Phase I/II Study of DFP-10917 in Relapsed/Refractory AML Demonstrates Efficacy and Safety Profile Suitable for Phase III Study

Background:

DFP-10917 is a nucleoside analog similar to cytarabine with a unique mechanism of action when administered at a low dose. Upon prolonged administration, DFP-10917 is converted to its nucleotide form and incorporated into tumor DNA, causing DNA strand breaks. Resulting G2/M phase-arrest by cell-checkpoint regulators ultimately leads to apoptosis of tumor cells.

Methods:

In the Phase 1, DFP-10917 was administered by 7-day continuous infusion (CI) followed by 21 days rest (Phase 1 Stage 1) or 14-day CI followed by 14 days rest (Phase 1 Stage 2) in patients (pts) with relapsed or refractory acute leukemia, to determine the maximum tolerated dose (MTD), recommended phase 2 dose (RP2D) and dose-limiting toxicities (DLT). Phase 2 was an open label, single arm, two-stage study of DFP-10917 administration at the RP2D using a 14-day CI in pts with relapsed or refractory acute myeloid leukemia (AML), or newly diagnosed AML pts ≥60 years not fit for intensive chemotherapy. A Simon 2-stage optimal design was used whereby if ≥1/10 pts responded (CR, CRi, CRp and PR) then an additional 19 pts were to be enrolled. Overall, if ≥4/29 pts respond, DFP-10917 warrants further investigation.

A total of 39 AML pts were enrolled in Phase 1 with mean age 65 years (yrs), range 26-85 yrs. In Phase 1 Stage 1 (7-day CI, n=27) 26 pts received DFP-10917 at 8 escalating doses ranging from 4 to 35 mg/m²/day. One pt had CRi after the first treatment cycle of DFP-10917 at 6 mg/m²/day x 7 days. At 35 mg/m², 1 pt experienced a cycle 1 DLT of grade 3 diarrhea. The starting dose for Phase 1 Stage 2 was calculated as 2/3 the cumulative 7-day dose at the MTD of 35 mg/m²/day divided by 14-day resulting in a dose of 10mg/m²/day×14 days.

In Phase 1 Stage 2, (14-day CI, n=12), DFP-10917 at 10 mg/m²/day×14 days resulted in DLTs of prolonged hypo-cellularity, and the MTD/RP2D was defined as 6mg/m²/day×14days. Two pts had CR-one pt received 5 cycles of treatment and the second had continuous CR for over 22 cycles of DFP-10917 treatment.

A total of 30 pts, all refractory or relapsed AML, were enrolled in Phase 2, mean age 70 yrs, range 45-88 yrs. Phase 2 pts were treated with DFP-10917 at 6 mg/m²/day x 14 days CI. An overall response rate (ORR) of 48% was observed (6 CRs including 2 transitioned to stem cell transplantation (SCT), 7 CRi including 3 transitioned to SCT, and 1 CRp). Among the 14 responding pts, 3 were refractory, 4 were salvage-1 and 7 were salvage-2 or greater. The median Overall Survival was 6.9 months and median Duration of Response was 3.5 months.

The main drug-related AEs >grade 3 were: neutropenia (50%), thrombocytopenia (43%) or anemia (37%). Mild to moderate severity drug-related gastrointestinal AEs were frequently observed (43%) as well as fatigue (13%). No Phase 2 pts discontinued DFP-10917 treatment due to unacceptable drug-related toxicity.

Conclusions:

The RP2D of DFP-10917 was established at 6 mg/m²/day for 14-day CI with 14-day rest. In Phase 2, DFP-10917 demonstrated important anti-leukemia activity. The safety results of DFP-10917 continuous infusion indicated a tolerable safety profile in pts with relapsed or refractory AML. Overall, DFP-10917 shows promise as salvage treatment in pts with refractory or relapsed AML.

Clinical trial information: NCT01702155