Imatinib mesylate for targeting the platelet‐derived growth factor β receptor in combination with fluorouracil and leucovorin in patients with refractory pancreatic, bile duct, colorectal, or gastric cancer—A dose‐escalation Phase I trial

BACKGROUND. In previous experimental models, because of its ability to inhibit the activity of platelet‐derived growth factor β receptor, imatinib decreased the interstitial fluid pressure and improved the delivery and efficacy of anticancer drugs, including fluorouracil. The objective of this Phase I study was to define the dose‐limiting toxicity (DLT) and maximum tolerated dose (MTD) of imatinib in combination with fluorouracil and leucovorin in patients with chemotherapy‐refractory gastrointestinal cancer. METHODS. A 3‐patient cohort dose‐escalating study design was used. Patients received leucovorin 200 mg/m 2 followed by fluorouracil 2000 mg/m 2 as a 24‐hour infusion on Days 1 and 2 combined with imatinib on Days −4, −3, −2, −1, 1, 2, 3, and 4. Cycles were repeated every 2 weeks, and the imatinib dose was escalated from 300 mg daily to 700 mg daily in 100‐mg steps. RESULTS. Thirty patients were enrolled at 5 dose levels. Frequent and dose‐dependant National Cancer Institute Common Toxicity Criteria grade 1–4 adverse events with suspected relation to the treatment were anemia (43%), nausea (33%), fluid retention (27%), elevated serum γ‐glutamyl‐transpeptidase (20%), and diarrhea. DLTs were severe neutropenia, central fluid retention, and severe nausea observed in 1 patient each, resulting in an MTD for imatinib of 600 mg per day. There were no differences in imatinib pharmacokinetics before or during chemotherapy. A minor response was observed; and signs of clinical activity, including the resolution of ascites and improvement in performance status, were noted in some patients. CONCLUSIONS. The combination of biweekly fluorouracil/leucovorin and imatinib 600 mg daily given in a week‐on/week‐off schedule was feasible and safe. Nausea and fluid retention represented the DLTs. Cancer 2007. © 2007 American Cancer Society.