Phase I study of capecitabine and oxaliplatin in combination with the proteasome inhibitor bortezomib in patients with advanced solid tumors.

Purpose: The combination of capecitabine and oxaliplatin has clinical benefit in a variety of gastrointestinal malignancies. The proteasome inhibitor bortezomib enhances the cytotoxic activity of fluoropyrimidines and platinum agents in vivo, and targeting of NF-kappaB may overcome chemotherapy resistance. Thus, we performed this phase I study to document the safety and obtain preliminary efficacy data for the combination of capecitabine, oxaliplatin, and bortezomib.

Patients And Methods: Patients with advanced solid tumors were treated with oxaliplatin 130 mg/m(2) intravenously on day 1, capecitabine 750-900 mg/m(2) twice daily orally for 14 days, and bortezomib 1.0, 1.3, or 1.6 mg/m(2) intravenously on days 1 and 8 of 21 day cycles. CT scans were repeated every 2 cycles.

Results: Thirteen patients received 45 cycles of treatment (median, 2; range, 1-8). No dose-limiting toxicities were noted at all bortezomib dose levels when administered with full dose capecitabine and oxaliplatin. The most common grade 3 nonhematologic toxicities during any cycle of therapy included elevated transaminases (3), vomiting, diarrhea, and dehydration (2 each). Only one patient experienced grade 3 peripheral neuropathy in cycle 8. Three objective tumor responses were noted (squamous cell of anus, adenocarcinoma of unknown primary, adenocarcinoma of rectum).

Conclusions: Weekly bortezomib can be safely combined with full doses of capecitabine and oxaliplatin. As 1.6 mg/m(2) weekly of bortezomib is the maximum tolerated dose in single-agent studies, no further dose escalation was performed in this study. Preliminary evidence of antitumor activity is demonstrated. The further evaluation of this combination in diseases for which capecitabine and oxaliplatin have efficacy should be considered.