Flavopiridol is a synthetic flavone that inhibits cyclin-dependent kinases. It has been shown to enhance apoptosis when administered after taxanes in human breast cancer cell lines. We are conducting a phase I/II clinical trial of flavopiridol and docetaxel in patients with locally advanced and metastatic breast cancer. We propose that flavopiridol is synergistic with docetaxel and will increase its efficacy. Incorporated in this study is the serial examination of molecular parameters, cyclin D1, p53, bc12, and mib1, in accessible tumor biopsies and from the buccal mucosa, as a potential surrogate tissue, to see if desired biochemical effects are achieved with this combination. The development of target-based anticancer drugs, such as small molecule inhibitors of epidermal growth factor tyrosine kinase (EGFRTK), is becoming an attractive therapeutic strategy in the oncology field. The examination of the effects of these mechanism-based drugs at the cellular level is a logical approach to test these compounds and may in the future replace the traditional way of determining the appropriate dose of new agents. The development of reproducible assays and tools to assess the effect of a drug on targets, such as inhibition of enzyme activity, the validation of surrogate endpoints to check the desired effect of the drug, and the implementation of novel clinical trial designs that allow the testing of biologic endpoints as a primary aim, will become a challenge to both clinicians and basic scientists in the new era of targeted therapy. We are conducting a pilot study of an EGFRTK inhibitor to address these issues. Adjuvant therapy of breast cancer has clearly provided a significant survival benefit for women in all age groups. Though screening mammography has resulted in earlier detection, still 50 percent of patients with early breast cancer present with node-positive disease. There is a significant recurrence rate in these patients, even with doxorubicin-based chemotherapy. Approaches for increasing the survival include the addition of taxanes. A multicenter trial, NSABP B30, for which Dr. Swain is the protocol chair, is a three-arm trial that will explore the efficacy of docetaxel on survival and quality of life. The three arms include a combination of docetaxel and doxorubicin versus a combination of docetaxel, doxorubicin, and cyclophosphamide, versus doxorubicin and cyclophosphamide followed sequentially by docetaxel. This trial will include 4,000 patients with node-positive breast cancer and has currently accrued 2,100 patients. A quality of life question is being asked in all patients and also specifically in premenopausal women. It has been shown in a meta-analysis of ovarian ablation that this approach increases survival to the same degree as chemotherapy. Therefore, the trial will evaluate ovarian suppression induced by chemotherapy and determine whether this suppression leads to an increased survival. The other quality of life issues relate to the toxicity of the three combinations. Other research areas with NSABP include membership in the Cardiology Advisory Panel for the adjuvant Herceptin trial (NSABP B31) and Protocol Chair for the IressaTM trial. Iressa is an epidermal growth factor tyrosine kinase inhibitor and will be evaluated with docetaxel in metastatic breast cancer.
| Denduluri, Neelima; Lee, James J; Walshe, Janice et al. (2007) Phase II trial of ixabepilone, an epothilone B analog, given daily for three days every three weeks, in metastatic breast cancer. Invest New Drugs 25:63-7 |
| Walshe, Janice M; Denduluri, Neelima; Berman, Arlene W et al. (2006) A phase II trial with trastuzumab and pertuzumab in patients with HER2-overexpressed locally advanced and metastatic breast cancer. Clin Breast Cancer 6:535-9 |
| Lee, James J; Low, Jennifer A; Croarkin, Earllaine et al. (2006) Changes in neurologic function tests may predict neurotoxicity caused by ixabepilone. J Clin Oncol 24:2084-91 |
| Low, Jennifer A; Wedam, Suparna B; Lee, James J et al. (2005) Phase II clinical trial of ixabepilone (BMS-247550), an epothilone B analog, in metastatic and locally advanced breast cancer. J Clin Oncol 23:2726-34 |
