Indication:Patients with Advanced c-MET-positive Non-Small Cell Lung Cancer

Phase Ib (China only):

Approximately 90 patients

Phase Ⅱ (globally):

Approximately 78 evaluable patients; addition of at least 6 patients in Safety Run-in (US only)

Phase Ib study population

Approximately 90 patients with locally advanced or metastatic NSCLC (Stage IIIb, IIIc or IV) including pulmonary sarcomatoid carcinoma (PSC). All patients should carry at least one of the following MET alterations (confirmed by local or central laboratory):

• Patients with METex14 skipping mutation who had previously treated by other MET inhibitor(s)
• Patients with METex14 skipping mutation who had received 3 or more lines prior systemic therapies without MET inhibitor for the advanced NSCLC
• Patients with MET amplification (GCN ≥ 4 or MET/CEP7 ratio ≥ 2)
• Patients with MET over-expression (IHC2+) Phase II - Safety Run-in Population (US only) A minimum of 6 patients who meeting the eligibility for either Phase Ib or Phase II.

Phase II study population (globally) Approximately 78 evaluable patients with locally advanced or metastatic NSCLC (Stage IIIb, IIIc or IV, including PSC) harboring METex14 skipping mutation that have been pre-screened by local or Sponsor-designated central laboratory, who are not eligible for chemotherapy or refuse of chemotherapy after well-informed or have failed one or two prior lines of systemic therapies and have not had prior MET inhibitor for the advanced NSCLC.

Inclusion criteria:

1. Provide informed consent voluntarily.

2. 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).

3. Histologically or cytologically confirmed diagnosis of NSCLC including PSC.

4. 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).

5. 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 treated by other MET inhibitor(s) or
   • METex14 skipping mutation who had received 3 or more lines prior systemic therapies without MET inhibitor for the advanced NSCLC or
   • MET amplification GCN ≥ 4 or MET/CEP7 ratio ≥ 2) or
   • MET over-expression (IHC2+).

6. For Phase II study, patients with METex14 skipping mutation in tumor or ctDNA samples (local testing is acceptable for eligibility, however if the results of the central laboratory is available, the report of the central laboratory shall prevail); 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.

7. Availability of tumor tissue sample (either fresh tumor biopsy or archival tumor tissue sample); for patients of phase II study (not mandatory for safety run-in), if screened and enrolled based on local test results of METex14 skipping, the tumor tissue sample must be available for central laboratory testing before C2D1; if local testing results meet the requirements, patients of phase Ib are exempt from the central laboratory confirm.

8. For Phase II study, patients are not eligible for chemotherapy or refuse chemotherapy after well-informed or have failed one or two prior lines of systemic therapies for the advanced NSCLC.

   • Treatment failure is defined as documented disease progression or intolerance to treatment.
   • Maintenance therapy given after first line chemotherapy will be considered as part of the first line if given to patients with documented response or stable disease before starting the maintenance therapy.
   • Prior neoadjuvant/adjuvant systematic therapies will count as one prior line of treatment, provided that disease recurred within 12 months of completion of neoadjuvant/adjuvant therapy.

9. For Phase II study, 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.)

10. ECOG Performance Status (PS): 0-1.

11. 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)

Exclusion Criteria:

Patients who meet any of the following criteria shall be excluded from the study:

1. Patients with targetable activating EGFR mutation, ALK rearrangement, ROS1 rearrangement, BRAF mutation or NTRK fusion that have available standard of care therapies.

2. 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.)

3. Prior exposure to MET-directed therapy (except patients harboring METex14 skipping in Phase Ib study).

4. 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).

5. 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);

6. 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.

7. 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. Patients with a history of interstitial lung disease (ILD), drug-induced ILD, radiation pneumonitis which required steroid treatment or any evidence of clinically active 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. Man and woman with childbearing potential (WOCBP refer to appendix 3) not using effective contraception (refer to appendix 3) during the trial and within 6 months after the end of treatment