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

Study Type:	Interventional
Study Design:	Allocation: Randomized; Endpoint Classification: Safety/Efficacy Study; Intervention Model: Parallel Assignment; Masking: Double Blind (Subject, Investigator, Outcomes Assessor); Primary Purpose: Treatment
Condition:	Carcinoma, Renal Cell
Interventions:	Drug: Sorafenib (Nexavar, BAY43-9006) Drug: Placebo

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
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

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
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.

Reporting Groups

	Description
Sorafenib (Nexavar, BAY43-9006)	Sorafenib was to be orally administered as 2 x 200 mg tablets bid (twice daily).
Placebo	Subjects received matching placebo tablets administered orally twice a day. [until ~31 May 2005]
Placebo Randomized, Switch to Sorafenib; Sorafenib Period Only	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).

Participant Flow for 2 periods

Period 1: Double-Blind (DB, as of ~31May2005)

	Sorafenib (Nexavar, BAY43-9006)	Placebo
STARTED	451	452
Participants Received Treatment	451	451
COMPLETED	254	299
NOT COMPLETED	197	153
Adverse Event	22	17
Lost to Follow-up	1	6
Withdrawal by Subject	6	11
Protocol Violation	1	1
Non-compliant with Study medication	1	2
Unknown reason.	1	0
Protocol driven decision point	0	1
entered Open Label (OL); Sorafenib only	165	114
Subject did not receive treatment	0	1

Period 2: Open Label-Sorafenib Only [30Jun2008]

	Sorafenib (Nexavar, BAY43-9006)	Placebo	Placebo Randomized, Switch to Sorafenib; Sorafenib Period Only
STARTED	254	0 ^[1]	299
Entered OL With Sorafenib Only Phase	219	0	216
COMPLETED	120	0	143
NOT COMPLETED	134	0	156
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

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Reporting Groups

	Description
Sorafenib (Nexavar, BAY43-9006)	Sorafenib was to be orally administered as 2 x 200 mg tablets bid (twice daily). Dose modification due to toxicity was permitted.
Placebo	Subjects received matching placebo tablets administered orally twice a day. [until ~31 May 2005]

Baseline Measures

	Sorafenib (Nexavar, BAY43-9006)	Placebo	Total
Number of Participants [units: participants]	451	452	903
Age [units: Years] Median ( Full Range )	58.0 ( 19.0 to 86.0 )	59.0 ( 29.0 to 84.0 )	59.0 ( 19.0 to 86.0 )
Age, Customized [units: Participants]
<65 years	304	328	632
>= 65 years	147	124	271
Gender [units: Participants]
Female	136	112	248
Male	315	340	655
Motzer Category (Low, intermediate or high) ^[1] [units: Participants]
Low	234	219	453
Intermediate	217	232	449
Missing	0	1	1
ECOG Performance Status (PS) ^[2] [units: Participants by scale]
PS 0	219	211	430
PS 1	223	235	458
PS 2	7	4	11
Missing	2	2	4
TNM Classification at study entry ^[3] [units: Participants]
Stage III	18	14	32
Stage IV	433	438	871
Cancer Subtypes ^[4] [units: Participants with carcinoma type]
Clear Cell	449	447	896
Papillary	1	3	4
Granular	1	2	3

[1]	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.
[2]	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).
[3]	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]
[4]	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

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1. Primary:

Final Overall Survival (OS) - Primary Analysis in the ITT (Intent To Treat) Population [ 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 ]

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2. Primary:

Final Overall Survival - Secondary Analysis (Placebo Data Censored at 30June2005) in the ITT Population [ 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 ]

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3. Secondary:

Final Progression-Free Survival (PFS) - Independent Radiological Review [ 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. ]

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4. Secondary:

Best Overall Response - Independent Radiological Review [ 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. ]

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5. Secondary:

Health-related Quality of Life (HRQOL) by FKSI-10 (Functional Assessment of General Therapy Kidney Symptom Index 10) Assessment [ 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. ]

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6. Secondary:

Health-related Quality of Life (HRQOL) by Physical Well-Being (PWB) Score of the FACT-G (Functional Assessment of Cancer Therapy-General Version) Assessment [ 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. ]

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Serious Adverse Events

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Other Adverse Events

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More Information

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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 agreement is:

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.

Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed.

Restriction Description:

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.

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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.

Results Point of Contact:

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

No publications provided by Bayer

Publications automatically indexed to this study:

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.

Responsible Party:	Therapeutic Area Head, Bayer HealthCare Pharmaceuticals Inc.
ClinicalTrials.gov Identifier:	NCT00073307 History of Changes
Other Study ID Numbers:	11213
Study First Received:	November 19, 2003
Results First Received:	August 2, 2011
Last Updated:	November 9, 2011
Health Authority:	United States: Food and Drug Administration