Abstract 313TiP
Background
Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor in adults. Patients with GBM have traditionally been thought to have poor prognosis. Although Temozolomide (TMZ) has been widely used as the first-line chemotherapy drug for gliomas, the mechanisms by which TMZ affects characteristics or capacities of GBM cells remain elusive. The research shows that poly(ADP-ribose) polymerase inhibitor (PARPi) restores TMZ cytotoxicity selectively in GBM cells characterized by mismatch repair(MMR)-mediated TMZ resistance, both in vitro and in vivo. Over the past two decades, PARP inhibitors have been developed with the aim of counteracting DNA repair-mediated resistance of cancer cells to chemo-radiotherapy. Several reports indicate that successful targeting of PARP, a primary sensor of single-strand breaks (SSBs), can sensitize GBM cells to ionizing radiation and chemotherapy despite functional HR and BRCA1/2 genes being intact. To improve the progression-free survival (PFS) and objective response rate (ORR), this study was designed to investigate the efficacy and safety of the PARPi fluzoparib combined with TMZ in the treatment of primary GBM.
Trial design
This is a prospective, one-arm, exploratory clinical study. It is estimated that 40 patients with pathologically confirmed high-grade glioma patients will be included from April 2022 to April 2024. This study is divided into two substages, the first is the dose exploration stage, 3-6 cases will be determined the maximum tolerated dose of fluzoparib combined with TMZ. Then, continue with the enrollment of 34-37 cases in the second stage. Patients received oral fluzoparib 100/50mg bid and oral TMZ 200mg/m2/d1-d5/d28 until disease progression, intolerable toxicity, or withdrawal of consent. The primary endpoints were PFS and ORR. Secondary endpoints were maximum tolerated dose (MTD), survival time (OS) and drug safety. In this study, hierarchical analysis will be conducted according to IDH and MGMT status. The combination therapy of fluzoparib and TMZ may enhance drug efficacy of TMZ and prolong progression-free time in patients, and will help to identify genetic biomarkers predictive of PARPi efficacy as TMZ sensitizer.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Jiangsu Hengrui Medicine Co. Ltd.
Disclosure
All authors have declared no conflicts of interest.