17-N-Allylamino-17-Demethoxygeldanamycin in Treating Patients With Chronic Phase Chronic Myelogenous Leukemia That Did Not Respond to Imatinib Mesylate

OBJECTIVES:

Primary

• Determine the maximum tolerated dose and dose-limiting toxicity of 17-N-allylamino-17-demethoxygeldanamycin (17-AAG), in terms of frequency, severity, and duration of treatment-emergent adverse events, in patients with imatinib mesylate-resistant Philadelphia chromosome (Ph)-positive chronic phase chronic myelogenous leukemia.
• Determine the pharmacokinetics of this drug and its primary metabolite (17-amino-17-demethoxygeldanamycin) in these patients.

Secondary

• Determine the hematologic response rate, in terms of WBC count, platelet count, and assessment of blast cells in peripheral blood, in patients treated with this drug.
• Determine the cytogenic response rate, in terms of Ph-positive progenitor cells in the bone marrow, in patients treated with this drug.
• Assess the effect of this drug on pharmacodynamic markers (i.e., CRKL phosphorylation, BCR-ABL kinase activity, and BCR-ABL, RAF kinase, and HSP70 expression) in these patients.

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

Patients receive 17-N-allylamino-17-demethoxygeldanamycin (17-AAG) IV over 15 minutes or 1 hour (depending on the dose administered) once on days 1, 4, 8, 11, 15, 18, 22, and 25. Treatment repeats every 28 days for up to 3 courses in the absence of unacceptable toxicity or disease progression. Eligible patients may receive additional courses of 17-AAG at the discretion of the investigator.

Cohorts of 3-6 patients receive escalating doses of 17-AAG until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. Up to 10 additional patients are treated at the MTD.

Patients are followed for 1 month.

PROJECTED ACCRUAL: Approximately 40 patients will be accrued for this study.

DISEASE CHARACTERISTICS:

• Diagnosis of chronic phase chronic myelogenous leukemia

• Philadelphia chromosome (Ph)-positive disease
• Hematologic resistence after treatment with imatinib mesylate (400 mg per day or maximum tolerated dose [MTD]) as defined by 1 of the following criteria:

• Loss of complete hematologic response, defined as WBC count OR platelet count > upper limit of normal (ULN) on 2 separate occasions at least 2 weeks apart that cannot be attributed to other etiologies
• Absolute increase of ≥ 30% in Ph-positive cells while on a stable dose of imatinib mesylate for at least 6 months* NOTE: *Patients meeting this criterion are not eligible for enrollment into the expanded MTD cohort
• Less than 15% blasts in peripheral blood or bone marrow AND < 30% blasts and promyelocytes in peripheral blood or bone marrow

PATIENT CHARACTERISTICS:

Age

• 18 and over

Performance status

• ECOG 0-2

Life expectancy

• At least 6 months

Hematopoietic

• See Disease Characteristics

Hepatic

• Bilirubin < 1.5 times ULN (3 mg/dL for patients with Gilbert's syndrome)
• ALT or AST < 2 times ULN
• No known hepatitis positivity

Renal

• Creatinine < 1.5 times ULN OR
• Creatinine clearance > 60 mL/min

Cardiovascular

• No New York Heart Association class III or IV cardiac disease

Pulmonary

• No severe debilitating pulmonary disease, including any of the following:

• Dyspnea at rest
• Significant shortness of breath
• Chronic obstructive pulmonary disease

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for 1 month after study participation
• No known HIV positivity
• No psychological or social condition that would preclude study compliance
• No addictive disorder that would preclude study compliance
• No family problems that would preclude study compliance
• No known allergy or sensitivity to soy or other excipient components of study drug
• No other illness or condition that may affect safety of study treatment or evaluation of study endpoints

PRIOR CONCURRENT THERAPY:

Biologic therapy

• More than 2 weeks since prior interferon
• No concurrent interferon

Chemotherapy

• More than 2 weeks since prior cytarabine (4 weeks for doses > 100 mg)
• More than 6 weeks since prior busulfan
• No concurrent cytarabine
• No concurrent hydroxyurea during the second study treatment course and beyond
• No concurrent anagrelide during the second study treatment course and beyond

Endocrine therapy

• Not specified

Radiotherapy

• Not specified

Surgery

• Not specified

Other

• More than 2 days since prior imatinib mesylate
• More than 1 week since prior and no concurrent drugs that alter metabolism by cytochrome P450 3A4, including the following:

• Diltiazem
• Nifedipine
• Verapamil
• Fluconazole
• Itraconazole
• Ketoconazole
• Lovastatin
• Simvastatin
• Indinavir
• Nelfinavir
• Ritonavir
• Alprazolam
• Diazepam
• Midazolam
• Triazolam
• Phenobarbital
• Phenytoin
• Carbamazepine
• Azithromycin
• Clarithromycin
• Erythromycin
• Rifampin
• Rifamycin
• Astemizole
• Terfenidine
• Amiodarone
• Cimetidine
• Cisapride
• Cyclosporine
• Grapefruit juice
• Hypericum perforatum (St. John's wort)
• Warfarin
• More than 4 weeks since prior investigational drugs and recovered
• No concurrent imatinib mesylate