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MAGE-A3 immunotherapeutic as adjuvant therapy for patients with resected, MAGE-A3-positive, stage III melanoma (DERMA): a double-blind, randomised, placebo-controlled, phase 3 trial
B. Dreno, JF. Thompson, BM. Smithers, M. Santinami, T. Jouary, R. Gutzmer, E. Levchenko, P. Rutkowski, JJ. Grob, S. Korovin, K. Drucis, F. Grange, L. Machet, P. Hersey, I. Krajsova, A. Testori, R. Conry, B. Guillot, WHJ. Kruit, L. Demidov, JA....
Jazyk angličtina Země Anglie, Velká Británie
Typ dokumentu klinické zkoušky, fáze III, časopisecké články, multicentrická studie, randomizované kontrolované studie, práce podpořená grantem
NLK
ProQuest Central
od 2000-09-01 do Před 2 měsíci
Nursing & Allied Health Database (ProQuest)
od 2000-09-01 do Před 2 měsíci
Health & Medicine (ProQuest)
od 2000-09-01 do Před 2 měsíci
Public Health Database (ProQuest)
od 2000-09-01 do Před 2 měsíci
- MeSH
- adjuvantní chemoterapie MeSH
- analýza přežití MeSH
- antigeny nádorové účinky léků genetika MeSH
- dospělí MeSH
- dvojitá slepá metoda MeSH
- hodnocení rizik MeSH
- imunokonjugáty terapeutické užití MeSH
- imunoterapie metody MeSH
- injekce intramuskulární MeSH
- internacionalita MeSH
- invazivní růst nádoru patologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- melanom farmakoterapie mortalita patologie chirurgie MeSH
- nádorové proteiny účinky léků genetika MeSH
- nádory kůže farmakoterapie mortalita patologie chirurgie MeSH
- přežití bez známek nemoci MeSH
- prognóza MeSH
- senioři MeSH
- staging nádorů MeSH
- výsledek terapie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze III MeSH
- multicentrická studie MeSH
- práce podpořená grantem MeSH
- randomizované kontrolované studie MeSH
BACKGROUND: Despite newly approved treatments, metastatic melanoma remains a life-threatening condition. We aimed to evaluate the efficacy of the MAGE-A3 immunotherapeutic in patients with stage IIIB or IIIC melanoma in the adjuvant setting. METHODS: DERMA was a phase 3, double-blind, randomised, placebo-controlled trial done in 31 countries and 263 centres. Eligible patients were 18 years or older and had histologically proven, completely resected, stage IIIB or IIIC, MAGE-A3-positive cutaneous melanoma with macroscopic lymph node involvement and an Eastern Cooperative Oncology Group performance score of 0 or 1. Randomisation and treatment allocation at the investigator sites were done centrally via the internet. We randomly assigned patients (2:1) to receive up to 13 intramuscular injections of recombinant MAGE-A3 with AS15 immunostimulant (MAGE-A3 immunotherapeutic; 300 μg MAGE-A3 antigen plus 420 μg CpG 7909 reconstituted in AS01B to a total volume of 0·5 mL), or placebo, over a 27-month period: five doses at 3-weekly intervals, followed by eight doses at 12-weekly intervals. The co-primary outcomes were disease-free survival in the overall population and in patients with a potentially predictive gene signature (GS-positive) identified previously and validated here via an adaptive signature design. The final analyses included all patients who had received at least one dose of study treatment; analyses for efficacy were in the as-randomised population and for safety were in the as-treated population. This trial is registered with ClinicalTrials.gov, number NCT00796445. FINDINGS: Between Dec 1, 2008, and Sept 19, 2011, 3914 patients were screened, 1391 randomly assigned, and 1345 started treatment (n=895 for MAGE-A3 and n=450 for placebo). At final analysis (data cutoff May 23, 2013), median follow-up was 28·0 months [IQR 23·3-35·5] in the MAGE-A3 group and 28·1 months [23·7-36·9] in the placebo group. Median disease-free survival was 11·0 months (95% CI 10·0-11·9) in the MAGE-A3 group and 11·2 months (8·6-14·1) in the placebo group (hazard ratio [HR] 1·01, 0·88-1·17, p=0·86). In the GS-positive population, median disease-free survival was 9·9 months (95% CI 5·7-17·6) in the MAGE-A3 group and 11·6 months (5·6-22·3) in the placebo group (HR 1·11, 0·83-1·49, p=0·48). Within the first 31 days of treatment, adverse events of grade 3 or worse were reported by 126 (14%) of 894 patients in the MAGE-A3 group and 56 (12%) of 450 patients in the placebo group, treatment-related adverse events of grade 3 or worse by 36 (4%) patients given MAGE-A3 vs six (1%) patients given placebo, and at least one serious adverse event by 14% of patients in both groups (129 patients given MAGE-A3 and 64 patients given placebo). The most common adverse events of grade 3 or worse were neoplasms (33 [4%] patients in the MAGE-A3 group vs 17 [4%] patients in the placebo group), general disorders and administration site conditions (25 [3%] for MAGE-A3 vs four [<1%] for placebo) and infections and infestations (17 [2%] for MAGE-A3 vs seven [2%] for placebo). No deaths were related to treatment. INTERPRETATION: An antigen-specific immunotherapeutic alone was not efficacious in this clinical setting. Based on these findings, development of the MAGE-A3 immunotherapeutic for use in melanoma has been stopped. FUNDING: GlaxoSmithKline Biologicals SA.
Biostatistics Department Janssen Research and Development Beerse Belgium
Cancer Research Center Moscow Russia
Centrum Medyczne Bieńkowski Klinika Chirurgii Plastycznej Bydgoszcz Poland
Columbus Clinic Center Milan Italy
Département de Dermatologie Centre Hospitalier Universitaire Hôpital Saint Éloi Montpellier France
Department of Dermatology Centre Hospitalier Universitaire Tours France
Department of Dermatooncology Hotel Dieu Nantes University Hospital Nantes France
Department of Medical Oncology Erasmus MC Cancer institute Rotterdam Netherlands
Department of Oncological Surgery Oncology Center Bydgoszcz Poland
Department of Skin and Soft Tissue Tumours National Cancer Institute Kiev Ukraine
Department of Surgical Oncology Gdansk Medical University Gdansk Poland
Dermato oncology Department General University Hospital Prague Czech Republic
Dermatology Department Hôpital Robert Debré Université de Reims Champagne Ardenne Reims France
GlaxoSmithKline Rixensart Belgium
Immunology Translational Medicine UCB Brussels Belgium
Instituto de Oncología Ángel H Roffo Universidad de Buenos Aires Buenos Aires Argentina
Laboratoires Servier Paris France
Melanoma Immunology and Oncology Group Centenary Institute University of Sydney Sydney NSW Australia
Melanoma Institute Australia Sydney NSW Australia
Melanoma Institute Australia The University of Sydney Sydney NSW Australia
Melanoma Sarcoma Unit Fondazione IRCCS Istituto Nazionale Tumori Milan Italy
Petrov Research Institute of Oncology St Petersburg Russia
Seattle Cancer Care Alliance University of Washington Seattle WA USA
Service d'Oncologie Médicale Hôpital François Mitterrand Pau France
Skin Cancer Center Hannover Department of Dermatology Hannover Medical School Hannover Germany
Swissmed Centrum Zdrowia Gdansk Poland
UFR de Médecine Université François Rabelais Tours France
University Hospitals Leuven Leuven Belgium
Citace poskytuje Crossref.org
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- $a BACKGROUND: Despite newly approved treatments, metastatic melanoma remains a life-threatening condition. We aimed to evaluate the efficacy of the MAGE-A3 immunotherapeutic in patients with stage IIIB or IIIC melanoma in the adjuvant setting. METHODS: DERMA was a phase 3, double-blind, randomised, placebo-controlled trial done in 31 countries and 263 centres. Eligible patients were 18 years or older and had histologically proven, completely resected, stage IIIB or IIIC, MAGE-A3-positive cutaneous melanoma with macroscopic lymph node involvement and an Eastern Cooperative Oncology Group performance score of 0 or 1. Randomisation and treatment allocation at the investigator sites were done centrally via the internet. We randomly assigned patients (2:1) to receive up to 13 intramuscular injections of recombinant MAGE-A3 with AS15 immunostimulant (MAGE-A3 immunotherapeutic; 300 μg MAGE-A3 antigen plus 420 μg CpG 7909 reconstituted in AS01B to a total volume of 0·5 mL), or placebo, over a 27-month period: five doses at 3-weekly intervals, followed by eight doses at 12-weekly intervals. The co-primary outcomes were disease-free survival in the overall population and in patients with a potentially predictive gene signature (GS-positive) identified previously and validated here via an adaptive signature design. The final analyses included all patients who had received at least one dose of study treatment; analyses for efficacy were in the as-randomised population and for safety were in the as-treated population. This trial is registered with ClinicalTrials.gov, number NCT00796445. FINDINGS: Between Dec 1, 2008, and Sept 19, 2011, 3914 patients were screened, 1391 randomly assigned, and 1345 started treatment (n=895 for MAGE-A3 and n=450 for placebo). At final analysis (data cutoff May 23, 2013), median follow-up was 28·0 months [IQR 23·3-35·5] in the MAGE-A3 group and 28·1 months [23·7-36·9] in the placebo group. Median disease-free survival was 11·0 months (95% CI 10·0-11·9) in the MAGE-A3 group and 11·2 months (8·6-14·1) in the placebo group (hazard ratio [HR] 1·01, 0·88-1·17, p=0·86). In the GS-positive population, median disease-free survival was 9·9 months (95% CI 5·7-17·6) in the MAGE-A3 group and 11·6 months (5·6-22·3) in the placebo group (HR 1·11, 0·83-1·49, p=0·48). Within the first 31 days of treatment, adverse events of grade 3 or worse were reported by 126 (14%) of 894 patients in the MAGE-A3 group and 56 (12%) of 450 patients in the placebo group, treatment-related adverse events of grade 3 or worse by 36 (4%) patients given MAGE-A3 vs six (1%) patients given placebo, and at least one serious adverse event by 14% of patients in both groups (129 patients given MAGE-A3 and 64 patients given placebo). The most common adverse events of grade 3 or worse were neoplasms (33 [4%] patients in the MAGE-A3 group vs 17 [4%] patients in the placebo group), general disorders and administration site conditions (25 [3%] for MAGE-A3 vs four [<1%] for placebo) and infections and infestations (17 [2%] for MAGE-A3 vs seven [2%] for placebo). No deaths were related to treatment. INTERPRETATION: An antigen-specific immunotherapeutic alone was not efficacious in this clinical setting. Based on these findings, development of the MAGE-A3 immunotherapeutic for use in melanoma has been stopped. FUNDING: GlaxoSmithKline Biologicals SA.
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