Phase Ib study population
Approximately 15 patients with locally advanced or metastatic NSCLC (Stage IIIb, IIIc or IV).
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 responded to and later
progressed on another MET inhibitor
- Patients with MET amplification (FISH GCN ≥ 5 or MET/CEP7 ratio ≥ 2)
- Patients with MET over-expression (IHC3+) 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 90 patients with locally advanced or
metastatic NSCLC (Stage IIIb, IIIc or IV) harboring METex14 skipping mutation that have been
pre-screened by local or Sponsor-designated central laboratory, who are either systemic
treatment naïve (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 and have not had prior MET inhibitor for the advanced NSCLC. It is planned that
approximately 30% of the enrolled patients are systemic treatment naïve for the advanced
After approximately 90 patients have been enrolled, if the proportion of patients at sites in
Japan is < 10% of the total population, enrollment may continue in Japan until the proportion
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.
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
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 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:
1. Only one MET inhibitor as monotherapy has been treated previously.
2. Achieved one of the following objective clinical benefits on MET inhibitor
- Documented confirmed partial or complete response (RECIST)
- Significant and long-lasting (≥ 3 months) clinical benefits of stable
disease as defined by RECIST
3. Had radiologic progression on MET inhibitor treatment
6. 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).
7. Availability of tumor tissue sample (either fresh tumor biopsy or archival tumor
tissue sample) or ctDNA sample.
8. For Phase II study, patients are either systemic treatment naïve (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.
9. 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
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
- 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:
1. Patients with targetable activating EGFR mutation, ALK rearrangement, ROS1
rearrangement, BRAF mutation or NTRK fusion that have available standard of care
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
- Left ventricular ejection fraction (LVEF) < 50%;
- Fridericia's corrected QT interval (QTcF) > 460 ms on ECG conducted during
- 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
- 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
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
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.