A Study With Neoadjuvant mFOLFOX7 Plus Cetuximab to Determine the Surgical Conversion Rate for Unresectable Colorectal Cancer With Metastases Confined to the Liver
A Study With Neoadjuvant mFOLFOX7 Plus Cetuximab to Determine the Surgical Conversion Rate for Unresectable Colorectal Cancer With Metastases Confined to the Liver
FC-6 is a Phase II, multi-center clinical trial for patients with unresectable, wild-type
 K-RAS, colorectal cancer with metastases confined to the liver. Liver metastases must be
 determined by FC-6 criteria to be unresectable, and the colorectal cancer (CRC) tumor
 (primary or metastatic) must be found to be wild-type K-RAS. Patients with mutant K-RAS
 tumors are ineligible. K-RAS testing can be done through the local hospital or a tumor sample
 can be submitted to the FC-6 central lab (Esoterix Clinical Trial Services).

 A primary aim of this study is to evaluate the surgical conversion rate using cytotoxic
 combination chemotherapy and biologic therapy with cetuximab, a monoclonal antibody targeted
 against the epidermal growth factor receptor. A second primary aim is to evaluate the safety
 and tolerability of a chemotherapy/targeted therapy regimen in this patient population.
 Secondary aims include determination of clinical response rate, recurrence-free survival for
 patients undergoing complete resection and/or ablation of liver metastases, and overall
 survival.
All patients will receive the FC-6 study treatment regimen every 2 weeks during each 8-week
 cycle for a total of 3 cycles.

 Baseline imaging of the chest, abdomen, and pelvis will be performed. CT scan or MRI of the
 abdomen will be performed after 1 cycle of neoadjuvant therapy to assess clinical response
 and resectability of liver metastases. If liver metastases are not deemed to be resectable at
 this assessment, but tumor assessment demonstrates stable disease or partial response,
 therapy will continue with re-assessment for clinical response and resectability after Cycle
 2 and, if necessary, after Cycle 3.

 After a minimum of 1 cycle of therapy, patients who meet the guidelines for resection of
 liver metastases will undergo liver metastasectomy (tumor resection and/or ablation) as soon
 as judged technically feasible by the hepatic surgeon in order to minimize chemotherapy
 damage to the liver and morbidity from surgery. At the investigator's discretion, the
 chemotherapy and cetuximab regimen may be continued for 1 additional treatment given at least
 2 weeks before the planned date of surgery. This additional treatment, if given, will not be
 considered to be part of the 3 study therapy cycles.

 The surgical goal is to perform a curative (R0) resection and/or ablation. If curative
 surgery was performed and if only 1 or 2 cycles of therapy were administered before surgery,
 postoperative therapy using the same regimen will resume 4-6 weeks following surgery to
 complete 3 cycles of study treatment. Following discontinuation of study therapy, all
 patients who undergo R0 resection (with or without ablation) will be followed every 3 months
 for the first 2 years on the study and then every 6 months for years 3 through 5.

 Further therapy for patients who do not undergo R0 resection/ablation will be at the
 investigator's discretion. These patients will only be followed for vital status every 12
 months for the remainder of the 5-year period following study entry.

 A total sample size of 60 patients will be enrolled in the FC-6 trial.
Conditions for patient eligibility

 -  Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of
 0 or 1 and must be considered a potential candidate for a major hepatic surgical
 procedure.

 -  The patient must have histologic or cytologic confirmation of a diagnosis of
 colorectal adenocarcinoma.

 -  There must be documentation by PET/CT scan, CT scan, MRI, or intraoperative palpation
 (at the time of resection of the primary colorectal tumor, if applicable) that the
 patient has evidence of hepatic metastasis. (Histologic confirmation of hepatic
 metastasis is not required.)

 -  Patients are eligible with any of the following: primary tumor and regional nodes
 resected with clear surgical margins and no evidence of extrahepatic disease or;
 unresected primary tumor with plans to resect the primary tumor prior to study entry
 or; unresected primary tumor with plans to resect the primary tumor and the liver
 metastases in a single surgical procedure performed within 2-7 weeks after the last
 preoperative dose of chemotherapy/cetuximab or; unresected primary with plans to
 resect the primary tumor and the liver metastases in staged procedures performed
 within 2-7 weeks after the last preoperative dose of chemotherapy/cetuximab.

 -  The colorectal primary tumor or metastatic tumor must be determined to be wild-type
 K-RAS. The K-RAS test may have been performed through the local hospital, or a tumor
 sample may be submitted to the FC-6 central lab for K-RAS testing. If local K-RAS test
 results are reported as indeterminate, submission of a tumor sample for central
 testing is required. Note: Needle biopsy of liver metastasis is not recommended for
 the express purpose of obtaining tissue for K-RAS testing because of the risk of
 needle track dissemination of malignant cells.

 -  There must be documentation that the liver metastases must have been determined by a
 hepatic surgeon approved (by protocol defined criteria) to participate in FC-6 to be
 unresectable based on at least one of the following criteria: All of the liver
 metastases cannot be resected (and/or ablated) with negative margins, i.e., lesion(s)
 located in an area that would result in the resection of all of the hepatic veins or
 the main portal vein or the right and left hepatic arteries or the common bile duct;
 Complete resection and/or ablation would require greater than 60% of the liver
 parenchyma to be removed. Note: At the discretion of the hepatic surgeon, portal vein
 embolization (PVE) may be utilized preoperatively following neoadjuvant therapy to
 enhance the volume of the hepatic remnant. However, the determination of
 unresectability will be based on the estimate, at the time of study entry, of the
 percentage of liver parenchyma that would need to be removed. PVE may be employed
 preoperatively to enhance the overall safety, but not specifically the resectability
 of the liver metastasis(es).

 -  There must be documentation that: at least 3 of the 8 hepatic segments are free of
 metastases or; based on imaging studies, the patient is anticipated to have at least
 40% of the liver will remain intact after surgery.

 -  If an adjuvant therapy regimen of 5-FU given alone or in combination with leucovorin,
 irinotecan, capecitabine, oxaliplatin, cetuximab, or bevacizumab was administered, the
 adjuvant therapy must have been discontinued more than 6 months prior to study entry.

 -  The patient must have had the following tests and exams within 4 weeks prior to study
 entry: medical history and physical exam; consultation with a hepatic surgeon approved
 for FC-6; and PET/CT scan or both a PET scan and a CT scan of the chest, abdomen, and
 pelvis must be performed. (MRI scan can be substituted for the CT scan.)

 -  There must be evidence of adequate bone marrow function: absolute neutrophil count
 (ANC) greater than or equal to 1500/mm3; Hemoglobin greater than or equal to 10 g/dL;
 Platelets greater than or equal to 100,000/mm3

 -  There must be evidence of adequate hepatic function: Total bilirubin less than or
 equal to upper limit of normal (ULN) for the lab; aspartate aminotransferase (AST)
 less than or equal to 5.0 x ULN for the lab

 -  Serum creatinine must be less than or equal to 1.5 mg/dL.

 Conditions for patient ineligibility

 -  Diagnosis of anal or small bowel carcinoma.

 -  Colorectal cancers other than adenocarcinoma, e.g., sarcoma, lymphoma, carcinoid.

 -  Unresected primary tumor in the colon or rectum with significant symptoms related to
 obstruction or that will require radiation therapy.

 -  Evidence of extrahepatic metastases or non-contiguous extension of intrahepatic
 metastases to non-hepatic tissues.

 -  Radiographic evidence of metastases to portal lymph nodes (node greater than 1 cm in
 diameter) unless the node(s) are proven by biopsy to be negative.

 -  Previous hepatic resection and/or ablation, hepatic arterial infusion therapy, or any
 systemic therapy for metastatic disease. (Patients who have only had an excisional
 biopsy are eligible.)

 -  Radiation therapy to the liver.

 -  Pre-existing chronic hepatic disease (e.g., chronic active hepatitis, cirrhosis) that,
 in the opinion of the investigator and hepatic surgeon, would limit the patient's
 ability to undergo hepatic metastasectomy.

 -  Common Toxicity Criteria for Adverse Effects (CTCAE) v3.0 grade 3 or 4 anorexia or
 nausea related to metastatic disease.

 -  CTCAE v3.0 greater than or equal to grade 2 vomiting related to metastatic disease.

 -  CTCAE v3.0 greater than or equal to grade 2 sensory/motor neuropathy.

 -  Any of the following cardiac conditions: Documented congestive heart failure;
 Myocardial infarction within 6 months prior to study entry; Unstable angina within 6
 months prior to study entry; Symptomatic arrhythmia.

 -  Serious or non-healing wound, skin ulcers, or bone fracture.

 -  History of bleeding diathesis or coagulopathy. (Patients on stable anticoagulant
 therapy are eligible.)

 -  Symptomatic interstitial lung disease or definitive evidence of interstitial lung
 disease described on CT scan, MRI, or chest x-ray in asymptomatic patients.

 -  Any evidence of active infection.

 -  Active inflammatory bowel disease.

 -  Other malignancies unless the patient is considered to be disease-free and has
 completed therapy for the malignancy greater than or equal to 12 months prior to study
 entry. Patients with the following cancers are eligible if diagnosed and treated
 within the past 12 months: carcinoma in situ of the cervix, colorectal carcinoma in
 situ, melanoma in situ, and basal cell and squamous cell carcinoma of the skin.

 -  Previous serious hypersensitivity reaction to monoclonal antibodies.

 -  Psychiatric or addictive disorders or other conditions that, in the opinion of the
 investigator, would preclude the patient from meeting the study requirements.

 -  Pregnancy or lactation at the time of study entry. (WOCBP must have a negative
 pregnancy test within 2 weeks prior to study entry. Male and female patients of
 reproductive potential must agree to use adequate contraceptive methods during and for
 2 months after study therapy. )

 -  Any other serious concomitant medical condition that, in the opinion of the
 investigator, would compromise the safety of the patient or compromise the patient's
 ability to participate in the study.

 -  Use of any investigational product within 30 days prior to study entry.