Document Detail


Oral sapacitabine for the treatment of acute myeloid leukaemia in elderly patients: a randomised phase 2 study.
MedLine Citation:
PMID:  23075701     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: Available treatments for acute myeloid leukaemia (AML) have limited durable activity and unsatisfactory safety profiles in most elderly patients. We assessed the efficacy and toxicity of sapacitabine, a novel oral cytosine nucleoside analogue, in elderly patients with AML.
METHODS: In this randomised, phase 2 study, we recruited patients with AML who were either treatment naive or at first relapse and who were aged 70 years or older from 12 centres in the USA. We used a computer-generated randomisation sequence to randomly allocate eligible patients to receive one of three schedules of oral sapacitabine (1:1:1; stratified by a history of AML treatment): 200 mg twice a day for 7 days (group A); 300 mg twice a day for 7 days (group B); and 400 mg twice a day for 3 days each week for 2 weeks (group C). All schedules were given in 28 day cycles. To confirm the safety and tolerability of dosing schedules, after 20 patients had been treated in a group we enrolled an expanded cohort of 20-25 patients to that group if at least four patients had achieved complete remission or complete remission with incomplete blood count recovery, and if the 30 day death rate was 20% or less. Our primary endpoint was 1-year overall survival, analysed by intention-to-treat (ie, patients who have received at least one dose of sapacitabine) in those patients who had been randomly allocated to treatment. This trial is registered with ClinicalTrials.gov, number NCT00590187.
RESULTS: Between Dec 27, 2007, and April 21, 2009, we enrolled 105 patients: 86 patients were previously untreated and 19 were at first relapse. Of the 60 patients randomly allocated to treatment, 1-year overall survival was 35% (95% CI 16-59) in group A, 10% (2-33) in group B, and 30% (13-54) in group C. 14 (13%) of 105 patients died within 30 days and 27 (26%) died within 60 days. The most common grade 3-4 adverse events were anaemia (eight of 40 patients in group A, 12 of 20 patients in group B, and 15 of 45 patients in group C), neutropenia (14 in group A, 10 in group B, 11 in group C), thrombocytopenia (24 in group A, 12 in group B, and 22 in group C), febrile neutropenia (16 in group A, nine in group B, and 22 in group C), and pneumonia (seven in group A, five in group B, and 10 in group C). The most common grade 5 events were pneumonia (two in group A, one in group B, and three in group C) and sepsis (six in group A, three in group B, and one in group C). Seven deaths were thought to be probably or possibly related to sapacitabine treatment.
INTERPRETATION: Sapacitabine seems active and tolerable in elderly patients with AML. The 400 mg dose schedule had the best efficacy profile. Future investigations should aim to combine sapacitabine with other low-intensity therapies in elderly patients with AML.
FUNDING: Cyclacel Limited.
Authors:
Hagop Kantarjian; Stefan Faderl; Guillermo Garcia-Manero; Selina Luger; Parameswaran Venugopal; Lori Maness; Meir Wetzler; Steven Coutre; Wendy Stock; David Claxton; Stuart L Goldberg; Martha Arellano; Stephen A Strickland; Karen Seiter; Gary Schiller; Elias Jabbour; Judy Chiao; William Plunkett
Publication Detail:
Type:  Clinical Trial, Phase II; Journal Article; Randomized Controlled Trial; Research Support, Non-U.S. Gov't     Date:  2012-10-15
Journal Detail:
Title:  The lancet oncology     Volume:  13     ISSN:  1474-5488     ISO Abbreviation:  Lancet Oncol.     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-11-02     Completed Date:  2013-04-03     Revised Date:  2014-03-06    
Medline Journal Info:
Nlm Unique ID:  100957246     Medline TA:  Lancet Oncol     Country:  England    
Other Details:
Languages:  eng     Pagination:  1096-104     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 Elsevier Ltd. All rights reserved.
Data Bank Information
Bank Name/Acc. No.:
ClinicalTrials.gov/NCT00590187
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MeSH Terms
Descriptor/Qualifier:
Administration, Oral
Aged
Aged, 80 and over
Anemia / chemically induced,  pathology
Arabinonucleosides / administration & dosage*,  adverse effects*
Cytosine / administration & dosage,  adverse effects,  analogs & derivatives*
Disease-Free Survival
Drug Administration Schedule
Female
Humans
Kaplan-Meier Estimate
Leukemia, Myeloid, Acute / drug therapy*,  mortality,  pathology*
Male
Neutropenia / chemically induced,  pathology
Pneumonia / chemically induced,  pathology
Thrombocytopenia / chemically induced,  pathology
Grant Support
ID/Acronym/Agency:
P30 CA016672/CA/NCI NIH HHS; P50 CA100632/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Arabinonucleosides; 0/sapacitabine; 8J337D1HZY/Cytosine
Comments/Corrections
Comment In:
Lancet Oncol. 2012 Nov;13(11):1065-6   [PMID:  23116996 ]

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