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

Fatih M. Uckun, Christopher R. Cogle, Tara L. Lin, Sanjive Qazi, Vuong N. Trieu, Gary Schiller, Justin M. Watts

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article number74
JournalCancers
Volume12
Issue number1
DOIs
StatePublished - Jan 2020

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Diphosphates
Cytarabine
Acute Myeloid Leukemia
Febrile Neutropenia
Maximum Tolerated Dose
Safety
Survival
Myelodysplastic Syndromes
Drug-Related Side Effects and Adverse Reactions
Heterografts
Respiratory Insufficiency
Thrombocytopenia
Hypotension
Blood Vessels
Asp(5)-oxytocin
Oxi 4503
Clinical Studies
combretastatin A-1
Anemia
Pneumonia

Keywords

  • AML
  • Clinical study
  • Combretastatin
  • Leukemia
  • OXA

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

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. / Uckun, Fatih M.; Cogle, Christopher R.; Lin, Tara L.; Qazi, Sanjive; Trieu, Vuong N.; Schiller, Gary; Watts, Justin M.

In: Cancers, Vol. 12, No. 1, 74, 01.2020.

Research output: Contribution to journalArticle

Uckun, Fatih M. ; Cogle, Christopher R. ; Lin, Tara L. ; Qazi, Sanjive ; Trieu, Vuong N. ; Schiller, Gary ; Watts, Justin M. / 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. In: Cancers. 2020 ; Vol. 12, No. 1.
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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.",
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