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Study With AG-013736 Combined With Chemotherapy And Bevacizumab In Patients With Metastatic Colorectal Cancer

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ClinicalTrials.gov Identifier: NCT00460603
Recruitment Status : Completed
First Posted : April 16, 2007
Results First Posted : June 4, 2013
Last Update Posted : December 6, 2013
Sponsor:
Information provided by (Responsible Party):
Pfizer

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Colorectal Neoplasms
Interventions Drug: bevacizumab
Drug: AG-013726
Drug: AG-013736 (axitinib)
Enrollment 187
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Phase 1: Axitinib + Bevacizumab + FOLFOX (Cohort 1) Phase 1: Axitinib + Bevacizumab + FOLFOX (Cohort 2) Phase 1: Axitinib + Bevacizumab + FOLFOX (Cohort 3) Phase 1: Axitinib + FOLFIRI (Cohort 4) Phase 1: Axitinib + FOLFOX (Cohort 5) Phase 1: Axitinib + FOLFIRI (Cohort 6) Phase 1: Axitinib + FOLFOX (Cohort 7) Phase 1: Axitinib + FOLFIRI (Cohort 8) Phase 1: Axitinib + FOLFIRI (Cohort 9) Phase 2: Axitinib + FOLFOX Phase 2: Bevacizumab + FOLFOX Phase 2: Axitinib + Bevacizumab + FOLFOX
Hide Arm/Group Description Bevacizumab 1 milligram per kilogram (mg/kg) intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 milligram per square meter (mg/m^2) intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-fluorouracil (5-FU) 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered following bevacizumab infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion. Bevacizumab 2 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered following bevacizumab infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion. Bevacizumab 5 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered following bevacizumab infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion. FOLFIRI combination chemotherapy on Day 1 of each 14-day cycle consisting of irinotecan 180 mg/m^2 intravenous infusion over 90 minutes, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with irinotecan, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered prior to irinotecan infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion. FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered prior to oxaliplatin infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion. FOLFIRI combination chemotherapy on Day 1 of each 14-day cycle consisting of irinotecan 180 mg/m^2 intravenous infusion over 90 minutes, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with irinotecan, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily from Day 3 to Day 12 in each 14-day cycle administered following completion of 5-FU infusion on Day 3. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion. FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 to Day 12 in each 14-day cycle administered following completion of 5-FU infusion on Day 3. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion. Axitinib (AG-13736) tablet 7 mg orally twice daily for 7 days in 2-week lead-in period prior to Day 1 Cycle 1. FOLFIRI combination chemotherapy on Day 1 of each 14-day cycle consisting of irinotecan 180 mg/m^2 intravenous infusion over 90 minutes, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with irinotecan, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 7 mg to 10 mg orally twice daily from Day 3 to Day 9 in each 14-day cycle administered following completion of 5-FU infusion on Day 3. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion. Axitinib (AG-13736) tablet 7 mg orally twice daily for 7 days in 2-week lead-in period prior to Day 1 Cycle 1. FOLFIRI combination chemotherapy on Day 1 of each 14-day cycle consisting of irinotecan 180 mg/m^2 intravenous infusion over 90 minutes, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with irinotecan, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 10 mg orally twice daily from Day 3 to Day 9 in each 14-day cycle administered following completion of 5-FU infusion on Day 3. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion. FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily in each 14-day cycle administered prior to oxaliplatin infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion. Bevacizumab 5 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion. Bevacizumab 2 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily in each 14-day cycle administered following bevacizumab infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
Period Title: Phase 1
Started 6 6 4 8 6 4 6 3 18 0 0 0
Completed 0 0 0 0 0 0 0 0 0 0 0 0
Not Completed 6 6 4 8 6 4 6 3 18 0 0 0
Reason Not Completed
Death             1             0             0             2             0             0             0             0             1             0             0             0
Adverse Event             3             1             1             2             0             0             3             0             4             0             0             0
Lack of Efficacy             1             0             1             2             2             2             2             2             11             0             0             0
Withdrawal by Subject             1             2             1             1             3             0             1             0             2             0             0             0
Other             0             3             1             1             1             2             0             1             0             0             0             0
Period Title: Phase 2
Started 0 0 0 0 0 0 0 0 0 42 43 41
Treated 0 0 0 0 0 0 0 0 0 39 43 41
Completed 0 0 0 0 0 0 0 0 0 0 0 0
Not Completed 0 0 0 0 0 0 0 0 0 42 43 41
Reason Not Completed
Ongoing in study A4061008 (NCT00828919)             0             0             0             0             0             0             0             0             0             1             0             0
Adverse Event             0             0             0             0             0             0             0             0             0             12             9             10
Death             0             0             0             0             0             0             0             0             0             4             2             2
Protocol Violation             0             0             0             0             0             0             0             0             0             1             1             0
Lost to Follow-up             0             0             0             0             0             0             0             0             0             1             0             0
Other             0             0             0             0             0             0             0             0             0             6             16             7
Objective Progression or Relapse             0             0             0             0             0             0             0             0             0             9             10             17
Global Deterioration of Health Status             0             0             0             0             0             0             0             0             0             0             1             0
Withdrawal by Subject             0             0             0             0             0             0             0             0             0             5             4             5
Randomized, but not treated             0             0             0             0             0             0             0             0             0             3             0             0
Arm/Group Title Phase 1: Axitinib + Bevacizumab + FOLFOX (Cohort 1) Phase 1: Axitinib + Bevacizumab + FOLFOX (Cohort 2) Phase 1: Axitinib + Bevacizumab + FOLFOX (Cohort 3) Phase 1: Axitinib + FOLFIRI (Cohort 4) Phase 1: Axitinib + FOLFOX (Cohort 5) Phase 1: Axitinib + FOLFIRI (Cohort 6) Phase 1: Axitinib + FOLFOX (Cohort 7) Phase 1: Axitinib + FOLFIRI (Cohort 8) Phase 1: Axitinib + FOLFIRI (Cohort 9) Phase 2: Axitinib + FOLFOX Phase 2: Bevacizumab + FOLFOX Phase 2: Axitinib + Bevacizumab + FOLFOX Total
Hide Arm/Group Description Bevacizumab 1 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered following bevacizumab infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion. Bevacizumab 2 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered following bevacizumab infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion. Bevacizumab 5 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered following bevacizumab infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion. FOLFIRI combination chemotherapy on Day 1 of each 14-day cycle consisting of irinotecan 180 mg/m^2 intravenous infusion over 90 minutes, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with irinotecan, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered prior to irinotecan infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion. FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered prior to oxaliplatin infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion. FOLFIRI combination chemotherapy on Day 1 of each 14-day cycle consisting of irinotecan 180 mg/m^2 intravenous infusion over 90 minutes, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with irinotecan, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily from Day 3 to Day 12 in each 14-day cycle administered following completion of 5-FU infusion on Day 3. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion. FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 to Day 12 in each 14-day cycle administered following completion of 5-FU infusion on Day 3. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion. Axitinib (AG-13736) tablet 7 mg orally twice daily for 7 days in 2-week lead-in period prior to Day 1 Cycle 1. FOLFIRI combination chemotherapy on Day 1 of each 14-day cycle consisting of irinotecan 180 mg/m^2 intravenous infusion over 90 minutes, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with irinotecan, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 7 mg to 10 mg orally twice daily from Day 3 to Day 9 in each 14-day cycle administered following completion of 5-FU infusion on Day 3. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion. Axitinib (AG-13736) tablet 7 mg orally twice daily for 7 days in 2-week lead-in period prior to Day 1 Cycle 1. FOLFIRI combination chemotherapy on Day 1 of each 14-day cycle consisting of irinotecan 180 mg/m^2 intravenous infusion over 90 minutes, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with irinotecan, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 10 mg orally twice daily from Day 3 to Day 9 in each 14-day cycle administered following completion of 5-FU infusion on Day 3. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion. FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily in each 14-day cycle administered prior to oxaliplatin infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion. Bevacizumab 5 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion. Bevacizumab 2 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily in each 14-day cycle administered following bevacizumab infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion. Total of all reporting groups
Overall Number of Baseline Participants 6 6 4 8 6 4 6 3 18 42 43 41 187
Hide Baseline Analysis Population Description
[Not Specified]
Age, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 6 participants 6 participants 4 participants 8 participants 6 participants 4 participants 6 participants 3 participants 18 participants 42 participants 43 participants 41 participants 187 participants
Less than (<) 18 years 0 0 0 0 0 0 0 0 0 0 0 0 0
18 to 44 years 1 2 0 1 1 1 0 0 1 2 4 8 21
45 to 64 years 2 1 3 3 2 1 5 3 13 22 18 23 96
Greater than or equal to (>=) 65 years 3 3 1 4 3 2 1 0 4 18 21 10 70
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 6 participants 6 participants 4 participants 8 participants 6 participants 4 participants 6 participants 3 participants 18 participants 42 participants 43 participants 41 participants 187 participants
Female
3
  50.0%
1
  16.7%
2
  50.0%
2
  25.0%
1
  16.7%
2
  50.0%
2
  33.3%
0
   0.0%
7
  38.9%
17
  40.5%
15
  34.9%
15
  36.6%
67
  35.8%
Male
3
  50.0%
5
  83.3%
2
  50.0%
6
  75.0%
5
  83.3%
2
  50.0%
4
  66.7%
3
 100.0%
11
  61.1%
25
  59.5%
28
  65.1%
26
  63.4%
120
  64.2%
1.Primary Outcome
Title Percentage of Participants With Objective Response: Phase 2
Hide Description Percentage of participants with objective response (OR) based assessment of confirmed complete response(CR) or confirmed partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST). Confirmed CR defined as disappearance of all lesions and no appearance of new lesions. Confirmed PR defined as >=30 percent (%) decrease in sum of the longest dimensions (LD) of the target lesions taking as reference the baseline sum LD , without progression of nontarget lesions and no appearance of new lesions. Confirmed responses are those that persist on repeat imaging study >=4 weeks after initial documentation of response.
Time Frame Baseline (Phase 2) until disease progression, assessed every 6 weeks up to Week 148 (Phase 2) or follow-up (every 6 weeks after last dose of study drug until progression or start of alternate therapy)
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat (ITT) population included all randomized participants, with study drug assignment designated according to initial randomization, regardless of whether participants received study drug or received a different drug from that to which they were randomized.
Arm/Group Title Phase 2: Axitinib + FOLFOX Phase 2: Bevacizumab + FOLFOX Phase 2: Axitinib + Bevacizumab + FOLFOX
Hide Arm/Group Description:
FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily in each 14-day cycle administered prior to oxaliplatin infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
Bevacizumab 5 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
Bevacizumab 2 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily in each 14-day cycle administered following bevacizumab infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
Overall Number of Participants Analyzed 42 43 41
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of participants
28.6
(15.7 to 44.6)
48.8
(33.3 to 64.5)
39.0
(24.2 to 55.5)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Phase 2: Axitinib + FOLFOX, Phase 2: Bevacizumab + FOLFOX
Comments One-sided Cochran-Mantel-Haenszel test of treatment stratified by prior adjuvant chemotherapy (yes versus [vs.] no) and prior pelvic irradiation (yes vs. no) was used for the analysis.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.9726
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Ratio (RR)
Estimated Value 0.585
Confidence Interval (2-Sided) 95%
0.332 to 1.031
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Phase 2: Axitinib + FOLFOX, Phase 2: Axitinib + Bevacizumab + FOLFOX
Comments One-sided Cochran-Mantel-Haenszel test of treatment stratified by prior adjuvant chemotherapy (yes vs. no) and prior pelvic irradiation (yes vs. no) was used for the analysis.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.8391
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Ratio (RR)
Estimated Value 0.735
Confidence Interval (2-Sided) 95%
0.399 to 1.352
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Phase 2: Bevacizumab + FOLFOX, Phase 2: Axitinib + Bevacizumab + FOLFOX
Comments One-sided Cochran-Mantel-Haenszel test of treatment stratified by prior adjuvant chemotherapy (yes vs. no) and prior pelvic irradiation (yes vs. no) was used for the analysis.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.8192
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Ratio (RR)
Estimated Value 0.797
Confidence Interval (2-Sided) 95%
0.489 to 1.299
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Area Under the Concentration-Time Curve From Time Zero to Last Quantifiable Concentration (AUClast) For Axitinib: Phase 1
Hide Description Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast). Pharmacokinetic (PK) parameters of axitinib (AG-013736) were combined for Cohorts 1, 2, and 3. AUClast for axitinib in absence of bevacizumab + FOLFOX was estimated from Cycle 1 Day 8 data and in presence of bevacizumab + FOLFOX was estimated from Cycle 2 Day 1 data. Results were normalized to axitinib 5 mg dose.
Time Frame Predose, 1, 2, 2.5, 4, 6 and 8 hours postdose on Cycle 1 Day 8, Cycle 2 Day 1
Hide Outcome Measure Data
Hide Analysis Population Description
PK parameter analysis set included all treated participants who had at least 1 estimated PK parameters of primary interest. PK assessments were done only for cohort 1 to 5, as per planned analysis. Here 'N' (Number of participants analyzed) signifies those participants who were evaluable for this measure.
Arm/Group Title Phase 1: Axitinib + Bevacizumab + FOLFOX (Cohort 1-3) Phase 1: Axitinib + FOLFIRI (Cohort 4) Phase 1: Axitinib + FOLFOX (Cohort 5)
Hide Arm/Group Description:
Bevacizumab 1, 2 or 5 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered following bevacizumab infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
FOLFIRI combination chemotherapy on Day 1 of each 14-day cycle consisting of irinotecan 180 mg/m^2 intravenous infusion over 90 minutes, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with irinotecan, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered prior to irinotecan infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered prior to oxaliplatin infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
Overall Number of Participants Analyzed 12 6 6
Geometric Mean (95% Confidence Interval)
Unit of Measure: nanogram hour per milliliter (ng*hr/mL)
Cycle 1 Day 8
119.02
(56.17 to 252.21)
106.76
(27.27 to 417.89)
97.05
(49.01 to 192.16)
Cycle 2 Day 1
95.70
(45.16 to 202.80)
143.68
(36.70 to 562.43)
117.47
(59.32 to 232.60)
3.Secondary Outcome
Title Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)] For Axitinib: Phase 1
Hide Description AUC (0 - ∞)= Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - ∞). It was obtained from AUC (0 - t) plus AUC (t - ∞). PK parameters of axitinib (AG-013736) were combined for Cohorts 1, 2, and 3. AUC (t - ∞] for axitinib in absence of bevacizumab + FOLFOX was estimated from Cycle 1 Day 8 data and in presence of bevacizumab + FOLFOX was estimated from Cycle 2 Day 1 data. Results were normalized to axitinib 5 mg dose.
Time Frame Predose, 1, 2, 2.5, 4, 6, 8 hours postdose on Cycle 1 Day 8, Cycle 2 Day 1
Hide Outcome Measure Data
Hide Analysis Population Description
PK parameter analysis set included all treated participants who had at least 1 estimated PK parameters of primary interest. PK assessments were done only for cohort 1 to 5, as per planned analysis. Here 'N' (Number of participants analyzed) signifies those participants who were evaluable for this measure.
Arm/Group Title Phase 1: Axitinib + Bevacizumab + FOLFOX (Cohort 1-3) Phase 1: Axitinib + FOLFIRI (Cohort 4) Phase 1: Axitinib + FOLFOX (Cohort 5)
Hide Arm/Group Description:
Bevacizumab 1, 2 or 5 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered following bevacizumab infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
FOLFIRI combination chemotherapy on Day 1 of each 14-day cycle consisting of irinotecan 180 mg/m^2 intravenous infusion over 90 minutes, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with irinotecan, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered prior to irinotecan infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered prior to oxaliplatin infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
Overall Number of Participants Analyzed 8 4 3
Geometric Mean (95% Confidence Interval)
Unit of Measure: ng*hr/mL
Cycle 1 Day 8
190.51
(77.99 to 465.35)
113.20
(8.89 to 1442.19)
205.41
(53.61 to 787.01)
Cycle 2 Day 1
224.46
(91.89 to 548.29)
168.07
(13.19 to 2141.15)
178.46
(46.58 to 683.73)
4.Secondary Outcome
Title Maximum Observed Plasma Concentration (Cmax) For Axitinib: Phase 1
Hide Description PK parameters of axitinib (AG-013736) were combined for Cohorts 1, 2, and 3.Cmax for axitinib (AG-013736) in absence of bevacizumab + FOLFOX was estimated from Cycle 1 Day 8 data and in presence of bevacizumab + FOLFOX was estimated from Cycle 2 Day 1 data. Results were normalized to axitinib 5 mg dose.
Time Frame Predose, 1, 2, 2.5, 4, 6, 8 hours postdose on Cycle 1 Day 8, Cycle 2 Day 1
Hide Outcome Measure Data
Hide Analysis Population Description
PK parameter analysis set included all treated participants who had at least 1 estimated PK parameters of primary interest. PK assessments were done only for cohort 1 to 5, as per planned analysis. Here 'N' (Number of participants analyzed) signifies those participants who were evaluable for this measure.
Arm/Group Title Phase 1: Axitinib + Bevacizumab + FOLFOX (Cohort 1-3) Phase 1: Axitinib + FOLFIRI (Cohort 4) Phase 1: Axitinib + FOLFOX (Cohort 5)
Hide Arm/Group Description:
Bevacizumab 1, 2 or 5 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered following bevacizumab infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
FOLFIRI combination chemotherapy on Day 1 of each 14-day cycle consisting of irinotecan 180 mg/m^2 intravenous infusion over 90 minutes, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with irinotecan, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered prior to irinotecan infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered prior to oxaliplatin infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
Overall Number of Participants Analyzed 12 6 6
Geometric Mean (95% Confidence Interval)
Unit of Measure: ng/mL
Cycle 1 Day 8
35.57
(18.37 to 68.89)
27.14
(7.40 to 99.49)
24.23
(14.32 to 40.98)
Cycle 2 Day 1
27.51
(14.20 to 53.28)
42.48
(11.59 to 155.73)
32.62
(19.29 to 55.18)
5.Secondary Outcome
Title Minimum Observed Plasma Trough Concentration (Cmin) For Axitinib: Phase 1
Hide Description [Not Specified]
Time Frame Predose, 1, 2, 2.5, 4, 6, 8 hours postdose on Cycle 1 Day 8, Cycle 2 Day 1
Hide Outcome Measure Data
Hide Analysis Population Description
PK assessments were done only for cohort 1 to 5, as per planned analysis. Results for Cmin are not reported because Cmin could not be assessed from the data obtained from the study.
Arm/Group Title Phase 1: Axitinib + Bevacizumab + FOLFOX (Cohort 1-3) Phase 1: Axitinib + FOLFIRI (Cohort 4) Phase 1: Axitinib + FOLFOX (Cohort 5)
Hide Arm/Group Description:
Bevacizumab 1, 2 or 5 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered following bevacizumab infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
FOLFIRI combination chemotherapy on Day 1 of each 14-day cycle consisting of irinotecan 180 mg/m^2 intravenous infusion over 90 minutes, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with irinotecan, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered prior to irinotecan infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered prior to oxaliplatin infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
Overall Number of Participants Analyzed 0 0 0
No data displayed because Outcome Measure has zero total analyzed.
6.Secondary Outcome
Title Apparent Oral Clearance (CL/F) For Axitinib: Phase 1
Hide Description Clearance (CL) of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed (F). Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. PK parameters of axitinib (AG-013736) were combined for Cohorts 1, 2, and 3. CL/F for axitinib (AG-013736) in absence of bevacizumab + FOLFOX was estimated from Cycle 1 Day 8 data and in presence of bevacizumab + FOLFOX was estimated from Cycle 2 Day 1 data.
Time Frame Predose, 1, 2, 2.5, 4, 6, 8 hours postdose on Cycle 1 Day 8, Cycle 2 Day 1
Hide Outcome Measure Data
Hide Analysis Population Description
PK parameter analysis set included all treated participants who had at least 1 estimated PK parameters of primary interest. PK assessments were done only for cohort 1 to 5, as per planned analysis. Here 'N' (Number of participants analyzed) signifies those participants who were evaluable for this measure.
Arm/Group Title Phase 1: Axitinib + Bevacizumab + FOLFOX (Cohort 1-3) Phase 1: Axitinib + FOLFIRI (Cohort 4) Phase 1: Axitinib + FOLFOX (Cohort 5)
Hide Arm/Group Description:
Bevacizumab 1, 2 or 5 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered following bevacizumab infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
FOLFIRI combination chemotherapy on Day 1 of each 14-day cycle consisting of irinotecan 180 mg/m^2 intravenous infusion over 90 minutes, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with irinotecan, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered prior to irinotecan infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered prior to oxaliplatin infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
Overall Number of Participants Analyzed 8 4 3
Geometric Mean (95% Confidence Interval)
Unit of Measure: Liter per hour (L/hr)
Cycle 1 Day 8
30.01
(15.05 to 59.82)
47.10
(3.72 to 596.29)
28.49
(9.32 to 87.03)
Cycle 2 Day 1
30.08
(15.09 to 59.96)
33.33
(2.63 to 421.92)
28.90
(9.46 to 88.31)
7.Secondary Outcome
Title Plasma Decay Half-Life (t1/2) For Axitinib: Phase 1
Hide Description Plasma decay half-life (t1/2) is the time measured for the plasma concentration to decrease by one half. PK parameters of axitinib (AG-013736) were combined for Cohorts 1, 2, and 3. t1/2 for axitinib in absence of bevacizumab + FOLFOX was estimated from Cycle 1 Day 8 data and in presence of bevacizumab + FOLFOX was estimated from Cycle 2 Day 1 data.
Time Frame Predose, 1, 2, 2.5, 4, 6, 8 hours postdose on Cycle 1 Day 8, Cycle 2 Day 1
Hide Outcome Measure Data
Hide Analysis Population Description
PK parameter analysis set included all treated participants who had at least 1 estimated PK parameters of primary interest. PK assessments were done only for cohort 1 to 5, as per planned analysis. Here 'N' (Number of participants analyzed) signifies those participants who were evaluable for this measure.
Arm/Group Title Phase 1: Axitinib + Bevacizumab + FOLFOX (Cohort 1-3) Phase 1: Axitinib + FOLFIRI (Cohort 4) Phase 1: Axitinib + FOLFOX (Cohort 5)
Hide Arm/Group Description:
Bevacizumab 1,2 or 5 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered following bevacizumab infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
FOLFIRI combination chemotherapy on Day 1 of each 14-day cycle consisting of irinotecan 180 mg/m^2 intravenous infusion over 90 minutes, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with irinotecan, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered prior to irinotecan infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered prior to oxaliplatin infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
Overall Number of Participants Analyzed 8 4 3
Mean (Standard Deviation)
Unit of Measure: hours
Cycle 1 Day 8 3.26  (3.943) 2.23  (0.702) 3.47  (2.820)
Cycle 2 Day 1 6.12  (7.450) 3.09  (0.889) 1.73  (0.456)
8.Secondary Outcome
Title Area Under the Concentration-Time Curve From Time Zero to Last Quantifiable Concentration (AUClast) For Oxaliplatin: Phase 1
Hide Description Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast). PK parameters of oxaliplatin, assessed by estimating total platinum in plasma ultrafiltrate, were combined for Cohorts 1, 2, and 3. AUClast for oxaliplatin in absence of axitinib was estimated from Cycle 1 Day 1 data and in presence of axitinib was estimated from Cycle 2 Day 1 data. Results were normalized to Cycle 1 Day 1 oxaliplatin dose.
Time Frame Predose, 1, 2, 2.25, 2.5, 4, 6, 8, 24, 36-48 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1
Hide Outcome Measure Data
Hide Analysis Population Description
PK parameter analysis set included all treated participants who had at least 1 estimated PK parameters of primary interest. PK assessments were done only for cohort 1 to 5, as per planned analysis. Here 'N' (Number of participants analyzed) signifies those participants who were evaluable for this measure.
Arm/Group Title Phase 1: Axitinib + Bevacizumab + FOLFOX (Cohort 1-3) Phase 1: Axitinib + FOLFOX (Cohort 5)
Hide Arm/Group Description:
Bevacizumab 1,2 or 5 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered following bevacizumab infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered prior to oxaliplatin infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
Overall Number of Participants Analyzed 15 5
Geometric Mean (95% Confidence Interval)
Unit of Measure: ng*hr/mL
Cycle 1 Day 1
4814.87
(4079.46 to 5682.84)
4308.71
(2822.77 to 6576.87)
Cycle 2 Day 1
5231.71
(4432.64 to 6174.83)
5303.66
(3474.59 to 8095.57)
9.Secondary Outcome
Title Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)] For Oxaliplatin: Phase 1
Hide Description AUC (0 - ∞)= Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - ∞). It was obtained from AUC (0 - t) plus AUC (t - ∞). PK parameters of oxaliplatin, assessed by estimating total platinum in plasma ultrafiltrate, were combined for Cohorts 1, 2, and 3. AUC (0 - ∞) for oxaliplatin in absence of axitinib was estimated from Cycle 1 Day 1 data and in presence of axitinib was estimated from Cycle 2 Day 1 data. Results were normalized to Cycle 1 Day 1 oxaliplatin dose.
Time Frame Predose, 1, 2, 2.25, 2.5, 4, 6, 8, 24, 36-48 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1
Hide Outcome Measure Data
Hide Analysis Population Description
PK parameter analysis set included all treated participants who had at least 1 estimated PK parameters of primary interest. PK assessments were done only for cohort 1 to 5, as per planned analysis. Here 'N' (Number of participants analyzed) signifies those participants who were evaluable for this measure.
Arm/Group Title Phase 1: Axitinib + Bevacizumab + FOLFOX (Cohort 1-3) Phase 1: Axitinib + FOLFOX (Cohort 5)
Hide Arm/Group Description:
Bevacizumab 1, 2 or 5 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered following bevacizumab infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered prior to oxaliplatin infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
Overall Number of Participants Analyzed 15 5
Geometric Mean (95% Confidence Interval)
Unit of Measure: ng*hr/mL
Cycle 1 Day 1
5955.70
(4615.41 to 7685.21)
5137.31
(3296.14 to 8006.93)
Cycle 2 Day 1
6744.06
(5226.35 to 8702.50)
6430.67
(4125.97 to 10022.74)
10.Secondary Outcome
Title Maximum Observed Plasma Concentration (Cmax) For Oxaliplatin: Phase 1
Hide Description PK parameters of oxaliplatin, assessed by estimating total platinum in plasma ultrafiltrate, were combined for Cohorts 1, 2, and 3. Cmax for oxaliplatin in absence of axitinib was estimated from Cycle 1 Day 1 data and in presence of axitinib was estimated from Cycle 2 Day 1 data. Results were normalized to Cycle 1 Day 1 oxaliplatin dose.
Time Frame Predose, 1, 2, 2.25, 2.5, 4, 6, 8, 24, 36-48 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1
Hide Outcome Measure Data
Hide Analysis Population Description
PK parameter analysis set included all treated participants who had at least 1 estimated PK parameters of primary interest. PK assessments were done only for cohort 1 to 5, as per planned analysis. Here 'N' (Number of participants analyzed) signifies those participants who were evaluable for this measure.
Arm/Group Title Phase 1: Axitinib + Bevacizumab + FOLFOX (Cohort 1-3) Phase 1: Axitinib + FOLFOX (Cohort 5)
Hide Arm/Group Description:
Bevacizumab 1, 2 or 5 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered following bevacizumab infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered prior to oxaliplatin infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
Overall Number of Participants Analyzed 15 5
Geometric Mean (95% Confidence Interval)
Unit of Measure: ng/mL
Cycle 1 Day 1
278.81
(201.38 to 386.03)
265.05
(67.62 to 1038.93)
Cycle 2 Day 1
318.99
(230.40 to 441.66)
374.03
(95.42 to 1466.10)
11.Secondary Outcome
Title Minimum Observed Plasma Trough Concentration (Cmin) For Oxaliplatin: Phase 1
Hide Description [Not Specified]
Time Frame Predose, 1, 2, 2.25, 2.5, 4, 6, 8, 24, 36-48 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1
Hide Outcome Measure Data
Hide Analysis Population Description
PK assessments were done only for cohort 1 to 5, as per planned analysis. Results for Cmin are not reported because Cmin could not be assessed from the data obtained from the study.
Arm/Group Title Phase 1: Axitinib + Bevacizumab + FOLFOX (Cohort 1-3) Phase 1: Axitinib + FOLFOX (Cohort 5)
Hide Arm/Group Description:
Bevacizumab 1, 2 or 5 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered following bevacizumab infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered prior to oxaliplatin infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
Overall Number of Participants Analyzed 0 0
No data displayed because Outcome Measure has zero total analyzed.
12.Secondary Outcome
Title Clearance (CL) For Oxaliplatin: Phase 1
Hide Description CL is a quantitative measure of the rate at which a drug substance is removed from the body. PK parameters of oxaliplatin, assessed by estimating total platinum in plasma ultrafiltrate, were combined for Cohorts 1, 2, and 3. CL for oxaliplatin in absence of axitinib was estimated from Cycle 1 Day 1 data and in presence of axitinib was estimated from Cycle 2 Day 1 data.
Time Frame Predose, 1, 2, 2.25, 2.5, 4, 6, 8, 24, 36-48 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1
Hide Outcome Measure Data
Hide Analysis Population Description
PK parameter analysis set included all treated participants who had at least 1 estimated PK parameters of primary interest. PK assessments were done only for cohort 1 to 5, as per planned analysis. Here 'N' (Number of participants analyzed) signifies those participants who were evaluable for this measure.
Arm/Group Title Phase 1: Axitinib + Bevacizumab + FOLFOX (Cohort 1-3) Phase 1: Axitinib + FOLFOX (Cohort 5)
Hide Arm/Group Description:
Bevacizumab 1, 2 or 5 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered following bevacizumab infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered prior to oxaliplatin infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
Overall Number of Participants Analyzed 15 5
Geometric Mean (95% Confidence Interval)
Unit of Measure: L/hr
Cycle 1 Day 1
27.51
(21.56 to 35.11)
30.74
(18.48 to 51.13)
Cycle 2 Day 1
24.29
(19.04 to 31.00)
24.56
(14.76 to 40.85)
13.Secondary Outcome
Title Plasma Decay Half-Life (t1/2) For Oxaliplatin: Phase 1
Hide Description Plasma decay half-life (t1/2) is the time measured for the plasma concentration to decrease by one half. PK parameters of oxaliplatin, assessed by estimating total platinum in plasma ultrafiltrate, were combined for Cohorts 1, 2, and 3. t1/2 for oxaliplatin in absence of axitinib was estimated from Cycle 1 Day 1 data and in presence of axitinib was estimated from Cycle 2 Day 1 data.
Time Frame Predose, 1, 2, 2.25, 2.5, 4, 6, 8, 24, 36-48 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1
Hide Outcome Measure Data
Hide Analysis Population Description
PK parameter analysis set included all treated participants who had at least 1 estimated PK parameters of primary interest. PK assessments were done only for cohort 1 to 5, as per planned analysis. Here 'N' (Number of participants analyzed) signifies those participants who were evaluable for this measure.
Arm/Group Title Phase 1: Axitinib + Bevacizumab + FOLFOX (Cohort 1-3) Phase 1: Axitinib + FOLFOX (Cohort 5)
Hide Arm/Group Description:
Bevacizumab 1, 2 or 5 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered following bevacizumab infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered prior to oxaliplatin infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
Overall Number of Participants Analyzed 15 5
Mean (Standard Deviation)
Unit of Measure: hours
Cycle 1 Day 1 20.63  (6.513) 18.38  (3.004)
Cycle 2 Day 1 23.30  (14.975) 19.86  (4.110)
14.Secondary Outcome
Title Area Under the Concentration-Time Curve From Time Zero to Last Quantifiable Concentration (AUClast) For 5-Fluorouracil: Phase 1
Hide Description Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast). PK parameters of 5-FU were combined for Cohorts 1, 2, and 3. AUClast for 5-FU in absence of axitinib was estimated from Cycle 1 Day 1 data and in presence of axitinib was estimated from Cycle 2 Day 1 data. Results were normalized to Cycle 1 Day 1 5-FU dose.
Time Frame Pre-5-FU bolus, 5 min (post-5-FU bolus), 0.25, 0.5, 0.75, 2, 4, 6, 22, 34-46 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1
Hide Outcome Measure Data
Hide Analysis Population Description
PK parameter analysis set included all treated participants who had at least 1 estimated PK parameters of primary interest. PK assessments were done only for cohort 1 to 5, as per planned analysis. Here 'N' (Number of participants analyzed) signifies those participants who were evaluable for this measure.
Arm/Group Title Phase 1: Axitinib + Bevacizumab + FOLFOX (Cohort 1-3) Phase 1: Axitinib + FOLFIRI (Cohort 4) Phase 1: Axitinib + FOLFOX (Cohort 5)
Hide Arm/Group Description:
Bevacizumab 1, 2 or 5 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered following bevacizumab infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
FOLFIRI combination chemotherapy on Day 1 of each 14-day cycle consisting of irinotecan 180 mg/m^2 intravenous infusion over 90 minutes, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with irinotecan, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered prior to irinotecan infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered prior to oxaliplatin infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
Overall Number of Participants Analyzed 14 7 5
Geometric Mean (95% Confidence Interval)
Unit of Measure: ng*hr/mL
Cycle 1 Day 1
39212.03
(22388.50 to 68677.39)
40955.29
(23831.07 to 70384.39)
52164.28
(4725.16 to 575877.57)
Cycle 2 Day 1
45087.71
(25743.27 to 78968.27)
36533.84
(21258.32 to 62785.83)
95123.13
(8616.47 to 1050129.94)
15.Secondary Outcome
Title Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)] For 5-Fluorouracil: Phase 1
Hide Description AUC (0 - ∞)= Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - ∞). It was obtained from AUC (0 - t) plus AUC (t - ∞). PK parameters of 5-FU were combined for Cohorts 1, 2, and 3. AUC (0 - ∞) for 5-FU in absence of axitinib was estimated from Cycle 1 Day 1 data and in presence of axitinib was estimated from Cycle 2 Day 1 data. Results were normalized to Cycle 1 Day 1 5-FU dose.
Time Frame Pre-5-FU bolus, 5 min (post-5-FU bolus), 0.25, 0.5, 0.75, 2, 4, 6, 22, 34-46 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1
Hide Outcome Measure Data
Hide Analysis Population Description
PK parameter analysis set included all treated participants who had at least 1 estimated PK parameters of primary interest. PK assessments were done only for cohort 1 to 5, as per planned analysis. Here 'N' (Number of participants analyzed) signifies those participants who were evaluable for this measure.
Arm/Group Title Phase 1: Axitinib + Bevacizumab + FOLFOX (Cohort 1-3) Phase 1: Axitinib + FOLFIRI (Cohort 4) Phase 1: Axitinib + FOLFOX (Cohort 5)
Hide Arm/Group Description:
Bevacizumab 1, 2 or 5 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered following bevacizumab infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
FOLFIRI combination chemotherapy on Day 1 of each 14-day cycle consisting of irinotecan 180 mg/m^2 intravenous infusion over 90 minutes, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with irinotecan, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered prior to irinotecan infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered prior to oxaliplatin infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
Overall Number of Participants Analyzed 9 7 5
Geometric Mean (95% Confidence Interval)
Unit of Measure: ng*hr/mL
Cycle 1 Day 1
36314.14
(19623.50 to 67200.90)
41460.50
(23968.34 to 71718.51)
52430.15
(4751.38 to 578551.86)
Cycle 2 Day 1
38983.80
(21066.13 to 72141.23)
36776.79
(21260.68 to 63616.60)
96632.41
(8757.13 to 1066311.16)
16.Secondary Outcome
Title Maximum Observed Plasma Concentration (Cmax) For 5-Fluorouracil: Phase 1
Hide Description PK parameters of 5-FU were combined for Cohorts 1, 2, and 3. Cmax for 5-FU in absence of axitinib was estimated from Cycle 1 Day 1 data and in presence of axitinib was estimated from Cycle 2 Day 1 data. Results were normalized to Cycle 1 Day 1 5-FU dose.
Time Frame Pre-5-FU bolus, 5 min (post-5-FU bolus), 0.25, 0.5, 0.75, 2, 4, 6, 22, 34-46 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1
Hide Outcome Measure Data
Hide Analysis Population Description
PK parameter analysis set included all treated participants who had at least 1 estimated PK parameters of primary interest. PK assessments were done only for cohort 1 to 5, as per planned analysis. Here 'N' (Number of participants analyzed) signifies those participants who were evaluable for this measure.
Arm/Group Title Phase 1: Axitinib + Bevacizumab + FOLFOX (Cohort 1-3) Phase 1: Axitinib + FOLFIRI (Cohort 4) Phase 1: Axitinib + FOLFOX (Cohort 5)
Hide Arm/Group Description:
Bevacizumab 1, 2 or 5 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered following bevacizumab infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
FOLFIRI combination chemotherapy on Day 1 of each 14-day cycle consisting of irinotecan 180 mg/m^2 intravenous infusion over 90 minutes, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with irinotecan, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered prior to irinotecan infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered prior to oxaliplatin infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
Overall Number of Participants Analyzed 14 7 5
Geometric Mean (95% Confidence Interval)
Unit of Measure: ng/mL
Cycle 1 Day 1
16160.85
(6975.82 to 37439.78)
34436.94
(22763.46 to 52096.78)
19622.74
(2754.12 to 139809.41)
Cycle 2 Day 1
16249.77
(7014.20 to 37645.79)
39730.46
(26262.58 to 60104.90)
34180.87
(4797.41 to 243534.09)
17.Secondary Outcome
Title Minimum Observed Plasma Trough Concentration (Cmin) For 5-Fluorouracil: Phase 1
Hide Description [Not Specified]
Time Frame Pre-5-FU bolus, 5 min (post-5-FU bolus), 0.25, 0.5, 0.75, 2, 4, 6, 22, 34-48 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1
Hide Outcome Measure Data
Hide Analysis Population Description
PK assessments were done only for cohort 1 to 5, as per planned analysis. Results for Cmin are not reported because Cmin could not be assessed from the data obtained from the study.
Arm/Group Title Phase 1: Axitinib + Bevacizumab + FOLFOX (Cohort 1-3) Phase 1: Axitinib + FOLFIRI (Cohort 4) Phase 1: Axitinib + FOLFOX (Cohort 5)
Hide Arm/Group Description:
Bevacizumab 1, 2 or 5 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered following bevacizumab infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
FOLFIRI combination chemotherapy on Day 1 of each 14-day cycle consisting of irinotecan 180 mg/m^2 intravenous infusion over 90 minutes, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with irinotecan, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered prior to irinotecan infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered prior to oxaliplatin infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
Overall Number of Participants Analyzed 0 0 0
No data displayed because Outcome Measure has zero total analyzed.
18.Secondary Outcome
Title Clearance (CL) For 5-Fluorouracil: Phase 1
Hide Description CL is a quantitative measure of the rate at which a drug substance is removed from the body. PK parameters of 5-FU were combined for Cohorts 1, 2, and 3. CL for 5-FU in absence of axitinib was estimated from Cycle 1 Day 1 data and in presence of axitinib was estimated from Cycle 2 Day 1 data.
Time Frame Pre-5-FU bolus, 5 min (post-5-FU bolus), 0.25, 0.5, 0.75, 2, 4, 6, 22, 34-46 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1
Hide Outcome Measure Data
Hide Analysis Population Description
PK parameter analysis set included all treated participants who had at least 1 estimated PK parameters of primary interest. PK assessments were done only for cohort 1 to 5, as per planned analysis. Here 'N' (Number of participants analyzed) signifies those participants who were evaluable for this measure.
Arm/Group Title Phase 1: Axitinib + Bevacizumab + FOLFOX (Cohort 1-3) Phase 1: Axitinib + FOLFIRI (Cohort 4) Phase 1: Axitinib + FOLFOX (Cohort 5)
Hide Arm/Group Description:
Bevacizumab 1, 2 or 5 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered following bevacizumab infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
FOLFIRI combination chemotherapy on Day 1 of each 14-day cycle consisting of irinotecan 180 mg/m^2 intravenous infusion over 90 minutes, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with irinotecan, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered prior to irinotecan infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered prior to oxaliplatin infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
Overall Number of Participants Analyzed 9 7 5
Geometric Mean (95% Confidence Interval)
Unit of Measure: L/hr
Cycle 1 Day 1
147.43
(77.38 to 280.93)
128.28
(73.44 to 224.05)
99.36
(10.18 to 969.40)
Cycle 2 Day 1
137.34
(72.08 to 261.70)
144.62
(82.80 to 252.59)
53.92
(5.53 to 526.06)
19.Secondary Outcome
Title Plasma Decay Half-Life (t1/2) For 5-Fluorouracil: Phase 1
Hide Description Plasma decay half-life (t1/2) is the time measured for the plasma concentration to decrease by one half. PK parameters of 5-FU were combined for Cohorts 1, 2, and 3. t1/2 for 5-FU in absence of axitinib was estimated from Cycle 1 Day 1 data and in presence of axitinib was estimated from Cycle 2 Day 1 data.
Time Frame Pre-5-FU bolus, 5 min (post-5-FU bolus), 0.25, 0.5, 0.75, 2, 4, 6, 22, 34-46 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1
Hide Outcome Measure Data
Hide Analysis Population Description
PK parameter analysis set included all treated participants who had at least 1 estimated PK parameters of primary interest. PK assessments were done only for cohort 1 to 5, as per planned analysis. Here 'N' (Number of participants analyzed) signifies those participants who were evaluable for this measure.
Arm/Group Title Phase 1: Axitinib + Bevacizumab + FOLFOX (Cohort 1-3) Phase 1: Axitinib + FOLFIRI (Cohort 4) Phase 1: Axitinib + FOLFOX (Cohort 5)
Hide Arm/Group Description:
Bevacizumab 1, 2 or 5 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered following bevacizumab infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
FOLFIRI combination chemotherapy on Day 1 of each 14-day cycle consisting of irinotecan 180 mg/m^2 intravenous infusion over 90 minutes, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with irinotecan, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered prior to irinotecan infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered prior to oxaliplatin infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
Overall Number of Participants Analyzed 9 7 5
Mean (Standard Deviation)
Unit of Measure: hours
Cycle 1 Day 1 0.26  (0.218) 0.19  (0.069) 0.39  (0.291)
Cycle 2 Day 1 0.25  (0.142) 0.14  (0.029) 0.24  (0.131)
20.Secondary Outcome
Title Area Under the Concentration-Time Curve From Time Zero to Last Quantifiable Concentration (AUClast) For Irinotecan: Phase 1
Hide Description Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast). AUClast for irinotecan in absence of axitinib was estimated from Cycle 1 Day 1 data and in presence of axitinib was estimated from Cycle 2 Day 1 data. Results were normalized to Cycle 1 Day 1 irinotecan dose.
Time Frame Predose, 1, 2, 2.5, 4, 6, 8, 24 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1
Hide Outcome Measure Data
Hide Analysis Population Description
PK parameter analysis set included all treated participants who had at least 1 estimated PK parameters of primary interest. PK assessments were done only for cohort 1 to 5, as per planned analysis. Here 'N' (Number of participants analyzed) signifies those participants who were evaluable for this measure.
Arm/Group Title Phase 1: Axitinib + FOLFIRI (Cohort 4)
Hide Arm/Group Description:
FOLFIRI combination chemotherapy on Day 1 of each 14-day cycle consisting of irinotecan 180 mg/m^2 intravenous infusion over 90 minutes, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with irinotecan, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered prior to irinotecan infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
Overall Number of Participants Analyzed 7
Geometric Mean (95% Confidence Interval)
Unit of Measure: ng*hr/mL
Cycle 1 Day 1
12081.58
(8805.17 to 16577.15)
Cycle 2 Day 1
11496.32
(8378.62 to 15774.11)
21.Secondary Outcome
Title Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)] For Irinotecan: Phase 1
Hide Description AUC (0 - ∞)= Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - ∞). It was obtained from AUC (0 - t) plus AUC (t - ∞). AUC (0 - ∞) for irinotecan in absence of axitinib was estimated from Cycle 1 Day 1 data and in presence of axitinib was estimated from Cycle 2 Day 1 data. Results were normalized to Cycle 1 Day 1 irinotecan dose.
Time Frame Predose, 1, 2, 2.5, 4, 6, 8, 24 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1
Hide Outcome Measure Data
Hide Analysis Population Description
PK parameter analysis set included all treated participants who had at least 1 estimated PK parameters of primary interest. PK assessments were done only for cohort 1 to 5, as per planned analysis. Here 'N' (Number of participants analyzed) signifies those participants who were evaluable for this measure.
Arm/Group Title Phase 1: Axitinib + FOLFIRI (Cohort 4)
Hide Arm/Group Description:
FOLFIRI combination chemotherapy on Day 1 of each 14-day cycle consisting of irinotecan 180 mg/m^2 intravenous infusion over 90 minutes, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with irinotecan, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered prior to irinotecan infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
Overall Number of Participants Analyzed 7
Geometric Mean (95% Confidence Interval)
Unit of Measure: ng*hr/mL
Cycle 1 Day 1
13055.88
(9371.39 to 18188.96)
Cycle 2 Day 1
12459.89
(8943.60 to 17358.66)
22.Secondary Outcome
Title Maximum Observed Plasma Concentration (Cmax) For Irinotecan: Phase 1
Hide Description Cmax for irinotecan in absence of axitinib was estimated from Cycle 1 Day 1 data and in presence of axitinib was estimated from Cycle 2 Day 1 data. Results were normalized to Cycle 1 Day 1 irinotecan dose.
Time Frame Predose, 1, 2, 2.5, 4, 6, 8, 24 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1
Hide Outcome Measure Data
Hide Analysis Population Description
PK parameter analysis set included all treated participants who had at least 1 estimated PK parameters of primary interest. PK assessments were done only for cohort 1 to 5, as per planned analysis. Here 'N' (Number of participants analyzed) signifies those participants who were evaluable for this measure.
Arm/Group Title Phase 1: Axitinib + FOLFIRI (Cohort 4)
Hide Arm/Group Description:
FOLFIRI combination chemotherapy on Day 1 of each 14-day cycle consisting of irinotecan 180 mg/m^2 intravenous infusion over 90 minutes, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with irinotecan, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered prior to irinotecan infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
Overall Number of Participants Analyzed 7
Geometric Mean (95% Confidence Interval)
Unit of Measure: ng/mL
Cycle 1 Day 1
1910.25
(1561.45 to 2336.97)
Cycle 2 Day 1
1788.69
(1462.08 to 2188.26)
23.Secondary Outcome
Title Minimum Observed Plasma Trough Concentration (Cmin) For Irinotecan: Phase 1
Hide Description [Not Specified]
Time Frame Predose, 1, 2, 2.5, 4, 6, 8, 24 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1
Hide Outcome Measure Data
Hide Analysis Population Description
PK assessments were done only for cohort 1 to 5, as per planned analysis. Results for Cmin are not reported because Cmin could not be assessed from the data obtained from the study.
Arm/Group Title Phase 1: Axitinib + FOLFIRI (Cohort 4)
Hide Arm/Group Description:
FOLFIRI combination chemotherapy on Day 1 of each 14-day cycle consisting of irinotecan 180 mg/m^2 intravenous infusion over 90 minutes, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with irinotecan, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered prior to irinotecan infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
Overall Number of Participants Analyzed 0
No data displayed because Outcome Measure has zero total analyzed.
24.Secondary Outcome
Title Clearance (CL) For Irinotecan: Phase 1
Hide Description CL is a quantitative measure of the rate at which a drug substance is removed from the body. CL for irinotecan in absence of axitinib was estimated from Cycle 1 Day 1 data and in presence of axitinib was estimated from Cycle 2 Day 1 data.
Time Frame Predose, 1, 2, 2.5, 4, 6, 8, 24 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1
Hide Outcome Measure Data
Hide Analysis Population Description
PK parameter analysis set included all treated participants who had at least 1 estimated PK parameters of primary interest. PK assessments were done only for cohort 1 to 5, as per planned analysis. Here 'N' (Number of participants analyzed) signifies those participants who were evaluable for this measure.
Arm/Group Title Phase 1: Axitinib + FOLFIRI (Cohort 4)
Hide Arm/Group Description:
FOLFIRI combination chemotherapy on Day 1 of each 14-day cycle consisting of irinotecan 180 mg/m^2 intravenous infusion over 90 minutes, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with irinotecan, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered prior to irinotecan infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
Overall Number of Participants Analyzed 7
Geometric Mean (95% Confidence Interval)
Unit of Measure: L/hr
Cycle 1 Day 8
26.09
(18.10 to 37.61)
Cycle 2 Day 1
27.34
(18.97 to 39.40)
25.Secondary Outcome
Title Plasma Decay Half-Life (t1/2) For Irinotecan: Phase 1
Hide Description Plasma decay half-life (t1/2) is the time measured for the plasma concentration to decrease by one half. t1/2 for irinotecan in absence of axitinib was estimated from Cycle 1 Day 1 data and in presence of axitinib was estimated from Cycle 2 Day 1 data.
Time Frame Predose, 1, 2, 2.5, 4, 6, 8, 24 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1
Hide Outcome Measure Data
Hide Analysis Population Description
PK parameter analysis set included all treated participants who had at least 1 estimated PK parameters of primary interest. PK assessments were done only for cohort 1 to 5, as per planned analysis. Here 'N' (Number of participants analyzed) signifies those participants who were evaluable for this measure.
Arm/Group Title Phase 1: Axitinib + FOLFIRI (Cohort 4)
Hide Arm/Group Description:
FOLFIRI combination chemotherapy on Day 1 of each 14-day cycle consisting of irinotecan 180 mg/m^2 intravenous infusion over 90 minutes, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with irinotecan, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered prior to irinotecan infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
Overall Number of Participants Analyzed 7
Mean (Standard Deviation)
Unit of Measure: hours
Cycle 1 Day 1 6.45  (1.406)
Cycle 2 Day 1 6.75  (0.886)
26.Secondary Outcome
Title Area Under the Concentration-Time Curve From Time Zero to Last Quantifiable Concentration (AUClast) For Bevacizumab: Phase 1
Hide Description Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast). PK parameters of bevacizumab were combined for Cohorts 1, 2, and 3. AUClast for bevacizumab in absence of axitinib was estimated from Cycle 1 Day 1 data and in presence of axitinib was estimated from Cycle 2 Day 1 data. The bevacizumab pharmacokinetic parameters were normalized to 1 mg/kg dose.
Time Frame Predose, 1, 2, 2.25, 2.5, 4, 6, 8, 24, 36-48 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1
Hide Outcome Measure Data
Hide Analysis Population Description
PK parameter analysis set included all treated participants who had at least 1 estimated PK parameters of primary interest. PK assessments were done only for cohort 1 to 5, as per planned analysis. Here 'N' (Number of participants analyzed) signifies those participants who were evaluable for this measure.
Arm/Group Title Phase 1: Axitinib + Bevacizumab + FOLFOX (Cohort 1-3)
Hide Arm/Group Description:
Bevacizumab 1, 2 or 5 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered following bevacizumab infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
Overall Number of Participants Analyzed 9
Geometric Mean (95% Confidence Interval)
Unit of Measure: ng*hr/mL
Cycle 1 Day 1
3394758.83
(2453600.72 to 4696928.65)
Cycle 2 Day 1
3554899.52
(2569344.23 to 4918496.49)
27.Secondary Outcome
Title Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)] For Bevacizumab: Phase 1
Hide Description AUC (0 - ∞)= Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - ∞). It was obtained from AUC (0 - t) plus AUC (t - ∞). PK parameters of bevacizumab were combined for Cohorts 1, 2, and 3. AUC (0 - ∞) for bevacizumab in absence of axitinib was estimated from Cycle 1 Day 1 data and in presence of axitinib was estimated from Cycle 2 Day 1 data. The bevacizumab pharmacokinetic parameters were normalized to 1 mg/kg dose.
Time Frame Predose, 1, 2, 2.25, 2.5, 4, 6, 8, 24, 36-48 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1
Hide Outcome Measure Data
Hide Analysis Population Description
PK parameter analysis set included all treated participants who had at least 1 estimated PK parameters of primary interest. PK assessments were done only for cohort 1 to 5, as per planned analysis. Here 'N' (Number of participants analyzed) signifies those participants who were evaluable for this measure.
Arm/Group Title Phase 1: Axitinib + Bevacizumab + FOLFOX (Cohort 1-3)
Hide Arm/Group Description:
Bevacizumab 1, 2 or 5 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered following bevacizumab infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
Overall Number of Participants Analyzed 9
Geometric Mean (95% Confidence Interval)
Unit of Measure: ng*hr/mL
Cycle 1 Day 1
4987528.96
(3395240.62 to 7326563.24)
Cycle 2 Day 1
5114888.84
(3481940.36 to 7513651.92)
28.Secondary Outcome
Title Maximum Observed Plasma Concentration (Cmax) For Bevacizumab: Phase 1
Hide Description PK parameters of bevacizumab were combined for Cohorts 1, 2, and 3. Cmax for bevacizumab in absence of axitinib was estimated from Cycle 1 Day 1 data and in presence of axitinib was estimated from Cycle 2 Day 1 data. The bevacizumab pharmacokinetic parameters were normalized to 1 mg/kg dose.
Time Frame Predose, 1, 2, 2.25, 2.5, 4, 6, 8, 24, 36-48 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1
Hide Outcome Measure Data
Hide Analysis Population Description
PK parameter analysis set included all treated participants who had at least 1 estimated PK parameters of primary interest. PK assessments were done only for cohort 1 to 5, as per planned analysis. Here 'N' (Number of participants analyzed) signifies those participants who were evaluable for this measure.
Arm/Group Title Phase 1: Axitinib + Bevacizumab + FOLFOX (Cohort 1-3)
Hide Arm/Group Description:
Bevacizumab 1, 2 or 5 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered following bevacizumab infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
Overall Number of Participants Analyzed 9
Geometric Mean (95% Confidence Interval)
Unit of Measure: ng/mL
Cycle 1 Day 1
26460.05
(19574.60 to 35767.50)
Cycle 2 Day 1
26850.12
(19863.16 to 36294.76)
29.Secondary Outcome
Title Minimum Observed Plasma Trough Concentration (Cmin) For Bevacizumab: Phase 1
Hide Description [Not Specified]
Time Frame Predose, 1, 2, 2.25, 2.5, 4, 6, 8, 24, 36-48 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1
Hide Outcome Measure Data
Hide Analysis Population Description
PK assessments were done only for cohort 1 to 5, as per planned analysis. Results for Cmin are not reported because Cmin could not be assessed from the data obtained from the study.
Arm/Group Title Phase 1: Axitinib + Bevacizumab + FOLFOX (Cohort 1-3)
Hide Arm/Group Description:
Bevacizumab 1, 2 or 5 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered following bevacizumab infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
Overall Number of Participants Analyzed 0
No data displayed because Outcome Measure has zero total analyzed.
30.Secondary Outcome
Title Clearance (CL) For Bevacizumab: Phase 1
Hide Description CL is a quantitative measure of the rate at which a drug substance is removed from the body. PK parameters of bevacizumab were combined for Cohorts 1, 2, and 3. CL for bevacizumab in absence of axitinib was estimated from Cycle 1 Day 1 data and in presence of axitinib was estimated from Cycle 2 Day 1 data.
Time Frame Predose, 1, 2, 2.25, 2.5, 4, 6, 8, 24, 36-48 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1
Hide Outcome Measure Data
Hide Analysis Population Description
PK parameter analysis set included all treated participants who had at least 1 estimated PK parameters of primary interest. PK assessments were done only for cohort 1 to 5, as per planned analysis. Here 'N' (Number of participants analyzed) signifies those participants who were evaluable for this measure.
Arm/Group Title Phase 1: Axitinib + Bevacizumab + FOLFOX (Cohort 1-3)
Hide Arm/Group Description:
Bevacizumab 1, 2 or 5 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered following bevacizumab infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
Overall Number of Participants Analyzed 9
Geometric Mean (95% Confidence Interval)
Unit of Measure: L/hr
Cycle 1 Day 1
0.01
(0.01 to 0.02)
Cycle 2 Day 1
0.02
(0.01 to 0.02)
31.Secondary Outcome
Title Plasma Decay Half-Life (t1/2) For Bevacizumab: Phase 1
Hide Description Plasma decay half-life (t1/2) is the time measured for the plasma concentration to decrease by one half. PK parameters of bevacizumab were combined for Cohorts 1, 2, and 3. t1/2 for bevacizumab in absence of axitinib was estimated from Cycle 1 Day 1 data and in presence of axitinib was estimated from Cycle 2 Day 1 data.
Time Frame Predose, 1, 2, 2.25, 2.5, 4, 6, 8, 24, 36-48 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1
Hide Outcome Measure Data
Hide Analysis Population Description
PK parameter analysis set included all treated participants who had at least 1 estimated PK parameters of primary interest. PK assessments were done only for cohort 1 to 5, as per planned analysis. Here 'N' (Number of participants analyzed) signifies those participants who were evaluable for this measure.
Arm/Group Title Phase 1: Axitinib + Bevacizumab + FOLFOX (Cohort 1-3)
Hide Arm/Group Description:
Bevacizumab 1, 2 or 5 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered following bevacizumab infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
Overall Number of Participants Analyzed 9
Mean (Standard Deviation)
Unit of Measure: hours
Cycle 1 Day 1 205.97  (46.454)
Cycle 2 Day 1 210.22  (55.317)
32.Secondary Outcome
Title Duration of Response (DR): Phase 2
Time Frame Baseline (Phase 2) until disease progression, assessed every 6 weeks up to Week 148 (Phase 2) or follow-up (every 6 weeks after last dose of study drug until progression or start of alternate therapy)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT population included all randomized participants, with study drug assignment designated according to initial randomization, regardless of whether participants received study drug or received a different drug from that to which they were randomized. 'N' (Number of participants analyzed)= those participants who were evaluable for this measure.
Arm/Group Title Phase 2: Axitinib + FOLFOX Phase 2: Bevacizumab + FOLFOX Phase 2: Axitinib + Bevacizumab + FOLFOX
Hide Arm/Group Description:
FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently or followed by oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily in each 14-day cycle administered prior to oxaliplatin infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
Bevacizumab 5 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently or followed by oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
Bevacizumab 2 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently or followed by oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily in each 14-day cycle administered following bevacizumab infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
Overall Number of Participants Analyzed 12 21 16
Median (95% Confidence Interval)
Unit of Measure: days
434.0
(246.0 to 666.0)
NA [1] 
(232.0 to NA)
343.0
(168.0 to 490.0)
[1]
Data was not estimable since high number of participants was censored for this measure.
33.Secondary Outcome
Title Progression-Free Survival (PFS): Phase 2
Hide Description Time in days from date of randomization to first documentation of objective tumor progression or death due to any cause. PFS was calculated as first event date minus the date of first dose of study medication plus 1. Tumor progression was determined from oncologic assessment data (where data meet the criteria for progressive disease [PD]), or from adverse event (AE) data (where the outcome was "Death"). Progression: >=20% increase in sum of LD of target lesions taking as references the smallest sum LD recorded since treatment start, unequivocal progression of existing nontarget lesions, or appearance of new lesions, occurrence of pleural effusion/ascites, substantiated by cytologic investigation.
Time Frame Baseline (Phase 2) until disease progression, assessed every 6 weeks up to Week 148 (Phase 2) or follow-up (every 6 weeks after last dose of study drug until progression or start of alternate therapy)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT population included all randomized participants, with study drug assignment designated according to initial randomization, regardless of whether participants received study drug or received a different drug from that to which they were randomized.
Arm/Group Title Phase 2: Axitinib + FOLFOX Phase 2: Bevacizumab + FOLFOX Phase 2: Axitinib + Bevacizumab + FOLFOX
Hide Arm/Group Description:
FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently or followed by oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily in each 14-day cycle administered prior to oxaliplatin infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
Bevacizumab 5 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently or followed by oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
Bevacizumab 2 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently or followed by oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily in each 14-day cycle administered following bevacizumab infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
Overall Number of Participants Analyzed 42 43 41
Median (95% Confidence Interval)
Unit of Measure: days
336
(225.0 to 749.0)
485 [1] 
(276.0 to NA)
381
(238.0 to 425.0)
[1]
Data was not estimable since high number of participants was censored for this measure.
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Phase 2: Axitinib + FOLFOX, Phase 2: Bevacizumab + FOLFOX
Comments Hazard ratio and corresponding 95% confidence interval (CI) was calculated based on the Cox proportional hazards model stratified by prior adjuvant chemotherapy (yes vs. no) and prior pelvic irradiation (yes vs. no). One-sided p-value was derived from the log-rank test stratified by prior adjuvant chemotherapy (yes vs. no) and prior pelvic irradiation (yes vs. no).
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.5699
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.08
Confidence Interval (2-Sided) 95%
0.47 to 2.45
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Phase 2: Axitinib + FOLFOX, Phase 2: Axitinib + Bevacizumab + FOLFOX
Comments Hazard ratio and corresponding 95% CI was calculated based on the Cox proportional hazards model stratified by prior adjuvant chemotherapy (yes vs. no) and prior pelvic irradiation (yes vs. no). One-sided p-value was derived from the log-rank test stratified by prior adjuvant chemotherapy (yes vs. no) and prior pelvic irradiation (yes vs. no).
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2167
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.73
Confidence Interval (2-Sided) 95%
0.33 to 1.61
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Phase 2: Bevacizumab + FOLFOX, Phase 2: Axitinib + Bevacizumab + FOLFOX
Comments Hazard ratio and corresponding 95% CI was calculated based on the Cox proportional hazards model stratified by prior adjuvant chemotherapy (yes vs. no) and prior pelvic irradiation (yes vs. no). One-sided p-value was derived from the log-rank test stratified by prior adjuvant chemotherapy (yes vs. no) and prior pelvic irradiation (yes vs. no).
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.8746
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.49
Confidence Interval (2-Sided) 95%
0.75 to 2.98
Estimation Comments [Not Specified]
34.Secondary Outcome
Title Time to Treatment Failure (TTF): Phase 2
Hide Description TTF is defined as the time from the randomization to the date of the first documentation of PD, symptomatic deterioration, death due to any cause, or treatment discontinuation due to adverse event, refusal or other reasons. Progression: >=20% increase in sum of LD of target lesions taking as references the smallest sum LD recorded since treatment start, unequivocal progression of existing nontarget lesions, or appearance of new lesions, occurrence of pleural effusion/ascites, substantiated by cytologic investigation.
Time Frame Baseline (Phase 2) until disease progression, assessed every 6 weeks up to Week 148 (Phase 2) or follow-up (every 6 weeks after last dose of study drug until progression or start of alternate therapy)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT population included all randomized participants, with study drug assignment designated according to initial randomization, regardless of whether participants received study drug or received a different drug from that to which they were randomized.
Arm/Group Title Phase 2: Axitinib + FOLFOX Phase 2: Bevacizumab + FOLFOX Phase 2: Axitinib + Bevacizumab + FOLFOX
Hide Arm/Group Description:
FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently or followed by oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily in each 14-day cycle administered prior to oxaliplatin infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
Bevacizumab 5 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently or followed by oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
Bevacizumab 2 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently or followed by oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily in each 14-day cycle administered following bevacizumab infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
Overall Number of Participants Analyzed 42 43 41
Median (95% Confidence Interval)
Unit of Measure: days
187.0
(162.0 to 315.0)
241.0
(205.0 to 344.0)
238.0
(155.0 to 333.0)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Phase 2: Axitinib + FOLFOX, Phase 2: Bevacizumab + FOLFOX
Comments Hazard ratio and corresponding 95% CI was calculated based on the Cox proportional hazards model stratified by prior adjuvant chemotherapy (yes vs. no) and prior pelvic irradiation (yes vs. no). One-sided p-value was derived from the log-rank test stratified by prior adjuvant chemotherapy (yes vs. no) and prior pelvic irradiation (yes vs. no).
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.8884
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.40
Confidence Interval (2-Sided) 95%
0.81 to 2.41
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Phase 2: Axitinib + FOLFOX, Phase 2: Axitinib + Bevacizumab + FOLFOX
Comments Hazard ratio and corresponding 95% CI was calculated based on the Cox proportional hazards model stratified by prior adjuvant chemotherapy (yes vs. no) and prior pelvic irradiation (yes vs. no). One-sided p-value was derived from the log-rank test stratified by prior adjuvant chemotherapy (yes vs. no) and prior pelvic irradiation (yes vs. no).
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.6648
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.12
Confidence Interval (2-Sided) 95%
0.66 to 1.89
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Phase 2: Bevacizumab + FOLFOX, Phase 2: Axitinib + Bevacizumab + FOLFOX
Comments Hazard ratio and corresponding 95% CI was calculated based on the Cox proportional hazards model stratified by prior adjuvant chemotherapy (yes vs. no) and prior pelvic irradiation (yes vs. no). One-sided p-value was derived from the log-rank test stratified by prior adjuvant chemotherapy (yes vs. no) and prior pelvic irradiation (yes vs. no).
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.8065
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.25
Confidence Interval (2-Sided) 95%
0.75 to 2.07
Estimation Comments [Not Specified]
35.Secondary Outcome
Title Overall Survival (OS): Phase 2
Hide Description Time in days from randomization date to date of death due to any cause. OS was calculated as the death date minus the date of first dose of study medication plus 1. Death was determined from adverse event data (where outcome was death) or from follow-up contact data (where the participant current status was death).
Time Frame Every 3 months after discontinuation of study treatment until death due to any cause or 1 year after randomization of the last participant
Hide Outcome Measure Data
Hide Analysis Population Description
ITT population included all randomized participants , with study drug assignment designated according to initial randomization, regardless of whether participants received study drug or received a different drug from that to which they were randomized.
Arm/Group Title Phase 2: Axitinib + FOLFOX Phase 2: Bevacizumab + FOLFOX Phase 2: Axitinib + Bevacizumab + FOLFOX
Hide Arm/Group Description:
FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently or followed by oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily in each 14-day cycle administered prior to oxaliplatin infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
Bevacizumab 5 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently or followed by oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
Bevacizumab 2 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently or followed by oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily in each 14-day cycle administered following bevacizumab infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
Overall Number of Participants Analyzed 42 43 41
Median (95% Confidence Interval)
Unit of Measure: days
552.0
(443.0 to 911.0)
659.0
(493.0 to 899.0)
601.0
(533.0 to 882.0)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Phase 2: Axitinib + FOLFOX, Phase 2: Bevacizumab + FOLFOX
Comments Hazard ratio and corresponding 95% CI was calculated based on the Cox proportional hazards model stratified by prior adjuvant chemotherapy (yes vs. no) and prior pelvic irradiation (yes vs. no). One-sided p-value was derived from the log-rank test stratified by prior adjuvant chemotherapy (yes vs. no) and prior pelvic irradiation (yes vs. no).
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.6904
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.155
Confidence Interval (2-Sided) 95%
0.656 to 2.033
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Phase 2: Axitinib + FOLFOX, Phase 2: Axitinib + Bevacizumab + FOLFOX
Comments Hazard ratio and corresponding 95% CI was calculated based on the Cox proportional hazards model stratified by prior adjuvant chemotherapy (yes vs. no) and prior pelvic irradiation (yes vs. no). One-sided p-value was derived from the log-rank test stratified by prior adjuvant chemotherapy (yes vs. no) and prior pelvic irradiation (yes vs. no).
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.7364
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.203
Confidence Interval (2-Sided) 95%
0.676 to 2.141
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Phase 2: Bevacizumab + FOLFOX, Phase 2: Axitinib + Bevacizumab + FOLFOX
Comments Hazard ratio and corresponding 95% CI was calculated based on the Cox proportional hazards model stratified by prior adjuvant chemotherapy (yes vs. no) and prior pelvic irradiation (yes vs. no). One-sided p-value was derived from the log-rank test stratified by prior adjuvant chemotherapy (yes vs. no) and prior pelvic irradiation (yes vs. no).
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.4140
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.941
Confidence Interval (2-Sided) 95%
0.535 to 1.653
Estimation Comments [Not Specified]
36.Secondary Outcome
Title Change From Baseline in M.D. Anderson Symptom Assessment Inventory - Diarrhea (MDASI-D) Symptom Severity and Interference Subscale Scores at Day 1 of Cycle 2 Through Day 1 Cycle 42 and Follow-up: Phase 2
Hide Description PROs included assessment of symptom severity and interference which were measured using M.D. Anderson Symptom Assessment Inventory-Diarrhea (MDASI-D), 20-item questionnaire which assesses the severity of 14 symptoms over the past 24 hours, as well as symptoms interference with 6 areas of function (e.g., walking, work, mood), when the symptom was “at its worst”. Each item is scored from 0 to 10, with ‘0’ indicating that the symptom was either not present or did not interfere with their activities, and ‘10’ indicating that the symptom was “as bad as you can imagine” or “interfered completely” with their life. The 2 subscales, symptom severity score and symptom interference score were average of respective items and ranged from 0 to 10, higher score indicating greater severity or interference of symptoms.
Time Frame Cycle 1 Day 1 (baseline), every 2 weeks for the first 2 months (Cycle 2 Day 1 [C2D1], Cycle 3 Day 1, and Cycle 4 Day 1) then monthly thereafter starting Cycle 6 Day 1, and 28 days after the last dose
Hide Outcome Measure Data
Hide Analysis Population Description
ITT population included all randomized participants, with study drug assignment designated according to initial randomization, regardless of whether participants received study drug or received a different drug from that to which they were randomized.
Arm/Group Title Phase 2: Axitinib + FOLFOX Phase 2: Bevacizumab + FOLFOX Phase 2: Axitinib + Bevacizumab + FOLFOX
Hide Arm/Group Description:
FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently or followed by oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily in each 14-day cycle administered prior to oxaliplatin infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
Bevacizumab 5 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently or followed by oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
Bevacizumab 2 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently or followed by oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily in each 14-day cycle administered following bevacizumab infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
Overall Number of Participants Analyzed 42 43 41
Mean (Standard Deviation)
Unit of Measure: units on scale
Severity Scale: Baseline (n=41,43,40) 1.62  (1.57) 2.20  (1.93) 2.18  (2.06)
Severity Scale: C2D1 (n=37,37,37) 0.63  (1.22) 0.04  (1.16) 0.80  (1.32)
Severity Scale: C3D1 (n=32,38,32) 0.68  (1.29) -0.22  (1.17) 0.63  (1.61)
Severity Scale: C4D1 (n=23,37,30) 0.88  (1.41) -0.40  (1.27) 0.64  (1.68)
Severity Scale: C5D1 (n=23,34,29) 0.72  (1.37) -0.34  (1.59) 0.60  (2.13)
Severity Scale: C6D1 (n=15,38,26) 0.70  (1.80) 0.09  (1.44) 0.96  (1.60)
Severity Scale: C7D1 (n=12,30,22) 0.28  (1.51) -0.16  (1.55) 0.26  (1.22)
Severity Scale: C8D1 (n=17,29,22) 0.28  (1.45) -0.13  (1.56) 0.42  (1.74)
Severity Scale: C9D1 (n=11,24,21) -0.15  (1.55) -0.03  (1.67) 0.76  (1.50)
Severity Scale: C10D1 (n=14,27,21) 0.28  (1.37) 0.06  (1.52) 0.77  (1.52)
Severity Scale: C11D1 (n=10,20,19) 0.15  (1.57) -0.05  (1.59) 0.57  (1.33)
Severity Scale: C12D1 (n=11,23,16) 0.32  (1.40) 0.47  (1.37) 0.38  (1.14)
Severity Scale: C13D1 (n=8,13,12) -0.09  (1.43) 0.10  (1.35) 0.73  (1.55)
Severity Scale: C14D1 (n=8,17,14) 0.03  (0.81) 0.38  (1.48) -0.05  (1.44)
Severity Scale: C15D1 (n=7,11,9) 0.28  (1.50) 0.42  (1.49) 0.71  (1.34)
Severity Scale: C16D1 (n=7,17,14) -0.30  (0.88) 0.11  (1.46) 0.05  (2.08)
Severity Scale: C17D1 (n=5,11,6) -0.20  (0.70) 0.21  (1.69) 0.72  (1.07)
Severity Scale: C18D1 (n=6,14,9) 0.02  (0.85) 0.31  (1.15) 0.61  (1.55)
Severity Scale: C19D1 (n=4,8,16) -0.18  (0.54) 0.34  (1.42) 0.81  (2.32)
Severity Scale: C20D1 (n=5,14,8) -0.06  (0.54) 0.15  (1.21) -0.06  (1.67)
Severity Scale: C21D1 (n=4,5,5) -0.25  (0.71) 0.27  (1.90) 1.20  (1.35)
Severity Scale: C22D1 (n=3,11,8) 0.57  (0.45) 0.81  (0.95) 0.09  (1.37)
Severity Scale: C23D1 (n=4,5,3) 0.30  (0.80) 0.64  (1.32) 1.05  (1.11)
Severity Scale: C24D1 (n=5,11,7) 0.91  (2.07) 0.37  (1.10) -0.20  (1.62)
Severity Scale: C25D1 (n=4,5,5) 0.25  (0.96) -0.03  (1.12) -0.30  (1.63)
Severity Scale: C26D1 (n=4,6,7) -0.05  (0.76) 0.46  (0.72) -0.13  (1.79)
Severity Scale: C27D1 (n=4,3,4) -0.21  (0.65) 0.07  (0.99) 0.34  (2.70)
Severity Scale: C28D1 (n=4,5,7) 0.12  (0.82) 0.74  (1.01) -0.43  (2.00)
Severity Scale: C29D1 (n=2,3,4) 3.00  (2.12) -0.14  (0.58) -0.09  (2.51)
Severity Scale: C30D1 (n=3,6,3) 1.05  (1.70) 0.45  (1.05) 0.64  (0.68)
Severity Scale: C31D1 (n=1,1,3) -0.50 [1]   (NA) -0.64 [1]   (NA) 1.55  (1.69)
Severity Scale: C32D1 (n=2,4,4) 0.11  (0.25) 0.80  (0.93) 1.29  (1.03)
Severity Scale: C33D1 (n=0,0,2) NA [2]   (NA) NA [2]   (NA) 0.89  (1.26)
Severity Scale: C34D1 (n=2,4,3) 0.04  (0.15) 0.75  (0.89) 0.43  (0.74)
Severity Scale: C35D1 (n=0,0,1) NA [2]   (NA) NA [2]   (NA) 0.79 [1]   (NA)
Severity Scale: C36D1 (n=2,3,2) 0.29  (0.51) 1.24  (1.22) -0.18  (0.25)
Severity Scale: C37D1 (n=0,1,0) NA [2]   (NA) 0.86 [1]   (NA) NA [2]   (NA)
Severity Scale: C38D1 (n=2,2,1) 0.13  (0.28) 1.68  (1.97) 0.86 [1]   (NA)
Severity Scale: C39D1 (n=0,1,0) NA [2]   (NA) 0.86 [1]   (NA) NA [2]   (NA)
Severity Scale: C40D1 (n=2,2,2) 0.18  (0.35) 1.29  (1.11) 0.43  (0.61)
Severity Scale: C42D1 (n=2,2,1) 0.18  (0.35) 1.25  (1.26) 0.00 [1]   (NA)
Severity Scale: Follow_Up (n=4,15,14) 1.29  (2.75) -0.00  (1.66) 0.29  (1.72)
Interference Scale: Baseline (n=41,43,40) 2.50  (2.70) 2.79  (2.57) 2.47  (2.66)
Interference Scale: C2D1 (n=37,37,36) 0.46  (1.80) -0.08  (1.74) 0.78  (2.55)
Interference Scale: C3D1 (n=31,38,30) 0.60  (2.37) -0.57  (1.88) 1.09  (2.37)
Interference Scale: C4D1 (n=23,36,30) 0.92  (2.16) -0.54  (1.89) 1.15  (2.37)
Interference Scale: C5D1 (n=23,34,29) 0.65  (2.20) -0.59  (1.98) 1.19  (2.90)
Interference Scale: C6D1 (n=15,38,26) 0.32  (2.01) -0.18  (2.33) 0.99  (2.54)
Interference Scale: C7D1 (n=12,30,22) 0.43  (1.25) -0.59  (2.13) 0.55  (2.05)
Interference Scale: C8D1 (n=17,29,22) 0.01  (1.58) -0.10  (2.00) 0.48  (1.87)
Interference Scale: C9D1 (n=11,24,21) -0.14  (1.08) -0.39  (2.31) 0.75  (1.76)
Interference Scale: C10D1 (n=14,27,21) -0.18  (1.80) 0.15  (2.06) 0.99  (2.12)
Interference Scale: C11D1 (n=10,20,19) 0.42  (1.23) -0.51  (1.75) 0.84  (2.50)
Interference Scale: C12D1 (n=10,23,16) 0.03  (0.78) 0.17  (2.23) 0.38  (1.51)
Interference Scale: C13D1 (n=8,13,12) -0.50  (1.56) -0.31  (2.49) 0.31  (1.70)
Interference Scale: C14D1 (n=8,17,14) -0.10  (0.84) 0.15  (2.57) 0.29  (2.12)
Interference Scale: C15D1 (n=7,11,9) -0.52  (0.85) 0.27  (1.91) 0.70  (2.36)
Interference Scale: C16D1 (n=7,17,14) -0.02  (0.33) -0.48  (2.31) -0.01  (2.38)
Interference Scale: C17D1 (n=5,11,6) -0.90  (1.31) -0.29  (3.16) 1.17  (1.28)
Interference Scale: C18D1 (n=6,14,9) 0.06  (0.34) 0.04  (2.38) 1.00  (2.26)
Interference Scale: C19D1 (n=4,8,6) 0.04  (0.34) 0.54  (2.25) 1.04  (1.84)
Interference Scale: C20D1 (n=5,14,8) 0.27  (0.65) -0.08  (2.34) 0.35  (2.07)
Interference Scale: C21D1 (n=4,5,5) -0.04  (0.86) -0.97  (3.50) 1.83  (1.28)
Interference Scale: C22D1 (n=3,11,8) 0.44  (0.84) 0.74  (1.71) 0.83  (2.05)
Interference Scale: C23D1 (n=4,5,3) 0.21  (0.42) 1.13  (2.58) 1.28  (1.80)
Interference Scale: C24D1 (n=5,11,7) 2.00  (3.25) 0.30  (2.65) 0.55  (2.33)
Interference Scale: C25D1 (n=4,5,5) 0.00  (0.41) 0.10  (2.45) 0.90  (0.88)
Interference Scale: C26D1 (n=4,6,7) 0.33  (0.85) 0.67  (1.80) 0.33  (2.11)
Interference Scale: C27D1 (n=4,3,4) 0.04  (0.52) 0.11  (1.13) 1.63  (2.44)
Interference Scale: C28D1 (n=4,5,7) 0.71  (1.19) 0.97  (1.81) 0.19  (2.40)
Interference Scale: C29D1 (n=2,3,4) 3.25  (3.89) -0.56  (0.96) 1.33  (2.97)
Interference Scale: C30D1 (n=3,6,3) 0.94  (1.49) 1.08  (2.16) 1.06  (1.83)
Interference Scale: C31D1 (n=1,1,3) 0.00 [1]   (NA) -0.17 [1]   (NA) 2.33  (2.08)
Interference Scale: C32D1 (n=2,4,4) 0.08  (0.12) 1.50  (2.26) 2.17  (1.81)
Interference Scale: C33D1 (n=0,0,2) NA [2]   (NA) NA [2]   (NA) 1.92  (2.71)
Interference Scale: C34D1 (n=2,4,3) 0.17  (0.24) 1.25  (1.89) 1.11  (1.51)
Interference Scale: C35D1 (n=0,0,1) NA [2]   (NA) NA [2]   (NA) 1.67 [1]   (NA)
Interference Scale: C36D1 (n=2,3,2) 0.17  (0.24) 1.89  (2.18) 1.33  (1.89)
Interference Scale: C37D1 (n=0,1,0) NA [2]   (NA) 0.83 [1]   (NA) NA [2]   (NA)
Interference Scale: C38D1 (n=2,2,1) 0.08  (0.12) 2.25  (2.47) -0.17 [1]   (NA)
Interference Scale: C39D1 (n=0,1,0) NA [2]   (NA) 0.50 [1]   (NA) NA [2]   (NA)
Interference Scale: C40D1 (n=2,2,2) 0.42  (0.59) 2.50  (2.12) 0.25  (0.35)
Interference Scale: C42D1 (n=2,2,1) 0.25  (0.35) 2.58  (2.24) 0.00 [1]   (NA)
Interference Scale: Follow Up (n=4,15,14) 1.33  (2.48) -0.21  (2.44) 0.91  (1.65)
[1]
Standard deviation was not estimable since only one participant was evaluable.
[2]
Data was not analyzed as no participants were evaluable.
Time Frame [Not Specified]
Adverse Event Reporting Description The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
 
Arm/Group Title Phase 1: Axitinib + FOLFOX + Bevacizumab (Cohort 1) Phase 1: Axitinib + FOLFOX + Bevacizumab (Cohort 2) Phase 1: Axitinib + FOLFOX + Bevacizumab (Cohort 3) Phase 1: Axitinib + FOLFIRI (Cohort 4) Phase 1: Axitinib + FOLFOX (Cohort 5) Phase 1: Axitinib + FOLFIRI (Cohort 6) Phase 1: Axitinib + FOLFOX (Cohort 7) Phase 1: Axitinib + FOLFIRI (Cohort 8) Phase 1: Axitinib + FOLFOX (Cohort 9) Phase 2: Axitinib + FOLFOX Phase 2: Bevacizumab + FOLFOX Phase 2: Axitinib + Bevacizumab + FOLFOX
Hide Arm/Group Description Bevacizumab 1 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently or followed by oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered following bevacizumab infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion. Bevacizumab 2 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently or followed by oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered following bevacizumab infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion. Bevacizumab 5 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently or followed by oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered following bevacizumab infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion. FOLFIRI combination chemotherapy on Day 1 of each 14-day cycle consisting of irinotecan 180 mg/m^2 intravenous infusion over 90 minutes, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently or followed by irinotecan, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered prior to irinotecan infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion. FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently or followed by oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered prior to oxaliplatin infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion. FOLFIRI combination chemotherapy on Day 1 of each 14-day cycle consisting of irinotecan 180 mg/m^2 intravenous infusion over 90 minutes, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently or followed by irinotecan, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily from Day 3 to Day 12 in each 14-day cycle administered following completion of 5-FU infusion on Day 3. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion. FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently or followed by oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 to Day 12 in each 14-day cycle administered following completion of 5-FU infusion on Day 3. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion. Axitinib (AG-13736) tablet 7 mg orally twice daily for 7 days in 2-week lead-in period prior to Day 1 Cycle 1. FOLFIRI combination chemotherapy on Day 1 of each 14-day cycle consisting of irinotecan 180 mg/m^2 intravenous infusion over 90 minutes, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently or followed by irinotecan, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 7 mg to 10 mg orally twice daily from Day 3 to Day 9 in each 14-day cycle administered following completion of 5-FU infusion on Day 3. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion. Axitinib (AG-13736) tablet 7 mg orally twice daily for 7 days in 2-week lead-in period prior to Day 1 Cycle 1. FOLFIRI combination chemotherapy on Day 1 of each 14-day cycle consisting of irinotecan 180 mg/m^2 intravenous infusion over 90 minutes, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently or followed by irinotecan, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 10 mg orally twice daily from Day 3 to Day 9 in each 14-day cycle administered following completion of 5-FU infusion on Day 3. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion. FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently or followed by oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily in each 14-day cycle administered prior to oxaliplatin infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion. Bevacizumab 5 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently or followed by oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion. Bevacizumab 2 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently or followed by oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily in each 14-day cycle administered following bevacizumab infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
All-Cause Mortality
Phase 1: Axitinib + FOLFOX + Bevacizumab (Cohort 1) Phase 1: Axitinib + FOLFOX + Bevacizumab (Cohort 2) Phase 1: Axitinib + FOLFOX + Bevacizumab (Cohort 3) Phase 1: Axitinib + FOLFIRI (Cohort 4) Phase 1: Axitinib + FOLFOX (Cohort 5) Phase 1: Axitinib + FOLFIRI (Cohort 6) Phase 1: Axitinib + FOLFOX (Cohort 7) Phase 1: Axitinib + FOLFIRI (Cohort 8) Phase 1: Axitinib + FOLFOX (Cohort 9) Phase 2: Axitinib + FOLFOX Phase 2: Bevacizumab + FOLFOX Phase 2: Axitinib + Bevacizumab + FOLFOX
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/--   --/--   --/--   --/--   --/--   --/--   --/--   --/--   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Phase 1: Axitinib + FOLFOX + Bevacizumab (Cohort 1) Phase 1: Axitinib + FOLFOX + Bevacizumab (Cohort 2) Phase 1: Axitinib + FOLFOX + Bevacizumab (Cohort 3) Phase 1: Axitinib + FOLFIRI (Cohort 4) Phase 1: Axitinib + FOLFOX (Cohort 5) Phase 1: Axitinib + FOLFIRI (Cohort 6) Phase 1: Axitinib + FOLFOX (Cohort 7) Phase 1: Axitinib + FOLFIRI (Cohort 8) Phase 1: Axitinib + FOLFOX (Cohort 9) Phase 2: Axitinib + FOLFOX Phase 2: Bevacizumab + FOLFOX Phase 2: Axitinib + Bevacizumab + FOLFOX
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   3/6 (50.00%)   2/6 (33.33%)   2/4 (50.00%)   3/8 (37.50%)   5/6 (83.33%)   1/4 (25.00%)   1/6 (16.67%)   1/3 (33.33%)   8/18 (44.44%)   15/39 (38.46%)   17/43 (39.53%)   23/41 (56.10%) 
Blood and lymphatic system disorders                         
Neutropenia * 1  0/6 (0.00%)  1/6 (16.67%)  0/4 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  0/43 (0.00%)  0/41 (0.00%) 
Anaemia * 1  0/6 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  2/43 (4.65%)  0/41 (0.00%) 
Febrile neutropenia * 1  0/6 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/18 (0.00%)  1/39 (2.56%)  1/43 (2.33%)  1/41 (2.44%) 
Cardiac disorders                         
Bradycardia * 1  1/6 (16.67%)  0/6 (0.00%)  0/4 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/18 (0.00%)  1/39 (2.56%)  0/43 (0.00%)  0/41 (0.00%) 
Cardiac failure congestive * 1  0/6 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  1/43 (2.33%)  0/41 (0.00%) 
Cardiomyopathy * 1  0/6 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  1/43 (2.33%)  0/41 (0.00%) 
Left ventricular dysfunction * 1  0/6 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  0/43 (0.00%)  1/41 (2.44%) 
Myocardial infarction * 1  0/6 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  1/18 (5.56%)  0/39 (0.00%)  1/43 (2.33%)  1/41 (2.44%) 
Sinus bradycardia * 1  0/6 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  0/43 (0.00%)  1/41 (2.44%) 
Eye disorders                         
Blindness * 1  0/6 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  0/43 (0.00%)  1/41 (2.44%) 
Gastrointestinal disorders                         
Abdominal pain * 1  1/6 (16.67%)  1/6 (16.67%)  0/4 (0.00%)  1/8 (12.50%)  1/6 (16.67%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  1/18 (5.56%)  2/39 (5.13%)  1/43 (2.33%)  2/41 (4.88%) 
Constipation * 1  0/6 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  1/18 (5.56%)  0/39 (0.00%)  0/43 (0.00%)  1/41 (2.44%) 
Diarrhoea * 1  0/6 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/8 (0.00%)  1/6 (16.67%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/18 (0.00%)  1/39 (2.56%)  1/43 (2.33%)  0/41 (0.00%) 
Diverticular perforation * 1  0/6 (0.00%)  0/6 (0.00%)  1/4 (25.00%)  0/8 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  0/43 (0.00%)  0/41 (0.00%) 
Dysphagia * 1  0/6 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  1/43 (2.33%)  0/41 (0.00%) 
Enteritis * 1  0/6 (0.00%)  1/6 (16.67%)  0/4 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  0/43 (0.00%)  0/41 (0.00%) 
Gastric ulcer * 1  0/6 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  1/43 (2.33%)  0/41 (0.00%) 
Gastric ulcer haemorrhage * 1  0/6 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/18 (0.00%)  1/39 (2.56%)  0/43 (0.00%)  0/41 (0.00%) 
Gastrointestinal haemorrhage * 1  0/6 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/8 (0.00%)  1/6 (16.67%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  2/43 (4.65%)  0/41 (0.00%) 
Gastrointestinal stenosis * 1  0/6 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/18 (0.00%)  1/39 (2.56%)  0/43 (0.00%)  0/41 (0.00%) 
Haemorrhoids * 1  0/6 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/18 (0.00%)  1/39 (2.56%)  0/43 (0.00%)  0/41 (0.00%) 
Melaena * 1  0/6 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  1/43 (2.33%)  0/41 (0.00%) 
Nausea * 1  0/6 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/18 (0.00%)  1/39 (2.56%)  0/43 (0.00%)  3/41 (7.32%) 
Intestinal obstruction * 1  0/6 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/8 (0.00%)  1/6 (16.67%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  0/43 (0.00%)  0/41 (0.00%) 
Oesophagitis * 1  0/6 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  1/43 (2.33%)  0/41 (0.00%) 
Proctalgia * 1  0/6 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  0/43 (0.00%)  1/41 (2.44%) 
Small intestinal obstruction * 1  0/6 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  1/8 (12.50%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  1/18 (5.56%)  0/39 (0.00%)  1/43 (2.33%)  0/41 (0.00%) 
Stomatitis * 1  0/6 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/18 (0.00%)  1/39 (2.56%)  0/43 (0.00%)  0/41 (0.00%) 
Vomiting * 1  0/6 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/8 (0.00%)  1/6 (16.67%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/18 (0.00%)  1/39 (2.56%)  1/43 (2.33%)  3/41 (7.32%) 
General disorders                         
Asthenia * 1  0/6 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/18 (0.00%)  4/39 (10.26%)  1/43 (2.33%)  1/41 (2.44%) 
Chest discomfort * 1  0/6 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  1/43 (2.33%)  0/41 (0.00%) 
Chest pain * 1  0/6 (0.00%)  0/6 (0.00%)  1/4 (25.00%)  0/8 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  1/43 (2.33%)  2/41 (4.88%) 
Disease progression * 1  0/6 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  1/18 (5.56%)  1/39 (2.56%)  0/43 (0.00%)  1/41 (2.44%) 
Fatigue * 1  0/6 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  1/18 (5.56%)  0/39 (0.00%)  0/43 (0.00%)  0/41 (0.00%) 
Mucosal inflammation * 1  0/6 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  1/43 (2.33%)  1/41 (2.44%) 
Non-cardiac chest pain * 1  0/6 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/18 (0.00%)  1/39 (2.56%)  0/43 (0.00%)  0/41 (0.00%) 
Pain * 1  1/6 (16.67%)  0/6 (0.00%)  0/4 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  0/43 (0.00%)  0/41 (0.00%) 
Pyrexia * 1  1/6 (16.67%)  0/6 (0.00%)  0/4 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  1/18 (5.56%)  0/39 (0.00%)  3/43 (6.98%)  0/41 (0.00%) 
Hepatobiliary disorders                         
Cholangitis * 1  0/6 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/8 (0.00%)  1/6 (16.67%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  0/43 (0.00%)  0/41 (0.00%) 
Cholecystitis * 1  0/6 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/8 (0.00%)  1/6 (16.67%)  1/4 (25.00%)  0/6 (0.00%)  0/3 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  0/43 (0.00%)  0/41 (0.00%) 
Cholecystitis acute * 1  0/6 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  0/43 (0.00%)  1/41 (2.44%) 
Cholelithiasis * 1  0/6 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/4 (25.00%)  0/6 (0.00%)  0/3 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  0/43 (0.00%)  0/41 (0.00%) 
Immune system disorders                         
Hypersensitivity * 1  0/6 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/8 (0.00%)  1/6 (16.67%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  0/43 (0.00%)  0/41 (0.00%) 
Infections and infestations                         
Abscess intestinal * 1  0/6 (0.00%)  0/6 (0.00%)  1/4 (25.00%)  0/8 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  0/43 (0.00%)  0/41 (0.00%) 
Abdominal abscess * 1  0/6 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  0/43 (0.00%)  1/41 (2.44%) 
Bacteraemia * 1  0/6 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  1/43 (2.33%)  0/41 (0.00%) 
Bacterial sepsis * 1  0/6 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  1/18 (5.56%)  0/39 (0.00%)  0/43 (0.00%)  0/41 (0.00%) 
Device related infection * 1  1/6 (16.67%)  0/6 (0.00%)  0/4 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/18 (0.00%)  1/39 (2.56%)  0/43 (0.00%)  0/41 (0.00%) 
Pneumonia * 1  0/6 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  3/43 (6.98%)  0/41 (0.00%) 
Rectal abscess * 1  0/6 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/18 (0.00%)  1/39 (2.56%)  0/43 (0.00%)  0/41 (0.00%) 
Sepsis * 1  1/6 (16.67%)  0/6 (0.00%)  0/4 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/18 (0.00%)  1/39 (2.56%)  1/43 (2.33%)  1/41 (2.44%) 
Sepsis syndrome * 1  0/6 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  1/8 (12.50%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  1/43 (2.33%)  0/41 (0.00%) 
Septic shock * 1  0/6 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  1/43 (2.33%)  0/41 (0.00%) 
Staphylococcal infection * 1  0/6 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  1/3 (33.33%)  1/18 (5.56%)  1/39 (2.56%)  0/43 (0.00%)  0/41 (0.00%) 
Urinary tract infection * 1  0/6 (0.00%)  1/6 (16.67%)  0/4 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  3/43 (6.98%)  0/41 (0.00%) 
Injury, poisoning and procedural complications                         
Lower limb fracture * 1  0/6 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  1/18 (5.56%)  0/39 (0.00%)  0/43 (0.00%)  0/41 (0.00%) 
Procedural haemorrhage * 1  0/6 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/18 (0.00%)  1/39 (2.56%)  0/43 (0.00%)  0/41 (0.00%) 
Toxicity to various agents * 1  0/6 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  0/43 (0.00%)  1/41 (2.44%) 
Wound dehiscence * 1  0/6 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  0/43 (0.00%)  0/41 (0.00%) 
Investigations                         
Aspartate aminotransferase increased * 1  0/6 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  1/18 (5.56%)  0/39 (0.00%)  0/43 (0.00%)  0/41 (0.00%) 
Hepatic enzyme increased * 1  1/6 (16.67%)  0/6 (0.00%)  0/4 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  0/43 (0.00%)  0/41 (0.00%) 
Haemoglobin decreased * 1  0/6 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/18 (0.00%)  1/39 (2.56%)  0/43 (0.00%)  0/41 (0.00%) 
International normalised ratio increased * 1  0/6 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/8 (0.00%)  1/6 (16.67%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  0/43 (0.00%)  0/41 (0.00%) 
Metabolism and nutrition disorders                         
Dehydration * 1  0/6 (0.00%)  2/6 (33.33%)  0/4 (0.00%)  0/8 (0.00%)  2/6 (33.33%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/18 (0.00%)  3/39 (7.69%)  2/43 (4.65%)  7/41 (17.07%) 
Decreased appetite * 1  0/6 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/18 (0.00%)  1/39 (2.56%)  0/43 (0.00%)  1/41 (2.44%) 
Hyponatraemia * 1  0/6 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  1/18 (5.56%)  0/39 (0.00%)  1/43 (2.33%)  0/41 (0.00%) 
Malnutrition * 1  0/6 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/18 (0.00%)  1/39 (2.56%)  0/43 (0.00%)  0/41 (0.00%) 
Musculoskeletal and connective tissue disorders                         
Fistula * 1  0/6 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  1/43 (2.33%)  0/41 (0.00%) 
Musculoskeletal pain * 1  0/6 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/18 (0.00%)  1/39 (2.56%)  0/43 (0.00%)  0/41 (0.00%) 
Nervous system disorders                         
Convulsion * 1  0/6 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  1/6 (16.67%)  0/3 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  0/43 (0.00%)  2/41 (4.88%) 
Altered state of consciousness * 1  0/6 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  0/43 (0.00%)  1/41 (2.44%) 
Cerebral haemorrhage * 1  0/6 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/18 (0.00%)  1/39 (2.56%)  0/43 (0.00%)  0/41 (0.00%) 
Cerebrovascular accident * 1  0/6 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/18 (0.00%)  1/39 (2.56%)  0/43 (0.00%)  1/41 (2.44%) 
Encephalopathy * 1  0/6 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  0/43 (0.00%)  1/41 (2.44%) 
Haemorrhage intracranial * 1  0/6 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  0/43 (0.00%)  1/41 (2.44%) 
Headache * 1  0/6 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  0/43 (0.00%)  2/41 (4.88%) 
Hemiparesis * 1  0/6 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/8 (0.00%)  1/6 (16.67%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  0/43 (0.00%)  0/41 (0.00%) 
Peripheral motor neuropathy * 1  0/6 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  0/43 (0.00%)  1/41 (2.44%) 
Speech disorder * 1  0/6 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/18 (0.00%)  1/39 (2.56%)  0/43 (0.00%)  0/41 (0.00%) 
Syncope * 1  0/6 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  0/43 (0.00%)  1/41 (2.44%) 
Psychiatric disorders                         
Confusional state * 1  0/6 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/18 (0.00%)  1/39 (2.56%)  0/43 (0.00%)  1/41 (2.44%) 
Mental status changes * 1  0/6 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/18 (0.00%)  1/39 (2.56%)  0/43 (0.00%)  1/41 (2.44%) 
Renal and urinary disorders                         
Dysuria * 1  0/6 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/18 (0.00%)  1/39 (2.56%)  0/43 (0.00%)  0/41 (0.00%) 
Renal failure * 1  0/6 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/18 (0.00%)  1/39 (2.56%)  0/43 (0.00%)  1/41 (2.44%) 
Renal failure acute * 1  0/6 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  1/43 (2.33%)  1/41 (2.44%) 
Reproductive system and breast disorders                         
Testicular pain * 1  0/6 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  0/43 (0.00%)  1/41 (2.44%) 
Respiratory, thoracic and mediastinal disorders                         
Acute respiratory distress syndrome * 1  0/6 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  1/43 (2.33%)  0/41 (0.00%) 
Acute respiratory failure * 1  0/6 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  0/43 (0.00%)  1/41 (2.44%) 
Chronic obstructive pulmonary disease * 1  0/6 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  1/43 (2.33%)  0/41 (0.00%) 
Dyspnoea * 1  0/6 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  1/18 (5.56%)  1/39 (2.56%)  0/43 (0.00%)  1/41 (2.44%) 
Pulmonary embolism * 1  0/6 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  1/18 (5.56%)  3/39 (7.69%)  1/43 (2.33%)  1/41 (2.44%) 
Respiratory failure * 1  1/6 (16.67%)  0/6 (0.00%)  0/4 (0.00%)  1/8 (12.50%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  1/43 (2.33%)  0/41 (0.00%) 
Pneumothorax * 1  0/6 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/18 (0.00%)  1/39 (2.56%)  0/43 (0.00%)  1/41 (2.44%) 
Pleural effusion * 1  0/6 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  0/43 (0.00%)  1/41 (2.44%) 
Pulmonary fibrosis * 1  0/6 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  1/43 (2.33%)  0/41 (0.00%) 
Vascular disorders                         
Aortic thrombosis * 1  0/6 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  0/43 (0.00%)  1/41 (2.44%) 
Deep vein thrombosis * 1  0/6 (0.00%)  0/6 (0.00%)  1/4 (25.00%)  0/8 (0.00%)  1/6 (16.67%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/18 (0.00%)  2/39 (5.13%)  1/43 (2.33%)  2/41 (4.88%) 
Flushing * 1  0/6 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/18 (0.00%)  0/39 (0.00%)  1/43 (2.33%)  0/41 (0.00%) 
Hypertension * 1  0/6 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)