Condition category
Cancer
Date applied
31/05/2016
Date assigned
06/06/2016
Last edited
24/11/2016
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
Recruiting

Plain English Summary

Lay summary under review with external organisation

Trial website

Contact information

Type

Scientific

Primary contact

Prof Anthony Chalmers

ORCID ID

Contact details

Beatson West of Scotland Cancer Centre
Glasgow
G12 0YH
United Kingdom

Type

Scientific

Additional contact

Mrs Anna Morris

ORCID ID

Contact details

Beatson West of Scotland Cancer Centre
Glasgow
G12 0YH
United Kingdom
0141 301 7184
anna.morris@glasgow.ac.uk

Additional identifiers

EudraCT number

2016-000865-22

ClinicalTrials.gov number

Protocol/serial number

PARADIGM2-2016

Study information

Scientific title

PARADIGM-2:OlaPArib and RADIotherapy or olaparib and radiotherapy plus temozolomide in newly-diagnosed Glioblastoma stratified by MGMT status: 2 parallel phase I studies

Acronym

PARADIGM-2

Study hypothesis

The trial hypothesis is that combining olaparib with radiotherapy +/- temozolomide will improve outcomes for patients with newly diagnosed glioblastoma, without exacerbating toxicity.

Ethics approval

West of Scotland REC1, ref: 16/WS/0089 - pending (expected June 2016)

Study design

2 parallel, multi-centre, open-label, non-randomised, dose-escalation phase I studies within one clinical trial protocol.

Primary study design

Interventional

Secondary study design

Non randomised study

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Not available in web format, please use contact details to request a participant information sheet.

Condition

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

Phase

Phase I

Drug names

Olaparib

Primary outcome measures

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 trial start date

01/08/2015

Overall trial end date

31/01/2019

Reason abandoned

Eligibility

Participant 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)

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

Approximately 50

Participant 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

Recruitment start date

01/08/2016

Recruitment end date

31/07/2018

Locations

Countries of recruitment

United Kingdom

Trial participating centre

Beatson West of Scotland Cancer Centre
Glasgow
G12 0YH
United Kingdom

Trial participating centre

The Christie NHS Foundation Trust
Manchester
M20 4BX
United Kingdom

Trial participating centre

St James University Hospital
Leeds
LS9 7TF
United Kingdom

Trial participating centre

Addenbrookes Hospital
Cambridge
CB2 0QQ
United Kingdom

Sponsor information

Organisation

NHS Greater Glasgow & Clyde and University of Glasgow

Sponsor details

Research and Development Office
West Glasgow Ambulatory Care Hospital
Dalnair Street
Glasgow
G3 8SW
United Kingdom

Sponsor type

Hospital/treatment centre

Website

Funders

Funder type

Charity

Funder name

Cancer Research UK

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Funder name

The Brain Tumour Charity

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Funder name

Astra Zeneca

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Results and Publications

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.

Intention to publish date

31/12/2019

Participant level data

Available on request

Results - basic reporting

Publication summary

Publication citations

Additional files

Editorial Notes

24/11/2016: Internal review.