| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The primary objective of Phase I is to identify a recommended dose of olaparib to be administered in combination with radiotherapy.
The primary objective of Phase II is to determine the effect of olaparib administered in combination with radiotherapy compared with placebo administered in combination with radiotherapy on life expectancy (overall survival) in patients with MGMT unmethylated, newly diagnosed glioblastoma who are not fit enough to receive aggressive treatment with both chemotherapy and radiotherapy.
The primary objective of the dose escalation substudy is to identify a recommended dose of olaparib in combination with temozolomide and radiotherapy in patients with MGMT methylated, newly diagnosed glioblastoma. |
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| E.2.2 | Secondary objectives of the trial |
The secondary objectives of Phase I are to identify the DLT (Dose-Limiting Toxicity) of olaparib to be administered in combination with radiotherapy, and to explore the safety and tolerability of olaparib when administered in combination with radiotherapy.
The secondary objectives of Phase II are to compare progression-free survival (PFS) survival in patients treated with olaparib administered in combination with radiotherapy or placebo administered in combination with radiotherapy,to further describe the safety and tolerability of olaparib when administered in combination with radiotherapy or placebo administered in combination with radiotherapy in this patient population, and to assess the impact of olaparib on quality of life.
The secondary objectives of the dose escalation substudy are to identify the Dose Limiting Toxicity of olaparib when administered in combination with radiotherapy and concomitant temozolomide, and to explore the safety and tolerability of olaparib when admin |
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| Dose Escalation substudy has been incorporated into the current version of the protocol- Version 7 dated 17th May 2018. Related objectives have been listed above in E2-1 and E2-2. |
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| E.3 | Principal inclusion criteria |
1. Age ≥70: WHO performance status 0 or 1 at initial oncology consultation
2. Phase I only: 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
3. Phase II and dose escalation substudy only:Age 65- 69; WHO performance status 0, 1 or 2 at initial oncology consultation and unsuitable for radical radiotherapy with concomitant and adjuvant temozolomide
4. Phase II and dose escalation substudy only: Age 18- 64; WHO performance status 2 at initial oncology consultation or performance status 0-1 but otherwise unsuitable for radical radiotherapy with concomitant and adjuvant temozolomide
5. Histologically confirmed diagnosis of glioblastoma
6. Phase II and dose escalation substudy only; Sufficient tumour material for MGMT promoter methylation assay
7. Life expectancy greater than 12 weeks
8. No previous radiotherapy or chemotherapy for primary or secondary CNS malignancy
9. Adequate haematological, hepatic and renal function defined as below:
•Haemoglobin ≥ 100 g/L (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 radio-isotope technique or by 24-hour urine collection as per local practice
10. Ability to provide written informed consent prior to participating in the trial and any trial related procedures being performed
11. Willingness to comply with scheduled visits, treatment plans and laboratory tests and other trial procedures
12. Ability to swallow oral medications
13. Evidence of non-childbearing status for women of childbearing potential: negative urine or serum pregnancy test within 7 days of trial entry
Post-menopausal is defined as:
•Amenorrheic for 1 year or more following cessation of exogenous hormonal treatments
•LH and FSH levels in the post-menopausal range for women under 50
•Or surgical sterilisation (bilateral oophorectomy or hysterectomy)
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| E.4 | Principal exclusion criteria |
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 listed as 'prohibited' or 'excluded' 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 detailed in section 7.1.12, effective at the first administration of olaparib, throughout the trial, and for at least one month 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 detailed in section 7.1.12, effective at the first administration of IMP, throughout the trial, and for three months afterwards or 6 months if receiving temozolomide). Men with pregnant or lactating partners should be advised to use barrier method contraception to prevent exposure to the foetus or neonate. Female partners (of childbearing potential) of male patients should also use a highly effective form of contraception as detailed in section 7.1.12
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 28 days prior to trial entry
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 temozolomide or dacarbazine 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
17. Phase II only: Methylation of MGMT promoter region confirmed by central laboratory testing, or an inconclusive MGMT test result
18. Dose escalation substudy only: Unmethylation of MGMT promoter region confirmed by central laboratory testing, or an inconclusive MGMT test result
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary outcome measure of the Phase I part of the trial will be the recommended dose of olaparib when administered in combination with radiotherapy.
For Phase II, the primary outcome measure is overall survival.
For the dose escalation substudy, the primary outcome measure is the recommended dose of olaparin when administered in combination with radiotherapy and concomitant temozolomide. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The timepoint of evaluation of the primary endpoint for phase I is at the completion of phase I (estimated to be 18 months).
For phase II, the current status of patients will be evaluated 2 monthly during follow-up and an overall evaluation of the primary endpoint of overall survival will be done at the end of the trial.
The timepoint of evaluation of the primary endpoint for the dose escalation substudy is at the completion of the substudy (estimated to be 24 months). |
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| E.5.2 | Secondary end point(s) |
The secondary endpoints of Phase I are the DLT (Dose-Limiting Toxicity) and the safety and tolerability of olaparib administered in combination with radiotherapy.
The secondary endpoints of Phase II are progression-free survival measured by MRI scans during follow-up and will be assessed in accordance with the RANO guidelines, toxicity measured using the CTCAE v.4.0 criteria and recorded at each follow-up visit, and 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.
The secondary endpoints of the dose escalation substudy are the Dose-Limiting Toxicity (DLT) and the safety and tolerability of olaparib administered in combination with radiotherapy and concomitant temozolomide. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Phase I secondary endpoints are monitored continuously throughout phase I, in particular at the end of each dose cohort.
For phase II, the current status of patients will be evaluated 2 monthly during follow-up and an overall evaluation of the progression free survival will be done at the end of the trial.
Dose escalation substudy secondary endpoints are monitored continuously throughout recruitment to the substudy, in particular at the end of each dose cohort.
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| Dose escalation study in combination with short-course radiotherapy |
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| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Dose escalation substudy open label |
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| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 24 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.5.1 | Number of sites anticipated in the EEA | 1 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| The end of trial will be the date of the last data capture or when the last patient attends their last follow-up visit for the trial. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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