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

Sponsor

Jonsson Comprehensive Cancer Center (Other)

Overall Status

Completed

CT.gov ID

NCT00064233

Collaborator

Bristol-Myers Squibb (Industry)

Enrollment

Location

Duration (Months)

1.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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 or Disease	Intervention/Treatment	Phase
Leukemia	Drug: dasatinib	Phase 1

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

42 participants

Masking:

None (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

Study Start Date :

Nov 1, 2003

Actual Primary Completion Date :

Oct 1, 2006

Actual Study Completion Date :

Oct 1, 2006

Outcome Measures

Primary Outcome Measures

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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