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A Phase II Study to Determine the Surgical Conversion Rate in Patients Receiving Neoadjuvant mFOLFOX7 + Cetuximab for Unresectable Wild-Type K-RAS Colorectal Cancer With Metastases Confined to the Liver

Phase 2
18 Years
Open (Enrolling)
Metastatic Colorectal Cancer

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Trial Information

A Phase II Study to Determine the Surgical Conversion Rate in Patients Receiving Neoadjuvant mFOLFOX7 + Cetuximab for Unresectable Wild-Type K-RAS Colorectal Cancer With Metastases Confined to the Liver

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.

Inclusion 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

- 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

- 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

- 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.

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

The percentage of patients who had a curative (R0) liver metastasectomy following protocol treatment, i.e., metastatic disease that can be completely resected and/or ablated with no postoperative evidence of residual malignant disease (R0 resection).

Outcome Time Frame:

8 months

Safety Issue:


Principal Investigator

Norman Wolmark, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

NSABP Foundation, Inc.


United States: Institutional Review Board

Study ID:




Start Date:

January 2010

Completion Date:

January 2018

Related Keywords:

  • Metastatic Colorectal Cancer
  • Cetuximab
  • Oxaliplatin
  • Leucovorin
  • 5-FU
  • colorectal cancer
  • KRAS wild type
  • metastatic colorectal cancer
  • Erbitux
  • Eloxatin
  • Liver resection
  • Liver ablation
  • Metastasectomy
  • Colorectal Neoplasms
  • Neoplasm Metastasis



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