Abstract
BACKGROUND
Poly (ADP-ribose) polymerase (PARP) mediates DNA damage response; niraparib is an investigational PARP1/2-selective inhibitor. This Phase 0 study evaluates newly-diagnosed glioblastoma (GBM) tumor pharmacokinetics (PK) and pharmacodynamics (PD), graduating patients to a therapeutic regimen of niraparib plus fractionated radiotherapy when high unbound drug concentrations are present in gadolinium-nonenhancing tumor.
METHODS
Presumed newly-diagnosed GBM patients received 4 days of niraparib (300 mg QD) prior to planned resection at 3-5 or 8-12 hours following the last dose. Tumor tissue (enhancing and nonenhancing regions), cerebrospinal fluid (CSF), and plasma were collected. Total and unbound niraparib concentrations were measured using validated LC-MS/MS methods. A PK ‘trigger’ determined eligibility for the therapeutic expansion phase and was defined as unbound [niraparib] > 5-fold biochemical IC50 (i.e., 19 nM) in non-enhancing tumor. PARP inhibition was assessed by quantification of PAR induction after 10 Gy ex vivo irradiation in surgical tissue compared to non-irradiated control tissue. Patients with unmethylated MGMT tumors exceeding the PK threshold were eligible for expansion phase dosing of niraparib plus radiotherapy followed by a maintenance phase of niraparib.
RESULTS
Nineteen patients were enrolled into the Phase 0 study; all tumors met the study’s PK threshold and five unmethylated patients continued onto the expansion phase. One expansion phase patient experienced treatment-related Grade 3 serious adverse event (ALT and AST elevation) and four remain on treatment (median 4.2 months). In nonenhancing regions, the mean unbound concentrations of niraparib were 353.4 nM and 331.9 nM in the 3-5 hr cohort (n= 17) and the 8-12 hr (n = 3) cohort, respectively. The suppression of PAR levels after ex vivo radiation was observed in 69% of the patients (11/16).
CONCLUSIONS
Niraparib achieves pharmacologically-relevant concentrations in non-enhancing, newly-diagnosed GBM tissue in excess of any other studied PARP inhibitor.