ELEVATE – evaluating Temozolomide and Nivolumab in patients with advanced unresectable previously treated oesophagogastric adenocarcinoma with MGMT methylation: study protocol for a single arm phase II trial
Abstract Background For patients with oesophagogastric adenocarcinoma, surgery is the only curative option and despite the use of multimodality therapy, which combines it with chemotherapy and/or radiotherapy, more than 50% of patients will relapse and die. Many UK patients present with advanced dis...
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| Format: | Article |
| Language: | English |
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BMC
2022-09-01
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| Series: | BMC Cancer |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12885-022-09891-9 |
| _version_ | 1828736512524550144 |
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| author | Elizabeth Smyth Kelly Cozens Daniel Griffiths Kathryn L. Clark Sean Ewings Russell Petty Tim Underwood Rebecca C. Fitzgerald James Tanner Olivier Giger Shubha Anand Gareth Griffiths |
| author_facet | Elizabeth Smyth Kelly Cozens Daniel Griffiths Kathryn L. Clark Sean Ewings Russell Petty Tim Underwood Rebecca C. Fitzgerald James Tanner Olivier Giger Shubha Anand Gareth Griffiths |
| author_sort | Elizabeth Smyth |
| collection | DOAJ |
| description | Abstract Background For patients with oesophagogastric adenocarcinoma, surgery is the only curative option and despite the use of multimodality therapy, which combines it with chemotherapy and/or radiotherapy, more than 50% of patients will relapse and die. Many UK patients present with advanced disease which is already inoperable or metastatic at diagnosis. For these patients, standard care chemotherapy only offers them survival of less than a year. Nivolumab, a checkpoint blockade inhibitor, has been found to work in some advanced cancers. It is proposed, for those where immunotherapy hasn’t worked, that these immunologically evasive tumours need to be sensitized to immunotherapy drugs to allow them to act. Methods ELEVATE is a single arm phase II trial testing the overall response to nivolumab following temozolomide treatment in patients with advanced unresectable previously treated adenocarcinoma which is O6-methylguanine-DNA-methyltransferase (MGMT) methylated. 18 patients are being recruited from UK secondary care sites. To be eligible, participants must have been treated with at least 3 months of platinum and fluoropyrimidine chemotherapy. Participants will receive 50 mg/m2 temozolomide continuously for 3 months. If their disease progresses during the 3 months, they will stop temozolomide and start nivolumab at a dose of 240mg every 2 weeks. If there is no progression after 3 months the participant will continue taking temozolomide in combination with nivolumab. All treatment will stop once the participant progresses on nivolumab. The primary endpoint is the best overall response to nivolumab, using both Response Evaluation Criteria in Solid Tumours version 1.1 and immunotherapy modified Response Evaluation Criteria in Solid Tumours. Secondary endpoints include progression-free survival, overall survival, and quality of life. Discussion ELEVATE will provide evidence for whether giving nivolumab after temozolomide in patients with previously treated advanced oesophagogastric adenocarcinoma is safe and biologically effective prior to future randomised trials. Trial registrations EudraCT Number: 2020-004771-41 (issued 01 October 2020); ISCRTN11398887 (registered 14 July 2021). |
| first_indexed | 2024-04-12T23:27:53Z |
| format | Article |
| id | doaj.art-1fbe26fc1abc48ce98b26d076e0a6aee |
| institution | Directory Open Access Journal |
| issn | 1471-2407 |
| language | English |
| last_indexed | 2024-04-12T23:27:53Z |
| publishDate | 2022-09-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Cancer |
| spelling | doaj.art-1fbe26fc1abc48ce98b26d076e0a6aee2022-12-22T03:12:22ZengBMCBMC Cancer1471-24072022-09-0122111310.1186/s12885-022-09891-9ELEVATE – evaluating Temozolomide and Nivolumab in patients with advanced unresectable previously treated oesophagogastric adenocarcinoma with MGMT methylation: study protocol for a single arm phase II trialElizabeth Smyth0Kelly Cozens1Daniel Griffiths2Kathryn L. Clark3Sean Ewings4Russell Petty5Tim Underwood6Rebecca C. Fitzgerald7James Tanner8Olivier Giger9Shubha Anand10Gareth Griffiths11Cambridge University Hospitals National Health Service Foundation TrustSouthampton Clinical Trials Unit, University of Southampton and University Hospital Southampton NHS Foundation TrustSouthampton Clinical Trials Unit, University of Southampton and University Hospital Southampton NHS Foundation TrustSouthampton Clinical Trials Unit, University of Southampton and University Hospital Southampton NHS Foundation TrustSouthampton Clinical Trials Unit, University of Southampton and University Hospital Southampton NHS Foundation TrustUniversity of DundeeSchool of Cancer Sciences, University of Southampton and University Hospital Southampton NHS Foundation TrustUniversity of CambridgeCambridge University Hospitals National Health Service Foundation TrustCambridge University Hospitals National Health Service Foundation TrustUniversity of CambridgeSouthampton Clinical Trials Unit, University of Southampton and University Hospital Southampton NHS Foundation TrustAbstract Background For patients with oesophagogastric adenocarcinoma, surgery is the only curative option and despite the use of multimodality therapy, which combines it with chemotherapy and/or radiotherapy, more than 50% of patients will relapse and die. Many UK patients present with advanced disease which is already inoperable or metastatic at diagnosis. For these patients, standard care chemotherapy only offers them survival of less than a year. Nivolumab, a checkpoint blockade inhibitor, has been found to work in some advanced cancers. It is proposed, for those where immunotherapy hasn’t worked, that these immunologically evasive tumours need to be sensitized to immunotherapy drugs to allow them to act. Methods ELEVATE is a single arm phase II trial testing the overall response to nivolumab following temozolomide treatment in patients with advanced unresectable previously treated adenocarcinoma which is O6-methylguanine-DNA-methyltransferase (MGMT) methylated. 18 patients are being recruited from UK secondary care sites. To be eligible, participants must have been treated with at least 3 months of platinum and fluoropyrimidine chemotherapy. Participants will receive 50 mg/m2 temozolomide continuously for 3 months. If their disease progresses during the 3 months, they will stop temozolomide and start nivolumab at a dose of 240mg every 2 weeks. If there is no progression after 3 months the participant will continue taking temozolomide in combination with nivolumab. All treatment will stop once the participant progresses on nivolumab. The primary endpoint is the best overall response to nivolumab, using both Response Evaluation Criteria in Solid Tumours version 1.1 and immunotherapy modified Response Evaluation Criteria in Solid Tumours. Secondary endpoints include progression-free survival, overall survival, and quality of life. Discussion ELEVATE will provide evidence for whether giving nivolumab after temozolomide in patients with previously treated advanced oesophagogastric adenocarcinoma is safe and biologically effective prior to future randomised trials. Trial registrations EudraCT Number: 2020-004771-41 (issued 01 October 2020); ISCRTN11398887 (registered 14 July 2021).https://doi.org/10.1186/s12885-022-09891-9Oesophagogastric adenocarcinomaImmunotherapyMGMT methylatedPhase II |
| spellingShingle | Elizabeth Smyth Kelly Cozens Daniel Griffiths Kathryn L. Clark Sean Ewings Russell Petty Tim Underwood Rebecca C. Fitzgerald James Tanner Olivier Giger Shubha Anand Gareth Griffiths ELEVATE – evaluating Temozolomide and Nivolumab in patients with advanced unresectable previously treated oesophagogastric adenocarcinoma with MGMT methylation: study protocol for a single arm phase II trial BMC Cancer Oesophagogastric adenocarcinoma Immunotherapy MGMT methylated Phase II |
| title | ELEVATE – evaluating Temozolomide and Nivolumab in patients with advanced unresectable previously treated oesophagogastric adenocarcinoma with MGMT methylation: study protocol for a single arm phase II trial |
| title_full | ELEVATE – evaluating Temozolomide and Nivolumab in patients with advanced unresectable previously treated oesophagogastric adenocarcinoma with MGMT methylation: study protocol for a single arm phase II trial |
| title_fullStr | ELEVATE – evaluating Temozolomide and Nivolumab in patients with advanced unresectable previously treated oesophagogastric adenocarcinoma with MGMT methylation: study protocol for a single arm phase II trial |
| title_full_unstemmed | ELEVATE – evaluating Temozolomide and Nivolumab in patients with advanced unresectable previously treated oesophagogastric adenocarcinoma with MGMT methylation: study protocol for a single arm phase II trial |
| title_short | ELEVATE – evaluating Temozolomide and Nivolumab in patients with advanced unresectable previously treated oesophagogastric adenocarcinoma with MGMT methylation: study protocol for a single arm phase II trial |
| title_sort | elevate evaluating temozolomide and nivolumab in patients with advanced unresectable previously treated oesophagogastric adenocarcinoma with mgmt methylation study protocol for a single arm phase ii trial |
| topic | Oesophagogastric adenocarcinoma Immunotherapy MGMT methylated Phase II |
| url | https://doi.org/10.1186/s12885-022-09891-9 |
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