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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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)

Conditions
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Leukemia

Intervention / Treatment
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* 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


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|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|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose |  | 21 days after the beginning of treatment | 
| Toxicity as assessed by NCI CTCAE v3.0 |  | 21 days from the beginning of the last course of treatment | 
| Response rate |  | One year after treatment completion | 
| Objective tumor response |  | One year after treatment completion | 
| Survival |  | One year after treatment completion | 
| Time to treatment failure |  | One year after treatment completion | 
| Duration of response |  | One year after treatment completion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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