Work

Safety, feasibility and preliminary efficacy of single agent combretastatin A1 diphosphate (OXi4503) in patients with relapsed or refractory acute myeloid leukemia or myelodysplastic syndromes

Year: 2020

Type: article

Abstract: Dear Editor, Refractory disease is one of the greatest challenges in managing patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS).1 Previously, we identified blood vessels as a sanctuary site for relapsed or refractory (R/R) AML.2,3 Given the numerous mechanisms by which endothelial cells (ECs) protect and promote AML cells, we reasoned that a broader strategy of vascular disruption, rather than pinpoint inhibition of angiogenesis, may be necessary for therapeutic purposes. The vascular disrupting agent, combretastatin-A1 disphosphate (CA1P, OXi4503), has two mechanisms of action when regressing AML: it alters EC shape and reduces AML adhesiveness, and it generates cytotoxic reactive oxygen species (ROS) in AML cells.4,5 In preclinical models of systemic and extramedullary AML, CA1P was found to be safe and effective in regressing AML.5-7 This phase IA clinical trial was undertaken to examine the safety and feasibility of CA1P (OXi4503) in patients with R/R AML or MDS. To our knowledge, this is the first report on the clinical effects of vascular disruption in patients with hematological malignancies. A total of 19 adult R/R AML and MDS patients received weekly intravenous (IV) injections with single agent CA1P (OXi4503) (Data S1). A standard '3 + 3' clinical trial design was used, and safety and efficacy were assessed using standardized national and international criteria (Data S1). A summary of patient demographics and disease characteristics are presented in Table I. CA1P (OXi4503) was tested at 5 dose levels, ranging from 2.5 to 7.81 mg/m2. An overview of CA1P dosing per patient and their best overall responses (BOR) is presented in Table II. All AEs, of any grade, possibly, probably or definitely attributed to CA1P are listed in Table SI by system organ classification and preferred term. Two patients experienced a Grade 5 AE: one with intracranial hemorrhage associated with DIC and one with ARDS. Treatment-emergent AEs that were possibly, probably or definitely attributed to CA1P are listed in Table SII. The most common Grade 3/4 AEs included increased D-dimer, thrombocytopenia, febrile neutropenia, bone/back pain, and flu-like symptoms. D-dimer increases occurred in nearly 80% of patients and was used as a pharmacodynamic (PD) marker for drug exposure. Using the phase 1A protocol definition of MTD, 6.25 mg/m2 was identified as the MTD and recommended phase 2 dose level (RP2D). Neither bone marrow myeloblast percentage, nor myeloblast immunophenotype, nor patient age, nor bone marrow vascularity (measured as microvessels per area), nor genetic mutations, nor D-dimer increase correlated with treatment response. This phase IA clinical trial was undertaken to examine the safety and feasibility of CA1P (OXi4503) in patients with R/R AML or MDS. Our results provide unprecedented clinical evidence that CA1P can be safely administered in an outpatient setting for vascular disruption at dose levels as high as 6.25 mg/m2. CA1P showed a reproducible and medically manageable safety profile but required standard supportive care as well as specific medications for risk mitigation related to subclinical DIC, bone pain, flu-like symptoms, hypertension, myelosuppression and febrile neutropenia. Previously, we reported that the coagulation effects from CA1P were due to shedding of prothrombotic microparticles from treated myeloblasts.8 We also discovered with preclinical AML models CA1P chemosensitized AML cells to cytarabine and other chemotherapy drugs.8 In particular, we found that we could maintain experimental remission rates by combining reduced doses of CA1P with cytarabine. The safety and feasibility data from this clinical study and the newly generated experimental data led to a phase IB clinical study of CA1P combined with cytarabine (OXA regimen) in patients with relapsed or refractory AML or MDS.9 In summary, CA1P monotherapy was feasible and demonstrated a tolerable safety profile in R/R AML or MDS patients, with preliminary evidence of efficacy. The authors thank the patients and families, research coordinators, and clinical support staff. This study was supported by the Leukemia & Lymphoma Society Therapy Acceleration Program. CRC received a Scholar in Clinical Research award from the Leukemia & Lymphoma Society (grant 2400-13). BC and DT were supported by the Medical Student Research Program at the University of Florida. CA1P (OXi4503) was provided by (OXiGENE, South San Francisco, CA, USA). Publication costs were covered by the Gatorade Foundation, which is administered by the University of Florida Department of Medicine. CRC and LCP designed the study. WSM, JSM, JH, JH, RB, MN, JRW and CRC recruited and treated patients. LCP and CC collected the data. FU analyzed the results. CRC, BC, DT, KH and ZB wrote the manuscript. All authors reviewed the manuscript, provided edits, and gave final approval. FU was an employee of Oncotelic which has licensed the rights to use CA1P for the treatment of AML or MDS. All other authors declare no conflict of interest. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Source: British Journal of Haematology

DOI: 10.1111/bjh.16629