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

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Conference Proceeding

Publication Date


Publication Title

Neuro Oncol


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.

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Not assigned.





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