OXi4503 (combretastatin A1 di-phosphate / CA1P) is a dual-mechanism vascular disrupting agent that is being developed in clinical trials for the treatment of leukemias. Like its structural analog, ZYBRESTAT, OXi4503 has been observed to block and destroy tumor vasculature, resulting in extensive tumor cell death and necrosis. In addition, in preclinical studies published in the journal Blood, OXi4503 demonstrated potent activity against AML in animal models.

OXi4503 is currently being investigated in an investigator sponsored Phase 1 study of OXi4503 for the treatment of patients with acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS).  The open-label, dose-escalating study, which isbeing conducted by researchers at the University of Florida and is sponsored in part by The Leukemia & Lymphoma Society's Therapy Acceleration Program, will be conducted in patients with relapsed or refractory AML or MDS and will evaluate the safety profile, maximum tolerated dose (MTD) and biologic activity of OXi4503. For more information on this ongoing study, please visit our clinical trials page.

Clinical data from the Phase 1 trial were presented as an online abstract at the 2012 annual meeting of the American Society of Hematology in Atlanta, Georgia. The data showed responses and a manageable safety profile in this first-in-man trial of a VDA in AML. The ongoing open-label, dose-escalating study is evaluating the safety profile, maximum tolerated dose (MTD) and biologic activity of OXi4503. Results were presented on 5 patients with refractory AML enrolled between May, 2011 and August, 2012. The median number of prior therapies was 4 (range, 1-7). Two subjects were assigned to the 2.5 mg/m2 dosing cohort, 2 received 3.75 mg/m2 and 1 received 5 mg/m2. None of these patients developed dose-limiting toxicities. Adverse events attributable to OXi4503 infusion included bone pain, fever, anemia and thrombocytopenia. Hypertension was manageable and plasma LDH and uric acid increased by at least two-fold within hours after OXi4503 infusions, suggesting leukemia cell destruction.

Overall response was 2/5 (40%), with 1 patient achieving a marrow complete remission (mCR) and 1 patient achieving a partial remission (PR). The median number of cycles was 1 (range 1-6). Three of 5 subjects discontinued the study due to AML progression and one due to pneumonia. One patient with AML treated with 5 mg/m2 OXi4503 has received 6 months of treatment and continues to receive weekly infusions.

In this preclinical study, researchers administered OXi4503 to mice that were carriers of human AML, which were then studied for disease regression. The data from these models showed that OXi4503 produced remissions in AML models of differing subtypes, including those with activating mutations in the high-risk subtype FLT3.

Additional information regarding the study can be found online at http://news.medinfo.ufl.edu/articles/from-the-lab/uf-oncologists-fight-leukemia-with-two-pronged-therapy-clinical-trials-to-start-within-months/.