Phase 1b study of first-line fuzuloparib combined with modified FOLFIRINOX followed by fuzuloparib maintenance monotherapy in pancreatic adenocarcinoma

• Published in: BMC medicine Vol. 22; no. 1; pp. 365 - 11
• Main Authors: Wei, Miaoyan, Liu, Rujiao, Xu, Yunyun, Chen, Xiaobing, Liu, Chao, Bai, Xueli, Zhang, Xiaochen, Gao, Shuiping, Li, Jialin, Sheng, Zhen, Lian, Jianpo, Wang, Wenliang, Zhang, Jian, Shi, Si, Xu, Jin, Yu, Xianjun
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 04.09.2024; BioMed Central; BMC
• Subjects: Adenocarcinoma; Adenocarcinoma - drug therapy; Adult; Aged; Antimitotic agents; Antineoplastic agents; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Antitumor agents; Cancer; Cancer therapies; Care and treatment; Chemotherapy; Chemotherapy, Combination; Disease control; Dosage and administration; Drug therapy; Effectiveness; Enzyme inhibitors; Female; First-line; Fluorouracil - administration & dosage; Fluorouracil - therapeutic use; Fuzuloparib; Humans; Irinotecan - administration & dosage; Irinotecan - therapeutic use; Leucovorin; Leucovorin - administration & dosage; Leucovorin - therapeutic use; Maintenance; Male; Maximum Tolerated Dose; Medical research; Medicine, Experimental; Metastases; Metastasis; Middle Aged; Mutation; Neutropenia; Neutrophils; Ovarian cancer; Oxaliplatin - administration & dosage; Oxaliplatin - therapeutic use; Pancreas; Pancreatic cancer; Pancreatic Neoplasms - drug therapy; Patients; Pharmacokinetics; Response rates; Testing; Toxicity; Treatment Outcome; Tumors; China; First-line; Chemotherapy; Maintenance; Pancreatic cancer; Fuzuloparib
• ISSN: 1741-7015; 1741-7015
• DOI: 10.1186/s12916-024-03581-y

Chemotherapy remains the standard first-line treatment for pancreatic adenocarcinoma, but with limited efficacy. We aimed to explore the feasibility of adding the PARP inhibitor fuzuloparib to mFOLFIRINOX in the locally advanced/metastatic (LA/M) setting. This was the dose-escalation and -expansion, phase 1b portion of a phase 1b/2 study. Patients were given oral fuzuloparib at escalating doses starting at 30 mg twice daily (BID) plus intravenous mFOLFIRINOX q2w for 8-12 cycles, followed by maintenance fuzuloparib at 150 mg BID. Cohorts at the maximal tolerated dose (MTD) and lower dose of fuzuloparib were expanded. Primary endpoints were dose-limiting toxicity (DLT), MTD, and recommended phase 2 dose (RP2D). As of data cutoff on Jan 15, 2023, 39 patients were recruited. 12 patients were enrolled during dose escalation (30 mg [n = 4]; 60 mg [n = 6]; 100 mg [n = 2]). DLT occurred in 1 patient in 60 mg cohort and 1 patient in 100 mg cohort. 60 mg BID was determined to be the MTD, and then 60 and 30 mg cohorts were expanded to 22 and 15 patients, respectively. The most common grade ≥ 3 treatment-related adverse events were hematologic toxicities. Efficacy in 60 mg cohort seemed to be most favorable, with an objective response rate of 50.0% (95% CI, 26.0-74.0) and disease control rate of 94.4% (95% CI, 72.7-99.9). First-line fuzuloparib plus mFOLFIRINOX followed by maintenance fuzuloparib was generally safe and showed encouraging anti-tumor activity in patients with LA/M pancreatic adenocarcinoma. The RP2D of fuzuloparib combination was 60 mg BID. ClinicalTrials.gov, NCT04228601.