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Phase 1/2 study of DFP‐10917 administered by continuous intravenous infusion in patients with recurrent or refractory acute myeloid leukemia
Author(s) -
Kantarjian Hagop M.,
Jabbour Elias J.,
GarciaManero Guillermo,
Kadia Tapan M.,
DiNardo Courtney D.,
Daver Naval G.,
Borthakur Gautam,
Jain Nitin,
Waukau Jane B.,
Kwari Monica I.,
Ravandi Farhad,
Anderson Barry D.,
Iizuka Kenzo,
Jin Cheng,
Zhang Chun,
Plunkett William K.
Publication year - 2019
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/cncr.31923
Subject(s) - medicine , continuous infusion , vomiting , refractory (planetary science) , mucositis , anesthesia , phases of clinical research , gastroenterology , nausea , toxicity , surgery , physics , astrobiology
Abstract Background DFP‐10917, a deoxycytidine nucleoside analogue, has a unique mechanism of action resulting in leukemic cell death when administered for prolonged periods at low doses. The current phase 1/2 study investigated the safety, maximum tolerated dose, and evidence of antileukemic activity for DFP‐10917 administered by 7‐day or 14‐day continuous intravenous infusion in patients with recurrent or refractory acute myeloid leukemia (AML). Methods In the phase 1 dose escalation portion of the study, patients were administered DFP‐10917 by 7‐day continuous intravenous infusion plus 21‐day rest (stage 1) or 14‐day continuous intravenous infusion plus 14‐day rest (stage 2). The primary objectives of phase 1 were to determine the maximum tolerated dose, the phase 2 dose, and the dose‐limiting toxicities (DLTs) of DFP‐10917. The primary objectives of phase 2 were to evaluate the overall response rate of DFP‐10917 using complete response (CR), CR without platelet recovery (CRp), CR with incomplete blood count recovery (CRi) or partial response. Results In stage 1 of phase 1 (4‐35 mg/m 2 /day as a 7‐day continuous intravenous infusion), a DLT of grade 3 diarrhea occurred at a dose of 35 mg/m 2 /day. In stage 2 of phase 1, a dose of 10 mg/m 2 /day as a 14‐day continuous intravenous infusion resulted in DLTs of prolonged hypocellularity, abdominal pain, diarrhea, and vomiting. The dose of 6 mg/m 2 /day as a 14‐day continuous intravenous infusion was found to be well tolerated and was selected for phase 2. Response rates in patients in phase 2 (N = 29) were 20.7% CR, 3.4% CRp, and 24.1% CRi. The overall response rate was 48.3% (95% confidence interval, 29.4%‐67.5%). Conclusions DFP‐10917 as a 14‐day continuous intravenous infusion at a dose of 6 mg/m 2 /day can be administered safely and appears to be effective in patients with recurrent or refractory AML. A phase 3 investigation comparing DFP‐10917 monotherapy versus standard of care in an early recurrent or refractory AML setting is warranted.