BMS-354825 in Treating Patients With Chronic Phase Chronic Myelogenous Leukemia That Is Resistant to Imatinib Mesylate

This study has been completed.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Jonsson Comprehensive Cancer Center
ClinicalTrials.gov Identifier:
NCT00064233
First received: July 8, 2003
Last updated: August 2, 2012
Last verified: August 2012
  Purpose

RATIONALE: BMS-354825 may stop the growth of cancer cells by stopping the enzymes necessary for cancer cell growth.

PURPOSE: This phase I trial is studying the side effects and best dose of BMS-354825 in treating patients with chronic phase chronic myelogenous leukemia that is resistant to imatinib mesylate.


Condition Intervention Phase
Leukemia
Drug: dasatinib
Phase 1

Study Type: Interventional
Study Design: Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I Dose-Escalation Study To Determine The Safety, Pharmacokinetics, And Pharmacodynamics Of BMS-354825 In The Treatment Of Patients With Chronic Phase Chronic Myelogenous Leukemia Who Have Hematologic Resistance To Imatinib Mesylate (Gleevec

Resource links provided by NLM:


Further study details as provided by Jonsson Comprehensive Cancer Center:

Enrollment: 42
Study Start Date: November 2003
Study Completion Date: October 2006
Primary Completion Date: October 2006 (Final data collection date for primary outcome measure)
Detailed Description:

OBJECTIVES:

  • Determine the maximum tolerated dose, maximum administered dose, dose-limiting toxicity, and a recommended phase II dose of BMS-354825 in patients with chronic phase chronic myelogenous leukemia who have hematologic resistance to imatinib mesylate.
  • Determine the safety and tolerability of this drug in these patients.
  • Determine the plasma pharmacokinetics of this drug in these patients.
  • Determine, preliminarily, the efficacy of this drug, in terms of hematologic, cytogenetic, and molecular responses in these patients.

OUTLINE: This is an open-label, dose-escalation, multicenter study.

Patients receive oral BMS-354825 once daily on days 1-5. Courses repeat every 7 days for at least 3 months in the absence of disease progression or unacceptable toxicity. Patients may receive further treatment in the absence of disease progression.

Cohorts of 3-6 patients receive escalating doses of BMS-354825 until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 6 patients experience dose-limiting toxicity.

Once the MTD is determined, 20 additional patients receive treatment as in phase I at the MTD of BMS-354825.

Patients are followed for at least 30 days.

PROJECTED ACCRUAL: Approximately 50 patients (30 for phase I and 20 for phase II) will be accrued for this study within 12-18 months.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

INCLUSION CRITERIA:

  • Diagnosis of Philadelphia chromosome positive, chronic phase chronic myelogenous leukemia (CML) meeting all of the following criteria*:
  • Less than 15% blasts in peripheral blood and bone marrow
  • Less than 20% basophils in peripheral blood
  • Less than 30% blasts and promyelocytes in peripheral blood and bone marrow
  • Platelet count at least 100,000/mm^3 NOTE: *Patients who previously met the criteria for accelerated phase or blast phase CML, responded to treatment, and currently meet the criteria for chronic phase CML are eligible
  • Primary or acquired hematologic resistance to imatinib mesylate OR intolerance to imatinib mesylate defined as follows:
  • Primary hematologic resistance is defined as failure to reach complete hematologic response (CHR) with a dose of 400 mg/day continued for at least 3 months

    • Patients with hematological progression (i.e., WBC at least 10,000/mm^3 and rising consistently on at least 2 consecutive measurements obtained at least 14 days apart) while receiving imatinib mesylate of 400 mg/day are eligible if they have received less than 3 months of therapy
  • Acquired hematologic resistance is defined as achieving a CHR, but subsequently developing a rising WBC to at least 10,000/mm^3

    • WBC must be at least 10,000/mm^3 and rising on at least 2 measurements obtained at least 14 days apart with at least 1 of these measurements greater than 15,000/mm^3
  • Intolerance is defined as having discontinued imatinib mesylate due to nonhematologic toxicity of any grade

    • CD4^+ T-cell count at least 350/mm^3
  • 18 and over
  • ECOG 0-1
  • Life expectancy, At least 6 months.
  • Hepatic

    • Bilirubin no greater than 1.5 mg/dL
    • ALT and AST no greater than 2.0 times upper limit of normal (ULN)
  • Renal

    • Creatinine no greater than 1.5 times ULN
    • Potassium normal*
    • Magnesium normal*
    • Serum calcium or ionized calcium at least lower limit of normal NOTE: *Patients with low levels may be repleted to be eligible
  • Negative pregnancy test
  • Fertile patients must use effective contraception for 1 month before, during, and 1 month after study participation
  • More than 14 days since prior interferon
  • More than 14 days since prior cytarabine
  • More than 3 days since prior hydroxyurea
  • More than 28 days since other prior investigational or antineoplastic agents
  • More than 7 days since prior imatinib mesylate
  • At least 5 days or 5 half-lives since prior medications that inhibit platelet function, including the following:
  • Aspirin
  • Dipyridamole
  • Epoprostenol
  • Eptifibatide
  • Clopidogrel
  • Cilostazol
  • Abciximab
  • Ticlopidine
  • At least 5 days or 5 half-lives since prior anticoagulants such as warfarin or heparin/low molecular weight heparin (e.g., danaparoid, dalteparin, tinzaparin, enoxaparin)
  • At least 5 days or 5 half-lives since prior drugs accepted to have a risk of causing torsades de pointes, including the following:
  • Class IA antiarrhythmic agents (e.g., quinidine, procainamide, or disopyramide)
  • Class III antiarrhythmic agents (e.g., amiodarone, sotalol, ibutilide, or dofetilide)
  • Macrolide antibiotics (e.g., erythromycin or clarithromycin)
  • Antipsychotics (e.g., chlorpromazine, haloperidol, thioridazine, or pimozide)
  • Tricyclic antidepressants
  • Cisapride
  • Bepridil
  • Inapsine
  • Methadone
  • Arsenic
  • Concurrent anagrelide for thrombocytosis due to CML allowed

Exclusion Criteria:

  • extramedullary involvement (other than liver or spleen)
  • significant bleeding disorder unrelated to CML
  • acquired bleeding disorder within the past year (e.g., acquired antifactor VIII antibodies)
  • congenital bleeding disorders (e.g., von Willebrand disease)
  • uncontrolled or significant cardiovascular disease
  • uncontrolled angina within the past 6 months
  • congestive heart failure within the past 6 months
  • myocardial infarction within the past 12 months
  • history of clinically significant ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, or torsades de pointes)
  • history of second or third degree heart block (may be eligible if patient has a pacemaker)
  • diagnosed or suspected congenital long QT syndrome
  • prolonged QTc interval on pre-entry EKG (i.e., greater than 450 msec)
  • heart rate less than 50/minute on pre-entry EKG
  • uncontrolled hypertension
  • vasculitis
  • pregnant or nursing
  • gastrointestinal tract bleeding within the past 6 months
  • connective tissue disorders
  • other serious uncontrolled medical disorder or active infection that would impair the ability to receive study therapy
  • dementia or altered mental status that would preclude giving informed consent
  • evidence of organ dysfunction or any clinically significant deviation from normal in physical examination, vital signs, EKG, or clinical laboratory determinations unrelated to CML
  • prisoners or patients who are compulsorily detained (e.g., involuntary incarceration for treatment of either a psychiatric or physical [e.g., infectious disease] illness)
  • concurrent drugs accepted to have a risk of causing torsades de pointes
  • other concurrent treatment for CML
  • concurrent dolasetron or droperidol
  • concurrent anticoagulants
  • concurrent medications that inhibit platelet function
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00064233

Locations
United States, California
Jonsson Comprehensive Cancer Center at UCLA
Los Angeles, California, United States, 90095-1781
Sponsors and Collaborators
Jonsson Comprehensive Cancer Center
Investigators
Principal Investigator: Charles Sawyers, MD Jonsson Comprehensive Cancer Center
  More Information

Additional Information:
Publications:
Cortes J, Sawyers CL, Kantarjian HM, et al.: Long-term efficacy of dasatinib in chronic-phase CML: results from the phase I trial (CA180002). [Abstract] Blood 110 (11): A-1026, 2007.
Talpaz M, Kantarjian HM, Paquette R, et al.: A phase I study of BMS-354825 in patients with imatinib-resistant and intolerant chronic phase chronic myeloid leukemia (CML): results from CA180002. [Abstract] J Clin Oncol 23 (Suppl 16): A-6519, 564s, 2005.

Responsible Party: Jonsson Comprehensive Cancer Center
ClinicalTrials.gov Identifier: NCT00064233     History of Changes
Other Study ID Numbers: CDR0000310142, P30CA016042, UCLA-0303035, BMS-CA180002
Study First Received: July 8, 2003
Last Updated: August 2, 2012
Health Authority: United States: Federal Government

Keywords provided by Jonsson Comprehensive Cancer Center:
chronic phase chronic myelogenous leukemia
relapsing chronic myelogenous leukemia
Philadelphia chromosome positive chronic myelogenous leukemia

Additional relevant MeSH terms:
Leukemia, Myeloid
Leukemia, Myeloid, Chronic-Phase
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Leukemia
Neoplasms by Histologic Type
Neoplasms
Myeloproliferative Disorders
Bone Marrow Diseases
Hematologic Diseases
Imatinib
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on September 16, 2014