Paclitaxel, Nab-paclitaxel, or Ixabepilone With or Without Bevacizumab in Treating Patients With Stage IIIC or Stage IV Breast Cancer

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ClinicalTrials.gov Identifier: NCT00785291

Recruitment Status : Completed

First Posted : November 5, 2008

Results First Posted : July 2, 2015

Last Update Posted : October 10, 2022

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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	Estrogen Receptor Negative Estrogen Receptor Positive HER2/Neu Negative HER2/Neu Positive Progesterone Receptor Negative Progesterone Receptor Positive Recurrent Breast Carcinoma Stage IIIC Breast Cancer AJCC v6 Stage IV Breast Cancer AJCC v6 and v7
Interventions	Biological: Bevacizumab Drug: Ixabepilone Other: Laboratory Biomarker Analysis Drug: Nab-paclitaxel Drug: Paclitaxel Other: Questionnaire Administration
Enrollment	799

Participant Flow

Recruitment Details	Between October 2008 - November 2011, a total of 799 participants were recruited.
Pre-assignment Details


Arm/Group Title	Arm A (Paclitaxel)	Arm B (Nab-paclitaxel)	Arm C (Ixabepilone)
Arm/Group Description	Patients receive 90 mg/m^2 paclitax...	Patients receive paclitaxel albumin...	Patients receive ixabepilone IV ove...
Arm/Group Description	Patients receive 90 mg/m^2 paclitaxel IV over 1 hour on days 1, 8, and 15. Patients may receive 10 mg/kg bevacizumab IV over 30-90 minutes on days 1 and 15. Treatment continues until progression.	Patients receive paclitaxel albumin-stabilized nanoparticle formulation IV over 30 minutes on days 1, 8, and 15. Patients may also receive 10 mg/kg bevacizumab IV over 30-90 minutes on days 1 and 15. Treatment continues until progression.	Patients receive ixabepilone IV over 60 minutes on days 1, 8, and 15. Patients may also receive 10 mg/kg bevacizumab IV over 30-90 minutes on days 1 and 15. Treatment continues until progression. (closed to accrual as of 7/18/11)
Period Title: Overall Study
Started	283	271	245
Completed	147	122	139
Not Completed	136	149	106
Reason Not Completed
Never began treatment	8	4	4
Adverse Event	39	70	56
Death	7	4	3
Withdrawal by Subject	35	36	17
Alternative Therapy	12	6	7
Complicating illness	6	4	4
Other Medical Reasons	29	25	15

Baseline Characteristics

Arm/Group Title		Arm A (Paclitaxel)	Arm B (Nab-paclitaxel)	Arm C (Ixabepilone)	Total
Arm/Group Description		Patients receive 90 mg/m^2 paclitax...	Patients receive paclitaxel albumin...	Patients receive ixabepilone IV ove...	Total of all reporting groups
Arm/Group Description		Patients receive 90 mg/m^2 paclitaxel IV over 1 hour on days 1, 8, and 15. Patients may receive 10 mg/kg bevacizumab IV over 30-90 minutes on days 1 and 15. Treatment continues until progression.	Patients receive paclitaxel albumin-stabilized nanoparticle formulation IV over 30 minutes on days 1, 8, and 15. Patients may also receive 10 mg/kg bevacizumab IV over 30-90 minutes on days 1 and 15. Treatment continues until progression.	Patients receive ixabepilone IV over 60 minutes on days 1, 8, and 15. Patients may also receive 10 mg/kg bevacizumab IV over 30-90 minutes on days 1 and 15. Treatment continues until progression. (closed to accrual as of 7/18/11)	Total of all reporting groups
Overall Number of Baseline Participants		283	271	245	799
Baseline Analysis Population Description		...
Baseline Analysis Population Description		All randomized participants are included in baseline characteristics.
Age, Customized Measure Type: Number Unit of measure: Participants	Number Analyzed	283 participants	271 participants	245 participants	799 participants
20-29		2	2	1	5
30-39		15	18	17	50
40-49		52	56	55	163
50-59		109	89	86	284
60-69		74	74	68	216
70-79		24	28	15	67
80+		7	4	3	14
Sex: Female, Male Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	283 participants	271 participants	245 participants	799 participants
	Female	277 97.9%	268 98.9%	243 99.2%	788 98.6%
	Male	6 2.1%	3 1.1%	2 0.8%	11 1.4%
Ethnicity (NIH/OMB) Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	283 participants	271 participants	245 participants	799 participants
	Hispanic or Latino	19 6.7%	15 5.5%	13 5.3%	47 5.9%
	Not Hispanic or Latino	252 89.0%	239 88.2%	221 90.2%	712 89.1%
	Unknown or Not Reported	12 4.2%	17 6.3%	11 4.5%	40 5.0%
Race (NIH/OMB) Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	283 participants	271 participants	245 participants	799 participants
	American Indian or Alaska Native	2 0.7%	1 0.4%	2 0.8%	5 0.6%
	Asian	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Native Hawaiian or Other Pacific Islander	3 1.1%	0 0.0%	1 0.4%	4 0.5%
	Black or African American	42 14.8%	45 16.6%	26 10.6%	113 14.1%
	White	220 77.7%	214 79.0%	206 84.1%	640 80.1%
	More than one race	1 0.4%	1 0.4%	2 0.8%	4 0.5%
	Unknown or Not Reported	15 5.3%	10 3.7%	8 3.3%	33 4.1%
Region of Enrollment Measure Type: Number Unit of measure: Participants
United States	Number Analyzed	283 participants	271 participants	245 participants	799 participants
United States		283	271	245	799
Prior Adjuvant Taxane Measure Type: Number Unit of measure: Participants	Number Analyzed	283 participants	271 participants	245 participants	799 participants
Yes		125	120	107	352
No		158	151	138	447
Hormone Receptor Status Measure Type: Number Unit of measure: Participants	Number Analyzed	283 participants	271 participants	245 participants	799 participants
ER/PgR Positive		201	195	178	574
ER/PgR Negative		82	76	67	225
Physician's Decision to use Bevacizumab Measure Type: Number Unit of measure: Participants	Number Analyzed	283 participants	271 participants	245 participants	799 participants
Bevacizumab planned		51	44	15	110
Bevacizumab not planned		8	4	8	20
Bevacizumab required		224	223	222	669

Outcome Measures

1.Primary Outcome


Title	Progression Free Survival
Description	Progression-free survival (PFS) is defined as the interval from regist...
Description	Progression-free survival (PFS) is defined as the interval from registration until first disease progression, regardless of site, or death resulting from any cause, which ever occurred first. Distribution was estimated using the Kaplan Meier product-limit method. Progression is defined as a 20% increase in the sum of longest diameter of target lesions (per Response Evaluation Criteria in Solid Tumors [RECIST] criteria).
Time Frame	Time from randomization to progression or death due to any cause, whichever occurs first (up to 5 years)

Outcome Measure Data

Analysis Population Description

Participants who never began protocol treatment were excluded.


Arm/Group Title	Arm A (Paclitaxel)	Arm B (Nab-paclitaxel)	Arm C (Ixabepilone)
Arm/Group Description:	Patients receive 90 mg/m^2 paclitax...	Patients receive paclitaxel albumin...	Patients receive ixabepilone IV ove...
Arm/Group Description:	Patients receive 90 mg/m^2 paclitaxel IV over 1 hour on days 1, 8, and 15. Patients may receive 10 mg/kg bevacizumab IV over 30-90 minutes on days 1 and 15. Treatment continues until progression.	Patients receive paclitaxel albumin-stabilized nanoparticle formulation IV over 30 minutes on days 1, 8, and 15. Patients may also receive 10 mg/kg bevacizumab IV over 30-90 minutes on days 1 and 15. Treatment continues until progression.	Patients receive ixabepilone IV over 60 minutes on days 1, 8, and 15. Patients may also receive 10 mg/kg bevacizumab IV over 30-90 minutes on days 1 and 15. Treatment continues until progression. (closed to accrual as of 7/18/11)
Overall Number of Participants Analyzed	275	267	241
Median (95% Confidence Interval) Unit of Measure: months
	10.97 (9.79 to 12.42)	9.3 (8.15 to 10.45)	7.36 (6.21 to 8.18)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A (Paclitaxel), Arm B (Nab-paclitaxel)
	Comments	Stratified log-rank tests are used for the two primary comparisons of PFS within an experimental arm relative to PFS within the control arm. The family-wise error rate will be controlled at a one-sided 0.025 level. This is achieved in a 3-arm trial with a common control group by conducting the marginal log-rank tests with a one-sided α = 0.0135. Sample size calculations are based on having high power to detect a hazard ratio of 1.36, in the control arm as compared to the experimental arms.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.054
	Comments	Tests were stratified by prior taxane therapy (yes/no) and hormone receptor status (positive/negative). P-values are for a test of inferiority 2-sided and are unadjusted for multiple comparisons.
	Method	Log Rank
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.20
	Confidence Interval	(2-Sided) 95% 1.00 to 1.45
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Arm A (Paclitaxel), Arm C (Ixabepilone)
	Comments	Stratified log-rank tests are used for the two primary comparisons of PFS within an experimental arm relative to PFS within the control arm. The family-wise error rate will be controlled at a one-sided 0.025 level. This is achieved in a 3-arm trial with a common control group by conducting the marginal log-rank tests with a one-sided α = 0.0135. Sample size calculations are based on having high power to detect a hazard ratio of 1.36, in the control arm as compared to the experimental arms.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Tests were stratified by prior taxane therapy (yes/no) and hormone receptor status (positive/negative). P-values are for a test of inferiority 2-sided and are unadjusted for multiple comparisons.
	Method	Log Rank
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.55
	Confidence Interval	(2-Sided) 95% 1.28 to 1.87
	Estimation Comments	[Not Specified]

2.Secondary Outcome


Title	Objective Tumor Response Rate
Description	Response was defined by the Response Evaluation Criteria in Solid Tumo...
Description	Response was defined by the Response Evaluation Criteria in Solid Tumors (RECIST). A responding participant had either a Complete Response (disappearance of all target lesions) or Partial Response (30% decrease in sum of longest diameter of target lesions).
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]


Arm/Group Title	Arm A (Paclitaxel)	Arm B (Nab-paclitaxel)	Arm C (Ixabepilone)
Arm/Group Description:	Patients receive 90 mg/m^2 paclitax...	Patients receive paclitaxel albumin...	Patients receive ixabepilone IV ove...
Arm/Group Description:	Patients receive 90 mg/m^2 paclitaxel IV over 1 hour on days 1, 8, and 15. Patients may receive 10 mg/kg bevacizumab IV over 30-90 minutes on days 1 and 15. Treatment continues until progression.	Patients receive paclitaxel albumin-stabilized nanoparticle formulation IV over 30 minutes on days 1, 8, and 15. Patients may also receive 10 mg/kg bevacizumab IV over 30-90 minutes on days 1 and 15. Treatment continues until progression.	Patients receive ixabepilone IV over 60 minutes on days 1, 8, and 15. Patients may also receive 10 mg/kg bevacizumab IV over 30-90 minutes on days 1 and 15. Treatment continues until progression. (closed to accrual as of 7/18/11)
Overall Number of Participants Analyzed	275	267	241
Measure Type: Number Unit of Measure: percentage of participants
	38.2	34.1	25.6

3.Secondary Outcome


Title	Time to Treatment Failure
Description	Time from registration until treatment failure, defined as early termi...
Description	Time from registration until treatment failure, defined as early termination of protocol therapy for any reason, first disease progression or death without progression. Surviving participants who were failure free were censored as date last known alive and failure free. Distribution was estimated using the Kaplan Meier product-limit method.
Time Frame	Time from randomization until progression, death, or yearly termination of protocol therapy (up to 5 years)

Outcome Measure Data

Analysis Population Description

Participants who never began protocol treatment were excluded.


Arm/Group Title	Arm A (Paclitaxel)	Arm B (Nab-paclitaxel)	Arm C (Ixabepilone)
Arm/Group Description:	Patients receive 90 mg/m^2 paclitax...	Patients receive paclitaxel albumin...	Patients receive ixabepilone IV ove...
Arm/Group Description:	Patients receive 90 mg/m^2 paclitaxel IV over 1 hour on days 1, 8, and 15. Patients may receive 10 mg/kg bevacizumab IV over 30-90 minutes on days 1 and 15. Treatment continues until progression.	Patients receive paclitaxel albumin-stabilized nanoparticle formulation IV over 30 minutes on days 1, 8, and 15. Patients may also receive 10 mg/kg bevacizumab IV over 30-90 minutes on days 1 and 15. Treatment continues until progression.	Patients receive ixabepilone IV over 60 minutes on days 1, 8, and 15. Patients may also receive 10 mg/kg bevacizumab IV over 30-90 minutes on days 1 and 15. Treatment continues until progression. (closed to accrual as of 7/18/11)
Overall Number of Participants Analyzed	275	267	241
Median (95% Confidence Interval) Unit of Measure: months
	6.6 (5.62 to 7.2)	5.19 (4.83 to 5.55)	4.93 (4.21 to 5.29)

4.Secondary Outcome


Title	12 Month Progression Free Survival
Description	Percentage of participants who were alive and progression free at 12 m...
Description	Percentage of participants who were alive and progression free at 12 months. The 12 month progression free survival, with 95% confidence interval, was estimated using the Kaplan Meier method.
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

Participants who never began protocol treatment were excluded.


Arm/Group Title	Arm A (Paclitaxel)	Arm B (Nab-paclitaxel)	Arm C (Ixabepilone)
Arm/Group Description:	Patients receive 90 mg/m^2 paclitax...	Patients receive paclitaxel albumin...	Patients receive ixabepilone IV ove...
Arm/Group Description:	Patients receive 90 mg/m^2 paclitaxel IV over 1 hour on days 1, 8, and 15. Patients may receive 10 mg/kg bevacizumab IV over 30-90 minutes on days 1 and 15. Treatment continues until progression.	Patients receive paclitaxel albumin-stabilized nanoparticle formulation IV over 30 minutes on days 1, 8, and 15. Patients may also receive 10 mg/kg bevacizumab IV over 30-90 minutes on days 1 and 15. Treatment continues until progression.	Patients receive ixabepilone IV over 60 minutes on days 1, 8, and 15. Patients may also receive 10 mg/kg bevacizumab IV over 30-90 minutes on days 1 and 15. Treatment continues until progression. (closed to accrual as of 7/18/11)
Overall Number of Participants Analyzed	275	267	241
Measure Type: Number Number (95% Confidence Interval) Unit of Measure: percentage of participants
	45 (39 to 51)	36 (30 to 42)	28 (23 to 35)

5.Secondary Outcome


Title	Overall Survival
Description	Overall survival was measured as the interval from study entry until d...
Description	Overall survival was measured as the interval from study entry until death, from any cause, or last contact. Distribution was estimated using the Kaplan Meier product-limit method.
Time Frame	Time from randomization to death or last follow-up (up to 5 years)

Outcome Measure Data

Analysis Population Description

[Not Specified]


Arm/Group Title	Arm A (Paclitaxel)	Arm B (Nab-paclitaxel)	Arm C (Ixabepilone)
Arm/Group Description:	Patients receive 90 mg/m^2 paclitax...	Patients receive paclitaxel albumin...	Patients receive ixabepilone IV ove...
Arm/Group Description:	Patients receive 90 mg/m^2 paclitaxel IV over 1 hour on days 1, 8, and 15. Patients may receive 10 mg/kg bevacizumab IV over 30-90 minutes on days 1 and 15. Treatment continues until progression.	Patients receive paclitaxel albumin-stabilized nanoparticle formulation IV over 30 minutes on days 1, 8, and 15. Patients may also receive 10 mg/kg bevacizumab IV over 30-90 minutes on days 1 and 15. Treatment continues until progression.	Patients receive ixabepilone IV over 60 minutes on days 1, 8, and 15. Patients may also receive 10 mg/kg bevacizumab IV over 30-90 minutes on days 1 and 15. Treatment continues until progression. (closed to accrual as of 7/18/11)
Overall Number of Participants Analyzed	275	267	241
Median (95% Confidence Interval) Unit of Measure: months
	26.55 (23.8 to 32.9)	23.52 (20.4 to 28.2)	23.53 (19.9 to 25.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A (Paclitaxel), Arm B (Nab-paclitaxel)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.20
	Comments	Tests were stratified by prior taxane therapy (yes/no) and hormone receptor status (positive/negative).
	Method	Log Rank
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.17
	Confidence Interval	(2-Sided) 95% 0.92 to 1.47
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Arm A (Paclitaxel), Arm C (Ixabepilone)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.038
	Comments	Tests were stratified by prior taxane therapy (yes/no) and hormone receptor status (positive/negative).
	Method	Log Rank
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.28
	Confidence Interval	(2-Sided) 95% 1.01 to 1.61
	Estimation Comments	[Not Specified]

Adverse Events

Time Frame	[Not Specified]
Adverse Event Reporting Description	Adverse event data was submitted on 774 participants (Arm A: 272, Arm B: 264, Arm C: 238)

Arm/Group Title	Arm A (Paclitaxel)		Arm B (Nab-paclitaxel)		Arm C (Ixabepilone)
Arm/Group Description	Patients receive 90 mg/m^2 paclitax...		Patients receive paclitaxel albumin...		Patients receive ixabepilone IV ove...
Arm/Group Description	Patients receive 90 mg/m^2 paclitaxel IV over 1 hour on days 1, 8, and 15. Patients may receive 10 mg/kg bevacizumab IV over 30-90 minutes on days 1 and 15. Treatment continues until progression.		Patients receive paclitaxel albumin-stabilized nanoparticle formulation IV over 30 minutes on days 1, 8, and 15. Patients may also receive 10 mg/kg bevacizumab IV over 30-90 minutes on days 1 and 15. Treatment continues until progression.		Patients receive ixabepilone IV over 60 minutes on days 1, 8, and 15. Patients may also receive 10 mg/kg bevacizumab IV over 30-90 minutes on days 1 and 15. Treatment continues until progression. (closed to accrual as of 7/18/11)
All-Cause Mortality
	Arm A (Paclitaxel)		Arm B (Nab-paclitaxel)		Arm C (Ixabepilone)
	Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)
Total	--/--		--/--		--/--
Serious Adverse Events Serious Adverse Events
	Arm A (Paclitaxel)		Arm B (Nab-paclitaxel)		Arm C (Ixabepilone)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	65/272 (23.90%)		80/264 (30.30%)		59/238 (24.79%)
Blood and lymphatic system disorders
Blood disorder ^† 1	0/272 (0.00%)	0	1/264 (0.38%)	2	0/238 (0.00%)	0
Bone marrow hypocellular ^† 1	0/272 (0.00%)	0	1/264 (0.38%)	1	0/238 (0.00%)	0
Febrile neutropenia ^† 1	1/272 (0.37%)	1	0/264 (0.00%)	0	1/238 (0.42%)	1
Hemoglobin decreased ^† 1	14/272 (5.15%)	17	18/264 (6.82%)	22	12/238 (5.04%)	14
Lymphatic disorder ^† 1	0/272 (0.00%)	0	1/264 (0.38%)	1	0/238 (0.00%)	0
Cardiac disorders
Atrial fibrillation ^† 1	0/272 (0.00%)	0	2/264 (0.76%)	2	0/238 (0.00%)	0
Atrial tachycardia ^† 1	0/272 (0.00%)	0	0/264 (0.00%)	0	1/238 (0.42%)	1
Left ventricular dysfunction ^† 1	0/272 (0.00%)	0	4/264 (1.52%)	4	0/238 (0.00%)	0
Left ventricular failure ^† 1	0/272 (0.00%)	0	3/264 (1.14%)	3	4/238 (1.68%)	5
Myocardial ischemia ^† 1	1/272 (0.37%)	1	1/264 (0.38%)	1	0/238 (0.00%)	0
Palpitations ^† 1	0/272 (0.00%)	0	0/264 (0.00%)	0	1/238 (0.42%)	1
Pericardial effusion ^† 1	1/272 (0.37%)	1	0/264 (0.00%)	0	0/238 (0.00%)	0
Restrictive cardiomyopathy ^† 1	0/272 (0.00%)	0	1/264 (0.38%)	1	0/238 (0.00%)	0
Sinus tachycardia ^† 1	2/272 (0.74%)	2	1/264 (0.38%)	1	1/238 (0.42%)	1
Stokes-Adams syndrome ^† 1	1/272 (0.37%)	1	0/264 (0.00%)	0	0/238 (0.00%)	0
Supraventricular tachycardia ^† 1	0/272 (0.00%)	0	0/264 (0.00%)	0	1/238 (0.42%)	1
Endocrine disorders
Cushingoid ^† 1	1/272 (0.37%)	1	0/264 (0.00%)	0	0/238 (0.00%)	0
Hypothyroidism ^† 1	1/272 (0.37%)	1	0/264 (0.00%)	0	0/238 (0.00%)	0
Eye disorders
Dry eye syndrome ^† 1	0/272 (0.00%)	0	0/264 (0.00%)	0	1/238 (0.42%)	1
Eye pain ^† 1	1/272 (0.37%)	1	0/264 (0.00%)	0	0/238 (0.00%)	0
Retinopathy ^† 1	0/272 (0.00%)	0	1/264 (0.38%)	1	0/238 (0.00%)	0
Vision blurred ^† 1	2/272 (0.74%)	2	0/264 (0.00%)	0	2/238 (0.84%)	2
Watering eyes ^† 1	0/272 (0.00%)	0	0/264 (0.00%)	0	1/238 (0.42%)	1
Gastrointestinal disorders
Abdominal distension ^† 1	2/272 (0.74%)	2	1/264 (0.38%)	1	0/238 (0.00%)	0
Abdominal pain ^† 1	2/272 (0.74%)	2	2/264 (0.76%)	2	4/238 (1.68%)	4
Ascites ^† 1	1/272 (0.37%)	1	0/264 (0.00%)	0	1/238 (0.42%)	1
Cecum perforation ^† 1	0/272 (0.00%)	0	1/264 (0.38%)	1	0/238 (0.00%)	0
Colitis ^† 1	1/272 (0.37%)	1	0/264 (0.00%)	0	2/238 (0.84%)	2
Colonic obstruction ^† 1	1/272 (0.37%)	1	0/264 (0.00%)	0	0/238 (0.00%)	0
Colonic perforation ^† 1	1/272 (0.37%)	1	5/264 (1.89%)	5	0/238 (0.00%)	0
Constipation ^† 1	5/272 (1.84%)	5	6/264 (2.27%)	7	9/238 (3.78%)	10
Diarrhea ^† 1	7/272 (2.57%)	7	11/264 (4.17%)	12	11/238 (4.62%)	12
Dry mouth ^† 1	0/272 (0.00%)	0	0/264 (0.00%)	0	1/238 (0.42%)	1
Duodenal hemorrhage ^† 1	1/272 (0.37%)	1	0/264 (0.00%)	0	0/238 (0.00%)	0
Duodenal perforation ^† 1	1/272 (0.37%)	1	0/264 (0.00%)	0	0/238 (0.00%)	0
Duodenal ulcer ^† 1	0/272 (0.00%)	0	0/264 (0.00%)	0	1/238 (0.42%)	1
Dyspepsia ^† 1	0/272 (0.00%)	0	0/264 (0.00%)	0	2/238 (0.84%)	2
Fecal incontinence ^† 1	0/272 (0.00%)	0	1/264 (0.38%)	1	0/238 (0.00%)	0
Gastric hemorrhage ^† 1	1/272 (0.37%)	1	1/264 (0.38%)	1	0/238 (0.00%)	0
Gastrointestinal disorder ^† 1	1/272 (0.37%)	1	2/264 (0.76%)	4	0/238 (0.00%)	0
Gastrointestinal pain ^† 1	0/272 (0.00%)	0	0/264 (0.00%)	0	1/238 (0.42%)	1
Gingival pain ^† 1	0/272 (0.00%)	0	1/264 (0.38%)	1	0/238 (0.00%)	0
Hemorrhoidal hemorrhage ^† 1	1/272 (0.37%)	1	1/264 (0.38%)	1	0/238 (0.00%)	0
Hemorrhoids ^† 1	0/272 (0.00%)	0	1/264 (0.38%)	1	0/238 (0.00%)	0
Ileus ^† 1	0/272 (0.00%)	0	1/264 (0.38%)	1	0/238 (0.00%)	0
Intra-abdominal hemorrhage ^† 1	1/272 (0.37%)	1	0/264 (0.00%)	0	1/238 (0.42%)	1
Lower gastrointestinal hemorrhage ^† 1	0/272 (0.00%)	0	1/264 (0.38%)	1	0/238 (0.00%)	0
Mucositis oral ^† 1	2/272 (0.74%)	2	6/264 (2.27%)	6	1/238 (0.42%)	1
Nausea ^† 1	6/272 (2.21%)	6	19/264 (7.20%)	21	21/238 (8.82%)	24
Oral hemorrhage ^† 1	0/272 (0.00%)	0	0/264 (0.00%)	0	1/238 (0.42%)	1
Oral pain ^† 1	2/272 (0.74%)	2	0/264 (0.00%)	0	0/238 (0.00%)	0
Rectal hemorrhage ^† 1	0/272 (0.00%)	0	0/264 (0.00%)	0	2/238 (0.84%)	2
Small intestinal obstruction ^† 1	0/272 (0.00%)	0	1/264 (0.38%)	1	0/238 (0.00%)	0
Small intestinal perforation ^† 1	0/272 (0.00%)	0	0/264 (0.00%)	0	1/238 (0.42%)	1
Stomach pain ^† 1	0/272 (0.00%)	0	1/264 (0.38%)	1	0/238 (0.00%)	0
Toothache ^† 1	1/272 (0.37%)	1	0/264 (0.00%)	0	0/238 (0.00%)	0
Upper gastrointestinal hemorrhage ^† 1	1/272 (0.37%)	1	0/264 (0.00%)	0	0/238 (0.00%)	0
Vomiting ^† 1	6/272 (2.21%)	6	12/264 (4.55%)	14	15/238 (6.30%)	16
General disorders
Chest pain ^† 1	1/272 (0.37%)	1	2/264 (0.76%)	2	3/238 (1.26%)	3
Chills ^† 1	0/272 (0.00%)	0	2/264 (0.76%)	2	0/238 (0.00%)	0
Death NOS ^† 1	2/272 (0.74%)	2	2/264 (0.76%)	2	0/238 (0.00%)	0
Disease progression ^† 1	1/272 (0.37%)	1	1/264 (0.38%)	1	2/238 (0.84%)	2
Edema limbs ^† 1	1/272 (0.37%)	1	2/264 (0.76%)	2	3/238 (1.26%)	4
Fatigue ^† 1	43/272 (15.81%)	56	56/264 (21.21%)	64	40/238 (16.81%)	44
Fever ^† 1	2/272 (0.74%)	2	7/264 (2.65%)	7	2/238 (0.84%)	3
General symptom ^† 1	0/272 (0.00%)	0	2/264 (0.76%)	2	0/238 (0.00%)	0
Localized edema ^† 1	1/272 (0.37%)	1	0/264 (0.00%)	0	0/238 (0.00%)	0
Multi-organ failure ^† 1	1/272 (0.37%)	1	0/264 (0.00%)	0	0/238 (0.00%)	0
Pain ^† 1	2/272 (0.74%)	2	1/264 (0.38%)	1	2/238 (0.84%)	2
Hepatobiliary disorders
Cholecystitis ^† 1	0/272 (0.00%)	0	0/264 (0.00%)	0	1/238 (0.42%)	1
Hepatic failure ^† 1	0/272 (0.00%)	0	0/264 (0.00%)	0	2/238 (0.84%)	2
Hepatobiliary disease ^† 1	0/272 (0.00%)	0	1/264 (0.38%)	1	0/238 (0.00%)	0
Immune system disorders
Cytokine release syndrome ^† 1	0/272 (0.00%)	0	0/264 (0.00%)	0	1/238 (0.42%)	1
Hypersensitivity ^† 1	3/272 (1.10%)	3	2/264 (0.76%)	2	2/238 (0.84%)	2
Infections and infestations
Abdominal infection ^† 1	0/272 (0.00%)	0	2/264 (0.76%)	3	0/238 (0.00%)	0
Anorectal infection ^† 1	2/272 (0.74%)	2	0/264 (0.00%)	0	0/238 (0.00%)	0
Biliary tract infection ^† 1	0/272 (0.00%)	0	1/264 (0.38%)	1	0/238 (0.00%)	0
Bladder infection ^† 1	1/272 (0.37%)	1	1/264 (0.38%)	1	0/238 (0.00%)	0
Catheter related infection ^† 1	5/272 (1.84%)	5	4/264 (1.52%)	4	3/238 (1.26%)	3
Colitis, infectious (e.g., Clostridium difficile) ^† 1	0/272 (0.00%)	0	1/264 (0.38%)	1	0/238 (0.00%)	0
Device related infection ^† 1	0/272 (0.00%)	0	1/264 (0.38%)	1	0/238 (0.00%)	0
Encephalitis infection ^† 1	0/272 (0.00%)	0	1/264 (0.38%)	1	0/238 (0.00%)	0
Eye infection ^† 1	0/272 (0.00%)	0	1/264 (0.38%)	1	0/238 (0.00%)	0
Gallbladder infection ^† 1	0/272 (0.00%)	0	0/264 (0.00%)	0	1/238 (0.42%)	1
Infection ^† 1	0/272 (0.00%)	0	3/264 (1.14%)	3	4/238 (1.68%)	5
Infection without neutropenia ^† 1	1/272 (0.37%)	1	0/264 (0.00%)	0	0/238 (0.00%)	0
Infectious colitis ^† 1	2/272 (0.74%)	2	0/264 (0.00%)	0	2/238 (0.84%)	2
Kidney infection ^† 1	0/272 (0.00%)	0	0/264 (0.00%)	0	1/238 (0.42%)	1
Mucosal infection ^† 1	0/272 (0.00%)	0	0/264 (0.00%)	0	1/238 (0.42%)	1
Opportunistic infection ^† 1	1/272 (0.37%)	1	0/264 (0.00%)	0	1/238 (0.42%)	1
Peritoneal infection ^† 1	0/272 (0.00%)	0	1/264 (0.38%)	1	0/238 (0.00%)	0
Pneumonia ^† 1	4/272 (1.47%)	4	5/264 (1.89%)	6	7/238 (2.94%)	7
Salivary gland infection ^† 1	0/272 (0.00%)	0	0/264 (0.00%)	0	2/238 (0.84%)	2
Sepsis ^† 1	3/272 (1.10%)	3	4/264 (1.52%)	4	1/238 (0.42%)	1
Sinusitis ^† 1	1/272 (0.37%)	1	2/264 (0.76%)	2	0/238 (0.00%)	0
Skin infection ^† 1	5/272 (1.84%)	5	4/264 (1.52%)	4	0/238 (0.00%)	0
Soft tissue infection ^† 1	0/272 (0.00%)	0	0/264 (0.00%)	0	1/238 (0.42%)	1
Tooth infection ^† 1	1/272 (0.37%)	1	0/264 (0.00%)	0	0/238 (0.00%)	0
Upper respiratory infection ^† 1	0/272 (0.00%)	0	1/264 (0.38%)	1	2/238 (0.84%)	2
Urinary tract infection ^† 1	2/272 (0.74%)	2	6/264 (2.27%)	6	5/238 (2.10%)	5
Uterine infection ^† 1	0/272 (0.00%)	0	1/264 (0.38%)	1	0/238 (0.00%)	0
Vulvitis ^† 1	1/272 (0.37%)	2	0/264 (0.00%)	0	0/238 (0.00%)	0
Wound infection ^† 1	1/272 (0.37%)	1	3/264 (1.14%)	4	0/238 (0.00%)	0
Injury, poisoning and procedural complications
Fracture ^† 1	0/272 (0.00%)	0	2/264 (0.76%)	2	3/238 (1.26%)	3
Injury to carotid artery ^† 1	1/272 (0.37%)	1	0/264 (0.00%)	0	0/238 (0.00%)	0
Intraoperative gastrointestinal injury - Teeth ^† 1	1/272 (0.37%)	1	0/264 (0.00%)	0	0/238 (0.00%)	0
Vascular access complication ^† 1	0/272 (0.00%)	0	1/264 (0.38%)	3	1/238 (0.42%)	1
Wound dehiscence ^† 1	2/272 (0.74%)	3	2/264 (0.76%)	2	0/238 (0.00%)	0
Investigations
ADH abnormal ^† 1	0/272 (0.00%)	0	0/264 (0.00%)	0	1/238 (0.42%)	1
Activated partial thromboplastin time prolonged ^† 1	1/272 (0.37%)	1	1/264 (0.38%)	1	0/238 (0.00%)	0
Alanine aminotransferase increased ^† 1	1/272 (0.37%)	1	3/264 (1.14%)	3	1/238 (0.42%)	1
Alkaline phosphatase increased ^† 1	1/272 (0.37%)	1	3/264 (1.14%)	4	3/238 (1.26%)	3
Aspartate aminotransferase increased ^† 1	1/272 (0.37%)	1	4/264 (1.52%)	4	6/238 (2.52%)	7
Blood bilirubin increased ^† 1	1/272 (0.37%)	1	1/264 (0.38%)	1	1/238 (0.42%)	1
Creatinine increased ^† 1	2/272 (0.74%)	2	2/264 (0.76%)	3	3/238 (1.26%)	3
INR increased ^† 1	0/272 (0.00%)	0	2/264 (0.76%)	3	2/238 (0.84%)	2
Laboratory test abnormal ^† 1	0/272 (0.00%)	0	1/264 (0.38%)	1	0/238 (0.00%)	0
Leukocyte count decreased ^† 1	7/272 (2.57%)	8	17/264 (6.44%)	19	7/238 (2.94%)	9
Lymphocyte count decreased ^† 1	3/272 (1.10%)	3	2/264 (0.76%)	2	6/238 (2.52%)	6
Neutrophil count decreased ^† 1	16/272 (5.88%)	19	36/264 (13.64%)	39	14/238 (5.88%)	16
Platelet count decreased ^† 1	3/272 (1.10%)	3	13/264 (4.92%)	13	10/238 (4.20%)	10
Weight gain ^† 1	1/272 (0.37%)	1	0/264 (0.00%)	0	0/238 (0.00%)	0
Weight loss ^† 1	0/272 (0.00%)	0	5/264 (1.89%)	7	4/238 (1.68%)	6
Metabolism and nutrition disorders
Anorexia ^† 1	6/272 (2.21%)	7	10/264 (3.79%)	12	7/238 (2.94%)	7
Blood bicarbonate decreased ^† 1	0/272 (0.00%)	0	3/264 (1.14%)	3	0/238 (0.00%)	0
Blood glucose increased ^† 1	6/272 (2.21%)	7	8/264 (3.03%)	9	8/238 (3.36%)	10
Blood uric acid increased ^† 1	0/272 (0.00%)	0	0/264 (0.00%)	0	1/238 (0.42%)	1
Dehydration ^† 1	3/272 (1.10%)	3	9/264 (3.41%)	10	11/238 (4.62%)	12
Serum albumin decreased ^† 1	1/272 (0.37%)	1	9/264 (3.41%)	10	6/238 (2.52%)	7
Serum calcium decreased ^† 1	4/272 (1.47%)	6	8/264 (3.03%)	9	4/238 (1.68%)	4
Serum magnesium decreased ^† 1	0/272 (0.00%)	0	0/264 (0.00%)	0	1/238 (0.42%)	1
Serum phosphate decreased ^† 1	2/272 (0.74%)	2	3/264 (1.14%)	3	1/238 (0.42%)	1
Serum potassium decreased ^† 1	5/272 (1.84%)	5	5/264 (1.89%)	6	9/238 (3.78%)	9
Serum potassium increased ^† 1	0/272 (0.00%)	0	0/264 (0.00%)	0	1/238 (0.42%)	1
Serum sodium decreased ^† 1	3/272 (1.10%)	3	8/264 (3.03%)	9	7/238 (2.94%)	7
Serum sodium increased ^† 1	0/272 (0.00%)	0	1/264 (0.38%)	1	0/238 (0.00%)	0
Musculoskeletal and connective tissue disorders
Arthralgia ^† 1	1/272 (0.37%)	1	5/264 (1.89%)	5	5/238 (2.10%)	6
Back pain ^† 1	4/272 (1.47%)	5	8/264 (3.03%)	10	5/238 (2.10%)	6
Bone pain ^† 1	1/272 (0.37%)	1	3/264 (1.14%)	3	5/238 (2.10%)	5
Chest wall pain ^† 1	4/272 (1.47%)	5	1/264 (0.38%)	1	1/238 (0.42%)	1
Joint disorder ^† 1	0/272 (0.00%)	0	1/264 (0.38%)	1	0/238 (0.00%)	0
Muscle weakness ^† 1	1/272 (0.37%)	1	4/264 (1.52%)	4	4/238 (1.68%)	5
Muscle weakness lower limb ^† 1	1/272 (0.37%)	2	0/264 (0.00%)	0	1/238 (0.42%)	1
Musculoskeletal disorder ^† 1	0/272 (0.00%)	0	0/264 (0.00%)	0	1/238 (0.42%)	1
Myalgia ^† 1	8/272 (2.94%)	10	12/264 (4.55%)	13	10/238 (4.20%)	10
Osteonecrosis ^† 1	1/272 (0.37%)	1	0/264 (0.00%)	0	0/238 (0.00%)	0
Pain in extremity ^† 1	3/272 (1.10%)	5	0/264 (0.00%)	0	2/238 (0.84%)	2
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumor pain ^† 1	0/272 (0.00%)	0	1/264 (0.38%)	1	0/238 (0.00%)	0
Nervous system disorders
Ataxia ^† 1	0/272 (0.00%)	0	2/264 (0.76%)	2	0/238 (0.00%)	0
Cognitive disturbance ^† 1	1/272 (0.37%)	1	0/264 (0.00%)	0	0/238 (0.00%)	0
Depressed level of consciousness ^† 1	1/272 (0.37%)	1	0/264 (0.00%)	0	0/238 (0.00%)	0
Dizziness ^† 1	2/272 (0.74%)	2	3/264 (1.14%)	3	3/238 (1.26%)	4
Dysgeusia ^† 1	0/272 (0.00%)	0	1/264 (0.38%)	1	2/238 (0.84%)	2
Headache ^† 1	4/272 (1.47%)	6	5/264 (1.89%)	6	5/238 (2.10%)	5
Intracranial hemorrhage ^† 1	0/272 (0.00%)	0	0/264 (0.00%)	0	1/238 (0.42%)	1
Ischemia cerebrovascular ^† 1	1/272 (0.37%)	1	1/264 (0.38%)	1	0/238 (0.00%)	0
Leukoencephalopathy ^† 1	0/272 (0.00%)	0	0/264 (0.00%)	0	1/238 (0.42%)	1
Mini mental status examination abnormal ^† 1	0/272 (0.00%)	0	0/264 (0.00%)	0	1/238 (0.42%)	1
Neuralgia ^† 1	0/272 (0.00%)	0	0/264 (0.00%)	0	2/238 (0.84%)	2
Neurological disorder NOS ^† 1	0/272 (0.00%)	0	1/264 (0.38%)	1	0/238 (0.00%)	0
Peripheral motor neuropathy ^† 1	5/272 (1.84%)	5	10/264 (3.79%)	11	8/238 (3.36%)	8
Peripheral sensory neuropathy ^† 1	35/272 (12.87%)	45	43/264 (16.29%)	50	32/238 (13.45%)	38
Seizure ^† 1	0/272 (0.00%)	0	0/264 (0.00%)	0	2/238 (0.84%)	2
Speech disorder ^† 1	0/272 (0.00%)	0	0/264 (0.00%)	0	1/238 (0.42%)	1
Syncope ^† 1	1/272 (0.37%)	1	2/264 (0.76%)	2	0/238 (0.00%)	0
Psychiatric disorders
Anxiety ^† 1	1/272 (0.37%)	1	2/264 (0.76%)	2	0/238 (0.00%)	0
Confusion ^† 1	1/272 (0.37%)	1	4/264 (1.52%)	4	3/238 (1.26%)	3
Depression ^† 1	0/272 (0.00%)	0	2/264 (0.76%)	2	2/238 (0.84%)	2
Insomnia ^† 1	1/272 (0.37%)	1	3/264 (1.14%)	3	2/238 (0.84%)	2
Renal and urinary disorders
Glomerular filtration rate decreased ^† 1	0/272 (0.00%)	0	1/264 (0.38%)	1	0/238 (0.00%)	0
Hemoglobin urine positive ^† 1	0/272 (0.00%)	0	1/264 (0.38%)	1	0/238 (0.00%)	0
Hemorrhage urinary tract ^† 1	0/272 (0.00%)	0	2/264 (0.76%)	2	0/238 (0.00%)	0
Proteinuria ^† 1	8/272 (2.94%)	9	10/264 (3.79%)	10	7/238 (2.94%)	7
Renal failure ^† 1	3/272 (1.10%)	3	1/264 (0.38%)	1	1/238 (0.42%)	1
Ureteric fistula ^† 1	0/272 (0.00%)	0	1/264 (0.38%)	1	0/238 (0.00%)	0
Ureteric obstruction ^† 1	0/272 (0.00%)	0	1/264 (0.38%)	1	0/238 (0.00%)	0
Urinary incontinence ^† 1	0/272 (0.00%)	0	1/264 (0.38%)	1	0/238 (0.00%)	0
Urogenital disorder ^† 1	0/272 (0.00%)	0	1/264 (0.38%)	1	0/238 (0.00%)	0
Reproductive system and breast disorders
Pelvic pain ^† 1	1/272 (0.37%)	1	0/264 (0.00%)	0	0/238 (0.00%)	0
Perineal pain ^† 1	1/272 (0.37%)	1	0/264 (0.00%)	0	0/238 (0.00%)	0
Respiratory, thoracic and mediastinal disorders
Adult respiratory distress syndrome ^† 1	0/272 (0.00%)	0	2/264 (0.76%)	2	0/238 (0.00%)	0
Allergic rhinitis ^† 1	0/272 (0.00%)	0	1/264 (0.38%)	1	0/238 (0.00%)	0
Cough ^† 1	6/272 (2.21%)	6	4/264 (1.52%)	6	3/238 (1.26%)	3
Dyspnea ^† 1	12/272 (4.41%)	12	13/264 (4.92%)	15	15/238 (6.30%)	17
Epistaxis ^† 1	2/272 (0.74%)	2	3/264 (1.14%)	4	9/238 (3.78%)	9
Hypoxia ^† 1	2/272 (0.74%)	2	4/264 (1.52%)	4	3/238 (1.26%)	3
Laryngoscopy abnormal ^† 1	0/272 (0.00%)	0	1/264 (0.38%)	1	2/238 (0.84%)	2
Nasal congestion ^† 1	1/272 (0.37%)	1	0/264 (0.00%)	0	1/238 (0.42%)	1
Pleural effusion ^† 1	1/272 (0.37%)	1	4/264 (1.52%)	4	2/238 (0.84%)	2
Pleuritic pain ^† 1	0/272 (0.00%)	0	2/264 (0.76%)	2	0/238 (0.00%)	0
Pneumonitis ^† 1	1/272 (0.37%)	1	4/264 (1.52%)	4	3/238 (1.26%)	3
Pneumothorax ^† 1	0/272 (0.00%)	0	1/264 (0.38%)	1	0/238 (0.00%)	0
Pulmonary hypertension ^† 1	0/272 (0.00%)	0	1/264 (0.38%)	1	0/238 (0.00%)	0
Respiratory disorder ^† 1	1/272 (0.37%)	1	0/264 (0.00%)	0	0/238 (0.00%)	0
Voice alteration ^† 1	0/272 (0.00%)	0	0/264 (0.00%)	0	1/238 (0.42%)	2
Skin and subcutaneous tissue disorders
Alopecia ^† 1	4/272 (1.47%)	5	7/264 (2.65%)	9	6/238 (2.52%)	7
Decubitus ulcer ^† 1	0/272 (0.00%)	0	0/264 (0.00%)	0	1/238 (0.42%)	1
Hand-and-foot syndrome ^† 1	0/272 (0.00%)	0	3/264 (1.14%)	3	0/238 (0.00%)	0
Nail disorder ^† 1	0/272 (0.00%)	0	1/264 (0.38%)	1	1/238 (0.42%)	1
Pain of skin ^† 1	1/272 (0.37%)	1	2/264 (0.76%)	2	0/238 (0.00%)	0
Petechiae ^† 1	0/272 (0.00%)	0	1/264 (0.38%)	1	0/238 (0.00%)	0
Pruritus ^† 1	1/272 (0.37%)	1	1/264 (0.38%)	1	1/238 (0.42%)	1
Rash acneiform ^† 1	0/272 (0.00%)	0	0/264 (0.00%)	0	2/238 (0.84%)	3
Rash desquamating ^† 1	2/272 (0.74%)	2	3/264 (1.14%)	3	2/238 (0.84%)	2
Skin disorder ^† 1	0/272 (0.00%)	0	1/264 (0.38%)	1	0/238 (0.00%)	0
Skin ulceration ^† 1	1/272 (0.37%)	1	1/264 (0.38%)	1	0/238 (0.00%)	0
Sweating ^† 1	0/272 (0.00%)	0	2/264 (0.76%)	2	0/238 (0.00%)	0
Urticaria ^† 1	1/272 (0.37%)	1	0/264 (0.00%)	0	0/238 (0.00%)	0
Vascular disorders
Hemorrhage ^† 1	1/272 (0.37%)	1	0/264 (0.00%)	0	0/238 (0.00%)	0
Hypertension ^† 1	15/272 (5.51%)	17	17/264 (6.44%)	17	17/238 (7.14%)	17
Hypotension ^† 1	0/272 (0.00%)	0	4/264 (1.52%)	4	4/238 (1.68%)	4
Lymphedema ^† 1	2/272 (0.74%)	3	0/264 (0.00%)	0	0/238 (0.00%)	0
Phlebitis ^† 1	1/272 (0.37%)	1	1/264 (0.38%)	1	0/238 (0.00%)	0
Thrombosis ^† 1	7/272 (2.57%)	9	7/264 (2.65%)	7	4/238 (1.68%)	4
Vascular disorder ^† 1	1/272 (0.37%)	1	0/264 (0.00%)	0	1/238 (0.42%)	1
† Indicates events were collected by systematic assessment 1 Term from vocabulary, MedDRA 6
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	0%
	Arm A (Paclitaxel)		Arm B (Nab-paclitaxel)		Arm C (Ixabepilone)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	263/272 (96.69%)		248/264 (93.94%)		230/238 (96.64%)
Blood and lymphatic system disorders
Anemia ^† 1	0/272 (0.00%)	0	1/264 (0.38%)	1	0/238 (0.00%)	0
Blood disorder ^† 1	1/272 (0.37%)	4	2/264 (0.76%)	5	2/238 (0.84%)	4
Bone marrow hypocellular ^† 1	3/272 (1.10%)	6	1/264 (0.38%)	2	2/238 (0.84%)	2
Febrile neutropenia ^† 1	1/272 (0.37%)	1	0/264 (0.00%)	0	1/238 (0.42%)	1
Hemoglobin decreased ^† 1	49/272 (18.01%)	202	49/264 (18.56%)	165	40/238 (16.81%)	128
Lymph node pain ^† 1	1/272 (0.37%)	1	0/264 (0.00%)	0	0/238 (0.00%)	0
Lymphatic disorder ^† 1	1/272 (0.37%)	4	0/264 (0.00%)	0	1/238 (0.42%)	1
Cardiac disorders
Atrial fibrillation ^† 1	1/272 (0.37%)	3	0/264 (0.00%)	0	1/238 (0.42%)	1
Atrial tachycardia ^† 1	1/272 (0.37%)	1	0/264 (0.00%)	0	0/238 (0.00%)	0
Cardiac disorder ^† 1	1/272 (0.37%)	1	0/264 (0.00%)	0	0/238 (0.00%)	0
Cardiac pain ^† 1	1/272 (0.37%)	1	0/264 (0.00%)	0	0/238 (0.00%)	0
Edema ^† 1	3/272 (1.10%)	5	0/264 (0.00%)	0	0/238 (0.00%)	0
Left ventricular dysfunction ^† 1	1/272 (0.37%)	1	0/264 (0.00%)	0	0/238 (0.00%)	0
Left ventricular failure ^† 1	0/272 (0.00%)	0	2/264 (0.76%)	4	0/238 (0.00%)	0
Myocardial ischemia ^† 1	1/272 (0.37%)	1	1/264 (0.38%)	1	0/238 (0.00%)	0
Palpitations ^† 1	0/272 (0.00%)	0	0/264 (0.00%)	0	1/238 (0.42%)	1
Pericardial effusion ^† 1	0/272 (0.00%)	0	0/264 (0.00%)	0	1/238 (0.42%)	1
Sinus bradycardia ^† 1	1/272 (0.37%)	1	1/264 (0.38%)	2	0/238 (0.00%)	0
Sinus tachycardia ^† 1	3/272 (1.10%)	20	3/264 (1.14%)	7	3/238 (1.26%)	3
Supraventricular tachycardia ^† 1	0/272 (0.00%)	0	0/264 (0.00%)	0	1/238 (0.42%)	1
Ear and labyrinth disorders
Ear disorder ^† 1	0/272 (0.00%)	0	0/264 (0.00%)	0	1/238 (0.42%)	1
Ear pain ^† 1	1/272 (0.37%)	1	1/264 (0.38%)	1	1/238 (0.42%)	1
Hearing impaired ^† 1	1/272 (0.37%)	2	0/264 (0.00%)	0	0/238 (0.00%)	0
Tinnitus ^† 1	1/272 (0.37%)	1	1/264 (0.38%)	2	3/238 (1.26%)	5
Endocrine disorders
Cushingoid ^† 1	1/272 (0.37%)	2	0/264 (0.00%)	0	0/238 (0.00%)	0
Eye disorders
Cataract ^† 1	2/272 (0.74%)	28	2/264 (0.76%)	3	0/238 (0.00%)	0
Diplopia ^† 1	1/272 (0.37%)	1	0/264 (0.00%)	0	0/238 (0.00%)	0
Dry eye syndrome ^† 1	1/272 (0.37%)	1	2/264 (0.76%)	4	3/238 (1.26%)	3
Eye disorder ^† 1	2/272 (0.74%)	2	4/264 (1.52%)	5	0/238 (0.00%)	0
Flashing vision ^† 1	1/272 (0.37%)	1	0/264 (0.00%)	0	1/238 (0.42%)	1
Optic nerve disorder ^† 1	0/272 (0.00%)	0	1/264 (0.38%)	1	0/238 (0.00%)	0
Photophobia ^† 1	1/272 (0.37%)	1	1/264 (0.38%)	1	0/238 (0.00%)	0
Vision blurred ^† 1	4/272 (1.47%)	12	13/264 (4.92%)	31	2/238 (0.84%)	3
Vitreous hemorrhage ^† 1	0/272 (0.00%)	0	0/264 (0.00%)	0	1/238 (0.42%)	1
Watering eyes ^† 1	2/272 (0.74%)	2	9/264 (3.41%)	19	0/238 (0.00%)	0
Gastrointestinal disorders
Abdominal distension ^† 1	2/272 (0.74%)	4	2/264 (0.76%)	2	0/238 (0.00%)	0
Abdominal pain ^† 1	9/272 (3.31%)	13	7/264 (2.65%)	10	10/238 (4.20%)	12
Anal fistula ^† 1	0/272 (0.00%)	0	1/264 (0.38%)	1	0/238 (0.00%)	0
Anal hemorrhage ^† 1	2/272 (0.74%)	2	1/264 (0.38%)	1	1/238 (0.42%)	2
Anal pain ^† 1	0/272 (0.00%)	0	0/264 (0.00%)	0	1/238 (0.42%)	1
Ascites ^† 1	0/272 (0.00%)	0	0/264 (0.00%)	0	1/238 (0.42%)	1
Cheilitis ^† 1	1/272 (0.37%)	4	0/264 (0.00%)	0	1/238 (0.42%)	1
Colitis ^† 1	0/272 (0.00%)	0	0/264 (0.00%)	0	1/238 (0.42%)	1
Colonic hemorrhage ^† 1	1/272 (0.37%)	2	0/264 (0.00%)	0	0/238 (0.00%)	0
Constipation ^† 1	35/272 (12.87%)	84	36/264 (13.64%)	95	45/238 (18.91%)	87
Diarrhea ^† 1	35/272 (12.87%)	74	36/264 (13.64%)	67	45/238 (18.91%)	85
Dry mouth ^† 1	3/272 (1.10%)	6	3/264 (1.14%)	4	4/238 (1.68%)	6
Dyspepsia ^† 1	11/272 (4.04%)	20	13/264 (4.92%)	19	20/238 (8.40%)	34
Dysphagia ^† 1	4/272 (1.47%)	5	3/264 (1.14%)	4	1/238 (0.42%)	1
Ear, nose and throat examination abnormal ^† 1	3/272 (1.10%)	3	5/264 (1.89%)	6	5/238 (2.10%)	6
Esophagitis ^† 1	2/272 (0.74%)	2	1/264 (0.38%)	1	0/238 (0.00%)	0
Flatulence ^† 1	1/272 (0.37%)	1	0/264 (0.00%)	0	0/238 (0.00%)	0
Gastric ulcer ^† 1	0/272 (0.00%)	0	1/264 (0.38%)	1	0/238 (0.00%)	0
Gastritis ^† 1	1/272 (0.37%)	1	1/264 (0.38%)	1	2/238 (0.84%)	2
Gastrointestinal disorder ^† 1	5/272 (1.84%)	11	1/264 (0.38%)	1	3/238 (1.26%)	5
Gastroscopy abnormal ^† 1	0/272 (0.00%)	0	1/264 (0.38%)	2	0/238 (0.00%)	0
Gingival pain ^† 1	2/272 (0.74%)	5	1/264 (0.38%)	1	2/238 (0.84%)	2
Hemorrhoidal hemorrhage ^† 1	3/272 (1.10%)	5	1/264 (0.38%)	1	0/238 (0.00%)	0
Hemorrhoids ^† 1	3/272 (1.10%)	3	2/264 (0.76%)	6	8/238 (3.36%)	15
Lower gastrointestinal hemorrhage ^† 1	1/272 (0.37%)	1	0/264 (0.00%)	0	0/238 (0.00%)	0
Mucositis oral ^† 1	21/272 (7.72%)	35	22/264 (8.33%)	40	16/238 (6.72%)	32
Nausea ^† 1	48/272 (17.65%)	92	52/264 (19.70%)	123	75/238 (31.51%)	160
Oral hemorrhage ^† 1	1/272 (0.37%)	1	4/264 (1.52%)	4	5/238 (2.10%)	9
Oral pain ^† 1	2/272 (0.74%)	2	4/264 (1.52%)	10	1/238 (0.42%)	1
Pancreatitis ^† 1	1/272 (0.37%)	1	0/264 (0.00%)	0	0/238 (0.00%)	0
Periodontal disease ^† 1	1/272 (0.37%)	1	0/264 (0.00%)	0	2/238 (0.84%)	11
Peritoneal pain ^† 1	1/272 (0.37%)	1	0/264 (0.00%)	0	0/238 (0.00%)	0
Proctitis ^† 1	1/272 (0.37%)	2	0/264 (0.00%)	0	0/238 (0.00%)	0
Rectal bleeding/hematochezia ^† 1	0/272 (0.00%)	0	1/264 (0.38%)	1	0/238 (0.00%)	0
Rectal hemorrhage ^† 1	9/272 (3.31%)	24	8/264 (3.03%)	11	5/238 (2.10%)	8
Rectal pain ^† 1	0/272 (0.00%)	0	1/264 (0.38%)	1	0/238 (0.00%)	0
Stomach pain ^† 1	1/272 (0.37%)	1	1/264 (0.38%)	2	1/238 (0.42%)	1
Tooth development disorder ^† 1	1/272 (0.37%)	1	0/264 (0.00%)	0	0/238 (0.00%)	0
Tooth disorder ^† 1	0/272 (0.00%)	0	1/264 (0.38%)	1	0/238 (0.00%)	0
Toothache ^† 1	1/272 (0.37%)	1	1/264 (0.38%)	2	1/238 (0.42%)	1
Upper gastrointestinal hemorrhage ^† 1	0/272 (0.00%)	0	0/264 (0.00%)	0	2/238 (0.84%)	2
Vomiting ^† 1	18/272 (6.62%)	24	27/264 (10.23%)	45	29/238 (12.18%)	48
General disorders
Chest pain ^† 1	6/272 (2.21%)	11	2/264 (0.76%)	2	3/238 (1.26%)	3
Chills ^† 1	2/272 (0.74%)	2	4/264 (1.52%)	7	4/238 (1.68%)	5
Edema limbs ^† 1	11/272 (4.04%)	37	13/264 (4.92%)	37	11/238 (4.62%)	46
Facial pain ^† 1	0/272 (0.00%)	0	1/264 (0.38%)	1	0/238 (0.00%)	0
Fatigue ^† 1	208/272 (76.47%)	1397	213/264 (80.68%)	1186	205/238 (86.13%)	1036
Fever ^† 1	4/272 (1.47%)	5	5/264 (1.89%)	6	7/238 (2.94%)	14
Flu-like symptoms ^† 1	1/272 (0.37%)	1	2/264 (0.76%)	2	1/238 (0.42%)	1
Gait abnormal ^† 1	0/272 (0.00%)	0	1/264 (0.38%)	2	0/238 (0.00%)	0
General symptom ^† 1	1/272 (0.37%)	4	2/264 (0.76%)	4	2/238 (0.84%)	3
Ill-defined disorder ^† 1	1/272 (0.37%)	1	0/264 (0.00%)	0	0/238 (0.00%)	0
Injection site reaction ^† 1	0/272 (0.00%)	0	0/264 (0.00%)	0	3/238 (1.26%)	5
Localized edema ^† 1	4/272 (1.47%)	13	1/264 (0.38%)	2	2/238 (0.84%)	2
Pain ^† 1	21/272 (7.72%)	34	13/264 (4.92%)	16	12/238 (5.04%)	24
Hepatobiliary disorders
Gallbladder obstruction ^† 1	1/272 (0.37%)	5	0/264 (0.00%)	0	0/238 (0.00%)	0
Hepatic failure ^† 1	1/272 (0.37%)	1	1/264 (0.38%)	1	0/238 (0.00%)	0
Hepatic pain ^† 1	1/272 (0.37%)	1	0/264 (0.00%)	0	0/238 (0.00%)	0
Immune system disorders
Hypersensitivity ^† 1	23/272 (8.46%)	32	28/264 (10.61%)	48	17/238 (7.14%)	19
Immune system disorder ^† 1	1/272 (0.37%)	1	0/264 (0.00%)	0	0/238 (0.00%)	0
Infections and infestations
Bladder infection ^† 1	3/272 (1.10%)	7	3/264 (1.14%)	5	2/238 (0.84%)	2
Bronchitis ^† 1	3/272 (1.10%)	4	1/264 (0.38%)	1	2/238 (0.84%)	2
Catheter related infection ^† 1	4/272 (1.47%)	4	1/264 (0.38%)	1	0/238 (0.00%)	0
Colitis, infectious (e.g., Clostridium difficile) ^† 1	0/272 (0.00%)	0	0/264 (0.00%)	0	1/238 (0.42%)	1
Conjunctivitis infective ^† 1	0/272 (0.00%)	0	1/264 (0.38%)	1	0/238 (0.00%)	0
Device related infection ^† 1	2/272 (0.74%)	7	0/264 (0.00%)	0	2/238 (0.84%)	3
Esophageal infection ^† 1	1/272 (0.37%)	1	0/264 (0.00%)	0	0/238 (0.00%)	0
Eye infection ^† 1	1/272 (0.37%)	1	1/264 (0.38%)	1	0/238 (0.00%)	0
Gingival infection ^† 1	1/272 (0.37%)	1	0/264 (0.00%)	0	0/238 (0.00%)	0
Infection ^† 1	8/272 (2.94%)	9	6/264 (2.27%)	7	1/238 (0.42%)	1
Infection with grade 3 or 4 neutropenia ^† 1	1/272 (0.37%)	1	0/264 (0.00%)	0	0/238 (0.00%)	0
Infection without neutropenia ^† 1	1/272 (0.37%)	1	0/264 (0.00%)	0	1/238 (0.42%)	1
Infectious colitis ^† 1	0/272 (0.00%)	0	0/264 (0.00%)	0	1/238 (0.42%)	1
Kidney infection ^† 1	2/272 (0.74%)	2	0/264 (0.00%)	0	0/238 (0.00%)	0
Laryngitis ^† 1	0/272 (0.00%)	0	1/264 (0.38%)	1	0/238 (0.00%)	0
Mucosal infection ^† 1	0/272 (0.00%)	0	2/264 (0.76%)	4	0/238 (0.00%)	0
Nail infection ^† 1	2/272 (0.74%)	2	3/264 (1.14%)	5	2/238 (0.84%)	2
Otitis media ^† 1	1/272 (0.37%)	1	0/264 (0.00%)	0	0/238 (0.00%)	0
Paranasal sinus infection ^† 1	1/272 (0.37%)	1	0/264 (0.00%)	0	0/238 (0.00%)	0
Peripheral nerve infection ^† 1	1/272 (0.37%)	1	1/264 (0.38%)	2	0/238 (0.00%)	0
Pneumonia ^† 1	4/272 (1.47%)	4	0/264 (0.00%)	0	1/238 (0.42%)	1
Rhinitis infective ^† 1	2/272 (0.74%)	2	0/264 (0.00%)	0	0/238 (0.00%)	0
Salivary gland infection ^† 1	0/272 (0.00%)	0	1/264 (0.38%)	1	0/238 (0.00%)	0
Sepsis ^† 1	1/272 (0.37%)	1	1/264 (0.38%)	1	0/238 (0.00%)	0
Sinusitis ^† 1	6/272 (2.21%)	7	6/264 (2.27%)	7	3/238 (1.26%)	6
Skin infection ^† 1	4/272 (1.47%)	4	2/264 (0.76%)	2	1/238 (0.42%)	1
Small intestine infection ^† 1	0/272 (0.00%)	0	0/264 (0.00%)	0	1/238 (0.42%)	1
Soft tissue infection ^† 1	1/272 (0.37%)	2	0/264 (0.00%)	0	0/238 (0.00%)	0
Tooth infection ^† 1	2/272 (0.74%)	2	3/264 (1.14%)	3	2/238 (0.84%)	2
Upper aerodigestive tract infection ^† 1	0/272 (0.00%)	0	1/264 (0.38%)	1	0/238 (0.00%)	0
Upper respiratory infection ^† 1	5/272 (1.84%)	5	4/264 (1.52%)	5	6/238 (2.52%)	6
Ureteritis ^† 1	1/272 (0.37%)	2	1/264 (0.38%)	1	0/238 (0.00%)	0
Urinary tract infection ^† 1	9/272 (3.31%)	12	6/264 (2.27%)	6	9/238 (3.78%)	14
Vaginal infection ^† 1	1/272 (0.37%)	1	1/264 (0.38%)	1	0/238 (0.00%)	0
Vulvitis ^† 1	1/272 (0.37%)	1	0/264 (0.00%)	0	0/238 (0.00%)	0
Wound infection ^† 1	0/272 (0.00%)	0	2/264 (0.76%)	2	2/238 (0.84%)	2
Injury, poisoning and procedural complications
Bruising ^† 1	0/272 (0.00%)	0	4/264 (1.52%)	5	1/238 (0.42%)	1
Dermatitis radiation ^† 1	0/272 (0.00%)	0	1/264 (0.38%)	2	0/238 (0.00%)	0
Fracture ^† 1	3/272 (1.10%)	3	1/264 (0.38%)	1	0/238 (0.00%)	0
Intraoperative breast injury ^† 1	1/272 (0.37%)	1	0/264 (0.00%)	0	0/238 (0.00%)	0
Seroma ^† 1	1/272 (0.37%)	1	0/264 (0.00%)	0	0/238 (0.00%)	0
Vascular access complication ^† 1	0/272 (0.00%)	0	1/264 (0.38%)	1	1/238 (0.42%)	1
Wound dehiscence ^† 1	10/272 (3.68%)	28	10/264 (3.79%)	32	9/238 (3.78%)	15
Investigations
Alanine aminotransferase increased ^† 1	14/272 (5.15%)	18	18/264 (6.82%)	28	18/238 (7.56%)	35
Alkaline phosphatase ^† 1	0/272 (0.00%)	0	1/264 (0.38%)	1	1/238 (0.42%)	1
Alkaline phosphatase increased ^† 1	11/272 (4.04%)	31	11/264 (4.17%)	27	18/238 (7.56%)	31
Aspartate aminotransferase increased ^† 1	15/272 (5.51%)	21	18/264 (6.82%)	31	17/238 (7.14%)	39
Blood bilirubin increased ^† 1	1/272 (0.37%)	1	0/264 (0.00%)	0	4/238 (1.68%)	6
Creatinine increased ^† 1	9/272 (3.31%)	16	4/264 (1.52%)	7	2/238 (0.84%)	14
Electrocardiogram QTc interval prolonged ^† 1	0/272 (0.00%)	0	1/264 (0.38%)	3	0/238 (0.00%)	0
Gamma-glutamyltransferase increased ^† 1	0/272 (0.00%)	0	0/264 (0.00%)	0	1/238 (0.42%)	3
INR increased ^† 1	2/272 (0.74%)	3	3/264 (1.14%)	6	0/238 (0.00%)	0
Laboratory test abnormal ^† 1	1/272 (0.37%)	1	1/264 (0.38%)	1	6/238 (2.52%)	9
Leukocyte count decreased ^† 1	55/272 (20.22%)	188	87/264 (32.95%)	242	41/238 (17.23%)	98
Lymphocyte count decreased ^† 1	7/272 (2.57%)	26	10/264 (3.79%)	27	5/238 (2.10%)	13
Neutrophil count decreased ^† 1	116/272 (42.65%)	447	178/264 (67.42%)	650	64/238 (26.89%)	144
Platelet count decreased ^† 1	23/272 (8.46%)	50	28/264 (10.61%)	65	16/238 (6.72%)	44
Serum cholesterol increased ^† 1	2/272 (0.74%)	2	0/264 (0.00%)	0	1/238 (0.42%)	1
Weight gain ^† 1	3/272 (1.10%)	9	0/264 (0.00%)	0	3/238 (1.26%)	6
Weight loss ^† 1	11/272 (4.04%)	19	13/264 (4.92%)	35	14/238 (5.88%)	31
Metabolism and nutrition disorders
Anorexia ^† 1	24/272 (8.82%)	50	25/264 (9.47%)	48	30/238 (12.61%)	61
Blood bicarbonate decreased ^† 1	1/272 (0.37%)	2	3/264 (1.14%)	7	1/238 (0.42%)	6
Blood glucose increased ^† 1	32/272 (11.76%)	129	29/264 (10.98%)	64	29/238 (12.18%)	64
Dehydration ^† 1	6/272 (2.21%)	6	7/264 (2.65%)	9	6/238 (2.52%)	6
Serum albumin decreased ^† 1	10/272 (3.68%)	17	8/264 (3.03%)	19	11/238 (4.62%)	23
Serum calcium decreased ^† 1	9/272 (3.31%)	18	8/264 (3.03%)	12	10/238 (4.20%)	16
Serum calcium increased ^† 1	3/272 (1.10%)	3	2/264 (0.76%)	2	1/238 (0.42%)	1
Serum glucose decreased ^† 1	1/272 (0.37%)	1	3/264 (1.14%)	4	2/238 (0.84%)	2
Serum magnesium decreased ^† 1	1/272 (0.37%)	1	1/264 (0.38%)	1	0/238 (0.00%)	0
Serum magnesium increased ^† 1	1/272 (0.37%)	2	2/264 (0.76%)	2	0/238 (0.00%)	0
Serum phosphate decreased ^† 1	2/272 (0.74%)	2	1/264 (0.38%)	1	1/238 (0.42%)	1
Serum potassium decreased ^† 1	11/272 (4.04%)	21	9/264 (3.41%)	15	12/238 (5.04%)	21
Serum potassium increased ^† 1	4/272 (1.47%)	15	3/264 (1.14%)	3	1/238 (0.42%)	1
Serum sodium decreased ^† 1	11/272 (4.04%)	33	10/264 (3.79%)	19	14/238 (5.88%)	25
Serum sodium increased ^† 1	1/272 (0.37%)	1	2/264 (0.76%)	2	0/238 (0.00%)	0
Serum triglycerides increased ^† 1	3/272 (1.10%)	3	0/264 (0.00%)	0	0/238 (0.00%)	0
Musculoskeletal and connective tissue disorders
Arthralgia ^† 1	42/272 (15.44%)	122	38/264 (14.39%)	75	37/238 (15.55%)	117
Arthritis ^† 1	2/272 (0.74%)	2	2/264 (0.76%)	2	1/238 (0.42%)	1
Back pain ^† 1	16/272 (5.88%)	28	12/264 (4.55%)	33	26/238 (10.92%)	51
Bone pain ^† 1	20/272 (7.35%)	41	11/264 (4.17%)	21	13/238 (5.46%)	30
Buttock pain ^† 1	1/272 (0.37%)	1	0/264 (0.00%)	0	0/238 (0.00%)	0
Chest wall pain ^† 1	4/272 (1.47%)	5	3/264 (1.14%)	5	2/238 (0.84%)	2
Fibrosis ^† 1	0/272 (0.00%)	0	0/264 (0.00%)	0	1/238 (0.42%)	1
Joint range of motion decreased cervical spine ^† 1	1/272 (0.37%)	1	0/264 (0.00%)	0	0/238 (0.00%)	0
Muscle weakness ^† 1	2/272 (0.74%)	9	9/264 (3.41%)	19	3/238 (1.26%)	6
Muscle weakness lower limb ^† 1	3/272 (1.10%)	5	1/264 (0.38%)	1	2/238 (0.84%)	2
Musculoskeletal disorder ^† 1	3/272 (1.10%)	9	1/264 (0.38%)	2	4/238 (1.68%)	6
Myalgia ^† 1	92/272 (33.82%)	336	99/264 (37.50%)	295	77/238 (32.35%)	210
Neck pain ^† 1	6/272 (2.21%)	7	1/264 (0.38%)	3	3/238 (1.26%)	4
Osteonecrosis ^† 1	3/272 (1.10%)	7	0/264 (0.00%)	0	1/238 (0.42%)	1
Osteoporosis ^† 1	1/272 (0.37%)	2	0/264 (0.00%)	0	0/238 (0.00%)	0
Pain in extremity ^† 1	17/272 (6.25%)	27	9/264 (3.41%)	12	11/238 (4.62%)	21
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumor pain ^† 1	0/272 (0.00%)	0	1/264 (0.38%)	1	0/238 (0.00%)	0
Nervous system disorders
Ataxia ^† 1	0/272 (0.00%)	0	3/264 (1.14%)	4	2/238 (0.84%)	2
Cognitive disturbance ^† 1	1/272 (0.37%)	1	1/264 (0.38%)	1	1/238 (0.42%)	2
Depressed level of consciousness ^† 1	2/272 (0.74%)	2	0/264 (0.00%)	0	0/238 (0.00%)	0
Dizziness ^† 1	13/272 (4.78%)	20	11/264 (4.17%)	14	15/238 (6.30%)	27
Dysgeusia ^† 1	12/272 (4.41%)	61	15/264 (5.68%)	40	29/238 (12.18%)	59
Encephalopathy ^† 1	1/272 (0.37%)	2	0/264 (0.00%)	0	0/238 (0.00%)	0
Extrapyramidal disorder ^† 1	0/272 (0.00%)	0	0/264 (0.00%)	0	1/238 (0.42%)	1
Headache ^† 1	20/272 (7.35%)	28	22/264 (8.33%)	43	30/238 (12.61%)	50
Intracranial hemorrhage ^† 1	0/272 (0.00%)	0	1/264 (0.38%)	1	0/238 (0.00%)	0
Ischemia cerebrovascular ^† 1	1/272 (0.37%)	1	0/264 (0.00%)	0	0/238 (0.00%)	0
Memory impairment ^† 1	2/272 (0.74%)	4	3/264 (1.14%)	3	1/238 (0.42%)	1
Mini mental status examination abnormal ^† 1	2/272 (0.74%)	2	0/264 (0.00%)	0	0/238 (0.00%)	0
Neuralgia ^† 1	0/272 (0.00%)	0	1/264 (0.38%)	1	3/238 (1.26%)	5
Neurological disorder NOS ^† 1	0/272 (0.00%)	0	1/264 (0.38%)	1	0/238 (0.00%)	0
Peripheral motor neuropathy ^† 1	46/272 (16.91%)	110	66/264 (25.00%)	208	47/238 (19.75%)	204
Peripheral sensory neuropathy ^† 1	216/272 (79.41%)	1533	206/264 (78.03%)	1320	175/238 (73.53%)	1043
Radiculitis brachial ^† 1	0/272 (0.00%)	0	0/264 (0.00%)	0	1/238 (0.42%)	1
Seizure ^† 1	0/272 (0.00%)	0	0/264 (0.00%)	0	1/238 (0.42%)	1
Speech disorder ^† 1	1/272 (0.37%)	1	0/264 (0.00%)	0	1/238 (0.42%)	1
Syncope ^† 1	5/272 (1.84%)	5	1/264 (0.38%)	1	4/238 (1.68%)	4
Syncope vasovagal ^† 1	1/272 (0.37%)	1	1/264 (0.38%)	1	1/238 (0.42%)	1
Tremor ^† 1	0/272 (0.00%)	0	1/264 (0.38%)	2	0/238 (0.00%)	0
Psychiatric disorders
Agitation ^† 1	2/272 (0.74%)	3	0/264 (0.00%)	0	0/238 (0.00%)	0
Anxiety ^† 1	16/272 (5.88%)	29	7/264 (2.65%)	11	10/238 (4.20%)	19
Confusion ^† 1	2/272 (0.74%)	4	2/264 (0.76%)	2	1/238 (0.42%)	1
Depression ^† 1	13/272 (4.78%)	33	14/264 (5.30%)	20	14/238 (5.88%)	33
Euphoria ^† 1	1/272 (0.37%)	1	0/264 (0.00%)	0	0/238 (0.00%)	0
Insomnia ^† 1	18/272 (6.62%)	41	13/264 (4.92%)	25	19/238 (7.98%)	35
Libido decreased ^† 1	1/272 (0.37%)	4	1/264 (0.38%)	1	1/238 (0.42%)	8
Psychosis ^† 1	1/272 (0.37%)	1	0/264 (0.00%)	0	0/238 (0.00%)	0
Renal and urinary disorders
Bladder hemorrhage ^† 1	2/272 (0.74%)	5	0/264 (0.00%)	0	1/238 (0.42%)	1
Bladder pain ^† 1	0/272 (0.00%)	0	1/264 (0.38%)	2	1/238 (0.42%)	2
Cystitis ^† 1	3/272 (1.10%)	4	1/264 (0.38%)	1	0/238 (0.00%)	0
Glomerular filtration rate decreased ^† 1	0/272 (0.00%)	0	1/264 (0.38%)	1	0/238 (0.00%)	0
Hematuria (in the absence of vaginal bleeding) ^† 1	1/272 (0.37%)	1	0/264 (0.00%)	0	0/238 (0.00%)	0
Hemoglobin urine positive ^† 1	2/272 (0.74%)	2	2/264 (0.76%)	2	1/238 (0.42%)	1
Hemorrhage urinary tract ^† 1	3/272 (1.10%)	5	3/264 (1.14%)	4	2/238 (0.84%)	3
Kidney pain ^† 1	1/272 (0.37%)	1	0/264 (0.00%)	0	0/238 (0.00%)	0
Proteinuria ^† 1	58/272 (21.32%)	211	64/264 (24.24%)	188	50/238 (21.01%)	125
Ureteric hemorrhage ^† 1	0/272 (0.00%)	0	0/264 (0.00%)	0	1/238 (0.42%)	1
Ureteric obstruction ^† 1	0/272 (0.00%)	0	0/264 (0.00%)	0	1/238 (0.42%)	1
Ureteric stenosis ^† 1	0/272 (0.00%)	0	0/264 (0.00%)	0	1/238 (0.42%)	1
Urethral hemorrhage ^† 1	0/272 (0.00%)	0	1/264 (0.38%)	1	0/238 (0.00%)	0
Urethral pain ^† 1	0/272 (0.00%)	0	1/264 (0.38%)	1	0/238 (0.00%)	0
Urinary frequency ^† 1	4/272 (1.47%)	7	0/264 (0.00%)	0	0/238 (0.00%)	0
Urinary incontinence ^† 1	5/272 (1.84%)	6	0/264 (0.00%)	0	0/238 (0.00%)	0
Urinary retention ^† 1	0/272 (0.00%)	0	0/264 (0.00%)	0	1/238 (0.42%)	1
Urogenital disorder ^† 1	2/272 (0.74%)	2	3/264 (1.14%)	5	0/238 (0.00%)	0
Reproductive system and breast disorders
Breast pain ^† 1	1/272 (0.37%)	1	2/264 (0.76%)	4	2/238 (0.84%)	3
Irregular menstruation ^† 1	2/272 (0.74%)	7	0/264 (0.00%)	0	0/238 (0.00%)	0
Ovulation pain ^† 1	0/272 (0.00%)	0	0/264 (0.00%)	0	1/238 (0.42%)	1
Pelvic pain ^† 1	3/272 (1.10%)	4	1/264 (0.38%)	1	2/238 (0.84%)	6
Perineal pain ^† 1	1/272 (0.37%)	1	0/264 (0.00%)	0	0/238 (0.00%)	0
Vaginal discharge ^† 1	0/272 (0.00%)	0	0/264 (0.00%)	0	1/238 (0.42%)	5
Vaginal dryness ^† 1	0/272 (0.00%)	0	0/264 (0.00%)	0	1/238 (0.42%)	3
Vaginal hemorrhage ^† 1	2/272 (0.74%)	2	5/264 (1.89%)	5	2/238 (0.84%)	5
Vaginal pain ^† 1	1/272 (0.37%)	1	0/264 (0.00%)	0	0/238 (0.00%)	0
Respiratory, thoracic and mediastinal disorders
Allergic rhinitis ^† 1	8/272 (2.94%)	14	7/264 (2.65%)	10	14/238 (5.88%)	22
Aspiration ^† 1	0/272 (0.00%)	0	0/264 (0.00%)	0	2/238 (0.84%)	5
Bronchospasm ^† 1	1/272 (0.37%)	1	0/264 (0.00%)	0	0/238 (0.00%)	0
Cough ^† 1	26/272 (9.56%)	65	20/264 (7.58%)	43	24/238 (10.08%)	54
Dyspnea ^† 1	27/272 (9.93%)	62	29/264 (10.98%)	61	36/238 (15.13%)	91
Epistaxis ^† 1	68/272 (25.00%)	174	56/264 (21.21%)	185	47/238 (19.75%)	112
Hiccups ^† 1	0/272 (0.00%)	0	2/264 (0.76%)	3	1/238 (0.42%)	1
Hypoxia ^† 1	0/272 (0.00%)	0	2/264 (0.76%)	9	2/238 (0.84%)	2
Laryngeal mucositis ^† 1	0/272 (0.00%)	0	1/264 (0.38%)	3	0/238 (0.00%)	0
Laryngoscopy abnormal ^† 1	5/272 (1.84%)	7	9/264 (3.41%)	19	5/238 (2.10%)	6
Nasal congestion ^† 1	5/272 (1.84%)	9	5/264 (1.89%)	9	5/238 (2.10%)	12
Pharyngeal mucositis ^† 1	1/272 (0.37%)	1	0/264 (0.00%)	0	2/238 (0.84%)	3
Pharyngolaryngeal pain ^† 1	2/272 (0.74%)	2	5/264 (1.89%)	7	4/238 (1.68%)	9
Pleural effusion ^† 1	0/272 (0.00%)	0	0/264 (0.00%)	0	2/238 (0.84%)	2
Pneumonitis ^† 1	0/272 (0.00%)	0	1/264 (0.38%)	1	1/238 (0.42%)	2
Pulmonary hemorrhage ^† 1	0/272 (0.00%)	0	0/264 (0.00%)	0	1/238 (0.42%)	1
Respiratory disorder ^† 1	4/272 (1.47%)	10	7/264 (2.65%)	9	6/238 (2.52%)	8
Respiratory tract hemorrhage ^† 1	3/272 (1.10%)	3	1/264 (0.38%)	1	0/238 (0.00%)	0
Tracheal fistula ^† 1	0/272 (0.00%)	0	1/264 (0.38%)	1	0/238 (0.00%)	0
Voice alteration ^† 1	5/272 (1.84%)	11	3/264 (1.14%)	7	6/238 (2.52%)	14
Skin and subcutaneous tissue disorders
Alopecia ^† 1	35/272 (12.87%)	151	26/264 (9.85%)	65	40/238 (16.81%)	116
Chest wall necrosis ^† 1	0/272 (0.00%)	0	1/264 (0.38%)	1	0/238 (0.00%)	0
Decubitus ulcer ^† 1	3/272 (1.10%)	4	0/264 (0.00%)	0	0/238 (0.00%)	0
Dry skin ^† 1	3/272 (1.10%)	3	4/264 (1.52%)	7	7/238 (2.94%)	10
Erythema multiforme ^† 1	1/272 (0.37%)	1	2/264 (0.76%)	2	0/238 (0.00%)	0
Hand-and-foot syndrome ^† 1	5/272 (1.84%)	16	7/264 (2.65%)	15	2/238 (0.84%)	3
Nail disorder ^† 1	32/272 (11.76%)	96	24/264 (9.09%)	63	16/238 (6.72%)	28
Pain of skin ^† 1	1/272 (0.37%)	2	0/264 (0.00%)	0	0/238 (0.00%)	0
Petechiae ^† 1	1/272 (0.37%)	1	1/264 (0.38%)	2	0/238 (0.00%)	0
Photosensitivity ^† 1	1/272 (0.37%)	1	2/264 (0.76%)	2	0/238 (0.00%)	0
Pruritus ^† 1	8/272 (2.94%)	9	8/264 (3.03%)	19	4/238 (1.68%)	17
Rash acneiform ^† 1	1/272 (0.37%)	1	7/264 (2.65%)	11	3/238 (1.26%)	6
Rash desquamating ^† 1	17/272 (6.25%)	28	34/264 (12.88%)	71	14/238 (5.88%)	33
Scalp pain ^† 1	2/272 (0.74%)	3	0/264 (0.00%)	0	0/238 (0.00%)	0
Skin disorder ^† 1	11/272 (4.04%)	17	5/264 (1.89%)	6	1/238 (0.42%)	1
Skin hyperpigmentation ^† 1	3/272 (1.10%)	15	4/264 (1.52%)	10	1/238 (0.42%)	3
Skin ulceration ^† 1	3/272 (1.10%)	6	2/264 (0.76%)	4	2/238 (0.84%)	4
Sweating ^† 1	3/272 (1.10%)	3	3/264 (1.14%)	8	1/238 (0.42%)	1
Urticaria ^† 1	1/272 (0.37%)	1	0/264 (0.00%)	0	0/238 (0.00%)	0
Vascular disorders
Flushing ^† 1	1/272 (0.37%)	1	2/264 (0.76%)	2	1/238 (0.42%)	1
Hematoma ^† 1	2/272 (0.74%)	2	0/264 (0.00%)	0	0/238 (0.00%)	0
Hemorrhage ^† 1	3/272 (1.10%)	4	3/264 (1.14%)	3	2/238 (0.84%)	2
Hot flashes ^† 1	5/272 (1.84%)	15	9/264 (3.41%)	12	10/238 (4.20%)	25
Hypertension ^† 1	127/272 (46.69%)	596	97/264 (36.74%)	418	90/238 (37.82%)	345
Hypotension ^† 1	1/272 (0.37%)	1	4/264 (1.52%)	4	5/238 (2.10%)	6
Lymphedema ^† 1	0/272 (0.00%)	0	0/264 (0.00%)	0	1/238 (0.42%)	1
Phlebitis ^† 1	1/272 (0.37%)	18	0/264 (0.00%)	0	0/238 (0.00%)	0
Thrombosis ^† 1	7/272 (2.57%)	30	8/264 (3.03%)	13	3/238 (1.26%)	3
† Indicates events were collected by systematic assessment 1 Term from vocabulary, MedDRA 6

Limitations and Caveats

[Not Specified]

More Information

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

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Name/Title:	Hope Rugo, M.D.
Organization:	UCSF Comprehensive Cancer Center
EMail:	hrugo@medicine.ucsf.edu

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Quintanilha JCF, Wang J, Sibley AB, Jiang C, Etheridge AS, Shen F, Jiang G, Mulkey F, Patel JN, Hertz DL, Dees EC, McLeod HL, Bertagnolli M, Rugo H, Kindler HL, Kelly WK, Ratain MJ, Kroetz DL, Owzar K, Schneider BP, Lin D, Innocenti F. Bevacizumab-induced hypertension and proteinuria: a genome-wide study of more than 1000 patients. Br J Cancer. 2022 Feb;126(2):265-274. doi: 10.1038/s41416-021-01557-w. Epub 2021 Oct 6. Erratum In: Br J Cancer. 2021 Dec 1;:

Mehrotra S, Sharma MR, Gray E, Wu K, Barry WT, Hudis C, Winer EP, Lyss AP, Toppmeyer DL, Moreno-Aspitia A, Lad TE, Valasco M, Overmoyer B, Rugo H, Ratain MJ, Gobburu JV. Kinetic-Pharmacodynamic Model of Chemotherapy-Induced Peripheral Neuropathy in Patients with Metastatic Breast Cancer Treated with Paclitaxel, Nab-Paclitaxel, or Ixabepilone: CALGB 40502 (Alliance). AAPS J. 2017 Sep;19(5):1411-1423. doi: 10.1208/s12248-017-0101-9. Epub 2017 Jun 15.

Rugo HS, Barry WT, Moreno-Aspitia A, Lyss AP, Cirrincione C, Leung E, Mayer EL, Naughton M, Toppmeyer D, Carey LA, Perez EA, Hudis C, Winer EP. Randomized Phase III Trial of Paclitaxel Once Per Week Compared With Nanoparticle Albumin-Bound Nab-Paclitaxel Once Per Week or Ixabepilone With Bevacizumab As First-Line Chemotherapy for Locally Recurrent or Metastatic Breast Cancer: CALGB 40502/NCCTG N063H (Alliance). J Clin Oncol. 2015 Jul 20;33(21):2361-9. doi: 10.1200/JCO.2014.59.5298. Epub 2015 Jun 8.

Layout table for additonal information

Responsible Party:	National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:	NCT00785291
Other Study ID Numbers:	NCI-2009-00476 NCI-2009-00476 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ) CTSU 40502 CDR0000617539 NCCTG N063H CALGB-40502 PCALGB-40502_A11PAMDREVW01 CALGB 40502 ( Other Identifier: Alliance for Clinical Trials in Oncology ) CALGB-40502 ( Other Identifier: CTEP ) U10CA180821 ( U.S. NIH Grant/Contract ) U10CA031946 ( U.S. NIH Grant/Contract )
First Submitted:	November 4, 2008
First Posted:	November 5, 2008
Results First Submitted:	June 5, 2015
Results First Posted:	July 2, 2015
Last Update Posted:	October 10, 2022

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