Trial of ipilimumab immunotherapy in recently diagnosed glioblastoma brain tumours
| ISRCTN | ISRCTN84434175 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN84434175 |
| EudraCT/CTIS number | 2018-000095-15 |
| IRAS number | 238638 |
| Secondary identifying numbers | CPMS 37562, IRAS 238638 |
- Submission date
- 12/11/2018
- Registration date
- 12/11/2018
- Last edited
- 10/04/2024
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Cancer
Plain English Summary
Contact information
Scientific
Trial Manager: IPI-GLIO
Oncology Clinical Trials Office
Department of Oncology
Old Road Campus Research Building
Roosevelt Drive
Headington
Oxford
OX3 7DQ
United Kingdom
| Phone | +44 (0)1865617080 |
|---|---|
| octo-ipiglio@oncology.ox.ac.uk |
Scientific
University College London Hospitals
250 Euston Road
London
NW1 2PG
United Kingdom
| p.mulholland@ucl.ac.uk |
Scientific
Western General Hospital
Edinburgh Cancer Centre Crewe Road South
Edinburgh
EH4 2XU
United Kingdom
Scientific
Addenbrookes Hospital
Hills Rd
Cambridge
CB2 1QQ
United Kingdom
Scientific
Guy’s Hospital
Great Maze Pond
London
SE1 9RT
United Kingdom
Scientific
Churchill Hospital
Old Road
Oxford
OX3 7LE
United Kingdom
Scientific
The Christie
Wilmslow Road
Manchester
M20 4BX
United Kingdom
Study information
| Study design | Randomized; Interventional; Design type: Treatment, Drug, Immunotherapy |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | Not available in web format, please use the contact details to request a patient information sheet |
| Scientific title | A Phase II, open label, randomised study of ipilimumab with temozolomide versus temozolomide alone after surgery and chemoradiotherapy in patients with recently diagnosed glioblastoma (IPI-GLIO) |
| Study acronym | IPI-GLIO |
| Study hypothesis | Glioblastoma is the most common malignant primary brain tumour. The trialists are trying to find out whether after chemoradiotherapy it is better to continue with standard treatment with temozolomide, or if adding a drug called ipilimumab to standard treatment is better in terms of survival and/or safety and tolerability. They hypothesise that adding ipilimumab to standard treatment is better. |
| Ethics approval(s) | South Central – Oxford B Research Ethics Committee, 02/11/2018, ref: 18/SC/0525 |
| Condition | Glioblastoma |
| Intervention | Current interventions as of 07/06/2021: This is an unblinded, open labelled stratified randomised Phase II multicentre clinical trial (CTIMP). Patients with newly diagnosed de-novo glioblastoma following surgery and radical radiotherapy with concomitant temozolomide will be recruited from hospitals in the UK. The study will have statistical power of 80% to show a significant difference between 22.5-month median survival in the ipilimumab and temozolomide arm and 15-month median survival in the temozolomide arm. To allow this, 120 patients need to be recruited (80 to the ipilimumab and temozolomide arm and 40 to the temozolomide arm) This assumes an 18 month recruitment period and survival follow-up for a minimum of 18 months after the last participant randomised (maximum of 5 years after individual participant randomisation) and 72 events. A 2:1 randomisation was chosen to aid recruitment and because there is already 10 years of experience of temozolomide in the public domain. All analyses will be on an intention-to-treat basis. This means that patients will be analysed as they are randomised irrespective of the treatment actually received. The intention-to-treat population will include all patients who have given their informed consent and for whom there is confirmation of successful allocation of a randomisation number. It is therefore important that every effort is made to encourage patients, including those patients who do not receive/complete their allocated treatment, to attend for follow-up clinic visits to avoid bias in the analysis of the results. No interim analyses are planned. Patients will be randomly allocated in a 2:1 ratio to receive either: Arm A: ipilimumab + temozolomide, 80 patients Arm B: temozolomide, 40 patients Ipilimumab given by intravenous infusion at a dosage of 3mg/kg every 3 weeks for a total of 4 doses. Temozolomide is taken orally for 6 cycles. Each cycle is 28 days long once daily for 5 days followed by 23 days without treatment. Patients take 150 mg/m^2/day for Cycle 1 (Dose Level 0), and then 200 mg/m^2/day (Dose Level 1) during Cycles 2-6 in the absence of toxicity except in cases as described in the protocol where it is taken at Dose Level -1. The dose may be reduced to 100 mg/m^2/day (Dose Level -1) in case of toxicity. The duration of study treatment is 24 weeks and the end of study visit is at 52 weeks. Survival data and other information relevant to survival will be collected from medical records at 2 and 3 years from individual participant randomisation dates and at a timepoint up to 18 months from 30th April 2021, which is anticipated to be near the date the last patient is randomised. No 2- and/or 3-year follow-up will occur after 18 months from 30th April 2021. Progression-free survival will be collected at 18 months from 30th April 2021. Previous interventions: This is an unblinded, open labelled stratified randomised Phase II multicentre clinical trial (CTIMP). Patients with newly diagnosed de-novo glioblastoma following surgery and radical radiotherapy with concomitant temozolomide will be recruited from hospitals in the UK. The study will have statistical power of 80% to show a significant difference between 22.5-month median survival in the ipilimumab and temozolomide arm and 15-month median survival in the temozolomide arm. To allow this, 120 patients need to be recruited (80 to the ipilimumab and temozolomide arm and 40 to the temozolomide arm) This assumes an 18 month recruitment period and survival follow-up for a minimum of 18 months after the last participant randomised (maximum of 5 years after individual participant randomisation). A 2:1 randomisation was chosen to aid recruitment and because there is already 10 years of experience of temozolomide in the public domain. All analyses will be on an intention-to-treat basis. This means that patients will be analysed as they are randomised irrespective of the treatment actually received. The intention-to-treat population will include all patients who have given their informed consent and for whom there is confirmation of successful allocation of a randomisation number. It is therefore important that every effort is made to encourage patients, including those patients who do not receive/complete their allocated treatment, to attend for follow-up clinic visits to avoid bias in the analysis of the results. No interim analyses are planned. Patients will be randomly allocated in a 2:1 ratio to receive either: Arm A: ipilimumab + temozolomide, 80 patients Arm B: temozolomide, 40 patients Ipilimumab given by intravenous infusion at a dosage of 3 mg/kg every 3 weeks for a total of 4 doses. Temozolomide is taken orally for 6 cycles. Each cycle is 28 days long once daily for 5 days followed by 23 days without treatment. Patients take 150 mg/m^2/day for Cycle 1 (Dose Level 0), and then 200 mg/m^2/day (Dose Level 1) during Cycles 2-6 in the absence of toxicity except in cases as described in the protocol where it is taken at Dose Level -1. The dose may be reduced to 100 mg/m^2/day (Dose Level -1) in case of toxicity. The duration of study treatment is 24 weeks and the end of study visit is at 52 weeks. Survival data and other information relevant to survival will be collected from medical records at 18 months from the last participant's randomisation and 2, 3, and 5 years from individual participant randomisation dates. |
| Intervention type | Drug |
| Pharmaceutical study type(s) | |
| Phase | Phase II |
| Drug / device / biological / vaccine name(s) | Ipilimumab, temozolomide |
| Primary outcome measure | Overall survival (OS). The treatment comparison will be reported as the hazard ratio (HR) plus 80% confidence interval. 18-month survival rates per treatment groups will be reported; Timepoint(s): 18 months from the last patient's randomisation |
| Secondary outcome measures | Current secondary outcome measures as of 07/06/2021: 1. Any toxicity grade ≥3 graded according to CTCAE v4.03 and length of time for toxicity to resolve; Timepoint(s): From the time of patient consent until patient's end of study 2. Overall survival at 3 years including a treatment effect reported as a hazard ratio; Timepoint(s): 3 years from the patient's randomisation date 4. Progression-free survival (PFS) measured at 18 months from 30th April 2021 Previous secondary outcome measures: 1. Any toxicity grade ≥3 graded according to CTCAE v4.03 and length of time for toxicity to resolve; Timepoint(s): From the time of patient consent until patient's end of study 2. Overall survival at 5 years including a treatment effect reported as a hazard ratio; Timepoint(s): 5 years from the patient's randomisation date |
| Overall study start date | 10/01/2018 |
| Overall study end date | 31/10/2022 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Upper age limit | 70 Years |
| Sex | Both |
| Target number of participants | Planned Sample Size: 120; UK Sample Size: 120 |
| Total final enrolment | 119 |
| Participant inclusion criteria | Current participant inclusion criteria as of 24/04/2023: 1. Newly diagnosed histologically-confirmed de-novo supratentorial glioblastoma (including gliosarcoma), by WHO guidelines with >20% surgical debulking (surgeon defined) 2. Radiotherapy to have begun within 49 days of surgery 3. Completed standard radiotherapy and concurrent temozolomide 4. Clinically appropriate for adjuvant temozolomide and capable of completing adjuvant temozolomide without dose reduction, based on investigator judgement 5. Male or female, age 18-70 years 6. Life expectancy of at least 12 weeks 7. ECOG performance status of 0-1 8. The patient is willing and able to comply with the protocol scheduled follow-up visits and examinations for the duration of the study 9. Written (signed and dated) informed consent 10. Haematological and biochemical indices within stated ranges Lab Test Value required: Haemoglobin (Hb) ≥9 g/dL (blood transfusions not permitted to maintain haemoglobin) Platelet count ≥100 x 109/L Absolute Neutrophil Count ≥1.0 x 109/L (G-CSF not permitted to maintain ANC) Lymphocyte count ≥0.5 x 109/L Serum creatinine < 1.5 x ULN or a creatinine clearance of ≥ 50mL/min calculated by Cockcroft-Gault formula Female CrCl = (140-age in years) x weight in kg x 1.04 serum creatinine in µmol/L Male CrCl = (140-age in years) x weight in kg x 1.23 serum creatinine in µmol/L Total bilirubin ≤ 1.5 x ULN (except for patients with known Gilbert’s Syndrome who may have total bilirubin ≤ 3 x ULN) ALT and AST ≤ 3 x ULN Previous participant inclusion criteria as of 17/10/2019: 1. Newly diagnosed histologically-confirmed de-novo supratentorial glioblastoma (including gliosarcoma), by WHO guidelines with >20% surgical debulking (surgeon defined) 2. Radiotherapy to have begun within 49 days of surgery 3. Completed standard radiotherapy and concurrent temozolomide 4. Clinically appropriate for adjuvant temozolomide and capable of completing adjuvant temozolomide without dose reduction, based on investigator judgement 5. Male or female, age 18-70 years 6. Life expectancy of at least 12 weeks 7. ECOG performance status of 0-1 8. The patient is willing and able to comply with the protocol scheduled follow-up visits and examinations for the duration of the study 9. Written (signed and dated) informed consent 10. Haematological and biochemical indices within stated ranges Previous participant inclusion criteria: 1. Newly diagnosed histologically-confirmed de-novo supratentorial glioblastoma (including gliosarcoma), by WHO guidelines with >20% surgical debulking (surgeon defined) 2. Radiotherapy to have begun within 49 days of surgery 3. Completed standard radiotherapy (60 Gray in 30 Fractions) given with concurrent temozolomide 4. Completed all planned concomitant temozolomide (75mg/m2 for 42 days) in combination with radiotherapy 5. Clinically appropriate for adjuvant temozolomide, based on investigator judgement 6. Male or female, age 18-70 years 7. Life expectancy of at least 12 weeks 8. ECOG performance status of 0-1 9. The patient is willing and able to comply with the protocol scheduled follow-up visits and examinations for the duration of the study 10. Written (signed and dated) informed consent 11. Haematological and biochemical indices within stated ranges |
| Participant exclusion criteria | Current exclusion criteria as of 07/06/2021: 1. Pregnant or breastfeeding women or women of childbearing potential unless effective methods of contraception are used 2. Multifocal glioblastoma 3. Secondary glioblastoma (i.e. previous histological or radiological diagnosis of lower grade glioma) 4. Known extracranial metastatic or leptomeningeal disease 5. Any treatment for glioblastoma other than surgical resection/biopsy and temozolomide chemoradiotherapy 6. Dexamethasone dose >3 mg daily (or equivalent) at time of randomisation 7. Intratumoural or peritumoural haemorrhage deemed significant by the treating physician 8. Clinically relevant, active, known or suspected autoimmune disease 9. History of significant gastrointestinal impairment, as judged by the investigator 10. Any evidence of severe or uncontrolled diseases (e.g. unstable or uncompensated respiratory, cardiac, hepatic or renal disease) 11. Known hypersensitivity to trial medications or any of their excipients 12. Past medical history of interstitial lung disease, idiopathic pulmonary fibrosis, drug-induced interstitial disease which required steroid treatment or any evidence of clinically active interstitial lung disease 13. Any condition requiring systemic treatment with corticosteroids (dexamethasone 3 mg or equivalent) or other immunosuppressive medications within 14 days or randomisation. Inhaled or topical steroids, and adrenal replacement steroid doses > 10mg daily prednisolone or equivalent are permitted in the absence of active autoimmune disease 14. Treatment with any other investigational agent, or participation in another interventional clinical trial (on the interventional arm) within 28 days prior to enrolment. Participation in other interventional trials after the final IPI-GLIO visit is permitted 15. Any other active malignancy requiring treatment/whose prognosis will prevent readout from trial-endpoints, exceptions include adequately treated cone-biopsied in situ carcinoma of the cervix uteri and non-melanoma skin lesions Previous exclusion criteria: 1. Pregnant or breastfeeding women or women of childbearing potential unless effective methods of contraception are used 2. Multifocal glioblastoma 3. Secondary glioblastoma (i.e. previous histological or radiological diagnosis of lower grade glioma) 4. Known extracranial metastatic or leptomeningeal disease 5. Any treatment for glioblastoma other than surgical resection/biopsy and temozolomide chemoradiotherapy 6. Dexamethasone dose >3 mg daily (or equivalent) at time of randomisation 7. Intratumoural or peritumoural haemorrhage deemed significant by the treating physician 8. Clinically relevant, active, known or suspected autoimmune disease 9. History of significant gastrointestinal impairment, as judged by the investigator 10. Any evidence of severe or uncontrolled diseases (e.g. unstable or uncompensated respiratory, cardiac, hepatic or renal disease) 11. Known hypersensitivity to trial medications or any of their excipients 12. Past medical history of interstitial lung disease, idiopathic pulmonary fibrosis, drug-induced interstitial disease which required steroid treatment or any evidence of clinically active interstitial lung disease 13. Any condition requiring systemic treatment with corticosteroids (>10 mg prednisolone daily or equivalent) or other immunosuppressive medications within 14 days or randomisation. Inhaled or topical steroids, and adrenal replacement steroid doses >10 mg daily prednisolone or equivalent are permitted in the absence of active autoimmune disease |
| Recruitment start date | 21/12/2018 |
| Recruitment end date | 12/05/2021 |
Locations
Countries of recruitment
- England
- Scotland
- United Kingdom
Study participating centres
Rickmansworth Rd
Northwood
HA6 2RN
United Kingdom
Crewe Road South
Edinburgh
EH4 2XU
United Kingdom
Cambridge
CB2 1QQ
United Kingdom
London
SE1 9RT
United Kingdom
Oxford
OX3 7LE
United Kingdom
London
NW1 2PG
United Kingdom
Manchester
M20 4BX
United Kingdom
Sponsor information
University/education
Clinical Trials & Research Governance
Joint Research Office
Boundary Brook House
Headington
Oxford
OX3 7GB
England
United Kingdom
"ROR" |
https://ror.org/052gg0110 |
|---|
Funders
Funder type
Industry
Government organisation / For-profit companies (industry)
- Alternative name(s)
- Bristol-Myers Squibb Company, BMS
- Location
- United States of America
No information available
Results and Publications
| Intention to publish date | 30/07/2024 |
|---|---|
| Individual participant data (IPD) Intention to share | No |
| IPD sharing plan summary | Data sharing statement to be made available at a later date |
| Publication and dissemination plan | Planned publication in a high-impact peer reviewed journal. |
| IPD sharing plan | The 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? |
|---|---|---|---|---|---|
| Protocol article | protocol | 12/03/2020 | 24/04/2023 | Yes | No |
| HRA research summary | 26/07/2023 | No | No |
Editorial Notes
10/04/2024: IRAS number added. The intention to publish date was changed from 30/04/2024 to 30/07/2024.
24/04/2023: The following changes have been made:
1. The participant inclusion criteria have been changed.
2. A scientific contact was updated.
3. Publication reference added.
08/06/2021: Total final enrolment number added.
07/06/2021: The interventions, secondary outcome measures and exclusion criteria were updated.
10/05/2021: The recruitment end date was changed from 30/04/2021 to 12/05/2021.
19/10/2020: The following changes have been made:
1. The recruitment end date has been changed from 31/08/2020 to 30/04/2021.
2. The overall trial end date has been changed from 31/08/2025 to 31/10/2022.
3. The intention to publish date has been changed from 31/08/2026 to 30/04/2024.
05/08/2020: The following changes have been made:
1. The overall trial end date has been changed from 07/06/2026 to 31/08/2025.
2. The intention to publish date has been changed from 07/06/2027 to 31/08/2026.
29/07/2020: Recruitment to this study is no longer paused. The recruitment end date was changed from 21/06/2020 to 31/08/2020.
23/04/2020: Due to current public health guidance, recruitment for this study has been paused.
17/10/2019: The participant inclusion criteria have been changed.
11/06/2019: Contact details updated.
11/04/2019: The Christie was added to the trial participating centres.
25/03/2019: The condition has been changed from "Specialty: Cancer, Primary sub-specialty: Brain Cancer; Health Category: Cancer and neoplasms; Disease/Condition: Malignant neoplasms of eye, brain and other parts of central nervous system" to "Glioblastoma" following a request from the NIHR.
05/03/2019: Internal review.
20/02/2019: Funders updated: The National Hospital for Neurology and Neurosurgery Development Foundation was replaced with The National Brain Appeal.
19/02/2019: Cancer Research UK lay summary link added to plain English summary field.
19/02/2019: The following changes were made to the trial record:
1. Churchill Hospital and University College London Hospitals NHS Foundation Trust were added as trial participating centres.
2. The recruitment end date was changed from 07/06/2020 to 21/06/2020.
06/02/2019: New contact added.
25/01/2019: University College London Hospitals Charities was removed from the funders - this was added in error.
27/12/2018: Guy’s Hospital, Addenbrookes Hospital and Western General Hospital have been added to the trial participating centres
21/12/2018: The following changes have been made:
1. The recruitment start date has been changed from 07/12/2018 to 21/12/2018.
2. Mount Vernon Cancer Centre has been added to the trial participating centres.
