This phase I trial is studying the side effects and best dose of 17-AAG when given together with sorafenib in treating patients with unresectable or metastatic solid tumors. Drugs used in chemotherapy, such as 17-AAG, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Sorafenib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. Giving 17-AAG together with sorafenib may kill more tumor cells.
PRIMARY OBJECTIVES: I. To recommend a phase II dose for 17AAG (once weekly intravenously for 3 of 4 weeks), in combination with BAY 43-9006 (twice daily orally), by determining the feasibility, safety, dose limiting toxicities and the maximally tolerated dose. SECONDARY OBJECTIVES: I. To evaluate the modulation of pharmacodynamic effects and to investigate the interaction between the two mechanisms of action when used in combination by: Studying surrogate tissue and tumor cell signaling by Western blotting. Evaluating tumor blood flow utilizing dynamic contrast enhanced MRI. II. To study any pharmacokinetic interactions between these two agents. III. To assess preliminary anti-tumor activity of this combination. OUTLINE: This is an open-label, multicenter, dose-escalation study of 17-N-allylamino 17-demethoxygeldanamycin (17-AAG). Patients receive oral sorafenib twice daily on days -14 to 28 in course 1 and on days 1-28 in all subsequent courses. Patients also receive 17-AAG IV over 3 hours on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 5-6 patients receive escalating doses of 17-AAG until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that which 2 of 6 patients experience dose-limiting toxicity. After completion of study therapy, patients are followed for 60 days.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
54
Given orally
Given IV
Correlative studies
Correlative studies
Correlative studies
Barbara Ann Karmanos Cancer Institute
Detroit, Michigan, United States
Maximum-tolerated dose (MTD) based on the incidence of dose-limiting toxicity (DLT) as assessed by NCI CTCAE version 3.0
Time frame: 42 days
DLT as assessed by NCI CTCAE version 3.0
Time frame: 42 days
Pharmacokinetic parameters of sorafenib tosylate and tanespimycin
Descriptive PK studies will be performed for the combination to determine if there is any correlation with toxicity, efficacy or interaction. Plasma concentrations will be compared with in vitro and in vivo concentrations found to be effective in pre-clinical studies.
Time frame: At baseline, at 0.5, 1, 2, 3, 4, 6, 9, and 12 hours of day 1, at 0.5, 1, and 2 hours on day 15, at 24 and 48 hours on days 16 and 17
Pharmacodynamic effects of sorafenib tosylate and tanespimycin on surrogate markers and tumor tissue signaling by Western blotting
Time frame: At baseline and at day -1, 14, and 18
Change in blood flow using dynamic contract enhanced MRI
Time frame: At baseline, at days -3 to 1, and at days 15-22
Antitumor activity of this combination according to RECIST
Time frame: Up to 60 days after completion of study treatment
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