TY - JOUR
T1 - Phase 1/2 study of DFP-10917 administered by continuous intravenous infusion in patients with recurrent or refractory acute myeloid leukemia
AU - Kantarjian, Hagop M.
AU - Jabbour, Elias J.
AU - Garcia-Manero, Guillermo
AU - Kadia, Tapan M.
AU - DiNardo, Courtney D.
AU - Daver, Naval G.
AU - Borthakur, Gautam
AU - Jain, Nitin
AU - Waukau, Jane B.
AU - Kwari, Monica I.
AU - Ravandi, Farhad
AU - Anderson, Barry D.
AU - Iizuka, Kenzo
AU - Jin, Cheng
AU - Zhang, Chun
AU - Plunkett, William K.
N1 - Publisher Copyright:
© 2019 American Cancer Society
PY - 2019/5/15
Y1 - 2019/5/15
N2 - 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.
AB - 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.
KW - acute myeloid leukemia (AML)
KW - deoxycytidine
KW - recurrent AML
KW - refractory AML
KW - sapacitabine
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U2 - 10.1002/cncr.31923
DO - 10.1002/cncr.31923
M3 - Article
C2 - 30668890
AN - SCOPUS:85060555833
SN - 0008-543X
VL - 125
SP - 1665
EP - 1673
JO - Cancer
JF - Cancer
IS - 10
ER -