17-N-Allylamino-17-Demethoxygeldanamycin and Paclitaxel in Treating Patients With Metastatic or Unresectable Solid Tumor

OBJECTIVES:

I. Determine the maximum tolerated dose and recommended phase II dose of 17-N-allylamino-17-demethoxygeldanamycin (17-AAG) when administered with paclitaxel in patients with metastatic or unresectable solid malignancy.

II. Determine the dose-limiting and non-dose-limiting toxic effects of this regimen in these patients.

III. Determine the pharmacokinetics of this regimen in these patients. IV. Determine tumor response in patients treated with this regimen.

OUTLINE: This is a multicenter, dose-escalation study of 17-N-allylamino-17-demethoxygeldanamycin (17-AAG). Patients receive 17-AAG IV over 1 hour on days 1*, 4, 8, 11, 15 and 18 and paclitaxel IV over 1 hour on days 1, 8, and 15. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity.

NOTE: *17-AAG is not administered on day 1 of course 1. 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. Once the MTD is determined, 6-12 patients are treated at the recommended phase II dose.

Inclusion criteria

• Histologically confirmed solid malignancy

• Metastatic or unresectable disease
• Not amenable to standard curative or palliative therapy
• No known brain metastases
• Performance status - ECOG 0-2
• More than 12 weeks
• Absolute neutrophil count ≥ 1,500/mm^3
• Platelet count ≥ 100,000/mm^3
• WBC ≥ 3,000/mm^3
• AST and ALT ≤ 2.5 times upper limit of normal
• Bilirubin normal
• Creatinine normal
• Creatinine clearance ≥ 60 mL/min
• QTc < 450 msec for male patients (470 msec for female patients)
• LVEF > 40% by MUGA
• No history of serious ventricular arrhythmia (i.e., ventricular tachycardia or ventricular fibrillation ≥ 3 beats in a row)
• No myocardial infarction within the past year
• No New York Heart Association class III or IV congestive heart failure
• No poorly controlled angina
• No history of uncontrolled dysrhythmia or requirement for antiarrhythmic drugs
• No history of congenital long QT syndrome
• No active ischemic heart disease within the past year
• No left bundle branch block
• No other significant cardiac disease
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective double barrier contraception for at least 1 week before, during, and for at least 2 weeks after study participation
• No prior allergy to eggs
• No prior allergic reaction to compounds of similar chemical or biologic composition to 17-AAG or paclitaxel
• No peripheral neuropathy > grade 1
• No concurrent uncontrolled illness
• No active or ongoing infection
• No psychiatric illness or social situation that would preclude study compliance
• No concurrent granulocyte colony-stimulating factors
• Prior paclitaxel allowed
• More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin) and recovered
• No prior 17-N-allylamino-17-demethoxygeldanamycin (17-AAG)
• More than 4 weeks since prior radiotherapy
• No prior radiotherapy that included the heart in the field (e.g., mantle radiotherapy)
• No concurrent combination antiretroviral therapy for HIV-positive patients
• No concurrent therapeutic-dose warfarin for anticoagulation
• No concurrent medications that may prolong QTc interval
• No other concurrent investigational agents
• No other concurrent anticancer agents or therapies