5-FU, Aflibercept, and Radiation (RT) for Preoperative and Postoperative Patients With Stage II/III Rectal Cancer

Phase 2

Completed

• Conditions: Rectal Cancer
• Interventions: Radiation: Radiation; Drug: Aflibercept; Procedure: Surgery; Drug: FOLFOX6

• Registration Number: NCT01749956
• Lead Sponsor: SCRI Development Innovations, LLC

Brief Summary

The purpose of this Phase II study will be to investigate the antiangiogenic agent, aflibercept, in combination with chemoradiation as preoperative treatment for patients with stage II/III rectal cancer, followed by 4 months of FOLFOX6 plus aflibercept adjuvantly.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2012-12-12
• Study First Submitted QC: 2012-12-14
• Study First Posted: 2012-12-17
• Study Start: 2013-01
• Primary Completion: 2015-09
• Study Completion: 2015-09
• Results First Submitted: 2016-10-14
• Status Verified: 2016-12
• Results First Submitted QC: 2016-12-13
• Last Update Submitted: 2016-12-13
• Results First Posted: 2017-02-07
• Last Update Posted: 2017-02-07

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 39

Inclusion Criteria

1. Patients with histologically confirmed stage II or III rectal cancer (adenocarcinoma)
2. Patients must be candidates for preoperative chemoradiation
3. Male or female patients ≥18 years-of-age
4. Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0 or 1
5. Adequate hematologic, liver and renal function
6. Male patients willing to use adequate contraceptive measures
7. Female patients who are not of child-bearing potential, and female patients of child-bearing potential who agree to use adequate contraceptive measures, who are not breastfeeding, and who have a negative serum or urine pregnancy test <7 days prior to start of treatment
8. Life expectancy ≥12 weeks
9. Willingness and ability to comply with the trial and follow-up procedures
10. Ability to understand the nature of this trial and give written informed consent.

Exclusion Criteria

1. Treatment with prior chemotherapy or radiation for rectal cancer.
2. Patients who have received any other investigational agents within the 28 days prior to Day 1 of the study.
3. Known to be human immunodeficiency virus positive or hepatitis B or C positive
4. Women who are pregnant or breastfeeding
5. History of acute myocardial infarction within the previous 6 months, uncontrolled hypertension (blood pressure >150/100 mmHg and/or diastolic blood pressure >100 mmHg), unstable angina, New York Heart Association Grade 2 or greater congestive heart failure, serious cardiac arrhythmia requiring medication (excluding atrial fibrillation), or ≥ Grade 2 peripheral vascular disease.
6. History of hypertensive crisis or hypertensive encephalopathy.
7. History of stroke or transient ischemic attack within the past 6 months.
8. Significant vascular disease (eg, aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to initiation of therapy.
9. History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 6 months.
10. Patients with symptomatic sensory or peripheral neuropathy (Grade 2 or above).
11. Patients may not have received other agents, either investigational or marketed, that act by primary anti-angiogenic mechanisms.
12. Prior malignancy (except for adequately treated basal-cell or squamous-cell skin cancers, in situ carcinomas, or low grade [Gleason score of 3+3 or less] localized prostate cancer) in the past 5 years.
13. Patients with active concurrent infections or patients with serious underlying medical conditions.
14. Patients receiving full-dose oral or parenteral/SC anticoagulation must be on a stable dosing schedule prior to enrollment; a coumadin dose must be stable for 1 week. If this cannot be achieved, the patient will be ineligible for enrollment.
15. Major surgical procedure or significant traumatic injury within 28 days prior to study initiation, or anticipation of need for major surgical procedure during the course of the study.
16. Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to initiation of therapy.
17. Patients with proteinuria, as demonstrated by a urine protein of 2+ or greater at screening. If 2+ or greater proteinuria, a 24-hour urine can be obtained, and if the result is <1 gm/24 hours, the patient is eligible.
18. Any non-healing wound, ulcer, or bone fracture.
19. Any clinical evidence or history of a bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation).
20. History of hemoptysis (≥½ teaspoon of bright red blood per episode) within 1 month prior to initiation of therapy.
21. History of any other disease, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates use of an investigational drug or that might affect interpretation of the

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
FOLFOX6/Aflibercept/Radiation/Surgery	Radiation	Preoperative Chemoradiation: (6 weeks) * 5-FU: 225 mg/m2 per day by intravenous continuous infusion (IVCI), Days 1 thru 42; * Radiation: 50.4 Gy (1.8 Gy/day or 28 fractions) Mon thru Fri, Weeks 1 thru 6; * Aflibercept: 4 mg/ kg, via IV infusion, Days 1 and 15. Surgery at least 6 weeks after last day of aflibercept: Patients will undergo abdominoperineal or low anterior resection with total mesorectal excision, per standard treatment guidelines. Postoperative Chemotherapy and Aflibercept Treatments (four 28-day cycles): * Aflibercept (administered first): 4 mg/kg IV for approximately 1 hour (no more than 2 hours) on Days 1 and 15 of each cycle. * Modified FOLFOX6: * Leucovorin: 400 mg/m2 as a 2-hour infusion prior to 5-FU on Days 1 and 15 of each cycle. * Oxaliplatin: 85 mg/m2 IV as a 2-hour infusion prior to 5-FU on Days 1 and 15 of each cycle. * 5-FU: 400-mg/m2 bolus for 2 to 4 minutes followed by 2400 mg/m2 for 46 hours on Days 1 and 15 of each cycle.
FOLFOX6/Aflibercept/Radiation/Surgery	Surgery	Preoperative Chemoradiation: (6 weeks) * 5-FU: 225 mg/m2 per day by intravenous continuous infusion (IVCI), Days 1 thru 42; * Radiation: 50.4 Gy (1.8 Gy/day or 28 fractions) Mon thru Fri, Weeks 1 thru 6; * Aflibercept: 4 mg/ kg, via IV infusion, Days 1 and 15. Surgery at least 6 weeks after last day of aflibercept: Patients will undergo abdominoperineal or low anterior resection with total mesorectal excision, per standard treatment guidelines. Postoperative Chemotherapy and Aflibercept Treatments (four 28-day cycles): * Aflibercept (administered first): 4 mg/kg IV for approximately 1 hour (no more than 2 hours) on Days 1 and 15 of each cycle. * Modified FOLFOX6: * Leucovorin: 400 mg/m2 as a 2-hour infusion prior to 5-FU on Days 1 and 15 of each cycle. * Oxaliplatin: 85 mg/m2 IV as a 2-hour infusion prior to 5-FU on Days 1 and 15 of each cycle. * 5-FU: 400-mg/m2 bolus for 2 to 4 minutes followed by 2400 mg/m2 for 46 hours on Days 1 and 15 of each cycle.
FOLFOX6/Aflibercept/Radiation/Surgery	FOLFOX6	Preoperative Chemoradiation: (6 weeks) * 5-FU: 225 mg/m2 per day by intravenous continuous infusion (IVCI), Days 1 thru 42; * Radiation: 50.4 Gy (1.8 Gy/day or 28 fractions) Mon thru Fri, Weeks 1 thru 6; * Aflibercept: 4 mg/ kg, via IV infusion, Days 1 and 15. Surgery at least 6 weeks after last day of aflibercept: Patients will undergo abdominoperineal or low anterior resection with total mesorectal excision, per standard treatment guidelines. Postoperative Chemotherapy and Aflibercept Treatments (four 28-day cycles): * Aflibercept (administered first): 4 mg/kg IV for approximately 1 hour (no more than 2 hours) on Days 1 and 15 of each cycle. * Modified FOLFOX6: * Leucovorin: 400 mg/m2 as a 2-hour infusion prior to 5-FU on Days 1 and 15 of each cycle. * Oxaliplatin: 85 mg/m2 IV as a 2-hour infusion prior to 5-FU on Days 1 and 15 of each cycle. * 5-FU: 400-mg/m2 bolus for 2 to 4 minutes followed by 2400 mg/m2 for 46 hours on Days 1 and 15 of each cycle.
FOLFOX6/Aflibercept/Radiation/Surgery	Aflibercept	Preoperative Chemoradiation: (6 weeks) * 5-FU: 225 mg/m2 per day by intravenous continuous infusion (IVCI), Days 1 thru 42; * Radiation: 50.4 Gy (1.8 Gy/day or 28 fractions) Mon thru Fri, Weeks 1 thru 6; * Aflibercept: 4 mg/ kg, via IV infusion, Days 1 and 15. Surgery at least 6 weeks after last day of aflibercept: Patients will undergo abdominoperineal or low anterior resection with total mesorectal excision, per standard treatment guidelines. Postoperative Chemotherapy and Aflibercept Treatments (four 28-day cycles): * Aflibercept (administered first): 4 mg/kg IV for approximately 1 hour (no more than 2 hours) on Days 1 and 15 of each cycle. * Modified FOLFOX6: * Leucovorin: 400 mg/m2 as a 2-hour infusion prior to 5-FU on Days 1 and 15 of each cycle. * Oxaliplatin: 85 mg/m2 IV as a 2-hour infusion prior to 5-FU on Days 1 and 15 of each cycle. * 5-FU: 400-mg/m2 bolus for 2 to 4 minutes followed by 2400 mg/m2 for 46 hours on Days 1 and 15 of each cycle.

Primary Outcome Measures

Name	Time	Method
Pathologic Complete Response Rate	Between days 57 and 98 after preoperative chemotherapy	The Pathologic Complete Response (pCR) Rate is defined as the number of pathologic complete responders among all patients evaluable for response, including evaluable patients who did not proceed to surgery. A pCR is defined as the absence of any residual abnormality detected in a pathological specimen.

Secondary Outcome Measures

Name	Time	Method
Overall Survival Probability at 6 and 12 Months	up to 1 year	The probability of overall survival at 6 months and 12 months from date of first protocol treatment until date of death.
Sphincter Preservation Rate	Between days 57 and 98 after preoperative chemotherapy.	The percentage of patients who had Low Anterior Resection during surgery..
Disease Free Survival Probability at 6 and 12 Months	Up to 1 year	The probability of disease free survival at 6 and 12 months after initiating protocol treatment.
Overall Survival	Every 3 months (±1 month) following documented progression, up to 5 years or death, whichever comes first.	Measured from date of first protocol treatment until date of death.
The Number of Participants Who Experienced Serious or Non-Serious Adverse Events as a Measure of Safety.	weekly for 6 weeks pre-op then every 2 weeks post-op, approximately 36 weeks	Adverse events and serious adverse events (AEs and SAEs) were graded according to National Cancer Institute Common Technology Criteria for Adverse Events (NCI CTCAE) v4.0. Specific AE and SAE terms are provided in the Adverse Event module.
Disease-Free Survival	Patients without evidence of progression will be followed every 3 months (±1 month) from date of last dose of study drug during Years 1-2, every 6 months during Years 3-4, and annually thereafter or until disease progression, estimated 5 years.

Trial Locations

Locations (10)

Virginia Cancer Institute; 🇺🇸 Richmond, Virginia, United States

Baptist Hospital East; 🇺🇸 Louisville, Kentucky, United States

Space Coast Cancer Center; 🇺🇸 Titusville, Florida, United States

Florida Cancer Specialists; 🇺🇸 St. Petersburg, Florida, United States

Oncology Hematology Care, Inc.; 🇺🇸 Cincinnati, Ohio, United States

Oklahoma University; 🇺🇸 Oklahoma City, Oklahoma, United States

South Carolina Oncology Associates; 🇺🇸 Columbia, South Carolina, United States

Tennessee Oncology - Chattanooga; 🇺🇸 Chattanooga, Tennessee, United States

Tennessee Oncology, PLLC; 🇺🇸 Nashville, Tennessee, United States

Woodlands Medical Specialists; 🇺🇸 Pensacola, Florida, United States