Olaparib and radiotherapy or olaparib and radiotherapy plus temozolomide in newly-diagnosed glioblastoma stratified by MGMT status
| ISRCTN | ISRCTN51253312 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN51253312 |
| EudraCT/CTIS number | 2016-000865-22 |
| Secondary identifying numbers | PARADIGM2-2016 |
- Submission date
- 31/05/2016
- Registration date
- 06/06/2016
- Last edited
- 14/11/2024
- Recruitment status
- No longer recruiting
- Overall study status
- Ongoing
- Condition category
- Cancer
Prospectively registered
Protocol
Statistical analysis plan
Results
Individual participant data
Record updated in last year
Plain English summary of protocol
Contact information
Prof Anthony Chalmers
Scientific
Scientific
Beatson West of Scotland Cancer Centre
Glasgow
G12 0YH
United Kingdom
Ms Lorna Sweeting
Scientific
Scientific
Cancer Research UK Clinical Trials Unit
Level 0
Beatson West of Scotland Cancer Centre
1053 Great Western Road
Glasgow
G12 0YH
United Kingdom
| Phone | +44 (0)141 301 7194 |
|---|---|
| Lorna.Sweeting@glasgow.ac.uk |
Study information
| Study design | Two parallel multi-centre open-label non-randomized dose-escalation Phase I studies within one clinical trial protocol |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Non randomised study |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | Not available in web format, please use contact details to request a participant information sheet. |
| Scientific title | PARADIGM-2: OlaPArib and RADIotherapy or olaparib and radiotherapy plus temozolomide in newly-diagnosed Glioblastoma stratified by MGMT status: two parallel Phase I studies |
| Study acronym | PARADIGM-2 |
| Study objectives | The trial hypothesis is that combining olaparib with radiotherapy +/- temozolomide will improve outcomes for patients with newly diagnosed glioblastoma, without exacerbating toxicity. |
| Ethics approval(s) | West of Scotland REC1, 15/06/2016, ref: 16/WS/0089 |
| Health condition(s) or problem(s) studied | Glioblastoma |
| Intervention | Parallel 1 (Methylation of MGMT promoter region) – Patients will receive partial brain radiotherapy, consisting of 60 Gray in 30 fractions over 6 weeks (Monday to Friday), planned and delivered using Intensity Modulated Radiotherapy (IMRT) with fixed fields or arcs. Patients will receive oral temozolomide chemotherapy (75mg/m2) daily throughout radiotherapy, with concomitant, intermittent once daily olaparib starting on day 1 of radiotherapy and for 4 weeks immediaitely following completion of radiotherapy (total 70 +/- 2 days). Olaparib treatment will be on an intermittent schedule as defined by dose cohort. Patients will then receive 6 cycles of adjuvant temozolomide chemotherapy at standard dose and schedule. Parallel 2 (Unmethylated MGMT promoter region) – Patients will receive partial brain radiotherapy, consisting of 60 Gray in 30 fractions over 6 weeks (Monday to Friday), planned and delivered using Intensity Modulated Radiotherapy (IMRT) with fixed fields or arcs. Patients will receive oral olaparib delivered daily in combination with radiotherapy, commencing 3 days prior to radiotherapy and for 4 weeks immediately afterwards (total 73 +/- 2 days). Olaparib treatment will be continuous during this period. |
| Intervention type | Drug |
| Pharmaceutical study type(s) | |
| Phase | Phase I |
| Drug / device / biological / vaccine name(s) | Olaparib |
| Primary outcome measure | The maximum tolerated dose and schedule of olaparib in combination with radiotherapy and temozolomide (parallel 1) and in combination with radiotherapy alone (parallel 2). This will be measured by clinical and laboratory toxicity, NCI-CTC version 4.03. |
| Secondary outcome measures | 1. Toxicity, including acute and subacute neurotoxicity – measured by clinical and laboratory toxicity, NCI-CTC version 4.03 2. Progression free survival – measured by MRI scan, reported using RANO criteria 3. Overall survival – measured by date of death/date patient last assessed |
| Overall study start date | 01/08/2015 |
| Completion date | 30/08/2026 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Upper age limit | 70 Years |
| Sex | Both |
| Target number of participants | Approximately 50 |
| Key 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) |
| Key exclusion criteria | 1. Age ≥70 years 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 the PARADIGM-2 protocol 8. Female patients who are able to become pregnant (or are already pregnant or lactating). Lactating patients should not breastfeed 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 |
| Date of first enrolment | 01/08/2016 |
| Date of final enrolment | 01/04/2025 |
Locations
Countries of recruitment
- England
- Scotland
- United Kingdom
- Wales
Study participating centres
Beatson West of Scotland Cancer Centre
Glasgow
G12 0YH
United Kingdom
G12 0YH
United Kingdom
The Christie NHS Foundation Trust
Manchester
M20 4BX
United Kingdom
M20 4BX
United Kingdom
St James University Hospital
Leeds
LS9 7TF
United Kingdom
LS9 7TF
United Kingdom
Addenbrookes Hospital
Cambridge
CB2 0QQ
United Kingdom
CB2 0QQ
United Kingdom
Bristol Haematology and Oncology Centre
Bristol
BS2 8ED
United Kingdom
BS2 8ED
United Kingdom
Velindre Cancer Centre
Cardiff
CF14 2TL
United Kingdom
CF14 2TL
United Kingdom
Sponsor information
NHS Greater Glasgow & Clyde and University of Glasgow
Hospital/treatment centre
Hospital/treatment centre
Research and Development Office
West Glasgow Ambulatory Care Hospital
Dalnair Street
Glasgow
G3 8SW
Scotland
United Kingdom
"ROR" |
https://ror.org/05kdz4d87 |
|---|
Funders
Funder type
Charity
Cancer Research UK
No information available
The Brain Tumour Charity
No information available
Astra Zeneca
No information available
Results and Publications
| Intention to publish date | 30/11/2026 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Available on request |
| Publication and dissemination plan | The PARADIGM-2 TMG is responsible for approving the content and dissemination of all publications, abstracts and presentations arising from the trialand for assuring the confidentiality and integrity of the trial. It will provide collaborators with the International Committee of Medical Journal Editors (ICMJE) criteria which will be used to ensure all those who have contributed to the study are appropriately acknowledged. No site or individual will publish data without prior approval of the TMG. The data arising from PARADIGM-2 will belong to the trial Co-Sponsors NHS Greater Glasgow & Clyde and The University of Glasgow. The TMG shall act as custodian of this data. |
| IPD sharing plan | The datasets generated during and/or analysed during the current study are/will be available upon request from Anna Morris, Project Manager, anna.morris@glasgow.ac.uk |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| HRA research summary | 28/06/2023 | No | No |
Editorial Notes
14/11/2024: The following changes were made to the study record:
1. The recruitment end date was changed from 05/01/2023 to 01/04/2025.
2. The overall study end date was changed from 31/12/2020 to 30/08/2026.
3. The intention to publish date was changed from 05/07/2023 to 30/11/2026.
05/08/2020: The following changes have been made:
1. The recruitment end date has been changed from 01/04/2020 to 30/04/2021.
2. The overall trial end date has been changed from 30/04/2021 to 05/01/2023.
3. The intention to publish date has been changed from 31/12/2019 to 05/07/2023.
4. A trial contact has been updated.
05/09/2017: Recruitment end date has been updated from 31/07/2018 to 01/04/2020. Overall trial end date has been updated from 31/01/2019 to 31/12/2020. Participant level data sharing statement has been added.
01/09/2017: Ethics approval information added. Bristol Haematology and Oncology Centre and Velindre Cancer Centre have been added as trial participating centres.
19/12/2016: Cancer Help UK lay summary link added.
