Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outline
Published Results
Trial Contact Information
Registry Information

Alternate Title

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

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase I	Treatment	Closed	18 and over	NCI, Pharmaceutical / Industry	UCLA-0303035 BMS-CA180002, NCT00064233

Objectives

1. 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.
2. Determine the safety and tolerability of this drug in these patients.
3. Determine the plasma pharmacokinetics of this drug in these patients.
4. Determine, preliminarily, the efficacy of this drug, in terms of hematologic, cytogenetic, and molecular responses in these patients.

Entry 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/mm³
  • 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/mm³ 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/mm³
    • WBC must be at least 10,000/mm³ and rising on at least 2 measurements obtained at least 14 days apart with at least 1 of these measurements greater than 15,000/mm³
  • Intolerance is defined as having discontinued imatinib mesylate due to nonhematologic toxicity of any grade



• CD4⁺ T-cell count at least 350/mm³

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

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)

Expected Enrollment

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

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.

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, Shah NP, Kantarjian H, et al.: Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med 354 (24): 2531-41, 2006.[PUBMED Abstract]

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.

Trial Contact Information

Trial Lead Organizations

Jonsson Comprehensive Cancer Center at UCLA

Charles Sawyers, MD, Principal investigator		Ph: 310-206-5585; 888-798-0719

Registry Information
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 (GleevecTM
Trial Start Date		2003-11-11
Registered in ClinicalTrials.gov		NCT00064233
Date Submitted to PDQ		2003-05-28
Information Last Verified		2006-04-11
NCI Grant/Contract Number		CA16042

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