A Combined Phase 0/2 "Trigger" Trial of Niraparib in Combination with Radiation in Patients with Newly-Diagnosed Glioblastoma

Abstract

Poly ADP-ribose (PAR) polymerase (PARP) mediates DNA damage response. Niraparib is an investigational PARP1/2-selective inhibitor. We conducted a combined phase 0/2 study to evaluate niraparib pharmacokinetics (PK) and pharmacodynamics (PD) in patients with newly-diagnosed glioblastoma (GBM), graduating patients to a phase 2 study evaluating a therapeutic regimen of niraparib with concurrent conventionally-fractionated radiotherapy (RT) in O6-methylguanine methyltransferase (MGMT) unmethylated tumors exceeding a prespecified PK threshold in non-enhancing tumor. Patients with presumed newly-diagnosed GBM were enrolled in a phase 0 study receiving 4 days of niraparib (300 or 200 mg QD) prior to planned resection 3-5 or 8-12 hours following the last dose. Tumor tissue (enhancing and non-enhancing regions), cerebrospinal fluid (CSF), and plasma were collected. Total and unbound niraparib concentrations were measured using validated LC-MS/MS methods. PARP inhibition was assessed by quantification of PAR induction after 10 Gy ex vivo irradiation in surgical tissue compared to non-irradiated control tissue. A PK 'trigger' determined eligibility for the therapeutic phase 2 expansion portion of the study. This was defined as unbound [niraparib] > 5-fold biochemical IC50 (i.e., 19 nM) in non-enhancing tumor. Patients with MGMT unmethylated tumors exceeding this PK threshold were eligible for expansion phase dosing of niraparib with concurrent RT followed by a maintenance phase of niraparib. Patients with MGMT methylated tumors were not eligible for the expansion phase and proceeded with temozolomide (TMZ) plus RT followed by maintenance TMZ. RT dose was 60 Gy in 30 fractions using volumetric-modulated arc therapy (VMAT). All 29 patients enrolled in the phase 0 portion of the study met the PK threshold. In non-enhancing regions, the mean unbound concentration of niraparib was 258.2 nM. The suppression of PAR levels after ex vivo RT was observed in 79% of the patients (17/22). Sixteen patients had unmethylated tumors, and of those, 11 patients enrolled in phase 2. Five of the 6 initial patients enrolled in phase 2 experienced thrombocytopenia related to niraparib, and 3/5 cases were deemed serious and life-threatening. Consequently, starting dose in both phases was lowered to 200 mg, and no serious AEs were observed thereafter. At a median follow-up of 8.1 months [range: 6.0-12.9 months], 6-month PFS was 64% with 4 patients remaining on treatment and 5 patients ongoing survival follow-up. Niraparib achieves pharmacologically-relevant concentrations in non-enhancing, newly-diagnosed GBM tissue in excess of any other studied PARP inhibitor. When delivered with concurrent RT, niraparib was well-tolerated, with low rates of grade 3+ toxicity. Initial clinical efficacy data are encouraging.