Assessment of Anti-tumor and Safety in Glumetinib in Patients With c-MET-positive Non-Small Cell Lung Cancer

Inclusion criteria:

1. Provide informed consent voluntarily.
2. Male and female patients ≥ 18 years of age (or having reached the age of majorityaccording 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 surgicalresection 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 METalterations (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 systemictherapies 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 centrallaboratory is available, the report of the central laboratory shall prevail); allpatients in Phase II study will have confirmation of METex14 skipping mutation bySponsor-designated central laboratory but this result is not necessary foreligibility.
7. Availability of tumor tissue sample (either fresh tumor biopsy or archival tumortissue sample); for patients of phase II study (not mandatory for safety run-in), ifscreened and enrolled based on local test results of METex14 skipping, the tumortissue sample must be available for central laboratory testing before C2D1; if localtesting results meet the requirements, patients of phase Ib are exempt from thecentral laboratory confirm.
8. For Phase II study, patients are not eligible for chemotherapy or refuse chemotherapyafter well-informed or have failed one or two prior lines of systemic therapies forthe advanced NSCLC.

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

9. For Phase II study, at least one measurable lesion as per RECIST 1.1. (A previouslyirradiated site lesion may only be counted as a target lesion if there is clear signof 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 bedetermined 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, ROS1rearrangement, BRAF mutation or NTRK fusion that have available standard of caretherapies.
2. Patients who have symptomatic CNS metastasis which is neurologically unstable or thosewho have CNS disease requiring increase in the dose of steroid. (Note: Patients withcontrolled CNS metastasis can participate in the trial. Before entering the study,patients should have finished radiotherapy, or have received operation for CNS tumormetastasis at least two weeks before. Patients' neurological function must be in astable state; no new neurological deficit is found during clinical examination and nonew problem is found during CNS imaging examinations. If patients need to use steroidsto treat CNS metastasis, the therapeutic dose of steroid should be stable for ≥ 3months at least two weeks prior to entering the study with treatment dose no more thandexamethasone 4 mg daily or an equivalent dose of steroids.)
3. Prior exposure to MET-directed therapy (except patients harboring METex14 skipping inPhase Ib study).
4. Evidence of past or current primary malignancies other than NSCLC (except fornon-melanoma skin cancer, in situ breast cancer or in situ cervical carcinoma andsuperficial bladder cancer, or other cancer curatively treated and with no evidence ofdisease 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 arrhythmiasrequiring drug therapy;
• Acute myocardial infarction, severe or unstable angina pectoris, coronary arteryor peripheral artery bypass graft received within 6 months prior to the firstdose;
• Left ventricular ejection fraction (LVEF) < 50%;
• Fridericia's corrected QT interval (QTcF) > 460 ms on ECG conducted duringscreening;
• Congenital long QT syndrome, or any known history of torsade de pointes (TdP), orfamily 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 ofstarting 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 Band hepatitis C. Patients whose test results meet one of the following will not beenrolled:

• for patients in China and Japan, confirmed HIV antibody positive. For patients inthe US, patients with a history of HIV but no history of AIDS or an AIDS-definingopportunistic 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, whenHBsAb or HBcAb positive, the patients whose HBV DNA < 200 IU/ml or 1000 copies/mLcould be enrolled.
• serum HCV antibody and HCV RNA positive.

8. Anticancer therapy (including chemotherapy, targeted therapy, biotherapy, hormonetherapy 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 notrecovered 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 receivedlocal palliative radiation therapy for bone metastases within 2 weeks.
10. Major surgery or had significant traumatic injury within 28 days prior to the firstdose 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 [Hypericumperforatum L.] and Sevillia orange etc. should also be avoided.) that is prohibitedduring 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 excludedin safety run-in part of the study.
12. Any diseases or medical conditions, at the investigator's discretion, that may beunstable or influence their safety or study compliance, including organtransplantation, abuse of psychotropic medication, alcohol abuse or history of drugabuse.
13. Other serious illness or medical conditions at the investigator's discretion, that mayinfluence 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 clinicallyactive ILD.
15. Pregnant or breast-feeding patients. Pregnancy refers to the state of a woman betweenfertilization and the end of pregnancy confirmed by positive laboratory hCG test (> 5mIU/mL). Breast-feeding woman can become eligible for this study if she stopsbreast-feeding, however, cannot restart the breast-feeding on/after the completion ofthe study treatment.
16. Man and woman with childbearing potential (WOCBP refer to appendix 3) not usingeffective contraception (refer to appendix 3) during the trial and within 6 monthsafter the end of treatment