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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)


Phase 1
18 Years
N/A
Not Enrolling
Both
Leukemia

Thank you

Trial Information

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)


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.

Inclusion 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

Type of Study:

Interventional

Study Design:

Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Maximum tolerated dose

Outcome Time Frame:

21 days after the beginning of treatment

Safety Issue:

Yes

Principal Investigator

David Snyder, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Beckman Research Institute

Authority:

United States: Institutional Review Board

Study ID:

08047

NCT ID:

NCT00816283

Start Date:

September 2008

Completion Date:

June 2011

Related Keywords:

  • Leukemia
  • 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
  • Blast Crisis
  • Leukemia
  • Leukemia, Lymphoid
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Leukemia, Myeloid
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive
  • Philadelphia Chromosome

Name

Location

City of Hope Comprehensive Cancer CenterDuarte, California  91010
City of Hope Medical GroupPasadena, California  91105