Study of BAY43-9006 in Patients With Unresectable and/or Metastatic Renal Cell Cancer

• ClinicalTrials.gov Identifier: NCT00073307
• Recruitment Status: Completed
• First Posted: November 21, 2003
• Results First Posted: December 14, 2011
• Last Update Posted: February 6, 2014
• Sponsor: Bayer
• Collaborator: Amgen
• Information provided by (Responsible Party): Bayer

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Carcinoma, Renal Cell
• Interventions: Drug: Sorafenib (Nexavar, BAY43-9006); Drug: Placebo
• Enrollment: 903

Participant Flow

Recruitment Details	From randomization start on 01 Dec 2003 to 31 May 2005 [last subject randomized]. One subject randomized in Placebo did not receive treatment. This study was conducted at 120 centers from 19 countries.
Pre-assignment Details	Enrollment included outpatients with documented unresectable and/or metastatic RCC (Renal Cell Carcinoma), and subjects who had 1 prior systemic therapy for advanced disease on which the subject progressed, at least 1 unidimensional measurable lesion, intermediate or low Motzer risk score, life expectancy of 12 weeks.

Arm/Group Title	Sorafenib (Nexavar, BAY43-9006)	Placebo	Placebo Randomized, Switch to Sorafenib; Sorafenib Period Only
Arm/Group Description	Sorafenib was to be orally administered as 2 x 200 mg tablets bid (twice daily).	Subjects received matching placebo tablets administered orally twice a day. [until ~31 May 2005]	Subjects received matching placebo tablets administered orally twice a day(as of ~31 May 2005) when after unblinding subjects switched over to receive Sorafenib orally administered as 2 x 200 mg tablets bid (twice daily).
Period Title: Double-Blind (DB, as of ~31May2005)
Started	451	452	0
Participants Received Treatment	451	451	0
Completed	254	299	0
Not Completed	197	153	0
Reason Not Completed
Adverse Event	22	17	0
Lost to Follow-up	1	6	0
Withdrawal by Subject	6	11	0
Protocol Violation	1	1	0
Non-compliant with Study medication	1	2	0
Unknown reason.	1	0	0
Protocol driven decision point	0	1	0
entered Open Label (OL); Sorafenib only	165	114	0
Subject did not receive treatment	0	1	0
Period Title: Open Label-Sorafenib Only [30Jun2008]
Started	254	0 [1]	299
Entered OL With Sorafenib Only Phase	219	0	216
Completed	120	0	143
Not Completed	134	0	156
Reason Not Completed
Adverse Event	17	0	19
Lost to Follow-up	2	0	2
Withdrawal by Subject	19	0	9
Study terminated by Sponsor	37	0	28
Per Investigator, not protocol driven	1	0	1
Switched to commercial drug	1	0	1
Switched to commercial drug (code error)	0	0	3
Missing	3	0	1
No record of treatment discontinuation	19	0	9
Did not enter OL/ Sorafenib only phase	35	0	83
[1] Placebo treatment ended ~ 31May2005. Those who continued, switched to receive Sorafenib.

Baseline Characteristics

Arm/Group Title		Sorafenib (Nexavar, BAY43-9006)	Placebo	Total
Arm/Group Description		Sorafenib was to be orally administered as 2 x 200 mg tablets bid (twice daily). Dose modification due to toxicity was permitted.	Subjects received matching placebo tablets administered orally twice a day. [until ~31 May 2005]	Total of all reporting groups
Overall Number of Baseline Participants		451	452	903
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Median (Full Range); Unit of measure: Years
	Number Analyzed	451 participants	452 participants	903 participants
		58.0; (19.0 to 86.0)	59.0; (29.0 to 84.0)	59.0; (19.0 to 86.0)
Age, Customized; Measure Type: Number; Unit of measure: Participants	Number Analyzed	451 participants	452 participants	903 participants
<65 years		304	328	632
>= 65 years		147	124	271
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	451 participants	452 participants	903 participants
	Female	136 30.2%	112 24.8%	248 27.5%
	Male	315 69.8%	340 75.2%	655 72.5%
Motzer Category (Low, intermediate or high) [1]; Measure Type: Number; Unit of measure: Participants	Number Analyzed	451 participants	452 participants	903 participants
Low		234	219	453
Intermediate		217	232	449
Missing		0	1	1
		[1] Measure Description: The Motzer score risk factors predicting survival in participants with metastatic RCC are as following: • Low ECOG performance status (PS>2) • High lactate dehydrogenase (>1.5 times upper limit of normal) • Low serum hemoglobin (<lower limit of normal) • High corrected serum calcium (>10 mg/dL) • Absence of prior nephrectomy factors.
ECOG Performance Status (PS) [1]; Measure Type: Number; Unit of measure: Participants by scale	Number Analyzed	451 participants	452 participants	903 participants
PS 0		219	211	430
PS 1		223	235	458
PS 2		7	4	11
Missing		2	2	4
		[1] Measure Description: ECOG = Eastern cooperative oncology group PS levels are 0 (Fully active, able to carry on all pre-disease performance), 1 (ambulatory and able to carry out work of a light or sedentary), 2 (Ambulatory and capable of all selfcare but unable to carry out any work activities), 3 (Capable of only limited selfcare, confined to bed or chair more than 50% of awake time), 4 (Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair) and 5 (death).
TNM Classification at study entry [1]; Measure Type: Number; Unit of measure: Participants	Number Analyzed	451 participants	452 participants	903 participants
Stage III		18	14	32
Stage IV		433	438	871
		[1] Measure Description: TNM=Tumor, primary (T); Nodes, regional lymph nodes (N); Metastasis, distant (M). T0/N0/M0=no evidence of aspect. N1=metastasis in single regional lymph node, M1=distant metastasis. T1=tumor 7 cm or less in greatest dimension limited to kidney. T2= tumor >7 cm in greatest dimension limited to kidney. T3=tumor extends into major veins, invades adrenal gland, or peripheric tissues but not beyond Gerota's fascia. T4=tumor invades beyond Gerota's fascia. [Stage I: T1, N0, M0][Stage II=T2, N0, M0][Stage IV=T4, N0, M0; T4, N1, M0; any T, N2, M0; any T, any N, M1][Stage III=remaining combinations]
Cancer Subtypes [1]; Measure Type: Number; Unit of measure: Participants with carcinoma type	Number Analyzed	451 participants	452 participants	903 participants
Clear Cell		449	447	896
Papillary		1	3	4
Granular		1	2	3
		[1] Measure Description: Histopathological characterization of renal cell carcinomas that subjects had included clear cell, papillary or granular carcinomas. Clear cell renal cell carcinoma is a renal cortical tumor typically characterized by malignant epithelial cells with clear cytoplasm and a compact-alveolar (nested) or acinar growth pattern interspersed with intricate, arborizing vasculature. Tumors in which eosinophilic cells predominate were classified as "granular cell" carcinoma. Papillary renal cell carcinoma is an uncommon subtype that has distinctive gross, histologic, and cytogenetic features.

Outcome Measures

1. Primary Outcome

Title	Final Overall Survival (OS) - Primary Analysis in the ITT (Intent To Treat) Population
Description	Overall survival determined as the time (days) from the date of randomization at start of study to the date of death, due to any cause. Outcome measure was assessed regularly, i.e. every 3 weeks for the first 24 weeks during treatment and every 4 weeks thereafter and approximately every 3 months during post-treatment.
Time Frame	From start of randomization of the first subject (1Dec2003) until the data cut-off (8Sep2006) for the final OS analysis, approximately 33 months later

Outcome Measure Data

Analysis Population Description

Evaluations based on ITT population. Subjects alive at time of analysis were censored at last date of follow-up (FU) (last visit or contact or at data cut-off date). In case of incomplete date, day was missing, day 15 was used.

Arm/Group Title	Sorafenib (Nexavar, BAY43-9006)	Placebo
Arm/Group Description:	Sorafenib was to be orally administered as 2 x 200 mg tablets bid (twice daily). Dose modification due to toxicity was permitted.	Subjects received matching placebo tablets administered orally twice a day. [until ~31 May 2005]
Overall Number of Participants Analyzed	451	452
Median (95% Confidence Interval); Unit of Measure: days
	542; (500 to 598)	461; (408 to 526)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sorafenib (Nexavar, BAY43-9006), Placebo
	Comments	Sample size based on primary efficacy endpoint of OS. Clinically meaningful improvement defined as 33.3% improvement in median OS (i.e. HR of 0.75, Sorafenib over Placebo). With overall two-sided alpha of 0.04, 90% power and randomization of 1:1, two formal interim analyses and one final analysis were planned using O'Brien-Fleming type error spending function, and a total of approximately 540 events (deaths) were required for the final analysis.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.146
	Comments	According to O'Brien-Fleming type alpha spending function and total actual deaths at final analysis, threshold for statistical significance was alpha=0.037 (two-sided).
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.88
	Confidence Interval	95%; 0.74 to 1.04
	Estimation Comments	Two treatment groups compared using log-rank test (Sorafenib over Placebo) stratified by country and Motzer category

2. Primary Outcome

Title	Final Overall Survival - Secondary Analysis (Placebo Data Censored at 30June2005) in the ITT Population
Description	Overall survival determined as the time (days) from the date of randomization at start of study to the date of death, due to any cause. Outcome measure was assessed regularly, i.e. every 3 weeks for the first 24 weeks during treatment and every 4 weeks thereafter and approximately every 3 months during post-treatment.
Time Frame	From start of randomization of the first subject (1Dec2003) until the data cut-off (8Sep2006) for the final OS analysis, approximately 33 months later

Outcome Measure Data

Analysis Population Description

Evaluations based on ITT population. Subjects alive at time of analysis were censored at last date of FU (last visit or contact or at data cut-off date). In case of incomplete date, missing day, day 15 was used. Placebo censored at 30June2005, approximate time of crossover of placebo subjects to sorafenib. NA - not estimable due to censored data.

Arm/Group Title	Sorafenib (Nexavar, BAY43-9006)	Placebo
Arm/Group Description:	Sorafenib was to be orally administered as 2 x 200 mg tablets bid (twice daily). Dose modification due to toxicity was permitted.	Subjects received matching placebo tablets administered orally twice a day. [until ~31 May 2005]
Overall Number of Participants Analyzed	451	452
Median (95% Confidence Interval); Unit of Measure: days
	542; (500 to 598)	436 [1]; (385 to NA)

[1]

not estimable due to censored data.

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sorafenib (Nexavar, BAY43-9006), Placebo
	Comments	Sample size based on primary efficacy endpoint of OS. Clinically meaningful improvement defined as 33.3% improvement in median OS (i.e. HR of 0.75, Sorafenib over Placebo). With overall two-sided alpha of 0.04, 90% power and randomization of 1:1, two formal interim analyses and one final analysis were planned using O'Brien-Fleming type error spending function, and a total of approximately 540 events (deaths) were required for the final analysis.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0287
	Comments	According to O'Brien-Fleming type alpha spending function and total actual deaths at final analysis, threshold for statistical significance was alpha=0.037 (two-sided).
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.78
	Confidence Interval	95%; 0.62 to 0.97
	Estimation Comments	Two treatment groups compared using log-rank test (Sorafenib over Placebo) stratified by country and Motzer category

3. Secondary Outcome

Title	Final Progression-Free Survival (PFS) - Independent Radiological Review
Description	PFS determined as the time (days) from the date of randomization at start of study to the actual date of disease progression (PD) (radiological or clinical) or death due to any cause, if death occurred before PD. Outcome measure was assessed approximately every 8 weeks using RECIST v1.0 criteria by independent radiologic review. Radiological PD defined as at least 20% increase in sum of longest diameter (LD) of measured lesions taking as reference smallest sum LD recorded since treatment started or appearance of new lesions.
Time Frame	From start of randomization of the first subject (1Dec2003) until the data cut-off (28Jan2005), approximately 14 months later, tumors assessed every 8 weeks.

Outcome Measure Data

Analysis Population Description

Evaluations based on ITT population as of 28Jan2005 data cut; 769 subjects randomized at that time. PFS determined as time from randomization to actual date of disease progression (PD) (radiological or clinical) or death, if death occurred before PD. Subjects without PD or death at time of analysis were censored at last date of tumor assessment.

Arm/Group Title	Sorafenib (Nexavar, BAY43-9006)	Placebo
Arm/Group Description:	Sorafenib was to be orally administered as 2 x 200 mg tablets bid (twice daily). Dose modification due to toxicity was permitted.	Placebo tablets matching in appearance were to be orally administered twice a day.
Overall Number of Participants Analyzed	384	385
Median (95% Confidence Interval); Unit of Measure: days
	167; (139 to 174)	84; (78 to 91)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sorafenib (Nexavar, BAY43-9006), Placebo
	Comments	The planned final PFS analysis was to be performed when approximately 363 progressions or deaths (if death occurred before progression) were observed. The analysis had power of 90% to detect a 50% increase in PFS using a two-sided alpha of 0.01
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.000001
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.44
	Confidence Interval	95%; 0.35 to 0.55
	Estimation Comments	Two treatment groups compared using log-rank test (Sorafenib over Placebo) stratified by country and Motzer category

4. Secondary Outcome

Title	Best Overall Response - Independent Radiological Review
Description	Best overall response was determined according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.0 by independent radiologic review. Categories: complete response (CR, tumor disappears), partial response (PR, sum of lesion sizes decreased), stable disease (SD, steady state of disease), progressive disease (PD, sum of lesion sizes increased) and not evaluated.
Time Frame	From start of randomization of the first subject (1Dec2003) until the data cut-off (28Jan2005), approximately 14 months later, tumors assessed every 8 weeks.

Outcome Measure Data

Analysis Population Description

Evaluations of best overall response based on the valid for response population, where as per protocol, subjects were to have first post-baseline tumor evaluation performed at the end of Cycle 1 (6 weeks post-randomization). Of the ITT population that met this criteria as of the 28Jan2005 data cut, 672 subjects were valid for response.

Arm/Group Title	Sorafenib (Nexavar, BAY43-9006)	Placebo
Arm/Group Description:	Sorafenib was to be orally administered as 2 x 200 mg tablets bid (twice daily). Dose modification due to toxicity was permitted.	Placebo tablets matching in appearance were to be orally administered twice a day.
Overall Number of Participants Analyzed	335	337
Measure Type: Number; Unit of Measure: percentage of participants
Complete Response	0.0	0.0
Partial Response	2.1	0.0
Stable Disease	77.9	55.2
Progressive Disease	8.7	30.3
Not Evaluated	11.3	14.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sorafenib (Nexavar, BAY43-9006), Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	[Not Specified]
	Comments	[Not Specified]
	Method	Cochran-Mantel-Haenszel
	Comments	Adjustments for country and Motzer category
Method of Estimation	Estimation Parameter	Difference in response rates (CR+PR)
	Estimated Value	-2.1
	Confidence Interval	95%; -3.7 to -0.6
	Estimation Comments	difference in response rates (CR+PR) = Placebo - Sorafenib

5. Secondary Outcome

Title	Health-related Quality of Life (HRQOL) by FKSI-10 (Functional Assessment of General Therapy Kidney Symptom Index 10) Assessment
Description	Primary Analysis for FKSI-10 patient-reported outcome (PRO) measure defined as longitudinal analysis of mean score over the first 5 treatment cycles. FKSI-10 patient responses for each question range from "0=not at all" to "4=very much" and after reverse coding the range of values for FKSI-10 total score is from 0 to 40; higher score represents better HRQOL.
Time Frame	From start of randomization of the first subject (1Dec2003) until the data cut-off (31May2005), approximately 18 months later, PRO data collected at Day 1 of each cycle and end of treatment.

Outcome Measure Data

Analysis Population Description

Evaluations based on ITT population with a PRO assessment. Day 1, Cycle 1 served as baseline assessment.

Arm/Group Title	Sorafenib (Nexavar, BAY43-9006)	Placebo
Arm/Group Description:	Sorafenib was to be orally administered as 2 x 200 mg tablets bid (twice daily). Dose modification due to toxicity was permitted.	Subjects received matching placebo tablets administered orally twice a day. [until ~31 May 2005]
Overall Number of Participants Analyzed	451	452
Least Squares Mean (Standard Error); Unit of Measure: Scores on a scale
Cycle 2, Day 1	27.77 (0.23)	27.78 (0.22)
Cycle 3, Day 1	27.27 (0.22)	27.28 (0.23)
Cycle 4, Day 1	26.77 (0.25)	26.78 (0.26)
Cycle 5, Day 1	26.27 (0.30)	26.28 (0.31)
Cycles 1-5 (Overall)	27.19 (0.23)	27.20 (0.23)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sorafenib (Nexavar, BAY43-9006), Placebo
	Comments	Approximately 200 subjects per group, assuming a 10% drop out rate, were required to detect a 2 point difference between sorafenib and placebo at approximately 80% power with a two-sided alpha of 0.05
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.98
	Comments	[Not Specified]
	Method	random coefficient model
	Comments	Random coefficient model adjusted for baseline Motzer score, baseline FKSI-10 score and relative day of FKSI-10 completion.

6. Secondary Outcome

Title	Health-related Quality of Life (HRQOL) by Physical Well-Being (PWB) Score of the FACT-G (Functional Assessment of Cancer Therapy-General Version) Assessment
Description	Primary Analysis for FACT-G (using PWB score) patient-reported outcome (PRO) measure defined as longitudinal analysis of mean score over the first 5 treatment cycles. FACT-G (PWB score) patient responses for each question range from "0=not at all" to "4=very much" and after reverse coding the total FACT-G (PWB score) range of values is from 0 to 28; higher score represents better HRQOL.
Time Frame	From start of randomization of the first subject (1Dec2003) until the data cut-off (31May2005), approximately 18 months later, PRO data collected at Day 1 of each cycle and end of treatment.

Outcome Measure Data

Analysis Population Description

Evaluations based on ITT population with a PRO assessment. Day 1, Cycle 1 served as baseline assessment.

Arm/Group Title	Sorafenib (Nexavar, BAY43-9006)	Placebo
Arm/Group Description:	Sorafenib was to be orally administered as 2 x 200 mg tablets bid (twice daily). Dose modification due to toxicity was permitted.	Subjects received matching placebo tablets administered orally twice a day. [until ~31 May 2005]
Overall Number of Participants Analyzed	451	452
Least Squares Mean (Standard Error); Unit of Measure: Scores on a scale
Cycle 2, Day 1	21.21 (0.17)	21.16 (0.19)
Cycle 3, Day 1	20.77 (0.17)	20.72 (0.19)
Cycle 4, Day 1	20.33 (0.19)	20.28 (0.22)
Cycle 5, Day 1	19.89 (0.24)	19.84 (0.26)
Cycles 1-5 (Overall)	20.70 (0.17)	20.65 (0.19)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sorafenib (Nexavar, BAY43-9006), Placebo
	Comments	Approximately 200 subjects per group, assuming a 10% drop out rate, were required to detect a 2 point difference between sorafenib and placebo at approximately 80% power with a two-sided alpha of 0.05
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.83
	Comments	[Not Specified]
	Method	random coefficient model
	Comments	Random coefficient model adjusted for baseline Motzer score, baseline PWB score and relative day of PWB completion.

Adverse Events

Time Frame	In addition, 1 participant who was not randomized to double-blind treatment received sorafenib treatment on a compassionate-use basis in the crossover phase and was included in the safety population only.
Adverse Event Reporting Description	DIC (disseminated intravascular coagulation), AT (Atrial tachycardia), NOS (not otherwise specified), GI (gastro-intestinal), CTCAE (Common Terminology Criteria for Adverse Events), ANC (absolute neutrophil count), CNS (central nervous system), CN (cranial nerve), GU (genitourinary)
Arm/Group Title	Sorafenib (Nexavar, BAY43-9006)-31May2005 DB	Placebo-31May2005 DB	Sorafenib (Nexavar, BAY43-9006)-30Jun2008	Placebo ~31May2005, Then Switched to Sorafenib Only-30Jun2008
Arm/Group Description	Sorafenib was to be orally administered as 2 x 200 mg tablets bid (twice daily). Double Blind period-31May2005	Subjects received matching placebo tablets administered orally twice a day. [until ~31 May 2005]	Sorafenib was to be orally administered as 2 x 200 mg tablets bid (twice daily). Double Blind-30Jun2008. In addition, 1 participant who was not randomized to double-blind treatment received sorafenib treatment on a compassionate-use basis in the open-label/Sorafenib only phase and was included in the safety population only. Participants affected may deviate from double-blind phase due to data update and cleaning.	Sorafenib period only-30Jun2008: Subjects received matching placebo tablets administered orally twice a day(as of ~31 May 2005) when after unblinding subjects switched over to receive Sorafenib orally administered as 2 x 200 mg tablets bid (twice daily). Open Label/Sorafenib only period-30Jun2008
All-Cause Mortality
	Sorafenib (Nexavar, BAY43-9006)-31May2005 DB	Placebo-31May2005 DB	Sorafenib (Nexavar, BAY43-9006)-30Jun2008	Placebo ~31May2005, Then Switched to Sorafenib Only-30Jun2008
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	--/--	--/--	--/--	--/--
Serious Adverse Events
	Sorafenib (Nexavar, BAY43-9006)-31May2005 DB	Placebo-31May2005 DB	Sorafenib (Nexavar, BAY43-9006)-30Jun2008	Placebo ~31May2005, Then Switched to Sorafenib Only-30Jun2008
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	154/451 (34.15%)	110/451 (24.39%)	245/452 (54.20%)	124/216 (57.41%)
Blood and lymphatic system disorders
Hemoglobin * 1	8/451 (1.77%)	11/451 (2.44%)	16/452 (3.54%)	9/216 (4.17%)
Blood - Other * 1	1/451 (0.22%)	1/451 (0.22%)	2/452 (0.44%)	0/216 (0.00%)
Platelets * 1	1/451 (0.22%)	0/451 (0.00%)	1/452 (0.22%)	0/216 (0.00%)
DIC * 1	0/451 (0.00%)	0/451 (0.00%)	1/452 (0.22%)	0/216 (0.00%)
Edema: Limb * 1	0/451 (0.00%)	0/451 (0.00%)	1/452 (0.22%)	0/216 (0.00%)
Lymphatics - Other * 1	2/451 (0.44%)	0/451 (0.00%)	1/452 (0.22%)	0/216 (0.00%)
Cardiac disorders
Supraventricular Arrhythmia, Atrial Fibrillation * 1	1/451 (0.22%)	1/451 (0.22%)	3/452 (0.66%)	1/216 (0.46%)
Supraventricular Arrhythmia,supraventricular Arrhythmia NOS * 1	1/451 (0.22%)	0/451 (0.00%)	1/452 (0.22%)	0/216 (0.00%)
Cardiac Arrhythmia - Other * 1	1/451 (0.22%)	0/451 (0.00%)	1/452 (0.22%)	1/216 (0.46%)
Supraventricular Arrhythmia, ATrial Tach/Paroxysmal AT * 1	1/451 (0.22%)	0/451 (0.00%)	1/452 (0.22%)	1/216 (0.46%)
Supraventricular Arrhythmia, Sinus Tachycardia * 1	0/451 (0.00%)	1/451 (0.22%)	0/452 (0.00%)	0/216 (0.00%)
Cardiac Arrest * 1	5/451 (1.11%)	1/451 (0.22%)	0/452 (0.00%)	0/216 (0.00%)
Restrictive Cardiomyopathy * 1	0/451 (0.00%)	1/451 (0.22%)	0/452 (0.00%)	0/216 (0.00%)
Left Ventricular Diastolic Dysfunction * 1	2/451 (0.44%)	0/451 (0.00%)	2/452 (0.44%)	0/216 (0.00%)
Pericardial Effusion * 1	0/451 (0.00%)	0/451 (0.00%)	1/452 (0.22%)	0/216 (0.00%)
Hypertension * 1	5/451 (1.11%)	0/451 (0.00%)	6/452 (1.33%)	3/216 (1.39%)
Cardiac Ischemia/Infarction * 1	11/451 (2.44%)	2/451 (0.44%)	18/452 (3.98%)	3/216 (1.39%)
Hypotension * 1	1/451 (0.22%)	0/451 (0.00%)	2/452 (0.44%)	0/216 (0.00%)
Myocarditis * 1	1/451 (0.22%)	0/451 (0.00%)	1/452 (0.22%)	0/216 (0.00%)
Cardiac General - Other * 1	2/451 (0.44%)	0/451 (0.00%)	13/452 (2.88%)	9/216 (4.17%)
Left Ventricular Systolic Dysfunction * 1	1/451 (0.22%)	0/451 (0.00%)	4/452 (0.88%)	4/216 (1.85%)
Eye disorders
Eyelid Dysfunction * 1	0/451 (0.00%)	0/451 (0.00%)	1/452 (0.22%)	0/216 (0.00%)
Ocular - Other * 1	0/451 (0.00%)	1/451 (0.22%)	1/452 (0.22%)	0/216 (0.00%)
Retinal Detachment * 1	0/451 (0.00%)	0/451 (0.00%)	1/452 (0.22%)	0/216 (0.00%)
Retinopathy * 1	1/451 (0.22%)	0/451 (0.00%)	0/452 (0.00%)	0/216 (0.00%)
Gastrointestinal disorders
Anorexia * 1	1/451 (0.22%)	0/451 (0.00%)	2/452 (0.44%)	0/216 (0.00%)
Ascites * 1	1/451 (0.22%)	0/451 (0.00%)	1/452 (0.22%)	2/216 (0.93%)
Colitis * 1	1/451 (0.22%)	0/451 (0.00%)	1/452 (0.22%)	0/216 (0.00%)
Constipation * 1	4/451 (0.89%)	2/451 (0.44%)	5/452 (1.11%)	2/216 (0.93%)
Dehydration * 1	4/451 (0.89%)	1/451 (0.22%)	6/452 (1.33%)	0/216 (0.00%)
Diarrhea * 1	3/451 (0.67%)	0/451 (0.00%)	5/452 (1.11%)	3/216 (1.39%)
Dysphagia * 1	0/451 (0.00%)	0/451 (0.00%)	4/452 (0.88%)	0/216 (0.00%)
Enteritis * 1	1/451 (0.22%)	0/451 (0.00%)	1/452 (0.22%)	0/216 (0.00%)
Esophagitis * 1	0/451 (0.00%)	0/451 (0.00%)	1/452 (0.22%)	0/216 (0.00%)
Fistula, GI, Colon/Cecum/Appendix * 1	0/451 (0.00%)	0/451 (0.00%)	1/452 (0.22%)	0/216 (0.00%)
Fistula, GI, Duodenum * 1	1/451 (0.22%)	0/451 (0.00%)	1/452 (0.22%)	0/216 (0.00%)
Gastritis * 1	0/451 (0.00%)	0/451 (0.00%)	1/452 (0.22%)	0/216 (0.00%)
Mucositis (Functional/Symptomatic), Esophagus * 1	0/451 (0.00%)	0/451 (0.00%)	0/452 (0.00%)	1/216 (0.46%)
Mucositis (Functional/Symptomatic), Oral Cavity * 1	0/451 (0.00%)	0/451 (0.00%)	0/452 (0.00%)	1/216 (0.46%)
Nausea * 1	1/451 (0.22%)	5/451 (1.11%)	1/452 (0.22%)	1/216 (0.46%)
Ileus * 1	0/451 (0.00%)	2/451 (0.44%)	0/452 (0.00%)	0/216 (0.00%)
Obstruction, GI, Colon * 1	1/451 (0.22%)	1/451 (0.22%)	1/452 (0.22%)	1/216 (0.46%)
Obstruction, GI, Duodenum * 1	1/451 (0.22%)	0/451 (0.00%)	1/452 (0.22%)	0/216 (0.00%)
Obstruction, GI, Gallbladder * 1	1/451 (0.22%)	0/451 (0.00%)	1/452 (0.22%)	0/216 (0.00%)
Obstruction, GI, Ileum * 1	1/451 (0.22%)	0/451 (0.00%)	2/452 (0.44%)	0/216 (0.00%)
Obstruction, GI, Small Bowel NOS * 1	0/451 (0.00%)	1/451 (0.22%)	0/452 (0.00%)	1/216 (0.46%)
GI - Other * 1	3/451 (0.67%)	1/451 (0.22%)	8/452 (1.77%)	4/216 (1.85%)
Perforation, GI, Colon * 1	1/451 (0.22%)	1/451 (0.22%)	1/452 (0.22%)	2/216 (0.93%)
Perforation, GI, Small Bowel NOS * 1	0/451 (0.00%)	0/451 (0.00%)	0/452 (0.00%)	1/216 (0.46%)
Perforation, GI, Stomach * 1	0/451 (0.00%)	0/451 (0.00%)	0/452 (0.00%)	1/216 (0.46%)
Stricture, GI, Biliary Tree * 1	1/451 (0.22%)	0/451 (0.00%)	1/452 (0.22%)	0/216 (0.00%)
Stricture, GI, Small Bowel NOS * 1	1/451 (0.22%)	0/451 (0.00%)	1/452 (0.22%)	0/216 (0.00%)
Ulcer, GI, Duodenum * 1	0/451 (0.00%)	1/451 (0.22%)	0/452 (0.00%)	1/216 (0.46%)
Vomiting * 1	2/451 (0.44%)	5/451 (1.11%)	4/452 (0.88%)	2/216 (0.93%)
General disorders
Death Not Associated With CTCAE Term, Death NOS * 1	0/451 (0.00%)	1/451 (0.22%)	3/452 (0.66%)	0/216 (0.00%)
Death Not Associated With CTCAE Term, Disease Progression NOS * 1	11/451 (2.44%)	10/451 (2.22%)	39/452 (8.63%)	32/216 (14.81%)
Death Not Associated With CTCAE Term, Multi-Organ Failure * 1	0/451 (0.00%)	0/451 (0.00%)	1/452 (0.22%)	1/216 (0.46%)
Death Not Associated With CTCAE Term, Sudden Death * 1	0/451 (0.00%)	1/451 (0.22%)	0/452 (0.00%)	0/216 (0.00%)
Fever * 1	4/451 (0.89%)	2/451 (0.44%)	4/452 (0.88%)	2/216 (0.93%)
Fatigue * 1	7/451 (1.55%)	4/451 (0.89%)	13/452 (2.88%)	6/216 (2.78%)
Weight Loss * 1	0/451 (0.00%)	0/451 (0.00%)	1/452 (0.22%)	0/216 (0.00%)
Constitutional Symptoms - Other * 1	10/451 (2.22%)	7/451 (1.55%)	11/452 (2.43%)	6/216 (2.78%)
Pain, Back * 1	1/451 (0.22%)	2/451 (0.44%)	5/452 (1.11%)	3/216 (1.39%)
Pain, Chest/Thorax NOS * 1	0/451 (0.00%)	1/451 (0.22%)	1/452 (0.22%)	2/216 (0.93%)
Pain, Chest Wall * 1	1/451 (0.22%)	0/451 (0.00%)	1/452 (0.22%)	0/216 (0.00%)
Pain, Extremity-Limb * 1	0/451 (0.00%)	5/451 (1.11%)	1/452 (0.22%)	1/216 (0.46%)
Pain, Tumor Pain * 1	7/451 (1.55%)	4/451 (0.89%)	7/452 (1.55%)	2/216 (0.93%)
Pain, Abdomen NOS * 1	4/451 (0.89%)	1/451 (0.22%)	7/452 (1.55%)	4/216 (1.85%)
Pain, Head/Headache * 1	1/451 (0.22%)	2/451 (0.44%)	2/452 (0.44%)	0/216 (0.00%)
Pain, Joint * 1	0/451 (0.00%)	0/451 (0.00%)	1/452 (0.22%)	0/216 (0.00%)
Pain, Bone * 1	3/451 (0.67%)	3/451 (0.67%)	6/452 (1.33%)	4/216 (1.85%)
Pain, Other * 1	4/451 (0.89%)	1/451 (0.22%)	3/452 (0.66%)	3/216 (1.39%)
Pain, Pelvis * 1	0/451 (0.00%)	0/451 (0.00%)	0/452 (0.00%)	1/216 (0.46%)
Pain, Neck * 1	0/451 (0.00%)	1/451 (0.22%)	0/452 (0.00%)	0/216 (0.00%)
Pain, Neuralgia/Peripheral Nerve * 1	0/451 (0.00%)	1/451 (0.22%)	0/452 (0.00%)	2/216 (0.93%)
Pain, Pain NOS * 1	1/451 (0.22%)	0/451 (0.00%)	2/452 (0.44%)	0/216 (0.00%)
Flu-Like Syndrome * 1	0/451 (0.00%)	0/451 (0.00%)	0/452 (0.00%)	1/216 (0.46%)
Tumor Lysis Syndrome * 1	0/451 (0.00%)	0/451 (0.00%)	0/452 (0.00%)	1/216 (0.46%)
Syndromes - Other * 1	1/451 (0.22%)	0/451 (0.00%)	1/452 (0.22%)	0/216 (0.00%)
Not Coded Yet * 1	1/451 (0.22%)	0/451 (0.00%)	0/452 (0.00%)	0/216 (0.00%)
Hepatobiliary disorders
Cholecystitis * 1	0/451 (0.00%)	2/451 (0.44%)	1/452 (0.22%)	2/216 (0.93%)
Liver Dysfunction * 1	2/451 (0.44%)	2/451 (0.44%)	3/452 (0.66%)	1/216 (0.46%)
Hepatobiliary - Other * 1	1/451 (0.22%)	0/451 (0.00%)	3/452 (0.66%)	3/216 (1.39%)
Pancreatitis * 1	2/451 (0.44%)	1/451 (0.22%)	2/452 (0.44%)	2/216 (0.93%)
Immune system disorders
Allergic Reaction * 1	0/451 (0.00%)	0/451 (0.00%)	1/452 (0.22%)	0/216 (0.00%)
Allergy - Other * 1	0/451 (0.00%)	0/451 (0.00%)	0/452 (0.00%)	1/216 (0.46%)
Infections and infestations
Infection (Documented Clinically), Blood * 1	1/451 (0.22%)	0/451 (0.00%)	1/452 (0.22%)	1/216 (0.46%)
Infection (Documented Clinically), Bronchus * 1	0/451 (0.00%)	1/451 (0.22%)	0/452 (0.00%)	0/216 (0.00%)
Infection (Documented Clinically), Catheter-Related * 1	0/451 (0.00%)	0/451 (0.00%)	1/452 (0.22%)	0/216 (0.00%)
Infection (Documented Clinically), Colon * 1	1/451 (0.22%)	0/451 (0.00%)	1/452 (0.22%)	0/216 (0.00%)
Infection (Documented Clinically), Lung (Pneumonia) * 1	2/451 (0.44%)	0/451 (0.00%)	3/452 (0.66%)	0/216 (0.00%)
Infection (Documented Clinically), Meninges (Meningitis) * 1	0/451 (0.00%)	0/451 (0.00%)	1/452 (0.22%)	0/216 (0.00%)
Infection (Documented Clinically), Skin (Cellulitis) * 1	0/451 (0.00%)	0/451 (0.00%)	0/452 (0.00%)	1/216 (0.46%)
Infection (Documented Clinically), Urinary Tract NOS * 1	1/451 (0.22%)	0/451 (0.00%)	2/452 (0.44%)	1/216 (0.46%)
Infection (Documented Clinically), Vein * 1	0/451 (0.00%)	1/451 (0.22%)	0/452 (0.00%)	0/216 (0.00%)
Infection (Documented Clinically), Wound * 1	0/451 (0.00%)	1/451 (0.22%)	1/452 (0.22%)	0/216 (0.00%)
Infection With Normal ANC, Appendix * 1	0/451 (0.00%)	0/451 (0.00%)	1/452 (0.22%)	0/216 (0.00%)
Infection With Normal ANC, Bronchus * 1	0/451 (0.00%)	0/451 (0.00%)	0/452 (0.00%)	3/216 (1.39%)
Infection With Normal ANC, Catheter-Related * 1	1/451 (0.22%)	0/451 (0.00%)	1/452 (0.22%)	0/216 (0.00%)
Infection With Normal ANC, Lung (Pneumonia) * 1	0/451 (0.00%)	1/451 (0.22%)	0/452 (0.00%)	1/216 (0.46%)
Infection With Normal ANC, PANCreas * 1	0/451 (0.00%)	0/451 (0.00%)	1/452 (0.22%)	0/216 (0.00%)
Infection With Normal ANC, Pelvis NOS * 1	0/451 (0.00%)	0/451 (0.00%)	1/452 (0.22%)	0/216 (0.00%)
Infection With Normal ANC, Urinary Tract NOS * 1	0/451 (0.00%)	1/451 (0.22%)	0/452 (0.00%)	0/216 (0.00%)
Opportunistic Infection * 1	1/451 (0.22%)	1/451 (0.22%)	0/452 (0.00%)	0/216 (0.00%)
Infection - Other * 1	1/451 (0.22%)	1/451 (0.22%)	2/452 (0.44%)	3/216 (1.39%)
Infection With Unknown ANC, Abdomen NOS * 1	0/451 (0.00%)	0/451 (0.00%)	0/452 (0.00%)	1/216 (0.46%)
Infection With Unknown ANC, Bronchus * 1	0/451 (0.00%)	0/451 (0.00%)	0/452 (0.00%)	1/216 (0.46%)
Infection With Unknown ANC, Lung (Pneumonia) * 1	1/451 (0.22%)	1/451 (0.22%)	2/452 (0.44%)	1/216 (0.46%)
Infection With Unknown ANC, Meninges (Meningitis) * 1	1/451 (0.22%)	0/451 (0.00%)	1/452 (0.22%)	0/216 (0.00%)
Infection With Unknown ANC, Upper Airway NOS * 1	0/451 (0.00%)	0/451 (0.00%)	0/452 (0.00%)	1/216 (0.46%)
Infection With Unknown ANC, Urinary Tract NOS * 1	1/451 (0.22%)	0/451 (0.00%)	1/452 (0.22%)	0/216 (0.00%)
Injury, poisoning and procedural complications
Intraop Injury, Liver * 1	0/451 (0.00%)	0/451 (0.00%)	1/452 (0.22%)	0/216 (0.00%)
Intraop Injury, Extremity - Upper * 1	0/451 (0.00%)	1/451 (0.22%)	0/452 (0.00%)	0/216 (0.00%)
Intraop Injury, Bone * 1	2/451 (0.44%)	0/451 (0.00%)	0/452 (0.00%)	2/216 (0.93%)
Intraop Injury, Soft Tissue NOS * 1	0/451 (0.00%)	0/451 (0.00%)	0/452 (0.00%)	1/216 (0.46%)
Intraop Injury - Other * 1	1/451 (0.22%)	0/451 (0.00%)	2/452 (0.44%)	1/216 (0.46%)
Metabolism and nutrition disorders
Creatinine * 1	0/451 (0.00%)	0/451 (0.00%)	0/452 (0.00%)	1/216 (0.46%)
Hypercalcemia * 1	3/451 (0.67%)	6/451 (1.33%)	3/452 (0.66%)	0/216 (0.00%)
Hyperkalemia * 1	0/451 (0.00%)	1/451 (0.22%)	3/452 (0.66%)	1/216 (0.46%)
Hypernatremia * 1	0/451 (0.00%)	0/451 (0.00%)	1/452 (0.22%)	0/216 (0.00%)
Hypoalbuminemia * 1	1/451 (0.22%)	0/451 (0.00%)	1/452 (0.22%)	0/216 (0.00%)
Hypocalcemia * 1	1/451 (0.22%)	0/451 (0.00%)	2/452 (0.44%)	3/216 (1.39%)
Hypoglycemia * 1	0/451 (0.00%)	1/451 (0.22%)	0/452 (0.00%)	0/216 (0.00%)
Lipase * 1	1/451 (0.22%)	0/451 (0.00%)	3/452 (0.66%)	0/216 (0.00%)
Hypokalemia * 1	0/451 (0.00%)	0/451 (0.00%)	1/452 (0.22%)	0/216 (0.00%)
Hyponatremia * 1	2/451 (0.44%)	0/451 (0.00%)	3/452 (0.66%)	1/216 (0.46%)
Metabolic/Lab - Other * 1	1/451 (0.22%)	0/451 (0.00%)	3/452 (0.66%)	0/216 (0.00%)
Proteinuria * 1	0/451 (0.00%)	0/451 (0.00%)	1/452 (0.22%)	1/216 (0.46%)
Musculoskeletal and connective tissue disorders
Osteonecrosis * 1	1/451 (0.22%)	0/451 (0.00%)	1/452 (0.22%)	1/216 (0.46%)
Extremity-Upper (Function) * 1	0/451 (0.00%)	1/451 (0.22%)	0/452 (0.00%)	0/216 (0.00%)
Fracture * 1	7/451 (1.55%)	5/451 (1.11%)	12/452 (2.65%)	3/216 (1.39%)
Musculoskeletal - Other * 1	2/451 (0.44%)	4/451 (0.89%)	7/452 (1.55%)	5/216 (2.31%)
Gait/Walking * 1	1/451 (0.22%)	0/451 (0.00%)	1/452 (0.22%)	0/216 (0.00%)
Muscle Weakness, Extremity-Lower * 1	0/451 (0.00%)	0/451 (0.00%)	1/452 (0.22%)	0/216 (0.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Secondary Malignancy (Possibly Related To Cancer Treatment) * 1	2/451 (0.44%)	0/451 (0.00%)	3/452 (0.66%)	1/216 (0.46%)
Nervous system disorders
CNS Ischemia * 1	1/451 (0.22%)	3/451 (0.67%)	7/452 (1.55%)	1/216 (0.46%)
Pyramidal Tract Disfunction * 1	0/451 (0.00%)	1/451 (0.22%)	0/452 (0.00%)	0/216 (0.00%)
Neuropathy: Cranial, CN VII Motor-Face; Sensory-Taste * 1	0/451 (0.00%)	0/451 (0.00%)	0/452 (0.00%)	1/216 (0.46%)
Cognitive DisturbANCe * 1	1/451 (0.22%)	0/451 (0.00%)	1/452 (0.22%)	0/216 (0.00%)
Confusion * 1	1/451 (0.22%)	1/451 (0.22%)	3/452 (0.66%)	3/216 (1.39%)
Dizziness * 1	1/451 (0.22%)	0/451 (0.00%)	1/452 (0.22%)	2/216 (0.93%)
Speech Impairment * 1	0/451 (0.00%)	1/451 (0.22%)	0/452 (0.00%)	1/216 (0.46%)
Involuntary Movement * 1	0/451 (0.00%)	1/451 (0.22%)	0/452 (0.00%)	0/216 (0.00%)
Mood Alteration, Depression * 1	2/451 (0.44%)	0/451 (0.00%)	3/452 (0.66%)	0/216 (0.00%)
Neuropathy: Motor * 1	0/451 (0.00%)	0/451 (0.00%)	1/452 (0.22%)	0/216 (0.00%)
Neurology - Other * 1	5/451 (1.11%)	7/451 (1.55%)	11/452 (2.43%)	8/216 (3.70%)
Seizure * 1	0/451 (0.00%)	0/451 (0.00%)	1/452 (0.22%)	0/216 (0.00%)
Syncope * 1	2/451 (0.44%)	2/451 (0.44%)	2/452 (0.44%)	0/216 (0.00%)
Tremor * 1	1/451 (0.22%)	0/451 (0.00%)	1/452 (0.22%)	0/216 (0.00%)
Renal and urinary disorders
Cystitis * 1	1/451 (0.22%)	0/451 (0.00%)	1/452 (0.22%)	0/216 (0.00%)
Urinary Electrolyte Wasting * 1	0/451 (0.00%)	0/451 (0.00%)	1/452 (0.22%)	0/216 (0.00%)
Renal Failure * 1	8/451 (1.77%)	2/451 (0.44%)	9/452 (1.99%)	4/216 (1.85%)
Renal - Other * 1	4/451 (0.89%)	2/451 (0.44%)	13/452 (2.88%)	6/216 (2.78%)
Obstruction, GU, Ureter * 1	0/451 (0.00%)	0/451 (0.00%)	1/452 (0.22%)	1/216 (0.46%)
Respiratory, thoracic and mediastinal disorders
Atelectasis * 1	1/451 (0.22%)	0/451 (0.00%)	1/452 (0.22%)	0/216 (0.00%)
Cough * 1	2/451 (0.44%)	0/451 (0.00%)	2/452 (0.44%)	0/216 (0.00%)
Pleural Effusion * 1	8/451 (1.77%)	4/451 (0.89%)	11/452 (2.43%)	2/216 (0.93%)
Edema: Larynx * 1	0/451 (0.00%)	0/451 (0.00%)	0/452 (0.00%)	1/216 (0.46%)
Hypoxia * 1	1/451 (0.22%)	1/451 (0.22%)	2/452 (0.44%)	0/216 (0.00%)
Airway Obstruction, Bronchus * 1	2/451 (0.44%)	2/451 (0.44%)	2/452 (0.44%)	0/216 (0.00%)
Pulmonary - Other * 1	5/451 (1.11%)	4/451 (0.89%)	9/452 (1.99%)	3/216 (1.39%)
Pneumonitis * 1	6/451 (1.33%)	1/451 (0.22%)	7/452 (1.55%)	5/216 (2.31%)
Pneumothorax * 1	0/451 (0.00%)	1/451 (0.22%)	0/452 (0.00%)	0/216 (0.00%)
Dyspnea (Shortness Of Breath) * 1	11/451 (2.44%)	8/451 (1.77%)	21/452 (4.65%)	10/216 (4.63%)
Skin and subcutaneous tissue disorders
Dermatitis, Chemoradiation * 1	1/451 (0.22%)	0/451 (0.00%)	1/452 (0.22%)	0/216 (0.00%)
Decubitus * 1	1/451 (0.22%)	0/451 (0.00%)	1/452 (0.22%)	0/216 (0.00%)
Hand-Foot Skin Reaction * 1	2/451 (0.44%)	0/451 (0.00%)	2/452 (0.44%)	1/216 (0.46%)
Wound Complication, Non-Infectious * 1	1/451 (0.22%)	0/451 (0.00%)	1/452 (0.22%)	0/216 (0.00%)
Dermatology - Other * 1	1/451 (0.22%)	0/451 (0.00%)	2/452 (0.44%)	1/216 (0.46%)
Dermatitis, Radiation * 1	0/451 (0.00%)	0/451 (0.00%)	0/452 (0.00%)	1/216 (0.46%)
Rash/Desquamation * 1	1/451 (0.22%)	0/451 (0.00%)	1/452 (0.22%)	3/216 (1.39%)
Skin Ulceration * 1	0/451 (0.00%)	0/451 (0.00%)	0/452 (0.00%)	1/216 (0.46%)
Vascular disorders
CNS Hemorrhage * 1	1/451 (0.22%)	1/451 (0.22%)	2/452 (0.44%)	0/216 (0.00%)
Hemorrhage, GI, Abdomen NOS * 1	0/451 (0.00%)	0/451 (0.00%)	1/452 (0.22%)	0/216 (0.00%)
Hemorrhage, GI, Anus * 1	1/451 (0.22%)	0/451 (0.00%)	1/452 (0.22%)	0/216 (0.00%)
Hemorrhage, GI, Colon * 1	0/451 (0.00%)	0/451 (0.00%)	1/452 (0.22%)	0/216 (0.00%)
Hemorrhage, GI, Duodenum * 1	1/451 (0.22%)	0/451 (0.00%)	2/452 (0.44%)	0/216 (0.00%)
Hemorrhage, GI, Stomach * 1	0/451 (0.00%)	0/451 (0.00%)	3/452 (0.66%)	0/216 (0.00%)
Hemorrhage, GI, Jejunum * 1	0/451 (0.00%)	0/451 (0.00%)	1/452 (0.22%)	0/216 (0.00%)
Hemorrhage, GI, Lower GI NOS * 1	0/451 (0.00%)	0/451 (0.00%)	2/452 (0.44%)	0/216 (0.00%)
Hemorrhage, GI, Rectum * 1	2/451 (0.44%)	0/451 (0.00%)	2/452 (0.44%)	1/216 (0.46%)
Hemorrhage, GI, Upper GI NOS * 1	0/451 (0.00%)	2/451 (0.44%)	4/452 (0.88%)	0/216 (0.00%)
Hemorrhage With Surgery * 1	0/451 (0.00%)	1/451 (0.22%)	0/452 (0.00%)	0/216 (0.00%)
Hemorrhage - Other * 1	3/451 (0.67%)	1/451 (0.22%)	4/452 (0.88%)	2/216 (0.93%)
Hemorrhage Pulmonary, Bronchopulmonary NOS * 1	3/451 (0.67%)	2/451 (0.44%)	4/452 (0.88%)	2/216 (0.93%)
Hemorrhage Pulmonary, Bronchus * 1	0/451 (0.00%)	2/451 (0.44%)	0/452 (0.00%)	0/216 (0.00%)
Hemorrhage Pulmonary, Larynx * 1	0/451 (0.00%)	0/451 (0.00%)	1/452 (0.22%)	0/216 (0.00%)
Hemorrhage Pulmonary, Lung * 1	1/451 (0.22%)	1/451 (0.22%)	1/452 (0.22%)	0/216 (0.00%)
Hemorrhage Pulmonary, Nose * 1	1/451 (0.22%)	0/451 (0.00%)	1/452 (0.22%)	2/216 (0.93%)
Hemorrhage Pulmonary, Pleura * 1	0/451 (0.00%)	1/451 (0.22%)	0/452 (0.00%)	0/216 (0.00%)
Hemorrhage Pulmonary, Respiratory Tract NOS * 1	2/451 (0.44%)	0/451 (0.00%)	3/452 (0.66%)	1/216 (0.46%)
Hemorrhage, GU, Uterus * 1	1/451 (0.22%)	0/451 (0.00%)	1/452 (0.22%)	0/216 (0.00%)
Hemorrhage, GU, Urinary NOS * 1	1/451 (0.22%)	0/451 (0.00%)	1/452 (0.22%)	1/216 (0.46%)
Thrombosis/Embolism (Vascular Access) * 1	2/451 (0.44%)	0/451 (0.00%)	1/452 (0.22%)	2/216 (0.93%)
Vascular - Other * 1	0/451 (0.00%)	0/451 (0.00%)	4/452 (0.88%)	1/216 (0.46%)
Thrombosis/Thrombus/Embolism * 1	4/451 (0.89%)	5/451 (1.11%)	9/452 (1.99%)	6/216 (2.78%)
* Indicates events were collected by non-systematic assessment; 1 Term from vocabulary, NCI-CTCAE v. 3.0
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Sorafenib (Nexavar, BAY43-9006)-31May2005 DB	Placebo-31May2005 DB	Sorafenib (Nexavar, BAY43-9006)-30Jun2008	Placebo ~31May2005, Then Switched to Sorafenib Only-30Jun2008
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	407/451 (90.24%)	346/451 (76.72%)	425/452 (94.03%)	200/216 (92.59%)
Blood and lymphatic system disorders
Hemoglobin * 1	30/451 (6.65%)	29/451 (6.43%)	61/452 (13.50%)	23/216 (10.65%)
Edema: Limb * 1	28/451 (6.21%)	22/451 (4.88%)	42/452 (9.29%)	16/216 (7.41%)
Cardiac disorders
Hypertension * 1	74/451 (16.41%)	8/451 (1.77%)	101/452 (22.35%)	39/216 (18.06%)
Gastrointestinal disorders
Anorexia * 1	73/451 (16.19%)	57/451 (12.64%)	111/452 (24.56%)	58/216 (26.85%)
Constipation * 1	66/451 (14.63%)	48/451 (10.64%)	79/452 (17.48%)	31/216 (14.35%)
Diarrhea * 1	195/451 (43.24%)	58/451 (12.86%)	244/452 (53.98%)	118/216 (54.63%)
Heartburn * 1	21/451 (4.66%)	10/451 (2.22%)	27/452 (5.97%)	8/216 (3.70%)
Mucositis (Functional/Symptomatic), Oral Cavity * 1	17/451 (3.77%)	11/451 (2.44%)	27/452 (5.97%)	26/216 (12.04%)
Mucositis (Clinical Exam), Oral Cavity * 1	30/451 (6.65%)	3/451 (0.67%)	36/452 (7.96%)	11/216 (5.09%)
Nausea * 1	102/451 (22.62%)	86/451 (19.07%)	121/452 (26.77%)	42/216 (19.44%)
GI - Other * 1	25/451 (5.54%)	18/451 (3.99%)	37/452 (8.19%)	7/216 (3.24%)
Vomiting * 1	72/451 (15.96%)	51/451 (11.31%)	89/452 (19.69%)	28/216 (12.96%)
General disorders
Fever * 1	36/451 (7.98%)	34/451 (7.54%)	48/452 (10.62%)	16/216 (7.41%)
Insomnia * 1	16/451 (3.55%)	20/451 (4.43%)	35/452 (7.74%)	9/216 (4.17%)
Fatigue * 1	162/451 (35.92%)	122/451 (27.05%)	221/452 (48.89%)	86/216 (39.81%)
Weight Loss * 1	46/451 (10.20%)	25/451 (5.54%)	102/452 (22.57%)	60/216 (27.78%)
Constitutional Symptoms - Other * 1	38/451 (8.43%)	20/451 (4.43%)	41/452 (9.07%)	19/216 (8.80%)
Sweating * 1	28/451 (6.21%)	17/451 (3.77%)	33/452 (7.30%)	11/216 (5.09%)
Pain, Back * 1	33/451 (7.32%)	39/451 (8.65%)	52/452 (11.50%)	17/216 (7.87%)
Pain, Chest/Thorax NOS * 1	18/451 (3.99%)	12/451 (2.66%)	26/452 (5.75%)	6/216 (2.78%)
Pain, Extremity-Limb * 1	26/451 (5.76%)	20/451 (4.43%)	44/452 (9.73%)	16/216 (7.41%)
Pain, Tumor Pain * 1	27/451 (5.99%)	20/451 (4.43%)	32/452 (7.08%)	8/216 (3.70%)
Pain, Abdomen NOS * 1	46/451 (10.20%)	41/451 (9.09%)	69/452 (15.27%)	23/216 (10.65%)
Pain, Head/Headache * 1	46/451 (10.20%)	26/451 (5.76%)	57/452 (12.61%)	17/216 (7.87%)
Pain, Joint * 1	45/451 (9.98%)	29/451 (6.43%)	59/452 (13.05%)	12/216 (5.56%)
Pain, Muscle * 1	41/451 (9.09%)	21/451 (4.66%)	48/452 (10.62%)	6/216 (2.78%)
Pain, Bone * 1	33/451 (7.32%)	34/451 (7.54%)	61/452 (13.50%)	23/216 (10.65%)
Pain, Other * 1	31/451 (6.87%)	16/451 (3.55%)	60/452 (13.27%)	28/216 (12.96%)
Infections and infestations
Infection - Other * 1	35/451 (7.76%)	26/451 (5.76%)	56/452 (12.39%)	21/216 (9.72%)
Musculoskeletal and connective tissue disorders
Musculoskeletal - Other * 1	23/451 (5.10%)	21/451 (4.66%)	36/452 (7.96%)	12/216 (5.56%)
Nervous system disorders
Dizziness * 1	17/451 (3.77%)	23/451 (5.10%)	24/452 (5.31%)	6/216 (2.78%)
Mood Alteration, Depression * 1	12/451 (2.66%)	16/451 (3.55%)	25/452 (5.53%)	8/216 (3.70%)
Neuropathy: Sensory * 1	59/451 (13.08%)	29/451 (6.43%)	67/452 (14.82%)	21/216 (9.72%)
Respiratory, thoracic and mediastinal disorders
Cough * 1	59/451 (13.08%)	64/451 (14.19%)	92/452 (20.35%)	27/216 (12.50%)
Pulmonary - Other * 1	25/451 (5.54%)	15/451 (3.33%)	38/452 (8.41%)	11/216 (5.09%)
Dyspnea (Shortness Of Breath) * 1	58/451 (12.86%)	49/451 (10.86%)	94/452 (20.80%)	29/216 (13.43%)
Voice Changes * 1	19/451 (4.21%)	1/451 (0.22%)	23/452 (5.09%)	6/216 (2.78%)
Skin and subcutaneous tissue disorders
Alopecia * 1	122/451 (27.05%)	15/451 (3.33%)	143/452 (31.64%)	76/216 (35.19%)
Dry Skin * 1	50/451 (11.09%)	18/451 (3.99%)	63/452 (13.94%)	22/216 (10.19%)
Hand-Foot Skin Reaction * 1	133/451 (29.49%)	30/451 (6.65%)	156/452 (34.51%)	84/216 (38.89%)
Dermatology - Other * 1	67/451 (14.86%)	20/451 (4.43%)	84/452 (18.58%)	30/216 (13.89%)
Pruritus * 1	85/451 (18.85%)	29/451 (6.43%)	90/452 (19.91%)	27/216 (12.50%)
Rash/Desquamation * 1	179/451 (39.69%)	70/451 (15.52%)	196/452 (43.36%)	70/216 (32.41%)
Flushing * 1	33/451 (7.32%)	13/451 (2.88%)	40/452 (8.85%)	9/216 (4.17%)
Vascular disorders
Hematoma * 1	18/451 (3.99%)	5/451 (1.11%)	23/452 (5.09%)	2/216 (0.93%)
* Indicates events were collected by non-systematic assessment; 1 Term from vocabulary, NCI-CTCAE v. 3.0

Limitations and Caveats

Per final PFS data (N=769) study unblinded; placebo-randomized subjects switched to sorafenib ~31May2005 (N=216) that diluted final OS, sorafenib treatment effect. Final ITT, N=903, reported safety data include additional data and cleaning.

More Information

Certain Agreements

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreed point of publication is 12-18 months after database lock at the earliest.

• Bayer will have up to 30/45 days to review publications, and may request an additional publication delay of up to 60 days to allow for filing a Patent Application (if applicable).
• No publication of single center data should be done prior of publication if multi -center data.

Results Point of Contact

• Name/Title: Therapeutic Area Head
• Organization: BAYER
• EMail: clinical-trials-contact@bayerhealthcare.com

Publications of Results:

Antoun S, Birdsell L, Sawyer MB, Venner P, Escudier B, Baracos VE. Association of skeletal muscle wasting with treatment with sorafenib in patients with advanced renal cell carcinoma: results from a placebo-controlled study. J Clin Oncol. 2010 Feb 20;28(6):1054-60. doi: 10.1200/JCO.2009.24.9730. Epub 2010 Jan 19.

Bellmunt J, Eisen T, Fishman M, Quinn D. Experience with sorafenib and adverse event management. Crit Rev Oncol Hematol. 2011 Apr;78(1):24-32. doi: 10.1016/j.critrevonc.2010.03.006. Epub 2010 Apr 18.

Massard C, Zonierek J, Gross-Goupil M, Fizazi K, Szczylik C, Escudier B. Incidence of brain metastases in renal cell carcinoma treated with sorafenib. Ann Oncol. 2010 May;21(5):1027-31. doi: 10.1093/annonc/mdp411. Epub 2009 Oct 22.

Negrier S, Jager E, Porta C, McDermott D, Moore M, Bellmunt J, Anderson S, Cihon F, Lewis J, Escudier B, Bukowski R. Efficacy and safety of sorafenib in patients with advanced renal cell carcinoma with and without prior cytokine therapy, a subanalysis of TARGET. Med Oncol. 2010 Sep;27(3):899-906. doi: 10.1007/s12032-009-9303-z. Epub 2009 Sep 12.

Pena C, Lathia C, Shan M, Escudier B, Bukowski RM. Biomarkers predicting outcome in patients with advanced renal cell carcinoma: Results from sorafenib phase III Treatment Approaches in Renal Cancer Global Evaluation Trial. Clin Cancer Res. 2010 Oct 1;16(19):4853-63. doi: 10.1158/1078-0432.CCR-09-3343. Epub 2010 Jul 22.

Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Staehler M, Negrier S, Chevreau C, Desai AA, Rolland F, Demkow T, Hutson TE, Gore M, Anderson S, Hofilena G, Shan M, Pena C, Lathia C, Bukowski RM. Sorafenib for treatment of renal cell carcinoma: Final efficacy and safety results of the phase III treatment approaches in renal cancer global evaluation trial. J Clin Oncol. 2009 Jul 10;27(20):3312-8. doi: 10.1200/JCO.2008.19.5511. Epub 2009 May 18.

Eisen T, Oudard S, Szczylik C, Gravis G, Heinzer H, Middleton R, Cihon F, Anderson S, Shah S, Bukowski R, Escudier B; TARGET Study Group. Sorafenib for older patients with renal cell carcinoma: subset analysis from a randomized trial. J Natl Cancer Inst. 2008 Oct 15;100(20):1454-63. doi: 10.1093/jnci/djn319. Epub 2008 Oct 7.

Bukowski R, Cella D, Gondek K, Escudier B; Sorafenib TARGETs Clinical Trial Group. Effects of sorafenib on symptoms and quality of life: results from a large randomized placebo-controlled study in renal cancer. Am J Clin Oncol. 2007 Jun;30(3):220-7. doi: 10.1097/01.coc.0000258732.80710.05.

Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, Negrier S, Chevreau C, Solska E, Desai AA, Rolland F, Demkow T, Hutson TE, Gore M, Freeman S, Schwartz B, Shan M, Simantov R, Bukowski RM; TARGET Study Group. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007 Jan 11;356(2):125-34. doi: 10.1056/NEJMoa060655. Erratum In: N Engl J Med. 2007 Jul 12;357(2):203.

Kane RC, Farrell AT, Saber H, Tang S, Williams G, Jee JM, Liang C, Booth B, Chidambaram N, Morse D, Sridhara R, Garvey P, Justice R, Pazdur R. Sorafenib for the treatment of advanced renal cell carcinoma. Clin Cancer Res. 2006 Dec 15;12(24):7271-8. doi: 10.1158/1078-0432.CCR-06-1249.

Lamuraglia M, Escudier B, Chami L, Schwartz B, Leclere J, Roche A, Lassau N. To predict progression-free survival and overall survival in metastatic renal cancer treated with sorafenib: pilot study using dynamic contrast-enhanced Doppler ultrasound. Eur J Cancer. 2006 Oct;42(15):2472-9. doi: 10.1016/j.ejca.2006.04.023. Epub 2006 Sep 11. Erratum In: Eur J Cancer. 2007 May;43(8):1336.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Quintanilha JCF, Geyer S, Etheridge AS, Racioppi A, Hammond K, Crona DJ, Pena CE, Jacobson SB, Marmorino F, Rossini D, Cremolini C, Sanoff HK, Abou-Alfa GK, Innocenti F. KDR genetic predictor of toxicities induced by sorafenib and regorafenib. Pharmacogenomics J. 2022 Dec;22(5-6):251-257. doi: 10.1038/s41397-022-00279-3. Epub 2022 Apr 28.

Quintanilha JCF, Racioppi A, Wang J, Etheridge AS, Denning S, Pena CE, Skol AD, Crona DJ, Lin D, Innocenti F. PIK3R5 genetic predictors of hypertension induced by VEGF-pathway inhibitors. Pharmacogenomics J. 2022 Feb;22(1):82-88. doi: 10.1038/s41397-021-00261-5. Epub 2021 Nov 13. Erratum In: Pharmacogenomics J. 2021 Dec 21;:

• Responsible Party: Bayer
• ClinicalTrials.gov Identifier: NCT00073307
• Other Study ID Numbers: 11213
• First Submitted: November 19, 2003
• First Posted: November 21, 2003
• Results First Submitted: August 2, 2011
• Results First Posted: December 14, 2011
• Last Update Posted: February 6, 2014