bms-354825 in treating patients with chronic phase chronic myelogenous leukemia that is resistant to imatinib mesylate

Conditions: Leukemia

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.

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:
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

Keywords: chronic phase chronic myelogenous leukemia relapsing chronic myelogenous leukemia philadelphia chromosome positive chronic myelogenous leukemia