Phase 1b/2 Pharmacokinetic/Pharmacodynamic (PK/PD) Study of Combination Voreloxin and Cytarabine in Relapsed or Refractory Acute Myeloid Leukemia Patients.

Abstract 635

Background: Voreloxin is a first-in-class anticancer quinolone derivative (AQD) that intercalates DNA and inhibits topoisomerase II, inducing apoptosis. Nonclinical studies showed synergistic activity when combined with cytarabine (ara-C). We report preliminary results of a Phase (Ph) 1b/2 study of combination voreloxin plus ara-C in relapsed/refractory AML patients. Objectives: 1) safety, tolerability and MTD of escalating doses of voreloxin in combination with ara-C; 2) voreloxin PK; 3) clinical activity by IWG; 4) pharmacodynamic (PD) markers; 5) ex vivo voreloxin resistance in bone marrow aspirates (BMA). Methods: Ph 1b/2 study with dose escalation of voreloxin given on Days 1 and 4 in combination with 2 schedules (sch) of ara-C: Sch A (A-CIV): 400 mg/m²/d continuous IV infusion ara-C X 5 days; Sch B (B-Bolus): 1 g/m²/d 2 hr IV infusion ara-C X 5 days. Voreloxin Ph 1b doses: 10 - 90 mg/m² (A-CIV); 70 - 90 mg/m²(B-Bolus). At MTD, pts are enrolled into Ph 2 arms (dose expansion) to assess response and safety in a first relapse (1^st REL) population (both sch), and a primary refractory (1^oREF) population (B-Bolus only). Pre- and post-dose PBMC were probed for mechanism-based PD responses by western blot probing for DNA damage markers. Pt BMA taken prior to dosing were analyzed ex vivo for resistance to voreloxin and ara-C by a proliferation assay. Clinical response was determined by IWG criteria. Results: To date, 94 patients have been treated. Preliminary safety and overall response rate (ORR = CR + CRp) are available for Ph 1b for both cytarabine schedules and Ph 2 1^st REL for A-CIV. Ph 2 B-Bolus 1^st REL has completed enrollment (N=15); enrollment continues for Ph 2 B-Bolus (1^oREF). Grade 3 or higher non-hematologic AEs ≥ 10% incidence were markedly reduced in Ph 1b B-bolus vs Ph1b A-CIV, notably for infection related AEs and mucositis and 30-day all-cause mortality. Activity: Tabulated results show activity with both ara-C schedules; CR+CRp seen in difficult-to-treat pt populations. In Ph 1b at doses ≥ 80 mg/m², 1^oREF pts ORR was 36% (5 of 14); all but one had failed multiple cycles of induction therapy. A high number of pts have been bridged to transplant (BMT): 8 BMT of 20 CR and 1 PR. CR + CRp have been noted in both B-Bolus Ph 2 expansions, but outcome and safety data are immature. PK/PD: Voreloxin PK were dose proportional from 10–90 mg/m². DNA damage PD response markers, increased pDNA-PKcs and/or pCHK2, were seen in 12 of 23 patients analyzed who received ≥ 34 mg/m² voreloxin. Ex vivo resistance assays of pts' BMA to voreloxin and ara-C suggest that voreloxin is a major contributor to the observed CRs and that the combination has enhanced activity. Conclusions: Voreloxin given in combination with continuous infusion ara-C is well-tolerated, with an encouraging number of pt successfully bridged to BMT. An ORR of 33% was observed in 1^st REL pts txd with ≥ 80 mg/m² voreloxin (all remissions were in pts txd at MTD, 80 mg/m² voreloxin). An ORR rate of 36% was observed in 1^oREF pts, a population with an historical remission rate of 10-15%. CR + CRp have been noted in both B-Bolus Ph 2 expansions, but outcome and safety data are in process. Enrollment in Ph 2 B-Bolus 1^oREF patients is ongoing.