Short-course radiotherapy plus olaparib for newly diagnosed glioblastoma in patients unsuitable for radical chemoradiation: a randomised phase II clinical trial preceded by a lead-in phase I dose escalation study.

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 ≥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 ≥ 10 g/dL (no blood transfusions in the 28 days prior to trial entry) •Absolute neutrophil count ≥ 1.5 x 109/L •White Blood Cells > 3x109/L •Platelet count ≥ 100 x 109/L •Bilirubin ≤ 1.5 x upper limit of normal (ULN) •Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤ 2.5 x ULN •Adequate renal function with creatinine clearance / glomerular filtration rate > 50 ml/min. If the creatinine clearance / glomerular filtration rate is less than 50 ml/min as calculated by the Cockroft-Gault/ Wright formula, then the creatinine clearance / glomerular filtration rate should be measured by either a radioisotope technique or by 24-hour urine collection 7. Ability to provide written informed consent prior to participating in the trial and any trial related procedures being performed 8. Willingness to comply with scheduled visits, treatment plans and laboratory tests and other trial procedures 9. Ability to swallow oral tablets/capsules 10. Evidence of non-childbearing status for women of childbearing potential: negative urine or serum pregnancy test within 28 days of trial treatment, confirmed prior to treatment on day 1 Posmenopausal is defined as: •Amenorrheic for 1 year or more following cessation of exogenous hormonal treatments •LH and FSH levels in the postmenopausal range for women under 50 •Or surgical sterilisation (bilateral oophorectomy or hysterectomy)

1. WHO performance status > 2 2. Life expectancy less than 12 weeks 3. Active concurrent malignancy (except non-melanoma skin cancer or in situ carcinoma of the cervix). If history of prior malignancy, must be disease-free for > 5 years 4. Prior treatment for primary or secondary CNS malignancy 5. Confusion or altered mental state that would prohibit understanding and giving of informed consent 6. Concomitant treatment with medicines detailed in section 5.10 of protocol 7. Female patients who are able to become pregnant (or already pregnant or lactating). However, those female patients who have a negative serum or urine pregnancy test before enrolment and agree to use two highly effective forms of contraception (oral, injected or implanted hormonal contraception and condom, have an intrauterine device and condom, diaphragm with spermicidal gel and condom) effective at the first administration of either IMP, throughout the trial, and for six months afterwards, are considered eligible 8. Male patients with partners of child-bearing potential (unless they agree to take measures not to father children by using one form of highly effective contraception [condom plus spermicide] effective at the first administration of IMP, throughout the trial, and for six months afterwards). Men with pregnant or lactating partners should be advised to use barrier method contraception (for example, condom plus spermicidal gel) to prevent exposure to the foetus or neonate 9. Administration of any investigational drug within 28 days prior to receiving the first dose of trial treatment 10. Any previous treatment with a PARP inhibitor, including olaparib 11. Blood transfusions within 1 month prior to trial start 12. Patients with myelodysplastic syndrome/acute myeloid leukaemia 13. Major surgery within 14 days of starting trial treatment and patients must have recovered from any effects of major surgery 14. Patients with a known hypersensitivity to olaparib or any of the excipients of the product 15. Patients with uncontrolled seizures 16. Patients who are known to be HIV positive, or who are known to have positive Hepatitis B or C serology