Safety of ON 01910.Na in Patients With Myelodysplasia

The myelodysplastic syndromes (MDS) and acute myelogenous leukemias (AML) are a group of heterogeneous diseases with wide variation in clinical presentation and disease severity. Typically patients are older adults with co-morbidities. AML and MDS are characterized by variable degrees of cytopenias (anemia, neutropenia, thrombocytopenia) due to ineffective hematopoiesis and dysplastic bone marrow morphology or hematological malignancy. Treatment of MDS is unsatisfactory: chemotherapy has a limited role in the management of leukemic progression; autologous stem cell transplantation does not prolong relapse-free survival and stem cell transplantation is poorly tolerated in older individuals. Some MDS patients have been shown to respond to a wide variety of immunosuppressive agents ranging from corticosteroids to cyclosporine (CsA) and horse antithymocyte globulin (h-ATG). However, the overall response rate is less than 30% and relapse continues to be a problem. Few treatments appear to change the natural history of MDS however, growth factors, decitabine, and lenalidomide can improve cytopenias, and 5-azacytidine, can reduce transfusion requirements, and improve quality of life when compared to supportive care. In addition most MDS patients are older and tolerate aggressive therapies poorly. Some AML patients can be cured with chemotherapy or by allogeneic stem cell transplantation. However standard treatment approaches are not effective for patients who become refractory to chemotherapy, elderly patients, and those who relapse after transplantation. The management of MDS and relapsed/refractory AML patients therefore remains unsatisfactory and targeted therapies are needed. One such investigational drug, ON 01910.Na, is a potent inhibitor of cyclin D1 and mitosis. ON01910.Na shows activity against a broad spectrum of tumor cell lines. Animal model studies show little toxicity with a high therapeutic index in these tumors. In addition, the fact that MDS bone marrow (particularly trisomy 8) and patients with AML with the trisomy 8 abnormality (Sloand, unpublished data) over-express cyclin D1 and in vitro studies have demonstrated activity against cytogenetically abnormal cells and blasts despite minimal inhibition of normal hematopoiesis provides a rationale for its use in select patients with MDS or AML. We therefore propose a non-randomized, pilot, dose escalating Phase I study of ON 01910.Na in MDS and patients with refractory AML with trisomy 8. The primary objective is to determine the safety (including the maximum tolerated dose and/or dosing regimen) of ON 01910.Na when administered in escalating doses in select patients with MDS or AML. Secondary objectives include plasma pharmacokinetics and biological effects of ON 01910.Na on cell-cycle pathways of MDS or AML cells, and bone marrow RNA analysis to assess if gene expression can predict clinical response to ON 01910.Na in subjects with MDS. The primary endpoint will be the toxicity profile at each dose level. Secondary endpoints will include the evaluation of early evidence of disease response by blast and cytogenetic improvement.