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

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ClinicalTrials.gov Identifier: NCT01749956
Recruitment Status : Completed
First Posted : December 17, 2012
Results First Posted : February 7, 2017
Last Update Posted : February 7, 2017
Sponsor:
Collaborator:
Sanofi
Information provided by (Responsible Party):
SCRI Development Innovations, LLC

Study Type Interventional
Study Design Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Rectal Cancer
Interventions Radiation: Radiation
Drug: Aflibercept
Procedure: Surgery
Drug: FOLFOX6
Enrollment 39
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.
Pre-assignment Details  
Arm/Group Title FOLFOX6/Aflibercept/Radation/Surgery
Hide 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
Arm/Group Title FOLFOX6/Aflibercept/Radation/Surgery
Hide Arm/Group Description Preoperative Chemoradiation (6 weeks) Surgery (6 weeks from last dose of aflibercept) Postoperative Chemotherapy and aflibercept (four 28-day cycles)
Overall Number of Baseline Participants 39
Hide Baseline Analysis Population Description
All enrolled patients
Age, Continuous  
Median (Full Range)
Unit of measure:  Years
Number Analyzed 39 participants
60
(36 to 89)
Gender  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 39 participants
Female
14
  35.9%
Male
25
  64.1%
Race/Ethnicity, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 39 participants
White/Caucasian 38
Black/African American 1
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 39 participants
39
Carcinoma Stage at Initial Diagnosis   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 39 participants
Stage II 12
Stage III 27
[1]
Measure Description: Eligible patients with a histologically confirmed diagnosis of Stage II or Stage III rectal cancer, staged according to the American Joint Committee on Cancer (AJCC) Staging Manual - Edition 7.
Baseline ECOG Performance Status   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 39 participants
ECOG Performance Status = 0 32
ECOG Performance Status = 1 7
[1]
Measure Description:

Eastern Cooperative Oncology Group (ECOG) Performance Status

0=Fully active, able to carry on all pre-disease performance without restriction

  1. Restricted in physically strenuous activity. Ambulatory and able to carry out work of a light or sedentary nature
  2. Ambulatory and capable of all selfcare but unable to carry out any work activities; up and about more than 50% of waking hours
  3. Capable of only limited selfcare; confined to bed or chair more than 50% of waking hours
  4. Completely disabled; cannot carry on any selfcare; totally confined to bed or chair
  5. Dead
Histologic Grade at Baseline  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 39 participants
Well differentiated 4
Moderately differentiated 28
Poorly differentiated 2
Could not be assessed 5
1.Primary Outcome
Title Pathologic Complete Response Rate
Hide 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
Hide Outcome Measure Data
Hide 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
Hide Arm/Group Description:
Preoperative Chemoradiation (6 weeks) Surgery (6 weeks from last dose of aflibercept) Postoperative Chemotherapy and aflibercept (four 28-day cycles)
Overall Number of Participants Analyzed 35
Measure Type: Number
Unit of Measure: participants
7
2.Secondary Outcome
Title Overall Survival
Hide 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.
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title FOLFOX6/Aflibercept/Radiation/Surgery
Hide Arm/Group Description:
Preoperative Chemoradiation (6 weeks) Surgery (6 weeks from last dose of aflibercept) Postoperative Chemotherapy and aflibercept (four 28-day cycles)
Overall Number of Participants Analyzed 39
Median (95% Confidence Interval)
Unit of Measure: participants
NA [1] 
(NA to NA)
[1]
Median OS was not reached by time of data analysis.
3.Secondary Outcome
Title Overall Survival Probability at 6 and 12 Months
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title FOLFOX6/Aflibercept/Radiation/Surgery
Hide Arm/Group Description:
Preoperative Chemoradiation (6 weeks) Surgery (6 weeks from last dose of aflibercept) Postoperative Chemotherapy and aflibercept (four 28-day cycles)
Overall Number of Participants Analyzed 39
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: probability
6-month OS probability
0.97
(0.82 to 0.99)
12 month OS probability
0.94
(0.79 to 0.99)
4.Secondary Outcome
Title Sphincter Preservation Rate
Hide Description The percentage of patients who had Low Anterior Resection during surgery..
Time Frame Between days 57 and 98 after preoperative chemotherapy.
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title FOLFOX6/Aflibercept/Radation/Surgery
Hide Arm/Group Description:
Preoperative Chemoradiation (6 weeks) Surgery (6 weeks from last dose of aflibercept) Postoperative Chemotherapy and aflibercept (four 28-day cycles)
Overall Number of Participants Analyzed 39
Measure Type: Number
Unit of Measure: percentage of patients
62
5.Secondary Outcome
Title Disease-Free Survival
Hide Description [Not Specified]
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.
Hide Outcome Measure Data
Hide Analysis Population Description
All evaluable patients.
Arm/Group Title FOLFOX6/Aflibercept/Radation/Surgery
Hide Arm/Group Description:
Preoperative Chemoradiation (6 weeks) Surgery (6 weeks from last dose of aflibercept) Postoperative Chemotherapy and aflibercept (four 28-day cycles)
Overall Number of Participants Analyzed 33
Median (95% Confidence Interval)
Unit of Measure: percentage of participants
NA [1] 
(NA to NA)
[1]
At a median follow-up of 12 months, median DFS was not reached.
6.Secondary Outcome
Title Disease Free Survival Probability at 6 and 12 Months
Hide Description The probability of disease free survival at 6 and 12 months after initiating protocol treatment.
Time Frame Up to 1 year
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title FOLFOX6/Aflibercept/Radiation/Surgery
Hide Arm/Group Description:
Preoperative Chemoradiation (6 weeks) Surgery (6 weeks from last dose of aflibercept) Postoperative Chemotherapy and aflibercept (four 28-day cycles)
Overall Number of Participants Analyzed 33
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: probability
6-month DFS probability
0.95
(0.71 to 0.99)
12-month DFS probability
0.87
(0.54 to 0.97)
7.Secondary Outcome
Title The Number of Participants Who Experienced Serious or Non-Serious Adverse Events as a Measure of Safety.
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
All patients who received at least one dose of protocol treatment.
Arm/Group Title FOLFOX6/Aflibercept/Radiation/Surgery
Hide Arm/Group Description:
Preoperative Chemoradiation (6 weeks) Surgery (6 weeks from last dose of aflibercept) Postoperative Chemotherapy and aflibercept (four 28-day cycles)
Overall Number of Participants Analyzed 39
Measure Type: Number
Unit of Measure: participants
AEs 38
SAEs 9
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
Hide 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 (%)
Total   --/--    
Show Serious Adverse Events Hide Serious Adverse Events
FOLFOX6/Aflibercept/Radiation/Surgery
Affected / at Risk (%) # Events
Total   9/39 (23.08%)    
Blood and lymphatic system disorders   
Neutropenia * 1  1/39 (2.56%)  1
Gastrointestinal disorders   
Small Intestinal Obstruction * 1  2/39 (5.13%)  2
Enteritis * 1  1/39 (2.56%)  1
Faecaloma * 1  1/39 (2.56%)  1
Gastrointestinal Fistula * 1  1/39 (2.56%)  1
Gastrointestinal Haemorrhage * 1  1/39 (2.56%)  1
Rectal Ulcer * 1  1/39 (2.56%)  1
General disorders   
Mucosal Inflammation * 1  1/39 (2.56%)  1
Infections and infestations   
Pelvic Abscess * 1  2/39 (5.13%)  2
Abscess * 1  1/39 (2.56%)  1
Device Related Infection * 1  1/39 (2.56%)  1
Sepsis * 1  1/39 (2.56%)  1
Metabolism and nutrition disorders   
Dehydration * 1  1/39 (2.56%)  1
Vascular disorders   
Embolism Venous * 1  1/39 (2.56%)  1
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, NCI CTCAE 4.0
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
FOLFOX6/Aflibercept/Radiation/Surgery
Affected / at Risk (%) # Events
Total   38/39 (97.44%)    
Blood and lymphatic system disorders   
Anaemia * 1  11/39 (28.21%) 
Neutropenia * 1  10/39 (25.64%) 
Thrombocytopenia * 1  8/39 (20.51%) 
Leukopenia * 1  4/39 (10.26%) 
Gastrointestinal disorders   
Diarrheoea * 1  29/39 (74.36%) 
Nausea * 1  20/39 (51.28%) 
Constipation * 1  14/39 (35.90%) 
Proctalgia * 1  12/39 (30.77%) 
Abdominal Pain * 1  8/39 (20.51%) 
Stomatitis * 1  7/39 (17.95%) 
Vomiting * 1  7/39 (17.95%) 
Rectal Haemorrhage * 1  6/39 (15.38%) 
Gastrooesophageal Reflux Disease * 1  6/39 (15.38%) 
Dyspepsia * 1  2/39 (5.13%) 
Oral Pain * 1  2/39 (5.13%) 
General disorders   
Fatigue * 1  29/39 (74.36%) 
Muscousal Inflammation * 1  16/39 (41.03%) 
Temperature Intolerance * 1  5/39 (12.82%) 
Asthenia * 1  3/39 (7.69%) 
Catheter Site Pain * 1  3/39 (7.69%) 
Infections and infestations   
Device Related Infection * 1  5/39 (12.82%) 
Upper Respiratory Tract Infection * 1  4/39 (10.26%) 
Injury, poisoning and procedural complications   
Radiation Skin Injury * 1  4/39 (10.26%) 
Investigations   
Weight Decreased * 1  8/39 (20.51%) 
Neutrophil Count Decreased * 1  3/39 (7.69%) 
Metabolism and nutrition disorders   
Decreased Appetite * 1  10/39 (25.64%) 
Dehydration * 1  9/39 (23.08%) 
Hypokalaemia * 1  4/39 (10.26%) 
Hyperkalaemia * 1  2/39 (5.13%) 
Musculoskeletal and connective tissue disorders   
Arthralgia * 1  6/39 (15.38%) 
Pain in Extremity * 1  4/39 (10.26%) 
Back Pain * 1  3/39 (7.69%) 
Myalgia * 1  3/39 (7.69%) 
Nervous system disorders   
Headache * 1  13/39 (33.33%) 
Dysgeusia * 1  7/39 (17.95%) 
Peripheral Sensory Neuropathy * 1  4/39 (10.26%) 
Paraesthesia * 1  3/39 (7.69%) 
Peripheral Neuropathy * 1  10/39 (25.64%) 
Renal and urinary disorders   
Proteinuria * 1  15/39 (38.46%) 
Haematuria * 1  5/39 (12.82%) 
Respiratory, thoracic and mediastinal disorders   
Dysphonia * 1  8/39 (20.51%) 
Epistaxis * 1  7/39 (17.95%) 
Oropharyngeal Pain * 1  6/39 (15.38%) 
Dyspnoea * 1  4/39 (10.26%) 
Nasal Congestion * 1  2/39 (5.13%) 
Skin and subcutaneous tissue disorders   
Palmar-Plantar Erythrodysaesthesia Syndrome * 1  6/39 (15.38%) 
Rash * 1  5/39 (12.82%) 
Dry Skin * 1  3/39 (7.69%) 
Vascular disorders   
Hypertension * 1  16/39 (41.03%) 
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, NCI CTCAE 4.0
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
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.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Charles Davis, RAC
Organization: SCRI Development Innovations
Phone: 615-524-4341
EMail: charles.davis2@scri-innovations.com
Layout table for additonal information
Responsible Party: SCRI Development Innovations, LLC
ClinicalTrials.gov Identifier: NCT01749956     History of Changes
Other Study ID Numbers: SCRI GI 168
First Submitted: December 12, 2012
First Posted: December 17, 2012
Results First Submitted: October 14, 2016
Results First Posted: February 7, 2017
Last Update Posted: February 7, 2017