Phase I/IIa Study of Concomitant Radiotherapy With Olaparib and Temozolomide in Unresectable High Grade Gliomas Patients (OLA-TMZ-RTE-01)
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.
|Malignant Gliomas Radiotherapy PARP Inhibitor||Drug: Olaparib Drug: Temozolomide (TMZ) Radiation: IMRT (Intensity Modulated Radiation Therapy)||Phase 1 Phase 2|
|Study Design:||Intervention Model: Sequential Assignment
Masking: No masking
Primary Purpose: Treatment
|Official Title:||Phase I/IIa Study of Concomitant Radiotherapy With Olaparib and Temozolomide in Unresectable High Grade Gliomas Patients|
- The Recommended Phase II Dose (RP2D) - Phase I [ Time Frame: The RP2D will be evaluated 4 weeks after the end of radiotherapy ]The primary objective for the phase I is to determine the Recommended Phase II Dose (RP2D) of olaparib combined with the Stupp protocol (TMZ and concomitant fractionated radiotherapy: 60Gy/30 fractions/6 weeks) in first line treatment of patients with unresectable high-grade gliomas
- Overall survival - Phase II [ Time Frame: 18 months after the first administration of treatment ]The primary objective for the phase II is to assess the 18-month overall survival of the combination
|Anticipated Study Start Date:||September 1, 2017|
|Estimated Study Completion Date:||June 30, 2022|
|Estimated Primary Completion Date:||January 31, 2022 (Final data collection date for primary outcome measure)|
Experimental: IMRT - Temozolomide - Olaparib
The therapeutic regimen will be divided into 2 different periods:
We propose 7 dose levels to reach the target dose of 400 mg per day (200 mg twice daily) of olaparib continuously
We propose 7 dose levels to reach the target dose of 400 mg per day (200 mg twice daily) of olaparib continuously DL1 (starting dose level) : Olaparib 50 mg Q12H Monday to wednesday DL2 : Olaparib 100mg Q12H Monday to wednesday DL3: Olaparib 100mg Q12H Monday to friday DL4 : Olaparib 200mg Q12H Monday to wednesday DL5: Olaparib 200mg Q12H Monday to friday DL6: Olaparib 200mg Q12H, continouslyDrug: Temozolomide (TMZ)
TMZ will be given at the dose of 75mg/m²/day during radiotherapy period. TMZ will be re-introduced 4 weeks after the end of radiotherapy at the dose of 150mg/m²/day on days 1 to 5 every 28 days, for a total of 6 cycles.Radiation: IMRT (Intensity Modulated Radiation Therapy)
Radiotherapy consists of fractionated focal irradiation at a dose of 2 Gy per fraction given once daily five days per week over 6 weeks, for a total dose of 60 Gy by 3D- Intensity-Modulated RT (IMRT)
HGGs are the most common and most aggressive primary brain tumor. There is a real need to improve care management of GBM patients. Attempts to achieve cure by increasing radiation dose result in unacceptable neurotoxicity. As for radiosensitizers, they can exacerbate normal tissue damage.
Since GBM represent a rapidly dividing cell population within the nonreplicating normal brain, the therapeutic ratio may be enhanced by specific radiosensitization of proliferating cells. Resistance to apoptosis is a paramount issue in the treatment of HGG. Targeting PARP by the inhibitors like olaparib can reduce proliferation and lowers the apoptotic threshold of HGG (effect showed in vivo and in vitro).
In this context, we propose a phase I-IIa trail to investigate the toxicity and efficacy of olaparib and TMZ concomitantly with radiotherapy in first line treatment of unresectable high risk HGG.
Correlation between treatment response and tumor profiling will allow us to identify biomarkers that can be useful in treatment improvement and/or present a prognostic value. Then, the transfer of this approach will be evaluated in terms of compatibility with the requirements of diagnostic.
Please refer to this study by its ClinicalTrials.gov identifier: NCT03212742
|Contact: Dinu STEFAN, MD||33 2 31 45 50 firstname.lastname@example.org|
|Contact: Jean-Michel GRELLARDemail@example.com|
|CHU||Not yet recruiting|
|Contact: Aymeri HUCHET, MD|
|Principal Investigator: Aymeri HUCHET, MD|
|Centre François Baclesse||Not yet recruiting|
|Caen, France, 14076|
|Contact: Dinu STEFAN, MD 33 2 31 45 50 50 firstname.lastname@example.org|
|Contact: Jean-Michel GRELLARD|
|Principal Investigator: Dinu STEFAN, MD|
|Sub-Investigator: Julien GEFFRELOT, MD|
|Sub-Investigator: Ioana HRAB, MD|
|Centre Antoine Lacassagne|
|Hôpitaux universitaires La Pitié Salpétrière - Charles Foix||Not yet recruiting|
|Contact: Loic FEUVRET, MD|
|Principal Investigator: Loic FEUVRET, MD|
|Sub-Investigator: Florence LAIGLE-DONADEY, MD|
|Sub-Investigator: Khe HOANG-XUAN, MD|
|Sub-Investigator: Ahmed IBDAIH, Pr|
|Institut Curie||Not yet recruiting|
|Contact: Hamid MAMMAR, MD|
|Principal Investigator: Hamid MAMMAR, MD|
|Sub-Investigator: Laurence BOZEC LE MOAL, MD|
|Sub-Investigator: Coraline DUBOT, MD|
|Sub-Investigator: Patricia TRESCA, MD|
|Sub-Investigator: Patricia MOISSON, MD|
|Institut Claudius Regaud||Not yet recruiting|
|Contact: Elisabeth MOYAL COHEN-JONATHAN, Pr|
|Principal Investigator: Elisabeth MOYAL COHEN-JONATHAN, Pr|
|Sub-Investigator: Ioana CARPUC, MD|
|Sub-Investigator: Jean-Pierre DELORD, MD|
|Sub-Investigator: Cécile GANDY, MD|
|Sub-Investigator: Carlos Alberto GOMEZ-ROCA, MD|
|Sub-Investigator: Anouchka MODESTO, MD|
|Sub-Investigator: Thibaud VALENTIN, MD|