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

April 13, 2016 updated by: Virginia Commonwealth University

Phase I Study of Belinostat (PXD-101) and Velcade (Bortezomib) in Relapsed or Refractory Acute Leukemia/ Myelodysplastic Syndrome

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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

Enrollment (Actual)

41

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Texas
      • Houston, Texas, United States, 77030
        • M D Anderson Cancer Center
    • Virginia
      • Richmond, Virginia, United States, 23298
        • Virginia Commonwealth University

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion

  • 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

Exclusion

  • 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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: NA
  • Interventional Model: SINGLE_GROUP
  • Masking: NONE

Arms and Interventions

Participant Group / 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.
Other: laboratory biomarker analysis
Correlative studies
Other Names:
  • sample collection
Other: flow cytometry
Correlative studies
Other Names:
  • sample analysis
Other: pharmacological study
Correlative studies
Other Names:
  • pharmacological studies
Drug: bortezomib
Given IV
Other Names:
  • MLN341
  • PS-341
  • LDP 341
  • VELCADE
Genetic: western blotting
Correlative studies
Other Names:
  • Blotting, Western
  • Western Blot
Drug: belinostat
Given IV
Other Names:
  • PXD101

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Recommended phase II doses for the combination of bortezomib and belinostat
Time Frame: 2 years
2 years

Secondary Outcome Measures

Outcome Measure
Time Frame
Toxicity
Time Frame: 2 years
2 years
Pharmacodynamic response
Time Frame: 2 years
2 years
Activity of belinostat and bortezomib
Time Frame: 3 years
3 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Virginia Commonwealth University

Collaborators

National Cancer Institute (NCI)

Investigators

  • Study Chair: Steven Grant, Virginia Commonwealth University

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

May 1, 2010

Primary Completion (ACTUAL)

February 1, 2015

Study Completion (ACTUAL)

February 1, 2015

Study Registration Dates

First Submitted

February 15, 2010

First Submitted That Met QC Criteria

February 23, 2010

First Posted (ESTIMATE)

February 25, 2010

Study Record Updates

Last Update Posted (ESTIMATE)

April 15, 2016

Last Update Submitted That Met QC Criteria

April 13, 2016

Last Verified

April 1, 2016

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • MCC-12517
  • NCI-2010-00127 (REGISTRY: CTRP)
  • RC2CA148431 (NIH)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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