Sheng, Shijie

15553 Background: 17-Allylamino-17-Demethoxygeldanamycin (17-AAG) is a benzoquinone ansamycin antibiotic with anti- proliferative activity in several mouse xenograft models including prostate cancer models. Serum IL-6, IL-8, and maspin are potentially important markers of prostate cancer biology. Methods: Patients (pts) with metastatic, hormone-refractory prostate cancer progressing on at least one prior systemic therapy with rising PSA were eligible. All pts received 17-AAG at a dose of 300 mg/m2 IV weekly for three out of four weeks. Primary objective was to assess the PSA response (50% decrease in PSA). Secondary objectives included Adverse Events (AEs) and correlative serum markers including IL-6, IL-8 and maspin levels. A Simon two-stage design required a total of 25 pts with early termination if < 2 responses occurred among the 1st 16 eligible patients. Results: Seventeen pts were enrolled of which 15 were deemed eligible. Median age was 68 and median PSA was 252 ng/mL. Pts received 17-AAG for a median number of 2 cycles. No pt had a PSA response. No grade 4/5 AEs occurred. Grade 3 AEs included fatigue (4 pts), lymphopenia (2 pts) and back pain (2 pts). The median PSA progression free survival was 1.8 months (95% CI: 1.3–3.4 months). The six-month overall survival was 61% (95% CI: 37%-100%). Due to the lack of PSA response, accrual was stopped per study design. At day 15, the median IL-6 and IL-8 increase from baseline was 0.4 pg/ml (p=0.57) and 3 pg/ml (p=0.73), respectively. Maspin levels had day 15 increase of 6-fold (p=0.44). At treatment failure (TF), the median IL-6 increase from baseline was 4.47 pg/ml (p=0.03) and IL-8 decrease was 1.8 pg/ml (p=0.31). Maspin levels had a 29-fold increase at TF (p=0.09). Conclusions: 17-AAG did not show any activity with regards to PSA response. Serum IL-6 was significantly increased at the time of TF. Further evaluation of 17-AAG at a dose of 300 mg/m2 IV weekly in this patient population is not warranted. No significant financial relationships to disclose.

Abstract Purpose: 17-Allylamino-17-demethoxygeldanamycin (17-AAG) is a benzoquinone ansamycin antibiotic with antiproliferative activity in several mouse xenograft models, including prostate cancer models. A two-stage phase II study was conducted to assess the activity and toxicity profile of 17-AAG administered to patients with metastatic, hormone-refractory prostate cancer. Experimental Design: Patients with at least one prior systemic therapy and a rising prostate-specific antigen (PSA) were eligible. Patients received 17-AAG at a dose of 300 mg/m2 i.v. weekly for 3 of 4 weeks. The primary objective was to assess the PSA response. Secondary objectives were to determine overall survival, to assess toxicity, and to measure interleukin-6, interleukin-8, and maspin levels and quality of life. Results: Fifteen eligible patients were enrolled. The median age was 68 years and the median PSA was 261 ng/mL. Patients received 17-AAG for a median number of two cycles. Severe adverse events included grade 3 fatigue (four patients), grade 3 lymphopenia (two patients), and grade 3 back pain (two patients). The median PSA progression-free survival was 1.8 months (95% confidence interval, 1.3-3.4 months). The 6-month overall survival was 71% (95% confidence interval, 52-100%). Conclusions: 17-AAG did not show any activity with regard to PSA response. Due to insufficient PSA response, enrollment was stopped at the end of first stage per study design. The most significant severe toxicity was grade 3 fatigue. Further evaluation of 17-AAG at a dose of 300 mg/m2 i.v. weekly as a single agent in patients with metastatic, hormone-refractory prostate cancer who received at least one prior systemic therapy is not warranted.