A Randomized, Double-Blinded, Placebo-Controlled Study of Sorafenib in Patients With Advanced Hepatocellular Carcinoma
Sponsor
Bayer (Industry)
Overall Status
Completed
CT.gov ID
NCT00492752
Collaborator
(none)
226
23
2
45
9.8
0.2
Study Details
Study Description
Brief Summary
The purpose of the study is
-
Find out if patients receiving Sorafenib will live longer
-
Find out if Sorafenib has any effect on patient reported outcomes
-
Find out if Sorafenib prevents the growth or shrinks liver tumors and / or their metastases
-
Determine the pharmacokinetics (PK) in patients with liver cancer
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 3 |
Study Design
Study Type:
Interventional
Actual Enrollment
:
226 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose:
Treatment
Official Title:
A Randomized, Double-blinded, Placebo-controlled Study of Sorafenib in Patients With Advanced Hepatocellular Carcinoma
Study Start Date
:
Oct 1, 2005
Actual Primary Completion Date
:
Mar 1, 2007
Actual Study Completion Date
:
Jul 1, 2009
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Sorafenib (Nexavar, BAY43-9006) Sorafenib was administered orally at a dose of 400 mg (2 x 200 mg tablets) bid (twice daily); 2 dose reductions to predefined levels of 400 mg (2 x 200 mg tablets) once daily (od) and 400 mg (2 x 200 mg tablets) every 2 days were permitted for treatment-emergent adverse events related to study treatment. |
Drug: Sorafenib (Nexavar, BAY43-9006)
multikinase inhibitor; Sorafenib 400 mg (orally) twice daily
|
| Placebo Comparator: Placebo Placebo tablets matching in appearance were orally administered bid (twice daily). |
Drug: Placebo
Matching placebo (orally) twice daily
|
Outcome Measures
Primary Outcome Measures
- Overall Survival [From randomization of the first subject until the data cut-off date approximately 23 months after start of randomization]
Overall Survival (OS) was defined as the time from date of randomization to death due to any cause. Subjects still alive at the time of analysis were censored at their last date of last contact.
Secondary Outcome Measures
- Time to Symptomatic Progression (TTSP) [From randomization of the first subject until the data cut-off date approximately 23 months after start of randomization]
Time to Symptomatic Progression (TTSP) was defined as the time from date of randomization to symptomatic progression. Subjects without symptomatic progression at the time of analysis were censored at their last date of tumor evaluation.
- Time to Progression (TTP) [From randomization of the first subject until the data cut-off date approximately 23 months after start of randomization]
Time to progression (TTP) was defined as the time from date of randomization to radiologically documented disease progression. Subjects without progression at the time of analysis were censored at their last date of tumor evaluation。
- Disease Control [From randomization of the first subject until the data cut-off date approximately 23 months after start of randomization]
Disease Control (DC) was defined as the total number of subjects whose best response was not Progressive Disease (PD: an increase in the sum of tumor lesions sizes) according to Response Evaluation Criteria in Solid Tumors (RECIST) (= total number of Complete Response (CR: disappearance of tumor lesions) + total number of Partial Response (PR: a decrease of at least 30% in the sum of tumor lesion sizes) + total number of Stable Disease (SD: steady state of disease); CR, PR, or SD had to be maintained for at least 28 days from the first demonstration of that rating).
- Change in Functional Assessment of Cancer Therapy (FACT) Hepatobiliary Symptom Index-8 (FHSI-8) Score From Baseline to Cycle 1 and Cycle 3 [Baseline up to Cycle 1 and Cycle 3. From randomization of the first subject until the data cut-off date approximately 23 months after start of randomization]
The FHSI-8 questionnaire was completed at baseline and every 3 weeks during treatment and at the end of treatment visit only for subjects who withdrew for reasons other than symptomatic progression. Patient reported outcome was measured using the FHSI-8 score changes from baseline throughout the study period. FHSI-8 assesses hepatobiliary cancer symptoms with total score ranges from 0 to 32 (0 = the best quality of life; 32 = the worst quality of life with severe symptoms)..
- Change in Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep) Score From Baseline to Cycle 3 and End of Treatment [Baseline up to Cycle 3 and end of treatment. From randomization of the first subject until the data cut-off date approximately 23 months after start of randomization]
The FACT-Hep questionnaire was also completed to assess patient reported outcome. The FACT-Hep assesses hepatobiliary cancer-related quality of life. FACT-Hep total score ranges from 0 to 180 (0=All questions answered "Not at all"; 180=All questions answered "Very much").
- Number of Participants With Different Tumor Response [From randomization/start of treatment of the first subject until approximately 23 months after randomization when the subjects on placebo were offered the option to crossover to sorafenib treatment]
Tumor Response (= Best Overall Response) of a subject was defined as the best tumor response (confirmed Complete Response (CR: disappearance of tumor lesions), confirmed* Partial Response (PR: a decrease of at least 30% in the sum of tumor lesion sizes), Stable Disease (SD: steady state of disease), or Progressive Disease (PD: an increase in the sum of tumor lesions sizes)) observed during trial period assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria.
- Duration of Response [From randomization of the first subject until the data cut-off date approximately 23 months after start of randomization]
Duration of Response was defined as the time from date of first response (Complete Response (CR) or Partial Response (PR)) to the date when Progressive Disease (PD) is first documented, or to the date of death, whichever occurs first. Subjects still having CR or PR at the time of analysis were censored at their last tumor assessment.
- Time to Response [From randomization of the first subject until the data cut-off date approximately 23 months after start of randomization]
Time to Response (TTR) for subjects who achieved a response (Complete Response (CR) or Partial Response (PR) ) was defined as the time from date of randomization to the earliest date that the response was first documented.
- Area Under the Curve From Time 0 to 12 Hours Post-dose (AUC 0-12) After 21 Days of Sorafenib Treatment [PK assessments made at following times: pre-dose, 1 h, 2h, 4h, 8h,and 12h after at least 21 consecutive doses during Cycle 1]
The AUC is a measure of systemic drug exposure, which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample. A plot of concentration vs time after dosing is created, and the area under this curve is calculated by standard methods (eg, trapezoidal rule) to provide a measure of how much drug was in the bloodstream following dosing.
- Normalized Area Under the Curve (AUC Norm) After 21 Days of Sorafenib Treatment [PK assessments made at following times: pre-dose, 1 h, 2h, 4h, 8h,and 12h after at least 21 consecutive doses during Cycle 1]
The AUC is a measure of systemic drug exposure, which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample. A plot of concentration vs time after dosing is created, and the area under this curve is calculated by standard methods (eg, trapezoidal rule) to provide a measure of how much drug was in the bloodstream following dosing.
- Maximum Concentration (Cmax) After 21 Days of Sorafenib Treatment [PK assessments made at following times: pre-dose, 1 h, 2h, 4h, 8h,and 12h after at least 21 consecutive doses during Cycle 1]
Cmax refers to the highest plasma concentration of drug reached after dosing. It is obtained by collecting a series of blood samples after dosing, and analyzing them for drug content by a sensitive and specific analytical method. The highest measured concentration is referred to as the Cmax.
- Normalized Maximum Concentration (Cmaxnorm) After 21 Days of Sorafenib Treatment [PK assessments made at following times: pre-dose, 1 h, 2h, 4h, 8h,and 12h after at least 21 consecutive doses during Cycle 1]
Cmaxnorm refers to the maximum plasma concentration of Sorafenib corrected for dose and body weight (Cmaxnorm = Cmax/(mg/kg)).
- Time of Maximum Concentration (Tmax) After 21 Days of Sorafenib Treatment [PK assessments made at following times: pre-dose, 1 h, 2h, 4h, 8h,and 12h after at least 21 consecutive doses during Cycle 1]
Tmax refers to the time after dosing when a drug attains its maximum concentration in the blood. It is obtained by collecting a series of blood samples at various times after dosing, and measuring them for drug content. The time corresponding to the highest measurable concentration (Cmax) is referred to as Tmax.
Eligibility Criteria
Criteria
Ages Eligible for Study:
18 Years
and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion Criteria:
-
Ages eligible for study: 18 years and above, Genders eligible for study: both
-
Patients who have a life expectancy of at least 12 weeks
-
Patients with advanced Hepatocellular carcinoma (HCC) (unresectable, and/or metastatic) which has been histologically or cytologically documented
-
Patients must have at least one tumor lesion that meets both of the following criteria
-
Accurately measured in at least one dimension according to Response Evaluation Criteria in Solid Tumors (RECIST)
-
Not been previously treated with local therapy
-
Patients who have received local therapy, such as surgery, radiation therapy, hepatic arterial embolization, chemoembolization, radiofrequency ablation, percutaneous ethanol injection or cryoablation are eligible. Previously treated lesions will not be selected as target lesions. Local therapy must be completed at least 4 weeks prior to the baseline scan
-
Patients who have an Eastern Co-operative Oncology Group (ECOG) Performance Status of 0, 1, or 2
Exclusion Criteria:
-
Previous or concurrent cancer that is distinct in primary site or histology from HCC, EXCEPT cervical carcinoma in situ, treated basal cell carcinoma, superficial bladder tumors (Ta [Noninvasive papillary carcinoma], Tis [Carcinoma in situ: "flat tumor"]&T1 [Tumor invades subepithelial connective tissue]). Any cancer curatively treated > 3 years prior to entry is permitted
-
History of cardiac disease
-
Active clinically serious infections
-
Known history of human immunodeficiency virus (HIV) infection
-
Known central nervous system (CNS) tumors including metastatic brain disease
-
Patients with clinically significant gastrointestinal bleeding within 30 days prior to study entry
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Hefei | Anhui | China | 230022 | |
| 2 | Guangzhou | Guangdong | China | 510060 | |
| 3 | Guangzhou | Guangdong | China | 510515 | |
| 4 | Wuhan | Hubei | China | 430030 | |
| 5 | Nanjing | Jiangsu | China | 210003 | |
| 6 | Nanjing | Jiangsu | China | 210009 | |
| 7 | Dalian | Liaoning | China | 116011 | |
| 8 | Dalian | Liaoning | China | 116027 | |
| 9 | Hangzhou | Zhejiang | China | 310016 | |
| 10 | Beijing | China | 100021 | ||
| 11 | Beijing | China | 100039 | ||
| 12 | Chongqing | China | 400038 | ||
| 13 | Shanghai | China | 200003 | ||
| 14 | Shanghai | China | 200032 | ||
| 15 | Tianjin | China | |||
| 16 | Seoul | Seoul Teugbyeolsi | Korea, Republic of | 152-703 | |
| 17 | Daegu | Korea, Republic of | 702-701 | ||
| 18 | Seoul | Korea, Republic of | 138-736 | ||
| 19 | Changhua | Taiwan | 500 | ||
| 20 | Tainan | Taiwan | 736 | ||
| 21 | Taipei | Taiwan | 10016 | ||
| 22 | Taipei | Taiwan | 251 | ||
| 23 | Taoyuan | Taiwan | 333 |
Sponsors and Collaborators
- Bayer
Investigators
- Study Director: Bayer Study Director, Bayer
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.Responsible Party:
Bayer
ClinicalTrials.gov Identifier:
NCT00492752
Other Study ID Numbers:
- 11849
First Posted:
Jun 27, 2007
Last Update Posted:
Apr 16, 2014
Last Verified:
Mar 1, 2014
Study Results
Participant Flow
| Recruitment Details | Subjects with advanced hepatocellular carcinoma were enrolled from 12 Oct 2005 to 26 Jan 2007 at 23 centers in China (15 centers), Taiwan (5 centers), and Korea (3 centers). |
|---|---|
| Pre-assignment Detail | 271 subjects were enrolled in a 28-day screening period; 226 subjects were randomized either to Sorafenib or placebo (2:1 ratio) (intent-to-treat [ITT] population: for efficacy analysis); 224 subjects received at least one dose of study drug (safety population: for safety analysis). Majority of screen failures did not meet the inclusion criteria. |
| Arm/Group Title | A1) Sorafenib (Nexavar, BAY43-9006) - no Open Label Phase | A2) Sorafenib (Nexavar, BAY43-9006) - With Open Label Phase | B1) Placebo - no Open Label Phase | B2) Placebo First - Then Open Label Sorafenib Treatment Phase |
|---|---|---|---|---|
| Arm/Group Description | Participants randomized to Sorafenib treatment until unblinding (August 19, 2007), Sorafenib administered orally at a dose of 400 mg (2 x 200 mg tablets) twice daily (bid); 2 dose reductions to predefined levels of 400 mg (2 x 200 mg tablets) once daily and 400 mg (2 x 200 mg tablets) every 2 days were permitted for treatment-emergent adverse events related to study treatment. Note: Safety Data of participants in the arm presented here are part of the data reported in Reporting Group (RG) 1. | Participants randomized to Sorafenib treatment from until unblinding (August 19, 2007) until end of trial (July 27, 2009), Sorafenib administered orally at a dose of 400 mg (2 x 200 mg tablets) twice daily (bid); 2 dose reductions to predefined levels of 400 mg (2 x 200 mg tablets) once daily and 400 mg (2 x 200 mg tablets) every 2 days were permitted for treatment-emergent adverse events related to study treatment. Note: Safety Data of participants in the arm presented here are part of the data reported in Reporting Group (RG) 1. | Participants randomized to Sorafenib-matching Placebo until unblinding (August 19, 2007), Placebo tablets matching in appearance were orally administered twice daily (bid). Note: Safety Data of participants in the arm presented here are part of the data reported in Reporting Group (RG) 2. | Participants switched to Open-label Sorafenib treatment from Placebo after unblinding (August 19, 2007), Sorafenib administered orally at a dose of 400 mg (2 x 200 mg tablets) twice daily (bid); 2 dose reductions to predefined levels of 400 mg (2 x 200 mg tablets) once daily and 400 mg (2 x 200 mg tablets) every 2 days were permitted for treatment-emergent adverse events related to study treatment. Note: Safety Data of participants in the arm presented here are the data reported in Reporting Group (RG) 3. |
| Period Title: Double Blind Treatment | ||||
| STARTED | 134 | 16 | 70 | 6 |
| Received Treatment | 133 | 16 | 69 | 6 |
| COMPLETED | 120 | 16 | 67 | 6 |
| NOT COMPLETED | 14 | 0 | 3 | 0 |
| Period Title: Double Blind Treatment | ||||
| STARTED | 120 | 16 | 67 | 6 |
| Follow-up Only (no Open Label Treatment) | 120 | 0 | 67 | 0 |
| Follow-up First, Then Open Label | 0 | 16 | 0 | 6 |
| COMPLETED | 34 | 0 | 20 | 0 |
| NOT COMPLETED | 86 | 16 | 47 | 6 |
Baseline Characteristics
| Arm/Group Title | Sorafenib (Nexavar, BAY43-9006) | Placebo | Total |
|---|---|---|---|
| Arm/Group Description | Sorafenib was administered orally at a dose of 400 mg (2 x 200 mg tablets) bid (twice daily); 2 dose reductions to predefined levels of 400 mg (2 x 200 mg tablets) once daily (od) and 400 mg (2 x 200 mg tablets) every 2 days were permitted for treatment-emergent adverse events related to study treatment. | Placebo tablets matching in appearance were orally administered bid (twice daily). | Total of all reporting groups |
| Overall Participants | 150 | 76 | 226 |
| Age (Years) [Median (Full Range) ] | |||
| Median (Full Range) [Years] |
51
|
52
|
51
|
| Age, Customized (Number) [Number] | |||
| <65 years |
131
87.3%
|
63
82.9%
|
194
85.8%
|
| >=65 years |
19
12.7%
|
13
17.1%
|
32
14.2%
|
| Sex: Female, Male (Count of Participants) | |||
| Female |
127
84.7%
|
66
86.8%
|
193
85.4%
|
| Male |
23
15.3%
|
10
13.2%
|
33
14.6%
|
| Baseline Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) (Number) [Number] | |||
| 0 |
33
22%
|
22
28.9%
|
55
24.3%
|
| 1 |
108
72%
|
50
65.8%
|
158
69.9%
|
| 2 |
9
6%
|
4
5.3%
|
13
5.8%
|
| Tumor burden (Number) [Number] | |||
| Absent |
32
21.3%
|
15
19.7%
|
47
20.8%
|
| Present |
118
78.7%
|
61
80.3%
|
179
79.2%
|
Outcome Measures
| Title | Overall Survival |
|---|---|
| Description | Overall Survival (OS) was defined as the time from date of randomization to death due to any cause. Subjects still alive at the time of analysis were censored at their last date of last contact. |
| Time Frame | From randomization of the first subject until the data cut-off date approximately 23 months after start of randomization |
Outcome Measure Data
| Analysis Population Description |
|---|
| In this study the overall survival was measured for the ITT population from the date of randomization until the date of death due to any cause. For patients alive or lost to follow-up at the time of analysis, time to death was to be censored at their last date of follow-up, or at the data cut-off of 09 Aug 2007 (23 months after randomization). |
| Arm/Group Title | Sorafenib (Nexavar, BAY43-9006) | Placebo |
|---|---|---|
| Arm/Group Description | Sorafenib was administered orally at a dose of 400 mg (2 x 200 mg tablets) bid (twice daily); 2 dose reductions to predefined levels of 400 mg (2 x 200 mg tablets) once daily (od) and 400 mg (2 x 200 mg tablets) every 2 days were permitted for treatment-emergent adverse events related to study treatment. | Placebo tablets matching in appearance were orally administered bid (twice daily). |
| Measure Participants | 150 | 76 |
| Median (95% Confidence Interval) [days] |
198
|
127
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Sorafenib (Nexavar, BAY43-9006), Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.014144 |
| Comments | ||
| Method | Log Rank | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.6783 | |
| Confidence Interval |
() 95% 0.4962 to 0.9272 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Hazard ratio is for Sorafenib vs placebo. | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Sorafenib (Nexavar, BAY43-9006), Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.003464 |
| Comments | ||
| Method | Log Rank | |
| Comments | log rank test stratified by country, tumor burden, and ECOG. | |
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.6208 | |
| Confidence Interval |
() 95% 0.4498 to 0.8568 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Hazard ratio is for Sorafenib vs placebo | |
| Title | Time to Symptomatic Progression (TTSP) |
|---|---|
| Description | Time to Symptomatic Progression (TTSP) was defined as the time from date of randomization to symptomatic progression. Subjects without symptomatic progression at the time of analysis were censored at their last date of tumor evaluation. |
| Time Frame | From randomization of the first subject until the data cut-off date approximately 23 months after start of randomization |
Outcome Measure Data
| Analysis Population Description |
|---|
| Time to Symptomatic Progression was measured for the ITT population (all randomized subjects) up to the data cut-off date of of 09 Aug 2007 (23 months after randomization) |
| Arm/Group Title | Sorafenib (Nexavar, BAY43-9006) | Placebo |
|---|---|---|
| Arm/Group Description | Sorafenib was administered orally at a dose of 400 mg (2 x 200 mg tablets) bid (twice daily); 2 dose reductions to predefined levels of 400 mg (2 x 200 mg tablets) once daily (od) and 400 mg (2 x 200 mg tablets) every 2 days were permitted for treatment-emergent adverse events related to study treatment. | Placebo tablets matching in appearance were orally administered bid (twice daily). |
| Measure Participants | 150 | 76 |
| Median (95% Confidence Interval) [days] |
105
|
103
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Sorafenib (Nexavar, BAY43-9006), Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.497537 |
| Comments | ||
| Method | Log Rank | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.9032 | |
| Confidence Interval |
() 95% 0.6705 to 1.2165 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Hazard ratio is for Sorafenib vs placebo. | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Sorafenib (Nexavar, BAY43-9006), Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.437926 |
| Comments | ||
| Method | Log Rank | |
| Comments | log rank test stratified by country, tumor burden, and ECOG. | |
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.8831 | |
| Confidence Interval |
() 95% 0.6449 to 1.2093 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Hazard ratio is for Sorafenib vs placebo | |
| Title | Time to Progression (TTP) |
|---|---|
| Description | Time to progression (TTP) was defined as the time from date of randomization to radiologically documented disease progression. Subjects without progression at the time of analysis were censored at their last date of tumor evaluation。 |
| Time Frame | From randomization of the first subject until the data cut-off date approximately 23 months after start of randomization |
Outcome Measure Data
| Analysis Population Description |
|---|
| Time to progression was measured for the ITT population (all randomized subjects) up to the data cut-off date of 09 Aug 2007 (23 months after randomization). |
| Arm/Group Title | Sorafenib (Nexavar, BAY43-9006) | Placebo |
|---|---|---|
| Arm/Group Description | Sorafenib was administered orally at a dose of 400 mg (2 x 200 mg tablets) bid (twice daily); 2 dose reductions to predefined levels of 400 mg (2 x 200 mg tablets) once daily (od) and 400 mg (2 x 200 mg tablets) every 2 days were permitted for treatment-emergent adverse events related to study treatment. | Placebo tablets matching in appearance were orally administered bid (twice daily). |
| Measure Participants | 150 | 76 |
| Median (95% Confidence Interval) [days] |
84
|
41.5
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Sorafenib (Nexavar, BAY43-9006), Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.000537 |
| Comments | ||
| Method | Log Rank | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.5744 | |
| Confidence Interval |
() 95% 0.4154 to 0.7942 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Hazard ratio is for Sorafenib vs placebo | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Sorafenib (Nexavar, BAY43-9006), Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.000540 |
| Comments | ||
| Method | Log Rank | |
| Comments | log rank test stratified by country, tumor burden, and ECOG. | |
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.5375 | |
| Confidence Interval |
() 95% 0.3763 to 0.7677 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Hazard ratio is for Sorafenib vs placebo | |
| Title | Disease Control |
|---|---|
| Description | Disease Control (DC) was defined as the total number of subjects whose best response was not Progressive Disease (PD: an increase in the sum of tumor lesions sizes) according to Response Evaluation Criteria in Solid Tumors (RECIST) (= total number of Complete Response (CR: disappearance of tumor lesions) + total number of Partial Response (PR: a decrease of at least 30% in the sum of tumor lesion sizes) + total number of Stable Disease (SD: steady state of disease); CR, PR, or SD had to be maintained for at least 28 days from the first demonstration of that rating). |
| Time Frame | From randomization of the first subject until the data cut-off date approximately 23 months after start of randomization |
Outcome Measure Data
| Analysis Population Description |
|---|
| Disease control rate was measured for the ITT population (all randomized subjects) |
| Arm/Group Title | Sorafenib (Nexavar, BAY43-9006) | Placebo |
|---|---|---|
| Arm/Group Description | Sorafenib was administered orally at a dose of 400 mg (2 x 200 mg tablets) bid (twice daily); 2 dose reductions to predefined levels of 400 mg (2 x 200 mg tablets) once daily (od) and 400 mg (2 x 200 mg tablets) every 2 days were permitted for treatment-emergent adverse events related to study treatment. | Placebo tablets matching in appearance were orally administered bid (twice daily). |
| Measure Participants | 150 | 76 |
| Yes |
53
35.3%
|
12
15.8%
|
| No |
97
64.7%
|
64
84.2%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Sorafenib (Nexavar, BAY43-9006) |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Disease control rate |
| Estimated Value | 0.3533 | |
| Confidence Interval |
() 95% 0.2771 to 0.4355 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Disease control rate |
| Estimated Value | 0.1579 | |
| Confidence Interval |
() 95% 0.0843 to 0.2596 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Change in Functional Assessment of Cancer Therapy (FACT) Hepatobiliary Symptom Index-8 (FHSI-8) Score From Baseline to Cycle 1 and Cycle 3 |
|---|---|
| Description | The FHSI-8 questionnaire was completed at baseline and every 3 weeks during treatment and at the end of treatment visit only for subjects who withdrew for reasons other than symptomatic progression. Patient reported outcome was measured using the FHSI-8 score changes from baseline throughout the study period. FHSI-8 assesses hepatobiliary cancer symptoms with total score ranges from 0 to 32 (0 = the best quality of life; 32 = the worst quality of life with severe symptoms).. |
| Time Frame | Baseline up to Cycle 1 and Cycle 3. From randomization of the first subject until the data cut-off date approximately 23 months after start of randomization |
Outcome Measure Data
| Analysis Population Description |
|---|
| FHSI-8 score changes from baseline by visit were assessed for the ITT population. |
| Arm/Group Title | Sorafenib (Nexavar, BAY43-9006) | Placebo |
|---|---|---|
| Arm/Group Description | Sorafenib was administered orally at a dose of 400 mg (2 x 200 mg tablets) bid (twice daily); 2 dose reductions to predefined levels of 400 mg (2 x 200 mg tablets) once daily (od) and 400 mg (2 x 200 mg tablets) every 2 days were permitted for treatment-emergent adverse events related to study treatment. | Placebo tablets matching in appearance were orally administered bid (twice daily). |
| Measure Participants | 150 | 76 |
| cycle 1 |
26
(4.8)
|
26
(4.8)
|
| cycle 3 |
24
(6.3)
|
25
(5.3)
|
| Title | Change in Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep) Score From Baseline to Cycle 3 and End of Treatment |
|---|---|
| Description | The FACT-Hep questionnaire was also completed to assess patient reported outcome. The FACT-Hep assesses hepatobiliary cancer-related quality of life. FACT-Hep total score ranges from 0 to 180 (0=All questions answered "Not at all"; 180=All questions answered "Very much"). |
| Time Frame | Baseline up to Cycle 3 and end of treatment. From randomization of the first subject until the data cut-off date approximately 23 months after start of randomization |
Outcome Measure Data
| Analysis Population Description |
|---|
| FACT-Hep score changes from baseline by visit were assessed for the ITT population. |
| Arm/Group Title | Sorafenib (Nexavar, BAY43-9006) | Placebo |
|---|---|---|
| Arm/Group Description | Sorafenib was administered orally at a dose of 400 mg (2 x 200 mg tablets) bid (twice daily); 2 dose reductions to predefined levels of 400 mg (2 x 200 mg tablets) once daily (od) and 400 mg (2 x 200 mg tablets) every 2 days were permitted for treatment-emergent adverse events related to study treatment. | Placebo tablets matching in appearance were orally administered bid (twice daily). |
| Measure Participants | 150 | 76 |
| cycle 3 |
-10
(25.5)
|
-3
(19.9)
|
| end of treatment |
-25
(27.2)
|
-23
(31.3)
|
| Title | Number of Participants With Different Tumor Response |
|---|---|
| Description | Tumor Response (= Best Overall Response) of a subject was defined as the best tumor response (confirmed Complete Response (CR: disappearance of tumor lesions), confirmed* Partial Response (PR: a decrease of at least 30% in the sum of tumor lesion sizes), Stable Disease (SD: steady state of disease), or Progressive Disease (PD: an increase in the sum of tumor lesions sizes)) observed during trial period assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. |
| Time Frame | From randomization/start of treatment of the first subject until approximately 23 months after randomization when the subjects on placebo were offered the option to crossover to sorafenib treatment |
Outcome Measure Data
| Analysis Population Description |
|---|
| The tumor response was measured for the ITT population. |
| Arm/Group Title | Sorafenib (Nexavar, BAY43-9006) | Placebo |
|---|---|---|
| Arm/Group Description | Sorafenib was administered orally at a dose of 400 mg (2 x 200 mg tablets) bid (twice daily); 2 dose reductions to predefined levels of 400 mg (2 x 200 mg tablets) once daily (od) and 400 mg (2 x 200 mg tablets) every 2 days were permitted for treatment-emergent adverse events related to study treatment. | Placebo tablets matching in appearance were orally administered bid (twice daily). |
| Measure Participants | 150 | 76 |
| Complete Response (CR) |
0
0%
|
0
0%
|
| Partial Response (PR) |
5
3.3%
|
1
1.3%
|
| Stable Disease (SD) |
81
54%
|
21
27.6%
|
| Progressive Disease (PD) |
46
30.7%
|
41
53.9%
|
| Not assessable |
18
12%
|
13
17.1%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Sorafenib (Nexavar, BAY43-9006), Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.67 |
| Comments | ||
| Method | Fisher Exact | |
| Comments | based on tumor response rate (CR+PR) | |
| Title | Duration of Response |
|---|---|
| Description | Duration of Response was defined as the time from date of first response (Complete Response (CR) or Partial Response (PR)) to the date when Progressive Disease (PD) is first documented, or to the date of death, whichever occurs first. Subjects still having CR or PR at the time of analysis were censored at their last tumor assessment. |
| Time Frame | From randomization of the first subject until the data cut-off date approximately 23 months after start of randomization |
Outcome Measure Data
| Analysis Population Description |
|---|
| The duration of response was measured for the ITT population. |
| Arm/Group Title | Sorafenib (Nexavar, BAY43-9006) | Placebo |
|---|---|---|
| Arm/Group Description | Sorafenib was administered orally at a dose of 400 mg (2 x 200 mg tablets) bid (twice daily); 2 dose reductions to predefined levels of 400 mg (2 x 200 mg tablets) once daily (od) and 400 mg (2 x 200 mg tablets) every 2 days were permitted for treatment-emergent adverse events related to study treatment. | Placebo tablets matching in appearance were orally administered bid (twice daily). |
| Measure Participants | 5 | 1 |
| Median (Full Range) [days] |
210
|
252
|
| Title | Time to Response |
|---|---|
| Description | Time to Response (TTR) for subjects who achieved a response (Complete Response (CR) or Partial Response (PR) ) was defined as the time from date of randomization to the earliest date that the response was first documented. |
| Time Frame | From randomization of the first subject until the data cut-off date approximately 23 months after start of randomization |
Outcome Measure Data
| Analysis Population Description |
|---|
| The time to response was measured for the ITT population. |
| Arm/Group Title | Sorafenib (Nexavar, BAY43-9006) | Placebo |
|---|---|---|
| Arm/Group Description | Sorafenib was administered orally at a dose of 400 mg (2 x 200 mg tablets) bid (twice daily); 2 dose reductions to predefined levels of 400 mg (2 x 200 mg tablets) once daily (od) and 400 mg (2 x 200 mg tablets) every 2 days were permitted for treatment-emergent adverse events related to study treatment. | Placebo tablets matching in appearance were orally administered bid (twice daily). |
| Measure Participants | 5 | 1 |
| Median (Full Range) [days] |
84
|
42
|
| Title | Area Under the Curve From Time 0 to 12 Hours Post-dose (AUC 0-12) After 21 Days of Sorafenib Treatment |
|---|---|
| Description | The AUC is a measure of systemic drug exposure, which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample. A plot of concentration vs time after dosing is created, and the area under this curve is calculated by standard methods (eg, trapezoidal rule) to provide a measure of how much drug was in the bloodstream following dosing. |
| Time Frame | PK assessments made at following times: pre-dose, 1 h, 2h, 4h, 8h,and 12h after at least 21 consecutive doses during Cycle 1 |
Outcome Measure Data
| Analysis Population Description |
|---|
| The stated goal in the protocol was to obtain PK data from approximately 39 patients. As this was only descriptive information, the sample size was not critical. All patients who provided PK data were included in the analysis. |
| Arm/Group Title | Sorafenib (Nexavar, BAY43-9006) | Placebo |
|---|---|---|
| Arm/Group Description | Sorafenib was administered orally at a dose of 400 mg (2 x 200 mg tablets) bid (twice daily); 2 dose reductions to predefined levels of 400 mg (2 x 200 mg tablets) once daily (od) and 400 mg (2 x 200 mg tablets) every 2 days were permitted for treatment-emergent adverse events related to study treatment. | Placebo tablets matching in appearance were orally administered bid (twice daily). |
| Measure Participants | 24 | 0 |
| Geometric Mean (Full Range) [mg*h/L] |
35.7
|
| Title | Normalized Area Under the Curve (AUC Norm) After 21 Days of Sorafenib Treatment |
|---|---|
| Description | The AUC is a measure of systemic drug exposure, which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample. A plot of concentration vs time after dosing is created, and the area under this curve is calculated by standard methods (eg, trapezoidal rule) to provide a measure of how much drug was in the bloodstream following dosing. |
| Time Frame | PK assessments made at following times: pre-dose, 1 h, 2h, 4h, 8h,and 12h after at least 21 consecutive doses during Cycle 1 |
Outcome Measure Data
| Analysis Population Description |
|---|
| The stated goal in the protocol was to obtain PK data from approximately 39 patients. As this was only descriptive information, the sample size was not critical. All patients who provided PK data were included in the analysis. |
| Arm/Group Title | Sorafenib (Nexavar, BAY43-9006) | Placebo |
|---|---|---|
| Arm/Group Description | Sorafenib was administered orally at a dose of 400 mg (2 x 200 mg tablets) bid (twice daily); 2 dose reductions to predefined levels of 400 mg (2 x 200 mg tablets) once daily (od) and 400 mg (2 x 200 mg tablets) every 2 days were permitted for treatment-emergent adverse events related to study treatment. | Placebo tablets matching in appearance were orally administered bid (twice daily). |
| Measure Participants | 24 | 0 |
| Geometric Mean (Full Range) [g*h/L] |
6.6
|
| Title | Maximum Concentration (Cmax) After 21 Days of Sorafenib Treatment |
|---|---|
| Description | Cmax refers to the highest plasma concentration of drug reached after dosing. It is obtained by collecting a series of blood samples after dosing, and analyzing them for drug content by a sensitive and specific analytical method. The highest measured concentration is referred to as the Cmax. |
| Time Frame | PK assessments made at following times: pre-dose, 1 h, 2h, 4h, 8h,and 12h after at least 21 consecutive doses during Cycle 1 |
Outcome Measure Data
| Analysis Population Description |
|---|
| The stated goal in the protocol was to obtain PK data from approximately 39 patients. As this was only descriptive information, the sample size was not critical. All patients who provided PK data were included in the analysis. |
| Arm/Group Title | Sorafenib (Nexavar, BAY43-9006) | Placebo |
|---|---|---|
| Arm/Group Description | Sorafenib was administered orally at a dose of 400 mg (2 x 200 mg tablets) bid (twice daily); 2 dose reductions to predefined levels of 400 mg (2 x 200 mg tablets) once daily (od) and 400 mg (2 x 200 mg tablets) every 2 days were permitted for treatment-emergent adverse events related to study treatment. | Placebo tablets matching in appearance were orally administered bid (twice daily). |
| Measure Participants | 24 | 0 |
| Geometric Mean (Full Range) [mg/L] |
4.44
|
| Title | Normalized Maximum Concentration (Cmaxnorm) After 21 Days of Sorafenib Treatment |
|---|---|
| Description | Cmaxnorm refers to the maximum plasma concentration of Sorafenib corrected for dose and body weight (Cmaxnorm = Cmax/(mg/kg)). |
| Time Frame | PK assessments made at following times: pre-dose, 1 h, 2h, 4h, 8h,and 12h after at least 21 consecutive doses during Cycle 1 |
Outcome Measure Data
| Analysis Population Description |
|---|
| The stated goal in the protocol was to obtain PK data from approximately 39 patients. As this was only descriptive information, the sample size was not critical. All patients who provided PK data were included in the analysis. |
| Arm/Group Title | Sorafenib (Nexavar, BAY43-9006) | Placebo |
|---|---|---|
| Arm/Group Description | Sorafenib was administered orally at a dose of 400 mg (2 x 200 mg tablets) bid (twice daily); 2 dose reductions to predefined levels of 400 mg (2 x 200 mg tablets) once daily (od) and 400 mg (2 x 200 mg tablets) every 2 days were permitted for treatment-emergent adverse events related to study treatment. | Placebo tablets matching in appearance were orally administered bid (twice daily). |
| Measure Participants | 24 | 0 |
| Geometric Mean (Full Range) [g/mL] |
0.66
|
| Title | Time of Maximum Concentration (Tmax) After 21 Days of Sorafenib Treatment |
|---|---|
| Description | Tmax refers to the time after dosing when a drug attains its maximum concentration in the blood. It is obtained by collecting a series of blood samples at various times after dosing, and measuring them for drug content. The time corresponding to the highest measurable concentration (Cmax) is referred to as Tmax. |
| Time Frame | PK assessments made at following times: pre-dose, 1 h, 2h, 4h, 8h,and 12h after at least 21 consecutive doses during Cycle 1 |
Outcome Measure Data
| Analysis Population Description |
|---|
| The stated goal in the protocol was to obtain PK data from approximately 39 patients. As this was only descriptive information, the sample size was not critical. All patients who provided PK data were included in the analysis. |
| Arm/Group Title | Sorafenib (Nexavar, BAY43-9006) | Placebo |
|---|---|---|
| Arm/Group Description | Sorafenib was administered orally at a dose of 400 mg (2 x 200 mg tablets) bid (twice daily); 2 dose reductions to predefined levels of 400 mg (2 x 200 mg tablets) once daily (od) and 400 mg (2 x 200 mg tablets) every 2 days were permitted for treatment-emergent adverse events related to study treatment. | Placebo tablets matching in appearance were orally administered bid (twice daily). |
| Measure Participants | 24 | 0 |
| Median (Full Range) [hours] |
4.0
|
Adverse Events
| Time Frame | Reporting Group (RG) 1 + 2: Data from start of treatment until end of this trial (July 27, 2009); RG 3: Data after unblinding (August 19, 2007) until end of this trial (July 27, 2009). | |||||
|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | Acronyms in Adverse Event section: Gastrointestinal (GI), Common Terminology Criteria for Adverse Events (CTCAE), not otherwise specified (NOS), absolute neutrophil count (ANC), Central nervous system (CNS), Partial thromboplastin time (PTT), Alanine transaminase (ALT), Aspartate transaminase (AST), Gamma glutamyl transpeptidase (GGT). | |||||
| Arm/Group Title | Sorafenib, All (Double-Blind and Open Label Phase) | Placebo, All (Double-Blind and Open Label Phase) | Placebo, Open Label Only (Participants Switched to Sorafenib) | |||
| Arm/Group Description | Reporting Group 1 (RG 1): All participants randomized to Sorafenib treatment (data from start of treatment until end of trial [July 27, 2009]). Sorafenib administered orally at a dose of 400 mg (2 x 200 mg tablets) twice daily (bid); 2 dose reductions to predefined levels of 400 mg (2 x 200 mg tablets) once daily and 400 mg (2 x 200 mg tablets) every 2 days were permitted for treatment-emergent adverse events related to study treatment. | Reporting Group 2 (RG 2): All participants randomized to Sorafenib-matching Placebo (data from start of treatment until end of trial [July 27, 2009]). Treatment for Double-Blind phase (before unblinding [August 19, 2007]): Placebo tablets matching in appearance were orally administered twice daily (bid); Treatment for Open Label phase (after unblinding [August 19, 2007]): Sorafenib administered orally at a dose of 400 mg (2 x 200 mg tablets) twice daily (bid); 2 dose reductions to predefined levels of 400 mg (2 x 200 mg tablets) once daily and 400 mg (2 x 200 mg tablets) every 2 days were permitted for treatment-emergent adverse events related to study treatment. | Reporting Group 3 (RG 3): Participants switched to Open-label Sorafenib treatment from Placebo ( Data after unblinding [August 19, 2007] until end of this trial [July 27, 2009]). Sorafenib administered orally at a dose of 400 mg (2 x 200 mg tablets) twice daily (bid); 2 dose reductions to predefined levels of 400 mg (2 x 200 mg tablets) once daily and 400 mg (2 x 200 mg tablets) every 2 days were permitted for treatment-emergent adverse events related to study treatment. | |||
All Cause Mortality |
||||||
| Sorafenib, All (Double-Blind and Open Label Phase) | Placebo, All (Double-Blind and Open Label Phase) | Placebo, Open Label Only (Participants Switched to Sorafenib) | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | / (NaN) | / (NaN) | / (NaN) | |||
Serious Adverse Events |
||||||
| Sorafenib, All (Double-Blind and Open Label Phase) | Placebo, All (Double-Blind and Open Label Phase) | Placebo, Open Label Only (Participants Switched to Sorafenib) | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 76/149 (51%) | 34/75 (45.3%) | 3/6 (50%) | |||
| Blood and lymphatic system disorders | ||||||
| Edema: Limb | 2/149 (1.3%) | 0/75 (0%) | 0/6 (0%) | |||
| Cardiac disorders | ||||||
| Hypertension | 1/149 (0.7%) | 0/75 (0%) | 0/6 (0%) | |||
| Cardiac General - Other | 0/149 (0%) | 1/75 (1.3%) | 0/6 (0%) | |||
| Gastrointestinal disorders | ||||||
| Anorexia | 2/149 (1.3%) | 0/75 (0%) | 0/6 (0%) | |||
| Ascites | 7/149 (4.7%) | 3/75 (4%) | 0/6 (0%) | |||
| Colitis | 1/149 (0.7%) | 0/75 (0%) | 0/6 (0%) | |||
| Diarrhea | 4/149 (2.7%) | 0/75 (0%) | 0/6 (0%) | |||
| Distension | 2/149 (1.3%) | 2/75 (2.7%) | 0/6 (0%) | |||
| Dysphagia | 1/149 (0.7%) | 0/75 (0%) | 0/6 (0%) | |||
| Mucositis (Functional/Symptomatic), Oral Cavity | 1/149 (0.7%) | 0/75 (0%) | 0/6 (0%) | |||
| Nausea | 1/149 (0.7%) | 0/75 (0%) | 0/6 (0%) | |||
| Ileus | 0/149 (0%) | 1/75 (1.3%) | 0/6 (0%) | |||
| GI - Other | 2/149 (1.3%) | 1/75 (1.3%) | 0/6 (0%) | |||
| Stricture, GI, Biliary Tree | 2/149 (1.3%) | 0/75 (0%) | 0/6 (0%) | |||
| Vomiting | 1/149 (0.7%) | 0/75 (0%) | 0/6 (0%) | |||
| General disorders | ||||||
| Death Not Associated With CTCAE Term, Disease Progression NOS | 22/149 (14.8%) | 8/75 (10.7%) | 1/6 (16.7%) | |||
| Death Not Associated With CTCAE Term, Multi - Organ Failure | 3/149 (2%) | 3/75 (4%) | 1/6 (16.7%) | |||
| Death Not Associated With CTCAE Term, Sudden Death | 3/149 (2%) | 1/75 (1.3%) | 0/6 (0%) | |||
| Fever | 5/149 (3.4%) | 3/75 (4%) | 0/6 (0%) | |||
| Fatigue | 2/149 (1.3%) | 1/75 (1.3%) | 0/6 (0%) | |||
| Constitutional Symptoms - Other | 1/149 (0.7%) | 0/75 (0%) | 0/6 (0%) | |||
| Rigors / Chills | 1/149 (0.7%) | 0/75 (0%) | 0/6 (0%) | |||
| Pain, Back | 1/149 (0.7%) | 1/75 (1.3%) | 0/6 (0%) | |||
| Pain, Chest Wall | 1/149 (0.7%) | 0/75 (0%) | 0/6 (0%) | |||
| Pain, Tumor Pain | 1/149 (0.7%) | 0/75 (0%) | 0/6 (0%) | |||
| Pain, Abdomen NOS | 7/149 (4.7%) | 3/75 (4%) | 0/6 (0%) | |||
| Pain, Bone | 0/149 (0%) | 1/75 (1.3%) | 0/6 (0%) | |||
| Pain, Other | 1/149 (0.7%) | 0/75 (0%) | 0/6 (0%) | |||
| Pain, Pelvis | 1/149 (0.7%) | 0/75 (0%) | 0/6 (0%) | |||
| Hepatobiliary disorders | ||||||
| Liver Dysfunction | 6/149 (4%) | 8/75 (10.7%) | 0/6 (0%) | |||
| Hepatobiliary - Other | 1/149 (0.7%) | 1/75 (1.3%) | 0/6 (0%) | |||
| Infections and infestations | ||||||
| Febrile Neutropenia | 1/149 (0.7%) | 0/75 (0%) | 0/6 (0%) | |||
| Infection - Other | 2/149 (1.3%) | 1/75 (1.3%) | 0/6 (0%) | |||
| Infection With Unknown ANC, Biliary Tree | 0/149 (0%) | 1/75 (1.3%) | 0/6 (0%) | |||
| Infection With Unknown ANC, Lung (Pneumonia) | 4/149 (2.7%) | 1/75 (1.3%) | 0/6 (0%) | |||
| Infection With Unknown ANC, Wound | 1/149 (0.7%) | 0/75 (0%) | 0/6 (0%) | |||
| Metabolism and nutrition disorders | ||||||
| Bilirubin (Hyperbilirubinemia) | 3/149 (2%) | 1/75 (1.3%) | 0/6 (0%) | |||
| Hypoglycemia | 1/149 (0.7%) | 0/75 (0%) | 0/6 (0%) | |||
| Hypokalemia | 1/149 (0.7%) | 0/75 (0%) | 0/6 (0%) | |||
| Metabolic / Lab - Other | 1/149 (0.7%) | 0/75 (0%) | 0/6 (0%) | |||
| Musculoskeletal and connective tissue disorders | ||||||
| Fracture | 1/149 (0.7%) | 0/75 (0%) | 0/6 (0%) | |||
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||||
| Secondary Malignancy (Possibly Related to Cancer Treatment) | 1/149 (0.7%) | 0/75 (0%) | 0/6 (0%) | |||
| Nervous system disorders | ||||||
| CNS Ischemia | 2/149 (1.3%) | 0/75 (0%) | 0/6 (0%) | |||
| Encephalopathy | 1/149 (0.7%) | 3/75 (4%) | 0/6 (0%) | |||
| Neuropathy: Motor | 1/149 (0.7%) | 0/75 (0%) | 0/6 (0%) | |||
| Neurology - Other | 1/149 (0.7%) | 0/75 (0%) | 1/6 (16.7%) | |||
| Seizure | 1/149 (0.7%) | 0/75 (0%) | 0/6 (0%) | |||
| Syncope (Fainting) | 0/149 (0%) | 1/75 (1.3%) | 0/6 (0%) | |||
| Renal and urinary disorders | ||||||
| Renal Failure | 1/149 (0.7%) | 0/75 (0%) | 0/6 (0%) | |||
| Renal - Other | 1/149 (0.7%) | 0/75 (0%) | 0/6 (0%) | |||
| Respiratory, thoracic and mediastinal disorders | ||||||
| Aspiration | 0/149 (0%) | 1/75 (1.3%) | 0/6 (0%) | |||
| Pulmonary - Other | 3/149 (2%) | 1/75 (1.3%) | 0/6 (0%) | |||
| Pneumothorax | 0/149 (0%) | 0/75 (0%) | 1/6 (16.7%) | |||
| Dyspnea (Shortness of Breath) | 4/149 (2.7%) | 1/75 (1.3%) | 0/6 (0%) | |||
| Skin and subcutaneous tissue disorders | ||||||
| Hand-Foot Skin Reaction | 1/149 (0.7%) | 0/75 (0%) | 0/6 (0%) | |||
| Vascular disorders | ||||||
| CNS Hemorrhage | 1/149 (0.7%) | 0/75 (0%) | 0/6 (0%) | |||
| Hemorrhage, GI, Abdomen NOS | 1/149 (0.7%) | 0/75 (0%) | 0/6 (0%) | |||
| Hemorrhage, GI, Anus | 0/149 (0%) | 1/75 (1.3%) | 0/6 (0%) | |||
| Hemorrhage, GI, Varices (Esophageal) | 4/149 (2.7%) | 1/75 (1.3%) | 0/6 (0%) | |||
| Hemorrhage, GI, Stomach | 1/149 (0.7%) | 0/75 (0%) | 0/6 (0%) | |||
| Hemorrhage, GI, Liver | 0/149 (0%) | 1/75 (1.3%) | 0/6 (0%) | |||
| Hemorrhage, GI, Upper GI NOS | 9/149 (6%) | 4/75 (5.3%) | 0/6 (0%) | |||
| Hemorrhage - Other | 1/149 (0.7%) | 0/75 (0%) | 0/6 (0%) | |||
| Hemorrhage Pulmonary, Nose | 1/149 (0.7%) | 0/75 (0%) | 0/6 (0%) | |||
| Hemorrhage Pulmonary, Respiratory Tract NOS | 0/149 (0%) | 1/75 (1.3%) | 0/6 (0%) | |||
| Thrombosis/Thrombus/Embolism | 1/149 (0.7%) | 0/75 (0%) | 0/6 (0%) | |||
Other (Not Including Serious) Adverse Events |
||||||
| Sorafenib, All (Double-Blind and Open Label Phase) | Placebo, All (Double-Blind and Open Label Phase) | Placebo, Open Label Only (Participants Switched to Sorafenib) | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 144/149 (96.6%) | 65/75 (86.7%) | 4/6 (66.7%) | |||
| Blood and lymphatic system disorders | ||||||
| Blood - Other | 8/149 (5.4%) | 1/75 (1.3%) | 0/6 (0%) | |||
| Hemoglobin | 29/149 (19.5%) | 10/75 (13.3%) | 0/6 (0%) | |||
| Leukocytes | 18/149 (12.1%) | 4/75 (5.3%) | 0/6 (0%) | |||
| Platelets | 35/149 (23.5%) | 10/75 (13.3%) | 1/6 (16.7%) | |||
| PTT | 12/149 (8.1%) | 4/75 (5.3%) | 0/6 (0%) | |||
| Edema: Limb | 10/149 (6.7%) | 8/75 (10.7%) | 0/6 (0%) | |||
| Cardiac disorders | ||||||
| Hypertension | 33/149 (22.1%) | 4/75 (5.3%) | 0/6 (0%) | |||
| Ear and labyrinth disorders | ||||||
| Tinnitus | 12/149 (8.1%) | 0/75 (0%) | 0/6 (0%) | |||
| Endocrine disorders | ||||||
| Hypothyroidism | 0/149 (0%) | 0/75 (0%) | 1/6 (16.7%) | |||
| Eye disorders | ||||||
| Cataract | 1/149 (0.7%) | 0/75 (0%) | 1/6 (16.7%) | |||
| Optic Disc Edema | 0/149 (0%) | 0/75 (0%) | 1/6 (16.7%) | |||
| Gastrointestinal disorders | ||||||
| Anorexia | 46/149 (30.9%) | 13/75 (17.3%) | 0/6 (0%) | |||
| Ascites | 41/149 (27.5%) | 13/75 (17.3%) | 0/6 (0%) | |||
| Constipation | 20/149 (13.4%) | 12/75 (16%) | 0/6 (0%) | |||
| Diarrhea | 64/149 (43%) | 12/75 (16%) | 3/6 (50%) | |||
| Distension | 24/149 (16.1%) | 15/75 (20%) | 0/6 (0%) | |||
| GI - Other | 10/149 (6.7%) | 1/75 (1.3%) | 0/6 (0%) | |||
| Mucositis (Clinical Exam), Oral Cavity | 6/149 (4%) | 2/75 (2.7%) | 1/6 (16.7%) | |||
| Nausea | 37/149 (24.8%) | 19/75 (25.3%) | 0/6 (0%) | |||
| Vomiting | 25/149 (16.8%) | 13/75 (17.3%) | 0/6 (0%) | |||
| General disorders | ||||||
| Fatigue | 51/149 (34.2%) | 15/75 (20%) | 0/6 (0%) | |||
| Fever | 38/149 (25.5%) | 8/75 (10.7%) | 0/6 (0%) | |||
| Insomnia | 25/149 (16.8%) | 17/75 (22.7%) | 0/6 (0%) | |||
| Weight Loss | 62/149 (41.6%) | 13/75 (17.3%) | 0/6 (0%) | |||
| Pain, Abdomen NOS | 54/149 (36.2%) | 16/75 (21.3%) | 0/6 (0%) | |||
| Pain, Back | 23/149 (15.4%) | 9/75 (12%) | 0/6 (0%) | |||
| Pain, Chest Wall | 12/149 (8.1%) | 2/75 (2.7%) | 0/6 (0%) | |||
| Pain, Chest/Thorax NOS | 1/149 (0.7%) | 2/75 (2.7%) | 1/6 (16.7%) | |||
| Pain, Dental/Teeth/Peridontal | 1/149 (0.7%) | 0/75 (0%) | 1/6 (16.7%) | |||
| Pain, Head/Headache | 12/149 (8.1%) | 1/75 (1.3%) | 1/6 (16.7%) | |||
| Pain, Joint | 6/149 (4%) | 0/75 (0%) | 1/6 (16.7%) | |||
| Pain, Liver | 10/149 (6.7%) | 9/75 (12%) | 0/6 (0%) | |||
| Pain, Muscle | 10/149 (6.7%) | 1/75 (1.3%) | 0/6 (0%) | |||
| Pain, Other | 11/149 (7.4%) | 2/75 (2.7%) | 0/6 (0%) | |||
| Pain, Stomach | 3/149 (2%) | 4/75 (5.3%) | 0/6 (0%) | |||
| Pain, Throat/Pharynx/Larynx | 10/149 (6.7%) | 1/75 (1.3%) | 1/6 (16.7%) | |||
| Flu - Like Syndrome | 3/149 (2%) | 1/75 (1.3%) | 1/6 (16.7%) | |||
| Pain, Bone | 8/149 (5.4%) | 5/75 (6.7%) | 0/6 (0%) | |||
| Hepatobiliary disorders | ||||||
| Hepatobiliary - Other | 8/149 (5.4%) | 6/75 (8%) | 0/6 (0%) | |||
| Immune system disorders | ||||||
| Allergic Reaction | 2/149 (1.3%) | 4/75 (5.3%) | 0/6 (0%) | |||
| Infections and infestations | ||||||
| Infection - Other | 10/149 (6.7%) | 6/75 (8%) | 0/6 (0%) | |||
| Metabolism and nutrition disorders | ||||||
| Alkaline Phosphatase | 39/149 (26.2%) | 14/75 (18.7%) | 0/6 (0%) | |||
| ALT | 49/149 (32.9%) | 18/75 (24%) | 2/6 (33.3%) | |||
| Amylase | 8/149 (5.4%) | 0/75 (0%) | 0/6 (0%) | |||
| AST | 63/149 (42.3%) | 23/75 (30.7%) | 1/6 (16.7%) | |||
| Bilirubin (Hyperbilirubinemia) | 56/149 (37.6%) | 24/75 (32%) | 2/6 (33.3%) | |||
| Creatinine | 10/149 (6.7%) | 3/75 (4%) | 0/6 (0%) | |||
| GGT | 9/149 (6%) | 7/75 (9.3%) | 0/6 (0%) | |||
| Hyperglycemia | 8/149 (5.4%) | 7/75 (9.3%) | 0/6 (0%) | |||
| Hyperkalemia | 7/149 (4.7%) | 5/75 (6.7%) | 0/6 (0%) | |||
| Hyperuricemia | 10/149 (6.7%) | 6/75 (8%) | 0/6 (0%) | |||
| Hypoalbuminemia | 34/149 (22.8%) | 16/75 (21.3%) | 0/6 (0%) | |||
| Hypocalcemia | 12/149 (8.1%) | 3/75 (4%) | 0/6 (0%) | |||
| Hypokalemia | 11/149 (7.4%) | 2/75 (2.7%) | 0/6 (0%) | |||
| Hyponatremia | 23/149 (15.4%) | 10/75 (13.3%) | 0/6 (0%) | |||
| Hypophosphatemia | 17/149 (11.4%) | 4/75 (5.3%) | 1/6 (16.7%) | |||
| Lipase | 19/149 (12.8%) | 4/75 (5.3%) | 0/6 (0%) | |||
| Metabolic / Lab - Other | 33/149 (22.1%) | 9/75 (12%) | 0/6 (0%) | |||
| Nervous system disorders | ||||||
| Dizziness | 4/149 (2.7%) | 5/75 (6.7%) | 1/6 (16.7%) | |||
| Memory Impairment | 0/149 (0%) | 0/75 (0%) | 1/6 (16.7%) | |||
| Respiratory, thoracic and mediastinal disorders | ||||||
| Cough | 29/149 (19.5%) | 12/75 (16%) | 2/6 (33.3%) | |||
| Dyspnea (Shortness of Breath) | 17/149 (11.4%) | 12/75 (16%) | 0/6 (0%) | |||
| Pulmonary - Other | 11/149 (7.4%) | 7/75 (9.3%) | 0/6 (0%) | |||
| Skin and subcutaneous tissue disorders | ||||||
| Alopecia | 40/149 (26.8%) | 1/75 (1.3%) | 0/6 (0%) | |||
| Dermatology - Other | 15/149 (10.1%) | 3/75 (4%) | 0/6 (0%) | |||
| Hand - Foot Skin Reaction | 69/149 (46.3%) | 2/75 (2.7%) | 2/6 (33.3%) | |||
| Pruritus | 19/149 (12.8%) | 9/75 (12%) | 0/6 (0%) | |||
| Rash / Desquamation | 33/149 (22.1%) | 7/75 (9.3%) | 0/6 (0%) | |||
| Vascular disorders | ||||||
| Hemorrhage Pulmonary, Respiratory Tract NOS | 2/149 (1.3%) | 1/75 (1.3%) | 1/6 (16.7%) | |||
Limitations/Caveats
On review of unblinded data, up to 19 Mar. 2007, the independent Data Monitoring Committee concluded the efficacy results can be considered positive, recommended subjects under placebo to cross over to Sorafenib; study continued to extension phase.
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
The Investigator must send a draft manuscript to be submitted for publication or to be presented or abstract to Bayer at least 60 days in advance of submission in order to obtain approval prior to submission of the final version for publication or presentation. In case of a difference of opinion between Bayer and the Investigator(s), the contents of the publication will be discussed in order to find a solution, which satisfies both parties.
Results Point of Contact
| Name/Title | Therapeutic Area Head |
|---|---|
| Organization | BAYER |
| Phone | <not disclosed> |
| clinical-trials-contact@bayerhealthcare.com |
Responsible Party:
Bayer
ClinicalTrials.gov Identifier:
NCT00492752
Other Study ID Numbers:
- 11849
First Posted:
Jun 27, 2007
Last Update Posted:
Apr 16, 2014
Last Verified:
Mar 1, 2014