A Phase II Study of ABN401 in Advanced Solid Tumors With c-MET Gene Aberration
c-MET is a member of the receptor tyrosine kinase (RTK) family. Essential components of signal transduction pathways regulating processes including cell proliferation, differentiation, migration, metabolism, and cell cycle control, RTKs are established targets as treatment strategies for various cancers. c-MET is expressed mainly in epithelial tissues and is subject to dysregulation manifesting as mutations, amplifications, and overexpression. c-MET is implicated in both primary oncogenesis, metastasis and also as a mechanism of drug resistance. c-MET has a high affinity for its naturally occurring ligand, Hepatocyte Growth Factor (HGF, also known as Scatter Factor). Binding of HGF to c-MET induces several complex signaling pathways, resulting in cell proliferation, survival, motility, induction of cells polarity, scattering, angiogenesis, and invasion. c-MET alterations are identified in various cancers. Several drugs targeting c-MET inhibition have been developed, and capmatinib was approved by FDA in patients with non-small cell lung cancer harboring MET exon 14 skipping mutation. ABN401 competitively attaches to the ATP binding sites in the kinase domain of c-MET with high specificity to inhibit phosphorylation of downstream signaling pathways. Following several animal studies of advanced solid cancers, the first-in-human trial of ABN401 showed anti-tumor activity without DLT, and the phase 2 trial is ongoing. Recently, the basket trials have been emphasized for tissue agnostic approach targeting certain genetic alterations, and the NCI-MATCH (National Cancer Institute-MATCH) trials in 3,000 patients with advanced solid cancers are ongoing. Similarly, the KOSMOS-II study is ongoing in Korea. This study is the basket trial that Next-generation sequencing (NGS)-based genetic alterations, which is confirmed in Molecular Tumor Board (MTB), provide the individual treatment approach.
• 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