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

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

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.

Study Overview

• Status: Completed
• Conditions: Colorectal Cancer; Rectal Cancer; Cancer of the Rectum
• Intervention / Treatment: Drug: 5-Fluorouracil; Drug: Bevacizumab; Procedure: Radiation Therapy; Drug: Oxaliplatin; Drug: Leucovorin

Detailed Description

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

• Study Type: Interventional
• Enrollment (Actual): 66
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Anniston, Alabama, United States, 36207
      • Northeast Alabama Regional Medical Center
  • Arkansas
    • Jonesboro, Arkansas, United States, 72401
      • Northeast Arkansas Clinic
  • Florida
    • Fort Myers, Florida, United States, 33901
      • Florida Cancer Specialists
    • Jacksonville, Florida, United States, 32256
      • Integrated Community Oncology Network
    • Lakeland, Florida, United States, 33805
      • Watson Clinic Center for Cancer Care and Research
  • Georgia
    • Gainesville, Georgia, United States, 30501
      • Northeast Georgia Medical Center
    • Marietta, Georgia, United States, 30060
      • Wellstar Cancer Research
  • Kentucky
    • Louisville, Kentucky, United States, 40207
      • Consultants in Blood Disorders and Cancer
  • Pennsylvania
    • Drexel Hill, Pennsylvania, United States, 19026
      • Consultants in Medical Oncology and Hematology
  • South Carolina
    • Spartanburg, South Carolina, United States, 29303
      • Spartanburg Regional Medical Center
  • Tennessee
    • Chattanooga, Tennessee, United States, 37404
      • Chattanooga Oncology Hematology Associates
    • Nashville, Tennessee, United States, 37205
      • Tennessee Oncology
  • Texas
    • San Antonio, Texas, United States, 78258
      • South Texas Oncology And Hematology
  • Virginia
    • Newport News, Virginia, United States, 23601
      • Peninsula Cancer Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Cohort A - Preoperative; 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; 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; Other Names: 5-FU; Fluorouracil; Efudex; Drug: Bevacizumab; Combined Modality Treatment: bevacizumab 5mg/kg IV infusion days 1, 15, and 29 Systemic Treatment: bevacizumab 5 mg/kg days 1 and 15; Other Names: Avastin; Procedure: Radiation Therapy; radiation 1.8 Gy/day or 28 fractions weeks 1-6; Drug: Oxaliplatin; Systemic Treatment: oxaliplatin 85 mg/m2 days 1 and 15; Other Names: Eloxatin; Drug: Leucovorin; Systemic Treatment: leucovorin 350 mg prior to FU on days 1 and 15; Other Names: Folinic acid
EXPERIMENTAL: Cohort B - Combined Modality; 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; 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; Other Names: 5-FU; Fluorouracil; Efudex; Drug: Bevacizumab; Combined Modality Treatment: bevacizumab 5mg/kg IV infusion days 1, 15, and 29 Systemic Treatment: bevacizumab 5 mg/kg days 1 and 15; Other Names: Avastin; Procedure: Radiation Therapy; radiation 1.8 Gy/day or 28 fractions weeks 1-6; Drug: Oxaliplatin; Systemic Treatment: oxaliplatin 85 mg/m2 days 1 and 15; Other Names: Eloxatin; Drug: Leucovorin; Systemic Treatment: leucovorin 350 mg prior to FU on days 1 and 15; Other Names: Folinic acid

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: SCRI Development Innovations, LLC
• Collaborators: Genentech, Inc.

Publications and helpful links

General Publications

• Spigel DR, Bendell JC, McCleod M, Shipley DL, Arrowsmith E, Barnes EK, Infante JR, Burris HA 3rd, Greco FA, Hainsworth JD. Phase II study of bevacizumab and chemoradiation in the preoperative or adjuvant treatment of patients with stage II/III rectal cancer. Clin Colorectal Cancer. 2012 Mar;11(1):45-52. doi: 10.1016/j.clcc.2011.04.002. Epub 2011 Aug 15.

Study record dates

Study Major Dates

• Study Start: March 1, 2006
• Primary Completion (ACTUAL): April 1, 2009
• Study Completion (ACTUAL): February 1, 2012

Study Registration Dates

• First Submitted: March 28, 2006
• First Submitted That Met QC Criteria: March 28, 2006
• First Posted (ESTIMATE): March 29, 2006

Study Record Updates

• Last Update Posted (ACTUAL): December 10, 2021
• Last Update Submitted That Met QC Criteria: November 11, 2021
• Last Verified: November 1, 2021

More Information

Terms related to this study

• Keywords: Bevacizumab; Colorectal Cancer; Rectal Cancer; Cancer of the Rectum
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Rectal Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protective Agents; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Micronutrients; Vitamins; Antidotes; Vitamin B Complex; Fluorouracil; Oxaliplatin; Bevacizumab; Leucovorin
• Other Study ID Numbers: SCRI GI 65; AVF3105s (OTHER: Genentech-Roche)