FOCUS 3 - A Study to Determine the Feasibility of Molecular Selection of Therapy Using KRAS, BRAF and Topo-1 in Patients With Metastatic or Locally Advanced Colorectal Cancer

Brief Summary

Detailed Description

OBJECTIVES: Primary - Feasibility Study * To determine the proportion of consenting patients that can provide a formalin-fixed paraffin-embedded block containing tumor. * To determine the feasibility of topoisomerase-1 (topo-1) IHC and K-ras, BRAF mutational status determination being completed with 10 working days of initial consent. * To determine reproducibility of results between reference laboratories. * To determine the real costs of molecular testing. * To determine the patients' ability to comprehend the study and their attitude during the waiting period for testing. * To assess patients' ability to fully comprehend the trial as explained to them. Secondary - Feasibility Study * To further identify the EGFR-responsive subset within the K-ras wildtype population. Primary - Definitive Study * Compare the clinical outcomes of patients with metastatic or locally advanced colorectal cancer and low topo-1-expressing tumors treated with fluorouracil alone versus irinotecan hydrochloride, fluorouracil, and leucovorin calcium (IrMdG). * Compare the progression-free survival of patients with high topo-1-expressing tumors treated with oxaliplatin and IrMdG versus IrMdG alone. * Compare the response rate in patients with K-ras wildtype tumor treated with cetuximab and IrMdG versus IrMdG alone. * Compare the response rate in patients with K-ras mutant tumors who are unlikely to respond to EGFR inhibition treated with bevacizumab and IrMdG versus IrMdG alone. OUTLINE: This is a multicenter, 2-part study. * Part I (feasibility study): Once consent for tissue block release has been obtained and patient is registered, the block is requested from the Pathology Department. This begins the 10 working-day time line. Treatment commences once the results of the testing are known. The following evaluations are performed during this period: * The frequency of EGFR gene amplification on FISH, PI3K gene mutation, PTEN loss by IHC, estimation of mRNA for EGFR ligands (amphiregulin and epiregulin), and other protein assessments. * An evaluation of the impact on the use or further investigation of these markers in the main study. * Patients consenting to trial entry and (if agreeable to data collection) patients refusing trial entry complete a questionnaire assessing patients' ability to fully comprehend the trial as explained to them. * Patients are interviewed before allocation of treatment about their attitudes about the waiting period necessary for tumor testing. * Part II (definitive study): Patients are stratified according to availability of both lab tests (K-ras mutation \[yes vs no\], BRAF mutation \[yes vs no\], and topoisomerase-1 \[topo-1\] expression \[low vs high\]). Patients are assigned to 1 of 4 treatment groups based on their biomarker test results. * Group 1 (low topo-1 and both K-ras and BRAF wildtype): Patients are randomized to 1 of 3 treatment arms. * Arm I (regimen A \[IrMdG\]): Patients receive irinotecan hydrochloride IV over 30 minutes, leucovorin calcium IV over 2 hours, and fluorouracil IV bolus followed by infusion over 46 hours on day 1. Treatment repeats every 2 weeks for at least 6 months in the absence of disease progression or unacceptable toxicity. * Arm II (regimen B \[MdG\]): Patients receive leucovorin calcium IV over 2 hours and fluorouracil IV bolus followed by infusion over 46 hours on day 1. Treatment repeats every 2 weeks for at least 6 months in the absence of disease progression or unacceptable toxicity. * Arm III (regimen D \[IrMdG and cetuximab\]): Patients receive cetuximab IV over 1-2 hours, irinotecan hydrochloride IV over 30 minutes, leucovorin calcium IV over 2 hours, and fluorouracil IV bolus followed by infusion over 46 hours on day 1. Treatment repeats every 2 weeks for at least 6 months in the absence of disease progression or unacceptable toxicity. * Group 2 (low topo-1 and either K-ras or BRAF mutation): Patients are randomized to 1 of 3 treatment arms. * Arm I (regimen A \[IrMdG\]): Patients receive irinotecan hydrochloride, leucovorin calcium, and fluorouracil as in group 1, arm I. * Arm II (regimen B \[MdG\]): Patients receive leucovorin calcium and fluorouracil as in group 1, arm II. * Arm III (regimen E \[IrMdG and bevacizumab\]): Patients receive bevacizumab IV over 30-90 minutes, irinotecan hydrochloride IV over 30 minutes, leucovorin calcium IV over 2 hours, and fluorouracil IV bolus followed by infusion over 46 hours on day 1. Treatment repeats every 2 weeks for at least 6 months in the absence of disease progression or unacceptable toxicity. * Group 3 (high topo-1 and both K-ras and BRAF wildtype): Patients are randomized to 1 of 3 treatment arms. * Arm I (regimen A \[IrMdG\]): Patients receive irinotecan hydrochloride, leucovorin calcium, and fluorouracil as in group 1, arm I. * Arm II (regimen C \[IrOxMdG\]): Patients receive irinotecan hydrochloride IV over 30 minutes, leucovorin calcium IV over 2 hours, oxaliplatin IV over 2 hours, and fluorouracil IV bolus followed by infusion over 46 hours on day 1. Treatment repeats every 2 weeks for at least 6 months in the absence of disease progression or unacceptable toxicity. * Arm III (regimen D \[IrMdG and cetuximab\]): Patients receive cetuximab, irinotecan hydrochloride, leucovorin calcium, and fluorouracil IV as in group 1, arm III. * Group 4 (high topo-1 and either K-ras or BRAF mutation): Patients are randomized to 1 of 3 treatment arms. * Arm I (regimen A \[IrMdG\]): Patients receive irinotecan hydrochloride, leucovorin calcium, and fluorouracil as in group 1, arm I. * Arm II (regimen C \[IrOxMdG\]): Patients receive irinotecan hydrochloride, leucovorin calcium, oxaliplatin, and fluorouracil as in group 3, arm II. * Arm III (regimen E \[IrMdG and bevacizumab\]): Patients receive bevacizumab, irinotecan hydrochloride, leucovorin calcium, and fluorouracil IV as group 2, arm III. After completion of study therapy, patients are followed up periodically. PROJECTED ACCRUAL: A total of 240 patients will be accrued for the feasibility study and approximately 3,000 patients will be accrued for the definitive study.

Primary Outcomes

Secondary Outcomes

• Time from release of tumor block to receipt by pathology lab
• If applicable, reason that RZ did not occur
• Time from registration to treatment start
• Time from data presentation to investigator to date of RZ
• Reproducibility of K-ras, BRAF, and topo-1 results
• Distribution frequencies
• Costs of molecular testing
• Toxicity according to NCI CTCAE v.3
• Response rates
• Progression-free survival
• Attitudes of patients about tests and treatment