ReoGlio: REOLYSIN® plus GM-CSF in combination with standard of care chemotherapy and radiotherapy for patients with glioblastoma multiforme (GBM)

ISRCTN	ISRCTN70044565
DOI	https://doi.org/10.1186/ISRCTN70044565
Clinical Trials Information System (CTIS)	2016-001632-35
Protocol serial number	31893
Sponsor	University of Leeds
Funders	Cancer Research UK, Oncolytics Biotech, Brain Tumour Charity

Submission date: 06/02/2017
Registration date: 06/02/2017
Last edited: 02/11/2021

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Cancer

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Plain English summary of protocol

https://www.cancerresearchuk.org/about-cancer/find-a-clinical-trial/a-trial-of-reolysin-and-gm-csf-for-glioblastoma-multiforme-reoglio

Contact information

Miss Amber Reid
Public

Leeds Institute of Clinical Trials Research
University of Leeds
Leeds
LS2 9JT
United Kingdom

Phone	+44 113 3438391
Email	CTRU-reoglio@leeds.ac.uk

Mr George Picard
Public

Clinical Trials Research Unit
Level 10, Worsley Building
Clarendon Way
University of Leeds
Leeds
LS2 9LU
United Kingdom

Phone	+44 (0)113 343 9077
Email	G.Picard@leeds.ac.uk

Study information

Primary study design	Interventional
Study design	Non-randomised; Both; Design type: Treatment, Drug, Radiotherapy, Cohort study
Secondary study design	Non randomised study
Study type	Participant information sheet
Scientific title	A dose-finding study of the safety and tolerability of intravenous reovirus (REOLYSIN®) (pelareorep) plus granulocyte-macrophage colony-stimulating factor (GM-CSF) in combination with standard of care chemoradiotherapy (CTRT) /adjuvant chemotherapy for Glioblastoma Multiforme (GBM)
Study objectives	The aim of the dose escalation phase of the trial is to determine the Maximum Tolerated Dose (MTD) of REOLYSIN® and GM-CSF in combination with standard of care chemoradiotherapy (CTRT) in adult participants with glioblastoma multiforme (GBM), to determine a recommended dose to take forward to the expansion phase. The dose expansion phase will assess the longer-term toxicity and safety of REOLYSIN® and GM-CSF in combination with standard of care CTRT in adult participants with GBM.
Ethics approval(s)	East of England – Cambridge East Research Ethics Committee, 22/12/2016, ref: 16/EE/0494
Health condition(s) or problem(s) studied	Specialty: Cancer, Primary sub-specialty: Brain Cancer; UKCRC code/ Disease: Cancer/ Malignant neoplasms of eye, brain and other parts of central nervous system
Intervention	Where possible trial treatment should start within 31 days of biopsy/debulking surgery. However trial treatment must start within a maximum of 42 days (6 weeks) after biopsy/surgery. Participants will receive: Chemoradiotherapy 1. Focal brain external beam radiotherapy consisting of 60Gy in 30 2Gy fractions over 42 days (6 weeks,from Monday to Friday) as per standard treatment. Up to a 7 day delay in radiotherapy is permitted; maximum duration of delivery will be 49 days (7 weeks). 2. Concurrent temozolomide 75mg/m2/day po given daily from the first to the last day of radiotherapy as per standard treatment for a maximum of 49 days 3. Trial treatment (Weeks 1 and 4): GM-CSF 50µg/day sc on days 1-3 plus REOLYSIN® iv on days 4-5. If delays in radiotherapy and/or temozolomide occur without a trial treatment-related DLT, GM-CSF and REOLYSIN® should be delivered on schedule Adjuvant treatment Adjuvant treatment should start within 28 to 31 days after the final dose of radiotherapy, and must start within 42 days. If adjuvant treatment cannot start within 42 days of the final dose of radiotherapy due to toxicity, the participant will come off trial treatment. Adjuvant treatment will comprise up to six 28-day cycles of 2. Temozolomide 150mg/m2 po on days 1-5 of the first cycle; increased to 200mg/m2 po on days 1-5 of cycles 2 to 6 if cycle 1 tolerated with acceptable toxicity, as per standard treatment 2. Trial treatment (each cycle): GM-CSF 50µg/day sc on days 1-3 plus REOLYSIN® iv on days 4-5 At the escalation phase, the dose of REOLYSIN® used will depend on which cohort the participant is in. Dose escalation will start at dose level 1 (1x1010TCID50) and proceed to either dose level -1 (5x109 TCID50) or dose level 2 (3x1010TCID50) depending on the number of DLTs experienced by participants in the original cohort. The total duration of follow-up for all participants Follow-up assessments will take place every 84 days until disease progression or the initiation of a new systemic anticancer treatment. The duration of protocol treatment for individual participants will vary. The median progression free survival of patients with GBM is approximately 8-9 months from diagnosis.
Intervention type	Mixed
Primary outcome measure(s)	Dose escalation phase Dose limiting toxicities’ (DLTs) will be assessed between day 1 of chemoradiotherapy treatment and up to (but not including) day 1 of planned adjuvant chemotherapy, and will be reviewed in patient notes. Dose expansion phase Adverse events and serious adverse events will be assessed from the time of consent until 30 days post treatment. SARs and SUSARs will be assessed from the time of consent until the end of the trial.
Key secondary outcome measure(s)	1. Safety will be reported based on the occurrence of SAEs, SARs and SUSARs. Toxicity will be reported based on adverse events as graded by CTCAE V4.0. SAEs and AEs will be reported up to 30 days post treatment and SUSARs, SARs and ARs will be reported until the end of trial. 2. Progression free survival will be calculated from the date of registration to first documented evidence of disease progression or death whichever is sooner and will be reviewed in patient notes. 3. For participants with measurable disease, response is assessed using RANO criteria and is defined as the proportion of participants achieving each response category at the time of each follow-up MRI (every 84 days). This will be reviewed in patient notes. 4. Overall survival (OS) will be calculated from the date of registration to death and will be reviewed in patient notes. 5. Treatment compliance will include details of any dose reductions, delays, omissions and withdrawals. and will be reviewed in patient notes.
Completion date	25/02/2020

Eligibility

Participant type(s)	Patient
Age group	Adult
Sex	All
Target sample size at registration	24
Key inclusion criteria	1. Male or female subjects with a histologically confirmed diagnosis of Glioblastoma Multiforme (WHO Grade IV, including variants). 2. Previous biopsy or debulking surgery. 3. Trial treatment must start within a maximum of 42 days (6 weeks) after biopsy/surgery. 4. Eligible for first line standard treatment with Stupp regimen (radiotherapy concomitant with temozolomide followed by adjuvant temozolomide) 5. If the participant is receiving dexamethasone (or equivalent) this must be a maximum of 8mg dexamethasone daily (or equivalent) 6. Aged over 16 7. ECOG performance status 0-1 (see appendix 2) 8. Life expectancy ≥ 4 months 9. Required laboratory values within 7 days prior to registration 9.1. Absolute neutrophil count (ANC) ≥ 1.5 x 109 [SI units 109/L] 9.2. Platelets ≥100 x109 [SI units 109/L] (without platelet transfusion) 9.3. Haemoglobin ≥9.0 g/dL [SI units gm/L] (with or without RBC transfusion) 9.4. Serum creatinine ≤1.5 x upper limit of normal (ULN) 9.5. Bilirubin ≤1.5 x ULN 9.6. AST/ALT ≤2.5 x ULN 10. Proteinuria ≤ Grade 1 or Urinary protein < 1 g/24hr 11. Ability to provide written informed consent prior to participating in the trial and any trial-related procedures being performed. 12. Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests and any other trial procedures. 13. Female participants of child-bearing potential must agree to use dual methods of contraception for the duration of the trial . Male participants must agree to use dual methods of contraception for the duration of the trial and for 6 months after the last dose of trial treatment is received if sexually active with a female of child-bearing potential.
Key exclusion criteria	1. Pregnant (positive pregnancy test, serum or urine acceptable) or breast feeding 2. Previous treatment for GBM other than debulking surgery 3. Concurrent or previous malignancies (< 12 months post end of treatment) at other sites, with the exception of appropriately treated localised epithelial skin or cervical cancer. Participants with histories (> = 12 months) of other tumours may be entered 4. Patients seropositive for HIV, Hepatitis B or C infection 5. Immunosuppressive therapy other than steroids (maximum of 8mg daily dexamethasone or equivalent) 6. Any history of hypersensitivity to any of the trial medications or excipients 7. Participants with active uncontrolled infections 8. Participants with peripheral neuropathy > = CTC grade 3 9. Poorly controlled or serious medical or psychiatric illness that, in the Investigator’s opinion, is likely to interfere with participation and/or compliance in this clinical trial 10. Patients with the following significant cardiovascular diseases within 1 year of consent; history of arrhythmia, myocardial infarction, symptomatic heart failure, uncontrolled hypertension, or history of QTc abnormalities 11. Participants must not have received G-CSF since confirmed diagnosis of Glioblastoma Multiforme
Date of first enrolment	19/09/2017
Date of final enrolment	01/09/2018

Locations

Countries of recruitment

United Kingdom
England
Scotland

Study participating centres

Beatson West of Scotland Cancer Centre

1053 Great Western Road
Glasgow
G12 0YN
United Kingdom

St James' University Hospital

Beckett Street
Leeds
LS9 7JT
United Kingdom

Christie NHS Foundation Trust

550 Wilmslow Road
Manchester
M20 4BX
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	The current data sharing plans for the current study are unknown and will be made available at a later date.

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Basic results	version 1	24/02/2021	24/02/2021	No	No
Basic results	version 2	02/11/2021	02/11/2021	No	No
HRA research summary			26/07/2023	No	No
Participant information sheet	Participant information sheet	11/11/2025	11/11/2025	No	Yes
Study website	Study website	11/11/2025	11/11/2025	No	Yes

Additional files

ISRCTN70044565_BasicResults_24Feb2021.pdf: Basic results
ISRCTN70044565_BasicResults_02Nov21.pdf: Basic results

Editorial Notes

02/11/2021: The following changes were made to the trial record:
1. The updated basic results of this trial have been uploaded as an additional file.
2. The intention to publish date was changed from 01/11/2020 to 17/12/2021.
24/02/2021: The basic results of this trial have been uploaded as an additional file.
10/09/2020: One of the public contacts has been changed.
07/09/2020: The intention to publish date has been changed from 01/03/2020 to 01/11/2020.
09/06/2020: The overall end date was changed from 01/06/2019 to 25/02/2020.
06/06/2018: The following changes were made:
1. The Brain Tumour Charity was added as a co-funder.
2. Trial Coordinator Chris Taylor was added as a contact.
14/05/2018: Cancer Research UK lay summary link added to plain English summary field
16/01/2018: Internal review.
10/01/2018: The recruitment start date was changed from 30/06/2017 to 19/09/2017, and Royal Marsden Hospital was removed as a trial participating centre.
16/10/2017: Internal review.
03/04/2017: The recruitment start date has been updated from 01/03/2017 to 30/06/2017.
08/02/2017: Verified study information with principal investigator.