TR115 in ARID1A-Mutated Advanced Solid Tumors

An Open-Label, Multicenter, Phase II Exploratory Study to Evaluate the Efficacy and Safety of TR115 in Patients With ARID1A-Mutated Advanced Solid Tumors

This is an open-label, multicenter, exploratory Phase II study to evaluate the efficacy and safety of TR115, an EZH2 inhibitor, in patients with advanced solid tumors carrying ARID1A gene mutations. Approximately 50 participants will be enrolled into three cohorts: platinum-resistant ovarian clear cell carcinoma, endometrial cancer with prior immunotherapy failure, and other solid tumors including gastric and urothelial cancers. All participants will receive TR115 at 1200 mg orally twice daily in continuous 28-day cycles until disease progression or unacceptable toxicity. The primary endpoint is objective response rate (ORR). Secondary endpoints include duration of response, progression-free survival, overall survival, disease control rate, and safety. Exploratory biomarker analyses will also be conducted.

Inclusion Criteria:

• Able to understand and provide written informed consent.
• Age 18 to 70 years, inclusive.
• Histologically or cytologically confirmed advanced solid tumor with ARID1A mutation.
• Cohort 1: Platinum-resistant ovarian/fallopian tube/peritoneal clear cell carcinoma with disease progression after ≥1 prior platinum-based regimen. Cohort 2: Endometrial cancer with disease progression after ≥1 prior platinum-based regimen and prior immunotherapy failure or intolerance. Cohort 3: Other advanced solid tumors (including gastric cancer, urothelial carcinoma) with disease progression after ≥1 prior standard systemic therapy.
• ECOG performance status 0-1.
• Life expectancy ≥3 months.
• At least one measurable lesion per RECIST v1.1.
• Adequate organ function: ANC ≥1.5×10⁹/L, PLT ≥100×10⁹/L, Hb ≥100 g/L (no growth factor or transfusion support within 14 days prior to first dose), TBIL ≤1.5×ULN, ALT/AST ≤2.5×ULN (≤5×ULN if liver metastasis), CrCl ≥50 mL/min, LVEF ≥50%, QTcF <450 ms (male) or <470 ms (female).
• Willing to provide archival or fresh tumor tissue for biomarker analysis.
• Male and female participants of childbearing potential must agree to use medically approved contraception during the study and for 6 months after the last dose.

Exclusion Criteria:

• Prior treatment with EZH2 or EZH1/2 inhibitors resulting in disease progression (intolerance permitted).
• Third-space fluid accumulation not controllable by drainage or other means.
• Systemic corticosteroid therapy (>10 mg/day prednisone or equivalent) within 14 days prior to first dose, except for inhaled or topical use.
• Inability to swallow oral medication or conditions significantly affecting drug absorption.
• Known central nervous system (CNS) involvement.
• Tumor invasion or encasement of major vessels.
• Active infection requiring systemic therapy.
• Active hepatitis B or C requiring treatment, or HIV infection.
• Active autoimmune disease requiring systemic immunosuppressive therapy.
• Significant cardiovascular disease (e.g., myocardial infarction within 6 months, NYHA Class III/IV heart failure, uncontrolled arrhythmia).
• Pregnancy, lactation, or positive pregnancy test.
• Other primary malignancy within 5 years, except cured non-melanoma skin cancer, carcinoma in situ, or thyroid carcinoma.
• Prior anti-tumor therapy-related adverse events not recovered to ≤Grade 1 (CTCAE v6.0), except alopecia or peripheral neuropathy Grade ≤2.
• Use of strong or moderate CYP3A4 inhibitors/inducers within 14 days prior to first dose.
• Any other condition that in the investigator's opinion makes the participant unsuitable for the study.