Melanoma progression is angiogenesis dependent. Pre-clinical studies have suggested that several chemotherapeutic agents possess antiangiogenic effects at below cytotoxic concentrations. In preliminary studies we have confirmed the antiangiogenic effects of the chemotherapeutic agent paclitaxel at concentrations 100 to 1000-fold lower than cytotoxic concentrations. In addition, we have found that paclitaxel's antiangiogenic effects are enhanced by co-treatment with COX-2 inhibitors. Also, in preliminary studies, we have demonstrated that low dose, continuous infusion paclitaxel combined with the COX-2 inhibitor celecoxib can be safely administered in five patients with advanced cancer, and that antiangiogenic activity can be demonstrated in patients' blood while on treatment. Moreover, the biologic effects seen in the blood of two patients seems to correlate with clinical benefit. Translation of these findings into a clinical trial for patients with advanced melanoma forms the basis of this proposal as follows:
Specific Aim 1 : To evaluate the safety/tolerability and demonstrate the clinical efficacy of combination antiangiogenic therapy as a novel strategy to treat patients with advanced melanoma.
Specific Aim 2 : To evaluate the patients' blood angiogenic profile and measure plasma drug levels before and during therapy.
Specific Aim 3 : To develop predictive rules relating baseline and changes in the angiogenic profile, and serum levels of paclitaxel and celecoxib to clinical outcome. Encouraging results from this clinical trial of two already FDA approved drugs could be immediately translated to other tumor types. Additionally, the resulting analyses may find novel biomarkers that could be useful as monitoring tools in future antiangiogenesis clinical trials. ? ?
| Bhatt, Rupal S; Merchan, Jaime; Parker, Robert et al. (2010) A phase 2 pilot trial of low-dose, continuous infusion, or ""metronomic"" paclitaxel and oral celecoxib in patients with metastatic melanoma. Cancer 116:1751-6 |
