Phase I study of fluzoparib, a PARP1 Inhibitor in combination with apatinib and paclitaxel in patients (pts) with advanced gastric and gastroesophageal junction (GEJ) adenocarcinoma.

Abstract

4060 Background: Fluzoparib (SHR3162) is an oral, selective PARP1 inhibitor. In our gastric cancer PDX model, fluzoparib + apatinib + paclitaxel demonstrated significant tumor growth inhibition as compared to apatinib alone, and fluzoparib + paclitaxel. In this phase I study, we hypothesized that the combination of fluzoparib+apatinib+paclitaxel should be safe and active in pts with advanced gastric and GEJ cancer. Methods: Dose-escalation phase (P1) explored 4 dose levels of fluzoparib with a 3+3 design to identify a recommended phase II dose (RP2D) for further study. Pts received fluzoparib (20, 30, 40, 60 mg/twice daily)+apatinib (250mg/day)+paclitaxel (60mg/m2, Day1, 8, 15). Dose-expansion phase (P2) was to assess safety and efficacy. Pts received RP2D of fluzoparib+apatinib+paclitaxel until progression or intolerant toxicity. Treatment was repeated every 4 weeks. Pts had to have progressive disease after standard platinum-based regimen treatment. Adverse events (AE), PK, and response per RECIST 1.1 (every 8 wks in pts with measurable disease) were assessed. Results: 39 pts (median age 58) have been treated in P1 and P2, including fluzoparib 20mg (n=4), 30mg (n=27; 6 pts in P1, 21 pts in P2), 40mg (n=6), and 60mg (n=2). The median treatment duration for this study was 2.8 months. No DLTs were reported in 20mg cohort. One DLT occurred in 30 mg cohort (grade 3 [G3] hypophosphatemia), 1 DLTs (1 grade 4 [G4] febrile neutropenia) occurred and 1 G4 neutropenia occurred and recovered in 3 days in 40mg cohort, 2 DLTs (1 G4 neutropenia, 1 G4 febrile neutropenia) in 60mg cohort. Therefore, 40 mg dose was deemed the MTD. There were no treatment-related deaths on study. The most common AEs≥G3 were neutropenia, febrile neutropenia, and hypertension. 1 treatment-related discontinuation was observed. Of 36 evaluable pts, 12 (30.0%) had confirmed partial response and 13 had stable disease (36.1%). Median progression-free survival was 4.9 months. PK analysis will be presented. Conclusions: The RP2D of combination of fluzoparib + apatinib + paclitaxel is well tolerated and has activity in pts with advanced gastric and EGJ cancer who have failed to platinum-based regimen. Clinical trial information: NCT 03026881.