Bevacizumab, Erlotinib and 5-Fluorouracil With External Beam Radiation Therapy in Locally Advanced Rectal Cancer

Study Overview
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Brief Summary
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The purpose of this study is determine the safety of 5-fluorouracil, bevacizumab and erlotinib when administered in combination with external beam radiation therapy(Phase I portion) as well as to begin to collect information about whether this combination treatment is effective in treating(Phase II portion) patients with locally advanced rectal cancer.

Detailed Description
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All participants will receive the following drugs: 5-fluorouracil (5-FU) given as a continuous 24-hour infusion; Bevacizumab given intravenously; erlotinib given orally at home. In the Phase I portion, we are looking for the highest dose of erlotinib that can be given safely in combination with the 5-FU, bevacizumab and radiation therapy. Therefore the dose of erlotinib may not be the same for each participant. The dose will increase until we find the highest dose without causing serious or unmanageable side effects. Study treatment is given as an outpatient and consists of 14 day cycles with a total of 3 cycles. Patients will be given all three study drugs and radiation therapy on a monday (unless a monday falls on on a holiday). This will be day 1 of the first treatment cycle. 5-FU is given continuously days 1-14. Bevacizumab is given on day 1. Erlotinib will be given on days 1-14. Radiation therapy will be performed on Days 1-5 and 8-12. The following tests and procedures will be performed weekly while participants are receiving study treatment: physical examination, measurement of vital signs, height and weight; performance status; blood work, urine sample. At the end of treatment the following tests will be performed: physical examination and measurement of vital signs; performance status; blood work; CT scans of chest, abdomen and pelvis. Patients will also be evaluated for surgery at this time. Patients will be followed every three months for the first three years after surgery, then every 6 months for the next two years.

Official Title
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A Phase I/II Study of Bevacizumab, Erlotinib and 5-fluorouracil With Concurrent External Beam Radiation Therapy in Locally Advanced Rectal Cancer

Conditions
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Rectal Cancer, Adenocarcinoma of the Rectum

Intervention / Treatment
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* Drug: 5-fluorouracil
* Drug: bevacizumab
* Drug: erlotinib
* Procedure: External beam radiation therapy (EBRT)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed primary adenocarcinoma of the rectum that begins within 15cm of the anal verge as determined by sigmoidoscopy or colonoscopy Clinical T3 or T4 tumors as determined by endoscopic ultrasound and/or rectal MRI ECOG performance status of 0-2 18 years of age or older Creatinine of < 2.0 Adequate hepatic function Adequate hematopoietic function Use of effective means of contraception in subjects of child-bearing potential Exclusion Criteria: Evidence of metastatic disease as determined by chest/abdominal/pelvic CT or physical exam Prior chemotherapy or radiation therapy for treatment of colorectal cancer Prior treatment with 5-FU Prior treatment with a tyrosine kinase inhibitor, EGFR inhibitor, or VEGF inhibitor Patients must not be receiving any other investigational agent Prior malignancy within the last 5 years except for completely excised skin cancer, in situ cervical cancer Warfarin anticoagulation Co-existent malignant disease Current or recent participation in a clinical trial (within 4 weeks from the first day of treatment) Pregnancy Blood pressure of >150/100 mmHg Unstable angina NYHA Grade II or greater congestive heart failure History of myocardial infarction within 6 months History of stroke within 6 months Clinically significant peripheral vascular disease Evidence of bleeding diathesis or coagulopathy Presence of central nervous system or brain metastases Major surgical procedure, open biopsy, or significant trauma injury within 28 days prior to day 0, anticipation of need for major surgical procedure during the course of the study Minor surgical procedures, fine needle aspirations or core biopsies within 7 days prior to day 0 Pregnant or lactating Urine protein:creatinine ratio > or equal to one at screening History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to day 0] Serious, non-healing wound, ulcer, or bone fracture

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: Chemotherapy and radiation<br>Continuous infusion 5-fluorouracil 225 mg/M2/d, bevacizumab 5 mg/kg IV q 14 days, erlotinib 50-150 mg orally daily for duration of radiation. | Drug: 5-fluorouracil<br>* Given as a 24-hour infusion on days 1-14 of each 14-day cycle for a total of 3 cycles.<br>Drug: bevacizumab<br>* Given intravenously on day 1 of each 14-day cycle for a total of 3 cycles.<br>Drug: erlotinib<br>* Taken orally on days 1-14 of each 14-day cycle for a total of 3 cycles.<br>Procedure: External beam radiation therapy (EBRT)<br>* Given on days 1-5 and 8-12<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) of Erlotinib When Administered in Combination With 5-fluorouracil (5-FU), Bevacizumab, and External Beam Radiation Therapy | MTD of Erlotinib was determined using a traditional 3 + 3 dose escalation scheme of three dose levels (50,100,150mg). Successive cohorts of 3-6 patients were enrolled into dose escalation cohorts for 14 day cycles. MTD reflects the highest dose of Erlotinib that had ≤1 out of 6 patients with Dose-Limiting Toxicity (DLT) at the highest dose level below the maximally administered dose. The maximally administered dose is the first dose that causes DLT in >33% of patients. DLT was defined as: Any grade 4 neutropenia, Any grade 3 thrombocytopenia, or Any ≥ grade 3 non-hematologic toxicity that results in greater than 7 days interruption in therapy. | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Summary of Grade 3 or Greater Toxicity | Summary of grade 3 or greater toxicity by grade and type. All adverse events were evaluated using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. Grade 3: Severe or medically significant but not immediately life threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care activities of daily living. Grade 4 Life-threatening consequences; urgent intervention indicated. | 3 years | 
| Percentage of Participants With Disease-free Survival | Summary of disease free survival at 1, 2, and 3 years. Disease free survival is the length of time after primary treatment for cancer ends that the participant survives without any clinical signs or symptoms of that cancer. The data is shown of the percentage of participants still in disease free survival at one, two, and three years. | 1, 2, 3 years | 
| Post-operative Complications After Resection of Rectal Cancers Following Preoperative 5-FU, Bevacizumab, Erlotinib, and External Beam Radiation Therapy. | Surgical morbidity following R0 resection with one of the following procedures: abdominal perineal resection, low anterior resection, and low anterior resection with coloanal anastomosis. | 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Fluorouracil, bevacizumab, erlotinib, external beam radiation therapy, EBRT