A phase II study to determine the efficacy and tolerability of intravenous ZD9331 in heavily pretreated patients with ovarian cancer.

OBJECTIVES: This Phase II, multicenter, open-label study was conducted to assess the efficacy and tolerability of ZD9331, a novel direct-acting thymidylate synthase inhibitor, in heavily pretreated patients with ovarian cancer. METHODS: The study recruited 44 women with ovarian cancer or primary peritoneal cancer previously treated with platinum therapy and paclitaxel and with progressive disease after, or intolerance to, topotecan administered as the most recent therapy. ZD9331 was administered as an intravenous infusion at 130 mg/m(2) on Days 1 and 8 of 3-week cycles, until objective evidence of disease progression. A cutoff date of 3 months after the last patient received the first dose was set for data collection. RESULTS: Patients received a mean of 3.3 cycles of ZD9331 and a total of 143 cycles were administered. Among the 42 patients evaluated for best overall tumor response, one achieved a complete response and two achieved a partial response, giving an objective tumor response rate of 7%. The complete response occurred at Day 15 of Cycle 2 in a patient receiving ZD9331 as her eighth-line therapy. Seven patients had stable disease, giving a disease control rate of 23%. Thirty-one patients (71%) had disease progression and the median time to progression was 53 days. Most patients (89%) experienced drug-related adverse events, most commonly nausea (73%), vomiting (48%), and neutropenia (50%). Six patients (14%) were withdrawn from treatment due to adverse events. CONCLUSIONS: The preliminary evidence of efficacy and acceptable tolerability of ZD9331 in this heavily pretreated population with ovarian cancer warrants further investigation, especially in a less heavily pretreated patient population.

Blinded, randomized, multicenter study to evaluate single administration pegfilgrastim once per cycle versus daily filgrastim as an adjunct to chemotherapy in patients with high-risk stage II or stage III/IV breast cancer.

PURPOSE: This multicenter, randomized, double-blind, active-control study was designed to determine whether a single subcutaneous injection of pegfilgrastim (SD/01, sustained-duration filgrastim; 100 microg/kg) is as safe and effective as daily filgrastim (5 microg/kg/d) for reducing neutropenia in patients who received four cycles of myelosuppressive chemotherapy. PATIENTS AND METHODS: Sixty-two centers enrolled 310 patients who received chemotherapy with docetaxel 75 mg/m(2) and doxorubicin 60 mg/m(2) on day 1 of each cycle for a maximum of four cycles. Patients were randomized to receive on day 2 either a single subcutaneous injection of pegfilgrastim 100 microg/kg per chemotherapy cycle (154 patients) or daily subcutaneous injections of filgrastim 5 microg/kg/d (156 patients). Absolute neutrophil count (ANC), duration of grade 4 neutropenia, and safety parameters were monitored. RESULTS: One dose of pegfilgrastim per chemotherapy cycle was comparable to daily subcutaneous injections of filgrastim with regard to all efficacy end points, including the duration of severe neutropenia and the depth of ANC nadir in all cycles. Febrile neutropenia across all cycles occurred less often in patients who received pegfilgrastim. The difference in the mean duration of severe neutropenia between the pegfilgrastim and filgrastim treatment groups was less than 1 day. Pegfilgrastim was safe and well tolerated, and it was similar to filgrastim. Adverse event profiles in the pegfilgrastim and filgrastim groups were similar. CONCLUSION: A single injection of pegfilgrastim 100 microg/kg per cycle was as safe and effective as daily injections of filgrastim 5 microg/kg/d in reducing neutropenia and its complications in patients who received four cycles of doxorubicin 60 mg/m(2) and docetaxel 75 mg/m(2).

Flow cytometric analysis of fluorescein-conjugated estradiol (E-BSA-FITC) binding in breast cancer suspensions.

With greater utilization of histochemical methods for detecting estrogen binding (ER) in tumor cells, there is an increasing need to quantitate objectively these fluorescently stained cells. This study utilizes flow cytometry (FCM) to examine the binding specificity and kinetics of 17 beta-estradiol-6-CMO-BSA-FITC(E-BSA-FITC) in two human mammary carcinoma cell lines, MCF-7 and 47-DN. Cells are rendered permeable to this ligand by freeze-thawing, a process analogous to the routine staining of frozen tumor sections with E-BSA-FITC for the clinical detection of ER. FCM quantification of E-BSA-FITC binding intensity demonstrates a saturable dose-response that is specifically reduced in the presence of diethylstilbestrol (DES) in doses known to saturate Type I ER. Scatchard analysis suggests that E-BSA-FITC binding occurs with receptors of varying affinities (Kd). Lineweaver-Burk plots show that the DES inhibition is competitive for a high-affinity receptor binding to E-BSA-FITC with a Kd of approximately 50 nM. This report also compares both FCM and biochemical methods of quantitating ER under two conditions of tumor cell growth potentially encountered in clinical specimens: quiescent versus actively proliferating cells, and cells pretreated with the antiestrogen tamoxifen. By FCM analysis, the cells with greater proliferating activity contain tenfold more specifically bound E-BSA-FITC, and tamoxifen pretreatment reduces this specific binding by 50%. These FCM measurements correlate well with biochemical results and suggest that this new methodology may supplement the detection of E-BSA-FITC binding by fluorescence microscopy.