RO4929097 and Capecitabine in Treating Patients With Refractory Solid Tumors

PRIMARY OBJECTIVES: I. To determine the maximum tolerated dose (MTD) of RO4929097 and capecitabine administered in subjects with advanced solid tumors. (Part 1) II. To describe the dose-limiting toxicities (DLTs) of combined RO492097 and capecitabine. (Part 1) III. To determine the safety of RO4929097 and capecitabine administered in combination. (Part 1) IV. To determine the safety of RO4929097 and capecitabine in subjects with metastatic CRC. (Part 2a) V. To evaluate the safety of RO4929097 and capecitabine in combination for subjects with HER2/neu negative MBC. (Part 2b) SECONDARY OBJECTIVES: I. To determine the clinical activity of RO4929097 and capecitabine administered in combination to subjects with advanced solid tumors. (Parts 1, 2a, and 2b) II. To evaluate the changes in the expression of Notch1 signaling pathway members and downstream targets of Notch by PCR including HEs1, 3 and 5; Hey 1 and 2 after treatment with RO4929097 at the MTD expansion cohorts. (Parts 1, 2a, and 2b) III. To determine the pharmacokinetic and pharmacogenomic profiles of the combination of RO4929097 and capecitabine. (Parts 1, 2a, and 2b) IV. To determine the progression-free survival (PFS) of RO4929097 and capecitabine when administered at the MTD level in patients with metastatic colorectal cancer (CRC) and a history of 1 or 2 prior therapies. (Part 2a) V. To determine the response and overall survival (OS) rates following RO4929097 and capecitabine administration at the MTD level in subjects with metastatic CRC. (Part 2a) VI. To determine the overall response rate (ORR) of RO4929097 and capecitabine when administered at the MTD level to subjects when administered first or second line for HER2/neu negative metastatic breast cancer (MBC). (Part 2b) V. To determine the progression-free and overall survival rates following RO4929097 and capecitabine administration at the MTD level in subjects with HER2/neu negative MBC. (Part 2b) OUTLINE: This is a multicenter, dose-escalation study of gamma-secretase inhibitor RO4929097. Patients receive oral gamma-secretase inhibitor RO4929097 once daily on days 1-3, 8-10, and 15-17 and oral capecitabine twice daily on days 1-14. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients may undergo tumor biopsy before and after treatment for biomarker analysis and blood sample collection periodically for pharmacokinetic and pharmacogenomic studies. After completion of study treatment, patients are followed up for 30 days (Part 1) or every 3 months (Parts 2a and 2b).