TY - JOUR
T1 - ELEVATE - evaluating Temozolomide and Nivolumab in patients with advanced unresectable previously treated oesophagogastric adenocarcinoma with MGMT methylation
T2 - study protocol for a single arm phase II trial
AU - Smyth, Elizabeth
AU - Cozens, Kelly
AU - Griffiths, Daniel
AU - Clark, Kathryn L.
AU - Ewings, Sean
AU - Petty, Russell
AU - Underwood, Tim
AU - Fitzgerald, Rebecca C.
AU - Tanner, James
AU - Giger, Olivier
AU - Anand, Shubha
AU - Griffiths, Gareth
N1 - Funding Information:
Recruitment is supported by the research nurses and staff within the NIHR Clinical Research Network in England and equivalent in Scotland. Name and contact information for the trial sponsor: University of Southampton (email: [email protected]), sponsor reference number: 61191. The study sponsor was not involved in the study design; writing of the protocol paper; or the decision to submit the paper for publication. The study is supported through supply of nivolumab and a grant from Bristol Myers Squibb (IST-LY-801).
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/9/1
Y1 - 2022/9/1
N2 - 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).
AB - 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).
KW - Adenocarcinoma/chemically induced
KW - Antineoplastic Combined Chemotherapy Protocols/adverse effects
KW - Clinical Trials, Phase II as Topic
KW - DNA Modification Methylases/genetics
KW - DNA Repair Enzymes/genetics
KW - Humans
KW - Methylation
KW - Neoplasm Recurrence, Local/drug therapy
KW - Nivolumab
KW - Quality of Life
KW - Temozolomide/therapeutic use
KW - Tumor Suppressor Proteins
KW - MGMT methylated
KW - Phase II
KW - Oesophagogastric adenocarcinoma
KW - Immunotherapy
UR - http://www.scopus.com/inward/record.url?scp=85137114812&partnerID=8YFLogxK
U2 - 10.1186/s12885-022-09891-9
DO - 10.1186/s12885-022-09891-9
M3 - Article
C2 - 36050653
SN - 1471-2407
VL - 22
JO - BMC Cancer
JF - BMC Cancer
M1 - 946
ER -
