A Study With Neoadjuvant mFOLFOX7 Plus Cetuximab to Determine the Surgical Conversion Rate for Unresectable Colorectal Cancer With Metastases Confined to the Liver

Metastatic Colorectal Cancer Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00803647
• Other study ID #: NSABP FC-6
• Status: Completed
• Phase: Phase 2
• Start date: January 2010
• Est. completion date: November 2014

Study information

• Verified date: October 2021
• Source: NSABP Foundation Inc
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 20
• Est. completion date: November 2014
• Est. primary completion date: July 2013
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Colorectal Neoplasms
• Metastatic Colorectal Cancer

Intervention

Biological:
• cetuximab
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.

Drug:
• 5-FU
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.
• oxaliplatin
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.
• leucovorin
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.

Locations

Country	Name	City	State
United States	Franklin Square Hospital Center	Baltimore	Maryland
United States	Vermont Cancer Center at University of Vermont	Burlington	Vermont
United States	CCOP, Dayton, OH	Dayton	Ohio
United States	Henry Ford Health System	Detroit	Michigan
United States	CCOP - NorthShore University HealthSystem	Evanston	Illinois
United States	CCOP - Grand Rapids Clinical Oncology Program	Grand Rapids	Michigan
United States	University of Iowa	Iowa City	Iowa
United States	Loma Linda University Medical Center	Loma Linda	California
United States	NortonHealthcare, Inc.	Louisville	Kentucky
United States	Medical College of Wisconsin	Milwaukee	Wisconsin
United States	Edward Hospital	Naperville	Illinois
United States	CCOP - Christiana Care Health Services	Newark	Delaware
United States	St. Joseph Hospital	Orange	California
United States	M.D. Anderson Cancer Center - Orlando	Orlando	Florida
United States	Thomas Jefferson University Hospital	Philadelphia	Pennsylvania
United States	Allegheny Cancer Center at Allegheny General Hospital	Pittsburgh	Pennsylvania
United States	NSABP Foundation, Inc.	Pittsburgh	Pennsylvania
United States	University of Pittsburgh	Pittsburgh	Pennsylvania
United States	CCOP, William Beaumont Hospital	Royal Oak	Michigan
United States	CCOP - Metro-Minnesota	Saint Louis Park	Minnesota
United States	Kaiser Permanente-San Diego	San Diego	California
United States	CCOP - Upstate Carolina	Spartanburg	South Carolina
United States	Kaiser Permanente Medical Center - Vallejo	Vallejo	California

Sponsors (2)

Lead Sponsor	Collaborator
NSABP Foundation Inc	Bristol-Myers Squibb

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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).		8 months
Primary	Reported Adverse Events.	19 participants experienced at least one adverse event. There were a total of 95 adverse events reported. (Note: multiple occurrences of the same adverse event in one individual are counted only once.) Refer to the Adverse Events section for specifics. The Other Adverse Events section lists only those events occurring above 5% frequency.	8 months
Secondary	Overall Survival (OS). Time From Study Entry Until Death From Any Cause.	The percentage of patients alive at 18 months.	18 months
Secondary	Objective Clinical Response Rate (cRR). Measureable Lesions That Can be Accurately Measured in at Least One Dimension With Conventional Radiologic Techniques or Spiral CT.	Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by PET/CT, CT scan, MRI or spiral CT: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Objective clinical Response Rate (cRR) = CR + PR during the 3 preoperative cycles, among the treated patients.	8 months
Secondary	Recurrence-free Survival (RFS). Time From Study Entry Until First Recurrence.		2 years