Phase i and preliminary phase 0 results of abtc 1801: A multi-arm clinical trial of the parp inhibitor pamiparib (bgb290) with very low dose metronomic temozolomide in recurrent idh mutant gliomas

Document Type

Conference Proceeding

Publication Date

11-12-2021

Publication Title

Neuro Oncol

Keywords

endogenous compound, nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase, pamiparib, temozolomide, adult, alkylation, blood toxicity, brain tumor, cancer inhibition, cancer model, cancer patient, cancer recurrence, cancer surgery, clinical trial, conference abstract, drug combination, drug therapy, drug toxicity, female, glioblastoma, human, human tissue, IC50, in vitro study, low drug dose, male, middle aged, neutropenia, oligodendroglioma, patient history of radiotherapy, phase 1 clinical trial, phase 2 clinical trial, relapse, thrombocytopenia

Abstract

BACKGROUND: Preclinical studies have demonstrated that IDH1-mutant (IDHmt) gliomas harbor a BRCAness phenotype with a defect in homologous recombination that confers PARP inhibitor sensitivity. Pamiparib (BeiGene BGB-290) is an effective PARP-trapping PARP inhibitor with demonstrated favorable brain penetration in animal models. METHODS: ABTC 1801 is a study examining the safety, pharmacokinetics, and efficacy of the combination of pamiparib with low dose metronomic temozolomide in recurrent IDHmt gliomas. The Phase I component utilized a 3 + 3 design with a target DLT rate ≤ 33%. Pamiparib dose was 60 mg BID and temozolomide dose 20 mg daily, with dose de-escalation levels for anticipated hematological toxicity. RESULTS: Seven patients were enrolled on the Phase I portion at dose level 1; one patient was replaced for inadequate dosing secondary to non-compliance. All patients had prior radiotherapy and temozolomide; 4/7 had received multiple lines of alkylator therapy including nitrosoureas. Median age was 45, KPS 90, and number of prior relapses 3. Four patients had anaplastic astrocytoma, 2 anaplastic oligodendroglioma, and 1 glioblastoma. One of 6 patients (16.7%) experienced DLT during the first cycle (grade 3 neutropenia and thrombocytopenia). Two additional patients had grade 2 neutropenia. Two patients remain on study treatment at 12+ and 10+ months, while a third progressed at 10.1 months (PFS-6 43%). Tumor tissue was collected from two patients in the surgical arm. In enhancing and non-enhancing tumors, the mean unbound pamiparib concentrations were 198 and 160 nmol/L (or nmol/kg), respectively, which were > 20-fold the in vitro IC50 for PARP inhibition; mean unbound tumor-to-plasma ratios were 0.65 and 0.38. CONCLUSIONS: Phase I results support pamiparib 60 mg BID with temozolomide 20 mg daily as the dosages for the Phase II study. Preliminary Phase 0 data suggest that pamiparib likely achieves sufficient pharmacologically active concentrations in both enhancing and non-enhancing brain tumors.

PubMed ID

Not assigned.

Volume

23

Issue

SUPPL 6

First Page

vi63

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