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

Sponsor

Virginia Commonwealth University (Other)

Overall Status

Completed

CT.gov ID

NCT01075425

Collaborator

National Cancer Institute (NCI) (NIH)

Enrollment

Locations

Arm

57.1

Duration (Months)

20.5

Patients Per Site

0.4

Patients Per Site Per Month

Study Details

Study Description

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:

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 Design

Study Type:

Interventional

Actual Enrollment :

41 participants

Allocation:

N/A

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 1, 2010

Actual Primary Completion Date :

Feb 1, 2015

Actual Study Completion Date :

Feb 1, 2015

Arms and Interventions

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 VELCADE Drug: belinostat Given IV Other Names: PXD101 Other: laboratory biomarker analysis Correlative studies Other Names: sample collection Genetic: western blotting Correlative studies Other Names: Blotting, Western Western Blot Other: pharmacological study Correlative studies Other Names: pharmacological studies Other: flow cytometry Correlative studies Other Names: sample analysis

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

VELCADE

Drug: belinostat

Given IV

Other Names:

PXD101

Other: laboratory biomarker analysis

Correlative studies

Other Names:

sample collection

Genetic: western blotting

Correlative studies

Other Names:

Blotting, Western

Western Blot

Other: pharmacological study

Correlative studies

Other Names:

pharmacological studies

Other: flow cytometry

Correlative studies

Other Names:

sample analysis

Outcome Measures

Primary Outcome Measures

Recommended phase II doses for the combination of bortezomib and belinostat [2 years]

Secondary Outcome Measures

Toxicity [2 years]
Pharmacodynamic response [2 years]
Activity of belinostat and bortezomib [3 years]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.