Phase I/IIa Study of Concomitant Radiotherapy With Olaparib and Temozolomide in Unresectable High Grade Gliomas Patients

Summary

The Stupp protocol is the standard treatment of glioblastoma multiform (GBM) which prognosis remains poor. The non-dividing nature of normal brain cells provides an opportunity to enhance the therapeutic ratio by combining radiation with inhibitors of replication-specific DNA repair pathways such poly(ADP-ribose) polymerase (PARP) inhibitors, thus inducing more cytotoxic effects of DNA-damage related to treatment modalities, including alkylating reagents like temozolomide (TMZ). Olaparib, a potent PARP inhibitor, overcomes apoptotic resistance and sensitizes GBM cells for death receptor-mediated apoptosis induced by TRAIL (Tumor necrosis factor-Related Apoptosis Inducing Ligand). Moreover, inhibition of PARP activity increases cellular sensitivity to ionizing radiation: it was even suggested to be more pronounced in tumors than in normal tissue. Lastly, progress in technical imaging and intensity-modulated-radiotherapy (IMRT) techniques provide new possibilities for sparing healthy tissues.

Timeline

Start

2017-09-04

Primary completion

2026-09-13

Completion

2026-12-31

Publications

• Background Lesueur P, Lequesne J, Grellard JM, Dugue A, Coquan E, Brachet PE, Geffrelot J, Kao W, Emery E, Berro DH, Castera L, Goardon N, Lacroix J, Lange M, Capel A, Leconte A, Andre B, Leger A, Lelaidier A, Clarisse B, Stefan D. Phase I/IIa study of concomitant radiotherapy with olaparib and temozolomide in unresectable or partially resectable glioblastoma: OLA-TMZ-RTE-01 trial protocol. BMC Cancer. 2019 Mar 4;19(1):198. doi: 10.1186/s12885-019-5413-y.
• Results Stefan D, Lesueur P, Lequesne J, Feuvret L, Bronnimann C, Castera M, Brachet PE, Hrab I, Ducloie M, Lacroix J, Lecornu M, Braux G, Christy F, Sunyach MP, Cohen-Jonathan Moyal E, Kao W, Faisant M, Emery E, Grellard JM, Sichel F, Laurent C, Fontanilles M, Clarisse B. Olaparib, Temozolomide, and Concomitant Radiotherapy for Partially Resected or Biopsy-Only Glioblastoma First-Line Treatment: Results from the OLA-TMZ-RTE-01 Phase I Study. Clin Cancer Res. 2025 Apr 1;31(7):1212-1222. doi: 10.1158/1078-0432.CCR-24-2974.
• Madhavan K, Balakrishnan I, Lakshmanachetty S, Pierce A, Sanford B, Fosmire S, Elajaili HB, Walker F, Wang D, Nozik ES, Mitra SS, Dahl NA, Vibhakar R, Venkataraman S. Venetoclax Cooperates with Ionizing Radiation to Attenuate Diffuse Midline Glioma Tumor Growth. Clin Cancer Res. 2022 Jun 1;28(11):2409-2424. doi: 10.1158/1078-0432.CCR-21-4002.

Drugs

Indications