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

• Published in: Cancers Vol. 12; no. 1; p. 74
• Main Authors: Uckun, Fatih M, Cogle, Christopher R, Lin, Tara L, Qazi, Sanjive, Trieu, Vuong N, Schiller, Gary, Watts, Justin M
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 26.12.2019; MDPI
• Subjects: Acute myeloid leukemia; Adverse events; aml; Animal models; Antitumor activity; Binding sites; Bone marrow; clinical study; combretastatin; Cytarabine; Cytotoxicity; Drug dosages; Hypertension; Hypotension; Leukemia; Medical prognosis; Myelodysplastic syndrome; Myeloid leukemia; Neutropenia; oxa; Patients; Pneumonia; Thrombocytopenia; Xenografts; AML; clinical study; combretastatin; leukemia; OXA
• DOI: 10.3390/cancers12010074
• ISSN: 2072-6694

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 ( = 2), pneumonia/acute respiratory failure ( = 1), and hypotension ( = 1). 9.76 mg/m was defined as the MTD of OXi4503 when administered in combination with 1 g/m 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, -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.