Phase I study of ursodeoxycholic acid in combination with 5-fluorouracil, leucovorin, oxaliplatin, and bevacizumab for metastatic colorectal cancer.

Abstract

e14182 Background: Significant treatment advances have doubled the median survival in patients with metastatic colorectal cancer (mCRC). An emerging body of literature links cancer with aberrant metabolism. These findings suggest that treatment directed against CRC metabolism may add to improved survival outcomes. The bile acid, ursodeoxycholic acid (UDCA), lowers cholesterol and improves insulin sensitivity when used clinically. Moreover, UDCA protects against intestinal polyp development in animal and human studies. UDCA effects may be mediated through activation of FXR, since bile acids are the endogenous ligands for this nuclear receptor. FXR is a tumor suppressor in mouse models of colon cancer and a prognostic biomarker in patients with CRC. Activation of FXR with bile acids in mouse models suppresses intestinal tumorigenesis. We propose to determine the dose and safety of UDCA when added to standard therapy for mCRC. Methods: Trial Design: UDCA doses will be escalated using a 3+3 design which will stop at the MTD or at two levels above an Active Dose (AD), whichever is the lowest. The AD is defined as the dose that will activate FXR. After a 7 day run-in period of UDCA only, cytotoxic combination chemotherapy and antiangiogenic agent for mCRC will be given along with the UDCA. The use of a run-in period allows for metabolic studies to identify serum biomarkers of FXR activation and to determine an AD. Treatment or intervention planned: UDCA is given during a run-in period of 7 days. At the end of the run-in period, standard doses of 5-fluorouracil, leucovorin, oxaliplatin, and bevacizumab are added. Patients are treated until excessive toxicity, progression of disease, or surgical resection. Major eligibility criteria: Patients with mCRC are eligible. Patients with greater than 10% body weight loss within 6 months of entering the protocol, a diagnosis of diabetes and active diabetes treatment are excluded from the study. Results: Current enrollment: Cohorts 1, 2, 3 have been completed without DLT. Enrollment to Cohort 4 began in 12/2011. Conclusions: Continue dose escalation until MTD or 2 levels above AD.Clinical trial registry number: NCT00873275.