Clinical trial NCT01667419
Conditions: Melanoma
Sponsor: Hoffmann-La Roche
Start date: 2012-09-24; Completion date: 2018-07-13
Enrollment: 498 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This multicenter, randomized, double-blind, placebo-controlled study will evaluate the efficacy and safety of vemurafenib in participants with completely resected, cutaneous BRAF mutation-positive melanoma at high risk for recurrence. Participants will be enrolled in two separate cohorts: Cohort 1 will include participants with completely resected Stage IIC, IIIA (participants with one or more nodal metastasis greater than \[\>\] 1 millimeter \[mm\] in diameter), or IIIB cutaneous melanoma, as defined by the American Joint Committee on Cancer (AJCC) Classification, Version 7; Cohort 2 will include participants with Stage IIIC cutaneous melanoma, as defined by this classification scheme. Within each cohort, participants will be randomized (1:1 ratio) to receive vemurafenib or matching placebo over a 52-week period.

Detailed description:

Arms: arm 1: Participants with completely resected Stage IIC, IIIA, or IIIB cutaneous melanoma) received vemurafenib, 960 milligrams (mg) twice daily, in 28-day cycles, for up to 52 weeks arm 2: Participants with completely resected Stage IIC, IIIA, or IIIB cutaneous melanoma) received vemurafenib-matching placebo twice daily, in 28-day cycles, for up to 52 weeks arm 3: Participants with Stage IIIC cutaneous melanoma received vemurafenib, 960 mg twice daily, in 28-day cycles, for up to 52 weeks arm 4: Participants with Stage IIIC cutaneous melanoma received vemurafenib-matching placebo twice daily, in 28-day cycles, for up to 52 weeks
Interventions: intervention 1: Vemurafenib intervention 2: Placebo
Intervention descriptions: intervention 1: 4 tablets of vemurafenib 240 mg each (total 960 mg) were administered orally as per the schedule specified in the respective arm. intervention 2: Placebo matching to vemurafenib were administered orally as per the schedule specified in the respective arm.

Protocol documents:
SAP_002.pdf: 
Official Title: PHASE III, RANDOMIZED, DOUBLE BLIND, 
PLACEBO-CONTROLLED STUDY OF 
VEMURAFENIB (RO5185426) ADJUVANT 
THERAPY IN PATIENTS WITH SURGICALLY 
RESECTED, CUTANEOUS BRAF-MUTANT 
MELANOMA AT HIGH RISK FOR RECURRENCE 
NCT Number:    NCT01667419 
Document Dates: STATISTICAL ANALYSIS PLAN  
Version 4: 17 March 2017 


Vemurafenib—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan GO27826 
 
1 
STATISTICAL ANALYSIS PLAN 
TITLE: 
A PHASE III, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED STUDY OF VEMURAFENIB 
(RO5185426) ADJUVANT THERAPY IN PATIENTS WITH 
SURGICALLY RESECTED, CUTANEOUS BRAF-MUTANT 
MELANOMA AT HIGH RISK FOR RECURRENCE 
PROTOCOL NUMBER: 
GO27826  
STUDY DRUG: 
Vemurafenib (RO5185426) 
VERSION NUMBER: 
4 
IND NUMBER: 
73620 
EUDRACT NUMBER: 
2011-004011-24 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
PLAN PREPARED BY: 
 Ph.D. 
DATE FINAL: 
See electronic date stamp below. 
  
Name
Reason for Signing
Date and Time
(UTC)
17-Mar-2017 16:00:01
Company Signatory (Clinical)


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Statistical Analysis Plan GO27826 
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RATIONALE FOR AMENDMENT (VERSION 4) TO THE STATISTICAL 
ANALYSIS PLAN   
The Statistical Analysis Plan (SAP) has been amended to change the primary 
disease-free survival (DFS) analysis for Cohort 2. 
The revised plan is to perform the primary DFS analysis for Cohort 2 at 
approximately 105 events, compared with120 events specified in the SAP 
Version 3.  A total of 105 DFS events provides approximately 80% power to 
detect a hazard ratio (HR) of 0.58 for the vemurafenib arm versus the placebo 
arm at an overall 2-sided 0.05 significance level, or approximately 74% power to 
detect a HR of 0.6 as specified in the previous SAP Version 3.  This change now 
corresponds to an improvement in median DFS from 7.7 months in the placebo 
arm to 13.3 months in the vemurafenib arm.  No change will be made to the 
analysis plan for Cohort 1.  The type 1 error rate would be strictly controlled at 
the 0.05 level by the continued use of the hierarchical testing procedure as pre-
specified in the previous SAP Version 3.  
 Additional minor changes have been made to improve clarity and consistency. 


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TABLE OF CONTENTS 
1. 
BACKGROUND ............................................................................................ 5 
2. 
STUDY DESIGN ........................................................................................... 5 
2.1 
Outcome Measures ................................................................. 6 
2.1.1 
Primary Efficacy Outcome Measure ........................................ 6 
2.1.2 
Secondary Efficacy Outcome Measures .................................. 6 
2.1.3 
Exploratory Efficacy Outcome Measures ................................. 6 
2.1.4 
Pharmacokinetic Efficacy Outcome Measures ........................ 7 
2.1.5 
Safety Outcome Measures ...................................................... 7 
2.1.6 
Patient-Reported Outcome Measure ....................................... 7 
2.2 
Determination of Sample Size ................................................. 7 
2.3 
Sample Size and Analysis Timing ........................................... 7 
2.3.1 
Cohort 1 ................................................................................... 7 
2.3.2 
Cohort 2 ................................................................................... 8 
3. 
STUDY CONDUCT ....................................................................................... 9 
3.1 
Randomization Issues ............................................................. 9 
3.2 
Independent Review Facility .................................................. 10 
3.3 
Data Monitoring ..................................................................... 10 
4. 
STATISTICAL METHODS .......................................................................... 10 
4.1 
Analysis Populations ............................................................. 10 
4.1.1 
Intent-to-Treat Population ...................................................... 10 
4.1.2 
Safety Population .................................................................. 10 
4.1.3 
Pharmacokinetic-Evaluable Population ................................. 10 
4.2 
Analysis of Study Conduct ..................................................... 10 
4.3 
Analysis of Treatment Group Comparability .......................... 11 
4.4 
Efficacy Analysis .................................................................... 11 
4.4.1 
Primary Efficacy Endpoint ...................................................... 11 
4.4.2 
Secondary Efficacy Endpoints ............................................... 13 
4.4.2.1 
Distant Metastasis−Free Survival .......................................... 13 
4.4.2.2 
Overall Survival ..................................................................... 13 
4.4.2.3 
Patient-Reported Outcomes .................................................. 14 


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4.4.2.4 
Type I Error Control for the Secondary Efficacy 
Endpoints ............................................................................... 14 
4.4.3 
Subgroup Analyses ............................................................... 15 
4.5 
Pharmacokinetic and Pharmacodynamic 
Analyses ................................................................................ 16 
4.5.1 
Pharmacokinetic Analyses ..................................................... 16 
4.6 
Exploratory Analyses ............................................................. 16 
4.7 
Safety Analyses ..................................................................... 16 
4.7.1 
Exposure of Study Medication ............................................... 16 
4.7.2 
Adverse Events ..................................................................... 17 
4.7.3 
Deaths ................................................................................... 17 
4.7.4 
Laboratory Data ..................................................................... 18 
4.7.5 
Vital Signs .............................................................................. 18 
4.8 
Missing Data .......................................................................... 18 
4.9 
Interim Analyses .................................................................... 18 
4.9.1 
Efficacy .................................................................................. 18 
5.
REFERENCES ........................................................................................... 20
LIST OF TABLES 
Table 1 
Assumptions and Characteristics for Disease-Free Survival 
Analyses by Cohort ....................................................................... 9 
Table 2 
Assumptions and Characteristics for Overall Survival 
Analyses by Cohort ..................................................................... 19 
LIST OF APPENDICES 
Appendix 1 
European Organisation for Research and Treatment of 
Cancer 30-Item Quality of Life Questionnaire (Version 3) ........... 21 


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1. 
BACKGROUND 
The Study GO27826 was designed as a pivotal study to support the submission 
of a supplemental New Drug Application for the use of vemurafenib for the 
adjuvant treatment of patients with surgically resected, cutaneous malignant 
melanoma at high risk for recurrence.  This Statistical Analysis Plan (SAP) 
provides the planned analyses for Study GO27826.  For purposes of registration, 
the analyses outlined in this SAP will supersede those specified in the protocol. 
2. 
STUDY DESIGN 
Study GO27826 is a Phase III, international, multicenter, double-blind, 
randomized, placebo-controlled study in patients with completely resected, 
BRAFV600 mutation−positive melanoma, as detected by the cobas® BRAF V600 
Mutation Test, at high risk for recurrence. 
Approximately 475 patients will be enrolled into two separate cohorts:   
• 
Cohort 1 (approximately 300 patients) will include patients with completely 
resected Stage IIC, IIIA (patients with one or more nodal metastasis > 1 mm 
in diameter), or IIIB cutaneous melanoma, as defined by the American Joint 
Committee on Cancer Classification, Version 7 (Balch et al. 2009). 
• 
Cohort 2 (approximately 175 patients) will include patients with Stage IIIC 
cutaneous melanoma, as defined by this classification scheme.   
 
Eligible patients will be randomized (1:1 ratio) to receive placebo or vemurafenib 
over a 52-week period, with randomization stratified by pathologic stage (Stage 
IIC, Stage IIIA, Stage IIIB) and region (North America, Australia/New 
Zealand/South Africa/Latin America, rest of the world) in Cohort 1 and by region 
(North America, Australia/New Zealand/South Africa/Latin America, rest of the 
world) in Cohort 2. 
Within each cohort, patients will receive study treatment according to one of the 
following treatment arms: 
• 
Arm A:  placebo orally, twice daily (BID) for 52 weeks (thirteen 28-day cycles) 
• 
Arm B:  vemurafenib 960 mg orally, BID for 52 weeks (thirteen 28-day cycles) 
 
Randomization will occur within 90 days after definitive surgery (i.e., the last 
surgery required for the treatment or the diagnosis of melanoma), and study 
treatment will begin within 4 calendar days after randomization. 
Crossover to vemurafenib treatment will not be allowed for patients receiving 
placebo. 


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The final analysis of the primary endpoint of disease-free survival (DFS) will 
occur for each cohort after the targeted number of events for each cohort is 
reached (approximately 120 DFS events for Cohort 1 and 105 DFS events for 
Cohort 2). 
2.1 
OUTCOME MEASURES 
2.1.1 
Primary Efficacy Outcome Measure 
The primary outcome measure for this study is as follows: 
•
DFS will be defined as the time from randomization until the date of the first
local, regional, or distant melanoma recurrence, occurrence of new primary
melanoma, or death from any cause.  The DFS component of melanoma
recurrence will be assessed by the investigator.  The DFS component of an
occurrence of a new primary melanoma will be based upon the diagnosis
made by a Roche-designated central pathology laboratory.  See Protocol
Section 4.5.1.4 for histopathologic and imaging requirements for
documentation of recurrence.
2.1.2 
Secondary Efficacy Outcome Measures 
The secondary outcome measures for this study are as follows: 
•
Distant metastasis−free survival (DMFS) will be defined as the time from
randomization until the date of diagnosis of distant (i.e., non-locoregional)
metastases or death from any cause.
•
Overall survival (OS) will be defined as the time from randomization to the
date of death from any cause.
2.1.3 
Exploratory Efficacy Outcome Measures 
The exploratory outcome measures for this study are as follows: 
•
Retrospective identification of study patients whose tumors harbor non-E,
activating mutations of BRAF kinase at amino acid position 600
(e.g., BRAFV600K), with use of DNA sequencing methods as a means to
assess clinical outcomes in this patient subgroup
•
Levels of candidate tumor biomarkers in plasma and serum (e.g., circulating
mutant BRAF DNA) at different timepoints during the study compared with
baseline as a means to monitor for and predict melanoma recurrence or
occurrence of a new primary melanoma
•
Candidate tumor biomarkers at the protein, RNA, and DNA levels
(including RAS mutations) that may characterize the molecular phenotype of
tumors at melanoma recurrence or occurrence of a new primary melanoma
as well as predict development of resistance to adjuvant vemurafenib
treatment


  
 
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• 
Molecular characterization of squamous cell carcinoma (SCC; cutaneous 
[including keratoacanthoma/KA] and non-cutaneous) or other new primary 
neoplasms that may be observed in patients treated with vemurafenib 
 
2.1.4 
Pharmacokinetic Efficacy Outcome Measures 
The pharmacokinetic (PK) outcome measures for this study are as follows: 
• 
Plasma concentrations of vemurafenib at clinically relevant timepoints, 
including steady−state trough values as well as those associated with 
diagnosis of SCC, dose interruption, and/or reduction for toxicity, melanoma 
recurrence, and occurrence of a new primary melanoma 
 
2.1.5 
Safety Outcome Measures 
The safety outcome measures for this study are as follows: 
• 
Incidence, nature, and severity of adverse events, serious adverse events, 
and adverse events of special interest.  Severity will be graded according to 
National Cancer Institute Common Terminology Criteria for Adverse Events 
(NCI CTCAE), v4.0. 
• 
Changes from baseline in ECG findings and targeted clinical laboratory 
analytes during the course of study treatment 
 
2.1.6 
Patient-Reported Outcome Measure 
The patient-reported outcome (PRO) measure for this study is as follows: 
• 
To assess patient-reported symptoms, functional interference, and 
health−related quality of life in the vemurafenib and placebo treatment arms 
with use of European Organisation for Research and Treatment of Cancer 
30-item Quality of Life Questionnaire (EORTC QLQ-C30) 
 
2.2 
DETERMINATION OF SAMPLE SIZE 
The overall Type I error (α) for this study is 0.05 (two sided).  The primary 
objective of the protocol to assess efficacy as measured by DFS will be 
evaluated separately for each of the two cohorts.  The sample size determination 
was evaluated separately for each cohort.   
2.3 
SAMPLE SIZE AND ANALYSIS TIMING 
The final primary efficacy endpoint (DFS) analyses for the two cohorts will be 
conducted according to the procedure specified in Section 4.4.1. 
2.3.1 
Cohort 1 
The final analysis of the primary endpoint of DFS for Cohort 1 will take place 
when approximately 120 DFS events have occurred, on the basis of the following 
assumptions: 
• 
Two-sided, stratified log-rank test at the 0.05 significance level 


  
 
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• 
80% power 
• 
Median DFS for the control arm of 24 months and estimated median DFS in 
the vemurafenib treatment arm of 40 months (which corresponds to a hazard 
ratio [HR] of 0.60) 
• 
5% annual loss to follow-up for DFS 
• 
No interim analysis 
 
Assuming an accrual rate of 8 patients per month in Cohort 1 and a 17−month 
ramp-up period to reach steady-state enrollment, approximately 300 patients will 
be required to be enrolled in Cohort 1 during 43 months and followed for an 
additional 7 months in order to observe 120 DFS events. 
On the basis of the assumptions above, 120 DFS events are projected to occur 
in Cohort 1 approximately 50 months after the first patient is randomized in this 
study.  At that time, it is projected that median follow-up time will be 21 months in 
Cohort 1, and the minimum follow-up time (e.g., for the last patient randomized) 
is projected to be 7 months.  Also on the basis of the assumptions of 120 DFS 
events required and a target HR of 0.60, it is projected that an observed HR of 
0.70 or better in the DFS analysis will result in a statistically significant difference 
between treatment arms (i.e., HR of 0.70 is the minimally detectable difference 
for that analysis). 
A summary of the assumptions and characteristics of the DFS analysis for 
Cohort 1 is shown in Table 1. 
For Cohort 1, on the basis of the assumptions of a target HR of 0.60, 120 DFS 
events would provide 80% power to detect a 16% absolute increase in the 2-year 
DFS rate (50% vs. 66%, corresponding to a 40% risk reduction; i.e., HR of 0.60). 
2.3.2 
Cohort 2 
The final analysis of the primary endpoint of DFS for Cohort 2 will take place 
when approximately 105 DFS events have occurred, on the basis of the following 
assumptions: 
• 
Two-sided, stratified log-rank test at the 0.05 significance level 
• 
80% power 
• 
Median DFS for the control arm of 7.7 months and estimated median DFS in 
the vemurafenib treatment arm of 13.3 months (which corresponds to an HR 
of 0.58) 
• 
5% annual loss to follow-up for DFS 
• 
No interim analysis 
 


  
 
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Assuming an accrual rate of 5 patients per month in Cohort 2 and a 27−month 
ramp-up period to reach steady-state enrollment, approximately 175 patients will 
be required to be enrolled in Cohort 2 over 40 months in order to observe 
105 DFS events. 
A summary of the assumptions and characteristics of the DFS analysis for 
Cohort 2 is shown in Table 1. 
For Cohort 2, on the basis of the assumptions of a target HR of 0.58, 105 DFS 
events would provide 80% power to detect a 17% absolute increase in the 2-year 
DFS rate (12% vs. 29%, corresponding to a 42% risk reduction; i.e., HR of 0.58). 
Table 1 
Assumptions and Characteristics for Disease-Free Survival 
Analyses by Cohort 
 
Cohort 1  
Cohort 2  
Patients enrolled 
300 
175 
Hazard ratio targeted 
0.60 
0.58 
Target median (control) 
24 months 
7.7 months 
Target median (vemurafenib) 
40 months 
13.3 months 
Final DFS analysis  
 
 
Number of DFS events  
120  
105  
MDD hazard ratio a  
0.70 
0.68 
α level (two sided) 
0.05 
0.05 
Power  
80% 
80% 
DFS = disease-free survival; FPI = first patient in; MDD = minimum detectable difference. 
Note:  A 5% annual dropout rate is anticipated for DFS analyses. 
a Minimally detectable difference; the largest observed hazard ratio that is projected to be 
statistically significant. 
 
3. 
STUDY CONDUCT 
3.1 
RANDOMIZATION ISSUES 
After written informed consent has been obtained and eligibility has been 
established, each patient will be assigned an identification number and 
randomized to one of the two treatment arms with the use of an interactive voice 
or Web response system (IxRS).  As noted in Section 2, randomization will be 
stratified by pathologic stage (Stage IIC, Stage IIIA, Stage IIIB) and region (North 
America, Australia/New Zealand/South Africa/Latin America, rest of the world) in 
Cohort 1 and by region (North America, Australia/New Zealand/South Africa/Latin 
America, rest of the world) in Cohort 2.  A stratified, permuted, block 
randomization scheme will be used to obtain approximately a 1:1 allocation 
between the two treatment groups. 


  
 
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3.2 
INDEPENDENT REVIEW FACILITY 
An independent review facility will not be used for this study. 
3.3 
DATA MONITORING 
An independent Data Safety Monitoring Board (DSMB) will be employed to 
evaluate safety data from this study as specified in the DSMB Charter. 
4. 
STATISTICAL METHODS 
Descriptive summaries of continuous data for each cohort will include the mean, 
standard deviation, median, minimum, and maximum, and number of patients.  
Descriptive summaries of discrete data for each cohort will include the number of 
patients and incidence as a frequency and percentage. 
The baseline value of any variable will be defined as the last available value prior 
to the first administration of study treatment. 
4.1 
ANALYSIS POPULATIONS 
4.1.1 
Intent-to-Treat Population 
The intent-to-treat (ITT) population is defined as all randomized patients, whether 
or not study treatment was received.  The ITT population will be analyzed 
according to the treatment assigned at randomization. 
4.1.2 
Safety Population 
The safety population will include all patients who receive at least one dose of 
study treatment.  Patients who receive at least one dose of vemurafenib will be 
included in the vemurafenib safety population.  The safety population will be 
analyzed according to the patients’ safety group. 
4.1.3 
Pharmacokinetic-Evaluable Population 
The PK-evaluable population will include all patients who have received at least 
one dose of vemurafenib and have provided valid PK assessments.  The PK-
evaluable population will be analyzed according to the treatment received.  
The PK population at specific timepoints will vary, depending on the availability of 
results at confirmed dosing and PK assessment times. 
4.2 
ANALYSIS OF STUDY CONDUCT 
Enrollment, eligibility violations, and patient disposition will be summarized for 
randomized patients by treatment arm.  The summary of patient disposition will 
include whether treatment was completed or discontinued prematurely and the 
reason for premature treatment discontinuation.  Study treatment administration 
will be summarized by treatment arm for all treated patients. 


  
 
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4.3 
ANALYSIS OF TREATMENT GROUP COMPARABILITY 
Demographic variables, stratification factors, and other baseline characteristics 
will be summarized for the ITT population by cohorts. 
4.4 
EFFICACY ANALYSIS 
Unless otherwise specified, all efficacy analyses will be performed on the ITT 
population.  The primary and all secondary objectives of this study will be 
evaluated separately for each cohort. 
4.4.1 
Primary Efficacy Endpoint 
The primary endpoint, DFS, is defined as the time from randomization until the 
date of the first local, regional, or distant melanoma recurrence, occurrence of 
new primary melanoma, or death from any cause.  The DFS component of 
melanoma recurrence will be assessed by the investigator.  The DFS component 
of an occurrence of a new primary melanoma will be based upon the diagnosis 
made by a Roche-designated central pathology laboratory.  For patients without 
a DFS event at the time of data cutoff, data will be censored at the date of the 
last disease assessment.  For patients who are treated with any non−protocol 
anti-cancer therapy (defined as systemic therapy or radiation therapy) without a 
DFS event, the data will be censored at the date of the last disease assessment.  
For patients without a DFS event for whom no post-randomization disease 
assessment is available, the data will be censored on the randomization date. 
For patients whose recurrence has been proven histologically, the date of 
melanoma recurrence will be defined as the earliest date of the scan or clinical 
examination that prompted the biopsy.  For patients whose suspicious lesions 
were deemed not amenable to biopsy (see Protocol Section 4.5.1.4) or for 
patients who refuse a biopsy, the date of melanoma recurrence will be defined as 
the earliest date of the scan or clinical examination that would have prompted a 
biopsy.  For patients with an occurrence of a new primary melanoma, the date of 
the new primary melanoma will be defined as the earliest date of the clinical 
examination or scan that prompted the biopsy. 
The duration of DFS will be calculated as the earliest DFS event date or 
censoring date minus the randomization date plus 1 day, converted to months.  
The final analysis of the primary endpoint of DFS will take place when 
approximately 120 DFS events have occurred for Cohort 1 and approximately 
105 DFS events have occurred for Cohort 2 (see Section 2.3).  The final DFS 
analyses for both cohorts will be conducted at the same time by using the 
dataset from the same data cutoff date for both cohorts.  The primary efficacy 
analyses will be comparisons of the two treatment groups, using a two-sided, 


  
 
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stratified log-rank test for Cohort 1 and Cohort 2 separately.  The statistical 
significance of the two DFS tests is defined by the rule outlined below. 
The hierarchical testing procedure, whereby Cohort 2 is tested first, will be used 
to adjust for comparison of two treatment groups (vemurafenib vs. control) for the 
two cohorts, in order to maintain an overall Type I error rate of 0.05 (two sided) 
for the final analysis of the primary endpoint of DFS.  If the p-value for Cohort 2 is 
≤ 0.05, i.e., the vemurafenib treatment group is statistically significantly different 
from the control group in Cohort 2, then, Cohort 1 will be tested.  If the p-value for 
Cohort 1 is ≤ 0.05, then the vemurafenib treatment group is also statistically 
significantly different from the control group in Cohort 1.  That is: 
• 
Step 1: If p2 ≤ 0.05, then vemurafenib treatment group is statistically 
significantly different from the control group in Cohort 2.  Go to step 2. 
• 
Step 2: If p1 ≤ 0.05, then vemurafenib treatment group is also statistically 
significantly different from the control group in Cohort 1. 
 
p1 and p2 are the p-values of final DFS analyses in Cohort 1 and Cohort 2, 
respectively. 
Median DFS time will be estimated using the Kaplan−Meier method, and the 
two-sided 95% CI will be calculated using the method of Brookmeyer and 
Crowley (1982) for each cohort.  In addition, Kaplan-Meier methodology will be 
used to estimate landmark (e.g., 1-year, 2-year, and 3-year) DFS rates and the 
associated two-sided 95% CIs for each treatment arm, and the Kaplan-Meier 
curves will be provided.  The HR for DFS (recurrence, new primary melanoma, or 
death) and the associated two-sided 95% CI will be computed using a stratified 
Cox proportional hazards model. 
The stratification factors in the stratified analyses are the stratification factors 
used in randomization of patients in each cohort.  For Cohort 1, stratified 
analyses will incorporate two stratification factors:  pathologic stage (Stage IIC, 
Stage IIIA, and Stage IIIB) and region (North America, Australia/New 
Zealand/South Africa/Latin America, rest of the world).  For Cohort 2, stratified 
analyses will incorporate one stratification factor, region (North America, 
Australia/New Zealand/South Africa/Latin America, rest of the world).  
As a sensitivity analysis, an unstratified log-rank test will be performed and the 
unstratified HR will be provided for each cohort. 


  
 
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In addition, the following sensitivity analyses will be performed for DFS by study 
cohort: 
• 
Missing assessments for patients later diagnosed with a DFS event:  
For patients with a DFS event (other than death) who missed two or more 
scheduled assessments immediately prior to the event, the date of the event 
will be replaced by the date of the last disease assessment, plus 1 day.  For 
patients whose DFS event was death and who died after missing two or 
more scheduled assessments, data will be censored at the date of the last 
disease assessment. 
• 
Off-schedule assessments with a DFS event:  For patients with a DFS event 
at an off-schedule visit, the date of event will be replaced by the date of the 
next scheduled disease-assessment visit. 
 
As an exploratory analysis, DFS analyses based on the pooled data from both 
cohorts will also be performed for descriptive purposes to characterize the benefit 
of vemurafenib in the total study population.  This exploratory analysis will be 
stratified by region. 
4.4.2 
Secondary Efficacy Endpoints 
4.4.2.1 
Distant Metastasis−Free Survival 
DMFS is defined as the time from randomization until the date of diagnosis of 
distant (i.e., non-locoregional) metastasis or death from any cause.  For patients 
without a DMFS event at the time of data cutoff, the data will be censored at the 
date of the last disease assessment.  If no post-randomization disease 
assessment is available, the observation will be censored on the randomization 
date.  
DMFS will be analyzed at the time of the final DFS analysis in each cohort.  
The analysis methods to be employed for DMFS are the same as those 
described for the primary endpoint of DFS. 
4.4.2.2 
Overall Survival 
OS is defined as the time from randomization until the date of death from any 
cause.  For patients still alive at the time of analysis, the data will be censored at 
the date the patient was last known to be alive.  If no post-randomization disease 
assessment is available, the data will be censored on the randomization date.  
The duration of OS will be calculated as the date of death or censoring date 
minus the randomization date plus 1 day, converted to months. 
The study is not powered for OS, so adequate power statistical testing for this 
endpoint is not possible.  However, some standard OS estimates will be provided 
by using the same analysis methods as those described for the primary endpoint 
of DFS. 


  
 
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The final OS analysis for Cohorts 1 and 2 will be performed after the occurrence 
of approximately 107 and 118 deaths, respectively (projected to occur at 
approximately Month 72 in each cohort) or at Month 72, whichever occurs first.  
One interim analysis of OS is planned in each of the two cohorts at the time of 
the final DFS analysis for both cohorts (see Section 4.9). 
OS will be compared between the two treatment arms using a two−sided 
stratified log-rank test at an overall two-sided 0.05 significance level for Cohort 1 
and Cohort 2 separately.  The HR for death will be estimated using a stratified 
Cox model.  Two-sided 95% CIs for the HR will be provided. 
Stratified analyses will incorporate the same stratification factors for the analysis 
of DFS.  
Kaplan-Meier methodology will be used to estimate median OS and landmark 
(e.g., 1-year, 2-year, and 3-year) OS rates and the associated two-sided 95% 
CIs for each treatment arm, and the Kaplan-Meier curves will be provided. 
As a sensitivity analysis, an unstratified log-rank test will be performed and the 
unstratified HR will be provided. 
As an exploratory analysis, OS analyses on the basis of the pooled data from 
both cohorts will also be performed for descriptive purposes to characterize the 
benefit of vemurafenib in the total study population. 
4.4.2.3 
Patient-Reported Outcomes 
Quality of life (QoL), as measured by EORTC QLQ-C30, will be evaluated for 
patients with a baseline assessment and at least one post-baseline QLQ-C30 
assessment that generate a score.  Total QLQ-C30, each domain score 
(i.e., physical functioning, role functioning, emotional functioning, cognitive 
functioning, and social functioning), symptom scales, and their changes from 
baseline will be examined for each timepoint with use of descriptive statistics, 
including mean, median, standard deviation, and range. 
Compliance rates for patients who complete PRO assessments will be assessed 
over time and by treatment arm.   
See Appendix 1 for a description of the calculation of each domain score and 
the total QLQ-C30. 
4.4.2.4 
Type I Error Control for the Secondary Efficacy Endpoints 
The following procedure will be performed separately for each cohort, provided 
that the cohort is statistically significant in the primary DFS analysis (according to 
the rules described in Section 4.4.1). 


  
 
Vemurafenib—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan GO27826 
 
15 
To control the Type I error rate at the 0.05 level (two sided) for the secondary 
efficacy endpoint tests, a hierarchical testing approach will be employed to 
evaluate the statistical significance of the secondary endpoints of DMFS and OS.  
If the primary DFS analysis meets statistical significance in either cohort, DMFS 
and then OS will be evaluated for statistical significance at the 0.05 level (two 
sided) for that cohort. 
The secondary endpoint of DMFS will be compared between treatment arms 
using a two-sided stratified log-rank test at an overall two-sided 0.05 significance 
level for Cohorts 1 and 2 separately.  For each cohort, if the DFS comparison is 
positive in favor of vemurafenib, the comparison of DMFS between the placebo 
and vemurafenib arms will be tested at an overall two-sided 0.05 significance 
level for each cohort.  Gated on the successful testing of the comparison of the 
secondary endpoint, DMFS, in each cohort, the secondary endpoint of OS will be 
compared between treatment arms using a two-sided stratified log-rank test at an 
overall two-sided 0.05 significance level for Cohorts 1 and 2 separately.  The 
Lan-DeMets implementation (Lan and DeMets 1983) of the O’Brien-Fleming use 
function will be used to control the overall Type I error for the OS comparison in 
each cohort at a two-sided 0.05 significance level.  See Section 4.9.1 for details. 
4.4.3 
Subgroup Analyses 
The consistency of the treatment effect of vemurafenib on DFS, OS, and DMFS 
across subgroups defined by demographic and baseline characteristics and 
stratification factors will be examined within each cohort.  Because some 
subgroups may have small sample sizes, these analyses will be considered 
exploratory. 
The subgroups to be considered include, but are not limited to, the following: 
• 
Disease stage (Stage IIC, Stage IIIA, and Stage IIIB) for Cohort 1 
• 
Age (≤ 50 years, > 50 years) at randomization 
• 
Age (≤ 65 years, > 65 years) at randomization 
• 
Tumor ulceration (or mitosis ≥ 1/mm2 for T1 lesions) present or not present at 
randomization 
• 
Race (non-White, White) 
• 
Sex (female, male) 
• 
Region (North America, Australia/New Zealand/South Africa/Latin America, 
rest of the world) 
• 
Eastern Cooperative Oncology Group Performance Status at randomization (0 
or 1) 
• 
Newly diagnosed versus first metachronous recurrence 
• 
Lymph node types:  macroscopic, microscopic, and N3 at randomization 


  
 
Vemurafenib—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan GO27826 
16 
• 
BRAF mutation status such as V600E versus non-V600E at randomization 
 
For DFS, OS, and DMFS, the Kaplan-Meier estimated median time will be 
summarized by treatment arm for each of the subgroups defined above along 
with a HR (treatment:control) estimated by unstratified Cox regression that is 
displayed as a Forest plot (Lewis and Clarke 2001). 
4.5 
PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES 
4.5.1 
Pharmacokinetic Analyses 
Descriptive statistics will be used to perform the analysis of plasma 
concentrations of vemurafenib at clinically relevant timepoints.  These timepoints 
will include all available Cycle 1 data and pre-dose values from all available 
cycles.  In addition, summary statistics may be provided for PK data from 
patients following the diagnosis of melanoma recurrence or occurrence of a new 
primary melanoma during study treatment, at the time of diagnosis of SCC 
(cutaneous [including KA] and non-cutaneous), and at the occurrence of dose-
limiting toxicity and concomitant decision to reduce the dose or interrupt or 
discontinue treatment.  The descriptive statistics will include arithmetic means, 
standard deviations, geometric means, coefficients of variation, medians, and 
ranges. 
Plasma concentrations that are below the limit of quantification for the assay will 
be replaced with zero for descriptive statistics.  Missing PK data points will not be 
replaced.  Pre-dose values that are determined to be measured post-dose will 
not be included in the analysis. 
4.6 
EXPLORATORY ANALYSES 
Descriptive statistics will be provided for the exploratory biomarker analyses.  
4.7 
SAFETY ANALYSES 
All safety analyses will be performed on the safety population, unless specified 
otherwise.  All safety data will be summarized using descriptive statistics. 
4.7.1 
Exposure of Study Medication 
Exposure to study treatment will be summarized, with the use of descriptive 
statistics, on the following: 
• 
Length of time on treatment 
• 
Number of days dosed 
• 
Cumulative dose 
• 
Dose intensity (%) (defined as total amount of study treatment received 
relative to total amount of study treatment expected between the first and last 
dose) 


  
 
Vemurafenib—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan GO27826 
17 
 
Dose modification (dose reduction or interruption) will be summarized as follows: 
• 
n (%) of patients with any dose modification (reduction or interruption) 
 
Dose reduction will be summarized as follows: 
• 
n (%) of patients with at least one dose reduction 
• 
Number of dose reductions per patient (mean, median, and range) 
• 
Final dose level after reduction 
• 
Reasons for change in dose  
 
Dose interruptions will be summarized as follows: 
• 
n (%) of patients with at least one dose interruption 
• 
Number of interruptions per patient (mean, median, and range) 
 
4.7.2 
Adverse Events 
Safety analyses will include all patients who receive any amount of study 
treatment (vemurafenib or placebo).  Patients who receive any amount of 
vemurafenib will be summarized in the vemurafenib treatment arm.  Safety will 
be assessed through summaries of all adverse events, including serious adverse 
events, adverse events of special interest, and adverse events leading to 
discontinuation of vemurafenib or placebo.  All verbatim descriptions of 
treatment−emergent adverse events will be mapped to MedDRA thesaurus terms 
and graded according to the NCI CTCAE v4.0. 
The following safety parameters will be summarized by treatment arm for 
patients in Cohort 1 and Cohort 2 separately as well as for all study patients 
pooled: 
• 
All adverse events 
• 
All adverse events leading to discontinuation of study treatment 
• 
All serious adverse events 
• 
Adverse events of interest (e.g., cutaneous SCC [including KA], QTc 
prolongation) 
• 
NCI CTCAE Grade 3 or greater adverse events 
• 
Adverse events resulting in death 
• 
All deaths 
 
4.7.3 
Deaths 
The following summaries of patient deaths will be provided: 
• 
All deaths by primary cause of death 
• 
Incidence and cause of deaths within 30 days of the start of treatment 


  
 
Vemurafenib—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan GO27826 
18 
4.7.4 
Laboratory Data 
Laboratory toxicities will be defined on the basis of local laboratory normal 
ranges and the NCI CTCAE v4.0.  Laboratory test results and normal ranges will 
be converted from local lab to Standard International units for analysis purposes.  
For each laboratory parameter, the toxicity grade at baseline and the worst 
toxicity grade during the treatment period will be summarized by treatment arm. 
4.7.5 
Vital Signs 
No analyses of vital signs or physical-examination findings are planned. 
4.8 
MISSING DATA 
For DFS, data from patients who are lost to follow-up without DFS event will be 
censored at the date of the last disease assessment.  If no post-randomization 
disease assessment is available, the data will be censored on the randomization 
date.  
For DMFS, data from patients who are lost to follow-up without documented 
distant melanoma recurrence will censored at the date of the last disease 
assessment.  The data of the patients without post-randomization disease 
assessments will be censored on date of randomization. 
For OS, data from patients who are lost to follow-up will be analyzed as censored 
observations on the date the patient was last known to be alive.  The data of 
patients without post-randomization disease assessments will be censored on 
date of randomization. 
4.9 
INTERIM ANALYSES 
An independent DSMB will monitor the safety of patients and will meet 
periodically to review summaries of selected safety data prepared by the 
independent Data Coordinating Center.  The detailed interim safety analysis plan 
and the role and responsibilities of the DSMB members are described in the 
interim analysis plan and separate charter for the DSMB, respectively. 
Interim analyses of OS will be performed by the Sponsor (see Section 4.4.2.2). 
4.9.1 
Efficacy 
No interim analyses of the primary endpoint, DFS, will be performed. 
Two OS analyses (one interim analysis and one final analysis) are planned for 
each cohort.  The OS interim analysis will be performed at the time of the final 
DFS analysis for both cohorts.  The final OS analysis for Cohorts 1 and 2 will be 
performed after the occurrence of approximately 107 and 118 deaths, 
respectively (projected to occur at approximately Month 72 in each cohort) or at 
Month 72, whichever occurs first.  


  
 
Vemurafenib—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan GO27826 
19 
The Lan-DeMets implementation (Lan and Demets 1983) of the O’Brien-Fleming 
use function will be used to control the overall Type I error for the OS comparison 
in each cohort at a two-sided 0.05 significance level.  Table 2 summarizes the 
assumptions and characteristics of the analyses for OS. 
Table 2 
Assumptions and Characteristics for Overall Survival Analyses 
by Cohort 
 
Cohort 1 
n = 300 
Cohort 2 
n = 175 
HR targeted 
0.70 
0.70 
Targeted median (control) 
61 months 
24.2 months 
Targeted median (vemurafenib) 
87.1 months 
34.6 months 
Interim OS 
(to be performed at time of final DFS analysis) 
 
 
Projected number of events (% of final events) 
64 (60%) 
59 (50%) 
Final OS 
 
 
Number of events (% of final events) 
107 (100%) 
118 (100%) 
Estimated cutoff date a 
72 months after FPI 
72 months after FPI 
α level (two sided) 
0.05 
0.05 
Power 
0.45 
0.49 
DFS = disease-free survival; FPI = first patient in; HR = hazard ratio; OS = overall survival. 
Note:  1% annual dropout rate is anticipated for OS analyses. 
a Estimated data cutoff time from study enrollment date.   
 


Vemurafenib—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan GO27826 
20 
5. 
REFERENCES 
Balch CM, Gershenwald JE, Soong SJ, et al. Final version of 2009 AJCC 
melanoma staging and classification. J Clin Oncol 2009;27:6199–206. 
Brookmeyer R, Crowley JJ. A confidence interval for median survival time. 
Biometrics 1982;38:29−41. 
Lan KKG and DeMets DL. Discrete sequential boundaries for clinical trials. 
Biometrika 1983;70;659–63. 
Lewis S, Clarke M. Forest plots: trying to see the wood and the trees. BMJ 
2001;322:1479–80. 


Vemurafenib—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan GO27826 
21 
Appendix 1 
European Organisation for Research and Treatment of Cancer 30-Item 
Quality of Life Questionnaire (Version 3) 
EORTC QLQ-C30 (version 3) 
We are interested in some things about you and your health.  Please answer all of the questions 
yourself by circling the number that best applies to you.  There are no "right" or "wrong" answers. 
The information that you provide will remain strictly confidential. 
Not at 
A 
Quite 
Very 
All 
Little 
a Bit 
Much 
1.
Do you have any trouble doing strenuous activities,
like carrying a heavy shopping bag or a suitcase?
1 
2 
3 
4 
2.
Do you have any trouble taking a long walk?
1 
2 
3 
4 
3.
Do you have any trouble taking a short walk outside of the house? 1
2 
3 
4 
4.
Do you need to stay in bed or a chair during the day?
1 
2 
3 
4 
5.
Do you need help with eating, dressing, washing
yourself or using the toilet?
1 
2 
3 
4 
During the past week: 
Not at 
A 
Quite 
Very 
All 
Little 
a Bit 
Much 
6.
Were you limited in doing either your work or other daily activities? 1
2 
3 
4 
7.
Were you limited in pursuing your hobbies or other
leisure time activities?
1 
2 
3 
4 
8.
Were you short of breath?
1 
2 
3 
4 
9.
Have you had pain?
1 
2 
3 
4 
10.
Did you need to rest?
1 
2 
3 
4 
11.
Have you had trouble sleeping?
1 
2 
3 
4 
12.
Have you felt weak?
1 
2 
3 
4 
13.
Have you lacked appetite?
1 
2 
3 
4 
14.
Have you felt nauseated?
1 
2 
3 
4 
15.
Have you vomited?
1 
2 
3 
4 
16.
Have you been constipated?
1 
2 
3 
4 
Please go on to the next page 


Vemurafenib—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan GO27826 
22 
Appendix 1 
European Organisation for Research and Treatment of Cancer 30-Item 
Quality of Life Questionnaire (Version 3) (cont.) 
During the past week: 
Not at 
A 
Quite 
Very 
All 
Little 
a Bit 
Much 
17.
Have you had diarrhea?
1 
2 
3 
4 
18.
Were you tired?
1 
2 
3 
4 
19.
Did pain interfere with your daily activities?
1 
2 
3 
4 
20.
Have you had difficulty in concentrating on things,
like reading a newspaper or watching television?
1 
2 
3 
4 
21.
Did you feel tense?
1 
2 
3 
4 
22.
Did you worry?
1 
2 
3 
4 
23.
Did you feel irritable?
1 
2 
3 
4 
24.
Did you feel depressed?
1 
2 
3 
4 
25.
Have you had difficulty remembering things?
1 
2 
3 
4 
26.
Has your physical condition or medical treatment
interfered with your family life?
1 
2 
3 
4 
27.
Has your physical condition or medical treatment
interfered with your social activities?
1 
2 
3 
4 
28.
Has your physical condition or medical treatment
caused you financial difficulties?
1 
2 
3 
4 
For the following questions please circle the number between 1 and 7 that 
best applies to you 
29.
How would you rate your overall health during the past week?
1 
2 
3 
4 
5 
6 
7 
Very poor 
Excellent 
30.
How would you rate your overall quality of life during the past week?
1 
2 
3 
4 
5 
6 
7 
Very poor 
Excellent 

Prot_001.pdf: 
Official Title: A PHASE III, RANDOMIZED, DOUBLE-BLIND, PLACEBO-
CONTROLLED STUDY OF VEMURAFENIB (RO5185426) 
ADJUVANT THERAPY IN PATIENTS WITH SURGICALLY 
RESECTED, CUTANEOUS BRAF-MUTANT MELANOMA AT 
HIGH RISK FOR RECURRENCE 
NCT Number: NCT01667419 
Document Date: Protocol Version 10: 24 Oct 17 


PROTOCOL AMENDMENT APPROVAL 
 
CONFIDENTIAL 
The information contained in this document, especially any unpublished data, is the property of 
F. Hoffmann-La Roche Ltd (or under its control) and therefore is provided to you in confidence as an 
investigator, potential investigator, or consultant, for review by you, your staff, and an applicable Ethics 
Committee or Institutional Review Board.  It is understood that this information will not be disclosed to 
others without written authorization from Roche except to the extent necessary to obtain informed 
consent from persons to whom the drug may be administered. 
 
 
Vemurafenib—F. Hoffmann-La Roche Ltd 
Protocol GO27826, Version 10  
PROTOCOL 
TITLE: 
A PHASE III, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED STUDY OF VEMURAFENIB 
(RO5185426) ADJUVANT THERAPY IN PATIENTS WITH 
SURGICALLY RESECTED, CUTANEOUS BRAF-
MUTANT MELANOMA AT HIGH RISK 
FOR RECURRENCE 
PROTOCOL NUMBER: 
GO27826 
VERSION NUMBER: 
10 
EUDRACT NUMBER: 
2011-004011-24 
IND NUMBER: 
73620 
TEST PRODUCT: 
Vemurafenib (RO5185426) 
MEDICAL MONITOR: 
, M.D. 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
DATE FINAL: 
Version 1:  24 February 2012 
DATES AMENDED: 
Version 2:  23 April 2012 
Version 3:  27 June 2012 
Version 4:  25 March 2013 
Version 5:  28 August 2013 
Version 6:  20 December 2013 
Version 7:  18 April 2014 
Version 8:  14 April 2015 
Version 9:  14 March 2017 
Version 10:  See electronic date stamp below. 
 
24-Oct-2017 19:11:10
Title
Approver's Name
Company Signatory
Date and Time (UTC)


Vemurafenib—F. Hoffmann-La Roche Ltd 
Protocol GO27826, Version 10 
2 
PROTOCOL AMENDMENT, VERSION 10: 
RATIONALE 
Protocol GO27826 has been amended as a result of the primary analysis of efficacy and 
safety (data cutoff 17 April 2017) and an analysis of secondary malignancies (data cutoff 
3 July 2017; approximately 94 weeks after the last patient started study treatment).  The 
study did not meet its primary endpoint.  A statistically meaningful disease-free survival 
benefit for vemurafenib treatment was not demonstrated in Cohort 2, as required by 
hierarchical testing defined in the Statistical Analysis Plan.  Safety analysis showed that 
patients treated in this study had a safety profile consistent with that of patients treated 
with vemurafenib for unresectable or metastatic melanoma with BRAFV600 mutation, an 
approved indication.  The analysis of secondary malignancies demonstrated that overall 
incidences of cutaneous squamous cell carcinoma (including keratoacanthoma) among 
the vemurafenib-treated patients in this study was similar to the incidence reported in 
vemurafenib-treated patients with unresectable or metastatic melanoma with BRAFV600 
mutation across studies: approximately 20%.  
Changes to the protocol are summarized below: 
•
The end of study definition has been refined (see Sections 3.2, 6.4, 6.9, and 
Appendix 1), the length of patient follow-up has been reduced (see Sections 3.1, 
3.2, 4.4.2, 4.5, 4.6, 5.1, 5.3, 5.4, 5.5, and Appendix 1), and in patients who had 
polyp(s) found at the 3-month post-treatment colonoscopy, a further colonoscopy 
after an additional 3 years is not required (see Sections 4.5, 5.1, and Appendix 1).  
The last patient in the treatment phase took their last dose of study medication on
14 September 2016.  The reduction in the length of follow-up and earlier closure of 
the study is based on the following considerations: 
The primary endpoint was not met; therefore, long-term overall survival data are 
no longer required, as registration plans are no longer being pursued. 
No new safety signals were identified in the primary analysis; therefore, there is 
no need for additional safety monitoring. 
An extensive safety database exists for vemurafenib, with more than 6,200 
patients having been treated in company-sponsored clinical trials and a 
cumulative market exposure to vemurafenib of more than 45,016 patients. 
•
The reporting of the term “sudden death” has been updated to also require the
presumed cause of death (Section 5.3.5.7).
•
Event reporting for hospitalization has been clarified (Section 5.3.5.9).
Additional minor changes have been made to improve clarity and consistency. 
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol. 


Vemurafenib—F. Hoffmann-La Roche Ltd 
Protocol GO27826, Version 10 
3 
PROTOCOL AMENDMENT, VERSION 10: 
SUMMARY OF CHANGES 
 
PROTOCOL SYNOPSIS 
The protocol synopsis has been updated to reflect the changes to the protocol, where 
applicable. 
SECTION 3.1:  DESCRIPTION OF STUDY 
During Years 3, 4, and 5 of the study, physical examination will be performed every 
13 ± 2 weeks, and the aforementioned imaging studies will be performed every 26 ± 4 
weeks until recurrence of melanoma or an occurrence of a new primary melanoma or for 
5 years after Cycle 1, Day 1until end of study treatment (see Section 3.2), whichever 
occurs earlier.   
In addition, all patients will undergo contrast-enhanced MRI of the brain (or CT if MRI is 
generally not available or is contraindicated) every 52 ± 4 weeks until recurrence of 
melanoma, occurrence of a new primary melanoma, or for 5 years after Cycle 1, Day 
1until end of study treatment (see Section 3.2), whichever occurs earlier.   
SECTION 3.2:  END OF STUDY 
All patients will be followed for melanoma recurrence or occurrence of new primary 
melanoma and overall survival for at least 2 years after Cycle 1, Day 1 of study 
treatment. Patients may be followed for melanoma recurrence or occurrence of new 
primary melanoma for up to 5 years and OS for up to 6 years after Cycle 1, Day 1 of 
study treatment.  Patients who exhibit recurrence of melanoma or a new primary 
melanoma prior to completion of Year 5 ofduring the study will be followed for OS.  No 
study related observations (including survival status) are planned after the completion of 
Year 6 of follow up. 
Data cutoff for The end of the final, prospectively study is defined OS analysis is 
projectedas the date of the last patient, last visit, which is expected to occur at 
approximately 72 6 months after the firstlast patient is enrolled (initiation of enrollment, 
Q3 2012; final OS cutoff, Q4 2018) (see Section 6.4).has been followed for 2 years after 
Cycle 1, Day 1 of the study. 
SECTION 4.4.2:  Prohibited Therapy 
Follow-up for efficacy, exploratory outcomes, and new primary malignancies will 
continue until melanoma recurrence or an occurrence of a new primary melanoma for up 
to 5 years after Cycle 1, Day 1until end of study (see Section 3.2) or loss to follow-up, 
withdrawal of consent, or death (whichever occurs first).  Patients will be followed for 
survival for up to 6 years after Cycle 1, Day 1.until end of study (see Section 3.2). 


Vemurafenib—F. Hoffmann-La Roche Ltd 
Protocol GO27826, Version 10 
4 
SECTION 4.5.1.3:  Physical Examinations 
During post-treatment follow-up, physical examinations will occur every 13 ± 2 weeks 
until recurrence of melanoma, occurrence of a new primary melanoma, or for 5 years 
after Cycle 1, Day 1until end of study treatment (see Section 3.2), whichever occurs 
earlier. 
SECTION 4.5.2.2:  Assessments during Study 
The following assessments will be done during the study: 
[…]  
• 
Physical examinations:  Cycle 1 (Day 15 ± 3 days), Cycle 2 (Days 1 and 15, each 
± 3 days), Day 1 (± 3 days) of every subsequent 4-week cycle, and at the 
end-of-treatment visit.  Thereafter, physical examinations done by the investigator 
will be obtained every 13 ± 2 weeks from the last dose of study drug until recurrence 
of melanoma, occurrence of a new primary melanoma, or for 5 years after Cycle 1, 
Day 1until end of study treatment,(see Section 3.2), whichever occurs earlier.  
Height will be obtained at screening only. 
• 
All patients will have a colonoscopy to the cecum, with adequate bowel preparation, 
by a gastroenterologist or his or her designee who is experienced in the 
colonoscopic diagnosis of colorectal polyps and colorectal cancer within 3 months of 
discontinuation of study drug.  Patients who have polyp(s) found at the colonoscopy 
will need a follow up colonoscopy performed after an additional 3 years ± 3 months.  
All polyps found at any of the colonoscopies will need to be adequately resected. 
[…] 
• 
Imaging studies (surveillance for melanoma recurrence):  Contrast-enhanced CT or 
MRI of the chest, abdomen, and pelvis every 13 ± 2 weeks until Week 104 and every 
26 ± 4 weeks thereafter until recurrence of melanoma, occurrence of a new primary 
melanoma, or for 5 years after Cycle 1, Day 1until end of study treatment,(see 
Section 3.2), whichever occurs earlier.  In addition, all patients will undergo contrast-
enhanced MRI of the brain (or CT if MRI is not available or is contraindicated) every 
52 ± 4 weeks until recurrence of melanoma, occurrence of a new primary melanoma, 
or for 5 years after Cycle 1, Day 1,until end of study (see Section 3.2), whichever 
occurs earlier.  Patients who have had a DFS event do not need additional scans or 
physical exams for melanoma recurrence surveillance.  However, these patients 
must still have a chest CT or MRI for SCC surveillance at 13 ± 2 weeks and 26 ± 2 
weeks after last dose of study drug. 
[…] 
• 
Serum and plasma samples for exploratory biomarker assessments:  Cycle 1 
(Day 15 ± 3 days), Cycle 2 (Day 1 ± 3 days), Cycle 3 (Day 1 ± 3 days).  Serum and 
plasma samples should also be collected at the end-of-treatment visit and every 
52 ± 2 weeks after last dose of study drug until the recurrence of melanoma, 
occurrence of a new primary melanoma, or for 5 years after Cycle 1, Day 1until end 
of study treatment,(see Section 3.2), whichever occurs earlier. 
[…] 


Vemurafenib—F. Hoffmann-La Roche Ltd 
Protocol GO27826, Version 10 
5 
•
PROs will be assessed at Cycle 1 (Day 15 ± 3 days), Cycle 2 (Days 1 and 15, each
± 3 days), Day 1 (± 3 days) of every subsequent 4-week cycle, at the
end-of-treatment visit, and at each scheduled and unscheduled visit during the
follow-up period, including the early termination visit.  In post-treatment follow-up,
the EORTC QLQ-C30 questionnaire will be completed every 13 ± 2 weeks from last
dose of study drug until recurrence of melanoma, occurrence of a new primary
melanoma, or until 5 years after Cycle 1, Day 1,end of study (see Section 3.2),
whichever occurs first.
SECTION 4.5.2.4:  Post-Treatment Follow-Up Assessments 
Patients who complete or discontinue study treatment without a recurrence or an 
occurrence of a new primary melanoma will continue to be followed with regular physical 
examinations (every 13 ± 2 weeks) and imaging studies for a maximum of 5 years from 
Cycle 1, Day 1 or until a melanoma recurrence or an occurrence of a new primary 
melanoma or until end of study (see Section 3.2), whichever occurs first.  All patients 
will be followed for the occurrence of new primary malignancies, regardless of 
melanoma recurrence or occurrence of a new primary melanoma, for 5 years from 
Cycle 1, Day 1.until end of study (see Section 3.2). 
SECTION 4.5.2.7:  Survival and New Primary Malignancy Follow-Up 
Assessments 
Survival follow-up information will be collected via telephone calls and/or clinic visits 
every 13 ± 2 weeks until death, loss to follow-up, or study termination by Roche or for a 
maximumuntil end of 6 years from Cycle 1, Day 1.study (see Section 3.2).  Patients will 
be followed for new primary malignancies for up to 5 years from Cycle 1, Day 1.until 
end of study (see Section 3.2).   
SECTION 4.6.1.2:  Withdrawal from Study 
Patients who withdraw their consent to be followed for the primary study endpoint (DFS) 
will be asked to continue follow-up for OS until a maximumof 6 years from Cycle 1, 
Day 1, end of study (see Section 3.2), as well as for new primary malignancies for up to 
5 years from Cycle 1, Day 1.until end of study (see Section 3.2).   
SECTION 5.1.2.3.4:  Colorectal Polyps 
All patients will be required to undergo a post-treatment colonoscopy within 3 months of 
discontinuation of study drug.  Patients who have polyp(s) found at the post-treatment 
colonoscopy will need a follow-up colonoscopy performed after an additional 
3 years ± 3 months. 
SECTION 5.1.2.3.5:  New Primary Cancers 
All new primary malignancies will be reported for up to 5 years after Cycle 1, Day 1,until 
end of study (see Section 3.2), whether or not a patient has exhibited recurrence of 
melanoma in the study. 


Vemurafenib—F. Hoffmann-La Roche Ltd 
Protocol GO27826, Version 10 
6 
SECTION 5.3.1:  Adverse Event Reporting Period 
After this period, investigators should report any deaths, serious adverse events, or 
other adverse events of concern that are believed to be related to prior treatment with 
study drug (see Section 5.6).  In addition, all new primary malignancies will be reported 
for up to 5 years after Cycle 1, Day 1,until end of study (see Section 3.2), whether or not 
a patient has exhibited recurrence of melanoma while in the study. 
SECTION 5.3.5.7:  Deaths 
The term “sudden death” should only be used for the occurrence of an abrupt and 
unexpected death due to presumed cardiac causes in a patient with or without 
preexisting heart disease within 1 hour of the onset of acute symptoms or, in the case of 
an unwitnessed death, within 24 hours after the patient was last seen alive and stable.  If 
the cause of death is unknown and cannot be ascertained at the time of reporting, 
“unexplained death” should be recorded on the Adverse Event eCRF.  If the cause of 
death later becomes available (e.g., after autopsy), “unexplained death” should be 
replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death"). 
SECTION 5.3.5.9:  Hospitalization or Prolonged Hospitalization 
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event:The following hospitalization 
scenarios are not considered to be serious adverse events: 
• 
Hospitalization for respite care 
• 
Planned hospitalization required by the protocol (e.g., complete regional 
lymphadenectomy)  
• 
Hospitalization for a preexisting condition, provided that all of the following criteria 
are met: 
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected normal 
progression of the disease. 
The patient has not suffered an adverse event. 
• 
Hospitalization due solely to recurrence/progression of the underlying melanoma 
 
An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead: 
• 
Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours 
 
SECTION 5.4.3.1:  Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant within the 5 years starting from Cycle 1, Day 
1.until end of study (see Section 3.2).   


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SECTION 5.4.3.2:  Pregnancies in Female Partners of Male Patients 
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant within the 5 years until end of 
study (see Section 3.2) starting from Cycle 1, Day 1.   
SECTION 5.5.1:  New Primary Cancers 
As noted in Section 5.1.2.3.5, all new primary cancers will be reported for up to 5 years 
after Cycle 1, Day 1until end of study, whether or not a patient has experienced 
melanoma recurrence or an occurrence of a new primary melanoma. 
SECTION 6.4.2.2:  Overall Survival 
The final OS analysis for Cohorts 1 and 2 will be performed afterat the occurrenceend of 
approximately 107 and 118 deaths, respectively (projected to occur at approximately 
Month 72 in each cohort) or at Month 72, whichever occurs first.  Additional details for 
interim analyses of OS are provided in Section 6.9 (Interim Analysesstudy (see 
Section 3.2). 
SECTION 6.9:  INTERIM ANALYSES 
The final OS analysis for Cohorts 1 and 2 (see Table 5) will be performed afterat the 
occurrenceend of approximately 107 and 118 deaths, respectively (projected to occur at 
approximately Month 72 in each cohort) or at Month 72, whichever occurs firststudy (see 
Section 3.2). 


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TABLE 5:  Assumptions and Characteristics for Overall Survival Analyses 
by Cohort 
 
Cohort 1 
n = 300 
Cohort 2 
n = 175 
HR targeted 
0.70 
0.70 
Targeted median (control) 
61 months 
24.2 months 
Targeted median 
(vemurafenib) 
87.1 months 
34.6 months 
Interim OS (to be performed at 
time of final DFS analysis)  
 
 
Projected number of events 
(% of final events) 
64 (60%) 
59 (50%) 
Final OS  
 
 
Number of events  
(% of final events) 
107 (100%) 
118 (100%) 
Estimated cutoff date a 
7230 months after 
FPILPI 
7230 months after FPILPI 
Alpha level (two sided) 
0.05 
0.05 
DFS = disease-free survival; FPI 
 first patient in; HR = hazard ratio; LPI = last patient in; 
MDD = minimum detectable difference; OS = overall survival. 
Note:  1% annual dropout rate is anticipated for OS analyses. 
a Estimated data cutoff time from study enrollment date. 
 
SECTION 9.4:  PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS 
For more information, see the Roche Global Policy on Sharing of Clinical Trials Data at 
the following Web site: 
http://www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.
pdf 
http://www.rochetrials.com/pdf/RocheGlobalDataSharingPolicy.pdf 
APPENDIX 1:  Schedule of Assessments 
Appendix 1 has been updated to reflect the changes to the protocol. 
 
 


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TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 16 
PROTOCOL SYNOPSIS .................................................................................... 17 
1. 
BACKGROUND .......................................................................................... 29 
1.1 
Background on Melanoma ..................................................... 29 
1.2 
Background on Vemurafenib ................................................. 32 
1.2.1 
Role of BRAF Kinase in Melanoma ....................................... 32 
1.2.2 
Vemurafenib BRAF Inhibitor .................................................. 32 
1.2.3 
Clinical Pharmacokinetics of Vemurafenib ............................. 32 
1.2.4 
Efficacy of Vemurafenib in Patients with 
BRAFV600 Mutation−Positive Metastatic 
Melanoma .............................................................................. 34 
1.2.5 
Safety of Vemurafenib ........................................................... 35 
1.3 
Study Rationale and Benefit-Risk Assessment ...................... 41 
2. 
OBJECTIVES .............................................................................................. 41 
2.1 
Primary Objective .................................................................. 41 
2.2 
Secondary Objectives ............................................................ 42 
2.3 
Exploratory Objectives ........................................................... 42 
3. 
STUDY DESIGN ......................................................................................... 42 
3.1 
Description of Study .............................................................. 42 
3.1.1 
Independent Review Committee ............................................ 45 
3.1.2 
Data Safety Monitoring Board ................................................ 45 
3.2 
End of Study .......................................................................... 45 
3.3 
Rationale for Study Design .................................................... 45 
3.3.1 
Rationale for Test Product Dosage ........................................ 45 
3.3.2 
Rationale for Patient Population ............................................ 46 
3.3.3 
Rationale for Control Group ................................................... 46 
3.3.4 
Rationale for Biomarker Assessments ................................... 47 
3.3.4.1 
Biomarkers Associated with Recurrence of 
Melanoma or Occurrence of New Primary 
Melanomas ............................................................................ 47 
3.3.4.2 
Cutaneous Squamous Cell Carcinoma or Other 
New Primary Neoplasms ....................................................... 47 


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3.3.4.3 
Disease Monitoring and Prediction of Early 
Relapse ................................................................................. 48 
3.4 
Outcome Measures ............................................................... 48 
3.4.1 
Efficacy Outcome Measures .................................................. 48 
3.4.1.1 
Primary Efficacy Outcome Measure ...................................... 48 
3.4.1.2 
Secondary Efficacy Outcome Measures ................................ 48 
3.4.2 
Safety Outcome Measures .................................................... 48 
3.4.3 
Pharmacokinetic Outcome Measures .................................... 49 
3.4.4 
Patient-Reported Outcome Measure ..................................... 49 
3.4.5 
Exploratory Outcome Measures ............................................ 49 
3.5 
Minimization of Bias ............................................................... 49 
4. 
MATERIALS AND METHODS .................................................................... 50 
4.1 
Patients .................................................................................. 50 
4.1.1 
Inclusion Criteria .................................................................... 50 
4.1.2 
Exclusion Criteria ................................................................... 52 
4.2 
Method of Treatment Assignment and Blinding ..................... 54 
4.3 
Study Treatment .................................................................... 55 
4.3.1 
Formulation, Packaging, and Handling .................................. 55 
4.3.1.1 
Active Study Drug (Vemurafenib) and Placebo ..................... 56 
4.3.2 
Dosage, Administration, and Compliance .............................. 56 
4.3.2.1 
Study Drug (Vemurafenib/Placebo) ....................................... 56 
4.3.3 
Investigational Medicinal Product Accountability ................... 57 
4.3.4 
Post-Study Access to Vemurafenib ....................................... 57 
4.4 
Concomitant Therapy ............................................................ 57 
4.4.1 
Permitted Therapy ................................................................. 57 
4.4.2 
Prohibited Therapy ................................................................ 58 
4.4.2.1 
Medication Precautions to Prevent Drug 
Interactions ............................................................................ 59 
4.4.2.2 
Medications Affecting the QT Interval .................................... 60 
4.5 
Study Assessments ............................................................... 61 
4.5.1 
Description of Study Assessments ........................................ 61 
4.5.1.1 
Medical History and Demographic Data ................................ 61 
4.5.1.2 
Vital Signs .............................................................................. 61 


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4.5.1.3 
Physical Examinations ........................................................... 61 
4.5.1.4 
Surveillance for Melanoma Recurrence:  Imaging 
Studies ................................................................................... 62 
4.5.1.5 
Dermatologic Examination ..................................................... 62 
4.5.1.6 
Head and Neck Evaluation .................................................... 63 
4.5.1.7 
Colonoscopy by Gastroenterologist ....................................... 63 
4.5.1.8 
Laboratory Assessments ....................................................... 64 
4.5.1.9 
BRAFV600 Mutation Testing .................................................... 65 
4.5.1.10 
Pharmacokinetic Assessments .............................................. 65 
4.5.1.11 
Electrocardiograms ................................................................ 66 
4.5.1.12 
Exploratory Biomarker Assessments ..................................... 66 
4.5.1.13 
Unscheduled Assessments ................................................... 68 
4.5.1.14 
Patient-Reported Outcomes .................................................. 68 
4.5.1.15 
Samples for Roche Clinical Repository.................................. 69 
4.5.2 
Timing of Study Assessments ............................................... 72 
4.5.2.1 
Screening and Pretreatment Assessments ............................ 72 
4.5.2.2 
Assessments during Study .................................................... 74 
4.5.2.3 
End-of-Treatment Visit ........................................................... 78 
4.5.2.4 
Post-Treatment Follow-Up Assessments............................... 78 
4.5.2.5 
Melanoma Recurrence or New Primary 
Melanoma Occurrence .......................................................... 78 
4.5.2.6 
Early Study Termination Visit (during 
Post-Treatment Follow-Up) .................................................... 78 
4.5.2.7 
Survival and New Primary Malignancy Follow-Up 
Assessments ......................................................................... 78 
4.5.2.8 
Adverse Event Follow-Up ...................................................... 79 
4.6 
Patient, Study, and Site Discontinuation ................................ 79 
4.6.1 
Patient Discontinuation .......................................................... 79 
4.6.1.1 
Discontinuation from Study Drug ........................................... 79 
4.6.1.2 
Withdrawal from Study........................................................... 80 
4.6.2 
Study and Site Discontinuation .............................................. 80 
5. 
ASSESSMENT OF SAFETY ....................................................................... 81 
5.1 
Safety Plan ............................................................................ 81 
5.1.1 
Background:  Vemurafenib Risks .......................................... 81 


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5.1.2 
General Plan to Manage Safety Concerns ............................ 81 
5.1.2.1 
Eligibility Criteria .................................................................... 81 
5.1.2.2 
Monitoring .............................................................................. 82 
5.1.2.3 
Monitoring and Management of Specific 
Toxicities and Conditions That May Arise with 
Vemurafenib Treatment ......................................................... 82 
5.1.3 
Management of Specific Adverse Events .............................. 89 
5.2 
Safety Parameters and Definitions ........................................ 90 
5.2.1 
Adverse Events ..................................................................... 90 
5.2.2 
Serious Adverse Events (Immediately Reportable 
to Roche) ............................................................................... 91 
5.2.3 
Non-Serious Adverse Events of Special Interest 
(Immediately Reportable to Roche) ....................................... 92 
5.3 
Methods and Timing for Capturing and 
Assessing Safety Parameters ................................................ 92 
5.3.1 
Adverse Event Reporting Period ........................................... 92 
5.3.2 
Eliciting Adverse Event Information ....................................... 93 
5.3.3 
Assessment of Severity of Adverse Events ........................... 93 
5.3.4 
Assessment of Causality of Adverse Events ......................... 94 
5.3.5 
Procedures for Recording Adverse Events ............................ 94 
5.3.5.1 
Diagnosis versus Signs and Symptoms................................. 94 
5.3.5.2 
Adverse Events Occurring Secondary to 
Other Events .......................................................................... 95 
5.3.5.3 
Persistent or Recurrent Adverse Events ................................ 95 
5.3.5.4 
Abnormal Laboratory Values ................................................. 95 
5.3.5.5 
Abnormal Vital Sign Values ................................................... 96 
5.3.5.6 
Abnormal Liver Function Tests .............................................. 97 
5.3.5.7 
Deaths ................................................................................... 97 
5.3.5.8 
Preexisting Medical Conditions .............................................. 98 
5.3.5.9 
Hospitalization or Prolonged Hospitalization .......................... 98 
5.3.5.10 
Overdoses ............................................................................. 98 
5.3.5.11 
Patient-Reported Outcome Data ........................................... 99 
5.4 
Immediate Reporting Requirements from 
Investigator to Sponsor .......................................................... 99 
5.4.1 
Medical Contacts ................................................................... 99 


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5.4.1.1 
NonMedical Emergency Medical Contacts .......................... 99 
5.4.1.2 
Medical Emergency Medical Contacts ................................. 100 
5.4.2 
Reporting Requirements for Serious Adverse 
Events and Non-Serious Adverse Events of 
Special Interest .................................................................... 100 
5.4.3 
Reporting Requirements for Pregnancies ............................ 100 
5.4.3.1 
Pregnancies in Female Patients .......................................... 100 
5.4.3.2 
Pregnancies in Female Partners of Male Patients ............... 101 
5.4.3.3 
Abortions ............................................................................. 101 
5.4.3.4 
Congenital Anomalies/Birth Defects .................................... 101 
5.5 
Follow-Up of Patients after Adverse Events ........................ 101 
5.5.1 
New Primary Cancers .......................................................... 101 
5.5.2 
Investigator Follow-Up ......................................................... 102 
5.5.3 
Sponsor Follow-Up .............................................................. 102 
5.6 
Post-Study Adverse Events ................................................. 102 
5.7 
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees ............................................................... 103 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ..................... 103 
6.1 
Determination of Sample Size ............................................. 103 
6.1.1 
Cohort 1 ............................................................................... 103 
6.1.2 
Cohort 2 ............................................................................... 104 
6.2 
Summaries of Conduct of Study .......................................... 105 
6.3 
Summaries of Treatment Group Comparability ................... 105 
6.4 
Efficacy Analyses ................................................................ 105 
6.4.1 
Primary Efficacy Endpoint .................................................... 105 
6.4.2 
Secondary Efficacy Endpoints ............................................. 107 
6.4.2.1 
Distant MetastasisFree Survival ........................................ 107 
6.4.2.2 
Overall Survival ................................................................... 107 
6.5 
Safety Analyses ................................................................... 107 
6.6 
Pharmacokinetic Analyses ................................................... 108 
6.7 
Patient-Reported Outcomes ................................................ 109 
6.8 
Other Analyses .................................................................... 109 
6.9 
Interim Analyses .................................................................. 109 


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7.
DATA COLLECTION AND MANAGEMENT ............................................. 110
7.1
Data Quality Assurance....................................................... 110
7.2
Electronic Case Report Forms............................................. 110
7.3
Source Data Documentation................................................ 111
7.4
Use of Computerized Systems ............................................ 111
7.5
Retention of Records........................................................... 112
8.
ETHICAL CONSIDERATIONS.................................................................. 112
8.1
Compliance with Laws and Regulations .............................. 112
8.2
Informed Consent................................................................ 112
8.3
Institutional Review Board or Ethics Committee.................. 113
8.4
Confidentiality...................................................................... 114
8.5
Financial Disclosure ............................................................ 114
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 114
9.1
Study Documentation .......................................................... 114
9.2
Site Inspections ................................................................... 115
9.3
Administrative Structure....................................................... 115
9.4
Publication of Data and Protection of Trade 
Secrets ................................................................................ 115
9.5
Protocol Amendments ......................................................... 116
10. REFERENCES ......................................................................................... 117
LIST OF TABLES
Table 1
Risks Associated with Melanoma on the Basis of AJCC 
Stage .......................................................................................... 30
Table 2
Dose Modification Schedule........................................................ 90
Table 3
Adverse Event Severity Grading Scale ....................................... 93
Table 4
Assumptions and Characteristics for Disease-Free Survival 
Analyses by Cohort................................................................... 105
Table 5
Assumptions and Characteristics for Overall Survival 
Analyses by Cohort................................................................... 110


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LIST OF APPENDICES
Appendix 1
Schedule of Assessments......................................................... 121
Appendix 2
Schedule of Pharmacokinetic Assessments ............................. 130
Appendix 3
New York Heart Association Guidelines ................................... 131
Appendix 4
European Organisation for Research and Treatment of 
Cancer 30-Item Quality of Life Questionnaire (Version 3)......... 132
Appendix 5
Excerpts from the Clinical Practice Guidelines for the 
Management of Melanoma in Australia and New Zealand........ 134
Appendix 6
Eastern Cooperative Oncology Group Performance Status 
Scale......................................................................................... 152
Appendix 7
Fitzpatrick Skin Phototypes....................................................... 153
Appendix 8
Impact of Vemurafenib on Concomitant Medications................ 154
Appendix 9
Medication Affecting QT Interval............................................... 157
Appendix 10
American Joint Committee on Cancer (Version 7):  
Melanoma of the Skin Staging .................................................. 158


 
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PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
A PHASE III, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED STUDY OF VEMURAFENIB 
(RO5185426) ADJUVANT THERAPY IN PATIENTS WITH 
SURGICALLY RESECTED, CUTANEOUS 
BRAF-MUTANT MELANOMA AT HIGH RISK 
FOR RECURRENCE 
PROTOCOL NUMBER: GO27826 
VERSION NUMBER: 
10 
EUDRACT NUMBER: 
2011-004011-24 
IND NUMBER: 
73620 
TEST PRODUCT: 
Vemurafenib (RO5185426) 
MEDICAL MONITOR: 
, M.D. 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator’s Name  (print) 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
Please return the signed original of this form to the Sponsor or its designee.  Please 
retain a copy for your study files. 


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PROTOCOL SYNOPSIS
TITLE:
A PHASE III, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED STUDY OF VEMURAFENIB 
(RO5185426) ADJUVANT THERAPY IN PATIENTS WITH 
SURGICALLY RESECTED, CUTANEOUS BRAF-MUTANT 
MELANOMA AT HIGH RISK FOR RECURRENCE
PROTOCOL NUMBER:
GO27826
VERSION NUMBER:
10
EUDRACT NUMBER:
2011-004011-24
IND NUMBER:
73620
TEST PRODUCT:
Vemurafenib (RO5185426)
PHASE:
III
INDICATION:
Melanoma
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives
Efficacy Objectives
The primary objective of this study is as follows:

To evaluate the efficacy of vemurafenib adjuvant treatment administered over a 52-week 
period in patients with completely resected BRAFV600 mutationpositive, cutaneous 
melanoma, as measured by disease-free survival (DFS)
The secondary objectives of this study are as follows:

To evaluate the efficacy of vemurafenib adjuvant treatment administered over a 52-week 
period, as measured by distant metastasisfree survival (DMFS)

To evaluate the efficacy of vemurafenib adjuvant treatment administered over a 52-week 
period, as measured by overall survival (OS)

To evaluate the safety and tolerability of vemurafenib in the adjuvant setting

To assess quality of life (QoL) as measured by EORTC 30-item Quality of Life 
Questionnaire (QLQ-C30)

To describe the pharmacokinetics of vemurafenib in the adjuvant setting, assess 
between-patient variability of pharmacokinetic (PK) parameters, and explore and quantify 
potential covariates that may contribute to between-patient differences in PK parameters, 
with use of a population PK approach


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Exploratory Objectives
The exploratory objectives of this study are as follows:

To assess the efficacy outcomes and safety profile of vemurafenib adjuvant treatment in 
patients whose melanomas harbor non-E mutations of BRAF kinase at amino acid position 
600, as detected by DNA sequencing methods

To assess the relationship between vemurafenib exposure and the risk of melanoma 
recurrence or occurrence of new primary melanomas, the occurrence of serious adverse 
events, and abnormalities in safety laboratory parameters

To assess the relationship between biomarkers and risk of melanoma recurrence or 
occurrence of new primary melanomas

To characterize the biomarkers associated with acquisition of resistance to vemurafenib in 
the adjuvant setting

To characterize the molecular phenotype of squamous cell carcinoma (SCC; cutaneous 
[including keratoacanthoma/KA] and non-cutaneous) or other new primary neoplasms that 
may be observed in patients treated with vemurafenib
Study Design
Description of Study
Study GO27826 is a Phase III, international, multicenter, double-blind, randomized, placebo-
controlled study of patients with completely resected, BRAFV600 mutationpositive melanoma, as 
detected by the cobasBRAF V600 Mutation Test, at high risk for recurrence.
A total of approximately 475 patients in two separate cohorts will be enrolled.

Cohort 1 (approximately 300 patients) will include patients with completely resected Stage 
IIC, IIIA (patients with one or more nodal metastasis 1 mm in diameter), or IIIB cutaneous 
melanoma, as defined by the American Joint Committee on Cancer (AJCC) Classification, 
Version 7 (Balch et al. 2009).

Cohort 2 (approximately 175 patients) will include patients with Stage IIIC cutaneous 
melanoma, as defined by this classification scheme.
The primary and secondary efficacy and safety objectives of this study will be evaluated 
separately for each cohort.
Eligible patients will be randomized (1:1 ratio) to receive placebo or vemurafenib over a 
52-week period, with randomization stratified by pathologic stage (Stage IIC, Stage IIIA, 
Stage IIIB) and region (North America, Australia/New Zealand/South Africa/Latin America, rest 
of the world) in Cohort 1 and by region (North America, Australia/New Zealand/South 
Africa/Latin America, rest of the world) in Cohort 2.
Within each cohort, patients will receive study treatment according to one of the following 
treatment arms:

Arm A:  placebo orally, twice daily (BID) for 52 weeks (thirteen 28-day cycles)

Arm B:  vemurafenib 960 mg orally, BID for 52 weeks (thirteen 28-day cycles)
All eligible patients must have either newly diagnosed melanoma or, at most, one metachronous 
lymph node recurrence (in the absence of prior lymph node involvement) that has undergone 
gross total resection; no prior systemic treatment for melanoma is permitted.  Full pathologic 
staging that incorporates the findings from sentinel lymph node biopsy and complete regional 
lymphadenectomy is required of all patients with lymph node involvement.
All patients will be required to provide a sample of tumor tissue for further BRAF mutation 
testing and exploratory biomarker and correlative science assessments at baseline.
Randomization will occur within 90 days after definitive surgery (i.e., the last surgery required 
for the treatment or the diagnosis of melanoma), and study drug administration will begin within 
4 calendar days after randomization.
The final analysis of the primary endpoint of DFS will occur for each cohort after the targeted 
number of events for each cohort is reached (approximately 120 DFS events for Cohort 1 and 


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approximately 105 DFS events for Cohort 2).  There will be no interim analyses of the primary 
endpoint of DFS.
For each cohort, patients without melanoma recurrence or an occurrence of a new primary 
melanoma and their physicians will remain blinded until the final DFS analysis for that cohort.  
Physicians may request unblinding for patients who have documented recurrence or an 
occurrence of a new primary melanoma for purposes of planning subsequent treatment.  
Unblinding requires prior approval of the Roche Medical Monitor or designee.
In this adjuvant trial, crossover to vemurafenib treatment will not be allowed for patients 
receiving placebo because this trial is designed to evaluate adjuvant vemurafenib therapy 
starting within 4 calendar days after randomization and no later than 94 calendar days after 
definitive melanoma surgery (i.e., the last surgery required for the treatment or the diagnosis of 
melanoma).
Number of Patients
A total of approximately 475 patients in two separate cohorts will be enrolled.
Target Population
Patients must meet all of the criteria listed below for study entry.
Inclusion Criteria
Disease-Specific Inclusion Criteria

All patients should have histologically confirmed melanoma of cutaneous origin.

All patients without clinical or radiologic evidence of regional lymph node involvement must 
undergo sentinel lymph node biopsy.  Patients must undergo a complete regional 
lymphadenectomy if a sentinel lymph node biopsy procedure cannot be performed or a 
sentinel lymph node cannot be detected.  All patients who have either clinical or 
radiographic evidence of regional lymph node involvement or evidence of melanoma 
involvement in the sentinel lymph node must undergo complete regional lymphadenectomy.  
Melanoma infiltration of lymph node(s) must be histologically confirmed.
Note:  Surgical management should comply with published guidelines for surgical 
standards of care.

Patients with lymph node involvement either at initial presentation or a first metachronous 
nodal recurrence are eligible:
Tany (including x) N at initial presentation
TanyN0 followed by N recurrence (i.e., first metachronous nodal recurrence)

Patients with BRAFV600 mutationpositive, cutaneous melanoma (either pathologic 
Stage IIC or Stage III according to AJCC Staging Criteria v7) that has been completely 
resected
Note:  Patients with Stage IIIA disease must have at least one lymph node metastasis 
measuring 1 mm in diameter (per the Rotterdam classification scheme) on pathologic 
staging.

BRAFV600 mutation status of the current primary tumor or involved lymph node determined 
to be positive using the cobasBRAF V600 Mutation Test

The patient must have been surgically rendered free of disease within 90 days of
randomization.

Eastern Cooperative Oncology Group Performance Status of 0 or 1
General Inclusion Criteria

Male or female patients aged 18 years

Ability to participate and willingness to give signed informed consent prior to performance of 
any study-related procedures and to comply with the study protocol

Life expectancy of at least 5 years

Patients must have fully recovered from the effects of any major surgery 
(including complete regional lymphadenectomy) or significant traumatic injury prior to the 
first dose of study drug.


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Note:  All staging-related procedures, including complete regional lymphadenectomy, 
must be completed within 90 days prior to randomization.

Negative stool occult blood
Note:  If stool occult blood is positive, the patient will need to be cleared for study 
inclusion by a gastroenterologist or appropriately trained designee.

For select patients with known personal history of adenomatous colorectal polyps or 
colorectal cancer, family history of colon cancer in which a first- and/or second-degree 
relative has been diagnosed with colorectal cancer at or after the age of 60 years, or signs 
or symptoms that could be related to colon cancer as determined by the site investigator or 
designee, a screening colonoscopy with adequate resection of all visualized polyps must be 
performed.
Note:  For select patients requiring a screening colonoscopy (described above), 
colonoscopy should be complete to the cecum, with adequate bowel preparation, and 
performed within the 90-day screening period.  For select patients (described above), 
screening colonoscopy is not required if colonoscopy to the cecum with adequate 
bowel preparation and adequate resection of all visualized polyps was performed 
within 1 year of the start of the 90-day screening period, unless the site investigator 
deems it necessary.
Note:  A history of colon cancer greater than 5 years prior to randomization does not 
preclude patients from being eligible.

Adequate hematologic, liver, and renal function, defined by the following laboratory results 
obtained within 28 days prior to randomization:
Absolute neutrophil count 1.5 109/L
Platelet count 100 109/L
Hemoglobin 9 g/dL
Bilirubin 1.5 the upper limit of normal (ULN)
AST, ALT, and alkaline phosphatase 2.5 ULN
Serum creatinine 1.5 ULN or creatinine clearance 50 mL/min on the basis of the 
CockroftGault glomerular filtration rate estimation:
[(140age) (weight in kg)(0.85 if female)]/[72 (serum creatinine in mg/dL)]
PT, INR, aPTT 1.5 ULN

Female patients of childbearing potential and male patients with partners of childbearing 
potential must agree to always use two effective forms of contraception beginning from the 
informed consent signature date until at least 6 months after completion of study therapy.
In general, effective forms of contraception include surgical sterilization, a reliable 
barrier method with spermicide, birth control pills or patches, intrauterine contraceptive 
device, or contraceptive hormone implants.  Please note that vemurafenib may 
decrease the plasma exposure of medicines predominantly metabolized by CYP3A4, 
including hormonal contraceptives; consider the use of alternative effective methods of 
contraception.
Female patients of childbearing potential are defined as sexually mature women 
without prior hysterectomy who have had any evidence of menses within the past 
12 months.
In order to be considered NOT of childbearing potential, amenorrhea for a period of 
12 months or longer must have occurred in the absence of chemotherapy, anti-
estrogens, or ovarian suppression.

Negative serum pregnancy test within 14 days prior to randomization in women of 
childbearing potential

Women of non-childbearing potential need not undergo pregnancy testing.

Absence of any psychological, familial, sociological, or geographical condition that has the 
potential to hamper compliance with the study protocol and follow-up schedule (such 
conditions should be discussed with the patient before trial entry)


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Exclusion Criteria
Patients who meet any of the criteria listed below will be excluded from study entry.
Cancer-Related Exclusion Criteria

History of any systemic or local therapy (e.g., chemotherapy, biologic or targeted therapy, 
hormonal therapy, or photodynamic therapy) for the treatment or prevention of melanoma, 
including interferon alpha-2b and pegylated interferon alpha-2b

History of limb perfusion therapy

History of radiotherapy for the treatment of melanoma including but not limited to radiation 
therapy to a resected nodal basin

History of radiotherapy for the treatment of prostate, cervical, or rectal cancer

Allergy or hypersensitivity to components of the vemurafenib formulation

Invasive malignancy other than melanoma at the time of enrollment or within 5 years prior 
to first study drug administration, except for adequately treated (with curative intent) basal 
or squamous cell carcinoma of the skin, in situ carcinoma of the cervix, in situ ductal 
adenocarcinoma of the breast, in situ prostate cancer, or limited stage bladder cancer
Note:  This requires that the pathology evaluation of the screening Papanicolaou 
smear and of any polyps resected at the screening colonoscopy does not show any 
invasive malignancy.

Family history of inherited colon cancer syndromes (e.g., familial adenomatous polyposis, 
attenuated adenomatous polyposis, MUTYH-associated polyposis, hyperplastic polyposis 
syndrome, Peutz-Jeghers syndrome, juvenile polyposis syndrome, Lynch syndrome, and 
Cowden syndrome) and/or history of colon cancer in which a first- and/or second-degree 
relative has been diagnosed with colorectal cancer before the age of 60 years

Known personal history of more than three (3) adenomatous colorectal polyps or a 
personal history of adenomatous colorectal polyp(s) 2 cm in size.  This also applies to the 
screening colonoscopy for select patients.

History of or current clinical, radiographic, or pathologic evidence of in-transit metastases,
satellite, or microsatellite lesions
Note:  In-transit metastases are any skin or subcutaneous metastases that are 2 cm 
from the primary lesion but are not beyond the regional nodal basin.  Satellite lesions 
are skin or subcutaneous lesions within 2 cm of the primary tumor that are considered 
intralymphatic extensions of the primary mass.  Microsatellite lesions are any 
discontinuous nest of metastatic cells more than 0.05 mm in diameter that are clearly 
separated by normal dermis (not fibrosis or inflammation) from the main invasive 
component of melanoma by a distance of at least 0.3 mm (McCardle et al. 2011).

History of or current clinical, radiographic, or pathologic evidence of recurrent lymph node 
involvement after resection of a primary melanoma with lymph node involvement at any 
time in the past

History of local and/or regional and/or distant melanoma recurrence (excluding first 
metachronous nodal recurrence)
Note:  This does not include patients who have had a new primary melanoma.

History or current radiographic or pathologic evidence of distant metastases as defined 
either by an abnormal contrast-enhanced brain magnetic resonance imaging (MRI; or brain 
computed tomography if MRI is not generally available or is contraindicated) or 
histologically proven, distant metastatic disease (visceral or cutaneous) in an extracranial 
site
Note:  This includes patients who have had their metastatic disease resected.


 
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Cardiac Exclusion Criteria 
• 
History of clinically significant cardiac or pulmonary dysfunction, including the following: 
Current, uncontrolled Grade ≥ 2 hypertension 
Unstable angina 
Current Grade ≥ 2 dyspnea or hypoxia or need for supplemental oxygen 
History of symptomatic congestive heart failure of Grade II−IV New York Heart 
Association Class (NYHA) (for the Criteria Committee of the NYHA 1994) 
Serious cardiac arrhythmia requiring treatment, with the exceptions of atrial fibrillation 
and paroxysmal supraventricular tachycardia 
History of myocardial infarction within 6 months prior to randomization 
History of congenital long QT syndrome or QTc interval > 450 ms at baseline 
History of or current uncorrectable electrolyte disorder affecting serum levels of 
potassium, calcium, or magnesium 
 
General Exclusion Criteria 
• 
Major surgical procedure (other than wide local excision, sentinel lymph node biopsy, or 
complete regional lymphadenectomy) or significant traumatic injury within 4 weeks prior to 
the first dose of study drug. 
• 
History of clinically significant liver disease (including cirrhosis), current alcohol abuse, or 
known infection with HIV, hepatitis B virus, or hepatitis C virus 
• 
Active infection or chronic infection requiring chronic suppressive antibiotics 
• 
Pregnancy or breastfeeding at the time of randomization 
• 
Autoimmune disease (e.g., systemic lupus erythematosus, autoimmune vasculitis, 
inflammatory bowel disease [Crohn’s disease and ulcerative colitis]) 
• 
Acromegaly 
• 
History of malabsorption or other clinically significant metabolic dysfunction 
• 
Any other serious concomitant medical condition that, in the opinion of the investigator, 
would compromise the safety of the patient or compromise the patient’s ability to participate 
in the study 
• 
Requirement for a concomitant medication or dietary supplement that is prohibited during 
the study  
• 
Unwillingness or inability to comply with study and follow-up procedures 
• 
Current, recent (within 28 days prior to randomization) or planned use of any investigational 
product outside of this study 
 
Length of Study 
All patients will be followed for melanoma recurrence or occurrence of new primary melanoma 
and overall survival for at least 2 years after Cycle 1, Day 1 of study treatment.  Patients 
may be followed for melanoma recurrence or occurrence of new primary melanoma for up to 
5 years and OS for up to 6 years after Cycle 1, Day 1 of study treatment.  Patients who exhibit 
recurrence of melanoma or a new primary melanoma during the study will be followed for OS.   
End of Study 
The end of the study is defined as the date of the last patient, last visit, which is expected to 
occur approximately 6 months after the last patient enrolled has been followed for 2 years after 
Cycle 1, Day 1 of the study.  The final OS analysis will occur at the end of study. 


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Outcome Measures
Efficacy Outcome Measures
The efficacy outcome measures for this study are described below.
Primary Efficacy Outcome Measure
DFS will be defined as the time from randomization until the date of the first local, regional, or 
distant melanoma recurrence, occurrence of new primary melanoma, or death from any cause.  
The DFS component of melanoma recurrence will be assessed by the investigator.  The DFS 
component of an occurrence of a new primary melanoma will be based upon the diagnosis 
made by a Roche-designated central pathology laboratory.
Secondary Efficacy Outcome Measures
DMFS will be defined as the time from randomization until the date of diagnosis of distant 
(i.e., non-locoregional) metastases or death from any cause.
OS will be defined as the time from randomization to the date of death from any cause.
Safety Outcome Measures
The safety outcome measures for this study are as follows:

Incidence, nature, and severity of adverse events, serious adverse events, and adverse 
events of special interest.  Severity will be graded according to the National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI CTCAE), v4.0.

Changes from baseline in ECG findings and targeted clinical laboratory analytes during the 
course of study treatment
Pharmacokinetic Outcome Measures
The PK outcome measures for this study are as follows:

Plasma concentrations of vemurafenib at clinically relevant timepoints, including 
steady-state trough values as well as those associated with diagnosis of SCC, dose 
interruption, and/or reduction for toxicity, melanoma recurrence, and occurrence of a new 
primary melanoma
Patient-Reported Outcome Measures
The patient-reported outcome measure for this study is as follows:

To assess patient-reported symptoms, functional interference, and health-related QoL in the 
vemurafenib and placebo treatment arms with use of EORTC QLQ-C30
Exploratory Outcome Measures
The exploratory outcome measures for this study are as follows:

Retrospective identification of study patients whose tumors harbor non-E, activating 
mutations of BRAF kinase at amino acid position 600 (e.g., BRAFV600K), with use of DNA 
sequencing methods as a means to assess clinical outcomes in this patient subgroup

Levels of candidate tumor biomarkers in plasma and serum (e.g., circulating mutant BRAF
DNA) at different timepoints during the study compared with baseline as a means to monitor 
for and predict melanoma recurrence or occurrence of a new primary melanoma

Candidate tumor biomarkers at the protein, RNA, and DNA levels (including RAS mutations) 
that may characterize the molecular phenotype of tumors at melanoma recurrence or 
occurrence of a new primary melanoma as well as predict development of resistance to 
adjuvant vemurafenib treatment

Molecular characterization of SCC (cutaneous [including KA] and non-cutaneous) or other 
new primary neoplasms that may be observed in patients treated with vemurafenib
Investigational Medicinal Products
Vemurafenib or placebo will be taken at home, orally, at a dose of 4 tablets BID for a maximum 
of 52 consecutive weeks (thirteen 28-day cycles).


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Test Product
Study drug will be taken at home, orally, at a dose of 4 tablets BID for a maximum of 
52 consecutive weeks (thirteen 28-day cycles). 
The first dose is to be taken in the morning, and the second dose is to be taken approximately 
12 hours later in the evening.  Study drug tablets are to be swallowed whole with water.  The 
tablets should not be chewed or crushed.  If a dose is missed, it can be taken 4 or more hours 
prior to the next dose to maintain the BID regimen.  Both doses should not be taken at the same 
time.  Missed days or drug holidays will not be made up, thereby maintaining 52 weeks of 
treatment.  A patient who has a break in dosing in excess of 28 consecutive days will be 
permanently discontinued from study treatment.
Patients will be asked to record the date and time of doses in a diary and to return all used and 
unused drug supply containers as a measure of compliance.  All supplies, including partially 
used or empty containers of study drug, must be returned to the Roche study monitor at the end 
of the study, unless alternative destruction has been authorized by Roche/designee or is 
required by local or institutional regulations.  Copies of all drug dispensing and inventory logs 
must be returned to the Roche study monitor at the end of the study.
Non-Investigational Medicinal Products
Not applicable.
Statistical Methods
Unless otherwise noted, all efficacy analyses will include all randomized patients (intent-to-treat 
analysis), and patients will be grouped according to the treatment assigned at randomization.  
The primary and all secondary objectives of this study will be evaluated separately for each 
cohort.
Primary Analysis
The primary endpoint, DFS, is defined as the time from randomization until the date of the first 
local, regional, or distant melanoma recurrence, occurrence of new primary melanoma, or death 
from any cause.  The DFS component of melanoma recurrence will be assessed by the 
investigator.  The DFS component of an occurrence of a new primary melanoma will be based 
upon the diagnosis made by a Roche-designated central pathology laboratory.  For patients 
without a DFS event at the time of data cutoff, data will be censored at the date of the last 
disease assessment.  Details on censoring in the analysis of this endpoint are described in the 
Statistical Analysis Plan (SAP). 
For patients whose recurrence has been proven histologically, the date of melanoma recurrence 
will be defined as the earliest date of the scan or clinical examination that prompted the biopsy. 
For patients whose suspicious lesions were deemed not amenable to biopsy or for patients who 
refuse a biopsy, the date of melanoma recurrence will be defined as the earliest date of the 
scan or clinical examination that would have prompted a biopsy.  For patients with an 
occurrence of a new primary melanoma, the date of the new primary melanoma will be defined 
as the earliest date of the clinical examination or scan that prompted the biopsy.
The final analysis of the primary endpoint of DFS will take place when approximately 120 DFS 
events have occurred for Cohort 1 and approximately 105 DFS events have occurred for Cohort 
2.  The final DFS analyses for both cohorts will be conducted at the same time by using the 
dataset from the same data cutoff date for both cohorts.  The primary efficacy analyses will be 
comparisons of the two treatment groups, using a two-sided, stratified log-rank test for Cohort 1 
and Cohort 2 separately.  To account for separate analysis for each cohort, the statistical 
significance of the comparison of DFS between treatment arms will be based an alpha level of 
0.05 (two sided) of the family-wise Type I error rate for two tests of two cohorts.  Detailed testing 
procedures will be provided in the SAP.
Median DFS time will be estimated using the Kaplan-Meier method, and the two-sided 95% CI 
will be calculated using the method of Brookmeyer and Crowley (1982) for each cohort.
The HR of DFS (recurrence, new primary melanoma, or death) and the associated two-sided 95% 
CI will be estimated by using a stratified Cox proportional hazards model.
The stratification factors in the stratified analyses are the stratification factors used in 
randomization of patients in each cohort.  For Cohort 1, stratified analyses will incorporate 
two stratification factors: pathologic stage (Stage IIC; Stage IIIA; Stage IIIB) and region (North 


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America, Australia/New Zealand/South Africa/Latin America, rest of the world).  For Cohort 2, 
stratified analyses will incorporate one stratification factor, region (North America, Australia/New 
Zealand/South Africa/Latin America, rest of the world).  
In addition, Kaplan-Meier methodology will be used to estimate landmark (e.g., 1-year, 2-year, 
and 3-year) DFS rates and the associated two-sided 95% CIs for each treatment arm, and the 
Kaplan-Meier curves will be provided.  
Subgroup analyses for the primary efficacy outcome, DFS, will be performed to assess the 
robustness of the results across patient subgroups in each cohort separately.  The subgroups 
will include but are not limited to the categories of demographic (age, sex), baseline disease 
characteristics, BRAF mutation status such as V600E versus non-V600E, and stratification 
variables.
Secondary Analysis
DMFS and OS are the secondary efficacy endpoints.
DMFS is defined as the time from randomization until the date of diagnosis of distant (i.e., non-
locoregional) metastasis or death from any cause.  Details on censoring in the analysis of this 
endpoint are described in the SAP.  DMFS will be analyzed at the time of the final DFS analysis 
in each cohort.  The analysis methods to be employed for DMFS are the same as those 
described for the primary endpoint of DFS.
OS is defined as the time from randomization until the date of death from any cause.  For 
patients still alive at the time of analysis, the data will be censored at the date the patient was 
last known to be alive.  The study is not powered for OS, so adequate power statistical testing 
for this endpoint is not possible.  However, some standard OS estimates will be provided by 
using the same analysis methods as those described for the primary endpoint of DFS.
Two OS analyses are planned for each cohort.  The OS interim analysis in each cohort will be 
performed at the time of the final DFS analysis for both cohorts.  The final OS analysis for 
Cohorts 1 and 2 will be performed at the end of study.
Determination of Sample Size
Cohort 1
The final analysis of the primary endpoint of DFS for Cohort 1 will take place when 
approximately 120 DFS events have occurred, on the basis of the following assumptions:

Two-sided, stratified log-rank test at the 0.05 significance level

80% power

Median DFS for the control arm of 24 months and estimated median DFS in the 
vemurafenib treatment arm of 40 months (which corresponds to an HR of 0.60)

5% annual loss to follow-up for DFS

No interim analysis
Assuming an accrual rate of 8 patients per month in Cohort 1 and a 17-month ramp-up period to 
reach steady-state enrollment, approximately 300 patients will be required to be enrolled in 
Cohort 1 during 43 months and followed for an additional 7 months in order to observe 120 DFS 
events.
On the basis of the assumptions above, 120 DFS events are projected to occur in Cohort 1
approximately 50 months after the first patient is randomized in this study.  At that time, it is 
projected that median follow-up time will be 21 months in Cohort 1, and the minimum follow-up 
time (e.g., for the last patient randomized) is projected to be 7 months.  Also on the basis of the 
assumptions of 120 DFS events required and a target HR of 0.60, it is projected that an 
observed HR of 0.70 or better in the DFS analysis will result in a statistically significant 
difference between treatment arms (i.e., HR of 0.70 is the minimally detectable difference for 
that analysis).
For Cohort 1, on the basis of the assumptions of a target HR of 0.60, 120 DFS events would 
also provide 80% power to detect a 16% absolute increase in the 2-year DFS rate 
(50% vs. 66%, corresponding to a 40% risk reduction; i.e., HR of 0.60).


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Cohort 2
The final analysis of the primary endpoint of DFS for Cohort 2 will take place when 
approximately 105 DFS events have occurred, on the basis of the following assumptions:

Two-sided, stratified log-rank test at the 0.05 significance level

80% power

Median DFS for the control arm of 7.7 months and estimated median DFS in the 
vemurafenib treatment arm of 13.3 months (which corresponds to an HR of 0.58)

5% annual loss to follow-up for DFS

No interim analysis
Assuming an accrual rate of 5 patients per month in Cohort 2 and a 27-month ramp-up period to 
reach steady-state enrollment, approximately 175 patients will be required to be enrolled in 
Cohort 2 over 40 months in order to observe 105 DFS events.
For Cohort 2, on the basis of the assumptions of a target HR of 0.58, 105 DFS events would 
provide 80% power to detect a 17% absolute increase in the 2-year DFS rate (12% vs. 29%, 
corresponding to a 42% risk reduction; i.e., HR of 0.58).
Interim Analyses
No interim analyses of the primary endpoint, DFS, will be performed.
As stated in the protocol, two OS analyses (one interim analysis and one final analysis) are 
planned for each cohort.  The OS interim analysis will be performed at the time of the final DFS 
analysis for each cohort.  The final OS analysis for Cohorts 1 and 2 will be performed at the end 
of study. The Lan-DeMets implementation (Lan and DeMets 1983) of the O’Brien-Fleming use 
function will be used to control the overall Type I error for the OS comparison in each cohort at 
a two-sided 0.05 significance level.


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
AJCC
American Joint Committee on Cancer
anti-HBc
hepatitis B core antibody
AUC
area under the concentration-time curve
AUC0last
area under the concentration-time curve from Time 0 to last 
measurable concentration
BID
twice daily
BORR
best overall response rate
CRO
contract research organization
CT
computed tomography (scan)
cuSCC
cutaneous squamous cell carcinoma
CYP
cytochrome P450
DFS
disease-free survival
DILI
drug-induced liver injury
DMFS
distant metastasisfree survival
DSMB
Data Safety Monitoring Board
DTIC
dacarbazine
EC
Ethics Committee
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report Form
EDC
electronic data capture
EORTC
European Organisation for Research and Treatment of 
Cancer
EORTC QLQ-C30
European Organisation for Research and Treatment of 
Cancer 30-item Quality of Life Questionnaire
ERK
extracellular-signal-regulated kinase
FDA
U.S. Food and Drug Administration
FDG-PET
fluorodeoxyglucosepositron emission tomography
FF
fresh frozen
FFPE
formalin-fixed paraffin-embedded
GGT
gamma glutamyl transferase
GM-CSF
granulocyte macrophage colonystimulating factor
HBsAg
hepatitis B surface antigen
HCV
hepatitis C virus
HIPAA
Health Insurance Portability and Accountability Act
HPV
human papilloma virus
HR
hazard ratio


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Abbreviation
Definition
IB
Investigator’s Brochure
ICH
International Conference on Harmonisation
IMP
investigational medicinal product
IND
Investigational New Drug Application
IRB
Institutional Review Board
IxRS
interactive voice or Web response system
KA
keratoacanthoma
MAPK
mitogen-activated protein kinase
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
NCI CTCAE
National Cancer Institute Common Terminology Criteria for 
Adverse Events
NYHA
New York Heart Association Class
OS
overall survival
Pap
Papanicolaou 
PFS
progression-free survival
P-gp
P-glycoprotein
PK
pharmacokinetic
PRO
patient-reported outcome
QoL
quality of life
QTc
corrected QT
RCR
Roche Clinical Repository
RFS
relapse-free survival
SAP
Statistical Analysis Plan
SCC
squamous cell carcinoma
TMA
tissue microarray
ULN
upper limit of normal


 
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1. 
BACKGROUND 
1.1 
BACKGROUND ON MELANOMA 
Melanoma is one of the most deadly skin cancers.  In the United States, a total of 
68,130 new cases of and 8700 deaths from melanoma are estimated to have occurred in 
2010 (Jemal et al. 2010).  In Europe, approximately 26,100 males and 33,300 females 
are diagnosed annually with melanoma, and approximately 8300 males and 
7600 females die from the disease every year (de Vries et al. 2003).  Australia has 
the highest incidence of melanoma in the world (Whiteman et al. 1997), and in the 
Australian state of Victoria, melanoma is the fourth most common cancer in males 
and the third most common in females (Victorian Cancer Registry 2011).  Worldwide, 
the incidence of melanoma has been increasing at a rapid rate (Linos et al. 2009; 
Rigel et al 2010).  Ultraviolet light exposure is a well-known environmental risk factor for 
melanoma (Erdei and Torres 2010).  
Detection and surgical treatment of early-stage disease seem to prevent progression in 
most cases.  However, patients with deep primary tumors or tumors that metastasize to 
regional lymph nodes frequently develop distant metastases.  Median survival after the 
onset of distant metastases is only 69 months, and the 5-year survival rate is  5% 
(Balch et al. 2009).  
The primary treatment modality for localized cutaneous melanoma is surgery.  Wide 
local excision and sentinel lymph node biopsy are considered the standard of care for 
patients with localized cutaneous melanoma (Garbe et al. 2012; National 
Comprehensive Cancer Network 2013).  Regional lymphadenectomy is indicated if the 
results of the sentinel lymph node biopsy reveal the presence of micrometastatic 
melanoma or if enlarged lymph nodes are present upon physical examination or 
radiographic imaging studies. 
Staging of localized, cutaneous melanoma is based on clinical and pathologic criteria 
(Balch et al. 2009) and relies on characteristics of the primary tumor (i.e., tumor 
thickness and the presence or absence of ulceration), the extent of involvement of 
regional lymph nodes, and the presence or absence of satellite or “in-transit” metastases.  
Appendix 10 describes the current staging algorithm promulgated by the American Joint 
Committee on Cancer (AJCC) for cutaneous melanoma (Balch et al. 2009). 
Data from cooperative group and surveillance epidemiology studies reveal a high risk of 
recurrence in patients with locally advanced, resectable melanomas.  Specifically, 
patients with Stage IIC and Stage III disease (patients with Stage IIIA disease having at 
least one nodal metastasis  1 mm in diameter) exhibit a  50% risk of melanoma 
recurrence and a 40%60% mortality rate at 5 years after surgical resection of their 
primary malignancy (see Table 1). 


 
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Table 1 
Risks Associated with Melanoma on the Basis of AJCC Stage 
Stage 
5-Year Risk of 
Recurrence 
RFS 
(median, months) 
OS  
at 5 yearsa 
Incidence per 1  105 
Populationb 
IIC 
 50% 
22.2c  
54% 
0.5 (2.2%) 
IIIAd 
 50% 
NA 
50%e 
— 
IIIB 
 50% 
18.7f 
59% 
0.5 (2.2%) 
IIIC 
 50% 
7.7f 
40% 
0.3 (1.32%) 
AJCC  American Joint Committee on Cancer; NA  not available; OS  overall survival; 
RFS  relapse-free survival. 
a Balch et al. 2009. 
b National Cancer Institute 2007. 
c Kirkwood et al. 2004. 
d At least one nodal metastasis  1 mm in diameter. 
e Eggermont AM, "Update on staging, tumor burden and adjuvant therapy," presented at 
Perspectives in Melanoma XIV Conference, Sept 1718, 2010. 
f Eggermont et al. 2008. 
 
The only widely approved adjuvant therapy for melanoma patients at high risk for 
recurrence is interferon alpha-2b with a high-dose regimen (PDR Network 2011).  
Interferon alpha-2b is administered intravenously at a dose of 20 million IU/m2 daily for 
5 days per week for a 4-week period followed by 10 million IU/m2 administered 
subcutaneously 3 days a week (every other day) for 48 weeks. 
A pooled analysis of results derived from Eastern Cooperative Oncology Group (ECOG) 
and Intergroup trials showed that high-dose interferon alpha-2b is associated with a 
relapse-free survival (RFS) but not an overall survival (OS) advantage 
(Kirkwood et al. 2004).  A recent meta-analysis in patients with high-risk melanoma 
(Mocellin et al. 2010) concluded that adjuvant interferon therapy improved both 
disease-free survival (DFS) and OS in patients with high-risk cutaneous melanoma; 
however, the randomized studies that were included in this meta-analysis were widely 
disparate with regard to dose, duration of therapy, and comparator arm. 
A large, randomized adjuvant therapy trial in Stage III melanoma patients treated with 
pegylated interferon alpha-2b was conducted by the European Organisation for 
Research and Treatment of Cancer (EORTC) Melanoma Study Group 
(Eggermont et al. 2008).  Patients were stratified by the presence of microscopically 
versus macroscopically involved lymph nodes.  The dose of pegylated interferon 
alpha-2b was 6 g/kg of body weight for the first 8 weeks followed by 3 g/kg for 5 years.  
The results indicate a statistically significant prolongation of RFS for all patients and a 
significant benefit in distant metastasisfree survival (DMFS) in patients with 
microscopic lymph node involvement.  There was no significant benefit in terms of OS 
for pegylated interferontreated patients.  Although this regimen was recently approved 


 
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in the United States, pegylated interferon is not currently approved in Europe for 
adjuvant melanoma therapy. 
High-dose and pegylated interferon have significant toxicities that affect the tolerability, 
compliance, and effectiveness of this agent in the adjuvant setting 
(Hauschild et al. 2008).  The most common toxicities include flu-like symptoms (fever, 
myalgia and fatigue, nausea, vomiting, headache), myelosuppression, liver function 
abnormalities, and depression (Hauschild et al. 2008; PDR Network 2011).  
Kirkwood et al. (1996) reported a 76% incidence of at least one severe or life-threatening 
adverse event as well as two lethal adverse events from hepatic toxicity in patients 
treated with high-dose interferon alpha-2b.  In this study (ECOG 1684), approximately 
one-third of interferon-treated patients required at least one reduction in dose for toxicity.  
In the recent EORTC 18991 trial that evaluated the adjuvant administration of pegylated 
interferon alpha-2b for up to 5 years, 31% of 608 pegylated interferontreated patients 
discontinued study treatment for toxicity, and the median duration of treatment was only 
12 months (Eggermont et al. 2008). 
A number of studies have focused on the safety and efficacy of low-dose interferon 
alpha-2b in the adjuvant treatment of resected cutaneous melanoma.  Patients in these 
studies have received 3 million IU three times per week for 624 months 
(Grob et al.1998; Pehamberger et al. 1998; Hancock et al. 2004; Richtig et al. 2005).  
These studies have either demonstrated no benefit on RFS or OS in association with 
low-dose interferon therapy (Hancock et al. 2004; Richtig et al. 2005) or enrolled only 
Stage II patients who did not have the benefit of sentinel lymph node biopsy 
(Grob et al. 1998; Pehamberger et al. 1998).  Thus, there are no studies that 
demonstrate durable effects of low-dose interferon on RFS in adequately staged patients 
with Stage IIC or Stage III disease. 
Prospective randomized studies using various non-specific immunostimulatory agents 
(such as bacille Calmette-Guérin, Corynebacterium parvum, levamisole, and mistletoe 
extract), cytokines (such as interferon gamma, interleukin-2, and granulocyte 
macrophage colony-stimulating factor [GM-CSF]), and melanoma-specific vaccines have 
not shown any therapeutic efficacy in the adjuvant setting (Garbe et al. 2008). 
In summary, there is currently no international consensus regarding the dose, duration, 
or use of interferon alpha-2b for the treatment of melanoma in the adjuvant setting 
(Hauschild et al. 2008).  There is no generally accepted standard of care for adjuvant 
therapy in patients with resected cutaneous melanoma at high risk for recurrence that is 
both effective and well tolerated (Balch et al. 2009; Dummer et al. 2010).  Consequently, 
patients are very often offered participation in clinical trials of investigational adjuvant 
therapies (Marsden et al. 2010). 


 
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1.2 
BACKGROUND ON VEMURAFENIB 
1.2.1 
Role of BRAF Kinase in Melanoma 
Recent advances in the understanding of the biology of melanoma have identified the 
role of BRAF kinase, a serine-threonine kinase downstream of RAS within the 
mitogen-activated protein kinase (MAPK) pathway.  Mutated BRAF dimers constitutively 
activate the MAPK pathway leading to the generation of transcriptional signaling that 
promotes tumor growth.  BRAF mutations have been identified in 50%68% of 
metastatic melanomas, specifically melanomas that arise from intermittent sun-exposed 
skin (e.g., in superficial spreading and nodular melanomas) (Maldonado et al. 2003; 
Beeram et al. 2005; Curtin et al. 2005; Lang and MacKie 2005).  BRAF mutations are 
uncommon in acral, mucosal, and uveal melanomas.  At the same time, BRAF mutations 
are common in benign nevi, suggesting that they are an early event in melanoma 
oncogenesis.  Approximately 90% of the BRAF mutations seen in metastatic melanoma 
occur in codon V600, and over 90% of the V600 mutations involve the substitution of 
valine for glutamate at amino acid 600 of the BRAF kinase (i.e., V600E; 1799 T→A) 
(Sanger Institute 2011).  Other uncommon variants, such as V600K, V600R, and V600D 
(in order of decreasing frequency), have also been identified, primarily in melanoma.  
Nonclinical data indicate that these variant mutations, similar to V600E, result in 
constitutive activation of the BRAF kinase.  Most of the transforming activity of BRAFV600 
is thought to occur through the constitutive activation of the MAPK pathway 
(Gray-Schopfer et al. 2007).  Depletion of mRNA that codes for oncogenic BRAF by 
small interfering RNA leads to growth inhibition of melanoma cell lines in vitro 
(Sumimoto et al. 2004), thus leading to the development of agents that can inhibit 
mutated BRAF kinase and to tests that can identify V600 mutations (Ascierto et al. 2010; 
Flaherty et al. 2010; Vultur et al. 2011). 
The cobas BRAF V600 Mutation Test and Sanger sequencing techniques have been 
used to identify BRAFV600E mutation status in clinical trials. 
1.2.2 
Vemurafenib BRAF Inhibitor 
Vemurafenib (formerly RO5185426) is a lowmolecular weight, orally available inhibitor 
of the oncogenic form of the BRAF kinase commonly found in melanoma.  It is a potent 
and highly selective inhibitor of V600-mutant BRAF. 
1.2.3 
Clinical Pharmacokinetics of Vemurafenib 
The clinical pharmacokinetics of vemurafenib are based on data available from 
five studies in patients who received the commercial (microprecipitated bulk powder) 
formulation:  Study NP22676, a cytochrome P450 (CYP) metabolism study in patients 
with BRAFV600 mutationpositive Stage IV melanoma; Study NP25158, a mass balance 
study in patients with BRAFV600 mutationpositive Stage IV melanoma; Study NP25163, 
a dose-escalation study in patients with BRAFV600 mutationpositive unresectable 
Stage IIIC or Stage IV melanoma; Study NP22657, a Phase II, open-label study in 
patients with BRAFV600 mutationpositive Stage IV melanoma, in which the effects of 


 
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vemurafenib on the QT interval were evaluated; and Study NO25026, a Phase III, 
randomized, controlled study in patients with BRAFV600 mutationpositive unresectable 
Stage IIIC or Stage IV melanoma.  Detailed descriptions of the design and 
pharmacokinetic (PK) results for each of these studies are provided in the Vemurafenib 
Investigator’s Brochure (IB). 
On the basis of dose-limiting toxicities reported at the 1120-mg twice daily (BID) dose 
level, the 960-mg BID dose was considered the maximum tolerated dose (MTD) and 
selected for use in all subsequent clinical trials, including the Phase I (Study PLX06-02) 
treatment extension cohorts, the aforementioned clinical pharmacology studies, and the 
Phase II (Study NP22657) and Phase III (Study NO25026) studies in patients with 
unresectable Stage IIIC or metastatic melanoma. 
Population PK analysis using pooled data from 458 patients estimated the median of the 
steady-state maximum plasma concentration (Cmax), minimum plasma concentration 
(Cmin), and area under the concentrationtime curve (AUC) from 0 to 12 hours (AUC012hr) 
to be 62 g/mL, 59 g/mL, and 734 g/mL  hour, respectively.  The pharmacokinetics of 
vemurafenib are shown to be dose proportional between 240 and 960 mg BID, and a 
population PK analysis also confirmed that the pharmacokinetics of vemurafenib are 
linear. 
Vemurafenib at a dose of 960 mg BID (240-mg film-coated tablets) is absorbed with a 
median time to maximum concentration (tmax) of approximately 4 hours.  Vemurafenib 
exhibits marked accumulation after repeat dosing at 960 mg BID, with high inter-patient 
variability.  The median accumulation ratio estimate for a BID regimen is 7.36.  In the 
Phase II study, mean vemurafenib plasma concentration 4 hours after dose increased 
from 3.6 g/mL on Day 1 to 49.0 g/mL on Day 15 (range: 5.4118 g/mL). 
At steady state, the mean vemurafenib exposure in plasma is stable (concentrations 
before and 24 hours after the morning dose), as indicated by the mean ratio of 1.13.  
Similar marked inter-patient variability in plasma exposure was observed at steady state, 
independent of dose reduction. 
Following oral dosing, the absorption rate constant for the population of metastatic 
melanoma patients is estimated to be 0.19 hr1 (with 101% between-patient variability). 
The apparent volume of distribution for vemurafenib in patients with metastatic 
melanoma on the basis of population PK analysis is estimated to be 91 L (with 64.8% 
between-patient variability).  It is highly bound to human plasma proteins in vitro ( 99%). 
The relative proportions of vemurafenib and its metabolites recovered in blood, urine, 
and feces were characterized in a human mass balance study at Genentech.  
On average, 95% of the dose was recovered within 18 days, the majority (94%) in feces, 


 
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with  1% recovered in urine.  The parent compound was the predominant component 
(95%) in plasma. 
The commercial dosage form of vemurafenib is the 240-mg film-coated tablet. 
1.2.4 
Efficacy of Vemurafenib in Patients with BRAFV600 
MutationPositive Metastatic Melanoma 
Among 32 evaluable patients with relapsed/refractory metastatic melanoma who 
enrolled in the extension cohort of the Phase I Study PLX06-02, the confirmed best 
overall response rate (BORR) following vemurafenib treatment was 56.3%:  3 patients 
(9.4%) achieved a complete response and 15 patients (46.9%) had a partial response.  
Ten patients (31.3%) had stable disease, and the remaining four patients had 
progressive disease.  The median duration of response and progression-free survival 
(PFS) were 7.6 and 7.8 months, respectively; the 1-year OS rate was 57% 
(Flaherty et al. 2010; Vemurafenib IB). 
Results of the Phase II, open-label, single-arm study (Study NP22657) of vemurafenib in 
132 patients with progression of metastatic melanoma after first-line treatment showed a 
confirmed BORR of 53% on the basis of independent review committee assessments.  
The median duration of response and PFS were 6.7 and 6.1 months, respectively 
(Vemurafenib IB). 
In Study NO25026 (Vemurafenib IB), a Phase III open-label, multicenter, international, 
randomized study of vemurafenib in previously untreated patients with BRAFV600 
mutationpositive unresectable or metastatic melanoma, patients were randomized to 
treatment with vemurafenib (960 mg BID) or dacarbazine (DTIC; 1000 mg/m2 every 
3 weeks). 
A total of 675 patients were randomized to vemurafenib (n  337) or DTIC (n  338).  
Randomization was stratified according to disease stage, LDH, ECOG Performance 
Status, and geographic region.  Baseline characteristics were well balanced between 
treatment groups.  Of the patients randomized to vemurafenib, most were male (59%) 
and White (99%), median age was 56 years (28% were  65 years), all patients had 
ECOG Performance Status of 0 or 1, and the majority of patients had Stage M1c 
disease (66%).  The co-primary efficacy endpoints of the study were OS and PFS. 
At the preplanned interim analysis for OS, the Data Safety Monitoring Board (DSMB) 
recommended a release of the study results because of the compelling efficacy findings.  
Statistically significant and clinically meaningful improvements were observed in the 
co-primary endpoints of OS (p  0.0001) and PFS (p  0.0001) (unstratified log-rank test).  
Statistical analyses used a clinical cutoff date of 31 March 2011.  After a median 
6.21 months of follow-up in the vemurafenib arm, the Kaplan-Meier estimate of median 
survival of patients randomized to vemurafenib was not reached (expected 
95% CI:  9.59 months).  For patients randomized to receive DTIC, after a median 


 
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4.46 months of follow-up, the Kaplan-Meier estimate of median survival was 
7.89 months (95% CI:  7.26, 9.63).  The Kaplan-Meier estimate of the 6-month survival 
rate for patients randomized to vemurafenib was 83% (95% CI:  79%, 87%) and 
63% (95% CI:  57%, 69%) for patients randomized to DTIC.  The hazard ratio (HR) for 
death was 0.44 (95% CI:  0.33, 0.59) in favor of vemurafenib.   
Treatment with vemurafenib resulted in a clinically meaningful and statistically significant 
improvement in PFS compared with DTIC treatment (p  0.0001).  There was a 
statistically significant improvement in BORR (confirmed) with vemurafenib (48.4%; 
95% CI:  41.6%, 55.2%) compared with DTIC (5.5%; 95% CI:  2.8%, 9.3%; p  0.0001), 
as assessed by the investigator. 
Detailed descriptions of the design and results for each of these studies are provided in 
the Vemurafenib IB. 
1.2.5 
Safety of Vemurafenib 
The safety evaluation of vemurafenib is based on results in patients from 
three Genentech clinical pharmacology studies (Study NP22676, n  25; Study NP25163, 
n  52; and Study NP25158, n  7), a Phase I study, (Study PLX06-02, n  108; 
Vemurafenib IB), a single-arm, Phase II study in previously treated patients with 
BRAFV600 mutationpositive Stage IV melanoma (Study NP22657, n  132; Vemurafenib 
IB; Sosman et al. 2012), and a Phase III, randomized, open-label, multicenter, global 
study in patients with unresectable Stage IIIC or Stage IV BRAFV600 mutationpositive 
melanoma (Study NO25026, n  675; Vemurafenib IB; Chapman et al. 2011).  The type 
and incidence of adverse events observed across all studies in patients with BRAFV600 
mutationpositive unresectable or metastatic melanoma patients were consistent. 
In the clinical pharmacology Study NP25163, all 52 patients (100%) had at least 
one adverse event.  Nearly all patients (96%) had at least one treatment-related adverse 
event.  The majority of adverse events were of mild or moderate intensity.  The most 
common adverse events (reported in  30% of patients) in the vemurafenib group were 
fatigue (58%), arthralgia (58%), nausea (50%), rash (38%), and diarrhea (33%).  
Fifty-four percent of patients had at least one Grade  3 adverse event; 40% of patients 
had at least one treatment-related adverse event.  The most commonly reported 
treatment-related adverse events (incidence  5%) were squamous cell carcinoma (SCC) 
of skin (23%), increased gamma glutamyl transferase (GGT; 9%), basal cell carcinoma 
(7%), rash (7%), maculopapular rash (6%), and arthralgia (6%).  Twelve patients (23%) 
experienced at least one Grade 4 adverse event, including 2 patients who experienced 
two Grade 4 adverse events.  Five of the 12 patients had Grade 4 adverse events that 
were assessed by the investigator as treatment related.  The most frequent Grade 4 
adverse event was increased GGT (n  5 patients, assessed as related to treatment in 4 
patients).  The other Grade 4 adverse events were hyperuricemia (assessed as related 
to treatment) and pneumonia, sepsis, convulsion, pseudomonas infection, 


 
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staphylococcal infection, multi-organ failure, and pulmonary embolism (all of which were 
assessed as unrelated to study treatment). 
Study PLX06-02 (Flaherty et al. 2010; Vemurafenib IB) assessed the safety of escalating 
doses of vemurafenib.  At the highest dose administered (1120 mg BID), dose-limiting 
rash (National Cancer Institute Common Terminology Criteria for Adverse Events 
[NCI CTCAE] Grade 3) and fatigue (Grade 3) were observed in multiple patients.  
Vemurafenib doses of up to 960 mg BID (the MTD) were generally well tolerated. 
In the Phase II clinical trial (Study NP22657) (Sosman et al. 2012), all patients 
experienced at least one adverse event, the most common of which were arthralgia 
(68%), fatigue (57%), rash (54%), photosensitivity (52%), nausea (42%), alopecia (38%), 
pruritus (32%), diarrhea (32%), skin papilloma (31%), and hyperkeratosis (30%).  
Seventy-three percent of patients experienced at least one Grade  3 adverse event.  
Sixty-one percent of patients had at least one Grade  3 treatment-related adverse event.  
The most commonly reported, treatment-related adverse events (incidence  5%) were 
SCC of skin (23%), increased serum GGT (9%), basal cell carcinoma (7%), rash (7%), 
maculopapular rash (6%), and arthralgia (6%).  The Vemurafenib IB contains detailed 
descriptions of study drug-related adverse events observed in Study NP22657.   
In the Phase III randomized study of vemurafenib versus DTIC (BRIM-3, 
Study NO25026, clinical cutoff:  1 March 2011) (Chapman et al. 2011; Vemurafenib IB), 
the safety results showed that vemurafenib was generally tolerable and toxicity was 
manageable with dose modifications.  Ninety-nine percent and ninety-one percent of 
patients in the vemurafenib and DTIC treatment groups, respectively, experienced at 
least one adverse event.  The majority of adverse events were of mild or moderate 
intensity.  The most common adverse events (reported in  30% of patients) in the 
vemurafenib group were in the system organ class of skin and subcutaneous tissue 
disorders; the most common of which were alopecia, rash, and photosensitivity.  Other 
adverse events that occurred in  10% of vemurafenib-treated patients and at an 
incidence of more than twice that observed in the DTIC group included SCC of skin, skin 
papilloma, arthralgia, headache, dysgeusia, pyrexia, peripheral edema, pain in extremity, 
myalgia, decreased appetite, diarrhea, hyperkeratosis, seborrheic keratosis, and dry skin.  
Of the 37 patients who switched from DTIC to vemurafenib, 32 patients (86%) had at 
least one adverse event and 26 patients (70%) reported at least one treatment-related 
adverse event.  The majority of adverse events were of mild or moderate intensity. 
Fifty-nine percent of patients in the vemurafenib arm and thirty-three percent of patients 
in the DTIC arm experienced one or more adverse events of Grade  3 in intensity.  
Treatment-related adverse events of Grade  3 occurred in 49% of patients in the 
vemurafenib arm and 20% in the DTIC arm.  Sixteen percent and nine percent of 
vemurafenib-treated patients had cutaneous SCC (cuSCC) and keratoacanthoma (KA), 
respectively, compared with  1% and 0% for DTIC-treated patients.  For reporting 
purposes, all cases of cuSCC and KA were considered to be treatment related, Grade 3, 


 
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and serious.  Other common Grade  3 adverse events in the vemurafenib group 
included photosensitivity reaction (9%), rash (8%), maculopapular rash (8%), 
and arthralgia (4%); the corresponding frequency of these adverse events in the DTIC 
group were 0%, 0%, 0%, and  1%.  The most common Grade  3 adverse event in the 
DTIC group was neutropenia, occurring in 9% of patients;  1% of patients in the 
vemurafenib group experienced neutropenia.  Of the 37 patients who crossed over from 
DTIC to vemurafenib, 11 (30%) experienced one or more Grade  3 adverse event after 
crossover.  These consisted of fatigue (2 patients), muscle weakness, pyrexia, anemia, 
hyperkeratosis, basal cell carcinoma, maculopapular rash, rash, cellulitis, palmarplantar 
erythrodysesthesia syndrome, and decreased neutrophil counts (all 1 patient each).  Of 
these, eight events were considered by the investigator to be treatment related. 
The percentage of patients who experienced one or more Grade 4 adverse events was 
lower in the vemurafenib group (13 patients [4%]) than in the DTIC group (22 patients 
[8%]).  Grade 4 adverse events in the vemurafenib group included pulmonary embolism 
(3 patients), increased GGT (2 patients), increased blood creatine phosphokinase (CPK), 
increased blood bilirubin, increased lipase, ageusia, intraventricular hemorrhage, 
pneumonia, pneumothorax, respiratory distress, and neutropenia (1 patient each).  
Five patients treated with vemurafenib had a total of six Grade 4 adverse events that 
were assessed as related to treatment (increased blood bilirubin, GGT increased 
[2 patients], ageusia, increased CPK, and neutropenia).  One of the 37 patients who 
crossed over experienced a Grade 4 decreased neutrophil count after crossover.  It was 
assessed as unrelated to treatment and non-serious. 
Grade 5 adverse events were reported in 6 patients (2%) in the vemurafenib group.  
Only one adverse event (intracranial tumor hemorrhage) was assessed as treatment 
related.  Each of the other 5 patients experienced the following Grade 5 adverse events 
(all unrelated to study treatment):  general physical health deterioration, cerebrovascular 
accident, pneumonia, aortic aneurysm rupture, and cardiac failure.  Grade 5 adverse 
events were reported in 8 DTIC-treated patients (3%).  Fatigue and mucosal 
inflammation, initially classified as Grade 5 adverse events in 1 patient, were 
subsequently considered to be symptoms of disease progression and downgraded to 
Grade 1, resulting in a total of 7 patients with Grade 5 adverse events.  Only one 
adverse event (shock) was assessed as treatment related.  Dyspnea, lung infection, 
cardiac arrest, and cardiac tamponade were reported in 1 patient each, 
and cardiopulmonary failure was reported in 2 patients.  No Grade 5 adverse events 
were reported in the 37 patients who crossed over from DTIC to vemurafenib. 
The incidence of cuSCC in vemurafenib-treated patients was approximately 20% across 
studies.  The majority of the excised lesions reviewed by an independent central 
dermatopathology laboratory were classified as SCC-KA subtype or with mixed KA 
features (52%), both of which are less invasive types of cuSCC.  Most lesions classified 
as “other” (43%) were benign skin lesions (e.g., verruca vulgaris, actinic keratosis, 
benign keratosis, cyst/benign cyst).  cuSCC usually occurred early in the course of 


 
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treatment, with a median time to the first appearance of 78 weeks.  Of the patients who 
experienced cuSCC, approximately 33% experienced more than one occurrence, with a 
median time between occurrences of 6 weeks.  Cases of cuSCC (including KA) were 
typically managed with simple excision, and patients generally continued on treatment 
without dose modification.  A risk mitigation plan, including regular dermatologic and 
head and neck examinations and chest computed tomography (CT) scans, has been 
established to monitor for and treat SCC (both cutaneous and non-cutaneous) in 
patients receiving vemurafenib in clinical trials (see Section 5.1.2.3). 
Eight skin lesions in 7 of 337 vemurafenib-treated patients were reported as new primary 
malignant melanomas in Study NO25026.  No cases were reported in 338 patients 
treated with DTIC.  Cases were managed with excision and without sequelae, and 
patients continued treatment without dose adjustment.  Surveillance measures to 
monitor for the occurrence of new primary melanomas as well as cuSCC are outlined in 
Section 4.5.1.5, Section 4.5.2.2, and Section 5.1.2.3.  Details for Study NO25026 are 
summarized in the Vemurafenib IB. 
The effects of vemurafenib on the QT interval were investigated as part of the Phase II 
Study NP22657.  This was not a “thorough” QT study as defined by health authorities 
because vemurafenib cannot be administered to healthy volunteers and it was not 
feasible to administer a positive or negative control to patients with metastatic melanoma.  
However, the centrally read ECG data obtained in triplicate at serial, time-matched 
points before and after dosing met the regulatory expectations for robust assessment of 
oncology therapeutics on the QT interval.  The maximum absolute corrected QT (QTc) 
values at any point after dosing were as follows:   450 milliseconds (ms), 49 patients 
(37.1%);  480 ms, 6 patients (4.5%);  500 ms (Grade 3), 2 patients (1.5%).  One 
patient (0.8%) had a maximal QTc increment  60 ms (Grade 2) compared with baseline.  
The upper boundary of the one-sided 95% CI for mean QTc prolongation reached a 
maximum of 17.7 ms on Day 105 of study treatment, on the basis of measurements in 
90 patients.  Mean QTc interval prolongation closely tracked with the mean vemurafenib 
steady-state concentration over time.  None of the QT prolongation events were serious 
or led to premature withdrawal from treatment or dose modification/interruption; none 
were clearly associated with prolongation of cardiac repolarization, arrhythmia, or any 
other cardiac function disorder.  Additional information on the relationship between 
vemurafenib exposure and QT interval prolongation may be found in the Vemurafenib IB. 
Two cases of SCC of the head and neck have been reported in two patients treated with 
vemurafenib in excess of 300 days while enrolled in a clinical trial.  Pathology 
examination of both tumors (one a primary tonsillar tumor, the other a primary tongue 
tumor) revealed the presence of invasive SCC.  Of note, the first patient’s medical 
history was significant for risk factors for head and neck cancer and the tumor tissue 
tested positive for human papilloma virus (HPV).  The second patient did not appear to 
possess any risk factors for head and neck cancer, and the preliminary examination of 


 
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the tumor tissue did not reveal the presence of HPV genome.  Full details are provided 
in the Vemurafenib IB. 
Five cases of adenomatous colonic polyps have been reported in patients treated with 
vemurafenib for 2 or more years while enrolled in a clinical trial (Chapman et al. 2012).  
The first patient developed an upper gastrointestinal bleed and, on work-up, was found 
to have duodenal ulceration (non-malignant), hyperplastic gastric polyps, and 5 colonic 
polyps (3 of which were adenomatous).  A previous colonoscopy in 2008, at the time of a 
jejunal resection for recurrent melanoma, documented no prior evidence of colonic 
polyps.  All polyps were resected, and the patient subsequently resumed vemurafenib 
therapy.  The second patient was found, on elective colonoscopy, to have 7 colonic 
polyps (5 of which were adenomatous), and all were detected and removed.  This 
patient had not undergone a previous colonoscopy.  The patient has discontinued 
treatment with vemurafenib.  The third patient had, on elective colonoscopy, 10 colonic 
polyps (7 of which were adenomatous).  This patient had a previous colonoscopy 
7 years prior to starting vemurafenib.  The fourth patient had, on elective colonoscopy, 
1 adenomatous colonic polyp.  The fifth patient had, on elective colonoscopy, 
3 adenomatous colonic polyps.  The latter two patients had histories of no prior 
colonoscopy.  In addition, a patient on the Expanded Access Program had 1 colonic 
adenoma discovered after being on vemurafenib for 0.57 years.  This patient had a 
colonoscopy 1.3 years prior to starting vemurafenib, and a polyp was found and 
resected at that time. 
One case of progression of NRAS-mutated chronic myelomonocytic leukemia occurred 
in a male patient with metastatic melanoma treated with vemurafenib for less than 
2weeks (Callahan et al. 2012).  After the first dose of vemurafenib, laboratory results 
showed a marked leukocytosis and monocytosis, and vemurafenib treatment was 
subsequently held.  There was a temporal relationship between vemurafenib treatment 
and increase in WBC and absolute monocyte counts through multiple cycles of 
dechallenge and rechallenge.  In vitro studies demonstrated proliferation of the leukemic 
cell population upon stimulation with a BRAF inhibitor, an effect that was reversed upon 
addition of a MEK inhibitor.  Further, the cells exhibited dose-dependent and reversible 
activation of extracellular-signal-regulated kinase (ERK) in the NRAS-mutated leukemic 
clone.  A second case of progression of a preexisting RAS-mutated malignancy 
(pancreatic adenocarcinoma with KRAS mutation) was reported with vemurafenib in 
2014.  On the basis of its mechanism of action, vemurafenib may cause progression of 
cancers associated with RAS mutations.  Vemurafenib should be used with caution in 
patients with a prior or concurrent cancer associated with RAS mutation.  Full details are 
provided in the Vemurafenib IB. 
As of 31 March 2013, 12 cases of drug reaction with eosinophilia and systemic 
symptoms (DRESS) syndrome have been observed with vemurafenib treatment.  No 
fatal cases have been reported.  The time to onset was 725 days.  In the majority of 
patients (n  7), vemurafenib was discontinued.  Some patients (n  5) were treated with 


 
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systemic steroids with corresponding improvement or resolution of symptoms.  In 
addition, 2 patients who were treated with vemurafenib after ipilimumab presented with 
Grade 3 rash and had biopsies that showed pathology consistent with drug 
hypersensitivity reaction (Harding et al. 2012).  Full details are provided in the 
Vemurafenib IB. 
In a Phase I trial (Study CA 184161, sponsored by Bristol-Myers Squibb), asymptomatic 
Grade 3 increases in transaminases and bilirubin occurred with concurrent 
administration of ipilimumab (3 mg/kg) and vemurafenib (960 mg BID or 720 mg BID) 
(Ribas et al. 2012).  All liver laboratory abnormalities were asymptomatic and reversible 
with permanent discontinuation of the study drugs or, in some cases, administration of 
corticosteroids.  On the basis of these data, concurrent administration of ipilimumab and 
vemurafenib is not recommended outside of a clinical trial.  Full details are provided in 
the Vemurafenib IB.  
An assessment of liver-related adverse events reported with vemurafenib use showed 
that 63 cases of medically confirmed serious adverse events were drug-induced liver 
injury (DILI) on the basis of clinical chemistry criteria from the DILI Expert Working 
Group (Aithal et al. 2011).  Of the 63 cases, two were assessed as severe; both were 
reported as hepatic failure.  The outcome of both cases of hepatic failure have been 
reported to be completely resolved following vemurafenib discontinuation.  There were 
no reported deaths among the 63 cases of liver injury.  The median time to onset of the 
adverse events was 44 days after initial dose.  The median ALT to alkaline phosphatase 
ratio was 1.5, suggesting a trend toward cholestatic pattern of liver injury.  There were 
no risk factors or populations at risk identified. 
A review of the Roche safety database found neutropenia to be an uncommon (6 cases 
per 1000 person-years, 0.6%) adverse drug reaction associated with the use of 
vemurafenib, often occurring during the first 612 weeks of treatment.  It appears to be 
reversibleusually within 2 weekswith temporary interruption, dose reduction, or 
discontinuation and, in some cases, was managed with GM-CSF. 
A safety review completed in 2014 identified pancreatitis as an adverse drug reaction in 
patients treated with vemurafenib.  Seventeen cases of pancreatitis with no strong risk 
factors or alternative explanations were reported.  Eight of the seventeen cases were 
assessed as likely associated with vemurafenib use on the basis of event onset latency 
and rechallenge/dechallenge information.  The clinical presentation in terms of severity, 
mild to moderate, was consistent with the clinical picture of drug-induced pancreatitis 
(Lankisch et al. 1995). 
As of Q4 2014, an adverse drug reaction of potentiation of radiation treatment toxicity 
has been identified in patients treated with radiation either prior, during, or subsequent to 
vemurafenib treatment.  This is based on twenty cases of radiation injuries, adjudicated 
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the events in all 20 cases were evaluated as worse than expected for the normal tissue 
tolerance to therapeutic radiation with fatal outcome in 3 cases.  The reaction was seen 
in the skin, esophagus, lung, liver, rectum, and urinary bladder.  Vemurafenib should be 
used with caution when given concomitantly or sequentially with radiation treatment.  
Full details are provided in the Vemurafenib IB. 
For a review of serious adverse events and adverse events that led to discontinuation of 
study treatment, please consult the Vemurafenib IB. 
See the Vemurafenib IB and/or prescribing information for additional details on 
nonclinical and clinical studies. 
1.3 
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT 
To date, clinical studies of vemurafenib in BRAFV600 locally advanced/unresectable or 
metastatic melanoma have demonstrated a highly favorable ratio of benefit versus risk, 
most compellingly revealed by the meaningful clinical benefit observed in the Phase III, 
randomized, comparative study (BRIM-3, Study NO25026) of vemurafenib versus DTIC.  
The clearly demonstrated benefit of vemurafenib in metastatic melanoma suggests that 
it might also be beneficial to patients with resected cutaneous melanoma who are at high 
risk for recurrencethat is, patients with Stage IIC and Stage III disease.  As noted 
above, interferon alpha-2b is the only widely approved adjuvant therapy for resected, 
cutaneous melanoma but its use is limited by the high incidence of debilitating side 
effects leading to treatment discontinuation in up to one-third of patients 
(Eggermont et al. 2008). 
Because the mutation of BRAF kinase appears to be an early event in the natural history 
of melanoma oncogenesis (Pollock et al. 2003; Kumar et al. 2004), it is likely that the 
prevalence of patients with resected cutaneous melanoma whose tumors harbor 
V600 mutations of BRAF kinase will approximate that observed in the metastatic disease 
setting. 
2. 
OBJECTIVES 
2.1 
PRIMARY OBJECTIVE 
The primary objective of this study is as follows: 
 
To evaluate the efficacy of vemurafenib adjuvant treatment administered over a 
52-week period in patients with completely resected BRAFV600 mutationpositive, 
cutaneous melanoma, as measured by DFS 
 


 
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2.2 
SECONDARY OBJECTIVES 
The secondary objectives of this study are as follows: 
 
To evaluate the efficacy of vemurafenib adjuvant treatment administered over a 
52-week period, as measured by DMFS 
 
To evaluate the efficacy of vemurafenib adjuvant treatment administered over a 
52-week period, as measured by OS 
 
To evaluate the safety and tolerability of vemurafenib in the adjuvant setting 
 
To assess quality of life (QoL) as measured by EORTC 30-item Quality of Life 
Questionnaire (QLQ-C30) 
 
To describe the pharmacokinetics of vemurafenib in the adjuvant setting, assess 
between-patient variability of PK parameters, and explore and quantify potential 
covariates that may contribute to between-patient differences in PK parameters, 
with use of a population PK approach 
 
2.3 
EXPLORATORY OBJECTIVES 
The exploratory objectives of this study are as follows: 
 
To assess the efficacy outcomes and safety profile of vemurafenib adjuvant 
treatment in patients whose melanomas harbor non-E mutations of BRAF kinase at 
amino acid position 600, as detected by DNA sequencing methods 
 
To assess the relationship between vemurafenib exposure and the risk of 
melanoma recurrence or occurrence of new primary melanomas, the occurrence of 
serious adverse events, and abnormalities in safety laboratory parameters 
 
To assess the relationship between biomarkers and risk of melanoma recurrence or 
occurrence of new primary melanomas 
 
To characterize the biomarkers associated with acquisition of resistance to 
vemurafenib in the adjuvant setting 
 
To characterize the molecular phenotype of SCC (cutaneous [including KA] and 
non-cutaneous) or other new primary neoplasms that may be observed in patients 
treated with vemurafenib 
 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF STUDY 
Study GO27826 is a Phase III, international, multicenter, double-blind, randomized, 
placebo-controlled study of patients with completely resected, BRAFV600 
mutationpositive melanoma, as detected by the cobas BRAF V600 Mutation Test, at 
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A total of approximately 475 patients in two separate cohorts will be enrolled. 
 
Cohort 1 (approximately 300 patients) will include patients with completely resected 
Stage IIC, IIIA (patients with one or more nodal metastasis  1 mm in diameter), or 
IIIB cutaneous melanoma, as defined by the AJCC Classification, Version 7 
(Balch et al. 2009). 
 
Cohort 2 (approximately 175 patients) will include patients with Stage IIIC cutaneous 
melanoma, as defined by this classification scheme. 
 
The primary and secondary efficacy and safety objectives of this study will be evaluated 
separately for each cohort. 
Eligible patients will be randomized (1:1 ratio) to receive placebo or vemurafenib over a 
52-week period, with randomization stratified by pathologic stage (Stage IIC, Stage IIIA, 
Stage IIIB) and region (North America, Australia/New Zealand/South Africa/Latin 
America, rest of the world) in Cohort 1 and by region (North America, Australia/New 
Zealand/South Africa/Latin America, rest of the world) in Cohort 2. 
Within each cohort, patients will receive study treatment according to one of the 
following treatment arms: 
 
Arm A:  placebo orally, BID for 52 weeks (thirteen 28-day cycles) 
 
Arm B:  vemurafenib 960 mg orally, BID for 52 weeks (thirteen 28-day cycles) 
 
All eligible patients must have either newly diagnosed melanoma or, at most, 
one metachronous lymph node recurrence (in the absence of prior lymph node 
involvement) that has undergone gross total resection; no prior systemic treatment for 
melanoma is permitted.  Full pathologic staging that incorporates the findings from 
sentinel lymph node biopsy and complete regional lymphadenectomy is required of all 
patients with lymph node involvement. 
All patients will be required to provide a sample of tumor tissue for further BRAF 
mutation testing and exploratory biomarker and correlative science assessments at 
baseline. 
Randomization will occur within 90 days after definitive surgery (i.e., the last surgery 
required for the treatment or the diagnosis of melanoma), and study drug administration 
will begin within 4 calendar days after randomization. 
After signing informed consent, all eligible patients will undergo screening procedures 
that include a contrast-enhanced magnetic resonance imaging (MRI) of the brain (or 
contrast-enhanced CT of the brain if an MRI is not generally available or is 
contraindicated) and contrast-enhanced CT or MRI of the chest, abdomen, and pelvis.  
While participating in the study, patients will undergo regular, periodic safety evaluations.  
Surveillance for tumor recurrence (including physical examination and 
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every 13  2 weeks until Week 104.  During Years 3, 4, and 5 of the study, physical 
examination will be performed every 13  2 weeks, and the aforementioned imaging 
studies will be performed every 26  4 weeks until recurrence of melanoma or an 
occurrence of a new primary melanoma or until end of study (see Section 3.2), 
whichever occurs earlier.   
In addition, all patients will undergo contrast-enhanced MRI of the brain (or CT if MRI is 
generally not available or is contraindicated) every 52  4 weeks until recurrence of 
melanoma, occurrence of a new primary melanoma, or until end of study (see 
Section 3.2), whichever occurs earlier.  Results of fluorodeoxyglucosepositron emission 
tomography (FDG-PET) scans alone will not be sufficient for purposes of documenting 
disease recurrence.  Evidence of recurrence must be documented by biopsy of a 
suspect lesion, except in patients whose suspicious lesions are deemed by the 
investigator not amenable to biopsy.  For patients with an isolated, suspected 
intracranial recurrence, histologic documentation of recurrence of surgically accessible 
lesions is highly recommended but not required; for these patients, MRI (or CT if MRI is 
not generally available or is contraindicated) documentation of recurrent disease is 
sufficient.  Surveillance studies to monitor for melanoma recurrence should use the 
same imaging modality that was used at screening. 
Patients who have had a DFS event do not need additional scans or physical exams for 
surveillance of melanoma recurrence.  These patients are also required to discontinue 
study drug if it was being administered at the time of final diagnosis of the DFS event.  
However, these patients must still have a chest CT or MRI for SCC surveillance at 13  2 
weeks and 26  2 weeks after the last dose of study drug. 
A schedule of assessments is provided in Appendix 1. 
Details about the first anti-cancer therapy given after melanoma recurrence or an 
occurrence of a new primary melanoma will be captured for all patients in the study. 
The final analysis of the primary endpoint of DFS will occur for each cohort after the 
targeted number of events for each cohort is reached (approximately 120 DFS events for 
Cohort 1 and approximately 105 DFS events for Cohort 2).  There will be no interim 
analyses of the primary endpoint of DFS. 
For each cohort, patients without melanoma recurrence or an occurrence of a new 
primary melanoma and their physicians will remain blinded until the final DFS analysis 
for that cohort.  Physicians may request unblinding for patients who have documented 
recurrence or an occurrence of a new primary melanoma for purposes of planning 
subsequent treatment.  Unblinding requires prior approval of the Roche Medical Monitor 
or designee. 


 
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In this adjuvant trial, crossover to vemurafenib treatment will not be allowed for patients 
receiving placebo because this trial is designed to evaluate adjuvant vemurafenib 
therapy starting within 4 calendar days after randomization and no later than 94 calendar 
days after definitive melanoma surgery (i.e., the last surgery required for the treatment or 
the diagnosis of melanoma). 
3.1.1 
Independent Review Committee 
An independent review committee will not be employed for this study. 
3.1.2 
Data Safety Monitoring Board 
An independent DSMB that has been involved in the review of safety data from prior and 
current vemurafenib studies will be employed for this study.  This committee will conduct 
periodic reviews of selected safety data according to procedures outlined in a DSMB 
charter. 
3.2 
END OF STUDY 
All patients will be followed for melanoma recurrence or occurrence of new primary 
melanoma and overall survival for at least 2 years after Cycle 1, Day 1 of study 
treatment.  Patients may be followed for melanoma recurrence or occurrence of new 
primary melanoma for up to 5 years and OS for up to 6 years after Cycle 1, Day 1 of 
study treatment.  Patients who exhibit recurrence of melanoma or a new primary 
melanoma during the study will be followed for OS. 
The end of the study is defined as the date of the last patient, last visit, which is 
expected to occur approximately 6 months after the last patient enrolled has been 
followed for 2 years after Cycle 1, Day 1 of the study.  
3.3 
RATIONALE FOR STUDY DESIGN 
3.3.1 
Rationale for Test Product Dosage 
The vemurafenib dose selected for the current study was based on clinical efficacy and 
safety initially observed in Study PLX06-02 (Phase I) at the MTD of 960 mg BID and 
further characterized in Studies NP22657 (Phase II) and NO25026 (Phase III) of 
vemurafenib in locally advanced/unresectable or metastatic melanoma.  This regimen is 
associated with suppression of pERK in tumor biopsy specimens and consistent with 
exposures in nonclinical models that were associated with anti-tumor activity.   
A 52-week period of adjuvant therapy has been selected because this is believed to 
balance the risks and tolerability of therapy with the expected benefit in the adjuvant 
setting, on the basis of an assessment of benefit versus risk observed in the metastatic 
setting. 


 
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3.3.2 
Rationale for Patient Population 
This study includes patients with AJCC v7 Stages IIC, IIIA (patients with at least 
one nodal metastasis  1 mm in diameter), IIIB, and IIIC melanoma, primarily because the 
risk of melanoma recurrence is in excess of 50% over the 5-year period after primary 
surgical resection and 5-year OS estimates vary from 40% to 60% in these patients 
(Balch et al. 2009).  This segment of the melanoma patient population has a high unmet 
medical need for effective adjuvant treatment. 
On the basis of historical data, the median recurrence-free interval in patients with 
Stages IICIIIB disease is expected to be approximately 24 months, on average.  In 
contrast, the median recurrence-free interval for Stage IIIC patients is expected to be a 
much shorter 7.7 months (Eggermont et al. 2008; Eggermont AM, "Update on staging, 
tumor burden and adjuvant therapy," presented at Perspectives in Melanoma XIV 
Conference, Sept 1718, 2010).  Because of the disparate distributions of time to 
melanoma recurrence for the different substages and in order to ensure adequate power 
to detect the hypothesized treatment effect across a broad spectrum of patients at high 
risk for recurrence, eligible patients will be grouped into two independently powered 
cohorts:  Stage IICIIIB patients will be in Cohort 1 and Stage IIIC patients will be in 
Cohort 2. 
3.3.3 
Rationale for Control Group 
This will be a placebo-controlled study.  Whereas the unique toxicity profile for 
vemurafenib may pose difficulty in effectively masking the proposed study, a placebo 
control will help to minimize bias in reporting of key assessments of safety, efficacy, and 
QoL. 
Although high-dose interferon alpha-2b is widely approved as an adjuvant treatment for 
resected cutaneous melanoma, a placebo control group will be used for the following 
reasons: 
 
There is no clear international consensus on the utility of adjuvant interferon 
alpha-2b in the management of resected, cutaneous melanoma. 
 
The treatment effect of adjuvant interferon alpha-2b as measured by recurrence-free 
survival is relatively modest (only about an 18% reduction in the risk of melanoma 
recurrence [Mocellin et al. 2010]). 
 
The considerable toxicity of interferon alpha-2b appears to be associated with 
substantial deterioration in QoL among recipients (Bottomley et al. 2009). 
 
A substantial proportion of interferon alpha-2btreated patients discontinue study 
treatment prematurely because of toxicity (Eggermont et al. 2008). 
 
Recent studies of other anti-melanoma therapies (e.g., ipilimumab) have 
demonstrated the feasibility of conducting a placebo-controlled study in the adjuvant 
setting. 
 


 
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3.3.4 
Rationale for Biomarker Assessments 
Roche is committed to the collection of biomarker samples in all clinical study protocols.  
The objective of biomarker profiling is to enable development of treatments specifically 
targeted for optimal patient benefit.  The rationale for the planned biomarker analyses is 
explained below.  However, because the body of knowledge of potential new biomarkers 
is evolving, the definitive list of analyses may be modified on the basis of new 
information. 
3.3.4.1 
Biomarkers Associated with Recurrence of Melanoma or 
Occurrence of New Primary Melanomas 
Despite high rates of objective response observed with vemurafenib monotherapy in 
locally advanced or metastatic melanoma, advanced disease is still not curable.  
Preliminary results suggest that resistance to BRAF kinase inhibition is driven by 
multiple mechanisms including alternate signaling via the MAPK pathway (as a result of 
NRAS mutations, CRAF activation, and MEK activation via COT kinase), signaling 
through the PI3K/AKT pathway (as a result of either AKT3 amplification or PTEN loss), 
or signaling via activation of cell surface receptors PDGFR or IFG-1R 
(Vultur et al. 2011).  Some or all of these biomarkers (and others that may be of interest 
as a result of further progress in the field) will be investigated in paired tumor specimens 
obtained at baseline and at melanoma recurrence or occurrence of a new primary 
melanoma in order to help researchers understand the molecular phenotype of tumors at 
the time of melanoma recurrence or occurrence of a new primary melanoma as well as 
potential mechanisms of resistance to adjuvant vemurafenib. 
3.3.4.2 
Cutaneous Squamous Cell Carcinoma or Other New Primary 
Neoplasms 
Cases of cuSCC (which include those classified as KA or mixed KA subtype) have been 
reported in patients treated with vemurafenib.  CuSCC (including the events of SCC of 
the skin and KA) is an adverse event of special interest.  In addition, other neoplastic 
lesions (SCC of the head and neck and adenomatous colonic polyps) have been 
observed in patients who received long-term vemurafenib therapy.  Biomarkers will be 
evaluated in a biopsy of cuSCC/KA (and compared with normal skin) and the other new 
primary neoplasms.  The objective of additional molecular analyses of cuSCC/KA 
lesions or other suspicious neoplasms that develop during the study is to explore their 
potential relationship to study treatment, to further understand the molecular profile of 
these lesions, and to identify factors that may be associated with development of these 
lesions.  Candidate mutations that have been implicated in the development of 
cuSCC/KAsuch as HRAS, NRAS, KRAS, and p53will be investigated.  Furthermore, 
expression levels of MAPK pathway proteins such as ERK phosphorylation may be 
investigated if further evidence develops, implicating these effector molecules in the 
development of cuSCC/KA or other suspicious neoplasms. 


 
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3.3.4.3 
Disease Monitoring and Prediction of Early Relapse 
One of the most critical challenges in adjuvant therapy has been the effective monitoring 
of the presence of minimal residual disease and the identification in an early and timely 
fashion of those patients with an increased risk for relapse.  Common serum markers 
such as LDH, MIA, and S100B have been shown to predict a poor prognosis in 
advanced melanoma (Perrotta et al. 2010).  However, LDH and S100B do not reliably 
identify the presence of low tumor burden or locoregional metastases in melanoma 
patients at high risk for recurrence (Egberts et al. 2009).  Longitudinal monitoring for the 
presence of or changes in the BRAFV600 mutation in blood (by measuring the level of 
circulating BRAF-mutant DNA) could potentially be an important marker to monitor for 
melanoma recurrence or the occurrence of new primary melanomas. 
3.4 
OUTCOME MEASURES 
3.4.1 
Efficacy Outcome Measures 
The efficacy outcome measures for this study are described below. 
3.4.1.1 
Primary Efficacy Outcome Measure 
DFS will be defined as the time from randomization until the date of the first local, 
regional, or distant melanoma recurrence, occurrence of new primary melanoma, or 
death from any cause.  The DFS component of melanoma recurrence will be assessed 
by the investigator.  The DFS component of an occurrence of a new primary melanoma 
will be based upon the diagnosis made by a Roche-designated central pathology 
laboratory.  See Section 4.5.1.4 for histopathologic and imaging requirements for 
documentation of recurrence. 
3.4.1.2 
Secondary Efficacy Outcome Measures 
DMFS will be defined as the time from randomization until the date of diagnosis of 
distant (i.e., non-locoregional) metastases or death from any cause. 
OS will be defined as the time from randomization to the date of death from any cause. 
3.4.2 
Safety Outcome Measures 
The safety outcome measures for this study are as follows: 
 
Incidence, nature, and severity of adverse events, serious adverse events, and 
adverse events of special interest.  Severity will be graded according to NCI CTCAE, 
Version 4.0. 
 
Changes from baseline in ECG findings and targeted clinical laboratory analytes 
during the course of study treatment 
 


 
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3.4.3 
Pharmacokinetic Outcome Measures 
The PK outcome measures for this study are as follows: 
 
Plasma concentrations of vemurafenib at clinically relevant timepoints, including 
steady-state trough values as well as those associated with diagnosis of SCC,dose 
interruption, and/or reduction for toxicity, melanoma recurrence, and occurrence of a 
new primary melanoma 
 
3.4.4 
Patient-Reported Outcome Measure 
The patient-reported outcome (PRO) measure for this study is as follows: 
 
To assess patient-reported symptoms, functional interference, and health-related 
QoL in the vemurafenib and placebo treatment arms with use of EORTC QLQ-C30 
(see Appendix 4) 
 
3.4.5 
Exploratory Outcome Measures 
The exploratory outcome measures for this study are as follows: 
 
Retrospective identification of study patients whose tumors harbor non-E, activating 
mutations of BRAF kinase at amino acid position 600 (e.g., BRAFV600K), with use of 
DNA sequencing methods as a means to assess clinical outcomes in this patient 
subgroup 
 
Levels of candidate tumor biomarkers in plasma and serum (e.g., circulating mutant 
BRAF DNA) at different timepoints during the study compared with baseline as a 
means to monitor for and predict melanoma recurrence or occurrence of a new 
primary melanoma 
 
Candidate tumor biomarkers at the protein, RNA, and DNA levels (including RAS 
mutations) that may characterize the molecular phenotype of tumors at melanoma 
recurrence or occurrence of a new primary melanoma as well as predict 
development of resistance to adjuvant vemurafenib treatment 
 
Molecular characterization of SCC (cutaneous [including KA] and non-cutaneous) 
or other new primary neoplasms that may be observed in patients treated with 
vemurafenib 
 
3.5 
MINIMIZATION OF BIAS 
Patients will be randomly assigned to receive placebo or vemurafenib through the use of 
an interactive voice or Web response system (IxRS).  Placebo tablets and packaging 
configurations will have physical characteristics that will not permit their identification as 
distinct from those of the active comparator, vemurafenib.  
A DSMB will be employed to conduct periodic evaluations of safety data.  All analyses 
for the DSMB’s review will be prepared by an independent data coordinating center.  
Sponsor’s personnel will not have access to by-arm efficacy and safety summaries or 
listings prior to the formal reporting of study results. 


 
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Patients who are free from melanoma recurrence and occurrence of a new primary 
melanoma will be blinded to treatment assignment until completion of the final DFS 
analysis for each cohort.  Only when knowledge of the investigational product is 
essential for a treatment decision (e.g., planning follow-on therapy in a patient who 
exhibits melanoma recurrence or an occurrence of a new primary melanoma prior to the 
final DFS analysis), clinical management, or the welfare of the patient, the investigator 
may request to unblind a patient’s treatment assignment.  In such cases, the IxRS 
system will be used to allow disclosure of an individual patient’s treatment assignment to 
the treating investigator without unblinding the study Sponsor.  Unblinding requires prior 
approval of the Roche Medical Monitor or designee. 
In this adjuvant trial, crossover to vemurafenib treatment will not be allowed for patients 
receiving placebo because this trial is designed to evaluate adjuvant vemurafenib 
therapy starting within 4 calendar days after randomization and no later than 94 calendar 
days after definitive melanoma surgery (i.e., the last surgery required for the treatment or 
the diagnosis of melanoma). 
4. 
MATERIALS AND METHODS 
4.1 
PATIENTS 
4.1.1 
Inclusion Criteria 
Patients must meet all of the criteria listed below for study entry. 
Disease-Specific Inclusion Criteria 
 
All patients should have histologically confirmed melanoma of cutaneous origin. 
 
All patients without clinical or radiologic evidence of regional lymph node 
involvement must undergo sentinel lymph node biopsy.  Patients must undergo a 
complete regional lymphadenectomy if a sentinel lymph node biopsy procedure 
cannot be performed or a sentinel lymph node cannot be detected.  All patients who 
have either clinical or radiographic evidence of regional lymph node involvement or 
evidence of melanoma involvement in the sentinel lymph node must undergo 
complete regional lymphadenectomy.  Melanoma infiltration of lymph node(s) must 
be histologically confirmed. 
Note:  Surgical management should comply with published guidelines for 
surgical standards of care (see Appendix 5).  
 
Patients with lymph node involvement either at initial presentation or a 
first metachronous nodal recurrence are eligible:  
Tany (including x) N  at initial presentation 
TanyN0 followed by N  recurrence (i.e., first metachronous nodal recurrence)  
 
Patients with BRAFV600 mutationpositive, cutaneous melanoma (either pathologic 
Stage IIC or Stage III according to AJCC Staging Criteria v7 [see Appendix 10]) that 
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Note:  Patients with Stage IIIA disease must have at least one lymph node 
metastasis measuring  1 mm in diameter (per the Rotterdam classification 
scheme) on pathologic staging. 
 
BRAFV600 mutation status of the current primary tumor or involved lymph node 
determined to be positive using the cobas BRAF V600 Mutation Test 
 
The patient must have been surgically rendered free of disease within 90 days of 
randomization. 
 
ECOG Performance Status of 0 or 1 (see Appendix 6) 
 
General Inclusion Criteria 
 
Male or female patients aged  18 years 
 
Ability to participate and willingness to give signed informed consent prior to 
performance of any study-related procedures and to comply with the study protocol 
 
Life expectancy of at least 5 years 
 
Patients must have fully recovered from the effects of any major surgery 
(including complete regional lymphadenectomy) or significant traumatic injury prior 
to the first dose of study drug. 
Note:  All staging-related procedures, including complete regional 
lymphadenectomy, must be completed within 90 days prior to randomization. 
 
Negative stool occult blood 
Note:  If stool occult blood is positive, the patient will need to be cleared for 
study inclusion by a gastroenterologist or appropriately trained designee. 
 
For select patients with known personal history of adenomatous colorectal polyps or 
colorectal cancer, family history of colon cancer in which a first- and/or 
second-degree relative has been diagnosed with colorectal cancer at or after the 
age of 60 years, or signs or symptoms that could be related to colon cancer as 
determined by the site investigator or designee, a screening colonoscopy with 
adequate resection of all visualized polyps must be performed. 
Note:  For select patients requiring a screening colonoscopy (described above), 
colonoscopy should be complete to the cecum, with adequate bowel 
preparation, and performed within the 90-day screening period.  For select 
patients (described above), screening colonoscopy is not required if 
colonoscopy to the cecum with adequate bowel preparation and adequate 
resection of all visualized polyps was performed within 1 year of the start of the 
90-day screening period, unless the site investigator deems it necessary. 
Note:  A history of colon cancer greater than 5 years prior to randomization 
does not preclude patients from being eligible. 
 
Adequate hematologic, liver, and renal function, defined by the following laboratory 
results obtained within 28 days prior to randomization: 
Absolute neutrophil count  1.5  109/L 
Platelet count  100  109/L 


 
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Hemoglobin  9 g/dL 
Bilirubin  1.5  the upper limit of normal (ULN) 
AST, ALT, and alkaline phosphatase  2.5  ULN 
Serum creatinine  1.5  ULN or creatinine clearance  50 mL/min on the basis of 
the CockroftGault glomerular filtration rate estimation: 
[(140age)  (weight in kg)  (0.85 if female)]/[72  (serum creatinine in mg/dL)] 
PT, INR, aPTT  1.5  ULN 
 
Female patients of childbearing potential and male patients with partners of 
childbearing potential must agree to always use two effective forms of contraception 
beginning from the informed consent signature date until at least 6 months after 
completion of study therapy. 
In general, effective forms of contraception include surgical sterilization, a reliable 
barrier method with spermicide, birth control pills or patches, intrauterine 
contraceptive device, or contraceptive hormone implants.  Please note that 
vemurafenib may decrease the plasma exposure of medicines predominantly 
metabolized by CYP3A4, including hormonal contraceptives; consider the use of 
alternative effective methods of contraception. 
Female patients of childbearing potential are defined as sexually mature women 
without prior hysterectomy who have had any evidence of menses within the past 
12 months. 
In order to be considered NOT of childbearing potential, amenorrhea for a period 
of 12 months or longer must have occurred in the absence of chemotherapy, 
anti-estrogens, or ovarian suppression. 
 
Negative serum pregnancy test within 14 days prior to randomization in women of 
childbearing potential 
 
Women of non-childbearing potential need not undergo pregnancy testing. 
 
Absence of any psychological, familial, sociological, or geographical condition that 
has the potential to hamper compliance with the study protocol and follow-up 
schedule (such conditions should be discussed with the patient before trial entry) 
 
4.1.2 
Exclusion Criteria 
Patients who meet any of the criteria listed below will be excluded from study entry. 
Cancer-Related Exclusion Criteria 
 
History of any systemic or local therapy (e.g., chemotherapy, biologic or targeted 
therapy, hormonal therapy, or photodynamic therapy) for the treatment or prevention 
of melanoma, including interferon alpha-2b and pegylated interferon alpha-2b 
 
History of limb perfusion therapy 
 
History of radiotherapy for the treatment of melanoma including but not limited to 
radiation therapy to a resected nodal basin 
 
History of radiotherapy for the treatment of prostate, cervical, or rectal cancer 


 
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 
Allergy or hypersensitivity to components of the vemurafenib formulation 
(see Section 4.3.1.1) 
 
Invasive malignancy other than melanoma at the time of enrollment or within 5 years 
prior to first study drug administration, except for adequately treated (with curative 
intent) basal or squamous cell carcinoma of the skin, in situ carcinoma of the cervix, 
in situ ductal adenocarcinoma of the breast, in situ prostate cancer, or limited stage 
bladder cancer 
Note:  This requires that the pathology evaluation of the screening 
Papanicolaou (Pap) smear and of any polyps resected at the screening 
colonoscopy does not show any invasive malignancy. 
 
Family history of inherited colon cancer syndromes (e.g., familial adenomatous 
polyposis, attenuated adenomatous polyposis, MUTYH-associated polyposis, 
hyperplastic polyposis syndrome, Peutz-Jeghers syndrome, juvenile polyposis 
syndrome, Lynch syndrome, and Cowden syndrome) and/or history of colon cancer 
in which a first- and/or second-degree relative has been diagnosed with colorectal 
cancer before the age of 60 years 
 
Known personal history of more than three ( 3) adenomatous colorectal polyps or a 
personal history of adenomatous colorectal polyp(s)  2 cm in size.  This also 
applies to the screening colonoscopy for select patients. 
 
History of or current clinical, radiographic, or pathologic evidence of in-transit 
metastases, satellite, or microsatellite lesions 
Note:  In-transit metastases are any skin or subcutaneous metastases that are 
 2 cm from the primary lesion but are not beyond the regional nodal basin.  
Satellite lesions are skin or subcutaneous lesions within 2 cm of the primary 
tumor that are considered intralymphatic extensions of the primary mass.  
Microsatellite lesions are any discontinuous nest of metastatic cells more than 
0.05 mm in diameter that are clearly separated by normal dermis (not fibrosis or 
inflammation) from the main invasive component of melanoma by a distance of at 
least 0.3 mm (McCardle et al. 2011).  
 
History of or current clinical, radiographic, or pathologic evidence of recurrent lymph 
node involvement after resection of a primary melanoma with lymph node 
involvement at any time in the past 
 
History of local and/or regional and/or distant melanoma recurrence (excluding first 
metachronous nodal recurrence) 
Note:  This does not include patients who have had a new primary melanoma. 
 
History or current radiographic or pathologic evidence of distant metastases as 
defined either by an abnormal contrast-enhanced brain MRI (or brain CT if MRI is 
not generally available or is contraindicated) or histologically proven, distant 
metastatic disease (visceral or cutaneous) in an extracranial site 
Note:  This includes patients who have had their metastatic disease resected. 
 


 
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Cardiac Exclusion Criteria 
 
History of clinically significant cardiac or pulmonary dysfunction, including 
the following: 
Current, uncontrolled Grade  2 hypertension 
Unstable angina 
Current Grade  2 dyspnea or hypoxia or need for supplemental oxygen 
History of symptomatic congestive heart failure of Grade IIIV New York Heart 
Association Class (NYHA) (for the Criteria Committee of the NYHA 1994, see 
Appendix 3) 
Serious cardiac arrhythmia requiring treatment, with the exceptions of atrial 
fibrillation and paroxysmal supraventricular tachycardia 
History of myocardial infarction within 6 months prior to randomization 
History of congenital long QT syndrome or QTc interval  450 ms at baseline 
History of or current uncorrectable electrolyte disorder affecting serum levels of 
potassium, calcium, or magnesium 
 
General Exclusion Criteria 
 
Major surgical procedure (other than wide local excision, sentinel lymph node biopsy, 
or complete regional lymphadenectomy) or significant traumatic injury within 
4 weeks prior to the first dose of study drug 
 
History of clinically significant liver disease (including cirrhosis), current alcohol 
abuse, or known infection with HIV, hepatitis B virus, or hepatitis C virus (HCV) 
 
Active infection or chronic infection requiring chronic suppressive antibiotics 
 
Pregnancy or breastfeeding at the time of randomization 
 
Autoimmune disease (e.g., systemic lupus erythematosus, autoimmune vasculitis, 
inflammatory bowel disease [Crohn’s disease and ulcerative colitis]) 
 
Acromegaly 
 
History of malabsorption or other clinically significant metabolic dysfunction 
 
Any other serious concomitant medical condition that, in the opinion of the 
investigator, would compromise the safety of the patient or compromise the patient’s 
ability to participate in the study 
 
Requirement for a concomitant medication or dietary supplement that is prohibited 
during the study (see Section 4.4.2) 
 
Unwillingness or inability to comply with study and follow-up procedures 
 
Current, recent (within 28 days prior to randomization), or planned use of any 
investigational product outside of this study 
 
4.2 
METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
After written informed consent has been obtained and eligibility has been established, 
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two treatment arms with the use of an IxRS.  Randomization will be stratified by 
pathologic stage (Stage IIC, Stage IIIA, Stage IIIB) and region (North America, 
Australia/New Zealand/South Africa/Latin America, rest of the world) in Cohort 1 and by 
region (North America, Australia/New Zealand/South Africa/Latin America, rest of the 
world) in Cohort 2.  A stratified, permuted, block randomization scheme will be used to 
obtain approximately a 1:1 ratio between the two treatment groups. 
The investigator, patient, and Sponsor will be blinded to treatment assignment.  Per 
health authority reporting requirements, the treatment code will be available through 
IxRS to the Roche Drug Safety Group for all unexpected serious adverse events that are 
considered by the investigator to be related to study drug (see Section 5.7). 
As noted in Section 3.5, patients who are free from melanoma recurrence or an 
occurrence of a new primary melanoma will be blinded to treatment assignment until 
completion of the final DFS analysis for each cohort.  Only when knowledge of the 
investigational product is essential for a treatment decision (e.g., planning follow-on 
therapy in a patient who exhibits melanoma recurrence or an occurrence of a new 
primary melanoma prior to the final DFS analysis), clinical management, or the welfare 
of the patient, the investigator may request to unblind a patient’s treatment assignment.  
In such cases, the IxRS system will be used to allow disclosure of an individual patient’s 
treatment assignment to the treating investigator without unblinding the study Sponsor. 
Any site requests for unblinding (whether for safety reasons or planning follow-on 
therapy in the setting of melanoma recurrence or an occurrence of a new primary 
melanoma) require prior approval of the Roche Medical Monitor or designee. 
4.3 
STUDY TREATMENT 
4.3.1 
Formulation, Packaging, and Handling 
Study drug packaging will be overseen by the Roche Clinical Trial Supplies department 
and bear a label with the identification required by local law as well as the protocol 
number.  The packaging and labeling of the study medication will be in accordance with 
Roche standards and local regulations.  
Local packaging and labeling requirements may differ in some countries. 
Upon arrival of investigational products at the site, site personnel should check for 
damage and verify proper identity, quantity, integrity of seals, and temperature 
conditions and report any deviations or product complaints to the study monitor upon 
discovery. 
Study drug will be stored at the clinical site under the recommended storage conditions:  
Do not store above 25C (77F) as indicated on the study drug label.  Patients will be 
requested to store study drug at the recommended storage conditions noted on the label, 
out of the reach of children or other co-inhabitants. 


 
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4.3.1.1 
Active Study Drug (Vemurafenib) and Placebo 
The active study drug (RO5185426/F17) is a pinkish white to orange white, oval, 
biconvex film-coated tablet with “ROCHE” engraved on one side.  It contains 240 mg of 
vemurafenib.  The inactive ingredients in the active study drug tablets are as follows:   
 
Kernel:  croscarmellose sodium, colloidal anhydrous silica, hydroxypropylcellulose, 
and magnesium stearate 
 
Film coat:  poly(vinyl alcohol), titanium dioxide, macrogol 3350, talc, and iron oxide 
red 
 
The placebo (RO5185426/F18) is a pinkish white to orange white, oval, biconvex 
film-coated tablet with “ROCHE” engraved on one side, matching the active study drug 
(RO5185426/F17).  It contains no drug substance.  The placebo tablet contains: 
 
Kernel:  lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, 
and magnesium stearate 
 
Film coat:  Poly(vinyl alcohol), titanium dioxide, macrogol 3350, talc, and iron oxide 
red 
 
Each placebo tablet contains 796 mg of lactose (3.2 g lactose per 4-tablet dose).  The 
effect of lactose on individuals varies from person to person dependent upon the lactose 
exposure, lactase deficiency, and lactose malabsorption.  A study (Suarez et al. 1995) 
found that individuals who self-reported severe lactose intolerance could drink one 
240 mL glass of milk with minimal, if any, symptoms.  There are approximately 12 g of 
lactose in 240 mL (8 oz) of milk.  In light of this, it is unlikely that most patients who are 
lactose intolerant will suffer any gastrointestinal discomfort from the 3.2 g BID of lactose 
in the placebo tablet. 
For further details, see the local prescribing information for vemurafenib or the 
Vemurafenib IB. 
4.3.2 
Dosage, Administration, and Compliance 
4.3.2.1 
Study Drug (Vemurafenib/Placebo) 
Study drug will be taken at home, orally, at a dose of 4 tablets BID for a maximum of 
52 consecutive weeks (thirteen 28-day cycles).  
The first dose is to be taken in the morning, and the second dose is to be taken 
approximately 12 hours later in the evening.  Study drug tablets are to be swallowed 
whole with water.  The tablets should not be chewed or crushed.  If a dose is missed, it 
can be taken 4 or more hours prior to the next dose to maintain the BID regimen.  Both 
doses should not be taken at the same time.  Missed days or drug holidays will not be 
made up, thereby maintaining 52 weeks of treatment.  A patient who has a break in 
dosing in excess of 28 consecutive days will be permanently discontinued from study 
treatment. 


 
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Patients will be asked to record the date and time of doses in a diary and to return all 
used and unused drug supply containers as a measure of compliance.  All supplies, 
including partially used or empty containers of study drug, must be returned to the 
Roche study monitor at the end of the study, unless alternative destruction has been 
authorized by Roche/designee or is required by local or institutional regulations.  Copies 
of all drug dispensing and inventory logs must be returned to the Roche study monitor at 
the end of the study.  
Guidelines for interruption, dose modification, and permanent discontinuation of study 
treatment are provided in Section 5.1. 
4.3.3 
Investigational Medicinal Product Accountability 
All investigational medicinal products (IMPs) required for completion of this study 
(vemurafenib, placebo) will be provided by Roche.  The investigational site will 
acknowledge receipt of IMPs with use of the IxRS to confirm the shipment condition and 
content.  Any damaged shipments will be replaced.  
IMPs will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure or returned to Roche with the appropriate documentation.  
The site’s method of IMP destruction must be agreed upon by Roche.  The site must 
obtain written authorization from Roche before any IMP is destroyed, and IMP 
destruction must be documented on the appropriate form. 
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of 
by the study site should be recorded on the Drug Inventory Log. 
4.3.4 
Post-Study Access to Vemurafenib 
Because this is an adjuvant study, Roche does not intend to provide vemurafenib or 
other study interventions to patients after conclusion of the protocol-specified treatment 
period (i.e., 52 weeks) or after patient withdrawal. 
4.4 
CONCOMITANT THERAPY 
4.4.1 
Permitted Therapy  
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter 
drugs, herbal/homeopathic remedies, nutritional supplements) used by a patient from 
7 days prior to the date of informed consent until the end-of-treatment visit.  Patients 
who use oral contraceptives or hormone replacement or maintenance therapies should 
continue their use as outlined in the eligibility criteria.  Please note that vemurafenib may 
decrease the plasma exposure of medicines predominantly metabolized by CYP3A4, 
including hormonal contraceptives; consider the use of an effective alternative method of 
contraception.  Refer to Section 4.1.1 for information on contraception.  Patients who 
experience toxicities may be treated symptomatically as clinically indicated.  All 


 
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concomitant medications should be reported to the investigator and recorded on the 
Concomitant Medications electronic Case Report Form (eCRF). 
At study initiation, patients should continue with their permitted concomitant therapies as 
directed by their physician.  Additionally, any diagnostic, therapeutic, or surgical 
procedure performed during the study period should be recorded, including the date, 
indication, description of the procedure(s), and any clinical findings. 
Anti-emetics and antidiarrheal medications should not be administered prophylactically 
before initial treatment with the study drug.  At the discretion of the investigator, 
prophylactic anti-emetic and antidiarrheal medication(s) may be used per standard 
clinical practice before subsequent doses of study drug.  Hematopoietic growth factors 
(e.g., erythropoietin and GM-CSF) and pain medications as dictated by standard practice 
are acceptable while the patient is enrolled in the study.  However, growth factors should 
not be administered prophylactically before initial treatment with study drug. 
4.4.2 
Prohibited Therapy 
Use of the following therapies is prohibited during the study treatment period (i.e., from 
the time of informed consent through the end-of-treatment visit): 
 
St. John’s wort or hyperforin, rifampicin/rifampin, rifabutin, rifapentine, 
carbamazepine, phenytoin, and phenobarbital 
 
Anti-platelet agents (except for low-dose aspirin) 
 
Use of the following therapies is prohibited during the study (i.e., from the time of 
informed consent through the study completion visit): 
 
Any concomitant therapy intended for the treatment of melanoma, either approved 
by health authorities or experimental, including chemotherapy, radiotherapy, 
immunotherapy, hormonal therapy, biologic therapy, investigational agents, or 
herbal therapy 
 
Chronic systemic corticosteroid use other than the management of toxicity related to 
study drug ( 10 mg of prednisone or equivalent dose of other anti-inflammatory 
corticosteroids for  7 days) or use of immunosuppressants 
 
Institution of corticosteroids during the study for the management of toxicity related to 
study drug is allowed as long as the minimum effective dose is utilized for the shortest 
period of time needed to adequately treat the patient and that a quick taper is instituted 
as soon as possible. 
Patients who require the use of any of these agents will be discontinued from study 
treatment and followed for safety outcomes for 4 weeks after the last dose of study drug 
or until initiation of another anti-cancer therapy, whichever comes first.  Follow-up for 
efficacy, exploratory outcomes, and new primary malignancies will continue until 
melanoma recurrence or an occurrence of a new primary melanoma until end of study 


 
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(see Section 3.2) or loss to follow-up, withdrawal of consent, or death (whichever occurs 
first).  Patients will be followed for survival until end of study (see Section 3.2).  
4.4.2.1 
Medication Precautions to Prevent Drug Interactions 
Results from a drugdrug interaction study in patients with metastatic melanoma 
demonstrated no interaction of vemurafenib with CYP2C19 and CYP2C9.  However, 
drug interactions were observed with CYP1A2 and CYP3A4. 
CYP1A2 inhibition was observed when a single dose of caffeine (a CYP1A2 substrate) 
was co-administered after repeat dosing with vemurafenib for 15 days, resulting in a 
2.6-fold increase in the mean AUC of caffeine. 
CYP3A4 induction was observed when a single dose of midazolam (a CYP3A4 
substrate) was co-administered after repeat dosing with vemurafenib for 15 days, 
resulting in a 39% decrease in the mean AUC of midazolam. 
An interaction between vemurafenib and dextromethorphan (a CYP2D6 substrate) was 
suggested by a mean increase in dextromethorphan area under the concentration-time 
curve from Time 0 to last measurable concentration (AUC0last) of 47% based on the 
no-effect 90% CI boundary.  However, this interaction is not likely to be because of the 
inhibition of CYP2D6 by vemurafenib because the AUC0last of the dextromethorphan 
metabolite dextrorphan also increased by 46%. 
In nonclinical studies, inhibition of CYP2C9 inhibition by vemurafenib was observed in 
vitro (i.e., IC50 of 5.9 M).  When a single dose of warfarin (a CYP2C9 substrate) was 
co-administered after repeat dosing with vemurafenib for 15 days, some patients 
exhibited increased warfarin exposure (mean, 18%). 
In another in vitro CYP inhibition study, the effect of vemurafenib on CYPs 2A6, 2B6, 
2C8, and 2E1 was studied at concentrations up to 100 M.  The determined IC50 values 
were  100,  100, 12, and  100 M, respectively.  Therefore, vemurafenib could 
potentially impact exposure of concomitant drugs which major clearance route relies on 
the CYP2C8 enzymatic pathway. 
In summary, vemurafenib may increase the plasma exposure of drugs predominantly 
metabolized by CYP1A2 and decrease the plasma exposure of drugs predominantly 
metabolized by CYP3A4.  In addition, vemurafenib could potentially impact exposure of 
concomitant drugs which major clearance route relies on the CYP2C8 enzymatic 
pathway. 
If CYP1A2 substrates must be co-administered with vemurafenib, investigators should 
assess the safety risk associated with a potential increase in plasma concentrations of 
CYP1A2-metabolized drugs.  If CYP3A4 substrates must be co-administered with 
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CYP3A4-metabolized drugs due to a potential decrease in their plasma concentration.  
Dose adjustments for medications predominantly metabolized via CYP1A2 or CYP3A4 
should be considered on the basis of their therapeutic windows before concomitantly 
treating with vemurafenib.  Doses of concomitant CYP1A2- and CYP3A4-metabolized 
drugs, but not the dose of vemurafenib, may be adjusted as necessary to alleviate the 
impact of drug interaction. 
Caution should be exercised when vemurafenib is co-administered with warfarin 
(CYP2C9) in patients with melanoma. 
No dose adjustment is recommended for drugs metabolized by CYP2D6 or CYP2C19. 
Little metabolism of vemurafenib ( 10%) was detected in nonclinical studies and in 
clinical data from a mass balance study with 14C-vemurafenib in patients with melanoma.  
Nonclinical studies suggest that CYP3A4 metabolism and subsequent glucuronidation 
are responsible for the metabolism of vemurafenib.  No clinical data are currently 
available evaluating the effects of CYP3A4 inducers or inhibitors on vemurafenib 
exposure. 
In vitro studies have demonstrated that vemurafenib is both a substrate and an inhibitor 
of the efflux transporter P-glycoprotein (P-gp).  In the clinical setting, the effects of 
vemurafenib on drugs that are substrates of P-gp and the effects of P-gp inducers and 
inhibitors on vemurafenib exposure are unknown. 
Refer to Appendix 8 for a list of typical examples of CYP1A2, CYP3A4, and CYP2C9 
substrates and CYP3A4 inducers and inhibitors.  A more extensive list of medications 
can be found online at the following link:  
http://medicine.iupui.edu/clinpharm/ddis/table.aspx. 
4.4.2.2 
Medications Affecting the QT Interval 
Certain medications could affect the QT interval in ECG measurements required in this 
study.  Specifically, anti-emetics other than those belonging to the 5-HT3 receptor 
antagonist class (i.e., granisetron, ondansetron, dolasetron, palonosetron) are preferred 
because the latter have the potential to prolong the QT interval.  Investigators are 
advised to avoid or take precautions in closely monitoring patients who are on 
medications or herbal and vitamin supplements that may increase the QT interval.  
Alternative treatment options for medications known to affect the QT interval should be 
discussed with each patient prior to his or her inclusion into this study.  A list of 
medications that may cause QT interval prolongation is provided in Appendix 9.  Refer to 
http://www.azcert.org/ for additional information and references. 


 
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4.5 
STUDY ASSESSMENTS 
4.5.1 
Description of Study Assessments 
4.5.1.1 
Medical History and Demographic Data 
Medical history includes clinically significant diseases within the previous 5 years, major 
surgeries, cancer history (including prior cancer therapies and procedures), and all 
medications (e.g., prescription drugs, over-the-counter drugs, herbal/homeopathic 
remedies, nutritional supplements) used by the patient within 7 days prior to the date of 
informed consent. 
Demographic data will include age, sex, and self-reported race/ethnicity (where 
applicable/permissible). 
4.5.1.2 
Vital Signs 
For all patients, systolic and diastolic blood pressure, heart rate, and temperature (°C) 
will be recorded.  Systolic and diastolic blood pressure and heart rate will be recorded 
with the patient in the seated position after a 5-minute rest period. 
4.5.1.3 
Physical Examinations 
A complete physical examination should include measurement of height and weight; 
head, eyes, ears, nose, and throat; neck; and the cardiovascular, dermatological, 
musculoskeletal, respiratory, gastrointestinal, and neurological systems.  Visual and 
digital evaluation of the anus and anal canal is required as part of a physical examination 
at screening, at Cycle 6, Day 1 ( 2 weeks), and at the end-of-treatment visit ( 2 weeks).  
In addition, all female patients will undergo a pelvic examination, including visual 
inspection of the uterine cervix and Pap smear, at screening, at Cycle 6, Day 1 
( 2 weeks), and at the end-of-treatment visit ( 2 weeks).  Pelvic examinations, including 
Pap smear, that were conducted up to 3 months prior to the start of the 90-day 
screening period and found to be normal, need not be repeated at screening. 
Changes from baseline should be noted at each subsequent physical examination, and 
new or worsened physical examination abnormalities should be recorded as adverse 
events, as appropriate.  An interval medical history that documents changes from 
baseline in new or concomitant diseases, medications, and allergies should be obtained 
coincident with each follow-up physical examination. 
Physical examinations will occur at regular intervals during study drug administration 
period as outlined in Appendix 1.  A physical examination is required at the 
end-of-treatment visit.  During post-treatment follow-up, physical examinations will occur 
every 13  2 weeks until recurrence of melanoma, occurrence of a new primary 
melanoma, or until end of study (see Section 3.2), whichever occurs earlier.  Patients 
who have had recurrence of melanoma or occurrence of new primary melanoma will not 
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4.5.1.4 
Surveillance for Melanoma Recurrence:  Imaging Studies 
All eligible patients will undergo a contrast-enhanced MRI of the brain (or 
contrast-enhanced CT if MRI is not generally available or is contraindicated) and 
contrast-enhanced CT or MRI of the chest, abdomen, and pelvis at screening 
(post-definitive surgery; i.e., the last surgery required for the treatment or the diagnosis 
of melanoma).  Surveillance imaging studies should use the same imaging modality that 
was used at screening. 
Results of FDG-PET scans alone will not be sufficient for purposes of documenting 
melanoma recurrence. 
If recurrent disease or occurrence of a new primary melanoma is suspected on clinical 
grounds, imaging studies (chest, abdomen, pelvis, and brain) must be performed 
expeditiously, even if not mandated in the schedule of assessments. 
All patients who present with findings suspicious for melanoma recurrence must undergo 
a biopsy for histopathologic confirmation, except patients whose suspicious lesions are 
deemed by the investigator not to be amenable to biopsy.  For patients with an isolated, 
suspected intracranial recurrence, histologic documentation of recurrence of surgically 
accessible lesions is highly recommended but not required.  For such patients, MRI (or 
CT if MRI is not generally available or is contraindicated) documentation of recurrent 
disease is sufficient. 
4.5.1.5 
Dermatologic Examination 
A complete history of dermatologic interventions and medications, cuSCC risk factors 
(i.e., Fitzpatrick skin type, radiotherapy, sun exposure, immunosuppression, prior SCC, 
use of tanning beds, and precursor lesions), and prior HPV vaccination must be 
collected at baseline.  Refer to Appendix 7 for a list of Fitzpatrick skin phototypes. 
Complete evaluation of the skin will be conducted at baseline and specified timepoints 
during the study by a dermatologist or his or her designee who is experienced in the 
diagnosis and management of melanoma, non-melanoma skin cancer, cuSCC/KA, and 
actinic keratosis. 
Any suspicious lesions identified from the screening period to the examination at 
26  2 weeks after last dose of study drug must be biopsied and excised and sent for 
pathologic examination.  The available specimen block/sections should be sent to the 
Roche-designated central pathology laboratory for confirmation of diagnosis.  Instruction 
manuals and supply kits will be provided for all central laboratory assessments.  Actinic 
keratosis, KA, or other skin conditions identified by the dermatologist should be treated 
per local standards of care.  


 
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4.5.1.6 
Head and Neck Evaluation 
For all patients, a thorough evaluation of the head and neck will be performed as part of 
the physical examination by the site investigator at screening and every 13  2 weeks 
during the study drug treatment period.  Once a patient completes the treatment period 
or discontinues study drug early, a thorough evaluation of the head and neck by the site 
investigator will be performed at the end-of-treatment visit as part of the physical 
examination.  Once a patient completes the treatment period or discontinues study drug 
early, a thorough head and neck exam to monitor for non-cuSCC will occur (as part of 
the physical examination for patients who continue to have physical examinations) at 
13  2 weeks and 26  2 weeks from the last dose of study drug.  For patients who no 
longer require physical examinations, the head and neck examination will occur 
independently at 13  2 weeks and 26  2 weeks from the last dose of study drug (except 
in the case of withdrawal of consent or loss to follow-up).  Evaluation will consist of at 
least a visual inspection of the oral mucosa and palpation of the tonsils, base of tongue, 
and lymph nodes. 
If, at any time, a head and neck cancer is suspected (e.g., on the basis of signs or 
symptoms), the patient will be referred to a head and neck surgeon/otorhinolaryngologist 
or his or her designee who is experienced in the diagnosis and management of SCC of 
the head and neck.  The head and neck surgeon/otorhinolaryngologist or designee will 
perform a complete evaluation of the head and neck including visual inspection of the 
oral mucosa, palpation of the tonsils, base of tongue, and lymph nodes and flexible 
fiberoptic laryngoscopy in order to evaluate at least the sinonasal cavity, the 
nasopharynx, the base of tongue, larynx, and hypopharynx.  For patients who have been 
referred to a head and neck surgeon/otorhinolaryngologist or designee, this complete 
evaluation of the head and neck by a head and neck surgeon/otorhinolaryngologist or 
designee who is experienced in the diagnosis and management of SCC of the head and 
neck will continue to be conducted every 26  2 weeks during the study drug 
administration period.  Once a patient completes the treatment period or discontinues 
study drug early, a complete evaluation of the head and neck by a head and neck 
surgeon/otorhinolaryngologist will be performed at 26  2 weeks after the last dose of 
study drug (except in the case of withdrawal of consent or loss to follow-up). 
An unscheduled examination may be performed for investigation of any new head and 
neck lesions that are suspected of being non-cuSCC. 
Any suspicious lesions identified must be biopsied and excised and sent for pathological 
examination with appropriate follow-up instituted.  Instruction manuals and supply kits 
will be provided for all central laboratory assessments. 
4.5.1.7 
Colonoscopy by Gastroenterologist 
For select patients with known personal history of adenomatous colorectal polyps or 
colorectal cancer, family history of colon cancer in which a first- and/or second-degree 
relative has been diagnosed with colorectal cancer at or after the age of 60 years, or 


 
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signs or symptoms that could be related to colon cancer as determined by the site 
investigator or designee, a screening colonoscopy will be conducted.  Patients with 
family history of inherited colon cancer syndromes and/or history of colon cancer in 
which a first- and/or second-degree relative has been diagnosed with colorectal cancer 
before the age of 60 years will be excluded from this study. 
Colonoscopy must be complete to the cecum, with adequate bowel preparation, and 
must be performed within the 90-day screening period by a gastroenterologist or his or 
her designee who is experienced in the colonoscopic diagnosis of colorectal polyps and 
colorectal cancer.  All visualized polyps found at the screening or subsequent 
colonoscopies will need to be adequately resected. 
For select patients (described above), the screening colonoscopy is not required if 
colonoscopy to the cecum with adequate bowel preparation and adequate resection of 
all visualized polyps was performed within 1 year of the start of the 90-day screening 
period, unless the site investigator deems it necessary.  Please note that patients with a 
known personal history of more than three ( 3) adenomatous colorectal polyps or a 
personal history of adenomatous colorectal polyp(s)  2 cm in size will be excluded from 
this study.  This also applies to the polyps visualized during the screening colonoscopy 
for select patients described above (see also Section 4.1.2).  
All patients will be required to undergo a post-treatment colonoscopy within 3 months of 
discontinuation of study drug.  Patients who have polyp(s) found at the post-treatment 
colonoscopy will need a follow-up colonoscopy performed after an additional 
3 years  3 months. 
4.5.1.8 
Laboratory Assessments 
Blood samples for hematology, coagulation screening studies, liver function tests, serum 
chemistry, pregnancy test, and hepatitis B and C serology will be analyzed at the study 
site’s local laboratory.  Stool for occult blood will be analyzed at the local site.  Blood and 
tumor tissue samples for biomarker and PK studies will be sent to one or several 
Roche-designated central laboratories or to the Sponsor for analysis.  Instruction 
manuals and supply kits will be provided for all central laboratory assessments.  All 
screening laboratory assessments should be obtained prior to initiation of study drug at 
Cycle 1, Day 1.   
Laboratory assessments will include the following: 
 
Hematology:  Hemoglobin, hematocrit, platelet count, WBC, WBC differential 
(absolute neutrophil count, lymphocyte, monocyte, eosinophil, and basophil counts 
and other cells) 
 
Coagulation:  PT, INR, and aPTT 
 
Serum chemistry:  urea (BUN), creatinine, sodium, potassium, chloride, bicarbonate, 
glucose, phosphorus, magnesium, total calcium, serum albumin, LDH, and uric acid 


 
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 
Liver function tests:  ALT, AST, total bilirubin, and alkaline phosphatase 
 
Pregnancy test:  All women of childbearing potential (including those who have had 
a tubal ligation) will have a serum pregnancy test at screening and every 3 cycles 
(i.e., Cycles 3, 6, 9, and 12 or every 12  2 weeks), starting from Cycle 1, Day 1, and 
at 12  2 weeks and 26  2 weeks after the last dose of study drug.  Urine pregnancy 
tests will be performed as needed.  If a urine pregnancy test is positive, it must be 
confirmed by a serum pregnancy test. 
 
Viral serology/detection:  Hepatitis B (hepatitis B surface antigen [HBsAg] and total 
hepatitis B core antibody [anti-HBc]) and HCV antibody 
 
Stool for occult blood 
 
4.5.1.9 
BRAFV600 Mutation Testing 
Assessment of BRAFV600 mutation status of primary tumor tissue will be investigated 
using the cobas BRAF V600 Mutation Test.  A formalin-fixed paraffin-embedded (FFPE) 
tumor block or at least five serially cut, unstained tumor tissue slides (5 mthick 
sections) from one block will be collected at screening from consented patients.  Patients 
whose tumors test positively for the BRAFV600 mutation will be eligible for enrollment in 
the clinical study if they meet other eligibility criteria. 
For patients whose tumors undergo cobas testing at a Roche-designated central 
testing facility, tumor blocks from the patients who are not eligible for the study will be 
returned after screening has been completed.  For patients eligible for the study, 
additional testing will be performed at Roche or a centralized specialty laboratory 
(see Section 4.5.1.12, Exploratory Biomarker Assessments).  These additional 
investigations will be performed retrospectively and will not influence patient’s eligibility 
for this study. 
4.5.1.10 
Pharmacokinetic Assessments 
Plasma concentrations of vemurafenib will be measured in a central laboratory using a 
validated assay.  Venous blood samples (2 mL) will be collected in sodium heparin 
according to the Schedule of Pharmacokinetic Assessments (Section 4.5.2.2 and 
Appendix 2). 
For all scheduled and unscheduled PK samples, the date and time of the last dose of 
study drug should be specified on the eCRF along with the actual time of the PK blood 
draw.  The procedures for the collection, handling, and shipping of PK samples can be 
found in the laboratory manual.  
The total volume of blood collected for PK assessments will be approximately 16 mL for 
Cycle 1 and an additional approximately 26 mL for patients who complete the full 
52-week treatment regimen.  Unscheduled PK samples are not considered in this 
calculation (see Section 4.5.2.2). 


 
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4.5.1.11 
Electrocardiograms 
All patients will undergo longitudinal ECG monitoring for surveillance of study 
drugmediated prolongation of the QT interval. 
Triplicate digital ECG recordings will be obtained within approximately 25 minutes of 
each other at timepoints specified below and in Appendix 1 (Schedule of Assessments).  
An average of the three readings will be used to determine ECG intervals (e.g., PR, QT).  
ECGs for each patient should be obtained using the same machine whenever possible.  
To minimize variability, it is important that patients be in a resting position for 
 10 minutes prior to each ECG evaluation.  Body position should be consistently 
maintained for each ECG evaluation to prevent changes in heart rate.  Environmental 
distractions (e.g., television, radio, conversation) should be avoided during the pre-ECG 
resting period and during ECG recording.  ECGs should be performed prior to 
administration of the first daily dose of study drug and any scheduled vital sign 
measurements and blood draws. 
This study will employ a central ECG reading facility. 
For safety monitoring purposes, the investigator or his or her designee must review, sign, 
and date all ECG tracings.  Patient management decisions should be based on ECG 
results obtained at the investigative site.  Overall ECG interpretations based on ECG 
results obtained at the investigative site will be documented on the eCRF.  In addition, 
ECG characteristics including heart rate, QRS duration, RR, PR, and QT intervals, and 
changes in T-wave and U-wave morphology will be electronically obtained from a central 
ECG reading facility.  One set of all ECG tracings should be printed and kept with the 
patient’s permanent study file at the site. 
4.5.1.12 
Exploratory Biomarker Assessments 
Patient specimens for dynamic (non-inherited) biomarker discovery and validation will be 
collected from all patients participating in the trial.  These specimens will be used for 
research purposes to identify biomarkers that correlate with response/resistance to 
adjuvant vemurafenib therapy and will help researchers to better understand the 
pathogenesis, course, and outcome of cutaneous melanoma and related diseases.  The 
biomarker analyses are listed below each objective (but may be amended if further 
scientific evidence justifies additional or modified areas of scientific inquiry): 
 
Identify potential biomarkers in blood to monitor for melanoma recurrence or 
occurrence of a new primary melanoma 
Circulating DNA that harbors the V600 mutation of BRAF 
 
Characterize the molecular phenotype of recurrent melanomas or occurrence of 
new primary melanomas and explore potential biomarkers in primary tumor tissue 
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BRAF mutation analysis by DNA sequencing to identify BRAF non-E mutations 
RAS and MEK mutations (other mutations in oncogenes and tumor suppressor 
genes) 
Expression of BRAF, PDGFR, IGF1R, PTEN, COT kinase, and other 
components of melanoma signaling pathways 
 
Characterize SCC (cutaneous [including KA] and non-cutaneous) or other new 
primary neoplasms and normal skin 
HRAS/KRAS/NRAS, BRAF, TP53 mutations as well as other tumor-specific 
mutations 
ERK phosphorylation and Ki-67 expression 
Additional markers dependent on the type of lesion or if new scientific evidence 
warrants 
 
Patients will be asked to provide the following samples: 
 
Melanoma tumor tissue 
Mandatory archival FFPE melanoma tumor tissue (collected prior to initiation of 
study drug).  Note:  1020 unstained FFPE slides will be accepted only if the 
tumor block cannot be provided. 
If additional consent is obtained, archival tumor tissue blocks will be used to 
create a tissue microarray (TMA) for immunohistochemistry analysis and 
potentially for the extraction of RNA and DNA. 
The tumor blocks will be used to set up a TMA:  Tissue cores from tumor 
and normal tissues will be taken out using a puncher and then rearranged 
as an array into a block of wax.  A single array may include tissue cores 
from different patients. 
Melanoma tumor tissue at the time of disease recurrence:  If the patient has a 
lesion accessible for biopsy, the lesion must be a progressing lesion.  If the 
patient is receiving study drug, the specimen should be obtained while the patient 
is still receiving drug (or at maximum, 7 days after last study dose). 
First priority should be given to the collection of a fresh frozen tumor sample (FF 
tumor block). 
Second priority (or if a FF tumor block cannot be obtained) should be given to the 
collection of a FFPE tissue block or 1020 slides. 
 
Serum and plasma samples 
One 6-mL blood sample anticoagulated in EDTA and one 6-mL blood sample in 
a serum separator tube at repeated timepoints (see Schedule of Assessments; 
Appendix 1) 
The total blood loss for plasma and serum biomarker assessments will be 
approximately 12 mL per study visit. 


 
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 
Presumed or suspected SCC (cutaneous [including KA] and non-cutaneous), new 
primary melanoma, other suspicious lesions, and normal skin 
FFPE tissue or 610 unstained FFPE slides from a presumed or suspected SCC 
(cutaneous [including KA] and non-cutaneous), new primary melanoma, or other 
suspicious lesion.  Blocks will be returned after analyses are complete. 
An FFPE specimen containing normal skin (sun exposed, if possible) from 
patients who develop cuSCC/KA or new primary melanoma (only one specimen 
of normal skin is required from patients who develop multiple cuSCCs/KAs during 
study treatment).  Note:  Normal skin biopsies should be collected at the time the 
cuSCC/KA lesion, new primary melanoma, or other suspicious lesion is excised 
in an area of skin with hair follicles present to the level of subcutaneous tissue.  
These samples may be obtained by using a 3- to 4-mm punch biopsy device, 
which should not require suturing. 
Biopsies of suspicious malignant lesions not thought to represent SCC (including 
KA) or new primary melanoma (e.g., basal cell carcinoma) may be submitted at 
the discretion of the investigator. 
 
Sampling procedures, storage conditions, and shipment instructions for all biomarker 
samples (including normal skin) will be detailed in a separate laboratory manual. 
The dynamic biomarker specimens will be subject to the confidentiality standards 
described in Section 8.4. 
Storage of Patient Specimens 
Exploratory biomarker samples (with the exception of the original archival tissue block) 
will be stored for up to 5 years after completion of the study.  Archival tissue blocks 
will be returned at the latest within 36 months.  Patients will have the option to consent 
to the storage of samples remaining after protocol-defined analyses for up to 15 years in 
the Roche Clinical Repository (RCR; see Section 4.5.1.15).  If no consent has been 
given for long-term storage, all samples will be destroyed no later than 5 years after the 
final close of the respective clinical database, unless regulatory authorities require that 
specimens be maintained for a longer period. 
4.5.1.13 
Unscheduled Assessments 
For the purposes of this study, unscheduled assessments may occur coincident with 
early discontinuation of study treatment, early study termination, suspected melanoma 
recurrence, or suspected occurrence of a new primary melanoma between 
protocol-specified study visits (see Section 4.5.2.2 and Section 4.5.2.4).  
4.5.1.14 
Patient-Reported Outcomes 
PRO data will be elicited from all patients in this study to more fully characterize the 
clinical profile of vemurafenib with use of the EORTC QLQ-C30.  The EORTC QLQ-C30 
is a validated and reliable self-report measure of QoL for patients with cancer.  The 
EORTC QLQ-C30 consists of 30 questions that are incorporated into five functional 


 
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domains (i.e., physical, role, cognitive, emotional, and social), a global health 
status/global QoL, three symptom scales (i.e., fatigue, pain, and nausea and vomiting), 
and six single items that assess additional symptoms (dyspnea, appetite loss, sleep 
disturbance, constipation, diarrhea, and the perceived financial burden of treatment 
experienced by cancer patients).  The PRO instrument, EORTC QLQ-C30, will be 
supplied in the local language of each participating country.  Paper-based instruments 
will be distributed by the investigative staff and completed in their entirety by the patient 
at specified timepoints during the study.  To ensure instrument validity and that data 
standards meet health authority requirements, PRO questionnaires should be 
self-administered at the investigative site prior to the completion of other study 
assessments and the administration of study drug. 
4.5.1.15 
Samples for Roche Clinical Repository 
Overview of the Roche Clinical Repository 
The RCR is a centrally administered group of facilities for the long-term storage of 
human biologic specimens, including body fluids, solid tissues, and derivatives thereof 
(e.g., DNA, RNA, proteins, peptides).  The collection and analysis of RCR specimens will 
facilitate the rational design of new pharmaceutical agents and the development of 
diagnostic tests, which may allow for individualized drug therapy for patients. 
Samples for exploratory biomarker analyses from patients who give specific consent to 
participate in this optional research will be stored in the RCR.  These specimens will be 
used to achieve the following objectives: 
 
To study the association of biomarkers with efficacy, adverse events, or other 
effects associated with medicinal products 
 
To increase knowledge and understanding of disease biology 
 
To study drug response, including drug effects and the processes of drug absorption 
and disposition 
 
To develop biomarker or diagnostic assays and establish the performance 
characteristics for these assays 
 
Approval by the Institutional Review Board or Ethics Committee 
Storage of samples in the RCR is contingent upon the review and approval of the RCR 
portion of the Informed Consent Form by each site's Institutional Review Board (IRB) or 
Ethics Committee (EC) and, if applicable, an appropriate regulatory body.  If a site is not 
granted approval for RCR sampling, this section of the protocol will not be applicable at 
that site. 
For all patients, date of consent should be recorded on the associated page of the eCRF. 
RCR specimens will be stored until completely depleted for up to 15 years after the final 
freeze of the respective clinical database, unless regulatory authorities require that 
specimens be maintained for a longer period.  The RCR storage period will be in 


 
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accordance with the IRB/EC-approved Informed Consent Form and applicable laws (e.g., 
health authority requirements). 
Optional Samples for the Roche Clinical Repository 
The following samples will be used for identification of dynamic (non-inherited) 
biomarkers: 
 
Remaining serum and plasma samples 
 
Remaining FFPE or FF tissue (with the exception of archival FFPE blocks, which 
will be returned to the sites) 
 
TMAs for tumor protein expression or somatic tumor-related RNA/DNA analyses 
 
The following sample will be used for identification of genetic (inherited) biomarkers: 
 
One 6-mL whole blood sample (anticoagulated in K3EDTA) at Cycle 1, Day 1 (or at 
the first visit following the RCR consent if this occurs after Cycle 1, Day 1). 
 
The dynamic biomarker specimens will be subject to the confidentiality standards 
described in Section 8.4.  The genetic biomarker specimens will undergo additional 
processes to ensure confidentiality, as described below. 
Confidentiality 
Given the sensitive nature of genetic data, Roche has implemented additional processes 
to ensure patient confidentiality for RCR specimens.  Upon receipt by the RCR, each 
specimen is double coded by replacing the patient identification number with a new 
independent number.  Data generated from the use of these specimens and all clinical 
data transferred from the clinical database and considered relevant are also labeled with 
this same independent number.  A linking key between the patient identification number 
and this new independent number is stored in a secure database system.  Access to the 
linking key is restricted to authorized individuals and is monitored by audit trail.  
Legitimate operational reasons for accessing the linking key are documented in a 
standard operating procedure.  Access to the linking key for any other reason requires 
written approval from the Pharma Repository Governance Committee and Roche’s Legal 
Department, as applicable. 
Data generated from RCR specimens must be available for inspection upon request by 
representatives of national and local health authorities and Roche monitors, 
representatives, and collaborators, as appropriate. 
Patient medical information associated with RCR specimens is confidential and may only 
be disclosed to third parties as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law. 
Data derived from RCR specimen analysis on individual patients will generally not be 
provided to study investigators, unless a request for research use is granted.  The 


 
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aggregate results of any research conducted using RCR specimens will be available in 
accordance with the effective Roche policy on study data publication. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RCR data will become and remain the exclusive and unburdened property 
of Roche, except where agreed otherwise. 
Consent to Participate in the Roche Clinical Repository 
The Informed Consent Form will contain a separate section that addresses participation 
in the RCR.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the RCR.  Patients will be 
told that they are free to refuse to participate and may withdraw their specimens at any 
time and for any reason during the 15-year storage period.  A separate, specific 
signature will be required to document a patient's agreement to provide RCR specimens.  
Patients who decline to participate will check a “no” box in the appropriate section and 
will not provide a separate signature. 
The investigator should document whether or not the patient has given consent to 
participate by completing the RCR Research Sample Informed Consent eCRF. 
In the event of an RCR participant’s death or loss of competence, the participant’s 
specimens and data will continue to be used as part of the RCR research. 
Withdrawal from the Roche Clinical Repository 
Patients who give consent to long-term storage of exploratory biomarker specimens for 
further research in the RCR have the right to withdraw their consent to long-term storage 
of their specimens at any time for any reason. If a patient wishes to withdraw consent to 
the long-term storage of his or her specimens, the investigator must inform the Medical 
Monitor in writing of the patient's wishes using the RCR Subject Withdrawal Form and, if 
the trial is ongoing, must enter the date of withdrawal on the RCR Research Sample 
Withdrawal of Informed Consent eCRF.  The patient will be provided with instructions on 
how to withdraw consent after the trial is closed.  A patient's withdrawal from Study 
GO27826 does not, by itself, constitute withdrawal of specimens from long-term storage 
in the RCR.  Similarly, a patient's withdrawal from long-term storage in the RCR does not 
constitute withdrawal from Study GO27826. 
Monitoring and Oversight 
RCR specimens will be tracked in a manner consistent with Good Clinical Practice by a 
quality-controlled, auditable, and appropriately validated laboratory information 
management system to ensure compliance with data confidentiality as well as 
adherence to authorized use of specimens as specified in this protocol and in the 
Informed Consent Form.  Roche monitors and auditors will have direct access to 
appropriate parts of records relating to patient participation in the RCR for the purposes 
of verifying the data provided to Roche.  The site will permit monitoring, audits, IRB/EC 


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review, and health authority inspections by providing direct access to source data and 
documents related to the RCR samples. 
In addition to an internal review body, an independent Science and Ethics Advisory 
Group, consisting of experts in the fields of biology, ethics, sociology, and law, will 
advise Roche regarding the use of RCR specimens and on the scientific and ethical 
aspects of handling genetic information.  
4.5.2 
Timing of Study Assessments 
4.5.2.1 
Screening and Pretreatment Assessments 
Written informed consent for participation in the study must be obtained before 
performing any study-specific screening tests or evaluations.  Informed Consent Forms 
for enrolled patients and for patients who are not subsequently enrolled will be 
maintained at the study site.  
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before the patient is randomized to study treatment.  Results of 
standard-of-care tests or examinations performed prior to obtaining informed consent 
and within 14 days prior to randomization may be used, and such tests do not need to 
be repeated for screening. 
For a complete description of study assessments, refer to Section 4.5.1 and Appendix 1. 
The following assessments will be performed at screening: 
•
Within 90 days prior to randomization:
Pathologic stage of melanoma according to the AJCC v7 classification, on the 
basis of the following: 
Physical examination 
Post-surgery imaging studies (contrast-enhanced CT or MRI of the chest, 
abdomen, and pelvis; contrast-enhanced MRI of the brain [or CT if MRI is 
not generally available or is contraindicated]) 
Sentinel lymph node biopsy and, if applicable, complete regional 
lymphadenectomy 
BRAFV600 mutation status of the primary tumor or involved lymph node 
confirmed using the cobas BRAF V600 Mutation Test 
A locally obtained cobas BRAF V600 Mutation Test using current primary or 
involved lymph node tissue can be used for screening purposes even if 
performed outside of the 90-day screening window. 
Melanoma tumor tissue for exploratory biomarker assessments 
Current primary or involved lymph node tissue can be submitted even if 
obtained outside of the 90-day screening window. 
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Pelvic examination, including visual inspection of the uterine cervix and Pap 
smear, unless this was done and found to be normal within the 3 months prior 
to the start of the 90-day screening period (women only) 
Anal examination 
Stool for occult blood 
For select patients described in Section 4.5.1.7, colonoscopy to the cecum, 
with adequate bowel preparation, by a gastroenterologist or his or her designee 
(unless colonoscopy to the cecum with adequate bowel preparation and 
adequate resection of all visualized polyps was performed within 1 year of the 
start of the 90-day screening period) 
Note:  All polyps found at the screening colonoscopy will need to be 
adequately resected. 
Please note that a patient with a known personal history of more than three (> 3) 
adenomatous colorectal polyps or a personal history of adenomatous colorectal 
polyp(s) > 2 cm in size will be excluded from this study; this also applies to the 
screening colonoscopy for select patients (see Section 4.1.2). 
Concomitant medications 
•
Within 28 days prior to randomization:
Medical history, complete physical examination (including height and weight), 
and vital signs 
Thorough head and neck examination by the investigator 
Hematology, coagulation screening studies, serum chemistry, and liver function 
tests 
Hepatitis B virus (HBsAg and total anti-HBc) and HCV serology 
Triplicate ECGs 
•
Within 14 days prior to randomization:
Serum pregnancy test 
The following assessments are required on Cycle 1, Day 1 (prior to administration of 
study drug): 
•
Baseline PRO assessment (i.e., EORTC QLQ-C30 questionnaire)
•
Triplicate ECG
Note:  If the screening ECG was performed within 7 days of the Cycle 1, Day 1 
visit, it does not have to be repeated at Day 1. 
•
Vital signs, physical examination
Note:  If vital signs and physical examination are assessed within 7 days of the 
Cycle 1, Day 1 visit, they do not have to be repeated at Day 1. 


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
Hematology, serum chemistry, and liver function tests
Note:  If screening laboratory specimens are collected within 7 days of the 
Cycle 1, Day 1 visit, they do not have to be repeated at Day 1. 

Blood samples for PK assessments (pre-dose, 14 hours after dose)

Serum and plasma samples for exploratory biomarker assessments (6 mL in EDTA;
6 mL in serum separator tube)

An optional whole blood sample (6 mL in EDTA) will be collected from patients
consenting to provide a sample for the RCR.
Note:  This specimen can be collected at the first visit following the RCR consent 
if this occurs after Cycle 1, Day 1. 
See Appendix 1 for the schedule of screening and pretreatment assessments. 
4.5.2.2 
Assessments during Study 
All assessments must be performed on the day of the specified visit, unless a time 
window is specified in the Schedule of Assessments (see Appendix 1).  Assessments 
scheduled on the day of study drug administration should be performed prior to 
administration of study drug, unless otherwise noted in the Schedule of Assessments.  
The PRO assessment (EORTC QLQ-C30) should be performed prior to the completion 
of other study assessments.  The timing of interval assessments (such as the head and 
neck examination and imaging studies) should be calculated from the Cycle 1, Day 1 
visit.  The frequency of the dermatological examination should be calculated from the 
date of the first dermatological examination, which should occur after 4 weeks of study 
drug administration. 
For a complete description of study assessments, refer to Section 4.5.1 and Appendix 1. 
The following assessments will be done during the study: 

Interval medical history, including documentation of new or worsening adverse
events:  Cycle 1 (Days 8, 15, and 22, each  3 days), Cycle 2 (Days 1 and 15, each
 3 days), Day 1 ( 3 days) of every subsequent 4-week cycle, and at the
end-of-treatment visit

Vital signs:  Cycle 1 (Day 15  3 days), Cycle 2 (Days 1 and 15, each  3 days),
Day 1 ( 3 days) of every subsequent 4-week cycle, and at the end-of-treatment visit

Physical examinations:  Cycle 1 (Day 15  3 days), Cycle 2 (Days 1 and 15, each
 3 days), Day 1 ( 3 days) of every subsequent 4-week cycle, and at the
end-of-treatment visit.  Thereafter, physical examinations done by the investigator
will be obtained every 13  2 weeks from the last dose of study drug until recurrence
of melanoma, occurrence of a new primary melanoma, or until end of study (see
Section 3.2), whichever occurs earlier.  Height will be obtained at screening only.


 
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Note:  For all patients, as part of the physical examination, a thorough head and 
neck evaluation to monitor for non-cuSCC, consisting of at least a visual 
inspection of the oral mucosa and lymph node palpation, must be performed by 
the site investigator every 13 ± 2 weeks during the study drug treatment period.  
Once a patient completes the treatment period or discontinues study drug early, 
a thorough evaluation of the head and neck by the study investigator will be 
performed at the end-of-treatment visit as part of the physical examination.  Once 
a patient completes the treatment period or discontinues study drug early, a 
thorough head and neck evaluation to monitor for non-cuSCC will occur (as part 
of the physical examination for patients who continue to have physical 
examinations) at 13 ± 2 weeks and 26 ± 2 weeks from the last dose of study drug.  
For patients who no longer require physical examinations, the head and neck 
examination will occur independently at 13 ± 2 weeks and 26 ± 2 weeks from the 
last dose of study drug (except in the case of withdrawal of consent or loss to 
follow-up).   
Patients with signs or symptoms consistent with head and neck cancer as 
determined by the site investigator will have a complete evaluation of the head 
and neck by a head and neck surgeon/otorhinolaryngologist or his or her 
designee who is experienced in the diagnosis and management of SCC of the 
head and neck:  every 26 ± 2 weeks during the study drug administration period.  
Once a patient completes the treatment period or discontinues study drug early, 
a complete evaluation of the head and neck by a head and neck 
surgeon/otorhinolaryngologist will be performed at 26 ± 2 weeks after the last 
dose of study drug (except in the case of withdrawal of consent or loss to 
follow-up). 
• 
All patients will have a colonoscopy to the cecum, with adequate bowel preparation, 
by a gastroenterologist or his or her designee who is experienced in the 
colonoscopic diagnosis of colorectal polyps and colorectal cancer within 3 months of 
discontinuation of study drug.  All polyps found at any of the colonoscopies will need 
to be adequately resected. 
• 
Hematology:  Day 1 (± 3 days) of each cycle and the end-of-treatment visit 
• 
Serum chemistry and liver function tests:  Cycle 1 (Days 8, 15, and 22, each 
± 3 days), Cycle 2 (Days 1 and 15, each ± 3 days), Day 1 (± 3 days) of every 
subsequent 4-week cycle and at the end-of-treatment visit 
• 
Serum pregnancy test for all women of childbearing potential (including those who 
have had a tubal ligation):  every three cycles (i.e., Cycles 3, 6, 9, and 12 or every 
12 ± 2 weeks), starting from Cycle 1, Day 1.  If a patient discontinues study drug 
early, a serum pregnancy test will be performed at 12 ± 2 weeks and 26 ± 2 weeks 
after the last dose of study drug (except in the case of withdrawal of consent or loss 
to follow-up). 
• 
Stool for occult blood:  Cycle 6, Day 1 (± 2 weeks) and end-of-treatment visit 
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 
An anal examination and pelvic examination (including visual inspection of the 
uterine cervix and Pap smear):  Cycle 6, Day 1 ( 2 weeks) and end-of-treatment 
visit ( 2 weeks) 
 
Triplicate ECGs:  Cycle 1 (Day 15  3 days), Cycle 2 (Days 1 and 15, each  3 days), 
Cycle 3, Day 1 ( 3 days), Day 1 ( 3 days) of every subsequent third cycle, and at the 
end-of-treatment visit 
 
Imaging studies (surveillance for melanoma recurrence):  Contrast-enhanced CT or 
MRI of the chest, abdomen, and pelvis every 13  2 weeks until Week 104 and every 
26  4 weeks thereafter until recurrence of melanoma, occurrence of a new primary 
melanoma, or until end of study (see Section 3.2), whichever occurs earlier.  In 
addition, all patients will undergo contrast-enhanced MRI of the brain (or CT if MRI 
is not available or is contraindicated) every 52  4 weeks until recurrence of 
melanoma, occurrence of a new primary melanoma, or until end of study (see 
Section 3.2), whichever occurs earlier.  Patients who have had a DFS event do not 
need additional scans or physical exams for melanoma recurrence surveillance.  
However, these patients must still have a chest CT or MRI for SCC surveillance at 
13  2 weeks and 26  2 weeks after last dose of study drug. 
 
Dermatologic examination performed by a dermatologist or his or her designee who 
is experienced in the diagnosis and management of cuSCC (surveillance for 
cuSCC/KA, new primary melanoma, or other suspicious lesions):  end of 
Cycle 1  1 week and then every 13  2 weeks during the study drug treatment 
period.  Once a patient completes the treatment period or discontinues study drug 
early, dermatologic examinations (including a complete evaluation of the skin) will 
occur at the end-of-treatment visit, at 13  2 weeks, and at 26  2 weeks from the last 
dose of study drug (except in the case of withdrawal of consent or loss to follow-up). 
 
An unscheduled dermatologic examination may be performed for investigation of 
any new skin lesions that are suspected of being cuSCC/KA or a new primary 
melanoma. 
 
Biopsy of suspected SCC (cutaneous [including KA] and non-cutaneous), new 
primary neoplasms (FFPE tissue blocks or 610 unstained tissue slides):  one 
sample of normal skin from patients who develop cuSCC/KA or new primary 
melanoma 
 
PK assessments (2 mL of whole blood per sample):  prior to and 14 hours after the 
morning dose in Cycle 1 (Days 8, 15, and 22, each  3 days), prior to the morning 
dose in Cycle 2 (Days 1 and 15, each  3 days), and prior to the morning dose on 
Day 1 ( 3 days) of each subsequent cycle until the end-of-treatment visit.  During 
Cycle 1, if drug is not administered on a visit day (Days 1, 8, 15, or 22), only one PK 
sample should be collected on that day.  In addition, an unscheduled PK sample will 
be collected (when feasible) at the following timepoints: 
End-of-treatment visit 
As soon as possible after the diagnosis of melanoma recurrence or occurrence of 
a new primary melanoma while on study treatment (i.e., in conjunction with the 
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Note:  In the event of melanoma recurrence or occurrence of a new primary 
melanoma during study treatment or if the patient discontinues study treatment 
because of other reasons, a PK sample should be taken upon drug 
discontinuation as well as at the study visit most proximate after study 
treatment discontinuation.  
Coincident with the diagnosis of SCC (cutaneous [including KA] and 
non-cutaneous) 
Coincident with any dose interruption and/or reduction for toxicity 
Note:  In the event of dose reduction or drug holiday, another unscheduled PK 
sample should be taken immediately before the patient resumes treatment at 
the modified dose as well as at Day 1 of the next cycle of treatment. 
 
Serum and plasma samples for exploratory biomarker assessments:  Cycle 1 
(Day 15  3 days), Cycle 2 (Day 1  3 days), Cycle 3 (Day 1  3 days).  Serum and 
plasma samples should also be collected at the end-of-treatment visit and every 
52  2 weeks after last dose of study drug until the recurrence of melanoma, 
occurrence of a new primary melanoma, or until end of study (see Section 3.2), 
whichever occurs earlier. 
Note:  In the event of melanoma recurrence or occurrence of a new primary 
melanoma during study treatment or if the patient discontinues study treatment 
because of other reasons, a sample should be taken upon drug discontinuation 
 
Melanoma tumor tissue:  at recurrence of melanoma, as pathologically documented, 
(FF tissue and FFPE tissue) or occurrence of a new primary melanoma (FFPE 
tissue) 
 
PROs will be assessed at Cycle 1 (Day 15  3 days), Cycle 2 (Days 1 and 15, each 
 3 days), Day 1 ( 3 days) of every subsequent 4-week cycle, at the 
end-of-treatment visit, and at each scheduled and unscheduled visit during the 
follow-up period, including the early termination visit.  In post-treatment follow-up, 
the EORTC QLQ-C30 questionnaire will be completed every 13  2 weeks from last 
dose of study drug until recurrence of melanoma, occurrence of a new primary 
melanoma, or until end of study (see Section 3.2), whichever occurs first. 
 
See Appendix 1 for the Schedule of Assessments performed during the treatment period. 


 
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4.5.2.3 
End-of-Treatment Visit 
Patients who complete study drug treatment or discontinue study drug treatment early 
will be asked to return to the clinic 28  3 days after the last dose of study drug for an 
end-of-treatment visit.  If the patient withdraws study consent prior to 28  3 days after 
the last dose of study drug, then the end-of-treatment visit can occur earlier.  Refer to 
Section 4.5.2.2 and Appendix 1 for the Schedule of Assessments required at the 
end-of-treatment visit. 
4.5.2.4 
Post-Treatment Follow-Up Assessments 
Patients who complete or discontinue study treatment without a recurrence or an 
occurrence of a new primary melanoma will continue to be followed with regular physical 
examinations (every 13  2 weeks) and imaging studies for a maximum of 5 years from 
Cycle 1, Day 1 or until a melanoma recurrence or an occurrence of a new primary 
melanoma or until end of study (see Section 3.2), whichever occurs first.  All patients 
will be followed for the occurrence of new primary malignancies, regardless of 
melanoma recurrence or occurrence of a new primary melanoma, until end of study 
(see Section 3.2). 
See Appendix 1 for the Schedule of Assessments performed during follow-up. 
4.5.2.5 
Melanoma Recurrence or New Primary Melanoma Occurrence 
See Appendix 1 for the assessments required for patients who develop a melanoma 
recurrence or have an occurrence of a new primary melanoma.  These patients will then 
continue in the study for post-recurrence follow-up. 
4.5.2.6 
Early Study Termination Visit (during Post-Treatment 
Follow-Up) 
Patients who discontinue post-treatment follow-up will be asked to return to the clinic for 
a final visit to complete study assessments within 28 days.  Assessments completed at 
melanoma recurrence or occurrence of a new primary melanoma do not need to be 
repeated at the early study termination visit.  See Appendix 1 for the assessments 
required at the early study termination visit.  Patients will continue to be followed for 
survival and new primary malignancy as outlined in Section 4.5.2.7. 
4.5.2.7 
Survival and New Primary Malignancy Follow-Up Assessments 
Survival follow-up information will be collected via telephone calls and/or clinic visits 
every 13  2 weeks until death, loss to follow-up, or study termination by Roche or until 
end of study (see Section 3.2).  Patients will be followed for new primary malignancies 
until end of study (see Section 3.2).  All patients will be followed for survival information 
and new primary malignancy unless the patient requests to be withdrawn from follow-up; 
this request must be documented in the patient’s medical record and signed by the 
investigator.  If the patient withdraws from study follow-up, the study staff may use a 
public information source (such as county records) to obtain information about survival 
status only. 


 
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4.5.2.8 
Adverse Event Follow-Up 
Ongoing adverse events thought to be related to study drug will be followed until the 
event has resolved to baseline grade, is assessed by the investigator as stable, new 
anti-tumor treatment is initiated, the patient is lost to follow-up or withdraws consent, or 
when it has been determined that the study treatment or participation is not the cause of 
the adverse event. 
After completion of study drug administration, adverse events should be followed as 
outlined in Section 5.5 and Section 5.6. 
4.6 
PATIENT, STUDY, AND SITE DISCONTINUATION 
4.6.1 
Patient Discontinuation 
The investigator has the right to discontinue a patient from study drug or withdraw a 
patient from the study at any time.  In addition, patients have the right to voluntarily 
discontinue study drug or withdraw from the study at any time for any reason.  Reasons 
for discontinuation of study drug or withdrawal from the study may include but are not 
limited to the following: 
 
Patient withdrawal of consent at any time 
 
Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient’s safety if he or she continues in the study 
 
Investigator or Sponsor determines it is in the best interest of the patient 
 
Patient non-compliance with the study protocol 
 
4.6.1.1 
Discontinuation from Study Drug 
Patients are to receive study drug for up to 52 weeks.  Patients must discontinue study 
drug if they experience any of the following: 
 
Pregnancy 
 
Histopathologic confirmation of occurrence of a new primary melanoma (diagnosed 
by Roche-designated central pathology laboratory).  Refer to Section 5.1.2.3 for a 
discussion on new primary melanoma 
 
Histopathologic confirmation of recurrent melanoma 
 
Radiographic and/or histopathologic findings consistent with recurrence of 
melanoma in brain 
 
Radiographic findings consistent with recurrence when suspicious lesions are 
deemed not amenable to biopsy by the investigator or the patient refuses biopsy 
confirmation 
 
Patients who discontinue study drug prematurely will be asked to return to the clinic for 
an end-of-treatment visit (see Section 4.5.2.2, Section 4.5.2.3 and Appendix 1) and may 
undergo follow-up assessments (see Section 4.5.2.2, Section 4.5.2.3, Section 4.5.2.4, 
and Appendix 1).  The primary reason for premature study drug discontinuation should 


 
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be documented on the appropriate eCRF.  Patients who discontinue study drug 
prematurely will not be replaced. 
4.6.1.2 
Withdrawal from Study 
The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF.  If patient is lost to follow-up, the investigator should make every 
effort to contact the patient by telephone or by sending a registered letter to establish as 
completely as possible the reason for the withdrawal and survival status.  These steps 
for contacting patients (who prematurely withdraw or who are lost to follow-up) will be 
documented in the patient informed consent form. 
Patients who withdraw their consent to be followed for the primary study endpoint (DFS) 
will be asked to continue follow-up for OS until end of study (see Section 3.2), as well as 
for new primary malignancies until end of study (see Section 3.2).  Patients will not be 
followed for any reason after full consent, for DFS, OS, and new primary malignancies, 
has been withdrawn.  Patients who withdraw from the study will not be replaced. 
An excessive rate of withdrawals can potentially render the study non-interpretable; 
therefore, unnecessary withdrawal of patients should be avoided.  Should a patient 
decide to withdraw, all efforts will be made to complete and report the observations prior 
to withdrawal as thoroughly as possible. 
4.6.2 
Study and Site Discontinuation 
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include but are not limited to the following: 
 
The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients. 
 
Patient enrollment is unsatisfactory. 
 
The Sponsor will notify the investigator if the study is placed on hold or if the Sponsor 
decides to discontinue the study or development program.   
The Sponsor has the right to replace a site at any time.  Reasons for replacing a site 
may include but are not limited to the following: 
 
Excessively slow recruitment 
 
Poor protocol adherence 
 
Inaccurate or incomplete data recording 
 
Non-compliance with the International Conference on Harmonisation (ICH) guideline 
for Good Clinical Practice 
 


 
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5. 
ASSESSMENT OF SAFETY  
5.1 
SAFETY PLAN 
Measures will be taken to ensure the safety of patients participating in this trial, 
in particular, the use of stringent inclusion and exclusion criteria and close monitoring of 
patients. 
5.1.1 
Background:  Vemurafenib Risks 
The toxicity profile for vemurafenib has been documented from safety data derived from 
seven studies of over 600 treated patients with locally advanced unresectable or 
metastatic melanoma.  The most common toxicities observed were rash, fatigue, 
arthralgia, myalgia, headache, nausea, photosensitivity, alopecia, and pruritus.  The 
most common laboratory abnormalities reported as adverse events included elevations 
of liver function tests (i.e., GGT, alkaline phosphatase, ALT, AST, and bilirubin).  The 
majority of adverse events reported in conjunction with Phase IIII clinical trials were of 
mild or moderate severity.  Approximately one-half of all patients treated with 
vemurafenib required interruption and/or reduction of dose on at least one occasion, 
although treatment discontinuation because adverse events has been rare. 
Approximately 20% of vemurafenib recipients developed one or more localized cuSCCs 
(mainly KA type).  The majority of these was observed within the first 78 weeks of 
vemurafenib exposure and was not treatment limiting.  As with all clinical studies of 
vemurafenib to date, the risk for cuSCC will be mitigated through the use of a Risk 
Management Plan as outlined in Section 5.1.2.3. 
Analysis of ECG data from the Phase II Study NP22657 of vemurafenib in patients with 
metastatic melanoma revealed a risk of QT interval prolongation without associated 
clinical symptomatology (as noted in Section 5.1.2.3.7).   
Two cases of SCC of the head and neck have been reported in 2 patients treated with 
vemurafenib in excess of 300 days while enrolled in a clinical trial.  In addition, 
five cases of adenomatous colonic polyps have been reported in patients who received 
vemurafenib for 2 or more years on a clinical trial.  One patient who was participating in 
the Expanded Access Program was found to have a colonic adenoma after being on 
vemurafenib for 0.57 years (see Section 1.2.5 and the Vemurafenib IB for additional 
details). 
5.1.2 
General Plan to Manage Safety Concerns 
5.1.2.1 
Eligibility Criteria 
Eligibility criteria promulgated for this study will guard the safety of patients in this trial.  
The exclusion criteria for safety shall include (but are not limited to) the following:  major 
surgical procedure (other than sentinel lymph node biopsy or complete regional 
lymphadenectomy) or significant traumatic injury within 4 weeks prior to first dose of 
study drug; pregnancy or breastfeeding; clinically significant cardiovascular disease; 


 
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history of congenital long QT syndrome or QTc interval  450 ms at baseline; inadequate 
bone marrow, hepatic, or renal function; and history of malabsorption or other clinically 
significant metabolic dysfunction. 
5.1.2.2 
Monitoring 
Safety will be evaluated in this study through the monitoring of all adverse events and 
targeted laboratory assessments.  Adverse event severity will be graded according to 
NCI CTCAE v4.0.  Patients will be monitored weekly during Cycle 1, every 2 weeks 
during Cycle 2, Day 1 of every subsequent cycle, and as needed until 4 weeks after the 
last dose of study treatment or initiation of other anti-melanoma therapy, whichever 
occurs first.  All treatment-emergent adverse events and serious adverse events whether 
or not deemed treatment related will be followed until they resolve or become stabilized, 
new anti-tumor treatment is initiated, the patient is lost to follow-up or withdraws consent, 
or it has been determined that the study treatment or participation is not the cause of the 
adverse event or serious adverse event.  General safety assessments will include serial 
interval histories, physical examinations, and specific laboratory studies including serum 
chemistry, liver function tests, and blood counts.  All serious adverse events and 
protocol-defined adverse event of special interest will be reported in an expedited 
fashion. 
In addition to the oversight provided by the Medical Monitor and Drug Safety personnel 
for this trial, an independent DSMB that has been tasked with monitoring safety data 
from vemurafenib studies will be employed to evaluate safety data from this study.  The 
DSMB will review safety data every 3 months starting 3 months after the data become 
available and continuing until the study is unblinded coincident with the final DFS 
analysis for each cohort.  The quarterly safety review will include summary tables of 
subject disposition, all adverse events, serious adverse events, deaths, adverse events 
leading to treatment discontinuations, adverse events of special interest, and treatment 
exposure. 
The Sponsor recommends that serum amylase and lipase testing is conducted as part of 
the workup of any suspected case of pancreatitis, in addition to other appropriate testing 
(e.g., CT abdomen). 
5.1.2.3 
Monitoring and Management of Specific Toxicities and 
Conditions That May Arise with Vemurafenib Treatment 
5.1.2.3.1 
NonSquamous Cell Carcinoma Skin Toxicity 
The non-SCC skin toxicities observed in patients treated with vemurafenib include rash, 
pruritus, palmar-plantar erythrodysesthesia, dry skin, and exfoliation.  Of these, the most 
common has been rash (maculopapular or acneiform), which has generally been 
manageable with supportive care.  Skin toxicities other than lesions suspected of being 
cuSCC/KA will be managed with supportive care according to institutional guidelines as 
well as by dose interruption/modification. 


 
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Mild to severe photosensitivity has been reported in patients who received vemurafenib 
in clinical studies.  All patients should be advised to avoid sun exposure while taking 
study drug.  Patients should be advised to wear protective clothing and use a broad 
spectrum UVA/UVB sunscreen and lip balm (SPF  30) when outdoors to help protect 
against sunburn.  For photosensitivity Grade  2 (intolerable) adverse reactions, dose 
modifications will be required. 
5.1.2.3.2 
NonCutaneous Squamous Cell Carcinoma 
For all patients, a thorough examination of the head and neck to monitor for non-cuSCC, 
consisting of at least a visual inspection of the oral mucosa and lymph node palpation, 
must be performed by the site investigator or designee according to Section 4.5.1.6 and 
Appendix 1.  In the case of a suspected head and neck cancer (e.g., on the basis of 
signs or symptoms), a flexible fiberoptic laryngoscopy will be performed by a head and 
neck surgeon/otorhinolaryngologist or his or her designee who is experienced in the 
diagnosis and management of SCC of the head and neck.  Assessment will consist of at 
least a visual inspection of the oral mucosa and palpation of the tonsils, base of tongue, 
and lymph nodes in order to evaluate the sinonasal cavity, the nasopharynx, the base of 
tongue, larynx, and hypopharynx. 
The routinely scheduled chest CT (or MRI) scan performed as part of the assessment for 
tumor recurrence will be used for SCC surveillance during study drug treatment and 
post-treatment follow-up at 13  2 weeks and 26  2 weeks after last dose of study drug.  
If intravenous contrast is contraindicated, then a non-contrasted CT (or MRI) scan of the 
chest is to be performed.  Patients who have had a DFS event do not need additional 
scans or physical examinations for melanoma recurrence surveillance; however, chest 
CT is required at 13  2 weeks and 26  2 weeks after last dose of study drug for SCC 
surveillance.   
Visual and digital evaluation of the anus and anal canal will be performed according to 
Section 4.5.2 and Appendix 1.  For female patients, a pelvic examination including visual 
inspection of the uterine cervix and Pap smear will occur according to Section 4.5.2 and 
Appendix 1. 
For patients who have been referred to a head and neck surgeon/otorhinolaryngologist 
because of suspected head and neck cancer, this assessment will occur at screening 
and every 26  2 weeks during the study drug administration period.  Patients who 
complete the treatment period or discontinue study drug early will have this assessment 
at 26  2 weeks after the last dose of study drug. 
An unscheduled examination may be performed for investigation of any new head and 
neck lesions that are suspected of being SCC.  Any suspicious lesions identified must be 
biopsied or excised, and a specimen (tissue block/sections) is sent to a Roche-
designated central laboratory for pathological examination and further molecular 
characterization.  In addition, appropriate follow-up must be instituted. 


 
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5.1.2.3.3 
Cutaneous Squamous Cell Carcinoma (including 
Keratoacanthoma) and New Primary Melanoma 
For all patients, a complete evaluation of the skin by a designated dermatologist or his or 
her designee who is experienced in the diagnosis and management of cuSCC/KA will be 
conducted at baseline (up to 90 days prior to randomization), during study drug 
treatment period, and post-treatment follow-up according to Section 4.5.2 and 
Appendix 1.  An unscheduled dermatology examination may be performed for 
investigation of any new skin lesions that are suspected of being cuSCC (including those 
classified as KA) or new primary melanomas.  If a patient develops cuSCC/KA either 
during or after the study drug administration period, this information must be collected 
and reported as a non-serious adverse event of special interest to the Sponsor, whether 
it is deemed related or unrelated to study drug.  If a patient develops a new primary 
melanoma either during or after the study drug administration period, this information 
must be collected and reported to the Sponsor, whether it is deemed related or unrelated 
to study drug.  The following bullet points detail the required monitoring/management of 
skin-associated vemurafenib risks: 
 
A dermatologist or his or her designee who is experienced in the diagnosis and 
management of cutaneous neoplasms will perform skin evaluations to monitor for 
cuSCC/KA, new primary melanoma, BCC, and actinic keratosis. 
 
A complete history of prior dermatologic interventions and medications, cuSCC risk 
factors (i.e., Fitzpatrick skin type, radiotherapy, sun exposure, immunosuppression, 
prior SCC, use of tanning beds, and precursor lesions), and prior HPV vaccination 
must be collected.  Refer to Appendix 7 for a list of Fitzpatrick skin phototypes. 
 
Any suspicious lesions identified at baseline and while on study drug and 
26  2 weeks after last dose of study drug must be biopsied and excised and sent for 
pathological examination. 
 
Available specimen block/sections should be sent to a Roche-designated central 
pathology laboratory for confirmation of diagnosis and further molecular 
characterization. 
 
Tissue from lesions that are suspicious for a new primary melanoma must be 
evaluated by both the local pathology laboratory and the Roche-designated central 
pathology laboratory.  For study purposes, a new primary melanoma will be 
diagnosed based on central pathology review.  Patients should remain on study 
drug until central pathology confirmation of new primary melanoma, unless the 
investigator determines that treatment should be discontinued for clinical reasons.  
Should this be the case, the investigator should contact the Medical Monitor. 
 
Actinic keratosis or other skin conditions identified by the dermatologist should be 
treated per local standards of care. 
 
The occurrence of any skin changes, including rash and photosensitivity, should be 
reported to the study investigator, and patients will be referred to the dermatologist 
as required. 
 


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5.1.2.3.4 
Colorectal Polyps 
For select patients with known personal history of adenomatous colorectal polyps or 
colorectal cancer, family history of colon cancer in which a first- and/or second-degree 
relative has been diagnosed with colorectal cancer at or after the age of 60 years, or 
signs or symptoms that could be related to colon cancer as determined by the site 
investigator or designee, a screening colonoscopy will be conducted.  Patients with 
family history of inherited colon cancer syndromes and/or history of colon cancer in 
which a first- and/or second-degree relative has been diagnosed with colorectal cancer 
before the age of 60 years will be excluded from this study. 
Colonoscopy must be complete to the cecum, with adequate bowel preparation, and 
must be performed within the 90-day screening period by a gastroenterologist or his or 
her designee who is experienced in the colonoscopic diagnosis of colorectal polyps and 
colorectal cancer.  All visualized polyps found at the screening or subsequent 
colonoscopies will need to be adequately resected.  For select patients (described 
above), the screening colonoscopy is not required if colonoscopy to the cecum with 
adequate bowel preparation and adequate resection of all visualized polyps was 
performed within 1 year of the start of the 90-day screening period, unless the site 
investigator deems it necessary.  Please note that patients with a personal history of 
more than three (> 3) adenomatous colorectal polyps or a personal history of 
adenomatous colorectal polyp(s) > 2 cm in size will be excluded from this study; this also 
applies to the screening colonoscopy for the select patients described above (see also 
Section 4.1.2). 
All patients will be required to undergo a post-treatment colonoscopy within 3 months of 
discontinuation of study drug.   
5.1.2.3.5 
New Primary Cancers 
All new primary malignancies will be reported until end of study (see Section 3.2), 
whether or not a patient has exhibited recurrence of melanoma in the study. 
Visual and digital evaluation of the anus and anal canal will be performed according to 
Section 4.5.2 and Appendix 1.  For female patients, a pelvic examination, including 
visual inspection of the uterine cervix and Pap smear, will occur according to 
Section 4.5.2 and Appendix 1. 
For all patients, a thorough evaluation of the head and neck will be performed as part of 
the physical examination by the site investigator according to Section 4.5.2 and 
Appendix 1.  Evaluation will consist of at least a visual inspection of the oral mucosa and 
palpation of the tonsils, base of tongue, and lymph nodes. 
If, at any time, head and neck cancer is suspected (e.g., on the basis of signs or 
symptoms), the patient will be referred to a head and neck surgeon/otorhinolaryngologist 
or designee who is experienced in the diagnosis and management of SCC of the head 


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and neck.  The head and neck surgeon/otorhinolaryngologist or designee will perform an 
assessment including at least a visual inspection of the oral mucosa, palpation of the 
tonsils, base of tongue, and lymph nodes and flexible fiberoptic laryngoscopy in order to 
evaluate at least the sinonasal cavity, the nasopharynx, the base of tongue, the larynx, 
and the hypopharynx.  For patients who have been referred to a head and neck 
surgeon/otorhinolaryngologist or designee who is experienced in the diagnosis and 
management of SCC of the head and neck, this assessment will occur at screening and 
every 26 ± 2 weeks during the study drug administration period.  Patients who complete 
the treatment period or discontinue study drug early will have this assessment at 26 ± 2 
weeks after the last dose of study drug (except in the case of withdrawal of consent or 
loss to follow-up). 
If a patient develops a new primary malignancy (other than cuSCC/KA or melanoma) 
either during or after study treatment, this information must be collected and reported as 
a serious adverse event to the Sponsor, whether it is deemed related or unrelated to 
study drug.  If the patient is still receiving study drug, the investigator should contact the 
Medical Monitor to discuss study drug administration.  For cuSCC/KA or new primary 
melanoma, refer to Section 5.1.2.3.3. 
Any suspicious lesion identified must be biopsied and excised, and a specimen 
(tissue block/sections) is sent to a Roche-designated central pathology laboratory for 
pathological examination and further molecular characterization. 
5.1.2.3.6 
Hepatic Toxicity 
Liver injury (ALT ≥ 5 × ULN, ALT ≥ 3 × ULN with bilirubin ≥ 2 × ULN, or alkaline 
phosphatase ≥ 2 × ULN with GGT elevation), including severe cases of liver injury 
(described as hepatic failure), has been reported in patients treated with vemurafenib. 
All patients will undergo liver function testing (i.e., AST, ALT, total bilirubin, and alkaline 
phosphatase) at periodic intervals while receiving study treatment (see Appendix 1).  In 
addition, Grade 4 elevations of AST, ALT, serum bilirubin OR cases of elevated ALT or 
AST in combination with either an elevated bilirubin or clinical jaundice, (as defined in 
Section 5.3.5.6) qualifies as a non-serious adverse event of special interest and must be 
reported to the Sponsor within 24 hours after learning of the event. 
Guidelines for interruption/dose reduction of study drug in the setting of liver function 
abnormality are provided in Table 2.  Please note that all Grade 2 liver function test 
abnormalities will be defined as “intolerable” for the purposes of interruption/dose 
reduction of study drug. 
5.1.2.3.7 
Cardiac Toxicity 
QT interval prolongation was observed in the ECG substudy of Study NP22657, the 
Phase II clinical trial of vemurafenib in patients with previously treated, metastatic 
melanoma (n = 132).  Vemurafenib treatment at a dose of 960 mg BID was associated 
with a prolongation of the QTc interval in some adult patients with metastatic melanoma, 


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and the largest mean QTc interval change from baseline noted was 15.1 ms (upper 
bound of the one-sided 95% CI, 17.7 ms).  The extent of change in the QTc interval from 
baseline was related to the vemurafenib steady-state concentration in plasma.  One 
patient (0.8%) had a QTc interval prolongation > 60 ms (Grade 2) compared with 
baseline, and 2 patients (1.5%) had an absolute QTc interval > 500 ms (Grade 3) on at 
least one occasion.  The mean QTc interval prolongation in the study population 
appeared to remain stable between 12 and 15 ms at all assessment timepoints after 
Cycle 1, Day 15.  To date, there have been no clinical adverse events, manifest cardiac 
arrhythmias, or other clinically significant cardiac events in clinical trials that are linked to 
QTc interval prolongation. 
As a result of these findings, the following guidelines will be implemented in this study to 
minimize the risk of ventricular arrhythmia in patients with melanoma treated with 
vemurafenib in this study: 
•
Patients with a baseline QTc interval > 450 ms or a history of congenital long QT 
syndrome will not be eligible to participate in this study.
•
Triplicate ECG monitoring will occur at baseline and at regular intervals during study 
treatment (see Appendix 1).
•
Combination therapy with other medications known to lead to prolongation of QTc 
interval should be avoided, if possible. 
Dose Interruption and Permanent Discontinuation for QTc Prolongation 
If QTc exceeds 500 ms (measured in triplicate ECG) but is less than or equal to a 60-ms 
increment compared with baseline OR the change from baseline is greater than 60 ms 
without QTc > 500 ms, study drug treatment should be temporarily interrupted. 
If QTc increases to 500 ms AND the change from baseline exceeds 60 ms, study drug 
treatment should be permanently discontinued.  Such patients will NOT be able to restart 
the study. 
Assessment and Management of QTc Prolongation 
Immediate action upon observation of QTc > 500 ms: 
•
Both the QTc interval and serum electrolytes with appropriate correction should be
monitored regularly until there is clear evidence that the QTc is < 500 ms.  Patients
should remain under close observation until the QTc returns to < 500 ms and/or
discharge is considered appropriate by consulting cardiologist.
•
Serum electrolytes (particularly potassium, magnesium, and corrected calcium)
must be evaluated, and any and all electrolyte abnormalities, with particular
attention to hypokalemia, hypomagnesemia, and hypocalcemia, must be corrected.
•
Patients must be closely monitored and, in particular, re-evaluated for other cardiac
risk factors (e.g., hypertension, congestive heart failure, cardiac ischemia,
bradyarrhythmias, diabetes).  Any other treatable risk factors (e.g., hypothyroidism)
should be corrected per standard of care.


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•
All concomitant medications must be re-evaluated, and consideration should be given 
to discontinuing those that could prolong the QTc interval and, if appropriate, 
substituting them with an alternative medication that does not affect the QTc interval.
•
Patients must have ECG re-evaluated within 48 hours to ensure QTc interval is 
improving after interruption of study medication and correction of aforementioned 
potential concomitant factors.
•
Study treatment will not be resumed until the QTc is clearly < 500 ms.  Upon 
resumption of study drug treatment, the study drug dose should be reduced.  Refer 
to Table 2.
•
Upon resumption of study drug treatment, ECG (measured in triplicate) and 
electrolytes should be monitored at Day 1 (i.e., day when study drug is resumed) pre-
dose, then every 2 weeks (± 3 days) for at least two cycles, then Day 1 (± 3 days) of 
the following cycle, and then Day 1 (± 3 days) of every subsequent third cycle. This 
replaces the protocol-mandated ECG monitoring that is outlined in Appendix 1.
•
A cardiologist must be consulted if any of the following occurs: 
The QTc does not return to baseline upon temporary or permanent interruption 
of study drug or upon correction of secondary causes (e.g., electrolyte 
abnormalities, concomitant medications known to prolong QT, cardiac ischemia, 
severe bradycardia).  
There are concomitant signs or symptoms of potential pro-arrhythmia 
(e.g., premature ventricular contractions [PVCs], persistent bradycardia, 
syncope, palpitations, etc.). 
The physician is not comfortable managing prolonged QTc according to the 
guidelines outlined above. 
For all patients with QTc change from baseline > 60 ms, without QTc > 500 ms: 
•
Serum electrolytes (particularly potassium, magnesium, and corrected calcium)
should be evaluated, and any and all electrolyte abnormalities, with particular
attention to hypokalemia, hypomagnesemia, and hypocalcemia, must be corrected.
•
Patients should be closely monitored and in, particular, re-evaluated for other
cardiac risk factors (e.g., hypertension, congestive heart failure, cardiac ischemia,
bradyarrhythmias, diabetes).  Any other treatable risk factors (e.g., hypothyroidism)
should be corrected per standard of care.
•
All concomitant medications should be re-evaluated, and consideration should be
given to discontinuing those that could prolong the QTc interval and, if appropriate,
substituting them with an alternative medication that does not affect the QTc interval.
•
Both the QTc interval and serum electrolytes (with appropriate correction) should be
monitored weekly until the QTc change from baseline is less than 60 ms before
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•
Upon resumption of study drug treatment, the study drug dose should be reduced. 
Refer to Table 2. 
Upon resumption of study drug treatment, the ECG (measured in triplicate) and 
electrolytes should be monitored at Day 1 (i.e., day when study drug is resumed) 
pre-dose, then every 2 weeks (± 3 days) for at least two cycles, then Day 1 
(± 3 days) of the following cycle, and then Day 1 (± 3 days) of every subsequent 
third cycle.  This replaces the protocol-mandated ECG monitoring that is outlined 
in Appendix 1. 
•
A cardiologist must be consulted if any of the following occurs:
The QTc does not return to baseline upon temporary or permanent interruption 
of study drug or upon correction of secondary causes (e.g., electrolyte 
abnormalities, concomitant medications known to prolong QT, cardiac ischemia, 
severe bradycardia).  
There are concomitant signs or symptoms of potential pro-arrhythmia 
(e.g., PVCs, persistent bradycardia, syncope, palpitations, etc.). 
The physician is not comfortable managing prolonged QTc according to the 
guidelines outlined above. 
5.1.3 
Management of Specific Adverse Events 
Management of symptomatic adverse events or QTc prolongation may require 
temporary interruption, dose reduction, or treatment discontinuation of study drug 
(see Table 2).  Dose modifications or interruptions are not recommended for cuSCC/KA 
adverse events.  Dose modifications or interruptions should occur in accordance with the 
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Table 2 
Dose Modification Schedule 
Grade a 
Recommended Dose Modification b 
Grade 1 or Grade 2 (tolerable) c 
Maintain study drug at a dose of 4 tablets twice 
daily  
Grade 2 (intolerable) c or Grade 3 
 
First appearance 
Interrupt treatment until Grade 0 or 1.   
Resume dosing at 3 tablets twice daily 
Second appearance 
Interrupt treatment until Grade 0 or 1.   
Resume dosing at 2 tablets twice daily 
Third appearance 
Discontinue permanently 
Grade 4 
 
First appearance 
Discontinue permanently or interrupt study drug 
treatment until Grade 0 or 1.   
Resume dosing at 2 tablets twice daily 
Second appearance 
Discontinue permanently 
a The intensity of clinical adverse events graded by the National Cancer Institute 
Common Terminology Criteria for Adverse Events, Version 4.0. 
b No dose modification is required in the setting of an isolated increase in gamma 
glutamyl transferase in the absence of a transaminitis, elevated serum bilirubin, or 
other hepatic symptoms. 
c All Grade 2 liver function test abnormalities will be defined as “intolerable.” 
 
5.2 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and non-serious adverse event of special interest, 
protocol-specified safety laboratory assessments, vital signs, and other protocol-
specified tests that are deemed critical to the safety evaluation of the study. 
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4. 
5.2.1 
Adverse Events 
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following: 
 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product 
 
Any new disease or exacerbation of an existing disease (a worsening in the 
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 
Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline 
 
Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug 
 
Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies) 
 
5.2.2 
Serious Adverse Events (Immediately Reportable to Roche) 
A serious adverse event is any adverse event that meets any of the following criteria: 
 
Fatal (i.e., the adverse event actually causes or leads to death) 
 
Life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death)  
This does not include any adverse event that, had it occurred in a more severe 
form or was allowed to continue, might have caused death. 
 
Requires or prolongs inpatient hospitalization (see Section 5.3.5.9) 
 
Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient’s ability to conduct normal life 
functions) 
 
Congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug 
 
Significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above) 
 
A new primary malignancy (other than cuSCC/KA) or progression or recurrence of a 
prior malignancy (other than the disease under study) will be categorized as a serious 
adverse event. 
Recurrence of melanoma is not reported as an adverse event if it is clearly consistent 
with the suspected recurrence of the disease under study.  Clinical signs or symptoms of 
recurrence may be reported as adverse events only if the symptom cannot be 
determined as exclusively due to the recurrence of the underlying malignancy or does 
not fit the expected pattern of recurrence for the disease under study.  If there is any 
uncertainty about an adverse event being due only to the extent of the disease under 
study, it should be reported as an adverse event or a serious adverse event. 
The terms “severe” and “serious” are not synonymous.  Severity refers to the intensity of 
an adverse event (rated as mild, moderate, or severe, or according to NCI CTCAE; see 
Section 5.3.3); the event itself may be of relatively minor medical significance (such as 
severe headache without any further findings). 


 
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Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF. 
Serious adverse events are required to be reported by the investigator to the Sponsor 
within 24 hours after learning of the event (see Section 5.4.2 for reporting instructions). 
5.2.3 
Non-Serious Adverse Events of Special Interest 
(Immediately Reportable to Roche) 
Non-serious adverse event of special interest are required to be reported by the 
investigator to the Sponsor within 24 hours after learning of the event (see Section 5.4.2 
for reporting instructions).  Adverse events of special interest for this study include the 
following: 
 
Grade  3 photosensitivity 
 
Grade 4 elevations of AST, ALT, serum bilirubin OR cases of elevated ALT or AST 
in combination with either an elevated bilirubin or clinical jaundice, as defined in 
Section 5.3.5.6 
 
cuSCC (including KA) 
 
Grade  3 QT interval prolongation 
 
Gastrointestinal polyps 
 
Suspected transmission of an infectious agent by study drug 
 
5.3 
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS 
The investigator is responsible for ensuring that all adverse events as defined in 
Section 5.2.1 are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Section 5.4 through 
Section 5.6. 
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2), severity (Section 5.3.3), and 
causality (Section 5.3.4).  
5.3.1 
Adverse Event Reporting Period 
Investigators will seek information on adverse events at each patient contact.  
All adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient’s medical record and on the Adverse Event eCRF. 
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported 
(e.g., serious adverse events related to invasive procedures such as biopsies). 
After initiation of study drug, all adverse events, regardless of relationship to study 
drug, will be reported up to and including 28 days after the last dose of study drug.  After 


 
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this period, investigators should report any deaths, serious adverse events, or other 
adverse events of concern that are believed to be related to prior treatment with study 
drug (see Section 5.6).  In addition, all new primary malignancies will be reported until 
end of study (see Section 3.2), whether or not a patient has exhibited recurrence of 
melanoma while in the study.  
5.3.2 
Eliciting Adverse Event Information 
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following: 
“How have you felt since your last clinic visit?” 
“Have you had any new or changed health problems since you were last here?”  
 
5.3.3 
Assessment of Severity of Adverse Events 
The adverse event severity grading scale for the NCI CTCAE v4.0 will be used for 
assessing adverse event severity.  Table 3 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE. 
Table 3 
Adverse Event Severity Grading Scale 
Grade 
Severity 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated 
2 
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a 
3 
Severe or medically significant but not immediately life threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b, c 
4 
Life-threatening consequences or urgent intervention indicated d 
5 
Death related to adverse event d 
NCI CTCAE  National Cancer Institute Common Terminology Criteria for Adverse Events. 
Note:  Based on the NCI CTCAE v4.0, which can be found at:  
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf 
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or clothes, 
using the telephone, managing money, etc. 
b Examples of self-care activities of daily living include bathing, dressing and undressing, feeding 
one’s self, using the toilet, and taking medications, as performed by patients who are not 
bedridden. 
c If an event is assessed as a “significant medical event,” it must be reported as a serious 
adverse event (see Section 5.4.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.2.2. 
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4.2 for 
reporting instructions), per the definition of serious adverse event in Section 5.2.2. 
 
 


 
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5.3.4 
Assessment of Causality of Adverse Events 
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether or 
not an adverse event is considered to be related to the study drug, indicating “yes” or “no” 
accordingly.  The following guidance should be taken into consideration: 
 
Temporal relationship of event onset to the initiation of study drug 
 
Course of the event, considering especially the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (where applicable) 
 
Known association of the event with the study drug or with similar treatments 
 
Known association of the event with the disease under study 
 
Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event 
 
Presence of nontreatment-related factors that are known to be associated with the 
occurrence of the event 
 
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy. 
5.3.5 
Procedures for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations. 
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF. 
5.3.5.1 
Diagnosis versus Signs and Symptoms 
A diagnosis (if known) should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases).  However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the Adverse Event 
eCRF.  If a diagnosis is subsequently established, all previously reported adverse events 
based on signs and symptoms should be nullified and replaced by one adverse event 
report based on the single diagnosis with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis. 


 
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5.3.5.2 
Adverse Events Occurring Secondary to Other Events 
In general, adverse events occurring secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  However, medically significant adverse events 
occurring secondary to an initiating event that are separated in time should be recorded 
as independent events on the Adverse Event eCRF.  For example: 
 
If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF. 
 
If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF. 
 
If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF. 
 
If dizziness leads to a fall and subsequent fracture, all three events should be 
reported separately on the eCRF. 
 
If neutropenia is accompanied by a mild, non-serious infection, only neutropenia 
should be reported on the eCRF. 
 
If neutropenia is accompanied by a severe or serious infection, both events should 
be reported separately on the eCRF. 
 
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated. 
5.3.5.3 
Persistent or Recurrent Adverse Events 
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity of the event should be recorded, and the 
severity should be updated to reflect the most extreme severity any time the event 
worsens.  If the event becomes serious, the Adverse Event eCRF should be updated to 
reflect this. 
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded 
separately on the Adverse Event eCRF. 
5.3.5.4 
Abnormal Laboratory Values 
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
should be reported as an adverse event if it meets any of the following criteria: 
 
Is accompanied by clinical symptoms 
 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
 
Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
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 
Is clinically significant in the investigator’s judgment  
 
It is the investigator’s responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event. 
If a clinically significant laboratory abnormality is a manifestation of a disease or 
syndrome (e.g., alkaline phosphatase and bilirubin 5  ULN associated with cholecystitis), 
only the diagnosis (i.e., cholecystitis) should be recorded on the Adverse Event eCRF. 
If a clinically significant laboratory abnormality is not a manifestation of a clearly 
discernible disease or syndrome, the abnormality itself should be recorded on the 
Adverse Event eCRF, along with a descriptor indicating if the test result is above or 
below the normal range (e.g., “elevated potassium,” as opposed to 
"abnormal potassium”).  If the laboratory abnormality can be characterized by a precise 
clinical term per standard definitions, the clinical term should be recorded as the adverse 
event.  For example, an elevated serum potassium level of 7.0 mEq/L should be 
recorded as “hyperkalemia.” 
Observations of the same clinically significant laboratory abnormality from visit to visit 
should not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes.  The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens. 
5.3.5.5 
Abnormal Vital Sign Values 
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result should 
be reported as an adverse event if it meets any of the following criteria: 
 
Accompanied by clinical symptoms 
 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
 
Results in a medical intervention or a change in concomitant therapy 
 
Clinically significant in the investigator’s judgment 
 
It is the investigator’s responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event. 
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF. 
Observations of the same clinically significant vital sign abnormality from visit to visit 
should not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 


 
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changes.  The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens. 
5.3.5.6 
Abnormal Liver Function Tests 
The finding of an elevated ALT or AST ( 3  the baseline value) in combination with 
either an elevated total bilirubin ( 2  ULN) or clinical jaundice in the absence of 
cholestasis or other causes of hyperbilirubinemia is considered to be an indicator of 
severe liver injury.  Therefore, investigators must report as an adverse event the 
occurrence of either of the following: 
 
Treatment-emergent ALT or AST  3  the baseline value in combination with total 
bilirubin  2  ULN (of which  35% is direct bilirubin) 
 
Treatment-emergent ALT or AST  3  the baseline value in combination with clinical 
jaundice 
 
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.1) 
and reported to the Sponsor within 24 hours after learning of the event, either as a 
serious adverse event or a non-serious adverse event of special interest 
(see Section 5.4.2). 
5.3.5.7 
Deaths 
For this protocol, mortality is a secondary efficacy endpoint.  All deaths must be 
recorded on the Study Completion/Discontinuation eCRF.   
Deaths that are attributed by the investigator solely to recurrence of melanoma are not 
considered an adverse event and should not be recorded on the Adverse Event eCRF.  
Rather, these deaths should be recorded on the Study Completion/Discontinuation 
eCRF. 
All other deaths, regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4.2).  
An independent DSMB will monitor the frequency of deaths from all causes. 
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, “unexplained death” should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), “unexplained death” should 
be replaced by the established cause of death.  The term "sudden death" should not 
be used unless combined with the presumed cause of death (e.g., "sudden cardiac 
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5.3.5.8 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF. 
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., “more frequent headaches”). 
5.3.5.9 
Hospitalization or Prolonged Hospitalization 
Any adverse event that results in hospitalization or prolonged hospitalization should be 
documented and reported as a serious adverse event (per the definition of serious 
adverse event in Section 5.2.2), except as outlined below.   
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event: 
 
Hospitalization for respite care 
 
Planned hospitalization required by the protocol (e.g., complete regional 
lymphadenectomy)  
 
Hospitalization for a preexisting condition, provided that all of the following criteria 
are met: 
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected normal 
progression of the disease. 
The patient has not suffered an adverse event. 
 
Hospitalization due solely to recurrence/progression of the underlying melanoma 
 
An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead: 
 
Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours 
 
5.3.5.10 
Overdoses 
Study drug overdose is the accidental or intentional use of the drug in an amount higher 
than the dose being studied.  An overdose or incorrect administration of study drug is not 
an adverse event unless it results in untoward medical effects. 
Any study drug overdose or incorrect administration of study drug should be noted on 
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All adverse events associated with an overdose or incorrect administration of study drug 
should be recorded on the Adverse Event eCRF.  If the associated adverse event fulfills 
serious criteria, the event should be reported to the Sponsor within 24 hours after 
learning of the event (see Section 5.4.2). 
5.3.5.11 
Patient-Reported Outcome Data 
Adverse event reports will not be derived from PRO data.  However, if any patient’s 
responses suggestive of a possible adverse event are identified during site review of the 
PRO questionnaires, site staff will alert the investigator, who will determine if the criteria 
for an adverse event have been met and will document the outcome of this assessment 
in the patient’s medical record per site practice.  If the event meets the criteria for an 
adverse event, it will be reported on the Adverse Event eCRF. 
5.4 
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR 
The investigator must report the following events to the Sponsor within 24 hours after 
learning of the event, regardless of relationship to study drug: 
 
Serious adverse events 
 
Non-serious adverse event of special interest 
 
Pregnancies 
 
The investigator must report new significant follow-up information for these events to the 
Sponsor within 24 hours after becoming aware of the information.  New significant 
information includes the following: 
 
New signs or symptoms or a change in the diagnosis 
 
Significant new diagnostic test results 
 
Change in causality based on new information 
 
Change in the event’s outcome, including recovery 
 
Additional narrative information on the clinical course of the event 
 
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC. 
5.4.1 
Medical Contacts 
5.4.1.1 
NonMedical Emergency Medical Contacts 
Contact the medical monitor or designee for your respective region.  Please refer to a 
Medical Contact List for the name and contact information.  Should you be unable to 
reach your regional medical monitor or designee, you can contact the global medical 
monitor (or back up) also listed in the Medical Contact List located in your Investigator 
Site file. 


 
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5.4.1.2 
Medical Emergency Medical Contacts 
24-HOUR MEDICAL COVERAGE (Roche Emergency Medical Call Center 
Help Desk): 
To ensure the safety of study patients, an Emergency Medical Call Center Help Desk will 
access the Roche Medical Emergency List, escalate emergency medical calls, provide 
medical translation service (if necessary), connect the investigator with a Roche Medical 
Monitor, and track all calls.  Please refer to the Emergency Medical Call Center Country 
Specific Toll-Free Number Details for your country, located in your Investigator Site File. 
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Non-Serious Adverse Events of Special Interest 
For reports of serious adverse events and non-serious adverse event of special interest, 
investigators should record all case details that can be gathered within 24 hours on the 
Adverse Event eCRF and submit the report via the electronic data capture (EDC) system.  
A report will be generated and sent to Roche Safety Risk Management by the EDC 
system. 
In the event that the EDC system is unavailable, a paper Serious Adverse 
Event/Non-Serious Adverse Event of Special Interest CRF and Fax Coversheet should 
be completed and faxed to Roche Safety Risk Management or its designee within 
24 hours after learning of the event, using the fax numbers provided to investigators (see 
“Protocol Administrative and Contact Information & List of Investigators”).  Once the 
EDC system is available, all information will need to be entered and submitted via the 
EDC system.   
5.4.3 
Reporting Requirements for Pregnancies 
5.4.3.1 
Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant until end of study (see Section 3.2).  All women of 
childbearing potential (including those who have had a tubal ligation) will have a serum 
pregnancy test at screening (within 14 days prior to randomization) and every three 
cycles (e.g., Cycles 3, 6, 9, and 12 or every 12  2 weeks), starting from Cycle 1, Day 1 
during study drug administration and at 12  2 weeks and 26  2 weeks after the last 
dose of study drug.  A Pregnancy Report eCRF should be completed by the investigator 
within 24 hours after learning of the pregnancy and submitted via the EDC system.  
A pregnancy report will automatically be generated and sent to Roche Safety Risk 
Management.  Pregnancy should not be recorded on the Adverse Event eCRF.  The 
investigator should discontinue study drug and counsel the patient, discussing the risks 
of the pregnancy and the possible effects on the fetus.  Monitoring of the patient should 
continue until conclusion of the pregnancy. 
In the event that the EDC system is unavailable, a Pregnancy Report worksheet and 
Pregnancy Fax Coversheet should be completed and faxed to Roche Safety Risk 
Management or its designee within 24 hours after learning of the pregnancy, using the 


 
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fax numbers provided to investigators (see “Protocol Administrative and Contact 
Information and List of Investigators”). 
5.4.3.2 
Pregnancies in Female Partners of Male Patients 
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant until end of study (see 
Section 3.2) starting from Cycle 1, Day 1.  A Pregnancy Report eCRF should be 
completed by the investigator within 24 hours after learning of the pregnancy and 
submitted via the EDC system.  Attempts should be made to collect and report details of 
the course and outcome of any pregnancy in the partner of a male patient exposed to 
study drug.  The pregnant partner will need to sign an Authorization for Use and 
Disclosure of Pregnancy Health Information to allow for follow-up on her pregnancy.  
Once the authorization has been signed, the investigator will update the Pregnancy 
Report eCRF with additional information on the course and outcome of the pregnancy.  
An investigator who is contacted by the male patient or his pregnant partner may provide 
information on the risks of the pregnancy and the possible effects on the fetus, to 
support an informed decision in cooperation with the treating physician and/or 
obstetrician. 
In the event that the EDC system is unavailable, follow reporting instructions provided in 
Section 5.4.3.1. 
5.4.3.3 
Abortions 
Any spontaneous abortion should be classified as a serious adverse event 
(as the Sponsor considers spontaneous abortions to be medically significant events), 
recorded on the Adverse Event eCRF, and reported to the Sponsor within 24 hours after 
learning of the event (see Section 5.4.2).   
5.4.3.4 
Congenital Anomalies/Birth Defects 
Any congenital anomaly/birth defect in a child born to a female patient or female partner 
of a male patient exposed to study drug should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor within 24 hours after 
learning of the event (see Section 5.4.2). 
5.5 
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS 
5.5.1 
New Primary Cancers 
In fulfillment of a post-marketing requirement as a condition of vemurafenib approval in 
the United States (for the treatment of unresectable or metastatic melanoma), all new 
primary cancers will be reported to the U.S. Food and Drug Administration (FDA) every 
12 months after the first patient enrolls and for 1 year after the last patient has 
completed study treatment.  As noted in Section 5.1.2.3.5, all new primary cancers will 
be reported for until end of study, whether or not a patient has experienced melanoma 
recurrence or an occurrence of a new primary melanoma. 


 
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5.5.2 
Investigator Follow-Up 
The investigator should follow each adverse event until the event has resolved to 
baseline grade or better, the event is assessed as stable by the investigator, new 
anti-tumor treatment is initiated, the patient is lost to follow-up, or the patient withdraws 
consent.  Every effort should be made to follow all serious adverse events considered to 
be related to study drug or trial-related procedures until a final outcome can be reported. 
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification.  If, after follow-up, return to baseline status or stabilization cannot be 
established, an explanation should be recorded on the Adverse Event eCRF.   
All pregnancies reported during the study should be followed until pregnancy outcome.  
If the EDC system is not available at the time of pregnancy outcome, follow reporting 
instructions provided in Section 5.4.3.1. 
5.5.3 
Sponsor Follow-Up 
For serious adverse events, non-serious adverse event of special interest, and 
pregnancies, the Sponsor or a designee may follow up by telephone, fax, electronic mail, 
and/or a monitoring visit to obtain additional case details and outcome information 
(e.g., from hospital discharge summaries, consultant reports, autopsy reports) in order to 
perform an independent medical assessment of the reported case. 
5.6 
POST-STUDY ADVERSE EVENTS 
At the study treatment completion/early termination visit, the investigator should instruct 
each patient to report to the investigator any subsequent adverse events that the 
patient’s personal physician believes could be related to prior study drug treatment or 
study procedures. 
The investigator should notify the Sponsor of any death, serious adverse event 
(including new primary malignancies), or other adverse event of concern occurring at 
any time after a patient has discontinued study participation if the event is believed to be 
related to prior study drug treatment or study procedures.  The Sponsor should also be 
notified if the investigator becomes aware of the development of cancer or a congenital 
anomaly/birth defect in a subsequently conceived offspring of a patient that participated 
in this study. 
The investigator should report these events to Roche Safety Risk Management on the 
Adverse Event eCRF.  If the Adverse Event eCRF is no longer available, the investigator 
should report the event directly to Roche Safety Risk Management via telephone 
(see Protocol Administrative and Contact Information & List of Investigators). 
During survival follow-up, deaths attributed to recurrence of melanoma should be 
recorded on the Study Completion/Discontinuation eCRF. 


 
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5.7 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES 
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference documents: 
 
Vemurafenib IB 
 
Local prescribing information for vemurafenib 
 
Vemurafenib Core Data Sheet 
 
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document. 
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed. 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
Descriptive summaries of continuous data for each cohort will include the mean, 
standard deviation, median, minimum, and maximum, and number of patients.  
Descriptive summaries of discrete data for each cohort will include the number of 
patients and incidence as a frequency and percentage. 
6.1 
DETERMINATION OF SAMPLE SIZE 
The overall Type I error (alpha) for this study is 0.05 (two sided).  The primary objective 
of the protocol to assess efficacy as measured by DFS will be evaluated separately for 
each of the two cohorts.  The sample size determination was evaluated separately for 
each cohort.  The final primary efficacy endpoint (DFS) analyses for the two cohorts will 
be conducted according to the procedure specified in Section 6.4.1.  The detailed 
analysis plan will be specified in Statistical Analysis Plan (SAP). 
6.1.1 
Cohort 1 
The final analysis of the primary endpoint of DFS for Cohort 1 will take place when 
approximately 120 DFS events have occurred, on the basis of the following assumptions: 
 
Two-sided, stratified log-rank test at the 0.05 significance level  
 
80% power 
 
Median DFS for the control arm of 24 months and estimated median DFS in the 
vemurafenib treatment arm of 40 months (which corresponds to an HR of 0.60) 
 
5% annual loss to follow-up for DFS 
 
No interim analysis 
 


 
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Assuming an accrual rate of 8 patients per month in Cohort 1 and a 17-month ramp-up 
period to reach steady-state enrollment, approximately 300 patients will be required to 
be enrolled in Cohort 1 during 43 months and followed for an additional 7 months in 
order to observe 120 DFS events. 
On the basis of the assumptions above, 120 DFS events are projected to occur in 
Cohort 1 approximately 50 months after the first patient is randomized in this study.  
At that time, it is projected that median follow-up time will be 21 months in Cohort 1, 
and the minimum follow-up time (e.g., for the last patient randomized) is projected to be 
7 months.  Also on the basis of the assumptions of 120 DFS events required and a 
target HR of 0.60, it is projected that an observed HR of 0.70 or better in the DFS 
analysis will result in a statistically significant difference between treatment arms (i.e., 
HR of 0.70 is the minimally detectable difference for that analysis). 
A summary of the assumptions and characteristics of the DFS analysis for Cohort 1 is 
shown in Table 4. 
For Cohort 1, on the basis of the assumptions of a target HR of 0.60, 120 DFS events 
would also provide 80% power to detect a 16% absolute increase in the 2-year DFS rate 
(50% vs. 66%, corresponding to a 40% risk reduction; i.e., HR of 0.60). 
6.1.2 
Cohort 2 
The final analysis of the primary endpoint of DFS for Cohort 2 will take place when 
approximately 105 DFS events have occurred, on the basis of the following assumptions: 
 
Two-sided, stratified log-rank test at the 0.05 significance level 
 
80% power 
 
Median DFS for the control arm of 7.7 months and estimated median DFS in the 
vemurafenib treatment arm of 13.3 months (which corresponds to an HR of 0.58) 
 
5% annual loss to follow-up for DFS 
 
No interim analysis 
 
Assuming an accrual rate of 5 patients per month in Cohort 2 and a 27-month ramp-up 
period to reach steady-state enrollment, approximately 175 patients will be required to 
be enrolled in Cohort 2 over 40 months in order to observe 105 DFS events. 
A summary of the assumptions and characteristics of the DFS analysis for Cohort 2 is 
shown in Table 4. 
For Cohort 2, on the basis of the assumptions of a target HR of 0.58, 105 DFS events 
would provide 80% power to detect a 17% absolute increase in the 2-year DFS rate 
(12% vs. 29%, corresponding to a 42% risk reduction; i.e., HR of 0.58). 


 
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Table 4 
Assumptions and Characteristics for Disease-Free Survival 
Analyses by Cohort 
 
Cohort 1 
Cohort 2 
Patients enrolled 
300 
175 
Hazard ratio targeted 
0.60 
0.58 
Target median (control) 
24 months 
7.7 months 
Target median (vemurafenib) 
40 months 
13.3 months 
Final DFS analysis 
 
 
Number of DFS events 
120 
105 
MDD hazard ratio a 
0.70 
0.68 
Alpha level (two sided) 
0.05 
0.05 
Power 
80% 
80% 
DFS  disease-free survival; FPI  first patient in; MDD  minimum detectable difference. 
Note:  A 5% annual dropout rate is anticipated for DFS analyses. 
a Minimally detectable difference; the largest observed hazard ratio that is projected to 
be statistically significant. 
 
6.2 
SUMMARIES OF CONDUCT OF STUDY 
Enrollment, eligibility violations, and patient disposition will be summarized for 
randomized patients by treatment arm.  The summary of patient disposition will include 
whether treatment was completed or discontinued prematurely and the reason for 
premature treatment discontinuation.  Study treatment administration will be summarized 
by treatment arm for all treated patients. 
6.3 
SUMMARIES OF TREATMENT GROUP COMPARABILITY 
Demographic variables, stratification factors, and other baseline characteristics will be 
summarized. 
6.4 
EFFICACY ANALYSES 
Unless otherwise noted, all efficacy analyses will include all randomized patients 
(intent-to-treat analysis), and patients will be grouped according to the treatment 
assigned at randomization.  The primary and all secondary objectives of this study will 
be evaluated separately for each cohort.  
6.4.1 
Primary Efficacy Endpoint 
The primary endpoint, DFS, is defined as the time from randomization until the date of 
the first local, regional, or distant melanoma recurrence, occurrence of new primary 
melanoma, or death from any cause.  The DFS component of melanoma recurrence will 
be assessed by the investigator.  The DFS component of an occurrence of a new 
primary melanoma will be based upon the diagnosis made by a Roche-designated 
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data will be censored at the date of the last disease assessment.  Details on censoring 
in the analysis of this endpoint are described in the SAP.  
For patients whose recurrence has been proven histologically, the date of melanoma 
recurrence will be defined as the earliest date of the scan or clinical examination that 
prompted the biopsy.  For patients whose suspicious lesions were deemed not 
amenable to biopsy (see Section 4.5.1.4) or for patients who refuse a biopsy, the date of 
melanoma recurrence will be defined as the earliest date of the scan or clinical 
examination that would have prompted a biopsy.  For patients with an occurrence of a 
new primary melanoma, the date of the new primary melanoma will be defined as the 
earliest date of the clinical examination or scan that prompted the biopsy. 
The final analysis of the primary endpoint of DFS will take place when approximately 
120 DFS events have occurred for Cohort 1 and approximately 105 DFS events have 
occurred for Cohort 2 (see Section 6.1).  The final DFS analyses for both cohorts will be 
conducted at the same time by using the dataset from the same data cutoff date for both 
cohorts.  The primary efficacy analyses will be comparisons of the two treatment groups, 
using a two-sided, stratified log-rank test for Cohort 1 and Cohort 2 separately.  To 
account for separate analysis for each cohort, the statistical significance of the 
comparison of DFS between treatment arms will be based an alpha level of 0.05 (two 
sided) of the family-wise Type I error rate for two tests of two cohorts.  Detailed testing 
procedures will be provided in the SAP. 
Median DFS time will be estimated using the Kaplan-Meier method, and the two-sided 
95% CI will be calculated using the method of Brookmeyer and Crowley (1982) for each 
cohort. 
The HR of DFS (recurrence, new primary melanoma, or death) and the associated 
two-sided 95% CI will be estimated by using a stratified Cox proportional hazards model. 
The stratification factors in the stratified analyses are the stratification factors used in 
randomization of patients in each cohort.  For Cohort 1, stratified analyses will 
incorporate two stratification factors:  pathologic stage (Stage IIC; Stage IIIA; Stage IIIB) 
and region (North America, Australia/New Zealand/South Africa/Latin America, rest of 
the world).  For Cohort 2, stratified analyses will incorporate one stratification factor, 
region (North America, Australia/New Zealand/South Africa/Latin America, rest of the 
world).   
In addition, Kaplan-Meier methodology will be used to estimate landmark (e.g., 1-year, 
2-year, and 3-year) DFS rates and the associated two-sided 95% CIs for each treatment 
arm, and the Kaplan-Meier curves will be provided.   
Subgroup analyses for the primary efficacy outcome, DFS, will be performed to assess 
the robustness of the results across patient subgroups in each cohort separately.  The 


 
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subgroups will include but are not limited to the categories of demographic (age, sex), 
baseline disease characteristics, BRAF mutation status such as V600E versus non-
V600E, and stratification variables. 
The following sensitivity analyses will be performed for DFS by study cohort.  Details are 
provided in the SAP: 
 
Unstratified log-rank test and HR 
 
DFS analysis accounting for missing disease assessments for patients later 
diagnosed with a DFS event 
 
DFS analysis accounting for DFS events reported at an off-schedule disease 
assessment 
 
As an exploratory analysis, DFS analyses based on the pooled data from both cohorts 
will also be performed for descriptive purposes to characterize the benefit of 
vemurafenib in the total study population.  This exploratory analysis will be stratified by 
region. 
6.4.2 
Secondary Efficacy Endpoints 
DMFS and OS are the secondary efficacy endpoints.  The Type I error management for 
secondary endpoints is described in the SAP. 
6.4.2.1 
Distant MetastasisFree Survival 
DMFS is defined as the time from randomization until the date of diagnosis of distant 
(i.e., non-locoregional) metastasis or death from any cause.  Details on censoring in the 
analysis of this endpoint are described in the SAP.  DMFS will be analyzed at the time of 
the final DFS analysis in each cohort.  The analysis methods to be employed for DMFS 
are the same as those described for the primary endpoint of DFS. 
6.4.2.2 
Overall Survival 
OS is defined as the time from randomization until the date of death from any cause.  
For patients still alive at the time of analysis, the data will be censored at the date the 
patient was last known to be alive.  The study is not powered for OS, so adequate power 
statistical testing for this endpoint is not possible.  However, some standard OS 
estimates will be provided by using the same analysis methods as those described for 
the primary endpoint of DFS. 
Two OS analyses are planned for each cohort.  The OS interim analysis in each cohort 
will be performed at the time of the final DFS analysis for both cohorts.  The final OS 
analysis for Cohorts 1 and 2 will be performed at the end of study (see Section 3.2). 
6.5 
SAFETY ANALYSES 
Safety analyses will include all patients who receive any amount of study treatment 
(vemurafenib or placebo), with patients grouped according to the patients’ safety group.  


 
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Patients who receive at least one dose of vemurafenib will be included in the 
vemurafenib safety population.  Safety will be assessed through summaries of all 
adverse events, including serious adverse events, adverse events of special interest, 
and adverse events leading to discontinuation of vemurafenib or placebo.  All verbatim 
descriptions of treatment-emergent adverse events will be summarized by MedDRA 
preferred terms.  Adverse events will be graded by the investigator according to 
NCI CTCAE v4.0. 
The following safety parameters will be summarized by treatment arm for patients in 
Cohort 1 and Cohort 2 separately as well as for all study patients pooled: 
 
All adverse events 
 
All adverse events leading to discontinuation of study treatment 
 
All deaths 
 
Serious adverse events 
 
Adverse event of special interest (see Section 5.2.3) 
 
In addition, treatment exposure, including cumulative dose and treatment duration, will 
be summarized by treatment arm. 
Selected laboratory data will be summarized by treatment arm and toxicity grade 
(NCI CTCAE v4.0).  Further details on safety analyses, including descriptions of the 
analyses of ECGs, are provided in the SAP. 
6.6 
PHARMACOKINETIC ANALYSES 
The PK-evaluable population will include all patients who have received at least one 
dose of vemurafenib and have provided valid PK assessments.  Summary statistics will 
be used as appropriate to perform the descriptive analysis of the plasma concentrations 
of vemurafenib at clinically relevant timepoints.  These timepoints will include all 
available Cycle 1 data and predose values from all available cycles.  In addition, 
summary statistics may be provided for PK data from patients after the diagnosis of 
melanoma recurrence or occurrence of a new primary melanoma during study treatment, 
at the time of diagnosis of SCC (cutaneous [including KA] and non-cutaneous), and at 
the occurrence of a dose-limiting toxicity and concomitant decision to reduce the dose or 
interrupt or discontinue treatment.  All PK parameters will be presented descriptively 
including arithmetic means, standard deviations, geometric means, coefficients of 
variation, medians, and ranges. 
In the scenario, in which major discrepancies are observed in the exposure levels and in 
the PK characteristics, nonlinear mixed-effects modeling (with software NONMEM [Beal 
and Sheiner 1998]) will be used to analyze the sparse PK concentrationtime data for 
vemurafenib, and the results of these analyses will be reported in a document separate 
from the Clinical Study Report.   


 
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Graphical analyses will be conducted to explore the possible relationship between 
vemurafenib exposure and the following parameters: 
 
The risk of melanoma recurrence or the occurrence of a new primary melanoma 
 
The occurrence of serious adverse events 
 
The abnormalities in selected safety laboratory parameters 
 
6.7 
PATIENT-REPORTED OUTCOMES 
The EORTC QLQ-C30 data will be scored according to the EORTC scoring manual.  For 
all questionnaire subscales, if  50% of the constituent items are completed, a pro-rated 
score will be computed consistent with the scoring manuals and validation papers.  For 
subscales with  50% of the items completed, the subscale will be considered as missing.  
All PRO data analyses will be performed on patients with baseline assessments and at 
least one post-baseline PRO assessment by treatment arm. 
QoL, as measured by EORTC QLQ-C30, will be evaluated for patients with a baseline 
assessment and at least one post-baseline QLQ-C30 assessment that generate a score.  
Total QLQ-C30, each domain score (i.e., physical functioning, role functioning, emotional 
functioning, cognitive functioning, and social functioning), symptom scales, and their 
changes from baseline will be examined for each timepoint with use of descriptive 
statistics, including mean, median, standard deviation, and range.  
Compliance rates for patients who complete QoL assessments will be assessed over 
time (i.e., QoL “drop out”) and by treatment arm. 
6.8 
OTHER ANALYSES 
Biomarker analyses will be provided in a separate report.  Descriptions of biomarker 
analyses will be provided in a Biomarker Analysis Plan. 
6.9 
INTERIM ANALYSES 
No interim analyses of the primary endpoint, DFS, will be performed. 
As stated in Section 6.4.2.2, two OS analyses (one interim analysis and 
one final analysis) are planned for each cohort.  The OS interim analysis will be 
performed at the time of the final DFS analysis for each cohort.  The final OS analysis for 
Cohorts 1 and 2 (see Table 5) will be performed at the end of study (see Section 3.2).  
The Lan-DeMets implementation (Lan and DeMets 1983) of the O’Brien-Fleming use 
function will be used to control the overall Type I error for the OS comparison in each 
cohort at a two-sided 0.05 significance level. 


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Table 5
Assumptions and Characteristics for Overall Survival Analyses 
by Cohort
Cohort 1
n300
Cohort 2
n175
HR targeted
0.70
0.70
Targeted median (control)
61 months
24.2 months
Targeted median 
(vemurafenib)
87.1 months
34.6 months
Interim OS (to be performed at 
time of final DFS analysis) 
Projected number of events 
(% of final events)
64 (60%)
59 (50%)
Final OS 
Estimated cutoff date
30 months after LPI
30 months after LPI
Alpha level (two sided)
0.05
0.05
DFSdisease-free survival; HRhazard ratio; LPI last patient in; MDDminimum 
detectable difference; OSoverall survival.
Note:  1% annual dropout rate is anticipated for OS analyses.
7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
A contract research organization (CRO) will be responsible for the data management of 
this study, including quality checking of the data.  Data entered manually will be 
collected via EDC using eCRFs.  Sites will be responsible for data entry into the EDC 
system.  In the event of discrepant data, the CRO will request data clarification from the 
sites, which the sites will resolve electronically in the EDC system.
Roche will perform oversight of the data management of this study.  Roche will produce 
an EDC Study Specification document that describes the quality checking to be 
performed on the data.  Other electronic data will be sent directly to Roche, using 
Roche’s standard procedures to handle and process the electronic transfer of these data.
eCRFs and correction documentation will be maintained in the EDC system’s audit trail.  
System backups for data stored at Roche and records retention for the study data will be 
consistent with Roche’s standard procedures.
Data from paper PRO questionnaires will be entered into the EDC system by site staff.
7.2
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed using a Sponsor-designated EDC system.  Sites will receive 
training and a have access to a manual for appropriate eCRF completion.  eCRFs will be 


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submitted electronically to Roche and should be handled in accordance with instructions 
from Roche.
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee.
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required.
7.3
SOURCE DATA DOCUMENTATION
Study monitors will perform ongoing source data verification to confirm that critical 
protocol data (i.e., source data) entered into the eCRFs by authorized site personnel are 
accurate, complete, and verifiable from source documents. 
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include but are not limited to hospital records, 
clinical and office charts, laboratory notes, memoranda, PROs, evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies of 
transcriptions that are certified after verification as being accurate and complete, 
microfiche, photographic negatives, microfilm or magnetic media, X-rays, patient files, 
and records kept at pharmacies, laboratories, and medico-technical departments 
involved in a clinical trial.
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data.
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.5.
To facilitate source data verification, the investigators and institutions must provide the 
Sponsor direct access to applicable source documents and reports for trial-related 
monitoring, Sponsor audits, and IRB/EC review.  The investigational site must also allow 
inspection by applicable health authorities.
7.4
USE OF COMPUTERIZED SYSTEMS
When clinical observations are entered directly into an investigational site’s 
computerized medical record system (i.e., in lieu of original hardcopy records), the 
electronic record can serve as the source document if the system has been validated in 
accordance with health authority requirements pertaining to computerized systems used 
in clinical research.  An acceptable computerized data collection system allows 


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preservation of the original entry of data.  If original data are modified, the system should 
maintain a viewable audit trail that shows the original data as well as the reason for the 
change, name of the person making the change, and date of the change.
7.5
RETENTION OF RECORDS
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, Informed Consent Forms, laboratory test results, and medication 
inventory records, must be retained by the lead investigator at each study site for at least 
15 years after completion or discontinuation of the study or for the length of time 
required by relevant national or local health authorities, whichever is longer.  After that 
period of time, the documents may be destroyed, subject to local regulations.  
No records may be disposed of without the written approval of Roche.  Written 
notification should be provided to Roche prior to transferring any records to another 
party or moving them to another location.
8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki or the laws and 
regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) Application will comply with U.S. FDA regulations and 
applicable local, state, and federal laws.  Studies conducted in the European 
Union/European Economic Area will comply with the E.U. Clinical Trial Directive 
(2001/20/EC).
8.2
INFORMED CONSENT
Roche’s sample Informed Consent Form (and ancillary sample Informed Consent Forms, 
if applicable) will be provided to each site.  If applicable, it will be provided in a certified 
translation of the local language.  Roche or its designee must review and approve any 
proposed deviations from Roche’s sample Informed Consent Forms or any alternate 
consent forms proposed by the site (collectively, the “Consent Forms”) before IRB/EC 
submission.  The final IRB/EC-approved Consent Forms must be provided to Roche for 
health authority submission purposes according to local requirements.
The Informed Consent Form will contain a separate section that addresses the use of 
remaining mandatory samples for optional exploratory research.  The investigator or 
authorized designee will explain to each patient the objectives of the exploratory 
research.  Patients will be told that they are free to refuse to participate and may 
withdraw their specimens at any time and for any reason during the 15-year storage 


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period.  A separate, specific signature will be required to document a patient’s 
agreement to allow any remaining specimens to be used for exploratory research.  
Patients who decline to participate will check a “no” box in the appropriate section and 
will not provide a separate signature.
The Consent Forms must be signed and dated by the patient or the patient’s legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study.
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
Roche for health authority submission purposes.
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study.
A copy of each signed Consent Form must be provided to the patient or the patient’s 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient’s study file or in the site file and must be available for verification by study 
monitors at any time.
For sites in the United States, each Consent Form may also include patient authorization 
to allow use and disclosure of personal health information in compliance with the 
U.S. Health Insurance Portability and Accountability Act (HIPAA) of 1996.  If the site 
utilizes a separate Authorization Form for patient authorization for use and disclosure of 
personal health information under the HIPAA regulations, the review, approval, 
and other processes outlined above apply except that IRB review and approval may not 
be required per study site policies.
8.3
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the lead study 
site investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC.  
The lead study site investigator is responsible for providing written summaries of the 
status of the study to the IRB/EC annually or more frequently in accordance with the 
requirements, policies, and procedures established by the IRB/EC.  Investigators are 


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also responsible for promptly informing the IRB/EC of any protocol amendments 
(see Section 9.5).
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from Roche.  Investigators are responsible for 
ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site’s study file.
8.4
CONFIDENTIALITY
Roche maintains confidentiality standards by coding each patient enrolled in the study 
through assignment of a unique patient identification number.  This means that patient 
names are not included in data sets that are transmitted to any Roche location.
Patient medical information obtained by this study is confidential and may only be 
disclosed to third parties as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare for treatment purposes.
Data generated by this study must be available for inspection upon request by 
representatives of the U.S. FDA and other national and local health authorities, Roche 
monitors, representatives, and collaborators, and the IRB/EC for each study site, as 
appropriate.
8.5
FINANCIAL DISCLOSURE
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the final DFS analysis for 
Cohorts 1 and 2.
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION
9.1
STUDY DOCUMENTATION
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including but not limited to the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 


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governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, which includes an audit trail containing a complete record of all changes 
to data.
9.2
SITE INSPECTIONS
Site visits will be conducted by Roche or an authorized representative for inspection of 
study data, patients’ medical records, and eCRFs.  The investigator will permit national 
and local health authorities, Roche monitors, representatives, and collaborators, and the 
IRBs/ECs to inspect facilities and records relevant to this study.
9.3
ADMINISTRATIVE STRUCTURE
The overall procedures for quality assurance of clinical study data are described in the 
Roche standard operational procedures.
This study will be sponsored by F. Hoffmann-La Roche and managed with the support of 
a CRO, which will provide clinical monitoring, sample management, and project 
management support.  Approximately 200 centers globally may participate in the study 
and will enroll approximately 475 patients.
Randomization will occur through an IxRS (see Section 4.2).  Central facilities will be 
used for study assessments (i.e., ECG, specified laboratory tests, pharmacokinetics, 
dermatology).  Accredited local laboratories will be used for routine monitoring; local 
laboratory ranges will be collected.  
Data for this study will be recorded via an EDC system using eCRF.  It will be 
transcribed by the site from the paper source documents onto the eCRF.  In no case is 
the eCRF to be considered as source data for this trial (see Section 7.2).
A DSMB will be utilized to ensure patient safety and will consist of external clinicians 
who are experts in the disease area and one external statistician.  Details of the DSMB’s 
responsibilities and logistics are outlined in the DSMB Charter.  The DSMB, which will 
review safety data from vemurafenib trials, will review available safety data from this trial 
at regularly scheduled intervals specified in the DSMB Charter.
9.4
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, both at scientific 
congresses and in peer-reviewed journals.  The Sponsor will comply with all 
requirements for publication of study results.  For more information, refer to the Roche 
Global Policy on Sharing of Clinical Trials Data at the following Web site:
http://www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.
pdf


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The results of this study may be published or presented at scientific meetings.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective clinical study report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound.
The investigator must agree to submit all manuscripts or abstracts to Roche prior to 
submission for publication or presentation.  This allows the Sponsor to protect
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator.
In accordance with standard editorial and ethical practice, Roche will generally support 
publication of multicenter trials only in their entirety and not as individual center data.  In 
this case, a coordinating investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Roche personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Roche personnel.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of Roche, except where agreed otherwise.
9.5
PROTOCOL AMENDMENTS
Any protocol amendments will be prepared by the Sponsor.  Investigators are 
responsible for promptly informing the IRB/EC of any amendments to the protocol.  
Approval must be obtained from the IRB/EC before implementation of any changes, 
except for changes necessary to eliminate an immediate hazard to patients or changes 
that involve logistical or administrative aspects only (e.g., change in Medical Monitor or 
contact information).


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10.
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Appendix 1
Schedule of Assessments
Screening (Days prior 
to Randomization)
Treatment Period, 28-Day Cycles
Melanoma 
Recurrence
/NPM
End of
Tx
Visit b,c
Post
Tx 
FU d
Early Study 
Term Visit b,e
(Post-
Treatment)
Post-
Recurrence
FU/End of 
Study
Cycle 1
Cycle 2
Cycle 
313
Every 
13 Wk a
Every 
26 Wk
Day(s)
90
28
14
1
8
15
22
1
15
1
Sign informed 
consent
x f
Tumor tissue for 
BRAFV600 mutation 
testing and 
exploratory 
analyses g
x h
x h
Medical history, 
baseline 
conditions, and 
demographics
x
Interval medical 
history
x
x
x
x
x
x
x
Vital signs i
x
x j
x
x
x
x
x
Physical exam k
x
x j
x
x
x
x
x
x
x l
x
Dermatology 
evaluation m
x
xm
x m
x
x m
x
Complete head and 
neck evaluation n
x
x
x


Appendix 1
Schedule of Assessments (cont.)
Vemurafenib—F. Hoffmann-La Roche Ltd
Protocol GO27826, Version 10
122
Screening (Days prior 
to Randomization)
Treatment Period, 28-Day Cycles
Melanoma 
Recurrence
/NPM
End of
Tx
Visit b,c
Post
Tx 
FU d
Early Study 
Term Visit b,e
(Post-
Treatment)
Post-
Recurrence
FU/End of 
Study
Cycle 1
Cycle 2
Cycle 
313
Every 
13 Wk a
Every 
26 Wk
Day(s)
90
28
14
1
8
15
22
1
15
1
Anal exam and 
pelvic exam 
with Pap smear o
x
x
x
Colonoscopy p
x p
x
Stool for occult 
blood q
x
x
x
Hematology r
x
x j
x
x
x
Serum chemistry s, 
LFTs
x
x j
x
x
x
x
x
x
x
PT/INR and aPTT
x
Serum pregnancy 
test t
x u
x v
x v
x w
Hepatitis B and C 
serology x
x
PK assessments
Refer to Appendix 2 (Schedule of Pharmacokinetic Assessments)
Triplicate ECG y
x
x j
x
x
x
x z
x
Study drug 
administration aa
x
x
x
x
x
x
x


Appendix 1
Schedule of Assessments (cont.)
Vemurafenib—F. Hoffmann-La Roche Ltd
Protocol GO27826, Version 10
123
Screening (Days prior 
to Randomization)
Treatment Period, 28-Day Cycles
Melanoma 
Recurrence
/NPM
End of
Tx
Visit b,c
Post
Tx 
FU d
Early Study 
Term Visit b,e
(Post-
Treatment)
Post-
Recurrence
FU/End of 
Study
Cycle 1
Cycle 2
Cycle 
313
Every 
13 Wk a
Every 
26 Wk
Day(s)
90
28
14
1
8
15
22
1
15
1
CT or MRI scan of 
chest, abdomen, 
and pelvis 
x
x bb
x bb
x bb
x cc
Brain MRI scan
x dd
x dd
x cc
x dd
x cc
Concomitant 
medications ee
x
x
x
x
x
x
x
x
Adverse events ff
x
x
x
x
x
x
x
x
SAEs and 
non-serious AESI ff
x gg
x
x
x
x
x
x
x
x
x
x
x
PROs hh
x
x
x
x
x hh
x
x
x hh
x
Plasma/serum 
sample 
(exploratory 
biomarker) ii
x
x
x
x
x
x
x
Optional whole 
blood (RCR) jj
x


Appendix 1
Schedule of Assessments (cont.)
Vemurafenib—F. Hoffmann-La Roche Ltd
Protocol GO27826, Version 10
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Screening (Days prior 
to Randomization)
Treatment Period, 28-Day Cycles
Melanoma 
Recurrence
/NPM
End of
Tx
Visit b,c
Post
Tx 
FU d
Early Study 
Term Visit b,e
(Post-
Treatment)
Post-
Recurrence
FU/End of 
Study
Cycle 1
Cycle 2
Cycle 
313
Every 
13 Wk a
Every 
26 Wk
Day(s)
90
28
14
1
8
15
22
1
15
1
Pathologic 
review/molecular 
analysis for 
SCC/KA, new 
primary neoplasms, 
and recurrence kk
Tissue sample(s) to be sent when identified
Follow-up for new 
primary malignancy 
and survival ll
x mm
x mm
AESI(non-serious) adverse event of special interest; anti-HBc hepatitis B core antibody; CT computed tomography; cuSCCcutaneous squamous cell carcinoma; 
eCRFelectronic Case Report Form; DFSdisease-free survival; EORTC QLQ-C30European Organisation for Research and Treatment of Cancer 30-item Quality of 
Life Questionnaire; FFfresh frozen; FFPEformalin-fixed paraffin-embedded; FUfollow-up; HBsAghepatitis B surface antigen; HCV hepatitis C virus; 
HEENT head, eyes, ears, nose, and throat; KAkeratoacanthoma; LFTliver function test; MRImagnetic resonance imaging; NPMnew primary melanoma; 
PKpharmacokinetic; PRO patient-reported outcome; QTccorrected QT; RCRRoche Clinical Repository; SAEserious adverse event; SCCsquamous cell 
carcinoma; Tx treatment; Wkweek.
Notes:  All assessments should be performed within 3 days of the scheduled visit, unless otherwise specified.  On treatment days, all assessments should be
performed prior to dosing, unless otherwise specified.  The timing interval assessments (such as the head and neck examination and imaging studies) should be 
calculated from the Cycle 1, Day 1 visit, unless indicated below.  The frequency of the dermatological examination will be calculated after the first examination, which 
should occur after 4 weeks of study drug administration.


Appendix 1 
Schedule of Assessments (cont.) 
Vemurafenib—F. Hoffmann-La Roche Ltd 
Protocol GO27826, Version 10 
125 
a Study assessments required every 13 weeks (e.g., surveillance for melanoma recurrence) may be performed within a window of ± 2 weeks. 
b Assessments completed at melanoma recurrence or occurrence of a new primary melanoma do not need to be repeated at the end-of-treatment or early termination 
visit. 
c Patients who complete study drug treatment or discontinue study drug treatment early will be asked to return to the clinic 28 ± 3 days after the last dose of study drug 
for an end-of-treatment visit. 
d All patients will be followed for recurrence of melanoma, occurrence of a new primary melanoma, and new primary malignancies until end of study.  Regular physical 
examinations are to be done every 13 ± 2 weeks until end of study (see Section 3.2) or until a melanoma recurrence or occurrence of a new primary melanoma, 
whichever occurs first.  Imaging studies are to be done as follows:  contrast-enhanced CT or MRI of the chest, abdomen, and pelvis every 13 ± 2 weeks until 
Week 104 and every 26 ± 4 weeks thereafter until recurrence of melanoma, occurrence of a new primary melanoma, or until end of study, whichever occurs earlier.  
In addition, all patients will undergo contrast-enhanced MRI of the brain (or CT if MRI is not generally available or is contraindicated) every 52 ± 4 weeks until 
recurrence of melanoma, occurrence of a new primary melanoma, or until end of study, whichever occurs earlier.  Note:  Patients who have had a DFS event do not 
need additional scans or physical examinations for melanoma recurrence surveillance.  However, these patients must still have a chest CT (or MRI) for SCC 
surveillance at 13 ± 2 weeks and 26 ± 2 weeks after last dose of study drug. 
e Patients who discontinue post-treatment follow-up early will be asked to return to the clinic to complete study assessments within 28 days. 
f Written informed consent for participation in the study must be obtained before performing any study-specific screening tests or evaluations.
g An FFPE tumor block is required for the assessment of BRAFV600 mutation status by using the cobas BRAF V600 Mutation Test.  If a tumor block cannot be 
provided, at least five serially cut, unstained tumor tissue slides (5-µm thick sections) from one block may be used.  A locally obtained cobas BRAF V600 Mutation 
Test using current primary or involved lymph node tissue can be used for screening purposes even if performed outside of the 90-day screening window. 
h For patients eligible for the study, the archival tissue sample will also be used for further molecular analyses; therefore, it is highly recommended that an FFPE tumor 
tissue block (alternatively, an additional 10−20 unstained slides will be acceptable) be provided at recurrence/occurrence of a new primary melanoma, and a FF tumor 
tissue block should be provided if lesions are accessible.  FF tissue should be prioritized over FFPE (tissue block or 10−20 slides) for recurrence tissue. 
i Includes temperature.  Heart rate and systolic and diastolic blood pressure to be recorded while the patient is in a seated position after a 5-minute rest period. 
j If performed within 7 days of the Cycle1, Day 1 visit for screening, the test does not need to be repeated at Cycle 1, Day 1. 
k Includes measurement of height (at baseline only) and weight and HEENT, neck, cardiovascular, dermatological, musculoskeletal, respiratory, gastrointestinal, and 
neurological system examinations.  Record abnormalities observed at baseline on the General Medical History and Baseline Conditions eCRF.  New or worsening 
abnormalities should be recorded on the Adverse Event eCRF, as appropriate.  An interval medical history should be obtained coincident with each follow-up physical 
examination that should document changes from baseline in new or concomitant diseases, medications, and allergies.  Physical exams will occur on Cycle 1 
(Day 15 ± 3 days), Cycle 2 (Days 1 and 15, each  ± 3 days), Day 1 (± 3 days) of every subsequent 4-week cycle, and at the end-of-treatment visit.  Thereafter, physical 
examinations done by the investigator will be obtained every 13 ± 2 weeks from the last dose of study drug until recurrence of melanoma, occurrence of a new primary 
melanoma, or until end of study, whichever occurs earlier.  Patients who have had recurrence of melanoma or occurrence of new primary melanoma will not be 


Appendix 1
Schedule of Assessments (cont.)
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126
required to continue to have physical examinations.  For all patients, as part of the physical examination, a thorough head and neck evaluation to monitor for non-
cuSCC, consisting of at least a visual inspection of the oral mucosa and lymph node palpation, must be performed by the site investigator every 13 2 weeks during 
the study drug administration period.
l
Physical examinations will occur every 13 2 weeks from last dose of study drug during post-treatment follow-up until recurrence of melanoma, occurrence of a new 
primary melanoma, or until end of study, whichever occurs earlier.  Patients who have had recurrence of melanoma or occurrence of new primary melanoma will not 
be required to continue to have physical examinations.  Once a patient completes the treatment period or discontinues study drug early, a thorough evaluation of the 
head and neck by the site investigator will be performed at the end-of-treatment visit as part of the physical examination.  During post-treatment follow-up, a thorough 
head and neck evaluation to monitor for non-cuSCC will occur (as part of the physical examination for patients who continue to have physical examinations) at 132 
weeks and 262 weeks from the last dose of study drug.  For patients who no longer require physical examinations, the head and neck examination will occur 
independently at 132 weeks and 262 weeks from the last dose of study drug (except in the case of withdrawal of consent or loss to follow-up).
m Complete evaluation of the skin by a designated dermatologist or his or her designee who is experienced in the diagnosis and management of cuSCC/KA will be 
conducted at baseline, after 4 weeks 1 week of study treatment (at Cycle 1) and every 132 weeks during the study drug treatment period.  Once a patient 
completes the treatment period or discontinues study drug early, dermatologic examinations (including a complete evaluation of the skin) will occur at the 
end-of-treatment visit, at 13 2 weeks, and at 262 weeks from the last dose of study drug (except in the case of withdrawal of consent or loss to follow-up).  Any 
suspicious lesions identified during the screening period to the examination at 26 2 week during post-treatment follow-up must be biopsied/excised and sent for 
pathologic examination.  The available specimen block/sections should be sent to the Roche-designated central pathology laboratory for confirmation of diagnosis.  
One normal skin punch biopsy (34 mm punch) is to be submitted as clinically indicated (only one per patient is required, regardless of the number of lesions 
submitted).
n If, at any time, a head and neck cancer is suspected (e.g., on the basis of signs or symptoms), the patient will be referred to a head and neck 
surgeon/otorhinolaryngologist or his or her designee who is experienced in the diagnosis and management of SCC of the head and neck.  The head and neck 
surgeon/otorhinolaryngologist or designee will perform a complete evaluation of the head and neck consisting of at least a visual inspection of the oral mucosa, 
palpation of the tonsils, base of tongue, and lymph nodes and flexible fiberoptic laryngoscopy in order to evaluate at least the sinonasal cavity, the nasopharynx, 
the base of tongue, larynx, and hypopharynx.  For patients who have been referred to a head and neck surgeon/otorhinolaryngologist or designee who is experienced 
in the diagnosis and management of SCC of the head and neck, this evaluation will continue to be conducted every 262 weeks during the study drug administration 
period.  Once a patient completes the treatment period or discontinues study drug early, a complete evaluation of the head and neck by a head and neck surgeon or 
otorhinolaryngologist will be performed at 26 2 weeks after the last dose of study drug (except in the case of withdrawal of consent or loss to follow-up).  Any 
suspicious lesions identified from the screening period to the examination at 262 weeks after last dose of study drug must be biopsied/excised and sent for 
pathologic examination.  The available specimen block/sections should be sent to the Roche-designated central pathology laboratory for confirmation of diagnosis.
o Visual and digital evaluation of the anus and anal canal is required as part of the physical examination at screening, at Cycle 6, Day 1 (2 weeks), and at the 
end-of-treatment visit (2 weeks).  In addition, all female patients will undergo a pelvic examination, including visual inspection of the uterine cervix and Pap smear, at 
screening, at Cycle 6, Day 1 (2 weeks), and at end-of-treatment visit (2 weeks).  Pelvic examinations, including Pap smear, that were conducted up to 3 months 


Appendix 1 
Schedule of Assessments (cont.) 
Vemurafenib—F. Hoffmann-La Roche Ltd 
Protocol GO27826, Version 10 
127 
prior to the start of the 90-day screening period and found to be normal, need not be repeated at screening.
p For patients with personal history of adenomatous colon polyps or colorectal cancer, family history of colon cancer in which a first- and/or second-degree relative has 
been diagnosed with colorectal cancer at or after the age of 60 years, or signs or symptoms that could be related to colon cancer as determined by the site 
investigator or designee, colonoscopy to the cecum, with adequate bowel preparation, will be performed by a gastroenterologist or his or her designee who is 
experienced in the colonoscopic diagnosis of colorectal polyps and colorectal cancer (within the 90-day screening period).  For select patients (described above), the 
screening colonoscopy is not required if colonoscopy to the cecum with adequate bowel preparation and adequate resection of all visualized polyps was performed 
within 1 year of the start of the 90-day screening period, unless the site investigator deems it necessary.  All patients must have colonoscopy within 3 months of 
discontinuation of study drug.  All polyps found at the screening or subsequent colonoscopies will need to be adequately resected.  Please note that a patient with a 
personal history of more than three (> 3) adenomatous colorectal polyps or a personal history of adenomatous colorectal polyp(s) > 2 cm in size will be excluded from 
this study; this also applies to the screening colonoscopy for the select patients described above (see Section 4.1.2). 
q Stool sample will be collected at screening, Cycle 6, Day 1 (± 2 weeks), and at the end-of-treatment visit (± 2 weeks).  If the stool occult sample is positive at 
screening, the patient must be cleared for study inclusion by a gastroenterologist or appropriately trained designee. 
r Includes hemoglobin, hematocrit, platelet count, WBC count, WBC differential (ANC), lymphocyte, monocyte, eosinophil, and basophil counts, and other cell counts. 
s Includes sodium, potassium, chloride, bicarbonate, glucose, BUN or urea, creatinine, calcium, total bilirubin, albumin, ALT, AST, alkaline phosphatase, phosphorus, 
magnesium, LDH, and uric acid. 
t If a patient discontinues study drug early, a serum pregnancy test will be performed at 12 ± 2 weeks and 26 ± 2 weeks after the last dose of study drug (except in the 
case of withdrawal of consent or loss to follow-up). 
u All women of childbearing potential (including those who have had a tubal ligation) will have a serum pregnancy test within 14 days prior to randomization.  Female 
patients of childbearing potential are defined as sexually mature women without prior hysterectomy who have had any evidence of menses within the past 12 months. 
v Serum pregnancy test to be conducted every three cycles (e.g., Cycles 3, 6, 9, and 12 or every 12 ± 2 weeks), starting from Cycle 1, Day 1, during study drug 
administration, and at 12 ± 2 weeks and 26 ± 2 weeks after the last dose of study drug. 
w Pregnancy test does not need to be performed if last pregnancy test was within 12 ± 2 weeks or if it has been 26 weeks since the last dose of study drug. 
x Hepatitis B (HBsAg and total anti-HBc) and HCV antibody. 
y Triplicate digital ECG recordings will be obtained within approximately 2−5 minutes of each other.  ECGs should be obtained from the same machine whenever 
possible.  Patients should be in a resting position for ≥ 10 minutes prior to each ECG evaluation.  Body position should be consistently maintained for each ECG 
evaluation to prevent changes in heart rate.  Environmental distractions (e.g., television, radio, and conversation) should be avoided during the pre-ECG resting period 
and during ECG recording.  ECGs should be performed prior to the first daily administration of study drug and any scheduled vital sign measurements and blood 
draws. 
z After Cycle 3, Day 1, monitor ECGs on Day 1 (± 3 days) of Cycles 6, 9, and 12 and at the end-of-treatment visit.  If vemurafenib treatment has been temporarily 
interrupted due to QTc > 500 ms (but ≤ 60-ms increment compared with baseline) OR due to change from baseline of greater than 60 ms without QTc > 500 ms, then 


Appendix 1 
Schedule of Assessments (cont.) 
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Protocol GO27826, Version 10 
128 
upon resumption of vemurafenib, ECG (measured in triplicate) and electrolytes should be monitored at Day 1 (i.e., day when study drug is resumed) pre-dose, then 
every 2 weeks (± 3 days) for at least two cycles, then Day 1 (± 3 days) of the following cycle, and then Day 1 (± 3 days) of every subsequent third cycle.  This replaces 
the protocol-mandated ECG monitoring that is outlined in this appendix.  ECG monitoring will be done at the end-of-treatment visit. 
aa Study drug will be administered at a dose of 4 tablets twice per day orally for 52 weeks (thirteen 28-day cycles).  The first dose is to be taken in the morning, and the 
second dose is to be taken approximately 12 hours later in the evening.  On most study days, the study drug is to be self-administered at home.  On study days that 
require either ECG monitoring and/or PK sample procurement, the first daily dose of study drug should be administered at the study site after completion of these 
assessments. 
bb Contrast-enhanced CT or MRI scan of the chest, abdomen, and pelvis will be performed every 13 ± 2 weeks until Week 104 and every 26 ± 4 weeks thereafter until 
recurrence of melanoma, occurrence of a new primary melanoma, or until end of study, whichever occurs earlier.  Unscheduled imaging studies must be performed if 
recurrent disease or an occurrence of a new primary melanoma is suspected on clinical grounds.  Patients who have had a DFS event do not need additional scans 
for melanoma recurrence surveillance.  However, these patients must still have a chest CT or MRI for SCC surveillance at 13 ± 2 weeks and 26 ± 2 weeks after last 
dose of study drug. 
cc Does not need to be performed if within 13 ± 2 weeks since the last assessment. 
dd Contrast-enhanced MRI of the brain (or CT if MRI is not generally available or is contraindicated) will be performed at screening and every 52 ± 4 weeks thereafter until 
recurrence of melanoma, occurrence of a new primary melanoma, or until end of study , whichever occurs earlier.  Unscheduled brain imaging studies must be 
performed if recurrent disease or an occurrence of a new primary melanoma is suspected on clinical grounds. 
ee Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter drugs, herbal/homeopathic remedies, and nutritional supplements) used by a 
patient from 7 days prior to the date of informed consent until the end-of-treatment visit. 
ff After initiation of study drug, all adverse events regardless of relationship to study drug will be reported up to and including 28 days after the last dose of study drug.  
Thereafter, only SAEs, any death, and other adverse events of concern that are believed to be related to prior treatment with study drug should be reported. 
gg After informed consent has been obtained but prior to initiation of study drug, only SAEs caused by a protocol-mandated intervention should be reported (e.g., SAEs 
related to invasive procedures such as biopsies). 
hh Patient-reported outcomes will be elicited from all patients with use of the EORTC QLQ-C30 questionnaire, which should be self-administered at the investigative site 
prior to the completion of other study assessments and the administration of study treatment.  In post-treatment follow-up, the EORTC QLQ-C30 questionnaire will be 
completed every 13 ± 2 weeks until recurrence or occurrence of a new primary melanoma or until end of study (see Section 3.2), whichever occurs first. 
ii Serum and plasma samples for exploratory biomarker assessments include one blood sample in a serum separator tube (6 mL) and one 6-mL blood sample that has 
been anti-coagulated in EDTA.  Samples are collected at Cycle 1 (Day 1 pre-dose and Day 15 ± 3 days), Cycle 2 (Day 1 ± 3 days), Cycle 3 (Day 1 ± 3 days), at the 
end-of-treatment visit, and every 52 ± 2 weeks after last dose of study drug, at the recurrence of melanoma, occurrence of a new primary melanoma, or until end of 
study, whichever occurs earlier.  In the event of melanoma recurrence or occurrence of a new primary melanoma during study treatment or if the patient discontinues 
study treatment because of other reasons, a sample should be taken upon drug discontinuation. 


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Schedule of Assessments (cont.) 
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Protocol GO27826, Version 10 
129 
jj An optional whole blood sample (6 mL in EDTA) will be collected from patients consenting to RCR guidelines.  The sample is collected at Cycle 1, Day 1 or at the first 
visit following the RCR consent if this occurs after Cycle 1, Day 1. 
kk All new primary malignancies will be reported until end of study, whether or not a patient has exhibited recurrence of melanoma or an occurrence of a new primary 
melanoma while in the study.  Melanoma tumor tissue will be collected at recurrence of melanoma, as (pathologically documented) FF tissue and FFPE tissue.  For 
presumed or suspected SCC (cutaneous [including KA] and non-cutaneous), new primary neoplasms (including new primary melanoma) or other suspicious lesions: 
FFPE tissue. 
ll Any suspicious lesions identified must be biopsied/excised and sent for pathologic examination.  For SCC and other primary neoplasms, the available specimen 
block/sections should be sent to the Roche-designated central pathology laboratory for confirmation of diagnosis and further molecular characterization until end of 
study, whether or not a patient has exhibited recurrence of melanoma or occurrence of a new primary melanoma while in the study. 
mm Overall survival follow-up (post-recurrence/occurrence of new primary melanoma) will occur via telephone calls and/or clinic visits every 13 ± 2 weeks until end of 
study.  For all patients including those without recurrence or a new primary melanoma a final overall survival follow-up via telephone call or clinic visit should 
occur at the end of study (see Section 3.2). 


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Appendix 2
Schedule of Pharmacokinetic Assessments
Cycle 1
Cycle 2
Cycles 
313
End-of-Treatment 
Visit/Unscheduled Visit a
Day
1
8 b
15 b
22 b
1 b
15 b
1 b
Any time during study 
visit
Time
Prior to morning dose and 
between 1 and 4 hours after 
morning dose
Prior to 
morning dose
Prior to 
morning 
dose
a Unscheduled pharmacokinetic assessments should also be obtained in the circumstances 
listed below:
As soon as possible after the diagnosis of melanoma recurrence or occurrence of a new 
primary melanoma while on study treatment (i.e., in conjunction with the tumor biopsy for 
biomarker assessments). 
Note:  In the event of melanoma recurrence or occurrence of a new primary melanoma 
during study treatment or if the patient discontinues study treatment because of other 
reasons, a pharmacokinetic sample should be taken upon drug discontinuation as well as at 
the study visit most proximate after study treatment discontinuation. 
Coincident with the diagnosis of squamous cell carcinoma while on study treatment.
Coincident with any dose interruption and/or reduction for toxicity.
Note:  In the event of dose reduction or dose interruption, an additional unscheduled 
pharmacokinetic sample should be taken immediately before the patient resumes treatment 
at the modified dose as well as at Day 1 of the next cycle of treatment.  During Cycle 1, if 
drug is not administered on a visit day, only one pharmacokinetic sample should be collected 
on that day.
b The pharmacokinetic assessments should be performed within 3 days of the scheduled visit.


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Appendix 3
New York Heart Association Guidelines
Class I
Patients with cardiac disease but without resulting limitations of physical activity.  
Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea or 
angina pain.
Class II
Patients with cardiac disease resulting in slight limitations of physical activity.  They
are comfortable at rest.  Ordinary physical activity results in fatigue, palpitation, 
dyspnea or angina pain.
Class III
Patients with cardiac disease resulting in marked limitations of physical activity.  They 
are comfortable at rest.  Less than ordinary physical activity causes fatigue, 
palpitation, dyspnea, or angina pain.
Class IV
Patients with cardiac disease resulting in inability to carry on any physical activity 
without discomfort.  Symptoms of cardiac insufficiency or of the angina syndrome 
may be present even at rest.  If any physical activity is undertaken, discomfort is 
increased.
Source:  Criteria Committee, New York Heart Association, Inc. Nomenclature and criteria for 
diagnosis of diseases of the heart and blood vessels. 6th revised ed. Boston: Little, Brown and
Co, 1994:114.


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Appendix 4
European Organisation for Research and Treatment of Cancer 
30-Item Quality of Life Questionnaire (Version 3)
EORTC QLQ-C30 (version 3)
We are interested in some things about you and your health. Please answer all of the questions 
yourself by circling the number that best applies to you. There are no "right" or "wrong" answers. 
The information that you provide will remain strictly confidential.
Not at
A
Quite
Very
All
Little
a Bit
Much
1.
Do you have any trouble doing strenuous activities, 
like carrying a heavy shopping bag or a suitcase?
1
2
3
4
2.
Do you have any trouble taking a long walk?
1
2
3
4
3.
Do you have any trouble taking a short wa k outside of the house?
1
2
3
4
4.
Do you need to stay in bed or a chair during the day?
1
2
3
4 
5.
Do you need help with eating, dressing, washing 
yourself or using the toilet?
1
2
3
4 
During the past week:
Not at
A
Quite
Very
All
Little
a Bit
Much
6.
Were you limited in doing either your work or other daily activities? 1
2
3
4
7.
Were you limited in pursuing your hobbies or other
leisure time activities?
1
2
3
4
8.
Were you short of breath?
1
2
3
4
9.
Have you had pain?
1
2
3
4
10.
Did you need to rest?
1
2
3
4
11.
Have you had trouble sleeping?
1
2
3
4
12.
Have you felt weak?
1
2
3
4
13.
Have you lacked appetite?
1
2
3
4
14.
Have you felt nauseated?
1
2
3
4
15.
Have you vomited?
1
2
3
4
16.
Have you been constipated?
1
2
3
4
Please go on to the next page


Appendix 4
European Organisation for Research and Treatment of Cancer 
30-item Quality of Life Questionnaire (Version 3) (cont.)
Vemurafenib—F. Hoffmann-La Roche Ltd
Protocol GO27826, Version 10
133
During the past week:
Not at
A
Quite
Very
All
Little
a Bit
Much
17.
Have you had diarrhea?
1
2
3
4
18.
Were you tired?
1
2
3
4
19.
Did pain interfere with your daily activities?
1
2
3
4
20.
Have you had difficulty in concentrating on things,
like reading a newspaper or watching television?
1
2
3
4
21.
Did you feel tense?
1
2
3
4
22.
Did you worry?
1
2
3
4
23.
Did you feel irritable?
1
2
3
4
24.
Did you feel depressed?
1
2
3
4
25.
Have you had difficulty remembering things?
1
2
3
4
26.
Has your physical condition or medical treatment
interfered with your family life?
1
2
3
4
27.
Has your physical condition or medical treatment
interfered with your social activities?
1
2
3
4
28.
Has your physical condition or medical treatment
caused you financial difficulties?
1
2
3
4
For the following questions please circle the number between 1 and 7 that 
best applies to you
29.
How would you rate your overall health during the past week?
1
2
3
4
5
6
7
Very poor
Excellent
30.
How would you rate your overall quality of life during the past week?
1
2
3
4
5
6
7
Very poor
Excellent


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Appendix 5
Excerpts from the Clinical Practice Guidelines for the 
Management of Melanoma in Australia and New Zealand
Full document available at:
http://www.nhmrc.gov.au/_files_nhmrc/publications/attachments/cp111.pdf


Appendix 5
Excerpts from the Clinical Practice Guidelines for the 
Management of Melanoma in Australia and New Zealand (cont.)
Vemurafenib—F. Hoffmann-La Roche Ltd
Protocol GO27826, Version 10
135


Appendix 5
Excerpts from the Clinical Practice Guidelines for the 
Management of Melanoma in Australia and New Zealand (cont.)
Vemurafenib—F. Hoffmann-La Roche Ltd
Protocol GO27826, Version 10
136






Appendix 5
Excerpts from the Clinical Practice Guidelines for the 
Management of Melanoma in Australia and New Zealand (cont.)
Vemurafenib—F. Hoffmann-La Roche Ltd
Protocol GO27826, Version 10
139


Appendix 5
Excerpts from the Clinical Practice Guidelines for the 
Management of Melanoma in Australia and New Zealand (cont.)
Vemurafenib—F. Hoffmann-La Roche Ltd
Protocol GO27826, Version 10
140


Appendix 5
Excerpts from the Clinical Practice Guidelines for the 
Management of Melanoma in Australia and New Zealand (cont.)
Vemurafenib—F. Hoffmann-La Roche Ltd
Protocol GO27826, Version 10
141






Appendix 5
Excerpts from the Clinical Practice Guidelines for the 
Management of Melanoma in Australia and New Zealand (cont.)
Vemurafenib—F. Hoffmann-La Roche Ltd
Protocol GO27826, Version 10
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Appendix 5
Excerpts from the Clinical Practice Guidelines for the 
Management of Melanoma in Australia and New Zealand (cont.)
Vemurafenib—F. Hoffmann-La Roche Ltd
Protocol GO27826, Version 10
146












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Appendix 6
Eastern Cooperative Oncology Group Performance Status Scale
Grade
Description
0
Fully active, able to carry on all pre-disease performance without 
restriction
1
Restricted in physically strenuous activity but ambulatory and able to 
carry out work of a light or sedentary nature (e.g., light housework or 
office work)
2
Ambulatory and capable of all self-care but unable to carry out any 
work activities.  Up and about 50% of waking hours
3
Capable of only limited self-care, confined to a bed or chair 50% of 
waking hours
4
Completely disabled.  Cannot carry on any self-care.  Totally confined 
to bed or chair
5
Dead


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Appendix 7
Fitzpatrick Skin Phototypes
Skin type
Reaction to sun exposurea
I
Always burns, never tans
II
Always burns, minimal tan
III
Burns minimally, gradually tans
IV
Burns minimally, tans well
V
Very rarely burns, tans profusely
VI
Never burns, tans deeply
a After the first 1 hour of sun exposure on untanned 
skin on the first day of spring.


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Appendix 8
Impact of Vemurafenib on Concomitant Medications


Appendix 8
Impact of Vemurafenib on Concomitant Medications (cont.)
Vemurafenib—F. Hoffmann-La Roche Ltd
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Appendix 8
Impact of Vemurafenib on Concomitant Medications (cont.)
Vemurafenib—F. Hoffmann-La Roche Ltd
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Appendix 9
Medication Affecting QT Interval
Albuterol 
Doxepin 
Lithium 
Quinidine 
Alfuzosin 
Droperidol 
Mesoridazine 
Ranolazine 
Amantadine 
Ephedrine 
Metaproterenol 
Risperidone 
Amiodarone 
Epinephrine 
Methadone 
Ritodrine 
Amitriptyline 
Erythromycin 
Methylphenidate 
Roxithromycin 
Amphetamine 
Felbamate 
Mexiletine 
Salmeterol 
Arsenic trioxide 
Fenfluramine 
Midodrine 
Sertindole 
Astemizole 
Flecainide
Moexipril 
Sertraline 
Atazanavir 
Fluconazole 
Moxifloxacin 
Sibutramine 
Atomoxetine 
Fluoxetine 
Nicardipine 
Sibutramine 
Azithromycin 
Foscarnet 
Nilotinib 
Solifenacin 
Bepridil 
Fosphenytoin 
Norepinephrine 
Sotalol 
Chloral hydrate 
Galantamine 
Nortriptyline 
Sparfloxacin 
Chloroquine 
Gatifloxacin 
Octreotide 
Sunitinib 
Chlorpromazine 
Gemifloxacin 
Ofloxacin 
Tacrolimus 
Ciprofloxacin 
Granisetron 
Ondansetron 
Tamoxifen 
Cisapride 
Halofantrine
Oxytocin 
Telithromycin 
Citalopram 
Haloperidol 
Paliperidone 
Terbutaline 
Clarithromycin 
Ibutilide
Paroxetine 
Terfenadine 
Clomipramine 
Imipramine
Pentamidine 
Thioridazine 
Clozapine 
Indapamide 
Perflutren lipid 
microspheres 
Tizanidine 
Cocaine 
Isoproterenol 
Phentermine 
Tolterodine 
Desipramine 
Isradipine 
Phenylephrine 
Trimethoprim-Sulfa 
Dexmethylphenidate 
Itraconazole
Phenylpropanolamine 
Trimipramine 
Disopyramide 
Ketoconazole
Pimozide 
Vardenafil 
Dobutamine 
Lapatinib 
Probucol 
Venlafaxine 
Dofetilide 
Levafloxacin 
Procainamide 
Voriconazole 
Dolasetron 
Levalbuterol 
Protriptyline 
Ziprasidone 
Domperidone 
Levomethadyl 
Pseudoephedrine 
Dopamine 
Lisdexamfetamine 
Quetiapine 


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Appendix 10
American Joint Committee on Cancer (Version 7):  Melanoma of 
the Skin Staging