Olaparib and radiotherapy In newly-diagnosed glioblastoma

ISRCTN	ISRCTN52658296
DOI	https://doi.org/10.1186/ISRCTN52658296
Clinical Trials Information System (CTIS)	2014-001216-19
Protocol serial number	GN13ON355
Sponsor	NHS Greater Glasgow and Clyde (UK)
Funder	Astra Zeneca (UK) - endorsed by Cancer Research UK

Submission date: 02/05/2014
Registration date: 02/06/2014
Last edited: 14/02/2025

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

http://www.cancerresearchuk.org/about-cancer/find-a-clinical-trial/a-trial-looking-at-olaparib-and-radiotherapy-for-people-with-glioblastoma-paradigm

Contact information

Prof Anthony Chalmers
Scientific

The Beatson West of Scotland Cancer Centre
1053 Great Western Road
Glasgow
G12 0YN
United Kingdom

ORCID ID	0000-0002-1746-7278
Phone	+44 (0)141 301 7092
Email	anthony.chalmers@glasgow.ac.uk

Study information

Primary study design	Interventional
Study design	Phase I dose-escalation study followed by a Phase II randomized double-blind study
Secondary study design	Randomised controlled trial
Study type	Participant information sheet
Scientific title	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
Study acronym	PARADIGM
Study objectives	The objective of phase I is to establish the maximum tolerated dose of olaparib when given in combination with radiotherapy. The objectives of phase II are to obtain evidence that adding olaparib to radiotherapy improves overall survival in this patient population, and to justify a subsequent phase III trial. Additional objectives are to document the safety, toxicity and quality of life associated with this combination.
Ethics approval(s)	West of Scotland Research Ethics Service, 13/11/2014, ref: 14/WS/1096
Health condition(s) or problem(s) studied	Gliomas
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.
Intervention type	Drug
Phase	Phase I/II
Drug / device / biological / vaccine name(s)	Olaparib
Primary outcome measure(s)	Phase I: The recommended dose of olaparib when administered in combination with radiotherapy Phase II: Overall survival
Key secondary outcome measure(s)	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
Completion date	31/12/2025

Eligibility

Participant type(s)	Patient
Age group	Adult
Lower age limit	18 Years
Sex	All
Target sample size at registration	140
Key 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 </= 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. 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
Key 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 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 intra-uterine 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 of receiving the first dose of trial treatment.
Date of first enrolment	03/03/2015
Date of final enrolment	31/03/2025

Locations

Countries of recruitment

United Kingdom
Scotland

Study participating centre

The Beatson West of Scotland Cancer Centre

Glasgow
G12 0YN
United Kingdom

Results and Publications

Individual participant data (IPD) Intention to share	No
IPD sharing plan summary	Data sharing statement to be made available at a later date
IPD sharing plan

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
HRA research summary			28/06/2023	No	No
Participant information sheet	Participant information sheet	11/11/2025	11/11/2025	No	Yes

Editorial Notes

14/02/2025: The following changes were made:
1. The recruitment end date was changed from 31/01/2025 to 31/03/2025.
25/11/2024: The following changes were made to the study record:
1. The recruitment end date was changed from 30/11/2016 to 31/01/2025.
2. The overall study end date was changed from 31/07/2018 to 31/12/2025.
3. The intention to publish date was changed from 31/03/2019 to 01/04/2026.
29/03/2016: Availability of participant level data added.
24/03/2016: Ethics approval information added.