Belinostat in Treating Patients With Myelodysplastic Syndromes

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

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.

Study Overview

• Status: Completed
• Conditions: Previously Treated Myelodysplastic Syndromes; Secondary Myelodysplastic Syndromes; de Novo Myelodysplastic Syndromes
• Intervention / Treatment: Drug: belinostat

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 21
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment (enzyme inhibitor therapy); 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; Given IV; Other Names: PXD101

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Amanda Cashen, Mayo Clinic

Study record dates

Study Major Dates

• Study Start: May 1, 2006
• Primary Completion (Actual): December 1, 2010
• Study Completion (Actual): December 1, 2010

Study Registration Dates

• First Submitted: July 26, 2006
• First Submitted That Met QC Criteria: July 26, 2006
• First Posted (Estimate): July 27, 2006

Study Record Updates

• Last Update Posted (Estimate): May 20, 2014
• Last Update Submitted That Met QC Criteria: May 2, 2014
• Last Verified: December 1, 2011

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Disease; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Syndrome; Myelodysplastic Syndromes; Preleukemia; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Histone Deacetylase Inhibitors; Belinostat
• Other Study ID Numbers: NCI-2009-00143 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); P30CA015083 (U.S. NIH Grant/Contract); N01CM62205 (U.S. NIH Grant/Contract); 7258 (Other Grant/Funding Number: DHHS); MAYO-MC0581; NCI-7258; CDR0000489197; MC0581 (Other Identifier: Mayo Clinic)