A phase I dose escalation study of pharmacobiologically based scheduling of capecitabine and mitomycin C (MMC) in patients with gastrointestinal solid malignancies

Abstract

15154 Background: A principal determinant of the therapeutic index of capecitabine-based treatment is the grade of thymidine phosphorylase(dThdPase) activity in malignant tissues. MMC, an agent that is active in gastrointestinal malignancies, produces significant upregulation of the dTHdPase starting 4–6 days after treatment and persisting for at least 10 days. On the basis of the time-dependency and transience of this upregulation, we performed a phase I study of capecitabine in combination with MMC. The aim was to determine the maximally tolerated dose of this combination. Methods: In this ongoing study, patients with advanced gastrointestinal solid malignancies received MMC on day 1 and capecitabine twice daily on days 8 and 21, every 4 weeks. The MMC dose was fixed at 6mg/m2, whereas capecitabine was escalated in successive patient cohorts. Patients were allowed to have had a maximum of 2 prior therapies for metastatic disease. The total cumulative dose of MMC was capped at 36 mg/m^2 to reduce the risk of cumulative toxicity. Results: So far 23 patients with a median age of 62 received capecitabine doses from 1000 to 2000 mg/m^2/d. The majority of the patients had at least 1 prior treatment (86%). Four patients were considered non-evaluable. No dose-limiting toxicities were observed as we reached our final dose level. Toxicities were generally mild with only 7 patients experiencing grade 3 toxicities and two experiencing grade 4 toxicities. The most common toxicities were fatigue (67%), nausea (43%), diarrhea (33%), and anemia (29%), and all toxicities were reversible. There were no objective responses; however, 32% of evaluable patients had prolonged stable disease (43% colorectal, 29% pancreas, 14% esophageal, and 14% gastric). Conclusions: Capecitabine in combination with MMC in the proposed schedule is well tolerated and has promising preliminary activity in various gastrointestinal malignancies. Recommended doses for phase II studies are capecitabine 1000 mg/m^2 twice daily and MMC 6 mg/m^2. This study is ongoing with 2 more patients being entered at the recommended phase II dose. No significant financial relationships to disclose.