Clinical Trial: RO4929097 and Capecitabine in Treating Patients With Refractory Solid Tumors

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

Official Title: A Phase 1 Study of RO4929097 (NSC749225) in Combination With Capecitabine in Refractory Solid Tumors

Brief Summary: 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.

Detailed Summary:

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
Sponsor: National Cancer Institute (NCI)

Current Primary Outcome:

  • 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) [ Time Frame: Up to 30 days after completion of study treatment ]
    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.
  • Incidence of adverse events graded according to NCI CTCAE version 4.0 (Parts 2a and 2b) [ Time Frame: Up to 24 months ]
    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.


Original Primary Outcome:

  • Maximum-tolerated dose of RO4929097 (Part 1)
  • Dose-limiting toxicities (Part 1)
  • Safety


Current Secondary Outcome:

  • Confirmed anti-tumor response rate validated by the RECIST (Part 1) [ Time Frame: Up to 30 days after completion of study treatment ]
    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.
  • Changes in the expression of Notch1 signaling pathway members (Part 1) [ Time Frame: From baseline to 30 days after completion of study treatment ]
    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.
  • Pharmacokinetics of the combination of RO4929097 and capecitabine, including Cmax, Tmax, AUC, t1/2, and CL (Part 1) [ 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 ]
    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.
  • PFS (Parts 2a and 2b) [ Time Frame: Up to 24 months ]
    Presented in a tabular format.
  • OS (Part 2a and 2b) [ Time Frame: Number of days from the day of first RO4929097 and capecitabine administration to the patient's death, assessed up to 24 months ]
    Presented in a tabular format.
  • Overall response rate (Parts 2a and 2b) [ Time Frame: Up to 24 months ]
    Confirmed anti-tumor response rate will be validated by RECIST. Responses will be summarized using descriptive statistics presented in tabular format.


Original Secondary Outcome:

  • Clinical activity
  • Pharmacokinetic and pharmacogenomic profiles
  • Progression-free and overall survival (Part 2a and 2b)
  • Overall response rate (Part 2a and 2b)


Information By: National Cancer Institute (NCI)

Dates:
Date Received: July 7, 2010
Date Started: June 2010
Date Completion:
Last Updated: November 6, 2014
Last Verified: June 2014