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

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.

DISEASE CHARACTERISTICS:

• Histologically confirmed colorectal adenocarcinoma meeting 1 of the following criteria:

• Prior or recurrent primary adenocarcinoma of the colon or rectum with clinical or radiological evidence of locally advanced or metastatic disease
• Metastatic adenocarcinoma with clinical and/or radiological evidence of colorectal primary tumor
• Inoperable metastatic or locoregional disease

• Patients suitable for surgical resection of metastatic disease after response to first-line or adjuvant chemotherapy not allowed and should be considered for the New-EPOC trial study
• Unidimensionally measurable disease (according to RECIST criteria)
• Must have completed adjuvant chemotherapy with fluorouracil +/- leucovorin calcium (FU +/- LC), capecitabine, or oxaliplatin combinations in the past 6 months

• QUASAR 2 patients who have continued bevacizumab for 6 months following completion of chemotherapy are allowed immediately after completion of bevacizumab
• Rectal chemotherapy with FU +/- LC or capecitabine for allowed if completed ≥ 1 month ago
• Single tumor block available
• No brain metastasis

PATIENT CHARACTERISTICS:

• WHO performance status 0-2
• ANC ≥ 1,500/mm^3
• Platelet count ≥ 100,000/mm^3
• Alkaline phosphatase ≤ 5 times upper limit of normal (ULN)
• Serum bilirubin ≤ 1.25 times ULN
• AST or ALT ≤ 2.5 times ULN
• Creatinine clearance ≥ 30 mL/min OR GFR ≥ 30 mL/min
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• Considered fit to undergo combination chemotherapy, with none of the following conditions:

• Severe uncontrolled concurrent medical illness likely to interfere with protocol treatments, including any of the following:

• Poorly controlled angina
• Uncontrolled hypertension
• Myocardial infarction within the past 3 months
• History of severe peptic ulcer disease
• Any psychiatric or neurological condition that is likely to compromise the patient's ability to give informed consent or to comply with oral medication
• Nephrotic syndrome
• Known coagulopathy
• No prior or current malignant disease that, in the judgement of the treating investigator, is likely to interfere with FOCUS 3 treatment or assessment of response
• No known hypersensitivity reactions to any of the components of the study treatments
• No personal or family history suggestive of dihydropyrimidine dehydrogenase (DPD) deficiency or with known DPD deficiency
• No history of uncontrolled seizures, central nervous system disorders, or psychiatric disability judged by the investigator to be clinically significant precluding informed consent
• Not able to attend or comply with treatment or follow-up scheduling

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• At least 4 weeks since prior surgery
• No prior systemic chemotherapy for metastatic disease
• No ongoing therapy with cyclosporin-A
• No ongoing treatment with a contraindicated concomitant medication