Sorafenib Dose Escalation in Renal Cell Carcinoma

• Sponsor: Bayer (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00618982
• Collaborator: (none)
• Enrollment: 83
• Locations: 22
• Arm: 1
• Duration (Months): 35
• Patients Per Site: 3.8
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

Sorafenib is a new drug, which is approved under the brand name Nexavar for the treatment of advanced kidney cancer. It is also currently being tested in various other cancers. Sorafenib works by stopping the development of new cancer cells and new blood vessels. By stopping the growth of new blood vessels around a tumor, it is believed that sorafenib prevents the growth of kidney cancer tumors.

This is an "open-label" study which means that the patient, the doctor and Bayer Healthcare will know what tablets the patient is taking. All patients in this study will receive sorafenib tablets. Sorafenib is taken orally as a tablet (two tablets are taken twice a day). Treatment with sorafenib will continue until the patient's tumor grows larger or spreads further or if the patient has intolerable side effects. The dose of sorafenib that the patient will receive in the study will increase at certain points during the patient's treatment, as long as the patient is not experiencing side effects and the patient's tumor has not grown.

Condition or Disease	Intervention/Treatment	Phase
Carcinoma, Renal Cell	Drug: Sorafenib (Nexavar, BAY43-9006)	Phase 2

Detailed Description

Issues on Outcome Measure "Safety and tolerability" will be addressed in the Adverse Events section.

Study Design

• Study Type: Interventional
• Actual Enrollment: 83 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II, Multi-centre, Open-label Study to Assess the Efficacy, Safety, Tolerability and Pharmacokinetics of Intrapatient Dose Escalation of Sorafenib as First Line Treatment for Metastatic Renal Cell Carcinoma.
• Study Start Date: Feb 1, 2008
• Actual Primary Completion Date: Apr 1, 2009
• Actual Study Completion Date: Jan 1, 2011

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Sorafenib (Nexavar, BAY43-9006) Intrapatient dose escalation of sorafenib from 400 mg orally twice daily (bid) for the first cycle, 600 mg bid for the second cycle and 800 mg bid until disease progression, unacceptable toxicity or withdrawal of consent. Dose reductions due to toxicities were allowed.

Drug: Sorafenib (Nexavar, BAY43-9006); The initial dose of sorafenib will be 400 mg bid administered orally, on a continuous basis. A treatment cycle is considered to be 28 days. Intrapatient dose escalation will occur according to the following schedule, providing no grade 3 or 4 toxicities are observed (except for alopecia, nausea and vomiting); Day 1-28 400 mg bid, Day 29-56 600 mg bid, Day 57 onwards 800 mg bid. Subjects will continue on treatment until progression, unacceptable toxicity, subject withdraws consent or the decision is taken to stop the study following the analysis of response rates.

Outcome Measures

Primary Outcome Measures

1. Best Response - mITT (Modified Intent-to-treat) Population [Radiological assessments were performed every 8 weeks (2 cycles) from start of the treatment. After completion of 6 cycles of treatment at the highest tolerated dose level, assessments were performed every 12 weeks for up to 34 months.]

   Best Response (Response Rate) of a subject was defined as the proportion of patients with confirmed Complete Response (CR) or Partial Response (PR) as their best response observed (by independent central assessment) during trial period assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST version 1.0) criteria. Confirmed CR was defined as disappearance of tumor and PR was defined as a decrease of at least 30% in the sum of tumor lesion sizes.

2. Tumor Response - ITT (Intent to Treat) Population [Radiological assessments were performed every 8 weeks (2 cycles) from start of the treatment. After completion of 6 cycles of treatment at the highest tolerated dose level, assessments were performed every 12 weeks for up to 34 months.]

   Tumor Response of a subject was defined as the best tumor response observed (by independent central assessment) during trial period assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST version 1.0) criteria. Confirmed Complete Response (CR) was defined as disappearance of tumor, Partial Response (PR) was defined as a decrease of at least 30% in the sum of target lesions, Stable Disease (SD) was defined as steady state of disease, and Progressive Disease (PD) was defined as at least a 20% increase in the sum of measured lesions or appearance of new lesions.

Secondary Outcome Measures

1. Pharmacokinetics (PK) Analysis - Area Under the Drug Concentration-time Curve From Time Zero to 10 Hours Postdose (AUC(0-10),ss) [Blood samples were collected at screening (blank) and on day 28 of the first cycle completed at each dose level. Samples were drawn at the following time points in relation to morning dose of sorafenib: pre-dose, 2, 4, 6, 8 and 10 hours post-dose.]

   AUC(0-10),ss was defined as an area under the plasma concentration versus time curve from time zero to 10 hours post-dose. Parameter was calculated for sorafenib and M2, an active metabolite of sorafenib.

2. Pharmacokinetics (PK) Analysis - Area Under the Drug Concentration-time Curve From Time Zero to 12 Hours Postdose (AUC(0-12),ss) [Blood samples were collected at screening (blank) and on day 28 of the first cycle completed at each dose level. Samples were drawn at the following time points in relation to morning dose of sorafenib: pre-dose, 2, 4, 6, 8, 10 and 12 hours post-dose.]

   AUC(0-12),ss was defined as an area under the plasma concentration versus time curve from time zero to 12 hours post-dose. Parameter was calculated for sorafenib and M2, an active metabolite of sorafenib.

3. Pharmacokinetics (PK) Analysis - Maximum Observed Concentration in Plasma (Cmax) [Blood samples were collected at screening (blank) and on day 28 of the first cycle completed at each dose level. Samples were drawn at the following time points in relation to morning dose of sorafenib: pre-dose, 2, 4, 6, 8, 10 and 12 hours post-dose.]

   Cmax was defined as a maximum plasma concentration at steady-state. Parameter was calculated for sorafenib and M2, an active metabolite of sorafenib.

4. Pharmacokinetics (PK) Analysis - Time to Maximum Concentration (Tmax) [Blood samples were collected at screening (blank) and on day 28 of the first cycle completed at each dose level. Samples were drawn at the following time points in relation to morning dose of sorafenib: pre-dose, 2, 4, 6, 8, 10 and 12 hours post-dose.]

   Tmax was defined as a time to maximum concentration at steady-state. Parameter was calculated for sorafenib and M2, an active metabolite of sorafenib.

5. Progression-free Survival (PFS) [Radiological assessments were performed every 8 weeks (2 cycles) from start of the treatment. After completion of 6 cycles of treatment at the highest tolerated dose level, assessments were performed every 12 weeks for up to 34 months.]

   Progression-free survival (PFS) was defined as the time from start of study medication to the first documented disease progression per RECIST (by independent radiological assessment) or clinical progression as per investigator assessment or death due to any cause whichever occurred first. For patients who had not recurred or died at the time of analysis, PFS was censored at their last date of evaluable scan.

6. Time to Progression (TTP) [Radiological assessments were performed every 8 weeks (2 cycles) from start of the treatment. After completion of 6 cycles of treatment at the highest tolerated dose level, assessments were performed every 12 weeks for up to 34 months.]

   Time to progression (TTP) was defined as the time from start of study medication to the first documented disease progression per RECIST (by independent radiological assessment) or clinical progression as per investigator assessment whichever occurred first. For patients who had not progressed at the time of analysis or died before progression, TTP was censored at their last date of evaluable scan.

Other Outcome Measures

1. Tumor Response - mITT Population [Radiological assessments were performed every 8 weeks (2 cycles) from start of the treatment. After completion of 6 cycles of treatment at the highest tolerated dose level, assessments were performed every 12 weeks for up to 34 months.]

   Tumor Response of a subject was defined as the best tumor response observed (by independent central assessment) during trial period assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST version 1.0) criteria. Confirmed Complete Response (CR) was defined as disappearance of tumor, Partial Response (PR) was defined as a decrease of at least 30% in the sum of target lesions, Stable Disease (SD) was defined as steady state of disease, and Progressive Disease (PD) was defined as at least a 20% increase in the sum of measured lesions or appearance of new lesions.

2. Disease Control - mITT Population [Radiological assessments were performed every 8 weeks (2 cycles) from start of the treatment. After completion of 6 cycles of treatment at the highest tolerated dose level, assessments were performed every 12 weeks for up to 34 months.]

   Disease Control (DC) of a subject was defined as the proportion of patients with confirmed Complete Response (CR), Partial Response (PR) or Stable Disease (SD) as their best response observed (by independent central assessment) during trial period assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST version 1.0) criteria. Confirmed CR was defined as disappearance of tumor, PR was defined as a decrease of at least 30% in the sum of tumor lesion sizes, and SD was defined as steady state of disease.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Age > 18 years.

• Metastatic clear cell RCC (renal cell carcinoma)

• Subjects with at least one uni-dimensional measurable lesion.

• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1

• Memorial Sloan Kettering Cancer Center (MSKCC) good or intermediate category

• Life expectancy of at least 12 weeks.

• Adequate bone marrow, liver and renal function as assessed by the following laboratory requirements to be conducted within 7 days prior to treatment

• Signed informed consent must be obtained prior to any study specific procedures.

• Subjects must have received no prior systemic anticancer therapy for the treatment of their renal cell carcinoma

• Prior total nephrectomy

Exclusion Criteria:

• History of cardiac disease

• History of human immunodeficiency virus (HIV) infection or chronic hepatitis B or C

• Active clinically serious infections (> grade 2 National Cancer Institute-Common Terminology Criteria for Adverse Events [NCI-CTCAE] version 3.0)

• Symptomatic metastatic brain or meningeal tumors unless the subject is > 6 months from definitive therapy, has a negative imaging study within 4 weeks of study entry and is clinically stable with respect to the tumor at the time of study entry.

• Subjects with evidence or history of bleeding diathesis

• Deep vein thrombosis and/or pulmonary embolus within 12 months of the start of treatment.

• Delayed healing of wounds, ulcers or bone fractures

• Subjects with pre-existing thyroid abnormality whose thyroid function cannot be maintained within the normal range by medication

• Subjects undergoing renal dialysis

• Pregnant or breast-feeding subjects. Women of childbearing potential must have a negative serum pregnancy test performed within 7 days prior to the start of treatment. Both men and women enrolled in this trial must use adequate barrier birth control measures during the course of the trial and three months after the completion of trial.

• Prior adjuvant sorafenib is excluded.

• Radiotherapy during study or within 3 weeks of start of study drug

• Major surgery within 4 weeks of start of study

• Investigational drug therapy outside of this trial during or within 4 weeks of study entry

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Bordeaux		France	33000
2		La Roche Sur Yon		France	85925
3		Marseille		France	13385
4		Nantes		France	44805
5		Paris Cedex 10		France	75475
6		Tours		France	37044
7		Tübingen	Baden-Württemberg	Germany	72076
8		Marburg	Hessen	Germany	35043
9		Hannover	Niedersachsen	Germany	30625
10		Mainz	Rheinland-Pfalz	Germany	55131
11		Jena	Thüringen	Germany	07740
12		Aviano	Pordenone	Italy	33081
13		Milano		Italy	20133
14		Pavia		Italy	27100
15		Olsztyn		Poland	10-226
16		Warszawa		Poland	02-781
17		Warszawa		Poland	04-141
18		Wroclaw		Poland	50 - 556
19		Greater Manchester	Manchester	United Kingdom	M20 4BX
20		Cardiff	South Glamorgan	United Kingdom	CF14 7TB
21		Glasgow		United Kingdom	G12 0YN
22		London		United Kingdom	SW3 6JJ

Sponsors and Collaborators

• Bayer

Investigators

• Study Director: Bayer Study Director, Bayer

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Click here and search for Bayer product information provided by EMA

Publications

None provided.

• Responsible Party: Bayer
• ClinicalTrials.gov Identifier: NCT00618982
• Other Study ID Numbers: 12913; 2007-004875-21
• First Posted: Feb 20, 2008
• Last Update Posted: Dec 24, 2015
• Last Verified: Nov 1, 2015

• Keywords provided by Bayer: Kidney cancer,; Sorafenib,; Dose escalation,; No previous treatment
• Additional relevant MeSH terms: Carcinoma; Carcinoma, Renal Cell; Sorafenib

Study Results

Participant Flow

Recruitment Details	Subjects were enrolled from 04 Feb to 05 Nov 2008 at 19 centers in 5 countries (Germany, France, United Kingdom, Italy and Poland).
Pre-assignment Detail	Of the 89 subjects enrolled, 83 were treated with the study drug. Safety population = 83 subjects who took at least one dose of study drug and had any data after baseline. Intent to treat population = 67 subjects treated with the study drug who had at least one efficacy evaluation after baseline.

Arm/Group Title	Sorafenib (Nexavar, BAY43-9006)
Arm/Group Description	Intrapatient dose escalation of sorafenib from 400 mg orally twice daily (bid) for the first cycle, 600 mg bid for the second cycle and 800 mg bid until disease progression, unacceptable toxicity or withdrawal of consent. Dose reductions due to toxicities were allowed.
Period Title: Overall Study
STARTED	83
COMPLETED	33
NOT COMPLETED	50

Baseline Characteristics

Arm/Group Title	Sorafenib (Nexavar, BAY43-9006)
Arm/Group Description	Intrapatient dose escalation of sorafenib from 400 mg orally twice daily (bid) for the first cycle, 600 mg bid for the second cycle and 800 mg bid until disease progression, unacceptable toxicity or withdrawal of consent. Dose reductions due to toxicities were allowed.
Overall Participants	83
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	61
Sex: Female, Male (Count of Participants)
Female	29 34.9%
Male	54 65.1%
ECOG (Eastern Cooperative Oncology Group) Performance Status (participants) [Number]
0	49 59%
1	34 41%
Stage at study entry (participants) [Number]
Stage III	1 1.2%
Stage IV	82 98.8%

Outcome Measures

1. Primary Outcome

Title	Best Response - mITT (Modified Intent-to-treat) Population
Description	Best Response (Response Rate) of a subject was defined as the proportion of patients with confirmed Complete Response (CR) or Partial Response (PR) as their best response observed (by independent central assessment) during trial period assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST version 1.0) criteria. Confirmed CR was defined as disappearance of tumor and PR was defined as a decrease of at least 30% in the sum of tumor lesion sizes.
Time Frame	Radiological assessments were performed every 8 weeks (2 cycles) from start of the treatment. After completion of 6 cycles of treatment at the highest tolerated dose level, assessments were performed every 12 weeks for up to 34 months.

Outcome Measure Data

Analysis Population Description

The population for the analysis of primary efficacy variable was the modified intent-to-treat (mITT) population defined as the patients treated for at least 6 months with 4 months at their highest tolerated dose.

Arm/Group Title	Sorafenib (Nexavar, BAY43-9006)
Arm/Group Description	Intrapatient dose escalation of sorafenib from 400 mg orally twice daily (bid) for the first cycle, 600 mg bid for the second cycle and 800 mg bid until disease progression, unacceptable toxicity or withdrawal of consent. Dose reductions due to toxicities were allowed.
Measure Participants	18
Number [Participants]	8 9.6%

2. Primary Outcome

Title	Tumor Response - ITT (Intent to Treat) Population
Description	Tumor Response of a subject was defined as the best tumor response observed (by independent central assessment) during trial period assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST version 1.0) criteria. Confirmed Complete Response (CR) was defined as disappearance of tumor, Partial Response (PR) was defined as a decrease of at least 30% in the sum of target lesions, Stable Disease (SD) was defined as steady state of disease, and Progressive Disease (PD) was defined as at least a 20% increase in the sum of measured lesions or appearance of new lesions.
Time Frame	Radiological assessments were performed every 8 weeks (2 cycles) from start of the treatment. After completion of 6 cycles of treatment at the highest tolerated dose level, assessments were performed every 12 weeks for up to 34 months.

Outcome Measure Data

Analysis Population Description

The population for the efficacy analysis was the intent-to-treat (ITT) population defined as all patients who received at least one dose of study medication with at least one valid tumor assessment post-baseline.

Arm/Group Title	Sorafenib (Nexavar, BAY43-9006)
Arm/Group Description	Intrapatient dose escalation of sorafenib from 400 mg orally twice daily (bid) for the first cycle, 600 mg bid for the second cycle and 800 mg bid until disease progression, unacceptable toxicity or withdrawal of consent. Dose reductions due to toxicities were allowed.
Measure Participants	67
Complete Response (CR)	0 0%
Partial Response (PR)	12 14.5%
Stable Disease (SD)	46 55.4%
Progressive Disease (PD)	9 10.8%

3. Secondary Outcome

Title	Pharmacokinetics (PK) Analysis - Area Under the Drug Concentration-time Curve From Time Zero to 10 Hours Postdose (AUC(0-10),ss)
Description	AUC(0-10),ss was defined as an area under the plasma concentration versus time curve from time zero to 10 hours post-dose. Parameter was calculated for sorafenib and M2, an active metabolite of sorafenib.
Time Frame	Blood samples were collected at screening (blank) and on day 28 of the first cycle completed at each dose level. Samples were drawn at the following time points in relation to morning dose of sorafenib: pre-dose, 2, 4, 6, 8 and 10 hours post-dose.

Outcome Measure Data

Analysis Population Description

PK Analysis Population. 40 participants in the 400 mg bid group that had an AUC(0-10)ss calculated; 30 participants in the 600 mg bid group that had an AUC(0-10)ss calculated; 26 participants and 27 participants in the 800 mg bid group that had an AUC(0-10)ss calculated, for sorafenib and M2 parameter respectively.

Arm/Group Title	Sorafenib (Nexavar, BAY43-9006)_400 mg	Sorafenib (Nexavar, BAY43-9006)_600 mg	Sorafenib (Nexavar, BAY43-9006)_800 mg
Arm/Group Description	Participants received 400 mg orally twice daily (bid)	Participants received 600 mg orally twice daily (bid)	Participants received 800 mg orally twice daily (bid)
Measure Participants	40	30	26
Sorafenib (N=40, 30, 26)	50.0 (39.2)	51.2 (43.7)	43.8 (47.8)
M2 (BAY67-3472) (N=40, 30, 27)	8.80 (74.3)	10.4 (82.1)	8.23 (87.2)

4. Secondary Outcome

Title	Pharmacokinetics (PK) Analysis - Area Under the Drug Concentration-time Curve From Time Zero to 12 Hours Postdose (AUC(0-12),ss)
Description	AUC(0-12),ss was defined as an area under the plasma concentration versus time curve from time zero to 12 hours post-dose. Parameter was calculated for sorafenib and M2, an active metabolite of sorafenib.
Time Frame	Blood samples were collected at screening (blank) and on day 28 of the first cycle completed at each dose level. Samples were drawn at the following time points in relation to morning dose of sorafenib: pre-dose, 2, 4, 6, 8, 10 and 12 hours post-dose.

Outcome Measure Data

Analysis Population Description

PK Analysis Population. 32 participants in the 400 mg bid group that had an AUC(0-12)ss calculated; 23 participants in the 600 mg bid group that had an AUC(0-12)ss calculated; 19 participants and 20 participants in the 800 mg bid group that had an AUC(0-12)ss calculated, for sorafenib and M2 parameter respectively.

Arm/Group Title	Sorafenib (Nexavar, BAY43-9006)_400 mg	Sorafenib (Nexavar, BAY43-9006)_600 mg	Sorafenib (Nexavar, BAY43-9006)_800 mg
Arm/Group Description	Participants received 400 mg orally twice daily (bid)	Participants received 600 mg orally twice daily (bid)	Participants received 800 mg orally twice daily (bid)
Measure Participants	32	23	19
Sorafenib (N=32, 23, 19)	57.2 (39.1)	57.6 (46.1)	47.0 (51.9)
M2 (BAY67-3472) (N=32, 23, 20)	9.58 (78.2)	11.2 (75.9)	8.41 (94.6)

5. Secondary Outcome

Title	Pharmacokinetics (PK) Analysis - Maximum Observed Concentration in Plasma (Cmax)
Description	Cmax was defined as a maximum plasma concentration at steady-state. Parameter was calculated for sorafenib and M2, an active metabolite of sorafenib.
Time Frame	Blood samples were collected at screening (blank) and on day 28 of the first cycle completed at each dose level. Samples were drawn at the following time points in relation to morning dose of sorafenib: pre-dose, 2, 4, 6, 8, 10 and 12 hours post-dose.

Outcome Measure Data

Analysis Population Description

PK Analysis Population. 40 participants in the 400 mg bid group that had Cmax calculated; 31 participants in the 600 mg bid group that had Cmax calculated; 28 participants in the 800 mg bid group that had Cmax calculated.

Arm/Group Title	Sorafenib (Nexavar, BAY43-9006)_400 mg	Sorafenib (Nexavar, BAY43-9006)_600 mg	Sorafenib (Nexavar, BAY43-9006)_800 mg
Arm/Group Description	Participants received 400 mg orally twice daily (bid)	Participants received 600 mg orally twice daily (bid)	Participants received 800 mg orally twice daily (bid)
Measure Participants	40	31	28
Sorafenib	7.53 (38.0)	7.62 (39.3)	6.64 (42.1)
M2 (BAY67-3472)	1.31 (80.8)	1.51 (81.4)	1.30 (88.5)

6. Secondary Outcome

Title	Pharmacokinetics (PK) Analysis - Time to Maximum Concentration (Tmax)
Description	Tmax was defined as a time to maximum concentration at steady-state. Parameter was calculated for sorafenib and M2, an active metabolite of sorafenib.
Time Frame	Blood samples were collected at screening (blank) and on day 28 of the first cycle completed at each dose level. Samples were drawn at the following time points in relation to morning dose of sorafenib: pre-dose, 2, 4, 6, 8, 10 and 12 hours post-dose.

Outcome Measure Data

Analysis Population Description

PK Analysis Population. 40 participants in the 400 mg bid group that had Tmax calculated; 31 participants in the 600 mg bid group that had Tmax calculated; 28 participants in the 800 mg bid group that had Tmax calculated.

Arm/Group Title	Sorafenib (Nexavar, BAY43-9006)_400 mg	Sorafenib (Nexavar, BAY43-9006)_600 mg	Sorafenib (Nexavar, BAY43-9006)_800 mg
Arm/Group Description	Participants received 400 mg orally twice daily (bid)	Participants received 600 mg orally twice daily (bid)	Participants received 800 mg orally twice daily (bid)
Measure Participants	40	31	28
Sorafenib	2	2	2
M2 (BAY67-3472)	2	2	1

7. Secondary Outcome

Title	Progression-free Survival (PFS)
Description	Progression-free survival (PFS) was defined as the time from start of study medication to the first documented disease progression per RECIST (by independent radiological assessment) or clinical progression as per investigator assessment or death due to any cause whichever occurred first. For patients who had not recurred or died at the time of analysis, PFS was censored at their last date of evaluable scan.
Time Frame	Radiological assessments were performed every 8 weeks (2 cycles) from start of the treatment. After completion of 6 cycles of treatment at the highest tolerated dose level, assessments were performed every 12 weeks for up to 34 months.

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT).

Arm/Group Title	Sorafenib (Nexavar, BAY43-9006)
Arm/Group Description	Intrapatient dose escalation of sorafenib from 400 mg orally twice daily (bid) for the first cycle, 600 mg bid for the second cycle and 800 mg bid until disease progression, unacceptable toxicity or withdrawal of consent. Dose reductions due to toxicities were allowed.
Measure Participants	67
Median (95% Confidence Interval) [months]	7.4

8. Secondary Outcome

Title	Time to Progression (TTP)
Description	Time to progression (TTP) was defined as the time from start of study medication to the first documented disease progression per RECIST (by independent radiological assessment) or clinical progression as per investigator assessment whichever occurred first. For patients who had not progressed at the time of analysis or died before progression, TTP was censored at their last date of evaluable scan.
Time Frame	Radiological assessments were performed every 8 weeks (2 cycles) from start of the treatment. After completion of 6 cycles of treatment at the highest tolerated dose level, assessments were performed every 12 weeks for up to 34 months.

Outcome Measure Data

Analysis Population Description

Intent-to treat (ITT).

Arm/Group Title	Sorafenib (Nexavar, BAY43-9006)
Arm/Group Description	Intrapatient dose escalation of sorafenib from 400 mg orally twice daily (bid) for the first cycle, 600 mg bid for the second cycle and 800 mg bid until disease progression, unacceptable toxicity or withdrawal of consent. Dose reductions due to toxicities were allowed.
Measure Participants	67
Median (95% Confidence Interval) [months]	7.4

9. Other Pre-specified Outcome

Title	Tumor Response - mITT Population
Description	Tumor Response of a subject was defined as the best tumor response observed (by independent central assessment) during trial period assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST version 1.0) criteria. Confirmed Complete Response (CR) was defined as disappearance of tumor, Partial Response (PR) was defined as a decrease of at least 30% in the sum of target lesions, Stable Disease (SD) was defined as steady state of disease, and Progressive Disease (PD) was defined as at least a 20% increase in the sum of measured lesions or appearance of new lesions.
Time Frame	Radiological assessments were performed every 8 weeks (2 cycles) from start of the treatment. After completion of 6 cycles of treatment at the highest tolerated dose level, assessments were performed every 12 weeks for up to 34 months.

Outcome Measure Data

Analysis Population Description

The population for the analysis of primary efficacy variable was the modified intent-to-treat (mITT) population defined as the patients treated for at least 6 months with 4 months at their highest tolerated dose.

Arm/Group Title	Sorafenib (Nexavar, BAY43-9006)
Arm/Group Description	Intrapatient dose escalation of sorafenib from 400 mg orally twice daily (bid) for the first cycle, 600 mg bid for the second cycle and 800 mg bid until disease progression, unacceptable toxicity or withdrawal of consent. Dose reductions due to toxicities were allowed.
Measure Participants	18
Complete response (CR)	0 0%
Partial response (PR)	8 9.6%
Stable disease (SD)	10 12%
Progressive disease (PD)	0 0%

10. Other Pre-specified Outcome

Title	Disease Control - mITT Population
Description	Disease Control (DC) of a subject was defined as the proportion of patients with confirmed Complete Response (CR), Partial Response (PR) or Stable Disease (SD) as their best response observed (by independent central assessment) during trial period assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST version 1.0) criteria. Confirmed CR was defined as disappearance of tumor, PR was defined as a decrease of at least 30% in the sum of tumor lesion sizes, and SD was defined as steady state of disease.
Time Frame	Radiological assessments were performed every 8 weeks (2 cycles) from start of the treatment. After completion of 6 cycles of treatment at the highest tolerated dose level, assessments were performed every 12 weeks for up to 34 months.

Outcome Measure Data

Analysis Population Description

The population for the analysis of primary efficacy variable was the modified intent-to-treat (mITT) population defined as the patients treated for at least 6 months with 4 months at their highest tolerated dose.

Arm/Group Title	Sorafenib (Nexavar, BAY43-9006)
Arm/Group Description	Intrapatient dose escalation of sorafenib from 400 mg orally twice daily (bid) for the first cycle, 600 mg bid for the second cycle and 800 mg bid until disease progression, unacceptable toxicity or withdrawal of consent. Dose reductions due to toxicities were allowed.
Measure Participants	18
Number [Participants]	18 21.7%

Adverse Events

Adverse Event Reporting Description	Abbreviations used in the Adverse Events section: Gastrointestinal (GI), Not Otherwise Specified (NOS), Absolute Neutrophil Count (ANC), Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), Gamma glutamyl transpeptidase (GGT)
Arm/Group Title	Sorafenib (Nexavar, BAY43-9006)
Arm/Group Description	Intrapatient dose escalation of sorafenib from 400 mg orally twice daily (bid) for the first cycle,600 mg bid for the second cycle and 800 mg bid until disease progression, unacceptable toxicity or withdrawal of consent. Dose reductions due to toxicities were allowed.
All Cause Mortality
	Sorafenib (Nexavar, BAY43-9006)
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Sorafenib (Nexavar, BAY43-9006)
	Affected / at Risk (%)	# Events
Total	45/83 (54.2%)
Blood and lymphatic system disorders
Hemoglobin	1/83 (1.2%)
Cardiac disorders
Cardiac arrhythmia - Other	2/83 (2.4%)
Cardiac general - Other	1/83 (1.2%)
Hypotension	1/83 (1.2%)
Left ventricular systolic dysfunction	2/83 (2.4%)
Gastrointestinal disorders
Colitis	1/83 (1.2%)
Diarrhea	2/83 (2.4%)
GI - Other	3/83 (3.6%)
General disorders
Constitutional symptoms - Other	1/83 (1.2%)
Fatigue	3/83 (3.6%)
Fever	1/83 (1.2%)
Pain, Abdomen NOS	1/83 (1.2%)
Pain, Back	2/83 (2.4%)
Pain, Bone	1/83 (1.2%)
Pain, Breast	1/83 (1.2%)
Pain, Chest/Thorax NOS	1/83 (1.2%)
Pain, Joint	1/83 (1.2%)
Pain, Other	1/83 (1.2%)
Pain, Stomach	1/83 (1.2%)
Hepatobiliary disorders
Cholecystitis	1/83 (1.2%)
Hepatobiliary - Other	2/83 (2.4%)
Immune system disorders
Allergic reaction	1/83 (1.2%)
Infections and infestations
Infection (Documented clinically), Kidney	1/83 (1.2%)
Infection (Documented clinically), Lung (Pneumonia)	2/83 (2.4%)
Infection with normal ANC, Abdomen NOS	1/83 (1.2%)
Infection with normal ANC, Anal/perianal	1/83 (1.2%)
Infection with normal ANC, Sinus	1/83 (1.2%)
Injury, poisoning and procedural complications
Intraop injury - Other	3/83 (3.6%)
Metabolism and nutrition disorders
Hypercalcemia	1/83 (1.2%)
Hyperglycemia	1/83 (1.2%)
Hyperkalemia	1/83 (1.2%)
Hypocalcemia	1/83 (1.2%)
Hypomagnesemia	1/83 (1.2%)
Hyponatremia	3/83 (3.6%)
Hypophosphatemia	1/83 (1.2%)
Musculoskeletal and connective tissue disorders
Fracture	1/83 (1.2%)
Musculoskeletal - Other	2/83 (2.4%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Secondary malignancy (possibly related to cancer treatment)	2/83 (2.4%)
Nervous system disorders
Confusion	1/83 (1.2%)
Dizziness	1/83 (1.2%)
Neurology - Other	1/83 (1.2%)
Neuropathy: motor	1/83 (1.2%)
Neuropathy: sensory	1/83 (1.2%)
Renal and urinary disorders
Renal failure	2/83 (2.4%)
Respiratory, thoracic and mediastinal disorders
Airway obstruction, Bronchus	1/83 (1.2%)
Pleural effusion	2/83 (2.4%)
Skin and subcutaneous tissue disorders
Dermatology - Other	2/83 (2.4%)
Erythema multiforme	1/83 (1.2%)
Hand-foot skin reaction	2/83 (2.4%)
Rash/desquamation	3/83 (3.6%)
Vascular disorders
Thrombosis/Thrombus/Embolism	2/83 (2.4%)
Other (Not Including Serious) Adverse Events
	Sorafenib (Nexavar, BAY43-9006)
	Affected / at Risk (%)	# Events
Total	80/83 (96.4%)
Blood and lymphatic system disorders
Edema: Limb	7/83 (8.4%)
Hemoglobin	12/83 (14.5%)
Neutrophils	3/83 (3.6%)
Platelets	7/83 (8.4%)
Cardiac disorders
Hypertension	40/83 (48.2%)
Hypotension	3/83 (3.6%)
Endocrine disorders
Hyperthyroidism	3/83 (3.6%)
Hypothyroidism	12/83 (14.5%)
Eye disorders
Dry eye	3/83 (3.6%)
Ocular - Other	3/83 (3.6%)
Gastrointestinal disorders
Anorexia	21/83 (25.3%)
Colitis	4/83 (4.8%)
Constipation	9/83 (10.8%)
Diarrhea	53/83 (63.9%)
Dry mouth	3/83 (3.6%)
GI - Other	13/83 (15.7%)
Gastritis	3/83 (3.6%)
Heartburn	8/83 (9.6%)
Hemorrhoids	3/83 (3.6%)
Mucositis (clinical exam), Oral cavity	6/83 (7.2%)
Mucositis (functional/symptomatic), Oral cavity	28/83 (33.7%)
Nausea	22/83 (26.5%)
Taste Alteration	11/83 (13.3%)
Vomiting	16/83 (19.3%)
General disorders
Constitutional symptoms - Other	15/83 (18.1%)
Fatigue	45/83 (54.2%)
Fever	14/83 (16.9%)
Flu-like syndrome	6/83 (7.2%)
Insomnia	4/83 (4.8%)
Pain, Abdomen NOS	10/83 (12%)
Pain, Back	8/83 (9.6%)
Pain, Bone	4/83 (4.8%)
Pain, Breast	3/83 (3.6%)
Pain, Chest wall	3/83 (3.6%)
Pain, Chest/Thorax NOS	5/83 (6%)
Pain, Dental/Teeth/peridontal	4/83 (4.8%)
Pain, Extremity - limb	8/83 (9.6%)
Pain, Head/Headache	7/83 (8.4%)
Pain, Joint	6/83 (7.2%)
Pain, Muscle	5/83 (6%)
Pain, Other	6/83 (7.2%)
Pain, Stomach	5/83 (6%)
Weight loss	14/83 (16.9%)
Immune system disorders
Allergy - Other	3/83 (3.6%)
Infections and infestations
Infection (Documented clinically), Bladder (urinary)	6/83 (7.2%)
Infection (Documented clinically), Skin (Cellulitis)	3/83 (3.6%)
Infection (Documented clinically), Urinary tract NOS	3/83 (3.6%)
Infection - Other	3/83 (3.6%)
Metabolism and nutrition disorders
ALT	7/83 (8.4%)
AST	6/83 (7.2%)
Amylase	5/83 (6%)
Creatinine	4/83 (4.8%)
GGT	3/83 (3.6%)
Hyperkalemia	5/83 (6%)
Hyperuricemia	4/83 (4.8%)
Hypoalbuminemia	6/83 (7.2%)
Hypocalcemia	7/83 (8.4%)
Hypokalemia	8/83 (9.6%)
Hyponatremia	4/83 (4.8%)
Hypophosphatemia	16/83 (19.3%)
Lipase	16/83 (19.3%)
Metabolic/Lab - Other	7/83 (8.4%)
Musculoskeletal and connective tissue disorders
Musculoskeletal - Other	10/83 (12%)
Nervous system disorders
Dizziness	4/83 (4.8%)
Mood Alteration, Anxiety	4/83 (4.8%)
Mood alteration, Depression	6/83 (7.2%)
Neurology - Other	4/83 (4.8%)
Neuropathy: sensory	12/83 (14.5%)
Renal and urinary disorders
Cystitis	3/83 (3.6%)
Renal - Other	3/83 (3.6%)
Respiratory, thoracic and mediastinal disorders
Cough	8/83 (9.6%)
Dyspnea (Shortness of breath)	15/83 (18.1%)
Pulmonary - Other	3/83 (3.6%)
Voice changes	11/83 (13.3%)
Skin and subcutaneous tissue disorders
Alopecia	36/83 (43.4%)
Dermatology - Other	19/83 (22.9%)
Dry skin	23/83 (27.7%)
Erythema multiforme	6/83 (7.2%)
Flushing	5/83 (6%)
Hand-foot skin reaction	54/83 (65.1%)
Nail changes	3/83 (3.6%)
Pruritus	15/83 (18.1%)
Rash/desquamation	46/83 (55.4%)
Vascular disorders
Hemorrhage pulmonary, Nose	3/83 (3.6%)
Hemorrhage, GI, Oral cavity	4/83 (4.8%)
Thrombosis/Thrombus/Embolism	3/83 (3.6%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The Principal Investigator (PI) can publish results following completion of study. The PI must discuss a publication with Bayer prior to release&obtain written consent to proceed. The Investigator must send a draft to Bayer at least 30d in advance of submission to obtain approval. Any submission to Bayer will be reviewed w/o unreasonable delay&approval not be withheld unreasonably. In difference of opinion publication will be discussed.