Olaparib and radiotherapy In newly-diagnosed glioblastoma

INTERVENTION: All patients will receive hypofractionated, short‐course radiotherapy (40 Gray in 15 fractions) over 19 ¨C 21 days. In the Phase I component, escalating doses of oral olaparib will be delivered daily throughout the radiotherapy treatment period. Olaparib will be commenced 3 days prior to radiation and will continue throughout treatment for a total of 22 ‐ 24 days. In Phase II, patients will be randomised to receive radiotherapy plus placebo PO (control arm) or radiotherapy plus olaparib PO at the maximum tolerated dose (MTD) established in Phase I (or a maximum dose of 200 mg PO twice daily if MTD not reached). Olaparib or placebo will be commenced 3 days prior to radiation and will continue throughout treatment for a total of 22 ‐ 24 days. CONDITION: Gliomas ; Cancer ; Malignant neoplasm of brain PRIMARY OUTCOME: Phase I: The recommended dose of olaparib when administered in combination with radiotherapy; Phase II: Overall survival SECONDARY OUTCOME: Phase I: The DLT (Dose‐Limiting Toxicity) and the safety and tolerability of olaparib administered in combination with radiotherapy. ; Phase II: ; 1. Progression‐free survival measured by MRI scans during follow‐up and will be assessed in accordance with the RANO guidelines; 2. Toxicity measured using the CTCAE v.4.0 criteria and recorded at each follow‐up visit; 3. Quality of life which will be measured by the completion of QLQ30, BN20 and EQ‐5D questionnaires completed by the participant at baseline and each follow‐up visit INCLUSION CRITERIA: 1. Age 18 ‐ 69: WHO performance status 2 at initial oncology consultation or performance status 0‐1 but otherwise unsuitable for radical radiotherapy with concomitant and adjuvant temozolomide. 2. Age over 70: WHO performance status 0 or 1 at initial oncology consultation 3. Histologically confirmed diagnosis of glioblastoma 4. Life expectancy greater than 12 weeks 5. No previous radiotherapy or chemotherapy for primary or secondary CNS malignancy 6. Adequate haematological, hepatic and renal function defined as below: Haemoglobin >/= 9.0 g/dL, absolute neutrophil count >/= 1.5 x 109/L, platelet count >/= 100 x 109/L, bilirubin 50 ml/min. If the creatinine clearance / glomerular filtration rate is less than 50 ml/min as calculated by the Cockroft‐Gau