Temozolomide and nivolumab as a treatment for cancer of the gullet
| ISRCTN | ISRCTN11398887 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN11398887 |
| EudraCT/CTIS number | 2020-004771-41 |
| IRAS number | 282284 |
| ClinicalTrials.gov number | NCT04984733 |
| Secondary identifying numbers | CPMS 48157, IRAS 282284 |
- Submission date
- 09/07/2021
- Registration date
- 14/07/2021
- Last edited
- 29/04/2025
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Cancer
Plain English summary of protocol
Background and study aims
Patients with advanced or metastatic cancer of the stomach or gullet (oesophagogastric cancer) cannot be cured with current treatments and do not have good survival outcomes compared to other cancers. This study is investigating whether chemotherapy treatment with temozolomide (TMZ) plus nivolumab (NIVO), an immunotherapy drug that is not currently licensed in Europe for oesophagogastric cancer (but is licensed and used in other cancers), will allow patients with MGMT-methylated tumours to improve their survival rates. There is evidence from laboratory models and other tumours to show that when TMZ is used in MGMT-methylated tumours that the number of mutations (mistakes in DNA) in the tumour increases. Tumours with high numbers of mutations tend to respond better to immunotherapy like nivolumab (NIVO). It is hoped that MGMT-methylated tumours will become sensitive to nivolumab by treating them with TMZ, which could lead to tumour shrinkage.
Who can participate?
Patients aged 18 years and over who have been diagnosed with advanced, previously treated and currently unresectable (inoperable) oesophagogastric cancer that is methylated in MGMT (an enzymatic protein) and have been treated with 3-6 months of first-line chemotherapy.
What does the study involve?
Patients will undergo screening to ensure that this trial is right for them. Once screened eligible patients will start the TMZ. TMZ is a capsule that participants will take every day for up to 3 months. During treatment with TMZ, they will have weekly blood tests and every 4 weeks a clinic visit to monitor their health and have a physical examination. If their disease progresses whilst on TMZ participants will stop that treatment and receive nivolumab treatment. If their disease doesn’t progress (grow) on TMZ, they will start NIVO at 3 months and continue with TMZ as well. Participants will visit the clinic every 2 weeks during nivolumab treatment to be monitored for health and progression. The nivolumab treatment will be given by an infusion (injected into a vein). At regular intervals participants will have CT scans to monitor the effect of the treatment. These are the same as what they would have normally to monitor their well-being although one would be additional to the standard of care. To ensure that the heart is well enough to receive the treatment participants will also have either an echocardiogram or a MUGA scan (multi-gated acquisition scan). At 3 months or when the TMZ treatment is stopped participants will undergo an endoscopy where a biopsy (sample) will be taken. Participants will also be asked to have one at the end of nivolumab treatment – but this one would be optional. Following disease progression (tumour growth) on nivolumab, participants will move into the follow-up phase of the trial to monitor for overall survival. Participants will give up to five additional blood samples; one at the start of the trial and the others during the treatment.
What are the possible benefits and risks of participating?
Participants may benefit from a longer period of disease remission by having the combination treatment of TMZ followed by nivolumab. However, this cannot be guaranteed and there may be no additional benefit in relation to how long the cancer is controlled.
The information from this study may help to treat future patients with the same condition in a more effective way. The inconvenience, side effects and impact on quality of life are similar to that of any course of chemotherapy and immunotherapy. Participants will be helping to further knowledge of how to treat cancer and this will also benefit society as a whole. During the trial, participants will have contrast-enhanced CT scans to assess their cancer. These tests use radiation, which has a limited increase to the risk of cancer in the future. These tests are part of standard care but participants will receive one additional scan by taking part in the trial. Participants will also be required to have an echocardiogram or MUGA, depending on their hospital’s practice, to ensure they are well enough to receive the full dose of chemotherapy. A contrast-enhanced CT scan involves radiation, using x-rays to get a detailed image of the body area. Participants will have up to 12 CT scans of their chest, abdomen and pelvis. Participants may also have a nuclear medicine MUGA scan to assess their heart function. Some of these will be extra to those that they would have if they did not take part. These procedures use ionising radiation to form images of the body or provide the doctor with other clinical information. Ionising radiation can cause cell damage that may, after many years or decades, turn cancerous. For the patients in this study the chance of this happening is extremely small.
Where is the study run from?
Southampton Clinical Trials Unit (UK)
When is the study starting and how long is it expected to run for?
November 2020 to October 2024
Who is funding the study?
Bristol Myers Squibb (USA)
Who is the main contact?
Dr Elizabeth Smyth
elizabeth.smyth2@nhs.net
Contact information
Public
Southampton Clinical Trials Unit, MP131
Southampton General Hospital
Tremona Road
Southampton
SO16 6YD
United Kingdom
| Phone | +44 (0)23 81204773 |
|---|---|
| k.l.clark@soton.ac.uk |
Scientific
Cambridge University Hospitals NHS Foundation Trust
Hill Road
Cambridge
CB2 0QQ
United Kingdom
 ORCID ID |
0000-0002-4667-1817 |
|---|---|
| Phone | +44 (0)746 3717859 |
| elizabeth.smyth2@nhs.net |
Study information
| Study design | Non-randomized; Interventional; Design type: Treatment, Drug |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Non randomised study |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | ISRCTN11398887_PIS_V3_13May21.docx |
| Scientific title | ELEVATE: Temozolomide + nivolumab in MGMT-deficient oesophagogastric cancer |
| Study acronym | ELEVATE |
| Study objectives | In O-6-methylguanine-DNA methyltransferase (MGMT)-methylated oesophagogastric adenocarcinoma, temozolomide will induce a hypermutated state and increase sensitivity to nivolumab. The aim of the trial is to determine the activity and safety of maintenance temozolomide (TMZ) dosing followed by nivolumab treatment to evaluate the potential for a future randomised trial against a standard of care control arm. The rationale to continue TMZ for 3 months or until disease progression (PD) is to evaluate the emergence of mismatch repair deficiency both with and without radiological PD, as clinically relevant mismatch repair deficiency (MMRd) may emerge before radiological progression. This will also reduce the number of patients who drop out due to symptomatic progressive disease. |
| Ethics approval(s) | Approved 15/03/2021, Cambridge South Research Ethics Committee (The Old Chapel, Royal Standard Place, Nottingham, NG1 6FS, UK; +44 (0)207 104 8104; cambridgesouth.rec@hra.nhs.uk), REC ref: 21/EE/0017 |
| Health condition(s) or problem(s) studied | Oesophagogastric cancer |
| Intervention | Patients previously treated with at least 3 months of platinum and fluoropyrimidine-based chemotherapy, with a known MGMT deficiency, will be recruited from secondary care settings. Once all screening procedures have been done and the patient is confirmed eligible, they will receive 50 mg/m² TMZ continuously for 3 months. TMZ is taken by mouth, daily. If their disease progresses during the 3 months they will stop TMZ and start nivolumab at a dose of 240 mg every 2 weeks. If there is no progression after 3 months the patient will continue taking TMZ alongside nivolumab. All treatment will stop once the patient progresses on nivolumab. During TMZ treatment patients will have weekly blood tests and 4 weekly physical exams to monitor their health and monitor any progression of disease. On the weeks when they are not in clinic for a physical exam, the site staff will contact them by phone to check on adverse events and TMZ compliance and confirm they are to continue taking them following blood results. During nivolumab treatment patients will be seen in clinic every 2 weeks, for physical exams and blood tests to monitor health and disease progression. Patients will have a CT scan at week 6, week 12 and then every 12 weeks until they cease nivolumab treatment. Patients will have a mandatory endoscopy for research purposes and they will be asked to have an optional one (for research) at progression. Following disease progression on nivolumab, patient notes will be used to monitor overall survival. |
| Intervention type | Drug |
| Pharmaceutical study type(s) | |
| Phase | Not Applicable |
| Drug / device / biological / vaccine name(s) | Temozolomide, nivolumab |
| Primary outcome measure | Objective response rate to nivolumab measured using Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 and iRECIST at 24 months |
| Secondary outcome measures | 1. Disease control rate, according to RECIST v1.1 and iRECIST, 6 months after starting nivolumab, and 3 months after starting TMZ, respectively 2. Progression-free survival (PFS), calculated from the time of registration to evidence of progression (RECIST v1.1 and iRECIST) or any death 3. Progression-free survival (PFS2), calculated from the time of starting nivolumab to evidence of progression (RECIST v1.1 and iRECIST) or any death (N.B. disease control rate at 3 months and progression-free survival will be assessed on TMZ before nivolumab therapy) 4. Overall survival (OS), calculated using [medical records] from the time of registration to any cause death 5. Overall survival (OS2), calculated using [medical records] from the time of starting nivolumab to any death 6. Toxicity assessed according to CTCAE version 5.0 at progression on NIVO/end of treatment 7. Tolerability assessed by the percentage of intended treatment dose delivered, and numbers of patients needing dose reductions and/or treatment breaks for each drug administration period at progression on NIVO/end of treatment 8. Quality of life measured using QLQ-C30, QLQ-OG25 and EQ-5D-5L questionnaires at progression on NIVO/end of treatment Exploratory: 1. Mismatch repair deficiency in tumours, according to standard immunohistochemistry testing for MLH1, MSH2, MSH6 or PSM2 at 24 months 2. MGMT protein expression and MGMT methylation in tumours measured using PCR method at progression on NIVO/end of treatment 3. Tumour mutation burden using 10/mB as a cut off for high vs low measured using next-generation sequencing of tumour tissue at progression on NIVO/end of treatment 4. Tumour immune cell infiltration quantifying CD8, CD4, Treg using cross validation testing at progression on NIVO/end of treatment 5. Relative abundance of peripheral blood T cell populations measured using mass cytometry at progression on NIVO/end of treatment |
| Overall study start date | 01/11/2020 |
| Completion date | 23/10/2024 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Sex | Both |
| Target number of participants | Planned Sample Size: 18; UK Sample Size: 18 |
| Total final enrolment | 13 |
| Key inclusion criteria | 1. Patients ≥18 years of age 2. Pathologically confirmed advanced unresectable or metastatic OGA 3. Loss of MGMT protein on IHC 4. Mismatch repair proficient (MSI-normal or MMR intact) 5. Previously treated with at least 3 months of platinum and fluoropyrimidine-based chemotherapy for advanced disease and suitable for maintenance therapy 6. Measurable disease per RECIST 1.1 and iRECIST guidelines 7. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 8. Can swallow TMZ capsules 9. Adequate organ function assessed within 7 days before randomization 10. Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) within 24 hours prior to randomization |
| Key exclusion criteria | 1. Previous treatment with TMZ 2. Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways 3. Active central nervous system metastases 4. Candidate for curative surgery 5. Previous malignancies are excluded unless a complete remission was achieved at least 5 years prior to study entry. Adequately treated cervical carcinoma in situ, and localized non-melanoma skin cancer are not exclusion criteria, regardless of time point of diagnosis. 6. Active, known, or suspected infectious or autoimmune disease (except for patients with Type I diabetes mellitus, residual hypothyroidism due to autoimmune thyroiditis only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment are permitted to enrol) 7. Conditions requiring systemic treatment with either corticosteroids (≥10 mg daily prednisolone or equivalent) or other immunosuppressive medications within 14 days of study drug administration 8. Interstitial lung disease 9. > Grade 1 peripheral neuropathy 10. Positive test result for HBV or HCV indicating acute or chronic infection 11. Known history of testing positive for HIV or known AIDS 12. Known hypersensitivity to the components or excipients of co-trimoxazole, temozolomide or nivolumab. (Please refer to nivolumab IB and SmPC for TMZ and co-trimoxazole) 13. Known hypersensitivity to dacarbazine (DTIC) 14. Clinically significant abnormal 12-lead ECG. If clinically indicated, cardiac function assessment using either echocardiography or MUGA Scan, if clinically significant the patient is ineligible 15. In the past 6 months serious cardiac illness or medical condition including but not confined to: 15.1. History of documented congestive heart failure (CHF) 15.2. High-risk uncontrolled arrhythmias 15.3. Angina pectoris requiring antianginal medication 15.4. Clinically significant valvular heart disease 15.5. Evidence of transmural infarction 15.6. Poorly controlled hypertension (e.g. systolic >180 mmHg or diastolic greater than 100 mmHg) 16. Patients with severe liver parenchymal damage 17. Patients with severe renal insufficiency where repeated measurements of the plasma concentration cannot be performed 18. Patients with a history of drug-induced immune thrombocytopenia with the use of trimethoprim and/or sulfonamides 19. Patients with acute porphyria 20. Patients with severe myelosuppression |
| Date of first enrolment | 01/09/2021 |
| Date of final enrolment | 31/12/2023 |
Locations
Countries of recruitment
- England
- Scotland
- United Kingdom
- Wales
Study participating centres
Hills Road
Cambridge
CB2 0QQ
United Kingdom
Kings' Cross
Clepington Road
Dundee
DD3 8EA
United Kingdom
Colney Lane
Colney
Norwich
NR4 7UY
United Kingdom
Southampton
SO16 6YD
United Kingdom
Nottingham University Hospitals NHS Trust
City Hospital Campus
Hucknall Road
Nottingham
NG5 1PB
United Kingdom
Sponsor information
University/education
c/o Alison Knight
University of Southampton, B28/2031
Highfield
Southampton
SO17 1BJ
England
United Kingdom
| Phone | +44 (0)2380595058 |
|---|---|
| rgoinfo@southampton.ac.uk | |
| Website | http://www.southampton.ac.uk/ |
"ROR" |
https://ror.org/01ryk1543 |
Funders
Funder type
Industry
Government organisation / For-profit companies (industry)
- Alternative name(s)
- Bristol-Myers Squibb Company, BMS
- Location
- United States of America
Results and Publications
| Intention to publish date | 30/03/2026 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Available on request |
| Publication and dissemination plan | Planned publication in a high-impact peer-reviewed journal |
| IPD sharing plan | Current IPD sharing statement as of 08/03/2023: The datasets generated during and/or analysed during the current study will be available upon request from Southampton Clinical Trials Unit (ctu@soton.ac.uk). As a minimum, anonymous data will be available for request from three months after the publication of an article, to researchers who provide a completed Data Sharing request form that describes a methodologically sound proposal, for the purpose of the approved proposal and if appropriate a signed Data Sharing Agreement. Data will be shared once all parties have signed relevant data-sharing documentation. Researchers interested in the trial data are asked to complete the Request for Data Sharing form [template located on the SCTU website, www.southampton.ac.uk/ctu] to provide a brief research proposal on how they wish to use the data. It will include; the objectives, what data are requested, timelines for use, intellectual property and publication rights, data release definition in the contract and participant informed consent etc. If considered necessary, a Data Sharing Agreement from Sponsor may be required. Previous IPD sharing statement: 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? |
|---|---|---|---|---|---|
| Participant information sheet | version V3 | 13/05/2021 | 14/07/2021 | No | Yes |
| Protocol article | protocol | 01/09/2022 | 08/03/2023 | Yes | No |
| HRA research summary | 28/06/2023 | No | No |
Additional files
- ISRCTN11398887_PIS_V3_13May21.docx
- Uploaded 14/07/2021
Editorial Notes
29/04/2025: Internal review.
04/03/2025: Total final enrolment added. The overall study end date has been changed from 30/03/2025 to 23/10/2024 and the plain English summary updated accordingly.
08/03/2023: The following changes have been made:
1. The recruitment end date has been changed from 31/03/2023 to 31/12/2023.
2. The overall study end date has been changed from 31/12/2024 to 30/03/2025 and the plain English summary updated accordingly.
3. The intention to publish date has been changed from 31/12/2025 to 30/03/2026.
4. The individual participant data (IPD) sharing statement and summary have been changed.
5. Publication reference added.
28/02/2023: Velindre Cancer Centre and St Mary's Hospital were removed from the trial participating centres.
04/08/2021: The following changes have been made:
1. The recruitment start date has been changed from 01/08/2021 to 01/09/2021.
2. The trial website has been added.
3. The ClinicalTrials.gov number has been added.
14/07/2021: The participant information sheet has been uploaded.
09/07/2021: Trial's existence confirmed by the NIHR.
