Pre-op Rectal ChemoRad +/- Cetuximab

Study Overview
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Brief Summary
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The purpose of this research study is to find out what effects (good and bad) cetuximab has on rectal cancer.

Detailed Description
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Rectal cancer remains a significant cause of morbidity and mortality in the United States. Standard treatment for patients with locally advanced rectal cancer generally includes combined chemotherapy and radiotherapy administered either before (neoadjuvant) or after (adjuvant) definitive surgical resection. Published data from Germany has suggested advantages to a neoadjuvant strategy. Currently, the standard concurrent chemoradiotherapy regimen in the United States is pelvic irradiation administered concurrently with 5-fluorouracil (5-FU) given as a protracted venous infusion. However, local recurrence remains a problem. Recently completed randomized trials of chemoradiotherapy have demonstrated local recurrence rates between 8-17% even with currently accepted standard chemoradiotherapy and adequate surgical management. Several recent trials have explored the use of radiotherapy and cetuximab with good results. Because of the non-overlapping toxicity profiles and the potentially diverse and complimentary mechanisms of action, the combination of chemotherapy plus ERBITUX given concurrently with pelvic radiotherapy may improve on the outcomes seen with current standards for patients with locally advanced adenocarcinoma of the rectum.

Official Title
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A Randomized Phase II Trial of Pre-operative Chemoradiotherapy With or Without Cetuximab (ERBITUX(R)) in Locally-advanced Adenocarcinoma of the Rectum

Conditions
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Rectal Cancer

Intervention / Treatment
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* Drug: Cetuximab
* Drug: 5-fluorouracil
* Radiation: Pelvic irradiation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Note: Please see Section 8.1 for the necessary Prestudy Assessments. A patient will be eligible for inclusion in this study if s/he meets all of the following criteria: Has a histologically confirmed diagnosis of newly diagnosed adenocarcinoma of the rectum (tumor within 15 cm of the anal verge). Location of tumor (lower 1/3rd vs. middle or upper 1/3rd) and pre-treatment nodal status (N0 vs. N1 or N2) will be recorded in the eCRF. Patients with only non-measurable disease are eligible as long as they meet the other disease requirements in this criterion as well as all other eligibility criteria. Has tumor that is locally advanced (T3/T4 or lymph node positive) by preoperative assessment with CT or MRI imaging or transrectal ultrasonography. Has no evidence of distant metastases by radiographic staging Has an ECOG Performance Status (PS) 0-1 Is greater than 18 years of age Has adequate marrow and organ system function as assessed by the following lab values: White blood cell (WBC) count See protocol for specific details Absolute neutrophil count (ANC) See protocol for specific details Hemoglobin See protocol for specific details Total bilirubin See protocol for specific details AST and ALT See protocol for specific details Serum creatinine See protocol for specific details Platelet count See protocol for specific details Sexually active women of childbearing potential must use an effective method of birth control during the course of the study, in a manner such that risk of failure is minimized. Prior to study enrollment, women of childbearing potential (WOCBP) must be advised of the importance of avoiding pregnancy during trial participation and the potential risk factors for an unintentional pregnancy. In addition, men enrolled on this study should understand the risks to any sexual partner of childbearing potential and should practice an effective method of birth control. All WOCBP MUST have a negative pregnancy test within 3 weeks prior to registration (confirmed within 7 days prior to first receiving investigational product). If the pregnancy test is positive, the patient must not receive investigational product and must not be enrolled in the study. In addition, all WOCBP should be instructed to contact the Investigator immediately if they suspect they might be pregnant (eg, missed or late menstrual period) at any time during study participation. The Investigator must immediately notify BMS in the event of a confirmed pregnancy in a patient participating in the study. Has signed a Patient Informed Consent Form Has signed a Patient Authorization Form Exclusion Criteria: A patient will be excluded from this study if s/he meets any of the following criteria: Has another disease similar to one being studied (ie, colon cancer) Has evidence of distant metastases by radiographic staging Has had prior treatment for the current disease Has had prior stem cell or bone marrow transplant or any organ transplant with the exception of corneal transplant or cadaver bone graft Has a history of hypersensitivity to any of study treatments Has had a prior severe infusion reaction to a monoclonal antibody Has received prior therapy, at any time, which specifically and directly targets the EGFR pathway Has a significant history of uncontrolled cardiac disease; ie, uncontrolled hypertension, unstable angina, recent myocardial infarction (within prior 6 months), uncontrolled congestive heart failure, or cardiomyopathy with decreased ejection fraction Has evidence of CNS involvement (CNS imaging is not required for study enrollment unless clinically suspected CNS disease is present.) Has a serious uncontrolled intercurrent medical or psychiatric illness, including serious infection or Gilbert's Syndrome Has a history of other malignancy within the last 5 years (except cured basal cell carcinoma of skin and carcinoma in situ of uterine cervix), which could affect the diagnosis or assessment of any of the study drugs. Patients, who have received prior radiotherapy to any regional site other than the pelvis, as long as all other inclusion criteria are met, could be considered for enrollment after discussion with Dr. McCollum. Is a pregnant or nursing woman Is unable to comply with requirements of study

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Chemoradiotherapy plus Cetuximab<br>Pelvic irradiation plus 5-fluorouracil plus cetuximab | Drug: Cetuximab<br> <br> * Other names: Erbitux;Drug: 5-fluorouracil<br> <br> * Other names: 5-FU;Radiation: Pelvic irradiation<br> <br> * Other names: Radiotherapy;|
| Active Comparator: Chemoradiotherapy alone<br>Pelvic irradiation plus 5-fluorouracil | Drug: 5-fluorouracil<br> <br> * Other names: 5-FU;Radiation: Pelvic irradiation<br> <br> * Other names: Radiotherapy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Pathologic Response Rate (pCR) With 95% Confidence Interval. | A pathologic complete response (pCR) is defined as no pathologic evidence of invasive disease at the primary site in the bowel wall or in examined mesorectal tissue and/or lymph nodes. | 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To Determine Objective Response Rate (ORR) Based on RECIST Local Recurrence-free Survival in These Patient Groups; Overall and Recurrence-free Survival in These Cohorts. | Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of the LD of target lesions taking as reference the baseline sum LD. | 5 years | 
| 5- Year Overall Survival (OS) Rate | Overall survival is measured from the date of randomization to the date of death for a dead patient. If a patient is still alive or is lost to follow up, the patient will be censored at the date of last contact. | 5 years | 
| Recurrence-free Survival (RFS) Rate at 5 Years | RFS is measured from the date of randomization to the date of first documented disease recurrence or date of death, whichever comes first. If a patient neither recurrences nor dies, this patient will be censored at the date of last contact. | 5 years | 
| KRAS Mutation Rate | Percentage of Participants with KRAS mutation. | 5 years |