Phase II study of gemcitabine and bevacizumab as first-line treatment in taxane-pretreated, HER2-negative, locally recurrent or metastatic breast cancer.

BACKGROUND: In first-line treatment of metastatic breast cancer, the best use of the available therapeutic agents is unclear. This study evaluated the efficacy and safety of combined therapy with bevacizumab and gemcitabine. PATIENTS: Women who were to undergo first-line treatment for locoregionally recurrent or metastatic breast cancer were eligible. Patients must have received a taxane-containing regimen in the neoadjuvant and/or adjuvant setting with a ≥ 12-month disease-free interval. METHODS: This was a single-arm, phase II trial. On day 1 of each 14-day cycle, patients received gemcitabine (2500 mg/m(2)) followed by bevacizumab (10 mg/kg). Patients were treated until complete response, progressive disease (PD), or intolerable toxicity. The primary endpoint was progression-free survival (PFS). RESULTS: Fifty-two women were enrolled and treated. The median PFS was 4.8 months (95% confidence interval [CI], 3.4-7.6), the 1-year overall survival rate was 68.7% (95% CI, 54.1%-79.5%), and the response rate was 21.4% (95% CI, 10.3%-36.8%). The clinical benefit rate was 35.7%. The median PFS in the triple-negative (n = 19) and non-triple-negative (n = 33) subsets was 3.9 months (95% CI, 2.7-11.7) and 4.9 months (95% CI, 3.4-8.1), respectively. The most common (all grades) drug-related adverse events (AEs) were nausea (51.9%), fatigue (46.2%), decreased appetite (25.0%), and anemia (25.0%). The most common grade 3 or grade 4 drug-related AEs were neutropenia (13.5%), leukopenia (11.5%), and hypertension (7.7%). CONCLUSION: Although the gemcitabine-bevacizumab doublet appears active, the median PFS was lower than expected. There were no unexpected safety signals at this dose and schedule of this combination.

Phase II study of concurrent radiation therapy, temozolomide, and bevacizumab followed by bevacizumab/everolimus as first-line treatment for patients with glioblastoma.

PURPOSE: To evaluate the efficacy of adding bevacizumab, a vascular endothelial growth factor (VEGF) inhibitor, and everolimus, a mammalian target of rapamycin (mTOR inhibitor), to standard radiation therapy/temozolomide in the first-line treatment of patients with glioblastoma. PATIENTS AND METHODS: Following surgical resection or biopsy, patients with newly diagnosed glioblastoma received standard radiation therapy/temozolomide plus bevacizumab 10 mg/kg intravenously (IV) every 2 weeks. Four weeks after the completion of radiation therapy, patients began oral everolimus 10 mg daily, and continued bevacizumab every 2 weeks; therapy continued until tumor progression or unacceptable toxicity. RESULTS: Sixty-eight patients were treated, 82% of whom had previously undergone partial or complete surgical resection. Sixty-four patients completed combined modality therapy, and 57 patients began maintenance therapy with bevacizumab/everolimus. Thirty-one of 51 patients (61%) with measurable tumor had objective responses. After a median follow-up of 17 months, the median progression-free survival (PFS) was 11.3 months (95% confidence interval [CI], 9.3-13.1 months); median overall survival was 13.9 months. Toxicity was consistent with the known toxicity profile of bevacizumab; grade 3/4 toxicities during maintenance therapy related to everolimus included fatigue (27%), pneumonitis (7%), and stomatitis (5%). CONCLUSIONS: The use of bevacizumab and everolimus as part of first-line combined modality therapy for glioblastoma was feasible and efficacious. The PFS compared favorably to previous reports with standard radiation therapy/temozolomide therapy, and is similar to results achieved in other phase II trials in which bevacizumab was added to fist-line treatment. Ongoing randomized phase III trials will clarify the role of bevacizumab in this setting.

Analysis of genetic stability at the EP300 and CREBBP loci in a panel of cancer cell lines.

EP300 (p300) and CREBBP (CBP) are highly related transcriptional co-activators possessing histone acetyltransferase activity. These proteins have been implicated in coordinating numerous transcriptional responses that are important in the processes of proliferation and differentiation. A role for EP300 and CREBBP as tumor suppressors in cancer has been suggested by the fact that they are targeted by viral oncogenes; there is an increased incidence of hematologic malignancies in mice monoallelic for CREBBP; and loss, albeit at a low frequency, of both EP300 alleles in epithelial cancers has been observed. Because the level of EP300/CREBBP appears to have a critical effect on integrating certain transcriptional processes, we sought to determine whether a loss in the combined gene dosage of EP300 and CREBBP might play a role in cancer. Accordingly, we screened a panel of 103 cell lines for loss of heterozygosity and found 35 and 51% LOH for the CREBBP and EP300 loci, respectively. Concordant loss of CREBBP and EP300 was not associated with mutations in important regions of the remaining EP300 or CREBBP genes. In addition, there did not appear to be a statistically significant selection in cancer cells, stratified by various criteria, for the concordant loss of EP300 and CREBBP. We conclude that EP300 and CREBBP rarely act as classical tumor suppressors in human cancer.