Phase I/IIa Study of Concomitant Radiotherapy With Olaparib and Temozolomide in Unresectable High Grade Gliomas Patients
Overview
- Phase
- Phase 1
- Intervention
- Olaparib
- Conditions
- Malignant Gliomas
- Sponsor
- Centre Francois Baclesse
- Enrollment
- 91
- Locations
- 13
- Primary Endpoint
- Overall survival - Phase II
- Status
- Active, not recruiting
- Last Updated
- 4 months ago
Overview
Brief 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.
Detailed Description
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Provision of signed informed consent prior to any study specific procedures
- •Histologically-confirmed diagnosis of glioblastoma (IDH-wildtype, IDH-mutant or NOS, except gliosarcoma), non resectable or partially resectable with a residual tumor on pre-radiotherapy MRI. The presence of a residual disease will be assessed by the radiologist on the pre-radiotherapy imaging as compared with initial imaging.
- •IMRT must start within 6 weeks after histological diagnosis
- •Age between 18 and 70 years ;
- •Neurologically asymptomatic or pauci-symptomatic patients. Patients with moderated neurological symptoms without systemic corticosteroids treatment or with a stable dose of corticosteroids during the study as long as these were started at least 4 weeks prior to treatment can be included.
- •Adequate bone marrow and organ function measured within 15 days prior to administration of study treatment as defined below:
- •Haemoglobin ≥ 10.0 g/dL with no blood transfusions (packed red blood cells and platelet transfusions) in the past 28 days before start of treatment
- •Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
- •o No features suggestive of MDS/AML on peripheral blood smear
- •Platelet count ≥ 100 x 109/L
Exclusion Criteria
- •Any prior radiotherapy to brain
- •Any prior chemotherapy or immunotherapy
- •Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site)
- •Candidate for a concomitant therapy with Tumor-Treating Fields during the maintenance treatment \[70\]
- •Previous enrolment in the present study
- •Participation in another clinical trial protocol within 30 days prior to enrolment;
- •Any previous treatment with a PARP inhibitor, including olaparib.
- •Patients with second primary cancer, except: adequately treated non-melanoma skin cancer, curatively treated in-situ cancer of the cervix, or other solid tumours curatively treated with no evidence of disease for ≥ 5 years
- •Gadolinium hypersensitivity, or any contraindication to undergo MRI examination (Pacemaker, brain aneurysms clips)
- •Patients who had no initial pre-surgery contrast enhanced MRI scan including the standard sequences (T1 non enhanced, T1 contrast enhanced, T2 FLAIR)
Arms & Interventions
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
Intervention: Olaparib
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
Intervention: Temozolomide (TMZ)
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
Intervention: IMRT (Intensity Modulated Radiation Therapy)
Outcomes
Primary Outcomes
Overall survival - Phase II
Time Frame: 12 months after the first administration of treatment
The primary objective for the phase II is to assess the 12-month overall survival of the combination
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