AML depends on blood vessel networks for disease progression and protection from chemotherapy. In prior preclinical work, we demonstrated that the vascular disrupting combretastatin, OXi4503, had significant activity against human AML by dual targeting of nascent blood vessels and malignant myeloblasts. Therefore, we initiated a phase I clinical study of OXi4503 in patients with relapsed and refractory AML and MDS.
The primary objectives of the phase I dose finding study (NCT01085656) were to assess safety and determine maximal tolerated dose (MTD) in patients with refractory AML or MDS (RAEB-1, RAEB-2). OXi4503 was administered by intravenous infusion over 10 minutes on Days 1, 8, 15 and 22 of each 28-day cycle, and escalated according to a defined dose schema. Continued weekly dosing was permitted until disease progression or unacceptable toxicities.
Between May 2011 and August 2013, 11 patients with refractory AML or advanced MDS were enrolled. The median age was 62 years (range, 24–76). Most patients were male (82%). Cytogenetics were unfavorable in 7 patients and intermediate in 4. The median number of prior therapies was 4 (range, 1–5). Two subjects received 2.5 mg/m2, two received 3.75 mg/m2, and seven received 5 mg/m2. The 5 mg/m2 cohort was expanded because 1 patient developed a grade 4 DIC without hemorrhage and 2 withdrew due to rapid disease progression. Median number of cycles was 1 (range, 0-10). 7/11 subjects (64%) had transient increases in D-dimer that resolved one week after OXi4503 infusion. Other adverse events attributable to OXi4503 infusion included bone pain, fever, anemia, and thrombocytopenia. No patients developed grade 3 or 4 hypertension or QT prolongation. Plasma LDH and Uric Acid increased by at least two-fold within hours after OXi4503 infusions. One patient treated with 2.5 mg/m2 achieved a marrow complete remission (mCR) within the first cycle of therapy and then died of a pneumonia in the second cycle. Another patient treated with 5 mg/m2 achieved a partial remission (PR) and received 10 cycles of therapy. 10/11 (91%) subjects discontinued the study due to disease progression and 1 due to pneumonia. Analysis of bone marrow after OXi4503 infusions revealed vascular sinusoids lined with plump endothelial cells (ECs) and increased VEGF, indicating treatment effects.
The vascular disrupting combretastatin OXi4503 is well tolerated with preliminary evidence of disease response in heavily pre-treated, refractory AML and advanced MDS. Biological activity associated with OXi4503 included transient increases in D-dimer, changes in bone marrow EC morphology, and an angiogenic cytokine response. The phase I study continues to recruit subjects, as an optimal dose has yet to be defined. It is estimated that an additional 12-15 subjects will be required to reach MTD.
Chaplin:OXiGENE: Consultancy. Cogle:OXiGENE: Research Funding; Leukemia & Lymphoma Society: Research Funding.
Asterisk with author names denotes non-ASH members.