Phase I Study of 17- Allylamino-17 Demethoxygeldanamycin (17-AAG) in Combination With Paclitaxel in Advanced Solid Malignancies
Phase I Study of 17- Allylamino-17 Demethoxygeldanamycin (17-AAG) in Combination With Paclitaxel in Advanced Solid Malignancies
This phase I trial is studying the side effects and best dose of 17-N-allylamino-17-demethoxygeldanamycin when given together with paclitaxel in treating patients with metastatic or unresectable solid tumor. Drugs used in chemotherapy, such as 17-N-allylamino-17-demethoxygeldanamycin and paclitaxel, work in different ways to stop tumor cells from dividing so they stop growing or die. Combining 17-N-allylamino-17-demethoxygeldanamycin with paclitaxel may kill more tumor cells
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
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