International randomized phase III study of elacytarabine versus investigator choice in patients with relapsed/refractory acute myeloid leukemia.
OBJECTIVE
Most patients with acute myeloid leukemia (AML) eventually experience relapse. Relapsed/refractory AML has a dismal prognosis and currently available treatment options are generally ineffective. The objective of this large, international, randomized clinical trial was to investigate the efficacy of elacytarabine, a novel elaidic acid ester of cytarabine, versus the investigator's choice of one of seven commonly used AML salvage regimens, including high-dose cytarabine, multiagent chemotherapy, hypomethylating agents, hydroxyurea, and supportive care.


METHODS
A total of 381 patients with relapsed/refractory AML were treated in North America, Europe, and Australia. Investigators selected a control treatment for individual patients before random assignment. The primary end point was overall survival (OS).


RESULTS
There were no significant differences in OS (3.5 v 3.3 months), response rate (23% v 21%), or relapse-free survival (5.1 v 3.7 months) between the elacytarabine and control arms, respectively. There was no significant difference in OS among any of the investigator's choice regimens. Prolonged survival was only achieved in a few patients in both study arms whose disease responded and who underwent allogeneic stem-cell transplantation.


CONCLUSIONS
Neither elacytarabine nor any of the seven alternative treatment regimens provided clinically meaningful benefit to these patients. OS in both study arms and for all treatments was extremely poor. Novel agents, novel clinical trial designs, and novel strategies of drug development are all desperately needed for this patient population.
Gail J. Roboz, Weill Cornell Medical College and the New York Presbyterian Hospital; Todd Rosenblat, Columbia University Medical Center, New York, NY; Martha Arellano, Winship Cancer Institute at Emory University; Scott R. Solomon, The Blood and Marrow Transplant Group of Georgia, Atlanta, GA; Jessica K. Altman, Francis J. Giles, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL; Casey O'Connell, University of Southern California Norris Comprehensive Cancer Center and Hospital, Los Angeles, CA; Marco Gobbi, Azienda Ospedaliera Universitaria San Martino, University of Genoa, Genoa, Italy; Pau Montesinos, Hospital Universitario y Politécnico La Fé, Valencia, Spain; Arnaud Pigneux, Centre Hospitalier Universitaire de Bordeaux Hôpital Haut-Lévêque, Pessac; Norbert Vey, L'Institut Paoli-Calmettes, Marseilles, France; Robert Hills, Cardiff University School of Medicine, Cardiff, United Kingdom; Tove Flem Jacobsen, Athos Gianella-Borradori, Øivind Foss, and Sylvia Vetrhus, Clavis Pharma ASA, Oslo, Norway. gar2001@med.cornell.edu.
Gail J
GJ
Roboz
Gail J. Roboz, Weill Cornell Medical College and the New York Presbyterian Hospital; Todd Rosenblat, Columbia University Medical Center, New York, NY; Martha Arellano, Winship Cancer Institute at Emory University; Scott R. Solomon, The Blood and Marrow Transplant Group of Georgia, Atlanta, GA; Jessica K. Altman, Francis J. Giles, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL; Casey O'Connell, University of Southern California Norris Comprehensive Cancer Center and Hospital, Los Angeles, CA; Marco Gobbi, Azienda Ospedaliera Universitaria San Martino, University of Genoa, Genoa, Italy; Pau Montesinos, Hospital Universitario y Politécnico La Fé, Valencia, Spain; Arnaud Pigneux, Centre Hospitalier Universitaire de Bordeaux Hôpital Haut-Lévêque, Pessac; Norbert Vey, L'Institut Paoli-Calmettes, Marseilles, France; Robert Hills, Cardiff University School of Medicine, Cardiff, United Kingdom; Tove Flem Jacobsen, Athos Gianella-Borradori, Øivind Foss, and Sylvia Vetrhus, Clavis Pharma ASA, Oslo, Norway.
Todd
T
Rosenblat
Gail J. Roboz, Weill Cornell Medical College and the New York Presbyterian Hospital; Todd Rosenblat, Columbia University Medical Center, New York, NY; Martha Arellano, Winship Cancer Institute at Emory University; Scott R. Solomon, The Blood and Marrow Transplant Group of Georgia, Atlanta, GA; Jessica K. Altman, Francis J. Giles, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL; Casey O'Connell, University of Southern California Norris Comprehensive Cancer Center and Hospital, Los Angeles, CA; Marco Gobbi, Azienda Ospedaliera Universitaria San Martino, University of Genoa, Genoa, Italy; Pau Montesinos, Hospital Universitario y Politécnico La Fé, Valencia, Spain; Arnaud Pigneux, Centre Hospitalier Universitaire de Bordeaux Hôpital Haut-Lévêque, Pessac; Norbert Vey, L'Institut Paoli-Calmettes, Marseilles, France; Robert Hills, Cardiff University School of Medicine, Cardiff, United Kingdom; Tove Flem Jacobsen, Athos Gianella-Borradori, Øivind Foss, and Sylvia Vetrhus, Clavis Pharma ASA, Oslo, Norway.
Martha
M
Arellano
Gail J. Roboz, Weill Cornell Medical College and the New York Presbyterian Hospital; Todd Rosenblat, Columbia University Medical Center, New York, NY; Martha Arellano, Winship Cancer Institute at Emory University; Scott R. Solomon, The Blood and Marrow Transplant Group of Georgia, Atlanta, GA; Jessica K. Altman, Francis J. Giles, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL; Casey O'Connell, University of Southern California Norris Comprehensive Cancer Center and Hospital, Los Angeles, CA; Marco Gobbi, Azienda Ospedaliera Universitaria San Martino, University of Genoa, Genoa, Italy; Pau Montesinos, Hospital Universitario y Politécnico La Fé, Valencia, Spain; Arnaud Pigneux, Centre Hospitalier Universitaire de Bordeaux Hôpital Haut-Lévêque, Pessac; Norbert Vey, L'Institut Paoli-Calmettes, Marseilles, France; Robert Hills, Cardiff University School of Medicine, Cardiff, United Kingdom; Tove Flem Jacobsen, Athos Gianella-Borradori, Øivind Foss, and Sylvia Vetrhus, Clavis Pharma ASA, Oslo, Norway.
Marco
M
Gobbi
Gail J. Roboz, Weill Cornell Medical College and the New York Presbyterian Hospital; Todd Rosenblat, Columbia University Medical Center, New York, NY; Martha Arellano, Winship Cancer Institute at Emory University; Scott R. Solomon, The Blood and Marrow Transplant Group of Georgia, Atlanta, GA; Jessica K. Altman, Francis J. Giles, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL; Casey O'Connell, University of Southern California Norris Comprehensive Cancer Center and Hospital, Los Angeles, CA; Marco Gobbi, Azienda Ospedaliera Universitaria San Martino, University of Genoa, Genoa, Italy; Pau Montesinos, Hospital Universitario y Politécnico La Fé, Valencia, Spain; Arnaud Pigneux, Centre Hospitalier Universitaire de Bordeaux Hôpital Haut-Lévêque, Pessac; Norbert Vey, L'Institut Paoli-Calmettes, Marseilles, France; Robert Hills, Cardiff University School of Medicine, Cardiff, United Kingdom; Tove Flem Jacobsen, Athos Gianella-Borradori, Øivind Foss, and Sylvia Vetrhus, Clavis Pharma ASA, Oslo, Norway.
Jessica K
JK
Altman
Gail J. Roboz, Weill Cornell Medical College and the New York Presbyterian Hospital; Todd Rosenblat, Columbia University Medical Center, New York, NY; Martha Arellano, Winship Cancer Institute at Emory University; Scott R. Solomon, The Blood and Marrow Transplant Group of Georgia, Atlanta, GA; Jessica K. Altman, Francis J. Giles, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL; Casey O'Connell, University of Southern California Norris Comprehensive Cancer Center and Hospital, Los Angeles, CA; Marco Gobbi, Azienda Ospedaliera Universitaria San Martino, University of Genoa, Genoa, Italy; Pau Montesinos, Hospital Universitario y Politécnico La Fé, Valencia, Spain; Arnaud Pigneux, Centre Hospitalier Universitaire de Bordeaux Hôpital Haut-Lévêque, Pessac; Norbert Vey, L'Institut Paoli-Calmettes, Marseilles, France; Robert Hills, Cardiff University School of Medicine, Cardiff, United Kingdom; Tove Flem Jacobsen, Athos Gianella-Borradori, Øivind Foss, and Sylvia Vetrhus, Clavis Pharma ASA, Oslo, Norway.
Pau
P
Montesinos
Gail J. Roboz, Weill Cornell Medical College and the New York Presbyterian Hospital; Todd Rosenblat, Columbia University Medical Center, New York, NY; Martha Arellano, Winship Cancer Institute at Emory University; Scott R. Solomon, The Blood and Marrow Transplant Group of Georgia, Atlanta, GA; Jessica K. Altman, Francis J. Giles, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL; Casey O'Connell, University of Southern California Norris Comprehensive Cancer Center and Hospital, Los Angeles, CA; Marco Gobbi, Azienda Ospedaliera Universitaria San Martino, University of Genoa, Genoa, Italy; Pau Montesinos, Hospital Universitario y Politécnico La Fé, Valencia, Spain; Arnaud Pigneux, Centre Hospitalier Universitaire de Bordeaux Hôpital Haut-Lévêque, Pessac; Norbert Vey, L'Institut Paoli-Calmettes, Marseilles, France; Robert Hills, Cardiff University School of Medicine, Cardiff, United Kingdom; Tove Flem Jacobsen, Athos Gianella-Borradori, Øivind Foss, and Sylvia Vetrhus, Clavis Pharma ASA, Oslo, Norway.
Casey
C
O'Connell
Gail J. Roboz, Weill Cornell Medical College and the New York Presbyterian Hospital; Todd Rosenblat, Columbia University Medical Center, New York, NY; Martha Arellano, Winship Cancer Institute at Emory University; Scott R. Solomon, The Blood and Marrow Transplant Group of Georgia, Atlanta, GA; Jessica K. Altman, Francis J. Giles, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL; Casey O'Connell, University of Southern California Norris Comprehensive Cancer Center and Hospital, Los Angeles, CA; Marco Gobbi, Azienda Ospedaliera Universitaria San Martino, University of Genoa, Genoa, Italy; Pau Montesinos, Hospital Universitario y Politécnico La Fé, Valencia, Spain; Arnaud Pigneux, Centre Hospitalier Universitaire de Bordeaux Hôpital Haut-Lévêque, Pessac; Norbert Vey, L'Institut Paoli-Calmettes, Marseilles, France; Robert Hills, Cardiff University School of Medicine, Cardiff, United Kingdom; Tove Flem Jacobsen, Athos Gianella-Borradori, Øivind Foss, and Sylvia Vetrhus, Clavis Pharma ASA, Oslo, Norway.
Scott R
SR
Solomon
Gail J. Roboz, Weill Cornell Medical College and the New York Presbyterian Hospital; Todd Rosenblat, Columbia University Medical Center, New York, NY; Martha Arellano, Winship Cancer Institute at Emory University; Scott R. Solomon, The Blood and Marrow Transplant Group of Georgia, Atlanta, GA; Jessica K. Altman, Francis J. Giles, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL; Casey O'Connell, University of Southern California Norris Comprehensive Cancer Center and Hospital, Los Angeles, CA; Marco Gobbi, Azienda Ospedaliera Universitaria San Martino, University of Genoa, Genoa, Italy; Pau Montesinos, Hospital Universitario y Politécnico La Fé, Valencia, Spain; Arnaud Pigneux, Centre Hospitalier Universitaire de Bordeaux Hôpital Haut-Lévêque, Pessac; Norbert Vey, L'Institut Paoli-Calmettes, Marseilles, France; Robert Hills, Cardiff University School of Medicine, Cardiff, United Kingdom; Tove Flem Jacobsen, Athos Gianella-Borradori, Øivind Foss, and Sylvia Vetrhus, Clavis Pharma ASA, Oslo, Norway.
Arnaud
A
Pigneux
Gail J. Roboz, Weill Cornell Medical College and the New York Presbyterian Hospital; Todd Rosenblat, Columbia University Medical Center, New York, NY; Martha Arellano, Winship Cancer Institute at Emory University; Scott R. Solomon, The Blood and Marrow Transplant Group of Georgia, Atlanta, GA; Jessica K. Altman, Francis J. Giles, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL; Casey O'Connell, University of Southern California Norris Comprehensive Cancer Center and Hospital, Los Angeles, CA; Marco Gobbi, Azienda Ospedaliera Universitaria San Martino, University of Genoa, Genoa, Italy; Pau Montesinos, Hospital Universitario y Politécnico La Fé, Valencia, Spain; Arnaud Pigneux, Centre Hospitalier Universitaire de Bordeaux Hôpital Haut-Lévêque, Pessac; Norbert Vey, L'Institut Paoli-Calmettes, Marseilles, France; Robert Hills, Cardiff University School of Medicine, Cardiff, United Kingdom; Tove Flem Jacobsen, Athos Gianella-Borradori, Øivind Foss, and Sylvia Vetrhus, Clavis Pharma ASA, Oslo, Norway.
Norbert
N
Vey
Gail J. Roboz, Weill Cornell Medical College and the New York Presbyterian Hospital; Todd Rosenblat, Columbia University Medical Center, New York, NY; Martha Arellano, Winship Cancer Institute at Emory University; Scott R. Solomon, The Blood and Marrow Transplant Group of Georgia, Atlanta, GA; Jessica K. Altman, Francis J. Giles, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL; Casey O'Connell, University of Southern California Norris Comprehensive Cancer Center and Hospital, Los Angeles, CA; Marco Gobbi, Azienda Ospedaliera Universitaria San Martino, University of Genoa, Genoa, Italy; Pau Montesinos, Hospital Universitario y Politécnico La Fé, Valencia, Spain; Arnaud Pigneux, Centre Hospitalier Universitaire de Bordeaux Hôpital Haut-Lévêque, Pessac; Norbert Vey, L'Institut Paoli-Calmettes, Marseilles, France; Robert Hills, Cardiff University School of Medicine, Cardiff, United Kingdom; Tove Flem Jacobsen, Athos Gianella-Borradori, Øivind Foss, and Sylvia Vetrhus, Clavis Pharma ASA, Oslo, Norway.
Robert
R
Hills
Gail J. Roboz, Weill Cornell Medical College and the New York Presbyterian Hospital; Todd Rosenblat, Columbia University Medical Center, New York, NY; Martha Arellano, Winship Cancer Institute at Emory University; Scott R. Solomon, The Blood and Marrow Transplant Group of Georgia, Atlanta, GA; Jessica K. Altman, Francis J. Giles, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL; Casey O'Connell, University of Southern California Norris Comprehensive Cancer Center and Hospital, Los Angeles, CA; Marco Gobbi, Azienda Ospedaliera Universitaria San Martino, University of Genoa, Genoa, Italy; Pau Montesinos, Hospital Universitario y Politécnico La Fé, Valencia, Spain; Arnaud Pigneux, Centre Hospitalier Universitaire de Bordeaux Hôpital Haut-Lévêque, Pessac; Norbert Vey, L'Institut Paoli-Calmettes, Marseilles, France; Robert Hills, Cardiff University School of Medicine, Cardiff, United Kingdom; Tove Flem Jacobsen, Athos Gianella-Borradori, Øivind Foss, and Sylvia Vetrhus, Clavis Pharma ASA, Oslo, Norway.
Tove Flem
TF
Jacobsen
Gail J. Roboz, Weill Cornell Medical College and the New York Presbyterian Hospital; Todd Rosenblat, Columbia University Medical Center, New York, NY; Martha Arellano, Winship Cancer Institute at Emory University; Scott R. Solomon, The Blood and Marrow Transplant Group of Georgia, Atlanta, GA; Jessica K. Altman, Francis J. Giles, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL; Casey O'Connell, University of Southern California Norris Comprehensive Cancer Center and Hospital, Los Angeles, CA; Marco Gobbi, Azienda Ospedaliera Universitaria San Martino, University of Genoa, Genoa, Italy; Pau Montesinos, Hospital Universitario y Politécnico La Fé, Valencia, Spain; Arnaud Pigneux, Centre Hospitalier Universitaire de Bordeaux Hôpital Haut-Lévêque, Pessac; Norbert Vey, L'Institut Paoli-Calmettes, Marseilles, France; Robert Hills, Cardiff University School of Medicine, Cardiff, United Kingdom; Tove Flem Jacobsen, Athos Gianella-Borradori, Øivind Foss, and Sylvia Vetrhus, Clavis Pharma ASA, Oslo, Norway.
Athos
A
Gianella-Borradori
Gail J. Roboz, Weill Cornell Medical College and the New York Presbyterian Hospital; Todd Rosenblat, Columbia University Medical Center, New York, NY; Martha Arellano, Winship Cancer Institute at Emory University; Scott R. Solomon, The Blood and Marrow Transplant Group of Georgia, Atlanta, GA; Jessica K. Altman, Francis J. Giles, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL; Casey O'Connell, University of Southern California Norris Comprehensive Cancer Center and Hospital, Los Angeles, CA; Marco Gobbi, Azienda Ospedaliera Universitaria San Martino, University of Genoa, Genoa, Italy; Pau Montesinos, Hospital Universitario y Politécnico La Fé, Valencia, Spain; Arnaud Pigneux, Centre Hospitalier Universitaire de Bordeaux Hôpital Haut-Lévêque, Pessac; Norbert Vey, L'Institut Paoli-Calmettes, Marseilles, France; Robert Hills, Cardiff University School of Medicine, Cardiff, United Kingdom; Tove Flem Jacobsen, Athos Gianella-Borradori, Øivind Foss, and Sylvia Vetrhus, Clavis Pharma ASA, Oslo, Norway.
Øivind
Ø
Foss
Gail J. Roboz, Weill Cornell Medical College and the New York Presbyterian Hospital; Todd Rosenblat, Columbia University Medical Center, New York, NY; Martha Arellano, Winship Cancer Institute at Emory University; Scott R. Solomon, The Blood and Marrow Transplant Group of Georgia, Atlanta, GA; Jessica K. Altman, Francis J. Giles, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL; Casey O'Connell, University of Southern California Norris Comprehensive Cancer Center and Hospital, Los Angeles, CA; Marco Gobbi, Azienda Ospedaliera Universitaria San Martino, University of Genoa, Genoa, Italy; Pau Montesinos, Hospital Universitario y Politécnico La Fé, Valencia, Spain; Arnaud Pigneux, Centre Hospitalier Universitaire de Bordeaux Hôpital Haut-Lévêque, Pessac; Norbert Vey, L'Institut Paoli-Calmettes, Marseilles, France; Robert Hills, Cardiff University School of Medicine, Cardiff, United Kingdom; Tove Flem Jacobsen, Athos Gianella-Borradori, Øivind Foss, and Sylvia Vetrhus, Clavis Pharma ASA, Oslo, Norway.
Sylvia
S
Vetrhusand
Gail J. Roboz, Weill Cornell Medical College and the New York Presbyterian Hospital; Todd Rosenblat, Columbia University Medical Center, New York, NY; Martha Arellano, Winship Cancer Institute at Emory University; Scott R. Solomon, The Blood and Marrow Transplant Group of Georgia, Atlanta, GA; Jessica K. Altman, Francis J. Giles, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL; Casey O'Connell, University of Southern California Norris Comprehensive Cancer Center and Hospital, Los Angeles, CA; Marco Gobbi, Azienda Ospedaliera Universitaria San Martino, University of Genoa, Genoa, Italy; Pau Montesinos, Hospital Universitario y Politécnico La Fé, Valencia, Spain; Arnaud Pigneux, Centre Hospitalier Universitaire de Bordeaux Hôpital Haut-Lévêque, Pessac; Norbert Vey, L'Institut Paoli-Calmettes, Marseilles, France; Robert Hills, Cardiff University School of Medicine, Cardiff, United Kingdom; Tove Flem Jacobsen, Athos Gianella-Borradori, Øivind Foss, and Sylvia Vetrhus, Clavis Pharma ASA, Oslo, Norway.
Francis J
FJ
Giles
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D003561:Cytarabine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D020732:Cytogenetic Analysis; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D006932:Hyperbilirubinemia / Q000139:chemically induced; D006937:Hypercholesterolemia / Q000139:chemically induced; D007391:International Cooperation; D053208:Kaplan-Meier Estimate; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D012008:Recurrence; D017211:Treatment Failure
D000970:Antineoplastic Agents; D003561:Cytarabine; C047645:5'-oleoyl cytarabine