Belinostat and Bortezomib in Treating Patients With Relapsed or Refractory Acute Leukemia or Myelodysplastic Syndrome

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01075425
Recruitment Status : Completed
First Posted : February 25, 2010
Last Update Posted : April 15, 2016
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Virginia Commonwealth University

Brief Summary:
RATIONALE: Belinostat and bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving belinostat together with bortezomib may kill more cancer cells. PURPOSE: This phase I trial is studying the side effects and best dose of giving belinostat together with bortezomib in treating patients with relapsed or refractory acute leukemia or myelodysplastic syndrome.

Condition or disease Intervention/treatment Phase
Acute Lymphocytic Leukemia Acute Myeloid Leukemia Myelodysplastic Syndrome Chronic Myelogenous Leukemia Drug: bortezomib Drug: belinostat Other: laboratory biomarker analysis Genetic: western blotting Other: pharmacological study Other: flow cytometry Phase 1

Detailed Description:
PRIMARY OBJECTIVES: I. To determine the recommended phase II doses for the combination of bortezomib and belinostat in patients with relapsed or refractory acute leukemia (AL), myelodysplasia (MDS), and chronic myelogenous leukemia in blast crisis. SECONDARY OBJECTIVES: I. Determine safety and tolerance and describe the toxicities of the combination. II. To demonstrate adequate methods for the assessment of pharmacodynamic response of leukemia cells from the bone marrow and/or peripheral blood in terms of effects on NF-kB (nuclear RelA by immunofluorescence microscopy), NF-kB dependent proteins XIAP and Bcl-xL, and BIM, and document pharmacodynamic responses observed in the course of this study. III. To document activity of the combination observed in the course of this study. OUTLINE: Patients receive belinostat IV over 30 minutes on days 1-5 and 8-12 and bortezomib IV on days 1, 4, 8, and 11. Treatment repeats every 21 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed periodically.

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 41 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I Study of Belinostat (PXD-101) and Velcade (Bortezomib) in Relapsed or Refractory Acute Leukemia/ Myelodysplastic Syndrome
Study Start Date : May 2010
Actual Primary Completion Date : February 2015
Actual Study Completion Date : February 2015

Arm Intervention/treatment
Experimental: Arm I
Patients receive belinostat IV over 30 minutes on days 1-5 and 8-12 and bortezomib IV on days 1, 4, 8, and 11. Treatment repeats every 21 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.
Drug: bortezomib
Given IV
Other Names:
  • LDP 341
  • MLN341
  • PS-341

Drug: belinostat
Given IV
Other Name: PXD101

Other: laboratory biomarker analysis
Correlative studies
Other Name: sample collection

Genetic: western blotting
Correlative studies
Other Names:
  • Blotting, Western
  • Western Blot

Other: pharmacological study
Correlative studies
Other Name: pharmacological studies

Other: flow cytometry
Correlative studies
Other Name: sample analysis

Primary Outcome Measures :
  1. Recommended phase II doses for the combination of bortezomib and belinostat [ Time Frame: 2 years ]

Secondary Outcome Measures :
  1. Toxicity [ Time Frame: 2 years ]
  2. Pharmacodynamic response [ Time Frame: 2 years ]
  3. Activity of belinostat and bortezomib [ Time Frame: 3 years ]

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No


  • Relapsed or refractory acute leukemia
  • acute myeloid leukemia (AML) other than APL
  • acute lymphocytic leukemia (ALL)
  • acute leukemia that has evolved from a prior myelodysplastic syndrome - no requirement for prior therapy
  • myelodysplastic Syndrome (MDS) - International Prognostic Scoring System (IPSS) intermediate-2 or greater
  • chronic myelogenous leukemia with myeloid or lymphoid blast crisis
  • WBC =< 50 x 10^9/L; hydroxyurea or leukopheresis may be used prior starting treatment
  • Prior allogeneic stem cell transplant is allowed provided that >/= 12 months have elapsed since allogeneic transplant; no graft versus host disease is present; not currently on immunosuppressive therapy
  • AST, ALT =< 2.5 x upper limit of normal (ULN)
  • Female subject who is post-menopausal or surgically sterilized or willing to use an acceptable method of birth control (i.e., oral or injectable hormonal methods; barrier methods such as intra-uterine device, diaphragm with spermicide, condom with spermicide, or abstinence) for the duration of the study
  • Male subject agrees to use an acceptable method for contraception for the duration of the study
  • Serum total bilirubin =< 1.5 x upper limit of normal
  • Serum potassium >= 3.5 mEq/L and serum magnesium >= 1.7 mEq/dL (electrolytes may be corrected with supplementation)
  • ECOG Performance Status (PS) =<2
  • Creatinine =< 1.5 x upper limit of normal or calculated or actual creatinine clearance > 45 mL/min


  • Willing and medically suitable for remission induction with other agents in anticipation of a potentially curative allogeneic bone marrow transplant
  • Known CNS malignant disease
  • Prior severe allergic reactions to bortezomib, mannitol, boron, belinostat or compounds of the hydroxamate class or arginine
  • Grade 1 with pain or Grade >= 2 peripheral neuropathy or paresthesias within 14 days before enrollment
  • History of sustained ventricular tachycardia, ventricular fibrillation, Torsade de Pointes, or resuscitated cardiac arrest

    • History of resuscitated cardiac arrest. Note: persons without pre-existing cardiovascular comorbidities who have experienced resuscitated cardiac arrest in the setting of sepsis ARE eligible provided they have no residual cardiac abnormalities and providing they do not require ongoing medication to manage cardiac issues as an outcome of such an event.

  • Conduction abnormality or concomitant treatment with an anti-arrhythmic agent to prevent or control arrhythmia
  • Known congenital long QT syndrome
  • Clinically significant infection including infection with HIV, or active hepatitis B or C
  • Significant cardiovascular disease, hypertrophic cardiomegaly or restrictive cardiomyopathy, myocardial infarction within the past 6 months, unstable angina
  • Baseline QTc interval > 450 msec
  • Planned or ongoing treatment with any drug that may be risk of causing Torsades de Pointes
  • Persistent blood pressure (BP) of >=160/95
  • Serious medical or psychiatric illness likely to interfere with patient participation
  • Pregnant or nursing
  • Diagnosis or treatment for another malignancy within 3 years of enrollment, with the exception of complete resection of basal cell carcinoma or squamous cell carcinoma of the skin, an in situ malignancy, or low risk prostate cancer after curative therapy
  • Planned ongoing treatment with other drugs thought to potentially adversely interact with belinostat
  • Strong or moderate CYP3A4 inhibitors
  • Patient has received other investigational drugs within 14 days before enrollment
  • If steroids for cancer control have been used, patients must be off these agents for >/= 1 week before starting treatment. Exception: maintenance therapy for non-malignant disease with prednisone or steroid equivalent dose < 10 mg/day is permitted.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01075425

United States, Texas
M D Anderson Cancer Center
Houston, Texas, United States, 77030
United States, Virginia
Virginia Commonwealth University
Richmond, Virginia, United States, 23298
Sponsors and Collaborators
Virginia Commonwealth University
National Cancer Institute (NCI)
Study Chair: Steven Grant Virginia Commonwealth University
Principal Investigator: Beata Holkova, MD Massey Cancer Center

Additional Information:
Responsible Party: Virginia Commonwealth University Identifier: NCT01075425     History of Changes
Other Study ID Numbers: MCC-12517
NCI-2010-00127 ( Registry Identifier: CTRP )
RC2CA148431 ( U.S. NIH Grant/Contract )
First Posted: February 25, 2010    Key Record Dates
Last Update Posted: April 15, 2016
Last Verified: April 2016

Keywords provided by Virginia Commonwealth University:
acute leukemia
chronic myelogenous leukemia
myelodysplastic syndrome
relapsed acute leukemia
refractory acute leukemia

Additional relevant MeSH terms:
Leukemia, Myeloid, Acute
Myelodysplastic Syndromes
Leukemia, Lymphoid
Leukemia, Myeloid
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Pathologic Processes
Neoplasms by Histologic Type
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Myeloproliferative Disorders
Antineoplastic Agents
Histone Deacetylase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action