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
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. Subseq...
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BMC
2021-07-01
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| Series: | BMC Cancer |
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| Online Access: | https://doi.org/10.1186/s12885-021-08509-w |
| _version_ | 1818792509042589696 |
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| author | Oliver Coen Pippa Corrie Helen Marshall Ruth Plummer Christian Ottensmeier Jane Hook Sue Bell Gurdeep S. Sagoo David Meads Janine Bestall Galina Velikova Ferdia A. Gallagher Alexandra Smith Helen Howard Ellen Mason Eszter Katona Shobha Silva Michelle Collinson Simon Rodwell Sarah Danson |
| author_facet | Oliver Coen Pippa Corrie Helen Marshall Ruth Plummer Christian Ottensmeier Jane Hook Sue Bell Gurdeep S. Sagoo David Meads Janine Bestall Galina Velikova Ferdia A. Gallagher Alexandra Smith Helen Howard Ellen Mason Eszter Katona Shobha Silva Michelle Collinson Simon Rodwell Sarah Danson |
| author_sort | Oliver Coen |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-18T15:28:22Z |
| format | Article |
| id | doaj.art-94e82f3219214bb495cb4463d0ad4aed |
| institution | Directory Open Access Journal |
| issn | 1471-2407 |
| language | English |
| last_indexed | 2024-12-18T15:28:22Z |
| publishDate | 2021-07-01 |
| publisher | BMC |
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| series | BMC Cancer |
| spelling | doaj.art-94e82f3219214bb495cb4463d0ad4aed2022-12-21T21:03:13ZengBMCBMC Cancer1471-24072021-07-0121111010.1186/s12885-021-08509-wThe DANTE trial protocol: a randomised phase III trial to evaluate the Duration of ANti-PD-1 monoclonal antibody Treatment in patients with metastatic mElanomaOliver Coen0Pippa Corrie1Helen Marshall2Ruth Plummer3Christian Ottensmeier4Jane Hook5Sue Bell6Gurdeep S. Sagoo7David Meads8Janine Bestall9Galina Velikova10Ferdia A. Gallagher11Alexandra Smith12Helen Howard13Ellen Mason14Eszter Katona15Shobha Silva16Michelle Collinson17Simon Rodwell18Sarah Danson19Leeds Teaching Hospitals NHS TrustCambridge University Hospitals NHS Foundation TrustUniversity of LeedsNewcastle UniversityUniversity of SouthamptonLeeds Teaching Hospitals NHS TrustUniversity of LeedsUniversity of LeedsUniversity of LeedsUniversity of LeedsLeeds Teaching Hospitals NHS TrustCambridge University Hospitals NHS Foundation TrustUniversity of LeedsUniversity of LeedsUniversity of LeedsUniversity of LeedsSheffield Teaching Hospitals NHS Foundation TrustUniversity of LeedsUniversity of SheffieldSheffield Teaching Hospitals NHS Foundation TrustAbstract 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.https://doi.org/10.1186/s12885-021-08509-wImmunotherapyCheckpoint inhibitorAnti-PD-1Metastatic melanomaScheduleEfficacy |
| spellingShingle | Oliver Coen Pippa Corrie Helen Marshall Ruth Plummer Christian Ottensmeier Jane Hook Sue Bell Gurdeep S. Sagoo David Meads Janine Bestall Galina Velikova Ferdia A. Gallagher Alexandra Smith Helen Howard Ellen Mason Eszter Katona Shobha Silva Michelle Collinson Simon Rodwell Sarah Danson 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 Immunotherapy Checkpoint inhibitor Anti-PD-1 Metastatic melanoma Schedule Efficacy |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | dante trial protocol a randomised phase iii trial to evaluate the duration of anti pd 1 monoclonal antibody treatment in patients with metastatic melanoma |
| topic | Immunotherapy Checkpoint inhibitor Anti-PD-1 Metastatic melanoma Schedule Efficacy |
| url | https://doi.org/10.1186/s12885-021-08509-w |
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