The study is a first-in-human (FIH), open-label, multi-center phase 1/2 study of TSN1611 in subjects with KRAS G12D mutant advanced solid tumors. This study will consist of a phase 1 dose escalation part and phase 2 dose expansion part. This study will evaluate the efficacy of TSN1611 at RP2D(s) through ORR using RECIST version 1.1, and determine and confirm the MTD/RP2D for TSN1611 in combination with cetuximab, in combination with cetuximab and mFOLFOX6, in combination with gemcitabine and albumin-bound paclitaxel in subjects with selected solid tumors.
The subject fully understands the requirements of the study and voluntarily signs the ICF.
At least 18 years of age at the time of informed consent.≤ 75 years of age for Cohort B and C.
Life expectancy of 3 months or more.
Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
Leptomeningeal disease or Active central nervous system (CNS) metastases.
Prior systemic anti-cancer treatment within 21 days or 5 half-lives (whichever is shorter will be used as the criteria) prior to the first dose of study drug.
Radical radiation within 4 weeks prior to the first dose of study drug; palliative radiotherapy within 1 week prior to the first dose of study drug.
Any unresolved Grade 2 or higher toxicity from previous anticancer therapy except alopecia.
Sequential
TSN1611
DrugTSN1611 will be administered at the assigned dose level, orally, until disease progression or intolerable toxicity.
TSN1611
DrugTSN1611 BID, Cetuximab will be administered via intravenous infusion at a dose of 500 mg/m² every 2 weeks.
TSN1611
DrugTSN1611 BID, Paclitaxel (albumin-bound) at 125 mg/m² and gemcitabine at 1000 mg/m² will be administered via intravenous infusion on Days 1, 8, and 15 of each 4-week cycle.
TSN1611
DrugTSN1611 BID everyday and Patients will be administered with mFOLFOX6 on Days 1 and 2, every 2 weeks.
Dose limiting toxicities (DLTs) in phase 1 part
To determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose(s) (RP2D\[s\]) of TSN1611 as monotherapy in subjects with KRAS G12D mutant advanced solid tumors.
Objective response rate (ORR) in phase 2 part
To evaluate the anti-tumor activity of TSN1611 using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
Adverse events
To assess the safety profile and tolerability of TSN1611 as monotherapy in subjects with KRAS G12D mutant advanced solid tumors.
Area under the plasma concentration-time curve (AUC)
To characterize the pharmacokinetic (PK) profile of TSN1611.
Maximum blood concentrations (Cmax)
To characterize the PK profile of TSN1611.
Time to maximum blood concentration (Tmax)
To characterize the PK profile of TSN1611.
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