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PXD101 and Azacitidine in Treating Patients With Advanced Hematologic Cancers or Other Diseases
This study is currently recruiting participants.
Verified by National Cancer Institute (NCI), November 2008
Sponsors and Collaborators: University of Chicago
National Cancer Institute (NCI)
Information provided by: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00351975
  Purpose

RATIONALE: PXD101 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 PXD101 together with azacitidine may kill more cancer cells.

PURPOSE: This phase I trial is studying the side effects and best dose of PXD101 when given together with azacitidine in treating patients with advanced hematologic cancers or other diseases.


Condition Intervention Phase
Chronic Myeloproliferative Disorders
Leukemia
Myelodysplastic Syndromes
Myelodysplastic/Myeloproliferative Diseases
Drug: azacitidine
Drug: belinostat
Phase I

MedlinePlus related topics: Cancer Leukemia, Adult Acute Leukemia, Adult Chronic
Drug Information available for: Azacitidine Belinostat
U.S. FDA Resources
Study Type: Interventional
Study Design: Treatment, Randomized
Official Title: A Phase I Study of PXD101 in Combination With Azacitadine (5-Aza) for Advanced Hematologic Malignancies

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

Primary Outcome Measures:
  • Maximum tolerated dose of PXD101 in combination with azacitidine [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Pharmacodynamics [ Designated as safety issue: No ]
  • Clinical activity (complete remission, partial remission, stable disease, hematologic improvement) [ Designated as safety issue: No ]

Estimated Enrollment: 33
Study Start Date: June 2006
Estimated Primary Completion Date: May 2007 (Final data collection date for primary outcome measure)
Detailed Description:

OBJECTIVES:

Primary

  • Determine the maximum tolerated dose of PXD101 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

  • Identify any additive or synergistic effects of this regimen on pharmacodynamic parameters, including apoptosis and re-expression of specific target genes.
  • 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 PXD101 followed by a randomized study.

Patients receive PXD101 IV over 30 minutes and azacitidine subcutaneously (SC) 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 PXD101 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 PXD101 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, on day 5 of course 1, and after course 2 for correlative studies. Samples are examined by gene expression analysis of p15 and p21, DNA methylation of p15INK4B, and flow cytometry. Pharmacodynamic assays are also performed.

After completion of study treatment, patients are followed periodically for up to 2 years.

PROJECTED ACCRUAL: A total of 33 patients will be accrued for this study.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

DISEASE CHARACTERISTICS:

  • 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

PATIENT CHARACTERISTICS:

  • 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 azacitadine
  • No history of allergic reactions to mannitol
  • No history of dose-limiting toxicity during prior treatment with azacitadine
  • 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

PRIOR CONCURRENT THERAPY:

  • 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
Please refer to this study by its ClinicalTrials.gov identifier: NCT00351975

Locations
United States, Illinois
University of Chicago Cancer Research Center Recruiting
Chicago, Illinois, United States, 60637-1470
Contact: Clinical Trials Office - University of Chicago Cancer Research     773-834-7424        
United States, Wisconsin
University of Wisconsin Paul P. Carbone Comprehensive Cancer Center Recruiting
Madison, Wisconsin, United States, 53792-6164
Contact: Clinical Trials Office - University of Wisconsin Paul P. Carbo     608-262-5223        
Canada, Ontario
Princess Margaret Hospital Recruiting
Toronto, Ontario, Canada, M5G 2M9
Contact: Karen W. L. Yee, MD     416-946-4495     karen.yee@uhn.on.ca    
Sponsors and Collaborators
University of Chicago
Investigators
Study Chair: Olatoyosi M. Odenike, MD University of Chicago
  More Information

Clinical trial summary from the National Cancer Institute's PDQ® database  This link exits the ClinicalTrials.gov site

Study ID Numbers: CDR0000486418, UCCRC-14510A, NCI-7285
Study First Received: July 13, 2006
Last Updated: December 4, 2008
ClinicalTrials.gov Identifier: NCT00351975  
Health Authority: Unspecified

Keywords provided by National Cancer Institute (NCI):
adult acute myeloid leukemia with 11q23 (MLL) abnormalities
adult acute myeloid leukemia with inv(16)(p13;q22)
adult acute myeloid leukemia with t(15;17)(q22;q12)
adult acute myeloid leukemia with t(16;16)(p13;q22)
adult acute myeloid leukemia with t(8;21)(q22;q22)
recurrent adult acute myeloid leukemia
secondary acute myeloid leukemia
recurrent adult acute lymphoblastic leukemia
myelodysplastic/myeloproliferative disease, unclassifiable
previously treated myelodysplastic syndromes
accelerated phase chronic myelogenous leukemia
blastic phase chronic myelogenous leukemia
chronic myelomonocytic leukemia
Philadelphia chromosome negative chronic myelogenous leukemia
chronic idiopathic myelofibrosis
Philadelphia chromosome positive chronic myelogenous leukemia
relapsing chronic myelogenous leukemia
de novo myelodysplastic syndromes
secondary myelodysplastic syndromes
adult acute promyelocytic leukemia (M3)
atypical chronic myeloid leukemia

Study placed in the following topic categories:
Philadelphia Chromosome
Blast Crisis
Leukemia, Lymphoid
Chronic myelogenous leukemia
Hematologic Neoplasms
Precancerous Conditions
Chronic myelomonocytic leukemia
Leukemia, Myeloid, Acute
Acute lymphoblastic leukemia, adult
Leukemia
Preleukemia
Chronic Myeloproliferative Disorders
Azacitidine
Leukemia, Promyelocytic, Acute
Neoplasm Metastasis
Acute myeloid leukemia, adult
Congenital Abnormalities
Acute myelocytic leukemia
Myelodysplastic syndromes
Myelofibrosis
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Hematologic Diseases
Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative
Leukemia, Myelomonocytic, Chronic
Myelodysplasia
Myelodysplastic Syndromes
Acute promyelocytic leukemia
Acute myelogenous leukemia
Myeloproliferative Disorders
Leukemia, Myeloid

Additional relevant MeSH terms:
Antimetabolites
Neoplasms
Antimetabolites, Antineoplastic
Pathologic Processes
Disease
Neoplasms by Histologic Type
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Therapeutic Uses
Syndrome
Enzyme Inhibitors
Pharmacologic Actions

ClinicalTrials.gov processed this record on January 14, 2009