Results of a Phase I/II Study of DFP-10917, a Nucleoside Analog, Given By Continuous Infusion (CI) in Patients (pts) with Relapsed or Refractory Acute Leukemia

Background:

DFP-10917 is a nucleoside analog similar to cytarabine with a unique mechanism of action upon prolonged administration at a low dose. Under such administration, DFP-10917 is converted to its nucleotide form and then incorporated into tumor DNA to cause DNA strand breaks resulting in G2/M phase-arrest by cell-checkpoint regulators and ultimately the apoptosis of tumor cells.

Methods:

In Phase I, DFP-10917 was administered by 7-day CI followed by 21 days rest (P1-stage 1) or 14-day CI followed by 14 days rest (P1-stage 2) in pts with relapsed or refractory acute leukemia to determine the maximum tolerated dose (MTD), recommended phase 2 dose (RP2D) and dose-limiting toxicity (DLT) of CI DFP-10917. 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 aged 60 years or older . The study design assumed that a response rate (CR, CRi, CRp and PR) of at least 20% would justify further study of DFP-10917, based on a Simon two-stage optimal design (i.e., > 1/10 pts respond in P2-stage 1, then an additional 19 pts to be enrolled in P2-stage 2). Overall, if > 4/29 pts respond, DFP-10917 warrants further investigation.

Results:

In P1-stage 1, 27 pts received a 7-day CI of DFP-10917 at eight escalating doses ranging from 4 to 35 mg/m²/day. At the 35 mg/m² dose level, one patient experienced a cycle 1 DLT of grade 3 diarrhea. The starting dose for P1-stage 2 was calculated as two-thirds the cumulative 7-day DFP-10917 dose at the MTD of 30 mg/ m²/day divided by 14-day resulting in a dose of 10 mg/m²/day x 14 days. In P1-stage 2, the 10 mg/m²/day x 14-day CI dose resulted in DLTs of prolonged hypo-cellularity in 2 of 4 pts. At the 6 mg/m²/day x 14-day dose level, 1 of 6 evaluable pts in a cohort experienced a DLT of prolonged hypo-cellularity, and the MTD/RD was defined as 6 mg/m²/day x 14-day CI. Initial efficacy assessments for P1-stage 2 include leukemia responses observed in 7 of 10 pts (70%) receiving the 14-day DFP-10917 CI; 3 were bone marrow complete responses, and 4 were partial responses. One patient has received more than 11 cycles of DFP-10917 CI to date with ongoing CR.

In P2-stage 1, 10 pts (8 salvage AML, 2 first-treatment for AML) were treated with the RP2D. 5 pts (50%) demonstrated responses; 2 pts had CR, including 1 patient that transitioned to stem cell transplantation (SCT), 1 patient had CRi, 2 patients had marrow CRs, including one patient that transitioned to SCT, and 1 patient with an early marrow response died of pneumonia.

The P2-stage 2 is to enroll an additional 19 pts and enrollment is ongoing. There have been no deaths related to DFP-10917 treatment to date.

Conclusions:

The RP2D of DFP-10917 in relapsed AML was established at 6 mg/m²/day for 14-day CI. In Phase 2, DFP-10917 demonstrates significant activity with a 50% response rate and a tolerable safety profile in relapsed or refractory AML, or pts aged ≥ 60 years with newly diagnosed AML. The final response rate and safety profile of DFP-10917 for the Phase 2 study will be presented.