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)
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)
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.
OBJECTIVES:
Secondary
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.
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:
In blastic phase (blast crisis), defined by the presence of ≥ 1 of the following:
Philadelphia chromosome-positive acute lymphoblastic leukemia meeting any of the following criteria:
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:
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:
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 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:
At least 7 days since prior and no concurrent medications that directly and durably inhibit platelet function, including any of the following:
At least 5 days since prior and no concurrent St. John's wort
No IV bisphosphonates during the first 8 weeks of dasatinib therapy