OBJECTIVES:

Primary

• Determine the major cytogenetic response (MCyR) rate in patients with imatinib mesylate-resistant or -intolerant Philadelphia chromosome-positive chronic phase chronic myelogenous leukemia treated with BMS-354825.

Secondary

• Determine the durability of MCyR and time to MCyR in patients treated with this drug.
• Determine the complete hematologic response (CHR) rate, duration of CHR, and time to CHR in patients treated with this drug.
• Determine the major molecular response rate in patients treated with this drug.
• Determine health-related quality of life of patients treated with this drug.
• Determine the safety and tolerability of this drug in these patients.
• Determine the pharmacokinetics of this drug in these patients.

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

Patients receive oral BMS-354825 twice daily. Treatment continues in the absence of disease progression or unacceptable toxicity.

Quality of life is assessed at baseline, at day 29, every 4 weeks for 24 weeks, every 12 weeks for the remainder of study treatment, and then at the completion of study treatment.

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

PROJECTED ACCRUAL: A minimum of 100 patients will be accrued for this study within 6-12 months.

DISEASE CHARACTERISTICS:

• Diagnosis of chronic phase chronic myelogenous leukemia (CML), defined by 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 ≥ 100,000/mm^3 (unless thrombocytopenia is due to recent therapy)
  • No extramedullary involvement (other than liver or spleen)
• Philadelphia chromosome (Ph)-positive disease by cytogenetic analysis

• Previously treated with imatinib mesylate* AND meets 1 of the following criteria:

  • Resistant disease during treatment with imatinib mesylate at a dose > 600 mg/day, as defined by 1 of the following criteria:

    • Acquired resistance after achieving a major cytogenetic response (MCyR) OR complete hematologic response (CHR) while on any dose of imatinib mesylate, defined by 1 of the following:

      • Loss of MCyR after achieving confirmed MCyR AND ≥ 30% increase in Ph-positive cells in metaphase on 2 cytogenetic analyses performed ≥ 4 weeks apart
      • Loss of CHR, as documented on all assessments performed over a 2-week period, after achieving confirmed CHR
      • Increasing WBC, defined as a doubling of the count from the nadir to > 20,000/mm^3 OR an increase of > 50,000/mm^3 on 2 occasions ≥ 2 weeks apart in patients who never achieved CHR despite receiving maximum tolerated doses of imatinib mesylate

    • Primary resistance, defined as no achievement of MCyR or CHR while on any dose of imatinib mesylate, AND meets 1 of the following criteria:

      • Continuously increasing WBC on ≥ 2 consecutive evaluations ≥ 2 weeks apart with a doubling of WBC from the nadir to ≥ 20,000/mm^3 OR an absolute increase of WBC > 50,000/mm^3 above the lowest count after beginning imatinib mesylate
      • No CHR after 3 months of imatinib mesylate
      • No cytogenetic response (CyR) after 6 months of imatinib mesylate
      • No MCyR after 12 months of imatinib mesylate
  • Resistant to imatinib mesylate at a dose of ≤ 600 mg/day AND carries a BCR-ABL gene mutation that is associated with a high level of resistance to imatinib mesylate (e.g., L248V, G250E, Q252H/R, Y253H/F, E255K/V, T315I/D, F317L, and H369P/R)

  • Intolerant of imatinib mesylate at any dose, defined as 1 of the following:

    • Progressive disease at a dose of 800 mg/day
    • Lack of CyR at doses ≤ 600 mg/day
    • Grade 3 or greater non-hematologic toxicity (related to imatinib mesylate)
    • Grade 4 hematologic toxicity lasting > 7 days (related to imatinib mesylate) NOTE: *Imatinib mesylate need not be the most recent treatment for CML

• No prior diagnosis of accelerated phase or blastic phase CML

  • Patients previously diagnosed with accelerated phase or blastic phase CML who achieved a CHR on prior imatinib mesylate and subsequently progressed to chronic phase CML are not eligible
• Ineligible for or unwilling to undergo transplantation

PATIENT CHARACTERISTICS:

Age

• 18 and over

Performance status

• ECOG 0-1

Life expectancy

• At least 3 months

Hematopoietic

• See Disease Characteristics

• No significant bleeding disorder unrelated to CML, including either of the following:

  • Diagnosed congenital bleeding disorders (e.g., von Willebrand's disease)
  • Acquired bleeding disorders (e.g., acquired anti-factor VIII antibodies) diagnosed within the past year

Hepatic

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

Renal

• Creatinine ≤ 1.5 times ULN
• Calcium normal (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 diagnosed or suspected congenital long QT syndrome
• No history of clinically significant ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, or torsades de pointes)
• No prolonged QTc interval (i.e., > 450 msec) on EKG 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 by EKG
• 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
• 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 other incurable malignancy
• No organ dysfunction that would preclude study participation
• No other 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 prisoners or patients who are compulsorily detained (involuntarily incarcerated) for treatment of a psychiatric or physical (e.g., infectious disease) illness NOTE: *Supplementation allowed

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 > 50,0000/mm^3)

Endocrine therapy

• Not specified

Radiotherapy

• Not specified

Surgery

• Not specified

Other

• No prior BMS-354825
• More than 14 days since prior targeted small molecule anticancer agents
• More than 7 days since prior imatinib mesylate
• More than 4 weeks since other prior investigational or antineoplastic agents
• 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)

• At least 5 days or 5 half-lives (whichever is greater) since prior and no concurrent medications known to have 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
  • Ziprasidone
  • Cisapride
  • Bepridil
  • Droperidol
  • Methadone
  • Arsenic trioxide
  • Chloroquine
  • Domperidone
  • Halofantrine
  • Levomethadyl
  • Pentamidine
  • Sparfloxacin
  • Lidoflazine

• At least 5 days or 5 half-lives (whichever is greater) since prior and no concurrent anticoagulants (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

• 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
• No concurrent antacids within 4 hours before or after study drug administration
• No concurrent CYP3A4 inhibitors (e.g., ketoconazole or ritonavir) or inducers (e.g., rifampin or efavirenz)
• No other concurrent therapy for CML