Phase I Study of ON 01910.Na in Refractory Leukemia or Myelodysplastic Syndrome (MDS)
This is an open-label, Phase I study to determine the highest amount of the study drug, ON 01910.Na, that can be safety given to patients with high risk myelodysplastic syndromes (MDS) or refractory leukemias. Patients will receive ON 01910.Na (at a starting dose of 650 mg/m2) intravenously by 3-day continuous infusion once every 2 weeks. Successive courses will use longer infusion times and/or higher doses of the drug until toxicity, effectiveness, or ineffectiveness is recognized. In addition, the amount of drug in the blood will be measured, any antitumor activity will be documented, and the biological effect of ON 01910.Na on cell-cycle pathways will be evaluated in peripheral blood mononuclear cells.
Acute Myelocytic Leukemia
Acute Lymphocytic Leukemia
Chronic Myelocytic Leukemia
Chronic Lymphocytic Leukemia
Drug: ON 01910.Na
|Study Design:||Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Phase I Dose Escalation Study of ON 01910.Na With Increasing Duration of an Initial 3-Day Continuous Infusion in Patients With Refractory Leukemia or MDS|
- Safety data, including laboratory parameters and adverse events, will be collected for all patients in order to determine the qualitative and quantitative toxicity, and reversibility of toxicity, of ON 01910.Na. [ Time Frame: 2 - 4 months ] [ Designated as safety issue: Yes ]
- To investigate the clinical pharmacology of ON 01910.Na including plasma pharmacokinetics, pharmacodynamics and biological effects on cell-cycle pathways. [ Time Frame: 2 - 4 months ] [ Designated as safety issue: No ]
|Study Start Date:||October 2008|
|Estimated Study Completion Date:||December 2013|
|Estimated Primary Completion Date:||August 2013 (Final data collection date for primary outcome measure)|
|Experimental: ON 01910.Na||
Drug: ON 01910.Na
The drug is a sterile, concentrated 75mg/mL solution in polyethylene glycol 400, in labeled, sealed glass vials. The Concentrate must be diluted with aqueous infusion solutions (0.9% NaCl, USP and Water for Injection, USP according to instructions) immediately prior to intravenous administration. The starting dose is 650 mg/m2 per day for 3 continuous days every 2 weeks. In successive courses, infusion time may be increased by 1 day up to 7 days every two weeks and/or drug dose may be increased (650, 1050, 1700 mg/m2/day, etc.). After 4 2-week cycles, cycle length may be extended to 3 or 4 weeks. Treatment continues until evidence of disease progression, intolerable adverse events or withdraw of consent.
Patients must have histologically documented or cytologically confirmed diagnosis of acute myelocytic leukemia refractory to standard induction treatment, or relapsed after standard therapy; acute lymphocytic leukemia refractory to induction treatment, or relapsed after effective therapy; chronic myelocytic leukemia refractory to imatinib therapy or second line tyrosine kinase inhibition, or relapsed after tyrosine kinase inhibition, in chronic, accelerated, or blastic phase; chronic lymphocytic leukemia refractory to standard therapy, or relapsed in second relapse; a myelodysplastic syndrome (including chronic myelomonocytic leukemia) refractory to azacitidine; and an int-2 or high myelodysplastic syndrome relapsed after a hypomethylating agent. Patients may not be eligible for, or must have declined, bone marrow transplantation or other chemotherapeutic regimens known to produce consistent remissions. Because hematopoietic criteria in leukemia and lymphoma are confounded by the nature of the diseases themselves, there are no hematologic exclusions from treatment. If leukopenia is clinically determined to be attributable to prior treatment, ON 01910.Na treatment may start when the leukocyte count increases on two successive determinations performed at least three days apart. Thrombocytopenia is not a criterion, and patients will be supported with platelet transfusions as clinically necessary. In the absence of leukopenia, a failed prior treatment may be succeeded immediately by entry into study of ON 01910.Na if the leukocyte count is stable or rising, on two successive determinations performed at least three days apart, in the absence of other drug toxicity.
The patient population will involve approximately 12 to 28 patients ≥ 18 years of age in the dose escalation portion of the protocol. All patients must have relapsed or refractory leukemia or poor risk MDS (i.e., int-2 or high risk MDS who have failed standard therapy). They must not be candidates for known regimens or protocol treatments of higher efficacy or priority. Patients with relapsed/refractory leukemia or poor risk MDS must have an ECOG Performance Status of 0, 1, or 2. Patients must have an expected survival, in the opinion of the Investigator, to allow a sufficient observation period for evaluating ON 01910.Na, and meet the eligibility criteria for patients with leukemia or poor risk MDS. After the maximally tolerated dose and the Recommended Phase II Dose (RPTD) and duration are determined, up to 12 additional patients with histologically documented or cytologically confirmed leukemia or poor risk MDS will be added to confirm the appropriateness of the RPTD. Inclusion criteria for the dose confirmation phase will be similar to those of the dose escalation phase of the study, but the ECOG Performance Status must be 0 or 1.
Safety data, including laboratory parameters and adverse events, will be collected for all patients in order to determine the qualitative and quantitative toxicity, and reversibility of toxicity, of ON 01910.Na. Leukemic cells and MDS cells in peripheral blood will be measured on a daily basis during infusion, and at least two times weekly during the following week. If leukemic cells disappear from the blood or blood counts improve as defined by IWG criteria in MDS patients, a bone marrow aspiration will be performed to determine response status in the bone marrow.
All patients may continue therapy for at least six cycles unless rapid disease progression is documented. Patients with an objective clinical response or stable disease can continue up to six more cycles. Further continuation will be determined by the clinical judgment of the Investigator.
|United States, New York|
|Mount Sinai Medical Center|
|New York, New York, United States, 10029|
|Principal Investigator:||Lewis R. Silverman, MD||Mount Sinai School of Medicine|