following the synchronization phase, wherein chemotherapy is further administered during the consolidation phase; or (iii) an additional phase before and after the synchronization phase, wherein the chemotherapy is further administered in the induction phase and the consolidation phase. CCRT is considered the standard of care for young patients with good behavioral status and minimal co-morbidity. SCRT is usually given to less robust patients. Each stage of treatment as described above may comprise one of a plurality of individual treatment cycles, as described further below.

The type of chemotherapy treatment and radiation treatment and the order of the chemotherapy treatment and radiation treatment may be important factors in how a given patient responds to EGFR-TKI treatment.

Thus, in one embodiment, chemo-radiotherapy therapy comprises synchronized radiotherapy therapy (CCRT).

In another embodiment, the chemo-radiotherapy therapy comprises sequential chemo-radiotherapy therapy (SCRT).

In another embodiment, the final chemotherapy cycle ends before or in synchronism with the final radiotherapy dose.

In another embodiment, the chemo-radiotherapy therapy comprises an induction phase.

In another embodiment, the chemo-radiotherapy therapy comprises a consolidation phase.

In another embodiment, the synchronized radiotherapy therapy comprises any one of the following: (i) a treatment period comprising at least 2 treatment cycles, wherein chemotherapy is administered concurrently with (such as simultaneously (same day) as) radiation therapy; or (ii) a treatment period comprising at least 5 week doses of chemo-radiotherapy, wherein chemotherapy is administered concurrently with radiotherapy (such as concurrently (same day) administration).

In another embodiment, the sequential radiotherapy treatment comprises a chemotherapy treatment of at least 2 treatment cycles prior to the radiation treatment.

In another embodiment, as part of chemo-radiation therapy, a total radiation therapy dose up to about 100Gy is administered to the patient. In another embodiment, the total radiotherapy dose administered to the patient is up to about 90 Gy. In another embodiment, the total radiotherapeutic dose administered to the patient is up to about 80 Gy. In another embodiment, the total radiotherapy dose administered to the patient is up to about 70 Gy. In another embodiment, the total radiotherapy dose administered to the patient is up to about 60 Gy.

In one embodiment, the platinum-based chemotherapy administered to the patient comprises a single platinum-based agent (such as cisplatin or carboplatin).

In another embodiment, the platinum-based chemotherapy comprises platinum-based duplex chemotherapy.

In another embodiment, the dual chemotherapy comprises cisplatin and a second chemotherapy selected from etoposide, vinorelbine, vinblastine, pemetrexed, a taxane (such as paclitaxel or docetaxel), or gemcitabine. In another embodiment, the dual chemotherapy comprises cisplatin and a second chemotherapy selected from etoposide, vinorelbine, vinblastine, pemetrexed or a taxane (such as paclitaxel or docetaxel). In another embodiment, the dual chemotherapy comprises cisplatin in combination with etoposide, or cisplatin in combination with vinorelbine, or cisplatin in combination with vinblastine, or cisplatin in combination with pemetrexed, or cisplatin in combination with a taxane (such as cisplatin in combination with paclitaxel, or cisplatin in combination with docetaxel), or cisplatin in combination with gemcitabine.

In another embodiment, the dual chemotherapy comprises carboplatin and a second chemotherapy selected from etoposide, vinorelbine, vinblastine, pemetrexed, a taxane (such as paclitaxel or docetaxel), or gemcitabine. In another embodiment, the dual chemotherapy comprises carboplatin and a second chemotherapy selected from etoposide, vinorelbine, vinblastine, pemetrexed, or a taxane (such as paclitaxel or docetaxel). In another embodiment, the duplex chemotherapy comprises carboplatin in combination with etoposide, or carboplatin in combination with vinorelbine, or carboplatin in combination with vinblastine, or carboplatin in combination with pemetrexed, or carboplatin in combination with a taxane (such as carboplatin in combination with paclitaxel, or carboplatin in combination with docetaxel), or carboplatin in combination with gemcitabine.

The total daily dose of cisplatin is generally calculated with reference to Body Surface Area (BSA), and the daily dose is generally about 50mg/m²To about 100mg/m²Within the range of (1). Thus, in one embodiment, the maximum daily dose of cisplatin is up to about 150mg/m²Such as up to about 120mg/m²Such as up to about 100mg/m²Such as up to about 90mg/m²Such as up to about 80mg/m²Such as up to about 70mg/m²Such as up to about 60mg/m²Such as up to about 50mg/m²。

Patients experiencing cisplatin CRT will not typically receive cisplatin daily, and cisplatin is typically administered during the treatment cycle. In one embodiment, the treatment cycle is at most 42 days, such as at most 35 days, such as at most 28 days, such as at most 21 days. In one embodiment, cisplatin is administered on day 1 of each treatment cycle. In one embodiment, cisplatin is administered on day 1 only of a 21 day treatment cycle. In one embodiment, cisplatin is administered on day 1 only of a 28 day treatment cycle. In one embodiment, cisplatin is administered on days 1 and 8 of a 28 day treatment cycle. In one embodiment, cisplatin is administered on days 1 and 29 of a treatment cycle lasting 35 days. In one embodiment, cisplatin is administered on days 1, 8, 29 and 36 of a 42 day treatment cycle.

The total daily dose of carboplatin for a given patient is typically calculated using a formula known to those skilled in the art, such as the Calvert formula, with reference to the area under the curve (AUC). Typical daily doses range from AUC 2 to AUC 6. In one embodiment, the maximum daily dose of carboplatin is up to AUC 6, such as up to AUC 5, such as up to AUC 4, such as up to AUC 3, such as up to AUC 2.

Patients undergoing carboplatin CRT typically do not receive carboplatin daily, and carboplatin is typically administered during the treatment cycle. In one embodiment, the treatment cycle is at most 21 days, such as at most 14 days, such as at most 7 days. In one embodiment, cisplatin is administered on day 1 of each treatment cycle. In one embodiment, cisplatin is administered on day 1 only of a treatment cycle lasting 7 days. In one embodiment, cisplatin is administered on day 1 only of a 21 day treatment cycle.

The total daily dose of the non-platinum based chemotherapeutic agents is typically calculated with reference to Body Surface Area (BSA).

In one embodiment, the total daily dose of etoposide is about 50mg/m²To about 100mg/m²Such as up to about 100mg/m²Such as up to about 90mg/m²Such as up to about 80mg/m²Such as up to about 70mg/m²Such as up to about 60mg/m²Such as up to about 50mg/m². In another embodiment, etoposide is administered on days 1, 2, and 3 of a treatment cycle lasting 21 days. In another embodiment, etoposide is administered on days 1, 2, 3, 4, 5, 29, 20, 31, 32, and 33 of a 42 day treatment cycle.

In one embodiment, the total daily dose of vinblastine is about 3mg/m²To about 20mg/m²Such as up to about 20mg/m²Such as up to about 15mg/m²Such as up to about 10mg/m²Such as up to about 5mg/m²Such as up to about 4mg/m²Such as up to about 3mg/m². In another embodiment, vinblastine is administered once per week, such as once per week over a treatment period lasting 5 weeks.

In one embodiment, the total daily dose of pemetrexed is up to about 500mg/m²Such as about 500mg/m². In another embodiment, pemetrexed is administered on day 1 of a treatment cycle lasting 21 days.

In one embodiment, the total daily dose of paclitaxel is about 45mg/m²To about 200mg/m²Such as up to about 200mg/m²Such as up to about 150mg/m²Such as up to about 100mg/m²Such as up to about 50mg/m²Such as up to about 45mg/m². In another embodiment, paclitaxel is administered once a week, such as once a week in a treatment cycle lasting 21 days. In another embodiment, paclitaxel is administered on day 1 only of a treatment cycle lasting 21 days.

In one embodiment, the total daily dose of vinorelbine is about 25mg/m²To about 30mg/m²Such as up to about 30mg/m²Such as up to about 25mg/m². In another embodiment, vinorelbine is administered on day 1 of each treatment cycle. In another embodiment, vinorelbine is administered on days 1 and 8 of a treatment cycle lasting 21 days. In another embodiment, vinorelbine is administered on days 1, 8, 15 and 22 of a 28 day treatment cycle.

In one embodiment, the total daily dose of gemcitabine is about 1000mg/m²To about 1500mg/m²Such as up to about 1500mg/m²Such as up to about 1250mg/m²Such as up to about 1000mg/m². In another embodiment, gemcitabine is administered on day 1 of each treatment cycle. In another embodiment, gemcitabine is administered on days 1 and 8 of a 21 day treatment cycle.

In one embodiment, the total daily dosage of docetaxel is up to about 75mg/m²Such as about 75mg/m². In another embodiment, docetaxel is administered on day 1 of each treatment cycle. In another embodiment, docetaxel is administered on day 1 of a 21 day treatment cycle.

A patient receiving CRT may undergo one or more treatment cycles. Thus, in one embodiment, platinum-based chemotherapy may be administered for up to 6 treatment cycles, or up to 5 treatment cycles, or up to 4 treatment cycles, or up to 3 treatment cycles, or up to 2 treatment cycles, or in a single treatment cycle.

In one embodiment, the CCRT protocol may be selected from:

a) a 42 day treatment cycle with a total daily dose of cisplatin of about 50mg/m on days 1, 8, 29 and 36²(ii) a The total daily dose of etoposide on days 1, 2, 3, 4, 5, 29, 30, 31, 32 and 33 is about 50mg/m²(ii) a And synchrotron radiation therapy;

b) a 35 day treatment cycle with a total daily dose of cisplatin of about 100mg/m on days 1 and 29²(ii) a The total daily dose of vinblastine is about 5mg/m²Administered weekly; and synchrotron radiation therapy;

c) a 21 day treatment cycle with a total daily dose of carboplatin AUC 5 on day 1; the total daily dose of pemetrexed on day 1 is about 500mg/m²(ii) a And synchrotron radiation therapy; and the total number of treatment cycles may be up to 4 cycles;

d) a 21 day treatment cycle with a total daily dose of cisplatin at day 1 of about 75mg/m²(ii) a The total daily dose of pemetrexed on day 1 is about 500mg/m²(ii) a And synchrotron radiation therapy; the total number of treatment cycles may be up to 3 cycles; and the pemetrexed alone may optionally be at about 500mg/m²Another 4 cycles were administered;

e) a7 day treatment cycle, total weekly dose of carboplatin AUC 2; the total weekly dose of paclitaxel is about 45mg/m²-50mg/m²(ii) a And synchrotron radiation therapy; to be provided withAnd optionally 2 additional cycles, wherein the total weekly dose of carboplatin is AUC 6 and the total weekly dose of paclitaxel is about 200mg/m²。

In one embodiment, the SCRT protocol may be selected from:

a) a 28 day treatment cycle with a total daily dose of cisplatin of about 50mg/m on days 1 and 8²(ii) a The total daily dose of vinorelbine on days 1, 8, 15 and 22 was about 25mg/m²(ii) a The total number of treatment cycles may be up to 4 cycles; followed by radiotherapy;

b) a 28 day treatment cycle with a total daily dose of cisplatin of about 100mg/m on day 1²(ii) a The total daily dose of vinorelbine on days 1, 8, 15 and 22 was about 30mg/m²(ii) a The total number of treatment cycles may be up to 4 cycles; followed by radiotherapy;

c) a 21 day treatment cycle with a total daily dose of cisplatin at day 1 of about 75mg/m²-80mg/m²(ii) a The total daily dose of vinorelbine on days 1 and 8 was about 25mg/m²-30mg/m²(ii) a The total number of treatment cycles may be up to 4 cycles; followed by radiotherapy;

d) a 28 day treatment cycle with a total daily dose of cisplatin of about 100mg/m on day 1²(ii) a The total daily dose of etoposide on days 1, 2 and 3 was about 100mg/m²(ii) a The total number of treatment cycles may be up to 4 cycles; followed by radiotherapy;

e) a 21 day treatment cycle with a total daily dose of cisplatin at day 1 of about 75mg/m²(ii) a The total daily dose of gemcitabine on days 1 and 8 is about 1250mg/m²(ii) a The total number of treatment cycles may be up to 4 cycles; followed by radiotherapy;

f) a 21 day treatment cycle with a total daily dose of cisplatin at day 1 of about 75mg/m²(ii) a The total daily dosage of docetaxel on day 1 is about 75mg/m²(ii) a The total number of treatment cycles may be up to 4 cycles; followed by radiotherapy;

g) a 21 day treatment cycle with a total daily dose of cisplatin at day 1 of about 75mg/m²(ii) a The total daily dose of pemetrexed on day 1 is about 500mg/m²(ii) a Total treatment cycleThe number may be up to 4 cycles; followed by radiotherapy;

h) a 21 day treatment cycle with a total daily dose of carboplatin AUC 6 on day 1; the total daily dose of paclitaxel on day 1 is about 200mg/m²(ii) a The total number of treatment cycles may be up to 4 cycles; followed by radiotherapy;

i) a 21 day treatment cycle with a total daily dose of carboplatin AUC 5 on day 1; the total daily dose of gemcitabine on days 1 and 8 is about 1000mg/m²(ii) a The total number of treatment cycles may be up to 4 cycles; followed by radiotherapy; and

j) a 21 day treatment cycle with a total daily dose of carboplatin AUC 5 on day 1; the total daily dose of pemetrexed on day 1 is about 500mg/m²(ii) a The total number of treatment cycles may be up to 4 cycles; followed by radiation therapy.

Hitinib and pharmaceutical composition thereof

Citinib has the following chemical structure:

the chemical name of the free base of cintinib is known as: n- (2- { 2-dimethylaminoethyl-methylamino } -4-methoxy-5- { [4- (1-methylindol-3-yl) pyrimidin-2-yl ] amino } phenyl) prop-2-enamide. Citinib is described in WO 2013/014448. Citinib is also known as AZD 9291.

Citinib may be present in the form of the following mesylate salt: n- (2- { 2-dimethylaminoethyl-methylamino } -4-methoxy-5- { [4- (1-methylindol-3-yl) pyrimidin-2-yl]Amino } phenyl) prop-2-enamide mesylate. Methanesulfonic acid Citinib is also known as TAGRISSO^TM。

Hitinib mesylate is currently approved as a once daily oral tablet formulation at a dose of 80mg (expressed as free base, equivalent to 95.4mg of Hitinib mesylate) for the treatment of patients with metastatic EGFR T790M mutation-positive NSCLC. If a dose change is required, 40mg once daily oral tablet formulation (expressed as free base, equivalent to 47.7mg of cintinib mesylate) can be used. The tablet core contains a drug diluent (such as mannitol and microcrystalline cellulose), a disintegrant (such as low substituted hydroxypropyl cellulose), and a lubricant (such as sodium stearyl fumarate). Tablet formulations are described in WO 2015/101791.

Thus, in one embodiment, cintinib is in the form of the mesylate salt: n- (2- { 2-dimethylaminoethyl-methylamino } -4-methoxy-5- { [4- (1-methylindol-3-yl) pyrimidin-2-yl ] amino } phenyl) prop-2-enamide methanesulfonate.

In another embodiment, cintinib, or a pharmaceutically acceptable salt thereof, is administered once daily. In another embodiment, the methanesulfonic acid cintinib is administered once daily.

In another embodiment, the total daily dose of cintinib is about 80 mg. In another embodiment, the total daily dose of cintinib mesylate is about 95.4 mg.

In another embodiment, the total daily dose of cintinib is about 40 mg. In another embodiment, the total daily dose of cintinib mesylate is about 47.7 mg.

In another embodiment, cintinib is administered in the form of a pharmaceutical composition comprising one or more pharmaceutically acceptable excipients. In another embodiment, the composition comprises one or more pharmaceutical diluents (such as mannitol and microcrystalline cellulose), one or more pharmaceutical disintegrants (such as low substituted hydroxypropyl cellulose) or one or more pharmaceutical lubricants (such as sodium stearyl fumarate).

In another embodiment, the composition is in the form of a tablet, wherein the core comprises: (a) from 2 parts to 70 parts Citinib, or a pharmaceutically acceptable salt thereof; (b)5 parts to 96 parts of two or more pharmaceutical diluents; (c)2 to 15 parts of one or more pharmaceutical disintegrants; and (d)0.5 to 3 parts of one or more pharmaceutical lubricants; and wherein the sum of parts (a) + (b) + (c) + (d) is 100, all parts being by weight.

In another embodiment, the composition is in the form of a tablet, wherein the core comprises: (a)7 to 25 parts cintinib or a pharmaceutically acceptable salt thereof; (b)55 parts to 85 parts of two or more pharmaceutical diluents, wherein the pharmaceutical diluents comprise microcrystalline cellulose and mannitol; (c)2 to 8 parts of a pharmaceutical disintegrant, wherein the pharmaceutical disintegrant comprises low-substituted hydroxypropylcellulose; (d)1.5 to 2.5 parts of a pharmaceutical lubricant, wherein the pharmaceutical lubricant comprises sodium stearyl fumarate; and wherein the sum of parts (a) + (b) + (c) + (d) is 100, all parts being by weight.

In another embodiment, the composition is in the form of a tablet, wherein the core comprises: (a) about 19 parts methanesulfonic acid cintinib; (b) about 59 parts mannitol; (c) about 15 parts microcrystalline cellulose; (d) about 5 parts low-substituted hydroxypropylcellulose; and (e) about 2 parts sodium stearyl fumarate; and wherein the sum of parts (a) + (b) + (c) + (d) + (e) ═ 100, all parts by weight.

Dosing regimens

Citinib, or a pharmaceutically acceptable salt thereof, will be administered to patients with locally advanced unresectable EGFR mutation-positive NSCLC (stage III) whose disease has not progressed following definitive platinizing radiotherapy. Progression can be assessed according to RECIST criteria. The skilled person will recognize RECIST criteria and suitable methods to assess evidence of disease progression following chemo-radiotherapy therapy (eur.j. cancer [ european journal of cancer ] [2009], volume 45 (2), 228-.

The order of chemo-radiotherapy treatment and treatment with cintinib may be an important factor in how a given patient responds. In particular, it may be important to administer cintinib to a patient after completion of chemo-radiation therapy and avoid the use of cintinib prior to or in synchronization with such chemo-radiation therapy.

Thus, in one embodiment, cintinib is administered to the patient after completion of the definitive platinizing radiotherapy therapy. In another embodiment, cintinib is not administered to the patient prior to completion of the definitive platinizing radiotherapy therapy. In another embodiment, cintinib is not administered to the patient in synchrony with definitive platinum-based radiotherapy therapy. In another embodiment, cintinib is not administered to the patient prior to or in synchrony with the definitive platinizing radiotherapy therapy.

In another embodiment, the patient will fully respond after definitive platinization radiotherapy therapy. In another embodiment, the patient will respond partially after definitive platinization radiotherapy therapy. In another embodiment, the patient will have stable disease after definitive platinization radiotherapy therapy.

It may be preferred that there is no significant period of time between completion of the chemo-radiotherapy therapy and the first administration of cintinib.

Thus, in one embodiment, the first dose of cintinib, or a pharmaceutically acceptable salt thereof, is administered no later than 12 weeks, such as no later than 10 weeks, such as no later than 8 weeks, such as no later than 6 weeks, such as no later than 4 weeks, such as no later than 2 weeks, such as no later than 1 week after completion of the chemo-radiotherapy therapy.

In another embodiment, cintinib, or a pharmaceutically acceptable salt thereof, is administered to the patient until the time of disease progression. In another embodiment, cintinib, or a pharmaceutically acceptable salt thereof, is administered to the patient for a period of up to five years after completion of the chemo-radiotherapy therapy, such as a period of up to 4 years, such as a period of up to 3 years, such as a period of up to 30 months, such as a period of up to 24 months, such as a period of up to 18 months, such as a period of up to 12 months.

In accordance with the present description, a patient with locally advanced unresectable NSCLC (stage III) who receives cintinib, or a pharmaceutically acceptable salt thereof, may benefit from an improved prognosis compared to existing standards of care. In particular, such patients may benefit from improved Progression Free Survival (PFS); improved objective response rate; improved duration of reaction (DoR); or improved Overall Survival (OS).

Thus, in one embodiment, the patient benefits from a progression free survival of at least 12 months, such as at least 14 months, such as at least 16 months, such as at least 18 months, such as at least 20 months, such as at least 22 months, such as at least 24 months, such as at least 26 months, such as at least 28 months, such as at least 30 months, such as at least 32 months, such as at least 34 months, such as at least 36 months. In another embodiment, the patient benefits from a duration of response of at least 15 months, such as at least 20 months, such as at least 25 months, such as at least 30 months, such as at least 35 months. In another embodiment, the patient benefits from an overall survival period of at least 30 months, such as at least 35 months, such as at least 40 months, such as at least 45 months, such as at least 50 months, such as at least 55 months, such as at least 60 months.

In accordance with the present description, a patient suffering from locally advanced unresectable NSCLC (stage III) receiving cintinib, or a pharmaceutically acceptable salt thereof, may particularly benefit from an improved prognosis compared to existing standards of care in terms of the occurrence and/or progression of central nervous system metastases, in particular brain metastases.

Thus, in one embodiment, a patient selected for treatment with cintinib, or a pharmaceutically acceptable salt thereof, according to the present description is at risk of developing a central nervous system metastasis (such as a brain metastasis).

In another embodiment, cintinib, or a pharmaceutically acceptable salt thereof, is provided for use in reducing the occurrence of a central nervous system metastasis (such as brain metastasis) in a patient.

In another embodiment, cintinib, or a pharmaceutically acceptable salt thereof, is provided for use in improving Progression Free Survival (PFS) in a patient at risk of developing a central nervous system metastasis, such as brain metastasis; duration of reaction (DoR); or overall lifetime (OS).

In another embodiment, cintinib, or a pharmaceutically acceptable salt thereof, is provided for use in improving Progression Free Survival (PFS) in a patient developing a central nervous system metastasis, such as a brain metastasis; duration of reaction (DoR); or overall lifetime (OS).

In another embodiment, the patient benefits from a progression free survival of the central nervous system of at least 12 months, such as at least 14 months, such as at least 16 months, such as at least 18 months, such as at least 20 months, such as at least 22 months, such as at least 24 months, such as at least 26 months, such as at least 28 months, such as at least 30 months, such as at least 32 months, such as at least 34 months, such as at least 36 months.

Further embodiments

In one embodiment, hitinib or a pharmaceutically acceptable salt thereof is provided for use in treating patients with locally advanced unresectable EGFR mutation positive NSCLC (stage III) whose disease has not progressed following definitive platinum-based chemo-radiation therapy, wherein the hitinib or a pharmaceutically acceptable salt thereof is administered once daily.

In another embodiment, there is provided a method of treating locally advanced unresectable EGFR mutation-positive NSCLC (stage III) in a human patient, the method comprising administering cintinib, or a pharmaceutically acceptable salt thereof, to the patient once daily, wherein the disease has not progressed following definitive platinum-based chemoradiotherapy therapy.

In another embodiment, there is provided a use of cintinib, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating patients having locally advanced unresectable EGFR mutation-positive NSCLC (stage III) whose disease has not progressed following definitive platinum-based radiotherapy therapy, wherein the cintinib, or a pharmaceutically acceptable salt thereof, is administered once daily.

In one embodiment, hitinib or a pharmaceutically acceptable salt thereof is provided for use in treating patients with locally advanced unresectable EGFR mutation-positive NSCLC (stage III) whose disease has not progressed following definitive platinum-based chemoradiotherapy therapy, wherein the hitnib or pharmaceutically acceptable salt thereof is administered once daily, and wherein the platinum-based chemoradiotherapy therapy comprises platinum-duplex chemotherapy.

In another embodiment, there is provided a method of treating locally advanced unresectable EGFR mutation-positive NSCLC (stage III) in a human patient, the method comprising administering cintinib, or a pharmaceutically acceptable salt thereof, to the patient once daily, wherein the disease has not progressed following definitive platinum-based chemoradiotherapy therapy, and wherein the platinum-based chemoradiotherapy therapy comprises platinum-based duplex chemotherapy.

In another embodiment, there is provided a use of cintinib, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating patients having locally advanced unresectable EGFR mutation-positive NSCLC (stage III) whose disease has not progressed following definitive platinum-based radiotherapy therapy, wherein the cintinib, or a pharmaceutically acceptable salt thereof, is administered once daily, and wherein the platinum-based radiotherapy therapy comprises platinum-based duplex chemotherapy.

In one embodiment, Hitinib, or a pharmaceutically acceptable salt thereof, is provided for use in treating patients having locally advanced unresectable EGFR mutation-positive NSCLC (stage III) whose disease has not progressed following definitive platinum-based chemo-radiation therapy, wherein the Hitinib, or a pharmaceutically acceptable salt thereof, is administered once daily, and wherein as part of chemo-radiation therapy, the total radiotherapeutic dose administered to the patient is up to about 100 Gy.

In another embodiment, there is provided a method of treating locally advanced unresectable EGFR mutation-positive NSCLC (stage III) in a human patient, the method comprising administering cintinib, or a pharmaceutically acceptable salt thereof, to the patient once daily, wherein the disease has not progressed following definitive platinum-based chemo-radiation therapy, and wherein the total dose of radiotherapy administered to the patient as part of chemo-radiation therapy is up to about 100 Gy.

In another embodiment, there is provided the use of cintinib, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating patients having locally advanced unresectable EGFR mutation-positive NSCLC (stage III) whose disease has not progressed following definitive platinum-based chemo-radiation therapy, wherein the cintinib, or a pharmaceutically acceptable salt thereof, is administered once daily, and wherein the total radiotherapeutic dose administered to the patient as part of chemo-radiation therapy is up to about 100 Gy.

In one embodiment, hitinib or a pharmaceutically acceptable salt thereof is provided for use in treating patients having locally advanced unresectable EGFR mutation-positive NSCLC (stage III) whose disease has not progressed following definitive platinum-based chemoradiotherapy therapy, wherein the hitnib or pharmaceutically acceptable salt thereof is administered once daily, and wherein the EGFR mutation-positive NSCLC comprises an activating mutation in EGFR selected from the group consisting of an exon 19 deletion or an L858R substitution mutation.

In another embodiment, there is provided a method of treating locally advanced unresectable EGFR mutation-positive NSCLC (stage III) in a human patient, the method comprising administering cintinib, or a pharmaceutically acceptable salt thereof, to the patient once daily, wherein the disease has not progressed following definitive platinum-based radiotherapy therapy, and wherein the EGFR mutation-positive NSCLC comprises an activating mutation in EGFR selected from the group consisting of an exon 19 deletion or an L858R substitution mutation.

In another embodiment, there is provided use of cintinib, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating patients having locally advanced unresectable EGFR mutation-positive NSCLC (stage III) whose disease has not progressed following definitive platinum-based radiotherapy therapy, wherein the cintinib, or a pharmaceutically acceptable salt thereof, is administered once daily, and wherein the EGFR mutation-positive NSCLC comprises an activating mutation in EGFR selected from an exon 19 deletion or an L858R substitution mutation.

Examples of the invention

Maintenance therapy for patients with locally advanced unresectable EGFR mutation-positive NSCLC (stage III) phase II, randomized, double-blind, placebo-controlled, multicenter, international study of Hitinib, in which the disease in these patients is being determined No progress has been made after the platinum-based chemo-radiotherapy treatment.

The following study was conducted to confirm the benefit of cintinib in patients with locally advanced unresectable EGFR mutation-positive NSCLC (stage III) whose disease had not progressed following definitive platinizing radiotherapy therapy.

Planned study center and number of patients

The research center: about 70. Approximately 200 patients will be randomized (after definitive platinization radiotherapy treatment, patients will respond fully [ CR ], partially [ PR ], or have stable disease [ SD ]).

Design of research

Phase III, randomized, double-blind, placebo-controlled, multicenter international study evaluating the efficacy and safety of cintinib as maintenance therapy compared to placebo for patients with locally advanced unresectable epidermal growth factor receptor mutation positive non-small cell lung cancer (phase III) whose disease has not progressed following definitive platinizing radiotherapy.

Study product, dosage and mode of administration

Citinib 80mg or a matching placebo will be administered orally once daily.

Purpose of study

Screening

The study will include 2 parts of the screening process. In part I, archived tumor samples of patients will be tested for EGFR mutation status in a central laboratory to determine patient eligibility after signing the section I screening consent. In addition, plasma samples for evaluation of EGFR mutations were collected for retrospective testing. No other screening evaluations are performed in section I. Part 1 screening may be performed before, during or after chemo-radiation. If the tissue EGFR mutation test was positive for either the Ex19Del or L858R mutations, the patient would enter part II of the screen and, after completion of chemo-radiotherapy and signing of the master consent, visit 1 assessment would begin to be completed after confirmation of patient compliance with the considerations.

Patients with pre-existing EGFR mutation positive test results, which are performed in Clinical Laboratory Improvement Amendments (CLIA) -certified (for the American center) or approved laboratories (outside the United states), can be directly entered into the partial II screenEGFR mutation test v 2.

Target patient population

Key inclusion criteria

Male and female patients must be at least 18 years of age. Patients from japan had an age of at least 20 years.

Patients with histologically documented NSCLC with predominantly non-squamous lesions, with locally advanced unresectable NSCLC (stage III) (according to the International Association for the study of Lung Cancer, IASLC]Breast oncology staging manual 2016, 8 th edition), tumors of these patients have an EGFR exon 19 deletion or exon 21(L858R) substitution mutation (alone or in combination with other EGFR mutations), such as by tissueEGFR mutation was detected by test v2 (Roche Diagnostics).

In addition to overt cT4 disease, the nodal state N2 or N3 should have been confirmed by biopsy, via endobronchial ultrasound, mediastinoscopy or thoracoscopy. Without biopsy, the whole body should be used¹⁸F-fluoro-deoxyglucose Positron Emission Tomography (PET) in combination with contrast enhanced Computed Tomography (CT) to confirm the junction status in addition to or in combination with PET.

Patients should not develop disease progression during or after definitive platinizing radiotherapy therapy. Allowing for simultaneous radiotherapy (CCRT) protocol and sequential radiotherapy (SCRT) as defined below:

CCRT-patients must receive at least 2 cycles of platinum-based chemotherapy (or 5 doses of a weekly platinum-based duplex regimen) in synchrony with radiation therapy, which must be completed within 6 weeks prior to the first dose IP in the study. Chemotherapy is allowed to be administered prior to CCRT. The final chemotherapy cycle must end before or in synchrony with the final radiotherapy dose. It is not allowed to administer consolidation chemotherapy after radiotherapy, but it is allowed to administer chemotherapy before CCRT.

SCRT-SCRT is defined as radiation therapy followed by chemotherapy, rather than chemotherapy. The patient had to receive at least 2 cycles of platinum-based chemotherapy (or a 5 dose weekly platinum-based doublet regimen) prior to radiation treatment, which had to be completed within 6 weeks prior to the first dose IP in the study. It is not allowed to administer consolidation chemotherapy after radiotherapy.

If the patient has received at least 2 cycles of platinum-based chemotherapy (or 5 doses of weekly platinum-based chemotherapy) and subsequently received one cycle of platinum-based chemotherapy or < 5 doses of weekly platinum-based chemotherapy concurrently with radiation therapy, this will be considered SCRT.

If the patient has received 1 cycle of platinum-based chemotherapy (or < 5 doses of weekly platinum-based chemotherapy) and subsequently received one cycle of platinum-based chemotherapy or < 5 doses of a weekly platinum-based doublet regimen in synchrony with the radiation therapy, this will not be considered CCRT or SCRT and the patient will be off-specification.

According to the local standard of care protocol, a platinum-based duplex chemotherapy regimen must contain one of the following agents: etoposide, vinblastine, vinorelbine, a taxane (paclitaxel or docetaxel) or pemetrexed. Gemcitabine is allowed to be used prior to, but not with, radiation therapy.

The final chemotherapy cycle for the patient must end before or in synchrony with the final radiotherapy dose.

As part of chemo-radiation therapy, patients must receive a total radiation dose of 60Gy + -10% (54Gy to 66 Gy). Patients who are recommended but do not require random grouping eligibility:

average lung dose < 20Gy and/or V20 < 35%

Average esophageal dose < 34Gy

Heart V50 ≦ 25%, V30 ≦ 50%, and V45 ≦ 35

At enrollment and random grouping, patients must have a World Health Organization (WHO) PS of 0 or 1.

Proper organ function

Key exclusion criteria

Prior to chemo-radiation therapy, patients had a history of symptomatic ILD disease.

Patients had symptomatic pneumonia following chemo-radiation therapy.

All Adverse events of unrelieved toxicity in patients are rated at grade 2 by the current chemo-radiation therapy, commonly termed the Common terminologic criterion for additive Event, CTCAE. After consulting a medical inspector of astrikon corporation (AstraZeneca), patients with irreversible toxicity (e.g., hearing loss) that is not reasonably expected to be exacerbated by study medication may be included.

Study assessment and patient follow-up

Randomization had to be performed within 6 weeks after completion of radiotherapy and the screening period would be performed within 28 days after study treatment was initiated. After randomization, patients were visited on weeks 2, 4, and every 4 weeks until week 24, every 8 weeks until week 48, and then every 12 weeks until discontinuing study medication.

cintinib (80mg oral, once daily) or a matched placebo will be administered orally once daily according to a randomized cohort schedule.

All subjects should continue to receive randomized study treatment until objective radiographic disease progression as assessed by BICR, or until treatment discontinuation criteria are met. Tumor assessment will be performed using (i) chest and abdomen (including liver and adrenal) contrast-enhanced Computed Tomography (CT). However, non-enhanced CT or MRI would be acceptable if the subject had contraindications for CT contrast agents, when (ii) contrast agent enhanced T1w Magnetic Resonance Imaging (MRI) of the brain is used. However, in those subjects who have contraindications for gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA) -based contrast agents, non-enhanced MRI will be sufficient. CT of the chest/abdomen and MRI of the brain will be performed at all tumor imaging visits. The baseline assessment is part of the screening program. Objective tumor assessments were performed every 8 weeks (relative to randomly grouped dates) for up to 48 weeks, followed by 12 weeks until objective radiation disease progression (whether the reason for discontinuing study drug and/or discontinuing subsequent therapy) as defined by the solid tumor Response assessment Criteria (RECIST) v1.1 and confirmed by BICR. If a clinical indication is present, i.e. if disease progression is suspected, a further scan should be performed. If an unplanned assessment is performed and the patient's disease has not progressed, then subsequent assessments should be attempted at the time of the planned visit.

Safety monitoring included collecting adverse events at all visits, physical exam assessments, vital signs, clinical chemistry, hematology, urinalysis, and ECG. Left ventricular ejection fraction will be performed periodically (via ECHO or MUGA).

Patient reporting of results

Patients will be assessed regularly during study drug administration and after disease progression to report symptoms, function and overall health status/QoL.

Pharmacokinetic assessment

The cereal PK samples were collected at week 4, week 12 and week 24.

No treatment codes should be revealed except for emergency medical situations where proper management of the patient requires knowledge of the treatment randomization group. In addition, at the request of the investigator, when BICR confirms disease progression, the patient may not be blinded if deemed critical for future management of the patient. Formal crossover (for male cross-over) with the Hitinib group was not allowed for those patients who were randomly assigned to the placebo group. The treatment that a patient receives after a relapse will be determined by a physician. Post-relapse cancer treatment and procedures will be recorded.

Following discontinuation of trial therapy, patients will be followed up until consent for post-death or withdrawal progression outcome assessment (PFS2, TFST, TSST) and overall survival assessment.