Leukemia
Conditions
Keywords
chronic phase chronic myelogenous leukemia, relapsing chronic myelogenous leukemia, Philadelphia chromosome positive chronic myelogenous leukemia
Brief 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.
Detailed description
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.
Interventions
DRUGdasatinib
Sponsors
Bristol-Myers Squibb
Jonsson Comprehensive Cancer Center
Study design
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Countries
United States
Outcome results
None listed