Phase Ib/II study of fluzoparib in combination with dalpiciclib in patients with locally advanced or metastatic sarcoma.

Abstract

11533 Background: Poly ADP-ribose polymerase (PARP) plays a role in DNA damage repair, and PARP inhibitors can exert anti-tumor efficiency in tumors with homologous recombination repair defection (HRD). Cyclin-dependent kinase (CDK) plays an important role in cell cycle regulation. Rb is the direct substrate of CDK4/6, and Rb/E2F participates the HR-mediated DNA repair. Therefore, selective CDK4/6 inhibition can theoretically aggravate HRD and hinder DNA repair of tumor cells treated with PARP inhibitors. Combined of CDK4/6 and PARP inhibitors may provide a potential new drug strategy for sarcomas. Methods: FOUNDS is a 2-part, open-label, phase 1/2 study. Key inclusion criteria are: (1) 12-75 years old; (2) Locally advanced or metastatic sarcomas after first-line treatment, with at least one measurable lesion according to RECIST 1.1 criteria. Patients(pts) will receive fluzoparib (0.1 or 0.15 g po., qd, q4w) and dalpiciclib (0.1, 0.125 or 0.15 g po., qd, d1-21, q4w) continuously until progressive disease (PD) or intolerable toxicity occurred. Part 1 is intended to establish the recommended phase 2 dose (RP2D) using a i3+3 dose escalation design. Part 2 will examine the safety and efficacy of fluzoparib + dalpiciclib using the method of Confidence Intervals for One Proportion. The primary endpoint is the objective response rate (ORR). Results: In the escalation part, 12 pts (median age 22 years) were included. At the data cut-off (Jun. 10, 2025), the median follow-up time was 7.93 month (95% CI 7.03-8.83). The DCR per RECIST v1.1 is 12.5% including 2 pts who achieved a stable disease. The most common treatment-emergent AEs (TEAEs, ≥20%) were leukopenia, neutropenia, etc. 3 pts (25%) had grade ≥3 TRAEs and no drug-related AEs led to death. In Cohort 4, 1 pt experienced dose-limiting toxicity (DLT) of grade 3 thrombocytopenia, and the other 1 pt experienced DLT of severe stun. The RP2D was determined as Fluzoparib 0.1g bid. plus Dalpiciclib 0.15g qd, d1-d21, q4w. Conclusions: This novel combination therapy of CDK4/6 inhibitor and PARP inhibitor showed manageable toxicity that could provide a strategy for advanced or metastatic sarcoma. Part 2 to evaluate safety and efficacy is currently recruiting pts. Clinical trial information: NCT05952128 . TRAEs with an incidence of ≥30% and any grade ≥3 TRAEs. Cohort 1 2 3 4 Total Dose every 4 weeks (q4w)Fluzoparib bid. + Dalpiciclib qd. d1-d21 0.1g+0.1g 0.1g+0.125g 0.1g+0.15g 0.15g+0.15g N 4 3 3 2 12 TEAEs, n (%) All grades 4(100) 3(100) 3(100) 2(100) 12(100) Leukopenia 3(75) 3(100) 3(100) 1(50) 10(83) Neutropenia 3(75) 2(67) 3(100) 1(50) 9(75) Anemia 1(25) 1(33) 3(100) 2(100) 7(58) Vomiting 2(50) 2(67) 1(33) 1(50) 6(50) Thrombocytopenia 2(50) 2(67) 1(33) 1(50) 6(50) Diarrhea 1(25) 1(33) 1(33) 1(50) 4(33) Cough 1(25) 1(33) 2(67) 0(0) 4(33) Fever 2(50) 1(33) 0(0) 0(0) 3(25) Stun 0(0) 1(33) 1(33) 1(50) 3(25) Grade ≥3 0(0) 1(33) 0(0) 2(100) 2(17)