Nab-Paclitaxel and Bevacizumab or Ipilimumab as First-Line Therapy in Treating Patients With Stage IV Melanoma That Cannot Be Removed by Surgery

• Sponsor: Academic and Community Cancer Research United (Other)
• Overall Status: Completed
• CT.gov ID: NCT02158520
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 24
• Locations: 13
• Arms: 2
• Actual Duration (Months): 72.4
• Patients Per Site: 1.8
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This randomized phase II trial studies how well nab-paclitaxel and bevacizumab or ipilimumab works as first-line therapy in treating patients with stage IV melanoma that cannot be removed by surgery. Drugs used in chemotherapy, such as nab-paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Bevacizumab may stop the growth of tumor cells by binding to a protein called vascular endothelial growth factor (VEGF) and by preventing the growth of new blood vessels that tumors need to grow. Ipilimumab blocks a substance called cytotoxic T-lymphocyte-associated antigen-4 (CTLA4) on the surface of T cells and may help the immune system kill cancer cells. It is not yet known whether nab-paclitaxel and bevacizumab is more effective than ipilimumab in treating melanoma.

Condition or Disease	Intervention/Treatment	Phase
Metastatic Melanoma; Mucosal Melanoma; Stage IV Cutaneous Melanoma AJCC v6 and v7; Stage IV Uveal Melanoma AJCC v7; Unresectable Melanoma	Biological: Bevacizumab; Biological: Ipilimumab; Other: Laboratory Biomarker Analysis; Drug: Nab-paclitaxel; Other: Pharmacological Study	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. To assess whether the combination nab-paclitaxel and bevacizumab (AB) prolongs progression-free status relative to ipilimumab as a treatment in patients with unresectable stage IV melanoma.

SECONDARY OBJECTIVES:

1. To estimate the hazard of death among those randomized to AB then ipilimumab relative to those randomized to ipilimumab then AB as treatment in patients with unresectable stage IV melanoma.

2. To assess whether tumor response rate (as determined by Response Evaluation Criteria in Solid Tumors [RECIST] criteria 1.1) differs with respect to first (1st) treatment course.

3. To estimate whether the tumor response rate differs with respect to second (2nd) treatment course for those who progressed during their first treatment course.

4. To further examine the safety profile of each of these regimens.

CORRELATIVE OBJECTIVES:

1. To examine the pharmacokinetics of nab-paclitaxel when combined with bevacizumab therapy.

2. To examine pharmacodynamic changes of blood-derived parameters (biomarkers) of angiogenesis and immunity as a function of therapy.

3. To examine whether changes in serum biomarkers are also seen in the tumor.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM A: Patients receive bevacizumab intravenously (IV) over 30-90 minutes on days 1 and 15 and nab-paclitaxel IV over 30 minutes on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients experiencing progressive disease may cross-over to Arm B within 2-4 weeks.

ARM B: Patients receive ipilimumab IV over 90 minutes on day 1. Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. Patients experiencing progressive disease may cross-over to Arm A within 2-4 weeks.

After completion of study treatment, patients are followed up for up to 5 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 24 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Randomized Phase II Study of AB (Nab-Paclitaxel [Abraxane?], Bevacizumab) Versus Ipilimumab for Therapy of Unresectable Stage IV Metastatic Malignant Melanoma
• Actual Study Start Date: Oct 18, 2013
• Actual Primary Completion Date: May 24, 2017
• Actual Study Completion Date: Oct 30, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm A (bevacizumab and nab-paclitaxel) Patients receive bevacizumab IV over 30-90 minutes on days 1 and 15 and nab-paclitaxel IV over 30 minutes on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients experiencing progressive disease may cross-over to Arm B within 2-4 weeks.	Biological: Bevacizumab; Given IV; Other Names: Anti-VEGF Anti-VEGF Humanized Monoclonal Antibody Anti-VEGF rhuMAb Avastin Bevacizumab Biosimilar BEVZ92 Bevacizumab Biosimilar BI 695502 Bevacizumab Biosimilar CBT 124 Bevacizumab Biosimilar FKB238 Bevacizumab Biosimilar MIL60 Bevacizumab Biosimilar QL 1101 BEVACIZUMAB, LICENSE HOLDER UNSPECIFIED Immunoglobulin G1 (Human-Mouse Monoclonal rhuMab-VEGF Gamma-Chain Anti-Human Vascular Endothelial Growth Factor), Disulfide With Human-Mouse Monoclonal rhuMab-VEGF Light Chain, Dimer Recombinant Humanized Anti-VEGF Monoclonal Antibody rhuMab-VEGF ; Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Nab-paclitaxel; Given IV; Other Names: ABI 007 ABI-007 Abraxane Albumin-bound Paclitaxel Albumin-Stabilized Nanoparticle Paclitaxel Nanoparticle Albumin-bound Paclitaxel Nanoparticle Paclitaxel paclitaxel albumin-stabilized nanoparticle formulation Protein-bound Paclitaxel ; Other: Pharmacological Study; Correlative studies
Experimental: Arm B (ipilimumab) Patients receive ipilimumab IV over 90 minutes on day 1. Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. Patients experiencing progressive disease may cross-over to Arm A within 2-4 weeks.	Biological: Ipilimumab; Given IV; Other Names: Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody BMS-734016 MDX-010 MDX-CTLA4 Yervoy ; Other: Laboratory Biomarker Analysis; Correlative studies; Other: Pharmacological Study; Correlative studies

Outcome Measures

Primary Outcome Measures

1. Progression-free Survival (PFS) [From randomization to the earliest documentation of progression as defined by the Response Evaluation Criteria in Solid Tumors (RECIST) criteria (version 1.1) or death from any cause without the documentation of progression, assessed up to 4 years]

   Progression free survival (PFS) is defined as the time from the date of randomization to the date of disease progression or death resulting from any cause, whichever comes first. Progression is defined according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. The median and 95% confidence intervals are estimated using the Kaplan-Meier estimator. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study or a measurable increase in a non-target lesion, or the appearance of new lesions.

Secondary Outcome Measures

1. Overall Survival (OS) [From registration to death due to any cause, assessed up to 4 years]

   Overall survival time is defined as the time from randomization to death due to any cause. The median and 95% confidence intervals are estimated using the Kaplan-Meier estimator.

2. Number of Patients With Tumor Response [Up to 4 years]

   Tumor response defined as complete or partial response using Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Complete response (CR): Disappearance of all evidence of disease, Partial response (PR): Regression of measurable disease and no new sites.

3. The Number of Patients Who Experienced Toxicity [Up to 4 years]

   The number of patients who experienced toxicity (grade 3 or higher adverse events considered at least possibly related to treatment) are reported below.

Other Outcome Measures

1. Changes in Biomarkers of Angiogenesis (Arm A) [Baseline to up to 5 years]

2. Changes in Biomarkers of Immunity [Baseline to up to 5 years]

3. Pharmacokinetic Changes in Paclitaxel Albumin-stabilized Nanoparticle Formulation Plasma Concentrations [Baseline, prior to the end of paclitaxel albumin-stabilized nanoparticle formulation infusion, and the morning after nab-paclitaxel infusion on days 1 and 8 of course 1]

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Histologic or cytologic proof of surgically unresectable stage IV malignant melanoma - including that of uveal and mucosal origin

• Note: biopsy can be of locoregional disease in setting of clinically evident stage IV disease; a biopsy of the primary tumor alone does not fulfill this requirement

• No more than 2 prior courses of systemic therapy for metastatic melanoma

• For patients with metastatic melanoma not of uveal origin, v-raf murine sarcoma viral oncogene homolog B1 (BRAF) V600 mutation determination using a Clinical Laboratory Improvement Amendments (CLIA)-approved testing method on metastatic tumor tissue

• NOTE: patients with metastatic melanoma of uveal origin do not need to have formal BRAF testing due to low probability of a BRAF V600 mutation in their metastatic tumor

• Measurable disease; note: disease that is measurable by physical examination only is not eligible

• Life expectancy of >= 4 months

• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1

• Absolute neutrophil count >=1500/mL (obtained =< 14 days prior to registration/randomization)

• Platelet count >= 100,000 x 10^9/L (obtained =< 14 days prior to registration/randomization)

• Hemoglobin >= 9 g/dL (obtained =< 14 days prior to registration/randomization) (patients may be transfused to meet this requirement)

• Creatinine =< 1.5 x upper limit of normal (ULN) (obtained =< 14 days prior to registration/randomization); institutional norms are acceptable

• Total bilirubin =< 1.5 mg/dL (obtained =< 14 days prior to registration/randomization) (exception: patients with documented Gilbert?s syndrome are allowed to participate despite elevated bilirubin)

• Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) =< 2.5 x ULN and serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 2.5 x ULN (obtained =< 14 days prior to registration/randomization)

• Alkaline phosphatase =< 2.5 x ULN (obtained =< 14 days prior to registration/randomization); if bone metastasis is present in the absence of liver metastasis then =< 5 x ULN

• Urine dipstick for proteinuria < 2+ (obtained =< 14 days prior to registration/randomization) (patients discovered to have >= 2+ proteinuria on dipstick urinalysis at baseline should undergo a 24 hour urine collection and must demonstrate =< 1 g of protein in 24 hours to be eligible)

• Negative serum pregnancy test done =< 7 days prior to registration/randomization, for women of childbearing potential only

• Note:

• Females: adequate contraception must be used by both patient and partner while receiving study drug and for 12 weeks after the last dose of study drug

• Males: adequate contraception must be used by both patient and partner while receiving study drug; men who have a partner of childbearing age should also avoid fathering a child for 6 months after the last dose of study drug

• Ability to understand and the willingness to sign a written informed consent document

• Mayo Rochester patients only: willingness to provide mandatory blood samples for research purposes

Exclusion Criteria:

• Brain metastases per magnetic resonance imaging (MRI) or computed tomography (CT)

• Note: patients who have had therapy for brain metastasis (i.e., surgical resection, whole brain radiation, or stereotactic radiosurgery [SRS] even if stable) are not eligible

• Other investigational agents =< 4 weeks prior to registration/ randomization

• Anti-cancer therapy (including immunotherapy) =< 4 weeks prior to registration/randomization; exception: adjuvant Leukine =< 14 days prior to registration/randomization

• Prior treatment in the adjuvant or metastatic setting with any of the following:

• Agents disrupting VEGF activity or targeting vascular endothelial growth factor receptor (VEGFR);

• Ipilimumab;

• Or taxane based chemotherapy regimens (including paclitaxel, docetaxel, cabazitaxel or nab-paclitaxel)

• Major surgical procedure, open biopsy, or significant traumatic injury =< 4 weeks prior to registration/randomization; (port-a-cath placement does not count as a major surgical procedure and patients can be enrolled at any time after placement)

• Fine needle aspirations or core biopsies =< 7 days prior to registration/ randomization

• Planned/or anticipated major surgical procedure during the course of the study

• Other medical conditions including but not limited to:

• History of liver disease such as cirrhosis, chronic active hepatitis, chronic persistent hepatitis or hepatitis B or C

• Active infection requiring parenteral antibiotics

• Poorly controlled high blood pressure (>= 150 mmHg systolic and/or 100 mmHg diastolic) despite treatment

• New York Heart Association class II-IV congestive heart failure

• Serious cardiac arrhythmia requiring medication

• Myocardial infarction or unstable angina =< 6 months prior to registration/randomization

• Clinically significant peripheral vascular disease

• Deep venous thrombosis or pulmonary embolus =< 1 year of registration/randomization

• Ongoing need for full-dose oral or parenteral anticoagulation

• Ongoing anti-platelet treatment other than low-dose aspirin (i.e., aspirin 81 mg by mouth daily)

• Active bleeding or pathological conditions that carry high risk of bleeding (e.g., known esophageal varices, etc.)

• Serious, non-healing wound (including wounds healing by secondary intention), ulcer or bone fracture

• History of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess =< 6 months prior to registration/randomization

• History of central nervous system (CNS) disease (e.g., vascular abnormalities, etc.), clinically significant stroke or transient ischemic attack (TIA) =< 6 months prior to registration/randomization, seizures not controlled with standard medical therapy

• Radiographically documented tumor invading major blood vessels

• History of hypertensive crisis or hypertensive encephalopathy

• Any of the following:

• Pregnant women

• Nursing women

• Men and women of reproductive potential who are not using effective birth control methods Note: women of childbearing potential must have a negative serum pregnancy test =< 7 days prior to registration/randomization; adequate contraception must be used while receiving study drug and for 12 weeks after the last dose of study drug, by both women and men and by both patient and partner; men who have a partner of childbearing potential should also avoid fathering a child for 6 months after the last dose of study drug

• Existence of peripheral sensory neuropathy >= grade 2 (from any cause)

• History of other malignancy =< 5 years with the exception of basal cell or squamous cell carcinoma of the skin, treated with local resection only, or carcinoma in situ (e.g. of the cervix, breast, prostate, etc.)

• Radiation therapy (other than palliative) =< 2 weeks prior to randomization; note: patients who have had > 25% of their functional bone marrow irradiated are not eligible for this trial

• Active or recent history of hemoptysis (>= 1/2 teaspoon of bright red blood per episode) =< 30 days prior to registration/randomization

• Known hypersensitivity to any of the components of ipilimumab, bevacizumab, or nab-paclitaxel

• History of inflammatory bowel disease (e.g., Crohn?s, ulcerative colitis) - note patients with irritable bowel syndrome are eligible

• Diagnosis of autoimmune disease (i.e., rheumatoid arthritis, scleroderma, systemic lupus erythematosus [SLE], autoimmune vasculitis, Guillain-Barre syndrome, etc.), regardless if patient is currently receiving treatment at time of registration/randomization

• Systemic corticosteroids use =< 2 weeks, regardless of indication; note: patients who are on inhaled corticosteroids are eligible

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Saint Mary's Medical Center	San Francisco	California	United States	94117
2	Mayo Clinic in Florida	Jacksonville	Florida	United States	32224-9980
3	University of Illinois	Chicago	Illinois	United States	60612
4	University of Iowa/Holden Comprehensive Cancer Center	Iowa City	Iowa	United States	52242
5	Siouxland Regional Cancer Center	Sioux City	Iowa	United States	51101
6	Cancer Research Consortium of West Michigan NCORP	Grand Rapids	Michigan	United States	49503
7	Mayo Clinic	Rochester	Minnesota	United States	55905
8	Metro Minnesota Community Oncology Research Consortium	Saint Louis Park	Minnesota	United States	55416
9	Missouri Valley Cancer Consortium	Omaha	Nebraska	United States	68106
10	Roswell Park Cancer Institute	Buffalo	New York	United States	14263
11	UNC Lineberger Comprehensive Cancer Center	Chapel Hill	North Carolina	United States	27599
12	Saint Vincent Hospital Cancer Center Green Bay	Green Bay	Wisconsin	United States	54301
13	University of Wisconsin Hospital and Clinics	Madison	Wisconsin	United States	53792

Sponsors and Collaborators

• Academic and Community Cancer Research United
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Svetomir N Markovic, Academic and Community Cancer Research United

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Oct 26, 2018

More Information

Publications

None provided.

• Responsible Party: Academic and Community Cancer Research United
• ClinicalTrials.gov Identifier: NCT02158520
• Other Study ID Numbers: ACCRU RU261206I; NCI-2013-01112; ML28605; RU261206I; ACCRU RU261206I; P30CA015083; NCT01879306
• First Posted: Jun 9, 2014
• Last Update Posted: Jan 21, 2020
• Last Verified: Feb 1, 2019

• Additional relevant MeSH terms: Melanoma; Paclitaxel; Albumin-Bound Paclitaxel; Bevacizumab; Ipilimumab; Antineoplastic Agents, Immunological; Endothelial Growth Factors; Antibodies; Immunoglobulins; Antibodies, Monoclonal; Immunoglobulin G

Study Results

Participant Flow

Recruitment Details	This study was closed to enroll on November 19, 2015 after having enrolled 24 patients (12 patients per arm) due to the FDA approval of new agents for this patient population.

Arm/Group Title	Arm A (Bevacizumab and Nab-paclitaxel)	Arm B (Ipilimumab)
Arm/Group Description	Patients receive bevacizumab 10mg/kg IV over 30-90 minutes on days 1 and 15 and nab-paclitaxel 150 mg/m^2 IV over 30 minutes on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients experiencing progressive disease may cross-over to Arm B within 2-4 weeks.	Patients receive ipilimumab 3 mg/kg IV over 90 minutes on day 1. Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. Patients experiencing progressive disease may cross-over to Arm A within 2-4 weeks.
Period Title: Overall Study
STARTED	12	12
AE Evaluated Prior to Crossover	12	12
Eligible for Crossover	8	8
Eligible for Crossover With AE Evaluated	7	7
Crossover Cohort	4	6
COMPLETED	12	12
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Arm A (Bevacizumab and Nab-paclitaxel)	Arm B (Ipilimumab)	Total
Arm/Group Description	Patients receive bevacizumab 10mg/kg IV over 30-90 minutes on days 1 and 15 and nab-paclitaxel 150 mg/m^2 IV over 30 minutes on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients experiencing progressive disease may cross-over to Arm B within 2-4 weeks.	Patients receive ipilimumab 3 mg/kg IV over 90 minutes on day 1. Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. Patients experiencing progressive disease may cross-over to Arm A within 2-4 weeks.	Total of all reporting groups
Overall Participants	12	12	24
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	60	61	61
Sex/Gender, Customized (Count of Participants)
Male	8 66.7%	7 58.3%	15 62.5%
Female	4 33.3%	4 33.3%	8 33.3%
Unknown	0 0%	1 8.3%	1 4.2%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	12 100%	12 100%	24 100%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Prior radiation therapy (Count of Participants)
Count of Participants [Participants]	4 33.3%	3 25%	7 29.2%

Outcome Measures

1. Primary Outcome

Title	Progression-free Survival (PFS)
Description	Progression free survival (PFS) is defined as the time from the date of randomization to the date of disease progression or death resulting from any cause, whichever comes first. Progression is defined according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. The median and 95% confidence intervals are estimated using the Kaplan-Meier estimator. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study or a measurable increase in a non-target lesion, or the appearance of new lesions.
Time Frame	From randomization to the earliest documentation of progression as defined by the Response Evaluation Criteria in Solid Tumors (RECIST) criteria (version 1.1) or death from any cause without the documentation of progression, assessed up to 4 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm A (Bevacizumab and Nab-paclitaxel)	Arm B (Ipilimumab)
Arm/Group Description	Patients receive bevacizumab 10mg/kg IV over 30-90 minutes on days 1 and 15 and nab-paclitaxel 150 mg/m^2 IV over 30 minutes on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients experiencing progressive disease may cross-over to Arm B within 2-4 weeks.	Patients receive ipilimumab 3 mg/kg IV over 90 minutes on day 1. Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. Patients experiencing progressive disease may cross-over to Arm A within 2-4 weeks.
Measure Participants	12	12
Median (95% Confidence Interval) [days]	139	94

2. Secondary Outcome

Title	Overall Survival (OS)
Description	Overall survival time is defined as the time from randomization to death due to any cause. The median and 95% confidence intervals are estimated using the Kaplan-Meier estimator.
Time Frame	From registration to death due to any cause, assessed up to 4 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm A (Bevacizumab and Nab-paclitaxel)	Arm B (Ipilimumab)
Arm/Group Description	Patients receive bevacizumab 10mg/kg IV over 30-90 minutes on days 1 and 15 and nab-paclitaxel 150 mg/m^2 IV over 30 minutes on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients experiencing progressive disease may cross-over to Arm B within 2-4 weeks.	Patients receive ipilimumab 3 mg/kg IV over 90 minutes on day 1. Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. Patients experiencing progressive disease may cross-over to Arm A within 2-4 weeks.
Measure Participants	12	12
Median (95% Confidence Interval) [months]	18.4	27.0

3. Secondary Outcome

Title	Number of Patients With Tumor Response
Description	Tumor response defined as complete or partial response using Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Complete response (CR): Disappearance of all evidence of disease, Partial response (PR): Regression of measurable disease and no new sites.
Time Frame	Up to 4 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm A (Bevacizumab and Nab-paclitaxel)	Arm B (Ipilimumab)
Arm/Group Description	Patients receive bevacizumab 10mg/kg IV over 30-90 minutes on days 1 and 15 and nab-paclitaxel 150 mg/m^2 IV over 30 minutes on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients experiencing progressive disease may cross-over to Arm B within 2-4 weeks.	Patients receive ipilimumab 3 mg/kg IV over 90 minutes on day 1. Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. Patients experiencing progressive disease may cross-over to Arm A within 2-4 weeks.
Measure Participants	12	12
CR	2 16.7%	0 0%
PR	1 8.3%	1 8.3%

4. Secondary Outcome

Title	The Number of Patients Who Experienced Toxicity
Description	The number of patients who experienced toxicity (grade 3 or higher adverse events considered at least possibly related to treatment) are reported below.
Time Frame	Up to 4 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm A (Bevacizumab and Nab-paclitaxel)	Arm B (Ipilimumab)
Arm/Group Description	Patients receive bevacizumab 10mg/kg IV over 30-90 minutes on days 1 and 15 and nab-paclitaxel 150 mg/m^2 IV over 30 minutes on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients experiencing progressive disease may cross-over to Arm B within 2-4 weeks.	Patients receive ipilimumab 3 mg/kg IV over 90 minutes on day 1. Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. Patients experiencing progressive disease may cross-over to Arm A within 2-4 weeks.
Measure Participants	12	12
Count of Participants [Participants]	9 75%	7 58.3%

5. Other Pre-specified Outcome

Title	Changes in Biomarkers of Angiogenesis (Arm A)
Time Frame	Baseline to up to 5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

6. Other Pre-specified Outcome

Title	Changes in Biomarkers of Immunity
Time Frame	Baseline to up to 5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

7. Other Pre-specified Outcome

Title	Pharmacokinetic Changes in Paclitaxel Albumin-stabilized Nanoparticle Formulation Plasma Concentrations
Time Frame	Baseline, prior to the end of paclitaxel albumin-stabilized nanoparticle formulation infusion, and the morning after nab-paclitaxel infusion on days 1 and 8 of course 1

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	Up to 4 years
Adverse Event Reporting Description	Adverse events are reported for each arm group (i.e. Arm A, Arm B, Arm A Eligible for Crossover, and Arm B Eligible for Crossover)
Arm/Group Title	Arm A (Bevacizumab and Nab-paclitaxel)		Arm B (Ipilimumab)		Arm A Eligible for Crossover		Arm B Eligible for Crossover
Arm/Group Description	Patients receive bevacizumab 10mg/kg IV over 30-90 minutes on days 1 and 15 and nab-paclitaxel 150 mg/m^2 IV over 30 minutes on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients experiencing progressive disease may cross-over to Arm B within 2-4 weeks.		Patients receive ipilimumab 3 mg/kg IV over 90 minutes on day 1. Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. Patients experiencing progressive disease may cross-over to Arm A within 2-4 weeks.		Arm A patients who experienced progressive disease and eligible for crossover to Arm B AND evaluated for adverse events.		Arm B patients who experienced progressive disease and eligible for crossover to Arm A AND evaluated for adverse events.
All Cause Mortality
	Arm A (Bevacizumab and Nab-paclitaxel)		Arm B (Ipilimumab)		Arm A Eligible for Crossover		Arm B Eligible for Crossover
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	10/12 (83.3%)		8/12 (66.7%)		6/7 (85.7%)		5/7 (71.4%)
Serious Adverse Events
	Arm A (Bevacizumab and Nab-paclitaxel)		Arm B (Ipilimumab)		Arm A Eligible for Crossover		Arm B Eligible for Crossover
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/12 (16.7%)		4/12 (33.3%)		2/7 (28.6%)		2/7 (28.6%)
Blood and lymphatic system disorders
Hemolytic uremic syndrome	1/12 (8.3%)	1	0/12 (0%)	0	1/7 (14.3%)	1	0/7 (0%)	0
Gastrointestinal disorders
Rectal hemorrhage	1/12 (8.3%)	1	0/12 (0%)	0	0/7 (0%)	0	0/7 (0%)	0
Injury, poisoning and procedural complications
Wound dehiscence	0/12 (0%)	0	0/12 (0%)	0	0/7 (0%)	0	1/7 (14.3%)	1
Investigations
Creatinine increased	0/12 (0%)	0	0/12 (0%)	0	1/7 (14.3%)	1	0/7 (0%)	0
Lymphocyte count decreased	0/12 (0%)	0	1/12 (8.3%)	1	0/7 (0%)	0	0/7 (0%)	0
Platelet count decreased	0/12 (0%)	0	0/12 (0%)	0	1/7 (14.3%)	1	0/7 (0%)	0
Metabolism and nutrition disorders
Dehydration	0/12 (0%)	0	0/12 (0%)	0	1/7 (14.3%)	1	0/7 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, mal, uncpec - Oth spec	0/12 (0%)	0	2/12 (16.7%)	2	0/7 (0%)	0	0/7 (0%)	0
Nervous system disorders
Peripheral sensory neuropathy	0/12 (0%)	0	0/12 (0%)	0	0/7 (0%)	0	1/7 (14.3%)	1
Renal and urinary disorders
Acute kidney injury	0/12 (0%)	0	3/12 (25%)	3	0/7 (0%)	0	0/7 (0%)	0
Other (Not Including Serious) Adverse Events
	Arm A (Bevacizumab and Nab-paclitaxel)		Arm B (Ipilimumab)		Arm A Eligible for Crossover		Arm B Eligible for Crossover
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/12 (91.7%)		9/12 (75%)		7/7 (100%)		7/7 (100%)
Blood and lymphatic system disorders
Anemia	1/12 (8.3%)	2	1/12 (8.3%)	3	1/7 (14.3%)	1	2/7 (28.6%)	2
Eye disorders
Cataract	1/12 (8.3%)	1	0/12 (0%)	0	0/7 (0%)	0	0/7 (0%)	0
Eye disorders - Other, specify	0/12 (0%)	0	0/12 (0%)	0	0/7 (0%)	0	1/7 (14.3%)	1
Retinopathy	0/12 (0%)	0	0/12 (0%)	0	0/7 (0%)	0	1/7 (14.3%)	1
Gastrointestinal disorders
Abdominal pain	0/12 (0%)	0	3/12 (25%)	5	2/7 (28.6%)	2	3/7 (42.9%)	7
Diarrhea	2/12 (16.7%)	4	0/12 (0%)	0	2/7 (28.6%)	2	1/7 (14.3%)	1
Gastroesophageal reflux disease	0/12 (0%)	0	0/12 (0%)	0	1/7 (14.3%)	1	0/7 (0%)	0
Mucositis oral	1/12 (8.3%)	1	0/12 (0%)	0	0/7 (0%)	0	0/7 (0%)	0
Nausea	0/12 (0%)	0	1/12 (8.3%)	1	0/7 (0%)	0	2/7 (28.6%)	3
Vomiting	0/12 (0%)	0	0/12 (0%)	0	0/7 (0%)	0	2/7 (28.6%)	3
General disorders
Fatigue	6/12 (50%)	7	2/12 (16.7%)	3	3/7 (42.9%)	3	6/7 (85.7%)	26
Immune system disorders
Allergic reaction	1/12 (8.3%)	1	0/12 (0%)	0	0/7 (0%)	0	0/7 (0%)	0
Infections and infestations
Catheter related infection	0/12 (0%)	0	0/12 (0%)	0	0/7 (0%)	0	1/7 (14.3%)	1
Infections and infestations - Oth spec	0/12 (0%)	0	1/12 (8.3%)	1	0/7 (0%)	0	0/7 (0%)	0
Papulopustular rash	1/12 (8.3%)	1	0/12 (0%)	0	0/7 (0%)	0	0/7 (0%)	0
Sinusitis	1/12 (8.3%)	1	0/12 (0%)	0	0/7 (0%)	0	0/7 (0%)	0
Wound infection	0/12 (0%)	0	0/12 (0%)	0	0/7 (0%)	0	1/7 (14.3%)	1
Investigations
Alkaline phosphatase increased	0/12 (0%)	0	2/12 (16.7%)	2	1/7 (14.3%)	1	0/7 (0%)	0
Aspartate aminotransferase increased	0/12 (0%)	0	2/12 (16.7%)	2	0/7 (0%)	0	0/7 (0%)	0
Blood bilirubin increased	0/12 (0%)	0	1/12 (8.3%)	1	0/7 (0%)	0	0/7 (0%)	0
Creatinine increased	1/12 (8.3%)	2	0/12 (0%)	0	0/7 (0%)	0	0/7 (0%)	0
Lymphocyte count decreased	0/12 (0%)	0	0/12 (0%)	0	0/7 (0%)	0	1/7 (14.3%)	1
Neutrophil count decreased	9/12 (75%)	21	0/12 (0%)	0	1/7 (14.3%)	1	4/7 (57.1%)	11
White blood cell decreased	8/12 (66.7%)	19	0/12 (0%)	0	1/7 (14.3%)	1	3/7 (42.9%)	10
Metabolism and nutrition disorders
Anorexia	2/12 (16.7%)	2	0/12 (0%)	0	0/7 (0%)	0	1/7 (14.3%)	2
Dehydration	1/12 (8.3%)	1	0/12 (0%)	0	0/7 (0%)	0	0/7 (0%)	0
Hyponatremia	0/12 (0%)	0	0/12 (0%)	0	0/7 (0%)	0	1/7 (14.3%)	1
Metabolism, nutrition disord - Oth spec	0/12 (0%)	0	1/12 (8.3%)	1	0/7 (0%)	0	0/7 (0%)	0
Musculoskeletal and connective tissue disorders
Arthralgia	3/12 (25%)	4	0/12 (0%)	0	1/7 (14.3%)	1	1/7 (14.3%)	2
Back pain	0/12 (0%)	0	1/12 (8.3%)	1	0/7 (0%)	0	0/7 (0%)	0
Myalgia	1/12 (8.3%)	2	1/12 (8.3%)	1	1/7 (14.3%)	1	1/7 (14.3%)	2
Pain in extremity	0/12 (0%)	0	1/12 (8.3%)	2	0/7 (0%)	0	0/7 (0%)	0
Nervous system disorders
Dysgeusia	1/12 (8.3%)	1	0/12 (0%)	0	0/7 (0%)	0	0/7 (0%)	0
Peripheral sensory neuropathy	1/12 (8.3%)	1	0/12 (0%)	0	2/7 (28.6%)	2	1/7 (14.3%)	1
Psychiatric disorders
Anxiety	1/12 (8.3%)	1	0/12 (0%)	0	0/7 (0%)	0	0/7 (0%)	0
Renal and urinary disorders
Proteinuria	1/12 (8.3%)	2	0/12 (0%)	0	0/7 (0%)	0	1/7 (14.3%)	2
Respiratory, thoracic and mediastinal disorders
Cough	0/12 (0%)	0	2/12 (16.7%)	4	0/7 (0%)	0	0/7 (0%)	0
Dyspnea	1/12 (8.3%)	1	0/12 (0%)	0	0/7 (0%)	0	0/7 (0%)	0
Pulmonary hypertension	0/12 (0%)	0	0/12 (0%)	0	0/7 (0%)	0	1/7 (14.3%)	1
Resp, thoracic, mediastinal - Oth spec	0/12 (0%)	0	0/12 (0%)	0	1/7 (14.3%)	1	0/7 (0%)	0
Skin and subcutaneous tissue disorders
Alopecia	6/12 (50%)	14	0/12 (0%)	0	1/7 (14.3%)	1	4/7 (57.1%)	13
Pruritus	0/12 (0%)	0	1/12 (8.3%)	2	1/7 (14.3%)	1	0/7 (0%)	0
Rash maculo-papular	0/12 (0%)	0	2/12 (16.7%)	3	0/7 (0%)	0	0/7 (0%)	0
Vascular disorders
Hypertension	5/12 (41.7%)	9	2/12 (16.7%)	2	0/7 (0%)	0	2/7 (28.6%)	6
Thromboembolic event	0/12 (0%)	0	1/12 (8.3%)	1	0/7 (0%)	0	0/7 (0%)	0

Limitations/Caveats

[Not Specified]

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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.