- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT00351975
Belinostat and Azacitidine in Treating Patients With Advanced Hematologic Cancers or Other Diseases
A Phase I Study of PXD101 in Combination With Azacitidine (5-Aza) for Advanced Hematologic Malignancies
Study Overview
Status
Conditions
- Primary Myelofibrosis
- Chronic Myelomonocytic Leukemia
- Previously Treated Myelodysplastic Syndrome
- Recurrent Adult Acute Myeloid Leukemia
- Secondary Acute Myeloid Leukemia
- Recurrent Disease
- Recurrent Adult Acute Lymphoblastic Leukemia
- Secondary Myelodysplastic Syndrome
- de Novo Myelodysplastic Syndrome
- Adult Acute Myeloid Leukemia With Inv(16)(p13.1q22); CBFB-MYH11
- Adult Acute Myeloid Leukemia With t(16;16)(p13.1;q22); CBFB-MYH11
- Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative
- Chronic Myelogenous Leukemia, BCR-ABL1 Positive
- Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable
- Philadelphia Chromosome Negative, BCR-ABL1 Positive Chronic Myelogenous Leukemia
- Blastic Phase
- Adult Acute Myeloid Leukemia With t(9;11)(p22;q23); MLLT3-MLL
- Adult Acute Promyelocytic Leukemia With t(15;17)(q22;q12); PML-RARA
- Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); RUNX1-RUNX1T1
- Accelerated Phase of Disease
Intervention / Treatment
Detailed Description
PRIMARY OBJECTIVES:
I. Determine the maximum tolerated dose of PXD101 (belinostat) when given in combination with azacitidine (when azacitidine is utilized at a dose range where its effects on cellular differentiation are known to be predominant) in patients with advanced hematologic cancers or other diseases.
SECONDARY OBJECTIVES:
I. Identify any additive or synergistic effects of this regimen on pharmacodynamic parameters, including apoptosis and re-expression of specific target genes.
II. Assess any evidence of clinical activity (complete remission, partial remission, hematologic improvement, stable disease) of this regimen in these patients.
OUTLINE: This is a dose-escalation study of belinostat followed by a randomized study.
Patients receive azacitidine subcutaneously (SC) and belinostat intravenously (IV) over 30 minutes on days 1-5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of belinostat until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 6 patients experience dose-limiting toxicity. After the MTD is determined, additional patients with myelodysplastic syndromes (MDS) or acute myeloid leukemia (with trilineage dysplasia or arising from MDS) are randomized to 1 of 2 treatment arms.
Arm I: Patients receive azacitidine SC on days 1-5.
Arm II: Patients receive azacitidine as in arm I and belinostat at the MTD IV over 30 minutes on days 1-5.
In both arms, courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. After receiving one course, patients randomized to arm I may crossover to receive treatment on arm II.
For patients enrolled in the randomized portion of the study, bone marrow aspirates are obtained at baseline, and after course 1 for correlative studies. Samples are examined by gene expression analysis of p15 and p21, DNA methylation of p15INK4B, and apoptosis by RT-PCR and flow cytometry. Pharmacodynamic assays are also performed.
After completion of study treatment, patients are followed periodically for up to 2 years.
Study Type
Enrollment (Actual)
Phase
- Phase 1
Contacts and Locations
Study Locations
-
-
Ontario
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Toronto, Ontario, Canada, M5G 2M9
- University Health Network-Princess Margaret Hospital
-
-
-
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Canterbury
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Cashmere, Canterbury, New Zealand, 8022
- Princess Margaret Hospital
-
-
-
-
Illinois
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Chicago, Illinois, United States, 60637
- University of Chicago Comprehensive Cancer Center
-
-
Wisconsin
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Madison, Wisconsin, United States, 53792
- University of Wisconsin Hospital and Clinics
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
Histologically confirmed diagnosis of 1 of the following:
- Relapsed or refractory acute myeloid leukemia (AML)
- Relapsed or refractory acute promyelocytic leukemia (must have failed both tretinoin and arsenic trioxide)
- Relapsed or refractory acute lymphoblastic leukemia
- Secondary AML, including AML arising from antecedent hematologic diseases, such as myelodysplastic syndromes (MDS) or myeloproliferative disorders, OR therapy-related AML
- Chronic myelogenous leukemia in accelerated or blast phase
Advanced phases of Philadelphia chromosome-negative (Ph-) chronic myeloproliferative disorders, as defined by ≥ 1 of the following:
- Presence of anemia (hemoglobin < 10 g/dL and/or red blood cell transfusion dependent)
- Presence of palpable splenomegaly
MDS, including chronic myelomonocytic leukemia
- Must have intermediate or high-risk International Prognostic Scoring System (IPSS) scores (≥ 0.5)
Low-risk IPSS scores allowed provided ≥ 1 of the following criteria are met:
- Hemoglobin < 10 g/dL and/or red blood cell transfusion dependent
- Platelet count < 50,000/mm³
- Absolute neutrophil count < 1,000/mm³
- Refractory disease OR no standard therapy exists
- Evidence of AML associated with dysplasia on bone marrow histology for elderly patients (i.e., > 60 years old) who are previously untreated and not candidates for or unwilling to undergoing induction therapy
- No known active CNS involvement with disease
- CALGB performance status (PS) 0-2 OR Karnofsky PS 60-100%
- Bilirubin ≤ 2.0 mg/dL (unless due to Gilbert's syndrome)
- ALT ≤ 3 times upper limit of normal (unless due to disease)
- Creatinine ≤ 2 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 or Azacitidine
- No history of allergic reactions to mannitol
- No history of dose-limiting toxicity during prior treatment with Azacitidine
No concurrent uncontrolled illness including, but not limited to, the following:
- Ongoing or active infection
- Symptomatic congestive heart failure
- Unstable angina pectoris
- Cardiac arrhythmia
- Psychiatric illness or social situation that would preclude compliance with study requirements
- No marked baseline prolongation of QT/QTc interval (e.g., repeated demonstration of a QTc interval > 500 msec)
- No long QT syndrome
No uncontrolled cardiovascular disease, including the following:
- Severe uncontrolled hypertension
- Uncontrolled congestive heart failure related to primary cardiac disease
- Uncontrolled cardiac arrhythmia
- Uncontrolled ischemic or severe valvular heart disease
- Myocardial infarction within the past 6 months
- See Disease Characteristics
- Recovered from prior therapy
- At least 2 weeks since prior chemotherapy (6 weeks for mitomycin C or nitrosoureas)
- At least 2 weeks since prior radiotherapy
- At least 4 weeks since prior investigational agents
- At least 24 hours since prior hydroxyurea
- At least 2 weeks since prior valproic acid
- No concurrent combination antiretroviral therapy for HIV-positive patients
- No other concurrent investigational agents
- No concurrent medication that may cause torsade de pointes
- No other concurrent anticancer therapy, including chemotherapy, radiotherapy, or biological agents
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Arm I (chemotherapy)
Patients receive azacitidine SC on days 1-5.
|
Correlative studies
Given SC
Other Names:
|
Experimental: Arm II (chemotherapy, enzyme inhibitor therapy)
Patients receive azacitidine as in arm I and belinostat at the MTD IV over 30 minutes on days 1-5.
|
Correlative studies
Given SC
Other Names:
Given IV
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Maximum tolerated dose of belinostat in combination with azacitidine
Time Frame: Course 1 (28 days)
|
Graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 or 4.0.
|
Course 1 (28 days)
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Changes in pharmacodynamic variables (target gene expression, apoptosis)
Time Frame: Course 1 (baseline to day 5)
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Compared between the two groups using two-sample t tests.
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Course 1 (baseline to day 5)
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Association of methylation status, categorized as positive or negative, with changes in target gene expression
Time Frame: Baseline, days 4 or 5, and days 25-28
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Distinguished by sequence-specific polymerase chain reaction (PCR) primers.
Compared using a two-sample t or Wilcoxon nonparametric test.
|
Baseline, days 4 or 5, and days 25-28
|
Clinical activity (complete remission, partial remission, stable disease, hematologic improvement)
Time Frame: After 4, 8, and 16 weeks
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Recorded and tabulated for both the MTD and randomized cohorts.
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After 4, 8, and 16 weeks
|
Collaborators and Investigators
Sponsor
Study record dates
Study Major Dates
Study Start
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Estimate)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Pathologic Processes
- Immune System Diseases
- Neoplasms by Histologic Type
- Neoplasms
- Lymphoproliferative Disorders
- Lymphatic Diseases
- Immunoproliferative Disorders
- Disease Attributes
- Disease
- Bone Marrow Diseases
- Hematologic Diseases
- Neoplastic Processes
- Precancerous Conditions
- Leukemia, Lymphoid
- Chromosome Aberrations
- Translocation, Genetic
- Syndrome
- Myelodysplastic Syndromes
- Primary Myelofibrosis
- Leukemia
- Leukemia, Myeloid
- Leukemia, Myeloid, Acute
- Neoplasm Metastasis
- Recurrence
- Preleukemia
- Leukemia, Myelomonocytic, Chronic
- Leukemia, Myelomonocytic, Juvenile
- Precursor Cell Lymphoblastic Leukemia-Lymphoma
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive
- Leukemia, Promyelocytic, Acute
- Myeloproliferative Disorders
- Myelodysplastic-Myeloproliferative Diseases
- Philadelphia Chromosome
- Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative
- Molecular Mechanisms of Pharmacological Action
- Enzyme Inhibitors
- Antimetabolites, Antineoplastic
- Antimetabolites
- Antineoplastic Agents
- Histone Deacetylase Inhibitors
- Azacitidine
- Belinostat
Other Study ID Numbers
- NCI-2009-00146 (Registry Identifier: CTRP (Clinical Trial Reporting Program))
- P30CA014599 (U.S. NIH Grant/Contract)
- U01CA132123 (U.S. NIH Grant/Contract)
- U01CA069852 (U.S. NIH Grant/Contract)
- U01CA062491 (U.S. NIH Grant/Contract)
- UCCRC-14510A
- NCI-7285
- CDR0000486418
- 14510A (Other Identifier: University of Chicago Comprehensive Cancer Center)
- 7285 (CTEP)
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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