| Purpose: |
|
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 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.
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| Study summary: |
|
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. |
| Criteria: |
|
Conditions for patient eligibility
- Patients must have an 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 that the patient has
evidence of hepatic metastasis. (Histologic confirmation of hepatic metastasis is
not required.)
- Patients are eligible with either synchronous or metachronous metastatic disease
(confined to the liver), but the primary colon or rectal tumor must have been
resected before study entry.
- 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.
- 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).
- At least 3 of the 8 hepatic segments must be free of metastases.
- 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: 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 ULN for the lab; 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.
- 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.
- 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 pneumonitis or definitive evidence of interstitial
pneumonitis 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. |