Dasatinib in Treating Patients With Previously Treated Metastatic Colorectal Cancer
This phase II trial is studying dasatinib to see how well it works in treating patients with previously treated metastatic colorectal cancer. Dasatinib may stop the growth of tumor cells by blocking some of the enzymes needed for their growth
Recurrent Colon Cancer
Recurrent Rectal Cancer
Stage IV Colon Cancer
Stage IV Rectal Cancer
|Study Design:||Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||A Phase II Study of Dasatinib (NSC 732517) in Previously-Treated Patients With Metastatic Colorectal Cancer|
- Progression-free Survival Rate [ Time Frame: From the start of treatment to the time of disease progression or death from any cause, assessed at 4 months after completion of treatment (i.e., up to 12 months.) ] [ Designated as safety issue: No ]Progression will be evaluated in this study using the new international criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee. Patients who are still alive and have not progressed will be censored at the date of the last negative examination. A Simon (1989), optimal, two-stage design will be employed. The progression-free survival count will be the proportion of subjects who are alive and progression-free at 4 months.
- Response Rate (RR) (Complete or Partial Responders) [ Time Frame: Every 2 courses, assessed up to 8 weeks after completion of study treatment (i.e., up to 10 months) ] [ Designated as safety issue: No ]Response will be evaluated in this study using the new international criteria proposed by the RECIST Committee. The response rate is the proportion of subjects who experienced a complete or partial response.
- Incidence of Somatic Mutations [ Time Frame: 1 year ] [ Designated as safety issue: No ]Multivariable analysis of progression-free survival duration will be performed using the Cox (1972) regression model to evaluate the prognostic value of somatic mutations. For the mutational analysis endpoints, genetic mutations will also be correlated with drug activity via Fisher's exact test for comparisons of responders with non-responders and for comparison of patients progression-free and 4 months vs. those with early progression or death
- Association Between the Incidence of Total C-src and Phosphorylated C-src Expression and Response [ Time Frame: 4 months ] [ Designated as safety issue: No ]Examined by comparing expression in those who have an objective response versus those who do not and in those with and without disease progression at 4 months using Fisher's exact test.
- Change in Plasma Vascular Endothelial Growth Factor (VEGF) Levels Over 15 Days [ Time Frame: At baseline and day 15 ] [ Designated as safety issue: No ]Changes of VEGF will be correlated with response rates and 4-month progression-free survival utilizing the Wilcoxon rank-sum test.
|Study Start Date:||May 2007|
|Primary Completion Date:||June 2011 (Final data collection date for primary outcome measure)|
Experimental: Dasatinib (tyrosine Kinase Inhibitor)
Patients receive oral dasatinib twice daily on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.
We conducted a multi-center phase II trial of dasatinib in unresectable, previously-treated metastatic colorectal cancer (CRC) patients. The primary endpoint of this study was the progression-free survival (PFS) rate at 4 months. Secondary endpoints included objective response rate (complete response + partial response), toxicity, and overall survival. PFS and overall survival were calculated from the start of study treatment. The trial was conducted using a Simon optimal 2-stage design to test the null hypothesis that the 4-month PFS rate was less than or equal to 20% versus the alternative that it was at least 40%. Nineteen patients were to be enrolled in the first stage, and all patients were to be evaluable for the primary endpoint. Those with early discontinuation of treatment or early death were considered treatment failures. If four or fewer patients were alive and progression-free at 4 months, the trial would be terminated for lack of efficacy. Otherwise, an additional 35 patients would be accrued, and if 16 or more patients (out of the 54) were alive and progression-free at 4 months, the drug would be considered worthy of further study. This design yields a 0.90 probability of a positive result if the true 4-month PFS rate is at least 40%. Progression-free and overall survival curves were constructed using the method of Kaplan and Meier. Confidence intervals for the median PFS and overall survival times were derived as described by Brookmeyer and Crowley.
I. Determine the progression-free survival of patients with metastatic colorectal cancer who have progressed on or following two prior chemotherapy regimens and are then treated with dasatinib.
I. Determine the objective response rates in patients treated with dasatinib. II. Determine the overall survival of patients treated with dasatinib. III. Determine the toxicity in patients treated with dasatinib.
I. Determine the incidence of somatic mutations in c-src, c-yes, fyn, lck, hck, lyn, yrk and csk in archival primary and metastatic colorectal cancer tissues from these patients and to correlate this with clinical outcome.
II. Determine the incidence of total c-src and phosphorylated c-src expression in archival primary and metastatic colorectal cancer specimens from these patients, and to correlate this with clinical outcome.
III. Evaluate the effect of dasatinib on serum vascular endothelial growth factor (VEGF) levels.
OUTLINE: This is a multicenter study. Patients receive oral dasatinib twice daily on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.
Blood is collected on days 1 (prior to the first dose of dasatinib) and 15 of course 1 for measurement of VEGF pre-and post-dasatinib administration. Archived tumor tissue (tumor or core biopsy; primary or metastatic lesion) is collected for identification of the incidence of somatic mutations and polymorphisms by polymerase chain reaction and electrophoresis and for measurement of total c-src and phosphorylated src expression by immunohistochemistry.
After completion of study treatment, patients are followed for at least 8 weeks.
|United States, Illinois|
|University of Chicago Comprehensive Cancer Center|
|Chicago, Illinois, United States, 60637-1470|
|Principal Investigator:||Hedy Kindler||University of Chicago Comprehensive Cancer Center|