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Belinostat and Azacitidine in Treating Patients With Advanced Hematologic Cancers or Other Diseases

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ClinicalTrials.gov Identifier: NCT00351975
Recruitment Status : Completed
First Posted : July 14, 2006
Last Update Posted : December 23, 2014
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief Summary:
This phase I trial is studying the side effects and best dose of belinostat when given together with azacitidine in treating patients with advanced hematologic cancers or other diseases. Belinostat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the cancer. Drugs used in chemotherapy, such as azacitidine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving belinostat together with azacitidine may kill more cancer cells.

Condition or disease Intervention/treatment Phase
Accelerated Phase of Disease Adult Acute Myeloid Leukemia With Inv(16)(p13.1q22); CBFB-MYH11 Adult Acute Myeloid Leukemia With t(16;16)(p13.1;q22); CBFB-MYH11 Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); RUNX1-RUNX1T1 Adult Acute Myeloid Leukemia With t(9;11)(p22;q23); MLLT3-MLL Adult Acute Promyelocytic Leukemia With t(15;17)(q22;q12); PML-RARA Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative Blastic Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive Chronic Myelomonocytic Leukemia de Novo Myelodysplastic Syndrome Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable Philadelphia Chromosome Negative, BCR-ABL1 Positive Chronic Myelogenous Leukemia Previously Treated Myelodysplastic Syndrome Primary Myelofibrosis Recurrent Adult Acute Lymphoblastic Leukemia Recurrent Adult Acute Myeloid Leukemia Recurrent Disease Secondary Acute Myeloid Leukemia Secondary Myelodysplastic Syndrome Drug: Belinostat Drug: Azacitidine Other: Laboratory Biomarker Analysis Phase 1

Detailed Description:


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.


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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 56 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I Study of PXD101 in Combination With Azacitidine (5-Aza) for Advanced Hematologic Malignancies
Study Start Date : June 2006
Actual Primary Completion Date : March 2013
Actual Study Completion Date : March 2013

Arm Intervention/treatment
Experimental: Arm I (chemotherapy)
Patients receive azacitidine SC on days 1-5.
Drug: Azacitidine
Given SC
Other Names:
  • 5-AC
  • 5-AZC
  • U-18496

Other: Laboratory Biomarker Analysis
Correlative studies

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.
Drug: Belinostat
Given IV
Other Names:
  • Beleodaq
  • PXD 101
  • PXD101

Drug: Azacitidine
Given SC
Other Names:
  • 5-AC
  • 5-AZC
  • U-18496

Other: Laboratory Biomarker Analysis
Correlative studies

Primary Outcome Measures :
  1. 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.

Secondary Outcome Measures :
  1. Changes in pharmacodynamic variables (target gene expression, apoptosis) [ Time Frame: Course 1 (baseline to day 5) ]
    Compared between the two groups using two-sample t tests.

  2. 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 ]
    Distinguished by sequence-specific polymerase chain reaction (PCR) primers. Compared using a two-sample t or Wilcoxon nonparametric test.

  3. Clinical activity (complete remission, partial remission, stable disease, hematologic improvement) [ Time Frame: After 4, 8, and 16 weeks ]
    Recorded and tabulated for both the MTD and randomized cohorts.

Information from the National Library of Medicine

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

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

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 ClinicalTrials.gov identifier (NCT number): NCT00351975

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United States, Illinois
University of Chicago Comprehensive Cancer Center
Chicago, Illinois, United States, 60637
United States, Wisconsin
University of Wisconsin Hospital and Clinics
Madison, Wisconsin, United States, 53792
Canada, Ontario
University Health Network-Princess Margaret Hospital
Toronto, Ontario, Canada, M5G 2M9
New Zealand
Princess Margaret Hospital
Cashmere, Canterbury, New Zealand, 8022
Sponsors and Collaborators
National Cancer Institute (NCI)
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Principal Investigator: Olatoyosi Odenike University of Chicago Comprehensive Cancer Center
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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00351975    
Obsolete Identifiers: NCT00336804
Other Study ID Numbers: NCI-2009-00146
NCI-2009-00146 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
14510A ( Other Identifier: University of Chicago Comprehensive Cancer Center )
7285 ( Other Identifier: CTEP )
U01CA069852 ( U.S. NIH Grant/Contract )
U01CA132123 ( U.S. NIH Grant/Contract )
P30CA014599 ( U.S. NIH Grant/Contract )
U01CA062491 ( U.S. NIH Grant/Contract )
First Posted: July 14, 2006    Key Record Dates
Last Update Posted: December 23, 2014
Last Verified: October 2013
Additional relevant MeSH terms:
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Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasm Metastasis
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Leukemia, Myelomonocytic, Chronic
Leukemia, Myelomonocytic, Juvenile
Leukemia, Promyelocytic, Acute
Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative
Myelodysplastic Syndromes
Primary Myelofibrosis
Myeloproliferative Disorders
Myelodysplastic-Myeloproliferative Diseases
Philadelphia Chromosome
Pathologic Processes
Neoplasms by Histologic Type
Disease Attributes
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Neoplastic Processes
Leukemia, Lymphoid
Lymphoproliferative Disorders
Lymphatic Diseases