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4604 Background: Interferon-alpha (IFNA) is a standard initial therapy in renal cell carcinoma (RCC) with anti-tumor effects via immunologic and anti-angiogenic mechanisms. Cyclooxygenase-2 (COX-2) is an enzyme involved in the formation of prostaglandin E2 and may play a major role in development of cancer through numerous mechanisms, including neovascularization. COX-2 is expressed in the majority of RCC tumors and correlates with stage, grade and microvessel density. Based on potential additive or synergistic anti-antiangiogenic effects, IFNA and celecoxib, an oral COX-2 inhibitor, were tested in metastatic RCC patients. Methods: Patients with untreated, metastatic RCC received IFNA 3 MU s.c. daily and celecoxib 400 mg p.o. BID continuously until disease progression or unacceptable toxicity. Plasma for bFGF and VEGF levels was collected at baseline, end of cycles 1, 2, and every other cycle until off-study. Parffin-embedded RCC tumor samples were stained for COX-2 expression. A 50% increase in the median time to disease progression (TTP) versus historical controls was sought as the primary endpoint. Results: Twenty patients have been treated to date. Two partial responses (10%) have been observed. The median TTP is 3.4 months (range 1.2–9.3+ months). There was no increase in observed toxicities over what was expected from IFNA alone. Dose reduction for toxicity was required to 2 MU QD (6 pts.) and to 1 MU QD (2 pts.). Median TTP was longer for pts. who had a treatment-induced decline in bFGF levels compared with patients with no decline in bFGF levels (5.6 vs. 3.9 months). The mean % change at cycle 2 versus baseline for bFGF was inversely correlated with TTP (r = -0.5, p = .05). Conclusions: Combination therapy of low dose, daily IFNA and celecoxib is safe and feasible in metastatic RCC. The final clinical efficacy of this combination is not yet determined. Change in bFGF levels at cycle 2 versus baseline may predict clinical outcome. Staining of archived RCC tumor samples is ongoing. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Research funding provided by NCCN through a grant from Pharmacia (now Pfizer)
Rini et al. (Thu,) studied this question.