Safety of ON 01910.Na in Patients With Myelodysplasia
Condition: Myelodysplastic Syndrome (MDS)
MeSH terms: Preleukemia; Myelodysplastic Syndromes; Syndrome
Study type: Interventional
Phase: Phase 1

Summary: 
      This study will determine the highest dose of the experimental drug ON 01910.Na that can
      safely be given to patients with the bone marrow disorder myelodysplasia (MDS) and patients
      with refractory AML with trisomy 8. In this disease, the bone marrow can make some blood
      cells, but very few of these cells are released into the blood for use in the body. ON
      01910.Na is an experimental drug that inhibits a protein called cyclinD1that is important for
      keeping MDS cells alive. In laboratory experiments, ON 01910.Na has acted against cyclinD1,
      causing MDS cells to die. The study will also evaluate how the body handles ON 01910.Na, the
      effect of the drug on MDS and AML and its side effects.

      Patients 18 to 85 years old with MDS or AML who do not have a suitable sibling donor for a
      marrow transplant or who are not willing to have a transplant may be eligible for this study.

      Participants receive ON 01910.Na in 2-week treatment cycles, with 3 to 5 days of drug
      infusion through a vein followed by 9 to 11 days of observation. To find the highest safe
      dose of ON 01910.Na, the first person enrolled in the study is given the smallest study dose
      of the drug for 3 days, followed 2 weeks later with a second dose for 3 days. If these doses
      are found safe, the next two people receive the same dose. If these subjects do well, the
      next group of patients receives the next higher dose level. The dose continues to be
      increased in groups of 3 to 6 subjects until the fourth and highest dose level is reached.
      Patients who do well on the treatment may receive an additional six cycles of ON 01910.Na (3
      to 5 days of infusion once every other week for 12 weeks).

      Before, during and after the treatment period, patients are periodically evaluated and
      monitored with the following tests and procedures:

        -  Physical examination and review of medical and medication history.

        -  Blood and urine tests.

        -  Pregnancy test for women of childbearing age.

        -  Electrocardiogram (EKG) and chest X-ray.

        -  Bone marrow biopsy.
    

Detailed description: 
      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.
    

Intervention name(s): ON 01910 Na
Intervention type(s): Drug
Intervention MeSH terms: ON 01910
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Myelodyplastic Syndrome (MDS); Selective Mitotic Inhibitor; Targeted Therapy; Myelodysplastic Syndrome; MDS