Bevacizumab Plus Ixabepilone to Treat Patients With Advanced Kidney Cancer

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00923130
• Collaborator: (none)
• Enrollment: 30
• Locations: 2
• Arm: 1
• Actual Duration (Months): 88.8
• Patients Per Site: 15
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

Background:

• Substantial preclinical antitumor synergy supports the exploration of the combination of antiangiogenic compounds (including sunitinib and bevacizumab) plus ixabepilone. In Vivo, synergistic activity between ixabepilone and bevacizumab has been demonstrated using the 151-B human renal carcinoma xenograft model and this synergy compares favorably with other antiangiogenic inhibitors (i.e. sunitinib).

• Combination therapies of bevacizumab with chemotherapy demonstrated improved benefit compared with single-agent cytotoxics in multiple animal models and in humans.

• Clinical activity of both compounds used as single agents has been demonstrated in a broad spectrum of solid tumors. Bevacizumab and ixabepilone, when used as a single agent, have demonstrated substantial activity in renal cell carcinoma.

• Phase II studies with bevacizumab and ixabepilone suggest the absence of overlapping toxicities.

• Development of a well-tolerated and active bevacizumab/ixabepilone combination has the potential to further improve the treatment of metastatic renal cell carcinoma (mRCC), and could represent a second-line option after sunitinib or sorafenib are no longer of benefit or are intolerable.

Primary Objectives:

• Determine the objective response rate of the combination of ixabepilone and bevacizumab in patients with relapsed or refractory mRCC.

• Determine progression-free survival.

• Characterize the toxicity of the combination of ixabepilone and bevacizumab in patients with mRCC.

• Determine changes in biomarkers and evaluate correlation with clinical outcomes.

Eligibility:

• Pathologic confirmation of renal cell carcinoma (clear cell histology) by the Laboratory of Pathology, National Cancer Institute (NCI), or the Medical University of South Carolina.

• Presence of metastatic renal carcinoma, after progression or intolerance to Vascular endothelial growth factor receptor (VEGFR) inhibitors (sunitinib and/or sorafenib).

• Adequate organ and bone marrow function.

Design:

• Multi-center, open labeled phase II study

• Following a Simon two-stage optimal design, a maximum of 58 patients with metastatic RCC will be accrued.

• Ixabepilone will be administered daily as a one hour infusion on five successive days (daily x 5), every three weeks (one cycle equals 3 weeks or 21 days +/- 5 days). Following cycle 6, cycles will be spread out to 4 weeks or 28 days +/- 5 days. The starting dose will be a daily dose of 6 mg/m(2)/day, for a total per cycle dose of 30 mg/m(2).

• In addition, 15 mg/kg bevacizumab will be administered intravenously on day 1 of each cycle. The first infusion of bevacizumab will be 90 minutes in duration, the second 60 minutes in duration, and in all subsequent cycles bevacizumab will be infused over 30 minutes if prior infusions are well tolerated.

Condition or Disease	Intervention/Treatment	Phase
Renal Cell Carcinoma	Drug: Bevacizumab; Drug: Ixabepilone	Phase 2

Detailed Description

Background:

• Substantial preclinical antitumor synergy supports the exploration of the combination of antiangiogenic compounds (including sunitinib and bevacizumab) plus ixabepilone. In Vivo, synergistic activity between ixabepilone and bevacizumab has been demonstrated using the 151-B human renal carcinoma xenograft model and this synergy compares favorably with other antiangiogenic inhibitors (i.e. sunitinib).

• Combination therapies of bevacizumab with chemotherapy demonstrated improved benefit compared with single-agent cytotoxics in multiple animal models and in humans.

• Clinical activity of both compounds used as single agents has been demonstrated in a broad spectrum of solid tumors. Bevacizumab and ixabepilone, when used as a single agent, have demonstrated substantial activity in renal cell carcinoma.

• Phase II studies with bevacizumab and ixabepilone suggest the absence of overlapping toxicities.

• Development of a well-tolerated and active bevacizumab/ixabepilone combination has the potential to further improve the treatment of metastatic renal cell carcinoma (mRCC), and could represent a second-line option after sunitinib or sorafenib are no longer of benefit or are intolerable.

Primary Objectives:

• Determine the objective response rate of the combination of ixabepilone and bevacizumab in patients with relapsed or refractory mRCC.

• Determine progression-free survival.

• Characterize the toxicity of the combination of ixabepilone and bevacizumab in patients with mRCC.

• Determine changes in biomarkers and evaluate correlation with clinical outcomes.

Eligibility:

• Pathologic confirmation of renal cell carcinoma (clear cell histology) by the Laboratory of Pathology, National Cancer Institute (NCI), or the Medical University of South Carolina.

• Presence of metastatic renal carcinoma, after progression or intolerance to vascular endothelial growth factor receptor (VEGFR) inhibitors (sunitinib and/or sorafenib).

• Adequate organ and bone marrow function.

Design:

• Multi-center, open labeled phase II study

• Following a Simon two-stage optimal design, a maximum of 58 patients with metastatic RCC will be accrued.

• Ixabepilone will be administered daily as a one hour infusion on five successive days (daily x 5), every three weeks (one cycle equals 3 weeks or 21 days +/- 5 days). Following cycle 6, cycles will be spread out to 4 weeks or 28 days +/- 5 days. The starting dose will be a daily dose of 6 mg/m(2)/day, for a total per cycle dose of 30 mg/m(2).

• In addition, 15 mg/kg bevacizumab will be administered intravenously on day 1 of each cycle. The first infusion of bevacizumab will be 90 minutes in duration, the second 60 minutes in duration, and in all subsequent cycles bevacizumab will be infused over 30 minutes if prior infusions are well tolerated.

Study Design

• Study Type: Interventional
• Actual Enrollment: 30 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Multi-Center Study of Bevacizumab in Combination With Ixabepilone in Subjects With Advanced Renal Cell Carcinoma
• Actual Study Start Date: Jan 7, 2009
• Actual Primary Completion Date: Mar 1, 2016
• Actual Study Completion Date: Jun 1, 2016

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Bevacizumab with Ixabepilone Bevacizumab 15mg/kg every 3 weeks Ixabepilone given on days 1,2,3,4 and 5 of each three week cycle at a dose of 6mg/m(2)/day

Drug: Bevacizumab; Bevacizumab will be administered intravenously every 3 weeks on an outpatient basis with the exception of admissions for the purpose of facilitating research studies. The dose of bevacizumab to be given is 15 mg/kg.; Other Names: Avastin ; Drug: Ixabepilone; Ixabepilone will be given on days 1, 2, 3, 4, and 5 of each three week cycle as a one hour intravenous infusion. The dose will be 6 mg/m(2)/day on five successive days.; Other Names: Ixempra

Outcome Measures

Primary Outcome Measures

1. Progression-free Survival [up to 44 months]

   The time between the first day of treatment to the day of disease progression. Progression is defined by the Response Evaluation Criteria in Solid Tumors (RECIST). Progression is at least a 20% increase in the sum of the longest diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions.

Secondary Outcome Measures

1. Number of Participants With an Objective Response (Complete Response (CR) or Partial Response (PR)) Per the Response Evaluation Criteria in Solid Tumors (RECIST) [Two Years]

   Response (complete response (CR) and partial response (PR)) was measured by the RECIST. Complete response is the disappearance of all target lesions. Partial response is at least a 30% decrease in the sum of the longest diameter (LD) of target lesions taking as reference the baseline sum LD.

2. Number of Participants With Adverse Events [Date treatment consent signed to date off study, approximately 84 months and 25 days]

   Here is the number of participants with adverse events. For the detailed list of adverse events, see the adverse event module. Adverse events are assessed by the Common Terminology Criteria for Adverse Events (CTCAE) v4.0.

3. Number of Participants Who Had Biopsies [Baseline and Cycle 2 Day 1]

   To obtain tumor tissue and perform analysis for molecular changes in the tumor before and after a cycle of chemotherapy.

4. Overall Survival [Time between the first day of treatment and the day of death, assessed up to approximately 7 years.]

   Time between the first day of treatment and the day of death.

Other Outcome Measures

1. Protein Profiling of Vascular Endothelial Growth Factor A (VEGF-A), Vascular Endothelial Growth Factor Receptor 2 (VEGFR-2), Vascular Endothelial Growth Factor Receptor 3 (VEGFR-3), Beta Fibroblast Growth Factor (βFGF) and Erythropoietin From Baseline [Cycle 1 Day 5 (C1D5), Cycle 2 Day 1 (C2D1), Cycle 4 and Cycle 6]

   This assessment was intended as an exploratory analysis.

2. Circulating Endothelial Cells (CECs) [Baseline, Day 5, and Cycle 2 Day 1]

   This assessment was intended as an exploratory analysis.

3. Micro Vessel Density [Prior to cycle 2]

   This assessment was intended as an exploratory analysis

4. Tumor Endothelial Markers (TEMs) [Cycle 1 Day 5, Cycle 2 Day 1, Cycle 4 Day 1, and Cycle 6 Day 1]

   This assessment was intended as an exploratory analysis.

5. Growth Rate Constant (g) [up to 50 days]

   This assessment was intended as an exploratory analysis.

6. Percentage of Participants With an Increase or Decrease in Forward Contrast Transfer Rate (Ktrans) Using MRI Versus Conventional Imaging [Cycle 1 before day 1 of treatment and day 5 following infusion]

   This assessment was intended as an exploratory analysis.

7. Percentage of Participants With an Increase or Decrease in Reverse Contrast Transfer Rate (Kep) Using MRI Versus Conventional Imaging [Cycle 1 before day 1 of treatment and day 5 following infusion]

   This assessment was intended as an exploratory analysis.

8. Regression Rate Constant (d) [up to 50 days]

   This assessment was intended as an exploratory analysis.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 99 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

• INCLUSION CRITERIA:

Subjects meeting all of the following criteria will be considered for enrollment into the study:

1. Pathologic confirmation of metastatic or unsectable renal cell carcinoma with predominant clear cell histology (greater than 70%) by the Laboratory of Pathology, National Cancer Institute (NCI) or the Medical University of South Carolina..

2. Progression on or after stopping treatment with an agent approved by the Food and Drug Administration (FDA) for the treatment of renal cell carcinoma (RCC). Patients must have received at least one FDA approved agent (axitinib, sunitinib, sorafenib, pazopanib, temsirolimus, interleukin-2 (IL-2), interferon or everolimus). Patients must be off prior IL-2 or interferon for 4 weeks prior to entry. They must be off sunitinib, sorafenib, pazopanib, axitinib, temsirolimus or everolimus or other tyrosine kinase inhibitor (TKIs) for 2 weeks prior to entry.

3. Eighteen years of age or older.

4. Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2.

5. Resolution of any toxic effects of prior therapy (except alopecia) to NCI Common Terminology Criteria in Solid Tumors (CTCAE) v.3.0 through 12/31/10 and version 4.0 beginning 1/1/11 grade less than or equal to 1 and to baseline laboratory values as defined in inclusion criterion # 6.

6. Adequate organ and bone marrow function as evidenced by:

• hemoglobin greater than or equal to 9.0 g/dL

• absolute neutrophil count greater than or equal to 1.5 x 10(9)/L

• platelet count greater than or equal to 100 x 10(9)/L

• creatinine less than or equal to 1.5 times the ULN, OR measured creatinine clearance greater than or equal to 40 ml/min

• urine proteinuria less than 20mg/dL on random protein creatinine ratio urine samples or a 24-hour urine protein less than 500 mg. NOTE: If on a random protein creatinine ratio the urine protein is greater that or equal to 20mg/dL, then obtain a 24 hour urine collection to accurately demonstrate that the 24 hour total is less than 500 mg/24 hours.

• aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT) and alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT) less than or equal to 2.5 times the upper limit of normal (ULN) (or less than or equal to 5 times the ULN if liver function abnormalities due to underlying malignancy)

• total bilirubin less than or equal to 1.5 times the ULN

1. Subjects must be postmenopausal, surgically sterile, or using effective contraception. All female subjects of childbearing potential must have a negative pregnancy test (serum or urine) within 7 days prior to enrollment. Effective contraception includes hormonal or barrier methods.

2. No other invasive malignancies within the past two years (with the exception of nonmelanoma skin cancers, non-invasive bladder cancer, stage I endometrial cancer or cervical cancer).

3. Subjects must agree to sign and date an Institutional Review Board (IRB)-approved subject informed consent form.

4. Subjects must be willing and able to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures.

5. Patients must have measurable disease either by conventional imaging or clinical examination.

EXCLUSION CRITERIA:

Subjects presenting with any of the following will not be included in the study:

1. Invasive procedures defined as follows:

• Major surgical procedure, open biopsy or significant traumatic injury within 6 weeks prior to Day 1 therapy

• Anticipation of need for major surgical procedures during the course of the study

• Minor surgery, such as port-a-cath placement, and dental procedures, within 2 weeks.

• (There will be no delay for percutaneous core biopsies or peripherally inserted central catheter (PICC)/internal jugular (IJ) line placement)

1. Cumulative radiation therapy to greater than 25% of the total bone marrow.

2. History of uncontrolled or labile hypertension, defined as blood pressure greater than 160/90 mm Hg (NCI CTCAE v.3.0 through 12/31/10 and version 4.0 beginning 1/1/11 grade greater than or equal to 2), on at least 2 repeated determinations on separate days within 15 days prior to study enrollment.

3. Any of the following within 6 months prior to study enrollment: myocardial infarction, severe/unstable angina pectoris, coronary/peripheral artery bypass graft, New York Heart Association (NYHA) class III or IV congestive heart failure; cerebrovascular accident or transient ischemic attack, grade greater than or equal to 2 peripheral neuropathy, peptic ulcer disease, erosive esophagitis or gastritis, infectious or inflammatory bowel disease, diverticulitis, or other thromboembolic event.

4. Symptomatic spinal cord compression.

5. Evidence of clinically significant bleeding diathesis or underlying coagulopathy.

6. Antiretroviral therapy for human immunodeficiency virus (HIV) disease.

7. Pregnant (positive pregnancy test) or nursing women. Both fertile men and women must agree to use adequate contraceptive measures during study therapy and for at least 6 months after the completion of bevacizumab therapy.

8. Other severe acute or chronic medical or psychiatric condition, or significant laboratory abnormality requiring further investigation that may cause undue risk for the subjects safety, 18 inhibit protocol participation, or interfere with interpretation of study results, and in the judgment of the investigator would make the subject inappropriate for entry into this study.

9. Prior therapy with bevacizumab

10. Prior therapy with ixabepilone.

11. Patients on anticoagulant therapy will be evaluated on a case by case basis for inclusion.

12. Serious or non-healing wound, ulcer or bone fracture

13. History of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess within 6 months prior to day 1

14. Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to Day 1

15. Known central nervous system (CNS) disease except for treated brain metastasis.

-Treated brain metastases are defined as having no ongoing requirement for steroids and no evidence of progression or hemorrhage after treatment for at least 3 months, as ascertained by clinical examination and brain imaging (magnetic resonance imaging (MRI) or computed tomography (CT)). (Stable dose of anticonvulsants are allowed). Treatment for brain metastases may include whole brain radiotherapy (WBRT), radiosurgery (RS; Gamma Knife, linear particle accelerator (LINAC), or equivalent) or a combination as deemed appropriate by the treating physician. Patients with CNS metastases treated by neurosurgical resection or brain biopsy performed within 3 months prior to Day 1 will be excluded.

1. Patients with known hypersensitivity of Chinese hamster ovary cell products or other recombinant human antibodies

2. Patients receiving cytochrome P450 3A4 (CYP3A4) inhibitors in section 3.6 that cannot be discontinued.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	National Institutes of Health Clinical Center, 9000 Rockville Pike	Bethesda	Maryland	United States	20892
2	University of South Carolina	Charleston	South Carolina	United States	29425

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Ravi A Madan, M.D., National Cancer Institute (NCI)

Study Documents (Full-Text)

• Study Protocol - Aug 13, 2015

More Information

Additional Information:

• NIH Clinical Center Detailed Web Page

Publications

• Ferrara N, Chen H, Davis-Smyth T, Gerber HP, Nguyen TN, Peers D, Chisholm V, Hillan KJ, Schwall RH. Vascular endothelial growth factor is essential for corpus luteum angiogenesis. Nat Med. 1998 Mar;4(3):336-40.
• Hellman S, Rosenthal DS, Moloney WC, Chaffey JT. The treatment of non-Hodgkin's lymphoma. Cancer. 1975 Aug;36(2):804-8.
• Ryan AM, Eppler DB, Hagler KE, Bruner RH, Thomford PJ, Hall RL, Shopp GM, O'Neill CA. Preclinical safety evaluation of rhuMAbVEGF, an antiangiogenic humanized monoclonal antibody. Toxicol Pathol. 1999 Jan-Feb;27(1):78-86. Review.

• Responsible Party: Ravi A. Madan, M.D., Principal Investigator, National Institutes of Health Clinical Center (CC)
• ClinicalTrials.gov Identifier: NCT00923130
• Other Study ID Numbers: 090057; 09-C-0057; NCT00820209
• First Posted: Jun 18, 2009
• Last Update Posted: Apr 17, 2018
• Last Verified: Mar 1, 2018

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Ravi A. Madan, M.D., Principal Investigator, National Institutes of Health Clinical Center (CC): Renal Cell Carcinoma; Bevacizumab; Ixabepilone; Phase II
• Additional relevant MeSH terms: Carcinoma; Carcinoma, Renal Cell; Bevacizumab

Study Results

Participant Flow

Arm/Group Title	Bevacizumab With Ixabepilone
Arm/Group Description	Bevacizumab 15mg/kg every 3 weeks Ixabepilone given on days 1,2,3,4 and 5 of each three week cycle at a dose of 6mg/m(2)/day Bevacizumab: Bevacizumab will be administered intravenously every 3 weeks on an outpatient basis with the exception of admissions for the purpose of facilitating research studies. The dose of bevacizumab to be given is 15 mg/kg. Ixabepilone: Ixabepilone will be given on days 1, 2, 3, 4, and 5 of each three week cycle as a one hour intravenous infusion. The dose will be 6 mg/m(2)/day on five successive days.
Period Title: Overall Study
STARTED	30
COMPLETED	5
NOT COMPLETED	25

Baseline Characteristics

Arm/Group Title	Bevacizumab With Ixabepilone
Arm/Group Description	Bevacizumab 15mg/kg every 3 weeks Ixabepilone given on days 1,2,3,4 and 5 of each three week cycle at a dose of 6mg/m(2)/day Bevacizumab: Bevacizumab will be administered intravenously every 3 weeks on an outpatient basis with the exception of admissions for the purpose of facilitating research studies. The dose of bevacizumab to be given is 15 mg/kg. Ixabepilone: Ixabepilone will be given on days 1, 2, 3, 4, and 5 of each three week cycle as a one hour intravenous infusion. The dose will be 6 mg/m(2)/day on five successive days.
Overall Participants	30
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	19 63.3%
>=65 years	11 36.7%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	61.17 (9.08)
Sex: Female, Male (Count of Participants)
Female	7 23.3%
Male	23 76.7%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	27 90%
Not Hispanic or Latino	2 6.7%
Unknown or Not Reported	1 3.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	1 3.3%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	3 10%
White	26 86.7%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (Count of Participants)
United States	30 100%
Prior Therapies (therapies) [Median (Full Range) ]
Median (Full Range) [therapies]	2

Outcome Measures

1. Primary Outcome

Title	Progression-free Survival
Description	The time between the first day of treatment to the day of disease progression. Progression is defined by the Response Evaluation Criteria in Solid Tumors (RECIST). Progression is at least a 20% increase in the sum of the longest diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions.
Time Frame	up to 44 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Bevacizumab With Ixabepilone
Arm/Group Description	Bevacizumab 15mg/kg every 3 weeks Ixabepilone given on days 1,2,3,4 and 5 of each three week cycle at a dose of 6mg/m(2)/day Bevacizumab: Bevacizumab will be administered intravenously every 3 weeks on an outpatient basis with the exception of admissions for the purpose of facilitating research studies. The dose of bevacizumab to be given is 15 mg/kg. Ixabepilone: Ixabepilone will be given on days 1, 2, 3, 4, and 5 of each three week cycle as a one hour intravenous infusion. The dose will be 6 mg/m(2)/day on five successive days.
Measure Participants	30
Median (95% Confidence Interval) [months]	8.3

2. Secondary Outcome

Title	Number of Participants With an Objective Response (Complete Response (CR) or Partial Response (PR)) Per the Response Evaluation Criteria in Solid Tumors (RECIST)
Description	Response (complete response (CR) and partial response (PR)) was measured by the RECIST. Complete response is the disappearance of all target lesions. Partial response is at least a 30% decrease in the sum of the longest diameter (LD) of target lesions taking as reference the baseline sum LD.
Time Frame	Two Years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Bevacizumab With Ixabepilone
Arm/Group Description	Bevacizumab 15mg/kg every 3 weeks Ixabepilone given on days 1,2,3,4 and 5 of each three week cycle at a dose of 6mg/m(2)/day Bevacizumab: Bevacizumab will be administered intravenously every 3 weeks on an outpatient basis with the exception of admissions for the purpose of facilitating research studies. The dose of bevacizumab to be given is 15 mg/kg. Ixabepilone: Ixabepilone will be given on days 1, 2, 3, 4, and 5 of each three week cycle as a one hour intravenous infusion. The dose will be 6 mg/m(2)/day on five successive days.
Measure Participants	30
Complete Response	0 0%
Partial Response	3 10%

3. Secondary Outcome

Title	Number of Participants With Adverse Events
Description	Here is the number of participants with adverse events. For the detailed list of adverse events, see the adverse event module. Adverse events are assessed by the Common Terminology Criteria for Adverse Events (CTCAE) v4.0.
Time Frame	Date treatment consent signed to date off study, approximately 84 months and 25 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Bevacizumab With Ixabepilone
Arm/Group Description	Bevacizumab 15mg/kg every 3 weeks Ixabepilone given on days 1,2,3,4 and 5 of each three week cycle at a dose of 6mg/m(2)/day Bevacizumab: Bevacizumab will be administered intravenously every 3 weeks on an outpatient basis with the exception of admissions for the purpose of facilitating research studies. The dose of bevacizumab to be given is 15 mg/kg. Ixabepilone: Ixabepilone will be given on days 1, 2, 3, 4, and 5 of each three week cycle as a one hour intravenous infusion. The dose will be 6 mg/m(2)/day on five successive days.
Measure Participants	30
Count of Participants [Participants]	30 100%

4. Secondary Outcome

Title	Number of Participants Who Had Biopsies
Description	To obtain tumor tissue and perform analysis for molecular changes in the tumor before and after a cycle of chemotherapy.
Time Frame	Baseline and Cycle 2 Day 1

Outcome Measure Data

Analysis Population Description

This outcome measure was not done because biopsy samples were not obtained.

Arm/Group Title	Bevacizumab With Ixabepilone
Arm/Group Description	Bevacizumab 15mg/kg every 3 weeks Ixabepilone given on days 1,2,3,4 and 5 of each three week cycle at a dose of 6mg/m(2)/day Bevacizumab: Bevacizumab will be administered intravenously every 3 weeks on an outpatient basis with the exception of admissions for the purpose of facilitating research studies. The dose of bevacizumab to be given is 15 mg/kg. Ixabepilone: Ixabepilone will be given on days 1, 2, 3, 4, and 5 of each three week cycle as a one hour intravenous infusion. The dose will be 6 mg/m(2)/day on five successive days.
Measure Participants	0

5. Secondary Outcome

Title	Overall Survival
Description	Time between the first day of treatment and the day of death.
Time Frame	Time between the first day of treatment and the day of death, assessed up to approximately 7 years.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Bevacizumab With Ixabepilone
Arm/Group Description	Bevacizumab 15mg/kg every 3 weeks Ixabepilone given on days 1,2,3,4 and 5 of each three week cycle at a dose of 6mg/m(2)/day Bevacizumab: Bevacizumab will be administered intravenously every 3 weeks on an outpatient basis with the exception of admissions for the purpose of facilitating research studies. The dose of bevacizumab to be given is 15 mg/kg. Ixabepilone: Ixabepilone will be given on days 1, 2, 3, 4, and 5 of each three week cycle as a one hour intravenous infusion. The dose will be 6 mg/m(2)/day on five successive days.
Measure Participants	30
Median (95% Confidence Interval) [months]	15.0

6. Other Pre-specified Outcome

Title	Protein Profiling of Vascular Endothelial Growth Factor A (VEGF-A), Vascular Endothelial Growth Factor Receptor 2 (VEGFR-2), Vascular Endothelial Growth Factor Receptor 3 (VEGFR-3), Beta Fibroblast Growth Factor (βFGF) and Erythropoietin From Baseline
Description	This assessment was intended as an exploratory analysis.
Time Frame	Cycle 1 Day 5 (C1D5), Cycle 2 Day 1 (C2D1), Cycle 4 and Cycle 6

Outcome Measure Data

Analysis Population Description

This outcome measure was not done. Data was not collected because the clinical data did not support further analysis and interest.

Arm/Group Title	Bevacizumab With Ixabepilone
Arm/Group Description	Bevacizumab 15mg/kg every 3 weeks Ixabepilone given on days 1,2,3,4 and 5 of each three week cycle at a dose of 6mg/m(2)/day Bevacizumab: Bevacizumab will be administered intravenously every 3 weeks on an outpatient basis with the exception of admissions for the purpose of facilitating research studies. The dose of bevacizumab to be given is 15 mg/kg. Ixabepilone: Ixabepilone will be given on days 1, 2, 3, 4, and 5 of each three week cycle as a one hour intravenous infusion. The dose will be 6 mg/m(2)/day on five successive days.
Measure Participants	0

7. Other Pre-specified Outcome

Title	Circulating Endothelial Cells (CECs)
Description	This assessment was intended as an exploratory analysis.
Time Frame	Baseline, Day 5, and Cycle 2 Day 1

Outcome Measure Data

Analysis Population Description

This outcome measure was not done. Data was not collected because the clinical data did not support further analysis and interest.

Arm/Group Title	Bevacizumab With Ixabepilone
Arm/Group Description	Bevacizumab 15mg/kg every 3 weeks Ixabepilone given on days 1,2,3,4 and 5 of each three week cycle at a dose of 6mg/m(2)/day Bevacizumab: Bevacizumab will be administered intravenously every 3 weeks on an outpatient basis with the exception of admissions for the purpose of facilitating research studies. The dose of bevacizumab to be given is 15 mg/kg. Ixabepilone: Ixabepilone will be given on days 1, 2, 3, 4, and 5 of each three week cycle as a one hour intravenous infusion. The dose will be 6 mg/m(2)/day on five successive days.
Measure Participants	0

8. Other Pre-specified Outcome

Title	Micro Vessel Density
Description	This assessment was intended as an exploratory analysis
Time Frame	Prior to cycle 2

Outcome Measure Data

Analysis Population Description

This outcome measure was not done. Data was not collected because the clinical data did not support further analysis and interest.

Arm/Group Title	Bevacizumab With Ixabepilone
Arm/Group Description	Bevacizumab 15mg/kg every 3 weeks Ixabepilone given on days 1,2,3,4 and 5 of each three week cycle at a dose of 6mg/m(2)/day Bevacizumab: Bevacizumab will be administered intravenously every 3 weeks on an outpatient basis with the exception of admissions for the purpose of facilitating research studies. The dose of bevacizumab to be given is 15 mg/kg. Ixabepilone: Ixabepilone will be given on days 1, 2, 3, 4, and 5 of each three week cycle as a one hour intravenous infusion. The dose will be 6 mg/m(2)/day on five successive days.
Measure Participants	0

9. Other Pre-specified Outcome

Title	Tumor Endothelial Markers (TEMs)
Description	This assessment was intended as an exploratory analysis.
Time Frame	Cycle 1 Day 5, Cycle 2 Day 1, Cycle 4 Day 1, and Cycle 6 Day 1

Outcome Measure Data

Analysis Population Description

This outcome measure was not done. Data was not collected because the clinical data did not support further analysis and interest.

Arm/Group Title	Bevacizumab With Ixabepilone
Arm/Group Description	Bevacizumab 15mg/kg every 3 weeks Ixabepilone given on days 1,2,3,4 and 5 of each three week cycle at a dose of 6mg/m(2)/day Bevacizumab: Bevacizumab will be administered intravenously every 3 weeks on an outpatient basis with the exception of admissions for the purpose of facilitating research studies. The dose of bevacizumab to be given is 15 mg/kg. Ixabepilone: Ixabepilone will be given on days 1, 2, 3, 4, and 5 of each three week cycle as a one hour intravenous infusion. The dose will be 6 mg/m(2)/day on five successive days.
Measure Participants	0

10. Other Pre-specified Outcome

Title	Growth Rate Constant (g)
Description	This assessment was intended as an exploratory analysis.
Time Frame	up to 50 days

Outcome Measure Data

Analysis Population Description

This outcome measure was not done. Data was not collected because the clinical data did not support further analysis and interest.

Arm/Group Title	Bevacizumab With Ixabepilone
Arm/Group Description	Bevacizumab 15mg/kg every 3 weeks Ixabepilone given on days 1,2,3,4 and 5 of each three week cycle at a dose of 6mg/m(2)/day Bevacizumab: Bevacizumab will be administered intravenously every 3 weeks on an outpatient basis with the exception of admissions for the purpose of facilitating research studies. The dose of bevacizumab to be given is 15 mg/kg. Ixabepilone: Ixabepilone will be given on days 1, 2, 3, 4, and 5 of each three week cycle as a one hour intravenous infusion. The dose will be 6 mg/m(2)/day on five successive days.
Measure Participants	0

11. Other Pre-specified Outcome

Title	Percentage of Participants With an Increase or Decrease in Forward Contrast Transfer Rate (Ktrans) Using MRI Versus Conventional Imaging
Description	This assessment was intended as an exploratory analysis.
Time Frame	Cycle 1 before day 1 of treatment and day 5 following infusion

Outcome Measure Data

Analysis Population Description

This outcome measure was not done. Data was not collected because the clinical data did not support further analysis and interest.

Arm/Group Title	Bevacizumab With Ixabepilone
Arm/Group Description	Bevacizumab 15mg/kg every 3 weeks Ixabepilone given on days 1,2,3,4 and 5 of each three week cycle at a dose of 6mg/m(2)/day Bevacizumab: Bevacizumab will be administered intravenously every 3 weeks on an outpatient basis with the exception of admissions for the purpose of facilitating research studies. The dose of bevacizumab to be given is 15 mg/kg. Ixabepilone: Ixabepilone will be given on days 1, 2, 3, 4, and 5 of each three week cycle as a one hour intravenous infusion. The dose will be 6 mg/m(2)/day on five successive days.
Measure Participants	0

12. Other Pre-specified Outcome

Title	Percentage of Participants With an Increase or Decrease in Reverse Contrast Transfer Rate (Kep) Using MRI Versus Conventional Imaging
Description	This assessment was intended as an exploratory analysis.
Time Frame	Cycle 1 before day 1 of treatment and day 5 following infusion

Outcome Measure Data

Analysis Population Description

This outcome measure was not done. Data was not collected because the clinical data did not support further analysis and interest.

Arm/Group Title	Bevacizumab With Ixabepilone
Arm/Group Description	Bevacizumab 15mg/kg every 3 weeks Ixabepilone given on days 1,2,3,4 and 5 of each three week cycle at a dose of 6mg/m(2)/day Bevacizumab: Bevacizumab will be administered intravenously every 3 weeks on an outpatient basis with the exception of admissions for the purpose of facilitating research studies. The dose of bevacizumab to be given is 15 mg/kg. Ixabepilone: Ixabepilone will be given on days 1, 2, 3, 4, and 5 of each three week cycle as a one hour intravenous infusion. The dose will be 6 mg/m(2)/day on five successive days.
Measure Participants	0

13. Other Pre-specified Outcome

Title	Regression Rate Constant (d)
Description	This assessment was intended as an exploratory analysis.
Time Frame	up to 50 days

Outcome Measure Data

Analysis Population Description

This outcome measure was not done. Data was not collected because the clinical data did not support further analysis and interest.

Arm/Group Title	Bevacizumab With Ixabepilone
Arm/Group Description	Bevacizumab 15mg/kg every 3 weeks Ixabepilone given on days 1,2,3,4 and 5 of each three week cycle at a dose of 6mg/m(2)/day Bevacizumab: Bevacizumab will be administered intravenously every 3 weeks on an outpatient basis with the exception of admissions for the purpose of facilitating research studies. The dose of bevacizumab to be given is 15 mg/kg. Ixabepilone: Ixabepilone will be given on days 1, 2, 3, 4, and 5 of each three week cycle as a one hour intravenous infusion. The dose will be 6 mg/m(2)/day on five successive days.
Measure Participants	0

Adverse Events

Time Frame	8Date treatment consent signed to date off study, approximately 4 months and 25 days
Arm/Group Title	Bevacizumab With Ixabepilone
Arm/Group Description	Bevacizumab 15mg/kg every 3 weeks Ixabepilone given on days 1,2,3,4 and 5 of each three week cycle at a dose of 6mg/m(2)/day Bevacizumab: Bevacizumab will be administered intravenously every 3 weeks on an outpatient basis with the exception of admissions for the purpose of facilitating research studies. The dose of bevacizumab to be given is 15 mg/kg. Ixabepilone: Ixabepilone will be given on days 1, 2, 3, 4, and 5 of each three week cycle as a one hour intravenous infusion. The dose will be 6 mg/m(2)/day on five successive days.
All Cause Mortality
	Bevacizumab With Ixabepilone
	Affected / at Risk (%)	# Events
Total	0/30 (0%)
Serious Adverse Events
	Bevacizumab With Ixabepilone
	Affected / at Risk (%)	# Events
Total	9/30 (30%)
Blood and lymphatic system disorders
Anemia	1/30 (3.3%)	1
Cardiac disorders
Cardiac arrest	1/30 (3.3%)	1
Gastrointestinal disorders
Esophageal hemorrhage	1/30 (3.3%)	1
Proteinuria	1/30 (3.3%)	1
Infections and infestations
Enterocolitis infectious	1/30 (3.3%)	1
Kidney infection	1/30 (3.3%)	1
Lung infection	1/30 (3.3%)	2
Presyncope	1/30 (3.3%)	1
Nervous system disorders
Urinary tract obstruction	1/30 (3.3%)	1
Renal and urinary disorders
Diarrhea	1/30 (3.3%)	1
Stroke	1/30 (3.3%)	1
Respiratory, thoracic and mediastinal disorders
Cough	1/30 (3.3%)	1
Other (Not Including Serious) Adverse Events
	Bevacizumab With Ixabepilone
	Affected / at Risk (%)	# Events
Total	30/30 (100%)
Blood and lymphatic system disorders
Anemia	20/30 (66.7%)	180
Blood and lymphatic system disorders - Other, bleeding gums and DVT	1/30 (3.3%)	2
Cardiac disorders
Chest pain - cardiac	1/30 (3.3%)	1
Conduction disorder	1/30 (3.3%)	1
Electrocardiogram QT corrected interval prolonged	1/30 (3.3%)	1
Sinus bradycardia	2/30 (6.7%)	16
Sinus tachycardia	3/30 (10%)	8
Ventricular arrhythmia	1/30 (3.3%)	1
Ear and labyrinth disorders
Ear pain	1/30 (3.3%)	1
External ear pain	1/30 (3.3%)	1
Hearing impaired	1/30 (3.3%)	1
Endocrine disorders
Hypothyroidism	1/30 (3.3%)	1
Eye disorders
Blurred vision	3/30 (10%)	3
Dry eye	1/30 (3.3%)	1
Watering eyes	1/30 (3.3%)	1
Gastrointestinal disorders
Abdominal distension	1/30 (3.3%)	1
Abdominal pain	5/30 (16.7%)	7
Anal hemorrhage	1/30 (3.3%)	3
Cheilitis	1/30 (3.3%)	1
Constipation	11/30 (36.7%)	13
Dental caries	1/30 (3.3%)	1
Diarrhea	16/30 (53.3%)	35
Enterocolitis	1/30 (3.3%)	1
Flatulence	1/30 (3.3%)	1
Gastrointestinal disorders - Other, excessive saliva	1/30 (3.3%)	1
Ileus	1/30 (3.3%)	1
Intra-abdominal hemorrhage	1/30 (3.3%)	1
Lower gastrointestinal hemorrhage	1/30 (3.3%)	1
Mucositis oral	5/30 (16.7%)	12
Nausea	15/30 (50%)	42
Rectal hemorrhage	1/30 (3.3%)	1
Vomiting	7/30 (23.3%)	14
General disorders
Chills	2/30 (6.7%)	2
Edema face	1/30 (3.3%)	1
Edema limbs	9/30 (30%)	15
Fatigue	2/30 (6.7%)	68
Fever	5/30 (16.7%)	5
Flu like symptoms	1/30 (3.3%)	1
Gait disturbance	1/30 (3.3%)	1
Malaise	1/30 (3.3%)	1
Pain	3/30 (10%)	4
Immune system disorders
Allergic reaction	2/30 (6.7%)	2
Infections and infestations
Bronchial infection	2/30 (6.7%)	2
Catheter related infection	1/30 (3.3%)	1
Enterocolitis infectious	2/30 (6.7%)	2
Esophageal infection	1/30 (3.3%)	1
Infections and infestations - Other, lung	1/30 (3.3%)	1
Laryngitis	1/30 (3.3%)	1
Lung infection	4/30 (13.3%)	5
Mucosal infection	1/30 (3.3%)	1
Nail infection	2/30 (6.7%)	2
Rhinitis infective	2/30 (6.7%)	3
Sinusitis	2/30 (6.7%)	3
Skin infection	2/30 (6.7%)	2
Upper respiratory infection	6/30 (20%)	8
Urinary tract infection	3/30 (10%)	3
Vaginal infection	1/30 (3.3%)	1
Injury, poisoning and procedural complications
Bruising	1/30 (3.3%)	2
Fracture	1/30 (3.3%)	1
Investigations
Activated partial thromboplastin time prolonged	16/30 (53.3%)	37
Alanine aminotransferase increased	6/30 (20%)	13
Alkaline phosphatase increased	8/30 (26.7%)	20
Aspartate aminotransferase increased	9/30 (30%)	31
Blood bilirubin increased	2/30 (6.7%)	2
CPK increased	4/30 (13.3%)	5
Creatinine increased	18/30 (60%)	140
Investigations - Other, bicarbonate low	1/30 (3.3%)	1
Lipase increased	1/30 (3.3%)	1
Lymphocyte count decreased	17/30 (56.7%)	206
Lymphocyte count increased	2/30 (6.7%)	6
Neutrophil count decreased	13/30 (43.3%)	26
Platelet count decreased	8/30 (26.7%)	40
Serum amylase increased	2/30 (6.7%)	2
Weight loss	4/30 (13.3%)	4
White blood cell decreased	15/30 (50%)	90
Metabolism and nutrition disorders
Anorexia	13/30 (43.3%)	26
Dehydration	2/30 (6.7%)	2
Hypercalcemia	9/30 (30%)	26
Hyperglycemia	3/30 (10%)	5
Hyperkalemia	14/30 (46.7%)	52
Hypermagnesemia	4/30 (13.3%)	7
Hypernatremia	4/30 (13.3%)	9
Hyperuricemia	4/30 (13.3%)	7
Hypoalbuminemia	20/30 (66.7%)	191
Hypocalcemia	4/30 (13.3%)	18
Hypoglycemia	2/30 (6.7%)	4
Hypokalemia	4/30 (13.3%)	5
Hypomagnesemia	11/30 (36.7%)	32
Hyponatremia	15/30 (50%)	48
Hypophosphatemia	13/30 (43.3%)	26
Musculoskeletal and connective tissue disorders
Arthralgia	8/30 (26.7%)	14
Arthritis	1/30 (3.3%)	3
Back pain	4/30 (13.3%)	7
Bone pain	1/30 (3.3%)	1
Generalized muscle weakness	1/30 (3.3%)	1
Muscle weakness lower limb	2/30 (6.7%)	2
Myalgia	5/30 (16.7%)	8
Pain in extremity	8/30 (26.7%)	8
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, basal cell	1/30 (3.3%)	1
Tumor pain	1/30 (3.3%)	1
Nervous system disorders
Cognitive disturbance	1/30 (3.3%)	1
Dizziness	5/30 (16.7%)	5
Dysesthesia	1/30 (3.3%)	1
Dysgeusia	7/30 (23.3%)	7
Headache	4/30 (13.3%)	4
Movements involuntary	1/30 (3.3%)	1
Nervous system disorders - Other, cold intolerance	1/30 (3.3%)	1
Olfactory nerve disorder	2/30 (6.7%)	2
Peripheral sensory neuropathy	18/30 (60%)	33
Presyncope	1/30 (3.3%)	1
Somnolence	2/30 (6.7%)	3
Syncope	3/30 (10%)	4
Psychiatric disorders
Agitation	1/30 (3.3%)	1
Anxiety	3/30 (10%)	3
Depression	2/30 (6.7%)	2
Insomnia	4/30 (13.3%)	5
Renal and urinary disorders
Acute kidney injury	1/30 (3.3%)	1
Hematuria	2/30 (6.7%)	2
Proteinuria	5/30 (16.7%)	17
Urinary retention	2/30 (6.7%)	2
Urinary tract pain	1/30 (3.3%)	1
Respiratory, thoracic and mediastinal disorders
Bronchopulmonary hemorrhage	2/30 (6.7%)	5
Cough	10/30 (33.3%)	22
Dyspnea	4/30 (13.3%)	5
Epistaxis	8/30 (26.7%)	12
Hoarseness	1/30 (3.3%)	2
Hypoxia	1/30 (3.3%)	1
Laryngeal inflammation	1/30 (3.3%)	1
Nasal congestion	2/30 (6.7%)	2
Pleural effusion	2/30 (6.7%)	2
Pneumonitis	1/30 (3.3%)	1
Postnasal drip	5/30 (16.7%)	5
Sinus disorder	1/30 (3.3%)	1
Voice alteration	1/30 (3.3%)	1
Wheezing	2/30 (6.7%)	2
Skin and subcutaneous tissue disorders
Allergic rhinitis	8/30 (26.7%)	13
Alopecia	12/30 (40%)	13
Dry skin	4/30 (13.3%)	5
Hyperhidrosis	1/30 (3.3%)	1
Nail discoloration	1/30 (3.3%)	1
Nail loss	12/30 (40%)	17
Pain of skin	1/30 (3.3%)	1
Pruritus	1/30 (3.3%)	2
Purpura	1/30 (3.3%)	1
Rash acneiform	3/30 (10%)	4
Rash maculo-papular	2/30 (6.7%)	4
Skin and subcutaneous tissue disorders - Other, specify	3/30 (10%)	4
Skin hyperpigmentation	2/30 (6.7%)	2
Skin ulceration	1/30 (3.3%)	2
Surgical and medical procedures
Surgical and medical procedures - Other, knee replacement	1/30 (3.3%)	1
Vascular disorders
Hot flashes	1/30 (3.3%)	2
Hypertension	16/30 (53.3%)	479
Hypotension	3/30 (10%)	5
Thromboembolic event	2/30 (6.7%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

There is NOT 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.