A Study of Vemurafenib in Metastatic Melanoma Participants With Brain Metastases

• Sponsor: Hoffmann-La Roche (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01378975
• Collaborator: (none)
• Enrollment: 146
• Locations: 33
• Arms: 2
• Duration (Months): 48
• Patients Per Site: 4.4
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This open-label, single-arm, multicenter study will evaluate the efficacy and safety in participants with metastatic melanoma who developed brain metastases. Participants may or may not have received prior systemic treatment for metastatic melanoma [except treatment with v-raf murine sarcoma viral oncogene homolog B (BRAF) or mitogen-activated protein kinase (MEK) inhibitors]. Participants will receive oral doses of 960 mg vemurafenib twice daily until disease progression, unacceptable toxicity or consent withdrawal.

Condition or Disease	Intervention/Treatment	Phase
Malignant Melanoma	Drug: Vemurafenib	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 146 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-label, Single-arm, Phase II, Multicenter Study, to Evaluate the Efficacy of Vemurafenib in Metastatic Melanoma Patients With Brain Metastases
• Study Start Date: Jul 1, 2011
• Actual Primary Completion Date: Jul 1, 2015
• Actual Study Completion Date: Jul 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cohort 1: Previously Untreated Participants Participants who had not received previous treatment for brain metastases [i.e., had never received brain stereotactic radiotherapy (SRT), whole-brain radiotherapy (WBRT), surgery, or any other treatment for their brain metastases] received Vemurafenib 960 milligram (mg) tablet orally, twice daily (BID) from Day 1 until development of progressive disease within the brain or outside of the brain (whichever occurred first), unacceptable toxicity, consent withdrawal, protocol violation endangering participant's safety, death, reasons deemed by the investigator, or study termination by the Sponsor.	Drug: Vemurafenib; 960 mg oral doses twice daily until disease progression, unacceptable toxicity or consent withdrawal.
Experimental: Cohort 2: Previously treated Participants Participants who were previously treated with brain SRT, WBRT, or surgery for their brain metastases and have progressed following this treatment, received Vemurafenib 960 milligram (mg) tablet orally, BID from Day 1 until development of progressive disease within the brain or outside of the brain (whichever occurred first), unacceptable toxicity, consent withdrawal, protocol violation endangering participant's safety, death, reasons deemed by the investigator, or study termination by the Sponsor.	Drug: Vemurafenib; 960 mg oral doses twice daily until disease progression, unacceptable toxicity or consent withdrawal.

Outcome Measures

Primary Outcome Measures

1. Best Overall Response Rate (BORR) Within Brain of Previously Untreated Participants (Assessed by Independent Review Committee [IRC] Using Modified Response Evaluation Criteria in Solid Tumors [RECIST]) [Baseline up to the disease progression or death from any cause (approximately 4 years)]

   BORR assessed by IRC is defined as percentage of participants who were responders [with best overall response (BOR) documented as confirmed complete response (CR) or partial response (PR)]. The RECIST v1.1 criteria modified for independent review of body and brain lesions was based on current radiology practices. The modifications to RECIST v1.1 included allowing target lesions in the brain to be >=5 mm by contrast-enhanced magnetic resonance imaging scan (in traditional RECIST v1.1 this is >=10 mm), allowing up to 5 target lesions in the brain (in traditional RECIST v1.1 only 2 target lesions), and examining the lesions within the brain and outside the brain separately for analytical purposes. CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (<) 10 millimeters (mm), PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

Secondary Outcome Measures

1. Best Overall Response Rate (BORR) in the Brain of Participants With Previously Treated or Untreated Brain Metastases as Assessed by the IRC Using RECIST v1.1 [Baseline up to the disease progression or death from any cause (approximately 4 years)]

   Percentage of participants who were responders with BOR documented as confirmed CR or PR, stable disease (SD), progressive disease (PD). CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.

2. Best Overall Response Rate (BORR) in the Brain of Participants With Previously Treated Brain Metastases as Assessed by the IRC Using RECIST v1.1 [Baseline up to the disease progression or death from any cause (approximately 4 years)]

   BORR within brain assessed by IRC is defined as percentage of participants who were responders (with BOR documented as confirmed CR or PR). According to RECIST v1.1 criteria modified for brain metastases, CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm, PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

3. Best Overall Response Rate Outside the Brain (Assessed by IRC) [Baseline up to the disease progression or death from any cause (approximately 4 years)]

   BORR outside of brain assessed by IRC is defined as percentage of participants who were responders (with BOR documented as confirmed CR or PR). According to RECIST v1.1 criteria modified for brain metastases, CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm, PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

4. Duration of Response (DOR) (Assessed by Investigator and IRC) [Date of the earliest qualifying response until the earliest date of PD or death from any cause (approximately up to 4 years)]

   Duration of response was defined as the time interval between the date of the earliest qualifying response and the earliest date of PD or death from any cause. For participants who were alive without progression following the qualifying response, DOR were censored on the date of last available tumor assessment on or before the data cutoff date.

5. Progression-Free Survival (PFS) Based on Overall Tumor Response (Assessed by Investigator) [Baseline up to the disease progression or death from any cause (approximately 4 years)]

   Progression-free survival was defined as the time between enrollment on Day 1 and the date of first radiographically documented progressive disease (within or outside the brain), clinical progressive disease, as assessed by the investigator or death whichever occurred first.

6. Progression-Free Survival (PFS) Based on Tumor Assessment Within Brain Only (Assessed by Investigator ) [Baseline up to the disease progression or death from any cause (approximately 4 years)]

   Progression-free survival was defined as the time between enrollment on Day 1 and the date of first radiographically documented progressive disease (within brain), clinical progressive disease, as assessed by the investigator or death whichever occurred first.

7. Time to Development of New Brain Metastases in Responders [Date of first treatment and the earliest date of documentation of new brain lesions (approximately up to 4 years)]

   Time to development of new lesions within the brain was defined as the interval between the date of first treatment and the earliest date of documentation of new brain lesions. Participants who were known to be free of new lesions were censored on the date of last tumor assessment.

8. Overall Survival [Baseline up to the disease progression or death from any cause (approximately 4 years)]

   Overall survival was defined as time between enrollment on Day 1 and date of death, irrespective of the cause of death. Participants for whom no death was captured on the clinical database were censored at the latest date they were known to be alive prior to or on the cutoff date.

9. Best Overall Response Rate (BORR) Within the Brain and Outside Brain (Assessed by Investigator) [Baseline up to the disease progression or death from any cause (approximately 4 years)]

   Percentage of participants who were responders with BOR documented as confirmed CR or PR, stable disease (SD), progressive disease (PD). CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.

10. Best Overall Response Rate (BORR) Within the Brain and Outside Brain (Not Necessarily Follows the RECIST Criteria - as Assessed by Investigator) [Baseline up to the disease progression or death from any cause (approximately 4 years)]

    Percentage of participants who were responders (with best overall response (BOR) documented as confirmed complete response [CR] or partial response [PR]) were reported.

11. Percentage of Participants With Adverse Events (AE) [From signing of informed consent form up to 28 days after the last dose of study drug (approximately up to 4 years)]

    An AE was considered any unfavorable and unintended sign, symptom, or disease associated with the use of the study drug, whether or not considered related to the study drug.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Adult participants, >/= 18 years of age

• Histologically confirmed metastatic melanoma (Stage IV, American Joint Committee on Cancer) with BRAF V600 mutation (cobas 4800 BRAF V600 Mutation Test)

• Measurable brain metastases, defined as lesions that were accurately measured in at least one dimension (longest diameter to be recorded) as ≥0.5 cm in the brain MRI with contrast, treated or untreated

• Participants may or may not have received prior systemic therapy for metastatic melanoma and either a) have received no prior treatment for brain metastases or b) have received prior treatment for brain metastases and have progressed

• Participants may or may not have symptoms related to their brain metastases

• Eastern Cooperative Oncology Group (ECOG) performance status 0-1

• Participants must have recovered from all side effects of their most recent systemic or local treatment for metastatic melanoma

Exclusion Criteria:

• Increasing corticosteroid dose during the 7 days prior to first dose of study drug

• Leptomeningeal involvement in participants with no prior treatment for brain metastases

• Previous malignancy requiring active treatment within the past 2 years, except for treated and controlled basal or squamous cell carcinoma of the skin, or carcinoma in-situ of the cervix

• Concurrent administration of any anticancer therapies other than those administered in the study

• Treatment with any cytotoxic, investigational drug or targeted therapy 4 weeks prior to first dose of study drug. Radiation therapy ≤1 week prior to first administration of vemurafenib; and stereotactic radiotherapy ≤1 day prior to prior to first administration of vemurafenib

• Prior treatment with BRAF or MEK inhibitors

• Clinically significant cardiovascular disease or event within the 6 months prior to first dose of study drug

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Los Angeles	California	United States	90025
2		Aurora	Colorado	United States	80045
3		Tampa	Florida	United States	33612-9497
4		Boston	Massachusetts	United States	02114
5		Boston	Massachusetts	United States	02215
6		Detroit	Michigan	United States	48201
7		Rochester	Minnesota	United States	55905
8		Saint Louis	Missouri	United States	63110
9		Charlotte	North Carolina	United States	28204-2839
10		Dallas	Texas	United States	75246
11		Seattle	Washington	United States	98195
12		Wentworthville	New South Wales	Australia	2145
13		Melbourne	Victoria	Australia	3002
14		Toronto	Ontario	Canada	M4N 3M5
15		Bordeaux		France	33075
16		Nice		France	06202
17		Paris		France	75006
18		Paris		France	75475
19		Essen		Germany	45122
20		Frankfurt		Germany	60596
21		Kiel		Germany	24105
22		Mannheim		Germany	68167
23		Münster		Germany	48157
24		Tübingen		Germany	72076
25		Tel-Hashomer		Israel	52621
26		Milano	Lombardia	Italy	20133
27		Siena	Toscana	Italy	53100
28		Amsterdam		Netherlands	1066 CX
29		Groningen		Netherlands	9713 GZ
30		Pamplona	Navarra	Spain	31008
31		Barcelona		Spain	08036
32		Madrid		Spain	28046
33		Northwood		United Kingdom	HA6 2RN

Sponsors and Collaborators

• Hoffmann-La Roche

Investigators

• Study Director: Clinical Trials, Hoffmann-La Roche

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Hoffmann-La Roche
• ClinicalTrials.gov Identifier: NCT01378975
• Other Study ID Numbers: MO25743
• First Posted: Jun 23, 2011
• Last Update Posted: Aug 1, 2016
• Last Verified: Apr 1, 2016

• Additional relevant MeSH terms: Melanoma; Brain Neoplasms; Vemurafenib

Study Results

Participant Flow

Arm/Group Title	Cohort 1: Previously Untreated Participants	Cohort 2: Previously Treated Participants
Arm/Group Description	Participants who had not received previous treatment for brain metastases [i.e., had never received brain stereotactic radiotherapy (SRT), whole-brain radiotherapy (WBRT), surgery, or any other treatment for their brain metastases] received Vemurafenib 960 milligram (mg) tablet orally, twice daily (BID) from Day 1 until development of progressive disease within the brain or outside of the brain (whichever occurred first), unacceptable toxicity, consent withdrawal, protocol violation endangering participant's safety, death, reasons deemed by the investigator, or study termination by the Sponsor.	Participants who were previously treated with brain SRT, WBRT, or surgery for their brain metastases and have progressed following this treatment, received Vemurafenib 960 milligram (mg) tablet orally, BID from Day 1 until development of progressive disease within the brain or outside of the brain (whichever occurred first), unacceptable toxicity, consent withdrawal, protocol violation endangering participant's safety, death, reasons deemed by the investigator, or study termination by the Sponsor.
Period Title: Overall Study
STARTED	90	56
COMPLETED	4	6
NOT COMPLETED	86	50

Baseline Characteristics

Arm/Group Title	Cohort 1: Previously Untreated Participants	Cohort 2: Previously Treated Participants	Total
Arm/Group Description	Participants who had not received previous treatment for brain metastases [i.e., had never received brain stereotactic radiotherapy (SRT), whole-brain radiotherapy (WBRT), surgery, or any other treatment for their brain metastases] received Vemurafenib 960 milligram (mg) tablet orally, twice daily (BID) from Day 1 until development of progressive disease within the brain or outside of the brain (whichever occurred first), unacceptable toxicity, consent withdrawal, protocol violation endangering participant's safety, death, reasons deemed by the investigator, or study termination by the Sponsor.	Participants who were previously treated with brain SRT, WBRT, or surgery for their brain metastases and have progressed following this treatment, received Vemurafenib 960 milligram (mg) tablet orally, BID from Day 1 until development of progressive disease within the brain or outside of the brain (whichever occurred first), unacceptable toxicity, consent withdrawal, protocol violation endangering participant's safety, death, reasons deemed by the investigator, or study termination by the Sponsor.	Total of all reporting groups
Overall Participants	90	56	146
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	55.7 (12.73)	52.7 (13.85)	54.5 (13.20)
Sex: Female, Male (Count of Participants)
Female	34 37.8%	22 39.3%	56 38.4%
Male	56 62.2%	34 60.7%	90 61.6%

Outcome Measures

1. Primary Outcome

Title	Best Overall Response Rate (BORR) Within Brain of Previously Untreated Participants (Assessed by Independent Review Committee [IRC] Using Modified Response Evaluation Criteria in Solid Tumors [RECIST])
Description	BORR assessed by IRC is defined as percentage of participants who were responders [with best overall response (BOR) documented as confirmed complete response (CR) or partial response (PR)]. The RECIST v1.1 criteria modified for independent review of body and brain lesions was based on current radiology practices. The modifications to RECIST v1.1 included allowing target lesions in the brain to be >=5 mm by contrast-enhanced magnetic resonance imaging scan (in traditional RECIST v1.1 this is >=10 mm), allowing up to 5 target lesions in the brain (in traditional RECIST v1.1 only 2 target lesions), and examining the lesions within the brain and outside the brain separately for analytical purposes. CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (<) 10 millimeters (mm), PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Time Frame	Baseline up to the disease progression or death from any cause (approximately 4 years)

Outcome Measure Data

Analysis Population Description

The intent to treat (ITT) population included all participants who were enrolled in the study.

Arm/Group Title	Cohort 1: Previously Untreated Participants
Arm/Group Description	Participants who had not received previous treatment for brain metastases [i.e., had never received brain stereotactic radiotherapy (SRT), whole-brain radiotherapy (WBRT), surgery, or any other treatment for their brain metastases] received Vemurafenib 960 milligram (mg) tablet orally, twice daily (BID) from Day 1 until development of progressive disease within the brain or outside of the brain (whichever occurred first), unacceptable toxicity, consent withdrawal, protocol violation endangering participant's safety, death, reasons deemed by the investigator, or study termination by the Sponsor.
Measure Participants	90
Number (95% Confidence Interval) [percentage of participants]	17.8 19.8%

2. Secondary Outcome

Title	Best Overall Response Rate (BORR) in the Brain of Participants With Previously Treated or Untreated Brain Metastases as Assessed by the IRC Using RECIST v1.1
Description	Percentage of participants who were responders with BOR documented as confirmed CR or PR, stable disease (SD), progressive disease (PD). CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.
Time Frame	Baseline up to the disease progression or death from any cause (approximately 4 years)

Outcome Measure Data

Analysis Population Description

The ITT population included all participants who were enrolled in the study.

Arm/Group Title	Cohort 1: Previously Untreated Participants	Cohort 2: Previously Treated Participants
Arm/Group Description	Participants who had not received previous treatment for brain metastases [i.e., had never received brain stereotactic radiotherapy (SRT), whole-brain radiotherapy (WBRT), surgery, or any other treatment for their brain metastases] received Vemurafenib 960 milligram (mg) tablet orally, twice daily (BID) from Day 1 until development of progressive disease within the brain or outside of the brain (whichever occurred first), unacceptable toxicity, consent withdrawal, protocol violation endangering participant's safety, death, reasons deemed by the investigator, or study termination by the Sponsor.	Participants who were previously treated with brain SRT, WBRT, or surgery for their brain metastases and have progressed following this treatment, received Vemurafenib 960 milligram (mg) tablet orally, BID from Day 1 until development of progressive disease within the brain or outside of the brain (whichever occurred first), unacceptable toxicity, consent withdrawal, protocol violation endangering participant's safety, death, reasons deemed by the investigator, or study termination by the Sponsor.
Measure Participants	90	56
Complete Response	2.2 2.4%	0.0 0%
Partial Response	15.6 17.3%	17.9 32%
Stable Disease	43.3 48.1%	41.1 73.4%
Progressive Disease	32.2 35.8%	33.9 60.5%
Unevaluable	6.7 7.4%	7.1 12.7%

3. Secondary Outcome

Title	Best Overall Response Rate (BORR) in the Brain of Participants With Previously Treated Brain Metastases as Assessed by the IRC Using RECIST v1.1
Description	BORR within brain assessed by IRC is defined as percentage of participants who were responders (with BOR documented as confirmed CR or PR). According to RECIST v1.1 criteria modified for brain metastases, CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm, PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Time Frame	Baseline up to the disease progression or death from any cause (approximately 4 years)

Outcome Measure Data

Analysis Population Description

The ITT population included all participants who were enrolled in the study.

Arm/Group Title	Cohort 2: Previously Treated Participants
Arm/Group Description	Participants who were previously treated with brain SRT, WBRT, or surgery for their brain metastases and have progressed following this treatment, received Vemurafenib 960 milligram (mg) tablet orally, BID from Day 1 until development of progressive disease within the brain or outside of the brain (whichever occurred first), unacceptable toxicity, consent withdrawal, protocol violation endangering participant's safety, death, reasons deemed by the investigator, or study termination by the Sponsor.
Measure Participants	56
Number (95% Confidence Interval) [percentage of participants]	17.9 19.9%

4. Secondary Outcome

Title	Best Overall Response Rate Outside the Brain (Assessed by IRC)
Description	BORR outside of brain assessed by IRC is defined as percentage of participants who were responders (with BOR documented as confirmed CR or PR). According to RECIST v1.1 criteria modified for brain metastases, CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm, PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Time Frame	Baseline up to the disease progression or death from any cause (approximately 4 years)

Outcome Measure Data

Analysis Population Description

The ITT population included all participants who were enrolled in the study. Here, number participants analyzed is the total number of participants who had measurable disease outside brain at baseline.

Arm/Group Title	Cohort 1: Previously Untreated Participants	Cohort 2: Previously Treated Participants
Arm/Group Description	Participants who had not received previous treatment for brain metastases [i.e., had never received brain stereotactic radiotherapy (SRT), whole-brain radiotherapy (WBRT), surgery, or any other treatment for their brain metastases] received Vemurafenib 960 milligram (mg) tablet orally, twice daily (BID) from Day 1 until development of progressive disease within the brain or outside of the brain (whichever occurred first), unacceptable toxicity, consent withdrawal, protocol violation endangering participant's safety, death, reasons deemed by the investigator, or study termination by the Sponsor.	Participants who were previously treated with brain SRT, WBRT, or surgery for their brain metastases and have progressed following this treatment, received Vemurafenib 960 milligram (mg) tablet orally, BID from Day 1 until development of progressive disease within the brain or outside of the brain (whichever occurred first), unacceptable toxicity, consent withdrawal, protocol violation endangering participant's safety, death, reasons deemed by the investigator, or study termination by the Sponsor.
Measure Participants	79	49
Number (95% Confidence Interval) [percentage of participants]	32.9 36.6%	22.5 40.2%

5. Secondary Outcome

Title	Duration of Response (DOR) (Assessed by Investigator and IRC)
Description	Duration of response was defined as the time interval between the date of the earliest qualifying response and the earliest date of PD or death from any cause. For participants who were alive without progression following the qualifying response, DOR were censored on the date of last available tumor assessment on or before the data cutoff date.
Time Frame	Date of the earliest qualifying response until the earliest date of PD or death from any cause (approximately up to 4 years)

Outcome Measure Data

Analysis Population Description

The ITT population included all participants who were enrolled in the study. Here, 'n' indicates number of participants who were responders within brain or outside brain assessed by investigator or IRC.

Arm/Group Title	Cohort 1: Previously Untreated Participants	Cohort 2: Previously Treated Participants
Arm/Group Description	Participants who had not received previous treatment for brain metastases [i.e., had never received brain stereotactic radiotherapy (SRT), whole-brain radiotherapy (WBRT), surgery, or any other treatment for their brain metastases] received Vemurafenib 960 milligram (mg) tablet orally, twice daily (BID) from Day 1 until development of progressive disease within the brain or outside of the brain (whichever occurred first), unacceptable toxicity, consent withdrawal, protocol violation endangering participant's safety, death, reasons deemed by the investigator, or study termination by the Sponsor.	Participants who were previously treated with brain SRT, WBRT, or surgery for their brain metastases and have progressed following this treatment, received Vemurafenib 960 milligram (mg) tablet orally, BID from Day 1 until development of progressive disease within the brain or outside of the brain (whichever occurred first), unacceptable toxicity, consent withdrawal, protocol violation endangering participant's safety, death, reasons deemed by the investigator, or study termination by the Sponsor.
Measure Participants	90	56
Investigator: DOR (Within Brain) (n=26, 13)	4.67	6.64
Investigator: DOR (Outside Brain) (n=25, 11)	5.55	10.74
IRC: DOR (Within Brain) (n=16, 10)	4.60	6.64
IRC: DOR (Outside Brain) (n=26, 9)	7.72	11.07

6. Secondary Outcome

Title	Progression-Free Survival (PFS) Based on Overall Tumor Response (Assessed by Investigator)
Description	Progression-free survival was defined as the time between enrollment on Day 1 and the date of first radiographically documented progressive disease (within or outside the brain), clinical progressive disease, as assessed by the investigator or death whichever occurred first.
Time Frame	Baseline up to the disease progression or death from any cause (approximately 4 years)

Outcome Measure Data

Analysis Population Description

The ITT population included all participants who were enrolled in the study.

Arm/Group Title	Cohort 1: Previously Untreated Participants	Cohort 2: Previously Treated Participants
Arm/Group Description	Participants who had not received previous treatment for brain metastases [i.e., had never received brain stereotactic radiotherapy (SRT), whole-brain radiotherapy (WBRT), surgery, or any other treatment for their brain metastases] received Vemurafenib 960 milligram (mg) tablet orally, twice daily (BID) from Day 1 until development of progressive disease within the brain or outside of the brain (whichever occurred first), unacceptable toxicity, consent withdrawal, protocol violation endangering participant's safety, death, reasons deemed by the investigator, or study termination by the Sponsor.	Participants who were previously treated with brain SRT, WBRT, or surgery for their brain metastases and have progressed following this treatment, received Vemurafenib 960 milligram (mg) tablet orally, BID from Day 1 until development of progressive disease within the brain or outside of the brain (whichever occurred first), unacceptable toxicity, consent withdrawal, protocol violation endangering participant's safety, death, reasons deemed by the investigator, or study termination by the Sponsor.
Measure Participants	90	56
Median (Full Range) [months]	3.65	3.71

7. Secondary Outcome

Title	Progression-Free Survival (PFS) Based on Tumor Assessment Within Brain Only (Assessed by Investigator )
Description	Progression-free survival was defined as the time between enrollment on Day 1 and the date of first radiographically documented progressive disease (within brain), clinical progressive disease, as assessed by the investigator or death whichever occurred first.
Time Frame	Baseline up to the disease progression or death from any cause (approximately 4 years)

Outcome Measure Data

Analysis Population Description

The ITT population included all participants who were enrolled in the study.

Arm/Group Title	Cohort 1: Previously Untreated Participants	Cohort 2: Previously Treated Participants
Arm/Group Description	Participants who had not received previous treatment for brain metastases [i.e., had never received brain stereotactic radiotherapy (SRT), whole-brain radiotherapy (WBRT), surgery, or any other treatment for their brain metastases] received Vemurafenib 960 milligram (mg) tablet orally, twice daily (BID) from Day 1 until development of progressive disease within the brain or outside of the brain (whichever occurred first), unacceptable toxicity, consent withdrawal, protocol violation endangering participant's safety, death, reasons deemed by the investigator, or study termination by the Sponsor.	Participants who were previously treated with brain SRT, WBRT, or surgery for their brain metastases and have progressed following this treatment, received Vemurafenib 960 milligram (mg) tablet orally, BID from Day 1 until development of progressive disease within the brain or outside of the brain (whichever occurred first), unacceptable toxicity, consent withdrawal, protocol violation endangering participant's safety, death, reasons deemed by the investigator, or study termination by the Sponsor.
Measure Participants	90	56
Median (Full Range) [months]	3.68	4.04

8. Secondary Outcome

Title	Time to Development of New Brain Metastases in Responders
Description	Time to development of new lesions within the brain was defined as the interval between the date of first treatment and the earliest date of documentation of new brain lesions. Participants who were known to be free of new lesions were censored on the date of last tumor assessment.
Time Frame	Date of first treatment and the earliest date of documentation of new brain lesions (approximately up to 4 years)

Outcome Measure Data

Analysis Population Description

The ITT population included all participants who were enrolled in the study. Here, number of participants analyzed is the participants who were responders.

Arm/Group Title	Cohort 1: Previously Untreated Participants	Cohort 2: Previously Treated Participants
Arm/Group Description	Participants who had not received previous treatment for brain metastases [i.e., had never received brain stereotactic radiotherapy (SRT), whole-brain radiotherapy (WBRT), surgery, or any other treatment for their brain metastases] received Vemurafenib 960 milligram (mg) tablet orally, twice daily (BID) from Day 1 until development of progressive disease within the brain or outside of the brain (whichever occurred first), unacceptable toxicity, consent withdrawal, protocol violation endangering participant's safety, death, reasons deemed by the investigator, or study termination by the Sponsor.	Participants who were previously treated with brain SRT, WBRT, or surgery for their brain metastases and have progressed following this treatment, received Vemurafenib 960 milligram (mg) tablet orally, BID from Day 1 until development of progressive disease within the brain or outside of the brain (whichever occurred first), unacceptable toxicity, consent withdrawal, protocol violation endangering participant's safety, death, reasons deemed by the investigator, or study termination by the Sponsor.
Measure Participants	26	13
Median (Full Range) [months]	14.92	14.52

9. Secondary Outcome

Title	Overall Survival
Description	Overall survival was defined as time between enrollment on Day 1 and date of death, irrespective of the cause of death. Participants for whom no death was captured on the clinical database were censored at the latest date they were known to be alive prior to or on the cutoff date.
Time Frame	Baseline up to the disease progression or death from any cause (approximately 4 years)

Outcome Measure Data

Analysis Population Description

The ITT population included all participants who were enrolled in the study.

Arm/Group Title	Cohort 1: Previously Untreated Participants	Cohort 2: Previously Treated Participants
Arm/Group Description	Participants who had not received previous treatment for brain metastases [i.e., had never received brain stereotactic radiotherapy (SRT), whole-brain radiotherapy (WBRT), surgery, or any other treatment for their brain metastases] received Vemurafenib 960 milligram (mg) tablet orally, twice daily (BID) from Day 1 until development of progressive disease within the brain or outside of the brain (whichever occurred first), unacceptable toxicity, consent withdrawal, protocol violation endangering participant's safety, death, reasons deemed by the investigator, or study termination by the Sponsor.	Participants who were previously treated with brain SRT, WBRT, or surgery for their brain metastases and have progressed following this treatment, received Vemurafenib 960 milligram (mg) tablet orally, BID from Day 1 until development of progressive disease within the brain or outside of the brain (whichever occurred first), unacceptable toxicity, consent withdrawal, protocol violation endangering participant's safety, death, reasons deemed by the investigator, or study termination by the Sponsor.
Measure Participants	90	56
Median (Full Range) [months]	8.87	9.63

10. Secondary Outcome

Title	Best Overall Response Rate (BORR) Within the Brain and Outside Brain (Assessed by Investigator)
Description	Percentage of participants who were responders with BOR documented as confirmed CR or PR, stable disease (SD), progressive disease (PD). CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.
Time Frame	Baseline up to the disease progression or death from any cause (approximately 4 years)

Outcome Measure Data

Analysis Population Description

The ITT population included all participants who were enrolled in the study. Here, 'n' indicates the number participants who were evaluable for within brain assessment and who had measurable disease outside brain at baseline for outside brain assessment.

Arm/Group Title	Cohort 1: Previously Untreated Participants	Cohort 2: Previously Treated Participants
Arm/Group Description	Participants who had not received previous treatment for brain metastases [i.e., had never received brain stereotactic radiotherapy (SRT), whole-brain radiotherapy (WBRT), surgery, or any other treatment for their brain metastases] received Vemurafenib 960 milligram (mg) tablet orally, twice daily (BID) from Day 1 until development of progressive disease within the brain or outside of the brain (whichever occurred first), unacceptable toxicity, consent withdrawal, protocol violation endangering participant's safety, death, reasons deemed by the investigator, or study termination by the Sponsor.	Participants who were previously treated with brain SRT, WBRT, or surgery for their brain metastases and have progressed following this treatment, received Vemurafenib 960 milligram (mg) tablet orally, BID from Day 1 until development of progressive disease within the brain or outside of the brain (whichever occurred first), unacceptable toxicity, consent withdrawal, protocol violation endangering participant's safety, death, reasons deemed by the investigator, or study termination by the Sponsor.
Measure Participants	90	56
Complete Response (Within Brain) (n=90, 56)	2.2 2.4%	0.0 0%
Partial Response (Within Brain) (n=90, 56)	26.7 29.7%	23.2 41.4%
Stable Disease (Within Brain) (n=90, 56)	40.0 44.4%	53.6 95.7%
Progressive Disease (Within Brain) (n=90, 56)	27.8 30.9%	19.6 35%
Unevaluable (Within Brain) (n=90, 56)	3.3 3.7%	3.6 6.4%
Complete Response (Outside Brain) (n=79, 40)	0.0 0%	5.0 8.9%
Partial Response (Outside Brain) (n=79, 40)	31.6 35.1%	22.5 40.2%
Stable Disease (Outside Brain) (n=79, 40)	49.4 54.9%	52.5 93.8%
Progressive Disease (Outside Brain) (n=79, 40)	11.4 12.7%	15.0 26.8%
Unevaluable (Outside Brain) (n=79, 40)	7.6 8.4%	5.0 8.9%

11. Secondary Outcome

Title	Best Overall Response Rate (BORR) Within the Brain and Outside Brain (Not Necessarily Follows the RECIST Criteria - as Assessed by Investigator)
Description	Percentage of participants who were responders (with best overall response (BOR) documented as confirmed complete response [CR] or partial response [PR]) were reported.
Time Frame	Baseline up to the disease progression or death from any cause (approximately 4 years)

Outcome Measure Data

Analysis Population Description

The ITT population included all participants who were enrolled in the study.

Arm/Group Title	Cohort 1: Previously Untreated Participants	Cohort 2: Previously Treated Participants
Arm/Group Description	Participants who had not received previous treatment for brain metastases [i.e., had never received brain stereotactic radiotherapy (SRT), whole-brain radiotherapy (WBRT), surgery, or any other treatment for their brain metastases] received Vemurafenib 960 milligram (mg) tablet orally, twice daily (BID) from Day 1 until development of progressive disease within the brain or outside of the brain (whichever occurred first), unacceptable toxicity, consent withdrawal, protocol violation endangering participant's safety, death, reasons deemed by the investigator, or study termination by the Sponsor.	Participants who were previously treated with brain SRT, WBRT, or surgery for their brain metastases and have progressed following this treatment, received Vemurafenib 960 milligram (mg) tablet orally, BID from Day 1 until development of progressive disease within the brain or outside of the brain (whichever occurred first), unacceptable toxicity, consent withdrawal, protocol violation endangering participant's safety, death, reasons deemed by the investigator, or study termination by the Sponsor.
Measure Participants	90	56
Number (95% Confidence Interval) [percentage of participants]	18.9 21%	17.9 32%

12. Secondary Outcome

Title	Percentage of Participants With Adverse Events (AE)
Description	An AE was considered any unfavorable and unintended sign, symptom, or disease associated with the use of the study drug, whether or not considered related to the study drug.
Time Frame	From signing of informed consent form up to 28 days after the last dose of study drug (approximately up to 4 years)

Outcome Measure Data

Analysis Population Description

The safety population included all participants who received at least one dose of study medication.

Arm/Group Title	Cohort 1: Previously Untreated Participants	Cohort 2: Previously Treated Participants
Arm/Group Description	Participants who had not received previous treatment for brain metastases [i.e., had never received brain stereotactic radiotherapy (SRT), whole-brain radiotherapy (WBRT), surgery, or any other treatment for their brain metastases] received Vemurafenib 960 milligram (mg) tablet orally, twice daily (BID) from Day 1 until development of progressive disease within the brain or outside of the brain (whichever occurred first), unacceptable toxicity, consent withdrawal, protocol violation endangering participant's safety, death, reasons deemed by the investigator, or study termination by the Sponsor.	Participants who were previously treated with brain SRT, WBRT, or surgery for their brain metastases and have progressed following this treatment, received Vemurafenib 960 milligram (mg) tablet orally, BID from Day 1 until development of progressive disease within the brain or outside of the brain (whichever occurred first), unacceptable toxicity, consent withdrawal, protocol violation endangering participant's safety, death, reasons deemed by the investigator, or study termination by the Sponsor.
Measure Participants	90	56
Number [percentage of participants]	97.8 108.7%	94.6 168.9%

Adverse Events

Time Frame	From signing of informed consent form up to 28 days after the last dose of study drug (Up to approximately 4 years)
Adverse Event Reporting Description	The safety population included all participants who received at least one dose of study medication.
Arm/Group Title	Cohort 1: Previously Untreated Participants		Cohort 2: Previously Treated Participants
Arm/Group Description	Participants who had not received previous treatment for brain metastases [i.e., had never received brain stereotactic radiotherapy (SRT), whole-brain radiotherapy (WBRT), surgery, or any other treatment for their brain metastases] received Vemurafenib 960 milligram (mg) tablet orally, twice daily (BID) from Day 1 until development of progressive disease within the brain or outside of the brain (whichever occurred first), unacceptable toxicity, consent withdrawal, protocol violation endangering participant's safety, death, reasons deemed by the investigator, or study termination by the Sponsor.		Participants who were previously treated with brain SRT, WBRT, or surgery for their brain metastases and have progressed following this treatment, received Vemurafenib 960 milligram (mg) tablet orally, BID from Day 1 until development of progressive disease within the brain or outside of the brain (whichever occurred first), unacceptable toxicity, consent withdrawal, protocol violation endangering participant's safety, death, reasons deemed by the investigator, or study termination by the Sponsor.
All Cause Mortality
	Cohort 1: Previously Untreated Participants		Cohort 2: Previously Treated Participants
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Cohort 1: Previously Untreated Participants		Cohort 2: Previously Treated Participants
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	37/90 (41.1%)		27/56 (48.2%)
Blood and lymphatic system disorders
Neutropenia	1/90 (1.1%)		0/56 (0%)
Pancytopenia	0/90 (0%)		1/56 (1.8%)
Cardiac disorders
Cardiac failure acute	0/90 (0%)		1/56 (1.8%)
Pericardial effusion	1/90 (1.1%)		0/56 (0%)
Pericarditis constrictive	1/90 (1.1%)		0/56 (0%)
Endocrine disorders
Hyperthyroidism	1/90 (1.1%)		0/56 (0%)
Eye disorders
Iridocyclitis	0/90 (0%)		1/56 (1.8%)
Ocular ischaemic syndrome	0/90 (0%)		1/56 (1.8%)
Papilloedema	0/90 (0%)		1/56 (1.8%)
Uveitis	0/90 (0%)		1/56 (1.8%)
Gastrointestinal disorders
Abdominal pain upper	2/90 (2.2%)		0/56 (0%)
Ileus	1/90 (1.1%)		0/56 (0%)
Intestinal obstruction	1/90 (1.1%)		0/56 (0%)
General disorders
Pyrexia	2/90 (2.2%)		0/56 (0%)
Hepatobiliary disorders
Cholecystitis acute	1/90 (1.1%)		0/56 (0%)
Cholestasis	0/90 (0%)		1/56 (1.8%)
Liver injury	0/90 (0%)		1/56 (1.8%)
Infections and infestations
Pneumonia	1/90 (1.1%)		2/56 (3.6%)
Abscess rupture	0/90 (0%)		1/56 (1.8%)
Bronchitis	0/90 (0%)		1/56 (1.8%)
Bronchopneumonia	0/90 (0%)		1/56 (1.8%)
Diabetic foot infection	1/90 (1.1%)		0/56 (0%)
Diarrhoea infectious	0/90 (0%)		1/56 (1.8%)
Post procedural cellulitis	1/90 (1.1%)		0/56 (0%)
Post procedural infection	0/90 (0%)		1/56 (1.8%)
Pyelonephritis	1/90 (1.1%)		0/56 (0%)
Sepsis	0/90 (0%)		1/56 (1.8%)
Streptococcal infection	0/90 (0%)		1/56 (1.8%)
Investigations
Alanine aminotransferase increased	1/90 (1.1%)		0/56 (0%)
Aspartate aminotransferase increased	1/90 (1.1%)		0/56 (0%)
Electrocardiogram QT prolonged	0/90 (0%)		1/56 (1.8%)
Gamma-glutamyltransferase increased	1/90 (1.1%)		0/56 (0%)
Hepatic enzyme increased	1/90 (1.1%)		0/56 (0%)
Lipase increased	1/90 (1.1%)		0/56 (0%)
Musculoskeletal and connective tissue disorders
Intervertebral disc degeneration	1/90 (1.1%)		0/56 (0%)
Muscular weakness	1/90 (1.1%)		0/56 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Squamous cell carcinoma of skin	11/90 (12.2%)		6/56 (10.7%)
Keratoacanthoma	11/90 (12.2%)		4/56 (7.1%)
Malignant melanoma	2/90 (2.2%)		2/56 (3.6%)
Basal cell carcinoma	1/90 (1.1%)		0/56 (0%)
Bowen's disease	0/90 (0%)		1/56 (1.8%)
Glioma	1/90 (1.1%)		0/56 (0%)
Intracranial tumour haemorrhage	0/90 (0%)		1/56 (1.8%)
Squamous cell carcinoma	0/90 (0%)		1/56 (1.8%)
Tonsillar neoplasm benign	0/90 (0%)		1/56 (1.8%)
Nervous system disorders
Haemorrhage intracranial	1/90 (1.1%)		1/56 (1.8%)
Seizure	1/90 (1.1%)		1/56 (1.8%)
Brain oedema	1/90 (1.1%)		0/56 (0%)
Central nervous system haemorrhage	0/90 (0%)		1/56 (1.8%)
Cerebral haemorrhage	1/90 (1.1%)		0/56 (0%)
Epilepsy	1/90 (1.1%)		0/56 (0%)
Headache	0/90 (0%)		1/56 (1.8%)
Psychiatric disorders
Confusional state	0/90 (0%)		2/56 (3.6%)
Mental status changes	0/90 (0%)		1/56 (1.8%)
Panic attack	0/90 (0%)		1/56 (1.8%)
Renal and urinary disorders
Nephrolithiasis	0/90 (0%)		1/56 (1.8%)
Renal failure	0/90 (0%)		1/56 (1.8%)
Respiratory, thoracic and mediastinal disorders
Pneumonia aspiration	1/90 (1.1%)		0/56 (0%)
Pulmonary embolism	1/90 (1.1%)		0/56 (0%)
Skin and subcutaneous tissue disorders
Rash	1/90 (1.1%)		0/56 (0%)
Other (Not Including Serious) Adverse Events
	Cohort 1: Previously Untreated Participants		Cohort 2: Previously Treated Participants
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	85/90 (94.4%)		53/56 (94.6%)
Blood and lymphatic system disorders
Anaemia	7/90 (7.8%)		6/56 (10.7%)
Neutropenia	1/90 (1.1%)		3/56 (5.4%)
Eye disorders
Photophobia	2/90 (2.2%)		3/56 (5.4%)
Visual impairment	1/90 (1.1%)		3/56 (5.4%)
Gastrointestinal disorders
Nausea	15/90 (16.7%)		14/56 (25%)
Diarrhoea	14/90 (15.6%)		10/56 (17.9%)
Vomoting	8/90 (8.9%)		8/56 (14.3%)
Constipation	5/90 (5.6%)		2/56 (3.6%)
Abdominal pain upper	1/90 (1.1%)		3/56 (5.4%)
Dyspepsia	0/90 (0%)		3/56 (5.4%)
Faecal incontinence	0/90 (0%)		3/56 (5.4%)
General disorders
Fatigue	22/90 (24.4%)		19/56 (33.9%)
Asthenia	13/90 (14.4%)		6/56 (10.7%)
Oedema peripheral	7/90 (7.8%)		8/56 (14.3%)
Pyrexia	11/90 (12.2%)		7/56 (12.5%)
Pain	6/90 (6.7%)		5/56 (8.9%)
Chest Pain	1/90 (1.1%)		4/56 (7.1%)
Xerosis	5/90 (5.6%)		1/56 (1.8%)
Immune system disorders
Contrast media allergy	0/90 (0%)		3/56 (5.4%)
Infections and infestations
Nasopharyngitis	5/90 (5.6%)		4/56 (7.1%)
Upper respiratory tract infection	2/90 (2.2%)		4/56 (7.1%)
Urinary tract infection	2/90 (2.2%)		4/56 (7.1%)
Conjunctivitis	2/90 (2.2%)		3/56 (5.4%)
Folliculitis	0/90 (0%)		3/56 (5.4%)
Injury, poisoning and procedural complications
Sunburn	6/90 (6.7%)		2/56 (3.6%)
Investigations
Electrocardiogram QT prolonged	22/90 (24.4%)		8/56 (14.3%)
Aspartate aminotransferase increased	6/90 (6.7%)		3/56 (5.4%)
Blood bilirubin increased	6/90 (6.7%)		4/56 (7.1%)
Alanine aminotransferase increased	6/90 (6.7%)		5/56 (8.9%)
Blood alkaline phosphatase increased	5/90 (5.6%)		2/56 (3.6%)
Weight decreased	6/90 (6.7%)		6/56 (10.7%)
Blood creatinine increased	5/90 (5.6%)		3/56 (5.4%)
Metabolism and nutrition disorders
Decreased appetite	8/90 (8.9%)		3/56 (5.4%)
Hypokalaemia	2/90 (2.2%)		5/56 (8.9%)
Musculoskeletal and connective tissue disorders
Arthralgia	31/90 (34.4%)		23/56 (41.1%)
Pain in extremity	8/90 (8.9%)		5/56 (8.9%)
Myalgia	8/90 (8.9%)		5/56 (8.9%)
Musculoskeletal pain	6/90 (6.7%)		3/56 (5.4%)
Back pain	5/90 (5.6%)		1/56 (1.8%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Skin papilloma	15/90 (16.7%)		12/56 (21.4%)
Seborrhoeic keratosis	7/90 (7.8%)		1/56 (1.8%)
Basal cell carcinoma	1/90 (1.1%)		3/56 (5.4%)
Nervous system disorders
Headache	16/90 (17.8%)		8/56 (14.3%)
Paraesthesia	9/90 (10%)		2/56 (3.6%)
Dysgeusia	6/90 (6.7%)		4/56 (7.1%)
Seizure	2/90 (2.2%)		6/56 (10.7%)
Dizziness	3/90 (3.3%)		3/56 (5.4%)
Balance disorder	0/90 (0%)		3/56 (5.4%)
Tremor	0/90 (0%)		5/56 (8.9%)
Psychiatric disorders
Insomnia	5/90 (5.6%)		7/56 (12.5%)
Confusional state	0/90 (0%)		4/56 (7.1%)
Respiratory, thoracic and mediastinal disorders
Cough	8/90 (8.9%)		6/56 (10.7%)
Dyspnoea	5/90 (5.6%)		3/56 (5.4%)
Oropharyngeal pain	3/90 (3.3%)		3/56 (5.4%)
Skin and subcutaneous tissue disorders
Hyperkeratosis	28/90 (31.1%)		13/56 (23.2%)
Rash	29/90 (32.2%)		17/56 (30.4%)
Photosensitivity Reaction	18/90 (20%)		17/56 (30.4%)
Erythema	13/90 (14.4%)		9/56 (16.1%)
Palmar-plantar erythrodysaesthesia syndrome	7/90 (7.8%)		8/56 (14.3%)
Alopecia	16/90 (17.8%)		13/56 (23.2%)
Pruritus	16/90 (17.8%)		6/56 (10.7%)
Dry skin	11/90 (12.2%)		10/56 (17.9%)
Actinic keratosis	6/90 (6.7%)		5/56 (8.9%)
Keratosis pilaris	9/90 (10%)		2/56 (3.6%)
Dermal cyst	4/90 (4.4%)		3/56 (5.4%)
Rash follicular	1/90 (1.1%)		3/56 (5.4%)
Vascular disorders
Hypertension	6/90 (6.7%)		4/56 (7.1%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.