Olaparib and radiotherapy or olaparib and radiotherapy plus temozolomide in newly-diagnosed glioblastoma stratified by MGMT status

Phase 1

• Conditions: Cancer; Glioblastoma

• Registration Number: ISRCTN51253312
• Lead Sponsor: HS Greater Glasgow & Clyde and University of Glasgow

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2016-06-06
• Last Update Posted: 17 August 2020
• Study Completion: 2020-12-31

Recruitment & Eligibility

• Status: Ongoing
• Sex: All
• Target Recruitment: 50

Inclusion Criteria

1. Age<70 years
2. Histologically confirmed diagnosis of glioblastoma (WHO grade 4, including variants)
3. WHO performance status 0 or 1
4. Sufficient tumour material for MGMT promoter methylation assay
5. Life expectancy greater than 12 weeks
6. No previous radiotherapy for primary or secondary CNS malignancy
7. Ability to provide informed consent prior to participating in the trial and any trial-related procedures being performed
8. Adequate haematological, hepatic and renal function defined as below:
8.1. Haemoglobin > 100g/L (no red blood cell transfusions in the 28 days prior to trial entry)
8.2. Absolute neutrophil count >1.5 x 109/L
8.3. White Blood Cells >3 x 109/L
8.4. Platelet count > 100 x 109/L
8.5. Bilirubin < 1.5 x upper limit of normal (ULN)
8.6. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) < 2.5 x ULN
8.7. Adequate renal function with creatinine clearance / glomerular filtration rate > 50 ml/min calculated by Cockcroft-Gault/Wright formula
9. Able to commence radiotherapy treatment within 6 weeks (+ 1 week if necessary) of surgery
10. Willingness to comply with scheduled visits, treatment plans, laboratory tests and any other trial procedures
11. Ability to swallow oral tablets or capsules
12. Evidence of non-childbearing status for women of childbearing potential: negative urine or serum pregnancy test within 7 days of trial entry
Postmenopausal is defined as:
12.1. Amenorrhoeic for 1 year or more following cessation of exogenous hormonal treatments
12.2. LH and FSH levels within the postmenopausal range for women under 50
12.3. Surgical sterilisation (bilateral oophrectomy or hysterectomy)

Exclusion Criteria

1. Age =70
2. WHO performance status >2
3. Life expectancy less than 12 weeks
4. 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
5. Prior treatment for primary or secondary CNS malignancies
6. Confusion or altered mental state that would prohibit patient understanding and giving of informed consent
7. Concomitant treatment with medicines detailed in section 5.8 of PARADIGM-2 protocol
8. Female patients who are able to become pregnant (or are already pregnant or lactating). Lactating patients should not breast feed during treatment or for 1 month after the last dose of olaparib. However, those female patients who have a negative serum or urine pregnancy test before enrolment and are not lactating and agree to the use of two highly effective forms of contraception (as detailed in section 7.1.7) effective at the first administration of IMP, throughout the trial and for at least one month afterwards are considered eligible
9. Male partners of child-bearing potential (unless they agree to take measures not to father children by using one form of highly effective contraception, as detailed in section 7.1.7, effective at the time of 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 to prevent exposure to the foetus or neonate
10. Administration of any investigational drug within 28 days prior to receiving the first dose of trial treatment
11. Any previous treatment with a PARP inhibitor, including olaparib
12. Any red blood cell transfusions within 28 days prior to trial entry (platelet and clotting factor transfusions are allowed)
13. Patients with myelodysplastic syndrome/acute myeloid leukaemia
14. Major surgery within 14 days of starting trial treatment; patients must have recovered from any effects of major surgery
15. Patients with a known hypersensitivity to any of the excipients of olaparib, temozolomide or dacarbazine (DTIC)
16. Patients with uncontrolled seizures
17.Patients who are known to be HIV positive, or who are known to have positive Hepatitis B or C serology

Study & Design

• Study Type: Interventional
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
<br> The maximum tolerated dose and schedule of olaparib in combination with radiotherapy and temozolomide (parallel 1) and in combination with radiotherapy alone (parallel 2).<br><br> This will be measured by clinical and laboratory toxicity, NCI-CTC version 4.03.<br>

Secondary Outcome Measures

Name	Time	Method
<br> 1. Toxicity, including acute and subacute neurotoxicity – measured by clinical and laboratory toxicity, NCI-CTC version 4.03<br> 2. Progression free survival – measured by MRI scan, reported using RANO criteria<br> 3. Overall survival – measured by date of death/date patient last assessed<br><br>