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Phase I/II Study of Capecitabine Plus Aflibercept to Treat Metastatic Colorectal Cancer (X-TRAP)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT01661972
Recruitment Status : Completed
First Posted : August 10, 2012
Results First Posted : July 11, 2017
Last Update Posted : October 29, 2018
Sponsor:
Collaborator:
Sanofi
Information provided by (Responsible Party):
John Strickler, M.D., Duke University

Study Type Interventional
Study Design Allocation: Non-Randomized;   Intervention Model: Sequential Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Metastatic Colorectal Cancer
Intervention Drug: Capecitabine and aflibercept
Enrollment 63
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Phase 1 Phase 2
Hide Arm/Group Description Capecitabine is given days 1-14 of a 21 day cycle. Cohort 1 will receive 850mg/m2 Capecitabine and Cohort 2 will receive 1000mg/m2. Aflibercept 6 mg/kg is given intravenously every 3 weeks. Capecitabine at the recommended dose based on Phase 1 (850mg/m2) given on days 1-14. Aflibercept 6 mg/kg given intravenously every 3 weeks. Both agents are administered on a 21-day cycle.
Period Title: Overall Study
Started 13 50
Completed 11 46
Not Completed 2 4
Reason Not Completed
Adverse Event             1             2
Death during Treatment period             1             1
Withdrawal by Subject             0             1
Arm/Group Title Phase 1 Phase 2 Total
Hide Arm/Group Description Capecitabine is given days 1-14 of a 21 day cycle. Cohort 1 will receive 850mg/m2 Capecitabine and Cohort 2 will receive 1000mg/m2. Aflibercept 6 mg/kg is given intravenously every 3 weeks. Capecitabine at the recommended dose based on Phase 1 (850mg/m2) given on days 1-14. Aflibercept 6 mg/kg given intravenously every 3 weeks. Both agents are administered on a 21-day cycle. Total of all reporting groups
Overall Number of Baseline Participants 13 50 63
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 13 participants 50 participants 63 participants
58.1  (12.3) 57.7  (9.9) 57.8  (10.3)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 13 participants 50 participants 63 participants
Female
6
  46.2%
20
  40.0%
26
  41.3%
Male
7
  53.8%
30
  60.0%
37
  58.7%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 13 participants 50 participants 63 participants
American Indian or Alaska Native
0
   0.0%
1
   2.0%
1
   1.6%
Asian
0
   0.0%
1
   2.0%
1
   1.6%
Native Hawaiian or Other Pacific Islander
0
   0.0%
1
   2.0%
1
   1.6%
Black or African American
2
  15.4%
14
  28.0%
16
  25.4%
White
11
  84.6%
29
  58.0%
40
  63.5%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
0
   0.0%
4
   8.0%
4
   6.3%
Region of Enrollment  
Measure Type: Count of Participants
Unit of measure:  Participants
United States Number Analyzed 13 participants 50 participants 63 participants
13
 100.0%
50
 100.0%
63
 100.0%
1.Primary Outcome
Title Recommended Phase II Dose (RPTD) for the Capecitabine and Aflibercept Doublet Combination
Hide Description Phase 1 of this study will be the dose escalation component to determine safety and the Recommended Phase II dose (RPTD) for the capecitabine plus aflibercept combination. Cohort 1 will receive 850mg/m2 capecitabine and 6mg/kg aflibercept. If less than 2 of 6 patients experience a dose limiting toxicity in Cohort 1, then the next patients will be enrolled in Cohort 2 at 1000mg/m2 capecitabine and 6mg/kg aflibercept. RPTD is determined by the number of dose limiting toxicities (Primary obj 2 for Phase I).
Time Frame RPTD for the study will be determined at the completion of Phase I; up to 1 year.
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Phase 1
Hide Arm/Group Description:
Aflibercept 6 mg/kg given intravenously every 3 weeks. Capecitabine was given at 850mg/m2 for the first cohort and at 1000mg/m2 for the second cohort.
Overall Number of Participants Analyzed 13
Measure Type: Number
Unit of Measure: mg/m2
850
2.Primary Outcome
Title Number of Dose-Limiting Toxicities (Phase 1)
Hide Description

Number of patients experiencing a dose-limiting toxicity in each cohort.

A dose-limiting toxicity is defined as Grade 4 neutropenia, thrombocytopenia or anemia or grade 3 neutropenia or thrombocytopenia lasting over 7 days Grade 3 thrombocytopenia associated with bleeding Febrile Neutropenia Nausea/Vomiting or Diarrhea ≥ grade 3 and lasting ≥ 4 days despite adequate supportive measures Grade ≥ 3 Bilirubin, ALT or AST > 7 days Other non-hematologic toxicity ≥ grade 3 excluding alopecia, anorexia, fatigue, hypertension, isolated lab abnormalities (not clinically significant) and/ rare, idiosyncratic reactions to any of the study drugs. Anorexia, fatigue and hypertension will be considered as DLT only if they reach grade 4 or are considered unmanageable Treatment delay of ≥ 14 days for cycle 2 due to unresolved toxicity Treatment-related death or clinically significant,treatment-related hospitalization

Time Frame 28 days
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Phase 1 Cohort 1 Phase 1 Cohort 2
Hide Arm/Group Description:
Capecitabine 850mg/m2 given days 1-14 and off days 15-21. Aflibercept 6 mg/kg given intravenously every 3 weeks. Both agents are administered on a 21-day cycle.
Capecitabine 1000 mg/m2 given days 1-14 and off days 15-21. Aflibercept 6 mg/kg given intravenously every 3 weeks. Both agents are administered on a 21-day cycle.
Overall Number of Participants Analyzed 7 6
Measure Type: Count of Participants
Unit of Measure: Participants
1
  14.3%
2
  33.3%
3.Primary Outcome
Title Median Progression Free Survival (PFS)
Hide Description Time in months from the start of study treatment to the date of first progression (PD) according to the RECIST criteria, or death due to any cause. Per RECIST criteria, a PD is indicated when there is at least a 20% increase in the sum of the longest diameters from target lesions relative to the smallest sum recorded since treatment is initiated. Median PFS was estimated using a Kaplan-Meier curve, and is the time at which 50% of patients remain alive without disease progression.
Time Frame approximately 5 months
Hide Outcome Measure Data
Hide Analysis Population Description
Patients enrolled in Phase 2 were included in the analysis
Arm/Group Title Phase 2
Hide Arm/Group Description:
Capecitabine at the recommended dose based on Phase 1, given days 1-14 and off days 15-21. Aflibercept 6 mg/kg given intravenously every 3 weeks. Both agents are administered on a 21-day cycle.
Overall Number of Participants Analyzed 50
Median (95% Confidence Interval)
Unit of Measure: Months
3.91
(2.30 to 4.47)
4.Secondary Outcome
Title Response Rate
Hide Description The percentage of patients for whom the best overall response is complete response (CR) or partial response (PR). A CR occurs when all lesions disappear; whereas, a PR is indicated when there is at least a 30% decrease in the sum of the longest diameters (LD) of the target lesion. A PD (progressive disease) occurs when there is at least a 20% increase in the sum of the LD relative to the smallest sum LD recorded since treatment is initiated. Disease is considered stable if there is no response and no PD. All patients were assigned a best response for inclusion in this calculation in accordance with the protocol.
Time Frame approximately every 9 weeks and/or restaging, through study completion
Hide Outcome Measure Data
Hide Analysis Population Description
All evaluable Phase 2 patients. 5 patients were not evaluable for response and were not included in the analysis.
Arm/Group Title Phase 2
Hide Arm/Group Description:
Capecitabine at the recommended dose based on Phase 1, given days 1-14 and off days 15-21. Aflibercept 6 mg/kg given intravenously every 3 weeks. Both agents are administered on a 21-day cycle.
Overall Number of Participants Analyzed 45
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
2.22
(0.06 to 11.77)
5.Secondary Outcome
Title Median Survival
Hide Description Time in months from the start of study treatment to date of death due to any cause. Median survival was estimated using a Kaplan-Meier curve and is the time point at which 50% of patients remain alive.
Time Frame Subjects will be followed until death which is estimated to be on average 6 months - 1 year after coming off protocol therapy
Hide Outcome Measure Data
Hide Analysis Population Description
Patients enrolled in Phase 2 were included in the analysis
Arm/Group Title Phase 2
Hide Arm/Group Description:
Capecitabine at the recommended dose based on Phase 1, given days 1-14 and off days 15-21. Aflibercept 6 mg/kg given intravenously every 3 weeks. Both agents are administered on a 21-day cycle.
Overall Number of Participants Analyzed 50
Median (95% Confidence Interval)
Unit of Measure: months
7.43
(5.78 to 10.68)
Time Frame All serious and non-serious adverse events will be collected from time of informed consent to 30 days after a subject's last dose of study agent.
Adverse Event Reporting Description Grade 2 and above adverse events for this study were collected using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
 
Arm/Group Title Phase 1 Phase 2
Hide Arm/Group Description Capecitabine is given days 1-14 of a 21 day cycle. Cohort 1 will receive 850mg/m2 Capecitabine and Cohort 2 will receive 1000mg/m2. Aflibercept 6 mg/kg is given intravenously every 3 weeks. Capecitabine at the recommended dose based on Phase 1 (850mg/m2) given on days 1-14. Aflibercept 6 mg/kg given intravenously every 3 weeks. Both agents are administered on a 21-day cycle.
All-Cause Mortality
Phase 1 Phase 2
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Phase 1 Phase 2
Affected / at Risk (%) Affected / at Risk (%)
Total   9/13 (69.23%)   18/50 (36.00%) 
Blood and lymphatic system disorders     
Anemia  1  0/13 (0.00%)  2/50 (4.00%) 
Cardiac disorders     
Aortic valve disease  1  0/13 (0.00%)  1/50 (2.00%) 
Supraventricular tachycardia  1  0/13 (0.00%)  1/50 (2.00%) 
Gastrointestinal disorders     
Abdominal pain  1  1/13 (7.69%)  2/50 (4.00%) 
Anal fistula  1  0/13 (0.00%)  1/50 (2.00%) 
Ascites  1  0/13 (0.00%)  1/50 (2.00%) 
Colonic obstruction  1  1/13 (7.69%)  0/50 (0.00%) 
Colonic perforation  1  1/13 (7.69%)  0/50 (0.00%) 
Diarrhea  1  0/13 (0.00%)  1/50 (2.00%) 
Gastric hemorrhage  1  0/13 (0.00%)  1/50 (2.00%) 
Nausea  1  0/13 (0.00%)  1/50 (2.00%) 
Vomiting  1  0/13 (0.00%)  1/50 (2.00%) 
General disorders     
Death NOS  1  3/13 (23.08%)  4/50 (8.00%) 
Fever  1  0/13 (0.00%)  1/50 (2.00%) 
Hepatobiliary disorders     
Cholecystitis  1  0/13 (0.00%)  1/50 (2.00%) 
Hepatic failure  1  1/13 (7.69%)  0/50 (0.00%) 
Infections and infestations     
Appendicitis  1  1/13 (7.69%)  0/50 (0.00%) 
Sepsis  1  1/13 (7.69%)  0/50 (0.00%) 
Investigations     
Blood bilirubin increased  1  1/13 (7.69%)  2/50 (4.00%) 
Metabolism and nutrition disorders     
Dehydration  1  0/13 (0.00%)  1/50 (2.00%) 
Hyponatremia  1  0/13 (0.00%)  1/50 (2.00%) 
Musculoskeletal and connective tissue disorders     
Bone pain  1  0/13 (0.00%)  1/50 (2.00%) 
Generalized muscle weakness  1  1/13 (7.69%)  0/50 (0.00%) 
Nervous system disorders     
Depressed level of consciousness  1  1/13 (7.69%)  0/50 (0.00%) 
Intracranial hemorrhage  1  0/13 (0.00%)  1/50 (2.00%) 
Syncope  1  1/13 (7.69%)  1/50 (2.00%) 
Psychiatric disorders     
Confusion  1  0/13 (0.00%)  1/50 (2.00%) 
Depression  1  0/13 (0.00%)  1/50 (2.00%) 
Respiratory, thoracic and mediastinal disorders     
Dyspnea  1  1/13 (7.69%)  0/50 (0.00%) 
Vascular disorders     
Hypertension  1  1/13 (7.69%)  1/50 (2.00%) 
Thromboembolic event  1  1/13 (7.69%)  1/50 (2.00%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, CTCAE (4.0)
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Phase 1 Phase 2
Affected / at Risk (%) Affected / at Risk (%)
Total   13/13 (100.00%)   46/50 (92.00%) 
Cardiac disorders     
Chest pain - cardiac  1  0/13 (0.00%)  1/50 (2.00%) 
Gastrointestinal disorders     
Abdominal pain  1  1/13 (7.69%)  3/50 (6.00%) 
Anal pain  1  0/13 (0.00%)  1/50 (2.00%) 
Ascites  1  2/13 (15.38%)  1/50 (2.00%) 
Bloating  1  1/13 (7.69%)  1/50 (2.00%) 
Constipation  1  4/13 (30.77%)  7/50 (14.00%) 
Diarrhea  1  1/13 (7.69%)  5/50 (10.00%) 
Dyspepsia  1  1/13 (7.69%)  3/50 (6.00%) 
Dysphagia  1  1/13 (7.69%)  1/50 (2.00%) 
Esophagitis  1  1/13 (7.69%)  0/50 (0.00%) 
Gastroesophageal reflux disease  1  1/13 (7.69%)  1/50 (2.00%) 
Hemorrhoids  1  0/13 (0.00%)  2/50 (4.00%) 
Mucositis oral  1  4/13 (30.77%)  8/50 (16.00%) 
Nausea  1  3/13 (23.08%)  2/50 (4.00%) 
Rectal pain  1  0/13 (0.00%)  2/50 (4.00%) 
Rectal ulcer  1  0/13 (0.00%)  1/50 (2.00%) 
Vomiting  1  1/13 (7.69%)  1/50 (2.00%) 
General disorders     
Fatigue  1  6/13 (46.15%)  11/50 (22.00%) 
Fever  1  0/13 (0.00%)  1/50 (2.00%) 
Flu like symptoms  1  0/13 (0.00%)  1/50 (2.00%) 
Pain  1  2/13 (15.38%)  5/50 (10.00%) 
Infections and infestations     
Anorectal infection  1  0/13 (0.00%)  1/50 (2.00%) 
Rhinitis infective  1  0/13 (0.00%)  1/50 (2.00%) 
Sinusitis  1  1/13 (7.69%)  2/50 (4.00%) 
Skin infection  1  0/13 (0.00%)  2/50 (4.00%) 
Upper respiratory infection  1  0/13 (0.00%)  1/50 (2.00%) 
Urinary tract infection  1  0/13 (0.00%)  3/50 (6.00%) 
Investigations     
Alanine aminotransferase increased  1  0/13 (0.00%)  1/50 (2.00%) 
Blood bilirubin increased  1  1/13 (7.69%)  5/50 (10.00%) 
Lymphocyte count decreased  1  0/13 (0.00%)  2/50 (4.00%) 
Neutrophil count decreased  1  1/13 (7.69%)  1/50 (2.00%) 
Platelet count decreased  1  1/13 (7.69%)  3/50 (6.00%) 
Urine output decreased  1  0/13 (0.00%)  1/50 (2.00%) 
Weight loss  1  4/13 (30.77%)  7/50 (14.00%) 
White blood cell decreased  1  0/13 (0.00%)  1/50 (2.00%) 
Metabolism and nutrition disorders     
Anorexia  1  5/13 (38.46%)  2/50 (4.00%) 
Dehydration  1  0/13 (0.00%)  1/50 (2.00%) 
Hypoalbuminemia  1  0/13 (0.00%)  3/50 (6.00%) 
Hypocalcemia  1  0/13 (0.00%)  1/50 (2.00%) 
Hypokalemia  1  0/13 (0.00%)  2/50 (4.00%) 
Musculoskeletal and connective tissue disorders     
Arthralgia  1  0/13 (0.00%)  1/50 (2.00%) 
Arthritis  1  0/13 (0.00%)  1/50 (2.00%) 
Back pain  1  0/13 (0.00%)  2/50 (4.00%) 
Chest wall pain  1  1/13 (7.69%)  1/50 (2.00%) 
Flank pain  1  0/13 (0.00%)  1/50 (2.00%) 
Muscle weakness lower limb  1  0/13 (0.00%)  1/50 (2.00%) 
Neck pain  1  0/13 (0.00%)  1/50 (2.00%) 
Pain in extremity  1  1/13 (7.69%)  4/50 (8.00%) 
Nervous system disorders     
Cognitive disturbance  1  0/13 (0.00%)  1/50 (2.00%) 
Headache  1  0/13 (0.00%)  2/50 (4.00%) 
Peripheral sensory neuropathy  1  1/13 (7.69%)  2/50 (4.00%) 
Seizure  1  0/13 (0.00%)  1/50 (2.00%) 
Psychiatric disorders     
Depression  1  0/13 (0.00%)  1/50 (2.00%) 
Insomnia  1  1/13 (7.69%)  1/50 (2.00%) 
Renal and urinary disorders     
Chronic kidney disease  1  0/13 (0.00%)  3/50 (6.00%) 
Hematuria  1  0/13 (0.00%)  1/50 (2.00%) 
Proteinuria  1  0/13 (0.00%)  9/50 (18.00%) 
Urinary retention  1  0/13 (0.00%)  1/50 (2.00%) 
Urinary urgency  1  1/13 (7.69%)  0/50 (0.00%) 
Reproductive system and breast disorders     
Gynecomastia  1  0/13 (0.00%)  1/50 (2.00%) 
Respiratory, thoracic and mediastinal disorders     
Allergic rhinitis  1  0/13 (0.00%)  1/50 (2.00%) 
Cough  1  0/13 (0.00%)  1/50 (2.00%) 
Dyspnea  1  3/13 (23.08%)  3/50 (6.00%) 
Hiccups  1  0/13 (0.00%)  1/50 (2.00%) 
Respiratory, thoracic and mediastinal disorders - Other, specify  1  0/13 (0.00%)  1/50 (2.00%) 
Sore throat  1  0/13 (0.00%)  1/50 (2.00%) 
Skin and subcutaneous tissue disorders     
Palmar-plantar erythrodysesthesia syndrome  1  6/13 (46.15%)  20/50 (40.00%) 
Pruritus  1  1/13 (7.69%)  0/50 (0.00%) 
Skin and subcutaneous tissue disorders - Other, specify  1  1/13 (7.69%)  0/50 (0.00%) 
Surgical and medical procedures     
Surgical and medical procedures - Other, specify  1  0/13 (0.00%)  1/50 (2.00%) 
Vascular disorders     
Hypertension  1  3/13 (23.08%)  20/50 (40.00%) 
Thromboembolic event  1  0/13 (0.00%)  2/50 (4.00%) 
Vascular disorders - Other, specify  1  0/13 (0.00%)  1/50 (2.00%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, CTCAE (4.0)
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
Results Point of Contact
Name/Title: John Strickler, M.D.
Organization: Duke University Medical Center
Phone: 919-668-1861
Responsible Party: John Strickler, M.D., Duke University
ClinicalTrials.gov Identifier: NCT01661972     History of Changes
Other Study ID Numbers: Pro00037688
First Submitted: July 31, 2012
First Posted: August 10, 2012
Results First Submitted: June 9, 2017
Results First Posted: July 11, 2017
Last Update Posted: October 29, 2018