Safety and Efficacy of Bevacizumab Plus RAD001 Versus Interferon Alfa-2a and Bevacizumab for the First-line Treatment in Adult Patients With Kidney Cancer

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00719264
• Collaborator: Roche Pharma AG (Industry)
• Enrollment: 365
• Locations: 108
• Arms: 2
• Actual Duration (Months): 53.1
• Patients Per Site: 3.4
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

To estimate the difference in efficacy and safety of bevacizumab and RAD001 compared to bevacizumab and interferon alfa-2a for first-line treatment of patients with metastatic carcinoma of the kidney.

Condition or Disease	Intervention/Treatment	Phase
Carcinoma; Adenocarcinoma; Renal Cell; Nephroid Carcinoma; Hypernephroid	Drug: RAD001(everolimus); Drug: interferon alfa-2a; Drug: bevacizumab	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 365 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized, Open-label, Multi-center Phase II Study to Compare Bevacizumab Plus RAD001 Versus Interferon Alfa-2a Plus Bevacizumab for the First-line Treatment of Patients With Metastatic Clear Cell Carcinoma of the Kidney
• Actual Study Start Date: Nov 12, 2008
• Actual Primary Completion Date: Dec 31, 2011
• Actual Study Completion Date: Apr 15, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: bevacizumab, RAD001 (everolimus) Participants received oral everolimus 10 mg qd plus intravenous bevacizumab 10mg/kg every 2 weeks	Drug: RAD001(everolimus); 10 mg qd; Other Names: Afinitor ; Drug: bevacizumab; 10 mg/kg every 2 weeks
Active Comparator: bevacizumab, interferon alfa-2a (IFN) Participants received subcutaneous IFN dose escalated from 3 MIU (million international unit) during week 1, 6 MIU during week 2, and 9 MIU during week 3 of treatment and subsequently (if tolerated), 3 times per week plus intravenous bevacizumab 10 mg/kg every 2 weeks	Drug: interferon alfa-2a; dose escalated from 3 MIU (million international unit) during week 1, 6 MIU during week 2, and 9 MIU during week 3; Drug: bevacizumab; 10 mg/kg every 2 weeks

Outcome Measures

Primary Outcome Measures

1. Progression-free Survival (PFS) of Participants Who Received RAD001 Plus Bevacizumab Versus Participants Who Received IFN Plus Bevacizumab [Time from randomization to the date of radiological progressive disease as per independent central review, death from any cause, or last tumor assessment, reported between date of first participant randomized until 31Dec2011, cutoff date.]

   Tumor response and disease progression were assessed using response evaluation criteria in solid tumors (RECIST), version 1.0. All target and non-target lesions identified at baseline were assessed using the same method, CT scan with contrast or MRI with contrast, throughout the trial. All scans were reviewed by independent, central radiology. Disease progression was defined as: 1) a 20% increase in the sum of the longest diameter of all target lesions, taking as reference the smallest sum of the longest diameters of all target lesions recorded at or after baseline or 2) the appearance of a new lesions or 3) the unequivocal progression of non-target lesions overall.

Secondary Outcome Measures

1. Overall Survival (OS) Treatment Effect in Participants Who Received RAD001 Plus Bevacizumab Versus Participants Who Received IFN Plus Bevacizumab [Time from randomization to the date of death from any cause, reported between date of first participant randomized and up to 2 years after the last participant randomized (data cutoff: 30Aug2012)]

   Overall survival (OS) was defined as the time of randomization to the date of death due to any cause.

2. Best Overall Response in Participants Who Received RAD001 Plus Bevacizumab Versus Participants Who Received IFN Plus Bevacizumab [Time from first participant randomized until 31Dec2011, cutoff date.]

   Overall response is defined as the number of participants having achieved confirmed Complete Response (CR) + Partial Response (PR). Confirmed CR = at least two determinations of CR at least 4 weeks apart before progression. Confirmed PR = at least two determinations of PR or better at least 4 weeks apart before progression. CR required a disappearance of all target and non-target lesions. PR required at least a 30% decrease in the sum of the longest diameters of all target lesions, taking as a reference the baseline sum of the longest diameters. Disease progression was defined as: 1) a 20% increase in the sum of the longest diameter of all target lesions, taking as reference the smallest sum of the longest diameters of all target lesions recorded at or after baseline or 2) the appearance of a new lesions or 3) the unequivocal progression of non-target lesions overall.

3. Response Duration Differences in Participants Who Received RAD001 Plus Bevacizumab Versus Participants Who Received IFN Plus Bevacizumab [Time from first documented response date of radiological progressive disease as per independent central review, death due to underlying cancer, or last tumor assessment, reported between date of first participant randomized until 31Dec2011, cut-off date.]

   The duration of response, applied only to participants with best overall response at CR or PR, is defined as the number of days between the date of first documented response (CR or PR) and the date of the event: radiological progression as per central review or death due to underlying cancer, whichever occurs first. If no event, participant is censored at the last adequate assessment.

4. Number of Participants Who Experienced Adverse Events (AEs), Serious Adverse Events and Deaths [From the first participant randomized until the last patient discontinued the study treatment + 28 days]

   Participants were monitored for adverse events, serious adverse events and deaths throughout the study. Participants were assessed continuously at each 28-day cycle.

5. Time to Definitive Deterioration of the Functional Assessment of Cancer Therapy Kidney Symptom Index, Disease Related Symptoms (FKSI-DRS) Risk Score by at Least 2 Score Units [Time from randomization to the date of definitive deterioration (defined as no later increase above the threshold observed during the study), or date of last assessment, reported between date of first patient randomized until 31Dec2011]

   The analysis of this outcome measure was based on the FKSI-DRS scale which is a validated disease-related symptom index containing 9 items that measure symptoms predominantly related to kidney cancer. Each item is scored on a 5-point scale (0 = not at all; 4 = very much). If at least 5 of the 9 questions have been answered, the FKSI-DRS total score is calculated by subtracting nine times the mean of the scores of the answered items from 36. Participants with less than 5 out of the 9 questions answered will have a missing FKSI-DRS total score. The FKSI-DRS total score ranges from 0 (most severe symptoms) to 36 (no symptoms). Definitive deterioration is defined as a decrease by at least 2 units compared to baseline, with no later increase above this threshold observed during the study. A single measure reporting a decrease of at least 2 units was considered definitive only if it is the last one available for the participant.

6. Time to Definitive Deterioration of the Global Health Status and the Physical Functioning (PF) Subscale Scores of the European Organization for the Research and Treatment of Cancer (EORTC)-Core Quality of Life Questionnaire (QLQ-C30) by at Least 10% [Time from randomization to the date of definitive deterioration (defined as no later increase above the threshold observed during the study), or date of last assessment, reported between date of first participant randomized until 31Dec2011]

   The EORTC QLQ-C30 contains 30 items. These include five functional scales (physical, role, emotional, social and cognitive functioning), three symptom scales (fatigue, pain, nausea, and vomiting), a global health status/QoL scale, and six single items (dyspnea, diarrhea, constipation, anorexia, insomnia and financial impact). The PF subscale consists of 5 questions each scored from 1 (not at all) to 4 (very much). The score for the PF subscale and global health status range from 0 to 100, with a higher score representing a high level of functioning/high quality of life. Definitive deterioration by at least 10% is defined as a decrease in score by at least 10% compared to baseline, with no later increase above this threshold observed during the course of the study. A single measure reporting a decrease of at least 10% is considered definitive only if it is the last one available for the participant.

7. Duration of Exposure of RAD001 in Participants Randomized to the Treatment Combination of RAD001 and Bevacizumab [From the date of the first participant treated until the last patient discontinued the study treatment + 28 days]

   This outcome measure was assessed continuously.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

1. Patients with metastatic renal cell carcinoma

2. Patients with at least one measurable lesion

3. Patients with progressive metastatic renal cell carcinoma

4. Patients who had a prior partial or complete nephrectomy

5. Patients with a Karnofsky Performance Status ≥70%.

6. Adequate bone marrow function

7. Adequate liver function

8. Adequate renal function

9. Adequate coagulation profile

Exclusion Criteria:

1. 4 weeks post-major surgery

2. Patients who had radiation therapy within 28 days prior to start of study

3. Patients in need for major surgical procedure during the course of the study.

4. Patients with a serious non-healing wound, ulcer, or bone fracture.

5. Patients with a history of seizure(s) not controlled with standard medical therapy.

6. Patients who have received prior systemic treatment for their metastatic RCC.

7. Patients who received prior therapy with VEGF pathway inhibitor

8. Patients who have previously received systemic mTOR inhibitors

9. Patients with a known hypersensitivity RAD001 (everolimus) or other rapamycins or to its excipients.

10. Patients with history or current central nervous system (CNS) metastases or spinal cord compression.

11. Patients with a history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to study enrollment.

12. Patients with proteinuria at screening.

13. Patients with inadequately controlled hypertension

14. Patients receiving ongoing or with recent need for full therapeutic dose of oral or parenteral anticoagulants or chronic daily treatment with aspirin

15. Patients receiving chronic systemic treatment with corticosteroids or another immunosuppressive agent.

16. Patients with a known history of HIV

17. Patients with hypersensitivity to interferon alfa-2a or any component of the product.

18. Patients with an active, bleeding diathesis or coagulopathy or recurrent thromboembolism

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

20. Left Ventricular Ejection Fraction < lower limit of institutional normal assessed by ECHO or MUGA

21. Patients who have a history of another primary malignancy ≤ 3 years

22. Female patients who are pregnant or breast feeding

23. Patients who are using other investigational agents or who had received investigational drugs ≤ 4 weeks prior to study treatment start.

24. Patients unwilling to or unable to comply with the protocol

Other protocol-defined inclusion/exclusion criteria may apply

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Highlands Oncology Group Dept of Highlands Oncology Grp	Fayetteville	Arkansas	United States	72703
2	City of Hope National Medical Center Dept.ofCityofHopeMedicalCtr(3)	Duarte	California	United States	91010-3000
3	USC/Kenneth Norris Comprehensive Cancer Center Regulatory Contact 3	Los Angeles	California	United States	90053
4	University of California at Los Angeles Dept. of Hem/Oncology	Los Angeles	California	United States	90095
5	Karmanos Cancer Institute Dept.of KarmanosCancerInst (5)	Detroit	Michigan	United States	48201
6	Nevada Cancer Institute Dept. of Nevada Cancer (3)	Las Vegas	Nevada	United States	89135
7	St. Luke's Hospital and Health Network St. Luke's Cancer Network	Bethlehem	Pennsylvania	United States
8	Las Colinas Hematology Oncology Grapevine	Irving	Texas	United States	75038
9	Seattle Cancer Care Alliance Dept. of SCCA	Seattle	Washington	United States	98105
10	Novartis Investigative Site	Bruxelles		Belgium	1070
11	Novartis Investigative Site	Bruxelles		Belgium	1200
12	Novartis Investigative Site	Charleroi		Belgium	6000
13	Novartis Investigative Site	Kortrijk		Belgium	8500
14	Novartis Investigative Site	Leuven		Belgium	3000
15	Novartis Investigative Site	Liege		Belgium	4000
16	Novartis Investigative Site	Rio de Janeiro	RJ	Brazil	20230-130
17	Novartis Investigative Site	Porto Alegre	RS	Brazil	90560-030
18	Novartis Investigative Site	Porto Alegre	RS	Brazil	90610-000
19	Novartis Investigative Site	Ribeirao Preto	SP	Brazil	14015-130
20	Novartis Investigative Site	Santo Andre	SP	Brazil	09060-650
21	Novartis Investigative Site	São Paulo	SP	Brazil	01246-000
22	Novartis Investigative Site	Olomouc		Czech Republic	775 20
23	Novartis Investigative Site	Prague		Czech Republic	140 00
24	Novartis Investigative Site	Cairo		Egypt
25	Novartis Investigative Site	Strasbourg	Cedex	France	67091
26	Novartis Investigative Site	Avignon		France	84000
27	Novartis Investigative Site	Bordeaux Cedex		France	33075
28	Novartis Investigative Site	Caen Cedex		France	14021
29	Novartis Investigative Site	La Roche sur Yon Cedex		France	85925
30	Novartis Investigative Site	Montellier cedex 5		France	34298
31	Novartis Investigative Site	Nantes cedex 2		France	44202
32	Novartis Investigative Site	Reims		France	51100
33	Novartis Investigative Site	Rouen Cedex		France	76031
34	Novartis Investigative Site	Strasbourg Cedex		France	67010
35	Novartis Investigative Site	Suresnes		France	92150
36	Novartis Investigative Site	Toulouse Cedex 9		France	31059
37	Novartis Investigative Site	Berlin		Germany	10117
38	Novartis Investigative Site	Berlin		Germany	13055
39	Novartis Investigative Site	Dessau		Germany	06846
40	Novartis Investigative Site	Essen		Germany	45122
41	Novartis Investigative Site	Frankfurt		Germany	60488
42	Novartis Investigative Site	Frankfurt		Germany	60590
43	Novartis Investigative Site	Göttingen		Germany	37075
44	Novartis Investigative Site	Hamburg		Germany	20246
45	Novartis Investigative Site	Hannover		Germany	30625
46	Novartis Investigative Site	Heidelberg		Germany	69115
47	Novartis Investigative Site	Leipzig		Germany	04109
48	Novartis Investigative Site	Mainz		Germany	55131
49	Novartis Investigative Site	Tübingen		Germany	72076
50	Novartis Investigative Site	Shatin, New Territories		Hong Kong
51	Novartis Investigative Site	Tuen Mun		Hong Kong
52	Novartis Investigative Site	Budapest		Hungary	1086
53	Novartis Investigative Site	Budapest		Hungary	1122
54	Novartis Investigative Site	Brescia	BS	Italy	25123
55	Novartis Investigative Site	Cremona	CR	Italy	26100
56	Novartis Investigative Site	Catanzaro	CZ	Italy	88100
57	Novartis Investigative Site	Firenze	FI	Italy	50134
58	Novartis Investigative Site	Milano	MI	Italy	20133
59	Novartis Investigative Site	Modena	MO	Italy	41100
60	Novartis Investigative Site	Perugia	PG	Italy	06129
61	Novartis Investigative Site	Aviano	PN	Italy	33081
62	Novartis Investigative Site	Pavia	PV	Italy	27100
63	Novartis Investigative Site	Roma	RM	Italy	00128
64	Novartis Investigative Site	Roma	RM	Italy	00152
65	Novartis Investigative Site	Trento	TN	Italy	38100
66	Novartis Investigative Site	Negrar	VR	Italy	37024
67	Novartis Investigative Site	Napoli		Italy	80131
68	Novartis Investigative Site	Goyang	Gyeonggi-do	Korea, Republic of	03722
69	Novartis Investigative Site	Seoul	Korea	Korea, Republic of	06351
70	Novartis Investigative Site	Daegu		Korea, Republic of	705-703
71	Novartis Investigative Site	Seoul		Korea, Republic of	136-705
72	Novartis Investigative Site	Taegu		Korea, Republic of	700 -721
73	Novartis Investigative Site	Leiden		Netherlands	2333 ZA
74	Novartis Investigative Site	Obninsk	Russia	Russian Federation	249036
75	Novartis Investigative Site	Moscow		Russian Federation	115478
76	Novartis Investigative Site	Moscow		Russian Federation	125284
77	Novartis Investigative Site	Saint Petersburg		Russian Federation	191104
78	Novartis Investigative Site	Saint-Petersburg		Russian Federation	197758
79	Novartis Investigative Site	Singapore		Singapore	258500
80	Novartis Investigative Site	Johannesburg		South Africa	2196
81	Novartis Investigative Site	Pretoria		South Africa	0001
82	Novartis Investigative Site	Pretoria		South Africa	0044
83	Novartis Investigative Site	Jaen	Andalucía	Spain	23007
84	Novartis Investigative Site	Santander	Cantabria	Spain	39008
85	Novartis Investigative Site	Barcelona		Spain	08041
86	Novartis Investigative Site	Madrid		Spain	28034
87	Novartis Investigative Site	Madrid		Spain	28041
88	Novartis Investigative Site	Santander		Spain	39008
89	Novartis Investigative Site	Zaragoza		Spain	50009
90	Novartis Investigative Site	Bern		Switzerland	3010
91	Novartis Investigative Site	Chur		Switzerland	7000
92	Novartis Investigative Site	Taipei	Taiwan, ROC	Taiwan	112
93	Novartis Investigative Site	Lin-Kou		Taiwan	33305
94	Novartis Investigative Site	Taichung		Taiwan	40705
95	Novartis Investigative Site	Taipei		Taiwan	10002
96	Novartis Investigative Site	Taipei		Taiwan	114
97	Novartis Investigative Site	Bangkok		Thailand	10330
98	Novartis Investigative Site	Songkla		Thailand	90110
99	Novartis Investigative Site	Adana		Turkey	01330
100	Novartis Investigative Site	Altunizade		Turkey	34662
101	Novartis Investigative Site	Ankara		Turkey	06100
102	Novartis Investigative Site	Antalya		Turkey	07070
103	Novartis Investigative Site	Balcova / Izmir		Turkey	35340
104	Novartis Investigative Site	Bursa		Turkey	16059
105	Novartis Investigative Site	Mecidiyekoy/Istanbul		Turkey	34394
106	Novartis Investigative Site	Northwood	Middlesex	United Kingdom	HA6 2RN
107	Novartis Investigative Site	Glasgow		United Kingdom	G12 0YN
108	Novartis Investigative Site	Southampton		United Kingdom	SO16 6YD

Sponsors and Collaborators

• Novartis Pharmaceuticals
• Roche Pharma AG

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Visit NovartisClinicalTrials.com: Pre-qualify for a trial, and view a list of trials and participating study centers.

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT00719264
• Other Study ID Numbers: CRAD001L2201; 2008-000077-38
• First Posted: Jul 21, 2008
• Last Update Posted: Mar 20, 2017
• Last Verified: Feb 1, 2017

• Keywords provided by Novartis Pharmaceuticals: Renal cell carcinoma; Adults; Bevacizumab; RAD001; Everolimus; Interferon; Clear; Roferon; Avastin; Nephrectomy; newly diagnosed
• Additional relevant MeSH terms: Carcinoma; Carcinoma, Renal Cell; Interferons; Interferon-alpha; Interferon alpha-2; Bevacizumab; Everolimus

Study Results

Participant Flow

Arm/Group Title	Bevacizumab, RAD001 (Everolimus)	Bevacizumab, Interferon Alfa-2a (IFN)
Arm/Group Description	Participants received oral everolimus 10 mg qd plus intravenous bevacizumab 10mg/kg every 2 weeks.	Participants received subcutaneous IFN dose escalated from 3 MIU (million international unit) during week 1, 6 MIU during week 2, and 9 MIU during week 3 of treatment and subsequently (if tolerated), 3 times per week plus intravenous bevacizumab 10 mg/kg every 2 weeks.
Period Title: Overall Study
STARTED	182	183
Full Analysis Set	182	183
Safety Set	180	181
COMPLETED	0	0
NOT COMPLETED	182	183

Baseline Characteristics

Arm/Group Title	Bevacizumab, RAD001 (Everolimus)	Bevacizumab, Interferon Alfa-2a (IFN)	Total
Arm/Group Description	Participants received oral everolimus 10 mg qd plus intravenous bevacizumab 10mg/kg every 2 weeks.	Participants received subcutaneous IFN dose escalated from 3 MIU (million international unit) during week 1, 6 MIU during week 2, and 9 MIU during week 3 of treatment and subsequently (if tolerated), 3 times per week plus intravenous bevacizumab 10 mg/kg every 2 weeks.	Total of all reporting groups
Overall Participants	182	183	365
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	60.71 (10.584)	59.93 (10.272)	60.32 (10.422)
Sex: Female, Male (Count of Participants)
Female	44 24.2%	52 28.4%	96 26.3%
Male	138 75.8%	131 71.6%	269 73.7%

Outcome Measures

1. Primary Outcome

Title	Progression-free Survival (PFS) of Participants Who Received RAD001 Plus Bevacizumab Versus Participants Who Received IFN Plus Bevacizumab
Description	Tumor response and disease progression were assessed using response evaluation criteria in solid tumors (RECIST), version 1.0. All target and non-target lesions identified at baseline were assessed using the same method, CT scan with contrast or MRI with contrast, throughout the trial. All scans were reviewed by independent, central radiology. Disease progression was defined as: 1) a 20% increase in the sum of the longest diameter of all target lesions, taking as reference the smallest sum of the longest diameters of all target lesions recorded at or after baseline or 2) the appearance of a new lesions or 3) the unequivocal progression of non-target lesions overall.
Time Frame	Time from randomization to the date of radiological progressive disease as per independent central review, death from any cause, or last tumor assessment, reported between date of first participant randomized until 31Dec2011, cutoff date.

Outcome Measure Data

Analysis Population Description

Full Analysis Set: This set consists of all randomized participants.

Arm/Group Title	Bevacizumab, RAD001 (Everolimus)	Bevacizumab, Interferon Alfa-2a (IFN)
Arm/Group Description	Participants received oral everolimus 10 mg qd plus intravenous bevacizumab 10mg/kg every 2 weeks.	Participants received subcutaneous IFN dose escalated from 3 MIU (million international unit) during week 1, 6 MIU during week 2, and 9 MIU during week 3 of treatment and subsequently (if tolerated), 3 times per week plus intravenous bevacizumab 10 mg/kg every 2 weeks.
Measure Participants	182	183
Median (95% Confidence Interval) [Months]	9.3	10.0

2. Secondary Outcome

Title	Overall Survival (OS) Treatment Effect in Participants Who Received RAD001 Plus Bevacizumab Versus Participants Who Received IFN Plus Bevacizumab
Description	Overall survival (OS) was defined as the time of randomization to the date of death due to any cause.
Time Frame	Time from randomization to the date of death from any cause, reported between date of first participant randomized and up to 2 years after the last participant randomized (data cutoff: 30Aug2012)

Outcome Measure Data

Analysis Population Description

Full Analysis Set: This set consists of all randomized participants.

Arm/Group Title	Bevacizumab, RAD001 (Everolimus)	Bevacizumab, Interferon Alfa-2a (IFN)
Arm/Group Description	Participants received oral everolimus 10 mg qd plus intravenous bevacizumab 10mg/kg every 2 weeks.	Participants received subcutaneous IFN dose escalated from 3 MIU (million international unit) during week 1, 6 MIU during week 2, and 9 MIU during week 3 of treatment and subsequently (if tolerated), 3 times per week plus intravenous bevacizumab 10 mg/kg every 2 weeks.
Measure Participants	182	183
Median (95% Confidence Interval) [Months]	27.1	27.1

3. Secondary Outcome

Title	Best Overall Response in Participants Who Received RAD001 Plus Bevacizumab Versus Participants Who Received IFN Plus Bevacizumab
Description	Overall response is defined as the number of participants having achieved confirmed Complete Response (CR) + Partial Response (PR). Confirmed CR = at least two determinations of CR at least 4 weeks apart before progression. Confirmed PR = at least two determinations of PR or better at least 4 weeks apart before progression. CR required a disappearance of all target and non-target lesions. PR required at least a 30% decrease in the sum of the longest diameters of all target lesions, taking as a reference the baseline sum of the longest diameters. Disease progression was defined as: 1) a 20% increase in the sum of the longest diameter of all target lesions, taking as reference the smallest sum of the longest diameters of all target lesions recorded at or after baseline or 2) the appearance of a new lesions or 3) the unequivocal progression of non-target lesions overall.
Time Frame	Time from first participant randomized until 31Dec2011, cutoff date.

Outcome Measure Data

Analysis Population Description

Full Analysis Set: This set consists of all randomized participants.

Arm/Group Title	Bevacizumab, RAD001 (Everolimus)	Bevacizumab, Interferon Alfa-2a (IFN)
Arm/Group Description	Participants received oral everolimus 10 mg qd plus intravenous bevacizumab 10mg/kg every 2 weeks.	Participants received subcutaneous IFN dose escalated from 3 MIU (million international unit) during week 1, 6 MIU during week 2, and 9 MIU during week 3 of treatment and subsequently (if tolerated), 3 times per week plus intravenous bevacizumab 10 mg/kg every 2 weeks.
Measure Participants	182	183
Complete response (CR)	0 0%	1 0.5%
Partial response (PR)	49 26.9%	50 27.3%
Stable disease (SD)	90 49.5%	84 45.9%
Progressive disease (PD)	25 13.7%	26 14.2%
Unknown response	18 9.9%	22 12%
Overall objective response (CR+PR)	49 26.9%	51 27.9%

4. Secondary Outcome

Title	Response Duration Differences in Participants Who Received RAD001 Plus Bevacizumab Versus Participants Who Received IFN Plus Bevacizumab
Description	The duration of response, applied only to participants with best overall response at CR or PR, is defined as the number of days between the date of first documented response (CR or PR) and the date of the event: radiological progression as per central review or death due to underlying cancer, whichever occurs first. If no event, participant is censored at the last adequate assessment.
Time Frame	Time from first documented response date of radiological progressive disease as per independent central review, death due to underlying cancer, or last tumor assessment, reported between date of first participant randomized until 31Dec2011, cut-off date.

Outcome Measure Data

Analysis Population Description

A subset of participants from the full analysis set were analyzed. The full analysis set consists of all randomized participants. the subset includes participants who were complete responders or partial responders.

Arm/Group Title	Bevacizumab, RAD001 (Everolimus)	Bevacizumab, Interferon Alfa-2a (IFN)
Arm/Group Description	Participants received oral everolimus 10 mg qd plus intravenous bevacizumab 10mg/kg every 2 weeks.	Participants received subcutaneous IFN dose escalated from 3 MIU (million international unit) during week 1, 6 MIU during week 2, and 9 MIU during week 3 of treatment and subsequently (if tolerated), 3 times per week plus intravenous bevacizumab 10 mg/kg every 2 weeks.
Measure Participants	49	51
Median (95% Confidence Interval) [Months]	13.3	11.3

5. Secondary Outcome

Title	Number of Participants Who Experienced Adverse Events (AEs), Serious Adverse Events and Deaths
Description	Participants were monitored for adverse events, serious adverse events and deaths throughout the study. Participants were assessed continuously at each 28-day cycle.
Time Frame	From the first participant randomized until the last patient discontinued the study treatment + 28 days

Outcome Measure Data

Analysis Population Description

Safety Set: The safety set included all participants who received at least one dose of study drug (everolimus, bevacizumab or IFN) and had a valid post-baseline assessment. No AE or occurrence of death, noted at assessment, constitutes a valid post-baseline safety assessment.

Arm/Group Title	Bevacizumab, RAD001 (Everolimus)	Bevacizumab, Interferon Alfa-2a (IFN)
Arm/Group Description	Participants received oral everolimus 10 mg qd plus intravenous bevacizumab 10mg/kg every 2 weeks.	Participants received subcutaneous IFN dose escalated from 3 MIU (million international unit) during week 1, 6 MIU during week 2, and 9 MIU during week 3 of treatment and subsequently (if tolerated), 3 times per week plus intravenous bevacizumab 10 mg/kg every 2 weeks.
Measure Participants	180	181
Adverse events (serious and non-serious)	179 98.4%	180 98.4%
Serious adverse events	79 43.4%	76 41.5%
Deaths	93 51.1%	95 51.9%

6. Secondary Outcome

Title	Time to Definitive Deterioration of the Functional Assessment of Cancer Therapy Kidney Symptom Index, Disease Related Symptoms (FKSI-DRS) Risk Score by at Least 2 Score Units
Description	The analysis of this outcome measure was based on the FKSI-DRS scale which is a validated disease-related symptom index containing 9 items that measure symptoms predominantly related to kidney cancer. Each item is scored on a 5-point scale (0 = not at all; 4 = very much). If at least 5 of the 9 questions have been answered, the FKSI-DRS total score is calculated by subtracting nine times the mean of the scores of the answered items from 36. Participants with less than 5 out of the 9 questions answered will have a missing FKSI-DRS total score. The FKSI-DRS total score ranges from 0 (most severe symptoms) to 36 (no symptoms). Definitive deterioration is defined as a decrease by at least 2 units compared to baseline, with no later increase above this threshold observed during the study. A single measure reporting a decrease of at least 2 units was considered definitive only if it is the last one available for the participant.
Time Frame	Time from randomization to the date of definitive deterioration (defined as no later increase above the threshold observed during the study), or date of last assessment, reported between date of first patient randomized until 31Dec2011

Outcome Measure Data

Analysis Population Description

Full Analysis Set: This set consists of all randomized participants.

Arm/Group Title	Bevacizumab, RAD001 (Everolimus)	Bevacizumab, Interferon Alfa-2a (IFN)
Arm/Group Description	Participants received oral everolimus 10 mg qd plus intravenous bevacizumab 10mg/kg every 2 weeks.	Participants received subcutaneous IFN dose escalated from 3 MIU (million international unit) during week 1, 6 MIU during week 2, and 9 MIU during week 3 of treatment and subsequently (if tolerated), 3 times per week plus intravenous bevacizumab 10 mg/kg every 2 weeks.
Measure Participants	182	183
Median (95% Confidence Interval) [Months]	7.4	8.0

7. Secondary Outcome

Title	Time to Definitive Deterioration of the Global Health Status and the Physical Functioning (PF) Subscale Scores of the European Organization for the Research and Treatment of Cancer (EORTC)-Core Quality of Life Questionnaire (QLQ-C30) by at Least 10%
Description	The EORTC QLQ-C30 contains 30 items. These include five functional scales (physical, role, emotional, social and cognitive functioning), three symptom scales (fatigue, pain, nausea, and vomiting), a global health status/QoL scale, and six single items (dyspnea, diarrhea, constipation, anorexia, insomnia and financial impact). The PF subscale consists of 5 questions each scored from 1 (not at all) to 4 (very much). The score for the PF subscale and global health status range from 0 to 100, with a higher score representing a high level of functioning/high quality of life. Definitive deterioration by at least 10% is defined as a decrease in score by at least 10% compared to baseline, with no later increase above this threshold observed during the course of the study. A single measure reporting a decrease of at least 10% is considered definitive only if it is the last one available for the participant.
Time Frame	Time from randomization to the date of definitive deterioration (defined as no later increase above the threshold observed during the study), or date of last assessment, reported between date of first participant randomized until 31Dec2011

Outcome Measure Data

Analysis Population Description

Full Analysis Set: This set consists of all randomized participants.

Arm/Group Title	Bevacizumab, RAD001 (Everolimus)	Bevacizumab, Interferon Alfa-2a (IFN)
Arm/Group Description	Participants received oral everolimus 10 mg qd plus intravenous bevacizumab 10mg/kg every 2 weeks.	Participants received subcutaneous IFN dose escalated from 3 MIU (million international unit) during week 1, 6 MIU during week 2, and 9 MIU during week 3 of treatment and subsequently (if tolerated), 3 times per week plus intravenous bevacizumab 10 mg/kg every 2 weeks.
Measure Participants	182	183
Global health status/QoL	7.4	7.8
Physical functioning	8.5	9.0

8. Secondary Outcome

Title	Duration of Exposure of RAD001 in Participants Randomized to the Treatment Combination of RAD001 and Bevacizumab
Description	This outcome measure was assessed continuously.
Time Frame	From the date of the first participant treated until the last patient discontinued the study treatment + 28 days

Outcome Measure Data

Analysis Population Description

Safety Set: The safety set included all participants who received at least one dose of study drug (everolimus, bevacizumab or IFN) and had a valid post-baseline assessment. No AE or occurrence of death, noted at assessment, constitutes a valid post-baseline safety assessment.

Arm/Group Title	Bevacizumab, RAD001 (Everolimus)
Arm/Group Description	Participants received oral everolimus 10 mg qd plus intravenous bevacizumab 10mg/kg every 2 weeks.
Measure Participants	180
Median (Full Range) [weeks]	37.0

Adverse Events

Arm/Group Title	Bevacizumab, RAD001 (Everolimus)		Bevacizumab, Interferon Alfa-2a (IFN)
Arm/Group Description	Participants received oral everolimus 10 mg qd plus intravenous bevacizumab 10mg/kg every 2 weeks.		Participants received subcutaneous IFN dose escalated from 3 MIU (million international unit) during week 1, 6 MIU during week 2, and 9 MIU during week 3 of treatment and subsequently (if tolerated), 3 times per week plus intravenous bevacizumab 10 mg/kg every 2 weeks.
All Cause Mortality
	Bevacizumab, RAD001 (Everolimus)		Bevacizumab, Interferon Alfa-2a (IFN)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Bevacizumab, RAD001 (Everolimus)		Bevacizumab, Interferon Alfa-2a (IFN)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	79/180 (43.9%)		76/181 (42%)
Blood and lymphatic system disorders
ANAEMIA	6/180 (3.3%)		8/181 (4.4%)
LEUKOPENIA	1/180 (0.6%)		0/181 (0%)
LYMPHADENOPATHY MEDIASTINAL	0/180 (0%)		1/181 (0.6%)
THROMBOCYTOPENIA	2/180 (1.1%)		0/181 (0%)
Cardiac disorders
ANGINA PECTORIS	1/180 (0.6%)		0/181 (0%)
CARDIAC ARREST	1/180 (0.6%)		2/181 (1.1%)
CARDIAC FAILURE	3/180 (1.7%)		0/181 (0%)
CARDIAC FAILURE ACUTE	1/180 (0.6%)		0/181 (0%)
CARDIAC FAILURE CONGESTIVE	3/180 (1.7%)		1/181 (0.6%)
TACHYCARDIA	0/180 (0%)		1/181 (0.6%)
VENTRICULAR TACHYCARDIA	0/180 (0%)		1/181 (0.6%)
Ear and labyrinth disorders
DEAFNESS	0/180 (0%)		1/181 (0.6%)
TINNITUS	1/180 (0.6%)		0/181 (0%)
VERTIGO	0/180 (0%)		1/181 (0.6%)
Gastrointestinal disorders
ABDOMINAL DISTENSION	1/180 (0.6%)		1/181 (0.6%)
ABDOMINAL PAIN	8/180 (4.4%)		3/181 (1.7%)
ABDOMINAL PAIN UPPER	0/180 (0%)		2/181 (1.1%)
ANAL FISSURE	1/180 (0.6%)		0/181 (0%)
ANAL FISTULA	1/180 (0.6%)		0/181 (0%)
ASCITES	2/180 (1.1%)		0/181 (0%)
COLITIS	0/180 (0%)		2/181 (1.1%)
DIARRHOEA	5/180 (2.8%)		1/181 (0.6%)
DYSPHAGIA	1/180 (0.6%)		0/181 (0%)
ENTERITIS	1/180 (0.6%)		1/181 (0.6%)
FLATULENCE	0/180 (0%)		1/181 (0.6%)
GASTRIC FISTULA	1/180 (0.6%)		0/181 (0%)
GASTRIC ULCER	1/180 (0.6%)		1/181 (0.6%)
GASTRIC ULCER HAEMORRHAGE	1/180 (0.6%)		0/181 (0%)
GASTRITIS	0/180 (0%)		1/181 (0.6%)
GASTROOESOPHAGEAL REFLUX DISEASE	1/180 (0.6%)		0/181 (0%)
HAEMORRHOIDAL HAEMORRHAGE	0/180 (0%)		1/181 (0.6%)
INTESTINAL ISCHAEMIA	1/180 (0.6%)		0/181 (0%)
INTESTINAL OBSTRUCTION	3/180 (1.7%)		1/181 (0.6%)
MOUTH HAEMORRHAGE	0/180 (0%)		1/181 (0.6%)
NAUSEA	4/180 (2.2%)		2/181 (1.1%)
PANCREATITIS	1/180 (0.6%)		1/181 (0.6%)
PANCREATITIS CHRONIC	1/180 (0.6%)		0/181 (0%)
PROCTITIS	1/180 (0.6%)		0/181 (0%)
RECTAL HAEMORRHAGE	1/180 (0.6%)		0/181 (0%)
RETROPERITONEUM CYST	1/180 (0.6%)		0/181 (0%)
SIGMOIDITIS	1/180 (0.6%)		0/181 (0%)
SMALL INTESTINAL OBSTRUCTION	1/180 (0.6%)		0/181 (0%)
STOMATITIS	3/180 (1.7%)		0/181 (0%)
TOOTHACHE	0/180 (0%)		1/181 (0.6%)
UPPER GASTROINTESTINAL HAEMORRHAGE	1/180 (0.6%)		0/181 (0%)
VOMITING	4/180 (2.2%)		2/181 (1.1%)
General disorders
ASTHENIA	1/180 (0.6%)		2/181 (1.1%)
DISEASE PROGRESSION	1/180 (0.6%)		3/181 (1.7%)
DRUG INEFFECTIVE	0/180 (0%)		1/181 (0.6%)
FATIGUE	2/180 (1.1%)		3/181 (1.7%)
GENERAL PHYSICAL HEALTH DETERIORATION	2/180 (1.1%)		4/181 (2.2%)
GENERALISED OEDEMA	1/180 (0.6%)		0/181 (0%)
HYPERPYREXIA	0/180 (0%)		1/181 (0.6%)
MULTI-ORGAN FAILURE	0/180 (0%)		1/181 (0.6%)
NON-CARDIAC CHEST PAIN	0/180 (0%)		2/181 (1.1%)
OEDEMA PERIPHERAL	1/180 (0.6%)		0/181 (0%)
PERFORMANCE STATUS DECREASED	1/180 (0.6%)		0/181 (0%)
PYREXIA	3/180 (1.7%)		0/181 (0%)
SUDDEN DEATH	1/180 (0.6%)		0/181 (0%)
Hepatobiliary disorders
BILE DUCT OBSTRUCTION	0/180 (0%)		1/181 (0.6%)
CHOLECYSTITIS	0/180 (0%)		1/181 (0.6%)
CHOLELITHIASIS	0/180 (0%)		1/181 (0.6%)
CHOLESTASIS	0/180 (0%)		1/181 (0.6%)
HEPATOTOXICITY	1/180 (0.6%)		0/181 (0%)
JAUNDICE	1/180 (0.6%)		0/181 (0%)
Infections and infestations
ANAL ABSCESS	3/180 (1.7%)		0/181 (0%)
BRONCHITIS	1/180 (0.6%)		0/181 (0%)
BRONCHOPNEUMONIA	1/180 (0.6%)		1/181 (0.6%)
ESCHERICHIA URINARY TRACT INFECTION	0/180 (0%)		1/181 (0.6%)
INJECTION SITE INFECTION	0/180 (0%)		1/181 (0.6%)
LARYNGITIS	0/180 (0%)		1/181 (0.6%)
LUNG INFECTION	0/180 (0%)		1/181 (0.6%)
MYELITIS	0/180 (0%)		1/181 (0.6%)
NECROTISING FASCIITIS	1/180 (0.6%)		0/181 (0%)
OSTEOMYELITIS	1/180 (0.6%)		1/181 (0.6%)
PHARYNGITIS	1/180 (0.6%)		0/181 (0%)
PNEUMONIA	6/180 (3.3%)		2/181 (1.1%)
PYELONEPHRITIS	0/180 (0%)		1/181 (0.6%)
RESPIRATORY TRACT INFECTION	2/180 (1.1%)		1/181 (0.6%)
SEPSIS	4/180 (2.2%)		1/181 (0.6%)
SEPTIC SHOCK	1/180 (0.6%)		0/181 (0%)
SINUSITIS BACTERIAL	0/180 (0%)		1/181 (0.6%)
TONSILLITIS	1/180 (0.6%)		0/181 (0%)
TUBERCULOSIS	0/180 (0%)		1/181 (0.6%)
URINARY TRACT INFECTION	1/180 (0.6%)		3/181 (1.7%)
Injury, poisoning and procedural complications
ALCOHOL POISONING	1/180 (0.6%)		0/181 (0%)
CEMENT EMBOLISM	1/180 (0.6%)		0/181 (0%)
CRANIOCEREBRAL INJURY	1/180 (0.6%)		0/181 (0%)
FALL	0/180 (0%)		1/181 (0.6%)
FEMUR FRACTURE	1/180 (0.6%)		0/181 (0%)
FRACTURE	1/180 (0.6%)		0/181 (0%)
HEPATIC HAEMATOMA	0/180 (0%)		1/181 (0.6%)
INCISIONAL HERNIA	1/180 (0.6%)		0/181 (0%)
LACERATION	0/180 (0%)		1/181 (0.6%)
SPINAL COMPRESSION FRACTURE	1/180 (0.6%)		0/181 (0%)
SUBDURAL HAEMATOMA	1/180 (0.6%)		0/181 (0%)
TOXICITY TO VARIOUS AGENTS	1/180 (0.6%)		1/181 (0.6%)
VASCULAR PSEUDOANEURYSM	0/180 (0%)		1/181 (0.6%)
Investigations
BLOOD CREATINE INCREASED	1/180 (0.6%)		0/181 (0%)
BLOOD CREATININE INCREASED	3/180 (1.7%)		0/181 (0%)
EJECTION FRACTION DECREASED	1/180 (0.6%)		0/181 (0%)
GAMMA-GLUTAMYLTRANSFERASE INCREASED	0/180 (0%)		1/181 (0.6%)
HAEMOGLOBIN DECREASED	1/180 (0.6%)		0/181 (0%)
WEIGHT DECREASED	1/180 (0.6%)		2/181 (1.1%)
Metabolism and nutrition disorders
CACHEXIA	1/180 (0.6%)		0/181 (0%)
DECREASED APPETITE	3/180 (1.7%)		4/181 (2.2%)
DEHYDRATION	3/180 (1.7%)		3/181 (1.7%)
DIABETES MELLITUS INADEQUATE CONTROL	1/180 (0.6%)		0/181 (0%)
HYPERCALCAEMIA	3/180 (1.7%)		1/181 (0.6%)
HYPERGLYCAEMIA	1/180 (0.6%)		0/181 (0%)
HYPERKALAEMIA	1/180 (0.6%)		1/181 (0.6%)
HYPERVOLAEMIA	0/180 (0%)		1/181 (0.6%)
HYPOALBUMINAEMIA	0/180 (0%)		1/181 (0.6%)
HYPOGLYCAEMIA	2/180 (1.1%)		0/181 (0%)
HYPOKALAEMIA	1/180 (0.6%)		0/181 (0%)
HYPONATRAEMIA	3/180 (1.7%)		3/181 (1.7%)
METABOLIC ACIDOSIS	1/180 (0.6%)		0/181 (0%)
Musculoskeletal and connective tissue disorders
ARTHRALGIA	1/180 (0.6%)		4/181 (2.2%)
BACK PAIN	1/180 (0.6%)		5/181 (2.8%)
BONE LOSS	1/180 (0.6%)		0/181 (0%)
BONE PAIN	1/180 (0.6%)		1/181 (0.6%)
GROIN PAIN	1/180 (0.6%)		0/181 (0%)
INTERVERTEBRAL DISC PROTRUSION	1/180 (0.6%)		0/181 (0%)
MUSCULAR WEAKNESS	1/180 (0.6%)		0/181 (0%)
PAIN IN EXTREMITY	0/180 (0%)		1/181 (0.6%)
PATHOLOGICAL FRACTURE	0/180 (0%)		3/181 (1.7%)
ROTATOR CUFF SYNDROME	1/180 (0.6%)		0/181 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
CANCER PAIN	0/180 (0%)		1/181 (0.6%)
INTESTINAL ADENOCARCINOMA	0/180 (0%)		1/181 (0.6%)
MALIGNANT NEOPLASM PROGRESSION	0/180 (0%)		1/181 (0.6%)
METASTASES TO BONE	1/180 (0.6%)		0/181 (0%)
PROSTATE CANCER	1/180 (0.6%)		0/181 (0%)
Nervous system disorders
CEREBRAL INFARCTION	1/180 (0.6%)		0/181 (0%)
CEREBRAL ISCHAEMIA	0/180 (0%)		1/181 (0.6%)
CEREBROVASCULAR ACCIDENT	0/180 (0%)		3/181 (1.7%)
COMA	0/180 (0%)		1/181 (0.6%)
CONVULSION	1/180 (0.6%)		1/181 (0.6%)
DIZZINESS	1/180 (0.6%)		1/181 (0.6%)
ENCEPHALOPATHY	0/180 (0%)		1/181 (0.6%)
EPILEPSY	0/180 (0%)		2/181 (1.1%)
HAEMORRHAGE INTRACRANIAL	1/180 (0.6%)		0/181 (0%)
HEADACHE	2/180 (1.1%)		0/181 (0%)
SPINAL CORD COMPRESSION	1/180 (0.6%)		1/181 (0.6%)
TRANSIENT ISCHAEMIC ATTACK	0/180 (0%)		2/181 (1.1%)
Psychiatric disorders
ACUTE PSYCHOSIS	0/180 (0%)		1/181 (0.6%)
ANXIETY	0/180 (0%)		1/181 (0.6%)
CONFUSIONAL STATE	0/180 (0%)		2/181 (1.1%)
DELIRIUM	1/180 (0.6%)		0/181 (0%)
DEPRESSION	0/180 (0%)		1/181 (0.6%)
MENTAL STATUS CHANGES	0/180 (0%)		1/181 (0.6%)
SOPOR	0/180 (0%)		1/181 (0.6%)
Renal and urinary disorders
BLADDER DILATATION	0/180 (0%)		1/181 (0.6%)
NEPHROTIC SYNDROME	1/180 (0.6%)		1/181 (0.6%)
OLIGURIA	1/180 (0.6%)		0/181 (0%)
PROTEINURIA	1/180 (0.6%)		2/181 (1.1%)
RENAL COLIC	1/180 (0.6%)		0/181 (0%)
RENAL FAILURE	5/180 (2.8%)		1/181 (0.6%)
RENAL FAILURE ACUTE	2/180 (1.1%)		0/181 (0%)
RENAL IMPAIRMENT	0/180 (0%)		2/181 (1.1%)
TUBULOINTERSTITIAL NEPHRITIS	1/180 (0.6%)		0/181 (0%)
URINARY RETENTION	1/180 (0.6%)		0/181 (0%)
Reproductive system and breast disorders
MENORRHAGIA	1/180 (0.6%)		0/181 (0%)
TESTICULAR PAIN	1/180 (0.6%)		0/181 (0%)
Respiratory, thoracic and mediastinal disorders
ACUTE PULMONARY OEDEMA	1/180 (0.6%)		0/181 (0%)
ATELECTASIS	0/180 (0%)		1/181 (0.6%)
BRONCHOSPASM	1/180 (0.6%)		0/181 (0%)
CHRONIC OBSTRUCTIVE PULMONARY DISEASE	2/180 (1.1%)		0/181 (0%)
COUGH	1/180 (0.6%)		0/181 (0%)
DYSPNOEA	6/180 (3.3%)		3/181 (1.7%)
DYSPNOEA EXERTIONAL	0/180 (0%)		1/181 (0.6%)
EMPHYSEMA	0/180 (0%)		1/181 (0.6%)
EPISTAXIS	5/180 (2.8%)		0/181 (0%)
HAEMOPTYSIS	2/180 (1.1%)		2/181 (1.1%)
PLEURAL EFFUSION	3/180 (1.7%)		2/181 (1.1%)
PNEUMONIA ASPIRATION	1/180 (0.6%)		0/181 (0%)
PNEUMONITIS	1/180 (0.6%)		0/181 (0%)
PULMONARY EMBOLISM	1/180 (0.6%)		2/181 (1.1%)
PULMONARY OEDEMA	1/180 (0.6%)		1/181 (0.6%)
RESPIRATORY FAILURE	1/180 (0.6%)		0/181 (0%)
SLEEP APNOEA SYNDROME	1/180 (0.6%)		0/181 (0%)
Vascular disorders
ACCELERATED HYPERTENSION	0/180 (0%)		1/181 (0.6%)
CIRCULATORY COLLAPSE	1/180 (0.6%)		0/181 (0%)
HYPERTENSION	4/180 (2.2%)		3/181 (1.7%)
HYPERTENSIVE CRISIS	2/180 (1.1%)		2/181 (1.1%)
HYPOTENSION	1/180 (0.6%)		0/181 (0%)
HYPOVOLAEMIC SHOCK	1/180 (0.6%)		0/181 (0%)
THROMBOSIS	0/180 (0%)		1/181 (0.6%)
Other (Not Including Serious) Adverse Events
	Bevacizumab, RAD001 (Everolimus)		Bevacizumab, Interferon Alfa-2a (IFN)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	173/180 (96.1%)		179/181 (98.9%)
Blood and lymphatic system disorders
ANAEMIA	35/180 (19.4%)		35/181 (19.3%)
LEUKOPENIA	4/180 (2.2%)		12/181 (6.6%)
LYMPHOPENIA	4/180 (2.2%)		11/181 (6.1%)
NEUTROPENIA	7/180 (3.9%)		21/181 (11.6%)
THROMBOCYTOPENIA	16/180 (8.9%)		29/181 (16%)
Cardiac disorders
TACHYCARDIA	9/180 (5%)		2/181 (1.1%)
Gastrointestinal disorders
ABDOMINAL PAIN	18/180 (10%)		19/181 (10.5%)
ABDOMINAL PAIN UPPER	10/180 (5.6%)		9/181 (5%)
CONSTIPATION	30/180 (16.7%)		26/181 (14.4%)
DIARRHOEA	71/180 (39.4%)		47/181 (26%)
DRY MOUTH	3/180 (1.7%)		11/181 (6.1%)
DYSPEPSIA	8/180 (4.4%)		11/181 (6.1%)
GINGIVAL BLEEDING	3/180 (1.7%)		11/181 (6.1%)
MOUTH ULCERATION	13/180 (7.2%)		3/181 (1.7%)
NAUSEA	38/180 (21.1%)		50/181 (27.6%)
STOMATITIS	111/180 (61.7%)		42/181 (23.2%)
TOOTHACHE	16/180 (8.9%)		12/181 (6.6%)
VOMITING	25/180 (13.9%)		26/181 (14.4%)
General disorders
ASTHENIA	39/180 (21.7%)		62/181 (34.3%)
CHILLS	4/180 (2.2%)		21/181 (11.6%)
FATIGUE	57/180 (31.7%)		75/181 (41.4%)
INFLUENZA LIKE ILLNESS	5/180 (2.8%)		32/181 (17.7%)
MALAISE	2/180 (1.1%)		11/181 (6.1%)
OEDEMA PERIPHERAL	44/180 (24.4%)		18/181 (9.9%)
PYREXIA	24/180 (13.3%)		63/181 (34.8%)
Infections and infestations
GINGIVITIS	10/180 (5.6%)		7/181 (3.9%)
INFLUENZA	10/180 (5.6%)		5/181 (2.8%)
SINUSITIS	10/180 (5.6%)		6/181 (3.3%)
UPPER RESPIRATORY TRACT INFECTION	18/180 (10%)		7/181 (3.9%)
URINARY TRACT INFECTION	16/180 (8.9%)		16/181 (8.8%)
Investigations
ALANINE AMINOTRANSFERASE INCREASED	9/180 (5%)		4/181 (2.2%)
ASPARTATE AMINOTRANSFERASE INCREASED	10/180 (5.6%)		5/181 (2.8%)
BLOOD CREATININE INCREASED	20/180 (11.1%)		7/181 (3.9%)
GAMMA-GLUTAMYLTRANSFERASE INCREASED	10/180 (5.6%)		13/181 (7.2%)
WEIGHT DECREASED	51/180 (28.3%)		58/181 (32%)
Metabolism and nutrition disorders
DECREASED APPETITE	48/180 (26.7%)		80/181 (44.2%)
HYPERCHOLESTEROLAEMIA	40/180 (22.2%)		8/181 (4.4%)
HYPERGLYCAEMIA	18/180 (10%)		5/181 (2.8%)
HYPERKALAEMIA	5/180 (2.8%)		11/181 (6.1%)
HYPERTRIGLYCERIDAEMIA	24/180 (13.3%)		17/181 (9.4%)
HYPERURICAEMIA	3/180 (1.7%)		14/181 (7.7%)
Musculoskeletal and connective tissue disorders
ARTHRALGIA	33/180 (18.3%)		37/181 (20.4%)
BACK PAIN	22/180 (12.2%)		26/181 (14.4%)
BONE PAIN	8/180 (4.4%)		10/181 (5.5%)
MUSCULOSKELETAL CHEST PAIN	9/180 (5%)		11/181 (6.1%)
MYALGIA	11/180 (6.1%)		34/181 (18.8%)
PAIN IN EXTREMITY	25/180 (13.9%)		17/181 (9.4%)
Nervous system disorders
DIZZINESS	11/180 (6.1%)		12/181 (6.6%)
DYSGEUSIA	21/180 (11.7%)		7/181 (3.9%)
HEADACHE	36/180 (20%)		38/181 (21%)
Psychiatric disorders
DEPRESSION	8/180 (4.4%)		25/181 (13.8%)
INSOMNIA	23/180 (12.8%)		25/181 (13.8%)
Renal and urinary disorders
DYSURIA	10/180 (5.6%)		10/181 (5.5%)
PROTEINURIA	90/180 (50%)		68/181 (37.6%)
Respiratory, thoracic and mediastinal disorders
COUGH	54/180 (30%)		34/181 (18.8%)
DYSPHONIA	11/180 (6.1%)		9/181 (5%)
DYSPNOEA	28/180 (15.6%)		32/181 (17.7%)
EPISTAXIS	62/180 (34.4%)		38/181 (21%)
OROPHARYNGEAL PAIN	18/180 (10%)		7/181 (3.9%)
PNEUMONITIS	12/180 (6.7%)		1/181 (0.6%)
RHINORRHOEA	13/180 (7.2%)		9/181 (5%)
Skin and subcutaneous tissue disorders
DERMATITIS	13/180 (7.2%)		2/181 (1.1%)
DERMATITIS ACNEIFORM	9/180 (5%)		1/181 (0.6%)
DRY SKIN	22/180 (12.2%)		16/181 (8.8%)
PRURITUS	31/180 (17.2%)		22/181 (12.2%)
RASH	42/180 (23.3%)		20/181 (11%)
Vascular disorders
HYPERTENSION	67/180 (37.2%)		39/181 (21.5%)

Limitations/Caveats

[Not Specified]

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Certain Agreements

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

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial or disclosure of trial results in their entirety.