A phase II study of oral enzastaurin in patients with metastatic breast cancer previously treated with an anthracycline and a taxane containing regimen.

PURPOSE: Enzastaurin is a potent, serine-threonine kinase inhibitor which selectively targets PKCß and PI3K/AKT signaling pathways to reduce cell proliferation, induce apoptosis, and inhibit angiogenesis. As PKCbeta and PI3K/AKT signaling are both involved in breast cancer pathogenesis, this phase II study evaluated the efficacy and toxicity of enzastaurin in previously treated patients with metastatic breast cancer (MBC). PATIENTS AND METHODS: Eligible patients had histologically confirmed MBC with measurable disease, and must have received prior anthracycline and taxane chemotherapy, but not more than two prior regimens for MBC. Human epidermal growth factor 2 (HER2)-positive patients must have progressed on prior trastuzumab therapy. Enzastaurin, 1,125-mg loading dose on day 1 followed by 500 mg daily, was administered orally in 28-day cycles. Response was assessed every 2 cycles according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. RESULTS: Twenty-one patients enrolled between November 2006 and September 2007. Fourteen (66.7%) patients completed at least two cycles of therapy. No patients developed Grade 3/4 hematologic toxicity. Grade 3 nonhematologic toxicity was rare (<5%) and most commonly attributed to MBC progression. There were no objective responses and no patients with stable disease for >/=6 months. Median progression-free survival was 1.68 months (95%CI: 1.02, 1.74). CONCLUSIONS: Enzastaurin monotherapy was well tolerated, but demonstrated no activity in patients with heavily pretreated MBC.

Phase II trial of gemcitabine/carboplatin (plus trastuzumab in HER2-positive disease) in patients with metastatic breast cancer.

BACKGROUND: Gemcitabine and carboplatin have significant preclinical synergy, and both provide synergistic antitumor activity in metastatic breast cancer (MBC) when used in combination with trastuzumab. The gemcitabine/ cisplatin combination is highly active in MBC with response rates (RRs) of approximately 50% in anthracycline- and taxane-pretreated patients and up to 80% in untreated subjects. This phase II trial studied the efficacy and safety of gemcitabine/carboplatin with or without trastuzumab in patients with MBC. PATIENTS AND METHODS: Patients were stratified into 3 groups: group 1, HER2-positive; group 2, HER2-negative and taxane- naive/remote (no taxanes within past 2 years); and group 3, HER2-negative and previous taxane therapy. Included were women aged > or = 18 years, Eastern Cooperative Oncology Group performance status of 0-2, with Response Evaluation Criteria in Solid Tumors-defined measurable MBC; HER2-negative or HER2 (3+) by immunohistochemistry or fluorescence in situ hybridization positive. All cycles were repeated every 14 days. On day 1, gemcitabine 1500 mg/m2 over 30 minutes was administered followed by carboplatin area under the curve of 2.5. Group 1 also received trastuzumab 8 mg/kg on day 1 of each cycle followed by 4 mg/kg for every 2 weeks thereafter. RESULTS: One hundred fifty patients were registered (50, 51, and 49 in groups 1, 2, and 3, respectively). The overall RRs were 64%, 27%, and 32%, respectively, with median time to progression of 7.2, 5.5, and 4.4 months, respectively. Overall, grade 3/4 toxicities included neutropenia (45%), leukopenia (17%), and thrombocytopenia (7%). Alopecia was infrequent: grade 1 (34%) and grade 2 (3%), and there was no significant cardiac toxicity. CONCLUSION: Gemcitabine/carboplatin/trastuzumab is highly active in patients with HER2-positive MBC. Gemcitabine/carboplatin is active in patients with HER2-negative MBC independent of previous taxane therapy. Gemcitabine/carboplatin with or without trastuzumab administered every 2 weeks is associated with a low frequency of serious toxicity.

A phase II trial of pemetrexed and gemcitabine in patients with metastatic breast cancer who have received prior taxane therapy.

PURPOSE: This phase II trial assessed efficacy and safety of pemetrexed plus gemcitabine to treat metastatic or locally advanced breast cancer in patients previously treated with taxanes. PATIENTS AND METHODS: Eligible women with advanced breast cancer treated with taxanes in the adjuvant or metastatic setting received pemetrexed 500 mg/m2 on day 1 followed by gemcitabine 1000 mg/m2 on days 1 and 8 of a 21-day cycle. Hematologic toxicities limiting day 8 gemcitabine dosing were observed in the first 20 patients, prompting a protocol amendment to evaluate pemetrexed 500 mg/m2 followed by gemcitabine 1500 mg/m2 on day 1 of a 14-day cycle. Patients received folic acid, vitamin B12, and dexamethasone. The primary endpoint was objective response rate (ORR). RESULTS: Between July 2003 and September 2006, 73 evaluable women (median age, 52.1 years; range, 28-73 years) were enrolled (21-day schedule: 21 patients, 52% estrogen receptor-positive, 24% HER2-positive; 14-day schedule: 52 patients, 58% ER-positive, 15% HER2-positive). For patients on the 21-day and 14-day schedules, median number of cycles was 4 (range, 1-8 cycles) and 5 (range, 1-38 cycles), respectively. The ORRs were 23.8% and 19.2%, respectively; median survival times were 16.2 months and 13.4 months. The most common grade 3/4 hematologic toxicities were neutropenia (71% vs. 33%) and leukopenia (24% vs. 14%); febrile neutropenia occurred in 10% and 6%. The most common grade 3/4 nonhematologic toxicity was fatigue (29% vs. 10%). CONCLUSION: Pemetrexed/gemcitabine given on a 21-day or 14-day schedule is active in patients with advanced breast cancer previously treated with taxanes. A 14-day schedule appears to result in fewer serious toxicities.