Belinostat in Treating Patients With Myelodysplastic Syndromes

Phase 2

Completed

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

Interventions: Drug: belinostat

Registration Number: NCT00357162

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 21

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)

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (enzyme inhibitor therapy)	belinostat	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.

Primary Outcome Measures

Name	Time	Method
Number of Confirmed Responses (Complete Response, Partial Response, or Hematologic Improvement) Noted on 2 Consecutive Evaluations at Least 4 Weeks Apart	12 weeks	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

Secondary Outcome Measures

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