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

Phase 1
18 Years
Open (Enrolling)
Acute Lymphocytic Leukemia, Acute Myeloid Leukemia, Myelodysplastic Syndrome, Chronic Myelogenous Leukemia

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Trial Information

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

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.

Inclusion Criteria


- 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

- 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

- Potent or moderate CYP3A4 inhibitors

- Patient has received other investigational drugs within 14 days before enrollment

- Patient may not be receiving any other anticancer agents for malignant disease

Type of Study:


Study Design:

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Recommended phase II doses for the combination of bortezomib and belinostat

Outcome Time Frame:

2 years

Safety Issue:


Principal Investigator

Steven Grant

Investigator Role:

Study Chair

Investigator Affiliation:

Virginia Commonwealth University


United States: Food and Drug Administration

Study ID:




Start Date:

May 2010

Completion Date:

May 2015

Related Keywords:

  • Acute Lymphocytic Leukemia
  • Acute Myeloid Leukemia
  • Myelodysplastic Syndrome
  • Chronic Myelogenous Leukemia
  • leukemia
  • acute leukemia
  • chronic myelogenous leukemia
  • myelodysplastic syndrome
  • relapsed acute leukemia
  • refractory acute leukemia
  • belinostat
  • bortezomib
  • Velcade
  • PXD-101
  • Leukemia
  • Leukemia, Lymphoid
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive
  • Myelodysplastic Syndromes
  • Preleukemia
  • Acute Disease



Virginia Commonwealth UniversityRichmond, Virginia