Belinostat in Treating Patients With Myelodysplastic Syndromes

Study Overview
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Brief Summary
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This phase II trial is studying how well belinostat works in treating patients with myelodysplastic syndromes. Belinostat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the cancer.

Detailed Description
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OBJECTIVES: I. Establish the efficacy and safety of PXD101 (belinostat) in patients with myelodysplastic syndromes that progressed after or is ineligible for azacitidine treatment. II. Assess the biological activity of PXD101 in these patients via assays of histone acetylation, gene expression profiling, and DNA methylation. OUTLINE: This is a multicenter study. Patients receive belinostat intravenously (IV) over 30 minutes on days 1-5. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients achieving complete response, partial response, or hematologic improvement after 4 courses receive 4 additional courses of therapy. After completion of study treatment, patients are followed every 3-6 months for up to 3 years.

Official Title
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Phase II Study of the Histone Deacetylase Inhibitor PXD101 for the Treatment of Myelodysplastic Syndrome

Conditions
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de Novo Myelodysplastic Syndromes, Previously Treated Myelodysplastic Syndromes, Secondary Myelodysplastic Syndromes

Intervention / Treatment
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* Drug: belinostat


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed myelodysplastic syndromes (MDS) De novo or secondary MDS Patients with < 5 % bone marrow blasts must meet ≥ 1 of the following criteria: Symptomatic anemia with either hemoglobin < 10.0 g/dL or required RBC transfusions within the past 3 months Thrombocytopenia with ≥ 2 platelet counts < 50,000/mm³ or significant hemorrhage requiring platelet transfusions Neutropenia with ≥ 2 absolute neutrophil counts < 1,000/mm³ No acute myeloid leukemia (≥ 20% bone marrow blasts) ECOG performance status 0-2 Life expectancy > 12 weeks Bilirubin ≤ 1.5 times upper limit of normal (ULN) AST ≤ 2 times ULN Creatinine ≤ 2.0 mg/dL Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No history of allergic reactions attributed to compounds of similar chemical or biologic composition to PXD101 No HIV positivity QTc interval ≤ 500 msec No long QT syndrome No significant cardiovascular disease, including any of the following: Unstable angina pectoris Uncontrolled hypertension Congestive heart failure related to primary cardiac disease Condition requiring anti-arrhythmic therapy Ischemic or severe valvular heart disease Myocardial infarction within the past 6 months No other uncontrolled serious medical condition (e.g., cardiac arrhythmias or diabetes) Recovered from prior therapy No more than 2 prior therapies for MDS Prior hematopoietic growth factors, androgens, and other supportive care agents allowed and are not considered in the prior therapy total No prior allogeneic stem cell transplantation More than 4 weeks since prior radiotherapy or chemotherapy (6 weeks for nitrosoureas or mitomycin C) No prior histone deacetylase (HDAC) inhibitors for treatment of MDS More than 2 weeks since prior valproic acid or other HDAC inhibitors No other concurrent investigational agents No concurrent medication that may cause torsades depointes, including any of the following: Disopyramide Dofetilide Ibutilide Procainamide Quinidine Sotalol Bepridil Methadone Amiodarone hydrochloride Arsenic trioxide Cisapride Calcium-channel blockers (e.g., lidoflazine) Anti-infective agents (i.e., clarithromycin, erythromycin, halofantrine, pentamidine, or sparfloxacin) Domperidone or droperidol Antipsychotic agents (i.e., chlorpromazine, haloperidol, mesoridazine, thioridazine, or pimozide)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (enzyme inhibitor therapy)<br>Patients receive belinostat IV over 30 minutes on days 1-5. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. | Drug: belinostat<br>* Given IV<br>* Other names: PXD101;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Confirmed Responses (Complete Response, Partial Response, or Hematologic Improvement) Noted on 2 Consecutive Evaluations at Least 4 Weeks Apart | Complete Response (CR) A CR is defined as a participant with bone marrow showing less than 5% myeloblasts with no evidence of dysplasia and with adequate peripheral blood counts for at least 2 months (hemoglobin > 11 g/dl, neutrophils ≥ 1500/mm3, platelets ≥ 100,000/mm3) and with no blasts in the peripheral. Partial Response (PR) All the CR criteria except bone marrow blasts decreased by ≥ 50% over pretreatment, or a less advanced WHO classification than pretreatment. Hematologic Improvement (HI) A 2g/dl increase in hemoglobin for participants with <11g/dl hemoglobin at pretreatment, or an increase of >30,000/mm^3 platelets for participants with <100,000/mm^3 at pretreatment, or a 100% increase in neutrophil counts for participants with <1500/mm^3 at pretreatment | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Progression | Estimated using the method of Kaplan-Meier. | Time from registration to the date of progression or last follow-up, assessed up to 3 years | 
| Overall Survival | Estimated using the method of Kaplan-Meier. | From date of registration to the date of last follow-up or death due to any cause, assessed up to 3 years | 
| Duration of Response | Estimated using the method of Kaplan-Meier. | From the date of documented response until the date of progression or last follow-up, assessed up to 3 years | 
| Toxicity of Belinostat in Patients With Myelodysplastic Syndrome | Graded using the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. Reporting events deemed at least possibly related to study treatment. | Prior to each course (every 21 days), and every 3 months for up to 3 years after completion of study treatment |