Randomized multicentric Phase II study of prolonged adjuvant Temozolomide or "stop and go" in glioblastoma patients

Study Objective

Primary objectives

• To determine whether prolonged administration of Temozolomide in glioblastoma patients increase their progression-free and overall survival at 6 months.

Secondary objectives

• To assess the safety and adverse event profile of prolonged adjuvant Temozolomide by using Common Terminology Criteria for Adverse Events (CTCAE 3.0).
• To compare the Health-Related Quality of Life of the patients randomized in the two treatment arms by using the EORTC QLQ-C30 questionnaire.
• To measure the overall tumor response in patients when they are rechallenge with Temozolomide in the Stop and Go arm.
• To measure the time to progression under Temozolomide in the Stop and Go arm.
• To compare the time to progression under Temozolomide defined as the time between randomization and progression under Temozolomide between the two randomized treatment arms.
• To determine if MGMT gene methylation status can predict a benefit of Temozolomide treatment in terms of Progression-Free Survival (both arms) and tumor response (only in the Stop and Go arm).

Participation conditions

Inclusion Criteria :

• Histopathologically confirmed diagnosis of GBM.
• Patients should have at least 1 block of tissue available (paraffin-embedded) in order to assess MGMT status.  This is not mandatory but strongly encouraged.
• Patients must have received radiation and Temozolomide for 6 weeks followed by 6 months of Temozolomide.
• Randomization and allocation to treatment arms should be performed in order to start treatment between 4 and 6 weeks after the last chemotherapy.
• A brain MRI must be performed before enrolment but after the last chemotherapy.  Pet-Scan methionine is optional but encouraged.
• Age ≥ 18 years.
• Karnofsky Performance status ≥ 60.
• Normal haematological functions: ANC ≥ 1.5 x 109cells/l, platelets  ≥ 100 x 109 cells/l.
• Normal liver function: total bilirubin < 1.5 x ULN, alkaline phosphatase and transaminases (ASAT/ALAT) < 2.5 times the upper limit of the normal range (ULN).
• Serum creatinine < 1.5 x ULN.
• Clinically normal cardiac function without history of ischemic heart disease in the past 12 months. Absence of cardiac insufficiency NYHA grade III and IV, instable angina, arrhythmia.
• All patients (male and female) with reproductive potential must use effective contraception.  Females must have a negative serum pregnancy test at entry to study.
• Signed informed consent from the patient or legal representative must be obtained.

Patients may be included based on local pathology; however, an independent centralized pathology review will be conducted on all patients and MGMT status will be performed centrally.  In case of a discrepancy between the assessment of the independent reviewer and the investigator, the assessment of the independent reviewer will take precedence.  The independent centralized pathology review will be completed prior data analysis.  All enrolled patients will be included in the intent-to-treat (ITT) patient population for data analysis.

Exclusion Criteria :

• Recurrent gliomas or gliosarcomas.
• Prior chemotherapy or radiosensitizers (including Gliadel wafers).
• Inability to comply with protocol or study procedures.
• No previous or current malignancy (except treated basal or squamous cell skin carcinoma, cervix cancer or in situ carcinoma of the breast).

Oncologists at Centre Hospitalier de Luxembourg