Geldanamycin Analogue in Treating Patients With Advanced Cancer

OBJECTIVES:

• Determine the maximum tolerated dose for a geldanamycin analogue, 17-allylamino-17-demethoxygeldanamycin (AAG), in patients with advanced malignancies.
• Determine the toxic effects and dose-limiting toxicity of AAG in this patient population.
• Determine the safe dose of AAG for a Phase II study.
• Measure the pharmacokinetic and pharmacodynamic profiles of AAG in these patients.
• Assess time to tumor progression and any antitumor activity in patients treated with AAG.

OUTLINE: This is a dose-escalation study.

Patients receive a geldanamycin analogue, 17-allylamino-17-demethoxygeldanamycin (AAG), IV over 15-30 minutes every week. Treatment continues in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of AAG until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which at least 2 of 6 patients experience dose-limiting toxicity.

Patients are followed at 4 weeks.

PROJECTED ACCRUAL: Approximately 20-40 patients will be accrued for this study.

DISEASE CHARACTERISTICS:

• Histologically or cytologically proven malignancies refractory to conventional treatment or for which no standard therapy exists
• Primary brain tumor or brain metastases allowed if stable symptoms within 2 weeks prior to study and able to give informed consent

PATIENT CHARACTERISTICS:

Age:

• 18 to 75

Performance status:

• WHO 0-2

Life expectancy:

• At least 3 months

Hematopoietic:

• WBC at least 3,500/mm^3
• Platelet count at least 100,000/mm^3
• Hemoglobin at least 10.0 g/dL
• Absolute neutrophil count at least 1,500/mm^3

Hepatic:

• Bilirubin less than 1.0 mg/dL
• AST and ALT no greater than 2.5 times upper limit of normal if due to liver metastases
• No chronic liver disease

Renal:

• Creatinine less than 1.47 mg/dL OR
• Creatinine clearance greater than 60 mL/min

Cardiovascular:

• No myocardial infarction within the past 6 months
• No angina requiring treatment within the past 6 months
• No uncompensated coronary artery disease by electrocardiogram or physical examination
• No prior transient ischemic attacks, stroke, or peripheral vascular disease
• LVEF at least 45%

Other:

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for 4 weeks after study
• No allergy to egg products
• No nonmalignant systemic disease that would increase risk
• No active uncontrolled infection
• No diabetes mellitus with evidence of severe peripheral vascular disease or diabetic ulcers

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• At least 4 weeks since prior immunotherapy and recovered

Chemotherapy:

• At least 4 weeks since prior chemotherapy (6 weeks for nitrosoureas and mitomycin) and recovered
• No other concurrent chemotherapy

Endocrine therapy:

• At least 4 weeks since other prior endocrine therapy and recovered
• Concurrent corticosteroids for symptom control allowed if no change in dose requirement within 2 weeks prior to study

Radiotherapy:

• At least 4 weeks since prior radiotherapy (except for palliative reasons) and recovered
• Concurrent radiotherapy allowed for control of bone pain or as indicated

Surgery:

• Not specified

Other:

• No other concurrent investigational treatment
• No concurrent treatment with drugs interfering with hepatic CYP3A4 metabolism (e.g., grapefruit juice or warfarin)