1627P First-line (1L) fuzuloparib plus mfolfirinox followed by maintenance fuzuloparib in patients (pts) with unresectable locally advanced or metastatic (LA/M) pancreatic cancer (PC): A phase Ib study

Chemotherapy regimens remain the standard 1L treatment for PC, but with limited anti-tumor activity. We amid to explore the feasibility of adding the PARPi fuzuloparib to mFOLFIRINOX in pts with LA/M PC. This was a dose escalation (ESC) and expansion (EXP) phase Ib study. Pts were given oral fuzuloparib at escalating doses starting at 30 mg bid plus intravenous mFOLFIRINOX q2w for 8–12 cycles, followed by maintenance fuzuloparib at 150 mg bid. Dose-limiting toxicities (DLTs) were observed during the first 2 cycles. At least 1 dose cohort would be selected for EXP to collect data supporting the determination of recommended phase II dose (RP2D). Primary endpoints were DLT, maximal tolerated dose (MTD), and RP2D. As of Jan 15, 2023, 39 pts were recruited. Of them, 12 pts were enrolled in ESC phase (30 mg [n=4]; 60 mg [n=6]; 100 mg [n=2]). DLT occurred in 1 pt in 60 mg cohort (grade 4 decreased platelet count and grade 4 decreased neutrophil count lasting for ≥5 d) and 1 pt in 100 mg cohort (grade 4 decreased neutrophil count lasting for ≥5 d). Based on the tolerability and safety data during ESC, 60 mg bid was determined to be the MTD. 60 and 30 mg cohorts were expanded to 22 and 15 pts, respectively. Overall, grade ≥3 treatment-related adverse events (TRAEs) were reported in 34 (87.2%) of 39 pts; the most common were decreased neutrophil count, decreased platelet count, decreased white blood cell count, and anemia. TRAEs led to discontinuation of any study agent in 5 (12.8%) pts. Efficacy in 60 mg cohort seemed to be most favorable, with ORR of 50.0%, DCR of 94.4%, median PFS of 7.2 mo, and median OS of 12.5 mo (Table).Table: 1627PEfficacy outcomes30 mg60 mg100 mgOverallConfirmed ORR∗, n/N (%; 95% CI)2/12 (16.7%; 2.1–48.4)9/18 (50.0%; 26.0–74.0)0/2 (0.0%; 0.0–84.2)11/32 (34.4%; 18.6–53.2)Confirmed DCR∗, n/N (%; 95% CI)10/12 (83.3%; 51.6–97.9)17/18 (94.4%; 72.7–99.9)1/2 (50.0%; 1.3–98.7)28/32 (87.5%; 71.0–96.5)PFS#Events, n/N (%)10/15 (66.7%)12/22 (54.5%)2/2 (100.0%)24/39 (61.5%)Median (95% CI), mo7.5 (1.9–10.1)7.2 (5.1–13.9)7.2 (1.6–NR)7.3 (5.3–10.1)OS#Events, n/N (%)10/15 (66.7%)15/22 (68.2%)1/2 (50.0%)26/39 (66.7%)Median (95% CI), mo11.5 (4.0–NR)12.5 (7.8–NR)NR (2.0–NR)11.5 (7.8–14.2)∗tumor response evaluable set;#full analysis set. Open table in a new tab ∗tumor response evaluable set;#full analysis set. 1L fuzuloparib plus mFOLFIRINOX followed by maintenance fuzuloparib was generally safe, with no unexpected toxicities, and showed encouraging efficacy in pts with LA/M PC. The RP2D of fuzuloparib combination was 60 mg bid.