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3804 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

Acute Myeloid Leukemia: Novel Therapy, excluding Transplantation
Program: Oral and Poster Abstracts
Session: 616. Acute Myeloid Leukemia: Novel Therapy, excluding Transplantation: Poster III
Monday, December 7, 2015, 6:00 PM-8:00 PM
Hall A, Level 2 (Orange County Convention Center)

Hagop Kantarjian, MD1, Elias Jabbour, MD1, Guillermo Garcia-Manero, MD2, Tapan Kadia, MD3, Courtney DiNardo, MD1, Naval Daver, MD1, Gautam Borthakur, MD1, Nitin Jain, MD1, Jane Waukau, RN, BSN1*, Monica Kwari, RN, BSN1, Barry Douglas Anderson, MD, PhD4*, Kenzo Iizuka5*, Cheng Jin, MD, PhD5* and William Plunkett, PhD1

1The University of Texas MD Anderson Cancer Center, Houston, TX
2Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX
3Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
4Theradex Systems Inc., Princeton, NJ
5Delta-Fly Pharma Inc., Tokushima, Japan

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.

Disclosures: DiNardo: Novartis: Research Funding . Waukau: The University of Texas MD Anderson Cancer Center: Employment . Kwari: The University of Texas MD Anderson Cancer Center: Employment . Iizuka: Delta-Fly Pharma, Inc.: Employment . Jin: Delta-Fly Pharma, Inc.: Employment .

*signifies non-member of ASH