Rigosertib versus best supportive care for patients with high-risk myelodysplastic syndromes after failure of hypomethylating drugs (ONTIME): A randomised, controlled, phase 3 trial

Guillermo Garcia-Manero, Pierre Fenaux, Aref Al-Kali, Maria R. Baer, Mikkael A. Sekeres, Gail J. Roboz, Gianluca Gaidano, Bart L. Scott, Peter Greenberg, Uwe Platzbecker, David P. Steensma, Suman Kambhampati, Karl Anton Kreuzer, Lucy A. Godley, Ehab Atallah, Robert Collins, Hagop Kantarjian, Elias Jabbour, Francois E. Wilhelm, Nozar AzarniaLewis R. Silverman

Research output: Contribution to journalArticle

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Abstract

Background: Hypomethylating drugs are the standard treatment for patients with high-risk myelodysplastic syndromes. Survival is poor after failure of these drugs; there is no approved second-line therapy. We compared the overall survival of patients receiving rigosertib and best supportive care with that of patients receiving best supportive care only in patients with myelodysplastic syndromes with excess blasts after failure of azacitidine or decitabine treatment. Methods: We did this randomised controlled trial at 74 hospitals and university medical centres in the USA and Europe. We enrolled patients with diagnosis of refractory anaemia with excess blasts (RAEB)-1, RAEB-2, RAEB-t, or chronic myelomonocytic leukaemia based on local site assessment, and treatment failure with a hypomethylating drug in the past 2 years. Patients were randomly assigned (2:1) to receive rigosertib 1800 mg per 24 h via 72-h continuous intravenous infusion administered every other week or best supportive care with or without low-dose cytarabine. Randomisation was stratified by pretreatment bone marrow blast percentage. Neither patients nor investigators were masked to treatment assignment. The primary outcome was overall survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT01241500. Findings: From Dec 13, 2010, to Aug 15, 2013, we enrolled 299 patients: 199 assigned to rigosertib, 100 assigned to best supportive care. Median follow-up was 19·5 months (IQR 11·9-27·3). As of Feb 1, 2014, median overall survival was 8·2 months (95% CI 6·1-10·1) in the rigosertib group and 5·9 months (4·1-9·3) in the best supportive care group (hazard ratio 0·87, 95% CI 0·67-1·14; p=0·33). The most common grade 3 or higher adverse events were anaemia (34 [18%] of 184 patients in the rigosertib group vs seven [8%] of 91 patients in the best supportive care group), thrombocytopenia (35 [19%] vs six [7%]), neutropenia (31 [17%] vs seven [8%]), febrile neutropenia (22 [12%] vs ten [11%]), and pneumonia (22 [12%] vs ten [11%]). 41 (22%) of 184 patients in the rigosertib group and 30 (33%) of 91 patients in the best supportive care group died due to adverse events and three deaths were attributed to rigosertib treatment. Interpretation: Rigosertib did not significantly improve overall survival compared with best supportive care. A randomised phase 3 trial of rigosertib (NCT 02562443) is underway in specific subgroups of patients deemed to be at high risk, including patients with very high risk per the Revised International Prognostic Scoring System criteria. Funding: Onconova Therapeutics, Leukemia & Lymphoma Society.

Original languageEnglish (US)
JournalThe Lancet Oncology
DOIs
StateAccepted/In press - 2016

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Myelodysplastic Syndromes
Patient Care
Pharmaceutical Preparations
Refractory Anemia with Excess of Blasts
Survival
decitabine
ON 01910
Therapeutics
Leukemia, Myelomonocytic, Chronic
Azacitidine
Febrile Neutropenia
Cytarabine
Random Allocation
Neutropenia
Treatment Failure
Intravenous Infusions
Thrombocytopenia
Anemia
Lymphoma
Pneumonia

ASJC Scopus subject areas

  • Oncology

Cite this

Rigosertib versus best supportive care for patients with high-risk myelodysplastic syndromes after failure of hypomethylating drugs (ONTIME) : A randomised, controlled, phase 3 trial. / Garcia-Manero, Guillermo; Fenaux, Pierre; Al-Kali, Aref; Baer, Maria R.; Sekeres, Mikkael A.; Roboz, Gail J.; Gaidano, Gianluca; Scott, Bart L.; Greenberg, Peter; Platzbecker, Uwe; Steensma, David P.; Kambhampati, Suman; Kreuzer, Karl Anton; Godley, Lucy A.; Atallah, Ehab; Collins, Robert; Kantarjian, Hagop; Jabbour, Elias; Wilhelm, Francois E.; Azarnia, Nozar; Silverman, Lewis R.

In: The Lancet Oncology, 2016.

Research output: Contribution to journalArticle

Garcia-Manero, G, Fenaux, P, Al-Kali, A, Baer, MR, Sekeres, MA, Roboz, GJ, Gaidano, G, Scott, BL, Greenberg, P, Platzbecker, U, Steensma, DP, Kambhampati, S, Kreuzer, KA, Godley, LA, Atallah, E, Collins, R, Kantarjian, H, Jabbour, E, Wilhelm, FE, Azarnia, N & Silverman, LR 2016, 'Rigosertib versus best supportive care for patients with high-risk myelodysplastic syndromes after failure of hypomethylating drugs (ONTIME): A randomised, controlled, phase 3 trial', The Lancet Oncology. https://doi.org/10.1016/S1470-2045(16)00009-7
Garcia-Manero, Guillermo ; Fenaux, Pierre ; Al-Kali, Aref ; Baer, Maria R. ; Sekeres, Mikkael A. ; Roboz, Gail J. ; Gaidano, Gianluca ; Scott, Bart L. ; Greenberg, Peter ; Platzbecker, Uwe ; Steensma, David P. ; Kambhampati, Suman ; Kreuzer, Karl Anton ; Godley, Lucy A. ; Atallah, Ehab ; Collins, Robert ; Kantarjian, Hagop ; Jabbour, Elias ; Wilhelm, Francois E. ; Azarnia, Nozar ; Silverman, Lewis R. / Rigosertib versus best supportive care for patients with high-risk myelodysplastic syndromes after failure of hypomethylating drugs (ONTIME) : A randomised, controlled, phase 3 trial. In: The Lancet Oncology. 2016.
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abstract = "Background: Hypomethylating drugs are the standard treatment for patients with high-risk myelodysplastic syndromes. Survival is poor after failure of these drugs; there is no approved second-line therapy. We compared the overall survival of patients receiving rigosertib and best supportive care with that of patients receiving best supportive care only in patients with myelodysplastic syndromes with excess blasts after failure of azacitidine or decitabine treatment. Methods: We did this randomised controlled trial at 74 hospitals and university medical centres in the USA and Europe. We enrolled patients with diagnosis of refractory anaemia with excess blasts (RAEB)-1, RAEB-2, RAEB-t, or chronic myelomonocytic leukaemia based on local site assessment, and treatment failure with a hypomethylating drug in the past 2 years. Patients were randomly assigned (2:1) to receive rigosertib 1800 mg per 24 h via 72-h continuous intravenous infusion administered every other week or best supportive care with or without low-dose cytarabine. Randomisation was stratified by pretreatment bone marrow blast percentage. Neither patients nor investigators were masked to treatment assignment. The primary outcome was overall survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT01241500. Findings: From Dec 13, 2010, to Aug 15, 2013, we enrolled 299 patients: 199 assigned to rigosertib, 100 assigned to best supportive care. Median follow-up was 19·5 months (IQR 11·9-27·3). As of Feb 1, 2014, median overall survival was 8·2 months (95{\%} CI 6·1-10·1) in the rigosertib group and 5·9 months (4·1-9·3) in the best supportive care group (hazard ratio 0·87, 95{\%} CI 0·67-1·14; p=0·33). The most common grade 3 or higher adverse events were anaemia (34 [18{\%}] of 184 patients in the rigosertib group vs seven [8{\%}] of 91 patients in the best supportive care group), thrombocytopenia (35 [19{\%}] vs six [7{\%}]), neutropenia (31 [17{\%}] vs seven [8{\%}]), febrile neutropenia (22 [12{\%}] vs ten [11{\%}]), and pneumonia (22 [12{\%}] vs ten [11{\%}]). 41 (22{\%}) of 184 patients in the rigosertib group and 30 (33{\%}) of 91 patients in the best supportive care group died due to adverse events and three deaths were attributed to rigosertib treatment. Interpretation: Rigosertib did not significantly improve overall survival compared with best supportive care. A randomised phase 3 trial of rigosertib (NCT 02562443) is underway in specific subgroups of patients deemed to be at high risk, including patients with very high risk per the Revised International Prognostic Scoring System criteria. Funding: Onconova Therapeutics, Leukemia & Lymphoma Society.",
author = "Guillermo Garcia-Manero and Pierre Fenaux and Aref Al-Kali and Baer, {Maria R.} and Sekeres, {Mikkael A.} and Roboz, {Gail J.} and Gianluca Gaidano and Scott, {Bart L.} and Peter Greenberg and Uwe Platzbecker and Steensma, {David P.} and Suman Kambhampati and Kreuzer, {Karl Anton} and Godley, {Lucy A.} and Ehab Atallah and Robert Collins and Hagop Kantarjian and Elias Jabbour and Wilhelm, {Francois E.} and Nozar Azarnia and Silverman, {Lewis R.}",
year = "2016",
doi = "10.1016/S1470-2045(16)00009-7",
language = "English (US)",
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TY - JOUR

T1 - Rigosertib versus best supportive care for patients with high-risk myelodysplastic syndromes after failure of hypomethylating drugs (ONTIME)

T2 - A randomised, controlled, phase 3 trial

AU - Garcia-Manero, Guillermo

AU - Fenaux, Pierre

AU - Al-Kali, Aref

AU - Baer, Maria R.

AU - Sekeres, Mikkael A.

AU - Roboz, Gail J.

AU - Gaidano, Gianluca

AU - Scott, Bart L.

AU - Greenberg, Peter

AU - Platzbecker, Uwe

AU - Steensma, David P.

AU - Kambhampati, Suman

AU - Kreuzer, Karl Anton

AU - Godley, Lucy A.

AU - Atallah, Ehab

AU - Collins, Robert

AU - Kantarjian, Hagop

AU - Jabbour, Elias

AU - Wilhelm, Francois E.

AU - Azarnia, Nozar

AU - Silverman, Lewis R.

PY - 2016

Y1 - 2016

N2 - Background: Hypomethylating drugs are the standard treatment for patients with high-risk myelodysplastic syndromes. Survival is poor after failure of these drugs; there is no approved second-line therapy. We compared the overall survival of patients receiving rigosertib and best supportive care with that of patients receiving best supportive care only in patients with myelodysplastic syndromes with excess blasts after failure of azacitidine or decitabine treatment. Methods: We did this randomised controlled trial at 74 hospitals and university medical centres in the USA and Europe. We enrolled patients with diagnosis of refractory anaemia with excess blasts (RAEB)-1, RAEB-2, RAEB-t, or chronic myelomonocytic leukaemia based on local site assessment, and treatment failure with a hypomethylating drug in the past 2 years. Patients were randomly assigned (2:1) to receive rigosertib 1800 mg per 24 h via 72-h continuous intravenous infusion administered every other week or best supportive care with or without low-dose cytarabine. Randomisation was stratified by pretreatment bone marrow blast percentage. Neither patients nor investigators were masked to treatment assignment. The primary outcome was overall survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT01241500. Findings: From Dec 13, 2010, to Aug 15, 2013, we enrolled 299 patients: 199 assigned to rigosertib, 100 assigned to best supportive care. Median follow-up was 19·5 months (IQR 11·9-27·3). As of Feb 1, 2014, median overall survival was 8·2 months (95% CI 6·1-10·1) in the rigosertib group and 5·9 months (4·1-9·3) in the best supportive care group (hazard ratio 0·87, 95% CI 0·67-1·14; p=0·33). The most common grade 3 or higher adverse events were anaemia (34 [18%] of 184 patients in the rigosertib group vs seven [8%] of 91 patients in the best supportive care group), thrombocytopenia (35 [19%] vs six [7%]), neutropenia (31 [17%] vs seven [8%]), febrile neutropenia (22 [12%] vs ten [11%]), and pneumonia (22 [12%] vs ten [11%]). 41 (22%) of 184 patients in the rigosertib group and 30 (33%) of 91 patients in the best supportive care group died due to adverse events and three deaths were attributed to rigosertib treatment. Interpretation: Rigosertib did not significantly improve overall survival compared with best supportive care. A randomised phase 3 trial of rigosertib (NCT 02562443) is underway in specific subgroups of patients deemed to be at high risk, including patients with very high risk per the Revised International Prognostic Scoring System criteria. Funding: Onconova Therapeutics, Leukemia & Lymphoma Society.

AB - Background: Hypomethylating drugs are the standard treatment for patients with high-risk myelodysplastic syndromes. Survival is poor after failure of these drugs; there is no approved second-line therapy. We compared the overall survival of patients receiving rigosertib and best supportive care with that of patients receiving best supportive care only in patients with myelodysplastic syndromes with excess blasts after failure of azacitidine or decitabine treatment. Methods: We did this randomised controlled trial at 74 hospitals and university medical centres in the USA and Europe. We enrolled patients with diagnosis of refractory anaemia with excess blasts (RAEB)-1, RAEB-2, RAEB-t, or chronic myelomonocytic leukaemia based on local site assessment, and treatment failure with a hypomethylating drug in the past 2 years. Patients were randomly assigned (2:1) to receive rigosertib 1800 mg per 24 h via 72-h continuous intravenous infusion administered every other week or best supportive care with or without low-dose cytarabine. Randomisation was stratified by pretreatment bone marrow blast percentage. Neither patients nor investigators were masked to treatment assignment. The primary outcome was overall survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT01241500. Findings: From Dec 13, 2010, to Aug 15, 2013, we enrolled 299 patients: 199 assigned to rigosertib, 100 assigned to best supportive care. Median follow-up was 19·5 months (IQR 11·9-27·3). As of Feb 1, 2014, median overall survival was 8·2 months (95% CI 6·1-10·1) in the rigosertib group and 5·9 months (4·1-9·3) in the best supportive care group (hazard ratio 0·87, 95% CI 0·67-1·14; p=0·33). The most common grade 3 or higher adverse events were anaemia (34 [18%] of 184 patients in the rigosertib group vs seven [8%] of 91 patients in the best supportive care group), thrombocytopenia (35 [19%] vs six [7%]), neutropenia (31 [17%] vs seven [8%]), febrile neutropenia (22 [12%] vs ten [11%]), and pneumonia (22 [12%] vs ten [11%]). 41 (22%) of 184 patients in the rigosertib group and 30 (33%) of 91 patients in the best supportive care group died due to adverse events and three deaths were attributed to rigosertib treatment. Interpretation: Rigosertib did not significantly improve overall survival compared with best supportive care. A randomised phase 3 trial of rigosertib (NCT 02562443) is underway in specific subgroups of patients deemed to be at high risk, including patients with very high risk per the Revised International Prognostic Scoring System criteria. Funding: Onconova Therapeutics, Leukemia & Lymphoma Society.

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