TY - JOUR
T1 - Two dosing regimens of tosedostat in elderly patients with relapsed or refractory acute myeloid leukaemia (OPAL)
T2 - A randomised open-label phase 2 study
AU - Cortes, Jorge
AU - Feldman, Eric
AU - Yee, Karen
AU - Rizzieri, David
AU - Advani, Anjali S.
AU - Charman, Anthony
AU - Spruyt, Richard
AU - Toal, Martin
AU - Kantarjian, Hagop
N1 - Funding Information:
The study was designed by the sponsor and steering committee members (JC, EF, KY). Data were obtained by study investigators and monitored by a contract research organisation funded by Chroma Therapeutics. The primary analysis was done by the contract research organisation and subsequent analysis by RS and reviewed by MT. The report was written by MT and reviewed, modified, and approved by all authors. All authors had access to all raw and processed data from the study. The corresponding author had final responsibility for the integrity of the data and submission of the report.
Funding Information:
JC, EF, and KY were members of the steering committee; JC and EF received compensation from Chroma Therapeutics for this role. JC, EF, KY, DR, ASA, and HK received research funding from Chroma Therapeutics for this study. JC is receiving research funding from Chroma Therapeutics and Cell Therapeutics for another study with tosedostat. AC, RS, and MT are employees of Chroma Therapeutics.
Funding Information:
The study was funded by Chroma Therapeutics, Abingdon, UK. The findings have been presented in part at the 2011 meeting of the American Society for Clinical Oncology, Chicago, IL, USA; the 6th International Congress on Myeloproliferative Diseases and Myelodysplastic Syndromes, Nov 3–4, 2011, New York, NY, USA; and the 53rd Annual Meeting of the American Society of Hematology, San Diego, CA, USA, Dec 10–13, 2011. We thank patients and their families who participated in the study, and the investigators and clinical trial sites for their participation in the OPAL study.
PY - 2013/4
Y1 - 2013/4
N2 - Background: Tosedostat is a novel oral aminopeptidase inhibitor with clinical activity in a previous phase 1-2 study in elderly patients with relapsed or refractory acute myeloid leukaemia (AML). We aimed to compare two dosing regimens of tosedostat. Methods: In this randomised phase 2 study, patients aged 60 years or older with AML that had relapsed after a first complete remission lasting less than 12 months, or had achieved no previous complete remission, were randomly assigned (1:1) to receive as first salvage tosedostat 120 mg once daily for 6 months or 240 mg once daily for 2 months followed by 120 mg for 4 months. Randomisation was by block method via an interactive web response system using a randomisation schedule generated by an external vendor, with no stratification. The study was open label. The primary endpoint was the proportion of patients who obtained a complete remission or complete remission with incomplete platelet recovery. Analyses included all patients randomly assigned to treatment groups who received at least one oral dose of tosedostat. The study is registered with ClinicalTrials.gov, number NCT00780598. Findings: 38 patients were randomly assigned to receive tosedostat 120 mg and 38 to receive the tosedostat 240 mg to 120 mg regimen. 38 patients in the 120 mg group and 35 in the 240 mg to 120 mg group received tosedostat. Seven patients (10%) had complete remission or complete remission with incomplete platelet recovery: two (5%) in the 120 mg group and five (14%) in the 240 mg to 120 mg group. The most common grade 3 or worse adverse events were febrile neutropenia (11 [29%] patients in the 120 mg group and ten [29%] of the 240 mg to 120 mg group), thrombocytopenia (eight [21%] and eight [23%] patients), fatigue (seven [18%] and eight [23%] patients), dyspnoea (five [13%] and seven [20%] patients), and pneumonia (four [11%] and six [17%] patients). There were five fatal adverse events deemed to be treatment-related: three in the 120 mg group and two in the 240 mg to 120 mg group. The events were acute hepatitis, respiratory failure, pneumonia, atrial fibrillation, and left ventricular dysfunction. Interpretation: Tosedostat, at either dose schedule, has activity in older patients with relapsed or refractory AML. Additional studies of tosedostat including combination with hypomethylating agents and low-dose cytarabine in patients with high-risk myelodysplastic syndromes and AML are ongoing or planned. Funding: Chroma Therapeutics.
AB - Background: Tosedostat is a novel oral aminopeptidase inhibitor with clinical activity in a previous phase 1-2 study in elderly patients with relapsed or refractory acute myeloid leukaemia (AML). We aimed to compare two dosing regimens of tosedostat. Methods: In this randomised phase 2 study, patients aged 60 years or older with AML that had relapsed after a first complete remission lasting less than 12 months, or had achieved no previous complete remission, were randomly assigned (1:1) to receive as first salvage tosedostat 120 mg once daily for 6 months or 240 mg once daily for 2 months followed by 120 mg for 4 months. Randomisation was by block method via an interactive web response system using a randomisation schedule generated by an external vendor, with no stratification. The study was open label. The primary endpoint was the proportion of patients who obtained a complete remission or complete remission with incomplete platelet recovery. Analyses included all patients randomly assigned to treatment groups who received at least one oral dose of tosedostat. The study is registered with ClinicalTrials.gov, number NCT00780598. Findings: 38 patients were randomly assigned to receive tosedostat 120 mg and 38 to receive the tosedostat 240 mg to 120 mg regimen. 38 patients in the 120 mg group and 35 in the 240 mg to 120 mg group received tosedostat. Seven patients (10%) had complete remission or complete remission with incomplete platelet recovery: two (5%) in the 120 mg group and five (14%) in the 240 mg to 120 mg group. The most common grade 3 or worse adverse events were febrile neutropenia (11 [29%] patients in the 120 mg group and ten [29%] of the 240 mg to 120 mg group), thrombocytopenia (eight [21%] and eight [23%] patients), fatigue (seven [18%] and eight [23%] patients), dyspnoea (five [13%] and seven [20%] patients), and pneumonia (four [11%] and six [17%] patients). There were five fatal adverse events deemed to be treatment-related: three in the 120 mg group and two in the 240 mg to 120 mg group. The events were acute hepatitis, respiratory failure, pneumonia, atrial fibrillation, and left ventricular dysfunction. Interpretation: Tosedostat, at either dose schedule, has activity in older patients with relapsed or refractory AML. Additional studies of tosedostat including combination with hypomethylating agents and low-dose cytarabine in patients with high-risk myelodysplastic syndromes and AML are ongoing or planned. Funding: Chroma Therapeutics.
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U2 - 10.1016/S1470-2045(13)70037-8
DO - 10.1016/S1470-2045(13)70037-8
M3 - Article
C2 - 23453583
AN - SCOPUS:84875803803
VL - 14
SP - 354
EP - 362
JO - The Lancet Oncology
JF - The Lancet Oncology
SN - 1470-2045
IS - 4
ER -