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Dasatinib and Vorinostat in Treating Patients With Accelerated Phase or Blastic Phase Chronic Myelogenous Leukemia or Acute Lymphoblastic Leukemia

This study has been completed.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
City of Hope Medical Center
ClinicalTrials.gov Identifier:
NCT00816283
First received: December 31, 2008
Last updated: July 16, 2012
Last verified: July 2012
  Purpose

RATIONALE: Dasatinib and vorinostat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving dasatinib together with vorinostat may kill more cancer cells.

PURPOSE: This phase I trial is studying the side effects and best dose of dasatinib when given together with vorinostat in treating patients with accelerated phase or blastic phase chronic myelogenous leukemia or acute lymphoblastic leukemia.


Condition Intervention Phase
Leukemia
Drug: dasatinib
Drug: vorinostat
Genetic: cytogenetic analysis
Genetic: gene expression analysis
Genetic: mutation analysis
Genetic: reverse transcriptase-polymerase chain reaction
Other: flow cytometry
Other: laboratory biomarker analysis
Phase 1

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: BMS CA180157: A Phase I Combination Study of Dasatinib Plus Vorinostat in Accelerated Phase, Chronic Phase Refractory to Second Line Therapy or Blast Crisis Chronic Myelogenous Leukemia (CML), and in Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia (ALL)

Resource links provided by NLM:


Further study details as provided by City of Hope Medical Center:

Primary Outcome Measures:
  • Maximum tolerated dose [ Time Frame: 21 days after the beginning of treatment ] [ Designated as safety issue: Yes ]
  • Toxicity as assessed by NCI CTCAE v3.0 [ Time Frame: 21 days from the beginning of the last course of treatment ] [ Designated as safety issue: Yes ]
  • Response rate [ Time Frame: One year after treatment completion ] [ Designated as safety issue: No ]
  • Objective tumor response [ Time Frame: One year after treatment completion ] [ Designated as safety issue: No ]
  • Survival [ Time Frame: One year after treatment completion ] [ Designated as safety issue: No ]
  • Time to treatment failure [ Time Frame: One year after treatment completion ] [ Designated as safety issue: No ]
  • Duration of response [ Time Frame: One year after treatment completion ] [ Designated as safety issue: No ]

Enrollment: 5
Study Start Date: September 2008
Study Completion Date: June 2011
Primary Completion Date: June 2011 (Final data collection date for primary outcome measure)
Intervention Details:
    Drug: dasatinib
    50 mg orally 2 times per day or 140 mg orally one time per day
    Drug: vorinostat
    100 mg orally 2 times per day
    Genetic: cytogenetic analysis
    Performed at the end of cycle two of treatment and every six cycles for patients with accelerated CML and every 3 cycles for patients with blast crisis or Ph+ ALL
    Genetic: gene expression analysis
    Bone marrow aspirate obtained pre-treatment, at first scheduled bone marrow assay and at relapse. Peripheral blood drawn pre-therapy, day +14 of first treatment cycle and at relapse.
    Genetic: mutation analysis
    Performed at baseline and at every bone marrow analysis on peripheral blood
    Genetic: reverse transcriptase-polymerase chain reaction
    Peripheral blood drawn prior to starting Vorinostat on Day 1 and on Day 14 of treatment
    Other: flow cytometry
    Performed at the end of cycle two of treatment and every six cycles for patients with accelerated CML and every 3 cycles for patients with blast crisis or Ph+ ALL
    Other: laboratory biomarker analysis
    Performed pre-treatment and day +14 of treatment
Detailed Description:

OBJECTIVES:

  • To define the maximum tolerated dose of dasatinib and vorinostat in patients with accelerated phase or blastic phase chronic myelogenous leukemia or Philadelphia chromosome-positive acute lymphoblastic leukemia.
  • To assess the toxicity of this regimen in these patients.
  • To assess, preliminarily, the efficacy of this regimen in these patients.

Secondary

  • To perform correlative studies relevant to this regimen.

OUTLINE: This is a multicenter study.

Patients receive oral dasatinib twice daily on days 1-21 and oral vorinostat twice daily on days 1-14. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Patients undergo bone marrow aspiration and blood sample collection periodically for correlative laboratory studies. Samples are assessed by RT-PCR for DNA damage response and proapoptotic elements (GADD45, FANC, and FOXO3A); cytogenetic analysis; flow cytometry; mutation analysis of bcr-abl; and gene expression array analysis.

  Eligibility

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

DISEASE CHARACTERISTICS:

  • Diagnosis of 1 of the following hematologic malignancies:

    • Chronic myelogenous leukemia meeting 1 of the following criteria:

      • In accelerated phase, defined by the presence of ≥ 1 of the following:

        • At least 15% but < 30% blasts in peripheral blood and/or bone marrow
        • At least 30% blasts plus promyelocytes in peripheral blood or bone marrow (providing that < 30% blasts are present in bone marrow)
        • At least 20% basophils in peripheral blood
        • Platelet count < 100,000/mm³ (unrelated to therapy) OR platelet count > 100,000/mm³ and unresponsive to therapy
        • Cytogenetic evidence of clonal evolution
        • Increasing spleen size and increasing WBC count and unresponsive to therapy
      • In blastic phase (blast crisis), defined by the presence of ≥ 1 of the following:

        • At least 30% blasts in peripheral blood and/or bone marrow
        • Extramedullary infiltrates of leukemic cells (other than liver or spleen involvement)
    • Philadelphia chromosome-positive acute lymphoblastic leukemia meeting any of the following criteria:

      • Newly diagnosed or relapsed disease
      • Previously treated with chemotherapy, stem cell transplantation, or tyrosine kinase inhibitors (TKIs)
  • No active CNS involvement

PATIENT CHARACTERISTICS:

  • ECOG performance status 0-2
  • Total bilirubin < 2.0 times upper limit of normal (ULN)
  • AST and ALT ≤ 2.5 times ULN
  • Serum sodium, potassium, magnesium, phosphate, and calcium ≥ lower limit of normal
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception during and for ≥ 4 weeks after discontinuation of study drug
  • Able to take oral medication
  • No active post-transplantation-related infections (e.g., fungal or viral infection)
  • No active acute graft-versus-host disease (GVHD) of any grade
  • No chronic GVHD (other than mild skin, oral, or ocular GVHD not requiring systemic immunosuppression)
  • No other malignancy that required radiotherapy or systemic treatment within the past 5 years
  • No concurrent medical condition that may increase the risk of toxicity, including pleural or pericardial effusion of any grade
  • No cardiac conditions, including any of the following:

    • Uncontrolled angina, congestive heart failure, or myocardial infarction within the past 6 months
    • Diagnosed congenital long QT syndrome
    • History of clinically significant ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, or Torsades de pointes)
    • Prolonged QTc interval (i.e., QTc > 450 msec) on baseline EKG
  • No hypokalemia or hypomagnesemia that cannot be corrected prior to dasatinib administration
  • No history of significant bleeding disorder unrelated to cancer, including any of the following:

    • Diagnosed congenital bleeding disorder (e.g., von Willebrand's disease)
    • Acquired bleeding disorder diagnosed within the past year (e.g., acquired anti-factor VIII antibodies)
    • Ongoing or recent (i.e., within the past 3 months) significant gastrointestinal bleeding
  • No prisoners or individuals who are compulsorily detained (i.e., involuntarily incarcerated) for treatment of either a psychiatric or physical (e.g., infectious) illness

PRIOR CONCURRENT THERAPY:

  • See Disease Characteristics
  • Recovered from prior therapy
  • No prior HDAC inhibitors or compounds with HDAC inhibitor-like activity (e.g., valproic acid) as anti-tumor therapy

    • Prior valproic acid for the treatment of seizures allowed provided it was not given within the past 30 days
  • Prior allogeneic stem cell transplantation allowed
  • More than 4 weeks since prior chemotherapy other than TKI (6 weeks for nitrosoureas and mitomycin)
  • More than 2 weeks since prior radiotherapy
  • At least 7 days since prior and no concurrent Category I drugs that are generally accepted to have a risk of causing Torsades de pointes, including any of the following:

    • Quinidine, procainamide, or disopyramide
    • Amiodarone, sotalol, ibutilide, or dofetilide
    • Erythromycin or clarithromycin
    • Chlorpromazine, haloperidol, mesoridazine, thioridazine, or pimozide
    • Cisapride, bepridil, droperidol, methadone, arsenic, chloroquine, domperidone, halofantrine, levomethadyl, pentamidine, sparfloxacin, or lidoflazine
  • At least 7 days since prior and no concurrent medications that directly and durably inhibit platelet function, including any of the following:

    • Aspirin or aspirin-containing combinations, clopidogrel, or dipyridamole
    • Tirofiban, epoprostenol, eptifibatide, cilostazol, abciximab, ticlopidine, or cilostazol
  • At least 5 days since prior and no concurrent St. John's wort
  • No IV bisphosphonates during the first 8 weeks of dasatinib therapy
  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 ClinicalTrials.gov identifier: NCT00816283

Locations
United States, California
City of Hope Comprehensive Cancer Center
Duarte, California, United States, 91010-3000
City of Hope Medical Group
Pasadena, California, United States, 91105
Sponsors and Collaborators
City of Hope Medical Center
Investigators
Principal Investigator: David Snyder, MD Beckman Research Institute
  More Information

Additional Information:
No publications provided

Responsible Party: City of Hope Medical Center
ClinicalTrials.gov Identifier: NCT00816283     History of Changes
Other Study ID Numbers: 08047, P30CA033572, CHNMC-08047, CDR0000631569
Study First Received: December 31, 2008
Last Updated: July 16, 2012
Health Authority: United States: Institutional Review Board

Keywords provided by City of Hope Medical Center:
accelerated phase chronic myelogenous leukemia
blastic phase chronic myelogenous leukemia
relapsing chronic myelogenous leukemia
Philadelphia chromosome positive adult precursor acute lymphoblastic leukemia
recurrent adult acute lymphoblastic leukemia
untreated adult acute lymphoblastic leukemia

Additional relevant MeSH terms:
Abnormal Karyotype
Blast Crisis
Leukemia
Leukemia, Lymphoid
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Leukemia, Myeloid
Philadelphia Chromosome
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Bone Marrow Diseases
Carcinogenesis
Cell Transformation, Neoplastic
Chromosome Aberrations
Hematologic Diseases
Immune System Diseases
Immunoproliferative Disorders
Lymphatic Diseases
Lymphoproliferative Disorders
Myeloproliferative Disorders
Neoplasms
Neoplasms by Histologic Type
Neoplastic Processes
Pathologic Processes
Translocation, Genetic
Dasatinib
Vorinostat
Antineoplastic Agents
Enzyme Inhibitors
Histone Deacetylase Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions

ClinicalTrials.gov processed this record on November 20, 2014