A Trial of 2 Schedules of Ixabepilone Plus Bevacizumab and Paclitaxel Plus Bevacizumab for Breast Cancer

• Sponsor: R-Pharm (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00370552
• Collaborator: (none)
• Enrollment: 136
• Locations: 25
• Arms: 3
• Duration (Months): 32.1
• Patients Per Site: 5.4
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The purpose of this clinical research study is to learn if ixabepilone plus bevacizumab is effective in shrinking or stopping the growth of cancer when given as first-line chemotherapy in participants with metastatic breast cancer. The study will also assess the safety of this combination treatment.

Condition or Disease	Intervention/Treatment	Phase
Metastatic Breast Cancer	Drug: Ixabepilone, 16 mg/m^2 + Bevacizumab, 10 mg/kg; Drug: Ixabepilone, 40 mg/m^2 + Bevacizumab, 15 mg/kg; Drug: Paclitaxel, 90 mg/m^2 + Bevacizumab, 10 mg/kg	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 136 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Open Label, Randomized, 3 Arm Trial of 2 Schedules of Ixabepilone Plus Bevacizumab and Paclitaxel Plus Bevacizumab as First Line Therapy for Locally Recurrent or Metastatic Breast Cancer
• Study Start Date: Mar 1, 2007
• Actual Primary Completion Date: Nov 1, 2009
• Actual Study Completion Date: Nov 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ixabepilone, 16 mg/m^2 + Bevacizumab, 10 mg/kg	Drug: Ixabepilone, 16 mg/m^2 + Bevacizumab, 10 mg/kg; Ixabepilone,16 mg/m^2, administered as a 1-hour intravenous (IV) infusion on Days 1, 8, and 15 of a 28-day cycle until disease progression or unacceptable toxicity. Bevacizumab, 10 mg/kg, administered as IV infusion every 2 weeks. Bevacizumab to be infused over 90 minutes for the first dose, and if well tolerated for 60 minutes, for the second dose. Then if still tolerated, over 30 minutes for subsequent infusions. Bevacizumab was to be dosed until disease progression or unacceptable toxicity.; Other Names: IXEMPRA BMS-247550
Experimental: Ixabepilone, 40 mg/m^2 + Bevacizumab, 15 mg/kg	Drug: Ixabepilone, 40 mg/m^2 + Bevacizumab, 15 mg/kg; Ixabepilone, 40 mg/m^2, administered as a 3-hour IV infusion on Day 1 of a 21-day cycle until disease progression or unacceptable toxicity (After Cycle 4, dose reduction to 32 mg/m^2 was to be implemented for all subsequent cycles.) Bevacizumab, 15 mg/kg, administered as IV infusion every 3 weeks. Bevacizumab to be infused over 90 minutes for the first dose, and if well tolerated for 60 minutes, for the second dose. Then if still tolerated, over 30 minutes for subsequent infusions. Bevacizumab was to be dosed until disease progression or unacceptable toxicity.; Other Names: IXEMPRA BMS-247550
Active Comparator: Paclitaxel, 90 mg/m^2 + Bevacizumab, 10 mg/kg	Drug: Paclitaxel, 90 mg/m^2 + Bevacizumab, 10 mg/kg; Paclitaxel, 90 mg/m^2, given as a 1-hour IV infusion on Days 1, 8, and 15 of a 28-day cycle until disease progression or unacceptable toxicity. Bevacizumab, 10 mg/kg, administered as IV infusion every 2 weeks. Bevacizumab infused over 90 minutes for the first dose, and if well tolerated, over 60 minutes for the second dose. If still tolerated, over 30 minutes for subsequent infusions. Bevacizumab was to be dosed until disease progression or unacceptable toxicity.; Other Names: TAXOL BMS-181339

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With Best Tumor Response of Partial Response (PR) or Complete Response (CR) While On-study [Baseline visit and then every 8 weeks to 12 months, then every 3 months until disease progression]

   CR=Disappearance of all clinical and radiologic evidence of target lesions; PR=At least 30% reduction in the sum of the longest diameter of all target lesions.

2. Number of Participants With Best Response As Assessed With Response Evaluation Criteria in Solid Tumors (RECIST) [Baseline visit and then every 8 weeks to 12 months, then every 3 months until disease progression]

   Best tumor response was assessed with RECIST. Complete response (CR)=Disappearance of all evidence of target lesions; Partial response (PR)=At least 30% reduction from baseline in the sum of the longest diameter (LD) of all target lesions; Progressive disease (PD)=At least a 20% increase from baseline in the sum of LD of target lesions or the appearance of 1 or more new lesions; Stable disease (SD)=Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. A response was confirmed if noted on 2 examinations at least 4 weeks apart.

Secondary Outcome Measures

1. Percentage of Participants With Progression-free Survival at Week 24 [Date of randomization to Week 24]

   Week 24 Progression-free Survival was defined as the number of participants who neither progressed nor died before Week 24. Computed using Kaplan-Meier estimates, only at the time of Interim Analysis, when all participants had been followed for 6 months.

2. Median Progression-free Survival (PFS) [Date of randomization to date of progression, death, or last tumor assessment (maximum participant PFS of 29 months)]

   PFS was defined as the time from randomization to progression or to death from any cause without prior documentation of progression. Participants who did not progress or die were to be censored on the date of their last tumor assessment.

3. Median Time to Response [Date of first PR or CR assessment to date of progression, death, or last tumor assessment (maximum participant time to response of 67 weeks)]

   Time to response was defined as the time from the first dose of study therapy until measurement criteria were first met for a PR or CR, whichever was recorded first. Time to response was computed only for participants whose best response was PR or CR.

4. Median Duration of Response [Date of first PR or CR assessment to date of progression, death, or last tumor assessment (maximum participant duration of response of 25 weeks)]

   Duration of response was computed for participants whose best response was either PR or CR. Duration of overall response was defined as the period from the time that measurement criteria were first met for PR or CR, whichever was recorded first, until the first date of documented PD or death. Participants who neither relapsed nor died were to be censored on the date of their last tumor assessment.

5. Percentage of Participants Surviving at 1 Year [Date first participant enrolled to 1 year]

   One year survival rates were computed using Kaplan-Meier estimates.

6. Number of Participants With Death as Outcome, Serious Adverse Events (SAEs) Treatment-related SAEs, Treatment-related Adverse Events (AEs) Leading to Discontinuation, AEs Leading to Discontinuation, Treatment-related AEs [At initiation of treatment throughout study, to a minimum of 30 days after last dose of study drug]

   An AE is any new untoward medical occurrence or worsening of a preexisting medical condition that does not necessarily have a causal relationship with this treatment. An SAE is any untoward medical event that at any dose: results in death, persistent or significant disability/incapacity, drug dependency or abuse; is life-threatening, an important medical event, a congenital anomaly/birth defect; requires inpatient hospitalization; or prolongs existing hospitalization. Treatment related=possibly, probably, or certainly related to and of unknown relationship to study treatment.

7. Number of Participants With Abnormalities in Hematology Laboratory Results by Worst Common Terminology Criteria (CTC) Grade [At initiation of treatment and throughout study, to a minimum of 30 days after last dose of study drug. Laboratory tests performed within 72 hours before start of each cycle]

   CTC, Version 3 used to assess parameters. CTC Gr=Grade; WBC=white blood cells; ANC=absolute neutrophil count. LLN=lower level of normal. WBC Gr 1:<LLN to 3.0*10^9/L, Gr 2:<3.0 to 2.0*10^9/L, Gr 3:<2.0 to 1.0*10^9/L, Gr 4:<1.0*10^9/L; ANC Gr 1:<LLN to 1.5*10^9/L, Gr 2:<1.5 to 1.0*10^9/L, Gr 3:<1.0 to 0.5*10^9/L, Gr 4:<0.5*10^9/L; Platelet count Gr 1:LLN to 75.0*10^9/L, Gr 2:<75.0 to 50.0*10^9/L, Gr 3:<50.0 to 25.0*10^9/L, Gr 4:<25.0 to 10^9/L; Hemoglobin Gr 1:<LLN to 10.0 g/dL, Gr 2:<10.0 to 8.0 g/dL, Gr 3:<8.0 to 6.5 g/dL, Gr 4:<6.5 g/dL.

8. Number of Participants With Abnormalities in Liver Function by Worst CTC Grade [At initiation of treatment and throughout study, to a minimum of 30 days after last dose of study drug. Laboratory tests performed within 72 hours before start of each cycle]

   ULN=Upper limit of normal.ALT Gr 1:>ULN to 2.5*ULN, Gr 2: >2.5 to 5.0*ULN, Gr 3: >5.0 to 20.0*ULN, Gr 4: >20.0*ULN; AST Gr 1: >ULN to 2.5*ULN, Gr 2: >2.5 to 5.0*ULN, Gr 3: >5.0 to 20.0*ULN, Gr 4: >20.0*ULN; ALP Gr 1:>ULN to 2.5*ULN, Gr 2: >2.5 to 5.0*ULN, Gr 3: >5.0 to 20.0*ULN, Gr 4: >20.0*ULN; Total bilirubin Gr 1: >ULN to 1.5*ULN, Gr 2: >1.5 to 3.0*ULN, Gr 3: >3.0 to 10.0*ULN, Gr 4: >10.0*ULN.

9. Number of Participants With Abnormalities in Renal Function by Worst CTC Grade [At initiation of treatment and throughout study, to a minimum of 30 days after last dose of study drug. Laboratory tests performed within 72 hours before start of each cycle]

   Creatine Gr 1: >ULN to 1.5*ULN, Gr 2: 1.5 to 3.0*ULN, Gr 3: >3.0 to 6.0*ULN, Gr 4: >6.0*ULN.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion criteria:

• Locally recurrent or metastatic breast cancer, previously untreated with chemotherapy for advanced disease.

• At least 1 target lesion per RECIST criteria. Locally recurrent disease must not be amenable to resection with curative intent.

• No previous cytotoxic chemotherapy for locally recurrent/metastatic disease.

• Relapse 12 months or more after completing prior adjuvant or neoadjuvant taxane therapy.

• No previous breast cancer known to overexpress or amplify the human epidermal growth factor receptor 2 gene.

• Prior hormonal therapy in adjuvant, recurrent, or metastatic setting allowed but must have been discontinued at least 2 weeks before randomization.

• Karnofsky performance status of 80 to 100 or Eastern Cooperative Oncology Group performance status of 0 to 1.

• Estimated life expectancy of at least 12 weeks.

• Recovery from recent therapy (except for alopecia), including chemotherapy, immunotherapy, biologic therapy, or investigational product. Any such therapy must have been completed at least 3 weeks before randomization and at least 6 weeks from use of nitrosourea, or mitomycin.

• Recovery from recent surgery and radiation therapy. At least 1 week since minor surgery and/or focal/palliative radiation therapy; at least 3 weeks from radiation; at least 4 weeks from major surgery; and at least 8 weeks from liver resection, thoracotomy, or neurosurgery.

• Absolute neutrophil count ≥1500/mm^3.

• Hemoglobin ≥9 g/dL.

• Platelets ≥100,000/mm^3.

• Total bilirubin ≤1.5 times the upper limit of normal (ULN).

• Aspartate aminotransferase or alanine aminotransferase ≤2.5*ULN.

• Normal partial thromboplastin time and either international normalized ratio or prothrombin time <1.5*ULN.

• Serum creatinine ≤1.5*ULN or 24-hour creatinine clearance >60 mL/min.

• Urine dipstick for proteinuria <2+ (negative, trace, or +1). Participants with ≥2+ proteinuria at baseline were to undergo 24-hour urine collection and demonstrate ≤1g of protein in 24 hours to be eligible.

Exclusion criteria:

• Women of child-bearing potential (WOCBP) unwilling or unable to use an acceptable method of birth control to avoid pregnancy for the entire study period and up to 6 months after treatment with bevacizumab.

• Women who were pregnant or breastfeeding.

• Women with a positive pregnancy test on enrollment or prior to study drug administration.

• Sexually active fertile men, whose partners were WOCBP, not using an adequate method of birth control.

• Evidence of baseline sensory or motor neuropathy.

• Serious infection or nonmalignant medical illnesses uncontrolled or the control of which could be jeopardized by this therapy.

• History of abdominal fistula, gastrointestinal perforation, intra-abdominal abscess, serious gastric ulcer, or bone fracture within 6 months of study entry.

• History of hypertensive crisis or hypertensive encephalopathy.

• Significant vascular disease.

• Clinically significant cardiovascular disease.

• Baseline left ventricular ejection fraction by multiple-gated acquisition scan or echocardiogram for subjects with prior exposure to anthracyclines not within institutional normal limits.

• Symptomatic peripheral vascular disease.

• History of high dose chemotherapy with bone marrow transplant or peripheral blood stem cell transplant within the previous 2 years.

• Evidence of bleeding diathesis or coagulopathy.

• Prior treatment with an epothilone or any antiangiogenic agent.

• Concurrent nonhealing wound, ulcer, or fracture.

• Any current or history of brain and/or leptomeningeal metastases. Psychiatric disorders or other conditions rendering the participant incapable of complying with the requirements of the protocol.

• Any concurrent active malignancy other than nonmelanoma skin cancer or carcinoma in situ of the cervix.

• Known allergy to any of the study drugs or their excipients.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	East Valley Hematology And Oncology Medical Group	Burbank	California	United States	91505
2	Wilshire Oncology Medical Group, Inc.	La Verne	California	United States	91750
3	Ucsf-Comprehensive Cancer Center	San Francisco	California	United States	94115
4	University Of Iowa Hospitals And Clinics	Iowa City	Iowa	United States	52242
5	Ellis Fischel Cancer Center	Columbia	Missouri	United States	65203
6	Weill Medical College Of Cornell University	New York	New York	United States	10021
7	Local Institution	Besancon Cedex		France	25030
8	Local Institution	Clermont-Ferrand		France	63000
9	Local Institution	Marseille Cedex 9		France	13273
10	Local Institution	Paris Cedex 10		France	75475
11	Local Institution	Saint Herblain		France	44805
12	Local Institution	Strasbourg Cedex		France	67085
13	Local Institution	Tours Cedex		France	37044
14	Local Institution	Cuneo		Italy	12100
15	Local Institution	Meldola Fc		Italy	47014
16	Local Institution	Milano		Italy	20132
17	Local Institution	Modena		Italy	41100
18	Local Institution	Napoli		Italy	80131
19	Local Institution	Roma		Italy	00161
20	Local Institution	Hospitalet De Llobregat		Spain	08907
21	Local Institution	Jaen		Spain	23007
22	Local Institution	Chelmsford	Essex	United Kingdom	CM1 7ET
23	Local Institution	Manchester	Greater Manchester	United Kingdom	M20 4BX
24	Local Institution	Nottingham	Nottinghamshire	United Kingdom	NG5 1PB
25	Local Institution	Merseyside		United Kingdom	CH63 4JY

Sponsors and Collaborators

• R-Pharm

Investigators

• Study Director: Bristol-Myers Squibb, Bristol-Myers Squibb

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: R-Pharm
• ClinicalTrials.gov Identifier: NCT00370552
• Other Study ID Numbers: CA163-115
• First Posted: Aug 31, 2006
• Last Update Posted: Mar 10, 2016
• Last Verified: Feb 1, 2016

• Additional relevant MeSH terms: Breast Neoplasms; Paclitaxel; Epothilones; Bevacizumab

Study Results

Participant Flow

Pre-assignment Detail	Of the 136 participants enrolled in this study, 123 were randomized. Of the 13 not randomized, 11 no longer met study criteria, 1 withdrew, and 1 was found to have extensive disease. Of the 123 randomized, 122 were treated, and 1 no longer met study criteria and was never treated.

Arm/Group Title	Ixabepilone, 16 mg/m^2 + Bevacizumab, 10 mg/kg	Ixabepilone, 40 mg/m^2 + Bevacizumab, 15 mg/kg	Paclitaxel, 90 mg/m^2 + Bevacizumab, 10 mg/kg
Arm/Group Description	Ixabepilone,16 mg/m^2, administered as a 1-hour intravenous (IV) infusion on Days 1, 8, and 15 of a 28-day cycle until disease progression or unacceptable toxicity. Bevacizumab, 10 mg/kg, administered after ixabepilone as IV infusion every 2 weeks. Bevacizumab to be infused over 90 minutes for the first dose, and if well tolerated for 60 minutes, for the second dose. Then if still tolerated, over 30 minutes for subsequent infusions. Bevacizumab was to be dosed until disease progression or unacceptable toxicity.	Ixabepilone, 40 mg/m^2, administered as a 3-hour IV infusion on Day 1 of a 21-day cycle until disease progression or unacceptable toxicity After Cycle 4, dose reduction to 32 mg/m^2 implemented for all subsequent cycles. Bevacizumab, 15 mg/kg, administered after ixabepilone as IV infusion every 3 weeks. Bevacizumab to be infused over 90 minutes for the first dose, and if well tolerated for 60 minutes, for the second dose. Then if still tolerated, over 30 minutes for subsequent infusions. Bevacizumab was to be dosed until disease progression or unacceptable toxicity.	Paclitaxel, 90 mg/m^2, given as a 1-hour IV infusion on Days 1, 8, and 15 of a 28-day cycle until disease progression or unacceptable toxicity. Bevacizumab, 10 mg/kg, administered as IV infusion every 2 weeks. Bevacizumab infused over 90 minutes for the first dose, and if well tolerated, over 60 minutes for the second dose. If still tolerated, over 30 minutes for subsequent infusions. Bevacizumab was to be dosed until disease progression or unacceptable toxicity.
Period Title: Overall Study
STARTED	46	45	32
COMPLETED	0	0	0
NOT COMPLETED	46	45	32

Baseline Characteristics

Arm/Group Title	Ixabepilone, 16 mg/m^2 + Bevacizumab, 10 mg/kg	Ixabepilone, 40 mg/m^2 + Bevacizumab, 15 mg/kg	Paclitaxel, 90 mg/m^2 + Bevacizumab, 10 mg/kg	Total
Arm/Group Description	Ixabepilone,16 mg/m^2, administered as a 1-hour intravenous (IV) infusion on Days 1, 8, and 15 of a 28-day cycle until disease progression or unacceptable toxicity. Bevacizumab, 10 mg/kg, administered after ixabepilone as IV infusion every 2 weeks. Bevacizumab to be infused over 90 minutes for the first dose, and if well tolerated for 60 minutes, for the second dose. Then if still tolerated, over 30 minutes for subsequent infusions. Bevacizumab was to be dosed until disease progression or unacceptable toxicity.	Ixabepilone, 40 mg/m^2, administered as a 3-hour IV infusion on Day 1 of a 21-day cycle until disease progression or unacceptable toxicity After Cycle 4, dose reduction to 32 mg/m^2 implemented for all subsequent cycles. Bevacizumab, 15 mg/kg, administered after ixabepilone as IV infusion every 3 weeks. Bevacizumab to be infused over 90 minutes for the first dose, and if well tolerated for 60 minutes, for the second dose. Then if still tolerated, over 30 minutes for subsequent infusions. Bevacizumab was to be dosed until disease progression or unacceptable toxicity.	Paclitaxel, 90 mg/m^2, given as a 1-hour IV infusion on Days 1, 8, and 15 of a 28-day cycle until disease progression or unacceptable toxicity. Bevacizumab, 10 mg/kg, administered as IV infusion every 2 weeks. Bevacizumab infused over 90 minutes for the first dose, and if well tolerated, over 60 minutes for the second dose. If still tolerated, over 30 minutes for subsequent infusions. Bevacizumab was to be dosed until disease progression or unacceptable toxicity.	Total of all reporting groups
Overall Participants	46	45	32	123
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	60.0	59.0	59.0	59.0
Age, Customized (participants) [Number]
Younger than 65 years	33 71.7%	29 64.4%	22 68.8%	84 68.3%
>=65 years	13 28.3%	16 35.6%	10 31.3%	39 31.7%
Sex: Female, Male (Count of Participants)
Female	46 100%	45 100%	32 100%	123 100%
Male	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	2 4.3%	1 2.2%	0 0%	3 2.4%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	4 8.9%	0 0%	4 3.3%
White	43 93.5%	40 88.9%	31 96.9%	114 92.7%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	1 2.2%	0 0%	1 3.1%	2 1.6%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Best Tumor Response of Partial Response (PR) or Complete Response (CR) While On-study
Description	CR=Disappearance of all clinical and radiologic evidence of target lesions; PR=At least 30% reduction in the sum of the longest diameter of all target lesions.
Time Frame	Baseline visit and then every 8 weeks to 12 months, then every 3 months until disease progression

Outcome Measure Data

Analysis Population Description

All randomized participants

Arm/Group Title	Ixabepilone, 16 mg/m^2 + Bevacizumab, 10 mg/kg	Ixabepilone, 40 mg/m^2 + Bevacizumab, 15 mg/kg	Paclitaxel, 90 mg/m^2 + Bevacizumab, 10 mg/kg
Arm/Group Description	Ixabepilone,16 mg/m^2, administered as a 1-hour intravenous (IV) infusion on Days 1, 8, and 15 of a 28-day cycle until disease progression or unacceptable toxicity. Bevacizumab, 10 mg/kg, administered after ixabepilone as IV infusion every 2 weeks. Bevacizumab to be infused over 90 minutes for the first dose, and if well tolerated for 60 minutes, for the second dose. Then if still tolerated, over 30 minutes for subsequent infusions. Bevacizumab was to be dosed until disease progression or unacceptable toxicity.	Ixabepilone, 40 mg/m^2, administered as a 3-hour IV infusion on Day 1 of a 21-day cycle until disease progression or unacceptable toxicity After Cycle 4, dose reduction to 32 mg/m^2 implemented for all subsequent cycles. Bevacizumab, 15 mg/kg, administered after ixabepilone as IV infusion every 3 weeks. Bevacizumab to be infused over 90 minutes for the first dose, and if well tolerated for 60 minutes, for the second dose. Then if still tolerated, over 30 minutes for subsequent infusions. Bevacizumab was to be dosed until disease progression or unacceptable toxicity.	Paclitaxel, 90 mg/m^2, given as a 1-hour IV infusion on Days 1, 8, and 15 of a 28-day cycle until disease progression or unacceptable toxicity. Bevacizumab, 10 mg/kg, administered as IV infusion every 2 weeks. Bevacizumab infused over 90 minutes for the first dose, and if well tolerated, over 60 minutes for the second dose. If still tolerated, over 30 minutes for subsequent infusions. Bevacizumab was to be dosed until disease progression or unacceptable toxicity.
Measure Participants	46	45	32
Number (95% Confidence Interval) [Percentage of participants]	47.8 103.9%	71.1 158%	62.5 195.3%

2. Secondary Outcome

Title	Percentage of Participants With Progression-free Survival at Week 24
Description	Week 24 Progression-free Survival was defined as the number of participants who neither progressed nor died before Week 24. Computed using Kaplan-Meier estimates, only at the time of Interim Analysis, when all participants had been followed for 6 months.
Time Frame	Date of randomization to Week 24

Outcome Measure Data

Analysis Population Description

All randomized participants

Arm/Group Title	Ixabepilone, 16 mg/m^2 + Bevacizumab, 10 mg/kg	Ixabepilone, 40 mg/m^2 + Bevacizumab, 15 mg/kg	Paclitaxel, 90 mg/m^2 + Bevacizumab, 10 mg/kg
Arm/Group Description	Ixabepilone,16 mg/m^2, administered as a 1-hour intravenous (IV) infusion on Days 1, 8, and 15 of a 28-day cycle until disease progression or unacceptable toxicity. Bevacizumab, 10 mg/kg, administered after ixabepilone as IV infusion every 2 weeks. Bevacizumab to be infused over 90 minutes for the first dose, and if well tolerated for 60 minutes, for the second dose. Then if still tolerated, over 30 minutes for subsequent infusions. Bevacizumab was to be dosed until disease progression or unacceptable toxicity.	Ixabepilone, 40 mg/m^2, administered as a 3-hour IV infusion on Day 1 of a 21-day cycle until disease progression or unacceptable toxicity After Cycle 4, dose reduction to 32 mg/m^2 implemented for all subsequent cycles. Bevacizumab, 15 mg/kg, administered after ixabepilone as IV infusion every 3 weeks. Bevacizumab to be infused over 90 minutes for the first dose, and if well tolerated for 60 minutes, for the second dose. Then if still tolerated, over 30 minutes for subsequent infusions. Bevacizumab was to be dosed until disease progression or unacceptable toxicity.	Paclitaxel, 90 mg/m^2, given as a 1-hour IV infusion on Days 1, 8, and 15 of a 28-day cycle until disease progression or unacceptable toxicity. Bevacizumab, 10 mg/kg, administered as IV infusion every 2 weeks. Bevacizumab infused over 90 minutes for the first dose, and if well tolerated, over 60 minutes for the second dose. If still tolerated, over 30 minutes for subsequent infusions. Bevacizumab was to be dosed until disease progression or unacceptable toxicity.
Measure Participants	46	45	32
Number (95% Confidence Interval) [Percentage of participants]	75 163%	86 191.1%	94 293.8%

3. Secondary Outcome

Title	Median Progression-free Survival (PFS)
Description	PFS was defined as the time from randomization to progression or to death from any cause without prior documentation of progression. Participants who did not progress or die were to be censored on the date of their last tumor assessment.
Time Frame	Date of randomization to date of progression, death, or last tumor assessment (maximum participant PFS of 29 months)

Outcome Measure Data

Analysis Population Description

All randomized participants.

Arm/Group Title	Ixabepilone, 16 mg/m^2 + Bevacizumab, 10 mg/kg	Ixabepilone, 40 mg/m^2 + Bevacizumab, 15 mg/kg	Paclitaxel, 90 mg/m^2 + Bevacizumab, 10 mg/kg
Arm/Group Description	Ixabepilone,16 mg/m^2, administered as a 1-hour intravenous (IV) infusion on Days 1, 8, and 15 of a 28-day cycle until disease progression or unacceptable toxicity. Bevacizumab, 10 mg/kg, administered after ixabepilone as IV infusion every 2 weeks. Bevacizumab to be infused over 90 minutes for the first dose, and if well tolerated for 60 minutes, for the second dose. Then if still tolerated, over 30 minutes for subsequent infusions. Bevacizumab was to be dosed until disease progression or unacceptable toxicity.	Ixabepilone, 40 mg/m^2, administered as a 3-hour IV infusion on Day 1 of a 21-day cycle until disease progression or unacceptable toxicity After Cycle 4, dose reduction to 32 mg/m^2 implemented for all subsequent cycles. Bevacizumab, 15 mg/kg, administered after ixabepilone as IV infusion every 3 weeks. Bevacizumab to be infused over 90 minutes for the first dose, and if well tolerated for 60 minutes, for the second dose. Then if still tolerated, over 30 minutes for subsequent infusions. Bevacizumab was to be dosed until disease progression or unacceptable toxicity.	Paclitaxel, 90 mg/m^2, given as a 1-hour IV infusion on Days 1, 8, and 15 of a 28-day cycle until disease progression or unacceptable toxicity. Bevacizumab, 10 mg/kg, administered as IV infusion every 2 weeks. Bevacizumab infused over 90 minutes for the first dose, and if well tolerated, over 60 minutes for the second dose. If still tolerated, over 30 minutes for subsequent infusions. Bevacizumab was to be dosed until disease progression or unacceptable toxicity.
Measure Participants	46	45	32
Median (95% Confidence Interval) [Months]	9.6	11.9	13.5

4. Secondary Outcome

Title	Median Time to Response
Description	Time to response was defined as the time from the first dose of study therapy until measurement criteria were first met for a PR or CR, whichever was recorded first. Time to response was computed only for participants whose best response was PR or CR.
Time Frame	Date of first PR or CR assessment to date of progression, death, or last tumor assessment (maximum participant time to response of 67 weeks)

Outcome Measure Data

Analysis Population Description

Participants whose best response was CR or PR, as assessed by the investigator.

Arm/Group Title	Ixabepilone, 16 mg/m^2 + Bevacizumab, 10 mg/kg	Ixabepilone, 40 mg/m^2 + Bevacizumab, 15 mg/kg	Paclitaxel, 90 mg/m^2 + Bevacizumab, 10 mg/kg
Arm/Group Description	Ixabepilone,16 mg/m^2, administered as a 1-hour intravenous (IV) infusion on Days 1, 8, and 15 of a 28-day cycle until disease progression or unacceptable toxicity. Bevacizumab, 10 mg/kg, administered after ixabepilone as IV infusion every 2 weeks. Bevacizumab to be infused over 90 minutes for the first dose, and if well tolerated for 60 minutes, for the second dose. Then if still tolerated, over 30 minutes for subsequent infusions. Bevacizumab was to be dosed until disease progression or unacceptable toxicity.	Ixabepilone, 40 mg/m^2, administered as a 3-hour IV infusion on Day 1 of a 21-day cycle until disease progression or unacceptable toxicity After Cycle 4, dose reduction to 32 mg/m^2 implemented for all subsequent cycles. Bevacizumab, 15 mg/kg, administered after ixabepilone as IV infusion every 3 weeks. Bevacizumab to be infused over 90 minutes for the first dose, and if well tolerated for 60 minutes, for the second dose. Then if still tolerated, over 30 minutes for subsequent infusions. Bevacizumab was to be dosed until disease progression or unacceptable toxicity.	Paclitaxel, 90 mg/m^2, given as a 1-hour IV infusion on Days 1, 8, and 15 of a 28-day cycle until disease progression or unacceptable toxicity. Bevacizumab, 10 mg/kg, administered as IV infusion every 2 weeks. Bevacizumab infused over 90 minutes for the first dose, and if well tolerated, over 60 minutes for the second dose. If still tolerated, over 30 minutes for subsequent infusions. Bevacizumab was to be dosed until disease progression or unacceptable toxicity.
Measure Participants	22	32	20
Median (Full Range) [Weeks]	8.2	8.3	8.1

5. Secondary Outcome

Title	Median Duration of Response
Description	Duration of response was computed for participants whose best response was either PR or CR. Duration of overall response was defined as the period from the time that measurement criteria were first met for PR or CR, whichever was recorded first, until the first date of documented PD or death. Participants who neither relapsed nor died were to be censored on the date of their last tumor assessment.
Time Frame	Date of first PR or CR assessment to date of progression, death, or last tumor assessment (maximum participant duration of response of 25 weeks)

Outcome Measure Data

Analysis Population Description

Participants whose best response was CR or PR, as assessed by the investigator.

Arm/Group Title	Ixabepilone, 16 mg/m^2 + Bevacizumab, 10 mg/kg	Ixabepilone, 40 mg/m^2 + Bevacizumab, 15 mg/kg	Paclitaxel, 90 mg/m^2 + Bevacizumab, 10 mg/kg
Arm/Group Description	Ixabepilone,16 mg/m^2, administered as a 1-hour intravenous (IV) infusion on Days 1, 8, and 15 of a 28-day cycle until disease progression or unacceptable toxicity. Bevacizumab, 10 mg/kg, administered after ixabepilone as IV infusion every 2 weeks. Bevacizumab to be infused over 90 minutes for the first dose, and if well tolerated for 60 minutes, for the second dose. Then if still tolerated, over 30 minutes for subsequent infusions. Bevacizumab was to be dosed until disease progression or unacceptable toxicity.	Ixabepilone, 40 mg/m^2, administered as a 3-hour IV infusion on Day 1 of a 21-day cycle until disease progression or unacceptable toxicity After Cycle 4, dose reduction to 32 mg/m^2 implemented for all subsequent cycles. Bevacizumab, 15 mg/kg, administered after ixabepilone as IV infusion every 3 weeks. Bevacizumab to be infused over 90 minutes for the first dose, and if well tolerated for 60 minutes, for the second dose. Then if still tolerated, over 30 minutes for subsequent infusions. Bevacizumab was to be dosed until disease progression or unacceptable toxicity.	Paclitaxel, 90 mg/m^2, given as a 1-hour IV infusion on Days 1, 8, and 15 of a 28-day cycle until disease progression or unacceptable toxicity. Bevacizumab, 10 mg/kg, administered as IV infusion every 2 weeks. Bevacizumab infused over 90 minutes for the first dose, and if well tolerated, over 60 minutes for the second dose. If still tolerated, over 30 minutes for subsequent infusions. Bevacizumab was to be dosed until disease progression or unacceptable toxicity.
Measure Participants	22	32	20
Median (95% Confidence Interval) [Months]	10.1	10.3	13.1

6. Secondary Outcome

Title	Percentage of Participants Surviving at 1 Year
Description	One year survival rates were computed using Kaplan-Meier estimates.
Time Frame	Date first participant enrolled to 1 year

Outcome Measure Data

Analysis Population Description

All randomized participants.

Arm/Group Title	Ixabepilone, 16 mg/m^2 + Bevacizumab, 10 mg/kg	Ixabepilone, 40 mg/m^2 + Bevacizumab, 15 mg/kg	Paclitaxel, 90 mg/m^2 + Bevacizumab, 10 mg/kg
Arm/Group Description	Ixabepilone,16 mg/m^2, administered as a 1-hour intravenous (IV) infusion on Days 1, 8, and 15 of a 28-day cycle until disease progression or unacceptable toxicity. Bevacizumab, 10 mg/kg, administered after ixabepilone as IV infusion every 2 weeks. Bevacizumab to be infused over 90 minutes for the first dose, and if well tolerated for 60 minutes, for the second dose. Then if still tolerated, over 30 minutes for subsequent infusions. Bevacizumab was to be dosed until disease progression or unacceptable toxicity.	Ixabepilone, 40 mg/m^2, administered as a 3-hour IV infusion on Day 1 of a 21-day cycle until disease progression or unacceptable toxicity After Cycle 4, dose reduction to 32 mg/m^2 implemented for all subsequent cycles. Bevacizumab, 15 mg/kg, administered after ixabepilone as IV infusion every 3 weeks. Bevacizumab to be infused over 90 minutes for the first dose, and if well tolerated for 60 minutes, for the second dose. Then if still tolerated, over 30 minutes for subsequent infusions. Bevacizumab was to be dosed until disease progression or unacceptable toxicity.	Paclitaxel, 90 mg/m^2, given as a 1-hour IV infusion on Days 1, 8, and 15 of a 28-day cycle until disease progression or unacceptable toxicity. Bevacizumab, 10 mg/kg, administered as IV infusion every 2 weeks. Bevacizumab infused over 90 minutes for the first dose, and if well tolerated, over 60 minutes for the second dose. If still tolerated, over 30 minutes for subsequent infusions. Bevacizumab was to be dosed until disease progression or unacceptable toxicity.
Measure Participants	46	45	32
Number (95% Confidence Interval) [Percentage of participants]	91 197.8%	89 197.8%	91 284.4%

7. Secondary Outcome

Title	Number of Participants With Death as Outcome, Serious Adverse Events (SAEs) Treatment-related SAEs, Treatment-related Adverse Events (AEs) Leading to Discontinuation, AEs Leading to Discontinuation, Treatment-related AEs
Description	An AE is any new untoward medical occurrence or worsening of a preexisting medical condition that does not necessarily have a causal relationship with this treatment. An SAE is any untoward medical event that at any dose: results in death, persistent or significant disability/incapacity, drug dependency or abuse; is life-threatening, an important medical event, a congenital anomaly/birth defect; requires inpatient hospitalization; or prolongs existing hospitalization. Treatment related=possibly, probably, or certainly related to and of unknown relationship to study treatment.
Time Frame	At initiation of treatment throughout study, to a minimum of 30 days after last dose of study drug

Outcome Measure Data

Analysis Population Description

All randomized participants who received any study drug.

Arm/Group Title	Ixabepilone, 16 mg/m^2 + Bevacizumab, 10 mg/kg	Ixabepilone, 40 mg/m^2 + Bevacizumab, 15 mg/kg	Paclitaxel, 90 mg/m^2 + Bevacizumab, 10 mg/kg
Arm/Group Description	Ixabepilone,16 mg/m^2, administered as a 1-hour intravenous (IV) infusion on Days 1, 8, and 15 of a 28-day cycle until disease progression or unacceptable toxicity. Bevacizumab, 10 mg/kg, administered after ixabepilone as IV infusion every 2 weeks. Bevacizumab to be infused over 90 minutes for the first dose, and if well tolerated for 60 minutes, for the second dose. Then if still tolerated, over 30 minutes for subsequent infusions. Bevacizumab was to be dosed until disease progression or unacceptable toxicity.	Ixabepilone, 40 mg/m^2, administered as a 3-hour IV infusion on Day 1 of a 21-day cycle until disease progression or unacceptable toxicity After Cycle 4, dose reduction to 32 mg/m^2 implemented for all subsequent cycles. Bevacizumab, 15 mg/kg, administered after ixabepilone as IV infusion every 3 weeks. Bevacizumab to be infused over 90 minutes for the first dose, and if well tolerated for 60 minutes, for the second dose. Then if still tolerated, over 30 minutes for subsequent infusions. Bevacizumab was to be dosed until disease progression or unacceptable toxicity.	Paclitaxel, 90 mg/m^2, given as a 1-hour IV infusion on Days 1, 8, and 15 of a 28-day cycle until disease progression or unacceptable toxicity. Bevacizumab, 10 mg/kg, administered as IV infusion every 2 weeks. Bevacizumab infused over 90 minutes for the first dose, and if well tolerated, over 60 minutes for the second dose. If still tolerated, over 30 minutes for subsequent infusions. Bevacizumab was to be dosed until disease progression or unacceptable toxicity.
Measure Participants	45	45	32
Deaths	12 26.1%	15 33.3%	5 15.6%
SAEs	15 32.6%	16 35.6%	9 28.1%
Treatment-related SAEs	7 15.2%	9 20%	5 15.6%
Treatment-related AEs Leading to Discontinuation	24 52.2%	23 51.1%	20 62.5%
AEs Leading to Discontinuation	26 56.5%	25 55.6%	21 65.6%
Treatment-related AEs	43 93.5%	45 100%	32 100%

8. Primary Outcome

Title	Number of Participants With Best Response As Assessed With Response Evaluation Criteria in Solid Tumors (RECIST)
Description	Best tumor response was assessed with RECIST. Complete response (CR)=Disappearance of all evidence of target lesions; Partial response (PR)=At least 30% reduction from baseline in the sum of the longest diameter (LD) of all target lesions; Progressive disease (PD)=At least a 20% increase from baseline in the sum of LD of target lesions or the appearance of 1 or more new lesions; Stable disease (SD)=Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. A response was confirmed if noted on 2 examinations at least 4 weeks apart.
Time Frame	Baseline visit and then every 8 weeks to 12 months, then every 3 months until disease progression

Outcome Measure Data

Analysis Population Description

All randomized participants

Arm/Group Title	Ixabepilone, 16 mg/m^2 + Bevacizumab, 10 mg/kg	Ixabepilone, 40 mg/m^2 + Bevacizumab, 15 mg/kg	Paclitaxel, 90 mg/m^2 + Bevacizumab, 10 mg/kg
Arm/Group Description	Ixabepilone,16 mg/m^2, administered as a 1-hour intravenous (IV) infusion on Days 1, 8, and 15 of a 28-day cycle until disease progression or unacceptable toxicity. Bevacizumab, 10 mg/kg, administered after ixabepilone as IV infusion every 2 weeks. Bevacizumab to be infused over 90 minutes for the first dose, and if well tolerated for 60 minutes, for the second dose. Then if still tolerated, over 30 minutes for subsequent infusions. Bevacizumab was to be dosed until disease progression or unacceptable toxicity.	Ixabepilone, 40 mg/m^2, administered as a 3-hour IV infusion on Day 1 of a 21-day cycle until disease progression or unacceptable toxicity After Cycle 4, dose reduction to 32 mg/m^2 implemented for all subsequent cycles. Bevacizumab, 15 mg/kg, administered after ixabepilone as IV infusion every 3 weeks. Bevacizumab to be infused over 90 minutes for the first dose, and if well tolerated for 60 minutes, for the second dose. Then if still tolerated, over 30 minutes for subsequent infusions. Bevacizumab was to be dosed until disease progression or unacceptable toxicity.	Paclitaxel, 90 mg/m^2, given as a 1-hour IV infusion on Days 1, 8, and 15 of a 28-day cycle until disease progression or unacceptable toxicity. Bevacizumab, 10 mg/kg, administered as IV infusion every 2 weeks. Bevacizumab infused over 90 minutes for the first dose, and if well tolerated, over 60 minutes for the second dose. If still tolerated, over 30 minutes for subsequent infusions. Bevacizumab was to be dosed until disease progression or unacceptable toxicity.
Measure Participants	46	45	32
Complete Response	2 4.3%	2 4.4%	4 12.5%
Partial Response	20 43.5%	30 66.7%	16 50%
Stable Disease	18 39.1%	9 20%	11 34.4%
Progressive Disease	5 10.9%	3 6.7%	0 0%
Unable to Determine	1 2.2%	1 2.2%	1 3.1%

9. Secondary Outcome

Title	Number of Participants With Abnormalities in Hematology Laboratory Results by Worst Common Terminology Criteria (CTC) Grade
Description	CTC, Version 3 used to assess parameters. CTC Gr=Grade; WBC=white blood cells; ANC=absolute neutrophil count. LLN=lower level of normal. WBC Gr 1:<LLN to 3.0*10^9/L, Gr 2:<3.0 to 2.0*10^9/L, Gr 3:<2.0 to 1.0*10^9/L, Gr 4:<1.0*10^9/L; ANC Gr 1:<LLN to 1.5*10^9/L, Gr 2:<1.5 to 1.0*10^9/L, Gr 3:<1.0 to 0.5*10^9/L, Gr 4:<0.5*10^9/L; Platelet count Gr 1:LLN to 75.0*10^9/L, Gr 2:<75.0 to 50.0*10^9/L, Gr 3:<50.0 to 25.0*10^9/L, Gr 4:<25.0 to 10^9/L; Hemoglobin Gr 1:<LLN to 10.0 g/dL, Gr 2:<10.0 to 8.0 g/dL, Gr 3:<8.0 to 6.5 g/dL, Gr 4:<6.5 g/dL.
Time Frame	At initiation of treatment and throughout study, to a minimum of 30 days after last dose of study drug. Laboratory tests performed within 72 hours before start of each cycle

Outcome Measure Data

Analysis Population Description

All randomized participants who received any study drug.

Arm/Group Title	Ixabepilone, 16 mg/m^2 + Bevacizumab, 10 mg/kg	Ixabepilone, 40 mg/m^2 + Bevacizumab, 15 mg/kg	Paclitaxel, 90 mg/m^2 + Bevacizumab, 10 mg/kg
Arm/Group Description	Ixabepilone,16 mg/m^2, administered as a 1-hour intravenous (IV) infusion on Days 1, 8, and 15 of a 28-day cycle until disease progression or unacceptable toxicity. Bevacizumab, 10 mg/kg, administered after ixabepilone as IV infusion every 2 weeks. Bevacizumab to be infused over 90 minutes for the first dose, and if well tolerated for 60 minutes, for the second dose. Then if still tolerated, over 30 minutes for subsequent infusions. Bevacizumab was to be dosed until disease progression or unacceptable toxicity.	Ixabepilone, 40 mg/m^2, administered as a 3-hour IV infusion on Day 1 of a 21-day cycle until disease progression or unacceptable toxicity After Cycle 4, dose reduction to 32 mg/m^2 implemented for all subsequent cycles. Bevacizumab, 15 mg/kg, administered after ixabepilone as IV infusion every 3 weeks. Bevacizumab to be infused over 90 minutes for the first dose, and if well tolerated for 60 minutes, for the second dose. Then if still tolerated, over 30 minutes for subsequent infusions. Bevacizumab was to be dosed until disease progression or unacceptable toxicity.	Paclitaxel, 90 mg/m^2, given as a 1-hour IV infusion on Days 1, 8, and 15 of a 28-day cycle until disease progression or unacceptable toxicity. Bevacizumab, 10 mg/kg, administered as IV infusion every 2 weeks. Bevacizumab infused over 90 minutes for the first dose, and if well tolerated, over 60 minutes for the second dose. If still tolerated, over 30 minutes for subsequent infusions. Bevacizumab was to be dosed until disease progression or unacceptable toxicity.
Measure Participants	45	45	32
White blood cells (WBC) (Grade 1)	11 23.9%	12 26.7%	12 37.5%
WBC (Grade 2)	14 30.4%	12 26.7%	11 34.4%
WBC (Grade 3)	1 2.2%	14 31.1%	3 9.4%
WBC (Grade 4)	2 4.3%	4 8.9%	0 0%
Absolute neutrophil count (ANC) (Grade 1)	10 21.7%	4 8.9%	6 18.8%
ANC (Grade 2)	9 19.6%	10 22.2%	13 40.6%
ANC (Grade 3)	5 10.9%	17 37.8%	6 18.8%
ANC (Grade 4)	2 4.3%	10 22.2%	1 3.1%
Platelet count (Grade 1)	4 8.7%	15 33.3%	3 9.4%
Platelet count (Grade 2)	1 2.2%	1 2.2%	0 0%
Platelet count (Grade 3)	0 0%	0 0%	0 0%
Platelet count (Grade 4)	2 4.3%	1 2.2%	0 0%
Hemoglobin (Grade 1)	21 45.7%	20 44.4%	17 53.1%
Hemoglobin (Grade 2)	3 6.5%	4 8.9%	3 9.4%
Hemoglobin (Grade 3)	1 2.2%	3 6.7%	2 6.3%
Hemoglobin (Grade 4)	1 2.2%	0 0%	0 0%

10. Secondary Outcome

Title	Number of Participants With Abnormalities in Liver Function by Worst CTC Grade
Description	ULN=Upper limit of normal.ALT Gr 1:>ULN to 2.5*ULN, Gr 2: >2.5 to 5.0*ULN, Gr 3: >5.0 to 20.0*ULN, Gr 4: >20.0*ULN; AST Gr 1: >ULN to 2.5*ULN, Gr 2: >2.5 to 5.0*ULN, Gr 3: >5.0 to 20.0*ULN, Gr 4: >20.0*ULN; ALP Gr 1:>ULN to 2.5*ULN, Gr 2: >2.5 to 5.0*ULN, Gr 3: >5.0 to 20.0*ULN, Gr 4: >20.0*ULN; Total bilirubin Gr 1: >ULN to 1.5*ULN, Gr 2: >1.5 to 3.0*ULN, Gr 3: >3.0 to 10.0*ULN, Gr 4: >10.0*ULN.
Time Frame	At initiation of treatment and throughout study, to a minimum of 30 days after last dose of study drug. Laboratory tests performed within 72 hours before start of each cycle

Outcome Measure Data

Analysis Population Description

All randomized participants who received any study drug and had samples available.

Arm/Group Title	Ixabepilone, 16 mg/m^2 + Bevacizumab, 10 mg/kg	Ixabepilone, 40 mg/m^2 + Bevacizumab, 15 mg/kg	Paclitaxel, 90 mg/m^2 + Bevacizumab, 10 mg/kg
Arm/Group Description	Ixabepilone,16 mg/m^2, administered as a 1-hour intravenous (IV) infusion on Days 1, 8, and 15 of a 28-day cycle until disease progression or unacceptable toxicity. Bevacizumab, 10 mg/kg, administered after ixabepilone as IV infusion every 2 weeks. Bevacizumab to be infused over 90 minutes for the first dose, and if well tolerated for 60 minutes, for the second dose. Then if still tolerated, over 30 minutes for subsequent infusions. Bevacizumab was to be dosed until disease progression or unacceptable toxicity.	Ixabepilone, 40 mg/m^2, administered as a 3-hour IV infusion on Day 1 of a 21-day cycle until disease progression or unacceptable toxicity After Cycle 4, dose reduction to 32 mg/m^2 implemented for all subsequent cycles. Bevacizumab, 15 mg/kg, administered after ixabepilone as IV infusion every 3 weeks. Bevacizumab to be infused over 90 minutes for the first dose, and if well tolerated for 60 minutes, for the second dose. Then if still tolerated, over 30 minutes for subsequent infusions. Bevacizumab was to be dosed until disease progression or unacceptable toxicity.	Paclitaxel, 90 mg/m^2, given as a 1-hour IV infusion on Days 1, 8, and 15 of a 28-day cycle until disease progression or unacceptable toxicity. Bevacizumab, 10 mg/kg, administered as IV infusion every 2 weeks. Bevacizumab infused over 90 minutes for the first dose, and if well tolerated, over 60 minutes for the second dose. If still tolerated, over 30 minutes for subsequent infusions. Bevacizumab was to be dosed until disease progression or unacceptable toxicity.
Measure Participants	43	44	32
Alanine aminotransferase (ALT) (Grade 1)	18 39.1%	13 28.9%	13 40.6%
ALT (Grade 2)	2 4.3%	4 8.9%	3 9.4%
ALT (Grade 3)	1 2.2%	0 0%	0 0%
ALT (Grade 4)	0 0%	0 0%	0 0%
AST (Grade 1)	20 43.5%	18 40%	15 46.9%
AST (Grade 2)	1 2.2%	1 2.2%	1 3.1%
AST (Grade 3)	1 2.2%	0 0%	0 0%
AST (Grade 4)	0 0%	0 0%	0 0%
Alkaline phosphatase (ALP) (Grade 1)	8 17.4%	11 24.4%	12 37.5%
ALP (Grade 2)	0 0%	3 6.7%	0 0%
ALP (Grade 3)	0 0%	0 0%	1 3.1%
ALP (Grade 4)	0 0%	0 0%	0 0%
Total bilirubin (Grade 1)	3 6.5%	3 6.7%	2 6.3%
Total bilirubin (Grade 2)	2 4.3%	0 0%	1 3.1%
Total bilirubin (Grade 3)	0 0%	0 0%	0 0%
Total bilirubin (Grade 4)	0 0%	0 0%	0 0%

11. Secondary Outcome

Title	Number of Participants With Abnormalities in Renal Function by Worst CTC Grade
Description	Creatine Gr 1: >ULN to 1.5*ULN, Gr 2: 1.5 to 3.0*ULN, Gr 3: >3.0 to 6.0*ULN, Gr 4: >6.0*ULN.
Time Frame	At initiation of treatment and throughout study, to a minimum of 30 days after last dose of study drug. Laboratory tests performed within 72 hours before start of each cycle

Outcome Measure Data

Analysis Population Description

All randomized participants who received any study drug and had samples available.

Arm/Group Title	Ixabepilone, 16 mg/m^2 + Bevacizumab, 10 mg/kg	Ixabepilone, 40 mg/m^2 + Bevacizumab, 15 mg/kg	Paclitaxel, 90 mg/m^2 + Bevacizumab, 10 mg/kg
Arm/Group Description	Ixabepilone,16 mg/m^2, administered as a 1-hour intravenous (IV) infusion on Days 1, 8, and 15 of a 28-day cycle until disease progression or unacceptable toxicity. Bevacizumab, 10 mg/kg, administered after ixabepilone as IV infusion every 2 weeks. Bevacizumab to be infused over 90 minutes for the first dose, and if well tolerated for 60 minutes, for the second dose. Then if still tolerated, over 30 minutes for subsequent infusions. Bevacizumab was to be dosed until disease progression or unacceptable toxicity.	Ixabepilone, 40 mg/m^2, administered as a 3-hour IV infusion on Day 1 of a 21-day cycle until disease progression or unacceptable toxicity After Cycle 4, dose reduction to 32 mg/m^2 implemented for all subsequent cycles. Bevacizumab, 15 mg/kg, administered after ixabepilone as IV infusion every 3 weeks. Bevacizumab to be infused over 90 minutes for the first dose, and if well tolerated for 60 minutes, for the second dose. Then if still tolerated, over 30 minutes for subsequent infusions. Bevacizumab was to be dosed until disease progression or unacceptable toxicity.	Paclitaxel, 90 mg/m^2, given as a 1-hour IV infusion on Days 1, 8, and 15 of a 28-day cycle until disease progression or unacceptable toxicity. Bevacizumab, 10 mg/kg, administered as IV infusion every 2 weeks. Bevacizumab infused over 90 minutes for the first dose, and if well tolerated, over 60 minutes for the second dose. If still tolerated, over 30 minutes for subsequent infusions. Bevacizumab was to be dosed until disease progression or unacceptable toxicity.
Measure Participants	44	44	32
Creatinine (Grade 1)	5 10.9%	3 6.7%	3 9.4%
Creatinine (Grade 2)	3 6.5%	1 2.2%	0 0%
Creatinine (Grade 3)	0 0%	0 0%	0 0%
Creatinine (Grade 4)	0 0%	0 0%	0 0%

Adverse Events

Time Frame	Continuously from first to last dose of study drug (24 weeks)and within 30 days following last dose.
Arm/Group Title	Ixabepilone, 16 mg/m^2 + Bevacizumab, 10 mg/kg		Ixabepilone, 40 mg/m^2 + Bevacizumab, 15 mg/kg		Paclitaxel, 90 mg/m^2 + Bevacizumab, 10 mg/kg
Arm/Group Description	Ixabepilone,16 mg/m^2, administered as a 1-hour intravenous (IV) infusion on Days 1, 8, and 15 of a 28-day cycle until disease progression or unacceptable toxicity. Bevacizumab, 10 mg/kg, administered after ixabepilone, as IV infusion every 2 weeks. Bevacizumab to be infused over 90 minutes for the first dose, and if well tolerated for 60 minutes, for the second dose. Then if still tolerated, over 30 minutes for subsequent infusions. Bevacizumab was to be dosed until disease progression or unacceptable toxicity.		Ixabepilone, 40 mg/m^2, administered as a 3-hour IV infusion on Day 1 of a 21-day cycle until disease progression or unacceptable toxicity. After Cycle 4, dose reduction to 32 mg/m^2 implemented for all subsequent cycles. Bevacizumab, 15 mg/kg, administered after ixabepilone, as IV infusion every 3 weeks. Bevacizumab to be infused over 90 minutes for the first dose, and if well tolerated for 60 minutes, for the second dose. Then if still tolerated, over 30 minutes for subsequent infusions. Bevacizumab was to be dosed until disease progression or unacceptable toxicity.		Paclitaxel, 90 mg/m^2, given as a 1-hour IV infusion on Days 1, 8, and 15 of a 28-day cycle until disease progression or unacceptable toxicity. Bevacizumab, 10 mg/kg, administered as IV infusion every 2 weeks. Bevacizumab infused over 90 minutes for the first dose, and if well tolerated, over 60 minutes for the second dose. If still tolerated, over 30 minutes for subsequent infusions. Bevacizumab was to be dosed until disease progression or unacceptable toxicity.
All Cause Mortality
	Ixabepilone, 16 mg/m^2 + Bevacizumab, 10 mg/kg		Ixabepilone, 40 mg/m^2 + Bevacizumab, 15 mg/kg		Paclitaxel, 90 mg/m^2 + Bevacizumab, 10 mg/kg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Ixabepilone, 16 mg/m^2 + Bevacizumab, 10 mg/kg		Ixabepilone, 40 mg/m^2 + Bevacizumab, 15 mg/kg		Paclitaxel, 90 mg/m^2 + Bevacizumab, 10 mg/kg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	15/45 (33.3%)		16/45 (35.6%)		9/32 (28.1%)
Blood and lymphatic system disorders
Anemia	1/45 (2.2%)		0/45 (0%)		0/32 (0%)
Leukopenia	0/45 (0%)		2/45 (4.4%)		0/32 (0%)
Neutropenia	0/45 (0%)		3/45 (6.7%)		0/32 (0%)
Thrombocytopenia	1/45 (2.2%)		0/45 (0%)		0/32 (0%)
Febrile neutropenia	0/45 (0%)		1/45 (2.2%)		0/32 (0%)
Cardiac disorders
Angina pectoris	0/45 (0%)		0/45 (0%)		1/32 (3.1%)
Atrial fibrillation	0/45 (0%)		1/45 (2.2%)		0/32 (0%)
Gastrointestinal disorders
Vomiting	1/45 (2.2%)		0/45 (0%)		0/32 (0%)
Diarrhea	1/45 (2.2%)		0/45 (0%)		0/32 (0%)
Abdominal pain	1/45 (2.2%)		0/45 (0%)		0/32 (0%)
Diverticular perforation	0/45 (0%)		1/45 (2.2%)		0/32 (0%)
Large intestine perforation	1/45 (2.2%)		0/45 (0%)		0/32 (0%)
General disorders
Hernia	0/45 (0%)		1/45 (2.2%)		0/32 (0%)
Malaise	1/45 (2.2%)		0/45 (0%)		0/32 (0%)
Pyrexia	1/45 (2.2%)		1/45 (2.2%)		1/32 (3.1%)
Asthenia	1/45 (2.2%)		0/45 (0%)		0/32 (0%)
Mucosal inflammation	0/45 (0%)		1/45 (2.2%)		0/32 (0%)
Hepatobiliary disorders
Cholecystitis	1/45 (2.2%)		0/45 (0%)		0/32 (0%)
Immune system disorders
Hypersensitivity	1/45 (2.2%)		2/45 (4.4%)		0/32 (0%)
Infections and infestations
Infection	0/45 (0%)		0/45 (0%)		1/32 (3.1%)
Pneumonia	1/45 (2.2%)		0/45 (0%)		0/32 (0%)
Anal abscess	0/45 (0%)		1/45 (2.2%)		0/32 (0%)
Tooth abscess	0/45 (0%)		1/45 (2.2%)		0/32 (0%)
Diverticulitis	0/45 (0%)		1/45 (2.2%)		0/32 (0%)
Abdominal abscess	0/45 (0%)		1/45 (2.2%)		0/32 (0%)
Neutropenic sepsis	1/45 (2.2%)		0/45 (0%)		0/32 (0%)
Bacterial infection	1/45 (2.2%)		0/45 (0%)		0/32 (0%)
Subcutaneous abscess	0/45 (0%)		1/45 (2.2%)		0/32 (0%)
Bacteroides infection	0/45 (0%)		0/45 (0%)		1/32 (3.1%)
Gastroenteritis viral	1/45 (2.2%)		0/45 (0%)		0/32 (0%)
Investigations
Blood creatinine increased	1/45 (2.2%)		0/45 (0%)		0/32 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/45 (0%)		1/45 (2.2%)		0/32 (0%)
Pain in extremity	0/45 (0%)		1/45 (2.2%)		0/32 (0%)
Musculoskeletal pain	0/45 (0%)		1/45 (2.2%)		0/32 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant neoplasm progression	2/45 (4.4%)		1/45 (2.2%)		0/32 (0%)
Nervous system disorders
Ataxia	0/45 (0%)		1/45 (2.2%)		0/32 (0%)
Headache	1/45 (2.2%)		0/45 (0%)		0/32 (0%)
Sciatica	1/45 (2.2%)		0/45 (0%)		0/32 (0%)
Complicated migraine	1/45 (2.2%)		0/45 (0%)		0/32 (0%)
Peripheral motor neuropathy	0/45 (0%)		1/45 (2.2%)		0/32 (0%)
Renal and urinary disorders
Bladder obstruction	1/45 (2.2%)		0/45 (0%)		0/32 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	0/45 (0%)		0/45 (0%)		1/32 (3.1%)
Dyspnea	0/45 (0%)		0/45 (0%)		1/32 (3.1%)
Dysphonia	0/45 (0%)		1/45 (2.2%)		1/32 (3.1%)
Pneumonitis	0/45 (0%)		0/45 (0%)		2/32 (6.3%)
Oropharyngeal pain	0/45 (0%)		0/45 (0%)		1/32 (3.1%)
Pulmonary embolism	0/45 (0%)		0/45 (0%)		1/32 (3.1%)
Skin and subcutaneous tissue disorders
Rash	0/45 (0%)		0/45 (0%)		1/32 (3.1%)
Urticaria	0/45 (0%)		1/45 (2.2%)		0/32 (0%)
Vascular disorders
Thrombosis	1/45 (2.2%)		0/45 (0%)		0/32 (0%)
Hypertension	1/45 (2.2%)		1/45 (2.2%)		0/32 (0%)
Hypertensive crisis	0/45 (0%)		1/45 (2.2%)		0/32 (0%)
Other (Not Including Serious) Adverse Events
	Ixabepilone, 16 mg/m^2 + Bevacizumab, 10 mg/kg		Ixabepilone, 40 mg/m^2 + Bevacizumab, 15 mg/kg		Paclitaxel, 90 mg/m^2 + Bevacizumab, 10 mg/kg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	45/45 (100%)		45/45 (100%)		32/32 (100%)
Blood and lymphatic system disorders
Anemia	1/45 (2.2%)		3/45 (6.7%)		4/32 (12.5%)
Neutropenia	7/45 (15.6%)		10/45 (22.2%)		8/32 (25%)
Cardiac disorders
Tachycardia	0/45 (0%)		1/45 (2.2%)		3/32 (9.4%)
Ear and labyrinth disorders
Vertigo	6/45 (13.3%)		1/45 (2.2%)		1/32 (3.1%)
Ear pain	0/45 (0%)		0/45 (0%)		2/32 (6.3%)
Eye disorders
Dry eye	0/45 (0%)		1/45 (2.2%)		2/32 (6.3%)
Vision blurred	3/45 (6.7%)		0/45 (0%)		3/32 (9.4%)
Gastrointestinal disorders
Nausea	18/45 (40%)		14/45 (31.1%)		12/32 (37.5%)
Vomiting	16/45 (35.6%)		6/45 (13.3%)		13/32 (40.6%)
Diarrhea	27/45 (60%)		14/45 (31.1%)		18/32 (56.3%)
Dry mouth	2/45 (4.4%)		1/45 (2.2%)		3/32 (9.4%)
Dyspepsia	2/45 (4.4%)		5/45 (11.1%)		2/32 (6.3%)
Gastritis	3/45 (6.7%)		1/45 (2.2%)		1/32 (3.1%)
Toothache	3/45 (6.7%)		2/45 (4.4%)		0/32 (0%)
Flatulence	0/45 (0%)		1/45 (2.2%)		3/32 (9.4%)
Gingivitis	0/45 (0%)		0/45 (0%)		2/32 (6.3%)
Stomatitis	4/45 (8.9%)		10/45 (22.2%)		5/32 (15.6%)
Odynophagia	0/45 (0%)		1/45 (2.2%)		2/32 (6.3%)
Constipation	20/45 (44.4%)		12/45 (26.7%)		10/32 (31.3%)
Hemorrhoids	4/45 (8.9%)		0/45 (0%)		1/32 (3.1%)
Esophagitis	0/45 (0%)		1/45 (2.2%)		2/32 (6.3%)
Abdominal pain	11/45 (24.4%)		11/45 (24.4%)		7/32 (21.9%)
Gingival bleeding	4/45 (8.9%)		1/45 (2.2%)		3/32 (9.4%)
Abdominal pain lower	0/45 (0%)		0/45 (0%)		3/32 (9.4%)
Abdominal pain upper	6/45 (13.3%)		7/45 (15.6%)		1/32 (3.1%)
General disorders
Pain	2/45 (4.4%)		3/45 (6.7%)		2/32 (6.3%)
Fatigue	13/45 (28.9%)		9/45 (20%)		10/32 (31.3%)
Pyrexia	7/45 (15.6%)		10/45 (22.2%)		9/32 (28.1%)
Asthenia	20/45 (44.4%)		23/45 (51.1%)		13/32 (40.6%)
Chest pain	4/45 (8.9%)		3/45 (6.7%)		2/32 (6.3%)
Chest discomfort	1/45 (2.2%)		0/45 (0%)		2/32 (6.3%)
Edema peripheral	5/45 (11.1%)		8/45 (17.8%)		4/32 (12.5%)
Mucosal inflammation	7/45 (15.6%)		10/45 (22.2%)		8/32 (25%)
Immune system disorders
Hypersensitivity	3/45 (6.7%)		2/45 (4.4%)		2/32 (6.3%)
Drug hypersensitivity	0/45 (0%)		0/45 (0%)		2/32 (6.3%)
Infections and infestations
Rhinitis	4/45 (8.9%)		2/45 (4.4%)		7/32 (21.9%)
Sinusitis	2/45 (4.4%)		1/45 (2.2%)		2/32 (6.3%)
Bronchitis	1/45 (2.2%)		3/45 (6.7%)		0/32 (0%)
Cellulitis	0/45 (0%)		0/45 (0%)		2/32 (6.3%)
Laryngitis	0/45 (0%)		3/45 (6.7%)		0/32 (0%)
Oral herpes	0/45 (0%)		1/45 (2.2%)		2/32 (6.3%)
Pharyngitis	1/45 (2.2%)		2/45 (4.4%)		3/32 (9.4%)
Folliculitis	1/45 (2.2%)		4/45 (8.9%)		0/32 (0%)
Tooth abscess	0/45 (0%)		1/45 (2.2%)		2/32 (6.3%)
Skin infection	0/45 (0%)		0/45 (0%)		2/32 (6.3%)
Gastroenteritis	4/45 (8.9%)		0/45 (0%)		1/32 (3.1%)
Nasopharyngitis	4/45 (8.9%)		3/45 (6.7%)		5/32 (15.6%)
Vaginal infection	0/45 (0%)		0/45 (0%)		2/32 (6.3%)
Urinary tract infection	2/45 (4.4%)		5/45 (11.1%)		4/32 (12.5%)
Upper respiratory tract infection	2/45 (4.4%)		1/45 (2.2%)		2/32 (6.3%)
Investigations
Weight decreased	7/45 (15.6%)		9/45 (20%)		3/32 (9.4%)
Weight increased	3/45 (6.7%)		1/45 (2.2%)		1/32 (3.1%)
Neutrophil count decreased	0/45 (0%)		2/45 (4.4%)		3/32 (9.4%)
Metabolism and nutrition disorders
Decreased appetite	10/45 (22.2%)		9/45 (20%)		4/32 (12.5%)
Musculoskeletal and connective tissue disorders
Myalgia	12/45 (26.7%)		12/45 (26.7%)		5/32 (15.6%)
Back pain	7/45 (15.6%)		9/45 (20%)		12/32 (37.5%)
Bone pain	9/45 (20%)		6/45 (13.3%)		3/32 (9.4%)
Neck pain	5/45 (11.1%)		2/45 (4.4%)		2/32 (6.3%)
Arthralgia	10/45 (22.2%)		10/45 (22.2%)		9/32 (28.1%)
Groin pain	0/45 (0%)		0/45 (0%)		2/32 (6.3%)
Muscle spasms	1/45 (2.2%)		4/45 (8.9%)		0/32 (0%)
Muscular weakness	2/45 (4.4%)		2/45 (4.4%)		2/32 (6.3%)
Pain in extremity	10/45 (22.2%)		8/45 (17.8%)		4/32 (12.5%)
Musculoskeletal pain	6/45 (13.3%)		6/45 (13.3%)		7/32 (21.9%)
Nervous system disorders
Headache	17/45 (37.8%)		15/45 (33.3%)		14/32 (43.8%)
Lethargy	3/45 (6.7%)		2/45 (4.4%)		3/32 (9.4%)
Migraine	1/45 (2.2%)		0/45 (0%)		2/32 (6.3%)
Sciatica	2/45 (4.4%)		1/45 (2.2%)		2/32 (6.3%)
Dizziness	4/45 (8.9%)		2/45 (4.4%)		4/32 (12.5%)
Dysgeusia	9/45 (20%)		9/45 (20%)		4/32 (12.5%)
Somnolence	0/45 (0%)		1/45 (2.2%)		2/32 (6.3%)
Dysaesthesia	3/45 (6.7%)		2/45 (4.4%)		2/32 (6.3%)
Paraesthesia	11/45 (24.4%)		11/45 (24.4%)		8/32 (25%)
Hypoaesthesia	2/45 (4.4%)		3/45 (6.7%)		2/32 (6.3%)
Neuropathy peripheral	12/45 (26.7%)		14/45 (31.1%)		14/32 (43.8%)
Peripheral motor neuropathy	4/45 (8.9%)		4/45 (8.9%)		1/32 (3.1%)
Peripheral sensory neuropathy	12/45 (26.7%)		19/45 (42.2%)		12/32 (37.5%)
Psychiatric disorders
Anxiety	5/45 (11.1%)		8/45 (17.8%)		4/32 (12.5%)
Insomnia	5/45 (11.1%)		9/45 (20%)		6/32 (18.8%)
Depression	3/45 (6.7%)		3/45 (6.7%)		3/32 (9.4%)
Depressed mood	1/45 (2.2%)		1/45 (2.2%)		2/32 (6.3%)
Renal and urinary disorders
Dysuria	5/45 (11.1%)		1/45 (2.2%)		1/32 (3.1%)
Pollakiuria	0/45 (0%)		0/45 (0%)		2/32 (6.3%)
Respiratory, thoracic and mediastinal disorders
Cough	12/45 (26.7%)		8/45 (17.8%)		8/32 (25%)
Dyspnea	8/45 (17.8%)		6/45 (13.3%)		8/32 (25%)
Dysphonia	3/45 (6.7%)		5/45 (11.1%)		4/32 (12.5%)
Epistaxis	23/45 (51.1%)		17/45 (37.8%)		21/32 (65.6%)
Rhinorrhea	1/45 (2.2%)		3/45 (6.7%)		3/32 (9.4%)
Oropharyngeal pain	3/45 (6.7%)		1/45 (2.2%)		2/32 (6.3%)
Skin and subcutaneous tissue disorders
Rash	8/45 (17.8%)		4/45 (8.9%)		7/32 (21.9%)
Alopecia	17/45 (37.8%)		22/45 (48.9%)		17/32 (53.1%)
Dry skin	3/45 (6.7%)		4/45 (8.9%)		6/32 (18.8%)
Erythema	2/45 (4.4%)		6/45 (13.3%)		7/32 (21.9%)
Onychalgia	0/45 (0%)		3/45 (6.7%)		0/32 (0%)
Nail disorder	10/45 (22.2%)		8/45 (17.8%)		15/32 (46.9%)
Nail dystrophy	0/45 (0%)		1/45 (2.2%)		2/32 (6.3%)
Skin hyperpigmentation	0/45 (0%)		1/45 (2.2%)		2/32 (6.3%)
Palmar-plantar erythrodysaesthesia syndrome	3/45 (6.7%)		2/45 (4.4%)		2/32 (6.3%)
Vascular disorders
Flushing	1/45 (2.2%)		0/45 (0%)		2/32 (6.3%)
Hot flush	3/45 (6.7%)		2/45 (4.4%)		5/32 (15.6%)
Haemorrhage	0/45 (0%)		0/45 (0%)		2/32 (6.3%)
Hypotension	4/45 (8.9%)		1/45 (2.2%)		1/32 (3.1%)
Hypertension	14/45 (31.1%)		22/45 (48.9%)		10/32 (31.3%)

Limitations/Caveats

[Not Specified]

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Bristol-Myers Squibb Co. agreements with investigators vary; constant is our right to embargo communications regarding trial results prior to public release for a period of 60 days or less from submittal for review. We will not prohibit investigators from publishing, but will prohibit the disclosure of previously undisclosed confidential information other than study results, and request postponement of single-center publications until after disclosure of the clinical trial's primary publication.