INTORACT: Study Comparing Bevacizumab + Temsirolimus vs. Bevacizumab + Interferon-Alfa In Advanced Renal Cell Carcinoma Subjects

• Sponsor: Pfizer (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00631371
• Collaborator: (none)
• Enrollment: 791
• Locations: 172
• Arms: 2
• Duration (Months): 84
• Patients Per Site: 4.6
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

Primary objective: Comparison of independently assessed progression free survival (PFS) in subjects administered Bevacizumab + Temsirolimus vs. those administered Bevacizumab + Interferon-Alfa. Secondary objectives: safety, Investigator assessed PFS, objective response rate (independently assessed), and overall survival.

Condition or Disease	Intervention/Treatment	Phase
Renal Cell Carcinoma	Drug: Bevacizumab; Drug: Temsirolimus; Drug: Bevacizumab; Drug: Interferon-Alfa 9MU	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 791 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase 3b, Randomized, Open-Label Study Of Bevacizumab + Temsirolimus Vs. Bevacizumab + Interferon-Alfa As First-Line Treatment In Subjects With Advanced Renal Cell Carcinoma
• Study Start Date: Apr 1, 2008
• Actual Primary Completion Date: Apr 1, 2012
• Actual Study Completion Date: Apr 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1 Bevacizumab 10 mg/kg intravenous (IV) q8wks + Temsirolimus 25 mg IV weekly	Drug: Bevacizumab; Bevacizumab 10 mg/kg intravenous (IV) q8wks; Other Names: Torisel ; Drug: Temsirolimus; Temsirolimus 25 mg IV weekly
Active Comparator: 2 Bevacizumab 10 mg/kg intravenous (IV) q8wks + Interferon-Alfa 9MU SC TIW	Drug: Bevacizumab; Bevacizumab 10 mg/kg intravenous (IV) q8wks; Drug: Interferon-Alfa 9MU; Interferon-Alfa 9MU SC TIW

Outcome Measures

Primary Outcome Measures

1. Progression-Free Survival (PFS): Independent-Assessment [Baseline until disease progression, initiation of new anticancer treatment, or death, assessed every 8 weeks (up to cut-off date: 19 April 2012)]

   PFS was defined as the interval from the date of randomization until the earlier date of progression or death. Progression was assessed by independent imaging reviewers using Response Evaluation Criteria in Solid Tumors (RECIST) criteria which is 20% increase in sum of longest diameter of target lesions from nadir (the lowest blood counts); measurable increase in non-target lesion; appearance of new lesions.

Secondary Outcome Measures

1. Progression-Free Survival (PFS): Investigator-Assessment [Baseline until disease progression, initiation of new anticancer treatment, or death, assessed every 8 weeks (up to cut-off date: 19 April 2012)]

   PFS was defined as the interval from the date of randomization until the earlier date of progression or death. Progression was assessed by investigator imaging reviewers using RECIST criteria which is 20% increase in sum of longest diameter of target lesions from nadir (the lowest blood counts); measurable increase in non-target lesion; appearance of new lesions.

2. Percentage of Participants With Objective Response (Complete Response/Partial Response): Independent-Assessment [Baseline until disease progression, initiation of new anticancer treatment, or death, assessed every 8 weeks (up to cut-off date: 19 April 2012)]

   Percentage of participants with OR based assessment of confirmed complete response (CR) or confirmed partial response (PR) according to RECIST. Confirmed response were those that persisted on repeat imaging study at least 4 weeks after initial documentation of response. CR was defined as disappearance of all lesions (target and/or non target). PR were those with at least 30% decrease in sum of the longest dimensions of target lesions taking as a reference the baseline sum longest dimensions, with non target lesions not increased or absent.

3. Overall Survival (OS) [Baseline until death due to any cause, assessed every 8 weeks (up to cut-off date: 19 April 2012)]

   OS was defined as the time from randomization to death due to any cause, censored at the last date known alive. Death was determined from adverse event data (where outcome was death) or from follow-up contact data (where the participant current status was death).

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Histologically and/or cytologically confirmed to have advanced renal cell carcinoma (RCC)

• Majority component of conventional clear-cell type is mandatory

• At least 1 measurable lesion (per RECIST)

Exclusion Criteria:

• Prior systemic treatment for RCC

• Evidence of current or prior central nervous system (CNS) metastases

• Cardiovascular disease

• Pregnant or nursing women

• Additional criteria applies

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Hematology Oncology Services of Arkansas	Little Rock	Arkansas	United States	72205
2	South County Hematology/Oncology	Chula Vista	California	United States	91911
3	Cancer Center Oncology Medical Group	La Mesa	California	United States	91942
4	UCLA Medical Center	Los Angeles	California	United States	90095-1694
5	UCLA	Los Angeles	California	United States	90095-6984
6	UCLA	Los Angeles	California	United States	90095
7	North County Oncology Medical Clinic	Oceanside	California	United States	92056
8	Medical Oncology Associates - SD	San Diego	California	United States	92123
9	Sharp Memorial Hospital Investigational Pharmacy	San Diego	California	United States	92123
10	Sharp Rees-Stealy	San Diego	California	United States	92123
11	California Pacific Medical Center	San Francisco	California	United States	94115
12	Pacific Hematology/Oncology Associates	San Francisco	California	United States	94115
13	San Francisco Oncology Associates	San francisco	California	United States	94115
14	Cohen & Hufford MD's INC	San Francisco	California	United States	94118
15	The Jones Clinic, PC	New Albany	Mississippi	United States	38652
16	The Cleveland Clinic	Cleveland	Ohio	United States	44195
17	Edmond Oncology Center	Edmond	Oklahoma	United States	73034
18	OU Medical Center	Oklahoma City	Oklahoma	United States	73104
19	OU Physician's Building	Oklahoma City	Oklahoma	United States	73104
20	University of Oklahoma	Oklahoma City	Oklahoma	United States	73104
21	The Jones Clinic, PC	Germantown	Tennessee	United States	38138
22	The Vanderbilt Clinic	Nashville	Tennessee	United States	37232
23	University of Washington Medical Center	Seattle	Washington	United States	96195
24	Virginia Mason Medical Center	Seattle	Washington	United States	98101
25	Seattle Cancer Care Alliance	Seattle	Washington	United States	98109-1023
26	Centro Oncológico Rosario	Rosario	Santa Fé	Argentina	S2000KZE
27	Centro Medico San Roque	San Miguel de Tucuman	Tucuman	Argentina	T4000IAK
28	ISIS Clinica Especializado	Santa Fe		Argentina	3000
29	Mater Adult Hospital	South Brisbane	Queensland	Australia	4101
30	Royal Adelaide Hospital	Adelaide	South Australia	Australia	5000
31	Ashford Cancer Center Research	Kurralta Park	South Australia	Australia	5037
32	Cancer Care SA	Kurralta Park		Australia	5037
33	Mater Private Hospital	South Brisbane		Australia	QLD 4101
34	ZNA Middelheim	Antwerpen		Belgium	2020
35	Universitair Ziekenhuis Gent	Gent		Belgium	9000
36	Jessa Ziekenhuis - campus Virga Jessa	Hasselt		Belgium	3500
37	Cliniques Universitaires de Mont-Godinne UCL	Mont-Godinne		Belgium	5530
38	Centro Goiano de Oncologia	Goiania	GO	Brazil	74075-040
39	Centro Goiano de Oncologia - CGO	Goiania	GO	Brazil	74130-015
40	ProCura - Centro Goiano de Pesquisa Clínica Ltda	Goiania	GO	Brazil	74140-050
41	Clínica de Oncologia de Porto Alegre Sociedade Simples Ltda	Porto Alegre	Rio Grande do Sul	Brazil	90430-090
42	Instituto Nacional de Cancer - INCA	Rio de Janeiro	RJ	Brazil	20230-130
43	Associaçao Hospital de Caridade Ijui	Ijui	RS	Brazil	98700-000
44	Hospital de Clinicas de Porto Alegre	Porto Alegre	RS	Brazil	90035-003
45	Clinica de Oncologia de Porto Alegre - Sociedade Simples Ltda.	Porto Alegre	RS	Brazil	90430-090
46	Fundação Pio XII - Hospital de Câncer de Barretos	Barretos	Sao Paulo	Brazil	14784-400
47	Instituto de Oncologia de Piracicaba S/S Ltda	Piracicaba	SP	Brazil	13419-155
48	Instituto do Cancer do Estado de Sao Paulo Octavio Frias de Oliveira - ICESP	Sao Paulo	SP	Brazil	01246-000
49	Irmandade da Santa Casa de Misericordia de Porto Alegre	Porto Alegre		Brazil	90050-170
50	Instituto Nacional do Cancer - INCA	Rio de Janeiro		Brazil	20231-050
51	Odette Cancer Centre, Sunnybrook Health Sciences Centre	Toronto	Ontario	Canada	M4N 3M5
52	Centre de Sante et de Services Sociaux de Rimouski - Neigette	Rimouski	Quebec	Canada	G5L 5T1
53	Instituto Nacional del Cancer	Santiago	Region Metropolitana / Chile	Chile	8380455
54	Fundacion Arturo Lopez Perez	Santiago		Chile
55	Instituto Clinico Oncologico del Sur	Santiago		Chile
56	Oncologos del Occidente S.A	Pereira	Risaralda	Colombia
57	Oblastni nemocnice Jicin a s	Jicin	Ceska republika	Czech Republic	506 43
58	Masarykuv onkologicky ustav	Brno		Czech Republic	656 53
59	Fakultni nemocnice Olomouc	Olomouc		Czech Republic	775 20
60	Krajska zdravotni, a.s.	Usti nad Labem		Czech Republic	401 13
61	Centre Jean Perrin	Clermont-Ferrand		France	63011
62	Clinique Sainte Marguerite	Hyères		France	83400
63	Hopital Andre Mignot	Le Chesnay		France	78157
64	Centre médical Oncogard	Nimes		France	30907
65	CHU de Poitiers	Poitiers Cedex		France	86021
66	CHU de Rouen	Rouen Cedex		France	76031
67	Centre rené Gauducheau	Saint-Herblain-Nantes		France	44805
68	Hopital Foch	Suresnes		France	92151
69	Institut Gustave Roussy	Villejuif Cedex		France	94805
70	Vivantes Klinikum am Urban, Neztwerk fuer Gesundheit GmbH	Berlin		Germany	10967
71	Universitaetsklinikum Hamburg Eppendorf	Hamburg		Germany	20246
72	Klinikum Region Hannover, Krankenhaus Siloah	Hannover		Germany	30449
73	TU Muenchen, rechts der Isar	Muenchen		Germany	81675
74	Pamela Youde Nethersole Eastern Hospital	Chai Wan		Hong Kong
75	Prince of Wales Hospital	Hong Kong		Hong Kong
76	Queen Mary Hospital	Hong Kong		Hong Kong
77	Orszagos Onkologiai Intezet	Budapest		Hungary	1122
78	Uzsoki Utcai Korhaz	Budapest		Hungary	1145
79	Petz Aladar Megyei Oktato Korhaz	Gyor		Hungary	9024
80	Josa Andras Oktato Korhaz Nonprofit Kft.	Nyiregyhaza		Hungary	4400
81	Szegedi Tudomanyegyetem, Urologiai Klinika	Szeged		Hungary	6725
82	Veszprem Megyei Csolnoky Ferenc	Veszprem		Hungary	8200
83	Vedanta Institute of Medical Sciences	Ahmedabad	Gujarat	India	380009
84	Healthcare Global Enterprises Limited	Bangalore	Karnataka	India	560027
85	Lakeshore Hospital & Research Center Limited	Kochi	Kerala	India	682304
86	Jawaharlal Nehru Cancer Hospital, Department of Medical Oncology	Bhopal	Madhya Pradesh	India	462001
87	Tata Memorial Center	Mumbai	Maharashtra	India	400012
88	Tata Memorial Centre	Navi Mumbai	Maharashtra	India	410210
89	Jehangir Hospital	Pune	Maharashtra	India	411001
90	Searoc Cancer Centre	Jaipur	Rajasthan	India	302013
91	Apollo Hospital	Chennai	Tamil Nadu	India	600035
92	Regional Cancer Centre	Kerela	Trivandrum	India	695011
93	Divisione di Urologia, Azienda Ospedaliera Policlinico Consorziale di Bari	Bari		Italy	70124
94	Sezione di Oncologia Medica Centro di Ricerca Clinica	Chieti		Italy	66013
95	Unità Operativa di Oncologia, Azienda Ospedaliera Policlinico di Modena	Modena		Italy	41100
96	Farmacia del Comitato Etico Provinciale di Modena	Modena		Italy	41124
97	Struttura Complessa di Oncologia Medica Ospedale Santa Maria della Misericordia	Perugia		Italy	06132
98	IFO- Istituti Fisioterapici Ospitalieri	Roma		Italy	00144
99	Azienda Ospedaliera S. Maria	Terni		Italy	05100
100	Samsung Medical Center	Seoul	Korea	Korea, Republic of	135-710
101	Yonsei University Health System-Severance Hospital	Seoul		Korea, Republic of	120-752
102	University Malaya Medical Centre	Kuala Lumpur		Malaysia	59100
103	Hospital Aranda de la Parra	Leon	Guanajuato	Mexico	37000
104	Spaarne Ziekenhuis	Hoofddorp		Netherlands	2134 TM
105	Uniwersyteckie Centrum Kliniczne	Gdansk		Poland	80952
106	Szpital Specjalistyczny im. L. Rydygiera Sp. z o.o.	Krakow		Poland	31-826
107	Centrum Onkologii Ziemi Lubelskiej im. sw Jana z Dukli	Lublin		Poland	20-090
108	Szpital Kliniczny Przemienienia Panskiego UM im. Karola Marcinkowskiego w Poznaniu	Poznan		Poland	60-569
109	Centrum Onkologii, Instytut im. M. Sklodowskiej-Curie	Warszawa		Poland	02-781
110	Centrum Medyczne Ostrobramska NZOZ "Magodent"	Warszawa		Poland	04-125
111	Wojskowy Instytut Medyczny, Pracownia Badan Cynnosciowych Ukladu Oddechowego, Klinika Chorob Wewnetr	Warszawa		Poland	04-141
112	Wojskowy Intsytut Medyczny, Zaklad Diagnostyki Laboratoryjnej CSK MON	Warszawa		Poland	04-141
113	Wojskowy Intsytut Medyczny, Zaklad Medycyny Nuklearnej CSK MON	Warszawa		Poland	04-141
114	Hospital de San Joao	Porto		Portugal	4200-319
115	Hospital de São João	Porto		Portugal	4200-319
116	Medical Radiology Research Center of the Minzdravsotsrazvitiya of Russia	Obninsk	Kaluga region	Russian Federation	249036
117	Leningrad Regional Oncology Dispensary	Saint-Petersburg	Leningradskaya oblast	Russian Federation	188663
118	Republican Clinical Oncology Dispensary of Minzdrav of Tatarstan Republic	Kazan		Russian Federation	420029
119	Chair of Radiology and Radiotherapy	Moscow		Russian Federation	105077
120	N.N. Blokhin Russian Cancer Research Center, Department of Clinical Pharmacology and Chemotherapy	Moscow		Russian Federation	115478
121	N.N. Blokhin Russian Cancer Research Center, Department of Urology	Moscow		Russian Federation	115478
122	Moscow Scientific Research Oncology Institute P.A. Herzen	Moscow		Russian Federation	125284
123	Privolzhskiy District Medical Center of Federal Biomedical Agency	Nizhni Novgorod		Russian Federation	603109
124	Scientific research Institute of Oncology N.N. Petrov	Pesochny, Saint-Petersburg		Russian Federation	197758
125	City Hospital No.26	Saint-Petersburg		Russian Federation	196247
126	City Pokrovskaya Hospital	Saint-Petersburg		Russian Federation	199106
127	Clinical Center of Serbia	Belgrade		Serbia	11000
128	Institute for Oncology and Radiology of Serbia	Belgrade		Serbia	11000
129	Military Medical Academy	Belgrade		Serbia	11000
130	National Cancer Centre Singapore	Singapore		Singapore	169610
131	Fakultna Nemocnica s poliklinikou F D Roosevelta	Banska Bystrica		Slovakia	974 01
132	Oddelenie funkcnej diagnostiky	Banska Bystrica		Slovakia	974 01
133	Klinika pneumologie a ftiziologie FNsP LFUK	Bratislava		Slovakia	826 06
134	Fakultna Nemocnica s poliklinikou akad L Derera	Bratislava		Slovakia	833 05
135	Klinica nuklcarncj mediciny	Martin		Slovakia	036 59
136	Klinika nuklearnej mediciny JLF UK a Martinskej fakultnej nemocnice	Martin		Slovakia	036 59
137	Klinika tuberkulozy a plucnych chorob UK JLF a Martinskej fakultnej nemocince	Martin		Slovakia	036 59
138	Nemocnica s poliklinikou Skalica	Skalica		Slovakia	909 82
139	KK MED, s.r.o.	Zilina		Slovakia	012 07
140	MEDIVASA s.r.o.	Zilina		Slovakia	012 07
141	Nemocnica s poliklinikou Zilina	Zilina		Slovakia	012 07
142	GVI Oncology Trial Unit	Kraaifontein	Cape Town	South Africa	7570
143	Westridge Medical Centre	Mayville	Durban	South Africa	4001
144	Pretoria Urology Hospital	Hatfield	Pretoria	South Africa	0083
145	Panorama Medical Centre	Panorama, Cape Town	Western Cape	South Africa	7500
146	University of the Witwatersrand Oncology	Parktown		South Africa	2193
147	Langenhoven Drive Oncology Centre	Port Elizabeth		South Africa	6006
148	Dr. Fourie & Voges	Pretoria		South Africa	0084
149	Institut Catala Doncologia	L'hospitalet de Llobregat	Barcelona	Spain	08907
150	Hospital Universitario Marques de Valdecilla	Santander	Cantabria	Spain	39008
151	Hospital Sant Creu I Sant Pau	Barcelona		Spain	08025
152	Hospital del mar de Barcelona	Barcelona		Spain	8003
153	Hospital de Madrid Norte-Sanchinarro	Madrid		Spain	28050
154	Instituto Valenciano de Oncología	Valencia		Spain	46009
155	Veterans General Hospital-Taipei	Taipei	ROC	Taiwan	11217
156	Tri-Service General Hospital	Neihu	Tapei	Taiwan	114
157	China Medical University Hospital	Taichung		Taiwan	404
158	National Taiwan University Hospital	Taipei TOC		Taiwan	100
159	Division of Oncology	Tao Yuan		Taiwan	333
160	Universitet, kafedra onkologyy	Chenivtsi		Ukraine	58013
161	A.P Romodanov Itstitut nejrohirurhii	Chernovtsi		Ukraine	58001
162	Uchbobo-naukovyi likuvalnyi kompleks DDMU im. M.Gor'kogo	Donetsk		Ukraine	83003
163	Donetskyy Oblasyy protypukhlynnyy Tsenter	Donetsk		Ukraine	83092
164	Donetske Obl. clinico-teritorial'ne medichne ob'yednannya	Donetsk		Ukraine	83099
165	"State Institution ""Institute for Occupational Health of the	Kiev		Ukraine	01033
166	R.E.Kavetsky Institute of experimental pathology, oncology and radiobiology NAS of Ukraine,Laborator	Kiev		Ukraine	03115
167	A.P Romodanov Itstitut nejrohirurhii	Kiyv		Ukraine	04050
168	Oblasnyy onkologychnyy dispanser, onkourologichne viddilennya, Ivano-Frankivskiy Derzhavniy Medichni	Medychna vul., Ivano-Frankivsk		Ukraine	76018
169	Southampton General Hospital	Southampton	Hampshire	United Kingdom	SO16 6YD
170	Christie Hospital	Withington	Manchester	United Kingdom	M20 4BX
171	University of Leeds	Leeds	North Yorkshire	United Kingdom	LS9 7TF
172	Guy's Hospital	London		United Kingdom	SE1 7EH

Sponsors and Collaborators

• Pfizer

Investigators

• Study Director: Pfizer CT.gov Call Center, Pfizer

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• To obtain contact information for a study center near you, click here.

Publications

None provided.

• Responsible Party: Pfizer
• ClinicalTrials.gov Identifier: NCT00631371
• Other Study ID Numbers: 3066K1-3311; B1771006; 2007-003793-26
• First Posted: Mar 7, 2008
• Last Update Posted: Apr 27, 2016
• Last Verified: Mar 1, 2016

• Keywords provided by Pfizer: temsirolimus; renal cell carcinoma; kidney cancer; urogenital cancer
• Additional relevant MeSH terms: Carcinoma; Carcinoma, Renal Cell; Interferons; Interferon-alpha; Sirolimus; Bevacizumab

Study Results

Participant Flow

Recruitment Details	Approximately 800 participants enrolled in this study at 200 sites.
Pre-assignment Detail	Participants were randomized in a 1:1 ratio, stratified by prior nephrectomy status (yes/no) and Memorial Sloan Kettering Cancer Center (MSKCC) risk factors (good/intermediate/poor), and received either the combination treatment of Temisirolimus + Bevacizumab (Temsr+Bev) or Interferon-alfa + Bevacizumab (IFN+Bev).

Arm/Group Title	Bevacizumab+Temsirolimus	Bevacizumab+ Interferon-Alfa
Arm/Group Description	Bevacizumab 10 milligram per kilogram (mg/kg) intravenous infusion over 90 minutes, 60 minutes or 30 minutes depending on the participant's tolerability every other week along with temsirolimus 25 mg intravenous infusion over at least 30 minutes once a week. Treatment was continued until disease progression, unacceptable toxicities, withdrawal of consent, or death.	Bevacizumab 10 mg/kg intravenous infusion over 90 minutes, 60 minutes or 30 minutes depending on the participant's tolerability every other week along with interferon-alfa (IFN) 9 million units (MU) subcutaneous injection every 3 times a week. Treatment was continued until disease progression, unacceptable toxicities, withdrawal of consent, or death.
Period Title: Overall Study
STARTED	400	391
Treated	393	391
COMPLETED	0	0
NOT COMPLETED	400	391

Baseline Characteristics

Arm/Group Title	Bevacizumab+Temsirolimus	Bevacizumab+ Interferon-Alfa	Total
Arm/Group Description	Bevacizumab 10 milligram per kilogram (mg/kg) intravenous infusion over 90 minutes, 60 minutes or 30 minutes depending on the participant's tolerability every other week along with temsirolimus 25 mg intravenous infusion over at least 30 minutes once a week. Treatment was continued until disease progression, unacceptable toxicities, withdrawal of consent, or death.	Bevacizumab 10 mg/kg intravenous infusion over 90 minutes, 60 minutes or 30 minutes depending on the participant's tolerability every other week along with interferon-alfa (IFN) 9 million units (MU) subcutaneous injection every 3 times a week. Treatment was continued until disease progression, unacceptable toxicities, withdrawal of consent, or death.	Total of all reporting groups
Overall Participants	400	391	791
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	58.6 (10.1)	58.2 (10.4)	58.4 (10.2)
Sex: Female, Male (Count of Participants)
Female	114 28.5%	121 30.9%	235 29.7%
Male	286 71.5%	270 69.1%	556 70.3%

Outcome Measures

1. Primary Outcome

Title	Progression-Free Survival (PFS): Independent-Assessment
Description	PFS was defined as the interval from the date of randomization until the earlier date of progression or death. Progression was assessed by independent imaging reviewers using Response Evaluation Criteria in Solid Tumors (RECIST) criteria which is 20% increase in sum of longest diameter of target lesions from nadir (the lowest blood counts); measurable increase in non-target lesion; appearance of new lesions.
Time Frame	Baseline until disease progression, initiation of new anticancer treatment, or death, assessed every 8 weeks (up to cut-off date: 19 April 2012)

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population included all participants who were randomized to the study.

Arm/Group Title	Bevacizumab+Temsirolimus	Bevacizumab+ Interferon-Alfa
Arm/Group Description	Bevacizumab 10 milligram per kilogram (mg/kg) intravenous infusion over 90 minutes, 60 minutes or 30 minutes depending on the participant's tolerability every other week along with temsirolimus 25 mg intravenous infusion over at least 30 minutes once a week. Treatment was continued until disease progression, unacceptable toxicities, withdrawal of consent, or death.	Bevacizumab 10 mg/kg intravenous infusion over 90 minutes, 60 minutes or 30 minutes depending on the participant's tolerability every other week along with interferon-alfa (IFN) 9 million units (MU) subcutaneous injection every 3 times a week. Treatment was continued until disease progression, unacceptable toxicities, withdrawal of consent, or death.
Measure Participants	400	391
Median (95% Confidence Interval) [months]	9.1	9.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bevacizumab+Temsirolimus, Bevacizumab+ Interferon-Alfa
	Comments	P value was based on 1-sided stratified log-rank test (stratification factors: prior nephrectomy [yes/no] and Memorial Sloan Kettering Cancer Center [MSKCC] risk factors [good/intermediate/poor] at time of randomization). The hazard ratio and corresponding 95 percent (%) confidence interval (CI) from the stratified cox proportional hazard model were also presented.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.1
	Confidence Interval	(2-Sided) 95%; 0.9 to 1.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Progression-Free Survival (PFS): Investigator-Assessment
Description	PFS was defined as the interval from the date of randomization until the earlier date of progression or death. Progression was assessed by investigator imaging reviewers using RECIST criteria which is 20% increase in sum of longest diameter of target lesions from nadir (the lowest blood counts); measurable increase in non-target lesion; appearance of new lesions.
Time Frame	Baseline until disease progression, initiation of new anticancer treatment, or death, assessed every 8 weeks (up to cut-off date: 19 April 2012)

Outcome Measure Data

Analysis Population Description

ITT population included all participants who were randomized to the study.

Arm/Group Title	Bevacizumab+Temsirolimus	Bevacizumab+ Interferon-Alfa
Arm/Group Description	Bevacizumab 10 milligram per kilogram (mg/kg) intravenous infusion over 90 minutes, 60 minutes or 30 minutes depending on the participant's tolerability every other week along with temsirolimus 25 mg intravenous infusion over at least 30 minutes once a week. Treatment was continued until disease progression, unacceptable toxicities, withdrawal of consent, or death.	Bevacizumab 10 mg/kg intravenous infusion over 90 minutes, 60 minutes or 30 minutes depending on the participant's tolerability every other week along with interferon-alfa (IFN) 9 million units (MU) subcutaneous injection every 3 times a week. Treatment was continued until disease progression, unacceptable toxicities, withdrawal of consent, or death.
Measure Participants	400	391
Median (95% Confidence Interval) [months]	9.1	10.8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bevacizumab+Temsirolimus, Bevacizumab+ Interferon-Alfa
	Comments	P-value was based on 1-sided stratified log-rank test (stratification factors: prior nephrectomy [yes/no] and MSKCC risk factors [good/intermediate/poor] at time of randomization). The hazard ratio and corresponding 95% CI from the stratified cox proportional hazard model were also presented.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.1
	Confidence Interval	(2-Sided) 95%; 1.0 to 1.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Percentage of Participants With Objective Response (Complete Response/Partial Response): Independent-Assessment
Description	Percentage of participants with OR based assessment of confirmed complete response (CR) or confirmed partial response (PR) according to RECIST. Confirmed response were those that persisted on repeat imaging study at least 4 weeks after initial documentation of response. CR was defined as disappearance of all lesions (target and/or non target). PR were those with at least 30% decrease in sum of the longest dimensions of target lesions taking as a reference the baseline sum longest dimensions, with non target lesions not increased or absent.
Time Frame	Baseline until disease progression, initiation of new anticancer treatment, or death, assessed every 8 weeks (up to cut-off date: 19 April 2012)

Outcome Measure Data

Analysis Population Description

ITT population included all participants who were randomized to the study.

Arm/Group Title	Bevacizumab+Temsirolimus	Bevacizumab+ Interferon-Alfa
Arm/Group Description	Bevacizumab 10 milligram per kilogram (mg/kg) intravenous infusion over 90 minutes, 60 minutes or 30 minutes depending on the participant's tolerability every other week along with temsirolimus 25 mg intravenous infusion over at least 30 minutes once a week. Treatment was continued until disease progression, unacceptable toxicities, withdrawal of consent, or death.	Bevacizumab 10 mg/kg intravenous infusion over 90 minutes, 60 minutes or 30 minutes depending on the participant's tolerability every other week along with interferon-alfa (IFN) 9 million units (MU) subcutaneous injection every 3 times a week. Treatment was continued until disease progression, unacceptable toxicities, withdrawal of consent, or death.
Measure Participants	400	391
Number (95% Confidence Interval) [percentage of participants]	27.0 6.8%	27.4 7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bevacizumab+Temsirolimus, Bevacizumab+ Interferon-Alfa
	Comments	P-value (2-sided), risk ratio and associated 95% CI were based on Cochran-Mantel-Haenszel test stratified by prior nephrectomy and MSKCC risk group as randomized.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	1.0
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	1.0
	Confidence Interval	(2-Sided) 95%; 0.8 to 1.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Overall Survival (OS)
Description	OS was defined as the time from randomization to death due to any cause, censored at the last date known alive. Death was determined from adverse event data (where outcome was death) or from follow-up contact data (where the participant current status was death).
Time Frame	Baseline until death due to any cause, assessed every 8 weeks (up to cut-off date: 19 April 2012)

Outcome Measure Data

Analysis Population Description

ITT population included all participants who were randomized to the study.

Arm/Group Title	Bevacizumab+Temsirolimus	Bevacizumab+ Interferon-Alfa
Arm/Group Description	Bevacizumab 10 milligram per kilogram (mg/kg) intravenous infusion over 90 minutes, 60 minutes or 30 minutes depending on the participant's tolerability every other week along with temsirolimus 25 mg intravenous infusion over at least 30 minutes once a week. Treatment was continued until disease progression, unacceptable toxicities, withdrawal of consent, or death.	Bevacizumab 10 mg/kg intravenous infusion over 90 minutes, 60 minutes or 30 minutes depending on the participant's tolerability every other week along with interferon-alfa (IFN) 9 million units (MU) subcutaneous injection every 3 times a week. Treatment was continued until disease progression, unacceptable toxicities, withdrawal of consent, or death.
Measure Participants	400	391
Median (95% Confidence Interval) [months]	25.8	25.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bevacizumab+Temsirolimus, Bevacizumab+ Interferon-Alfa
	Comments	P value was based on 1-sided stratified log-rank test (stratification factors: prior nephrectomy [yes/no] and MSKCC risk factors [good/intermediate/poor] at time of randomization). The hazard ratio and corresponding 95% CI from the stratified cox proportional hazard model were also presented.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.0
	Confidence Interval	(2-Sided) 95%; 0.9 to 1.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication.
Adverse Event Reporting Description	The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Arm/Group Title	Bevacizumab+Temsirolimus		Bevacizumab+ Interferon-Alfa
Arm/Group Description	Bevacizumab 10 milligram per kilogram (mg/kg) intravenous infusion over 90 minutes, 60 minutes or 30 minutes depending on the participant's tolerability every other week along with temsirolimus 25 mg intravenous infusion over at least 30 minutes once a week. Treatment was continued until disease progression, unacceptable toxicities, withdrawal of consent, or death.		Bevacizumab 10 mg/kg intravenous infusion over 90 minutes, 60 minutes or 30 minutes depending on the participant's tolerability every other week along with interferon-alfa (IFN) 9 million units (MU) subcutaneous injection every 3 times a week. Treatment was continued until disease progression, unacceptable toxicities, withdrawal of consent, or death.
All Cause Mortality
	Bevacizumab+Temsirolimus		Bevacizumab+ Interferon-Alfa
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Bevacizumab+Temsirolimus		Bevacizumab+ Interferon-Alfa
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	184/393 (46.8%)		158/391 (40.4%)
Blood and lymphatic system disorders
Anaemia	10/393 (2.5%)		12/391 (3.1%)
Disseminated intravascular coagulation	0/393 (0%)		1/391 (0.3%)
Neutropenia	0/393 (0%)		1/391 (0.3%)
Thrombocytopenia	0/393 (0%)		1/391 (0.3%)
Cardiac disorders
Acute coronary syndrome	1/393 (0.3%)		0/391 (0%)
Acute myocardial infarction	1/393 (0.3%)		1/391 (0.3%)
Angina pectoris	0/393 (0%)		1/391 (0.3%)
Atrial fibrillation	0/393 (0%)		1/391 (0.3%)
Cardiac failure	3/393 (0.8%)		0/391 (0%)
Cardiac valve disease	1/393 (0.3%)		0/391 (0%)
Cardiopulmonary failure	1/393 (0.3%)		1/391 (0.3%)
Coronary artery disease	1/393 (0.3%)		0/391 (0%)
Coronary ostial stenosis	0/393 (0%)		1/391 (0.3%)
Left ventricular dysfunction	0/393 (0%)		1/391 (0.3%)
Cardio-Respiratory Arrest	0/393 (0%)		1/391 (0.3%)
Ear and labyrinth disorders
Vertigo	0/393 (0%)		1/391 (0.3%)
Eye disorders
Retinopathy	0/393 (0%)		2/391 (0.5%)
Vitreous floaters	0/393 (0%)		1/391 (0.3%)
Gastrointestinal disorders
Abdominal pain	8/393 (2%)		6/391 (1.5%)
Anal fissure	2/393 (0.5%)		0/391 (0%)
Anal fistula	2/393 (0.5%)		2/391 (0.5%)
Anal haemorrhage	1/393 (0.3%)		0/391 (0%)
Ascites	0/393 (0%)		1/391 (0.3%)
Colitis	2/393 (0.5%)		0/391 (0%)
Constipation	0/393 (0%)		1/391 (0.3%)
Diarrhoea	7/393 (1.8%)		5/391 (1.3%)
Gastric fistula	0/393 (0%)		1/391 (0.3%)
Gastric ulcer haemorrhage	1/393 (0.3%)		0/391 (0%)
Gastritis	2/393 (0.5%)		0/391 (0%)
Gastrointestinal haemorrhage	0/393 (0%)		1/391 (0.3%)
Gastrointestinal perforation	0/393 (0%)		1/391 (0.3%)
Gastrooesophageal reflux disease	1/393 (0.3%)		0/391 (0%)
Haemorrhoidal haemorrhage	0/393 (0%)		1/391 (0.3%)
Haemorrhoids	1/393 (0.3%)		0/391 (0%)
Ileal perforation	1/393 (0.3%)		0/391 (0%)
Ileus	1/393 (0.3%)		1/391 (0.3%)
Ileus paralytic	1/393 (0.3%)		0/391 (0%)
Intestinal haemorrhage	0/393 (0%)		1/391 (0.3%)
Intestinal obstruction	2/393 (0.5%)		0/391 (0%)
Intestinal perforation	1/393 (0.3%)		1/391 (0.3%)
Large intestine perforation	2/393 (0.5%)		1/391 (0.3%)
Lower gastrointestinal haemorrhage	1/393 (0.3%)		0/391 (0%)
Mouth ulceration	1/393 (0.3%)		0/391 (0%)
Nausea	1/393 (0.3%)		0/391 (0%)
Painful defaecation	1/393 (0.3%)		0/391 (0%)
Pancreatitis	2/393 (0.5%)		2/391 (0.5%)
Pancreatitis acute	1/393 (0.3%)		1/391 (0.3%)
Proctitis	1/393 (0.3%)		0/391 (0%)
Rectal haemorrhage	0/393 (0%)		1/391 (0.3%)
Small intestinal obstruction	0/393 (0%)		1/391 (0.3%)
Stomatitis	1/393 (0.3%)		1/391 (0.3%)
Subileus	0/393 (0%)		1/391 (0.3%)
Upper gastrointestinal haemorrhage	1/393 (0.3%)		2/391 (0.5%)
Vomiting	7/393 (1.8%)		2/391 (0.5%)
General disorders
Asthenia	4/393 (1%)		5/391 (1.3%)
Chills	0/393 (0%)		1/391 (0.3%)
Death	0/393 (0%)		4/391 (1%)
Disease progression	13/393 (3.3%)		16/391 (4.1%)
Fatigue	1/393 (0.3%)		7/391 (1.8%)
General physical health deterioration	2/393 (0.5%)		6/391 (1.5%)
Injury associated with device	0/393 (0%)		1/391 (0.3%)
Mucosal inflammation	5/393 (1.3%)		0/391 (0%)
Multi-organ failure	2/393 (0.5%)		0/391 (0%)
Non-cardiac chest pain	0/393 (0%)		1/391 (0.3%)
Oedema peripheral	1/393 (0.3%)		0/391 (0%)
Pain	1/393 (0.3%)		2/391 (0.5%)
Pyrexia	9/393 (2.3%)		7/391 (1.8%)
Sudden death	5/393 (1.3%)		0/391 (0%)
Condition Aggravated	1/393 (0.3%)		0/391 (0%)
Hepatobiliary disorders
Acute hepatic failure	0/393 (0%)		1/391 (0.3%)
Cholangitis	0/393 (0%)		1/391 (0.3%)
Cholecystitis	3/393 (0.8%)		0/391 (0%)
Cholecystitis acute	1/393 (0.3%)		0/391 (0%)
Cholecystitis chronic	0/393 (0%)		1/391 (0.3%)
Cholelithiasis	0/393 (0%)		1/391 (0.3%)
Hepatitis toxic	0/393 (0%)		1/391 (0.3%)
Immune system disorders
Contrast media allergy	0/393 (0%)		1/391 (0.3%)
Drug hypersensitivity	1/393 (0.3%)		0/391 (0%)
Infections and infestations
Abdominal abscess	0/393 (0%)		1/391 (0.3%)
Abscess	0/393 (0%)		1/391 (0.3%)
Abscess intestinal	0/393 (0%)		1/391 (0.3%)
Anal abscess	5/393 (1.3%)		2/391 (0.5%)
Anorectal cellulitis	1/393 (0.3%)		0/391 (0%)
Appendicitis	1/393 (0.3%)		1/391 (0.3%)
Bronchitis	0/393 (0%)		1/391 (0.3%)
Bronchopneumonia	3/393 (0.8%)		1/391 (0.3%)
Cellulitis	0/393 (0%)		1/391 (0.3%)
Cystitis	0/393 (0%)		1/391 (0.3%)
Diarrhoea infectious	1/393 (0.3%)		0/391 (0%)
Erysipelas	1/393 (0.3%)		0/391 (0%)
Gangrene	1/393 (0.3%)		0/391 (0%)
Gastroenteritis viral	0/393 (0%)		1/391 (0.3%)
Haematoma infection	0/393 (0%)		1/391 (0.3%)
Haemorrhoid infection	1/393 (0.3%)		0/391 (0%)
Infection	1/393 (0.3%)		1/391 (0.3%)
Infectious pleural effusion	2/393 (0.5%)		0/391 (0%)
Injection site infection	0/393 (0%)		1/391 (0.3%)
Liver abscess	1/393 (0.3%)		0/391 (0%)
Lower respiratory tract infection	1/393 (0.3%)		1/391 (0.3%)
Lung abscess	2/393 (0.5%)		0/391 (0%)
Osteomyelitis chronic	1/393 (0.3%)		0/391 (0%)
Perirectal abscess	2/393 (0.5%)		0/391 (0%)
Peritoneal abscess	1/393 (0.3%)		0/391 (0%)
Peritonitis	3/393 (0.8%)		2/391 (0.5%)
Pharyngitis	2/393 (0.5%)		0/391 (0%)
Pneumonia	16/393 (4.1%)		5/391 (1.3%)
Post procedural infection	0/393 (0%)		1/391 (0.3%)
Rectal abscess	1/393 (0.3%)		0/391 (0%)
Respiratory tract infection	2/393 (0.5%)		1/391 (0.3%)
Scrotal abscess	0/393 (0%)		1/391 (0.3%)
Sepsis	2/393 (0.5%)		4/391 (1%)
Septic shock	1/393 (0.3%)		2/391 (0.5%)
Sinusitis	2/393 (0.5%)		0/391 (0%)
Subcutaneous abscess	1/393 (0.3%)		1/391 (0.3%)
Tooth infection	2/393 (0.5%)		0/391 (0%)
Urinary tract infection	5/393 (1.3%)		4/391 (1%)
Urosepsis	1/393 (0.3%)		0/391 (0%)
Viral infection	1/393 (0.3%)		0/391 (0%)
Viral pharyngitis	1/393 (0.3%)		0/391 (0%)
Colonic abscess	0/393 (0%)		1/391 (0.3%)
Epididymitis	0/393 (0%)		1/391 (0.3%)
Plasmodium Malariae Infection	1/393 (0.3%)		0/391 (0%)
Pulmonary Tuberculosis	1/393 (0.3%)		0/391 (0%)
Pyelonephritis Acute	0/393 (0%)		1/391 (0.3%)
Injury, poisoning and procedural complications
Femoral neck fracture	0/393 (0%)		1/391 (0.3%)
Femur fracture	1/393 (0.3%)		1/391 (0.3%)
Head injury	0/393 (0%)		1/391 (0.3%)
Humerus fracture	1/393 (0.3%)		0/391 (0%)
Incisional hernia	1/393 (0.3%)		0/391 (0%)
Post procedural fistula	1/393 (0.3%)		0/391 (0%)
Seroma	1/393 (0.3%)		0/391 (0%)
Thoracic vertebral fracture	0/393 (0%)		2/391 (0.5%)
Ulna fracture	0/393 (0%)		1/391 (0.3%)
Wound complication	0/393 (0%)		1/391 (0.3%)
Investigations
Blood pressure systolic decreased	1/393 (0.3%)		0/391 (0%)
Fibrin D dimer increased	1/393 (0.3%)		0/391 (0%)
Haemoglobin decreased	0/393 (0%)		2/391 (0.5%)
Protein urine present	0/393 (0%)		1/391 (0.3%)
Weight decreased	0/393 (0%)		1/391 (0.3%)
Blood Bilirubin Increased	1/393 (0.3%)		0/391 (0%)
Blood Creatinine Increased	1/393 (0.3%)		0/391 (0%)
Metabolism and nutrition disorders
Decreased appetite	2/393 (0.5%)		0/391 (0%)
Dehydration	4/393 (1%)		3/391 (0.8%)
Diabetes mellitus	1/393 (0.3%)		1/391 (0.3%)
Diabetes mellitus inadequate control	1/393 (0.3%)		0/391 (0%)
Fluid retention	1/393 (0.3%)		0/391 (0%)
Gout	0/393 (0%)		1/391 (0.3%)
Hypercalcaemia	3/393 (0.8%)		2/391 (0.5%)
Hyperglycaemia	4/393 (1%)		0/391 (0%)
Hyperkalaemia	1/393 (0.3%)		3/391 (0.8%)
Hypoalbuminaemia	1/393 (0.3%)		0/391 (0%)
Hyponatraemia	3/393 (0.8%)		2/391 (0.5%)
Hypophagia	1/393 (0.3%)		0/391 (0%)
Ketosis	1/393 (0.3%)		0/391 (0%)
Tumour lysis syndrome	1/393 (0.3%)		0/391 (0%)
Type 2 diabetes mellitus	1/393 (0.3%)		0/391 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	3/393 (0.8%)		1/391 (0.3%)
Back pain	3/393 (0.8%)		3/391 (0.8%)
Bone lesion	0/393 (0%)		1/391 (0.3%)
Bone pain	1/393 (0.3%)		0/391 (0%)
Fistula	0/393 (0%)		1/391 (0.3%)
Flank pain	0/393 (0%)		1/391 (0.3%)
Gouty arthritis	0/393 (0%)		1/391 (0.3%)
Muscular weakness	2/393 (0.5%)		2/391 (0.5%)
Musculoskeletal chest pain	1/393 (0.3%)		1/391 (0.3%)
Myalgia	0/393 (0%)		1/391 (0.3%)
Pain in extremity	0/393 (0%)		1/391 (0.3%)
Pathological fracture	2/393 (0.5%)		1/391 (0.3%)
Spinal pain	1/393 (0.3%)		0/391 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
B-cell lymphoma	1/393 (0.3%)		0/391 (0%)
Colon cancer	1/393 (0.3%)		1/391 (0.3%)
Metastases to lung	1/393 (0.3%)		0/391 (0%)
Metastases to lymph nodes	0/393 (0%)		1/391 (0.3%)
Metastases to meninges	0/393 (0%)		1/391 (0.3%)
Metastasis	1/393 (0.3%)		0/391 (0%)
Metastatic pain	0/393 (0%)		1/391 (0.3%)
Metastatic renal cell carcinoma	1/393 (0.3%)		0/391 (0%)
Neoplasm progression	1/393 (0.3%)		0/391 (0%)
Renal cell carcinoma	4/393 (1%)		1/391 (0.3%)
Tumour associated fever	2/393 (0.5%)		0/391 (0%)
Tumour haemorrhage	1/393 (0.3%)		1/391 (0.3%)
Tumour ulceration	1/393 (0.3%)		0/391 (0%)
Nervous system disorders
Brain stem infarction	0/393 (0%)		1/391 (0.3%)
Cerebral haemorrhage	1/393 (0.3%)		0/391 (0%)
Cerebral infarction	0/393 (0%)		2/391 (0.5%)
Cerebrovascular accident	0/393 (0%)		3/391 (0.8%)
Dizziness	1/393 (0.3%)		1/391 (0.3%)
Epilepsy	1/393 (0.3%)		1/391 (0.3%)
Facial paresis	1/393 (0.3%)		0/391 (0%)
Haemorrhage intracranial	0/393 (0%)		1/391 (0.3%)
Haemorrhagic stroke	0/393 (0%)		2/391 (0.5%)
Headache	4/393 (1%)		2/391 (0.5%)
Hypertensive encephalopathy	1/393 (0.3%)		0/391 (0%)
Loss of consciousness	0/393 (0%)		1/391 (0.3%)
Mental impairment	0/393 (0%)		1/391 (0.3%)
Somnolence	1/393 (0.3%)		0/391 (0%)
Spinal cord compression	1/393 (0.3%)		1/391 (0.3%)
Syncope	0/393 (0%)		4/391 (1%)
Transient ischaemic attack	0/393 (0%)		4/391 (1%)
Tremor	0/393 (0%)		1/391 (0.3%)
Balance Disorder	1/393 (0.3%)		0/391 (0%)
Central Nervous System Haemorrhage	0/393 (0%)		1/391 (0.3%)
Seizure	3/393 (0.8%)		1/391 (0.3%)
Toxic Encephalopathy	0/393 (0%)		1/391 (0.3%)
Vascular Encephalopathy	0/393 (0%)		1/391 (0.3%)
Psychiatric disorders
Confusional state	2/393 (0.5%)		3/391 (0.8%)
Completed Suicide	0/393 (0%)		1/391 (0.3%)
Depression	0/393 (0%)		1/391 (0.3%)
Renal and urinary disorders
Nephrectasia	0/393 (0%)		1/391 (0.3%)
Nephrolithiasis	0/393 (0%)		1/391 (0.3%)
Nephrotic syndrome	4/393 (1%)		2/391 (0.5%)
Proteinuria	2/393 (0.5%)		3/391 (0.8%)
Renal disorder	1/393 (0.3%)		0/391 (0%)
Renal failure	5/393 (1.3%)		2/391 (0.5%)
Renal impairment	1/393 (0.3%)		0/391 (0%)
Ureteral disorder	0/393 (0%)		1/391 (0.3%)
Ureteric obstruction	1/393 (0.3%)		0/391 (0%)
Ureteric stenosis	0/393 (0%)		1/391 (0.3%)
Urinary retention	1/393 (0.3%)		0/391 (0%)
Acute Kidney Injury	4/393 (1%)		3/391 (0.8%)
Reproductive system and breast disorders
Benign prostatic hyperplasia	1/393 (0.3%)		0/391 (0%)
Respiratory, thoracic and mediastinal disorders
Aspiration	1/393 (0.3%)		0/391 (0%)
Atelectasis	1/393 (0.3%)		0/391 (0%)
Bronchospasm	2/393 (0.5%)		0/391 (0%)
Cough	1/393 (0.3%)		1/391 (0.3%)
Dyspnoea	3/393 (0.8%)		10/391 (2.6%)
Epistaxis	2/393 (0.5%)		2/391 (0.5%)
Haemoptysis	2/393 (0.5%)		3/391 (0.8%)
Hiccups	0/393 (0%)		1/391 (0.3%)
Interstitial lung disease	2/393 (0.5%)		0/391 (0%)
Lung disorder	1/393 (0.3%)		0/391 (0%)
Nasal septum disorder	0/393 (0%)		1/391 (0.3%)
Oropharyngeal pain	1/393 (0.3%)		0/391 (0%)
Orthopnoea	1/393 (0.3%)		0/391 (0%)
Pleural effusion	2/393 (0.5%)		2/391 (0.5%)
Pleuritic pain	0/393 (0%)		2/391 (0.5%)
Pneumonia aspiration	0/393 (0%)		1/391 (0.3%)
Pneumonitis	4/393 (1%)		0/391 (0%)
Pneumothorax	1/393 (0.3%)		0/391 (0%)
Pulmonary artery thrombosis	1/393 (0.3%)		0/391 (0%)
Pulmonary embolism	5/393 (1.3%)		4/391 (1%)
Pulmonary hypertension	1/393 (0.3%)		0/391 (0%)
Respiratory failure	3/393 (0.8%)		1/391 (0.3%)
Sputum discoloured	0/393 (0%)		1/391 (0.3%)
Skin and subcutaneous tissue disorders
Dermatitis allergic	1/393 (0.3%)		0/391 (0%)
Skin haemorrhage	1/393 (0.3%)		0/391 (0%)
Skin ulcer	1/393 (0.3%)		1/391 (0.3%)
Surgical and medical procedures
Malignant tumour excision	1/393 (0.3%)		0/391 (0%)
Cancer Surgery	1/393 (0.3%)		0/391 (0%)
Vascular disorders
Arteriosclerosis	0/393 (0%)		1/391 (0.3%)
Circulatory collapse	1/393 (0.3%)		1/391 (0.3%)
Deep vein thrombosis	2/393 (0.5%)		1/391 (0.3%)
Haematoma	0/393 (0%)		1/391 (0.3%)
Haemorrhage	0/393 (0%)		1/391 (0.3%)
Hypertension	6/393 (1.5%)		4/391 (1%)
Hypertensive crisis	1/393 (0.3%)		1/391 (0.3%)
Lymphoedema	1/393 (0.3%)		0/391 (0%)
Peripheral ischaemia	1/393 (0.3%)		0/391 (0%)
Thrombosis	1/393 (0.3%)		0/391 (0%)
Venous thrombosis	1/393 (0.3%)		0/391 (0%)
Peripheral Venous Disease	1/393 (0.3%)		0/391 (0%)
Other (Not Including Serious) Adverse Events
	Bevacizumab+Temsirolimus		Bevacizumab+ Interferon-Alfa
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	383/393 (97.5%)		378/391 (96.7%)
Blood and lymphatic system disorders
Anaemia	80/393 (20.4%)		66/391 (16.9%)
Leukopenia	17/393 (4.3%)		40/391 (10.2%)
Lymphopenia	24/393 (6.1%)		38/391 (9.7%)
Neutropenia	18/393 (4.6%)		66/391 (16.9%)
Thrombocytopenia	50/393 (12.7%)		40/391 (10.2%)
Ear and labyrinth disorders
Vertigo	4/393 (1%)		20/391 (5.1%)
Gastrointestinal disorders
Abdominal pain	48/393 (12.2%)		42/391 (10.7%)
Abdominal pain upper	31/393 (7.9%)		21/391 (5.4%)
Constipation	43/393 (10.9%)		48/391 (12.3%)
Diarrhoea	126/393 (32.1%)		86/391 (22%)
Gingival bleeding	5/393 (1.3%)		21/391 (5.4%)
Haemorrhoids	28/393 (7.1%)		13/391 (3.3%)
Nausea	69/393 (17.6%)		78/391 (19.9%)
Stomatitis	102/393 (26%)		39/391 (10%)
Toothache	37/393 (9.4%)		14/391 (3.6%)
Vomiting	53/393 (13.5%)		53/391 (13.6%)
General disorders
Asthenia	95/393 (24.2%)		113/391 (28.9%)
Chills	15/393 (3.8%)		44/391 (11.3%)
Fatigue	92/393 (23.4%)		122/391 (31.2%)
Influenza like illness	14/393 (3.6%)		48/391 (12.3%)
Mucosal inflammation	105/393 (26.7%)		40/391 (10.2%)
Oedema peripheral	67/393 (17%)		32/391 (8.2%)
Pyrexia	79/393 (20.1%)		154/391 (39.4%)
Infections and infestations
Upper respiratory tract infection	20/393 (5.1%)		15/391 (3.8%)
Urinary tract infection	23/393 (5.9%)		21/391 (5.4%)
Investigations
Alanine aminotransferase increased	38/393 (9.7%)		35/391 (9%)
Aspartate aminotransferase increased	33/393 (8.4%)		41/391 (10.5%)
Blood creatinine increased	40/393 (10.2%)		25/391 (6.4%)
Weight decreased	90/393 (22.9%)		93/391 (23.8%)
Blood Alkaline Phosphatase Increased	20/393 (5.1%)		14/391 (3.6%)
Metabolism and nutrition disorders
Decreased appetite	103/393 (26.2%)		127/391 (32.5%)
Hypercholesterolaemia	126/393 (32.1%)		39/391 (10%)
Hyperglycaemia	86/393 (21.9%)		19/391 (4.9%)
Hyperkalaemia	29/393 (7.4%)		37/391 (9.5%)
Hypertriglyceridaemia	114/393 (29%)		82/391 (21%)
Hypocalcaemia	24/393 (6.1%)		13/391 (3.3%)
Hypomagnesaemia	20/393 (5.1%)		16/391 (4.1%)
Hyponatraemia	23/393 (5.9%)		21/391 (5.4%)
Hypophosphataemia	40/393 (10.2%)		18/391 (4.6%)
Hypokalaemia	20/393 (5.1%)		4/391 (1%)
Musculoskeletal and connective tissue disorders
Arthralgia	52/393 (13.2%)		49/391 (12.5%)
Back pain	47/393 (12%)		53/391 (13.6%)
Bone pain	18/393 (4.6%)		22/391 (5.6%)
Musculoskeletal chest pain	27/393 (6.9%)		19/391 (4.9%)
Musculoskeletal pain	14/393 (3.6%)		28/391 (7.2%)
Myalgia	19/393 (4.8%)		60/391 (15.3%)
Pain in extremity	43/393 (10.9%)		35/391 (9%)
Nervous system disorders
Dizziness	29/393 (7.4%)		37/391 (9.5%)
Dysgeusia	33/393 (8.4%)		21/391 (5.4%)
Headache	77/393 (19.6%)		82/391 (21%)
Psychiatric disorders
Anxiety	7/393 (1.8%)		21/391 (5.4%)
Depression	11/393 (2.8%)		22/391 (5.6%)
Insomnia	28/393 (7.1%)		31/391 (7.9%)
Renal and urinary disorders
Proteinuria	143/393 (36.4%)		111/391 (28.4%)
Respiratory, thoracic and mediastinal disorders
Cough	79/393 (20.1%)		70/391 (17.9%)
Dysphonia	13/393 (3.3%)		30/391 (7.7%)
Dyspnoea	36/393 (9.2%)		49/391 (12.5%)
Epistaxis	110/393 (28%)		82/391 (21%)
Oropharyngeal pain	28/393 (7.1%)		16/391 (4.1%)
Skin and subcutaneous tissue disorders
Dry skin	27/393 (6.9%)		13/391 (3.3%)
Pruritus	60/393 (15.3%)		26/391 (6.6%)
Rash	126/393 (32.1%)		32/391 (8.2%)
Vascular disorders
Hypertension	128/393 (32.6%)		102/391 (26.1%)

Limitations/Caveats

[Not Specified]

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Certain Agreements

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

Pfizer has the right to review disclosures, requesting a delay of less than 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), less than 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.