A Phase 1b (OX1222) Dose-Finding Study of OXi4503 Combined with Cytarabine in Patients with Relapsed/Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome

Introduction

The vascular disrupting agent OXi4503, induces apoptosis in malignant myeloblasts, removes their endothelial cell protection, and sensitizes blasts to the cytotoxic effects of cytarabine. Cogle et al confirmed the safety and feasibility of intravenous (IV) OXi4503 up to doses of 7.81 mg/m² (maximum tolerated dose [MTD] not reached) in patients with relapsed/refractory acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) (data on file). Based on these data, a Phase 1b dose-finding study was initiated to evaluate the safety and tolerability of combined therapy with OXi4503 and cytarabine for a similar patient population.

Methods

The primary objective of this ongoing study (NCT02576301) was to determine the MTD of OXi4503 in combination with intermediate-dose cytarabine in patients with relapsed/refractory AML or MDS. Pharmacokinetic/pharmacodynamic studies and a preliminary assessment of efficacy were secondary endpoints. Escalating doses of OXi4503 (based on a modified Fibonacci scheme and beginning at 3.75 mg/m²) were administered IV over 10 minutes on Days 1 and 4. Fixed dose cytarabine (1 g/m²) was administered IV over 2 hours on Days 1-5 and preceded infusion of OXi4503 on Days 1 and 4. Cycles were repeated every 28 days. Part 1 of the study was opened for patients with relapsed/refractory AML or MDS (following failure of at least 1 prior hypomethylating agent) who had good organ function, ECOG performance status of 0-2, and normal values for PT and INR (based on bleeding events observed with single-agent OXi4503). Key exclusion criteria included acute promyelocytic leukemia, absolute peripheral blood myeloblast count >20,000/mm³, uncontrolled hypertension, prolonged QTc, history of recent significant CV events, history of hemorrhagic stroke, and any requirement for full dose anti-coagulation.

Results

Between December 2015 and May 2016, 7 patients with relapsed/refractory AML were enrolled (6 evaluable). Median age was 51.5 years (range 26-68), 50% were male, 83% and 17% had ECOG performance status scores of 1 or 2, respectively. Subjects had failed a median of 4.2 (range: 2-6) prior therapies and all patients had intermediate- or adverse-risk cytogenetics. Five of 6 patients (83%) received 1 cycle of therapy while 1 patient received 2 cycles. Four of 6 patients (67%) withdrew from the study for progressive disease (PD) and 1 patient withdrew with stable disease (SD). The final patient achieved a morphological complete remission (mCR) after 2 cycles and proceeded to donor lymphocyte infusion. One patient in the 3.75 mg/m² cohort experienced a dose-limiting toxicity of hypofibrinogenemia, but no clinical evidence of bleeding. Following correction with cryoprecipitate, fibrinogen returned to normal and remained normal without further intervention. The most common (>10% incidence) Grade 3/4 treatment-emergent adverse events attributable to the combination of OXi4503 and cytarabine included neutropenic fever, anemia, platelet count decrease, neutrophil count decrease, fibrinogen decrease, AST increase, hypokalemia, and D-dimer increase.

Conclusions

The vascular disrupting agent OXi4503 (3.75 mg/m²) in combination with cytarabine (1 g/m²/day) is generally well tolerated with preliminary evidence of activity in heavily pretreated, refractory AML patients. This Phase 1b study continues to recruit patients into the second cohort, OXi4503 (4.68 mg/m²) plus cytarabine (1 g/m²/day), as the optimal dose combination has yet to be defined.