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

• Sponsor: SCRI Development Innovations, LLC (Other)
• Overall Status: Completed
• CT.gov ID: NCT01749956
• Collaborator: Sanofi (Industry)
• Enrollment: 39
• Locations: 11
• Arm: 1
• Duration (Months): 32
• Patients Per Site: 3.5
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Rectal Cancer	Radiation: Radiation; Drug: Aflibercept; Procedure: Surgery; Drug: FOLFOX6	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 39 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study of 5-Fluorouracil (5-FU), Aflibercept, and Radiation for the Preoperative and Adjuvant Treatment of Patients With Stage II/III Rectal Cancer
• Study Start Date: Jan 1, 2013
• Actual Primary Completion Date: Sep 1, 2015
• Actual Study Completion Date: Sep 1, 2015

Arms and Interventions

Arm

Intervention/Treatment

Experimental: FOLFOX6/Aflibercept/Radiation/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.

Radiation: Radiation; Drug: Aflibercept; Other Names: Eylea Zaltrap ; Procedure: Surgery; Abdominoperineal or low anterior resection with total mesorectal excision, per standard treatment guidelines; Drug: FOLFOX6; Other Names: Leucovorin (Folinic Acid) 5-Fluorouracil (5-FU; Efudex) Oxaliplatin (Eloxatin)

Outcome Measures

Primary Outcome Measures

1. 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

1. 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.

2. 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.

3. Sphincter Preservation Rate [Between days 57 and 98 after preoperative chemotherapy.]

   The percentage of patients who had Low Anterior Resection during surgery..

4. 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.]

5. 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.

6. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Florida Cancer Specialists	Fort Myers	Florida	United States	33916
2	Woodlands Medical Specialists	Pensacola	Florida	United States	32503
3	Florida Cancer Specialists	St. Petersburg	Florida	United States	33705
4	Space Coast Cancer Center	Titusville	Florida	United States	32796
5	Baptist Hospital East	Louisville	Kentucky	United States	40207
6	Oncology Hematology Care, Inc.	Cincinnati	Ohio	United States	45242
7	Oklahoma University	Oklahoma City	Oklahoma	United States	71304
8	South Carolina Oncology Associates	Columbia	South Carolina	United States	29210
9	Tennessee Oncology - Chattanooga	Chattanooga	Tennessee	United States	37404
10	Tennessee Oncology, PLLC	Nashville	Tennessee	United States	37203
11	Virginia Cancer Institute	Richmond	Virginia	United States	23230

Sponsors and Collaborators

• SCRI Development Innovations, LLC
• Sanofi

Investigators

• Study Chair: Johanna C Bendell, M.D., SCRI Development Innovations, LLC

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: SCRI Development Innovations, LLC
• ClinicalTrials.gov Identifier: NCT01749956
• Other Study ID Numbers: SCRI GI 168
• First Posted: Dec 17, 2012
• Last Update Posted: Feb 7, 2017
• Last Verified: Dec 1, 2016

• Keywords provided by SCRI Development Innovations, LLC: Rectal Cancer; Chemoradiation; Aflibercept; Surgery
• Additional relevant MeSH terms: Rectal Neoplasms; Leucovorin; Fluorouracil; Oxaliplatin; Aflibercept

Study Results

Participant Flow

Recruitment Details	Between January 2013 and July 2014, 39 patients with stage II or stage III rectal cancer were enrolled in the trial from multiple sites in the U.S.

Arm/Group Title	FOLFOX6/Aflibercept/Radation/Surgery
Arm/Group Description	Preoperative Chemoradiation (6 weeks): 5-FU: 225 mg/m2 per day by intravenous continuous infusion (IV), Days 1-42; Radiation: 50.4 Gy (1.8 Gy/day) Mon-Fri, Weeks 1 thru 6; Aflibercept: 4 mg/ kg, via IV infusion, Days 1 and 15. Surgery (6 weeks from last dose of aflibercep): abdominoperineal or low anterior resection with total mesorectal excision, per standard treatment guidelines. Postoperative Chemotherapy and Aflibercept: Aflibercept (administered first): 4 mg/kg IV for approximately 1 hour; Days 1 and 15 of each 28-day 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.
Period Title: Overall Study
STARTED	39
COMPLETED	24
NOT COMPLETED	15

Baseline Characteristics

Arm/Group Title	FOLFOX6/Aflibercept/Radation/Surgery
Arm/Group Description	Preoperative Chemoradiation (6 weeks) Surgery (6 weeks from last dose of aflibercept) Postoperative Chemotherapy and aflibercept (four 28-day cycles)
Overall Participants	39
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	60
Gender (Count of Participants)
Female	14 35.9%
Male	25 64.1%
Race/Ethnicity, Customized (participants) [Number]
White/Caucasian	38 97.4%
Black/African American	1 2.6%
Region of Enrollment (participants) [Number]
United States	39 100%
Carcinoma Stage at Initial Diagnosis (participants) [Number]
Stage II	12 30.8%
Stage III	27 69.2%
Baseline ECOG Performance Status (participants) [Number]
ECOG Performance Status = 0	32 82.1%
ECOG Performance Status = 1	7 17.9%
Histologic Grade at Baseline (participants) [Number]
Well differentiated	4 10.3%
Moderately differentiated	28 71.8%
Poorly differentiated	2 5.1%
Could not be assessed	5 12.8%

Outcome Measures

1. Primary Outcome

Title	Pathologic Complete Response Rate
Description	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.
Time Frame	Between days 57 and 98 after preoperative chemotherapy

Outcome Measure Data

Analysis Population Description

All patients enrolled in the trial who were evaluable for pathologic response. Four patients were not evaluable for response.

Arm/Group Title	FOLFOX6/Aflibercept/Radiation/Surgery
Arm/Group Description	Preoperative Chemoradiation (6 weeks) Surgery (6 weeks from last dose of aflibercept) Postoperative Chemotherapy and aflibercept (four 28-day cycles)
Measure Participants	35
Number [participants]	7 17.9%

2. Secondary Outcome

Title	Overall Survival
Description	Measured from date of first protocol treatment until date of death.
Time Frame	Every 3 months (±1 month) following documented progression, up to 5 years or death, whichever comes first.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	FOLFOX6/Aflibercept/Radiation/Surgery
Arm/Group Description	Preoperative Chemoradiation (6 weeks) Surgery (6 weeks from last dose of aflibercept) Postoperative Chemotherapy and aflibercept (four 28-day cycles)
Measure Participants	39
Median (95% Confidence Interval) [participants]	NA NaN

3. Secondary Outcome

Title	Overall Survival Probability at 6 and 12 Months
Description	The probability of overall survival at 6 months and 12 months from date of first protocol treatment until date of death.
Time Frame	up to 1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	FOLFOX6/Aflibercept/Radiation/Surgery
Arm/Group Description	Preoperative Chemoradiation (6 weeks) Surgery (6 weeks from last dose of aflibercept) Postoperative Chemotherapy and aflibercept (four 28-day cycles)
Measure Participants	39
6-month OS probability	0.97
12 month OS probability	0.94

4. Secondary Outcome

Title	Sphincter Preservation Rate
Description	The percentage of patients who had Low Anterior Resection during surgery..
Time Frame	Between days 57 and 98 after preoperative chemotherapy.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	FOLFOX6/Aflibercept/Radation/Surgery
Arm/Group Description	Preoperative Chemoradiation (6 weeks) Surgery (6 weeks from last dose of aflibercept) Postoperative Chemotherapy and aflibercept (four 28-day cycles)
Measure Participants	39
Number [percentage of patients]	62

5. Secondary Outcome

Title	Disease-Free Survival
Time Frame	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.

Outcome Measure Data

Analysis Population Description

All evaluable patients.

Arm/Group Title	FOLFOX6/Aflibercept/Radation/Surgery
Arm/Group Description	Preoperative Chemoradiation (6 weeks) Surgery (6 weeks from last dose of aflibercept) Postoperative Chemotherapy and aflibercept (four 28-day cycles)
Measure Participants	33
Median (95% Confidence Interval) [percentage of participants]	NA NaN

6. Secondary Outcome

Title	Disease Free Survival Probability at 6 and 12 Months
Description	The probability of disease free survival at 6 and 12 months after initiating protocol treatment.
Time Frame	Up to 1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	FOLFOX6/Aflibercept/Radiation/Surgery
Arm/Group Description	Preoperative Chemoradiation (6 weeks) Surgery (6 weeks from last dose of aflibercept) Postoperative Chemotherapy and aflibercept (four 28-day cycles)
Measure Participants	33
6-month DFS probability	0.95
12-month DFS probability	0.87

7. Secondary Outcome

Title	The Number of Participants Who Experienced Serious or Non-Serious Adverse Events as a Measure of Safety.
Description	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.
Time Frame	weekly for 6 weeks pre-op then every 2 weeks post-op, approximately 36 weeks

Outcome Measure Data

Analysis Population Description

All patients who received at least one dose of protocol treatment.

Arm/Group Title	FOLFOX6/Aflibercept/Radiation/Surgery
Arm/Group Description	Preoperative Chemoradiation (6 weeks) Surgery (6 weeks from last dose of aflibercept) Postoperative Chemotherapy and aflibercept (four 28-day cycles)
Measure Participants	39
AEs	38 97.4%
SAEs	9 23.1%

Adverse Events

Time Frame	From Day 1 of treatment thru 30 days after discontinuation or completion of study treatment, an average of 6 months.
Adverse Event Reporting Description	All patients who received at least one dose of protocol treatment during the trial.
Arm/Group Title	FOLFOX6/Aflibercept/Radiation/Surgery
Arm/Group Description	Preoperative Chemoradiation: 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: Patients will undergo abdominoperineal or low anterior resection with total mesorectal excision, per standard treatment guidelines. Postoperative Chemotherapy and Aflibercept Treatments: 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. Radiation Aflibercept Surgery: Abdominoperineal or low anterior resectio
All Cause Mortality
	FOLFOX6/Aflibercept/Radiation/Surgery
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	FOLFOX6/Aflibercept/Radiation/Surgery
	Affected / at Risk (%)	# Events
Total	9/39 (23.1%)
Blood and lymphatic system disorders
Neutropenia	1/39 (2.6%)	1
Gastrointestinal disorders
Small Intestinal Obstruction	2/39 (5.1%)	2
Enteritis	1/39 (2.6%)	1
Faecaloma	1/39 (2.6%)	1
Gastrointestinal Fistula	1/39 (2.6%)	1
Gastrointestinal Haemorrhage	1/39 (2.6%)	1
Rectal Ulcer	1/39 (2.6%)	1
General disorders
Mucosal Inflammation	1/39 (2.6%)	1
Infections and infestations
Pelvic Abscess	2/39 (5.1%)	2
Abscess	1/39 (2.6%)	1
Device Related Infection	1/39 (2.6%)	1
Sepsis	1/39 (2.6%)	1
Metabolism and nutrition disorders
Dehydration	1/39 (2.6%)	1
Vascular disorders
Embolism Venous	1/39 (2.6%)	1
Other (Not Including Serious) Adverse Events
	FOLFOX6/Aflibercept/Radiation/Surgery
	Affected / at Risk (%)	# Events
Total	38/39 (97.4%)
Blood and lymphatic system disorders
Anaemia	11/39 (28.2%)
Neutropenia	10/39 (25.6%)
Thrombocytopenia	8/39 (20.5%)
Leukopenia	4/39 (10.3%)
Gastrointestinal disorders
Diarrheoea	29/39 (74.4%)
Nausea	20/39 (51.3%)
Constipation	14/39 (35.9%)
Proctalgia	12/39 (30.8%)
Abdominal Pain	8/39 (20.5%)
Stomatitis	7/39 (17.9%)
Vomiting	7/39 (17.9%)
Rectal Haemorrhage	6/39 (15.4%)
Gastrooesophageal Reflux Disease	6/39 (15.4%)
Dyspepsia	2/39 (5.1%)
Oral Pain	2/39 (5.1%)
General disorders
Fatigue	29/39 (74.4%)
Muscousal Inflammation	16/39 (41%)
Temperature Intolerance	5/39 (12.8%)
Asthenia	3/39 (7.7%)
Catheter Site Pain	3/39 (7.7%)
Infections and infestations
Device Related Infection	5/39 (12.8%)
Upper Respiratory Tract Infection	4/39 (10.3%)
Injury, poisoning and procedural complications
Radiation Skin Injury	4/39 (10.3%)
Investigations
Weight Decreased	8/39 (20.5%)
Neutrophil Count Decreased	3/39 (7.7%)
Metabolism and nutrition disorders
Decreased Appetite	10/39 (25.6%)
Dehydration	9/39 (23.1%)
Hypokalaemia	4/39 (10.3%)
Hyperkalaemia	2/39 (5.1%)
Musculoskeletal and connective tissue disorders
Arthralgia	6/39 (15.4%)
Pain in Extremity	4/39 (10.3%)
Back Pain	3/39 (7.7%)
Myalgia	3/39 (7.7%)
Nervous system disorders
Headache	13/39 (33.3%)
Dysgeusia	7/39 (17.9%)
Peripheral Sensory Neuropathy	4/39 (10.3%)
Paraesthesia	3/39 (7.7%)
Peripheral Neuropathy	10/39 (25.6%)
Renal and urinary disorders
Proteinuria	15/39 (38.5%)
Haematuria	5/39 (12.8%)
Respiratory, thoracic and mediastinal disorders
Dysphonia	8/39 (20.5%)
Epistaxis	7/39 (17.9%)
Oropharyngeal Pain	6/39 (15.4%)
Dyspnoea	4/39 (10.3%)
Nasal Congestion	2/39 (5.1%)
Skin and subcutaneous tissue disorders
Palmar-Plantar Erythrodysaesthesia Syndrome	6/39 (15.4%)
Rash	5/39 (12.8%)
Dry Skin	3/39 (7.7%)
Vascular disorders
Hypertension	16/39 (41%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The sponsor can review/embargo results communications prior to public release for a period that is >60 days but ≤180 days from date submitted to sponsor, who may require changes to the communication in order to remove specifically identified confidential information (other than study data) and/or delay the proposed publication to enable the sponsor to seek patent protection for inventions. The PI may not publish its results until 18 mos. after the trial has been completed at all sites.