Basic Trial Information
Trial Description
     Summary
     Further Trial Information
     Eligibility Criteria
Trial Contact Information

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase I	Biomarker/Laboratory analysis, Treatment	Closed	18 and over	NCI, Other	CDR0000310142 UCLA-0303035, BMS-CA180002, NCT00064233

Trial Description

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.

Further Study Information

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 Criteria

DISEASE CHARACTERISTICS:

• 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

• No extramedullary involvement (other than liver or spleen) 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

PATIENT CHARACTERISTICS:

Age

• 18 and over

Performance status

• ECOG 0-1

Life expectancy

• At least 6 months

Hematopoietic

• See Disease Characteristics

• No significant bleeding disorder unrelated to CML

• No acquired bleeding disorder within the past year (e.g., acquired antifactor VIII antibodies)

• No congenital bleeding disorders (e.g., von Willebrand disease)

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

Cardiovascular

• No uncontrolled or significant cardiovascular disease

• No uncontrolled angina within the past 6 months

• No congestive heart failure within the past 6 months

• No myocardial infarction within the past 12 months

• No history of clinically significant ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, or torsades de pointes)

• No history of second or third degree heart block (may be eligible if patient has a pacemaker)

• No diagnosed or suspected congenital long QT syndrome

• No prolonged QTc interval on pre-entry EKG (i.e., greater than 450 msec)

• No heart rate less than 50/minute on pre-entry EKG

• No uncontrolled hypertension

• No vasculitis

Other

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective contraception for 1 month before, during, and 1 month after study participation

• No gastrointestinal tract bleeding within the past 6 months

• No connective tissue disorders

• No other serious uncontrolled medical disorder or active infection that would impair the ability to receive study therapy

• No dementia or altered mental status that would preclude giving informed consent

• No evidence of organ dysfunction or any clinically significant deviation from normal in physical examination, vital signs, EKG, or clinical laboratory determinations unrelated to CML

• No prisoners or patients who are compulsorily detained (e.g., involuntary incarceration for treatment of either a psychiatric or physical [e.g., infectious disease] illness)

PRIOR CONCURRENT THERAPY:

Biologic therapy

• More than 14 days since prior interferon

Chemotherapy

• More than 14 days since prior cytarabine

• More than 3 days since prior hydroxyurea

Endocrine therapy

• Not specified

Radiotherapy

• Not specified

Surgery

• Not specified

Other

• See Disease Characteristics

• 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

• No concurrent drugs accepted to have a risk of causing torsades de pointes

• No other concurrent treatment for CML

• No concurrent dolasetron or droperidol

• No concurrent anticoagulants

• No concurrent medications that inhibit platelet function

• Concurrent anagrelide for thrombocytosis due to CML allowed

Trial Contact Information

Trial Lead Organizations/Sponsors

Jonsson Comprehensive Cancer Center at UCLA

Charles Sawyers

Principal Investigator

Link to the current ClinicalTrials.gov record.
NLM Identifer NCT00064233
Information obtained from ClinicalTrials.gov on March 10, 2010

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