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

Abstract

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 naïve patient and no partial responses in gemcitabine resistant patients. Stable disease was seen in 6 patients (2 gemcitabine naïve 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.

Figure 1

A, Overall survival of patients in Cohort 1 (N=12) and Cohort 2 (N=11) entered on this study. B, Progression-free survival of patients in Cohort 1 (N=12) and Cohort 2 (N=11) entered on this study.

Figure 2

Maximum severity adverse events experienced per patient that were possible, probably or definitely related to treatment on this study.

Figure 3

Effects of tanespimycin on client protein levels. A, after the indicated ovarian cancer cell lines were treated with diluent (0.1% DMSO) or tanespimycin at 30, 100, 300, or 1000 nM for 24 h, whole cell lysates were subjected to SDS-PAGE followed by immunoblotting for the indicated antigen. B, lysates prepared from PBMCs prior to therapy (odd numbered lanes) and 24 h after the first dose of tanespimycin (even numbered lanes) were subjected to immunoblotting for the indicated antigens. HSP90β or β-actin served as loading controls in these studies. C, whole cell lysates prepared from ovarian cancer biopsies harvested prior to therapy (lanes 1, 3 and 5) or from the same tumors 22–26 h after the day 1 dose of tanespimycin (lanes 2, 4 and 6) were subjected to SDS-PAGE followed by immunoblotting. Dashed line indicates remove of intervening unequally loaded samples from the blots. Number at left, migration of molecular weight markers (kDa). Graphs at right show quantitation of signals for selected client proteins before and after tanespimycin treatment.