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

City of Hope

Status and phase

Completed

Phase 1

Conditions

Leukemia

Treatments

Drug: dasatinib

Genetic: cytogenetic analysis

Genetic: reverse transcriptase-polymerase chain reaction

Other: laboratory biomarker analysis

Other: flow cytometry

Drug: vorinostat

Genetic: mutation analysis

Genetic: gene expression analysis

Study type

Interventional

Funder types

Other

NIH

Identifiers

NCT00816283

08047 (Other Identifier)

P30CA033572 (U.S. NIH Grant/Contract)

CHNMC-08047

CDR0000631569 (Registry Identifier)

Details and patient eligibility

About

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.

Full 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.

Enrollment

5 patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

Inclusion and exclusion 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