c-MET Inhibitor in Advanced Solid Tumors With c-MET Gene Aberration

Α. Dose and cycle

• ABN401 800 mg will be administered orally once daily immediately after a meal [should be within 1 hour post-meal (fed state)] at approximately the same time each day in a 21-day cycle.

Β. Treatment duration

• ABN401 will be administered until disease progression, unacceptable toxicity, death, and consent withdrawal.
• Step I: enrolled 8 patients will receive ABN401
• Step II: if more than 3 out of 8 patients showed disease control (complete response, partial response, and stable disease), step II will be forwarded and additional 10 patients will be enrolled.
• If more than 7 out of 18 patients showed disease control, ABN401 will be considered an effective drug in this study.

Inclusion criteria

• Informed consent for KOSMOS-II master observation study
• Male or female ≥19 years of age
• Histologically confirmed advanced solid cancers who harboring c-MET alterations (patients who performed NGS tests and c-MET alterations confirmed in molecular tumor board [MTB]) - exon 14 skipping mutation except for non-small cell lung cancer (NSCLC)

• c-MET amplification GCN (gene copy no.) ≥6 by NGS
• Fluorescence/Silver In situ hybridization (FISH/SISH) result of the MET/CEP7 ratio ≥2
• Other MET alterations that are regarded to be actionable by the KOSMOS MTB
• Disease progression during or after standard therapy and without further treatment options, or no standard therapy, or ineligible for standard therapy
• At least one measurable or evaluable lesion based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
• Eastern Cooperative Oncology Group Performance Status 0-2
• Capable to eat food
• Adequate organ functions

• Absolute neutrophil count (ANC) ≥1500/mm3 (ie, 1.5×109/L by International - Unit [IU]); excluding measurements obtained within 7 days after administration of granulocyte colony stimulating factor (G-CSF)
• Platelet count ≥75000/mm3 (IU: ≥75×109/L); excluding measurements obtained within 7 days after transfusion of platelets.
• Hemoglobin value of ≥8.0 g/dL
• AST/ALT ≤3×upper limit of normal (ULN); if liver function abnormalities are due to underlying liver metastasis, AST / ALT ≤5×ULN
• Total serum bilirubin of ≤1.5×ULN
• Creatinine clearance (CrCl) of ≥50 mL/min (MDRD)
• Have a life expectancy of at least 90 days
• If not menopausal or surgically sterile, willing to practice at least one of the following highly effective methods of birth control for at least a (partner's) menstrual cycle before and for 3 months after study drug administration:

• Barrier type devices (examples are condom, diaphragm, and contraceptive sponge) used only in combination with a spermicide
• Sexual intercourse with vasectomized male/sterilized female partner
• Hormonal female contraceptive (oral, parenteral, intravaginal, implantable, or transdermal) for at least 3 consecutive months prior to investigational product administration (when not clinically contraindicated as in breast, ovarian and endometrial cancers)
• Use of an intrauterine contraceptive device

• Note: Abstinence, the rhythm method, and/or contraception by the partner are not acceptable methods of birth control
• Willing to provide available tissue specimens and consent to blood collection for evaluation of biomarkers

• Archival tissue specimens: formalin-fixed, paraffin-embedded tissues
• Optional fresh tissue collection prior to ABN401 administration

Exclusion criteria

• Previous treatment with c-MET inhibitor
• NSCLC with c-MET exon 14 skipping mutation
• Previous hypersensitivity reaction to any component of study drugs
• Presence or history of arrhythmia
• Past history of

① Major surgery within 4 weeks before study (must have complete recovery from surgical complications)

② Radiotherapy within 4 weeks before study or limited radiotherapy within 2 weeks

③ Chemotherapy or biologic agents within 3 weeks before study (targeted therapy within 2 weeks and mitomycin within 5 weeks)

• History of the following medical conditions

• Active central nervous system (CNS) metastasis (clinically unstable after stopping steroid for more than 2 months)
• Leptomeningeal metastasis
• Acute systemic infection
• Acute myocardial infarction, stable/unstable angina, symptomatic heart failure ((New York Heart Association [NYHA] class III or IV within the previous 6 months; if >6 months cardiac function must be within normal limits and the patient must be free of cardiac-related symptoms)
• Clinically critical chronic vomiting or diarrhea
• Uncontrolled hypertension (systolic blood pressure >150mmHg diastolic blood pressure>100mmHg)
• Proteinuria (urine dipstick or 24-hour urine collection > 1.0g): must have 24-hour urine collection if baseline urine dipstick ≥2+
• Active HBV/ HCV except for

• HBsAg (+) with undetectable HBV DNA
• If HBsAg (+) and HBV DNA (+), chronic state of infection and clinically stable after anti-viral therapy for more than 3 months
• If IgG anti-HBc (+) and past history of HBV infection, undetectable HBV DNA
• HCV Ab (+) with undetectable HCV RNA
• Severe psychiatric disorders
• Concurrent anticoagulants at therapeutic dose
• Past history of gastrointestinal perforation or fistula within 3 months before study, grade 3 or 4 of gastrointestinal bleeding/varix
• Toxicity with prior therapy (> grade 1) (except for alopecia, pigmentation, poor oral intake), and neuropathy (> grade 1)
• Pregnant or breastfeeding
• Patients with a corrected QT interval (using Fridericia's correction formula) (QTcF) of > 470 msec