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

Sponsor

City of Hope Medical Center (Other)

Overall Status

Completed

CT.gov ID

NCT00816283

Collaborator

National Cancer Institute (NCI) (NIH)

Enrollment

Locations

Duration (Months)

2.5

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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 or Disease	Intervention/Treatment	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

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

5 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (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)

Study Start Date :

Sep 1, 2008

Actual Primary Completion Date :

Jun 1, 2011

Actual Study Completion Date :

Jun 1, 2011

Outcome Measures

Primary Outcome Measures

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]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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