INTORSECT: Temsirolimus Versus Sorafenib As Second-Line Therapy In Patients With Advanced RCC Who Have Failed First-Line Sunitinib

• Sponsor: Pfizer (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00474786
• Collaborator: (none)
• Enrollment: 512
• Locations: 128
• Arms: 2
• Duration (Months): 64
• Patients Per Site: 4
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This is an international, randomized, open-label, outpatient, multicenter study. Subjects will be assigned in a 1:1 ratio to 1 of 2 treatment arms: temsirolimus 25 mg once weekly by intravenous (IV) infusion or sorafenib 400 mg by mouth (PO) twice daily (BID). These investigational drugs will be administered in 6-week cycles for the duration of the study, up to 24 months. Subjects will be stratified by nephrectomy status, duration of response to sunitinib therapy, Memorial Sloan Kettering Cancer Center (MSKCC) prognostic group, and RCC tumor histology.

Condition or Disease	Intervention/Treatment	Phase
Renal Cell Carcinoma	Drug: Sorafenib; Drug: temsirolimus (Torisel)	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 512 participants
• Allocation: Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized Trial Of Temsirolimus Versus Sorafenib As Second-Line Therapy In Patients With Advanced Renal Cell Carcinoma Who Have Failed First-Line Sunitinib Therapy
• Study Start Date: Sep 1, 2007
• Actual Primary Completion Date: Jan 1, 2012
• Actual Study Completion Date: Jan 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1	Drug: Sorafenib; Subjects randomized to arm B will take sorafenib 400 mg (2 x 200 mg tablets) PO, BID (total daily dose of 800 mg).
Experimental: 2	Drug: temsirolimus (Torisel); Subjects randomized to arm A will receive temsirolimus (Torisel) 25 mg via IV infusion once weekly. This infusion is to be administered over a 30-60 minute period. Subjects are to be pre-treated with 25-50 mg IV diphenhydramine (or comparable IV antihistamine) approximately 30 minutes before temsirolimus infusion.

Outcome Measures

Primary Outcome Measures

1. Progression-Free Survival (PFS) [Baseline up to 24 Months]

   Interval from date of randomization until documentation of progressive disease (PD) by an independent tumor assessment according to Response Evaluation Criteria in Solid Tumor (RECIST) or death for any reason whichever occurred first.

Secondary Outcome Measures

1. Progression Free Survival (PFS) by Investigator Assessment [Baseline up to 24 Months]

   Interval from date of randomization until documentation of PD by an investigator tumor assessment, symptomatic deterioration, or death for any reason whichever occurred first.

2. Percentage of Participants With Tumor Response [Baseline up to 24 Months]

   Percentage of participants with tumor response based on assessment of confirmed complete response (CR) or confirmed partial response (PR) according to RECIST and evaluated by independent central review. CR/PR persisted on repeat imaging study at least 4 weeks after initial documentation of response. PR had at least 30 percent decrease in the sum of the longest diameter (LD) of target lesions taking as reference the baseline sum LD.

3. Overall Survival (OS) [Baseline to date of death from any cause (up to 24 months)]

   Overall survival was the duration from randomization to death. For participants who are alive, overall survival was censored at the last contact.

4. Percentage of Participants With PFS Events at 12, 24 and 36 Weeks by Independent Assessment [Weeks 12, 24, and 36]

   PFS: Interval from date of randomization until documentation of PD by an independent tumor assessment according to RECIST or death for any reason whichever occurred first. PFS calculated as (Weeks)=(randomization date minus first dose date plus 1) divided by 7.

5. Duration of Response (DR) [Baseline up to 24 Months]

   Duration of response as defined by the time from CR or PR (whichever status recorded first) until the date of death or PD was objectively documented. Median and its 95 percent confidence interval (95% CI) were estimated using Kaplan-Meier method.

Other Outcome Measures

1. Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) [Baseline up to 24 months]

   Counts of participants who had treatment-emergent adverse events (TEAEs), defined as newly occurring or worsening after first dose. Relatedness to [study drug] was assessed by the investigator (Yes/No). Participants with multiple occurrences of an AE within a category were counted once within the category.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Histologically confirmed diagnosis of mRCC (regardless of histology or nephrectomy status) with well-documented Radiological PD by RECIST criteria or clinical PD as judged by the investigator while receiving first-line sunitinib therapy. Subjects must have at least 1 cycle of sunitinib therapy (minimum of four weeks continuously).

• At time of randomization, at least 2 weeks since prior treatment with sunitinib, palliative radiation therapy, and/or surgery.

• At time of randomization, there must be at least 1 measurable lesion per RECIST. Lesions that have been previously irradiated or embolized cannot be selected as target lesions.

• More criteria apply

Exclusion Criteria:

• Metastatic CNS from RCC.

• Subjects who discontinued Sutent therapy due specifically to intolerance.

• Prior systemic therapy for mRCC other than sunitinib.

• Active ketonuria, secondary to poorly controlled diabetes mellitus

• More criteria apply

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Pfizer Investigational Site	Duarte	California	United States	91010
2	Pfizer Investigational Site	La Jolla	California	United States	92037
3	Pfizer Investigational Site	La Jolla	California	United States	92093
4	Pfizer Investigational Site	Los Angeles	California	United States	90095-6984
5	Pfizer Investigational Site	Los Angeles	California	United States	90095
6	Pfizer Investigational Site	Orange	California	United States	92868
7	Pfizer Investigational Site	Riverside	California	United States	92505
8	Pfizer Investigational Site	San Diego	California	United States	92103
9	Pfizer Investigational Site	Meriden	Connecticut	United States	06451
10	Pfizer Investigational Site	Municie	Indiana	United States	47303
11	Pfizer Investigational Site	Louisville	Kentucky	United States	40202
12	Pfizer Investigational Site	Metairie	Louisiana	United States	70006
13	Pfizer Investigational Site	Baltimore	Maryland	United States	21201
14	Pfizer Investigational Site	Bethesda	Maryland	United States	20817
15	Pfizer Investigational Site	Tupelo	Mississippi	United States	38801
16	Pfizer Investigational Site	New York	New York	United States	10065
17	Pfizer Investigational Site	Cleveland	Ohio	United States	44195
18	Pfizer Investigational Site	Oklahoma City	Oklahoma	United States	73120
19	Pfizer Investigational Site	Tulsa	Oklahoma	United States	74104
20	Pfizer Investigational Site	Austin	Texas	United States	78731
21	Pfizer Investigational Site	Dallas	Texas	United States	75226
22	Pfizer Investigational Site	Dallas	Texas	United States	75246
23	Pfizer Investigational Site	San Antonio	Texas	United States	78229
24	Pfizer Investigational Site	Salt Lake City	Utah	United States	84112-5550
25	Pfizer Investigational Site	Salt Lake City	Utah	United States	84412
26	Pfizer Investigational Site	Seattle	Washington	United States	98101
27	Pfizer Investigational Site	Rosario	Santa Fé	Argentina	S2000KZE
28	Pfizer Investigational Site	Buenos Aires		Argentina	C1122AAL
29	Pfizer Investigational Site	Buenos Aires		Argentina	C1426ANZ
30	Pfizer Investigational Site	Buenos Aires		Argentina	C1437JCP
31	Pfizer Investigational Site	Nueva Cordoba		Argentina	X5006HBF
32	Pfizer Investigational Site	Tucuman		Argentina	T4000 IAK
33	Pfizer Investigational Site	Kogarah	New South Wales	Australia	2217
34	Pfizer Investigational Site	St Leonards	New South Wales	Australia	2065
35	Pfizer Investigational Site	Westmead	New South Wales	Australia	2145
36	Pfizer Investigational Site	South Brisbane	Queensland	Australia	4101
37	Pfizer Investigational Site	Adelaide	South Australia	Australia	5000
38	Pfizer Investigational Site	Elizabeth Vale	South Australia	Australia	5112
39	Pfizer Investigational Site	Woodville South	South Australia	Australia	5011
40	Pfizer Investigational Site	Salzburg		Austria	5020
41	Pfizer Investigational Site	Wien		Austria	1090
42	Pfizer Investigational Site	Edmonton	Alberta	Canada	T6G 1Z2
43	Pfizer Investigational Site	Kelowna	British Columbia	Canada	V1Y 5L3
44	Pfizer Investigational Site	Vancouver	British Columbia	Canada	V5Z 4E6
45	Pfizer Investigational Site	Victoria	British Columbia	Canada	V8R 6V5
46	Pfizer Investigational Site	Halifax	Nova Scotia	Canada	B3H 1V7
47	Pfizer Investigational Site	Halifax	Nova Scotia	Canada	B3H 2Y9
48	Pfizer Investigational Site	Halifax	Nova Scotia	Canada	B3H 3A7
49	Pfizer Investigational Site	Cornwall	Ontario	Canada	K6R 5S5
50	Pfizer Investigational Site	Hamilton	Ontario	Canada	L8N 4A6
51	Pfizer Investigational Site	London	Ontario	Canada	N6A 4G5
52	Pfizer Investigational Site	London	Ontario	Canada	N6A 4L6
53	Pfizer Investigational Site	Ottawa	Ontario	Canada	K1H 8L6
54	Pfizer Investigational Site	Ottawa	Ontario	Canada	K1Y 4K7
55	Pfizer Investigational Site	Toronto	Ontario	Canada	M4N 3M5
56	Pfizer Investigational Site	Toronto	Ontario	Canada	M5G 2M9
57	Pfizer Investigational Site	Montreal	Quebec	Canada	H3G 1A4
58	Pfizer Investigational Site	Providencia	Santiago	Chile
59	Pfizer Investigational Site	Hong Kong		China
60	Pfizer Investigational Site	Aarhus C		Denmark	8000
61	Pfizer Investigational Site	Herlev		Denmark	2730
62	Pfizer Investigational Site	Tampere		Finland	33 521
63	Pfizer Investigational Site	Turku		Finland	20 520
64	Pfizer Investigational Site	Montpellier	Cedex 5	France	34298
65	Pfizer Investigational Site	Angers		France	49100
66	Pfizer Investigational Site	Besancon		France	25000
67	Pfizer Investigational Site	Bordeaux		France	33075
68	Pfizer Investigational Site	Caen Cedex 05		France	14076
69	Pfizer Investigational Site	Clermont-Ferrand Cedex 1		France	63011
70	Pfizer Investigational Site	Dijon		France	21079
71	Pfizer Investigational Site	Lille		France	59000
72	Pfizer Investigational Site	Lyon Cedex 08		France	69373
73	Pfizer Investigational Site	Marseille Cedex 9		France	13273
74	Pfizer Investigational Site	Paris Cedex 15		France	75908
75	Pfizer Investigational Site	Poitiers Cedex		France	86021
76	Pfizer Investigational Site	Saint Herlain/Nantes Cedex		France	44805
77	Pfizer Investigational Site	Strasbourg		France	67091
78	Pfizer Investigational Site	Vandoeuvre Les Nancy		France	54511
79	Pfizer Investigational Site	Villejuif Cedex		France	94805
80	Pfizer Investigational Site	Berlin		Germany	10117
81	Pfizer Investigational Site	Dresden		Germany	01307
82	Pfizer Investigational Site	Heidelberg		Germany	69120
83	Pfizer Investigational Site	Kassel		Germany	34125
84	Pfizer Investigational Site	Luebeck		Germany	23538
85	Pfizer Investigational Site	Muenchen		Germany	81675
86	Pfizer Investigational Site	Neuss		Germany	41464
87	Pfizer Investigational Site	Ulm		Germany	89081
88	Pfizer Investigational Site	Budapest		Hungary	H-1122
89	Pfizer Investigational Site	Chieti		Italy	66013
90	Pfizer Investigational Site	Firenze		Italy	50134
91	Pfizer Investigational Site	Napoli		Italy	80131
92	Pfizer Investigational Site	Pavia		Italy	27100
93	Pfizer Investigational Site	Roma		Italy	00144
94	Pfizer Investigational Site	Roma		Italy	00152
95	Pfizer Investigational Site	Roma		Italy	0144
96	Pfizer Investigational Site	Seoul		Korea, Republic of	110-744
97	Pfizer Investigational Site	Seoul		Korea, Republic of	120-752
98	Pfizer Investigational Site	Seoul		Korea, Republic of	135-710
99	Pfizer Investigational Site	Seoul		Korea, Republic of	138-736
100	Pfizer Investigational Site	Dordrecht		Netherlands	3318 AT
101	Pfizer Investigational Site	Leeuwarden		Netherlands	8934 AD
102	Pfizer Investigational Site	Zwolle		Netherlands	8025 AB
103	Pfizer Investigational Site	Singapore		Singapore	169610
104	Pfizer Investigational Site	Oviedo	Asturias	Spain	33006
105	Pfizer Investigational Site	Badalona	Barcelona	Spain	08916
106	Pfizer Investigational Site	Sabadell	Barcelona	Spain	08208
107	Pfizer Investigational Site	Barcelona		Spain	08025
108	Pfizer Investigational Site	Madrid		Spain	28007
109	Pfizer Investigational Site	Madrid		Spain	28041
110	Pfizer Investigational Site	Sevilla		Spain	41013
111	Pfizer Investigational Site	Valencia		Spain	46010
112	Pfizer Investigational Site	Göteborg		Sweden	SE-413 45
113	Pfizer Investigational Site	Lund		Sweden	221 85
114	Pfizer Investigational Site	Malmo		Sweden	205 02
115	Pfizer Investigational Site	Kleinriehenstrasse 30	Basel	Switzerland
116	Pfizer Investigational Site	Basel	BS	Switzerland	4031
117	Pfizer Investigational Site	Geneva	GE	Switzerland	1221
118	Pfizer Investigational Site	Basel		Switzerland
119	Pfizer Investigational Site	Bruderholz		Switzerland
120	Pfizer Investigational Site	Luzern		Switzerland	6000
121	Pfizer Investigational Site	Rheinstrasse 26		Switzerland
122	Pfizer Investigational Site	Edgbaston	Birmingham	United Kingdom	B5 7UG
123	Pfizer Investigational Site	Cambridge	Cambridgeshire	United Kingdom	CB2 0QQ
124	Pfizer Investigational Site	Withington	Manchester	United Kingdom	M20 4BX
125	Pfizer Investigational Site	Birmingham		United Kingdom	B15 2TH
126	Pfizer Investigational Site	London		United Kingdom	SE1 9RT
127	Pfizer Investigational Site	Manchester		United Kingdom	M23 9LT
128	Pfizer Investigational Site	Newcastle upon Tyne		United Kingdom	NE4 6BE

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: NCT00474786
• Other Study ID Numbers: 3066K1-404; B1771003
• First Posted: May 17, 2007
• Last Update Posted: Nov 21, 2013
• Last Verified: Oct 1, 2013

• Keywords provided by Pfizer: Metastatic or Advanced Renal Cell Carcinoma
• Additional relevant MeSH terms: Carcinoma; Carcinoma, Renal Cell; Sirolimus; Sorafenib

Study Results

Participant Flow

Arm/Group Title	Temsirolimus	Sorafenib
Arm/Group Description	Temsirolimus 25 milligrams (mg) once weekly by intravenous (IV) infusion administered in 6 week cycles for up to 24 months, participants were premedicated with 25-50 mg IV diphenydramine 30 minutes before temsirolimus infusion. In event of toxicity, dose could be modified or held according to the protocol or at the discretion of the investigator.	Sorafenib 400 mg (two 200 mg tablets) by mouth (PO) twice daily (BID) administered in 6 week cycles for up to 24 months. In event of toxicity, dose could be modified or held according to the protocol or at the discretion of the investigator.
Period Title: Overall Study
STARTED	259	253
COMPLETED	0	0
NOT COMPLETED	259	253

Baseline Characteristics

Arm/Group Title	Temsirolimus	Sorafenib	Total
Arm/Group Description	Temsirolimus 25 milligrams (mg) once weekly by intravenous (IV) infusion administered in 6 week cycles for up to 24 months, participants were premedicated with 25-50 mg IV diphenydramine 30 minutes before temsirolimus infusion. In event of toxicity, dose could be modified or held according to the protocol or at the discretion of the investigator.	Sorafenib 400 mg (two 200 mg tablets) by mouth (PO) twice daily (BID) administered in 6 week cycles for up to 24 months. In event of toxicity, dose could be modified or held according to the protocol or at the discretion of the investigator.	Total of all reporting groups
Overall Participants	259	253	512
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	59.96 (10.20)	59.74 (10.33)	59.85 (10.25)
Sex: Female, Male (Count of Participants)
Female	66 25.5%	61 24.1%	127 24.8%
Male	193 74.5%	192 75.9%	385 75.2%

Outcome Measures

1. Primary Outcome

Title	Progression-Free Survival (PFS)
Description	Interval from date of randomization until documentation of progressive disease (PD) by an independent tumor assessment according to Response Evaluation Criteria in Solid Tumor (RECIST) or death for any reason whichever occurred first.
Time Frame	Baseline up to 24 Months

Outcome Measure Data

Analysis Population Description

Intent to Treat Population (ITT): all randomized participants according to their assigned treatment, regardless of whether they were received any study drug.

Arm/Group Title	Temsirolimus	Sorafenib
Arm/Group Description	Temsirolimus 25 milligrams (mg) once weekly by intravenous (IV) infusion administered in 6 week cycles for up to 24 months, participants were premedicated with 25-50 mg IV diphenydramine 30 minutes before temsirolimus infusion. In event of toxicity, dose could be modified or held according to the protocol or at the discretion of the investigator.	Sorafenib 400 mg (two 200 mg tablets) by mouth (PO) twice daily (BID) administered in 6 week cycles for up to 24 months. In event of toxicity, dose could be modified or held according to the protocol or at the discretion of the investigator.
Measure Participants	259	253
Median (95% Confidence Interval) [months]	4.28	3.91

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Temsirolimus, Sorafenib
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1933
	Comments	Stratified for nephrectomy status, duration of response to sunitinib therapy, tumor histology, and Memorial Sloan Kettering Cancer Center (MSKCC) prognostic group.
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	0.87
	Confidence Interval	(2-Sided) 95%; 0.71 to 1.07
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio less than (<) 1 means temsirolimus (TEMSR) is at lower risk.

2. Secondary Outcome

Title	Progression Free Survival (PFS) by Investigator Assessment
Description	Interval from date of randomization until documentation of PD by an investigator tumor assessment, symptomatic deterioration, or death for any reason whichever occurred first.
Time Frame	Baseline up to 24 Months

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	Temsirolimus	Sorafenib
Arm/Group Description	Temsirolimus 25 milligrams (mg) once weekly by intravenous (IV) infusion administered in 6 week cycles for up to 24 months, participants were premedicated with 25-50 mg IV diphenydramine 30 minutes before temsirolimus infusion. In event of toxicity, dose could be modified or held according to the protocol or at the discretion of the investigator.	Sorafenib 400 mg (two 200 mg tablets) by mouth (PO) twice daily (BID) administered in 6 week cycles for up to 24 months. In event of toxicity, dose could be modified or held according to the protocol or at the discretion of the investigator.
Measure Participants	259	253
Median (95% Confidence Interval) [months]	5.43	4.14

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Temsirolimus, Sorafenib
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1888
	Comments	Stratified for nephrectomy status, duration of response to sunitinib therapy, tumor histology, and Memorial Sloan Kettering Cancer Center (MSKCC) prognostic group.
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	0.87
	Confidence Interval	(2-Sided) 95%; 0.70 to 1.07
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio less than (<) 1 means temsirolimus (TEMSR) is at lower risk.

3. Secondary Outcome

Title	Percentage of Participants With Tumor Response
Description	Percentage of participants with tumor response based on assessment of confirmed complete response (CR) or confirmed partial response (PR) according to RECIST and evaluated by independent central review. CR/PR persisted on repeat imaging study at least 4 weeks after initial documentation of response. PR had at least 30 percent decrease in the sum of the longest diameter (LD) of target lesions taking as reference the baseline sum LD.
Time Frame	Baseline up to 24 Months

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	Temsirolimus	Sorafenib
Arm/Group Description	Temsirolimus 25 milligrams (mg) once weekly by intravenous (IV) infusion administered in 6 week cycles for up to 24 months, participants were premedicated with 25-50 mg IV diphenydramine 30 minutes before temsirolimus infusion. In event of toxicity, dose could be modified or held according to the protocol or at the discretion of the investigator.	Sorafenib 400 mg (two 200 mg tablets) by mouth (PO) twice daily (BID) administered in 6 week cycles for up to 24 months. In event of toxicity, dose could be modified or held according to the protocol or at the discretion of the investigator.
Measure Participants	259	253
Number (95% Confidence Interval) [percentage of participants]	7.7 3%	7.9 3.1%

4. Secondary Outcome

Title	Overall Survival (OS)
Description	Overall survival was the duration from randomization to death. For participants who are alive, overall survival was censored at the last contact.
Time Frame	Baseline to date of death from any cause (up to 24 months)

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	Temsirolimus	Sorafenib
Arm/Group Description	Temsirolimus 25 milligrams (mg) once weekly by intravenous (IV) infusion administered in 6 week cycles for up to 24 months, participants were premedicated with 25-50 mg IV diphenydramine 30 minutes before temsirolimus infusion. In event of toxicity, dose could be modified or held according to the protocol or at the discretion of the investigator.	Sorafenib 400 mg (two 200 mg tablets) by mouth (PO) twice daily (BID) administered in 6 week cycles for up to 24 months. In event of toxicity, dose could be modified or held according to the protocol or at the discretion of the investigator.
Measure Participants	259	253
Median (95% Confidence Interval) [months]	12.27	16.64

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Temsirolimus, Sorafenib
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0144
	Comments	Stratified for nephrectomy status, duration of response to sunitinib therapy, tumor histology, and MSKCC prognostic group.
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	1.31
	Confidence Interval	(2-Sided) 95%; 1.05 to 1.63
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio <1 means temsirolimus (TEMSR) is at lower risk.

5. Secondary Outcome

Title	Percentage of Participants With PFS Events at 12, 24 and 36 Weeks by Independent Assessment
Description	PFS: Interval from date of randomization until documentation of PD by an independent tumor assessment according to RECIST or death for any reason whichever occurred first. PFS calculated as (Weeks)=(randomization date minus first dose date plus 1) divided by 7.
Time Frame	Weeks 12, 24, and 36

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	Temsirolimus	Sorafenib
Arm/Group Description	Temsirolimus 25 milligrams (mg) once weekly by intravenous (IV) infusion administered in 6 week cycles for up to 24 months, participants were premedicated with 25-50 mg IV diphenydramine 30 minutes before temsirolimus infusion. In event of toxicity, dose could be modified or held according to the protocol or at the discretion of the investigator.	Sorafenib 400 mg (two 200 mg tablets) by mouth (PO) twice daily (BID) administered in 6 week cycles for up to 24 months. In event of toxicity, dose could be modified or held according to the protocol or at the discretion of the investigator.
Measure Participants	259	253
Baseline to Week 12	31.2 12%	36.7 14.5%
Week 13 to Week 24	20.9 8.1%	20.1 7.9%
Week 25 to Week 36	12.3 4.7%	11.2 4.4%

6. Secondary Outcome

Title	Duration of Response (DR)
Description	Duration of response as defined by the time from CR or PR (whichever status recorded first) until the date of death or PD was objectively documented. Median and its 95 percent confidence interval (95% CI) were estimated using Kaplan-Meier method.
Time Frame	Baseline up to 24 Months

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	Temsirolimus	Sorafenib
Arm/Group Description	Temsirolimus 25 milligrams (mg) once weekly by intravenous (IV) infusion administered in 6 week cycles for up to 24 months, participants were premedicated with 25-50 mg IV diphenydramine 30 minutes before temsirolimus infusion. In event of toxicity, dose could be modified or held according to the protocol or at the discretion of the investigator.	Sorafenib 400 mg (two 200 mg tablets) by mouth (PO) twice daily (BID) administered in 6 week cycles for up to 24 months. In event of toxicity, dose could be modified or held according to the protocol or at the discretion of the investigator.
Measure Participants	259	253
Median (95% Confidence Interval) [months]	8.26	6.96

7. Other Pre-specified Outcome

Title	Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
Description	Counts of participants who had treatment-emergent adverse events (TEAEs), defined as newly occurring or worsening after first dose. Relatedness to [study drug] was assessed by the investigator (Yes/No). Participants with multiple occurrences of an AE within a category were counted once within the category.
Time Frame	Baseline up to 24 months

Outcome Measure Data

Analysis Population Description

Safety population: all participants who received at least 1 dose of test article.

Arm/Group Title	Temsirolimus	Sorafenib
Arm/Group Description	Temsirolimus 25 milligrams (mg) once weekly by intravenous (IV) infusion administered in 6 week cycles for up to 24 months, participants were premedicated with 25-50 mg IV diphenydramine 30 minutes before temsirolimus infusion. In event of toxicity, dose could be modified or held according to the protocol or at the discretion of the investigator.	Sorafenib 400 mg (two 200 mg tablets) by mouth (PO) twice daily (BID) administered in 6 week cycles for up to 24 months. In event of toxicity, dose could be modified or held according to the protocol or at the discretion of the investigator.
Measure Participants	249	252
Serious AE	103 39.8%	86 34%
Any AE	248 95.8%	251 99.2%

Adverse Events

Time Frame	5.3 years approximately
Adverse Event Reporting Description	The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Arm/Group Title	Temsirolimus		Sorafenib
Arm/Group Description	Temsirolimus 25 milligrams (mg) once weekly by intravenous (IV) infusion administered in 6 week cycles for up to 24 months, participants were premedicated with 25-50 mg IV diphenydramine 30 minutes before temsirolimus infusion. In event of toxicity, dose could be modified or held according to the protocol or at the discretion of the investigator.		Sorafenib 400 mg (two 200 mg tablets) by mouth (PO) twice daily (BID) administered in 6 week cycles for up to 24 months. In event of toxicity, dose could be modified or held according to the protocol or at the discretion of the investigator.
All Cause Mortality
	Temsirolimus		Sorafenib
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Temsirolimus		Sorafenib
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	104/249 (41.8%)		87/252 (34.5%)
Blood and lymphatic system disorders
Anaemia	5/249 (2%)		4/252 (1.6%)
Febrile neutropenia	1/249 (0.4%)		0/252 (0%)
Lymphopenia	1/249 (0.4%)		0/252 (0%)
Thrombocytopenia	1/249 (0.4%)		0/252 (0%)
Cardiac disorders
Acute myocardial infarction	1/249 (0.4%)		0/252 (0%)
Atrial fibrillation	0/249 (0%)		3/252 (1.2%)
Atrial flutter	0/249 (0%)		1/252 (0.4%)
Cardiac arrest	1/249 (0.4%)		0/252 (0%)
Cardiac tamponade	1/249 (0.4%)		0/252 (0%)
Cardio-respiratory arrest	1/249 (0.4%)		1/252 (0.4%)
Cardiopulmonary failure	2/249 (0.8%)		0/252 (0%)
Myocardial infarction	1/249 (0.4%)		4/252 (1.6%)
Myocardial ischaemia	0/249 (0%)		1/252 (0.4%)
Palpitations	0/249 (0%)		1/252 (0.4%)
Pericardial effusion	1/249 (0.4%)		0/252 (0%)
Prinzmetal angina	1/249 (0.4%)		0/252 (0%)
Endocrine disorders
Hyperthyroidism	0/249 (0%)		1/252 (0.4%)
Toxic nodular goitre	0/249 (0%)		1/252 (0.4%)
Eye disorders
Retinal artery occlusion	0/249 (0%)		1/252 (0.4%)
Gastrointestinal disorders
Abdominal distension	1/249 (0.4%)		1/252 (0.4%)
Abdominal pain	7/249 (2.8%)		1/252 (0.4%)
Ascites	3/249 (1.2%)		1/252 (0.4%)
Constipation	1/249 (0.4%)		1/252 (0.4%)
Diarrhoea	3/249 (1.2%)		1/252 (0.4%)
Duodenal perforation	1/249 (0.4%)		0/252 (0%)
Dysphagia	0/249 (0%)		1/252 (0.4%)
Gastrointestinal haemorrhage	0/249 (0%)		1/252 (0.4%)
Gastrointestinal obstruction	2/249 (0.8%)		0/252 (0%)
Hernial eventration	1/249 (0.4%)		0/252 (0%)
Hiatus hernia	0/249 (0%)		1/252 (0.4%)
Intestinal obstruction	1/249 (0.4%)		0/252 (0%)
Intestinal ulcer perforation	1/249 (0.4%)		0/252 (0%)
Large intestine perforation	0/249 (0%)		1/252 (0.4%)
Nausea	1/249 (0.4%)		0/252 (0%)
Obstruction gastric	0/249 (0%)		1/252 (0.4%)
Oesophageal hypomotility	1/249 (0.4%)		0/252 (0%)
Rectal haemorrhage	1/249 (0.4%)		0/252 (0%)
Salivary hypersecretion	1/249 (0.4%)		0/252 (0%)
Stomatitis	1/249 (0.4%)		0/252 (0%)
Vomiting	6/249 (2.4%)		4/252 (1.6%)
General disorders
Asthenia	3/249 (1.2%)		1/252 (0.4%)
Chest pain	1/249 (0.4%)		3/252 (1.2%)
Fatigue	2/249 (0.8%)		4/252 (1.6%)
General physical health deterioration	8/249 (3.2%)		9/252 (3.6%)
Multi-organ failure	0/249 (0%)		1/252 (0.4%)
Oedema peripheral	2/249 (0.8%)		0/252 (0%)
Pain	1/249 (0.4%)		2/252 (0.8%)
Performance status decreased	1/249 (0.4%)		0/252 (0%)
Pyrexia	7/249 (2.8%)		4/252 (1.6%)
Sudden death	1/249 (0.4%)		1/252 (0.4%)
Systemic inflammatory response syndrome	0/249 (0%)		1/252 (0.4%)
Cholecystitis acute	1/249 (0.4%)		0/252 (0%)
Hepatobiliary disorders
Bile duct stone	1/249 (0.4%)		0/252 (0%)
Cholecystitis	1/249 (0.4%)		0/252 (0%)
Cholestasis	1/249 (0.4%)		0/252 (0%)
Gallbladder obstruction	0/249 (0%)		1/252 (0.4%)
Hepatobiliary disease	0/249 (0%)		1/252 (0.4%)
Immune system disorders
Anaphylactic reaction	1/249 (0.4%)		0/252 (0%)
Drug hypersensitivity	0/249 (0%)		1/252 (0.4%)
Infections and infestations
Abdominal infection	1/249 (0.4%)		0/252 (0%)
Abscess intestinal	0/249 (0%)		1/252 (0.4%)
Anal abscess	0/249 (0%)		1/252 (0.4%)
Bronchitis	1/249 (0.4%)		0/252 (0%)
Chest wall abscess	0/249 (0%)		1/252 (0.4%)
Cholangitis suppurative	0/249 (0%)		1/252 (0.4%)
Device related infection	2/249 (0.8%)		0/252 (0%)
Enterococcal bacteraemia	0/249 (0%)		1/252 (0.4%)
Hepatitis B	1/249 (0.4%)		0/252 (0%)
Herpes zoster	1/249 (0.4%)		0/252 (0%)
Infection	0/249 (0%)		1/252 (0.4%)
Infectious pleural effusion	0/249 (0%)		1/252 (0.4%)
Lobar pneumonia	1/249 (0.4%)		0/252 (0%)
Lower respiratory tract infection	2/249 (0.8%)		0/252 (0%)
Lung infection	1/249 (0.4%)		0/252 (0%)
Perirectal abscess	1/249 (0.4%)		0/252 (0%)
Pharyngitis	1/249 (0.4%)		0/252 (0%)
Pneumocystis jiroveci pneumonia	1/249 (0.4%)		0/252 (0%)
Pneumonia	7/249 (2.8%)		7/252 (2.8%)
Pneumonia influenzal	1/249 (0.4%)		0/252 (0%)
Pneumonia legionella	1/249 (0.4%)		0/252 (0%)
Pulmonary tuberculosis	0/249 (0%)		1/252 (0.4%)
Respiratory tract infection	1/249 (0.4%)		0/252 (0%)
Sepsis	2/249 (0.8%)		2/252 (0.8%)
Septic shock	1/249 (0.4%)		0/252 (0%)
Subcutaneous abscess	1/249 (0.4%)		0/252 (0%)
Tooth abscess	0/249 (0%)		1/252 (0.4%)
Urosepsis	0/249 (0%)		1/252 (0.4%)
Wound infection	0/249 (0%)		1/252 (0.4%)
Injury, poisoning and procedural complications
Compression fracture	1/249 (0.4%)		0/252 (0%)
Hip fracture	0/249 (0%)		1/252 (0.4%)
Humerus fracture	0/249 (0%)		1/252 (0.4%)
Infusion related reaction	1/249 (0.4%)		0/252 (0%)
Ligament sprain	0/249 (0%)		1/252 (0.4%)
Lumbar vertebral fracture	1/249 (0.4%)		0/252 (0%)
Overdose	0/249 (0%)		1/252 (0.4%)
Pelvic fracture	1/249 (0.4%)		0/252 (0%)
Radiation mucositis	0/249 (0%)		1/252 (0.4%)
Investigations
Alanine aminotransferase increased	0/249 (0%)		2/252 (0.8%)
Aspartate aminotransferase increased	0/249 (0%)		3/252 (1.2%)
Blood potassium increased	0/249 (0%)		1/252 (0.4%)
Prostatic specific antigen increased	0/249 (0%)		1/252 (0.4%)
Weight decreased	0/249 (0%)		1/252 (0.4%)
Metabolism and nutrition disorders
Cachexia	1/249 (0.4%)		0/252 (0%)
Decreased appetite	0/249 (0%)		2/252 (0.8%)
Dehydration	7/249 (2.8%)		6/252 (2.4%)
Diabetes mellitus inadequate control	1/249 (0.4%)		0/252 (0%)
Hypercalcaemia	1/249 (0.4%)		3/252 (1.2%)
Hypercholesterolaemia	1/249 (0.4%)		0/252 (0%)
Hyperglycaemia	2/249 (0.8%)		1/252 (0.4%)
Hyperkalaemia	0/249 (0%)		1/252 (0.4%)
Hypertriglyceridaemia	1/249 (0.4%)		0/252 (0%)
Hyponatraemia	0/249 (0%)		3/252 (1.2%)
Malnutrition	0/249 (0%)		1/252 (0.4%)
Musculoskeletal and connective tissue disorders
Arthralgia	2/249 (0.8%)		0/252 (0%)
Back pain	0/249 (0%)		3/252 (1.2%)
Bone lesion	1/249 (0.4%)		0/252 (0%)
Bone pain	1/249 (0.4%)		0/252 (0%)
Costochondritis	0/249 (0%)		1/252 (0.4%)
Flank pain	1/249 (0.4%)		0/252 (0%)
Intervertebral disc protrusion	0/249 (0%)		1/252 (0.4%)
Musculoskeletal chest pain	0/249 (0%)		1/252 (0.4%)
Musculoskeletal pain	1/249 (0.4%)		0/252 (0%)
Neck pain	0/249 (0%)		1/252 (0.4%)
Osteolysis	1/249 (0.4%)		1/252 (0.4%)
Pain in extremity	2/249 (0.8%)		3/252 (1.2%)
Pathological fracture	1/249 (0.4%)		0/252 (0%)
Spinal disorder	0/249 (0%)		1/252 (0.4%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant pleural effusion	1/249 (0.4%)		0/252 (0%)
Squamous cell carcinoma	0/249 (0%)		2/252 (0.8%)
Nervous system disorders
Cerebral infarction	0/249 (0%)		1/252 (0.4%)
Cerebral ischaemia	0/249 (0%)		1/252 (0.4%)
Cerebrovascular accident	2/249 (0.8%)		0/252 (0%)
Cognitive disorder	0/249 (0%)		1/252 (0.4%)
Convulsion	0/249 (0%)		1/252 (0.4%)
Headache	1/249 (0.4%)		1/252 (0.4%)
Hypoaesthesia	0/249 (0%)		1/252 (0.4%)
Paraesthesia	1/249 (0.4%)		0/252 (0%)
Peripheral motor neuropathy	0/249 (0%)		1/252 (0.4%)
Spinal cord compression	1/249 (0.4%)		2/252 (0.8%)
Syncope	0/249 (0%)		1/252 (0.4%)
Unresponsive to stimuli	0/249 (0%)		1/252 (0.4%)
Psychiatric disorders
Completed suicide	1/249 (0.4%)		1/252 (0.4%)
Confusional state	0/249 (0%)		3/252 (1.2%)
Renal and urinary disorders
Haematuria	1/249 (0.4%)		0/252 (0%)
Nephrotic syndrome	0/249 (0%)		1/252 (0.4%)
Renal failure	4/249 (1.6%)		1/252 (0.4%)
Renal failure acute	1/249 (0.4%)		1/252 (0.4%)
Renal tubular necrosis	1/249 (0.4%)		0/252 (0%)
Urinary retention	2/249 (0.8%)		0/252 (0%)
Reproductive system and breast disorders
Prostatic haemorrhage	0/249 (0%)		1/252 (0.4%)
Respiratory, thoracic and mediastinal disorders
Asthmatic crisis	0/249 (0%)		1/252 (0.4%)
Dyspnoea	7/249 (2.8%)		8/252 (3.2%)
Epistaxis	1/249 (0.4%)		0/252 (0%)
Haemoptysis	0/249 (0%)		1/252 (0.4%)
Interstitial lung disease	2/249 (0.8%)		0/252 (0%)
Lung disorder	2/249 (0.8%)		0/252 (0%)
Pleural effusion	7/249 (2.8%)		5/252 (2%)
Pleuritic pain	1/249 (0.4%)		0/252 (0%)
Pneumonitis	7/249 (2.8%)		0/252 (0%)
Pneumothorax	3/249 (1.2%)		0/252 (0%)
Pulmonary embolism	1/249 (0.4%)		0/252 (0%)
Respiratory arrest	0/249 (0%)		1/252 (0.4%)
Respiratory distress	1/249 (0.4%)		0/252 (0%)
Respiratory failure	2/249 (0.8%)		2/252 (0.8%)
Skin and subcutaneous tissue disorders
Palmar-plantar erythrodysaesthesia syndrome	0/249 (0%)		1/252 (0.4%)
Rash	1/249 (0.4%)		2/252 (0.8%)
Rash papular	0/249 (0%)		1/252 (0.4%)
Surgical and medical procedures
Lung operation	1/249 (0.4%)		0/252 (0%)
Medical device implantation	1/249 (0.4%)		0/252 (0%)
Vascular disorders
Haematoma	0/249 (0%)		1/252 (0.4%)
Haemorrhage	1/249 (0.4%)		0/252 (0%)
Hypertension	1/249 (0.4%)		0/252 (0%)
Hypotension	1/249 (0.4%)		0/252 (0%)
Thrombosis	1/249 (0.4%)		0/252 (0%)
Other (Not Including Serious) Adverse Events
	Temsirolimus		Sorafenib
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	243/249 (97.6%)		249/252 (98.8%)
Blood and lymphatic system disorders
Anaemia	83/249 (33.3%)		34/252 (13.5%)
Lymphopenia	21/249 (8.4%)		8/252 (3.2%)
Thrombocytopenia	23/249 (9.2%)		5/252 (2%)
Gastrointestinal disorders
Diarrhoea	74/249 (29.7%)		156/252 (61.9%)
Nausea	81/249 (32.5%)		71/252 (28.2%)
Constipation	57/249 (22.9%)		55/252 (21.8%)
Vomiting	53/249 (21.3%)		45/252 (17.9%)
Abdominal pain	33/249 (13.3%)		41/252 (16.3%)
Stomatitis	54/249 (21.7%)		18/252 (7.1%)
Abdominal pain upper	14/249 (5.6%)		25/252 (9.9%)
Dyspepsia	15/249 (6%)		18/252 (7.1%)
Oral pain	13/249 (5.2%)		5/252 (2%)
General disorders
Fatigue	99/249 (39.8%)		84/252 (33.3%)
Asthenia	63/249 (25.3%)		63/252 (25%)
Mucosal inflammation	74/249 (29.7%)		35/252 (13.9%)
Pyrexia	53/249 (21.3%)		28/252 (11.1%)
Oedema peripheral	57/249 (22.9%)		14/252 (5.6%)
Chest pain	23/249 (9.2%)		25/252 (9.9%)
Pain	20/249 (8%)		16/252 (6.3%)
Oedema	17/249 (6.8%)		5/252 (2%)
Chills	15/249 (6%)		6/252 (2.4%)
Infections and infestations
Nasopharyngitis	24/249 (9.6%)		16/252 (6.3%)
Investigations
Weight decreased	35/249 (14.1%)		51/252 (20.2%)
Blood creatinine increased	32/249 (12.9%)		6/252 (2.4%)
Aspartate aminotransferase increased	22/249 (8.8%)		15/252 (6%)
Blood alkaline phosphatase increased	26/249 (10.4%)		11/252 (4.4%)
Alanine aminotransferase increased	18/249 (7.2%)		17/252 (6.7%)
Blood lactate dehydrogenase increased	16/249 (6.4%)		13/252 (5.2%)
Haemoglobin decreased	19/249 (7.6%)		9/252 (3.6%)
Metabolism and nutrition disorders
Decreased appetite	76/249 (30.5%)		94/252 (37.3%)
Hypertriglyceridaemia	53/249 (21.3%)		18/252 (7.1%)
Hypercholesterolaemia	51/249 (20.5%)		16/252 (6.3%)
Hyperglycaemia	45/249 (18.1%)		13/252 (5.2%)
Hypophosphataemia	28/249 (11.2%)		30/252 (11.9%)
Hyponatraemia	14/249 (5.6%)		14/252 (5.6%)
Hypocalcaemia	10/249 (4%)		17/252 (6.7%)
Hyperkalaemia	11/249 (4.4%)		14/252 (5.6%)
Hypokalaemia	15/249 (6%)		9/252 (3.6%)
Musculoskeletal and connective tissue disorders
Back pain	50/249 (20.1%)		36/252 (14.3%)
Arthralgia	46/249 (18.5%)		29/252 (11.5%)
Pain in extremity	31/249 (12.4%)		38/252 (15.1%)
Musculoskeletal pain	24/249 (9.6%)		20/252 (7.9%)
Muscle spasms	18/249 (7.2%)		22/252 (8.7%)
Myalgia	20/249 (8%)		17/252 (6.7%)
Nervous system disorders
Headache	32/249 (12.9%)		44/252 (17.5%)
Dizziness	20/249 (8%)		20/252 (7.9%)
Dysgeusia	22/249 (8.8%)		10/252 (4%)
Paraesthesia	14/249 (5.6%)		10/252 (4%)
Psychiatric disorders
Insomnia	15/249 (6%)		16/252 (6.3%)
Anxiety	13/249 (5.2%)		7/252 (2.8%)
Renal and urinary disorders
Dysuria	13/249 (5.2%)		7/252 (2.8%)
Pollakiuria	13/249 (5.2%)		3/252 (1.2%)
Respiratory, thoracic and mediastinal disorders
Cough	85/249 (34.1%)		57/252 (22.6%)
Dyspnoea	67/249 (26.9%)		40/252 (15.9%)
Epistaxis	51/249 (20.5%)		13/252 (5.2%)
Dysphonia	5/249 (2%)		38/252 (15.1%)
Oropharyngeal pain	23/249 (9.2%)		15/252 (6%)
Rhinorrhoea	15/249 (6%)		7/252 (2.8%)
Pneumonitis	19/249 (7.6%)		0/252 (0%)
Productive cough	14/249 (5.6%)		5/252 (2%)
Skin and subcutaneous tissue disorders
Rash	104/249 (41.8%)		87/252 (34.5%)
Palmar-plantar erythrodysaesthesia syndrome	11/249 (4.4%)		131/252 (52%)
Pruritus	63/249 (25.3%)		64/252 (25.4%)
Alopecia	5/249 (2%)		78/252 (31%)
Dry skin	40/249 (16.1%)		36/252 (14.3%)
Erythema	15/249 (6%)		29/252 (11.5%)
Nail disorder	19/249 (7.6%)		0/252 (0%)
Pain of skin	2/249 (0.8%)		17/252 (6.7%)
Vascular disorders
Hypertension	8/249 (3.2%)		37/252 (14.7%)

Limitations/Caveats

[Not Specified]

More Information

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.