Basic Trial Information
Trial Description
     Summary
     Further Trial Information
     Eligibility Criteria
Trial Contact Information

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase II	Biomarker/Laboratory analysis, Treatment	Closed	18 and over	NCI, Other	CDR0000422432 UCLA-0411071-01, BMS-CA180015, EUDRACT-2004-002517-36, NCT00110097

Trial Description

Summary

RATIONALE: BMS-354825 may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

PURPOSE: This phase II trial is studying how well BMS-354825 works in treating patients with blastic phase chronic myelogenous leukemia or acute lymphoblastic leukemia that did not respond to previous imatinib mesylate.

Further Study Information

OBJECTIVES:

Primary

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

Secondary

• Determine the durability of hematologic response and time to complete and overall hematologic response in patients treated with this drug.

• Determine the cytogenetic and molecular response in patients treated with this drug.

• Determine the response rate in patients with no evidence of leukemia and in patients whose disease returns to chronic phase after treatment with this drug.

• Determine the hematologic, cytogenetic, and molecular response in patients with imatinib mesylate-intolerant CML or ALL treated with this drug.

• 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.

• Determine the health-related quality of life of patients treated with this drug.

• Determine the safety and tolerability of this drug in these patients.

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, every 2 weeks for the first 3 courses, monthly thereafter during study treatment, and 30 days after completion of study treatment.

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

PROJECTED ACCRUAL: A minimum of 60 patients (at least 30 with blastic phase chronic myelogenous leukemia and at least 30 with acute lymphoblastic leukemia) will be accrued for this study within 6 months.

Eligibility Criteria

DISEASE CHARACTERISTICS:

• Diagnosis of 1 of the following:

• Blastic phase chronic myelogenous leukemia (CML), meeting ≥ 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

• Acute lymphoblastic leukemia (ALL)

• Previously treated with standard induction or consolidation chemotherapy

• 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)

• ALL that progressed after OR did not respond to ≥ 4 weeks 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 blastic 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

• Patients who tolerated 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 or ALL prior to study entry

• Not eligible for OR unwilling to undergo transplantation

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:

• Diagnosis of congenital bleeding disorder (e.g., von Willebrand's disease)

• Diagnosis of 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 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 EKG by Bazett's correction or Fridericia correction

• No history of second or third degree heart block

• Patients with pacemakers may be eligible

• No heart rate consistently < 50 beats/minute on EKG

• No uncontrolled hypertension

• No other uncontrolled or significant cardiovascular disease

Gastrointestinal

• No clinically significant gastrointestinal tract bleeding within the past 6 months

• No evidence of digestive dysfunction that would preclude study participation

Other

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective contraception 1 month before, during, and for at least 3 months after completion of study treatment

• Potassium normal*

• Magnesium normal*

• 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 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

PRIOR CONCURRENT THERAPY:

Biologic therapy

• More than 14 days since prior interferon

Chemotherapy

• See Disease Characteristics

• More than 14 days since prior cytarabine

• Prior or concurrent hydroxyurea allowed for treatment of elevated WBC (i.e., WBC > 50,000/mm^3)

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 low-dose aspirin (≤ 325 mg/day)

• At least 14 days since prior high-dose aspirin (> 325 mg/day)

• More than 14 days since prior targeted small-molecule anticancer agents

• More than 28 days since prior investigational agents

• At least 5 days or 5 half-lives (whichever is longer) since prior and no concurrent drugs that may confer a risk of 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 longer) since prior and no concurrent medications that directly inhibit platelet function (except anagrelide for treatment of 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 longer) since prior and no concurrent anticoagulants (e.g., warfarin or heparin/low molecular weight heparin [e.g., danaparoid, dalteparin, tinzaparin, or enoxaparin])

• Concurrent prophylactic low-dose warfarin allowed for prevention of catheter thrombosis or for heparin-flush of IV lines

• No other concurrent therapy for CML

Trial Contact Information

Trial Lead Organizations/Sponsors

Jonsson Comprehensive Cancer Center at UCLA

Neil P. Shah

Study Chair

Link to the current ClinicalTrials.gov record.
NLM Identifer NCT00110097
Information obtained from ClinicalTrials.gov on October 19, 2009

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