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

Sponsor
Centre Francois Baclesse
Study ID
NCT03212742
Phase
PHASE1/PHASE2
Status
Active Not Recruiting

Conditions

  • Malignant Gliomas
  • PARP Inhibitor
  • Radiotherapy

Eligibility Criteria

Sex
ALL
Age
18 Years - 70 Years
Healthy Volunteers
Not accepted

Interventions

  • Olaparib — DRUG
    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, continously
  • Temozolomide (TMZ) — DRUG
    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.
  • IMRT (Intensity Modulated Radiation Therapy) — RADIATION
    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)

Study Details

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.

Key Dates

Start date
Sep 4, 2017
Status verified
Nov 2025
Primary completion
Sep 13, 2026
Completion
Dec 31, 2026

Study Design

Enrollment
91 participants (estimated)
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT

Arms

  • Experimental: IMRT - Temozolomide - Olaparib
    The therapeutic regimen will be divided into 2 different periods: * Radiotherapy period The patient will start IMRT (60Gy/30fr/6 weeks), TMZ(Temozolomide) chemotherapy (75mg/m²/day), and olaparib on the same day, on a Monday (day 1), within 6 weeks after surgery. The daily dose of TMZ (75 mg/m²) will be continued until the end of radiotherapy (6 weeks) and olaparib will be continued with the same dose until 4 weeks after the end of IMRT, as a single agent. * Maintenance period TMZ will then be re-introduced 4 weeks after the end of IMRT at the dose of 150 mg/m2/day on days 1 to 5 every 28 days, for a total of 6 cycles. Concomitantly, olaparib will be daily given at the maintenance dose level up to confirmed disease progression or unacceptable toxicities. We propose 7 dose levels to reach the target dose of 400 mg per day (200 mg twice daily) of olaparib continuously

Primary Outcome Measure

The Recommended Phase II Dose (RP2D) - Phase I [ Time Frame: The RP2D will be evaluated 4 weeks after the end of radiotherapy ]

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