A Phase 1B Clinical Study of Combretastatin A1 Diphosphate (OXi4503) and Cytarabine (ARA-C) in Combination (OXA) for Patients with Relapsed or Refractory Acute Myeloid Leukemia

Abstract

Combretastatin A1 (OXi4503) is a dual-function drug with vascular disrupting and cytotoxic properties that has exhibited single-agent anti-leukemia activity in murine xenograft models of acute myeloid leukemia (AML) and in a prior Phase 1A clinical study for relapsed/refractory (R/R) AML. The purpose of the present multicenter Phase 1B study was to define the maximum tolerated dose (MTD) and safety profile of OXi4503 and cytarabine (ARA-C) administered in combination (OXA). At four centers, 29 patients with R/R AML or myelodysplastic syndrome (MDS) were treated with OXA. The most common grade 3/4 treatment-emergent adverse events (AEs) were febrile neutropenia (28%), hypertension (17%), thrombocytopenia (17%), and anemia (14%). There were no treatment-emergent grade 5 AEs. Drug-related serious adverse events (SAEs) developed in 4/29 patients (14%) and included febrile neutropenia (N = 2), pneumonia/acute respiratory failure (N = 1), and hypotension (N = 1). 9.76 mg/m2 was defined as the MTD of OXi4503 when administered in combination with 1 g/m2 ARA-C. In 26 evaluable AML patients, there were 2 complete remissions (CR), 2 complete remissions with incomplete count recovery (CRi) and one partial response (PR), for an overall response rate (ORR) of 19%. The median overall survival (OS) time for the four patients who achieved a CR/CRi was 528 days (95% CI: 434–NA), which was significantly longer than the median OS time of 113 days (95% CI: 77–172) for the remaining 22 patients who did not achieve a CR/CRi (Log Rank Chi Square = 11.8, p-value = 0.0006). The safety and early evidence of efficacy of the OXA regimen in R/R AML patients warrant further investigation in a Phase 2 clinical study.

The Dynamic Interface Between the Bone Marrow Vascular Niche and Hematopoietic Stem Cells in Myeloid Malignancy

“…Phase 1B results were recently reported for OXi4503 in combination with cytarabine in 29 AML and MDS patients with relapsed/refractory disease. Safety profile was encouraging, with a 19% overall response rate observed, including four complete morphological remissions ( Uckun et al, 2019 ). Phase 2 evaluation is ongoing (NCT02576301).…”

Leukemia stem cell-bone marrow microenvironment interplay in acute myeloid leukemia development

“…Further research confirmed that combretastatin A1 also exhibited direct cytotoxic effects on leukemic cells, which was mediated by generation of ROS [ 132 ]. Later, a phase I clinical trials on a novel combination therapy with combretastatin A1 and cytarabine in patients with relapsed/refractory AML displayed a prolonged OS and well tolerance (NCT02576301) [ 133 ].…”

Therapeutic Targeting of the Leukaemia Microenvironment

“…Combretastatin-A1-diphosphate (OXi4503/CA1P), a microtubule-destabilising agent, has been shown to induce vascular disruption, delay tumour growth, and increase survival in HL60 leukaemia-bearing mice [103]. In addition, a recently completed clinical study demonstrated that CA1P administered with cytarabine showed early clinical activity and was well tolerated by patients with relapsed/refractory AML [104]. CA1P has been granted Rare Paediatric Disease designation by the FDA for children with AML, paving the way for further future clinical investigation.…”