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

This study has been completed.
Information provided by (Responsible Party):
National Cancer Institute (NCI) Identifier:
First received: July 13, 2006
Last updated: December 22, 2014
Last verified: October 2013
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 Intervention 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

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I Study of PXD101 in Combination With Azacitidine (5-Aza) for Advanced Hematologic Malignancies

Resource links provided by NLM:

Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Maximum tolerated dose of belinostat in combination with azacitidine [ Time Frame: Course 1 (28 days) ] [ Designated as safety issue: Yes ]
    Graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 or 4.0.

Secondary Outcome Measures:
  • Changes in pharmacodynamic variables (target gene expression, apoptosis) [ Time Frame: Course 1 (baseline to day 5) ] [ Designated as safety issue: No ]
    Compared between the two groups using two-sample t tests.

  • 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 ] [ Designated as safety issue: No ]
    Distinguished by sequence-specific polymerase chain reaction (PCR) primers. Compared using a two-sample t or Wilcoxon nonparametric test.

  • Clinical activity (complete remission, partial remission, stable disease, hematologic improvement) [ Time Frame: After 4, 8, and 16 weeks ] [ Designated as safety issue: No ]
    Recorded and tabulated for both the MTD and randomized cohorts.

Enrollment: 56
Study Start Date: June 2006
Study Completion Date: March 2013
Primary Completion Date: March 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

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.


Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its identifier: NCT00351975

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)
Principal Investigator: Olatoyosi Odenike University of Chicago Comprehensive Cancer Center
  More Information

Responsible Party: National Cancer Institute (NCI) Identifier: NCT00351975     History of Changes
Obsolete Identifiers: NCT00336804
Other Study ID Numbers: NCI-2009-00146  NCI-2009-00146  UCCRC-14510A  NCI-7285  CDR0000486418  14510A  7285  U01CA069852  U01CA132123  P30CA014599  U01CA062491 
Study First Received: July 13, 2006
Last Updated: December 22, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Leukemia, Lymphoid
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative
Leukemia, Myelomonocytic, Acute
Leukemia, Myelomonocytic, Chronic
Leukemia, Promyelocytic, Acute
Myelodysplastic Syndromes
Myelodysplastic-Myeloproliferative Diseases
Myeloproliferative Disorders
Neoplasm Metastasis
Philadelphia Chromosome
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Primary Myelofibrosis
Bone Marrow Diseases
Chromosome Aberrations
Hematologic Diseases
Immune System Diseases
Immunoproliferative Disorders
Lymphatic Diseases
Lymphoproliferative Disorders
Neoplasms by Histologic Type
Neoplastic Processes
Pathologic Processes processed this record on May 26, 2016