Abstract
TPS501 Background: Niraparib (N) is an orally selective poly(ADP-ribose) polymerase (PARP)-1/-2 inhibitor approved for maintenance treatment of patients (pt) with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer after complete or partial response to platinum-based chemotherapy (CT). Cabozantinib (C) is a tyrosine kinase (TK) inhibitor with activity against TKs including VEGFR2, MET and AXL, approved on kidney cancer pt after TK failure, that has demonstrated clinical activity in heavily pretreated, advanced UC pt. c-Met receptor TK is activated in urothelial carcinoma (UC) cells. c-Met activity can decrease response to PARP inhibitors, whereas treatment with c-Met inhibitors renders cells more sensitive to PARP inhibition. UC pt with tumors overexpressing c-Met may benefit from the combination of c-Met and PARP inhibitors. This multicenter, open-label phase (ph) I-II study is to explore the maximum-tolerated dose (MTD) of N + C combination in pt with advanced genitourinary malignancies (UC and kidney cancer) follow by a preliminary efficacy of the combination in advanced UC. Methods: Eligible pt have confirmed histopathology of UC or clear cell renal cell carcinoma, advanced or metastatic disease, age ≥18 years, ECOG PS ≤1, progressive disease after platinum-based CT, measurable lesions, no prior therapy with PARP or c-Met inhibitors and adequate bone marrow, liver and renal functions. The ph I portion is enrolling ≈24 pt to identify the MTD proposed to use in a ph II (RP2D). Pt will receive N and C p.o. once daily in 28-day cycles: Dose level 1 (DL1) N/C 100/20 mg; DL2 200/20 mg; DL3 200/40 mg; DL4 200/60 mg. Pt will be accrued to each dose level in cohorts of 6 pt until the MTD is achieved (the highest dose at which ≤1 out of 6 pt experience a dose-limiting toxicity [DLT]). DLT will be evaluated during the first 2 cycles. The ph 2 portion will enroll 51 UC pt to receive the RP2D. Tumor response will be assessed per RECIST v1.1. Endpoints of the ph 2 are 6-month PFS (primary), overall response rate, disease control rate, duration of response, PFS and OS. Tissue and plasma sample will be collected for translational study. Clinical trial information: NCT03425201.
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