Cetuximab, 5-FU and Radiation as Neoadjuvant Therapy for Patients With Locally Advanced Rectal Cancer

Study Overview
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Brief Summary
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The standard treatment for rectal cancer is to receive the chemotherapeutic drug 5-fluorouracil (5-FU) with radiation therapy before having surgery to remove the rectal cancer. This is known as neoadjuvant chemoradiotherapy. The purpose of this research study is to determine if Cetuximab improves the benefits of neoadjuvant chemoradiotherapy when given with 5-FU and radiation therapy.

Detailed Description
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The epidermal growth factor receptor (EGFR) present in normal and tumor cells is involved in signaling pathways affecting cellular growth, differentiation, proliferation and programmed cell death. Overexpression of EGFR has been associated with poorer prognosis in colorectal cancer. Cetuximab targets and blocks EGFR and has been shown to be safe and effective in treating colorectal cancer and head and neck cancers. The primary hypothesis is that cetuximab in combination with standard 5-FU and radiation as neoadjuvant therapy would improve pathological complete response (pCR) compared to the historical rate (30% versus 10%). The regimen would be considered promising if 5 or more of 25 evaluable participants achieve pCR. The probability of observing this outcome is 0.91 and 0.10 if the true pCR rate is 30% and 10%, respectively.

Official Title
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Phase II Study of Cetuximab, 5-FU and Radiation as Neoadjuvant Therapy for Patients With Locally Advanced Rectal Cancer

Conditions
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Rectal Cancer

Intervention / Treatment
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* Drug: Cetuximab
* Drug: 5-Fluorouracil
* Radiation: Radiation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed adenocarcinoma of the rectum that begins within 15cm of the anal verge as determined by sigmoidoscopy and/or colonoscopy, with no evidence of distant metastatic disease. A complete colonoscopy to the cecum is recommended prior to initiating protocol therapy. Staging with transrectal ultrasound or endorectal coil Magnetic resonance imaging (MRI) to confirm clinical stage of T3 or T4 or lymph node positive rectal adenocarcinoma Tumor is K-ras wildtype by method of choice at respective institution (testing codons 12 and 13) Performance status: Eastern Cooperative Oncology Group Performance Score (ECOG PS) less than or equal to 2 18 years of age or older No evidence of metastatic disease by abdominal/pelvic (Computed tomography) CT and chest imaging Adequate bone marrow, renal,and hepatic function as outlined in protocol All patients will be evaluated by a surgeon and considered a candidate for definitive surgery Coumadin or heparin management for line care of other indications is permitted. The International Normalised Ratio (INR) will be monitored weekly in patients taking coumadin. Exclusion Criteria: Prior treatment for this malignancy Prior history of pelvic radiation therapy Prior history of 5-FU based or EGFR receptor inhibitor therapy Prior history of an allergic reaction to a monoclonal antibody Uncontrolled serious medical or psychiatric illness Significant history of uncontrolled cardiac disease Sexually active women of childbearing potential must use an effective method of birth control during the course of the study Unwilling to agree to pre and post-cetuximab sigmoidoscopy and biopsy

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cetuximab, 5-FU and Radiation<br>Cetuximab: Participants first receive cetuximab at the initial dose of 400 mg/m2 intravenously (IV) administered over 120 minutes, followed by weekly infusions at 250 mg/m2 over 60 minutes. Cetuximab is given as single agent during the first 3 weeks on study and then in combination with 5-FU and radiation. Radiation: Radiation therapy given as standard of care is initiated after the 3rd dose of cetuximab with a total dose of 50.4 Gray (Gy) in 28 fractions over approximately 5.5 weeks. 5-FU: Participants receive 5-Fluorouracil (5-FU) continuous infusion through central venous access at 225 mg/m2/day given 7 days a week starting day 1 of radiation (no later than 3 days) and lasting the duration of radiation therapy. Duration of neoadjuvant therapy is estimated to be 9 weeks. Surgery follows at week 13-17. Sigmoidoscopy is performed for biopsy prior to the 1st dose and after 3rd dose of cetuximab before the initiation of radiation and/or 5-FU. | Drug: Cetuximab<br> <br> * Other names: Erbitux;Drug: 5-Fluorouracil<br> <br> * Other names: 5-FU;Radiation: Radiation<br> <br> * Other names: External Beam Radiation Therapy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathological Complete Response Rate | Pathological complete response (pCR) rate is the percentage of participants who achieve pCR defined as no evidence of tumor cells in the surgical specimen including the lymph nodes (down-staging to pathological T0, N0 after planned neoadjuvant therapy). | Disease is assessed at the time of surgery which in this study cohort occurred up to 24 weeks from date of registration. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Local Recurrence Rate | Local recurrence rate is the percentage of participants experiencing recurrence within the pelvis. | CT scans for surveillance recommended yearly x 3 years from date of surgery with additional scanning at discretion of treating oncologist. Mean follow-up for this study cohort was 4.4 years from study entry, up to 7.9 years. | 
| Complete Resection Rate | Complete resection rate is the percentage of participants having all gross disease removed by the surgeon at the time of operation. | Disease is assessed at the time of surgery which in this study cohort occurred up to 24 weeks from date of registration. | 
| Distant Recurrence Rate | Distant recurrence rate is the percentage of participants experiencing recurrence outside the pelvis. | CT scans for surveillance recommended yearly x 3 years from date of surgery with additional scanning at discretion of treating oncologist. Mean follow-up for this study cohort was 4.4 years from study entry, up to 7.9 years. | 
| Incidence of Grade 4 Treatment-Related Toxicity | All grade 4 adverse events (AE) with treatment attribution of possibly, probably or definite based on NCI Common Toxicity Criteria for Adverse Events version 3 (CTCAEv3) as reported on case report forms were counted. Incidence is the number of patients experiencing at least one treatment-related grade 4 AE of any type during the time of observation. | Disease is assessed through the time of surgery which in this study cohort occurred up to 24 weeks from date of registration. | 
| 1-Year Overall Survival Rate | 1-year overall survival is the percentage of participants remaining alive 1 year from study entry. | Mean follow-up for this study cohort was 4.4 years from study entry, up to 7.9 years. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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5-FU, cetuximab, radiation, adenocarcinoma of the rectum, neoadjuvant therapy