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).
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 (≤MTD1) during the MT period, assessing DLT from the first 2 cycles. For phase 2a, IMRT and TMZ are given according to the Stupp protocol. Olaparib is given at the MTD1 during the RT period and at the MTD2 during the MT period. Brain disease is assessed using RANO criteria. The trial includes ancillary studies on tumor biopsies, spectro-MRI and neurocognitive and quality of life assessment. Up to 79 pts will be enrolled: 30 pts in the phase 1 and 49 pts in the phase 2a (Case&Morgan two-stage design). This trial (NCT03212742) is granted by the French Cancer Institute and Health Ministry (PHRC-K15-135) and Astra-Zeneca for olaparib provision. First pt was enrolled on Oct 2017.
Clinical trial identification
Legal entity responsible for the study
Comprehensive Cancer Centre François Baclesse.
All authors have declared no conflicts of interest.