A Randomized Controlled Trial of Chemo-Radiotherapy Versus Biomarker-Guided Therapy for Elderly and Frail Patients With Newly Diagnosed Glioblastoma
Methods: Patients will be randomized to two treatment groups in a 1:1 ratio. Standard Arm: TMZ with concurrent RT (combined modality arm) Patients will receive 15 days of TMZ daily with concurrent RT. TMZ will be delivered at a dose of 75 mg/m2, given daily with RT. TMZ will be administered 1 hour before each session of RT. After a 4-week break, patients will receive six cycles of adjuvant TMZ according to the standard 5-day schedule (days 1-5) every 28 days, up to 6 cycles as tolerated by the patient. The dose will be 150 mg/m2 for the first cycle and increased to 200 mg/m2 beginning with the second cycle, so long as there are no hematologic adverse events, intractable nausea or fatigue. Investigational Arm: Biomarker based treatment MGMT (+): TMZ monotherapy Patients will receive TMZ at a dose of 75 mg/m2 daily for 15 days on weekdays (Monday through Friday). This will be followed by six cycles of TMZ according to the standard 5-day schedule (days 1-5) every 28 days. The dose will be 150 mg/m2 for the first cycle and increased to 200 mg/m2 beginning with the second cycle, so long as there are no hematologic adverse events. Dose will be determined using the body surface area (BSA) calculation. MGMT methylation (-): No TMZ will be given. Participants will receive radiation treatment with 40Gy / 15 fractions over a period of 21 days (3 weeks). Upon treatment completion, participants will be followed by every 3 months for 2 years and every 6 months for years 3-5. Response and progression will be evaluated using the new international criteria proposed by the Response Assessment in Neuro-Oncology working group (RANO).
• Newly-diagnosed, histologically proven, intracranial glioblastoma with maximal safe resection. Biopsy alone is expected if resection is not possible. MGMT promoter methylation status must be tested for all patients.
• History and physical examination, including neurological examination, within 14 days prior to randomization.
• Age ≥ 65 \& KPS of 60 - 70
• Stable or decreasing dose of corticosteroids for at least 14 days prior to randomization.
• Laboratory evaluation within 7 days prior to randomization, with adequate function as defined below:
‣ ANC ≥ 1.5 x 109/L
⁃ Platelets ≥ 100 x 109/L
⁃ Estimated Glomerular Filtration Rate (eGFR) \> 59
⁃ Total serum bilirubin ≤ 30 umol/L (ie ≤ 1.5 times ULN)
⁃ ALT \< 150 U/L (ie \< 3 times ULN)
⁃ AST \< 120 U/L (ie \< 3 times ULN)
⁃ Alkaline phosphatase \< 390 U/L (ie \< 3 times ULN)
• Patients must sign a study-specific informed consent prior to study registration.
• Patients of childbearing / reproductive potential should use highly effective birth control methods, as defined by the investigator, during the study treatment period and for a period of 6 months after the last dose of study drug. A highly effective method of birth control is defined as those that result in low failure rate (i.e. less than 1% per year) when used consistently and correctly.
• Note: abstinence is acceptable if this is established and preferred contraception for the patient and is accepted as a local standard.
⁃ This will apply for male patients only and their female partner if of child bearing potential.
⁃ Effective contraception should also be used by male patients taking temozolomide. Men being treated with temozolomide are advised not to father a child during or up to 6 months after discontinuation of treatment (male patients).
• Male patients should agree to not donate sperm during the study treatment and for six months post treatment completion.