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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.
National Cancer Institute (NCI)
Information provided by (Responsible Party):
City of Hope Medical Center Identifier:
First received: December 31, 2008
Last updated: July 16, 2012
Last verified: July 2012

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
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 ]
  • Toxicity as assessed by NCI CTCAE v3.0 [ Time Frame: 21 days from the beginning of the last course of treatment ]
  • Response rate [ Time Frame: One year after treatment completion ]
  • Objective tumor response [ Time Frame: One year after treatment completion ]
  • Survival [ Time Frame: One year after treatment completion ]
  • Time to treatment failure [ Time Frame: One year after treatment completion ]
  • Duration of response [ Time Frame: One year after treatment completion ]

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:


  • 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.


  • 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.


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


  • 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


  • 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


  • 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
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Please refer to this study by its identifier: NCT00816283

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
National Cancer Institute (NCI)
Principal Investigator: David Snyder, MD City of Hope Comprehensive Cancer Center
  More Information

Responsible Party: City of Hope Medical Center Identifier: NCT00816283     History of Changes
Other Study ID Numbers: 08047
P30CA033572 ( US NIH Grant/Contract Award Number )
CDR0000631569 ( Registry Identifier: NCI PDQ )
Study First Received: December 31, 2008
Last Updated: July 16, 2012

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:
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphoid
Leukemia, Myeloid
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Philadelphia Chromosome
Blast Crisis
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Myeloproliferative Disorders
Bone Marrow Diseases
Hematologic Diseases
Translocation, Genetic
Chromosome Aberrations
Pathologic Processes
Cell Transformation, Neoplastic
Neoplastic Processes
Antineoplastic Agents
Histone Deacetylase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Protein Kinase Inhibitors processed this record on May 25, 2017