A Study of Vemurafenib in Previously Treated Patients With Metastatic Melanoma

• Sponsor: Hoffmann-La Roche (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00949702
• Collaborator: (none)
• Enrollment: 132
• Locations: 15
• Arm: 1
• Actual Duration (Months): 56.1
• Patients Per Site: 8.8
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

This open-label single arm study will assess the efficacy, safety and tolerability of Vemurafenib in previously treated patients with metastatic melanoma. Patients will receive oral Vemurafenib [RG7204; PLEXXIKON: PLX4032] at a dose of 960 mg b.i.d. continuously until disease progression or withdrawal from study and will be assessed at regular intervals for tumour response and tolerability. Target sample size is <100 patients.

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 132 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-label Multicenter Study on the Efficacy of Continuous Oral Dosing of Vemurafenib on Tumour Response in Previously Treated Patients With Metastatic Melanoma
• Actual Study Start Date: Sep 30, 2009
• Actual Primary Completion Date: Sep 27, 2010
• Actual Study Completion Date: Jun 3, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Single arm	Drug: vemurafenib; 960 mg b.i.d. continuous oral dosing

Outcome Measures

Primary Outcome Measures

1. Best Overall Response (BOR) Assessed by an Independent Review Committee Using Response Evaluation Criteria In Solid Tumors (RECIST 1.1) [From first treatment through September 27, 2010]

   BOR was defined as a complete response (CR) or partial response (PR) confirmed per Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1. Patients who never received study treatment and treated patients without any post-baseline tumor assessments were considered as non-responders. CR: Disappearance of all target lesions, all non-target lesions, and no new lesion. Any pathological lymph nodes must have had reduction in the short axis to <10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions, no progression in non-target lesion, and no new lesion.

Secondary Outcome Measures

1. Best Overall Response (BOR) Assessed by the Investigator Using Response Evaluation Criteria In Solid Tumors (RECIST 1.1) [From first treatment through September 27, 2010]

   BOR was defined as a complete response (CR) or partial response (PR) confirmed per Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1. Patients who never received study treatment and treated patients without any post-baseline tumor assessments were considered as non-responders. CR: Disappearance of all target lesions, all non-target lesions, and no new lesion. Any pathological lymph nodes must have had reduction in the short axis to <10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions, no progression in non-target lesion, and no new lesion.

2. Duration of Response Assessed by an Independent Review Committee Using Response Evaluation Criteria In Solid Tumors (RECIST 1.1) [From first treatment through September 27, 2010]

   Duration of response was defined as the time interval between the date of the earliest qualifying response and the date of disease progression (PD) or death, only for those patients whose best overall response was complete response or partial response. PD: At least 20% increase in the sum of diameters of target lesions compared to Nadir (smallest sum of diameters on-study), unequivocal progression of existing non-target lesions, or presence of new lesion. For patients who were alive without progression, duration of response was censored on the date of the last evaluable tumor assessment.

3. Time to Response Assessed by an Independent Review Committee Using Response Evaluation Criteria In Solid Tumors (RECIST 1.1) [From first treatment through September 27, 2010]

   Time to response was defined as the interval between the date of the first treatment and the date of the first documentation of confirmed complete response (CR) or partial response (PR), whichever occurred first.

4. Progression Free Survival (PFS) Assessed by an Independent Review Committee Using Response Evaluation Criteria In Solid Tumors (RECIST 1.1) [From first treatment through September 27, 2010]

   PFS was defined the time interval between the date of the first treatment and the date of progression or death from any cause, whichever occurred first. Deaths that occurred in patients without disease progression were considered to be a PFS event on the date of death. Patients who neither progressed nor died were censored on the date of the last evaluable tumor assessment prior to the data cutoff date.

5. Overall Survival [From first treatment through September 27, 2010]

   Overall survival was defined as the time from the date of the first treatment to the date of death, regardless of the cause of death. For patients who were alive at the time of analysis, overall survival was censored at the last date the patient was known to be alive prior to the data cutoff date.

6. Improvement in Physical Symptoms (Improvement in Physician's Assessment of Global Performance Status and Oxygen Saturation Requirements, and Decrease in Total Dose and Frequency of Narcotic Pain Analgesics) During Treatment in Comparison to Baseline [From first treatment through September 27, 2010]

   Three parameters were measured. (1) Improvement in the Physician's Assessment of Global Performance status on a 7-point scale (1=very much better to 7=very much worse). (2) Improvement in oxygen saturation requirements, defined as a clinically meaningful increase in oxygen saturation requirement (from a baseline value < 95% to ≥ 95% saturation using a pulse oximeter). (3) A decrease in total dose and frequency of narcotic pain analgesics. The percentage of patients showing improvement (1 and 2) or a decrease (3) are reported.

7. Maximum Plasma Concentration (Cmax) of Vemurafenib on Day 15 of Cycle 1 [Pre-dose to 8 hours post-dose on Day 15 of Cycle 1]

   Blood samples for assessing the concentration of vemurafenib in plasma were drawn before the morning dose and at 2, 4, 6, and 8 hours post-dose on Day 15 of Cycle 1. Pharmacokinetic parameters were estimated by non-compartmental analysis (Win Non-Lin).

8. Vemurafenib Plasma Level Area Under the Curve From 0 to 8 Hours (AUC0-8h) on Day 15 of Cycle 1 [Pre-dose to 8 hours post-dose on Day 15 of Cycle 1]

   Blood samples for assessing the concentration of vemurafenib in plasma were drawn before the morning dose and at 2, 4, 6, and 8 hours post-dose on Day 15 of Cycle 1. Pharmacokinetic parameters were estimated by non-compartmental analysis (Win Non-Lin). AUC0-8h was calculated using the linear trapezoidal rule.

9. Vemurafenib Plasma Levels at Various Treatment Cycles [Pre-dose Cycle 1 Day 1 to 4 hours post-dose Cycle 10 Day 1]

   Blood samples for assessing the concentration of vemurafenib in plasma were drawn before the morning dose and 4 hours post-dose at Day 1 of Cycles 1, 2, 3, 4, 6, 8, and 10. Each Cycle was 3 weeks in duration.

10. Time-matched Change From Baseline in the Study Specific Corrected QT Interval (QTcP) [Pre-dose Cycle 1 Day 1 to pre-dose Cycle 6 Day 1]

    Three electrocardiograms (ECG) were obtained pre-dose and 2, 4, 6, and 8 hours post-dose at Days 1 and 15 of Cycle 1 and again pre-dose and 4 hours post-dose at various Cycles throughout treatment. Five baseline triplicate ECGs were obtained before the start of treatment at the same time points used during treatment. Reported is the largest mean time-matched QTcP change from baseline. QTcP=QT/(60/heart rate)^β (β=mean [calculated separately for males and females] log-transformed QT versus log-transformed RR regression slopes using all available pre-treatment (baseline) ECG values.

11. Percentage of Patients With Adverse Event [From first treatment through September 27, 2010]

    The intensity of adverse events was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events v 4.0 (CTCAE) on a 5-point scale (Grade 1 to 5: Mild, Moderate, Severe, Life-threatening, and Death).

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• adult patients >/=18 years of age

• histologically confirmed metastatic melanoma (Stage IV, AJCC)

• patients must have completed and failed at least one prior standard of care regimen (e.g. DTIC, temozolomide, etc.)

• BRAF V600E positive mutation (by Roche CoDx BRAF mutation assay)

• measurable disease by RECIST criteria

• negative pregnancy test and, for fertile men and women, effective contraception during treatment and for 6 months after completion

Exclusion Criteria:

• active CNS metastases on CT/MRI within 28 days prior to enrollment

• history of or known carcinomatous meningitis

• previous treatment with BRAF (sorafenib allowed) or MEK inhibitor

• cardiac dysrhythmias >2 NCI CTCAE or treatment with drugs with dysrhythmic potential

• uncontrolled hypertension(>150/100mmHg) despite optimal medical therapy

• infectious disease including HIV, HBV and HCV

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UCLA - School of Medicine; Division of Hematology/Oncology	Los Angeles	California	United States	90095-6984
2	University of Colorado	Denver	Colorado	United States	80262
3	Moffitt Cancer Center	Tampa	Florida	United States	33612
4	Massachusetts General Hospital;Hematology/ Oncology	Boston	Massachusetts	United States	02114
5	Dana Farber Cancer Inst. ; Dept. of Medical Oncology	Boston	Massachusetts	United States	02115
6	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02215
7	New York University Medical Center	New York	New York	United States	10036
8	Hospital of the Uni of Pennsylvania; Section of Hematology/Oncology	Philadelphia	Pennsylvania	United States	19104-4283
9	University of Pittsburgh	Pittsburgh	Pennsylvania	United States	15213
10	Vanderbilt-Ingram Cancer Ctr	Nashville	Tennessee	United States	37232
11	Texas Oncology-Baylor Sammons Cancer Center	Dallas	Texas	United States	75246
12	University of Texas M.D. Anderson Cancer Center	Houston	Texas	United States	77030
13	Calvary Mater Newcastle; Melanoma Clinic	Newcastle	New South Wales	Australia	2298
14	Westmead Hospital; Medical Oncology and Pallative Care	Westmead	New South Wales	Australia	2145
15	Peter Maccallum Cancer Institute; Medical Oncology	Melbourne	Victoria	Australia	3000

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: NCT00949702
• Other Study ID Numbers: NP22657
• First Posted: Jul 30, 2009
• Last Update Posted: Jul 25, 2017
• Last Verified: Jun 1, 2017

• Additional relevant MeSH terms: Melanoma; Vemurafenib

Study Results

Participant Flow

Arm/Group Title	Vemurafenib 960 mg
Arm/Group Description	Patients received vemurafenib 960 mg (four 240 mg tablets) bid (bis in die, twice daily) orally until disease progression, unacceptable toxicity, withdrawal of consent, or another reason as determined by the investigator.
Period Title: Overall Study
STARTED	132
COMPLETED	84
NOT COMPLETED	48

Baseline Characteristics

Arm/Group Title	Vemurafenib 960 mg
Arm/Group Description	Patients received vemurafenib 960 mg (four 240 mg tablets) bid (bis in die, twice daily) orally until disease progression, unacceptable toxicity, withdrawal of consent, or another reason as determined by the investigator.
Overall Participants	132
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	50.3 (14.70)
Sex: Female, Male (Count of Participants)
Female	51 38.6%
Male	81 61.4%

Outcome Measures

1. Primary Outcome

Title	Best Overall Response (BOR) Assessed by an Independent Review Committee Using Response Evaluation Criteria In Solid Tumors (RECIST 1.1)
Description	BOR was defined as a complete response (CR) or partial response (PR) confirmed per Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1. Patients who never received study treatment and treated patients without any post-baseline tumor assessments were considered as non-responders. CR: Disappearance of all target lesions, all non-target lesions, and no new lesion. Any pathological lymph nodes must have had reduction in the short axis to <10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions, no progression in non-target lesion, and no new lesion.
Time Frame	From first treatment through September 27, 2010

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: All enrolled patients who received at least one, or a partial dose of vemurafenib.

Arm/Group Title	Vemurafenib 960 mg
Arm/Group Description	Patients received vemurafenib 960 mg (four 240 mg tablets) bid (bis in die, twice daily) orally until disease progression, unacceptable toxicity, withdrawal of consent, or another reason as determined by the investigator.
Measure Participants	132
Number (95% Confidence Interval) [Percentage of participants]	52.3 39.6%

2. Secondary Outcome

Title	Best Overall Response (BOR) Assessed by the Investigator Using Response Evaluation Criteria In Solid Tumors (RECIST 1.1)
Description	BOR was defined as a complete response (CR) or partial response (PR) confirmed per Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1. Patients who never received study treatment and treated patients without any post-baseline tumor assessments were considered as non-responders. CR: Disappearance of all target lesions, all non-target lesions, and no new lesion. Any pathological lymph nodes must have had reduction in the short axis to <10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions, no progression in non-target lesion, and no new lesion.
Time Frame	From first treatment through September 27, 2010

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: All enrolled patients who received at least one, or a partial dose of vemurafenib.

Arm/Group Title	Vemurafenib 960 mg
Arm/Group Description	Patients received vemurafenib 960 mg (four 240 mg tablets) bid (bis in die, twice daily) orally until disease progression, unacceptable toxicity, withdrawal of consent, or another reason as determined by the investigator.
Measure Participants	132
Number (95% Confidence Interval) [Percentage of participants]	54.5 41.3%

3. Secondary Outcome

Title	Duration of Response Assessed by an Independent Review Committee Using Response Evaluation Criteria In Solid Tumors (RECIST 1.1)
Description	Duration of response was defined as the time interval between the date of the earliest qualifying response and the date of disease progression (PD) or death, only for those patients whose best overall response was complete response or partial response. PD: At least 20% increase in the sum of diameters of target lesions compared to Nadir (smallest sum of diameters on-study), unequivocal progression of existing non-target lesions, or presence of new lesion. For patients who were alive without progression, duration of response was censored on the date of the last evaluable tumor assessment.
Time Frame	From first treatment through September 27, 2010

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: All enrolled patients who received at least one, or a partial dose of vemurafenib.

Arm/Group Title	Vemurafenib 960 mg
Arm/Group Description	Patients received vemurafenib 960 mg (four 240 mg tablets) bid (bis in die, twice daily) orally until disease progression, unacceptable toxicity, withdrawal of consent, or another reason as determined by the investigator.
Measure Participants	69
Median (95% Confidence Interval) [Months]	6.5

4. Secondary Outcome

Title	Time to Response Assessed by an Independent Review Committee Using Response Evaluation Criteria In Solid Tumors (RECIST 1.1)
Description	Time to response was defined as the interval between the date of the first treatment and the date of the first documentation of confirmed complete response (CR) or partial response (PR), whichever occurred first.
Time Frame	From first treatment through September 27, 2010

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: All enrolled patients who received at least one, or a partial dose of vemurafenib.

Arm/Group Title	Vemurafenib 960 mg
Arm/Group Description	Patients received vemurafenib 960 mg (four 240 mg tablets) bid (bis in die, twice daily) orally until disease progression, unacceptable toxicity, withdrawal of consent, or another reason as determined by the investigator.
Measure Participants	69
Median (Inter-Quartile Range) [Months]	1.38

5. Secondary Outcome

Title	Progression Free Survival (PFS) Assessed by an Independent Review Committee Using Response Evaluation Criteria In Solid Tumors (RECIST 1.1)
Description	PFS was defined the time interval between the date of the first treatment and the date of progression or death from any cause, whichever occurred first. Deaths that occurred in patients without disease progression were considered to be a PFS event on the date of death. Patients who neither progressed nor died were censored on the date of the last evaluable tumor assessment prior to the data cutoff date.
Time Frame	From first treatment through September 27, 2010

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: All enrolled patients who received at least one, or a partial dose of vemurafenib.

Arm/Group Title	Vemurafenib 960 mg
Arm/Group Description	Patients received vemurafenib 960 mg (four 240 mg tablets) bid (bis in die, twice daily) orally until disease progression, unacceptable toxicity, withdrawal of consent, or another reason as determined by the investigator.
Measure Participants	132
Median (95% Confidence Interval) [Months]	6.1

6. Secondary Outcome

Title	Overall Survival
Description	Overall survival was defined as the time from the date of the first treatment to the date of death, regardless of the cause of death. For patients who were alive at the time of analysis, overall survival was censored at the last date the patient was known to be alive prior to the data cutoff date.
Time Frame	From first treatment through September 27, 2010

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: All enrolled patients who received at least one, or a partial dose of vemurafenib.

Arm/Group Title	Vemurafenib 960 mg
Arm/Group Description	Patients received vemurafenib 960 mg (four 240 mg tablets) bid (bis in die, twice daily) orally until disease progression, unacceptable toxicity, withdrawal of consent, or another reason as determined by the investigator.
Measure Participants	132
Median (95% Confidence Interval) [Months]	NA

7. Secondary Outcome

Title	Improvement in Physical Symptoms (Improvement in Physician's Assessment of Global Performance Status and Oxygen Saturation Requirements, and Decrease in Total Dose and Frequency of Narcotic Pain Analgesics) During Treatment in Comparison to Baseline
Description	Three parameters were measured. (1) Improvement in the Physician's Assessment of Global Performance status on a 7-point scale (1=very much better to 7=very much worse). (2) Improvement in oxygen saturation requirements, defined as a clinically meaningful increase in oxygen saturation requirement (from a baseline value < 95% to ≥ 95% saturation using a pulse oximeter). (3) A decrease in total dose and frequency of narcotic pain analgesics. The percentage of patients showing improvement (1 and 2) or a decrease (3) are reported.
Time Frame	From first treatment through September 27, 2010

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: All enrolled patients who received at least one, or a partial dose of vemurafenib.

Arm/Group Title	Vemurafenib 960 mg
Arm/Group Description	Patients received vemurafenib 960 mg (four 240 mg tablets) bid (bis in die, twice daily) orally until disease progression, unacceptable toxicity, withdrawal of consent, or another reason as determined by the investigator.
Measure Participants	132
Improvement in performance status	83.3 63.1%
Improvement in oxygen saturation requirement	4.5 3.4%
Decrease in use of narcotic pain analgesics	3.0 2.3%

8. Secondary Outcome

Title	Maximum Plasma Concentration (Cmax) of Vemurafenib on Day 15 of Cycle 1
Description	Blood samples for assessing the concentration of vemurafenib in plasma were drawn before the morning dose and at 2, 4, 6, and 8 hours post-dose on Day 15 of Cycle 1. Pharmacokinetic parameters were estimated by non-compartmental analysis (Win Non-Lin).
Time Frame	Pre-dose to 8 hours post-dose on Day 15 of Cycle 1

Outcome Measure Data

Analysis Population Description

Pharmacokinetic population: All patients who received all doses of vemurafenib without dose reduction up to and including Day 15 and who provided at least one of the pharmacokinetic assessments up to and including 8 hours after the first daily dose on Day 15.

Arm/Group Title	Vemurafenib 960 mg
Arm/Group Description	Patients received vemurafenib 960 mg (four 240 mg tablets) bid (bis in die, twice daily) orally until disease progression, unacceptable toxicity, withdrawal of consent, or another reason as determined by the investigator.
Measure Participants	87
Mean (Standard Deviation) [μg/mL]	56.73 (21.76)

9. Secondary Outcome

Title	Vemurafenib Plasma Level Area Under the Curve From 0 to 8 Hours (AUC0-8h) on Day 15 of Cycle 1
Description	Blood samples for assessing the concentration of vemurafenib in plasma were drawn before the morning dose and at 2, 4, 6, and 8 hours post-dose on Day 15 of Cycle 1. Pharmacokinetic parameters were estimated by non-compartmental analysis (Win Non-Lin). AUC0-8h was calculated using the linear trapezoidal rule.
Time Frame	Pre-dose to 8 hours post-dose on Day 15 of Cycle 1

Outcome Measure Data

Analysis Population Description

Pharmacokinetic population: All patients who received all doses of vemurafenib without dose reduction up to and including Day 15 and who provided at least one of the pharmacokinetic assessments up to and including 8 hours after the first daily dose on Day 15.

Arm/Group Title	Vemurafenib 960 mg
Arm/Group Description	Patients received vemurafenib 960 mg (four 240 mg tablets) bid (bis in die, twice daily) orally until disease progression, unacceptable toxicity, withdrawal of consent, or another reason as determined by the investigator.
Measure Participants	87
Mean (Standard Deviation) [μg⋅h/mL]	380.16 (143.56)

10. Secondary Outcome

Title	Vemurafenib Plasma Levels at Various Treatment Cycles
Description	Blood samples for assessing the concentration of vemurafenib in plasma were drawn before the morning dose and 4 hours post-dose at Day 1 of Cycles 1, 2, 3, 4, 6, 8, and 10. Each Cycle was 3 weeks in duration.
Time Frame	Pre-dose Cycle 1 Day 1 to 4 hours post-dose Cycle 10 Day 1

Outcome Measure Data

Analysis Population Description

Pharmacokinetic population: All patients who received all doses of vemurafenib without dose reduction up to and including Day 15 and who provided at least one of the pharmacokinetic assessments up to and including 8 hours after the first daily dose on Day 15.

Arm/Group Title	Vemurafenib 960 mg
Arm/Group Description	Patients received vemurafenib 960 mg (four 240 mg tablets) bid (bis in die, twice daily) orally until disease progression, unacceptable toxicity, withdrawal of consent, or another reason as determined by the investigator.
Measure Participants	122
Pre-dose Cycle 1 Day 15, n=108	47.55 (23.14)
Pre-dose Cycle 2 Day 1, n=122	41.12 (23.39)
Pre-dose Cycle 3 Day 1, n=109	45.20 (21.33)
Pre-dose Cycle 4 Day 1, n=109	50.31 (19.52)
Pre-dose Cycle 6 Day 1, n=96	50.38 (19.54)
Pre-dose Cycle 8 Day 1, n=71	50.42 (22.06)
Pre-dose Cycle 10 Day 1, n=50	50.78 (20.19)
4 hours post-dose Cycle 2 Day 22, n=93	48.38 (20.00)
4 hours post-dose Cycle 3 Day 43, n=78	50.79 (19.20)
4 hours post-dose Cycle 4 Day 1, n=75	55.76 (20.57)
4 hours post-dose Cycle 6 Day 1, n=58	58.92 (20.12)
4 hours post-dose Cycle 8 Day 1, n=43	58.95 (20.98)
4 hours post-dose Cycle 10 Day 1, n=27	63.27 (21.52)

11. Secondary Outcome

Title	Time-matched Change From Baseline in the Study Specific Corrected QT Interval (QTcP)
Description	Three electrocardiograms (ECG) were obtained pre-dose and 2, 4, 6, and 8 hours post-dose at Days 1 and 15 of Cycle 1 and again pre-dose and 4 hours post-dose at various Cycles throughout treatment. Five baseline triplicate ECGs were obtained before the start of treatment at the same time points used during treatment. Reported is the largest mean time-matched QTcP change from baseline. QTcP=QT/(60/heart rate)^β (β=mean [calculated separately for males and females] log-transformed QT versus log-transformed RR regression slopes using all available pre-treatment (baseline) ECG values.
Time Frame	Pre-dose Cycle 1 Day 1 to pre-dose Cycle 6 Day 1

Outcome Measure Data

Analysis Population Description

Electrocardiogram (ECG) evaluable population: All treated patients who had a baseline ECG and at least one ECG during treatment.

Arm/Group Title	Vemurafenib 960 mg
Arm/Group Description	Patients received vemurafenib 960 mg (four 240 mg tablets) bid (bis in die, twice daily) orally until disease progression, unacceptable toxicity, withdrawal of consent, or another reason as determined by the investigator.
Measure Participants	128
Cycle 1 Day 15 at 2 hours post-dose, n=109	12.8
Cycle 6 Day 1 at pre-dose, n=85	15.1

12. Secondary Outcome

Title	Percentage of Patients With Adverse Event
Description	The intensity of adverse events was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events v 4.0 (CTCAE) on a 5-point scale (Grade 1 to 5: Mild, Moderate, Severe, Life-threatening, and Death).
Time Frame	From first treatment through September 27, 2010

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: All enrolled patients who received at least one, or a partial dose of vemurafenib.

Arm/Group Title	Vemurafenib 960 mg
Arm/Group Description	Patients received vemurafenib 960 mg (four 240 mg tablets) bid (bis in die, twice daily) orally until disease progression, unacceptable toxicity, withdrawal of consent, or another reason as determined by the investigator.
Measure Participants	132
Number [Percentage of participants]	100.0 75.8%

Adverse Events

Time Frame	Screening through 6 months after the last patient enrolled
Arm/Group Title	Vemurafenib 960 mg
Arm/Group Description	Patients received vemurafenib 960 mg (four 240 mg tablets) bid (bis in die, twice daily) orally until disease progression, unacceptable toxicity, withdrawal of consent, or another reason as determined by the investigator.
All Cause Mortality
	Vemurafenib 960 mg
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Vemurafenib 960 mg
	Affected / at Risk (%)	# Events
Total	67/132 (50.8%)
Blood and lymphatic system disorders
ANAEMIA	1/132 (0.8%)
Cardiac disorders
PERICARDIAL EFFUSION	2/132 (1.5%)
ANGINA PECTORIS	1/132 (0.8%)
PERICARDITIS	1/132 (0.8%)
ATRIAL FLUTTER	1/132 (0.8%)
Eye disorders
RETINAL VEIN OCCLUSION	1/132 (0.8%)
Gastrointestinal disorders
DYSPHAGIA	3/132 (2.3%)
ABDOMINAL PAIN UPPER	2/132 (1.5%)
NAUSEA	2/132 (1.5%)
ABDOMINAL PAIN	1/132 (0.8%)
DIARRHOEA	1/132 (0.8%)
GASTROINTESTINAL HAEMORRHAGE	1/132 (0.8%)
OESOPHAGITIS	1/132 (0.8%)
PANCREATITIS	1/132 (0.8%)
VOMITING	1/132 (0.8%)
General disorders
PYREXIA	3/132 (2.3%)
MULTI-ORGAN FAILURE	1/132 (0.8%)
PAIN	1/132 (0.8%)
Hepatobiliary disorders
CHOLECYSTITIS	1/132 (0.8%)
HEPATIC CYST	1/132 (0.8%)
JAUNDICE	1/132 (0.8%)
Infections and infestations
PNEUMONIA	3/132 (2.3%)
CELLULITIS	2/132 (1.5%)
BREAST CELLULITIS	1/132 (0.8%)
PSEUDOMONAS INFECTION	1/132 (0.8%)
SALMONELLOSIS	1/132 (0.8%)
SKIN INFECTION	1/132 (0.8%)
STAPHYLOCOCCAL INFECTION	1/132 (0.8%)
WOUND INFECTION	1/132 (0.8%)
Injury, poisoning and procedural complications
FEMUR FRACTURE	1/132 (0.8%)
Investigations
GAMMA-GLUTAMYLTRANSFERASE INCREASED	3/132 (2.3%)
BLOOD ALKALINE PHOSPHATASE INCREASED	2/132 (1.5%)
BLOOD BILIRUBIN INCREASED	2/132 (1.5%)
ALANINE AMINOTRANSFERASE INCREASED	1/132 (0.8%)
BILIRUBIN CONJUGATED INCREASED	1/132 (0.8%)
Metabolism and nutrition disorders
DEHYDRATION	2/132 (1.5%)
TUMOUR LYSIS SYNDROME	1/132 (0.8%)
Musculoskeletal and connective tissue disorders
ARTHRALGIA	2/132 (1.5%)
ARTHRITIS	1/132 (0.8%)
MUSCULAR WEAKNESS	1/132 (0.8%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
SQUAMOUS CELL CARCINOMA OF SKIN	28/132 (21.2%)
BASAL CELL CARCINOMA	8/132 (6.1%)
KERATOACANTHOMA	6/132 (4.5%)
MALIGNANT MELANOMA	2/132 (1.5%)
Nervous system disorders
CONVULSION	3/132 (2.3%)
FACIAL PALSY	3/132 (2.3%)
Psychiatric disorders
DELIRIUM	1/132 (0.8%)
PSYCHOTIC DISORDER	1/132 (0.8%)
Renal and urinary disorders
RENAL FAILURE	1/132 (0.8%)
RENAL FAILURE ACUTE	1/132 (0.8%)
Respiratory, thoracic and mediastinal disorders
PULMONARY EMBOLISM	3/132 (2.3%)
DYSPNOEA	1/132 (0.8%)
RESPIRATORY FAILURE	1/132 (0.8%)
LEFT LUNG GROUND GLASS OPACITIES-PNEUMONITIS	1/132 (0.8%)
Skin and subcutaneous tissue disorders
EXFOLIATIVE RASH	1/132 (0.8%)
RASH	1/132 (0.8%)
RASH VESICULAR	1/132 (0.8%)
Vascular disorders
DEEP VEIN THROMBOSIS	1/132 (0.8%)
Other (Not Including Serious) Adverse Events
	Vemurafenib 960 mg
	Affected / at Risk (%)	# Events
Total	131/132 (99.2%)
Blood and lymphatic system disorders
ANAEMIA	11/132 (8.3%)
Eye disorders
VISION BLURRED	7/132 (5.3%)
Gastrointestinal disorders
NAUSEA	47/132 (35.6%)
DIARRHOEA	37/132 (28%)
VOMITING	33/132 (25%)
CONSTIPATION	21/132 (15.9%)
ABDOMINAL PAIN	12/132 (9.1%)
DYSPEPSIA	11/132 (8.3%)
General disorders
FATIGUE	71/132 (53.8%)
OEDEMA PERIPHERAL	30/132 (22.7%)
PYREXIA	20/132 (15.2%)
CHILLS	9/132 (6.8%)
PAIN	7/132 (5.3%)
Infections and infestations
FOLLICULITIS	12/132 (9.1%)
UPPER RESPIRATORY TRACT INFECTION	8/132 (6.1%)
NASOPHARYNGITIS	7/132 (5.3%)
Injury, poisoning and procedural complications
SUNBURN	19/132 (14.4%)
Investigations
GAMMA-GLUTAMYLTRANSFERASE INCREASED	17/132 (12.9%)
BLOOD ALKALINE PHOSPHATASE INCREASED	10/132 (7.6%)
ALANINE AMINOTRANSFERASE INCREASED	8/132 (6.1%)
ASPARTATE AMINOTRANSFERASE INCREASED	7/132 (5.3%)
BLOOD CREATININE INCREASED	12/132 (9.1%)
LYMPHOCYTE COUNT DECREASED	7/132 (5.3%)
BLOOD BILIRUBIN INCREASED	7/132 (5.3%)
WEIGHT DECREASED	12/132 (9.1%)
Metabolism and nutrition disorders
DECREASED APPETITE	28/132 (21.2%)
HYPOKALAEMIA	10/132 (7.6%)
HYPERGLYCAEMIA	7/132 (5.3%)
Musculoskeletal and connective tissue disorders
ARTHRALGIA	86/132 (65.2%)
MYALGIA	31/132 (23.5%)
MUSCULOSKELETAL PAIN	15/132 (11.4%)
BACK PAIN	14/132 (10.6%)
ARTHRITIS	12/132 (9.1%)
PAIN IN EXTREMITY	12/132 (9.1%)
JOINT SWELLING	7/132 (5.3%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MELANOCYTIC NAEVUS	7/132 (5.3%)
Nervous system disorders
HEADACHE	36/132 (27.3%)
DYSGEUSIA	14/132 (10.6%)
NEUROPATHY PERIPHERAL	13/132 (9.8%)
DIZZINESS	8/132 (6.1%)
Psychiatric disorders
DEPRESSION	11/132 (8.3%)
INSOMNIA	9/132 (6.8%)
ANXIETY	7/132 (5.3%)
Respiratory, thoracic and mediastinal disorders
COUGH	16/132 (12.1%)
OROPHARYNGEAL PAIN	13/132 (9.8%)
DYSPNOEA	10/132 (7.6%)
Skin and subcutaneous tissue disorders
RASH	68/132 (51.5%)
PHOTOSENSITIVITY REACTION	65/132 (49.2%)
ALOPECIA	47/132 (35.6%)
PRURITUS	40/132 (30.3%)
SKIN PAPILLOMA	39/132 (29.5%)
HYPERKERATOSIS	37/132 (28%)
RASH MACULO-PAPULAR	27/132 (20.5%)
ACTINIC KERATOSIS	22/132 (16.7%)
DRY SKIN	21/132 (15.9%)
RASH PAPULAR	17/132 (12.9%)
KERATOSIS PILARIS	12/132 (9.1%)
ERYTHEMA	11/132 (8.3%)
PALMAR-PLANTAR	11/132 (8.3%)
ERYTHRODYSAESTHESIA SYNDROME ACNE	10/132 (7.6%)
DERMATITIS ACNEIFORM	9/132 (6.8%)
SKIN EXFOLIATION	8/132 (6.1%)
SKIN LESION	8/132 (6.1%)
SEBORRHOEIC KERATOSIS	19/132 (14.4%)
ACNE	10/132 (7.6%)

Limitations/Caveats

[Not Specified]

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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.