This phase I clinical trial is studying the side effects and best dose of RO4929097 when given together with capecitabine in treating patients with refractory solid tumors. RO4929097 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving RO4929097 together with chemotherapy may kill more tumor cells.
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).
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
30
University of Wisconsin Hospital and Clinics
Madison, Wisconsin, United States
University Health Network-Princess Margaret Hospital
Toronto, Ontario, Canada
MTD of RO4929097 and capecitabine, defined as that dose level at which less than one-third of patients experience a dose-limiting toxicity (DLT) graded according to NCI CTCAE version 4.0 (Part 1)
Time frame: Up to 21 days
Incidence of adverse events graded according to NCI CTCAE version 4.0 (Part 1)
Possible adverse events will be reported in tabular format. To determine the severity of the reaction for adverse event reporting, the NCI CTCAE version 4.0 will be used.
Time frame: Up to 30 days after completion of study treatment
Incidence of adverse events graded according to NCI CTCAE version 4.0 (Parts 2a and 2b)
Possible adverse events will be reported in tabular format. To determine the severity of the reaction for adverse event reporting, the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be used.
Time frame: Up to 24 months
Confirmed anti-tumor response rate validated by the RECIST (Part 1)
Responses will be summarized using descriptive statistics presented in tabular format. Furthermore, two-sided 95% confidence intervals for the proportions of subjects with a confirmed anti-tumor response will be computed, while adjusting for multiplicity.
Time frame: Up to 30 days after completion of study treatment
Changes in the expression of Notch1 signaling pathway members (Part 1)
Relative and absolute changes will be calculated for each patient and results will be summarized by means and standard deviations. Paired t-tests will be used to compare baseline and post-study values in expression levels.
Time frame: From baseline to 30 days after completion of study treatment
Pharmacokinetics of the combination of RO4929097 and capecitabine, including Cmax, Tmax, AUC, t1/2, and CL (Part 1)
PK parameters will be summarized by using means, standard deviations and ranges. PK parameters between patients with a response (partial or complete) will be compared to PK parameters of patients with no response using a nonparametric Wilcoxon Rank Sum test.
Time frame: Baseline on day 1 of course 1; baseline and 1, 2, 3, 4, 8, 12, 16, and 24 hours on days 3 and 10 of course 1; and baseline on day 1 of all subsequent courses
PFS (Parts 2a and 2b)
Presented in a tabular format.
Time frame: Up to 24 months
OS (Part 2a and 2b)
Presented in a tabular format.
Time frame: Number of days from the day of first RO4929097 and capecitabine administration to the patient's death, assessed up to 24 months
Overall response rate (Parts 2a and 2b)
Confirmed anti-tumor response rate will be validated by RECIST. Responses will be summarized using descriptive statistics presented in tabular format.
Time frame: Up to 24 months
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