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

Alternate Title

BMS-354825 in Treating Patients With Blastic Phase Chronic Myelogenous Leukemia That Did Not Respond to Previous Imatinib Mesylate

Basic Trial Information

Phase Type Status Age Sponsor Protocol IDs Phase II Treatment Closed 18 and over NCI, Pharmaceutical / Industry UCLA-0411069-01 BMS-CA180006, EUDRACT-2004-002516-28, NCT00108719

Objectives

Primary

1. Determine the complete and overall hematologic response rate in patients with blastic phase chronic myelogenous leukemia (CML) with primary or acquired resistance to imatinib mesylate treated with BMS-354825.

Secondary

1. Determine the durability of complete and overall hematologic response in patients treated with this drug.
2. Determine time to complete and overall response in patients treated with this drug.
3. Determine the cytogenetic and molecular response in patients treated with this drug.
4. Determine the hematologic, cytogenetic, and molecular response in patients with imatinib mesylate-intolerant CML treated with this drug.
5. Determine the response rate in patients with no evidence of leukemia and in patients who return to chronic phase CML after treatment with this drug.
6. Determine the role of BCR-ABL mRNA expression and point mutations in the BCR-ABL gene as predictors or surrogates of response in patients treated with this drug.
7. Determine the health-related quality of life, as measured by the Functional Assessment of Cancer Therapy-General (FACT-G) questionnaire, in patients treated with this drug.
8. Determine the safety and tolerability of this drug in these patients.
9. Determine the pharmacokinetics of this drug in these patients.

Entry Criteria

Disease Characteristics:

• Diagnosis of blastic phase chronic myelogenous leukemia (CML), defined by ≥ 1 of the following criteria:
  • At least 30% myeloid blasts in peripheral blood or bone marrow
  • Extramedullary infiltrates of leukemic cells (other than in the spleen or liver) with peripheral blood myeloid blast morphology



• Philadelphia chromosome-positive OR BCR-ABL-positive disease



• Previously treated with imatinib mesylate AND meets 1 of the following criteria:
  • Primary* or acquired** hematologic resistance to imatinib mesylate, defined as 1 of the following:
    • Initial diagnosis of chronic phase CML that progressed to blastic phase CML during treatment with imatinib mesylate at a dose ≥ 400 mg/day
    • Initial diagnosis of accelerated phase CML that progressed to blastic phase CML during treatment with imatinib mesylate at a dose ≥ 600 mg/day ( 400-599 mg/day in patients intolerant to a dose ≥ 600 mg/day)
    • Initial diagnosis of blastic phase CML, meeting the criteria for blast crisis after ≥ 4 weeks (2 weeks for rapid disease progression) of treatment with imatinib mesylate at a dose ≥ 600 mg/day (400-599 mg/day in patients intolerant to a dose ≥ 600 mg/day)

     [Note: *Disease did not respond to treatment with imatinib mesylate]

     [Note: **Disease responded to treatment with imatinib mesylate but subsequently progressed to accelerated phase CML]

  • Intolerant to imatinib mesylate, defined as toxicity possibly related to treatment with imatinib mesylate at a dose ≤ 400 mg/day that led to discontinuation of therapy OR patient can only tolerate imatinib mesylate at doses < 400 mg/day
    • Patients who tolerate a dose of imatinib mesylate at 400 mg/day but are intolerant to higher doses are not considered intolerant to imatinib mesylate

   [Note: Imatinib mesylate need not be the most recent treatment for CML prior to study entry]




• Not eligible for OR refused to undergo transplantation

Prior/Concurrent Therapy:

Biologic therapy

• More than 14 days since prior interferon

Chemotherapy

• More than 14 days since prior cytarabine
• Prior or concurrent hydroxyurea allowed for treatment of elevated WBC (i.e., WBC > 50,000/mm³)

Endocrine therapy

• Not specified

Radiotherapy

• Not specified

Surgery

• Not specified

Other

• No prior BMS-354825
• More than 7 days since prior imatinib mesylate
• At least 7 days since prior and no concurrent low-dose aspirin (i.e., ≤ 325 mg/day)
• At least 14 days since prior and no concurrent high-dose aspirin (i.e., > 325 mg/day)
• More than 14 days since prior targeted small molecule anticancer agents
• More than 28 days since prior investigational or antineoplastic agents
• At least 5 days or 5 half-lives (whichever is greater) since prior and no concurrent drugs that carry a risk of causing torsades de pointes, including any of the following:
  • Quinidine
  • Procainamide
  • Disopyramide
  • Amiodarone
  • Sotalol
  • Ibutilide
  • Dofetilide
  • Erythromycin
  • Clarithromycin
  • Chlorpromazine
  • Haloperidol
  • Mesoridazine
  • Thioridazine
  • Pimozide
  • Cisapride
  • Bepridil
  • Droperidol
  • Methadone
  • Arsenic
  • Chloroquine
  • Domperidone
  • Halofantrine
  • Levomethadyl
  • Pentamidine
  • Sparfloxacin
  • Lidoflazine
• At least 5 days or 5 half-lives (whichever is greater) since prior and no concurrent medication that directly inhibits platelet function (except anagrelide for thrombocytosis due to CML), including any of the following:
  • Dipyridamole
  • Epoprostenol
  • Eptifibatide
  • Clopidogrel
  • Cilostazol
  • Abciximab
  • Ticlopidine
• At least 5 days or 5 half-lives (whichever is greater) since prior and no concurrent anticoagulant (e.g., warfarin, heparin, or low molecular weight heparin [e.g., danaparoid, dalteparin, tinzaparin, or enoxaparin])
  • Concurrent prophylactic low-dose warfarin for prevention of catheter thrombosis and heparin-flush for IV lines allowed
• No other concurrent therapy for CML

Patient Characteristics:

Age

• 18 and over

Performance status

• ECOG 0-2

Life expectancy

• Not specified

Hematopoietic

• See Disease Characteristics
• No history of significant bleeding disorder unrelated to CML, including any of the following:
  • Congenital bleeding disorder (e.g., von Willebrand's disease)
  • Acquired bleeding disorder within the past year (e.g., acquired anti-factor VIII antibodies)

Hepatic

• Bilirubin ≤ 2.0 times upper limit of normal (ULN)
• ALT and AST ≤ 2.5 times ULN

Renal

• Creatinine ≤ 1.5 times ULN
• Total calcium normal*

  OR

• Ionized calcium normal*

 [Note: *Supplementation allowed]

Cardiovascular

• No myocardial infarction within the past 6 months
• No uncontrolled angina within the past 3 months
• No congestive heart failure within the past 3 months
• No diagnosis or suspicion of congenital long QT syndrome
• No history of clinically significant ventricular arrhythmia (e.g., ventricular tachycardia, ventricular fibrillation, or torsades de pointes)
• No prolonged QTc interval (i.e., > 450 msec) on electrocardiogram determined by Bazett's correction or Fridericia correction
• No history of second or third degree heart block unless patient has a pacemaker
• No heart rate consistently < 50 beats/minute on electrocardiogram
• No uncontrolled hypertension
• No other uncontrolled or significant cardiovascular disease

Gastrointestinal

• No clinically significant gastrointestinal tract bleeding within the past 6 months
• No digestive dysfunction that would preclude study participation

Other

• Not pregnant or nursing
  • No nursing during and for ≥ 3 months after completion of study treatment
• Negative pregnancy test
• Fertile patients must use effective contraception for 1 month before, during, and for ≥ 3 months after completion of study treatment
• Potassium normal*
• Magnesium normal*
• No serious uncontrolled medical disorder or active infection that would preclude study participation
• No dementia or altered mental status that would preclude giving informed consent
• No evidence of organ dysfunction that would preclude study participation
• No prisoners or patients who are compulsorily detained (involuntarily incarcerated) for treatment of a psychiatric or physical (e.g., infectious disease) illness
• No other incurable malignancy

 [Note: *Supplementation allowed]

Expected Enrollment

A minimum of 60 patients will be accrued for this study within 6 months.

Outline

This is an open-label, multicenter study.

Patients receive oral BMS-354825 twice daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Quality of life is assessed at baseline, on day 15 of course 1, on days 1 and 15 of courses 2 and 3, once a month in all subsequent courses, and at the completion of study treatment.

After completion of study treatment, patients are followed for at least 30 days.

Cortes JE, Kim DW, Rosti G, et al.: Dasatinib (D) in patients (pts) with chronic myelogenous leukemia (CML) in myeloid blast crisis (MBC) who are imatinib-resistant (IM-R) or IM-intolerant (IM-I): results of the CA180006 'START-B' study. [Abstract] J Clin Oncol 24 (Suppl 18): A-6529, 344s, 2006.

Talpaz M, Rousselot P, Kim DW, et al.: A phase II study of dasatinib in patients with chronic myeloid leukemia (CML) in myeloid blast crisis who are resistant or intolerant to imatinib: first results of the CA180006 ‘START-B’ study. [Abstract] Blood 106 (11): A-40, 2005.

Cortes J, Rousselot P, Kim DW, et al.: Dasatinib induces complete hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in blast crisis. Blood 109 (8): 3207-13, 2007.[PUBMED Abstract]

Trial Contact Information

Trial Lead Organizations

Jonsson Comprehensive Cancer Center at UCLA

Neil Shah, MD, Protocol chair		Ph: 310-206-5111; 888-798-0719 Email: nshah@ucla.edu

Registry Information
Official Title		A Phase II Study of BMS-354825 in Subjects with Myeloid Blast Phase Chronic Myeloid Leukemia Resistant to or Intolerant of Imatinib Mesylate
Trial Start Date		2005-01-11
Registered in ClinicalTrials.gov		NCT00108719
Date Submitted to PDQ		2005-02-17
Information Last Verified		2006-04-11
NCI Grant/Contract Number		CA16042