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

NCT03212742 | Active Not Recruiting Phase 1 DMC

• 1 other identifier: OLA-TMZ-RTE-01
• Study Type: interventional
• Target: 91
• Locations: 1 country
• Sites: 15

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.

Conditions

Malignant Gliomas; Radiotherapy; PARP Inhibitor

Outcome Measures

Primary Outcomes (2)

• The Recommended Phase II Dose (RP2D) - Phase I

  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

  The RP2D will be evaluated 4 weeks after the end of radiotherapy

• Overall survival - Phase II

  The primary objective for the phase II is to assess the 12-month overall survival of the combination

  12 months after the first administration of treatment

Study Arms (1)

IMRT - Temozolomide - Olaparib

EXPERIMENTAL

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

Drug: Olaparib; Drug: Temozolomide (TMZ); Radiation: IMRT (Intensity Modulated Radiation Therapy)

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

IMRT - Temozolomide - Olaparib

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 - Temozolomide - Olaparib

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)

IMRT - Temozolomide - Olaparib

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• White blood cells (WBC) \> 3x109/L
• Total bilirubin ≤ 1.5 x institutional upper limit of normal
• AST (SGOT)/ALT (SGPT) ≤ 2.5 x institutional upper limit of normal
• Creatinine clearance estimated using the Cockcroft-Gault equation of ≥51 mL/min:
• Estimated creatinine clearance = \[(140-age(years)) x weight(kg) (x Fsex) \] / \[serum creatinine (mg/dL) x 72\] where Fsex=0.85 for females and Fsex=1 for males.

You may not qualify if:

• 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)
• Patients receiving any systemic chemotherapy, radiotherapy (except for palliative reasons), within 2 weeks from the last dose prior to study treatment. The patient can receive a stable dose of bisphosphonates for bone metastases, before and during the study as long as these were started at least 4 weeks prior to treatment with study drug.
• Concomitant use of known strong CYP3A inhibitors (eg. itraconazole, telithromycin, clarithromycin, protease inhibitors boosted) or moderate CYP3A inhibitors (eg. ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout period prior to starting olaparib is 2 weeks.
• Concomitant use of known strong (eg. phenobarbital, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, and St John's Wort ) or moderate CYP3A inducers (eg. bosentan, modafinil). The required washout period prior to starting olaparib is 5 weeks for phenobarbital and 3 weeks for other agents.
• Resting ECG with QTc \> 470 msec detected on 2 or more time points within a 24 hour period or family history of long QT syndrome. If ECG demonstrates QTc \> 470 msec, patient will be eligible only if repeat ECG demonstrates QTc ≤470 msec;
• Blood transfusions within 1 month prior to study start

Sponsors & Collaborators

• Centre Francois Baclesse: lead
• National Cancer Institute, France: collaborator

Study Sites (15)

CHU

Amiens, France

Location

Institut de Cancérologie de l'Ouest

Angers, France

Location

CHU

Bordeaux, France

Location

Centre François Baclesse

Caen, 14076, France

Location

Centre Guillaume le Conquérant

Le Havre, France

Location

CH du Havre

Le Havre, France

Location

GHBS

Lorient, France

Location

Centre léon Bérard

Lyon, France

Location

Hôpitaux universitaires La Pitié Salpétrière - Charles Foix

Paris, France

Location

Institut Curie

Paris, France

Location

Centre Hospitalier Lyon Sud

Pierre-Bénite, France

Location

Centre Eugène Marquis

Rennes, France

Location

Centre Henri Becquerel

Rouen, France

Location

Institut de Cancérologie de l'Ouest

Saint-Herblain, France

Location

Institut Claudius Regaud

Toulouse, France

Location

Related Publications (3)

• 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.

  PMID: 30832617 BACKGROUND

• 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.

  PMID: 39882966 RESULT

• 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.

  PMID: 35344040 DERIVED

MeSH Terms

Conditions

Glioma

Interventions

olaparib; Temozolomide; Radiotherapy, Intensity-Modulated

Condition Hierarchy (Ancestors)

Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Intervention Hierarchy (Ancestors)

Dacarbazine; Triazenes; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Radiotherapy, Conformal; Radiotherapy, Computer-Assisted; Radiotherapy; Therapeutics

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 6, 2017
• First Posted: July 11, 2017
• Study Start: September 4, 2017
• Primary Completion (Estimated): September 13, 2026
• Study Completion (Estimated): December 31, 2026
• Last Updated: December 4, 2025

Record last verified: 2025-11

Locations

FR (15)