Phase 1 pharmacokinetic and pharmacodynamic trial of docetaxel and 17AAG (17-allylamino-17-demethoxygeldanamycin)

Abstract

3032 Background: 17AAG is an ansamycin antibiotic that binds to the Hsp90 chaperone protein and inhibits its function. Hsp90 is required for the refolding of proteins during cellular stress and the conformational maturation of a subset of signaling proteins. Treatment of cancer cells with 17AAG causes the proteasomal degradation of Hsp90 client proteins, which include HER2, steroid receptors, Raf, cdk4, and Akt. The combination of 17AAG and taxanes is synergistic in cell culture and animal model systems. Methods: We initiated a phase 1 study of docetaxel and 17AAG to define the maximally tolerated dose, toxicity profile, and pharmacodynamics of these agents when administered in combination to patients (pts) with advanced solid tumors. Pts were treated with docetaxel (55 and 70 mg/m2) and 17AAG (80 to 300 mg/m2) in 6 cohorts. Docetaxel and 17AAG were administered sequentially (each over 1 hour) without delay on day 1 of each 21 day cycle. Results: To date, we have enrolled 16 pts (median age 61, range: 32–78) with cancers of the prostate (5), H&N (4), renal (2), melanoma (1) and others (4 pts). Pts have received a median of 3 cycles (range: 2–6). No dose limiting toxicities have been observed to date. Three pts had Grade 4 neutropenia of less than 7 days duration. No objective responses have been seen. Three pts had stable disease of at least 3 cycles duration and one pt with prostate cancer had a decline in PSA. Plasma serum levels of docetaxel and 17AAG were not altered by co-administration at the dose levels studied. Peripheral blood lymphocytes (PBL) were collected to study changes in Hsp90-dependent client proteins following therapy as a function of dose. Post-treatment increases in Hsp70 in PBL have been observed in all pts treated with 17-AAG at or above 110 mg/m2. Declines in Raf and Akt in PBL have been seen in some but not all pts treated at doses of 17-AAG above 160 mg/m2. Conclusions: The combination of docetaxel and 17AAG is well tolerated at the dose levels studied to date. Accrual continues at the 17AAG 300 mg/m2 dose level and at the time of the meeting updated accrual, response and correlative data will be reported. Supported by NIH P50-CA92629 and CaPCURE. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis; Conforma Aventis