5-Fluorouracil, Bevacizumab, and Radiation Followed by Modified FOLFOX6 and Bevacizumab in Stage II/III Rectal Cancer

Study Overview
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Brief Summary
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This phase II trial will investigate the combination of adjuvant 5-fluorouracil, radiation, and bevacizumab in patients with stage II and III rectal cancer, followed by FOLFOX6 and bevacizumab. Fluorouracil (FU) has proven to be an effective and safe regimen in the treatment of stage II and III rectal cancer. Recent evidence has proven fluorouracil/leucovorin (FL) in combination with bevacizumab is superior to FL alone and when combined with irinotecan is superior to (irinotecan plus fluorouracil/leucovorin (IFL) alone. This trial will be one of the first clinical trials to evaluate a combination of targeted therapy, radiation, and chemotherapy in the adjuvant treatment of a common solid tumor.

Detailed Description
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All eligible patients will receive combined modality treatment initially. Systemic treatment will begin 4-6 weeks after completion of the Combined Modality portion and will complete 4 cycles of a 4 week regimen. Patients with no evidence of disease following systemic therapy may continue single agent bevacizumab for up to one year. After all treatment is completed, patients will be re-evaluated with imaging to establish a new baseline. Patients will be re-evaluated thereafter for up to a total of 5 years. Combined Modality Treatment: bevacizumab 5mg/kg IV infusion days 1, 15, and 29 fluorouracil 225mg/m2 IV continuous infusion days 1-42 radiation 1.8 Gy/day or 28 fractions weeks 1-6 Systemic Treatment: 5-fluorouracil 400 mg/m2 bolus 5-fluorouracil 2400 mg/m2 over 46 hours days 1 and 15 leucovorin 350 mg prior to FU on days 1 and 15 oxaliplatin 85 mg/m2 days 1 and 15 bevacizumab 5 mg/kg days 1 and 15

Official Title
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A Phase II Study of 5-Fluorouracil, Bevacizumab (Avastin), and Radiation in the Preoperative or Adjuvant Treatment of Patients With Stage II / III Rectal Cancer

Conditions
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Rectal Cancer, Cancer of the Rectum, Colorectal Cancer

Intervention / Treatment
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* Drug: 5-Fluorouracil
* Drug: Bevacizumab
* Procedure: Radiation Therapy
* Drug: Oxaliplatin
* Drug: Leucovorin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed Stage I or II rectal cancer Patients must be candidates for preoperative or adjuvant chemoradiation. Patients enrolling in the adjuvant chemoradiation cohort must have undergone surgical resection of the primary rectal tumor between 28 and 56 days (i.e., 4-8 weeks) prior to study treatment. ECOG performance status 0-1 Adequate bone marrow, liver, and kidney function At least 18 years of age Able to give written informed consent Exclusion Criteria: Treatment with prior chemotherapy or radiation for rectal cancer History of myocardial infarction Uncontrolled hypertension, unstable angina, congestive heart failure, serious cardiac arrhythmia requiring medication or peripheral vascular disease History of stroke within 6 months History of abdominal fistula, gastrointestinal perforation, or intrabdominal abscess within 6 months Symptomatic sensory or peripheral neuropathy Prior treatment with anti-angiogenic agents Prior malignancy in the past 5 years Active infections or serious underlying medical condition Major surgery less than 28 days prior Women who are pregnant or lactating Thrombolytic therapy within 10 days of starting bevacizumab PEG tube, G-tube, or external biliary stents Proteinuria Non healing wound, ulcer or fracture History of bleeding diathesis or coagulopathy Hemoptysis Participation in another experimental trial within 28 days Uncontrolled anticoagulant therapy

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort A - Preoperative<br>Each patient enrolled in the preoperative cohort received 5-fluorouracil (5-FU) 225 mg/m2 as a continuous infusion (IVCI) on days 1-42 through a portable infusion pump and central venous catheter. Bevacizumab 5 mg/kg was administered intravenously (IV) on days 1 and 15. Additionally these patients received radiation therapy to 50.4 Gy (1.8 Gy/day or 28 fractions) Monday through Friday during weeks 1-6. At least 8 weeks after surgery, patients in cohort A began 4 months of chemotherapy and bevacizumab. This adjuvant treatment consisted of 5-FU 400 mg/m2 IV bolus over 2-4 minutes followed by 2400 mg/m2 IVCI over 46 hours, leucovorin 350 mg as a 2-hour infusion, oxaliplatin 85 mg/m2 IV (modified FOLFOX6) and bevacizumab 5 mg/kg IV all on days 1 and 15 of each cycle. | Drug: 5-Fluorouracil<br>* Combined Modality Treatment: fluorouracil 225mg/m2 IV continuous infusion days 1-42 Systemic Treatment: 5-fluorouracil 400 mg/m2 bolus 5-fluorouracil 2400 mg/m2 over 46 hours days 1 and 15<br>* Other names: 5-FU;Drug: Bevacizumab<br>* Combined Modality Treatment: bevacizumab 5mg/kg IV infusion days 1, 15, and 29 Systemic Treatment: bevacizumab 5 mg/kg days 1 and 15<br>* Other names: Avastin;Procedure: Radiation Therapy<br>* radiation 1.8 Gy/day or 28 fractions weeks 1-6<br>Drug: Oxaliplatin<br>* Systemic Treatment: oxaliplatin 85 mg/m2 days 1 and 15<br>* Other names: Eloxatin;Drug: Leucovorin<br>* Systemic Treatment: leucovorin 350 mg prior to FU on days 1 and 15<br>* Other names: Folinic acid;|
| Experimental: Cohort B - Combined Modality<br>All patients enrolled in cohort B received 5-fluorouracil (5-FU) 225 mg/m2 IVCI on days 1-42. Bevacizumab was administered at 5 mg/kg IV on day 1 every 2 weeks. These patients also received radiation to 50.4 Gy (1.8 Gy/day or 28 fractions)Monday through Friday during weeks 1-6. Six weeks after the completion of adjuvant 5-FU/radiation, patients began treatment with 5-FU 400 mg/m2 IV bolus over 2-4 minutes followed by 2400 mg/m2 IVCI over 46 hours, leucovorin 350 mg as a 2-hour infusion, oxaliplatin 85 mg/m2 IV (modified FOLFOX6) and bevacizumab 5 mg/kg IV all on days 1 and 15 of each cycle. | Drug: 5-Fluorouracil<br>* Combined Modality Treatment: fluorouracil 225mg/m2 IV continuous infusion days 1-42 Systemic Treatment: 5-fluorouracil 400 mg/m2 bolus 5-fluorouracil 2400 mg/m2 over 46 hours days 1 and 15<br>* Other names: 5-FU;Drug: Bevacizumab<br>* Combined Modality Treatment: bevacizumab 5mg/kg IV infusion days 1, 15, and 29 Systemic Treatment: bevacizumab 5 mg/kg days 1 and 15<br>* Other names: Avastin;Procedure: Radiation Therapy<br>* radiation 1.8 Gy/day or 28 fractions weeks 1-6<br>Drug: Oxaliplatin<br>* Systemic Treatment: oxaliplatin 85 mg/m2 days 1 and 15<br>* Other names: Eloxatin;Drug: Leucovorin<br>* Systemic Treatment: leucovorin 350 mg prior to FU on days 1 and 15<br>* Other names: Folinic acid;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease-Free Survival (DFS), The Proportion of Patients Predicted to be Alive Without Evidence of Disease Recurrence 24 Months After Completion of Protocol Treatment | The Proportion of Patients Predicted to be Alive Without Evidence of Disease Recurrence 24 Months After Completion of Protocol Treatment | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS), the Length of Time, in Months, That Patients Were Alive From Their First Date of Protocol Treatment Until Death | Overall Survival (OS) is defined ad the Length of time, in months, that patients were alive from their first date of protocol treatment until death. | 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cancer of the Rectum, Rectal Cancer, Colorectal Cancer, Bevacizumab