An investigator-initiated phase II trial of a PARP inhibitor niraparib monotherapy for patients with pre-treated, BRCA-mutated, unresectable/recurrent biliary tract, pancreatic, and other gastrointestinal cancers (NIR-B trial).

Abstract

TPS4174 Background: Recent comprehensive genomic profiling tests have revealed therapeutic target molecules. However, because many targets are present in only a small fraction of patients, a large number of patients need to be screened for enrollment in a single study. In order to overcome this patient identification barrier, the SCRUM-Japan, nationwide large-scale genomic profiling platform, efficiently has been performed umbrella- and basket-type clinical trials. Among the platforms, we have reported that there are BRCA1/2-mutated patients in biliary tract, pancreatic, and other gastrointestinal cancers. Niraparib is an anticancer drug belonging to poly(ADP-ribose) polymerase (PARP) inhibitors. Niraparib has been shown to be selective for PARP1/2, to be more cytotoxic among other PARP inhibitor because of its PARP trapping activity. Methods: This is an investigator-initiated, multicenter, three-cohort phase 2 study. Main eligibility criteria are unresectable, advanced or recurrent biliary tract cancers (cohort A), pancreatic cancers (cohort B), and other gastrointestinal cancers (cohort C) with BRCA1/2 gene mutations identified by germline test or genomic profiling test with either circulating tumor DNA (ctDNA) or tumor tissue, refractory or intolerant to previous treatments, and adequate organ function. Primary endpoint is the investigator-assessed objective response rate in each cohort with a threshold-response rate of 10% and an expected response rate of 35%. Key secondary endpoints are progression-free survival, overall survival, disease control rate, duration of response, and safety. Patients with body weight of 77 kg or more and a platelet count of 150,000 /µL or more receive 300 mg of niraparib, and less than 77 kg or having a platelet count less than 150,000 /µL receive 200 mg of niraparib, orally once daily. Furthermore, pre-treatment tumor tissue and serial ctDNA will be collected and analyzed to investigate the resistance mechanisms and provide clinically meaningful biomarker which may be used for identifying and implementing treatment changes. The trial was initiated in January 2021 with enrollment being ongoing. Thirty-three out of planned 60 patients (cohort A/B/C; 25/25/10, respectively) have been enrolled as of December 2021. Funding: Takeda Pharmaceutical Co., Ltd. Clinical trial information: jRCT2011200023.