A Combined Phase 0/2 "Trigger" Trial Evaluating Pamiparib or Olaparib with Concurrent Radiotherapy in Patients with Newly-Diagnosed or Recurrent Glioblastoma

Abstract

This study evaluates the pharmacokinetic (PK) and pharmacodynamic (PD) profiles and clinical efficacy of PARP1/2 selective inhibitors, pamiparib and olaparib, in newly-diagnosed or recurrent glioblastoma (GBM) patients in combination with radiotherapy (RT). In this combined phase 0/2 trial presumed newly-diagnosed (Arm A) or recurrent (Arm B) GBM patients received 4 days of pamiparib (60 mg BID) prior to resection either 2-4 or 8-12 hours following the final dose. Arm C enrolled patients with recurrent GBM to 4 days of olaparib (200 mg BID) prior to resection. Enhancing and nonenhancing tumor tissue, cerebrospinal fluid (CSF) and plasma were collected. Total and unbound drug concentrations were measured using validated LC-MS/MS methods. A PK 'trigger', defined as unbound drug and gt; 5-fold biochemical IC 50 in nonenhancing tumor, determined eligibility for the therapeutic expansion phase 2. PARP inhibition was assessed via ex vivo radiation and quantification of PAR levels compared to non-radiated control. Newly-diagnosed MGMT unmethylated GBMs and recurrent GBMs exceeding the PK threshold were eligible for an expansion phase of pamiparib (Arms A and B) or olaparib (Arm C) with concurrent RT followed by maintenance pamiparib or olaparib. RT was 60 Gy in 30 fractions in newly-diagnosed patients and 40 Gy in 15 fractions in recurrent patients, delivered using volumetric-modulated arc therapy (VMAT). A total of 38 patients (Arm A, n = 16; Arm B, n = 16; Arm C, n = 6) were enrolled in the initial phase 0 study. The mean unbound concentrations of pamiparib in nonenhancing tumor region for Arm A and Arm B were 167.3 nM and 109.4 nM respectively, and in Arm C the mean unbound concentration of olaparib was 5.2 nM. All patients in the pamiparib arms (n = 32/32) but only 1 of 6 patients in the olaparib Arm C exceeded the PK threshold. Radiation-induced PAR expression was 2.44-fold in untreated control vs 1.16 in Arm A (p<0.05), 0.85 in Arm B (p<0.01) and 1.11 in Arm C patients, respectively. In Arm A, 11 patients had unmethylated tumors, and of those, 7 patients enrolled in phase 2. In Arm B, 9 of the 16 clinically eligible patients with positive PK results were enrolled in phase 2. At a median follow-up of 8.4 months [range: 1.3-15.7 months], the median progression-free survival (PFS) was 5.4, 6.0, and 3.8 months for Arms A (n = 7), B (n = 9), and C (n = 1), respectively. Grade 3+ toxicities related to pamiparib occurred in 4 patients, with 2 adverse events resulting in treatment discontinuation. No grade 3+ toxicities were documented in the olaparib arm. Pamiparib achieved pharmacologically-relevant concentrations in nonenhancing GBM tissue and suppressed induction of PAR levels ex vivo post-radiation. The majority of patients with MGMT-unmethylated GBM advanced to the phase 2 portion of the trial, and pamiparib was generally well-tolerated in these patients.