Phase 1b/2 Pharmacokinetic/Pharmacodynamic (PK/PD) Study of Combination Voreloxin and Cytarabine in Relapsed or Refractory Acute Myeloid Leukemia Patients.
Authors: Lancet Jeffrey E , Roboz Gail J. , Cripe Larry D. , Maris Michael , List Alan F , Fox Judith , Michelson Glenn C , Karp Judith 
Published: October 2019

Abstract
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 (1st REL) population (both sch), and a primary refractory (1oREF) 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 1st REL for A-CIV. Ph 2 B-Bolus 1st REL has completed enrollment (N=15); enrollment continues for Ph 2 B-Bolus (1oREF). 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, 1oREF 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 1st 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 1oREF 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 1oREF patients is ongoing.DemographicsPhase1b A-CIV1b B-Bolus2 A-CIV2 B-Bolus2 B-BolusN391816156 of 25Gender71%M72%M69%MECOG 0-198%89%94%Disease StatusFrontline3%0%1st REL23%11%100%100%2nd REL15%11%1oREF33%55%100%REF REL21%22%Not available5%0%CytogeneticsPendingFavorable3%11%0%Intermediate64%28%50%Unfavorable31%22%31%Unknown3%6%6%Not available033%13%Safety–Grade 3 or Higher Adverse Events ≥ 10%Phase1b A-CIV1b B-Bolus2 A-CIVN391816Febrile N54%40%38%Pneumonia15%0%13%Sepsis/bact.38%27%56%Infections15%7%19%Upper GI13%7%6%Lower GI13%0%13%Hypokalaemia28%7%31%Hyperglycaemia13%7%13%Hypophosphataemia10%0%19%Hypoxia3%0%13%Pulmonary Hemorrhage0%0%13%Hypotension10%0%0%DLTN=2 of 7 pts at 90 mg/m2 Grade 3 diarrhea and bowel obstruction Grade 3 oral mucositis lasting ≥ 7 daysN=1 of 6 pts at 80 mg/m2and 90 mg/m2 Odynophagia Grade 3 oral mucositis lasting ≥ 7 daysMTD/Recommended Ph 2 Dose80 mg/m290 mg/m280 mg/m2Outcome1b A-CIV1b B-Bolus2 A-CIV2 B-Bolus2 B-BolusPopulationREL or REFREL or REF1st REL1st REL1oREFN391816156 of 25Median OS days (95% CI)209 (74-258)NANANANACR6363 CR, 1 CRp of 10 evaluable1 CR of 2 evaluableCRp311%CR+CRp22%23%44%TETETETE30-day all-cause mortality21%0%6%0 of 10 evaluable0 of 4 evaluable

Disclosures:
Lancet: Sunesis Pharmaceuticals: Study Steering Committee. Roboz:Sunesis Pharmaceuticals: Study Steering Committee. Cripe:Sunesis Pharmaceuticals: Research Funding. List:Sunesis Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Fox:Sunesis: Employment. Michelson:Sunesis: Employment. Karp:Sunesis Pharmaceuticals: Research Funding.