Phase I and pharmacokinetic study of mitomycin C and celecoxib as potential modulators of tumor resistance to irinotecan in patients with solid malignancies

Abstract

Based on the preclinical evidence of topoisomerase I (Topo-1) upregulation by mitomycin C(MMC) and decreased NF-kappaB activation by celecoxib, we evaluated combinations of irinotecan/MMC and irinotecan/MMC/celecoxib in patients with advanced solid malignancies. Initially, patients received MMC on day 1 and irinotecan on days 2, 8, 15 and 22, every 6 weeks. MMC dose was fixed at 6 mg/m(2) and cumulative doses of >36 mg/m(2) were not permitted. Irinotecan was escalated in 25 mg/m(2) increments. Due to late-onset diarrhea, the schedule was subsequently shortened to 4 weeks, omitting irinotecan on days 15 and 22. In the second part of the study, celecoxib 400 mg orally twice daily was added to irinotecan/MMC regimen. Potential pharmacokinetic interactions and Topo-1 and DT-diaphorase (NQ01) gene expressions in peripheral-mononuclear cells were evaluated. Forty-five patients were enrolled. Irinotecan 125 mg/m(2) on days 2 and 8 in combination with MMC 6 mg/m(2) on day 1 every 4 weeks is recommended for future studies; myelosuppression and diarrhea are dose-limiting. The addition of celecoxib resulted in unacceptable toxicities despite reductions on irinotecan's dose. No relevant pharmacokinetic interactions occurred between irinotecan and MMC, and mean increases in Topo-1, were observed. Sixteen of 36 patients evaluable for response-assessment had discernable anti-tumor activity, including 1 complete, 4 partial, 10 minor and 1 tumor marker response. Four patients had prolonged (>4 months) disease-stability (stable disease, not included in CR or PR). Patients experiencing complete and partial responses had higher increments in Topo-1 expression. Modulation of irinotecan by MMC is feasible, devoid of pharmacological interactions and active in solid malignancies. The lack of improvement in therapeutic index does not support the addition of celecoxib.