A Study With Neoadjuvant mFOLFOX7 Plus Cetuximab to Determine the Surgical Conversion Rate for Unresectable Colorectal Cancer With Metastases Confined to the Liver
Condition: Metastatic Colorectal Cancer
MeSH terms: Colorectal Neoplasms
Intervention: cetuximab; 5-FU; oxaliplatin; leucovorin
Intervention description: 500 mg/m2 IV every two weeks on days 1, 15, 29, and 43 of each 56 day cycle, for a total of 3 cycles. Cetuximab dose will be escalated by 100 mg/m2 every 2 weeks to a maximum dose of 800 mg/m2 if, at the time of retreatment, skin rash is less than or equal to grade 1, diarrhea is grade 0 (defined as less than or equal to 3 stools per day over baseline), and the patient is not experiencing any other greater than or equal to grade 2 toxicity attributed to cetuximab.; 3000 mg/m2 IV continuous infusion over 46 hours every two weeks on days 1, 15, 29, and 43 of each 56 day cycle, for a total of 3 cycles.; 85 mg/m2 IV every two weeks on days 1, 15, 29, and 43 of each 56 day cycle, for a total of 3 cycles.; 400 mg/m2 IV every two weeks on days 1, 15, 29, and 43 of each 56 day cycle, for a total of 3 cycles.
Intervention MeSH terms: Leucovorin; Fluorouracil; Oxaliplatin; Cetuximab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 20.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: NSABP; Cetuximab; FOLFOX7; Oxaliplatin; Leucovorin; 5-FU; colorectal cancer; KRAS wild type; metastatic colorectal cancer; Erbitux; Eloxatin; Liver resection; Liver ablation; Metastasectomy

Summary:

      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.
    

Eligibility criteria:

        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.