A phase I trial of gemcitabine (Gem), 17-allylaminogeldanamycin (17-AAG) and cisplatin (CDDP) in solid tumor patients

Abstract

3058 Background: 17-AAG, a benzoquinone ansamycin derivative that targets the heat shock protein hsp90, is currently undergoing clinical evaluation in phase I/II trials. We have demonstrated sequence dependent synergy with Gem and CDDP in combination with 17-AAG in vitro. Methods: A phase I trial was conducted in patients with solids tumors receiving the sequential administration of Gem → 17-AAG → CDDP. The goals were to establish the MTD, evaluate toxicity, clinical activity and effects on surrogate markers. Patients were given escalating doses of Gem (from 750–1000 mg/m2), and fixed doses of 17-AAG (154 mg/m2) and CDDP (40 mg/m2), on days 1 and 8, q21d. Peripheral blood mononuclear cells (PBMCs) were collected at 0, 6 and 25 hours after treatment for evaluation of surrogate markers. Results: To date, 12 patients (9F/3M; median age 51) have received 25 cycles of therapy. Tumor types included three ovarian, three lung and one each of thyroid, sarcoma, liver, appendix, breast and melanoma. Four DLTs, comprising gr3 ANC, gr3 elevated liver enzymes, dehydration, hyponatremia, nausea, vomiting and gr3 platelets, were observed at dose level 2 (Gem 1000 mg/m2, 17-AAG 154 mg/m2, CDDP 40 mg/m2). Non-dose limiting toxicities were anorexia (50%), constipation (33%), fatigue (42%), anemia (75%), leukopenia (67%), nausea (75%), neutropenia (42%), thrombocytopenia (42%), and vomiting (42%). Two PRs (ovarian cancer) and 2 SD (> 3 months for both) in NSCLC and breast cancer were seen out of 8 evaluable patients., There was a significant increase in hsp70 protein expression at 6 and 25 hours (p<0.03), and a decrease in the level of the hsp90 client protein, ILK at 6 hours (p=0.02), in PBMCs. Conclusions: The combination of Gem, 17-AAG, and CDDP demonstrated activity with significant toxicity, likely secondary to Gem and CDDP. Hsp70 and ILK are useful surrogate markers of 17-AAG effecting its target. Currently this study is being amended to administer 17-AAG in combination with either GEM or CDDP, alone. (Supported in part by CA15083, CA69912, CA90390, and M01-RR00585) Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Kosan Biosciences