Mogamulizumab versus vorinostat in previously treated cutaneous T-cell lymphoma (MAVORIC): an international, open-label, randomised, controlled phase 3 trial

MAVORIC Investigators

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Abstract

Background: Cutaneous T-cell lymphomas are rare non-Hodgkin lymphomas with substantial morbidity and mortality in advanced disease stages. We compared the efficacy of mogamulizumab, a novel monoclonal antibody directed against C-C chemokine receptor 4, with vorinostat in patients with previously treated cutaneous T-cell lymphoma. Methods: In this open-label, international, phase 3, randomised controlled trial, we recruited patients with relapsed or refractory mycosis fungoides or Sézary syndrome at 61 medical centres in the USA, Denmark, France, Italy, Germany, the Netherlands, Spain, Switzerland, the UK, Japan, and Australia. Eligible patients were aged at least 18 years (in Japan, ≥20 years), had failed (for progression or toxicity as assessed by the principal investigator) at least one previous systemic therapy, and had an Eastern Cooperative Oncology Group performance score of 1 or less and adequate haematological, hepatic, and renal function. Patients were randomly assigned (1:1) using an interactive voice web response system to mogamulizumab (1·0 mg/kg intravenously on a weekly basis for the first 28-day cycle, then on days 1 and 15 of subsequent cycles) or vorinostat (400 mg daily). Stratification was by cutaneous T-cell lymphoma subtype (mycosis fungoides vs Sézary syndrome) and disease stage (IB–II vs III–IV). Since this study was open label, patients and investigators were not masked to treatment assignment. The primary endpoint was progression-free survival by investigator assessment in the intention-to-treat population. Patients who received one or more doses of study drug were included in the safety analyses. This study is ongoing, and enrolment is complete. This trial was registered with ClinicalTrials.gov, number NCT01728805. Findings: Between Dec 12, 2012, and Jan 29, 2016, 372 eligible patients were randomly assigned to receive mogamulizumab (n=186) or vorinostat (n=186), comprising the intention-to-treat population. Two patients randomly assigned to mogamulizumab withdrew consent before receiving study treatment; thus, 370 patients were included in the safety population. Mogamulizumab therapy resulted in superior investigator-assessed progression-free survival compared with vorinostat therapy (median 7·7 months [95% CI 5·7–10·3] in the mogamulizumab group vs 3·1 months [2·9–4·1] in the vorinostat group; hazard ratio 0·53, 95% CI 0·41–0·69; stratified log-rank p<0·0001). Grade 3–4 adverse events of any cause were reported in 75 (41%) of 184 patients in the mogamulizumab group and 76 (41%) of 186 patients in the vorinostat group. The most common serious adverse events of any cause were pyrexia in eight (4%) patients and cellulitis in five (3%) patients in the mogamulizumab group; and cellulitis in six (3%) patients, pulmonary embolism in six (3%) patients, and sepsis in five (3%) patients in the vorinostat group. Two (67%) of three on-treatment deaths with mogamulizumab (due to sepsis and polymyositis) and three (33%) of nine on-treatment deaths with vorinostat (two due to pulmonary embolism and one due to bronchopneumonia) were considered treatment-related. Interpretation: Mogamulizumab significantly prolonged progression-free survival compared with vorinostat, and could provide a new, effective treatment for patients with mycosis fungoides and, importantly, for Sézary syndrome, a subtype that represents a major therapeutic challenge in cutaneous T-cell lymphoma. Funding: Kyowa Kirin.

Original languageEnglish (US)
Pages (from-to)1192-1204
Number of pages13
JournalThe Lancet Oncology
Volume19
Issue number9
DOIs
StatePublished - Sep 1 2018

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Cutaneous T-Cell Lymphoma
Mycosis Fungoides
Research Personnel
Disease-Free Survival
Therapeutics
vorinostat
mogamulizumab
Cellulitis
Pulmonary Embolism
Sepsis
Japan
Population
Safety
Polymyositis
Bronchopneumonia
CC Chemokines
Chemokine Receptors

ASJC Scopus subject areas

  • Oncology

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Mogamulizumab versus vorinostat in previously treated cutaneous T-cell lymphoma (MAVORIC) : an international, open-label, randomised, controlled phase 3 trial. / MAVORIC Investigators.

In: The Lancet Oncology, Vol. 19, No. 9, 01.09.2018, p. 1192-1204.

Research output: Contribution to journalArticle

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title = "Mogamulizumab versus vorinostat in previously treated cutaneous T-cell lymphoma (MAVORIC): an international, open-label, randomised, controlled phase 3 trial",
abstract = "Background: Cutaneous T-cell lymphomas are rare non-Hodgkin lymphomas with substantial morbidity and mortality in advanced disease stages. We compared the efficacy of mogamulizumab, a novel monoclonal antibody directed against C-C chemokine receptor 4, with vorinostat in patients with previously treated cutaneous T-cell lymphoma. Methods: In this open-label, international, phase 3, randomised controlled trial, we recruited patients with relapsed or refractory mycosis fungoides or S{\'e}zary syndrome at 61 medical centres in the USA, Denmark, France, Italy, Germany, the Netherlands, Spain, Switzerland, the UK, Japan, and Australia. Eligible patients were aged at least 18 years (in Japan, ≥20 years), had failed (for progression or toxicity as assessed by the principal investigator) at least one previous systemic therapy, and had an Eastern Cooperative Oncology Group performance score of 1 or less and adequate haematological, hepatic, and renal function. Patients were randomly assigned (1:1) using an interactive voice web response system to mogamulizumab (1·0 mg/kg intravenously on a weekly basis for the first 28-day cycle, then on days 1 and 15 of subsequent cycles) or vorinostat (400 mg daily). Stratification was by cutaneous T-cell lymphoma subtype (mycosis fungoides vs S{\'e}zary syndrome) and disease stage (IB–II vs III–IV). Since this study was open label, patients and investigators were not masked to treatment assignment. The primary endpoint was progression-free survival by investigator assessment in the intention-to-treat population. Patients who received one or more doses of study drug were included in the safety analyses. This study is ongoing, and enrolment is complete. This trial was registered with ClinicalTrials.gov, number NCT01728805. Findings: Between Dec 12, 2012, and Jan 29, 2016, 372 eligible patients were randomly assigned to receive mogamulizumab (n=186) or vorinostat (n=186), comprising the intention-to-treat population. Two patients randomly assigned to mogamulizumab withdrew consent before receiving study treatment; thus, 370 patients were included in the safety population. Mogamulizumab therapy resulted in superior investigator-assessed progression-free survival compared with vorinostat therapy (median 7·7 months [95{\%} CI 5·7–10·3] in the mogamulizumab group vs 3·1 months [2·9–4·1] in the vorinostat group; hazard ratio 0·53, 95{\%} CI 0·41–0·69; stratified log-rank p<0·0001). Grade 3–4 adverse events of any cause were reported in 75 (41{\%}) of 184 patients in the mogamulizumab group and 76 (41{\%}) of 186 patients in the vorinostat group. The most common serious adverse events of any cause were pyrexia in eight (4{\%}) patients and cellulitis in five (3{\%}) patients in the mogamulizumab group; and cellulitis in six (3{\%}) patients, pulmonary embolism in six (3{\%}) patients, and sepsis in five (3{\%}) patients in the vorinostat group. Two (67{\%}) of three on-treatment deaths with mogamulizumab (due to sepsis and polymyositis) and three (33{\%}) of nine on-treatment deaths with vorinostat (two due to pulmonary embolism and one due to bronchopneumonia) were considered treatment-related. Interpretation: Mogamulizumab significantly prolonged progression-free survival compared with vorinostat, and could provide a new, effective treatment for patients with mycosis fungoides and, importantly, for S{\'e}zary syndrome, a subtype that represents a major therapeutic challenge in cutaneous T-cell lymphoma. Funding: Kyowa Kirin.",
author = "{MAVORIC Investigators} and Kim, {Youn H.} and Martine Bagot and Lauren Pinter-Brown and Rook, {Alain H.} and Pierluigi Porcu and Horwitz, {Steven M.} and Sean Whittaker and Yoshiki Tokura and Maarten Vermeer and Zinzani, {Pier Luigi} and Lubomir Sokol and Stephen Morris and Kim, {Ellen J.} and Ortiz-Romero, {Pablo L.} and Herbert Eradat and Julia Scarisbrick and Athanasios Tsianakas and Craig Elmets and Stephane Dalle and Fisher, {David C.} and Ahmad Halwani and Brian Poligone and John Greer and Fierro, {Maria Teresa} and Amit Khot and Moskowitz, {Alison J.} and Amy Musiek and Andrei Shustov and Barbara Pro and Geskin, {Larisa J.} and Karen Dwyer and Junji Moriya and Mollie Leoni and Humphrey, {Jeffrey S.} and Stacie Hudgens and Grebennik, {Dmitri O.} and Kensei Tobinai and Madeleine Duvic and Sunil Abhyankar and Oleg Akilov and Onder Alpdogan and Marie Beylot-Barry and Erin Boh and Dolores Caballero and Richard Cowan and Brigitte Dreno and Reinhard Dummer and Timothy Fenske and Francine Foss and Lawrence Mark",
year = "2018",
month = "9",
day = "1",
doi = "10.1016/S1470-2045(18)30379-6",
language = "English (US)",
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pages = "1192--1204",
journal = "The Lancet Oncology",
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TY - JOUR

T1 - Mogamulizumab versus vorinostat in previously treated cutaneous T-cell lymphoma (MAVORIC)

T2 - an international, open-label, randomised, controlled phase 3 trial

AU - MAVORIC Investigators

AU - Kim, Youn H.

AU - Bagot, Martine

AU - Pinter-Brown, Lauren

AU - Rook, Alain H.

AU - Porcu, Pierluigi

AU - Horwitz, Steven M.

AU - Whittaker, Sean

AU - Tokura, Yoshiki

AU - Vermeer, Maarten

AU - Zinzani, Pier Luigi

AU - Sokol, Lubomir

AU - Morris, Stephen

AU - Kim, Ellen J.

AU - Ortiz-Romero, Pablo L.

AU - Eradat, Herbert

AU - Scarisbrick, Julia

AU - Tsianakas, Athanasios

AU - Elmets, Craig

AU - Dalle, Stephane

AU - Fisher, David C.

AU - Halwani, Ahmad

AU - Poligone, Brian

AU - Greer, John

AU - Fierro, Maria Teresa

AU - Khot, Amit

AU - Moskowitz, Alison J.

AU - Musiek, Amy

AU - Shustov, Andrei

AU - Pro, Barbara

AU - Geskin, Larisa J.

AU - Dwyer, Karen

AU - Moriya, Junji

AU - Leoni, Mollie

AU - Humphrey, Jeffrey S.

AU - Hudgens, Stacie

AU - Grebennik, Dmitri O.

AU - Tobinai, Kensei

AU - Duvic, Madeleine

AU - Abhyankar, Sunil

AU - Akilov, Oleg

AU - Alpdogan, Onder

AU - Beylot-Barry, Marie

AU - Boh, Erin

AU - Caballero, Dolores

AU - Cowan, Richard

AU - Dreno, Brigitte

AU - Dummer, Reinhard

AU - Fenske, Timothy

AU - Foss, Francine

AU - Mark, Lawrence

PY - 2018/9/1

Y1 - 2018/9/1

N2 - Background: Cutaneous T-cell lymphomas are rare non-Hodgkin lymphomas with substantial morbidity and mortality in advanced disease stages. We compared the efficacy of mogamulizumab, a novel monoclonal antibody directed against C-C chemokine receptor 4, with vorinostat in patients with previously treated cutaneous T-cell lymphoma. Methods: In this open-label, international, phase 3, randomised controlled trial, we recruited patients with relapsed or refractory mycosis fungoides or Sézary syndrome at 61 medical centres in the USA, Denmark, France, Italy, Germany, the Netherlands, Spain, Switzerland, the UK, Japan, and Australia. Eligible patients were aged at least 18 years (in Japan, ≥20 years), had failed (for progression or toxicity as assessed by the principal investigator) at least one previous systemic therapy, and had an Eastern Cooperative Oncology Group performance score of 1 or less and adequate haematological, hepatic, and renal function. Patients were randomly assigned (1:1) using an interactive voice web response system to mogamulizumab (1·0 mg/kg intravenously on a weekly basis for the first 28-day cycle, then on days 1 and 15 of subsequent cycles) or vorinostat (400 mg daily). Stratification was by cutaneous T-cell lymphoma subtype (mycosis fungoides vs Sézary syndrome) and disease stage (IB–II vs III–IV). Since this study was open label, patients and investigators were not masked to treatment assignment. The primary endpoint was progression-free survival by investigator assessment in the intention-to-treat population. Patients who received one or more doses of study drug were included in the safety analyses. This study is ongoing, and enrolment is complete. This trial was registered with ClinicalTrials.gov, number NCT01728805. Findings: Between Dec 12, 2012, and Jan 29, 2016, 372 eligible patients were randomly assigned to receive mogamulizumab (n=186) or vorinostat (n=186), comprising the intention-to-treat population. Two patients randomly assigned to mogamulizumab withdrew consent before receiving study treatment; thus, 370 patients were included in the safety population. Mogamulizumab therapy resulted in superior investigator-assessed progression-free survival compared with vorinostat therapy (median 7·7 months [95% CI 5·7–10·3] in the mogamulizumab group vs 3·1 months [2·9–4·1] in the vorinostat group; hazard ratio 0·53, 95% CI 0·41–0·69; stratified log-rank p<0·0001). Grade 3–4 adverse events of any cause were reported in 75 (41%) of 184 patients in the mogamulizumab group and 76 (41%) of 186 patients in the vorinostat group. The most common serious adverse events of any cause were pyrexia in eight (4%) patients and cellulitis in five (3%) patients in the mogamulizumab group; and cellulitis in six (3%) patients, pulmonary embolism in six (3%) patients, and sepsis in five (3%) patients in the vorinostat group. Two (67%) of three on-treatment deaths with mogamulizumab (due to sepsis and polymyositis) and three (33%) of nine on-treatment deaths with vorinostat (two due to pulmonary embolism and one due to bronchopneumonia) were considered treatment-related. Interpretation: Mogamulizumab significantly prolonged progression-free survival compared with vorinostat, and could provide a new, effective treatment for patients with mycosis fungoides and, importantly, for Sézary syndrome, a subtype that represents a major therapeutic challenge in cutaneous T-cell lymphoma. Funding: Kyowa Kirin.

AB - Background: Cutaneous T-cell lymphomas are rare non-Hodgkin lymphomas with substantial morbidity and mortality in advanced disease stages. We compared the efficacy of mogamulizumab, a novel monoclonal antibody directed against C-C chemokine receptor 4, with vorinostat in patients with previously treated cutaneous T-cell lymphoma. Methods: In this open-label, international, phase 3, randomised controlled trial, we recruited patients with relapsed or refractory mycosis fungoides or Sézary syndrome at 61 medical centres in the USA, Denmark, France, Italy, Germany, the Netherlands, Spain, Switzerland, the UK, Japan, and Australia. Eligible patients were aged at least 18 years (in Japan, ≥20 years), had failed (for progression or toxicity as assessed by the principal investigator) at least one previous systemic therapy, and had an Eastern Cooperative Oncology Group performance score of 1 or less and adequate haematological, hepatic, and renal function. Patients were randomly assigned (1:1) using an interactive voice web response system to mogamulizumab (1·0 mg/kg intravenously on a weekly basis for the first 28-day cycle, then on days 1 and 15 of subsequent cycles) or vorinostat (400 mg daily). Stratification was by cutaneous T-cell lymphoma subtype (mycosis fungoides vs Sézary syndrome) and disease stage (IB–II vs III–IV). Since this study was open label, patients and investigators were not masked to treatment assignment. The primary endpoint was progression-free survival by investigator assessment in the intention-to-treat population. Patients who received one or more doses of study drug were included in the safety analyses. This study is ongoing, and enrolment is complete. This trial was registered with ClinicalTrials.gov, number NCT01728805. Findings: Between Dec 12, 2012, and Jan 29, 2016, 372 eligible patients were randomly assigned to receive mogamulizumab (n=186) or vorinostat (n=186), comprising the intention-to-treat population. Two patients randomly assigned to mogamulizumab withdrew consent before receiving study treatment; thus, 370 patients were included in the safety population. Mogamulizumab therapy resulted in superior investigator-assessed progression-free survival compared with vorinostat therapy (median 7·7 months [95% CI 5·7–10·3] in the mogamulizumab group vs 3·1 months [2·9–4·1] in the vorinostat group; hazard ratio 0·53, 95% CI 0·41–0·69; stratified log-rank p<0·0001). Grade 3–4 adverse events of any cause were reported in 75 (41%) of 184 patients in the mogamulizumab group and 76 (41%) of 186 patients in the vorinostat group. The most common serious adverse events of any cause were pyrexia in eight (4%) patients and cellulitis in five (3%) patients in the mogamulizumab group; and cellulitis in six (3%) patients, pulmonary embolism in six (3%) patients, and sepsis in five (3%) patients in the vorinostat group. Two (67%) of three on-treatment deaths with mogamulizumab (due to sepsis and polymyositis) and three (33%) of nine on-treatment deaths with vorinostat (two due to pulmonary embolism and one due to bronchopneumonia) were considered treatment-related. Interpretation: Mogamulizumab significantly prolonged progression-free survival compared with vorinostat, and could provide a new, effective treatment for patients with mycosis fungoides and, importantly, for Sézary syndrome, a subtype that represents a major therapeutic challenge in cutaneous T-cell lymphoma. Funding: Kyowa Kirin.

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JF - The Lancet Oncology

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