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The DANTE trial protocol: a randomised phase III trial to evaluate the Duration of ANti-PD-1 monoclonal antibody Treatment in patients with metastatic mElanoma

The DANTE trial protocol: a randomised phase III trial to evaluate the Duration of ANti-PD-1 monoclonal antibody Treatment in patients with metastatic mElanoma
The DANTE trial protocol: a randomised phase III trial to evaluate the Duration of ANti-PD-1 monoclonal antibody Treatment in patients with metastatic mElanoma

Background: Immunotherapy is revolutionising the treatment of patients diagnosed with melanoma and other cancers. The first immune checkpoint inhibitor, ipilimumab (targeting cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4)), showed a survival advantage over standard chemotherapy. Subsequently the anti-programmed cell death protein 1 (PD-1) antibodies, nivolumab and pembrolizumab were shown to be more effective than ipilimumab. Ipilimumab combined with nivolumab gives an incremental gain in overall survival compared with nivolumab alone but increases the risk of severe, potentially life-threatening toxicities. In contrast to ipilimumab monotherapy, anti-PD-1 antibodies are licensed to be continued until disease progression. Follow-up of patients recruited to the first trials evaluating 2 years of pembrolizumab showed that three-quarters of responding patients continue responding after stopping treatment. Suggestive of early response, we hypothesised that continuing anti-PD-1 treatment beyond 1 year in progression-free patients may be unnecessary and so designed the DANTE trial. Methods: DANTE is a multicentre, randomised, phase III, non-inferiority trial to evaluate the duration of anti-PD-1 therapy in patients with metastatic (unresectable stage III and stage IV) melanoma. It uses a two-stage recruitment strategy, registering patients before they complete 1 year of first-line anti-PD-1 +/− CTLA-4 therapy and randomising eligible patients who have received 12 months of treatment and are progression-free at 1 year. At randomisation, 1208 patients are assigned (1:1) to either 1) continue anti-PD-1 treatment until disease progression/ unacceptable toxicity/ for at least 2 years in the absence of disease progression/ unacceptable toxicity or 2) to stop treatment. Randomisation stratifies for baseline prognostic factors. The primary outcome is progression-free survival at 3, 6, 9 and 12 months and then, 6-monthly for up to 4-years. Secondary outcomes collected at all timepoints include overall survival, response-rate and duration and safety, with quality of life and cost-effectiveness outcomes collected 3-monthly for up to 18-months. Sub-studies include a qualitative analysis of patient acceptance of randomisation and sample collection to inform future translational studies into response/ toxicity biomarkers. Discussion: DANTE is a unique prospective trial investigating the optimal duration of anti-PD-1 therapy in metastatic melanoma patients. Outcomes will inform future use of these high burden drugs. Trial registration: ISRCTN15837212, 31 July 2018.

Anti-PD-1, Checkpoint inhibitor, Efficacy, Immunotherapy, Metastatic melanoma, Quality of life, Safety, Schedule
1471-2407
761
Coen, Oliver
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Corrie, Pippa
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Marshall, Helen
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Plummer, Ruth
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Ottensmeier, Christian
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Hook, Jane
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Bell, Sue
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Sagoo, Gurdeep S.
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Meads, David
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Bestall, Janine
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Velikova, Galina
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Gallagher, Ferdia A.
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Smith, Alexandra
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Howard, Helen
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Mason, Ellen
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Katona, Eszter
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Silva, Shobha
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Collinson, Michelle
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Rodwell, Simon
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Danson, Sarah
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Coen, Oliver
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Corrie, Pippa
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Marshall, Helen
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Plummer, Ruth
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Ottensmeier, Christian
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Hook, Jane
c8001309-09e2-4ba2-9d46-ab57325f0e0d
Bell, Sue
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Sagoo, Gurdeep S.
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Meads, David
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Bestall, Janine
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Velikova, Galina
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Gallagher, Ferdia A.
c61663c3-e45a-4433-9d9b-b36ad30e69e2
Smith, Alexandra
a1819042-1b7a-484c-829a-2e64a2b8231c
Howard, Helen
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Mason, Ellen
c124f62c-878b-464f-9244-a6a376e45d63
Katona, Eszter
06b94d38-effa-4f42-95e2-556534afdb21
Silva, Shobha
d6e60492-5747-4ab8-a981-8c42239167a1
Collinson, Michelle
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Rodwell, Simon
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Danson, Sarah
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Coen, Oliver, Corrie, Pippa, Marshall, Helen, Plummer, Ruth, Ottensmeier, Christian, Hook, Jane, Bell, Sue, Sagoo, Gurdeep S., Meads, David, Bestall, Janine, Velikova, Galina, Gallagher, Ferdia A., Smith, Alexandra, Howard, Helen, Mason, Ellen, Katona, Eszter, Silva, Shobha, Collinson, Michelle, Rodwell, Simon and Danson, Sarah (2021) The DANTE trial protocol: a randomised phase III trial to evaluate the Duration of ANti-PD-1 monoclonal antibody Treatment in patients with metastatic mElanoma. BMC cancer, 21 (1), 761, [761]. (doi:10.1186/s12885-021-08509-w).

Record type: Article

Abstract

Background: Immunotherapy is revolutionising the treatment of patients diagnosed with melanoma and other cancers. The first immune checkpoint inhibitor, ipilimumab (targeting cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4)), showed a survival advantage over standard chemotherapy. Subsequently the anti-programmed cell death protein 1 (PD-1) antibodies, nivolumab and pembrolizumab were shown to be more effective than ipilimumab. Ipilimumab combined with nivolumab gives an incremental gain in overall survival compared with nivolumab alone but increases the risk of severe, potentially life-threatening toxicities. In contrast to ipilimumab monotherapy, anti-PD-1 antibodies are licensed to be continued until disease progression. Follow-up of patients recruited to the first trials evaluating 2 years of pembrolizumab showed that three-quarters of responding patients continue responding after stopping treatment. Suggestive of early response, we hypothesised that continuing anti-PD-1 treatment beyond 1 year in progression-free patients may be unnecessary and so designed the DANTE trial. Methods: DANTE is a multicentre, randomised, phase III, non-inferiority trial to evaluate the duration of anti-PD-1 therapy in patients with metastatic (unresectable stage III and stage IV) melanoma. It uses a two-stage recruitment strategy, registering patients before they complete 1 year of first-line anti-PD-1 +/− CTLA-4 therapy and randomising eligible patients who have received 12 months of treatment and are progression-free at 1 year. At randomisation, 1208 patients are assigned (1:1) to either 1) continue anti-PD-1 treatment until disease progression/ unacceptable toxicity/ for at least 2 years in the absence of disease progression/ unacceptable toxicity or 2) to stop treatment. Randomisation stratifies for baseline prognostic factors. The primary outcome is progression-free survival at 3, 6, 9 and 12 months and then, 6-monthly for up to 4-years. Secondary outcomes collected at all timepoints include overall survival, response-rate and duration and safety, with quality of life and cost-effectiveness outcomes collected 3-monthly for up to 18-months. Sub-studies include a qualitative analysis of patient acceptance of randomisation and sample collection to inform future translational studies into response/ toxicity biomarkers. Discussion: DANTE is a unique prospective trial investigating the optimal duration of anti-PD-1 therapy in metastatic melanoma patients. Outcomes will inform future use of these high burden drugs. Trial registration: ISRCTN15837212, 31 July 2018.

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More information

e-pub ahead of print date: 1 July 2021
Published date: 1 July 2021
Additional Information: Funding Information: PC has received speaker fees and sat on advisory boards for MSD, BMS, Novartis and Pierre Fabre. RP has received conference and travel support from MSD and BMS; and sat on advisory boards or received speaker fees from BMS, Pierre Faber and Novartis. FG has consulted for AstraZeneca and has research funding from GSK. SR is CEO of charity Melanoma Focus. SD has received conference and travel support from MSD, Pierre Fabre and BMS; and sat on advisory boards for MSD and BMS. The remaining authors declare no competing interests. Funding Information: DANTE is funded by the National Institute for Health Research Health Technology Assessment (HTA) Programme (project number 15/57/66). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. The trial sponsor is Sheffield Teaching Hospitals NHS Trust (reference: STH19290) with delegation of responsibility for day-to-day trial management to the CTRU. The funding body reviewed the design of the study, the sponsor had no involvement in design. Neither the sponsor nor the funding body will have a role in the collection, analysis or interpretation of data. Publisher Copyright: © 2021, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.
Keywords: Anti-PD-1, Checkpoint inhibitor, Efficacy, Immunotherapy, Metastatic melanoma, Quality of life, Safety, Schedule

Identifiers

Local EPrints ID: 451021
URI: http://eprints.soton.ac.uk/id/eprint/451021
ISSN: 1471-2407
PURE UUID: ff414d05-e294-414c-9d6d-149ab4583774

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Date deposited: 03 Sep 2021 16:30
Last modified: 10 May 2024 17:00

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Contributors

Author: Oliver Coen
Author: Pippa Corrie
Author: Helen Marshall
Author: Ruth Plummer
Author: Jane Hook
Author: Sue Bell
Author: Gurdeep S. Sagoo
Author: David Meads
Author: Janine Bestall
Author: Galina Velikova
Author: Ferdia A. Gallagher
Author: Alexandra Smith
Author: Helen Howard
Author: Ellen Mason
Author: Eszter Katona
Author: Shobha Silva
Author: Michelle Collinson
Author: Simon Rodwell
Author: Sarah Danson

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