Abstract
2022Background: Olaparib, a small molecule inhibitor of poly (ADP-ribose) polymerase (PARP), may improve GBM outcomes by enhancing cytotoxic effects of ionising radiation and TMZ. Clinical development of PARP inhibitors has been restricted by exacerbation of hematological toxicity. We investigated tumor pharmacokinetics (PK) of olaparib and safety and tolerability of its combination with TMZ. Methods: Dose escalation explored different schedules of olaparib (tablet formulation) with 42 day cycles of daily low dose TMZ. A dose expansion cohort evaluated the maximum tolerated schedule. PK analysis was performed on tumor and blood samples from patients undergoing neurosurgical resection, who received 4 olaparib doses pre-operatively. Results: 48 patients were recruited (median age 51(18-68); 29 male, 19 female) of whom 27 underwent surgery and 35 received olaparib/TMZ and were evaluable. 13 evaluable patients received expansion dose schedule (median age 54(21-67); 9 male, 4 female). Olaparib was detected in ...
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