Phase I-II study to evaluate safety and efficacy of niraparib plus cabozantinib in patients with advanced urothelial/kidney cancer (NICARAGUA trial): Preliminary data of phase I study.

Abstract

490 Background: Niraparib (N) is a (PARP)-1/-2 inhibitor and Cabozantinib (C) is a tyrosine kinase (TK) inhibitor that targets VEGF signalling via inhibition of multiple TK receptors including c-MET and TAM kinases (TYRO3, AXL, MER). The c-Met receptor TK is abnormally activated and could be decrease response to PARP inhibitors. Preclinical data reveals that treatment with c-Met inhibitors renders cells more sensitive to PARP inhibition. A phase (Ph) I-II study was designed to explore the safety and efficacy of the combination of N + C in genitourinary cancers. Methods: Multicenter, open-label Ph I-II study (NCT03425201). Confirmed histopathological diagnosis of either metastatic urothelial carcinoma (mUC) or advanced clear cell renal cell carcinoma previously treated with a maximum of two previous regimens. Adequate bone marrow, liver and renal functions were required. The Ph I portion aimed to identify the maximum tolerated dose (MTD) and recommended ph II dose (RP2D). Pt received 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. A further amendment developed DL1.1 100/40 mg. Pt were accrued to each dose level in cohorts of 6 pt until the MTD was achieved (defined as highest dose at which ≤1 out of 6 pt experience a DLT, evaluated during the first 2 cycles). Results: Nineteen evaluable pt for DLT were included, 14 of them had UC. There was no DLT at DL1. Two out of the first 6 evaluable pt in DL2 had DLT (G3 thrombopenia and anemia and G3 diarrhea respectively). Upon analysis of these pt it was agreed to include 3 additional new pt for evaluation. Two pt were included with one presenting a DLT (G3 hepatic toxicity). Enrolment then continued in a new DL 1.1 cohort and 1 of 6 pts had DLT (G3 mucositis), being then considered the RP2D. No toxic deaths were reported. Six pt (32%) received at least 10 cycles and 9 pt (47%) received at least 6 cycles. Three patients (16%) achieved partial response (all of them with mUC disease) and 14 (74%) stable disease. Conclusions: N plus C combination can be safely administered with a manageable toxicity profile and preliminary efficacy was reported in mUC heavily pretreated pts. The RP2D is N 100 mg plus C 40 mg qd. Ph II study is now recruiting mUC patients. Clinical trial information: NCT03425201. [Table: see text]