Phase 1/2 study of DFP-10917 administered by continuous intravenous infusion in patients with recurrent or refractory acute myeloid leukemia.

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/m2 /day as a 7-day continuous intravenous infusion), a DLT of grade 3 diarrhea occurred at a dose of 35 mg/m2 /day. In stage 2 of phase 1, a dose of 10 mg/m2 /day as a 14-day continuous intravenous infusion resulted in DLTs of prolonged hypocellularity, abdominal pain, diarrhea, and vomiting. The dose of 6 mg/m2 /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/m2 /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.

• Authors: Hagop M Kantarjian, Elias J Jabbour, Guillermo Garcia-Manero, Tapan M Kadia, Courtney D DiNardo, Naval G Daver, Gautam Borthakur, Nitin Jain, Jane B Waukau, Monica I Kwari, Farhad Ravandi, Barry D Anderson, Kenzo Iizuka, Cheng Jin, Chun Zhang, William K Plunkett
• Journal: Cancer (Cancer) Vol. 125 Issue 10 Pg. 1665-1673 (05 15 2019) ISSN: 1097-0142 [Electronic] United States
• PMID: 30668890 (Publication Type: Clinical Trial, Phase I, Clinical Trial, Phase II, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 American Cancer Society.

Chemical References

• DFP-10917
• Deoxycytidine

Topics

• Adult
• Aged
• Aged, 80 and over
• Deoxycytidine (administration & dosage, analogs & derivatives)
• Disease-Free Survival
• Dose-Response Relationship, Drug
• Drug Administration Schedule
• Female
• Humans
• Infusions, Intravenous
• Kaplan-Meier Estimate
• Leukemia, Myeloid, Acute (diagnosis, drug therapy, mortality)
• Male
• Maximum Tolerated Dose
• Middle Aged
• Multivariate Analysis
• Prognosis
• Recurrence
• Remission Induction
• Risk Assessment
• Salvage Therapy
• Severity of Illness Index
• Survival Analysis
• Treatment Outcome