A phase II study of gemcitabine in combination with tanespimycin in advanced epithelial ovarian and primary peritoneal carcinoma

作者：Hendrickson Andrea E Wahner; Oberg Ann L; Glaser Gretchen; Camoriano John K; Peethambaram Prema P; Colon Otero Gerardo; Erlichman Charles; Ivy S Percy; Kaufmann Scott H; Karnitz Larry M; Haluska Paul^*

来源：Gynecologic Oncology, 2012, 124(2): 210-215.

DOI：10.1016/j.ygyno.2011.10.002

• Phase I/II trials
• Tanespimycin
• Gemcitabine
• Ovarian cancer
• Peritoneal cancer
• Heat shock protein 90

Objective. To evaluate the efficacy and biological effects of the gemcitabine/tanespimycin combination in patients with advanced ovarian and peritoneal cancer. To assess the effect of tanespimycin on tumor cells, levels of the chaperone proteins HSP90 and HSP70 were examined in peripheral blood mononuclear cells (PBMC) and paired tumor biopsy lysates.
Methods. Two-cohort phase II clinical trial. Patients were grouped according to prior gemcitabine therapy. All participants received tanespimycin 154 mg/m(2) on days 1 and 9 of cycle 1 and days 2 and 9 of subsequent cycles. Patients also received gemcitabine 750 mg/m(2) on day 8 of the first treatment cycle and days 1 and 8 of subsequent cycles.
Results. The tanespimycin/gemcitabine combination induced a partial response in 1 gemcitabine naive patient and no partial responses in gemcitabine resistant patients. Stable disease was seen in 6 patients (2 gemcitabine naive and 4 gemcitabine resistant). The most common toxicities were hematologic (anemia and neutropenia) as well as nausea and vomiting. Immunoblotting demonstrated limited upregulation of HSP70 but little or no change in levels of most client proteins in PBMC and paired tumor samples.
Conclusions. Although well tolerated, the tanespimycin/gemcitabine combination exhibited limited anticancer activity in patients with advanced epithelial ovarian and primary peritoneal carcinoma, perhaps because of failure to significantly downregulate the client proteins at clinically achievable exposures.

• 出版日期2012-2