This phase 0 study evaluates glioblastoma (GBM) pharmacokinetics (PK) and pharmacodynamics (PD) of pamiparib, a PARP1/2-selective inhibitor, graduating patients to a therapeutic expansion phase of drug plus radiotherapy when high unbound drug concentrations are present in nonenhancing tumor.
Newly-diagnosed (Arm A) and recurrent GBM (Arm B) patients received 4 days of pamiparib (60 mg BID) prior to planned resection at 2-4 or 8-12 hours following the final dose. Arm C included recurrent GBM patients who received 4 days of olaparib (200 mg BID). Tumor tissue (enhancing and nonenhancing regions), 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 > 5-fold biochemical IC50 in nonenhancing tumor determined eligibility for the therapeutic expansion phase. PARP inhibition was assessed via 10 Gy ex vivo radiation of tumor tissue and quantification of PAR levels compared to non-radiated control. Newly-diagnosed, MGMT-unmethylated and recurrent GBM patients, irrespective of MGMT-status, exceeding the PK threshold were eligible for an expansion phase of study drug plus radiotherapy followed by maintenance dosing of study drug plus TMZ.
In Arms A (n=20) and B (n=14), the mean unbound concentrations of pamiparib in Gd-nonenhancing tumor region were 171.5 nM and 162.5 nM, respectively and in Arm C (n=4) the mean unbound concentration of olaparib was 11.0 nM. All patients in Arms A and B, but only one in Arm C, exceeded the PK threshold to qualify for the expansion phase of the study. Progression onto the expansion phase occurred in 12/20 (60%), 7/14 (50%), and 1/4 (25%) patients in Arms A, B, and C, respectively. Radiation-induced PAR expression was 2.44 fold in untreated control vs 1.16 in Arm A, 0.82 in Arm B and 1.11 in Arm C patients, respectively. The median progression-free survival was 5.8 (Arm A), 3.1 months (Arm B) (n=6), and 1.9 months (Arm C) (n=1), respectively.
Pamiparib was generally well-tolerated, achieved pharmacologically-relevant concentrations in nonenhancing GBM tissue and suppressed induction of PAR levels ex vivo post-radiation.
Clinical trial identification
Legal entity responsible for the study
Nader Sanai, St. Joseph's Hospital and Medical Center, Phoenix.
Ivy Brain Tumor Center at Barrow Neurological Institute, Phoenix, AZ.
All authors have declared no conflicts of interest.