Phase I/IIa study of concomitant radiotherapy with olaparib and temozolomide in unresectable high-grade gliomas patients: OLA-TMZ-RTE-01

Abstract

Background: The Stupp protocol is the standard treatment of glioblastoma multiform (GBM). The non-dividing nature of normal brain cells is an opportunity to enhance the therapeutic ratio by combining radiation with inhibitors of replication-specific DNA repair pathways such PARP inhibitors as olaparib. PARP inhibition also increases cellular sensitivity to radiation and may be higher in tumor than in normal tissue. Progress in technical imaging and intensity-modulated-radiotherapy (IMRT) techniques provide new possibilities for sparing healthy tissues. We propose a phase 1/2a trial to assess the safety and efficacy of Olaparib combined with TMZ plus fractionated IMRT as a first line treatment in unresectable GBM patients (pts). Trial design: Based on the Stupp phase 2 design, 2 treatment periods are considered. The radiotherapy (RT) period occurs after the last surgery: the pt receives IMRT, daily TMZ during IMRT and olaparib, given at the same dose until 4 weeks after the end of IMRT. For the maintenance (MT) period, the pt receives TMZ (days 1-5 every 28 days, for 6 cycles) plus olaparib (at the MT dose level up to disease progression or unacceptable toxicity). The phase 1 includes 2 consecutive dose escalations to separate both periods for DLT (Dose Limiting Toxicities) assessment. First 15 pts will receive olaparib only during the RT period to determine the MTD1 (Maximum-Tolerated Dose) among 7 dose levels, by assessing DLT on this period. Next 15 pts will all receive MTD1 during the RT period, and a new dose-escalation will determine MTD2 (