Provide informed consent voluntarily
Male and female patients 18 years of age (or having reached the age of majority according to local laws and regulations, if the age is > 18 years)
Histologically or cytologically confirmed diagnosis of NSCLC
Patients with stage IIIb or IIIc NSCLC who are not candidates for definitive surgical resection or concurrent chemoradiation or patients with stage IV NSCLC (AJCC version 8)
For Phase Ib study, patients should carry at least one of the following MET alterations (by local or Sponsor-designated central laboratory screening)
METex14 skipping mutation who had previously responded to and later progressed on another MET inhibitor or
MET amplification (FISH GCN 5 or MET/CEP7 ratio 2) or
MET over-expression (IHC3+)
Patients harboring METex14 skipping mutation who have been treated with
another MET inhibitor, should also meet all of the following requirements
Only one MET inhibitor as monotherapy has been treated previously
Achieved one of the following objective clinical benefits on MET inhibitor
treatment
Documented confirmed partial or complete response (RECIST)
Significant and long-lasting ( 3 months) clinical benefits of stable disease as defined by RECIST
Had radiologic progression on MET inhibitor treatment
For Phase II study, patients with METex14 skipping mutation in tumor or ctDNA samples (local testing is acceptable for eligibility; all patients in Phase II study will have confirmation of METex14 skipping mutation by Sponsor-designated central laboratory but this result is not necessary for eligibility)
Availability of tumor tissue sample (either fresh tumor biopsy or archival tumor tissue sample) or ctDNA sample
For Phase II study, patients are either systemic treatment nave (the patients should be chemotherapy intolerance or not eligible for chemotherapy or patients refusing of chemotherapy after well-informed) or no more than 2 prior systemic therapies for the advanced NSCLC. Prior neoadjuvant/adjuvant platinum containing chemotherapy will count as having received prior platinum, provided that disease recurred within 6 months of completion of neoadjuvant/adjuvant therapy
At least one measurable lesion as per RECIST 1.1. (A previously irradiated site lesion may only be counted as a target lesion if there is clear sign of progression since the irradiation.)
ECOG Performance Status (PS): 0-1
Adequate bone marrow reserve, renal and liver function
Absolute neutrophil count 1.5 109/L
Hemoglobin 9 g/dL
Platelet count 75 109/L
Serum total bilirubin ULN ( 3 ULN for patients with Gilbert's syndrome)
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 2.5 ULN ( 5.0 ULN for patients with hepatic metastasis)
Creatinine clearance (calculated _or measured value_ ) 50 mL/min
For calculated creatinine clearance (Ccr) value, the eligibility should be determined using the Cockcroft-Gault formula
Male Ccr (mL/mim) = body weight (kg) x (140-age)/[72 x creatinine (mg/dL)]
Female Ccr (mL/min) = male Ccr x 0.85 A measured value
International normalized ratio (INR) < 1.3 (or < 3.0 if on anticoagulation)
Patients who meet any of the following criteria shall be excluded from the
study
Patients with targetable activating EGFR mutation, ALK rearrangement, ROS1 rearrangement, BRAF mutation or NTRK fusion that have available standard of care therapies
Patients who have symptomatic CNS metastasis which is neurologically unstable or those who have CNS disease requiring increase in the dose of steroid. (Note: Patients with controlled CNS metastasis can participate in the trial. Before entering the study, patients should have finished radiotherapy, or have received operation for CNS tumor metastasis at least two weeks before. Patients' neurological function must be in a stable state; no new neurological deficit is found during clinical examination and no new problem is found during CNS imaging examinations. If patients need to use steroids to treat CNS metastasis, the therapeutic dose of steroid should be stable for 3 months at least two weeks prior to entering the study with treatment dose no more than dexamethasone 4 mg daily or an equivalent dose of steroids.)
Prior exposure to MET-directed therapy (except patients harboring METex14 skipping in Phase Ib study)
Evidence of past or current primary malignancies other than NSCLC (except for non-melanoma skin cancer, in situ breast cancer or in situ cervical carcinoma and superficial bladder cancer, or other cancer curatively treated and with no evidence of disease for at least 5 years)
Subjects with clinically significant cardiovascular disease, including
NYHA Class III or higher congestive heart failure
History or current evidence of serious uncontrolled ventricular arrhythmias requiring drug therapy
Acute myocardial infarction, severe or unstable angina pectoris, coronary artery or peripheral artery bypass graft received within 6 months prior to the first dose
Left ventricular ejection fraction (LVEF) < 50%
Fridericia's corrected QT interval (QTcF) > 460 ms on ECG conducted during screening
Congenital long QT syndrome, or any known history of torsade de pointes (TdP), or family history of unexplained sudden death
Clinically uncontrolled hypertension (after standard antihypertensive treatment, systolic blood pressure 140 mmHg and/or diastolic blood pressure 90 mmHg)
Any unresolved toxicities from prior therapy greater than CTCAE grade 1 at the time of starting study treatment with the exception of alopecia and grade 2 prior neuropathy
Known HIV infection with a history of acquired immunodeficiency syndrome (AIDS)-defining opportunity infection within the past 12 months; active hepatitis B and hepatitis C. Patients whose test results meet one of the following will not be
enrolled
for patients in China and Japan, confirmed HIV antibody positive. For patients in the US, patients with a history of HIV but no history of AIDS or an AIDS-defining opportunistic infection are allowed to be enrolled
serum HBsAg positive and HBV DNA>200 IU/ml or 1000 copies/mL
For patients in Japan, whose results are HBsAg antigen negative; however, when
HBsAb or HBcAb positive, the patients whose HBV DNA < 200 IU/ml or 1000
copies/mL could be enrolled
serum HCV antibody and HCV RNA positive. 8\. Anticancer therapy (including chemotherapy, targeted therapy, biotherapy, hormone therapy or other investigational agents) within 4 weeks or 5 times of half-lives (whichever is shorter) prior to the first dose of the study drug or who have not recovered from the side effect of such therapy. 9\. Radical radiation therapy (including radiation therapy for over 25% bone marrow) within 4 weeks prior to the first dose of the investigational product or received local palliative radiation therapy for bone metastases within 2 weeks. 10\. Major surgery or had significant traumatic injury within 28 days prior to the first dose of the investigational product. 11\. Patients who have to receive treatment (definite strong CYP3A4 inhibitor or inducer [appendix 6]; in addition, herbals/supplements containing St. John's wart [Hypericum perforatum L.] and Sevillia orange etc. should also be avoided.) that is prohibited during the study and those who cannot discontinue drugs (e.g. antiarrhythmic agent) that may lead to QTc interval prolongation or torsade de pointes. Additionally, patients who have to receive treatment of strong inhibitor for CYP2C8 and/or CYP2C9 [appendix 6] and substrates or inhibitor for transporter [appendix 7] will be excluded in safety run-in part of the study. 12\. Any diseases or medical conditions, at the investigator's discretion, that may be unstable or influence their safety or study compliance, including organ transplantation, abuse of psychotropic medication, alcohol abuse or history of drug abuse. 13\. Other serious illness or medical conditions at the investigator's discretion, that may influence study results, including but not limited to serious infection, diabetes, cardiovascular and cerebrovascular diseases or lung disease. 14\. Subjects with a history of interstitial lung disease (ILD). 15\. Pregnant or breast-feeding patients. Pregnancy refers to the state of a woman between fertilization and the end of pregnancy confirmed by positive laboratory hCG test (> 5 mIU/mL). Breast-feeding woman can become eligible for this study if she stops breast-feeding, however, cannot restart the breast-feeding on/after the completion of the study treatment. 16\. Male and female of childbearing potential not using effective contraception (e.g. intrauterine device (IUD), diaphragm with spermicide _, cervical cap_ with spermicide _, male condoms, female condoms_ with spermicide, oral hormonal contraceptive. not approved nor certified in Japan) during the trial and within 6 months after the end of treatment
Yes for serum HCV antibody and HCV RNA positive. 8\. Anticancer therapy (including chemotherapy, targeted therapy, biotherapy, hormone therapy or other investigational agents) within 4 weeks or 5 times of half-lives (whichever is shorter) prior to the first dose of the study drug or who have not recovered from the side effect of such therapy. 9\. Radical radiation therapy (including radiation therapy for over 25% bone marrow) within 4 weeks prior to the first dose of the investigational product or received local palliative radiation therapy for bone metastases within 2 weeks. 10\. Major surgery or had significant traumatic injury within 28 days prior to the first dose of the investigational product. 11\. Patients who have to receive treatment (definite strong CYP3A4 inhibitor or inducer [appendix 6]; in addition, herbals/supplements containing St. John's wart [Hypericum perforatum L.] and Sevillia orange etc. should also be avoided.) that is prohibited during the study and those who cannot discontinue drugs (e.g. antiarrhythmic agent) that may lead to QTc interval prolongation or torsade de pointes. Additionally, patients who have to receive treatment of strong inhibitor for CYP2C8 and/or CYP2C9 [appendix 6] and substrates or inhibitor for transporter [appendix 7] will be excluded in safety run-in part of the study. 12\. Any diseases or medical conditions, at the investigator's discretion, that may be unstable or influence their safety or study compliance, including organ transplantation, abuse of psychotropic medication, alcohol abuse or history of drug abuse. 13\. Other serious illness or medical conditions at the investigator's discretion, that may influence study results, including but not limited to serious infection, diabetes, cardiovascular and cerebrovascular diseases or lung disease. 14\. Subjects with a history of interstitial lung disease (ILD). 15\. Pregnant or breast-feeding patients. Pregnancy refers to the state of a woman between fertilization and the end of pregnancy confirmed by positive laboratory hCG test (> 5 mIU/mL). Breast-feeding woman can become eligible for this study if she stops breast-feeding, however, cannot restart the breast-feeding on/after the completion of the study treatment. 16\. Male and female of childbearing potential not using effective contraception (e.g. intrauterine device (IUD), diaphragm with spermicide _, cervical cap_ with spermicide _, male condoms, female condoms_ with spermicide, oral hormonal contraceptive. not approved nor certified in Japan) during the trial and within 6 months after the end of treatment exclusion criteria 23
No for serum HCV antibody and HCV RNA positive. 8\. Anticancer therapy (including chemotherapy, targeted therapy, biotherapy, hormone therapy or other investigational agents) within 4 weeks or 5 times of half-lives (whichever is shorter) prior to the first dose of the study drug or who have not recovered from the side effect of such therapy. 9\. Radical radiation therapy (including radiation therapy for over 25% bone marrow) within 4 weeks prior to the first dose of the investigational product or received local palliative radiation therapy for bone metastases within 2 weeks. 10\. Major surgery or had significant traumatic injury within 28 days prior to the first dose of the investigational product. 11\. Patients who have to receive treatment (definite strong CYP3A4 inhibitor or inducer [appendix 6]; in addition, herbals/supplements containing St. John's wart [Hypericum perforatum L.] and Sevillia orange etc. should also be avoided.) that is prohibited during the study and those who cannot discontinue drugs (e.g. antiarrhythmic agent) that may lead to QTc interval prolongation or torsade de pointes. Additionally, patients who have to receive treatment of strong inhibitor for CYP2C8 and/or CYP2C9 [appendix 6] and substrates or inhibitor for transporter [appendix 7] will be excluded in safety run-in part of the study. 12\. Any diseases or medical conditions, at the investigator's discretion, that may be unstable or influence their safety or study compliance, including organ transplantation, abuse of psychotropic medication, alcohol abuse or history of drug abuse. 13\. Other serious illness or medical conditions at the investigator's discretion, that may influence study results, including but not limited to serious infection, diabetes, cardiovascular and cerebrovascular diseases or lung disease. 14\. Subjects with a history of interstitial lung disease (ILD). 15\. Pregnant or breast-feeding patients. Pregnancy refers to the state of a woman between fertilization and the end of pregnancy confirmed by positive laboratory hCG test (> 5 mIU/mL). Breast-feeding woman can become eligible for this study if she stops breast-feeding, however, cannot restart the breast-feeding on/after the completion of the study treatment. 16\. Male and female of childbearing potential not using effective contraception (e.g. intrauterine device (IUD), diaphragm with spermicide _, cervical cap_ with spermicide _, male condoms, female condoms_ with spermicide, oral hormonal contraceptive. not approved nor certified in Japan) during the trial and within 6 months after the end of treatment exclusion criteria 23
Not sure for serum HCV antibody and HCV RNA positive. 8\. Anticancer therapy (including chemotherapy, targeted therapy, biotherapy, hormone therapy or other investigational agents) within 4 weeks or 5 times of half-lives (whichever is shorter) prior to the first dose of the study drug or who have not recovered from the side effect of such therapy. 9\. Radical radiation therapy (including radiation therapy for over 25% bone marrow) within 4 weeks prior to the first dose of the investigational product or received local palliative radiation therapy for bone metastases within 2 weeks. 10\. Major surgery or had significant traumatic injury within 28 days prior to the first dose of the investigational product. 11\. Patients who have to receive treatment (definite strong CYP3A4 inhibitor or inducer [appendix 6]; in addition, herbals/supplements containing St. John's wart [Hypericum perforatum L.] and Sevillia orange etc. should also be avoided.) that is prohibited during the study and those who cannot discontinue drugs (e.g. antiarrhythmic agent) that may lead to QTc interval prolongation or torsade de pointes. Additionally, patients who have to receive treatment of strong inhibitor for CYP2C8 and/or CYP2C9 [appendix 6] and substrates or inhibitor for transporter [appendix 7] will be excluded in safety run-in part of the study. 12\. Any diseases or medical conditions, at the investigator's discretion, that may be unstable or influence their safety or study compliance, including organ transplantation, abuse of psychotropic medication, alcohol abuse or history of drug abuse. 13\. Other serious illness or medical conditions at the investigator's discretion, that may influence study results, including but not limited to serious infection, diabetes, cardiovascular and cerebrovascular diseases or lung disease. 14\. Subjects with a history of interstitial lung disease (ILD). 15\. Pregnant or breast-feeding patients. Pregnancy refers to the state of a woman between fertilization and the end of pregnancy confirmed by positive laboratory hCG test (> 5 mIU/mL). Breast-feeding woman can become eligible for this study if she stops breast-feeding, however, cannot restart the breast-feeding on/after the completion of the study treatment. 16\. Male and female of childbearing potential not using effective contraception (e.g. intrauterine device (IUD), diaphragm with spermicide _, cervical cap_ with spermicide _, male condoms, female condoms_ with spermicide, oral hormonal contraceptive. not approved nor certified in Japan) during the trial and within 6 months after the end of treatment exclusion criteria 23
Definition of child-bearing potential: a female that fulfills the one of the
following criteria is considered to be without childbearing potential
spontaneous menopause for 12 consecutive months with appropriate clinical
features (e.g. proper age, a history of vasomotor diseases, etc.), or a
history of bilateral ovariectomy (with or without hysterectomy) or tubal
ligation performed at least 6 weeks. For patients with amenorrhea due to anti-
tumor agents, even amenorrhea over 12 months, a pregnancy test is necessary
If a female only received an ovariectomy, she will be considered as no
childbearing potential only after confirmation by hormone levels