Continuous intravenous infusion of DFP-10917 is well tolerated and appears effective in phase I/II trials in patients with relapsed or refractory acute myeloid leukemia

Cytotoxic chemotherapy is still a mainstay in acute myeloid leukemia (AML) treatment.¹ DFP-10917 is a deoxycytidine nucleoside analogue. Whilst structurally related to the nucleoside analogs gemcitabine, cytarabine and decitabine, DFP-10917 has a cyanide (CN) side chain, which provides a unique mechanism of inducing DNA damage.²

Hagop M. Kantarjian from The University of Texas MD Anderson Cancer Center and colleagues conducted a single-center, open-label phase I/II study (NCT01702155) to firstly determine the maximum tolerated dose (MTD), the phase II dose and dose-limiting toxicities (DLTs) of DFP-10917 treatment and secondly to evaluate the overall response rate (ORR).³

Phase I study design and patient population

• Adult patients (≥ 18 years old) with refractory or recurrent AML that was pathologically documented
• Eastern Cooperative Oncology Group (ECOG) performance <3
• No cardiac, renal or central nervous system illnesses
• Patients ≥3 previous treatment regimens: 53%
• Two-stage dose escalation: (n = 39):
  • Stage 1: 7-day continuous IV infusion plus 21-day rest (n = 27) with 8 dose levels of DFP-10917 (4–35 mg/m²/day) starting at 4 mg/m²/day
  • Stage 2: 14-day continuous IV infusion plus 14-day rest (n = 12) with a starting dose of 10 mg/m²/day, determined by the MTD and adverse events (AEs) reported during stage 1
• Primary objective: determine MTD, recommended dose for phase II (RP2D) and DLTs
• Secondary objectives:
  • Overall response rate (ORR) using complete response (CR), CR without platelet recovery (CRp), CR with incomplete blood count recovery (CRi), partial response (PR))
  • Pharmacokinetic profile of the drug

Phase I safety

Stage 1 (n = 27)

• DLTs:
  • Grade 3 diarrhea (n = 1) (dose: 35 mg/m²/day)
  • Two patients completed cycle 1 with no DLTs (dose: 35 mg/m²/day)
  • Grade 3 AE (tremor) during cycle 2 (n = 1) (dose: 25 mg/m²/day)
• Starting dose of 10 mg/m²/day as a 14-day continuous infusion was selected for Stage 2

Stage 2 (n = 12):

• Two patients out of 4 who completed course 1 (10 mg/m²/day as 14-day continuous IV infusion) experienced DLTs:
  • One patient had prolonged hyercellularity and delayed bone marrow recovery and the other Grade 3 abdominal pain, diarrhea and vomiting
• Of these two patients:
  • Dose decreased to 6 mg/m²/day and completed 5 cycles (n = 1)
  • Dose decreased to 6 mg/m²/day and then 4 mg/m²/day and completed 21 cycles (n = 1)
• The next cohort was treated at 6 mg/m²/day (n = 7):
  • No grade 3/4 non-hematologic AEs aside from 1 incidence of Grade 3 fatigue
  • MTD/RP2D: 6 mg/m²/day as 14-day continuous IV infusion

Phase I pharmacokinetic profile

• DFP-10917 concentrations at Day 8 (steady state) for dose 4 to 35 mg/m²/day as 7-day continuous infusion: 1.49–28.9 ng/mL
• CNDAU (metabolite) concentrations on Day 8: 3.49–40.1 ng/mL
• Higher CNDAU systemic concentrations were associated with DLT events

 Phase I efficacy

• Stage 1: evaluable for efficacy: n = 23
  • ORR: 4.3% (95% CI, 0.1%–21.9%)
  • CRi at 6 mg/m²/day
• Stage 2: evaluable for efficacy: (n = 10)
  • Two patients had a CR at the 10 mg/m²/day dose
  • Seven patients achieved ≥50% decrease bone marrow blasts
  • One patient initially was treated at 10 mg/m²/day with subsequent dose reductions to 6 mg/m²/day and then 4 mg/m²/day received 21 cycles of treatment with continuous remission
  • RP2D schedule: 14-day continuous intravenous infusion followed by 14-day rest

Phase II design and patient population

• Eligibility was limited to patients with histologically confirmed AML based on the WHO classification, disease that was refractory after standard therapy, or disease for which conventional systemic chemotherapy was not reliably effective or no effective therapy was available
• Patients with newly diagnosed AML over the age of 60 who were ineligible for, or who refused, standard of care, were eligible
• Patients ≥3 previous treatment regimens: 33%
• Cytogenetic profile (n = 30): 15 vs 13 vs 2 (intermediate risk vs high risk vs inadequate mitoses)
• DFP-10917 dose: 6 mg/m²/day 14-day continuous IV infusion as determined by phase I results (n = 30)
• Primary objective: ORR
• Secondary objectives:
  • CR, CRp, CRi
  • Duration of complete remission
  • Duration of overall response
  • Overall survival (OS)

Phase II safety (n = 30)

• No serious AEs or deaths related to DFP-10917
• Drug-related AEs ≥ Grade 3:
  • Decreased white blood cell court: 53.3% (n = 16)
  • Decreased platelet count: 46.7% (n = 14)
  • Anemia: 36.7% (n = 11)
  • Decreased neutrophil count: 16.7% (n = 5)
  • Fatigue: 3.3% (n = 1)
• Of patients receiving 3–6 courses (n = 7), dose reductions took place due to:
  • Myelosuppression (n = 4)
  • Fatigue (n = 1)

Phase II efficacy

• Evaluable for efficacy: 29 patients
• ORR and overall CR rate both: 48.3% (95% CI, 29.4–67.5%)
  • CR: 20.7% (n = 6)
  • CRp: 3.4% (n = 1)
  • CRi: 24.1% (n = 7)
  • Stable disease for 8 weeks: 6.9% (n = 2)
• Of the 14 patients with a CR or CRp/CRi: (n = 14)
  • CR achieved in the following cycles: cycle 1 (n = 11) vs cycle 2 (n = 2) vs cycle 3 (n = 1)
  • Cytogenetic profile: 11 vs 2 vs 1 (intermediate risk vs high risk vs inadequate mitoses)
  • Median duration of response: 137 days (95% CI, 75–208 days)
  • PFS at 1 vs 3 vs 4 vs 6 months: 92.9% vs 64.3% vs 50% vs 42.9%
• Median OS: 221 days (95% CI, 118–284 days)
  • OS at 6 vs 12 months: 58.6% vs 20.7%
• Stem cell transplant was subsequently conducted at the time of CR or CRi after 1–3 cycles of DFP-10917 in 5/30 patients.
  • All had received anthracycline and cytarabine induction therapy
  • DFP-10917 was their third or fourth line treatment
  • OS in these patients: 221, 236, 277, 540 and ≥ 1095 days from initiation of DFP-10917 treatment

This study demonstrates that 6mg/m²/day of DFP-10917 can be administered as a 14-day continuous intravenous infusion of a 28-day cycle and is effective and tolerated in patients with recurrent or refractory AML. The ORR of 48% is significant since DFP-10917 is a single agent showing significant antileukemic effect, which may improve the outcome of patients with advanced AML. The group plan to conduct a randomized phase III study comparing the standard of care to DFP-10917 monotherapy in early recurrent or refractory AML patients.