Trial of Paclitaxel/Bevacizumab +/- Everolimus for Patients With HER2-Negative Metastatic Breast Cancer

• Sponsor: SCRI Development Innovations, LLC (Other)
• Overall Status: Completed
• CT.gov ID: NCT00915603
• Collaborator: Novartis (Industry)
• Enrollment: 113
• Locations: 15
• Arms: 2
• Duration (Months): 60
• Patients Per Site: 7.5
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This randomized, double blind, placebo controlled trial will evaluate the impact of adding everolimus to the combination of weekly paclitaxel plus bevacizumab in the first-line treatment of women with HER2-negative metastatic breast cancer. Patients will be randomized (1:1) to receive either paclitaxel/bevacizumab/everolimus (Treatment Arm 1) or paclitaxel/ bevacizumab/placebo (Treatment Arm 2). Patients will be evaluated for response to treatment every 8 weeks; responding and/or stable patients will continue treatment, with re-evaluations every 8 weeks, until tumor progression or

intolerable toxicity occurs. Outcomes will be assessed for each treatment arm

separately. This trial is not intended to compare treatment arms primarily. Any such analyses are exploratory and will be conducted without adjustment for multiple hypothesis testing.

Condition or Disease	Intervention/Treatment	Phase
Metastatic Breast Cancer	Drug: Everolimus; Drug: Bevacizumab; Drug: Paclitaxel; Drug: Placebo; Drug: Bevacizumab; Drug: Paclitaxel	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 113 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-Blind, Placebo-Controlled Phase II Trial of Weekly Paclitaxel/Bevacizumab +/- Everolimus as First-Line Chemotherapy for Patients With HER2-Negative Metastatic Breast Cancer (MBC)
• Study Start Date: Jul 1, 2009
• Actual Primary Completion Date: Jun 1, 2014
• Actual Study Completion Date: Jul 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: paclitaxel/bevacizumab/everolimus Systemic Therapy	Drug: Everolimus; Everolimus 10mg PO daily continuously for all 28 days of a cycle; Other Names: Systemic therapy RAD001 Afinitor ; Drug: Bevacizumab; Bevacizumab 10mg/kg IV Days 1 and 15 of 28 day cycle; Other Names: Systemic therapy Avastin ; Drug: Paclitaxel; Paclitaxel 90mg/m2 1-hour IV infusion Days 1, 8 and 15 of 28 day cycle. Patients will receive standard pre-medication before each paclitaxel treatment to prevent a hypersensitivity reaction.; Other Names: Systemic therapy Taxol
Placebo Comparator: paclitaxel/bevacizumab/placebo Systemic Therapy	Drug: Placebo; Placebo PO daily continuously for all 28 days of a cycle; Other Names: Systemic therapy ; Drug: Bevacizumab; Bevacizumab 10mg/kg IV days 1 and 15 of 28 day cycle; Other Names: Systemic therapy Avastin ; Drug: Paclitaxel; Paclitaxel 90mg/m2 1-hour IV infusion Days 1, 8 and 15 of 28 day cycle. Patients will receive standard pre-medication before each paclitaxel treatment to prevent a hypersensitivity reaction.; Other Names: Systemic therapy Taxol

Outcome Measures

Primary Outcome Measures

1. Progression-Free Survival (PFS) [every 8 weeks until progressive disease, expected average of 18 months]

   Progression-free survival will be measured from Day 1 of study drug administration to disease progression defined by Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.1) as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions

Secondary Outcome Measures

1. Number of Patients With Treatment-related Adverse Events (AEs) as a Measure of Safety and Tolerability [every 4 weeks until intolerable toxicity occurs]

   Assessments will be made based on the analysis of reported incidence of treatment-emergent AEs

2. Overall Response Rate (ORR) [every 8 weeks until treatment discontinuation, expected average of 18 months]

   The number of patients with observed complete response [CR] or partial response [PR]. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR

3. Duration of Response (DOR) [every 8 weeks until treatment discontinuation, expected average 6 months]

   Defined as time between date of objective response and date of response to disease progression or death, as defined by RECIST v1.1 criteria. Objective response is defined as either complete response [CR] or partial response [PR]. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions

4. Overall Survival (OS) [every 8 weeks until treatment discontinuation, expected average 6 months]

   Assessed from Day 1 of study drug administration to date of death due to any cause.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

1. Female or male patients >=18 years of age.

2. Histologically confirmed invasive breast cancer, locally unresectable or metastatic.

3. No prior chemotherapy for MBC. Patients may have received adjuvant or

neoadjuvant chemotherapy (including taxanes and/or bevacizumab) as long as

treated was completed >12 months prior to relapse. Prior hormonal therapy in the

adjuvant or metastatic setting will be permitted.

1. Prior hormonal therapy in the adjuvant or metastatic setting is permitted. Estrogen receptor positive patients should be considered candidates for chemotherapy.

2. HER2-negative breast cancer, defined as follows:

• FISH-negative (FISH ratio <2.2), or

• IHC 0-1+, or

• IHC 2-3+ AND FISH-negative (FISH ratio <2.2).

1. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.

2. Adequate hematologic function, defined by:

· Absolute neutrophil count (ANC) >1500/mm3

• Platelet count >=100,000/mm3

• Hemoglobin >9 g/dL

1. Adequate liver function, defined by:

· AST and ALT <=2.5 x the upper limit of normal (ULN) or <=5 x ULN in

presence of liver metastases

• Total bilirubin <=1.5 x ULN

1. Adequate renal function, defined by:

· Serum creatinine <=1.5 x ULN or calculated creatinine clearance of

=40 ml/min

1. International normalized ratio (INR) <=1.5 or prothrombin time (PT)/partial

thromboplastin time (PTT) within normal limits (WNL) of the institution (if patient is not on anti-coagulation therapy). Patients receiving anti-coagulation treatment with an agent such as warfarin or heparin are eligible if the INR is stable and within the therapeutic range prior to study treatment initiation.

1. Adequate lipid profile: total cholesterol <=300 mg/dL OR <=7.75 mmol/L and fasting triglyceride 2.5 x ULN. Note: In case one or both of these thresholds are exceeded,the patient can only be included after initiation of appropriate lipid lowering medication.

2. Patients with proteinuria at screening as demonstrated by either:

· Urine protein creatinine (UPC) ration >1.0 at screening

or

• Urine dipstick for proteinuria >=2+ (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).

1. Measurable disease by RECIST criteria.

2. Life expectancy >=12 weeks.

3. Ability to swallow oral medications.

4. Adequate cardiac function, defined by baseline left ventricular ejection fraction (LVEF) value >= normal per institutional guidelines by MUGA scan or

echocardiogram (ECHO).

1. Adequate recovery from recent surgery.

• Major surgical procedure >28 days from study entry

• Minor surgical procedure >7 days from study entry (Portacath placement

excepted - patients can start treatment <7 days after portacath placement.)

1. Patients with previous history of invasive cancers (including breast cancer) are eligible if definitive treatment was completed more than 5 years prior to initiating current study treatment, and there is no evidence of recurrent disease.

2. Patient must be accessible for treatment and follow-up.

3. All patients must be able to understand the investigational nature of the study and give written informed consent prior to study entry.

Exclusion Criteria:

1. Patients with active brain metastases or meningeal metastases. Patients who have had brain metastases resected, or have received brain radiation therapy >4 weeks prior to study entry are eligible, if they meet all of the following criteria: 1) residual symptoms < grade 2, 2) no dexamethasone requirement, and 3) follow-up MRI shows regression of lesions after treatment and no new lesions appearing.

2. Previous treatment with an m-TOR inhibitor (sirolimus, temsirolimus, everolimus) or anti-angiogenesis agent unless:

• in the adjuvant setting, and

• =12 months prior to recurrence.

1. Previous radiotherapy for metastatic disease completed <2 weeks prior to study treatment initiation.

2. Patients who are current receiving systemic cancer therapy or have received

previous systemic therapy within 4 weeks of the start of study drug (e.g.

chemotherapy, antibody therapy, targeted agents).

1. Women who are pregnant or lactating. All patients with reproductive potential must agree to use effective contraception from time of study entry until at least 3 months after the last administration of study drug.

2. Uncontrolled hypertension defined as systolic blood pressure >150 mmHg or

diastolic pressure >100 mmHg, despite optimal medical management.

1. Concurrent use of CYP3A4 inhibitors and inducers from 72 hours prior to initiation of study treatment until the end of treatment with everolimus.

2. Cardiac disease, including: congestive heart failure (CHF) > Class II per New York Heart Association (NYHA) classification; unstable angina (anginal symptoms at rest) or new-onset angina (i.e., began within the last 3 months), or myocardial infarction within the past 6 months; symptomatic CHF, unstable angina pectoris, or cardiac ventricular arrhythmias requiring anti-arrhythmic therapy.

3. History of stroke or transient ischemic attack within 6 months prior to first

bevacizumab dose.

1. Patients with any non-healing wound, ulcer, or long-bone fracture.

2. Patients with clinical history of hemoptysis or hematemesis.

3. Patients with any history of a bleeding diathesis or coagulopathy.

4. Patients with a PEG or G tube cannot be enrolled into this trial.

5. History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to beginning bevacizumab.

6. Patients with an impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of everolimus (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection).

7. Patients who have any severe and/or uncontrolled medical conditions or other

conditions that could affect their participation such as:

• severe impaired lung functions as defined as spirometry and DLCO that is 50% of the normal predicted value and/or 02 saturation that is 88% or less at rest on room air

• uncontrolled diabetes as defined by fasting serum glucose >1.5 x ULN.

1. History of any other disease, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates use of an investigational drug, or that might affect interpretation of the results of this study, or render the subject at high risk for treatment complications.

2. History of hypersensitivity to Cremophor EL (polyoxyethylated castor oil) or a drug formulated in Cremophor EL, such as paclitaxel.

3. Patients may not receive any other investigational or anti-cancer treatments while participating in this study.

4. Patients receiving chronic, systemic treatment with corticosteroids or another immunosuppressive agent. Topical or inhaled corticosteroids are allowed.

5. Patients should not receive immunization with attenuated live vaccines within one week of study entry or during study period.

6. Concurrent severe, uncontrolled infection or intercurrent illness including, but not limited to, ongoing or active infection, or psychiatric illness/social situations that would limit compliance with study requirements.

7. Patients with a known hypersensitivity to RAD001 (everolimus) or other rapamycins (sirolimus, temsirolimus) or its excipients.

8. Patients with a known HIV seropositivity.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Wilshire Oncology Medical Group	LaVerne	California	United States	91750
2	Eastern Connecticut Hematology Oncology	Norwich	Connecticut	United States	06360
3	Aventura Medical Center	Aventura	Florida	United States	33180
4	Florida Cancer Specialists	Fort Myers	Florida	United States	33901
5	Mercy Hospital	Portland	Maine	United States	04101
6	Center for Cancer and Blood Disorders	Bethesda	Maryland	United States	20817
7	National Capital Clinical Research Associates	Bethesda	Maryland	United States	20817
8	Oncology Hematology Care	Cincinnati	Ohio	United States	45242
9	Mid Ohio Oncology/Hematology, Inc./ The Mark H. Zangmeister Center	Columbus	Ohio	United States	43219
10	South Carolina Oncology Associates, PA	Columbia	South Carolina	United States	29210
11	Chattanooga Oncology Hematology Associates	Chattanooga	Tennessee	United States	37404
12	Tennessee Oncology, PLLC	Nashville	Tennessee	United States	37023
13	Texas Oncology	Dallas	Texas	United States	75246
14	Fairfax Northern Virginia Hem-Onc	Fairfax	Virginia	United States	22031
15	Virginia Cancer Institute	Richmond	Virginia	United States	23235

Sponsors and Collaborators

• SCRI Development Innovations, LLC
• Novartis

Investigators

• Study Chair: Denise A. Yardley, M.D., SCRI Development Innovations, LLC

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: SCRI Development Innovations, LLC
• ClinicalTrials.gov Identifier: NCT00915603
• Other Study ID Numbers: SCRI BRE 154
• First Posted: Jun 8, 2009
• Last Update Posted: Dec 22, 2014
• Last Verified: Dec 1, 2014

• Keywords provided by SCRI Development Innovations, LLC: Metastatic Breast Cancer; Paclitaxel; Bevacizumab; Everolimus
• Additional relevant MeSH terms: Breast Neoplasms; Paclitaxel; Albumin-Bound Paclitaxel; Bevacizumab; Everolimus

Study Results

Participant Flow

Arm/Group Title	Paclitaxel/Carboplatin/Placebo	Paclitaxel/Carboplatin/Everolimus
Arm/Group Description
Period Title: Overall Study
STARTED	56	55
COMPLETED	0	0
NOT COMPLETED	56	55

Baseline Characteristics

Arm/Group Title	Paclitaxel/Carboplatin/Placebo	Paclitaxel/Carboplatin/Everolimus	Total
Arm/Group Description	Total of all reporting groups
Overall Participants	57	56	113
Age (Years) [Median (Full Range) ]
Median (Full Range) [Years]	57	61	58
Sex: Female, Male (Count of Participants)
Female	57 100%	56 100%	113 100%
Male	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	57 100%	56 100%	113 100%

Outcome Measures

1. Primary Outcome

Title	Progression-Free Survival (PFS)
Description	Progression-free survival will be measured from Day 1 of study drug administration to disease progression defined by Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.1) as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions
Time Frame	every 8 weeks until progressive disease, expected average of 18 months

Outcome Measure Data

Analysis Population Description

Includes all enrolled and randomized patients

Arm/Group Title	Paclitaxel/Bevacizumab/Everolimus	Paclitaxel/Bevacizumab/Placebo
Arm/Group Description	Systemic Therapy	Systemic Therapy
Measure Participants	56	57
Median (95% Confidence Interval) [months]	9.1	7.1

2. Secondary Outcome

Title	Number of Patients With Treatment-related Adverse Events (AEs) as a Measure of Safety and Tolerability
Description	Assessments will be made based on the analysis of reported incidence of treatment-emergent AEs
Time Frame	every 4 weeks until intolerable toxicity occurs

Outcome Measure Data

Analysis Population Description

Includes patients who were enrolled, randomized and treated

Arm/Group Title	Paclitaxel/Bevacizumab/Everolimus	Paclitaxel/Bevacizumab/Placebo
Arm/Group Description	Systemic Therapy	Systemic Therapy
Measure Participants	55	56
Neutropenia	27 47.4%	26 46.4%
Febrile neutropenia	2 3.5%	2 3.6%
Anemia	23 40.4%	8 14.3%
Thrombocytopenia	12 21.1%	8 14.3%
Fatigue	38 66.7%	29 51.8%
Mucositis/stomatitis	35 61.4%	18 32.1%
Neuropathy	32 56.1%	31 55.4%
Diarrhea	30 52.6%	17 30.4%
Rash	25 43.9%	13 23.2%
Nausea/vomiting	26 45.6%	19 33.9%
Epistaxis	20 35.1%	15 26.8%
Arthralgia/myalgia	19 33.3%	10 17.9%
Alopecia	19 33.3%	27 48.2%
Anorexia/weight loss	18 31.6%	13 23.2%
Proteinuria	17 29.8%	10 17.9%
Dysgeusia	11 19.3%	8 14.3%
Headache	11 19.3%	7 12.5%
Hypertension	10 17.5%	10 17.9%
Dyspnea	10 17.5%	9 16.1%
Hypercholesterolemia	9 15.8%	3 5.4%

3. Secondary Outcome

Title	Overall Response Rate (ORR)
Description	The number of patients with observed complete response [CR] or partial response [PR]. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR
Time Frame	every 8 weeks until treatment discontinuation, expected average of 18 months

Outcome Measure Data

Analysis Population Description

Includes patients who were enrolled and randomized

Arm/Group Title	Paclitaxel/Bevacizumab/Everolimus	Paclitaxel/Bevacizumab/Placebo
Arm/Group Description	Systemic Therapy	Systemic Therapy
Measure Participants	56	57
Number [participants]	35 61.4%	32 57.1%

4. Secondary Outcome

Title	Duration of Response (DOR)
Description	Defined as time between date of objective response and date of response to disease progression or death, as defined by RECIST v1.1 criteria. Objective response is defined as either complete response [CR] or partial response [PR]. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions
Time Frame	every 8 weeks until treatment discontinuation, expected average 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Paclitaxel/Bevacizumab/Everolimus	Paclitaxel/Bevacizumab/Placebo
Arm/Group Description	Systemic Therapy	Systemic Therapy
Measure Participants	35	32
Median (95% Confidence Interval) [months]	7.8	6.0

5. Secondary Outcome

Title	Overall Survival (OS)
Description	Assessed from Day 1 of study drug administration to date of death due to any cause.
Time Frame	every 8 weeks until treatment discontinuation, expected average 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Paclitaxel/Bevacizumab/Everolimus	Paclitaxel/Bevacizumab/Placebo
Arm/Group Description	Systemic Therapy	Systemic Therapy
Measure Participants	56	57
Median (95% Confidence Interval) [months]	17.5	19.6

Adverse Events

Adverse Event Reporting Description	Adverse Event analysis includes only patients who were enrolled, randomized and treated
Arm/Group Title	Paclitaxel/Bevacizumab/Everolimus		Paclitaxel/Bevacizumab/Placebo
Arm/Group Description
All Cause Mortality
	Paclitaxel/Bevacizumab/Everolimus		Paclitaxel/Bevacizumab/Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Paclitaxel/Bevacizumab/Everolimus		Paclitaxel/Bevacizumab/Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	16/55 (29.1%)		16/56 (28.6%)
Blood and lymphatic system disorders
NEUTROPENIA	1/55 (1.8%)	1	2/56 (3.6%)	8
FEBRILE NEUTROPENIA	1/55 (1.8%)	3	2/56 (3.6%)	3
PANCYTOPENIA	0/55 (0%)	0	1/56 (1.8%)	1
Cardiac disorders
LEFT VENTRICULAR DYSFUNCTION	1/55 (1.8%)	1	0/56 (0%)	0
TACHYCARDIA	0/55 (0%)	0	1/56 (1.8%)	1
Gastrointestinal disorders
ABDOMINAL PAIN	0/55 (0%)	0	1/56 (1.8%)	1
PANCREATITIS	1/55 (1.8%)	1	0/56 (0%)	0
HAEMATEMESIS	0/55 (0%)	0	1/56 (1.8%)	1
INTESTINAL PERFORATION	0/55 (0%)	0	1/56 (1.8%)	1
OESOPHAGEAL OBSTRUCTION	0/55 (0%)	0	1/56 (1.8%)	1
General disorders
MUCOSAL INFLAMMATION	1/55 (1.8%)	1	0/56 (0%)	0
Hepatobiliary disorders
JAUNDICE	1/55 (1.8%)	1	0/56 (0%)	0
Infections and infestations
BRONCHITIS	1/55 (1.8%)	1	0/56 (0%)	0
CLOSTRIDIUM DIFFICILE COLITIS	1/55 (1.8%)	1	0/56 (0%)	0
DIVERTICULITIS	1/55 (1.8%)	1	0/56 (0%)	0
INFECTION	1/55 (1.8%)	1	0/56 (0%)	0
PELVIC INFLAMMATORY DISEASE	1/55 (1.8%)	1	0/56 (0%)	0
PNEUMONIA	2/55 (3.6%)	2	0/56 (0%)	0
CATHETER RELATED INFECTION	0/55 (0%)	0	1/56 (1.8%)	1
CENTRAL LINE INFECTION	0/55 (0%)	0	1/56 (1.8%)	2
Metabolism and nutrition disorders
DEHYDRATION	3/55 (5.5%)	4	0/56 (0%)	0
HYPERGLYCAEMIA	1/55 (1.8%)	1	0/56 (0%)	0
Musculoskeletal and connective tissue disorders
MUSCULAR WEAKNESS	1/55 (1.8%)	1	0/56 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
LYMPHANGIOSIS CARCINOMATOSA	1/55 (1.8%)	1	0/56 (0%)	0
METASTASES TO CENTRAL NERVOUS SYSTEM	0/55 (0%)	0	1/56 (1.8%)	1
Nervous system disorders
CONVULSION	1/55 (1.8%)	1	0/56 (0%)	0
TRANSIENT ISCHAEMIC ATTACK	0/55 (0%)	0	1/56 (1.8%)	1
Psychiatric disorders
CONFUSIONAL STATE	0/55 (0%)	0	1/56 (1.8%)	1
Renal and urinary disorders
RENAL FAILURE ACUTE	1/55 (1.8%)	1	1/56 (1.8%)	1
RENAL FAILURE	0/55 (0%)	0	1/56 (1.8%)	1
Respiratory, thoracic and mediastinal disorders
CHRONIC OBSTRUCTIVE PULMONARY DISEASE	1/55 (1.8%)	1	0/56 (0%)	0
HYPOXIA	1/55 (1.8%)	1	0/56 (0%)	0
PULMONARY EMBOLISM	2/55 (3.6%)	2	1/56 (1.8%)	1
BRONCHIAL OBSTRUCTION	0/55 (0%)	0	1/56 (1.8%)	1
PNEUMONITIS	0/55 (0%)	0	1/56 (1.8%)	1
RESPIRATORY FAILURE	0/55 (0%)	0	2/56 (3.6%)	2
Vascular disorders
DEEP VEIN THROMBOSIS	1/55 (1.8%)	1	1/56 (1.8%)	1
THROMBOSIS	0/55 (0%)	0	1/56 (1.8%)	1
Other (Not Including Serious) Adverse Events
	Paclitaxel/Bevacizumab/Everolimus		Paclitaxel/Bevacizumab/Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	55/55 (100%)		56/56 (100%)
Blood and lymphatic system disorders
ANAEMIA	22/55 (40%)	67	8/56 (14.3%)	25
LEUKOPENIA	15/55 (27.3%)	43	10/56 (17.9%)	23
NEUTROPENIA	27/55 (49.1%)	71	24/56 (42.9%)	57
THROMBOCYTOPENIA	11/55 (20%)	29	7/56 (12.5%)	8
Gastrointestinal disorders
ABDOMINAL PAIN	9/55 (16.4%)	10	3/56 (5.4%)	4
ABDOMINAL PAIN UPPER	5/55 (9.1%)	5	3/56 (5.4%)	3
CONSTIPATION	17/55 (30.9%)	22	17/56 (30.4%)	26
DIARRHOEA	38/55 (69.1%)	68	24/56 (42.9%)	37
DRY MOUTH	4/55 (7.3%)	4	2/56 (3.6%)	2
DYSPEPSIA	5/55 (9.1%)	6	8/56 (14.3%)	8
GASTROOESOPHAGEAL REFLUX DISEASE	1/55 (1.8%)	1	10/56 (17.9%)	10
HAEMORRHOIDS	5/55 (9.1%)	5	2/56 (3.6%)	2
NAUSEA	30/55 (54.5%)	54	25/56 (44.6%)	34
ORAL PAIN	7/55 (12.7%)	10	1/56 (1.8%)	3
STOMATITIS	16/55 (29.1%)	39	4/56 (7.1%)	4
VOMITING	22/55 (40%)	29	13/56 (23.2%)	15
General disorders
ASTHENIA	5/55 (9.1%)	6	7/56 (12.5%)	7
FATIGUE	42/55 (76.4%)	86	37/56 (66.1%)	76
MUCOSAL INFLAMMATION	21/55 (38.2%)	33	14/56 (25%)	21
OEDEMA PERIPHERAL	8/55 (14.5%)	14	12/56 (21.4%)	17
PAIN	3/55 (5.5%)	5	5/56 (8.9%)	6
PYREXIA	14/55 (25.5%)	21	7/56 (12.5%)	9
Infections and infestations
SINUSITIS	11/55 (20%)	19	6/56 (10.7%)	6
UPPER RESPIRATORY TRACT INFECTION	8/55 (14.5%)	9	9/56 (16.1%)	13
URINARY TRACT INFECTION	11/55 (20%)	16	12/56 (21.4%)	15
Investigations
ASPARTATE AMINOTRANSFERASE INCREASED	4/55 (7.3%)	7	2/56 (3.6%)	3
WEIGHT DECREASED	16/55 (29.1%)	24	7/56 (12.5%)	7
Metabolism and nutrition disorders
ANOREXIA	13/55 (23.6%)	20	8/56 (14.3%)	9
DEHYDRATION	8/55 (14.5%)	8	5/56 (8.9%)	7
HYPERCHOLESTEROLAEMIA	7/55 (12.7%)	9	3/56 (5.4%)	3
HYPERGLYCAEMIA	5/55 (9.1%)	6	4/56 (7.1%)	5
HYPOKALAEMIA	5/55 (9.1%)	6	3/56 (5.4%)	3
Musculoskeletal and connective tissue disorders
ARTHRALGIA	13/55 (23.6%)	20	10/56 (17.9%)	19
BACK PAIN	8/55 (14.5%)	9	8/56 (14.3%)	11
BONE PAIN	7/55 (12.7%)	8	8/56 (14.3%)	12
MUSCULOSKELETAL CHEST PAIN	6/55 (10.9%)	6	3/56 (5.4%)	3
MUSCULOSKELETAL PAIN	2/55 (3.6%)	2	4/56 (7.1%)	4
MYALGIA	10/55 (18.2%)	13	6/56 (10.7%)	8
PAIN IN EXTREMITY	6/55 (10.9%)	17	7/56 (12.5%)	8
Nervous system disorders
DIZZINESS	4/55 (7.3%)	4	8/56 (14.3%)	10
DYSGEUSIA	11/55 (20%)	15	9/56 (16.1%)	11
HEADACHE	19/55 (34.5%)	24	15/56 (26.8%)	26
HYPOAESTHESIA	3/55 (5.5%)	3	4/56 (7.1%)	5
NEUROPATHY PERIPHERAL	22/55 (40%)	52	27/56 (48.2%)	52
PERIPHERAL SENSORY NEUROPATHY	13/55 (23.6%)	27	12/56 (21.4%)	21
Psychiatric disorders
ANXIETY	6/55 (10.9%)	9	6/56 (10.7%)	6
DEPRESSION	8/55 (14.5%)	10	6/56 (10.7%)	7
INSOMNIA	10/55 (18.2%)	10	8/56 (14.3%)	8
Renal and urinary disorders
DYSURIA	1/55 (1.8%)	2	7/56 (12.5%)	9
PROTEINURIA	19/55 (34.5%)	46	12/56 (21.4%)	24
Respiratory, thoracic and mediastinal disorders
COUGH	17/55 (30.9%)	21	16/56 (28.6%)	20
DYSPHONIA	4/55 (7.3%)	4	3/56 (5.4%)	4
DYSPNOEA	17/55 (30.9%)	19	13/56 (23.2%)	18
EPISTAXIS	28/55 (50.9%)	40	19/56 (33.9%)	24
NASAL CONGESTION	4/55 (7.3%)	5	2/56 (3.6%)	2
OROPHARYNGEAL PAIN	9/55 (16.4%)	13	6/56 (10.7%)	7
PRODUCTIVE COUGH	6/55 (10.9%)	6	3/56 (5.4%)	5
RHINORRHOEA	3/55 (5.5%)	3	4/56 (7.1%)	5
Skin and subcutaneous tissue disorders
ALOPECIA	19/55 (34.5%)	23	30/56 (53.6%)	38
DERMATITIS ACNEIFORM	5/55 (9.1%)	16	1/56 (1.8%)	1
DRY SKIN	3/55 (5.5%)	3	5/56 (8.9%)	5
NAIL DISORDER	6/55 (10.9%)	6	14/56 (25%)	20
NIGHT SWEATS	1/55 (1.8%)	1	5/56 (8.9%)	6
RASH	22/55 (40%)	36	15/56 (26.8%)	21
Vascular disorders
FLUSHING	2/55 (3.6%)	2	4/56 (7.1%)	4
HOT FLUSH	3/55 (5.5%)	3	8/56 (14.3%)	10
HYPERTENSION	12/55 (21.8%)	19	14/56 (25%)	30
LYMPHOEDEMA	3/55 (5.5%)	3	4/56 (7.1%)	4

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The sponsor can review/embargo results communications prior to public release for a period that is >60 days but ≤180 days from the date submitted to sponsor, who may require changes to the communication in order to remove specifically identified confidential information (other than study data) and/or delay the proposed publication to enable the sponsor to seek patent protection for inventions. The PI may not publish results until 18 mos. after the trial has been completed at all sites.