Study of Tumor Tissue Testing in Selecting Treatment for Patients With Metastatic or Locally Advanced Colorectal Cancer

Colorectal Cancer Clinical Trial

Official title: 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

Status Completed

Clinical Trial Summary

RATIONALE: Studying samples of tumor tissue from patients with cancer in the laboratory may help doctors learn more about changes that occur in DNA and identify biomarkers related to cancer. It may also help doctors select the best treatment for patients and predict their response to treatment.

PURPOSE: This randomized phase II/III trial is studying how well tumor tissue testing works in selecting treatment for patients with metastatic or locally advanced colorectal cancer.

Clinical Trial 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. ;

Study Design

Allocation: Randomized, Masking: Open Label, Primary Purpose: Diagnostic

Related Conditions & MeSH terms

• Colorectal Cancer
• Colorectal Neoplasms

• NCT number: NCT00975897
• Study type: Interventional
• Source: National Cancer Institute (NCI)
• Status: Completed
• Phase: Phase 2/Phase 3
• Start date: July 2009
• Completion date: December 2012