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Bevacizumab With or Without Anti-Endoglin Monoclonal Antibody TRC105 in Treating Patients With Recurrent Glioblastoma Multiforme

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ClinicalTrials.gov Identifier: NCT01648348
Recruitment Status : Completed
First Posted : July 24, 2012
Results First Posted : May 23, 2018
Last Update Posted : May 23, 2018
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Conditions Adult Anaplastic Astrocytoma
Adult Anaplastic Oligodendroglioma
Adult Giant Cell Glioblastoma
Adult Glioblastoma
Adult Gliosarcoma
Adult Mixed Glioma
Recurrent Adult Brain Neoplasm
Interventions Biological: Anti-Endoglin Chimeric Monoclonal Antibody TRC105
Biological: Bevacizumab
Other: Laboratory Biomarker Analysis
Other: Pharmacological Study
Other: Quality-of-Life Assessment
Enrollment 116
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Phase I: Bev + TRC105 (Dose 0, Cohort A) Phase I: Bev + TRC105 (Dose 1, Cohort A) Phase I: Bev + TRC105 (Dose 2, Cohort A) Phase I: Bev + TRC105 (Dose 2, Cohort B) Phase II: Bev + TRC105 (Arm I) Phase II: Bev Alone (Arm II)
Hide Arm/Group Description Patients receive 10 mg/kg bevacizumab IV over 30-90 minutes on day 1 and anti-endoglin monoclonal antibody TRC105 IV over 1-4 hours on days 8 (as 3 mg/kg IV) and 11 (as 3 mg/kg IV) of course 1 and days 1 (as 6 mg/kg IV)and 8 (as 6 mg/kg IV) of all subsequent courses. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. Patients receive 10 mg/kg bevacizumab IV over 30-90 minutes on day 1 and anti-endoglin monoclonal antibody TRC105 IV over 1-4 hours on days 8 (as 3 mg/kg IV) and 11 (as 5 mg/kg IV) of course 1 and days 1 (as 8 mg/kg IV)and 8 (as 8 mg/kg IV) of all subsequent courses. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. Patients receive 10 mg/kg bevacizumab IV over 30-90 minutes on day 1 and anti-endoglin monoclonal antibody TRC105 IV over 1-4 hours on days 8 (as 3 mg/kg IV) and 11 (as 7 mg/kg IV) of course 1 and days 1 (as 10 mg/kg IV)and 8 (as 10 mg/kg IV) of all subsequent courses. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. Patients receive 10 mg/kg bevacizumab IV over 30-90 minutes on day 1 and anti-endoglin monoclonal antibody TRC105 IV over 1-4 hours on days 8 (as 3 mg/kg IV) and 11 (as 7 mg/kg IV) of course 1 and days 1 (as 10 mg/kg IV)and 8 (as 10 mg/kg IV) of all subsequent courses. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. Experimental: Arm I (bevacizumab and TRC105): Patients receive 10 mg/kg bevacizumab IV over 30-90 minutes on day 1 and 10 mg/kg anti-endoglin monoclonal antibody TRC105 IV over 1-4 hours on days 8 and 11 of course 1 and days 1 and 8 of all subsequent courses. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. Active Comparator: Arm II (bevacizumab): Patients receive bevacizumab as in arm I. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.
Period Title: Overall Study
Started 5 3 4 3 52 49
Completed 3 3 3 3 49 43
Not Completed 2 0 1 0 3 6
Reason Not Completed
Cancel             1             0             0             0             3             6
Replaced for MTD analysis             1             0             1             0             0             0
Arm/Group Title Phase I: Bev + TRC105 (Dose 0-2) Phase II: Bev + TRC105 (Arm I) Phase II: Bev Alone (Arm II) Total
Hide Arm/Group Description Patients receive 10 mg/kg bevacizumab IV over 30-90 minutes on day 1 and anti-endoglin monoclonal antibody TRC105 IV over 1-4 hours on days 8 (as 3 mg/kg IV) and 11 (as 3/5/7 mg/kg IV) of course 1 and days 1 (as 6/8/10 mg/kg IV)and 8 (as 6/8/10 mg/kg IV) of all subsequent courses. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. Experimental: Arm I (bevacizumab and TRC105): Patients receive 10 mg/kg bevacizumab IV over 30-90 minutes on day 1 and 10 mg/kg anti-endoglin monoclonal antibody TRC105 IV over 1-4 hours on days 8 and 11 of course 1 and days 1 and 8 of all subsequent courses. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. Active Comparator: Arm II (bevacizumab): Patients receive bevacizumab as in arm I. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. Total of all reporting groups
Overall Number of Baseline Participants 15 52 49 116
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 15 participants 52 participants 49 participants 116 participants
53.4  (6.6) 56.8  (12.3) 55.6  (10.2) 55.8  (10.8)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 15 participants 52 participants 49 participants 116 participants
Female
4
  26.7%
17
  32.7%
12
  24.5%
33
  28.4%
Male
11
  73.3%
35
  67.3%
37
  75.5%
83
  71.6%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 15 participants 52 participants 49 participants 116 participants
15 52 49 116
1.Primary Outcome
Title Maximum Tolerated Dose (MTD) (Phase I) as Measured by the Number of Participants With Dose Limiting Toxicities
Hide Description MTD for this study will be defined as the highest safely tolerated dose level where at most 1 out of 6 patients experience dose-limiting toxicity (DLT) with the next higher dose having at least 2 patients out of a maximum of 6 patients experience DLT. A total of 6 patients treated at the MTD will be sufficient to identify common toxicities at the MTD. The number of DLT's will be reported here.
Time Frame 28 days
Hide Outcome Measure Data
Hide Analysis Population Description
All phase I patients who completed the study were eligible and analyzed for MTD.
Arm/Group Title Phase I: Bev + TRC105 (Dose 0, Cohort A) Phase I: Bev + TRC105 (Dose 1, Cohort A) Phase I: Bev + TRC105 (Dose 2, Cohort A + B)
Hide Arm/Group Description:
Patients receive 10 mg/kg bevacizumab IV over 30-90 minutes on day 1 and anti-endoglin monoclonal antibody TRC105 IV over 1-4 hours on days 8 (as 3 mg/kg IV) and 11 (as 3 mg/kg IV) of course 1 and days 1 (as 6 mg/kg IV)and 8 (as 6 mg/kg IV) of all subsequent courses. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.
Patients receive 10 mg/kg bevacizumab IV over 30-90 minutes on day 1 and anti-endoglin monoclonal antibody TRC105 IV over 1-4 hours on days 8 (as 3 mg/kg IV) and 11 (as 5 mg/kg IV) of course 1 and days 1 (as 8 mg/kg IV)and 8 (as 8 mg/kg IV) of all subsequent courses. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.
Patients receive 10 mg/kg bevacizumab IV over 30-90 minutes on day 1 and anti-endoglin monoclonal antibody TRC105 IV over 1-4 hours on days 8 (as 3 mg/kg IV) and 11 (as 7 mg/kg IV) of course 1 and days 1 (as 10 mg/kg IV)and 8 (as 10 mg/kg IV) of all subsequent courses. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.
Overall Number of Participants Analyzed 3 3 6
Measure Type: Count of Participants
Unit of Measure: Participants
0
   0.0%
0
   0.0%
1
  16.7%
2.Primary Outcome
Title Progression-free Survival (PFS) (Phase II)
Hide Description Progression Free Survival time is defined as the time from study randomization to documentation of disease progression. Patients who die without documentation of progression will be considered to have had tumor progression at the time of death. Patients who fail to return for evaluation after beginning therapy will be censored for progression on the last day of therapy or date last known to be alive, whichever is later. Patients who are still alive and have not progressed will be censored for progression at the time of the last tumor assessment. The time-to-progression distribution will be estimated using the Kaplan-Meier method.
Time Frame The time from study randomization to documentation of disease progression, assessed up to 2 years
Hide Outcome Measure Data
Hide Analysis Population Description
All phase II patients who started the study were eligible and analyzed for the primary outcome of Phase II.
Arm/Group Title Phase II: Bev + TRC105 (Arm I) Phase II: Bev Alone (Arm II)
Hide Arm/Group Description:
Experimental: Arm I (bevacizumab and TRC105): Patients receive 10 mg/kg bevacizumab IV over 30-90 minutes on day 1 and 10 mg/kg anti-endoglin monoclonal antibody TRC105 IV over 1-4 hours on days 8 and 11 of course 1 and days 1 and 8 of all subsequent courses. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.
Active Comparator: Arm II (bevacizumab): Patients receive bevacizumab as in arm I. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.
Overall Number of Participants Analyzed 52 49
Median (95% Confidence Interval)
Unit of Measure: months
2.9
(2.8 to 4.9)
3.2
(2.6 to 4.6)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Phase II: Bev + TRC105 (Arm I), Phase II: Bev Alone (Arm II)
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.57
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.14
Confidence Interval (2-Sided) 95%
0.73 to 1.77
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Overall Toxicity Rate for Grade 3 or Higher Adverse Events Considered at Least Possibly Related to Treatment (Phase II)
Hide Description The maximum grade for each type of toxicity will be recorded for each patient, and frequency tables will be reviewed to determine toxicity patterns within patient groups. The overall toxicity rates (percentages) for grade 3 or higher adverse events considered at least possibly related to treatment will be compared using a Fisher’s Exact test between the 2 treatment groups.
Time Frame Up to 2 years
Hide Outcome Measure Data
Hide Analysis Population Description
All phase II patients who completed the study were eligible and included in this analysis.
Arm/Group Title Phase II: Bev + TRC105 (Arm I) Phase II: Bev Alone (Arm II)
Hide Arm/Group Description:
Experimental: Arm I (bevacizumab and TRC105): Patients receive 10 mg/kg bevacizumab IV over 30-90 minutes on day 1 and 10 mg/kg anti-endoglin monoclonal antibody TRC105 IV over 1-4 hours on days 8 and 11 of course 1 and days 1 and 8 of all subsequent courses. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.
Active Comparator: Arm II (bevacizumab): Patients receive bevacizumab as in arm I. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.
Overall Number of Participants Analyzed 49 43
Measure Type: Number
Unit of Measure: percentage of patients
57.1 16.3
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Phase II: Bev + TRC105 (Arm I), Phase II: Bev Alone (Arm II)
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Fisher Exact
Comments [Not Specified]
4.Secondary Outcome
Title Overall Survival (Phase II)
Hide Description Survival time is defined to be the length of time from start of study therapy to death due to any cause. All patients meeting the eligibility criteria that have signed a consent form and begun treatment will be considered evaluable for estimation of the survival distribution. The distribution of overall survival for both groups of the study will be estimated using the Kaplan-Meier method, and be compared using log-rank tests.
Time Frame The time from start of study therapy to death due to any cause, assessed up to 2 years
Hide Outcome Measure Data
Hide Analysis Population Description
All phase II patients who started the study were eligible and included in this analysis.
Arm/Group Title Phase II: Bev + TRC105 (Arm I) Phase II: Bev Alone (Arm II)
Hide Arm/Group Description:
Experimental: Arm I (bevacizumab and TRC105): Patients receive 10 mg/kg bevacizumab IV over 30-90 minutes on day 1 and 10 mg/kg anti-endoglin monoclonal antibody TRC105 IV over 1-4 hours on days 8 and 11 of course 1 and days 1 and 8 of all subsequent courses. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.
Active Comparator: Arm II (bevacizumab): Patients receive bevacizumab as in arm I. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.
Overall Number of Participants Analyzed 52 49
Median (95% Confidence Interval)
Unit of Measure: months
9.7
(6.7 to 11.5)
7.4
(6.5 to 12.7)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Phase II: Bev + TRC105 (Arm I), Phase II: Bev Alone (Arm II)
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.82
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.06
Confidence Interval (2-Sided) 95%
0.66 to 1.69
Estimation Comments [Not Specified]
5.Secondary Outcome
Title Progression Free Survival at 6 Months (PFS6) (Phase II) as Measured by the Percentage of Participants With Progression Free Survival at 6 Months
Hide Description PFS6 is defined as the time from start of study therapy to the date of first observation of disease progression or death due to any cause (whichever comes first). The medians and confidence intervals given are the Kaplan-Meier estimates.
Time Frame The time from study randomization to documentation of disease progression, assessed at 6 months
Hide Outcome Measure Data
Hide Analysis Population Description
All phase II patients who started the study were eligible and included in this analysis.
Arm/Group Title Phase II: Bev + TRC105 (Arm I) Phase II: Bev Alone (Arm II)
Hide Arm/Group Description:
Experimental: Arm I (bevacizumab and TRC105): Patients receive 10 mg/kg bevacizumab IV over 30-90 minutes on day 1 and 10 mg/kg anti-endoglin monoclonal antibody TRC105 IV over 1-4 hours on days 8 and 11 of course 1 and days 1 and 8 of all subsequent courses. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.
Active Comparator: Arm II (bevacizumab): Patients receive bevacizumab as in arm I. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.
Overall Number of Participants Analyzed 52 49
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of progression-free patients
25.0
(15.3 to 40.8)
30.2
(18.8 to 48.4)
6.Secondary Outcome
Title Quality of Life (QOL) as Assessed by the EORTC QLQ-C15-PAL Questionnaire [Item 15: Global Health Status/Quality of Life] (Phase II)
Hide Description Quality of Life (QOL) as assessed by the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C15-PAL questionnaire, as measured by the change from baseline to the end of cycle 2 (4 weeks) in the EORTC QLQ-C15-PAL item 15, Global health status/quality of life, score. The assessment was scored using EORTC’s scoring algorithms. The score range is from 0-100 (0 corresponding to worst outcome; 100 corresponding to best outcome). Range of the change in scores from baseline to cycle 2 (4 weeks) is (-100,100). The mean change in score and 95% confidence interval of the change from baseline to the end of cycle 2 (4 weeks) are reported below.
Time Frame Baseline and 4 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
All phase II patients who completed the EORTC QLQ-C15-PAL questionnaire at baseline and at the end of cycle 2 were included in this analysis.
Arm/Group Title Phase II: Bev + TRC105 (Arm I) Phase II: Bev Alone (Arm II)
Hide Arm/Group Description:
Experimental: Arm I (bevacizumab and TRC105): Patients receive 10 mg/kg bevacizumab IV over 30-90 minutes on day 1 and 10 mg/kg anti-endoglin monoclonal antibody TRC105 IV over 1-4 hours on days 8 and 11 of course 1 and days 1 and 8 of all subsequent courses. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.
Active Comparator: Arm II (bevacizumab): Patients receive bevacizumab as in arm I. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.
Overall Number of Participants Analyzed 35 30
Mean (95% Confidence Interval)
Unit of Measure: units on a scale
-3.3
(-9.7 to 3.0)
4.4
(-5.8 to 14.6)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Phase II: Bev + TRC105 (Arm I), Phase II: Bev Alone (Arm II)
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.19
Comments [Not Specified]
Method t-test, 2 sided
Comments [Not Specified]
7.Secondary Outcome
Title QOL Assessed by EORTC-QLQ-BN20 Patient Questionnaire [Items 1-20] (Phase II)
Hide Description QOL assessed by EORTC-QLQ-BN20 Patient Questionnaire (Brain cancer module), as measured by the change from baseline to the end of cycle 2 (4 weeks) in the EORTC QLQ-BN20 Items 1-20 are used to score the following 11 symptom scales: Future uncertainty (Items 1-3,5), Visual disorder (Items 6-8), Motor dysfunction (Items 10,15, 19), Communication deficit (Items 11-13), Headaches (Item 4), Seizures (Item 9), Drowsiness (Item 14), Itchy Skin (Item 17), Hair Loss (Item 16), Weakness of legs (Item 18), and Bladder control (Item 20). The assessment was scored using EORTC's scoring algorithms. The score range for each of the 11 symptom scales is from 0-100 (0 corresponding to not severe;100 corresponding to most severe). Range of changes in scores from baseline to cycle 2 (4 weeks) is (-100,100). The mean change in score and 95% confidence interval of each symptom scale are reported below.
Time Frame Baseline and 4 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
All phase II patients who completed the EORTC-QLQ-BN20 patient questionnaire at baseline and at the end of cycle 2 were included in this analysis.
Arm/Group Title Phase II: Bev + TRC105 (Arm I) Phase II: Bev Alone (Arm II)
Hide Arm/Group Description:
Experimental: Arm I (bevacizumab and TRC105): Patients receive 10 mg/kg bevacizumab IV over 30-90 minutes on day 1 and 10 mg/kg anti-endoglin monoclonal antibody TRC105 IV over 1-4 hours on days 8 and 11 of course 1 and days 1 and 8 of all subsequent courses. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.
Active Comparator: Arm II (bevacizumab): Patients receive bevacizumab as in arm I. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.
Overall Number of Participants Analyzed 36 30
Mean (95% Confidence Interval)
Unit of Measure: units on a scale
Future uncertainty
-8.0
(-15.3 to -0.7)
-11.9
(-23.0 to -0.9)
Visual disorder
2.0
(-1.7 to 5.7)
5.9
(1.7 to 10.1)
Motor dysfunction
3.4
(-3.1 to 9.9)
3.3
(-3.8 to 10.5)
Communication deficit
0.3
(-6.3 to 6.9)
1.9
(-5.6 to 9.3)
Headaches
7.4
(-1.2 to 16.0)
0
(-6.5 to 6.5)
Seizures
-1.9
(-4.5 to 0.8)
-2.2
(-7.8 to 3.4)
Drowsiness
2.8
(-5.0 to 10.6)
4.4
(-8.1 to 17.0)
Itchy skin
-9.3
(-18.4 to -0.1)
-1.1
(-8.0 to 5.8)
Hair loss
-0.9
(-7.2 to 5.4)
-2.2
(-8.7 to 4.3)
Weakness of legs
10.2
(0.9 to 19.5)
-2.2
(-14.4 to 10.0)
Bladder control
5.6
(-1.8 to 12.9)
3.3
(-3.5 to 10.2)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Phase II: Bev + TRC105 (Arm I), Phase II: Bev Alone (Arm II)
Comments Future uncertainty symptom scale/item t-test, 2-sided, unpooled.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.55
Comments [Not Specified]
Method t-test, 2 sided
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Phase II: Bev + TRC105 (Arm I), Phase II: Bev Alone (Arm II)
Comments Visual disorder symptom scale/item t-test, 2-sided, unpooled.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.16
Comments [Not Specified]
Method t-test, 2 sided
Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Phase II: Bev + TRC105 (Arm I), Phase II: Bev Alone (Arm II)
Comments Motor dysfunction symptom scale/item t-test, 2-sided, unpooled.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.99
Comments [Not Specified]
Method t-test, 2 sided
Comments [Not Specified]
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Phase II: Bev + TRC105 (Arm I), Phase II: Bev Alone (Arm II)
Comments Communication deficit symptom scale/item t-test, 2-sided, unpooled.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.75
Comments [Not Specified]
Method t-test, 2 sided
Comments [Not Specified]
Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Phase II: Bev + TRC105 (Arm I), Phase II: Bev Alone (Arm II)
Comments Headaches symptom scale/item t-test, 2-sided, unpooled.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.17
Comments [Not Specified]
Method t-test, 2 sided
Comments [Not Specified]
Show Statistical Analysis 6 Hide Statistical Analysis 6
Statistical Analysis Overview Comparison Group Selection Phase II: Bev + TRC105 (Arm I), Phase II: Bev Alone (Arm II)
Comments Seizures symptom scale/item t-test, 2-sided, unpooled.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.90
Comments [Not Specified]
Method t-test, 2 sided
Comments [Not Specified]
Show Statistical Analysis 7 Hide Statistical Analysis 7
Statistical Analysis Overview Comparison Group Selection Phase II: Bev + TRC105 (Arm I), Phase II: Bev Alone (Arm II)
Comments Drowsiness symptom scale/item t-test, 2-sided, unpooled.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.82
Comments [Not Specified]
Method t-test, 2 sided
Comments [Not Specified]
Show Statistical Analysis 8 Hide Statistical Analysis 8
Statistical Analysis Overview Comparison Group Selection Phase II: Bev + TRC105 (Arm I), Phase II: Bev Alone (Arm II)
Comments Itchy skin symptom scale/item t-test, 2-sided, unpooled.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.15
Comments [Not Specified]
Method t-test, 2 sided
Comments [Not Specified]
Show Statistical Analysis 9 Hide Statistical Analysis 9
Statistical Analysis Overview Comparison Group Selection Phase II: Bev + TRC105 (Arm I), Phase II: Bev Alone (Arm II)
Comments Hair loss symptom scale/item t-test, 2-sided, unpooled.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.77
Comments [Not Specified]
Method t-test, 2 sided
Comments [Not Specified]
Show Statistical Analysis 10 Hide Statistical Analysis 10
Statistical Analysis Overview Comparison Group Selection Phase II: Bev + TRC105 (Arm I), Phase II: Bev Alone (Arm II)
Comments Weakness of legs symptom scale/item t-test, 2-sided, unpooled.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.10
Comments [Not Specified]
Method t-test, 2 sided
Comments [Not Specified]
Show Statistical Analysis 11 Hide Statistical Analysis 11
Statistical Analysis Overview Comparison Group Selection Phase II: Bev + TRC105 (Arm I), Phase II: Bev Alone (Arm II)
Comments Bladder control symptom scale/item t-test, 2-sided, unpooled.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.65
Comments [Not Specified]
Method t-test, 2 sided
Comments [Not Specified]
8.Secondary Outcome
Title QOL Assessed by WIWI Questionnaire (Phase II)
Hide Description Quality of life (QOL) assessed by Was it worth it? (WIWI) questionnaire, as measured by the percentage of patients answering yes to the question “Was it worthwhile for you to participate in this research study?”
Time Frame Up to 4 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
All phase II patients who completed the WIWI questionnaire were included in this analysis.
Arm/Group Title Phase II: Bev + TRC105 (Arm I) Phase II: Bev Alone (Arm II)
Hide Arm/Group Description:
Experimental: Arm I (bevacizumab and TRC105): Patients receive 10 mg/kg bevacizumab IV over 30-90 minutes on day 1 and 10 mg/kg anti-endoglin monoclonal antibody TRC105 IV over 1-4 hours on days 8 and 11 of course 1 and days 1 and 8 of all subsequent courses. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.
Active Comparator: Arm II (bevacizumab): Patients receive bevacizumab as in arm I. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.
Overall Number of Participants Analyzed 36 32
Measure Type: Number
Unit of Measure: percentage of patients answering yes
69.4 71.9
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Phase II: Bev + TRC105 (Arm I), Phase II: Bev Alone (Arm II)
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.83
Comments [Not Specified]
Method proportion test
Comments [Not Specified]
9.Other Pre-specified Outcome
Title Change in DCE-MRI Utility
Hide Description Associations between the change of DCE-MRI and PFS6 will be assessed using two-sample t-test.
Time Frame Baseline to up to 2 years
Outcome Measure Data Not Reported
10.Other Pre-specified Outcome
Title Change in MRI ADC Utility
Hide Description MRI ADC histogram metrics such as overall ADC, mean ADC of lower curve, percentage of ADC in lower curve, and skewness at baseline and change from baseline to the first follow-up MRI will be analyzed for association with progression free and overall survival. Kaplan-Meier survival curves, logrank and Cox regression tests will be used to estimate and compare the equality of the overall survival and progression-time distributions of patient subsets defined by the ADC histogram metrics.
Time Frame Baseline to up to 2 years
Outcome Measure Data Not Reported
11.Other Pre-specified Outcome
Title Changes in Tumor and Circulating Biomarkers
Hide Description Binary endpoints and categorical endpoints will be compared using Chi-Squared or Fisher’s Exact tests between treatment groups. Continuous endpoints will be analyzed using change-from-baseline measures and compared using t-tests between treatment groups and time-points. Cox proportional hazards regression will be used to determine if there are differences in PFS and OS between the treatment groups after correcting for each biomarker in conjunction with standard clinical variables.
Time Frame Baseline to up to 2 years
Outcome Measure Data Not Reported
Time Frame Up to 2 years.
Adverse Event Reporting Description The revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting. All graded AEs are reported. Cancels in the Participant Flow table did not receive treatment. Serious AE (SAE) reports for this study may include any secondary serious or non-serious events considered related to the primary event (the reason for filing an expedited report); collectively, these events are referred to as Expedited Adverse Events (EAEs), and appear in the SAE table.
 
Arm/Group Title Phase I: Bev + TRC105 (Dose 0, Cohort A) Phase I: Bev + TRC105 (Dose 1, Cohort A) Phase I: Bev + TRC105 (Dose 2, Cohort A) Phase I: Bev + TRC105 (Dose 2, Cohort B) Phase II: Bev + TRC105 (Arm I) Phase II: Bev Alone (Arm II)
Hide Arm/Group Description Patients receive 10 mg/kg bevacizumab IV over 30-90 minutes on day 1 and anti-endoglin monoclonal antibody TRC105 IV over 1-4 hours on days 8 (as 3 mg/kg IV) and 11 (as 3 mg/kg IV) of course 1 and days 1 (as 6 mg/kg IV)and 8 (as 6 mg/kg IV) of all subsequent courses. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. Patients receive 10 mg/kg bevacizumab IV over 30-90 minutes on day 1 and anti-endoglin monoclonal antibody TRC105 IV over 1-4 hours on days 8 (as 3 mg/kg IV) and 11 (as 5 mg/kg IV) of course 1 and days 1 (as 8 mg/kg IV)and 8 (as 8 mg/kg IV) of all subsequent courses. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. Patients receive 10 mg/kg bevacizumab IV over 30-90 minutes on day 1 and anti-endoglin monoclonal antibody TRC105 IV over 1-4 hours on days 8 (as 3 mg/kg IV) and 11 (as 7 mg/kg IV) of course 1 and days 1 (as 10 mg/kg IV)and 8 (as 10 mg/kg IV) of all subsequent courses. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. Patients receive 10 mg/kg bevacizumab IV over 30-90 minutes on day 1 and anti-endoglin monoclonal antibody TRC105 IV over 1-4 hours on days 8 (as 3 mg/kg IV) and 11 (as 7 mg/kg IV) of course 1 and days 1 (as 10 mg/kg IV)and 8 (as 10 mg/kg IV) of all subsequent courses. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. Experimental: Arm I (bevacizumab and TRC105): Patients receive 10 mg/kg bevacizumab IV over 30-90 minutes on day 1 and 10 mg/kg anti-endoglin monoclonal antibody TRC105 IV over 1-4 hours on days 8 and 11 of course 1 and days 1 and 8 of all subsequent courses. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. Active Comparator: Arm II (bevacizumab): Patients receive bevacizumab as in arm I. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.
All-Cause Mortality
Phase I: Bev + TRC105 (Dose 0, Cohort A) Phase I: Bev + TRC105 (Dose 1, Cohort A) Phase I: Bev + TRC105 (Dose 2, Cohort A) Phase I: Bev + TRC105 (Dose 2, Cohort B) Phase II: Bev + TRC105 (Arm I) Phase II: Bev Alone (Arm II)
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/4 (0.00%)      0/3 (0.00%)      0/4 (0.00%)      0/3 (0.00%)      2/49 (4.08%)      2/43 (4.65%)    
Show Serious Adverse Events Hide Serious Adverse Events
Phase I: Bev + TRC105 (Dose 0, Cohort A) Phase I: Bev + TRC105 (Dose 1, Cohort A) Phase I: Bev + TRC105 (Dose 2, Cohort A) Phase I: Bev + TRC105 (Dose 2, Cohort B) Phase II: Bev + TRC105 (Arm I) Phase II: Bev Alone (Arm II)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   3/4 (75.00%)      0/3 (0.00%)      1/4 (25.00%)      2/3 (66.67%)      15/49 (30.61%)      8/43 (18.60%)    
Blood and lymphatic system disorders             
Anemia  1  1/4 (25.00%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0 1/3 (33.33%)  1 2/49 (4.08%)  2 0/43 (0.00%)  0
Gastrointestinal disorders             
Diarrhea  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/49 (2.04%)  1 0/43 (0.00%)  0
Dry mouth  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/49 (2.04%)  1 0/43 (0.00%)  0
Duodenal hemorrhage  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/49 (2.04%)  1 0/43 (0.00%)  0
Gingival pain  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/49 (2.04%)  3 0/43 (0.00%)  0
Nausea  1  0/4 (0.00%)  0 0/3 (0.00%)  0 1/4 (25.00%)  1 0/3 (0.00%)  0 0/49 (0.00%)  0 0/43 (0.00%)  0
Oral hemorrhage  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/49 (2.04%)  3 0/43 (0.00%)  0
Vomiting  1  0/4 (0.00%)  0 0/3 (0.00%)  0 1/4 (25.00%)  1 0/3 (0.00%)  0 0/49 (0.00%)  0 0/43 (0.00%)  0
General disorders             
Fatigue  1  1/4 (25.00%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 2/49 (4.08%)  3 1/43 (2.33%)  1
Fever  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 2/49 (4.08%)  2 0/43 (0.00%)  0
Malaise  1  0/4 (0.00%)  0 0/3 (0.00%)  0 1/4 (25.00%)  1 0/3 (0.00%)  0 0/49 (0.00%)  0 0/43 (0.00%)  0
Infections and infestations             
Meningitis  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/49 (2.04%)  1 0/43 (0.00%)  0
Sepsis  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/49 (2.04%)  1 1/43 (2.33%)  1
Urinary tract infection  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 2/49 (4.08%)  2 0/43 (0.00%)  0
Wound infection  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/49 (2.04%)  1 0/43 (0.00%)  0
Injury, poisoning and procedural complications             
Fall  1  1/4 (25.00%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/49 (2.04%)  1 0/43 (0.00%)  0
Wound dehiscence  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/49 (2.04%)  1 0/43 (0.00%)  0
Investigations             
Creatinine increased  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/49 (2.04%)  1 0/43 (0.00%)  0
Platelet count decreased  1  1/4 (25.00%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/49 (0.00%)  0 1/43 (2.33%)  1
Metabolism and nutrition disorders             
Hyperglycemia  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 2/49 (4.08%)  3 0/43 (0.00%)  0
Musculoskeletal and connective tissue disorders             
Muscle weakness left-sided  1  1/4 (25.00%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/49 (2.04%)  1 0/43 (0.00%)  0
Muscle weakness lower limb  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/49 (2.04%)  1 0/43 (0.00%)  0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)             
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 2/49 (4.08%)  2 3/43 (6.98%)  3
Nervous system disorders             
Cerebrospinal fluid leakage  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/49 (2.04%)  1 0/43 (0.00%)  0
Depressed level of consciousness  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/49 (0.00%)  0 1/43 (2.33%)  1
Dysarthria  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/49 (2.04%)  1 0/43 (0.00%)  0
Headache  1  1/4 (25.00%)  2 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 3/49 (6.12%)  3 1/43 (2.33%)  1
Hydrocephalus  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 1/3 (33.33%)  1 0/49 (0.00%)  0 0/43 (0.00%)  0
Intracranial hemorrhage  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/49 (2.04%)  1 0/43 (0.00%)  0
Nervous system disorders - Other, specify  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/49 (0.00%)  0 2/43 (4.65%)  3
Seizure  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/49 (2.04%)  1 1/43 (2.33%)  1
Psychiatric disorders             
Confusion  1  1/4 (25.00%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/49 (2.04%)  1 0/43 (0.00%)  0
Renal and urinary disorders             
Acute kidney injury  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/49 (2.04%)  1 0/43 (0.00%)  0
Proteinuria  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/49 (2.04%)  1 0/43 (0.00%)  0
Respiratory, thoracic and mediastinal disorders             
Aspiration  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/49 (0.00%)  0 1/43 (2.33%)  1
Epistaxis  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 1/3 (33.33%)  1 4/49 (8.16%)  6 0/43 (0.00%)  0
Nasal congestion  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/49 (2.04%)  1 0/43 (0.00%)  0
Respiratory failure  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/49 (0.00%)  0 1/43 (2.33%)  1
Skin and subcutaneous tissue disorders             
Alopecia  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/49 (2.04%)  2 0/43 (0.00%)  0
Rash maculo-papular  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/49 (2.04%)  1 0/43 (0.00%)  0
Vascular disorders             
Flushing  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/49 (2.04%)  1 0/43 (0.00%)  0
Hypertension  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/49 (2.04%)  1 0/43 (0.00%)  0
Thromboembolic event  1  1/4 (25.00%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0 1/3 (33.33%)  1 2/49 (4.08%)  2 0/43 (0.00%)  0
1
Term from vocabulary, MedDRA 12
Indicates events were collected by systematic assessment
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Phase I: Bev + TRC105 (Dose 0, Cohort A) Phase I: Bev + TRC105 (Dose 1, Cohort A) Phase I: Bev + TRC105 (Dose 2, Cohort A) Phase I: Bev + TRC105 (Dose 2, Cohort B) Phase II: Bev + TRC105 (Arm I) Phase II: Bev Alone (Arm II)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   4/4 (100.00%)      3/3 (100.00%)      4/4 (100.00%)      3/3 (100.00%)      48/49 (97.96%)      38/43 (88.37%)    
Blood and lymphatic system disorders             
Anemia  1  1/4 (25.00%)  2 1/3 (33.33%)  2 2/4 (50.00%)  33 3/3 (100.00%)  25 36/49 (73.47%)  263 15/43 (34.88%)  38
Blood and lymphatic system disorders - Other, specify  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/49 (0.00%)  0 1/43 (2.33%)  1
Cardiac disorders             
Mitral valve disease  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/49 (2.04%)  1 0/43 (0.00%)  0
Myocardial infarction  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/49 (0.00%)  0 1/43 (2.33%)  1
Sinus tachycardia  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/49 (2.04%)  1 0/43 (0.00%)  0
Ear and labyrinth disorders             
Ear pain  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/49 (2.04%)  1 0/43 (0.00%)  0
Hearing impaired  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/49 (0.00%)  0 1/43 (2.33%)  2
Vertigo  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/49 (2.04%)  5 0/43 (0.00%)  0
Eye disorders             
Blurred vision  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/49 (2.04%)  1 2/43 (4.65%)  3
Eye disorders - Other, specify  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/49 (2.04%)  7 0/43 (0.00%)  0
Watering eyes  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/49 (0.00%)  0 1/43 (2.33%)  1
Gastrointestinal disorders             
Abdominal distension  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/49 (2.04%)  1 0/43 (0.00%)  0
Abdominal pain  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 2/49 (4.08%)  2 0/43 (0.00%)  0
Anal hemorrhage  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/49 (2.04%)  1 1/43 (2.33%)  1
Bloating  1  0/4 (0.00%)  0 0/3 (0.00%)  0 1/4 (25.00%)  2 0/3 (0.00%)  0 0/49 (0.00%)  0 0/43 (0.00%)  0
Constipation  1  3/4 (75.00%)  5 1/3 (33.33%)  1 2/4 (50.00%)  12 2/3 (66.67%)  21 17/49 (34.69%)  86 11/43 (25.58%)  39
Diarrhea  1  1/4 (25.00%)  1 1/3 (33.33%)  2 2/4 (50.00%)  3 2/3 (66.67%)  4 13/49 (26.53%)  37 6/43 (13.95%)  14
Dry mouth  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 2/49 (4.08%)  7 0/43 (0.00%)  0
Dyspepsia  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 2/49 (4.08%)  22 1/43 (2.33%)  1
Dysphagia  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/49 (2.04%)  2 0/43 (0.00%)  0
Fecal incontinence  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/49 (2.04%)  1 0/43 (0.00%)  0
Gastrointestinal disorders - Other, specify  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 1/3 (33.33%)  1 0/49 (0.00%)  0 1/43 (2.33%)  1
Gingival pain  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 2/49 (4.08%)  2 0/43 (0.00%)  0
Hemorrhoids  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/49 (2.04%)  1 0/43 (0.00%)  0
Mucositis oral  1  1/4 (25.00%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0 1/3 (33.33%)  3 5/49 (10.20%)  24 0/43 (0.00%)  0
Nausea  1  0/4 (0.00%)  0 1/3 (33.33%)  17 2/4 (50.00%)  35 0/3 (0.00%)  0 8/49 (16.33%)  12 7/43 (16.28%)  27
Oral hemorrhage  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 6/49 (12.24%)  21 0/43 (0.00%)  0
Oral pain  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/49 (2.04%)  1 0/43 (0.00%)  0
Periodontal disease  1  0/4 (0.00%)  0 0/3 (0.00%)  0 1/4 (25.00%)  4 0/3 (0.00%)  0 2/49 (4.08%)  16 0/43 (0.00%)  0
Toothache  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 2/49 (4.08%)  3 1/43 (2.33%)  1
Vomiting  1  0/4 (0.00%)  0 0/3 (0.00%)  0 1/4 (25.00%)  1 0/3 (0.00%)  0 5/49 (10.20%)  8 2/43 (4.65%)  2
General disorders             
Chills  1  0/4 (0.00%)  0 0/3 (0.00%)  0 1/4 (25.00%)  2 0/3 (0.00%)  0 0/49 (0.00%)  0 1/43 (2.33%)  3
Edema face  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 2/49 (4.08%)  4 0/43 (0.00%)  0
Edema limbs  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 7/49 (14.29%)  17 2/43 (4.65%)  11
Fatigue  1  3/4 (75.00%)  11 3/3 (100.00%)  21 3/4 (75.00%)  40 3/3 (100.00%)  18 44/49 (89.80%)  260 30/43 (69.77%)  254
Fever  1  1/4 (25.00%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 7/49 (14.29%)  9 2/43 (4.65%)  4
Gait disturbance  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 2/49 (4.08%)  2 1/43 (2.33%)  1
General disorders and administration site conditions - Other, specify  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/49 (2.04%)  1 0/43 (0.00%)  0
Infusion related reaction  1  2/4 (50.00%)  2 1/3 (33.33%)  1 1/4 (25.00%)  1 0/3 (0.00%)  0 11/49 (22.45%)  12 2/43 (4.65%)  2
Localized edema  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/49 (2.04%)  1 0/43 (0.00%)  0
Malaise  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/49 (2.04%)  1 0/43 (0.00%)  0
Non-cardiac chest pain  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/49 (2.04%)  1 0/43 (0.00%)  0
Pain  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/49 (0.00%)  0 1/43 (2.33%)  1
Infections and infestations             
Lung infection  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/49 (0.00%)  0 1/43 (2.33%)  1
Mucosal infection  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/49 (0.00%)  0 1/43 (2.33%)  1
Nail infection  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/49 (2.04%)  1 0/43 (0.00%)  0
Rash pustular  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/49 (2.04%)  2 0/43 (0.00%)  0
Sinusitis  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 2/49 (4.08%)  2 0/43 (0.00%)  0
Tooth infection  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/49 (2.04%)  2 1/43 (2.33%)  1
Urinary tract infection  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/49 (2.04%)  1 1/43 (2.33%)  1
Injury, poisoning and procedural complications             
Bruising  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/49 (2.04%)  2 3/43 (6.98%)  6
Fall  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/49 (2.04%)  1 0/43 (0.00%)  0
Wound complication  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/49 (2.04%)  1 0/43 (0.00%)  0
Wound dehiscence  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/49 (2.04%)  2 2/43 (4.65%)  3
Investigations             
Activated partial thromboplastin time prolonged  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/49 (2.04%)  1 1/43 (2.33%)  1
Alanine aminotransferase increased  1  0/4 (0.00%)  0 1/3 (33.33%)  5 1/4 (25.00%)  1 0/3 (0.00%)  0 6/49 (12.24%)  18 1/43 (2.33%)  1
Alkaline phosphatase increased  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/49 (2.04%)  1 2/43 (4.65%)  2
Aspartate aminotransferase increased  1  0/4 (0.00%)  0 1/3 (33.33%)  5 1/4 (25.00%)  1 0/3 (0.00%)  0 2/49 (4.08%)  2 0/43 (0.00%)  0
Blood bilirubin increased  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/49 (0.00%)  0 2/43 (4.65%)  3
Creatinine increased  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 3/49 (6.12%)  7 1/43 (2.33%)  1
Investigations - Other, specify  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/49 (2.04%)  2 1/43 (2.33%)  3
Lymphocyte count decreased  1  0/4 (0.00%)  0 0/3 (0.00%)  0 1/4 (25.00%)  2 1/3 (33.33%)  4 6/49 (12.24%)  7 5/43 (11.63%)  13
Neutrophil count decreased  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 4/49 (8.16%)  7 4/43 (9.30%)  7
Platelet count decreased  1  1/4 (25.00%)  1 1/3 (33.33%)  1 1/4 (25.00%)  1 0/3 (0.00%)  0 14/49 (28.57%)  47 19/43 (44.19%)  81
Weight loss  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/49 (2.04%)  1 1/43 (2.33%)  19
White blood cell decreased  1  0/4 (0.00%)  0 0/3 (0.00%)  0 1/4 (25.00%)  3 0/3 (0.00%)  0 8/49 (16.33%)  22 11/43 (25.58%)  58
Metabolism and nutrition disorders             
Anorexia  1  0/4 (0.00%)  0 0/3 (0.00%)  0 1/4 (25.00%)  1 0/3 (0.00%)  0 4/49 (8.16%)  9 3/43 (6.98%)  24
Dehydration  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/49 (0.00%)  0 1/43 (2.33%)  1
Hyperglycemia  1  0/4 (0.00%)  0 0/3 (0.00%)  0 1/4 (25.00%)  6 1/3 (33.33%)  5 9/49 (18.37%)  27 1/43 (2.33%)  1
Hyperkalemia  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/49 (2.04%)  1 0/43 (0.00%)  0
Hypermagnesemia  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/49 (2.04%)  1 0/43 (0.00%)  0
Hypernatremia  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/49 (2.04%)  1 1/43 (2.33%)  2
Hypoalbuminemia  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 3/49 (6.12%)  6 0/43 (0.00%)  0
Hypocalcemia  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/49 (2.04%)  1 2/43 (4.65%)  3
Hypokalemia  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 6/49 (12.24%)  10 1/43 (2.33%)  1
Hypomagnesemia  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/49 (2.04%)  9 0/43 (0.00%)  0
Hyponatremia  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 2/49 (4.08%)  2 2/43 (4.65%)  2
Hypophosphatemia  1  1/4 (25.00%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 5/49 (10.20%)  16 3/43 (6.98%)  4
Metabolism and nutrition disorders - Other, specify  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/49 (2.04%)  1 0/43 (0.00%)  0
Musculoskeletal and connective tissue disorders             
Arthralgia  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 2/49 (4.08%)  3 2/43 (4.65%)  26
Arthritis  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/49 (0.00%)  0 1/43 (2.33%)  1
Back pain  1  0/4 (0.00%)  0 1/3 (33.33%)  16 0/4 (0.00%)  0 0/3 (0.00%)  0 0/49 (0.00%)  0 0/43 (0.00%)  0
Bone pain  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/49 (0.00%)  0 2/43 (4.65%)  10
Flank pain  1  0/4 (0.00%)  0 0/3 (0.00%)  0 1/4 (25.00%)  1 0/3 (0.00%)  0 0/49 (0.00%)  0 0/43 (0.00%)  0
Generalized muscle weakness  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 4/49 (8.16%)  6 0/43 (0.00%)  0
Muscle weakness lower limb  1  0/4 (0.00%)  0 1/3 (33.33%)  1 0/4 (0.00%)  0 0/3 (0.00%)  0 1/49 (2.04%)  1 1/43 (2.33%)  1
Musculoskeletal and connective tissue disorder - Other, specify  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/49 (2.04%)  1 0/43 (0.00%)  0
Myalgia  1  0/4 (0.00%)  0 1/3 (33.33%)  16 0/4 (0.00%)  0 0/3 (0.00%)  0 1/49 (2.04%)  1 1/43 (2.33%)  1
Neck pain  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 2/49 (4.08%)  5 1/43 (2.33%)  1
Pain in extremity  1  0/4 (0.00%)  0 1/3 (33.33%)  17 1/4 (25.00%)  1 0/3 (0.00%)  0 0/49 (0.00%)  0 1/43 (2.33%)  1
Nervous system disorders             
Amnesia  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/49 (2.04%)  1 0/43 (0.00%)  0
Ataxia  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/49 (2.04%)  1 0/43 (0.00%)  0
Cognitive disturbance  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 2/49 (4.08%)  2 0/43 (0.00%)  0
Concentration impairment  1  0/4 (0.00%)  0 0/3 (0.00%)  0 1/4 (25.00%)  2 0/3 (0.00%)  0 0/49 (0.00%)  0 1/43 (2.33%)  1
Dizziness  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 2/49 (4.08%)  3 2/43 (4.65%)  4
Dysarthria  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 3/49 (6.12%)  3 0/43 (0.00%)  0
Dysgeusia  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/49 (2.04%)  8 0/43 (0.00%)  0
Dysphasia  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/49 (2.04%)  7 1/43 (2.33%)  2
Headache  1  3/4 (75.00%)  7 3/3 (100.00%)  20 3/4 (75.00%)  37 3/3 (100.00%)  17 31/49 (63.27%)  158 16/43 (37.21%)  117
Intracranial hemorrhage  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/49 (0.00%)  0 1/43 (2.33%)  1
Ischemia cerebrovascular  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/49 (2.04%)  1 2/43 (4.65%)  2
Leukoencephalopathy  1  1/4 (25.00%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/49 (2.04%)  1 1/43 (2.33%)  1
Memory impairment  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 3/49 (6.12%)  10 2/43 (4.65%)  3
Nervous system disorders - Other, specify  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 2/49 (4.08%)  9 0/43 (0.00%)  0
Olfactory nerve disorder  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/49 (2.04%)  7 0/43 (0.00%)  0
Paresthesia  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/49 (0.00%)  0 1/43 (2.33%)  1
Peripheral motor neuropathy  1  0/4 (0.00%)  0 1/3 (33.33%)  1 0/4 (0.00%)  0 0/3 (0.00%)  0 1/49 (2.04%)  1 0/43 (0.00%)  0
Peripheral sensory neuropathy  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 2/49 (4.08%)  4 1/43 (2.33%)  2
Presyncope  1  0/4 (0.00%)  0 0/3 (0.00%)  0 1/4 (25.00%)  1 0/3 (0.00%)  0 0/49 (0.00%)  0 0/43 (0.00%)  0
Seizure  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 2/49 (4.08%)  8 1/43 (2.33%)  1
Somnolence  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/49 (2.04%)  1 1/43 (2.33%)  1
Stroke  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/49 (0.00%)  0 1/43 (2.33%)  1
Syncope  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/49 (2.04%)  1 0/43 (0.00%)  0
Tremor  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/49 (2.04%)  1 0/43 (0.00%)  0
Psychiatric disorders             
Agitation  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/49 (2.04%)  1 1/43 (2.33%)  1
Confusion  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/49 (2.04%)  2 2/43 (4.65%)  2
Depression  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/49 (2.04%)  2 1/43 (2.33%)  1
Insomnia  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 7/49 (14.29%)  13 3/43 (6.98%)  22
Renal and urinary disorders             
Proteinuria  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 10/49 (20.41%)  15 11/43 (25.58%)  22
Renal and urinary disorders - Other, specify  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/49 (0.00%)  0 1/43 (2.33%)  1
Urinary frequency  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/49 (0.00%)  0 1/43 (2.33%)  1
Urinary incontinence  1  0/4 (0.00%)  0 0/3 (0.00%)  0 1/4 (25.00%)  2 0/3 (0.00%)  0 1/49 (2.04%)  1 1/43 (2.33%)  1
Urinary urgency  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/49 (2.04%)  1 0/43 (0.00%)  0
Reproductive system and breast disorders             
Vaginal hemorrhage  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/49 (2.04%)  1 0/43 (0.00%)  0
Respiratory, thoracic and mediastinal disorders             
Aspiration  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/49 (2.04%)  1 0/43 (0.00%)  0
Cough  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 1/3 (33.33%)  4 3/49 (6.12%)  8 1/43 (2.33%)  1
Dyspnea  1  1/4 (25.00%)  1 1/3 (33.33%)  2 0/4 (0.00%)  0 0/3 (0.00%)  0 13/49 (26.53%)  40 6/43 (13.95%)  34
Epistaxis  1  1/4 (25.00%)  1 2/3 (66.67%)  10 2/4 (50.00%)  30 2/3 (66.67%)  17 22/49 (44.90%)  141 4/43 (9.30%)  6
Hiccups  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/49 (2.04%)  1 0/43 (0.00%)  0
Hoarseness  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 1/3 (33.33%)  1 0/49 (0.00%)  0 0/43 (0.00%)  0
Nasal congestion  1  0/4 (0.00%)  0 0/3 (0.00%)  0 1/4 (25.00%)  2 0/3 (0.00%)  0 5/49 (10.20%)  20 1/43 (2.33%)  6
Productive cough  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/49 (0.00%)  0 1/43 (2.33%)  1
Respiratory, thoracic and mediastinal disorders - Other, specify  1  0/4 (0.00%)  0 0/3 (0.00%)  0 1/4 (25.00%)  1 0/3 (0.00%)  0 0/49 (0.00%)  0 0/43 (0.00%)  0
Sneezing  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/49 (0.00%)  0 1/43 (2.33%)  1
Voice alteration  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 1/3 (33.33%)  5 1/49 (2.04%)  1 0/43 (0.00%)  0
Skin and subcutaneous tissue disorders             
Alopecia  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/49 (2.04%)  5 0/43 (0.00%)  0
Body odor  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/49 (0.00%)  0 1/43 (2.33%)  1
Dry skin  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/49 (0.00%)  0 2/43 (4.65%)  3
Erythema multiforme  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 1/3 (33.33%)  8 0/49 (0.00%)  0 0/43 (0.00%)  0
Pruritus  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/49 (0.00%)  0 1/43 (2.33%)  2
Purpura  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/49 (0.00%)  0 1/43 (2.33%)  1
Rash acneiform  1  0/4 (0.00%)  0 1/3 (33.33%)  1 0/4 (0.00%)  0 0/3 (0.00%)  0 5/49 (10.20%)  16 1/43 (2.33%)  5
Rash maculo-papular  1  0/4 (0.00%)  0 0/3 (0.00%)  0 2/4 (50.00%)  20 0/3 (0.00%)  0 2/49 (4.08%)  10 2/43 (4.65%)  23
Skin and subcutaneous tissue disorders - Other, specify  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 2/49 (4.08%)  2 1/43 (2.33%)  1
Skin ulceration  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 1/3 (33.33%)  1 0/49 (0.00%)  0 0/43 (0.00%)  0
Telangiectasia  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 2/49 (4.08%)  32 0/43 (0.00%)  0
Vascular disorders             
Flushing  1  0/4 (0.00%)  0 1/3 (33.33%)  11 0/4 (0.00%)  0 0/3 (0.00%)  0 8/49 (16.33%)  17 4/43 (9.30%)  13
Hematoma  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/49 (2.04%)  1 0/43 (0.00%)  0
Hypertension  1  2/4 (50.00%)  2 0/3 (0.00%)  0 3/4 (75.00%)  37 1/3 (33.33%)  5 22/49 (44.90%)  136 28/43 (65.12%)  178
Hypotension  1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/49 (2.04%)  1 0/43 (0.00%)  0
Thromboembolic event  1  0/4 (0.00%)  0 1/3 (33.33%)  1 0/4 (0.00%)  0 0/3 (0.00%)  0 0/49 (0.00%)  0 0/43 (0.00%)  0
1
Term from vocabulary, MedDRA 12
Indicates events were collected by systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Evanthia Galanis, M.D.
Organization: Mayo Clinic
Phone: (507) 284-1370
EMail: galanis.evanthia@mayo.edu
Layout table for additonal information
Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01648348     History of Changes
Other Study ID Numbers: NCI-2012-01989
NCI-2012-01989 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
CDR0000737109
N1174
NCCTG-N1174
N1174 ( Other Identifier: Alliance for Clinical Trials in Oncology )
N1174 ( Other Identifier: CTEP )
U10CA180821 ( U.S. NIH Grant/Contract )
U10CA025224 ( U.S. NIH Grant/Contract )
First Submitted: July 20, 2012
First Posted: July 24, 2012
Results First Submitted: September 21, 2017
Results First Posted: May 23, 2018
Last Update Posted: May 23, 2018