Background: We have demonstrated that blood vessels can be a sanctuary site for acute myeloid leukemia (AML). Therefore, we evaluated a novel vascular disrupting agent, OXi4503, for the treatment of patients with AML and higher risk myelodysplastic syndromes (MDS).Methods: Patients with AML and MDS were treated with OXi4503 monotherapy in a phase IA 3x3 dose escalation/de-escalation study (ClinicalTrials.gov NCT01085656). Drug was administered via intravenous infusion on days 1, 8, 15, and 22 of a 28-day cycle. Dose escalation occurred as tolerated according to protocol. With the goal of defining maximum tolerated dose (MTD), patients were monitored for side effects and dose-limiting toxicities (DLTs). Therapy continued until drug intolerance or disease progression.Results: From May 2011 to May 2015, 18 patients diagnosed with refractory MDS (RAEB-1 or RAEB-2) or refractory AML were treated with OXi4503. Overall, 78% of patients were male, while 22% were female. The median patient age was 63 years (range, 24 to 80). Sixteen of 18 (89%) of patients had refractory AML and 2/18 (11%) had refractory MDS. For patients with AML, 11/16 (69%) were intermediate and 5/16 (31%) unfavorable cytogenetic risk. For patients with MDS, one had intermediate and one had very poor cytogenetic risk. The median number of prior therapies was 4 (range, 1-10). In two small run-up cohorts, two patients received 2.5 mg/m2 IV weekly and two received 3.75 mg/m2. In the main trial, nine patients received 5 mg/m2, three received 6.25 mg/m2, and two received 7.81 mg/m2. Expansion of the 5 mg/m2 cohort occurred after two patients withdrew due to disease progression and one patient withdrew due to grade 4 disseminated intravascular coagulopathy (DIC). The median number of cycles received was 1 (range, 1-10).Transient elevations in D-dimer were observed in 14/18 patients (78%). DIC was observed in 5/18 patients (28%). Four of five patients with DIC only had laboratory evidence and no clinical sequelae. One patient treated with 5 mg/m2 died of DIC; however, he also had evidence of infection. The coagulopathic laboratory changes typically resolved within 4-6 days. Fever occurred in 7/18 patients (39%) and typically resolved within 24 hours after drug administration. Fever was irrespective of coagulopathic laboratory changes. Other drug-related side effects (all grades) included bone pain in 5/18 (28%), flu-like symptoms in 5/18 (28%), hypertension in 5/18 (28%), thrombocytopenia in 5/18 (28%). Grade 3 or 4 hypertension and QT prolongation were not observed.One patient achieved a marrow complete remission after one cycle, but then died of fungal pneumonia. Another patient achieved partial remission and received 10 cycles of OXi4503 treatment. He eventually withdrew from the study due to disease progression.Conclusions: OXi4503 doses of up to 7.81 mg/m2 have been safely and feasibly administered to patients with AML and MDS. The MTD has not been reached and the trial is ongoing. Based on evidence that OXi4503 chemosensitizes AML cells to cell cycle agents, after reaching MTD, the next step is a phase IB/II clinical trial combining OXi4503 with cytarabine in relapsed/refractory AML and MDS. DisclosuresOff Label Use: OXi4503. Chaplin:OXiGENE: Employment. Cogle:OXiGENE: Research Funding.