Conditions: Malignant Melanoma
Keywords: Zelboraf vemurafenib RG7204 PLX4032 Genentech MEK inhibitor Genentech BRAF inhibitor Roche MEK inhibitor Roche BRAF inhibitor RO5185426 metastatic melanoma BRAF positive melanoma BRAF mutant melanoma advanced melanoma Genentech RAF inhibitor Roche RAF inhibitor BRAF V600E kinase inhibitor Oncogenic BRAF inhibitor BRAF kinase inhibitor GDC-0973 XL518 melanoma
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 495
Healthy volunteers: no

Brief summary:
To evaluate the efficacy of vemurafenib in combination with cobimetinib (GDC-0973), compared with vemurafenib and placebo, in previously untreated BRAF V600 mutation-positive patients with unresectable locally advanced or metastatic melanoma, as measured by progression-free survival (PFS), assessed by the study site investigator.

Detailed description:

Arms:
arm 1: Participants will receive placebo orally once daily on Days 1-21 of each 28-day cycle plus vemurafenib 960 milligrams (mg) orally twice a day on Days 1-28 of each 28-day cycle until disease progression, death, unacceptable toxicity, or withdrawal of consent, whichever occurs earliest. arm 2: Participants will receive cobimetinib 60 mg orally once daily on Days 1-21 of each 28-day cycle plus vemurafenib 960 mg orally twice a day on Days 1-28 of each 28-day cycle until disease progression, death, unacceptable toxicity, or withdrawal of consent, whichever occurs earliest.

Interventions: intervention 1: Placebo intervention 2: Vemurafenib intervention 3: Cobimetinib
Intervention descriptions: intervention 1: Placebo supplied as tablets intervention 2: Vemurafenib supplied as tablets intervention 3: Cobimetinib supplied as tablets

Protocol document:
Prot_001.pdf: 
Official Title: 
A Phase III, Double-Blind, Placebo-Controlled Study of Vemurafenib 
Versus Vemurafenib Plus GDC-0973 in Previously Untreated 
BRAFV600-Mutation Positive Patients With Unresectable Locally 
Advanced or Metastatic Melanoma 
NCT Number: 
NCT01689519 
Document Date: 
Protocol Version 8: 20-October-2016 


 
Title
20-Oct-2016 17:24:10
Date and Time (UTC)
Company Signatory
Approver's Name
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The information contained in this document, especially any unpublished data, is the property of 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 and Cobimetinib⎯F. Hoffmann-La Roche Ltd  
 
Protocol GO28141, Version 8  
 
PROTOCOL 
TITLE: 
A PHASE III, DOUBLE-BLIND, PLACEBO-CONTROLLED 
STUDY OF VEMURAFENIB VERSUS VEMURAFENIB 
PLUS GDC-0973 IN PREVIOUSLY UNTREATED 
BRAFV600-MUTATION POSITIVE PATIENTS WITH 
UNRESECTABLE LOCALLY ADVANCED OR 
METASTATIC MELANOMA 
PROTOCOL NUMBER: 
GO28141 
VERSION NUMBER: 
8 
EUDRACT NUMBER: 
2012-003008-11 
IND NUMBER: 
Vemurafenib (RO5185426):  109307 
Cobimetinib (GDC-0973/RO5514041/XL518):  76798 
TEST PRODUCT: 
Vemurafenib (RO5185426) 
Cobimetinib (GDC-0973/RO5514041/XL518) 
MEDICAL MONITOR: 
, M.D., Ph.D. 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
DATE FINAL: 
Version 1:  3 August 2012; Version 2:  4 October 2012 
Version 3:  24 April 2013  
Version 4:  12 September 2013 
Version 5:  24 February 2015  
Version 6:  20 October 2015 
Version 7:  30 March 2016 
Version 8:  See electronic date stamp below 




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PROTOCOL AMENDMENT, VERSION 8: 
RATIONALE 
Protocol GO28141 has been amended primarily to update the safety information for the 
identified risks of rhabdomyolysis and CPK elevations and hemorrhage associated with 
cobimetinib.  
Specific changes to the protocol are as follows: 
• 
Language around cobimetinib approval has been clarified (Section 5.1). 
• 
Safety language for rhabdomyolysis/CPK elevations and hemorrhage has been 
updated and moved to “identified risks associated with cobimetinib” (Section 5.1.2.1). 
• 
Language around impaired fertility and developmental toxicity was clarified (Section 
5.1.2.2). 
• 
The term “non-serious adverse events of special interest” has been updated to 
“adverse events of special interest” to reflect standard Roche terminology 
(Sections 5.1.4.1, 5.2, 5.2.3, 5.3.5.6, 5.4, 5.4.2, 5.5.2, and 5.7). 
• 
The dose modification table has been updated (Table 10 in Section 5.1.5.3). 
• 
Suspected transmission of an infectious agent by the study drug has been added to 
the list of adverse events of special interest (Section 5.2.3).  
• 
The title of Section 5.3.5.10 has been updated to Adverse Events Associated with 
an Overdose or Error in Drug Administration. 
• 
It has been clarified that safety analyses will not be performed using 
patient-reported outcome data (Section 5.3.5.11).  
• 
The term “spontaneous abortion” has been changed to “abortion” to reflect standard 
Roche terminology (Section 5.4.3.3). 
• 
The term “adverse event of concern” has been changed to “adverse event of special 
interest” for clarity (Section 5.6). 
 
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.


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PROTOCOL AMENDMENT, VERSION 8: 
SUMMARY OF CHANGES 
GLOBAL CHANGES 
The term “non-serious adverse event of special interest” and the term “adverse event of 
concern” have been changed to “adverse event of special interest.” 
SECTION 5.1:  Safety Plan 
Cobimetinib (for use with vemurafenib) is approved in the United States, Canada, and 
members of the European Union, as well asand other countries.   
SECTION 5.1.2.1:  Important Identified Risks Associated with Cobimetinib 
Hemorrhage 
Hemorrhage, including major hemorrhages defined as symptomatic bleeding in a 
critical area or organ, can occur with cobimetinib.  In clinical studies with cobimetinib, 
events of cerebral hemorrhage, gastrointestinal tract hemorrhage, reproductive tract 
hemorrhage, and hematuria, have been reported. 
In the Phase III study GO28141, Grade 1−4 hemorrhagic events were reported in 13.0% 
of patients treated with cobimetinib plus vemurafenib and in 7.3% of patients treated 
with placebo plus vemurafenib.  The majority of hemorrhagic events were Grade 1 or 2 
and non-serious.  Grade 3−4 hemorrhage events were reported in 1.2% of patients who 
received cobimetinib plus vemurafenib and 0.8% of patients who received placebo plus 
vemurafenib. 
Caution should be used in patients with additional risk factors for bleeding, such as 
brain metastases, and/or in patients who use concomitant medications that increase the 
risk of bleeding (including anti-platelet or anticoagulant therapy).  
Instructions and dose modifications for hemorrhage events are included in Table 10, in 
Section 5.1.5.3. 
Rhabdomyolysis and CPK Elevations 
Elevations in CPK have been observed in patients who received cobimetinib 
monotherapy as well as when administered with other agents.  The majority of CPK 
elevations reported were asymptomatic, non-serious, and resolved with or without 
study drug interruption.  One event of rhabdomyolysis was reported in the Phase III 
study GO28141 (cobimetinib plus vemurafenib), and rhabdomyolysis has been reported 
in post-marketing experience.  
In Study GO28141, elevated CPK was reported as an adverse event more frequently in 
patients treated with cobimetinib plus vemurafenib (32.4% all grades, 11.3% Grade ≥ 3 
events) than placebo plus vemurafenib (8.1% all grades, 0% Grade ≥ 3 events).   


 
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CPK will be monitored at baseline and monthly during treatment or as clinically 
indicated.  Instructions for dose modifications for elevated CPK and rhabdomyolysis are 
included in Table 10 in Section 5.1.5.3. 
SECTION 5.1.2.2:  Potential Risks Associated with Cobimetinib 
Increased CPK or Rhabdomyolysis 
Elevations in CPK have been observed in patients who received cobimetinib 
monotherapy as well as when combined with other agents.  In the Phase III study 
GO28141, CPK was evaluated at baseline and at regular intervals.  The majority of CPK 
elevations reported were asymptomatic, non serious, and resolved with or without study 
drug interruption.  While almost all elevations in CPK were asymptomatic laboratory 
findings, a clinical diagnosis of rhabdomyolysis was reported for 1 patient in each 
treatment arm in Study GO28141.  In the patient who received cobimetinib and 
vemurafenib, CPK levels were > 10 × ULN (Grade 4).  Thus, Grade 4 elevations in CPK 
levels may be associated with rhabdomyolysis, which has also been observed with other 
MEK inhibitors. 
In the Phase III study, elevated CPK was reported as an adverse event more frequently 
in patients treated with cobimetinib plus vemurafenib (29.9% all grades, 12% Grade ≥ 3 
events) than placebo plus vemurafenib (3.3% all grades, 0.4% Grade ≥ 3 events).  
No patients experienced Grade 5 events.  Serious adverse events were reported in 
2 patients (0.8%) treated with cobimetinib plus vemurafenib; in both cases the 
cobimetinib dose was reduced and the events resolved.  In the Phase I single agent 
study (MEK4592g), 1 patient experienced a Grade 3 increase in CPK. 
Impaired Female Fertility and Developmental Toxicity 
Title change only. 
Teratogenicity and Development Toxicity 
In a dedicated nonclinical embryo-fetal toxicity study, cobimetinib produced fetal toxicity 
(resorptions and reductions in fetal weight), and teratogenicity (malformations of the 
great vessels and skull) at similar systemic exposures in rat to those observed in 
patients administered the 60 mg dose. 
Section 5.1.2.3:  Other Risks Associated with Cobimetinib 
Hemorrhage 
Hemorrhage events, including cerebral hemorrhage, gastrointestinal tract hemorrhage, 
reproductive tract hemorrhage, and hematuria, have been reported in clinical studies of 
cobimetinib. 
In the Phase III study GO28141, hemorrhagic events were reported in 9.8% of patients 
treated with cobimetinib plus vemurafenib, and in 5.9% of patients treated with placebo 
plus vemurafenib.  Events that were reported at frequencies > 1% higher in patients 
treated with cobimetinib plus vemurafenib than placebo plus vemurafenib were 


 
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hematuria (2.0% vs. 0.8%, respectively) and cerebral hemorrhage (1.2% vs. 0%, 
respectively).  The majority of hemorrhagic events were Grade 1 or 2 and non serious.  
Grade 3−4 hemorrhage events were reported in 1.2% of patients who received 
cobimetinib plus vemurafenib and 0.8% of patients who received placebo plus 
vemurafenib. 
Hypersensitivity  
Please refer to the cobimetinib IB for additional safety information. 
SECTION 5.1.5.3:  Management of Specific Toxicities and Dose Modification 
Guidelines 
Table 10:  Management of Specific Toxicities and Dose Modification 
Guidelines  
The table has been updated to reflect the latest safety guidance. 
SECTION 5.2.3:  Non Serious Adverse Events of Special Interest 
Adverse events of special interest for this study include the following: 
• 
Suspected transmission of an infectious agent by the study drug, as defined below 
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product.  This term applies only 
when a contamination of the study drug is suspected. 
 
SECTION 5.3.5.10:  Adverse Events Associated with an Overdose or Error in 
Drug AdministrationOverdoses 
Title change only. 
SECTION 5.3.5.11:  Patient-Reported Outcome Data 
Adverse event reports will not be derived from PRO data, and safety analyses will not be 
performed using PRO data.   
SECTION 5.4.3.3:  Abortions 
Any spontaneous abortion associated with a pregnancy occurring during the study or 
within 6 months of the last dose of study drug 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 immediately 
(i.e., no more than 24 hours after learning of the event; see Section 5.4.2). 
 
 
 


 
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TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 17 
PROTOCOL SYNOPSIS .................................................................................... 18 
1. 
BACKGROUND AND RATIONALE............................................................. 31 
1.1 
Background on Melanoma..................................................... 31 
1.1.1 
Melanoma.............................................................................. 31 
1.1.2 
Role of BRAF Kinase in Melanoma ....................................... 31 
1.2 
Background on BRAF Inhibitor, Vemurafenib........................ 32 
1.2.1 
Clinical Pharmacokinetics of Vemurafenib............................. 32 
1.2.2 
Efficacy of Vemurafenib in Patients with 
BRAFV600 Mutation-Positive Metastatic 
Melanoma.............................................................................. 33 
1.2.3 
Safety of Vemurafenib ........................................................... 34 
1.2.3.1 
Dose-Limiting Toxicities of Vemurafenib................................ 35 
1.2.3.2 
Clinical Safety in Phase II Study NP22657 
(BRIM-2)................................................................................ 35 
1.2.3.3 
Clinical Safety in Phase III Trial: NO25026 
(BRIM-3)................................................................................ 35 
1.2.4 
Deaths and Serious Adverse Events among 
Patients Receiving Vemurafenib............................................ 36 
1.2.5 
Adverse Events of Special Interest for 
Vemurafenib .......................................................................... 36 
1.2.5.1 
Cutaneous Squamous Cell Carcinoma.................................. 36 
1.2.5.2 
Second Primary Melanomas.................................................. 37 
1.2.5.3 
Other Neoplasms................................................................... 37 
1.2.5.4 
ECG Analysis ........................................................................ 38 
1.2.5.5 
Liver Injury............................................................................. 39 
1.2.6 
Other Adverse Events of Clinical Significance....................... 39 
1.2.6.1 
Severe Dermatologic Reactions ............................................ 39 
1.2.6.2 
Neutropenia........................................................................... 39 
1.2.6.3 
Panniculitis ............................................................................ 39 
1.2.6.4 
Pancreatitis............................................................................ 40 
1.2.6.5 
Potentiation of Radiation Toxicity .......................................... 40 
1.2.6.6 
Acute Kidney Injury................................................................ 40 


 
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1.2.7 
Safety of Vemurafenib in Combination with 
Ipilimumab ............................................................................. 40 
1.3 
Background on MEK Inhibitor Cobimetinib ............................ 41 
1.3.1 
Role of MEK in Melanoma..................................................... 41 
1.3.2 
Cobimetinib / XL518 (MEK Inhibitor) ..................................... 41 
1.3.3 
Nonclinical Studies with Cobimetinib ..................................... 41 
1.3.4 
Phase I Clinical Study of Cobimetinib.................................... 41 
1.3.5 
Clinical Pharmacokinetics of Cobimetinib.............................. 42 
1.3.6 
Safety in Phase I Clinical Study of Cobimetinib 
(MEK4592g) .......................................................................... 43 
1.3.6.1 
Dose-Limiting Toxicities......................................................... 43 
1.3.7 
Adverse Events in Phase I Clinical Study of 
Cobimetinib (MEK4592g)....................................................... 43 
1.3.7.1 
Adverse Events Related to Cobimetinib ................................ 43 
1.3.7.2 
Grade ≥ 3 Adverse Events Related to 
Cobimetinib............................................................................ 45 
1.3.7.3 
Deaths and Serious Adverse Events of 
Cobimetinib............................................................................ 46 
1.3.7.4 
Adverse Events of Special Interest for 
Cobimetinib............................................................................ 47 
1.3.8 
Clinical Efficacy in Study MEK4592g..................................... 48 
1.4 
Background on Combined BRAF and MEK 
Inhibition ................................................................................ 49 
1.4.1 
Rationale for Combined BRAF and MEK 
Inhibition ................................................................................ 49 
1.4.2 
Preclinical Data of Combined BRAF and MEK 
Inhibition ................................................................................ 50 
1.4.3 
Study NO25395 – Phase Ib Cobimetinib in 
Combination with Vemurafenib.............................................. 51 
1.4.3.1 
Safety in Study NO25395 (BRIM-7)....................................... 52 
1.4.4 
Primary and Final Analysis of Study GO28141...................... 66 
1.5 
Study Rationale and Benefit-Risk Assessment...................... 66 
2. 
OBJECTIVES.............................................................................................. 67 
2.1 
Efficacy Objectives ................................................................ 67 
2.2 
Safety Objective .................................................................... 68 
2.3 
Pharmacokinetic Objective .................................................... 68 


 
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2.4 
Patient-Reported Outcome Objective .................................... 68 
2.5 
Exploratory Objectives........................................................... 68 
3. 
GO28141 STUDY DESIGN......................................................................... 68 
3.1 
Description of GO28141 Study Design.................................. 68 
3.2 
End of Study.......................................................................... 71 
3.3 
Rationale for Study Design.................................................... 71 
3.3.1 
Rationale for Test Product Dosage/Regimen ........................ 71 
3.3.2 
Rationale for Patient Population ............................................ 72 
3.3.3 
Rationale for Control Group................................................... 72 
3.3.4 
Rationale for Pharmacokinetic Assessments......................... 73 
3.3.5 
Rationale for Collection of DNA for Exploratory 
Analyses of Pharmacogenetic Polymorphisms...................... 73 
3.3.6 
Rationale for Biomarker Assessments................................... 74 
3.3.7 
Rationale for Health-Related Quality of Life 
Assessment and Health Economic Assessment.................... 74 
3.4 
Outcome Measures ............................................................... 75 
3.4.1 
Efficacy Outcome Measures.................................................. 75 
3.4.1.1 
Primary Efficacy Outcome Measure ...................................... 75 
3.4.1.2 
Secondary Efficacy Outcome Measures................................ 75 
3.4.2 
Safety Outcome Measures .................................................... 75 
3.4.3 
Pharmacokinetic Outcome Measures.................................... 75 
3.4.4 
Patient-Reported Outcome Measures ................................... 76 
3.4.5 
Exploratory Outcome Measures ............................................ 76 
3.5 
Minimization of Bias............................................................... 76 
4. 
METHODS AND MATERIALS .................................................................... 77 
4.1 
Patients.................................................................................. 77 
4.1.1 
Inclusion Criteria.................................................................... 77 
4.1.2 
Exclusion Criteria................................................................... 78 
4.2 
Method of Treatment Assignment, Blinding, and 
Unblinding.............................................................................. 80 
4.3 
Study Treatment.................................................................... 81 
4.3.1 
Formulation, Packaging, and Handling.................................. 81 
4.3.1.1 
Cobimetinib/Placebo.............................................................. 81 


 
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4.3.1.2 
Vemurafenib .......................................................................... 82 
4.3.2 
Dosage, Administration, and Compliance.............................. 82 
4.3.2.1 
Cobimetinib/Placebo.............................................................. 83 
4.3.2.2 
Vemurafenib .......................................................................... 83 
4.3.3 
Investigational Medicinal Product Accountability ................... 83 
4.3.4 
Post-Study Access to Vemurafenib and 
Cobimetinib............................................................................ 84 
4.4 
Concomitant Treatment ......................................................... 84 
4.4.1 
Permitted Therapy ................................................................. 84 
4.4.2 
Prohibited Therapy ................................................................ 84 
4.4.3 
Prohibited Foods and Supplements....................................... 85 
4.4.4 
Medication Precautions in Case of Drug−Drug 
Interactions............................................................................ 85 
4.4.5 
Medications Affecting the QT Interval.................................... 86 
4.5 
Study Assessments ............................................................... 87 
4.5.1 
Description of Study Assessments ........................................ 87 
4.5.1.1 
BRAFV600 Mutation Testing.................................................... 87 
4.5.1.2 
Medical History and Demographic Data ................................ 88 
4.5.1.3 
Vital Signs.............................................................................. 88 
4.5.1.4 
Physical Examinations........................................................... 89 
4.5.1.5 
Tumor and Response Evaluations......................................... 89 
4.5.1.6 
Dermatologic Examination..................................................... 90 
4.5.1.7 
Ophthalmology Examination.................................................. 90 
4.5.1.8 
Laboratory Assessments ....................................................... 91 
4.5.1.9 
Patient Reported Outcomes .................................................. 92 
4.5.1.10 
Pharmacokinetic Assessments.............................................. 92 
4.5.1.11 
Cardiac Evaluation – ECGs and Evaluation of 
Left Ventricular Function........................................................ 92 
4.5.1.12 
Exploratory Biomarker Assessments..................................... 94 
4.5.1.13 
Unscheduled Assessments ................................................... 96 
4.5.1.14 
Samples for Roche Clinical Repository.................................. 96 
4.5.2 
Timing of Study Assessments ............................................... 99 
4.5.2.1 
Screening and Pretreatment Assessments............................ 99 
4.5.2.2 
Assessments during Study .................................................. 101 


 
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4.5.2.3 
End-of-Study-Treatment Visit .............................................. 102 
4.5.2.4 
Post-Study Treatment and Survival Follow-Up 
Assessments ....................................................................... 103 
4.5.2.5 
Adverse Event Follow Up .................................................... 103 
4.6 
Patient, Study, and Site Discontinuation.............................. 103 
4.6.1 
Patient Discontinuation........................................................ 103 
4.6.1.1 
Discontinuation from Study Treatment ................................ 104 
4.6.1.2 
Withdrawal from Study......................................................... 104 
4.6.1.3 
Withdrawal of Patients from the Roche Clinical 
Repository ........................................................................... 104 
4.6.2 
Study and Site Discontinuation............................................ 104 
5. 
ASSESSMENT OF SAFETY..................................................................... 105 
5.1 
Safety Plan .......................................................................... 105 
5.1.1 
Risks Associated with Vemurafenib..................................... 105 
5.1.2 
Risks Associated with Cobimetinib ...................................... 106 
5.1.2.1 
Important Identified Risks Associated with 
Cobimetinib.......................................................................... 107 
5.1.2.2 
Potential Risks Associated with Cobimetinib ....................... 109 
5.1.2.3 
Other Risks Associated with Cobimetinib ............................ 110 
5.1.3 
General Safety Mitigation Plan ............................................ 111 
5.1.3.1 
Eligibility Criteria.................................................................. 111 
5.1.3.2 
Monitoring............................................................................ 111 
5.1.4 
Monitoring and Management of Specific 
Toxicities and Conditions that May Arise with 
Vemurafenib and/or Cobimetinib Treatment........................ 112 
5.1.4.1 
Primary Cutaneous Squamous Cell Carcinoma 
and Other New Cutaneous Malignancies ............................ 112 
5.1.4.2 
New Non-Cutaneous Primary Malignancies ........................ 112 
5.1.4.3 
Skin Toxicities Other than 
Neoplastic/Premalignant Lesions ........................................ 113 
5.1.4.4 
Ocular Toxicity..................................................................... 114 
5.1.4.5 
Cardiac Toxicity................................................................... 114 
5.1.4.6 
Hepatic Toxicity ................................................................... 115 
5.1.5 
Management of Specific Adverse Events ............................ 116 
5.1.5.1 
Rash Management .............................................................. 116 


 
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5.1.5.2 
Diarrhea Management......................................................... 117 
5.1.5.3 
Management of Specific Toxicities and Dose 
Modification Guidelines........................................................ 118 
5.2 
Safety Parameters and Definitions ...................................... 124 
5.2.1 
Adverse Events ................................................................... 125 
5.2.2 
Serious Adverse Events (Immediately Reportable 
to Roche)............................................................................. 125 
5.2.3 
Adverse Events of Special Interest 
(Immediately Reportable to Roche) ..................................... 126 
5.3 
Methods and Timing for Capturing and 
Assessing Safety Parameters.............................................. 127 
5.3.1 
Adverse Event Reporting Period ......................................... 127 
5.3.2 
Eliciting Adverse Event Information ..................................... 128 
5.3.3 
Assessment of Severity of Adverse Events ......................... 128 
5.3.4 
Assessment of Causality of Adverse Events ....................... 129 
5.3.5 
Procedures for Recording Adverse Events.......................... 129 
5.3.5.1 
Diagnosis versus Signs and Symptoms............................... 129 
5.3.5.2 
Adverse Events Occurring Secondary to Other 
Events.................................................................................. 130 
5.3.5.3 
Persistent or Recurrent Adverse Events.............................. 130 
5.3.5.4 
Abnormal Laboratory Values and ECG Findings................. 130 
5.3.5.5 
Abnormal Vital Sign Values ................................................. 131 
5.3.5.6 
Abnormal Liver Function Tests............................................ 132 
5.3.5.7 
Deaths ................................................................................. 132 
5.3.5.8 
Pre-Existing Medical Conditions.......................................... 133 
5.3.5.9 
Hospitalization or Prolonged Hospitalization........................ 133 
5.3.5.10 
Adverse Events Associated with an Overdose or 
Error in Drug Administration ................................................ 133 
5.3.5.11 
Patient-Reported Outcome Data ......................................... 134 
5.4 
Immediate Reporting Requirements from 
Investigator to Sponsor........................................................ 134 
5.4.1 
Emergency Medical Contacts.............................................. 134 
5.4.2 
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest................... 135 
5.4.3 
Reporting Requirements for Pregnancies............................ 135 


 
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5.4.3.1 
Pregnancies in Female Patients.......................................... 135 
5.4.3.2 
Pregnancies in Female Partners of Male Patients............... 136 
5.4.3.3 
Abortions ............................................................................. 136 
5.4.3.4 
Congenital Anomalies/Birth Defects .................................... 136 
5.4.4 
New Non-Cutaneous Primary Cancers................................ 137 
5.5 
Follow Up of Patients after Adverse Events......................... 137 
5.5.1 
Investigator Follow Up ......................................................... 137 
5.5.2 
Sponsor Follow Up .............................................................. 137 
5.6 
Post-Study Treatment Adverse Events................................ 137 
5.7 
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees............................................................... 138 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN..................... 138 
6.1 
Determination of Sample Size ............................................. 138 
6.1.1 
Progression-Free Survival ................................................... 138 
6.1.2 
Overall Survival ................................................................... 139 
6.2 
Summaries of Conduct of Study.......................................... 139 
6.3 
Summaries of Treatment Group Comparability ................... 139 
6.4 
Efficacy Analyses ................................................................ 139 
6.4.1 
Primary Efficacy Analysis .................................................... 139 
6.4.2 
Secondary Efficacy Analyses .............................................. 140 
6.5 
Safety Analyses................................................................... 141 
6.6 
Pharmacokinetic Analyses................................................... 141 
6.7 
Patient-Reported Outcomes ................................................ 142 
6.8 
Biomarker Analyses............................................................. 142 
6.9 
Interim Analyses.................................................................. 142 
6.9.1 
Interim Efficacy Analyses of Primary Endpoint .................... 142 
6.9.2 
Analysis of Overall Survival ................................................. 142 
7. 
DATA COLLECTION, MANAGEMENT, AND QUALITY 
ASSURANCE............................................................................................ 144 
7.1 
Data Quality Assurance....................................................... 144 
7.2 
Electronic Case Report Forms............................................. 144 
7.3 
Electronic Patient-Reported Outcome Data......................... 145 


 
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7.4 
Source Data Documentation................................................ 145 
7.5 
Use of Computerized Systems ............................................ 145 
7.6 
Retention of Records........................................................... 146 
8. 
ETHICAL CONSIDERATIONS.................................................................. 146 
8.1 
Compliance with Laws and Regulations .............................. 146 
8.2 
Informed Consent ................................................................ 146 
8.3 
Institutional Review Board or Ethics Committee.................. 147 
8.4 
Confidentiality...................................................................... 148 
8.5 
Financial Disclosure ............................................................ 148 
9. 
STUDY DOCUMENTATION, MONITORING AND 
ADMINISTRATION ................................................................................... 148 
9.1 
Study Documentation .......................................................... 148 
9.2 
Site Inspections ................................................................... 149 
9.3 
Administrative Structure....................................................... 149 
9.4 
Publication of Data and Protection of Trade 
Secrets ................................................................................ 149 
9.5 
Protocol Amendments ......................................................... 150 
10. REFERENCES ......................................................................................... 151 
 
 
LIST OF TABLES 
Table 1 
All Adverse Event Related to Cobimetinib Occurring in 
≥ 10% of Patients in Study MEK4592g-21/7 Dosing Regimen 
Safety Evaluable (Clinical Cutoff 29 May 2012).......................... 44 
Table 2 
All Adverse Events Related to Cobimetinib Occurring in 
≥ 10% of Patients in Study MEK4592g-14/14 Dosing 
Regimen Safety Evaluable (Clinical Cutoff 29 May 2012)........... 45 
Table 3 
MEK4592g: Cobimetinib Single Agent Responses in 
Melanoma Patients Treated at Maximum-Tolerated Dose 
(Clinical Cutoff Date 29 May 2012) ............................................. 49 
Table 4 
Cohort Summary of Patients Treated with Vemurafenib and 
Cobimetinib in Study NO25395 (Clinical Cutoff 6 July 2012) ...... 52 
Table 5 
Treatment-Emergent Adverse Events of Any Grade 
Occurring among ≥10% of Patients in Study NO25395 
(Clinical Cutoff 6 July 2012) ........................................................ 55 


 
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Table 6 
Treatment-Emergent Related Adverse Events of Any Grade 
Attributed to Vemurafenib and/or Cobimetinib in Study 
NO25395 (Clinical Cutoff 6 July 2012)........................................ 58 
Table 7 
All Grade ≥ 3 Adverse Events in Study NO25395 (Clinical 
Cutoff 6 July 2012)...................................................................... 60 
Table 8 
Serious Adverse Events in Study NO25395 (Clinical Cutoff 
6 July 2012) ................................................................................ 65 
Table 9 
Dose Level Reductions ............................................................. 116 
Table 10 
Management of Specific Toxicities and Dose Modification 
Guidelines................................................................................. 118 
Table 11 
Adverse Event Severity Grading Scale ..................................... 128 
Table 12 
Assumptions and Characteristics of the Interim and Final 
Analyses for Overall Survival .................................................... 143 
 
 
LIST OF FIGURES 
Figure 1 
Combination of Vemurafenib with a MEK Inhibitor 
(RO5068760) Demonstrates a Synergistic Anti-Proliferation 
Effect in the Acquired-Resistance Melanoma Cell Model ........... 50 
Figure 2 
In Vivo Combination of Vemurafenib and MEKi in the 
Vemurafenib-Resistant A375 Melanoma Xenograft Model 
Overcomes Acquired Resistance................................................ 51 
Figure 3 
Dose-Escalation Plan for the Combination of Vemurafenib 
and Cobimetinib Administered on a 14/14, 21/7, and 28/0 
(Continual) Schedule in BRIM-7 (Study NO25395)..................... 52 
Figure 4 
Study GO28141 Randomization Scheme ................................... 69 
Figure 5 
Study GO28141 Dosing Scheme................................................ 70 
 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Assessments and Procedures .............................. 154 
Appendix 2 
Schedule of Pharmacokinetic Assessments ............................. 163 
Appendix 3 
New Response Evaluation Criteria in Solid Tumors –  
Version 1.1 – Excerpt From Original Publication with Addition 
of Supplementary Explanations ................................................ 164 
Appendix 4 
ECOG Performance Status....................................................... 175 
Appendix 5 
Guidelines for Management of Asymptomatic Reduction in 
Ejection Fraction ....................................................................... 176 
Appendix 6 
ICH Guidelines for Clinical Safety Data Management, 
Definitions and Standards for Expedited Reporting, Topic E2 .. 177 
Appendix 7 
New York Heart Association Classification of Functional 
Cardiac Capacity....................................................................... 179 
Appendix 8 
AJCC TNM Staging for Melanoma............................................ 180 


 
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Appendix 9 
Medications Affecting QT Interval (Information Available on 
http://www.azcert.org) ............................................................... 181 
Appendix 10 Cobas® 4800 BRAF V600 Mutation Test Information............... 182 
Appendix 11 Impact of Vemurafenib on Concomitant Medications................ 183 


 
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PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
A PHASE III, DOUBLE-BLIND, PLACEBO-CONTROLLED 
STUDY OF VEMURAFENIB VERSUS VEMURAFENIB 
PLUS GDC-0973 IN PREVIOUSLY UNTREATED 
BRAFV600-MUTATION POSITIVE PATIENTS WITH 
UNRESECTABLE LOCALLY ADVANCED OR 
METASTATIC MELANOMA 
PROTOCOL NUMBER: 
GO28141 
VERSION NUMBER: 
8 
EUDRACT NUMBER: 
2012-003008-11 
IND NUMBER: 
Vemurafenib (RO5185426): 109307  
Cobimetinib (GDC-0973) (RO5514041)/XL518: 76798 
TEST PRODUCT: 
Vemurafenib (RO5185426) 
Cobimetinib (GDC-0973)/XL518 
MEDICAL MONITOR: 
, M.D., Ph.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 a copy of the form to your local study monitor.  Please retain the original 
for your study files. 
 


 
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PROTOCOL SYNOPSIS 
TITLE: 
A PHASE III, DOUBLE-BLIND, PLACEBO-CONTROLLED 
STUDY OF VEMURAFENIB VERSUS VEMURAFENIB PLUS 
GDC-0973 IN PREVIOUSLY UNTREATED 
BRAFV600-MUTATION POSITIVE PATIENTS WITH 
UNRESECTABLE LOCALLY ADVANCED OR METASTATIC 
MELANOMA 
PROTOCOL NUMBER: 
GO28141 
VERSION NUMBER: 
8 
EUDRACT NUMBER: 
2012-003008-11 
IND NUMBER: 
Vemurafenib (RO5185426): 109307 
Cobimetinib (GDC-0973)/XL518: 76798 
TEST PRODUCT: 
Vemurafenib (RO5185426) 
Cobimetinib (GDC-0973) (RO5514041)/XL518 
PHASE: 
III 
INDICATION: 
BRAFV600-mutation positive patients with unresectable locally 
advanced or metastatic melanoma 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
Objectives 
Efficacy Objectives 
The primary efficacy objective of Study GO28141 is as follows: 
• 
To evaluate the efficacy of vemurafenib in combination with cobimetinib, compared with 
vemurafenib and placebo, in previously untreated BRAFV600 mutation−positive patients with 
unresectable locally advanced or metastatic melanoma, as measured by prolongation of 
progression-free survival (PFS), as assessed by the study site investigator 
 
The secondary efficacy objective of Study GO28141 is as follows: 
• 
To evaluate the efficacy of vemurafenib in combination with cobimetinib, compared with 
vemurafenib and placebo, in previously untreated BRAFV600 mutation−positive patients with 
unresectable locally advanced or metastatic melanoma, as measured by overall survival 
(OS), objective response rate, duration of response, and PFS as assessed by independent 
review 
 
Safety Objectives 
The safety objective of Study GO28141 is as follows: 
• 
To characterize the toxicity profile in patients receiving vemurafenib and cobimetinib  versus 
vemurafenib and placebo 


 
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Pharmacokinetic Objectives  
The pharmacokinetic (PK) objective of Study GO28141 is as follows: 
• 
To characterize the pharmacokinetics of cobimetinib  and vemurafenib and to compare the 
pharmacokinetics of vemurafenib when administered with cobimetinib to the 
pharmacokinetics of vemurafenib when administered with placebo 
• 
To perform exploratory exposure-response analysis, including concentration-QT interval 
corrected (QTc) analysis 
 
Patient-Reported Outcome Objectives 
The patient-reported outcome (PRO) objective of Study GO28141 is as follows: 
• 
To evaluate health-related quality of life in patients receiving vemurafenib and cobimetinib  
versus vemurafenib and placebo as measured by the European Organization for Research 
and Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) and the EuroQol 
5 dimension (EQ-5D) questionnaire 
 
Exploratory Objectives  
The Sponsor 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 (personalized healthcare).  Specimens may be used for any of the 
following: 
• 
To explore the intrinsic and acquired mechanisms of resistance to MEK and BRAF inhibition 
in tumor samples obtained at baseline, during treatment, and at disease progression 
• 
To study the association of biomarkers with efficacy and/or adverse events associated with 
medicinal products 
• 
To increase knowledge and understanding of disease biology 
 
Study Design 
Description of Study 
Study GO28141 is a multicenter, randomized, double-blind, placebo-controlled Phase III clinical 
study to evaluate the safety and efficacy of vemurafenib in combination with cobimetinib  with 
vemurafenib alone, in previously untreated BRAFV600 mutation−positive patients with 
unresectable locally advanced or metastatic melanoma.  
Approximately 500 previously untreated BRAFV600 mutation-positive patients with unresectable 
locally advanced or metastatic melanoma will be randomized in a 1:1 ratio to receive treatment 
with one of the following regimens: 
• 
Arm A (control arm):  vemurafenib 960 mg by mouth (PO) twice daily (BID) on Days 1−28 
and placebo by mouth (PO) once daily (QD) on Days 1−21 of each 28-day treatment cycle 
• 
Arm B (investigational arm):  vemurafenib 960 mg PO BID on Days 1−28 and cobimetinib  
60 mg PO QD on Days 1−21 of each 28-day treatment cycle 
 
The stratified, permuted-block randomization scheme will be used for treatment allocation 
based on the following stratification factors: 
• 
Geographic region (North America, Europe, Australia/New Zealand/others) 
• 
Metastatic classification (unresectable Stage IIIc, M1a, and M1b; or M1c) 
 
After signing informed consent, patients will undergo screening procedures that include testing 
for the BRAFV600 mutation; laboratory tests (hematology, chemistries, liver function tests); 
12-lead ECG; left-ventricular function evaluation (echocardiogram or multigated acquisition 
[MUGA] scan), contrast-enhanced brain computed tomography (CT) or magnetic resonance 
imaging (MRI); contrast-enhanced CT or MRI of the chest, abdomen, and pelvis; and 
ophthalmologic and dermatologic assessments.  
All eligible patients will be randomized to treatment in either Arm A (vemurafenib and placebo) 
or Arm B (vemurafenib and cobimetinib).  Vemurafenib will be taken starting on Day 1 to Day 28 


 
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of each 28-day treatment cycle.  The first dose of vemurafenib should be taken in the morning, 
and the second dose should be taken in the evening.  The cobimetinib  or placebo tablet will be 
taken once daily starting on Day 1 to Day 21 of each 28-day treatment cycle.  The cobimetinib 
or placebo tablet should be taken at approximately the same time each day, preferably in the 
morning with the vemurafenib dose.  Vemurafenib and cobimetinib/placebo can be taken with or 
without a meal, and should be taken with a glass of water.  
All patients will be closely monitored for safety and tolerability during all cycles of therapy, at the 
end-of-study treatment visit, and during the follow-up period.  Patients will be assessed for 
adverse events every 2 weeks during the first 2 cycles, then prior to each subsequent cycle, 
and as necessary throughout the study.  
Tumor response will be evaluated according to Response Evaluation Criteria in Solid Tumors 
(RECIST) version 1.1.  Any evaluable and measurable disease must be documented at 
screening and re-assessed at each subsequent tumor evaluation.  Response will be assessed 
by the investigator at 8-week intervals.  At the investigator’s discretion, CT/MRI scans may be 
repeated at any time if progressive disease is suspected.  
The NCI Common Terminology Criteria for Adverse Events (CTCAE) v4.0 will be used to 
characterize the toxicity profile of the study treatments on all patients.  ECG monitoring for 
patients who receive vemurafenib will be conducted in accordance with the vemurafenib IB.  
Ongoing ECG monitoring is no longer required for patients who continue to receive only 
cobimetinib/placebo unless clinically indicated.   Dermatologic assessment will be performed at 
the beginning of Cycle 2 (± 1 week) and per local standard of care thereafter.  Ophthalmologic 
examinations and left ventricular function evaluation (echocardiogram or MUGA) are evaluated 
throughout the study. 
Treatment will continue until disease progression, death, unacceptable toxicity, or withdrawal of 
consent, whichever occurs earliest.  Patients on the vemurafenib and placebo treatment arm will 
be eligible to cross over to the vemurafenib and cobimetinib treatment arm prior to disease 
progression so long as the patient has not discontinued vemurafenib treatment should the 
investigator feel that the addition of cobimetinib may benefit the patient and the patient provides 
informed consent and continues to be followed for survival.  Patients who have previously 
discontinued vemurafenib and who are receiving only placebo may not cross over and should 
discontinue all study treatment. 
Number of Patients 
This study will enroll approximately 500 patients.  
Target Population 
Patients must meet the following criteria for study entry: 
Disease-Specific Inclusion Criteria: 
1. Patients with histologically confirmed melanoma, either unresectable Stage IIIc or 
Stage IV metastatic melanoma, as defined by the American Joint Committee on Cancer 
7th edition.  Unresectability of Stage IIIc disease must have confirmation from a surgical 
oncologist. 
2. Patients must be naïve to treatment for locally advanced unresectable or metastatic 
disease (i.e., NO prior systemic anti-cancer therapy for advanced disease; Stage IIIc 
and IV).  Prior adjuvant therapy (including immunotherapy, e.g., ipilimumab) is allowed. 
3. Documentation of BRAFV600 mutation−positive status in melanoma tumor tissue 
(archival or newly obtained tumor samples) using the cobas® 4800 BRAF V600 
mutation test 
4. Measurable disease per RECIST v1.1 
5. Eastern Cooperative Oncology Group Performance Status of 0 or 1  
6. Consent to provide archival tissue (either a paraffin-embedded tissue block or up to 
20 unstained slides) for biomarker analyses 
7. Consent to undergo tumor biopsies of accessible lesions on Cycle 2 Day 15 and at 
progression for biomarker analyses to explore intrinsic and acquired resistance  
 


 
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General Inclusion Criteria: 
8. Male or female patient aged ≥ 18 years  
9. Able to participate and willing to give written informed consent prior to performance of 
any study-related procedures and to comply with the study protocol 
10. Life expectancy ≥ 12 weeks 
11. Adequate hematologic and end organ function, defined by the following laboratory 
results obtained within 14 days prior to first dose of study drug treatment:      
o ANC ≥ 1.5 × 109/L                                                       
o Platelet count ≥ 100 × 109/L                                                                    
o Hemoglobin ≥ 9 g/dL                                                                                     
o Albumin ≥ 2.5 g/dL                                                                                      
o Bilirubin ≤ 1.5 × the upper limit of normal (ULN)                                                       
o AST, ALT, and alkaline phosphatase (ALP) ≤ 3 × ULN, with the following 
exceptions: 
 Patients with documented liver metastases:  AST and/or ALT ≤ 5 × ULN  
 Patients with documented liver or bone metastases:  ALP ≤ 5 × ULN 
o Serum creatinine ≤ 1.5 × ULN or creatinine clearance (CrCl) ≥ 40 mL/min on the 
basis of measured CrCl from a 24-hour urine collection or Cockroft-Gault 
glomerular filtration rate estimation: 
(140 − age) × (weight in kg) × (0.85 if female)  
72 × (serum creatinine in mg/dL) 
 
12. Female patients of childbearing potential and male patients with partners of 
childbearing potential must agree to always use 2 effective forms of contraception 
during the course of this study and for at least 6 months after completion of study 
therapy.  
o Females of childbearing potential are defined as sexually mature women without 
prior oophorectomy or hysterectomy who have had menses within the last 
12 months. 
o Females are not considered to be of childbearing potential if amenorrheic 
for > 12 months and follicle-stimulating hormone (FSH) level ≥ 40 IU/L. 
o For females who have been amenorrheic for ≥ 2 years, the requirement for 
FSH measurement at screening will be waived. 
o Effective forms of contraception include surgical sterilization, a reliable barrier 
method with spermicide, birth control pills, or contraceptive hormone implants.  
Please note that potential interactions between vemurafenib and hormonal 
contraceptives may decrease the effectiveness of hormonal contraceptives. 
o Male patients who are surgically sterilized are required to use barrier methods of 
contraception. 
13. Negative serum pregnancy test within 14 days prior to commencement of dosing 
in women of childbearing potential 
14. Absence of any psychological, familial, sociological, or geographical condition that 
potentially hampers compliance with the study protocol and follow-up after treatment 
discontinuation schedule; those conditions should be discussed with the patient before 
trial entry 
 
Patients who meet any of the following criteria will be excluded from study entry: 
Cancer-Related Exclusion Criteria: 
1. History of prior RAF or MEK pathway inhibitor treatment 
2. Palliative radiotherapy within 14 days prior to the first dose of study treatment 
3. Major surgery or traumatic injury within 14 days prior to first dose of study treatment 


 
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4. Patients with active malignancy (other than BRAF−mutated melanoma) or a previous 
malignancy within the past 3 years are excluded;  except for patients with resected 
melanoma, resected basal cell carcinoma (BCC), resected cutaneous squamous cell 
carcinoma (SCC), resected melanoma in-situ, resected carcinoma in-situ of the cervix, 
and resected carcinoma in-situ of the breast. 
5. History of isolated elevation in prostate-specific antigen in the absence of radiographic 
evidence of metastatic prostate cancer is allowed. 
 
Exclusion Criteria Based on Organ Function 
Ocular: 
6. History of or evidence of retinal pathology on ophthalmologic examination that is 
considered a risk factor for neurosensory retinal detachment / central serous 
chorioretinopathy, retinal vein occlusion (RVO), or neovascular macular degeneration  
7. The risk factors for RVO are listed below.  Patients will be excluded if they currently 
have the following conditions:  
a) Uncontrolled glaucoma with intra-ocular pressures ≥ 21 mmHg 
b) Serum cholesterol ≥ Grade 2 
c) Hypertriglyceridemia ≥ Grade 2 
d) Hyperglycemia (fasting) ≥ Grade 2 
 
Cardiac: 
8. History of clinically significant cardiac dysfunction, including the following: 
a) Current unstable angina 
b) Symptomatic congestive heart failure of New York Heart Association class 2 or 
higher (Appendix 7) 
c) History of congenital long QT syndrome or mean (average of triplicate 
measurements) QTc measured using Fridericia’s method ≥ 450 ms at baseline or 
uncorrectable abnormalities in serum electrolytes (sodium, potassium, calcium, 
magnesium, phosphorus).  Please refer to Section 4.5.1.11 
d) Uncontrolled hypertension ≥ Grade 2 (patients with a history hypertension controlled 
with anti-hypertensives to ≤ Grade 1 are eligible) 
e) Left ventricular ejection fraction (LVEF) below institutional lower limit of normal or 
below 50%, whichever is lower 
 
Central Nervous System: 
9. Patients with active CNS lesions (carcinomatous meningitis) are excluded. However, 
patients are eligible if: 
a) All known CNS lesions have been treated with stereotactic therapy or surgery, AND 
b) There has been no evidence of clinical and radiographic disease progression in the 
CNS for ≥ 3 weeks after radiotherapy or surgery 
c) Whole brain radiotherapy is not allowed, with the exception of patients who have 
had definitive resection or stereotactic therapy of all radiologically detectable 
parenchymal brain lesions. 
 
General Exclusion Criteria: 
10. Current severe, uncontrolled systemic disease  
11. History of malabsorption or other condition that would interfere with absorption of study 
drugs 
12. Pregnant, lactating, or breast feeding 
13. Unwillingness or inability to comply with study and follow-up procedures 


 
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14. The following foods/supplements are prohibited at least 7 days prior to initiation of and 
during study treatment: 
a) St. John’s wort or hyperforin (potent CYP3A4 enzyme inducer) 
b) Grapefruit juice (potent cytochrome P450 CYP3A4 enzyme inhibitor) 
 
Length of Study 
The enrollment period is approximately 14 months. The final OS analysis will be performed after 
the occurrence of approximately 250 deaths (projected to occur at approximately 31 months 
after the first patient was randomized). 
End of Study 
The study will end when all patients enrolled have been followed until death, withdrawal of 
consent, lost to follow-up, or the Sponsor decides to end the trial, whichever occurs first. 
Patients may continue on study treatment until the development of progressive disease, 
unacceptable toxicity, and/or consent withdrawal.  Patients who discontinue study treatment for 
any reason will be followed for SCC according to the risk management plan, followed for 
disease progression and followed for survival until death, withdrawal of consent, or they are lost 
to follow-up.  Patients who start subsequent anti-cancer treatment after study treatment 
discontinuation will still need to be followed for survival and SCC.   
Efficacy Outcome Measures 
The primary outcome measure for this study is as follows: 
• 
PFS, defined as the time from randomization to the first occurrence of disease progression, 
as determined by the investigator using RECIST v1.1, or death from any cause, whichever 
comes first.   
 
The secondary outcome measures are as follows: 
• 
Overall survival, defined as the time from randomization to death from any cause   
• 
Objective response rate for patients with measurable disease at baseline, defined as 
complete or partial response as assessed by investigator according to RECIST v1.1 
• 
Duration of response for patients with measurable disease at baseline, defined as the time 
from first occurrence of a documented objective response until the time of disease 
progression, as determined by investigator review of tumor assessments using RECIST 
v1.1, or death from any cause during the study (i.e., within 30 days after the last dose of 
study treatment) 
• 
PFS as assessed by independent review using RECIST v1.1 
 
Safety Outcome Measures 
Safety outcome measures for this study are as follows: 
• 
Incidence, nature, and severity of adverse events and serious adverse events, graded 
according to NCI CTCAE v4.0 
• 
Adverse events of special interest:  any RVO; any retinal detachment or central serous 
chorioretinopathy; Grade ≥ 2 LVEF reduction; Grade ≥ 3 photosensitivity; Grade ≥ 3 
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; Grade ≥ 3 
QT interval prolongation; and any cutaneous primary malignancy, including SCC, 
keratoacanthoma, BCC, and new primary melanoma.  
• 
Changes in vital signs, ECGs, and clinical laboratory results during the course of study 
 


 
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Pharmacokinetic Outcome Measures  
The following PK parameters will be analyzed using a population PK approach and will be 
reported as applicable.   
• 
Exposure following first dose and steady-state (area under the plasma − concentration time 
curve through 24 hours [AUC0-24])  
• 
Minimum observed plasma concentration (Cmin; trough concentration) 
• 
Apparent clearance following oral dosing (CL/F) 
 
Exploratory exposure-response analyses for efficacy and safety endpoints, including QTc, will 
be performed. 
Patient-Reported Outcome Measures 
The PRO measures for this study are as follows: 
• 
EORTC QLQ-C30 
• 
EuroQol’s EQ-5D Questionnaire  
 
Exploratory Outcome Measures 
The exploratory biomarker analyses in tumor tissue may investigate potential intrinsic and 
acquired resistance mechanisms to MEK and BRAF inhibition.  Pre-treatment tumor tissue 
(i.e., archived material or biopsies collected during screening, prior to initiation of study 
treatment) and tumor biopsies during treatment (Cycle 2 Day 15) and at the end of study 
treatment (at the time of PD) will be required. 
In order to investigate if chromosomal and molecular genetic aberrations are linked to 
therapeutic outcome and development of severe adverse events in patients treated with 
vemurafenib and cobimetinib, DNA may be isolated from a single whole blood collected at 
baseline as well as tumor tissues. 
Additional efficacy exploratory analyses will include PFS rates and OS rates at fixed timepoints 
(e.g., 3, 6, 9, 12 months, etc.). 
Investigational Medicinal Products 
Test Product 
Double-blind study drug will be administered in 28-day cycles. 
Cobimetinib or placebo should be taken once daily at approximately the same time each day 
with the morning vemurafenib dose, and no later than 4 hours after the scheduled time. 
Cobimetinib or placebo can be taken with or without a meal.  Cobimetinib or placebo tablets 
should never be chewed, cut, or crushed. 
At least 7 days off cobimetinib is required prior to starting a new treatment cycle.   
Vemurafenib will be taken orally, at a starting dose of 960 mg (4 tablets) BID.  The first dose of 
vemurafenib should be taken in the morning, and the second dose should be taken in the 
evening, at least 8 hours after the first dose (the ideal interval between doses is 12 hours).  
Vemurafenib can be taken with or without a meal, and should be taken with a glass of water.  
The vemurafenib tablets should never be chewed, cut, or crushed. 


 
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Statistical Methods 
Primary Analysis 
The primary analysis will be a comparison of PFS between the 2 treatment arms using a 
stratified log-rank test at an overall 0.05 significance level (2-sided).   
The statistical hypothesis of this study is as follows: 
H0: PFS(Arm A) = PFS(Arm B) 
H1: PFS(Arm A) ≠ PFS(Arm B) 
where PFS(Arm A) represents the survival function of PFS in the vemurafenib + placebo  arm and 
PFS(Arm B) represents the survival function of PFS in the vemurafenib + cobimetinib arm. 
PFS as assessed by Investigator will be the primary endpoint evaluated.  PFS is defined as the 
time between date of randomization and the date of first documented disease progression or 
death, whichever occurs first.  Disease progression will be determined based on investigator 
assessment using RECIST v1.1.  Data from patients who have not experienced disease 
progression or death will be censored at the last tumor assessment date.  Data from patients 
with no post-baseline tumor assessment will be censored at the randomization date.  
The hazard ratio for PFS will be estimated using a stratified Cox model.  Two-sided 95% CIs for 
the hazard ratio will be provided.  The stratified analyses will incorporate 2 stratification factors:  
geographic region (North America, Europe, Australia/New Zealand/others) and metastatic 
classification (unresectable Stage IIIc, M1a, and M1b; M1c).  Results from an unstratified 
log-rank test and the unstratified hazard ratio will also be presented.  Kaplan-Meier 
methodology will be used to estimate median PFS for each treatment arm, and the 
Kaplan-Meier curves will be provided.   
Determination of Sample Size   
Progression-free survival:   
The type 1 error (α) for the analysis of the primary endpoint of PFS is 0.05 (2-sided).   
Approximately 500 patients will be randomized to treatment.  The final analysis of the primary 
endpoint of PFS will take place when approximately 206 PFS events have occurred.  Statistical 
considerations are based on the following assumptions: 
• 
Stratified log-rank test at 0.05 significance level (2-sided) 
• 
6 months median PFS for the vemurafenib + placebo arm 
• 
11 months median PFS for the vemurafenib + cobimetinib arm 
• 
Accrual ramp-up time of 9 months to reach 65 patients per month thereafter for a total 
enrollment period of approximate 14 months 
• 
5% dropout rate 
• 
No interim analysis of PFS 
 
A total of 206 PFS events provides > 95% power to detect an improvement in median PFS from 
6 months in the vemurafenib + placebo arm to 11 months in the vemurafenib + cobimetinib arm 
(corresponding to a hazard ratio of 0.55, and the minimal detectable difference is 0.76).   
Overall survival:  
The type 1 error (α) for the analysis of the secondary endpoint of OS is 0.05 (2-sided).   
The final analysis of OS will be performed after the occurrence of approximately 250 deaths.  
A total of 250 deaths provides approximately 80% power to detect an improvement in median 
OS from 15 months in the vemurafenib + placebo arm to 21.4 months in the 
vemurafenib + cobimetinib arm (corresponding to a hazard ratio for death of 0.70) at an overall 
2-sided 0.05 significance level. 


 
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Interim Analyses  
Interim efficacy analysis of primary endpoint:   
No interim analyses of the primary endpoint (PFS) will be performed. 
Analysis of overall survival:   
The OS analyses plan for this study protocol (v5) and the statistical analysis plan (SAP) have 
been revised.  The study will incorporate 2 OS analyses (1 interim and 1 final analysis).  The 
first OS interim analysis was performed at the time of the primary PFS analysis (16 months after 
the first patient was randomized).  The originally planned final analysis for OS at 385 events is 
anticipated to occur in the second quarter of 2017.  The rapid development of other potentially 
effective therapies for patients with metastatic melanoma provides more treatment options for 
patients following disease progression, which may potentially confound the OS benefit of 
vemurafenib + cobimetinib in future OS analyses. Therefore, in order to minimize this potential 
impact while maintaining a statistically robust evaluation of the OS benefit associated with the 
combination, the protocol-defined OS analyses have been revised. 
The revised plan for OS analyses is to perform the final OS analysis at approximately 
250 deaths without further interim analyses.  The type 1 error rate would be strictly controlled at 
the 0.05 level by the continued use of the Lan-DeMets implementation of the O’Brien-Fleming 
use function as pre-specified in the original protocol and SAP.  
The final OS analysis will be performed after the occurrence of approximately 250 deaths 
(projected to occur at approximately 31 months after the first patient was randomized).  
The Lan-DeMets implementation of the O’Brien and Fleming use function will be used to control 
the overall type I error for the OS comparison at a 2-sided, 0.05 significance level.  
 


 
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GLOSSARY OF ABBREVIATIONS 
14/14 
14 days on/14 days off 
21/7 
21 days on/7 days off 
28/0 
28 days on/0 days off 
AJCC 
American Joint Committee on Cancer 
AKI 
acute kidney injury 
ALP 
alkaline phosphatase 
AUC 
area under the plasma concentration−time curve 
AUC0-8h 
area under the plasma concentration−time curve from time 0 to 8 
hours 
AUC0-12h 
area under the plasma concentration−time curve from time 0 to 
12 hours 
AUC0-24h 
area under the plasma concentration−time curve from time 0 to 
24 hours 
BCC 
basal cell carcinoma 
BID 
twice daily 
BORR 
best overall response rate 
BRAFi 
BRAF inhibitor 
CL/F 
apparent clearance following oral dosing 
Cmax 
maximum plasma concentration 
Cmin 
minimum plasma concentration 
CMML 
chronic myelomonocytic leukemia 
CNS 
central nervous system 
CR 
complete response 
CRC 
colorectal cancer 
CrCl 
creatinine clearance 
CRO 
contract research organization 
CSCR 
central serous chorioretinopathy 
CT  
computed tomography 
cuSCC 
cutaneous squamous cell carcinoma 
CYP 
cytochrome P450 
DLT 
dose-limiting toxicity 
DOR 
duration of response 


 
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DRESS 
drug reaction with eosinophilia and systemic symptoms 
DSMB 
Data Safety Monitoring Board 
DTIC 
dacarbazine 
EC 
Ethics Committee 
ECHO 
echocardiograph 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
EF 
ejection fraction 
EORTC  
European Organization for Research of Cancer 
EQ-5D 
EuroQol 5 dimension self-reported questionnaire 
ERK 
extracellular signal-regulated kinase 
FDA 
U.S. Food and Drug Administration 
FDG-PET 
fluorodeoxyglucose−positron emission tomography 
FFPE 
formalin-fixed paraffin-embedded  
FNA 
fine needle aspiration 
FSH 
follicle stimulating hormone 
GI 
gastrointestinal 
GGT 
γ glutamyltransferase 
HEENT 
head, eyes, ears, nose, throat 
hERG 
human ether-à-go-go 
HPV 
human papillomavirus 
HR 
heart rate 
HRQL 
Health-related quality of life 
IB 
Investigator’s Brochure 
IC50 
50% inhibitory concentration 
IRB 
Institutional Review Board 
ICH 
International Conference on Harmonisation 
IMP 
Investigational Medicinal Product 
IND 
Investigational New Drug 
IV 
intravenous 
IxRS 
interactive response system 


 
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KA 
keratoacanthoma 
LFT 
liver function test 
LVEF 
left ventricular ejection fraction 
MAD 
maximal administered dose 
MAPK 
mitogen-activated protein kinase 
MedDRA 
Medical Dictionary for Regulatory Affairs 
MEK 
mitogen-activated protein kinase 
MEKi 
MEK inhibitor 
MBP 
microprecipitated bulk powder 
MRI 
magnetic resonance imaging 
MTD 
maximal tolerated dose  
MUGA 
multi-gated acquisition 
NCI 
National Cancer Institute 
NCI CTCAE 
National Cancer Institute Common Toxicity Criteria for Adverse 
Events 
NRAS 
neuroblastoma RAS viral oncogene homolog 
OCT 
optical coherence tomography 
ORR 
objective response rate 
OS 
overall survival 
Pap 
Papanicolaou 
PD 
progressive disease 
PFS 
progression-free survival 
PK 
pharmacokinetic 
PO 
by mouth 
pop PK 
population pharmacokinetics 
PPI 
proton-pump inhibitor 
PR 
partial response 
QD 
once daily 
QTc 
QT interval corrected 
QTcB 
QT interval corrected using Bazett’s method 
QTcF 
QT interval corrected using Fridericia’s method 
RCR 
Roche Clinical Repository 
RECIST 
Response Evaluation Criteria in Solid Tumors 


 
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RVO 
retinal vein occlusion 
SAP 
statistical analysis plan 
SCC 
squamous cell carcinoma 
SD 
stable disease 
t1/2 
terminal half-life  
tmax 
time to maximum plasma concentration  
ULN 
upper limit of normal 
USPI 
United States Package Insert 
 


 
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1. 
BACKGROUND AND RATIONALE 
1.1 
BACKGROUND ON MELANOMA 
1.1.1 
Melanoma 
Approximately 160,000 new cases of melanoma are diagnosed globally each year 
(Ries et al. 2003).  According to a World Health Organization report, about 
48,000 melanoma-related deaths occur worldwide every year (Lucas 2006).  The highest 
incidence rates of melanoma occur in Australia and New Zealand, where the annual 
incidence is more than double the highest rates recorded in Europe.  In Australia, 
melanoma is the fourth most common cancer among males and the third most common 
cancer among females.  Currently, the lifetime risk for development of melanoma in 
Australia is 1 in 14 for men and 1 in 24 for women (SUNSMART 2007, Australian 
Department of Health and Ageing 2008).  According to the National Cancer Institute 
(NCI), it is estimated that more than 76,000 new melanoma cases will be diagnosed and 
more than 9000 patients will die from the disease in the United States during 2012 
(NCI 2012).  Further, incidence rates for melanoma have increased sharply by 
approximately 6% per year in the United States since the 1970s.  There are only a 
limited number of treatments available for metastatic melanoma. 
1.1.2 
Role of BRAF Kinase in Melanoma 
Recent advances in the understanding of the biology of melanoma have resulted in 
identification of the role of BRAF kinase in melanoma.  Mutated BRAF dimers 
constitutively activate the RAS-RAF pathway, leading to the generation of transcriptional 
signaling that promotes tumor growth.   
BRAF mutations in melanoma have been identified in 50%− 68% of metastatic 
melanomas, specifically melanomas that arise from intermittent sun-exposed skin 
(e.g., 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 BRAF mutations are an early event in 
melanoma oncogenesis.  
About 90% of the BRAF mutations seen in metastatic melanoma occur in codon V600 
and more than 90% of the V600 mutations are V600E (Sanger Institute 2012).  
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, like V600, result in constitutive activation of the BRAF 
kinase.  
Most of the transforming activity of the BRAFV600 is thought to result through the 
constitutive activation of the mitogen-activated protein kinase (MAPK) pathway 
(Gray-Schopfer et al. 2007).  The therapeutic relevance of BRAF is supported by the 
demonstration that depletion of messenger RNA for oncogenic BRAF by small interfering 


 
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RNA leads to growth inhibition of melanoma cell lines in vitro (Hingorani et al. 2003; 
Sumimoto et al. 2004).  This has led to the development of agents that can inhibit BRAF 
kinase and tests to identify mutations (Smalley et al. 2007; Ascierto et al. 2010; 
Flaherty et al. 2010).  The cobas® 4800 BRAF V600 mutation test and Sanger 
Sequencing techniques have been used to identify BRAFV600 mutation status in clinical 
trials. 
1.2 
BACKGROUND ON BRAF INHIBITOR, VEMURAFENIB 
Vemurafenib (RO5185426 or PLX4032) is a low-molecular-weight, orally available 
inhibitor of the V600-mutant BRAF kinase.  Vemurafenib is currently approved as a 
treatment for adult patients with unresectable or metastatic BRAFV600 mutation-positive 
melanoma who have been diagnosed with the cobas® 4800 BRAF V600 Mutation Test in 
a number of countries worldwide, including the United States, Brazil, Mexico, the 
European Union, Switzerland, Canada, Australia, New Zealand, and Israel. 
1.2.1 
Clinical Pharmacokinetics of Vemurafenib 
Based on dose-limiting toxicities (DLTs) reported at the 1120mg twice daily (BID) dose 
level, the 960 mg BID dose was considered the maximum tolerated dose (MTD) for 
vemurafenib.  This dose was selected for use in all subsequent clinical trials, including 
the Phase II (NP22657) and Phase III (NO25026) studies in patients with unresectable 
Stage IIIc or metastatic melanoma. 
Population pharmacokinetic (PK) analysis used pooled data from 458 patients to 
estimate the median of the steady-state maximum concentration (Cmax), minimum 
concentration (Cmin), and area under the plasma concentration − time curve (AUC) from 
0 to 12 hours (AUC0-12 h).  The Cmax, Cmin, and AUC0-12 h were estimated to be 62 μg/mL, 
59 μg/mL, and 734 μg/mL • h, respectively.  The pharmacokinetics of vemurafenib are 
dose proportional between 240 mg BID and 960 mg BID.  Population PK analysis also 
confirmed that the pharmacokinetics of vemurafenib are linear. 
Vemurafenib is absorbed with a median time to maximum plasma concentration (tmax) of 
approximately 4 hours.  Vemurafenib exhibits marked accumulation after repeat dosing 
at 960 mg BID with high interpatient variability.  The median accumulation ratio estimate 
for a BID regimen of vemurafenib is 7.36.  In the Phase II study, mean vemurafenib 
plasma concentrations at 4 hours after dose increased from 3.6 μg/mL on Day 1 to 
49.0 μg/mL on Day 15 (range: 5.4−118 μg/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, interpatient 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 h-1 (with 101% between-patient variability).  


 
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The apparent volume of distribution for vemurafenib in metastatic melanoma patients 
based on population PK analysis is estimated to be 91 L (with 64.8% between-patient 
variability).  Vemurafenib is highly bound to human plasma proteins in vitro (> 99%).  
On average, 95% of the dose was recovered within 18 days, the majority (94%) in feces, 
with < 1% recovered in urine.  The parent compound was the predominant component 
(95%) in plasma. 
Additional information can be obtained from the vemurafenib Investigator’s Brochure (IB). 
1.2.2 
Efficacy of Vemurafenib in Patients with BRAFV600 
Mutation-Positive Metastatic Melanoma 
Phase I, PLX06-02 Study 
Among 32 evaluable patients with relapsed/refractory metastatic melanoma who 
enrolled in the extension cohort of the Phase I, PLX06-02 study, the confirmed best 
overall response rate (BORR) following vemurafenib treatment was 56.3%:  3 patients 
(9.4%) achieved a complete response (CR), and 15 patients (46.9%) had a partial 
response (PR).  Ten patients (31.3%) had stable disease (SD), and the remaining 
4 patients had progressive disease (PD).  The median duration of response (DOR) and 
progression-free survival (PFS) were 7.6 months and 7.8 months, respectively; the 
1-year overall survival (OS) rate was 57% (Flaherty et al. 2010). 
Phase II, NP22657 (BRIM 2) 
Results of the Phase II, open-label, single-arm 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 DOR and PFS were 6.7 months and 6.8 months, respectively 
(Sosman et al. 2012). 
Phase III, NO25026 (BRIM 3) 
Study NO25026 is a Phase III open-label, multicenter, 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, Eastern Cooperative 
Oncology Group (ECOG) Performance Status, and geographic region.  Baseline 
characteristics were well balanced between treatment groups.  Of 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.  The co-primary efficacy endpoints of the 
study were OS and PFS. 


 
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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).   
The most recent statistical analyses used a clinical cutoff of 1 February 2012 
(Chapman et al. 2011).  After a median of 12.5 months of follow-up in the vemurafenib 
arm, the Kaplan-Meier estimate of median survival for patients randomized to 
vemurafenib was 13.6 months (95% confidence interval [CI]:  12.0−15.2 months).  
For patients randomized to DTIC, after a median of 8.4 months of follow-up, the 
Kaplan-Meier estimate of median survival was 9.7 months (95% CI:  7.9−12.8 months). 
The hazard ratio for death was 0.70 (95% CI:  0.57−0.87) in favor of vemurafenib.  
Treatment with vemurafenib resulted in clinically meaningful and statistically significant 
improvements in PFS compared with DTIC treatment (hazard ratio 0.38 
[95% CI: 0.32−0.46, p < 0.001]).  There was a statistically significant improvement in 
BORR (confirmed) with vemurafenib (57.0%) compared with DTIC (8.6%), as assessed 
by the investigator. 
1.2.3 
Safety of Vemurafenib 
Vemurafenib clinical safety information for the treatment of patients with BRAFV600 
mutation–positive unresectable or metastatic melanoma has been derived mainly from 
the following studies: 
• 
PLX06-02, Phase I: clinical cutoff:  3 June 2010.  
– 
Dose Escalation Phase: (patients with solid tumors); original formulation, n = 26; 
micro-precipitated bulk powder (MBP) formulation, n = 30  
– 
Treatment Extension Phase: metastatic melanoma patients, n = 32  
– 
Treatment Extension Phase:  metastatic colorectal cancer (CRC) patients, 
n = 21. 
• 
NP22657 (BRIM2), Phase II: clinical cutoff:  31 January, 2011; n = 132, update:  
1 February 2012 
• 
NO25026 (BRIM3), Phase III: clinical cutoff:  31 March 2011; vemurafenib n = 337; 
dacarbazine (DTIC) n = 338. Update: 1 February 2012 
• 
NP25163 Phase I clinical pharmacology study:  clinical cutoff:  1 March 2011; 
updated clinical cutoff:  30 May 2013; n = 52.  
• 
MO25515, post−approval safety study:  interim analysis:  February 2012, n = 2398.  
 
In addition, the pharmacokinetics of the MBP formulation have been evaluated in 
Phase I clinical pharmacology studies, including a CYP450 metabolism study 
(NP22676; n = 25), a study to evaluate the pharmacokinetics of the 240-mg MBP 
film-coated tablets (NP25163; n = 50), a mass balance study (NP25158; n = 7), and a 
food-effect study (NP25396; n = 40). Please refer to the vemurafenib IB for more 
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1.2.3.1 
Dose-Limiting Toxicities of Vemurafenib 
The Phase I study PLX06-02 demonstrated that vemurafenib has generally been well 
tolerated in patients in the dose-escalation and melanoma-extension cohorts at doses up 
to 960 mg BID.  At the highest dose level tested, 1120 mg BID, 4 of 6 patients developed 
protocol-defined, non−life-threatening DLTs (including Grade 3 rash with pruritus, fatigue, 
and arthralgia) that resolved with temporary drug interruption.  All 4 patients were 
rechallenged at a lower dose and continued on treatment. 
1.2.3.2 
Clinical Safety in Phase II Study NP22657 (BRIM-2) 
Study NP22657 (BRIM-2), was an open-label, multicenter, Phase II trial of 
132 previously treated patients who received vemurafenib for metastatic melanoma.  
All 132 (100%) patients had at least one adverse event.  Treatment-related adverse 
events occurred in 130 (98%) patients.  The majority of adverse events were mild or 
moderate in intensity.  The most commonly reported adverse events (occurring in 
≥ 30% of patients) were arthralgia (68%), fatigue (57%), rash (54%), photosensitivity 
reaction (52%), nausea (42%), alopecia (38%), pruritus (32%), diarrhea (32%), skin 
papilloma (31%), and hyperkeratosis (30%). 
Seventy-three percent of patients in Study NP22657 (BRIM-2) had at least 1 Grade 3 or 
higher adverse event.  Sixty-one percent of patients had at least 1 treatment-related 
Grade 3 or higher adverse event.  The most commonly reported treatment-related Grade 
3 or higher adverse events (incidence ≥ 5%) were:  squamous cell carcinoma (SCC) of 
skin (23%), serum γ glutamyltransferase (GGT) increase (9%), basal cell carcinoma (BCC; 
7%), rash (7%), maculo-papular rash (6%), and arthralgia (6%). 
Study NP22657 (BRIM-2) incorporated a QT/QT interval corrected (QTc) analysis with 
triplicate digital 12-lead ECGs obtained at 10 study visits throughout the study (see 
Section 1.2.5.4). 
1.2.3.3 
Clinical Safety in Phase III Trial: NO25026 (BRIM-3) 
Ninety-nine percent of patients in the vemurafenib group and 91% of patients in the 
DTIC group experienced at least 1 adverse event.  The majority of adverse events were 
mild or moderate in intensity.  The most commonly reported adverse events (occurring in 
≥ 30% of patients) in the vemurafenib group were in the skin-related adverse events 
body system (vemurafenib 93% vs. DTIC 23%); the most common skin-related adverse 
events were alopecia, rash, and photosensitivity.  
Other adverse events that occurred in ≥ 10% of vemurafenib-treated patients and at an 
incidence more than twice that observed in the DTIC group included cutaneous SCC 
(cuSCC), skin papilloma, arthralgia, headache, dysgeusia, pyrexia, peripheral edema, 
pain in extremity, myalgia, decreased appetite, diarrhea, hyperkeratosis, seborrheic 
keratosis, and dry skin. 


 
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Grade ≥ 3 Adverse Events 
Fifty-nine percent of patients in the vemurafenib arm and 33% of patients in the DTIC 
arm experienced at least 1 adverse event that was Grade 3 or higher in intensity.  The 
percentage of vemurafenib-treated patients with cuSCC and keratoacanthoma (KA) 
were 16% and 9%, respectively, compared with < 1% and 0% for DTIC-treated patients 
(all cases of cuSCC and KA were considered to be treatment-related, Grade 3 in 
intensity, and serious).  Other common Grade 3 or higher adverse events in the 
vemurafenib group included photosensitivity reaction (9%), rash (8%), maculo-papular 
rash (8%), and arthralgia (4%); the corresponding frequencies of these adverse events 
in the DTIC group were 0%, 0%, 0%, and < 1%.  
1.2.4 
Deaths and Serious Adverse Events among Patients Receiving 
Vemurafenib 
Across all studies, the majority of reported deaths were attributed to PD.  In the pivotal 
Phase III Study NO25026 (BRIM-3), 19% of patients in the vemurafenib group and 
34% of patients in the DTIC group died. 
Across the NO25026 (BRIM-3), NP22657 (BRIM-2), and NP25163 studies, the most 
commonly reported vemurafenib-related serious adverse event was cuSCC.  
In Study NO25026 (BRIM-3), 42% of patients in the vemurafenib group and 18% of 
patients in the DTIC group experienced at least 1 serious adverse event.  Thirty-one 
percent of patients in the vemurafenib group and 5% of patients in the DTIC group 
experienced at least 1 treatment-related serious adverse event.  The most common 
treatment-related serious adverse events in the vemurafenib group were cuSCC (17%) 
and KA (9%).  No other treatment-related serious adverse event occurred in > 1% of 
patients in either treatment group. 
1.2.5 
Adverse Events of Special Interest for Vemurafenib 
1.2.5.1 
Cutaneous Squamous Cell Carcinoma  
In Studies NO25026, NP22657, and NP25163, 79 (23.5%), 34 (25.8%), and 10 (19.2%) 
patients treated with vemurafenib developed cuSCC/KA, respectively.  
Suspicious lesions were surgically excised if possible and submitted to a central 
dermatopathology laboratory designated by the Sponsor for classification based on 
histologic characteristics (independent of the site’s local pathologic diagnosis).  As of 
12 May 2011, a total of 268 biopsies from 76 patients from Studies NO25026, NP22657, 
and NP25163 had been reviewed by the central dermatopathology laboratory.  
Approximately half of all lesions were diagnosed as “SCC”; the other half were 
diagnosed as “other.”  The majority of SCC lesions (132 of 138 lesions, 96%) were 
classified as KA type (well-differentiated neoplasms with very low potential for invasive 
or metastatic disease).  Lesions diagnosed as “other” included verruca vulgaris, actinic 


 
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keratosis, early KA, wart, benign keratosis, scar, no neoplasm, BCC, no diagnosis, and 
seborrheic keratosis. 
Although events of cuSCC are serious, cuSCC can be monitored and treated.  
The metastatic potential of cuSCC is < 5% in 5 years, especially for the KA type 
(Alam and Ratner 2001).  A careful follow-up or risk mitigation plan with regular 
dermatological examinations has been established to monitor and treat cuSCC in 
patients receiving vemurafenib and during follow-up (see Section 5.1.4.1). 
1.2.5.2 
Second Primary Melanomas 
Eight skin lesions were reported as new primary melanomas in 7 patients in the 
Phase III, NO25026 study.  These lesions were managed with excision and without 
sequelae, and patients continued vemurafenib treatment for their underlying metastatic 
melanoma without dose adjustment. 
1.2.5.3 
Other Neoplasms 
Non-Cutaneous Squamous Cell Carcinoma 
Rare cases of SCC of the head and neck have been reported in clinical trials where 
patients were treated with vemurafenib.  One case in study NO25026 involved a patient 
who had a confirmed tonsillar SCC after receiving vemurafenib for > 200 days.  
The patient had a 
 pack-year history of 
 use.  The patient’s biopsy tested 
strongly positive for p16 by immunohistochemistry, but no evidence of a RAS mutation 
or epidermal growth factor receptor amplification or mutation was present.  
A second case occurred in study NP25163 (a PK/pharmacodynamic study).  This patient 
had an invasive SCC of the tongue.  
 was previously treated for metastatic melanoma 
with ipilimumab, therapeutic vaccine (type not specified), and high dose interleukin-2, 
before enrollment on study NP25163.  The patient had no known risk factors for 
head-and-neck SCC, and preliminary testing of the tumor was negative for the presence 
of human papillomavirus (HPV) genome.  
A careful follow-up or risk mitigation plan, including head and neck examinations, anal 
examinations, pelvic examinations, and chest computed tomography (CT) scans, has 
been established to monitor and treat SCC in patients who receive vemurafenib 
(see Section 5.1.4.1). 
Colonic Polyps 
Rare cases of adenomatous colonic polyps have been reported in patients treated with 
vemurafenib for 2 or more years while enrolled in a clinical trial.  The clinical significance 
of colonic polyps is uncertain but physicians should be aware that they may occur in 
patients treated with vemurafenib. 
Progression of Cancers Associated with RAS Mutations 
Based on mechanism of action, vemurafenib may cause progression of cancers 
associated with RAS mutations.   


 
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One case of progression of NRAS-mutated chronic myelomonocytic leukemia (CMML) 
occurred in a male patient with metastatic melanoma who had been treated with 
vemurafenib for < 2 weeks (Callahan et al. 2012).  After the first dose of vemurafenib, 
laboratory results showed a marked leukocytosis and monocytosis, and vemurafenib 
treatment was subsequently stopped.  In subsequent cycles, 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 
vemurafenib, an effect that was reversed upon addition of a MEKi.  Further, the cells 
exhibited dose-dependent and reversible activation of ERK in the NRAS-mutated 
leukemic clone.  A second case of progression of a pre-existing RAS-mutated 
malignancy (pancreatic adenocarcinoma with KRAS mutation) was reported with 
vemurafenib in 2014 (Grey et al. 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 concurrent cancer 
associated with RAS mutation.  Full details are provided in the current vemurafenib IB. 
1.2.5.4 
ECG Analysis 
The effects of single and multiple doses of vemurafenib (960 mg BID) on ECG 
measurement were evaluated in 132 adult patients with metastatic melanoma in the 
Phase II Study NP22657.  
Vemurafenib (960 mg BID) did not appear to have a clinically meaningful effect on heart 
rate (HR) and did not cause a meaningful change from the time-matched baseline in 
either the QRS or the PR (PQ) interval.  
Two patients (1.5%) developed treatment-emergent absolute QTc prolongation 
values > 500 ms (Grade 3), while 49 (37.1%) and 6 (4.5%) patients exhibited QTc 
prolongation values > 450 ms and > 480 ms, respectively.  No patients had 
treatment-emergent QT (uncorrected) values > 500 ms.  Maximal treatment-emergent 
individual QTc prolongation changes from baseline of > 30 ms were observed in 
58 (43.9%) patients, but only 1 (0.8%) patient exhibited a QTc prolongation change from 
baseline of > 60 ms.  Vemurafenib is associated with concentration-dependent QTc 
interval prolongation.  In the first month of treatment, the largest mean change from 
baseline of 12.8 ms (upper boundary of the 2-sided 90% CI of 14.9 ms) was observed at 
2 hours post-dose on Day 15.  In the first 6 months of treatment, the largest observed 
mean change from baseline of 15.1 ms (upper boundary of the 2-sided 90% CI of 
17.7 ms) was detected at a pre-dose timepoint.  There were no cases of torsade des 
pointes in any vemurafenib-treated patient in metastatic melanoma studies. 
For a detailed summary of QTc prolongation among patients who received vemurafenib, 
see the vemurafenib IB or the USPi. 


 
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1.2.5.5 
Liver Injury 
An analysis of liver−related adverse events reported with vemurafenib use showed that 
63 cases (out of estimated exposure of approximately 20,000 patients) of medically 
confirmed serious adverse events were consistent with drug−induced liver injury based 
on clinical chemistry criteria from the Drug−Induced Liver Injury Expert Working Group 
(Aithal et al. 2011).  Of the 63 cases, 2 were assessed as severe, both reported as 
hepatic failure.  There were no reported deaths among the 63 cases of liver injury; the 
outcome of one case of severe liver injury was reported as completely resolved with 
vemurafenib discontinuation, while information on the outcome of the second case of 
severe liver injury is not available at this time.  The median time to onset of the adverse 
events was 44 days after initial dose.  The median ALT to alkaline phosphatase (ALP) 
ratio was calculated as 1.5, which suggested a trend towards cholestatic pattern of liver 
injury.  The analysis did not reveal any risk factors or populations at risk. 
1.2.6 
Other Adverse Events of Clinical Significance 
1.2.6.1 
Severe Dermatologic Reactions 
Severe dermatologic reactions have been reported in patients receiving vemurafenib, 
including rare cases of Stevens-Johnson syndrome and toxic epidermal necrolysis in the 
pivotal clinical trial. 
As of 31 March 2013, 12 cases of drug reaction with eosinophilia and systemic 
symptoms (DRESS) syndrome have been observed with vemurafenib treatment, but no 
case was reported to result in death.  The time to onset was 7 to 25 days.  In the 
majority of patients (7), vemurafenib was discontinued.  Some patients (5) were treated 
with systemic steroids with corresponding improvement or resolution of symptoms.  
In addition, 2 patients with Grade 3 rash, who were treated with vemurafenib after 
ipilimumab, had biopsies that showed pathology consistent with drug hypersensitivity 
reaction (Harding et al. 2012).  Full details are available in the current vemurafenib IB. 
1.2.6.2 
Neutropenia 
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, typically occurring during the first 6−12 weeks of treatment.  It appeared to 
be reversible, usually within 2 weeks, with either temporary interruption, dose reduction, 
or discontinuation of vemurafenib, and in some cases was managed with 
granulocyte-colony stimulating factor.  
1.2.6.3 
Panniculitis 
Twenty-six cases of medically confirmed panniculitis, out of an estimated 
14,926 vemurafenib-treated patients, have been reported; 85% of the cases were 
assessed as causally associated with vemurafenib treatment.  The majority of the cases 
have been in females (n = 21), and in most cases the latency was 10−20 days after the 
initial dose.  


 
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1.2.6.4 
Pancreatitis 
As of the second quarter of 2014, an adverse drug reaction of pancreatitis has been 
identified in patients being treated with vemurafenib.  Seventeen cases of pancreatitis 
with no strong risk factors or alternative explanations were reported.  Eight of the 
17 cases were assessed as likely associated with vemurafenib use based on event 
onset latency and re-challenge/de-challenge information.  The clinical presentation, 
including mild to moderate severity, was consistent with the clinical picture of 
drug-induced pancreatitis (Lankisch and Gottesleben 1995). 
1.2.6.5 
Potentiation of Radiation Toxicity 
Potentiation of radiation treatment toxicity is an adverse drug reaction for vemurafenib.  
As of the fourth quarter of 2014, an adverse 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 20 cases of radiation injuries 
adjudicated as radiation recall (n = 8) and radiation sensitization (n = 12 cases).  
The nature and severity of 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 current 
vemurafenib IB. 
1.2.6.6 
Acute Kidney Injury 
An adverse drug reaction of acute kidney injury (AKI), including interstitial nephritis 
following vemurafenib administration, has been identified in patients being treated with 
vemurafenib.  The majority of these cases were characterized by mild to moderate 
increases in serum creatinine (some observed in the setting of dehydration events) with 
recovery after dose modification.  Approximately 2% of cases were biopsy−proven 
interstitial nephritis, and approximately 3% of cases were acute tubular 
injury/necrosis.  No fatal cases were related to AKI.   
Renal function should be monitored in patients undergoing vemurafenib treatment.  
Vemurafenib dose modification guidelines should be utilized when applicable, and it is 
recommended to routinely monitor serum creatinine levels in all patients undergoing 
vemurafenib therapy.  
1.2.7 
Safety of Vemurafenib in Combination with Ipilimumab 
In a Phase I trial (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 


 
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vemurafenib is not recommended outside of a clinical trial.  Full details are available in 
the current vemurafenib IB. 
1.3 
BACKGROUND ON MEK INHIBITOR COBIMETINIB  
1.3.1 
Role of MEK in Melanoma 
The best characterized substrate of BRAF is MEK.  Phosphorylation of MEK by BRAF 
results in increased MEK catalytic activity.  Cancer cells transformed by BRAFV600 are 
exceptionally sensitive to MEK inhibition in vitro.  Allosteric MEK inhibitors (MEKi) can 
result in G1 phase growth arrest in melanoma cells (Smalley et al. 2006; Solit et al. 2006; 
Haass et al. 2008).  In vitro, MEKi reduce cell proliferation, soft agar colony formation, 
and matrigel invasion of BRAFV600-mutant melanoma cells, and are also effective against 
BRAFV600 melanoma xenografts, suggesting a potentially important role for MEKi in 
melanoma and other tumors harboring the BRAFV600 mutation (Solit et al. 2006).  
1.3.2 
Cobimetinib / XL518 (MEK Inhibitor) 
Cobimetinib (GDC-0973/RO5514041/XL518) is a potent and highly selective inhibitor of 
MEK1 and MEK2, central components of the RAS/RAF pathway. 
1.3.3 
Nonclinical Studies with Cobimetinib  
Cobimetinib inhibits proliferation of a variety of human tumor cell lines by inhibiting 
MEK1 and MEK2.  In addition, cobimetinib inhibits ERK phosphorylation in xenograft 
tumor models (breast, lung, colon, and melanoma) and stimulates apoptosis.  
Cobimetinib accumulates in tumor xenografts and remains at high concentrations in the 
tumor after plasma concentrations have declined.  The activity of cobimetinib to inhibit 
ERK1 phosphorylation is more closely correlated with its concentrations in tumor tissue 
than in plasma; in general, there is a good correlation between reduced ERK1 
phosphorylation and efficacy in tumor xenograft models.  Tumor regression has been 
observed in several human tumor xenograft models.  This tumor regression was dose 
dependent with up to 100% regression at the highest doses tested. The models studied 
included CRC, malignant melanoma, breast carcinoma, and anaplastic lung carcinoma. 
1.3.4 
Phase I Clinical Study of Cobimetinib 
Study MEK4592g is a multicenter, Phase I, non-randomized, open-label, 
dose-escalation study.  The primary objectives of this study are to evaluate the safety, 
tolerability, and MTD of cobimetinib administered orally as repeated doses in patients 
with solid tumors.  
As of the data cutoff date of 11 June 2013, 115 patients had been treated in 
Study MEK4592g. 
In Stage I, 36 patients with advanced solid malignancies were enrolled in successive 
cohorts and received cobimetinib on a 21-day on, 7-day off (21/7) dosing schedule at the 
following dose levels:  0.05 mg/kg, 0.10 mg/kg, and 0.20 mg/kg in liquid dosage 


 
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formulation and 10 mg, 20 mg, 40 mg, 60 mg, and 80 mg in capsule formulation 
(Cohorts 1 − 8, respectively).  The maximal administered dose (MAD) during Stage I was 
80 mg; the MTD is 60 mg when cobimetinib is administered on a 21/7 dosing schedule. 
In Stage IA, 20 patients were treated with cobimetinib on a 14-day on, 14-day off (14/14) 
dosing schedule in successive cohorts at the following dose levels:  60 mg, 80 mg, 
100 mg, and 125 mg in capsule formulation (Cohorts 1A−4A, respectively).  The MAD of 
Stage IA was 125 mg, and the MTD is 100 mg when cobimetinib is administered on a 
14/14 dosing schedule.  
Stages II and IIA are expansion stages that further evaluate the safety, potential efficacy, 
and pharmacodynamic effects of cobimetinib at the MTDs determined in Stage I and 
Stage IA in patients with RAS− or RAF-mutant tumors.  
In Stage II, 20 patients were enrolled and received 60 mg cobimetinib on a 21/7 dosing 
schedule. In Stage IIA, 21 patients were been enrolled and received 100 mg cobimetinib 
on a 14/14 dosing schedule.  
In Stage III, 18 advanced solid tumor patients were enrolled and received 60 mg 
cobimetinib on a 21/7 dosing schedule in a drug-drug interaction study to evaluate the 
possible effect of cobimetinib on the pharmacokinetics of dextromethorphan and 
midazolam.  
1.3.5 
Clinical Pharmacokinetics of Cobimetinib 
PK data are available from cancer patients treated with cobimetinib in the Phase I study 
(MEK4592g).  The PK parameters were reasonably consistent between both dosing 
schedules (14/14 and 21/7) at a given dose.   
Cobimetinib is rapidly absorbed, with tmax ranging from 1 hour to 6 hours across all doses.  
Cmax and AUC were dose proportional in the range from 0.05 mg/kg to 80 mg.  
Exposures at the 125-mg dose on a 14/14 schedule increased slightly more than 
dose-proportionally compared with exposures at 100 mg.  
On the basis of the mean terminal half-life (t1/2) of approximately 48.8 hours, a 2-fold to 
3-fold accumulation is expected with daily oral dosing, and steady-state exposures 
should be achieved in 8−10 days.  Cobimetinib has minimal renal elimination and is 
mainly eliminated by metabolism in the liver.  EXEL-0382, a putative metabolite of 
Cobimetinib, was found at very low levels in plasma and, therefore, not monitored. 
Cobimetinib has also been administered to healthy subjects in the following clinical 
pharmacology studies: 
• 
MEK4952g:  Phase I absolute bioavailability study comparing oral and intravenous 
(IV) administration of cobimetinib (n = 13) 


 
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• 
MEK4953g:  Phase I relative bioavailability and food-effect study of cobimetinib 
(n = 20) 
• 
MEK4954g:  Phase I study evaluating the effect of rabeprazole, a proton-pump 
inhibitor (PPI), on the relative bioavailability of cobimetinib (n = 20) 
 
The results from these 3 completed clinical pharmacology studies in healthy volunteers 
indicate that the pharmacokinetics of cobimetinib do not appear to be altered by food or 
co-administration with PPIs and that the absolute bioavailability of cobimetinib was 
45.9% (90% CI:  39.74%−53.06%). 
For more information, please refer to the cobimetinib IB. 
1.3.6 
Safety in Phase I Clinical Study of Cobimetinib (MEK4592g) 
1.3.6.1 
Dose-Limiting Toxicities 
As of 8 October 2012, 4 DLTs had been observed in Stage I (21/7 dosing schedule) of 
Study MEK4592g.  At the 40-mg dose level, a DLT of Grade 4 hepatic encephalopathy 
was reported, which resolved following lactulose therapy, routine supportive care, and 
discontinuation of cobimetinib.  At the 60-mg dose level, a DLT of Grade 3 rash was 
reported that improved with skin toxicity management and drug holiday.  At the 80-mg 
dose level, 2 DLTs were reported:  Grade 3 diarrhea despite treatment with 
anti-diarrheal medications and Grade 3 rash.  
Two DLTs were observed in Stage IA (14/14 dosing schedule) of Study MEK4592g.  
At the 125-mg dose level, 1 patient had Grade 3 rash and another had Grade 3 blurred 
vision associated with neurosensory detachment of the retina.  
1.3.7 
Adverse Events in Phase I Clinical Study of Cobimetinib 
(MEK4592g) 
1.3.7.1 
Adverse Events Related to Cobimetinib  
In Study MEK4592g, as of 29 May 2012, 48 of 56 patients (85.7%) in the 21/7 dosing 
group experienced an adverse event that was reported as related to cobimetinib 
(Table 1).  The most frequent adverse events attributed by the investigator to 
cobimetinib were diarrhea (48.2%); rash, including dermatitis acneiform and rash 
erythematous (51.8%); edema, including periorbital, peripheral, facial, and generalized 
edema 34.0%); and fatigue (30.4%). 


 
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Table 1 
All Adverse Event Related to Cobimetinib Occurring in ≥ 10% of 
Patients in Study MEK4592g⎯21/7 Dosing Regimen Safety 
Evaluable (Clinical Cutoff 29 May 2012) 
MedDRA 
System Organ 
Class  
Preferred Term 
0.05 
mg/kg 
(n=4) 
0.10 
mg/kg
(n=3) 
0.20 
mg/kg
(n=3) 
10 mg
(n=3) 
20 mg
(n=3) 
40 mg
(n=6) 
60 mg 
(n=27) 
80 mg
(n=7) 
All 
Patients
(n=56) 
Any adverse 
events, n (%) 
3 
 (75.0) 
3 
(100.0)
2 
 (66.7)
3 
(100.0)
2 
 (66.7)
5 
 (83.3)
23 
(85.2) 
7 
(100.0)
48 
 (85.7) 
Gastrointestinal 
disorders 
3 
 (75.0) 
1 
 (33.3)
1 
 (33.3)
1 
 (33.3)
2 
 (66.7)
2 
 (33.3)
18 
(66.7) 
6 
 (85.7)
34 
 (60.7) 
Diarrhea 
1 
 (25.0) 
1 
 (33.3)
1 
 (33.3)
1 
 (33.3)
2 
 (66.7)
1 
 (16.7)
15 
(55.6) 
5 
 (71.4)
27 
 (48.2) 
Nausea 
1 
 (25.0) 
 
 (0.0) 
 
 (0.0) 
1 
 (33.3)
 
 (0.0) 
 
 (0.0) 
6 
 (22.2) 
2 
 (28.6)
10 
 (17.9) 
Stomatitis 
 (0.0) 
 (0.0) 
 (0.0) 
 (0.0) 
 (0.0) 1 (16.7) 3 (11.1) 2 (28.6) 6 (10.7)
Vomiting 
 (0.0) 
 (0.0) 
 (0.0) 
 (0.0) 1 (33.3) 1 (16.7) 3 (11.1)  (0.0) 
5 (8.9) 
General 
disorders and 
administration 
site conditions 
2 
 (50.0) 
3 
(100.0)
 
 (0.0) 
1 
 (33.3)
 
 (0.0) 
1 
 (16.7)
15 
 (55.6) 
4 
 (57.1)
26 
 (46.4) 
Fatigue 
2 
 (50.0) 
2 
 (66.7)
 
 (0.0) 
1 
 (33.3)
 
 (0.0) 
 
 (0.0) 
9 
 (33.3) 
3 
 (42.9)
17 
 (30.4) 
Edema 
peripheral 
 (0.0) 
 (0.0) 
 (0.0) 
 (0.0) 
 (0.0) 1 (16.7) 7 (25.9) 3 (42.9) 11 (19.6)
Skin and 
subcutaneous 
tissue disorders
1 
 (25.0) 
 
 (0.0) 
1 
 (33.3)
1 
 (33.3)
1 
 (33.3)
3 
 (50.0)
19 
(70.4) 
6 
 (85.7)
32 
 (57.1) 
Rash 
1 
 (25.0) 
 
 (0.0) 
 
 (0.0) 
 
 (0.0) 
 
 (0.0) 
3 
 (50.0)
16 
(59.3) 
5 
 (71.4)
25 
 (44.6) 
Dry skin 
 (0.0) 
 (0.0) 
 (0.0) 1 (33.3)
 (0.0) 1 (16.7) 2 (7.4) 3 (42.9) 7 (12.5)
 
As of 29 May 2012, 39 of 41 patients (95.1%) in the 14/14 dosing group had 
experienced at least 1 adverse event that was reported as related to cobimetinib 
(Table 2).  The most frequent adverse events attributed by the investigator to 
cobimetinib were diarrhea (78.0%); rash (63.4%, including dermatitis acneiform, rash 
generalized, and rash maculo-papular); fatigue (48.8%); vomiting (41.5%); edema, 
including peripheral, facial (swelling of face), and periorbital (34.1%); nausea (36.6%); 
eye disorders, including blurred vision, macular degeneration, subretinal fluid, and 
vitreous floaters (29.3%); and abdominal pain (26.8%).   


 
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Table 2 
All Adverse Events Related to Cobimetinib Occurring in ≥ 10% of 
Patients in Study MEK4592g⎯14/14 Dosing Regimen Safety 
Evaluable (Clinical Cutoff 29 May 2012) 
MedDRA System Organ 
Class  
Preferred Term 
60 mg 
(n=3) 
80 mg 
(n=3) 
100 mg 
(n=29) 
125 mg 
(n=6) 
All Patients
(n=41) 
Any adverse events,  
n (%) 
3 (100.0) 
3 (100.0) 
27 (93.1) 
6 (100.0) 
39 (95.1) 
Eye disordersa 
 (0.0) 
1 (33.3) 
9 (31.0) 
4 (66.7) 
14 (34.1) 
Visual impairment 
 (0.0) 
 (0.0) 
3 (10.3) 
2 (33.3) 
5 (12.2) 
Gastrointestinal 
disorders 
2 (66.7) 
2 (66.7) 
26 (89.7) 
6 (100.0) 
36 (87.8) 
Diarrhea 
1 (33.3) 
2 (66.7) 
23 (79.3) 
6 (100.0) 
32 (78.0) 
Vomiting 
 (0.0) 
2 (66.7) 
14 (48.3) 
1 (16.7) 
17 (41.5) 
Nausea 
 (0.0) 
2 (66.7) 
12 (41.4) 
1 (16.7) 
15 (36.6) 
Abdominal pain 
 (0.0) 
 (0.0) 
9 (31.0) 
1 (16.7) 
10 (24.4) 
Stomatitis 
 (0.0) 
1 (33.3) 
3 (10.3) 
1 (16.7) 
5 (12.2) 
General disorders and 
administration site 
conditions 
1 (33.3) 
1 (33.3) 
20 (69.0) 
1 (16.7) 
23 (56.1) 
Fatigue 
 (0.0) 
 (0.0) 
19 (65.5) 
1 (16.7) 
20 (48.8) 
Edema peripheral 
 (0.0) 
 (0.0) 
6 (20.7) 
1 (16.7) 
7 (17.1) 
Edema 
1 (33.3) 
 (0.0) 
4 (13.8) 
(0.0) 
5 (12.2) 
Metabolism and nutrition 
disorders 
 (0.0) 
1 (33.3) 
13 (44.8) 
1 (16.7) 
15 (36.6) 
Decreased appetite 
 (0.0) 
1 (33.3) 
6 (20.7) 
 (0.0) 
7 (17.1) 
Skin and subcutaneous 
tissue disorders 
3 (100.0) 
2 (66.7) 
19 (65.5) 
3 (50.0) 
27 (65.9) 
Rash 
2 (66.7) 
2 (66.7) 
15 (51.7) 
2 (33.3) 
21 (51.2) 
Dermatitis acneiform 
 (0.0) 
 (0.0) 
3 (10.3) 
2 (33.3) 
5 (12.2) 
a Verbatim terms of serous macular detachment and serous retinal macular detachment were 
auto-encoded in error as the preferred term of macular detachment.  All events reported as 
macular degeneration were neurosensory detachment, a reversible accumulation of fluid 
between the layers of the retina. 
 
1.3.7.2 
Grade ≥ 3 Adverse Events Related to Cobimetinib  
For patients in the 21/7 dosing group, no Grade 3 or greater adverse events reported as 
treatment-related were reported at the following dose levels:  0.05 mg/kg, 0.10 mg/kg, 
0.20 mg/kg, 10 mg, or 20 mg.  Ten (17.9%) of 56 patients experienced a total of 
14 Grade 3 or higher adverse events reported as treatment-related at dose levels 
≥ 40 mg.  At the 40-mg dose level, 1 patient had Grade 3 elevated ammonia levels and 


 
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Grade 4 hepatic encephalopathy.  At the 60-mg dose level, 1 patient experienced 
Grade 3 atrial fibrillation and Grade 3 acneiform dermatitis; 3 patients experienced 
Grade 3 fatigue; 1 patient experienced Grade 3 nausea; and 1 patient experienced 
Grade 5 respiratory distress, for which other possible contributing etiological factors 
included the disease under study (metastatic melanoma).  At the 80-mg dose level, 
2 patients experienced Grade 3 diarrhea.  One patient experienced Grade 4 leukopenia, 
Grade 3 dysphagia, Grade 3 syncope, and Grade 3 rash.  
Among patients in the 14/14 dose group, 17 (41.5%) of 41 patients experienced Grade 3 
or higher adverse events reported as treatment related.  No treatment-related Grade 3 or 
higher adverse events were observed at the 60-mg dose level.  At the 80-mg dose level, 
1 patient experienced Grade 3 diarrhea.  At the 100-mg dose level, 1 patient 
experienced Grade 3 lymphopenia; 1 patient experienced Grade 3 anemia; 1 patient 
experienced Grade 3 elevated AST, Grade 3 elevated CPK-MM, and Grade 3 
hypertension; 1 patient experienced Grade 3 abdominal pain; 4 patients experienced 
Grade 3 diarrhea; 2 patients experienced Grade 3 fatigue; 1 patient experienced 
Grade 3 hypokalemia; and 3 patients experienced Grade 3 rash.  At the 125-mg dose 
level, 1 patient experienced Grade 3 blurred vision associated with neurosensory 
detachment of the retina; 1 patient experienced Grade 3 rash; 1 patient experienced 
Grade 3 urticaria; and 1 patient experienced Grade 5 cardio-respiratory arrest. 
1.3.7.3 
Deaths and Serious Adverse Events of Cobimetinib 
Deaths in Study MEK4592g 
As of 8 October 2012, 97 patients were evaluable for safety.  There were 26 deaths in 
Study MEK4592g, 14 of which occurred within 30 days of the last administration of study 
drug.  Of the 14 deaths, all but 2 were reported as due to disease progression. 
One patient died from cardiopulmonary arrest secondary to disease progression, and the 
other died from worsening ovarian cancer.  Refer to “Serious Adverse Events in 
Study MEK4592g” below for details on these 2 patients. 
Please refer to the cobimetinib IB for further details on deaths reported on 
Study MEK4592g. 
Serious Adverse Events in Study MEK4592g 
As of 8 October 2012, 41 patients had experienced at least 1 serious adverse event in 
Study MEK4592g.  Of those, 11 patients experienced at least 1 serious adverse event 
reported as related to cobimetinib.   
Two Grade 5 adverse events were attributed to cobimetinib by the investigator.  For one 
patient who experienced Grade 5 cardio-respiratory arrest (125 mg), the other suspected 
causes of the event included the disease under study (metastatic breast cancer) and 
other unspecified concurrent conditions.  For the other patient who experienced Grade 5 
fatal respiratory distress (60 mg), the other possible contributing etiological factor 


 
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included the disease under study (metastatic melanoma).  Please refer to the 
cobimetinib IB for additional details on other serious adverse events.  
1.3.7.4 
Adverse Events of Special Interest for Cobimetinib 
Ocular Toxicity in Study MEK4592g and Study MEK4752g 
In Study MEK4592g, visual disturbances associated with reversible accumulation of fluid 
between the layers of the retina were reported as related to cobimetinib in 12 patients:  
4 at 125 mg (14/14), 5 at 100 mg (14/14), and 3 at 60 mg (21/7).  Of the 12 patients 
affected, 2 had subretinal fluid observed incidentally on an ophthalmologic examination 
without visual symptoms (1 patient each at 100 mg and 60 mg); 8 patients resumed 
cobimetinib at the same (2 at 60 mg and 3 at 100 mg) or a reduced dose (2 at 125 mg 
and 1 at 100 mg); and 1 had symptom recurrence after a dose reduction from 125 mg to 
100 mg cobimetinib.  One DLT of Grade 3 blurred vision was reported at 125 mg; all 
other visual disturbances (including blurred vision and seeing flashing lights) were 
Grade 1−2.  All events resolved within 1 week of stopping cobimetinib.  These visual 
disturbances associated with reversible accumulation of fluid between the layers of the 
retina occurred only with doses at or above the MTD. 
In Study MEK4752g, 8 (7%) of 123 patients experienced Grade 1 eye disorders, 
including photophobia, blurred vision, and visual impairment attributed to cobimetinib 
and/or GDC-0941, which resolved without study drug interruption.  
In Study NO25395, 1 patient, who had a history of uveitis, developed Grade 2 uveitis, 
which was effectively treated with steroid eye drops.  The episode of uveitis occurred at 
Cycle 1 Day 22 coincident with development of a Grade 3 rash.  Vemurafenib was 
interrupted for the Grade 3 rash, which improved by Cycle 1 Day 27 with systemic 
steroid therapy.  Ophthalmologic examination at the time of the uveitis flare did not 
reveal any retinal abnormalities, such as neurosensory retinal detachment or retinal vein 
occlusion, and the patient continued on steroid eye drops as previously prescribed.   
One patient developed Grade 2 iritis in 
 left eye during Cycle 9 of study treatment.  
Ophthalmologic examination did not identify central serous chorioretinopathy (CSCR) or 
retinal vein occlusion.  Vemurafenib was temporarily interrupted without minimal 
improvement in 
 symptoms.  Cessation of cobimetinib during the scheduled 14-days 
off did improve the patient’s symptoms.  The patient continued on the study combination 
and 
 symptoms were controlled with steroid eye drops.  
One patient who experienced Grade 2 blurred vision started having visual symptoms at 
Cycle 1 Day 2.  The patient noted “
,” and the patient 
.  However, the patient was still able to drive to 
 
clinic appointment on Cycle 1 Day 8.  The patient was asked to stop cobimetinib, and an 
ophthalmology evaluation demonstrated serous retinopathy.  No surgical intervention 
was required, and, at Cycle 1 Day 14, the patient noticed improvement in 
 vision and 
restarted vemurafenib (the cobimetinib schedule was on 14 days on / 14 days off).  


 
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In subsequent cycles, the patient continued on combination therapy at vemurafenib 
960 mg BID and cobimetinib 40-mg once daily (QD) 14/14 without recurrence of serious 
retinopathy or visual symptoms.  
CPK Elevation in Study MEK4592g and Study MEK4752 
In Study MEK4592g, there is limited information as to the frequency of CPK elevation in 
patients receiving cobimetinib monotherapy, because CPK testing has not been a part of 
the routine safety laboratory assessments.  One patient who received cobimetinib at 
100 mg/day on a 14/14 schedule in Study MEK4592g had Grade 2−3 CK-MM elevations.  
The patient was asymptomatic and without clinical or laboratory evidence for myocardial 
injury or rhabdomyolysis.  
In Study MEK4752, 22 (17.9%) of 123 patients have experienced CPK elevations 
attributed to study drugs by the investigator.  Four (3.2%) of 123 patients experienced 
Grade 3 or higher CPK-MM elevations.  In Cohort 5 (40 mg cobimetinib + 130 mg 
GDC-0941, 21/7) 1 patient had a DLT and serious adverse event of Grade 4 CPK 
elevation.  In Cohort E (125 mg cobimetinib + 245 mg GDC-0941, intermittent MEK), 
1 patient experienced a Grade 4 CPK-MM elevation on Cycle 1 Day 15, with Grade 1 
CK-MB elevation.  In Cohort C (125 mg cobimetinib + 130 mg GDC-0941, intermittent 
MEK), 1 patient experienced a Grade 3 CPK-MM elevation on Cycle 1 Day 18.  In the 
pancreatic expansion cohort (125 mg cobimetinib + 180 mg GDC-0941, intermittent 
MEK) 1 patient experienced Grade 3 CPK elevation with elevated troponin in Cycle 1 
Day 8; study drugs were discontinued.  The CPK elevation resolved to Grade 2 within 
2 days, and on Cycle 1 Day 9 an serious adverse event of Grade 4 anaphylaxis was 
treated with corticosteroids and resolved within 24 hours.  The majority of CPK 
elevations reported were asymptomatic and resolved with or without study interruption.  
In Study NO25395, 14 (20%) patients have experience elevated CPK.  All CPK 
elevations were asymptomatic and were not associated with cardiac injury or 
rhabdomyolysis, and no interventions were required to specifically address this 
laboratory abnormality. 
1.3.8 
Clinical Efficacy in Study MEK4592g 
Preliminary analyses of efficacy (anti-tumor activity) of cobimetinib have been performed 
with data from ongoing Study MEK4592g.  Although not a primary objective of the study, 
clinical efficacy was measured by Response Evaluation Criteria in Solid Tumors 
(RECIST) v1.1, which classifies a favorable tumor response as a CR, a PR, or SD.    
As 29 May 2012, data from Study MEK4592g indicate that there was 1 unconfirmed 
complete response and 6 partial responses (5 confirmed and 1 unconfirmed).  Of these 
7 responders, 6 were patients with BRAFV600E mutation-positive melanoma and 1 was a 
patient with unknown mutation status.  These responses were durable with a median 
time on cobimetinib study drug treatment of 280 days (range 42−721 + days) (Table 3).    


 
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In addition, there were 5 patients in Study MEK4592g with prolonged stable disease 
of ≥ 5 months in the following tumor types: carcinoid (47 + months), non−small cell lung 
cancer (13 months), adenoid cystic carcinoma (7 months), esophageal cancer 
(6 months), and sarcoma (5 months). 
Table 3 
MEK4592g: Cobimetinib Single Agent Responses in Melanoma 
Patients Treated at Maximum-Tolerated Dose (Clinical Cutoff 
Date 29 May 2012) 
Subject 
Cancer Type/Genotype
Cobimetinib
Dose 
Schedule
Best 
RECIST 
Response 
Days on Study 
(as of 29May2012)
BRAFV600Kmelanoma 
100 
14/14 
SD 
67a 
BRAFV600Emelanoma 
60 
21/7 
NA 
31 
BRAFV600Kmelanoma 
60 
21/7 
cPR 
334 
RAS/BRAF wt melanoma
100 
14/14 
PD 
48 
Melanoma 
100 
14/14 
cPR 
721 
BRAFV600E PIK3CAE545K/D 
melanoma 
60 
21/7 
cPR 
158 
BRAFV600E melanoma 
60 
21/7 
cPR 
280 
BRAFV600E melanoma 
100 
14/14 
uPR 
42c 
NRAS Q61L melanoma 
100 
14/14 
NA 
14b 
BRAFV600E melanoma 
100 
14/14 
uCR 
464 +  
BRAFV600E melanoma 
100 
14/14 
cPR 
239 
Ocular melanoma 
60 
21/7 
PD 
14b 
cPR = confirmed partial response; NA = not applicable; PD = progressive disease; 
RECIST = Response Evaluation Criteria in Solid Tumors; SD = stable disease; uPR = unconfirmed 
partial response. 
a Discontinued due to serious adverse event. 
b Discontinued due to clinical PD. 
c Withdrew consent. 
 
1.4 
BACKGROUND ON COMBINED BRAF AND MEK INHIBITION 
1.4.1 
Rationale for Combined BRAF and MEK Inhibition 
Despite vemurafenib having significant clinical activity in patients with advanced 
BRAFV600 mutation-positive melanoma, the duration of disease control is brief at 
approximately 6 months.  Several mechanisms of acquired resistance to vemurafenib 
therapy have been described.  These result in reactivation of the RAS/RAF pathway 
(Johannessen et al. 2010; Nazarian et al. 2010; Villanueva et al. 2010; 
Poulikakos et al. 2011; Su et al. 2012; Wagle et al. 2011; Shi et al. 2012).  The addition 
of a MEKi to vemurafenib abrogates vemurafenib resistance (Nazarian et al. 2010; 
Villanueva et al. 2010; Atefi et al. 2011; Poulikakos et al. 2011; Shi et al. 2012; 


 
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Su et al. 2012).  These findings, together with preclinical evidence that combined 
inhibition of BRAF and MEK prevents the emergence of resistance (Paraiso et al. 2010), 
support the clinical evaluation of combination therapy strategies incorporating MEK 
inhibition with BRAF inhibitors (BRAFi) in order to combat emerging resistance. 
1.4.2 
Preclinical Data of Combined BRAF and MEK Inhibition 
In an in vitro resistance model, cells resistant to both BRAF and MEK inhibition were 
exposed to vemurafenib, to a combination of vemurafenib with RO5068760 (a MEKi), or 
to RO5068760.  The combination of BRAF inhibition by vemurafenib and MEK inhibition 
by RO5068760 (see Figure 1) abrogated the constitutive up-regulation of ERK 
phosphorylation, inhibited cell cycle progression, and induced apoptosis in the resistant 
cells to a greater extent than either agent alone.  
Figure 1 Combination of Vemurafenib with a MEK Inhibitor (RO5068760) 
Demonstrates a Synergistic Anti-Proliferation Effect in the 
Acquired-Resistance Melanoma Cell Model 
MEKi = MEK inhibitor; RO5185426 = vemurafenib. 
 
An in vivo efficacy study in nude mice bearing BRAFV600-positive A375 melanoma 
xenograft tumors with acquired resistance to vemurafenib demonstrated synergistic 
anti-tumor activity when vemurafenib was combined with the MEKi RO5068760 (see 
Figure 2) (Su et al. 2012).  Similar results have also been seen in the same model with 
cobimetinib in combination with vemurafenib (see the cobimetinib IB). 
These in vivo and in vitro studies suggest that combined RAF/MEK pharmacologic 
inhibition of the BRAF pathway is more effective than suppressing either alone.  
Combined inhibition may suppress the emergence of the pathway-specific resistance in 
tumors harboring the BRAFV600 mutation.  This supports the use of combined BRAF and 
MEK inhibition in previously untreated BRAFV600 mutation-positive patients with locally 
advanced unresectable or metastatic melanoma.   


 
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Figure 2 In Vivo Combination of Vemurafenib and MEKi in the 
Vemurafenib-Resistant A375 Melanoma Xenograft Model 
Overcomes Acquired Resistance 
MEKi = MEK inhibitor; SEM = standard error of the mean. 
 
1.4.3 
Study NO25395 – Phase Ib Cobimetinib in Combination with 
Vemurafenib 
Study NO25395 (BRIM-7) is a Phase Ib study designed to assess the safety, tolerability, 
and pharmacokinetics of combined MEK inhibition with cobimetinib and BRAF inhibition 
with vemurafenib.  This multicenter study has 2 stages:  a dose-escalation stage and a 
cohort-expansion stage. 
This study is being conducted in patients with BRAFV600 mutation-positive, unresectable 
locally advanced or metastatic melanoma who are either vemurafenib naive or have 
progressed on vemurafenib treatment.  Key inclusion criteria include the presence of the 
V600 mutation in melanoma tumor tissue using the cobas® 4800 BRAF V600 mutation 
test, measurable disease per RECIST v1.1, ECOG Performance Status of ≤ 1, and 
adequate hematologic and end organ function as assessed through key laboratory 
measures.   
All patients in the dose-escalation stage receive twice daily vemurafenib in combination 
with cobimetinib administered daily according to one of the following 28-day schedules:  
14 consecutive days of study drug followed by a 14-day drug holiday (14/14), 
21 consecutive days of study drug followed by a 7-day drug holiday (21/7), or as a 
continuous daily dose (28/0).  Each treatment cycle is 28 days. 
There are 10 dose-escalation cohorts of 3−6 patients per cohort (see Figure 3).  Patients 
in Cohort 1 received vemurafenib at a dose of 720 mg BID continually and cobimetinib 


 
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60 mg QD for 14 consecutive days of each 28-day cycle of combination dosing (14/14).  
Dose-escalation used the standard 3 + 3 design and proceeded in increments, taking into 
account the safety and tolerability of the combination.   
Figure 3 Dose-Escalation Plan for the Combination of Vemurafenib and 
Cobimetinib Administered on a 14/14, 21/7, and 28/0 (Continual) 
Schedule in BRIM-7 (Study NO25395) 
 
 
1.4.3.1 
Safety in Study NO25395 (BRIM-7) 
As of the clinical cutoff date of 6 July 2012, a total of 70 patients had received 
combination treatment with vemurafenib and cobimetinib (see Table 4). 
Table 4 
Cohort Summary of Patients Treated with Vemurafenib and 
Cobimetinib in Study NO25395 (Clinical Cutoff 6 July 2012) 
Cohort 
n 
Cohort 1:  vemurafenib 720 mg BID + cobimetinib 60 mg QD 14/14 
5 
Cohort 1A and Expansion Cohort 1A:  vemurafenib 720 mg BID + cobimetinib 
60 mg QD 21/7 
28 
Cohort 1B and Expansion Cohort 1B:  vemurafenib 960 mg BID + cobimetinib 
60 mg QD 21/7 
19 
Cohort 1C:  vemurafenib 720 mg BID + cobimetinib 60 mg QD 28/0 
3 
Cohort 2:  vemurafenib 720 mg BID + cobimetinib 80 mg QD 14/14 
4 
Cohort 2A:  vemurafenib 720 mg BID + cobimetinib 100 mg QD 14/14 
3 
Cohort 3:  vemurafenib 960 mg BID + cobimetinib 60 mg QD 14/14 
3 
Cohort 4:  vemurafenib 960 mg BID + cobimetinib 80 mg QD 14/14 
5 
BID = twice daily; QD = once daily. 
 


 
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Dose-Limiting Toxicities   
As of the clinical cutoff date of 6 July 2012, the following dose-levels have been deemed 
safe and tolerable: 
• 
Vemurafenib 720 mg BID + cobimetinib 60 mg QD 14/14 (Cohort 1) 
• 
Vemurafenib 720 mg BID + cobimetinib 80 mg QD 14/14 (Cohort 2) 
• 
Vemurafenib 960 mg BID + cobimetinib 60 mg QD 14/14 (Cohort 3) 
• 
Vemurafenib 720 mg BID + cobimetinib 60 mg QD 21/7 (Cohort 1A) 
• 
Vemurafenib 960 mg BID + cobimetinib 60 mg QD 21/7 (Cohort 1B) 
• 
Vemurafenib 720 mg BID + cobimetinib 60 mg QD 28/0 (Cohort 1C) 
 
There has been only one DLT observed, as of the clinical cutoff date of 6 July 2012.  
The DLT was Grade 3 QTc prolongation and this occurred in 1 of the first 3 patients in 
Cohort 1B (vemurafenib 960 mg BID + cobimetinib 60 mg QD 21/7).  The patient was a 
-year-old 
 with a history of 
 
.  The patient had a QTc 
interval of 458 ms approximately 4 months prior to starting vemurafenib; 
 QT interval 
corrected using Bazett’s method (QTcB) was 470 ms just prior to starting vemurafenib.  
After 2 months of vemurafenib monotherapy at 960 mg BID, the patient’s QTcB interval 
was 503 ms; however, 
 remained on vemurafenib without dose modification.  After 
approximately 4 months on vemurafenib monotherapy, 
 experienced disease 
progression and was enrolled in Study NO25395.  
 screening ECG (while still 
receiving vemurafenib 960 mg BID) showed a QTc interval of 449 ms (QTcB, 461 ms; 
QT interval corrected using Fridericia’s method [QTcF], 450 ms).  
 triplicate QTc 
intervals obtained just prior to starting combination therapy with vemurafenib and 
cobimetinib were 444, 446, and 473 ms (QTcB, 485, 497, and 513 ms; QTcF, 453, 459, 
and 484 ms).  At Cycle 1 Day 14, the patient’s QTc interval reached a peak of 527 ms 
(QTcB, 533 ms; QTcF, 528 ms), corresponding with a Grade 3 abnormality.  
Vemurafenib was discontinued, and the patient remained on cobimetinib.  The patient 
did not have any electrolyte abnormalities at the time of the Grade 3 QTc interval 
prolongation.  The patient’s subsequent QTc intervals while receiving cobimetinib 
monotherapy varied from 420 to 430 ms.  The patient subsequently discontinued from 
the study after experiencing progressive disease on cobimetinib monotherapy. 
As a result of the occurrence of one DLT among the first 3 patients at the vemurafenib 
960 mg BID + cobimetinib 60 mg QD 21/7 dosing schedule, an additional 3 patients were 
enrolled in this cohort.  No other patients treated at this dose level experienced a DLT.  
The dose-level was declared safe and tolerable with only 1 out of 6 patients having 
experienced a DLT.  Additional accrual to this dose level in the expansion stage is 
ongoing.  


 
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Adverse Events in Study NO25395   
As of the clinical cutoff date of 6 July 2012, out of the 70 patients treated with 
combination vemurafenib/cobimetinib, 68 patients (97.1%) had experienced at least 
1 treatment-emergent adverse event.  Mild to moderate adverse events (Grade 1 or 2) 
were observed in 41 patients (58.6%), and 26 patients (37.1%) experienced Grade 3 
(severe) or Grade 4 (life-threatening) adverse events.  There was one Grade 5 adverse 
event:  a cerebrovascular accident.    
The most common treatment-emergent adverse events observed in Study NO25395 are 
shown in Table 5. 
Diarrhea (54.3%), non-acneiform rash (54.3%), fatigue (38.6%), nausea (35.7%), and 
photosensitivity (31.4%) were the most common adverse events observed.  Most of 
these adverse events were mild or moderate in intensity.    
There were 21 patients with Grade 3 adverse events.  The most common Grade 3 
adverse events were non−acneiform rash (5 patients [7.1%]), diarrhea (4 patients [7%]), 
and ALP elevation (3 patients [4. 3%]).  There were 5 patients with Grade 4 adverse 
events (GGT elevation [2 patients–2.9%], tonsil SCC [1.4%], CPK elevation [1.4%], and 
GI hemorrhage [1.4%]).     
Liver function test (LFT) elevations were observed in 18 (25.7%) patients.  The most 
common abnormality noted was elevations in serum ALP.  Most elevations in LFTs were 
Grade 1 or 2 in intensity. 
Fourteen (20.0%) patients experienced CPK elevation: 1 patient with a Grade 4 event, 
2 patients with Grade 3 events, and 9 patients with Grade 2 events.  These events were 
all attributed to either cobimetinib or the combination of cobimetinib and vemurafenib.  
No reports of CPK elevation were associated with any symptoms or evidence of cardiac 
injury or rhabdomyolysis.  No interventions were required to specifically address this 
laboratory abnormality; all CPK elevations resolved spontaneously while the patient 
continued treatment with cobimetinib or during the treatment holiday period. 
The adverse event profile of vemurafenib in combination with cobimetinib observed in 
this current update (clinical cutoff date 6 July 2012) is consistent with that previously 
observed at the earlier clinical cutoffs. 


 
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Table 5 
Treatment-Emergent Adverse Events of Any Grade Occurring among ≥10% of Patients in Study 
NO25395 (Clinical Cutoff 6 July 2012) 
 
Grade 1 or 2 
Grade 3 or 4 
Total 
 
n 
% 
n 
% 
n 
% 
Non-acneiform rasha 
33 
47.1 
5 
7.1 
38 
54.3 
Diarrhea 
34 
48.6 
4 
5.7 
38 
54. 3 
Nausea 
24 
34.3 
1 
1.4 
25 
35.7 
Sunburn / photosensitivity 
22 
31.4 
0 
0 
22 
31.4 
Liver function test elevationb 
14 
20.0 
4 
5.7 
18 
25.7 
Decreased appetite 
15 
21.4 
0 
0 
15 
21.4 
Pyrexia 
15 
21.4 
0 
0 
15 
21.4 
Creatine phosphokinase elevation 
11 
15.7 
3 
4.3 
14 
20.0 
Vomiting 
12 
17.1 
0 
0 
12 
17.1 
Arthralgia 
10 
14.3 
1 
1.4 
11 
15.7 
Acneiform rashc 
9 
12.9 
1 
1.4 
10 
14.3 
Constipation 
10 
14.3 
0 
0 
10 
14.3 
Edema peripheral 
10 
14.3 
0 
0 
10 
14.3 
Chills 
9 
12.9 
0 
0 
9 
12.9 
Myalgia 
9 
12.9 
0 
0 
9 
12.9 
Pruritis 
8 
11.4 
0 
0 
8 
11.4 
Anemia 
6 
8.6 
1 
1.4 
7 
10.0 
Hypertension 
6 
8.6 
1 
1.4 
7 
10.0 
Alopecia 
7 
10.0 
0 
0 
7 
10.0 


 
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Table 5 
Treatment-Emergent Adverse Events of Any Grade Occurring among ≥10% of Patients in Study 
NO25395 (Clinical Cutoff 6 July 2012) (cont.)  
 
Grade 1 or 2 
Grade 3 or 4 
Total 
 
n 
% 
n 
% 
n 
% 
Creatinine elevation 
7 
10.0 
0 
0 
7 
10.0 
Dyspnea 
7 
10.0 
0 
0 
7 
10.0 
LFT = liver function test.  
a Non-acneiform rash includes MedDRA terms rash, rash generalised, rash maculo-papular, rash macular, rash papular, rash 
erythematous, erythema, rash pruritic, skin exfoliation, lividity (livedoid-like rash) 
b LFT elevation includes MedDRA terms liver function test abnormal, hepatic enzyme increased, ALP increased, bilirubin increased, 
hyperbilirubinaemia, AST and ALT increased, transaminases increased, and γ-glutamyltransferase increased 
c Acneiform rash includes MedDRA terms dermatitis acneiform, acne, rash pustular 
 


 
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Adverse Events Related to Study Treatment in Study NO25395 
The most common adverse events in Study NO25395 that were reported as related to 
vemurafenib and/or cobimetinib by the study investigator are described in Table  6.  
Treatment−emergent adverse events that were assessed as related to either study drug 
occurred in 67 patients (95.7%) out of 70 patients who were treated with the combination. 
Non-acneiform rash, diarrhea, photosensitivity / sunburn, fatigue, and nausea were the 
most common adverse events reported as related to either vemurafenib, cobimetinib, or 
both study drugs, occurring in 52.9%, 51.4%, 31.4%, 30.0% and 28.6% of patients, 
respectively.  Most of these adverse events were mild or moderate in severity (Grades 1 
or 2). 
the adverse events related to study treatment observed in this current update (clinical 
cutoff date 6 July 2012) were consistent with those previously observed in earlier clinical 
cutoffs.  


 
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Table  6 Treatment-Emergent Related Adverse Events of Any Grade 
Attributed to Vemurafenib and/or Cobimetinib in Study NO25395 
(Clinical Cutoff 6 July 2012)  
 
Grade 1 or 2 
Grade 3 or 4 
Total 
 
n 
% 
n 
% 
n 
% 
Non-acneiform rasha 
32 
47.1 
5 
7.1 
37 
52.9 
Diarrhea 
32 
45.7 
4 
5.7 
36 
51.4 
Photosensitivity / sunburn 
22 
31.4 
0 
0 
22 
31.4 
Fatigue 
20 
28.6 
1 
1.4 
21 
30.0 
Nausea 
19 
27.1 
1 
1.4 
20 
28.6 
Liver function test elevationb 
11 
15.7 
3 
4.3 
14 
20.0 
CPK elevation 
11 
15.7 
3 
4.3 
14 
20.0 
Pyrexia 
10 
14.3 
0 
0 
10 
14.3 
Acneiform rashc 
8 
11.4 
1 
1.4 
9 
12.9 
Decreased appetite 
9 
12.9 
0 
0 
9 
12.9 
Myalgia 
9 
12.9 
0 
0 
9 
12.9 
Vomiting 
9 
12.9 
0 
0 
9 
12.9 
Anemia 
5 
7.1 
1 
1.4 
6 
8.6 
Headache 
5 
7.1 
0 
0 
5 
7.1 
Edema peripheral 
5 
7.1 
0 
0 
5 
7.1 
Chills 
3 
4.3 
0 
0 
3 
4.3 
QT prolongation 
2 
2.9 
1 
1.4 
3 
4.3 
Constipation 
1 
1.4 
0 
0 
1 
1.4 
LFT = liver function test.  
a Non-acneiform rash includes MedDRA terms rash, rash generalised, rash maculo-papular, 
rash macular, rash papular, rash erythematous, erythema, rash pruritic, skin exfoliation, 
lividity (livedoid-like rash) 
b LFT elevation includes MedDRA terms liver function test abnormal, hepatic enzyme 
increased, ALP increased, bilirubin increased, hyperbilirubinaemia, AST and ALT increased, 
transaminases increased, and γ-glutamyltransferase increased 
c Acneiform rash includes MedDRA terms dermatitis acneiform, acne, rash pustular 
 
Grade ≥ 3 Adverse Events in Study NO25395   
As of the clinical cutoff date of 6 July 2012, 27 patients (38.6%) had experienced 
Grade 3 or higher adverse events (see Table 7).  
In this current update (clinical cutoff date of 6 July 2012), 1 Grade 5 adverse event was 
reported (cerebrovascular accident).  Five patients had Grade 4 adverse events (GGT 


 
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elevation [2 patients], tonsil SCC, CPK elevation, GI hemorrhage) and 21 patients had 
Grade 3 adverse events.  The cases of cerebrovascular accident, tonsil SCC, and GI 
hemorrhage are discussed in the following section on serious adverse event. 
Grade 3 non-acneiform rash was observed in 5 patients (7.1%).  Grade 3 or 4 CPK 
elevations were observed in 3 patients (4.3%); all CPK elevations were asymptomatic 
and were not associated with cardiac injury or rhabdomyolysis; no interventions were 
required to specifically address this laboratory abnormality.  
Four patients (5.7%) experienced Grade 3 diarrhea.  One patient in Cohort 2A 
(vemurafenib 720 mg BID and cobimetinib 100 mg QD on a 14/14 schedule) developed 
Grade 3 syncope, Grade 3 diarrhea, Grade 3 rash, and Grade 3 VIIth cranial nerve 
paralysis.  This patient initially developed a Grade 3 rash on Cycle 1 Day 20.  The rash 
resolved after vemurafenib treatment was interrupted for 1 week.  On Cycle 2 Day 13, 
the patient developed Grade 3 diarrhea.  The patient had a Grade 3 syncopal episode 
on Cycle 2 Day 14.  ECG evaluation showed no ECG abnormalities, including no QT 
interval abnormalities.  Vemurafenib was stopped (and cobimetinib was on treatment 
holiday) on Cycle 2 Day 14.  Vemurafenib 720 mg BID was restarted on Cycle 2 Day 22.  
At Cycle 2 Day 27, this patient developed VIIth cranial nerve paralysis, which interfered 
with activities of daily living.  Cranio-spinal imaging did not identify any pathology.  Both 
vemurafenib and cobimetinib were permanently discontinued after the patient decided to 
withdraw from the study.  After discontinuation of study drugs, there was gradual 
improvement of the VIIth cranial nerve paralysis with corticosteroid therapy over 
6 weeks.  The investigators reported the VIIth nerve paralysis as related to vemurafenib 
and/or cobimetinib treatment. 
Grade 3 and higher LFT elevations occurred in 4 patients (5.7%). The Grade 3 and 
higher LFT abnormalities observed were: 
• 
One patient – Grade 3 ALP elevation and Grade 3 transaminase elevation 
• 
One patient – Grade 3 ALP elevation and Grade 4 GGT elevation 
• 
One patient – Grade 4 GGT elevation  
• 
One patient – Grade 3 ALP elevation 
 
One patient developed Grade 3 hypotension and Grade 3 dehydration after being 
diagnosed with Grade 1 pneumonia.  
One patient with extensive bone metastasis developed a Grade 3 subtrochanteric 
fracture on Cycle 1 Day 25 of study therapy.  The patient subsequently underwent 
surgery for the femur fracture.  Post-operatively, the patient’s hemoglobin was 9.6 g/dL 
but approximately 4 weeks later, the patient’s hemoglobin decreased to 7.4 g/dL 
corresponding to Grade 3 anemia.  The investigator attributed the anemia to be related 
to combination therapy but recognized that other factors such as surgery and extensive 
bone metastases may have contributed to the anemia. 


 
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In addition, 1 patient developed Grade 3 pneumonia associated with Grade 3 mental 
status change and Grade 3 hypophosphatemia.  Another patient developed Grade 3 
malignant pleural effusion associated with Grade 3 hypoxia and Grade 3 lymphopenia.   
Table 7 
All Grade ≥ 3 Adverse Events in Study NO25395 (Clinical Cutoff 
6 July 2012) 
Adverse Events Grade ≥ 3, n = 70
Grade 3 
Grade 4 
Grade 5 
Total 
 
n 
% 
n 
% 
n 
% 
n 
% 
Cerebrovascular accident 1 
0 
0 
0 
0 
1 
1.4 
1 
1.4 
GGT elevation 2, 3 
0 
0 
2 
2.9 
0 
0 
2 
2.9 
CPK elevation 4 
2 
2.9 
1 
1.4 
0 
0 
3 
4.3 
Gastrointestinal hemorrhage 
0 
0 
1 
1.4 
0 
0 
1 
1.4 
Tonsil SCC  
0 
0 
1 
1.4 
0 
0 
1 
1.4 
Non-acneiform rash* 1, 2, 5 
5 
7.1 
0 
0 
0 
0 
5 
7.1 
Diarrhea 5, 6, 7 
4 
5.7 
0 
0 
0 
0 
4 
5.7 
ALP elevation 2, 8, 9 
3 
4.3 
0 
0 
0 
0 
3 
4.3 
Hypophosphataemia 4 
2 
2.9 
0 
0 
0 
0 
2 
2.9 
Convulsion 3 
1 
1.4 
0 
0 
0 
0 
1 
1.4 
Cutaneous SCC 4 
1 
1.4 
0 
0 
0 
0 
1 
1.4 
VIIth nerve paralysis 5 
1 
1.4 
0 
0 
0 
0 
1 
1.4 
Syncope 5 
1 
1.4 
0 
0 
0 
0 
1 
1.4 
Nausea 6 
1 
1.4 
0 
0 
0 
0 
1 
1.4 
Acneiform rash 7 
1 
1.4 
0 
0 
0 
0 
1 
1.4 
Fatigue 7 
1 
1.4 
0 
0 
0 
0 
1 
1.4 
Presyncope 8 
1 
1.4 
0 
0 
0 
0 
1 
1.4 
Transaminases elevation 8 
1 
1.4 
0 
0 
0 
0 
1 
1.4 
QT prolongation 9 
1 
1.4 
0 
0 
0 
0 
1 
1.4 
Dehydration 10 
1 
1.4 
0 
0 
0 
0 
1 
1.4 
Hypotension 10 
1 
1.4 
0 
0 
0 
0 
1 
1.4 
Hypoxia 11 
1 
1.4 
0 
0 
0 
0 
1 
1.4 
Pleural effusion 11 
1 
1.4 
0 
0 
0 
0 
1 
1.4 
Lymphopenia 11 
1 
1.4 
0 
0 
0 
0 
1 
1.4 
Pneumonia 12 
1 
1.4 
0 
0 
0 
0 
1 
1.4 
Mental status change 12 
1 
1.4 
0 
0 
0 
0 
1 
1.4 
Anemia 13 
1 
1.4 
0 
0 
0 
0 
1 
1.4 
Femur fracture 13 
1 
1.4 
0 
0 
0 
0 
1 
1.4 
Hypertension 
1 
1.4 
0 
0 
0 
0 
1 
1.4 
Abdominal distension 
1 
1.4 
0 
0 
0 
0 
1 
1.4 


 
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Table 7 
All Grade ≥ 3 Adverse Events in Study NO25395 (Clinical Cutoff 
6 July 2012) (cont.)  
Adverse Events Grade ≥ 3, n = 70
Grade 3 
Grade 4 
Grade 5 
Total 
 
n 
% 
n 
% 
n 
% 
n 
% 
Wound infection 
1 
1.4 
0 
0 
0 
0 
1 
1.4 
Hyponatremia 
1 
1.4 
0 
0 
0 
0 
1 
1.4 
Arthralgia 
1 
1.4 
0 
0 
0 
0 
1 
1.4 
Back pain 
1 
1.4 
0 
0 
0 
0 
1 
1.4 
Hyperkeratosis 
1 
1.4 
0 
0 
0 
0 
1 
1.4 
CPK = creatine phosphokinase; GGT = γ glutamyltransferase; SCC = squamous cell carcinoma.  
* Non-acneiform rash includes MedDRA terms rash maculo-papular and rash generalize 
1-13 
Patients who experienced more than one Grade ≥ 3 adverse event are each indicated with 
a different    superscript Arabic numeral after the name of each adverse event  they 
experienced. 
 
Serious Adverse Events in Study NO25395 
As of the clinical cutoff date of 6 July 2012, 15 patients (21.4%) had experienced serious 
adverse events in Study NO25395.  The serious adverse events are listed in Table 8.  
One patient experienced a Grade 5 serious adverse event in Study NO25395, a 
.  This patient was a 
-year-old 
 with metastatic 
melanoma with a known history of 
 
.  The patient 
started on Cycle 1 Day 1 of Study NO25395 on 
 with vemurafenib at 
720 mg BID and cobimetinib at 60 mg on a 21/7 schedule.  
 attained partial 
response as 
 best overall tumor response.  On 
, 
 developed 
 
and was hospitalized.  Brain magnetic resonance imaging (MRI) identified new brain 
metastasis, and 
.  On 
, 
while still recovering in hospital, 
 had an acute stroke and died on 
. 
Non-cutaneous SCC (Grade 4 tonsillar SCC) was observed in 1 patient in 
Study NO25395. This patient is a 
-year-old 
 diagnosed with metastatic melanoma 
in 
.  The patient received first-line treatment with vemurafenib 960 mg BID in 
Study NO25026 (BRIM-3) for approximately 13 months from 
.  
At the time of disease progression, abnormal metabolic activity in the patient’s left tonsil 
was noted on positron emission tomography (PET) scan.  Otolaryngology evaluation at 
that time noted tonsillar enlargement, but no additional diagnostic or therapeutic 
intervention was undertaken at that time.  The patient was subsequently enrolled in 
Study NO25395 (BRIM-7) and started combination therapy in Cohort 3 (vemurafenib 
960 mg BID + cobimetinib 60 mg on a 14/14 schedule) in 
.  The patient 
developed melanoma disease progression after 4 cycles of treatment and discontinued 
the study in 
.  The patient's left tonsil was re-assessed in early 
 


 
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and at that time was noted to be larger.  Clinical staging around that time (including CT 
scan) showed left tonsillar mass and regional lymph node enlargement.  A biopsy of the 
left tonsillar mass was performed shortly thereafter, which corroborated the diagnosis of 
SCC but, due to crush artifact, it was difficult to assign pathologic stage.  The biopsy 
stained strongly for p16, which is suggestive of HPV-mediated oncogenesis.  That 
patient had an additional risk factor for SCC of the head and neck, a 
 pack−year 
 history.  The patient subsequently underwent 
 in 
, 
which identified muscle invasion (T4), then subsequently received radiotherapy.  
Biomarker assessments on the 
 tissue confirmed the presence of HPV 
genome (serotype 16) in tumor tissue.  There was no evidence of epidermal growth 
factor receptor amplification of mutation and no evidence of NRAS mutation. 
One patient was hospitalized on two separate occasions, for Grade 1 syncope and 
Grade 4 GI hemorrhage.  The Grade 1 syncope occurred on Cycle 1 Day 19 while at 
church.  There were no ECG abnormalities or cardiac enzyme elevation.  Tilt-table 
testing was abnormal, suggesting a neurocardiogenic cause.  The patient was 
subsequently discharged and continued on study therapy without any dose modifications.  
At Cycle 2 Day 22, the patient developed GI hemorrhage requiring hospitalization and 
blood transfusion.  The bleeding source was found to be a pre-existing left mesenteric 
lesion. The patient subsequently underwent 
 and continued on study 
therapy. 
One patient was hospitalized for Grade 3 convulsions in Cycle 3.  This patient had a 
known history of 
 that was controlled on 
.  Brain MRI performed 
after the onset of 
 did not identify any brain metastasis.  
 
was added to improve 
 control and the patient continued of study therapy 
attaining a partial response.  
One patient developed well differentiated cuSCC, keratoacanthoma-type, while on study 
in Cohort 1B (vemurafenib 960 mg BID + cobimetinib 60 mg QD 21/7).  The cuSCC was 
identified on the skin of the patient’s left lower leg during Cycle 3 of study therapy.  
The patient underwent complete resection of the cuSCC and continued on study therapy. 
One patient developed Grade 2 facial edema and Grade 2 maculo-papular rash at 
Cycle 1 Day 10.  The patient required hospitalization to receive IV corticosteroid therapy 
for the facial edema, which resolved rapidly; the patient was able to restart study therapy 
1 day later without dose modification.  This patient subsequently was placed on a 
tapering course of oral corticosteroids without recurrent symptoms.  This patient also 
developed Grade 3 LFT elevation at Cycle 2 Day 22 that was managed with interruption 
of vemurafenib. 
One other patient was hospitalized for Grade 3 maculo-papular rash.  This 
treatment-naïve patient was treated with vemurafenib 960 mg BID + cobimetinib 80 mg 
QD on a 14/14 schedule. The patient developed a Grade 3 generalized maculo-papular 


 
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rash with Grade 1 fever, chills, and CPK elevation, leading to interruption both study 
drugs on Cycle 1 Day 10. The patient was hospitalized.  No infectious etiology was 
identified.  The rash resolved at Cycle 1 Day 16 and the patient resumed vemurafenib at 
720 mg BID (cobimetinib was not given because of 14 day off period). 
One patient was hospitalized for Grade 3 nausea.  This treatment-naïve patient had 
Grade 3 diarrhea at Cycle 1 Day 8, which was managed with supportive care and study 
drug interruption without dose reduction.  At Cycle 2 Day 14 the patient was hospitalized 
for Grade 3 nausea.  Brain MRI did not show evidence of brain metastasis. 
Esophagogastroduodenoscopy identified esophageal ulcers and gastric antrum 
erythema. Biopsy results showed acute and chronic esophagitis and ulceration.  
The patient was subsequently discharged on a PPI.  The patient continued on study 
therapy and attained a partial response. 
One patient with pre-existing bone metastasis developed a femur fracture on Cycle 1 
Day 25. The patient underwent 
 and was off study 
therapy for 1 day.  
One patient with known bone metastases was admitted to hospital for palliation of 
Grade 3 back pain from Cycle 1 Day 11 to Cycle 1 Day 15.  Spinal cord compression 
was not identified during the evaluation.  The patient’s pain medication was optimized 
and the patient was subsequently discharged.  The patient continued to receive study 
therapy during the hospitalization. 
One patient was admitted for Grade 3 wound infection.  This patient developed new 
brain metastasis and was taken off Study NO25395 as a result of disease progression.  
Eight days after stopping study therapy, 
 
.  The wound was sutured in the emergency room, but 6 days later the patient 
complained of discharge from 
 wound, which was diagnosed as a Grade 3 wound 
infection.  The patient was admitted and administered IV antibiotics and discharged 
2 days later on oral antibiotics.  
One patient developed hyperthyroidism during Cycle 2 Day 8 of treatment with 
vemurafenib and cobimetinib.  This patient had previously received ipilimumab 
approximately 7 months prior to starting in Study NO25395.  During the visit on Cycle 2 
Day 8 of study therapy, the patient developed Grade 1 fatigue, Grade 1 anorexia, and 
Grade 2 diarrhea.  An endocrinologic evaluation showed that the patient had a 
thyroid-stimulating hormone level 0.011 mIU/L (institution’s normal 0.4−4.0 mIU/L) and 
free thyroxine level over 6 ng/mL (institution’s normal 0.89−1.76 ng/ml).  The patient was 
started on proplythiouracil and continued on study therapy.  However, the patient’s 
fatigue and anorexia remained at Grade 1 and diarrhea resolved to Grade 1 with 
loperamide and diphenoxylate. 


 
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In addition, 1 patient was hospitalized for Grade 3 dehydration and hypotension, 
1 patient was hospitalized for Grade 3 mental status change coincident with Grade 3 
pneumonia, and 1 patient was hospitalized for a Grade 3 malignant pleural effusion.   
The following serious adverse event occurred after the 6 July 2012 cutoff but is included 
due to the seriousness of the event: 
On 
, (Cycle 6 Day 5), 1 patient was admitted to an outside hospital 
for dyspnea and diagnosed with systolic heart failure.  Both study drugs were held.  
A transthoracic-echocardiogram (
) showed a mildly dilated left 
ventricle, normal left ventricle thickness, left ventricular ejection fraction (LVEF) 
approximately 25%, and moderate mitral regurgitation.  A Regadenoson stress test 
(
) was negative for ischemia or infarction.  The LVEF was estimated 
at 27%.  The patient was managed for heart failure with metoprolol, lisinopril, furosemide, 
and spironolactone.  Upon discharge, the patient was seen at the clinic on 
.  However, 
 QTc was elevated (457 ms [average]).  The patient 
resumed vemurafenib, and cobimetinib was permanently discontinued.   


 
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Table 8 
Serious Adverse Events in Study NO25395 (Clinical Cutoff 
6 July 2012) 
Patient ID 
Cohort and Study Drug Doses 
Serious Adverse Eventsa 
 
Cohort−1A - V 720 mg BID + G 60 mg QD 21/7 
Grade 5 cerebrovascular accident 
Grade 2 convulsions 
 
Cohort−3 - V 960 mg BID + G 60 mg QD 14/14 
Grade 4 tonsil SCC 
 
Cohort–1C - V 720 mg BID + G 60 mg QD 28/0 
Grade 1 syncope  
Grade 4 gastrointestinal hemorrhage 
 
Cohort−1 - V 720 mg BID + G 60 mg QD 14/14 
Grade 3 dehydration 
Grade 3 hypotension 
 
Cohort–1A - V 720 mg BID + G 60 mg QD 21/7 
Grade 3 pneumonia 
Grade 3 mental status change 
 
Cohort–2A - V 720 mg BID + G 100 mg QD 
14/14 
Grade 3 pleural effusion 
 
Cohort–1A - V 720 mg BID + G 60 mg QD 21/7 
Grade 3 convulsions 
 
Cohort–1B - V 960 mg BID + G 60 mg QD 21/7 
Grade 3 well differentiated cuSCC, 
keratoacanthoma type 
 
Cohort–1A - V 720 mg BID + G 60 mg QD 21/7 
Grade 2 facial edema 
Grade 2 maculo-papular rash 
 
Cohort−4 - V 960 mg BID + G 80 mg QD 14/14 
Grade 3 maculo-papular rash 
 
Cohort−1A  - V 720 mg BID + G 60 mg QD 21/7 
Grade 3 nausea 
 
Cohort–1C - V 720 mg BID + G 60 mg QD 28/0 
Grade 3 femur fracture 
 
Cohort–1A - V 720 mg BID + G 60 mg QD 21/7 
Grade 3 back pain 


 
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Table 8 
Serious Adverse Events in Study NO25395 (Clinical Cutoff 
6 July 2012) (cont.)  
Patient ID 
Cohort and Study Drug Doses 
Serious Adverse Events* 
 
Cohort−2 - V 720 mg BID + G 80 mg QD 14/14 
Grade 3 wound infection 
 
Cohort–1C - V 720 mg BID + G 60 mg QD 28/0 
Grade 2 hyperthyroidism 
BID = twice daily; cuSCC = cutaneous squamous cell carcinoma; G = cobimetinib; QD = once 
daily; SCC = squamous cell carcinoma; V = vemurafenib. 
a In addition, 1 patient (discussed above) experienced the serious adverse event of cardiac 
failure after the 6 July 2012 clinical cutoff date.  This patient is not included in this table.  
 
Deaths in Study NO25395  
As of the clinical cutoff date of 6 July 2012, 15 patients (21.4%) who had received 
combination therapy in Study NO25395 had died; 10 patients died within 30 days of the 
last administration of study drug.  All but one death was attributable to disease 
progression (previously discussed in the serious adverse events portion of 
Section 1.4.3.1). 
1.4.4 
Primary and Final Analysis of Study GO28141 
Primary analysis of study GO28141 was conducted with a data cutoff of 9 May 2014 
(Larkin et al. 2014).  At the time, median PFS for the 247 patients enrolled in the 
vemurafenib + cobimetinib arm was 9.9 months versus 6.2 months for the 248 patients 
enrolled in the vemurafenib + placebo arm (hazard ratio:  0.51; 95% CI:  0.39, 0.68).  
Similarly objective response rate (ORR) was 68% versus 45% (p < 0.0001) for 
vemurafenib + cobimetinib versus vemurafenib + placebo.  Final analysis of OS occurred 
with a data cutoff of 28 August 2015.  At the time, median OS was 22.3 months for 
patients treated with vemurafenib + cobimetinib versus 17.4 months for patients treated 
with vemurafenib + placebo (hazard ratio:  0.70; 95% CI:  0.55, 0.90).  Overall, safety 
was consistent with a positive benefit-risk profile for the combination.   
1.5 
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT 
The clinical activity of vemurafenib in BRAFV600 mutation-positive advanced melanoma 
patients has been substantiated by the pivotal Phase III study of vemurafenib versus 
DTIC (NO25026 [BRIM-3]).  Despite prolongation of PFS and OS, disease progression 
occurs after a median of approximately 6−7 months for vemurafenib-treated patients.  
Several mechanisms of acquired resistance to vemurafenib therapy have been 
described that result in reactivation of the RAS/RAF pathway (Johannessen et al. 2010; 
Nazarian et al. 2010; Villanueva et al. 2010; Poulikakos et al. 2011; Wagle et al. 2011; 
Shi et al. 2012; Su et al. 2012).  Addition of a MEKi to vemurafenib abrogates 


 
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vemurafenib resistance (Nazarian et al. 2010; Villanueva et al. 2010; Atefi et al. 2011; 
Poulikakos et al. 2011; Shi et al. 2012; Su et al. 2012).  These findings, together with 
nonclinical evidence that combined inhibition of BRAF and MEK prevents the emergence 
of resistance (Paraiso et al. 2010), support the clinical evaluation of combination therapy 
strategies incorporating MEKi with BRAFi to combat emerging resistance. 
Data from the ongoing Phase Ib Study NO25395 (BRIM-7) has identified the proposed 
investigational dose (vemurafenib 960 mg BID on Days 1−28 and cobimetinib 60 mg QD 
Days 1−21, in 28-day treatment cycles) as safe and well tolerated.  Further 
characterization of the safety profile of the combination of vemurafenib and cobimetinib 
at their respective single-agent MTD is ongoing in the expansion stage of the Phase Ib 
study.  
The risks associated with this combination therapy are further reduced through a safety 
plan that incorporates into the eligibility criteria to exclude patients at unacceptable risk, 
enhanced monitoring of all patients, specific risk mitigation plans, and dose modification 
guidelines.  An independent DSMB reviewed unblinded safety data from the study every 
3 months up to the final efficacy analysis.  Following study unblinding and rigorous 
review of the safety data it was decided to discontinue quarterly DSMB review of 
unblinded safety data. 
Taking into account the efficacy and safety data of single-agent vemurafenib and 
cobimetinib observed to date, and the favorable adverse effect profile of the combination 
observed in the Phase Ib study, the potential benefits of combination therapy and the 
extent of safety monitoring proposed, the potential benefit for patients with unresectable 
locally advanced or metastatic melanoma who participate in Study GO28141 outweigh 
the potential risks. 
2. 
OBJECTIVES  
2.1 
EFFICACY OBJECTIVES 
The primary efficacy objective of Study GO28141 is as follows: 
• 
To evaluate the efficacy of vemurafenib in combination with cobimetinib, compared 
with vemurafenib and placebo, in previously untreated BRAFV600 mutation−positive 
patients with unresectable locally advanced or metastatic melanoma, as measured 
by prolongation of PFS, as assessed by the study site investigator 
 
The secondary efficacy objective of Study GO28141 is as follows: 
• 
To evaluate the efficacy of vemurafenib in combination with cobimetinib, compared 
with vemurafenib and placebo, in previously untreated BRAFV600 mutation-positive 
patients with unresectable locally advanced or metastatic melanoma, as measured 
by OS, ORR, DOR, and PFS as assessed by independent review 
 


 
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2.2 
SAFETY OBJECTIVE 
The safety objective of Study GO28141 is as follows: 
• 
To characterize the toxicity profile in patients receiving vemurafenib and cobimetinib 
versus vemurafenib and placebo 
 
2.3 
PHARMACOKINETIC OBJECTIVE 
The PK objective of Study GO28141 is as follows: 
• 
To characterize the pharmacokinetics of cobimetinib and vemurafenib and to 
compare the pharmacokinetics of vemurafenib when administered with cobimetinib 
to the pharmacokinetics of vemurafenib when administered with placebo 
• 
To perform exploratory exposure-response analysis, including concentration-QTc 
analysis 
 
2.4 
PATIENT-REPORTED OUTCOME OBJECTIVE 
The patient-reported outcome (PRO) objective of Study GO28141 is as follows: 
• 
To evaluate health-related quality of life (HRQL) in patients receiving vemurafenib 
and cobimetinib versus vemurafenib and placebo as measured by the European 
Organization for Research and Cancer (EORTC) Quality of Life Questionnaire 
(QLQ-C30) and the EuroQol 5 dimension (EQ-5D) questionnaire 
 
2.5 
EXPLORATORY OBJECTIVES  
The Sponsor 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 (personalized healthcare).  Specimens 
may be used for any of the following: 
• 
To explore the intrinsic and acquired mechanisms of resistance to MEK and BRAF 
inhibition in tumor samples obtained at baseline, during treatment, and at disease 
progression 
• 
To study the association of biomarkers with efficacy and/or adverse events 
associated with medicinal products 
• 
To increase knowledge and understanding of disease biology 
 
3. 
GO28141 STUDY DESIGN 
3.1 
DESCRIPTION OF GO28141 STUDY DESIGN 
GO28141 is a multicenter, randomized, double-blind, placebo-controlled Phase III 
clinical study to evaluate the safety and efficacy of vemurafenib in combination with 
cobimetinib with vemurafenib alone, in previously untreated BRAFV600 mutation-positive 
patients with unresectable locally advanced or metastatic melanoma.  


 
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Approximately 500 previously untreated BRAFV600 mutation-positive patients with 
unresectable locally advanced or metastatic melanoma will be randomized in a 1:1 ratio 
to receive treatment with one of the following regimens: 
• 
Arm A (control arm):  vemurafenib 960 mg by mouth (PO) BID on Days 1−28 and 
placebo PO QD on Days 1−21 of each 28-day treatment cycle 
• 
Arm B (investigational arm):  vemurafenib 960 mg PO BID on Days 1−28 and 
cobimetinib 60 mg PO QD on Days 1−21 of each 28-day treatment cycle 
 
The stratified, permuted-block randomization scheme will be used for treatment 
allocation based on the following stratification factors (Figure 4): 
• 
Geographic region (North America, Europe, Australia/New Zealand/others) 
• 
Metastatic classification (unresectable Stage IIIc, M1a, and M1b; or M1c) 
 
Figure 4 Study GO28141 Randomization Scheme 
 
BID = twice daily; QD = once daily. 
 
The schedule of study assessments and procedures are detailed in Appendix 1.  
After signing informed consent, patients will undergo screening procedures that include 
testing for the BRAFV600 mutation; laboratory tests (hematology, chemistries, LFTs); 
12-lead ECG; left-ventricular function evaluation (echocardiogram or MUGA), 
contrast-enhanced brain CT or MRI; contrast-enhanced CT or MRI of the chest, 
abdomen, and pelvis; and ophthalmologic and dermatologic assessments.  For a 
detailed list of screening assessments, please refer to Appendix 1.  


 
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All eligible patients will be randomized to treatment in either Arm A (vemurafenib and 
placebo) or Arm B (vemurafenib and cobimetinib).  Vemurafenib will be taken starting on 
Day 1 to Day 28 of each 28-day treatment cycle.  The first dose of vemurafenib should 
be taken in the morning, and the second dose should be taken in the evening.  The 
cobimetinib or placebo tablet will be taken once daily starting on Day 1 to Day 21 of each 
28-day treatment cycle.  The cobimetinib or placebo tablet should be taken at 
approximately the same time each day, preferably in the morning with the vemurafenib 
dose.  Vemurafenib and cobimetinib/placebo can be taken with or without a meal, and 
should be taken with a glass of water.  
Figure 5 shows the dosing scheme for vemurafenib and cobimetinib/placebo in the 
proposed study. 
Figure 5 Study GO28141 Dosing Scheme 
 
BID = twice daily; D = day; QD = once daily. 
 
All patients will be closely monitored for safety and tolerability during all cycles of therapy, 
at the end-of-study treatment visit, and during the follow-up period.  Patients will be 
assessed for adverse events every 2 weeks during the first 2 cycles, then prior to each 
subsequent cycle, and as necessary throughout the study.  
Tumor response will be evaluated according to RECIST v1.1.  Any evaluable and 
measurable disease must be documented at screening and re-assessed at each 
subsequent tumor evaluation.  Response will be assessed by the investigator at 8-week 
intervals.  At the investigator’s discretion, CT/MRI scans may be repeated at any time if 
PD is suspected.  
The NCI Common Terminology Criteria for Adverse Events (CTCAE) v4.0 will be used to 
characterize the toxicity profile of the study treatments on all patients.  ECG monitoring 
for patients who receive vemurafenib will be conducted in accordance with the 
vemurafenib IB.  Ongoing ECG monitoring is no longer required for patients who 
continue to receive only cobimetinib/placebo unless clinically indicated.   Dermatologic 
assessment will be performed at the beginning of Cycle 2 (± 1 week) and per local 


 
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standard of care thereafter.  Ophthalmologic examinations and left ventricular function 
evaluation (echocardiogram or MUGA) are evaluated throughout the study. 
Treatment will continue until disease progression, death, unacceptable toxicity, or 
withdrawal of consent, whichever occurs earliest.  Patients on the vemurafenib and 
placebo treatment arm will be eligible to cross over to the vemurafenib and cobimetinib 
treatment arm prior to disease progression so long as the patient has not discontinued 
vemurafenib treatment should the investigator feel that the addition of cobimetinib may 
benefit the patient and the patient provides informed consent and continues to be 
followed for survival.  Patients who have previously discontinued vemurafenib and who 
are receiving only placebo may not cross over and should discontinue all study 
treatment. 
3.2 
END OF STUDY 
The study will end when all patients enrolled have been followed until death, withdrawal 
of consent, loss to follow-up, or the Sponsor decides to end the trial, whichever occurs 
first. 
Patients may continue on study treatment until the development of progressive disease, 
unacceptable toxicity, and/or consent withdrawal.  Patients who discontinue study 
treatment for any reason will be followed for SCC according to the risk management plan 
(see Section 5.1.3), followed for disease progression and followed for survival until 
death, withdrawal of consent, or they are lost to follow-up.  Patients who start 
subsequent anti-cancer treatment after study treatment discontinuation will still need to 
be followed for survival and SCC.   
3.3 
RATIONALE FOR STUDY DESIGN 
3.3.1 
Rationale for Test Product Dosage/Regimen 
The vemurafenib dose selected was based on clinical efficacy and safety initially 
observed in Study PLX06-02 (Phase I) at the MTD of 960 mg BID.  This was further 
characterized in Studies NP22657 (Phase II) and NO25026 (Phase III) of vemurafenib in 
locally advanced unresectable or metastatic melanoma.  This dose is the recommended 
starting dose of vemurafenib. 
Study MEK4592g (Phase I) identified the MTD of single-agent cobimetinib to be 60 mg 
QD on a 21-day on, 7-day off (21/7) schedule and at 100 mg QD on a 14-day on, 14-day 
off (14/14) schedule.  The 21/7 dosing schedule for cobimetinib offers a longer duration 
of drug exposure and consequently, a more prolonged suppression of MEK compared to 
the 14/14 schedule.  The lower dose of cobimetinib in the 21/7 schedule is also 
associated with a lower rate of adverse events (including Grade ≥ 3 adverse events).   
In Study NO25395 (Phase Ib), the combination of vemurafenib and cobimetinib 21/7 was 
delivered at their respective single-agent MTDs.  This dose has cleared the DLT criteria 
and shown to be tolerable.  


 
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Continuous dosing of cobimetinib was not explored in the monotherapy Phase I study 
(MEK4592g).  In Study NO25395, two dose cohorts have been designated to explore 
continuous dosing cobimetinib with vemurafenib.  This dose level may potentially result 
in poor tolerability at doses that exceed the single−agent MTD of cobimetinib, and result 
in significant dose reductions that may not adequately suppress the activity of MEK in 
the tumor cells.  
3.3.2 
Rationale for Patient Population 
The proposed study will enroll treatment-naïve patients with unresectable locally 
advanced Stage IIIc or metastatic melanoma as defined by the American Joint 
Committee on Cancer (AJCC) classification v.7.  This study will be conducted only in 
patients whose melanoma harbors the BRAF V600 mutation.  This represents the 
population for which vemurafenib is indicated. The cobas® 4800 BRAF V600 mutation 
test is the approved companion diagnostic test for vemurafenib and will be used to 
determine the presence of the BRAF V600 mutation.   
Several exclusion criteria were put in place to ensure patient safety going into the study.  
Patients who are pregnant are not allowed on the study as the effect of vemurafenib and 
cobimetinib on the developing fetus is not known.  Similarly, patients and their partners 
are required to use of effective contraception. 
Given that vemurafenib results in mild QTc prolongation, patients will be required to 
have a baseline screening ECG and those whose QTc interval is > 450 ms or who have 
congenital long QT syndrome will be excluded.  
To mitigate the risk of ophthalmologic adverse events associated with MEKi as a class 
effect, patients are required to undergo ophthalmologic examination to evaluate risk 
factor for or findings indicative of neurosensory retinal detachment, CSCR or retinal vein 
occlusion (RVO) prior to starting study treatment.  Patients with such conditions will be 
excluded. 
3.3.3 
Rationale for Control Group 
Patients on the control arm will receive vemurafenib and placebo.  Vemurafenib is the 
current standard of care for patients with advanced BRAFV600 mutation-positive 
melanoma, and therefore, would be the standard in which future therapies should be 
compared against in this patient population. 
This will be a placebo-controlled, double-blind study.  Use of a placebo control will help 
to minimize bias in reporting of key assessments of safety, efficacy, and quality of life.  
After key assessments of these parameters have been assessed, placebo plus 
vemurafenib patients will be allowed to cross over to active therapy (vemurafenib plus 
cobimetinib) so long as the patient has not discontinued vemurafenib and provided that 
the treating physician believes that there will be additional benefit given that the 


 
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combination has demonstrated a positive benefit-risk profile over single-agent 
vemurafenib. 
3.3.4 
Rationale for Pharmacokinetic Assessments 
A sparse sampling strategy will be applied in this study.  Samples for PK 
characterization of cobimetinib and vemurafenib will be collected as outlined in 
Appendix 2.  Samples will be collected on Day 1 and Day 15 of Cycle 1 and Day 15 of 
Cycle 2.  The sampling schedule is designed to enable characterization of vemurafenib 
and cobimetinib using population PK methodology (pop PK) for characterization 
following first dose (Day 1) and steady-state (Day 15).  In addition, the vemurafenib PK 
data from Arm A and Arm B will allow evaluation of whether cobimetinib alters 
vemurafenib pharmacokinetics.  The cobimetinib PK data from Arm B will allow 
comparison to single-agent cobimetinib data to evaluate whether exposures are altered 
when administered in combination with vemurafenib. 
3.3.5 
Rationale for Collection of DNA for Exploratory Analyses of 
Pharmacogenetic Polymorphisms 
Genetic variants of drug-metabolizing enzymes and transporters can alter the 
pharmacokinetics of drugs, affecting their safety and efficacy.  For example, patients 
who carry defective alleles of the gene encoding uridine diphosphate 
glucuronosyltransferase 1A1 (UGT1A1), which facilitates the metabolism and excretion 
of SN-38 (the active metabolite of irinotecan), are at higher risk for adverse events 
associated with the use of standard doses of irinotecan (O’Dwyer and Catalano 2006).  
Results from in vitro metabolism studies suggest that cobimetinib is metabolized by 
cytochrome P450 enzymes CYP3A.  A blood sample for DNA isolation will be collected 
from all patients in this study for potential pharmacogenetic analysis of genes or 
biomarkers that may affect the pharmacokinetics of vemurafenib and cobimetinib.  The 
decision to analyze the samples will be based on a review of the PK data.  For example, 
if a patient in a given cohort has substantially higher cobimetinib plasma levels than 
other patients in that cohort, he or she may carry a defective allele of a gene important in 
the metabolism or transport of cobimetinib.  The genotyping efforts would be guided by 
results from in vitro metabolism studies and by results from ongoing clinical studies with 
cobimetinib and vemurafenib. 
The pharmacogenetic analysis, if needed, will be performed on identifiable DNA samples, 
because it is necessary to link a patient’s PK data with genotype.  This analysis may be 
restricted to the evaluation of genes that may be involved in the pharmacokinetics of 
cobimetinib and vemurafenib (e.g., drug metabolism, disposition, or elimination genes).  
Samples may be stored and analyzed up to 5 years after completion of the study, at 
which time all DNA samples collected for this analysis will be destroyed. 


 
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3.3.6 
Rationale for Biomarker Assessments 
The Sponsor 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. 
Investigation of Response and Resistance Biomarkers 
This study may explore biomarkers associated with treatment response and resistance, 
including intrinsic and acquired resistance to BRAF/MEK inhibition in tumor tissues at 
baseline and at the time of disease progression. 
Given the genetic heterogeneity of melanoma tumors, the magnitude of response to 
combined BRAF/MEK inhibition may be different in certain tumors.  To identify 
mechanisms of resistance, molecular analyses may include assessment of genetic and 
activation status of the targeted MAPK pathway, potential escape mechanisms such as 
receptor tyrosine kinases and PI3K/PTEN pathways, and components of the tumor 
stroma (e.g., tumor infiltrating lymphocytes).  These analyses may be conducted at the 
DNA, RNA, protein, and cell levels.  In addition, expression of melanoma prognostic 
markers and alternative drug targets may be explored.  These analyses are essential to 
identify patients who will benefit the most from the combination therapies and potential 
cause for resistance, which could help in considering future treatments.   
Investigation of biomarkers in plasma samples  
BRAFV600  mutation may be evaluated both in tumor biopsies and in plasma collected 
during this study.  It has been shown that tumor-specific mutations can be identified in 
plasma of patients.  Analysis and correlation of BRAF mutations in plasma and biopsy 
will help to further evaluate the option of using plasma for the detection of tumor specific 
mutations. 
3.3.7 
Rationale for Health-related Quality of Life Assessment and 
Health Economic Assessment 
The HRQL EORTC QLQ-C30 is included to characterize the impact of treatment on 
patients while receiving and following vemurafenib and cobimetinib exposure.  These 
data should allow for quantification of the health economic impact of these treatments, 
given the externally validated data generated from the EQ-5D self-reported 
questionnaire.  The collection of this type of data will provide greater insights for both the 
medical and patient communities to understand patient-reported value and quality of life 
when exposed to the combination of vemurafenib and cobimetinib treatments.  


 
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3.4 
OUTCOME MEASURES 
3.4.1 
Efficacy Outcome Measures 
3.4.1.1 
Primary Efficacy Outcome Measure 
The primary outcome measure for this study is as follows: 
• 
PFS, defined as the time from randomization to the first occurrence of disease 
progression, as determined by the investigator using RECIST v1.1 (Appendix 3), or 
death from any cause, whichever comes first.   
 
3.4.1.2 
Secondary Efficacy Outcome Measures 
The secondary outcome measures are as follows: 
• 
Overall survival, defined as the time from randomization to death from any cause   
• 
Objective response rate for patients with measurable disease at baseline, defined 
as complete or partial response as assessed by investigator according to RECIST 
v1.1 
• 
Duration of response for patients with measurable disease at baseline, defined as 
the time from first occurrence of a documented objective response until the time of 
disease progression, as determined by investigator review of tumor assessments 
using RECIST v1.1, or death from any cause during the study (i.e., within 30 days 
after the last dose of study treatment) 
• 
PFS as assessed by independent review using RECIST v1.1 
 
3.4.2 
Safety Outcome Measures 
Safety outcome measures for this study are as follows: 
• 
Incidence, nature, and severity of adverse events and serious adverse events, 
graded according to NCI CTCAE v4.0 
• 
Adverse events of special interest:  any RVO; any retinal detachment or CSCR; 
Grade ≥ 3 photosensitivity; Grade ≥ 2 LVEF reduction; Grade ≥ 3 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; Grade ≥ 3 QT 
interval prolongation; and any cutaneous and non-cutaneous primary malignancy, 
including SCC, KA, BCC, and new primary melanoma.  
• 
Changes in vital signs, ECGs, and clinical laboratory results during the course of 
study 
 
3.4.3 
Pharmacokinetic Outcome Measures 
The following PK parameters will be analyzed using a pop PK approach and will be 
reported as applicable.  Please see Section 6.6 for further details. 
• 
Exposure following first dose and steady-state (AUC0-24)  
• 
Minimum observed plasma concentration (Cmin; trough concentration) 
• 
Apparent clearance following oral dosing (CL/F) 
 


 
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Exploratory exposure-response analyses for efficacy and safety endpoints, including 
QTc, will be performed 
3.4.4 
Patient-Reported Outcome Measures 
The PRO measures for this study are as follows: 
• 
EORTC QLQ-C30 
• 
EuroQol's EQ-5D Questionnaire  
 
The PRO questionnaires (EORTC QLQ-C30 and EQ-5D) were supplied in the local 
language(s) of each participating country.  
3.4.5 
Exploratory Outcome Measures 
The exploratory biomarker analyses in tumor tissue may investigate potential intrinsic 
and acquired resistance mechanisms to MEK and BRAF inhibition.  Pre-treatment tumor 
tissue (i.e., archived material or biopsies collected during screening, prior to initiation of 
study treatment) and tumor biopsies during treatment (Cycle 2 Day 15) and at the end of 
study treatment (at the time of PD) will be required. 
In order to investigate if chromosomal and molecular genetic aberrations are linked to 
therapeutic outcome and development of severe adverse events in patients treated with 
vemurafenib and cobimetinib, DNA may be isolated from a single whole blood collected 
at baseline as well as tumor tissues. 
Additional efficacy exploratory analyses will include PFS rates and OS rates at fixed 
timepoints (e.g., 3, 6, 9, 12 months, etc.). 
3.5 
MINIMIZATION OF BIAS 
Patients will be randomly assigned to receive vemurafenib and placebo or vemurafenib 
and cobimetinib through use of an interactive response system (IxRS).  Placebo tablets 
for cobimetinib and packaging configurations will have physical characteristics that will 
not permit their identification as distinct from those of cobimetinib.  
Following the final efficacy analysis and extensive evaluation of safety data, quarterly 
DSMB review of unblinded safety data will no longer occur.  Sponsor personnel will not 
have access to by-arm efficacy and safety summaries or listings prior to the formal 
reporting of the primary efficacy results. 
Only when knowledge of the investigational product is essential for the safety of the 
patient, the investigator may 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.  If the investigator wishes to know the identity of 
the study drug for any other reason, he or she should contact the Medical Monitor 
directly (see Section 4.2).  


 
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4. 
METHODS AND MATERIALS 
4.1 
PATIENTS 
To be eligible for Study GO28141, patients must be previously untreated with 
unresectable locally advanced or metastatic melanoma.  Patients must have the 
BRAFV600 mutation confirmed on their melanoma tumor tissue using the cobas® 4800 
BRAF V600 mutation test (see Section 4.5.1.1 and Appendix 10).  All patients must meet 
all of the inclusion and none of the exclusion criteria detailed in Sections 4.1.1 and 4.1.2, 
respectively. 
4.1.1 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
Disease-Specific Inclusion Criteria: 
1. 
Patients with histologically confirmed melanoma, either unresectable Stage IIIc or 
Stage IV metastatic melanoma, as defined by AJCC 7th edition (Appendix 8).  
Unresectability of Stage IIIc disease must have confirmation from a surgical 
oncologist. 
2. 
Patients must be naïve to treatment for locally advanced unresectable or metastatic 
disease (i.e., NO prior systemic anti-cancer therapy for advanced disease; Stage IIIc 
and IV).  Prior adjuvant therapy (including immunotherapy, e.g., ipilimumab) is 
allowed. 
3. 
Documentation of BRAFV600 mutation-positive status in melanoma tumor tissue 
(archival or newly obtained tumor samples) using the cobas® 4800 BRAF V600 
mutation test. 
4. 
Measurable disease per RECIST v1.1 (Appendix 3). 
5. 
ECOG Performance Status of 0 or 1 (Appendix 4).  
6. 
Consent to provide archival tissue (either a paraffin-embedded tissue block or up to 
20 unstained slides) for biomarker analyses. 
7. 
Consent to undergo tumor biopsies of accessible lesions on Cycle 2 Day 15 and at 
progression for biomarker analyses to explore intrinsic and acquired resistance.  
 
General Inclusion Criteria: 
8. 
Male or female patient aged ≥ 18 years.  
9. 
Able to participate and willing to give written informed consent prior to performance 
of any study-related procedures and to comply with the study protocol. 
10. Life expectancy ≥ 12 weeks. 
11. Adequate hematologic and end organ function, defined by the following laboratory 
results obtained within 14 days prior to first dose of study drug treatment:      
o ANC ≥ 1.5 × 109/L                                                       
o Platelet count ≥ 100 × 109/L                                                                    


 
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o Hemoglobin ≥ 9 g/dL                                                                                     
o Albumin ≥ 2.5 g/dL                                                                                      
o Bilirubin ≤ 1.5 × the upper limit of normal (ULN)                                           
o AST, ALT, and ALP ≤ 3 × ULN, with the following exceptions:                                             
 Patients with documented liver metastases:  AST and/or 
ALT ≤ 5 × ULN  
 Patients with documented liver or bone metastases:  ALP ≤ 5 × ULN 
o Serum creatinine ≤ 1.5 × ULN or CrCl ≥ 40 mL/min on the basis of 
measured CrCl from a 24-hour urine collection or Cockroft-Gault 
glomerular filtration rate estimation: 
(140-age) × (weight in kg) × (0.85 if female)  
72 × (serum creatinine in mg/dL)  
12. Female patients of childbearing potential and male patients with partners of 
childbearing potential must agree to always use 2 effective forms of contraception 
during the course of this study and for at least 6 months after completion of study 
therapy.  
• Females of childbearing potential are defined as sexually mature women 
without prior oophorectomy or hysterectomy who have had menses within the 
last 12 months. 
• Females are not considered to be of childbearing potential if amenorrheic 
for > 12 months and follicle-stimulating hormone (FSH) level ≥ 40 IU/L. 
• For females who have been amenorrheic for ≥ 2 years, the requirement for 
FSH measurement at screening will be waived. 
• Effective forms of contraception includes surgical sterilization, a reliable barrier 
method with spermicide, birth control pills, or contraceptive hormone implants. 
Please note that potential interactions between vemurafenib and hormonal 
contraceptives may decrease the effectiveness of hormonal contraceptives. 
• Male patients who are surgically sterilized are required to use barrier methods 
of contraception. 
13. Negative serum pregnancy test within 14 days prior to commencement of dosing 
in women of childbearing potential. 
14. Absence of any psychological, familial, sociological, or geographical condition that 
potentially hampers compliance with the study protocol and follow-up after treatment 
discontinuation schedule; those conditions should be discussed with the patient 
before trial entry. 
 
4.1.2 
Exclusion Criteria 
Cancer-Related Exclusion Criteria: 
1. 
History of prior RAF or MEK pathway inhibitor treatment. 
2. 
Palliative radiotherapy within 14 days prior to the first dose of study treatment. 


 
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3. 
Major surgery or traumatic injury within 14 days prior to first dose of study treatment. 
4. 
Patients with active malignancy (other than BRAF−mutated melanoma) or a 
previous malignancy within the past 3 years are excluded;  except for patients with 
resected melanoma, resected BCC, resected cutaneous SCC, resected melanoma 
in-situ, resected carcinoma in-situ of the cervix, and resected carcinoma in-situ of 
the breast. 
5. 
History of isolated elevation in prostate-specific antigen in the absence of 
radiographic evidence of metastatic prostate cancer is allowed. 
 
Exclusion Criteria Based on Organ Function 
Ocular: 
6. 
History of or evidence of retinal pathology on ophthalmologic examination that is 
considered a risk factor for neurosensory retinal detachment / CSCR, RVO, or 
neovascular macular degeneration.  
7. 
The risk factors for RVO are listed below.  Patients will be excluded if they currently 
have the following conditions:  
a) Uncontrolled glaucoma with intra-ocular pressures > 21 mmHg 
b) Serum cholesterol ≥ Grade 2 
c) Hypertriglyceridemia ≥ Grade 2 
d) Hyperglycemia (fasting) ≥ Grade 2 
 
Cardiac: 
8. 
Clinically significant cardiac dysfunction, including the following: 
a) Current unstable angina 
b) Current symptomatic congestive heart failure of New York Heart Association 
class 2 or higher (Appendix 7) 
c) History of congenital long QT syndrome or mean (average of triplicate 
measurements) QTcF > 450 ms at baseline or uncorrectable abnormalities in 
serum electrolytes (sodium, potassium, calcium, magnesium, phosphorus).  
Please refer to Section 4.5.1.11. 
d) Current uncontrolled hypertension ≥ Grade 2 (patients with a history 
hypertension controlled with anti-hypertensives to ≤ Grade 1 are eligible).  
e) LVEF below institutional lower limit of normal or below 50%, whichever is 
lower 
 
Central Nervous System: 
9. 
Patients with active CNS lesions (including carcinomatous meningitis) are excluded. 
However, patients are eligible if: 
a) All known CNS lesions have been treated with stereotactic therapy or surgery, 
AND 


 
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b) There has been no evidence of clinical and radiographic disease progression 
in the CNS for ≥ 3 weeks after radiotherapy or surgery. 
c) Whole brain radiotherapy is not allowed, with the exception of patients who 
have had definitive resection or stereotactic therapy of all radiologically 
detectable parenchymal brain lesions. 
  
General Exclusion Criteria: 
10. Current severe, uncontrolled systemic disease.  
11. History of malabsorption or other condition that would interfere with absorption of 
study drugs. 
12. Pregnant, lactating, or breast feeding. 
13. Unwillingness or inability to comply with study and follow-up procedures 
14. The following foods/supplements are prohibited at least 7 days prior to initiation of 
and during study treatment:  
a) St. John’s wort or hyperforin (potent cytochrome P450 CYP3A4 enzyme 
inducer) 
b) Grapefruit juice (potent cytochrome P450 CYP3A4 enzyme inhibitor) 
 
4.2 
METHOD OF TREATMENT ASSIGNMENT, BLINDING, AND 
UNBLINDING 
After written informed consent has been obtained and eligibility has been established, 
each patient will be assigned an identification number and be randomized to 1 of the 
2 treatment arms through use of an IxRS.   
Randomization will be stratified by metastatic stage (unresectable Stage IIIc, M1a, and 
M1b; M1c) and region (North America, Europe, Australia/New Zealand/others).  
A stratified, permuted, block randomization scheme will be used to obtain approximately 
a 1:1 ratio between the 2 treatment groups.  There is no pre-specified gender or ethnicity 
distribution in this study.  It is expected that enrollment into this study will be 
representative of the gender and ethnicity distribution found in patients with unresectable 
or metastatic melanoma in the participating countries. 
The investigator, patient, and Sponsor will be blinded to treatment assignment until 
completion of the final efficacy analysis of OS.   
Prior to unblinding at the final overall survival efficacy analysis: 
Treatment codes should not be broken except in emergency situations.  In such cases, 
the IxRS system will be used to allow disclosure of an individual patient’s treatment 
assignment to the treating investigator.  If the investigator wishes to know the identity of 
the study drug for any other reason, he or she should contact the Medical Monitor 
directly.  The investigator should document and provide an explanation for any 


 
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premature unblinding (e.g., accidental unblinding, unblinding due to a serious adverse 
event).  
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). 
The investigator may request unblinding of a patient’s treatment assignment only when 
knowledge of the investigational product is essential for the safety of the patient.  In such 
cases, the IxRS system will be used to allow disclosure of an individual patient’s 
treatment assignment to the treating investigator.  Any site requests for unblinding, for 
any reason apart from emergency situations, require consultation with the Roche 
Medical Monitor. 
Upon completion of the final overall survival efficacy analysis: 
Upon completion of the final OS analysis and approval by the investigator’s local IRB/EC, 
investigators will receive a list of active patients at their site with their treatment 
assignments.  Unblinded patients in the placebo arm who remain on vemurafenib and 
who choose not to cross over will no longer receive placebo and will continue to receive 
vemurafenib only.   
4.3 
STUDY TREATMENT 
4.3.1 
Formulation, Packaging, and Handling 
Vemurafenib, cobimetinib, and placebo 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 drugs will be in 
accordance with the Sponsor’s standards and local regulations.  Local packaging and 
labeling requirements may differ in some countries. 
Upon delivery of the investigational products to the site, site personnel should check for 
damage and verify proper identity, quantity, integrity of seals, and temperature 
conditions.  Site personnel should report any deviations or product complaints to the 
study monitor upon discovery. 
Vemurafenib, cobimetinib, and placebo will be stored at the clinical site under the 
required storage conditions as indicated on the study drug labels.  Patients will be asked 
to store study drugs at the required storage conditions noted on the label, out of the 
reach of children or other co-inhabitants. 
4.3.1.1 
Cobimetinib/Placebo 
The 20 mg cobimetinib drug product is a film-coated, immediate release tablet.  The 
white tablet is round with the engraving “ROCHE” on one side.  Cobimetinib placebo 
tablets have been manufactured to match the size, shape, and color of the cobimetinib 


 
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active tablets and consist of the same inactive ingredients used in the corresponding 
active drug product.  Cobimetinib and placebo will be packaged in blister packs.   
The inactive ingredients in cobimetinib are as follows:  lactose monohydrate, 
microcrystalline cellulose, croscarmellose sodium, and magnesium stearate for the tablet 
core.  The tablet coating consists of polyvinyl alcohol-part hydrolyzed, titanium dioxide, 
polyethylene glycol 3350, and talc. 
Cobimetinib and placebo should not be stored above 25°C (77°F).  
If study drug is stored outside of the permitted temperature ranges, quarantine the 
affected supply and contact the monitor. 
The Sponsor may switch to the commercial supply of cobimetinib in the future.  At such 
time, the commercial drug product will be 20 mg, round, white, film-coated tablets with 
“COB” debossed on one side.  Cobimetinib tablets will be packaged in blister packs for 
clinical use.   
4.3.1.2 
Vemurafenib 
The 240 mg vemurafenib drug product is a tablet light pink in color, oval shaped, with the 
engraving “ROCHE.”  Vemurafenib will be packaged in bottles. 
The inactive ingredients in vemurafenib tablets are as follows:  hypromellose acetate 
succinate, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate, 
hydroxypropyl cellulose (tablet core), polyvinyl alcohol, titanium dioxide, polyethylene 
glycol 3350, talc, and iron oxide red (tablet coating). 
Vemurafenib will need to be stored at room temperature 20°C−25°C (68°F−77°F); 
excursions will be permitted between 15°C and 30°C (59°F and 86°F).  
If study drug is stored outside of the permitted temperature ranges, quarantine the 
affected supply and contact the monitor. 
4.3.2 
Dosage, Administration, and Compliance 
Patients must record the time and date they take each dose in a medication diary.  
Missed doses should also be recorded.  Patients will be instructed to bring all unused 
study drugs and their study drug diaries to each study visit for assessments of 
compliance.   
If a dose of study drug is missed (i.e., not taken within 4 hours after the scheduled 
dosing time), the patient should resume dosing with the next scheduled dose.  Missed or 
vomited doses will not be made up. 
At least 7 days off cobimetinib is required prior to starting a new treatment cycle.   


 
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Each study cycle is defined by the 28-day dosing cycle of cobimetinib (21 days on, 
7 days off).  In the event that cobimetinib dosing is interrupted beyond the 28-day dosing 
cycle, the next cycle will start when cobimetinib dosing resumes. If cobimetinib is 
discontinued permanently, a cycle is then defined by a 28-day dosing cycle of 
vemurafenib. 
Guidelines for interruption, dose modification, and permanent discontinuation of study 
drugs are provided in Section 5.1. 
4.3.2.1 
Cobimetinib/Placebo 
Cobimetinib or placebo should be taken once daily at approximately the same time each 
day with the morning vemurafenib dose, and no later than 4 hours after the scheduled 
time. 
Cobimetinib or placebo can be taken with or without a meal.  Cobimetinib or placebo 
tablets should never be chewed, cut, or crushed. 
Upon completion of the final OS analysis, patients in the placebo arm who are unblinded 
and choose not to cross over to cobimetinib will no longer need to receive placebo and 
will continue to receive vemurafenib only, unless they had previously discontinued 
vemurafenib, in which case they will discontinue all study treatment.   
4.3.2.2 
Vemurafenib 
Vemurafenib will be taken orally, at a starting dose of 960 mg (4 tablets) BID.  The first 
dose of vemurafenib should be taken in the morning, and the second dose should be 
taken in the evening, at least 8 hours after the first dose (the ideal interval between 
doses is 12 hours).  
Vemurafenib can be taken with or without a meal, and should be taken with a glass of 
water.  The vemurafenib tablets should never be chewed, cut, or crushed. 
4.3.3 
Investigational Medicinal Product Accountability 
All investigational medicinal products (IMPs) required for completion of this study 
(vemurafenib, cobimetinib, and placebo) will be provided by the Sponsor.  The 
investigational site will acknowledge receipt of IMPs using 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 the Sponsor with the appropriate 
documentation.  The site's method of IMP destruction must be agreed upon by the 
Sponsor.  The site must obtain written authorization from the Sponsor 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. 


 
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4.3.4 
Post-Study Access to Vemurafenib and Cobimetinib 
The Sponsor will evaluate the appropriateness of continuing to provide vemurafenib and 
cobimetinib to study patients after evaluating the primary efficacy outcome measure and 
safety data gathered in the study; these analyses may be conducted prior to completion 
of the study.  If these data are medically and statistically significant, the Sponsor may 
amend the protocol to continue to provide vemurafenib and cobimetinib in an open-label 
extension study to patients in that treatment arm who have shown a demonstrable 
benefit from vemurafenib and cobimetinib treatment during this study (as measured by 
improvement in investigator-assessed PFS).  
4.4 
CONCOMITANT TREATMENT  
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 Cycle 1 Day 1 through the end-of study treatment visit.  All concomitant 
medications should be reported to the investigator and recorded on the Concomitant 
Medications electronic Case Report Form (eCRF).  
Patients who use oral contraceptives, hormone-replacement therapy, or maintenance 
therapy should continue their use as outlined in the eligibility criteria.  Please note that 
potential interactions between vemurafenib and hormonal contraceptives may decrease 
the effectiveness of hormonal contraceptives.  
Pain medications may be administered according to local standard practice guidelines 
while the patient is in the study. 
Anti-emetics and anti-diarrheal medications should not be administered prophylactically 
before initial treatment with study drugs.  At the discretion of the investigator, 
prophylactic anti-emetic and anti-diarrheal medication(s) may be used per standard 
clinical practice before subsequent doses of study drugs.   
Hematopoietic growth factors should not be administered prophylactically before initial 
treatment with study drugs.  Hematopoietic growth factors may be administered 
according to local guidelines if indicated during the course of the study. 
4.4.2 
Prohibited Therapy  
Use of the following therapies is prohibited during the study and for at least 14 days prior 
to initiation of study treatment, unless otherwise specified below: 
• 
Any prior or concomitant therapy intended for the treatment of advanced melanoma, 
either approved by health authorities or experimental, including chemotherapy, 
radiation therapy, immunotherapy, hormonal therapy, biologic therapy, or 
investigational agents is prohibited.  Patients who received prior adjuvant 
immunotherapy are allowed on the study. 


 
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• 
Palliative radiotherapy or major surgery within 14 days prior to first dose of study 
treatment is prohibited. 
 
4.4.3 
Prohibited Foods and Supplements 
Use of the following foods is prohibited during the study and for at least 7 days prior to 
initiation of study treatment, unless otherwise specified below: 
• 
St. John’s wort or hyperforin (potent CYP3A4 enzyme inducer) 
• 
Grapefruit juice (potent CYP3A4 enzyme inhibitor) 
 
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 
treatment or until initiation of another subsequent anti-cancer therapy, whichever comes 
first.  These patients will also continue to be followed for survival.  
4.4.4 
Medication Precautions in Case of Drug−Drug Interactions 
Vemurafenib 
Results from an in vivo drug − drug interaction study in patients with cancer 
demonstrated that vemurafenib is a moderate cytochrome 1A2 inhibitor, a weak 
CYP2D6 inhibitor, and a CYP3A4 inducer.  Concomitant use of vemurafenib and agents 
with narrow therapeutic indices that are metabolized by CYP1A2, CYP2D6, and 
CYP3A4 is not recommended as vemurafenib may alter their concentrations.  
If co-administration cannot be avoided, exercise caution and consider a dose reduction 
of the concomitant CYP1A2 and CYP2D6 substrate drug. 
Based on in vitro data, vemurafenib is a substrate of CYP3A4, and therefore, 
concomitant administration of strong CYP3A4 inhibitors or inducers may alter 
vemurafenib concentrations.  Strong CYP3A4 inhibitors (e.g., ketoconazole, 
itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, 
indinavir, nelfinavir, voriconazole) and inducers (e.g., phenytoin, carbamazepine, 
rifampin, rifabutin, rifapentine, phenobarbital) should be used with caution when 
co-administered with vemurafenib.  Mild induction of CYP2B6 by vemurafenib was noted 
in vitro at a vemurafenib concentration of 10 µM.  It is currently unknown whether 
vemurafenib at a plasma level of 100 µM observed in patients at steady state 
(approximately 50 µg/mL) may decrease plasma concentrations of concomitantly 
administered CYP2B6 substrates, such as bupropion. 
Co-administration of vemurafenib resulted in an 18% increase in AUC of S-warfarin 
(CYP2C9 substrate) and as such, co-administration of vemurafenib and warfarin 
warrants caution.  While the in vitro 50% inhibitory concentration (IC50) value of 
vemurafenib was 11.9 μM for CYP2C8, therefore, a potential risk for clinical inhibitory 
effect on CYP2C8 cannot be excluded although a large effect appears unlikely.  


 
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Cobimetinib 
Based on in vitro data, cobimetinib is a substrate of CYP3A4 and UGT2B7.  It has also 
been shown to be an inhibitor of CYP3A4 and CYP2D6.  A study in cancer patients was 
conducted to determine if there is any clinically significant inhibition of a probe substrate 
of CYP3A (midazolam) or CYP2D6 (dextromethorphan).  Preliminary results from the 
study indicate no effect on either CYP3A or CYP2D6.  In the presence of steady-state 
cobimetinib, midazolam exposure was unchanged relative to midazolam alone, with a 
geometric mean ratio of 1.06 (95% CI: 0.84, 1.32) for midazolam AUC0−∞.  When 
dextromethorphan was administered with steady-state cobimetinib, dextromethorphan 
exposure was unchanged as compared to dextromethorphan alone, with geometric 
mean ratio of 1.04  (95% CI: 0.87, 1.23) for dextromethorphan AUC0−∞.  Given that 
cobimetinib is a substrate of CYP3A, potent inhibitors and inducers of CYP3A4 (listed 
below) may affect cobimetinib exposures and hence should be avoided.  If use of one 
these drugs is necessary, the risks and benefits and potential alternatives should be 
discussed with the Medical Monitor prior to its concomitant use with cobimetinib.   
• 
Strong CYP3A4/5 inhibitors such as, but not limited to, atazanavir, clarithromycin, 
indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, 
telithromycin, troleandomycin, and voriconazole. 
• 
Strong CYP3A4/5 inducers such as, but not limited to, rifampin, carbamazepine, 
rifapentine, phenytoin, and phenobarbital. 
 
The study protocol includes a non-exhaustive list of typical examples of CYP1A2, 
CYP2C9, CYP2D6, and CYP3A narrow therapeutic substrates that require caution for 
administering with vemurafenib.  CYP3A4, and CYP2C9 substrates and CYP3A4 
inducers and inhibitors.  The website http://medicine.iupui.edu/clinpharm/ddis/ provides 
information on drugs that are substrates, inhibitors and inducers of the various human 
cytochrome P450 enzymes (Appendix 11). 
4.4.5 
Medications Affecting the QT Interval 
Certain medications could affect the results of QT intervals on ECG measurements 
required in this study.  Caution should be exercised when the study drugs are 
co-administered with drugs that cause QTc prolongation or cardiac arrhythmia, and 
when patients have a pre-existing cardiac disease or ECG abnormality that may 
predispose them to cardiac dysrhythmia.  Investigators should closely monitor patients 
who are on medications and/or supplements that may affect the QT interval.  Alternative 
treatment options for medications known to affect QT interval should be discussed with 
each patient prior to their inclusion into this study.  A complete list of medications that 
may cause QT interval prolongation is provided in Appendix 9.  Please refer to 
http://www.azcert.org/ for additional information and references. 
Vemurafenib 
The effect of vemurafenib 960 mg administered BID on QTc intervals was evaluated in a 
multicenter, open-label, single-arm study in 132 previously treated patients with 


 
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BRAFV600 mutation-positive metastatic melanoma (Study NP22657).  No large changes 
in mean QTc interval from baseline (i.e., > 20 ms) were detected in the trial.  However, 
vemurafenib is associated with concentration-dependent QTc prolongation.  In the first 
month of treatment, the largest mean change from baseline of 12.8 ms (upper boundary 
of the 2-sided 90% CI-14.9 ms) was observed at 2 hours post-dose on Day 15.  In the 
first 6 months of treatment, the largest mean change from baseline of 15.1 ms (upper 
boundary of the 2-sided 90% CI-17.7 ms) was observed at a pre-dose timepoint. 
Cobimetinib 
Cobimetinib was shown to inhibit the human ether-à-go-go (hERG) channel activity with 
a concentration required to achieve 50% inhibition of 1 μM using single cellular 
electrophysiological recordings.  The in vitro hERG mean IC50 value of 1 μM 
(531 ng/mL, unbound), is approximately 8-fold higher than peak exposures up to 
64 ng/mL (free-fraction corrected) at the maximal dose evaluated in Phase I (125 mg) 
and 27-fold higher than peak exposures at the proposed Phase III dose (60 mg, free 
Cmax = 19 ng/mL).  Moreover, no effects on ECG or hemodynamic parameters were 
observed in a dedicated cardiovascular safety pharmacology study in 
telemetry-instrumented dogs, at up to 5.2 ng/mL (free-fraction corrected Cmax).  
Triplicate ECG data were collected in all patients in MEK4592g (Phase Ia single-agent 
study) and were analyzed for concentration-QTc relationship using matching cobimetinib 
concentration data.  ECG data were available from doses of 0.05 mg/kg to 125 mg QD. 
A preliminary analysis of concentration-QTc shows no relationship between cobimetinib 
plasma concentration and QTcF or QTcF change from baseline.  The probability of 
observing QTc outlying values > 500 ms is very unlikely in the plasma concentration 
range up to 1140 ng/mL. At 60 mg QD (the planned dose for combination with 
vemurafenib), the mean Cmax was 306 ng/mL and hence unlikely to be associated with 
any QTc prolongation based on this analysis. 
In this study (GO28141), no additive clinical effect on QT interval prolongation was 
observed when patients were treated with cobimetinib in combination with vemurafenib. 
4.5 
STUDY ASSESSMENTS 
The schedule of study assessments and procedures are detailed in Appendix 1. 
4.5.1 
Description of Study Assessments 
4.5.1.1 
BRAFV600 Mutation Testing  
BRAFV600 mutation testing must be performed with the cobas 4800 BRAF V600 mutation 
test (Appendix 10).  Only patients whose melanoma tumors test positive for the 
BRAFV600 mutation on the cobas® 4800 BRAF V600 mutation test will be eligible for 
enrollment in the clinical study if other eligibility criteria are met.  Tumor samples may be 
obtained from the primary melanoma tumor or any metastatic site, as long as the 
requirements below are met.  BRAFV600 mutation testing must be performed prior to 


 
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additional screening tests and requirements.  Standard-of-care tests or examinations 
may be performed concurrently with the BRAFV600 mutation testing.  The 28-day window 
(Day -28 to Day -1) for performing screening assessments opens at the time the first 
additional screening assessment is performed after the cobas® 4800 BRAF V600 
mutation test result is available. 
The cobas® 4800 BRAF V600 mutation may be tested at a Roche-designated Central 
Reference Laboratory or at a non-Roche-designated laboratory.  If a 
non−Roche-designated laboratory is used for BRAFV600 mutation testing, documentation 
of the test procedures and results must be included as source documentation. 
Archival or newly obtained formalin-fixed paraffin-embedded (FFPE) tumor specimens 
may be utilized for the cobas® 4800 BRAF V600 mutation test.  Tissues obtained from 
fine needle aspirations (FNA) are not permitted.  FFPE tumor block or 5 serially cut, 
unstained tumor tissue slides from each block will be collected at screening for the 
cobas test.   
For patients eligible for the study, additional testing will be performed at Roche or in a 
centralized specialty laboratory.  These additional investigations will be done 
retrospectively and not influence patient’s eligibility for this study.  
For patients whose tumor samples undergo cobas® 4800 BRAF V600 mutation testing at 
a Roche-designated central testing facility, tumor blocks from the patients who are not 
eligible for the study will be returned after mutation testing has been completed.   
4.5.1.2 
Medical History and Demographic Data 
Medical history includes clinically significant diseases within the previous 3 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 Cycle 1 
Day 1. Demographic data will include age, sex, and self-reported race/ethnicity (where 
applicable/permissible). 
4.5.1.3 
Vital Signs 
The following vital signs will be recorded for all patients: 
• 
Temperature (°C) 
• 
HR 
• 
Respiratory rate  
• 
Systolic and diastolic blood pressure  
o Blood pressure and HR measurements will be recorded with the patient in 
the seated position after a 5-minute rest period. 
 


 
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4.5.1.4 
Physical Examinations 
Patients will be asked specifically about skin and vision changes as part of each physical 
examination in addition to interval medical history.  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. 
A complete physical examination should include measurement of height and weight, and 
head, eye, ear, nose, and throat (HEENT), neck, cardiovascular, dermatological, 
musculoskeletal, respiratory, GI, and neurological system exams.  Examination of the 
HEENT must include visual inspection and/or palpation of the oral cavity and oropharynx, 
and palpation of the draining lymph nodes of the neck.  Visual evaluation of the anus 
and digital evaluation of the anal canal is required as part of the physical examination at 
screening and thereafter per local standard of care for vemurafenib-treated patients.  
Endoscopic examination (colonoscopy or sigmoidoscopy) is not required for examination 
of the anus or anal canal. 
All female patients will undergo a pelvic examination, including visual inspection of the 
uterine cervix and Papanicolaou (Pap) smear at screening and thereafter per local 
standard of care.  Pelvic examinations, including Pap smear, which were conducted up 
to 12 months prior to screening and found to be normal need not be repeated at 
screening. 
HEENT, anal, and gynecological examinations are part of the surveillance measures for 
identifying non-cuSCC (see Section 5.1.4.2).  Any non-cuSCC should be staged and 
managed per the local standard of care. 
Changes from baseline should be noted at each subsequent physical examination.  New 
or worsened physical exam abnormalities should be recorded as adverse events, if 
appropriate.  An interval medical history should be obtained coincident with each 
follow-up physical exam, which documents changes from baseline in new or concomitant 
diseases, medications, and allergies.  
4.5.1.5 
Tumor and Response Evaluations 
Following formal institutional approval of protocol v5, patients on study should be 
evaluated for disease progression according to the local standard of care with the same 
radiographic method employed during the conduct of the study.  The frequency of tumor 
assessments may be according to the local standard of care and treating physician’s 
usual practice. 
The Independent Review Committee will discontinue the review of tumor assessment 
data following the final PFS analysis. 


 
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For patients who discontinue study treatment for reasons other than 
investigator−determined disease progression, tumor assessments should continue to be 
performed according to the local standard of care and treating physician’s usual practice. 
For patients with palpable/superficial lesions, clinical disease assessments by physical 
examination should be performed at baseline and throughout study treatment as 
clinically indicated.   
4.5.1.6 
Dermatologic Examination 
A complete history of prior dermatologic interventions and cuSCC risk factors 
(i.e., radiation therapy, sun exposure, immunosuppression, prior SCC, use of tanning 
beds, precursor lesions, and phototherapy for psoriasis) must be collected at baseline. 
Complete evaluation of the skin by a dermatologist, or qualified equivalent medical 
specialist, will be conducted at baseline (up to 28 days prior to Cycle 1, Day 1), Cycle 2, 
Day 1 (± 1 week), and thereafter per local standard of care thereafter while receiving 
study treatment, and at the end of study treatment.   
Any suspicious lesions identified must be biopsied or resected 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 or qualified 
equivalent medical specialist should be treated per local standards of care. 
4.5.1.7 
Ophthalmology Examination 
All patients will undergo ophthalmologic examination at the following timepoints: 
• 
Screening 
• 
Cycle 2, Day 1 ± 1 week  
• 
On Day 1 of Cycles 5, 8 and 11 (every 3 treatment cycles) ± 2 weeks 
• 
On Day 1 of Cycles 15, 19, 23 (every 4 treatment cycles) ± 2 weeks 
• 
On Day 1 of Cycles 29, 35, 41, 47, etc. (every 6 treatment cycles) ± 2 weeks 
• 
End-of-study-treatment visit 
 
All patients will need to undergo baseline ophthalmologic examination to evaluate for 
evidence of retinal pathology that is considered a risk factor for neurosensory retinal 
detachment, RVO or neovascular macular degeneration.  Ophthalmologic examination 
must be performed by a qualified ophthalmologist.  Risk factors for RVO include 
elevated serum cholesterol, hypertriglyceridemia, hyperglycemia, hypertension, and 
glaucoma.  Patients with such conditions will be excluded from the study as detailed in 
the inclusion/exclusion criteria. 


 
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Baseline ophthalmologic examination will include visual acuity testing, intraocular 
pressure measurements by tonometry, slit lamp ophthalmoscopy, indirect 
ophthalmoscopy, and spectral domain optical coherence tomography (OCT; spectral 
domain OCT, if not available, may be substituted with time-domain OCT).  
Serial surveillance ophthalmologic examination will comprise all examinations performed 
at the baseline ophthalmologic examination.  Ophthalmologic examination does not need 
to be performed at end-of-study-treatment visit if one has been performed within the last 
12 weeks and there were no clinically significant findings and/or changes from prior 
exam. 
For patients who cross over from placebo to cobimetinib treatment, the ophthalmologic 
examination schedule should begin again, with exams at the following timepoints: 
• 
Within 28 days of, but not after the first day of cross over 
• 
Start of second cycle after cross over, Day 1 ± 1 week  
• 
On Day 1 of Cycles 5, 8 and 11 after cross over (every three treatment cycles) 
± 2 weeks 
• 
On Day 1 of Cycles 15, 19, 23 after cross over (every four treatment cycles) 
± 2 weeks 
• 
On Day 1 of Cycles 29, 35, 41, 47 after cross over, etc. (every six treatment cycles) 
± 2 weeks 
• 
End-of-study-treatment visit 
 
4.5.1.8 
Laboratory Assessments 
All screening laboratory assessments should be obtained within 14 days prior to initiation 
of study drug on Cycle 1, Day 1.  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. 
Laboratory assessments required on the study are as follows: 
Hematology: 
Hemoglobin, hematocrit, WBC count with differential 
(neutrophils, lymphocyte, monocyte, eosinophil and 
basophil counts, and other cells), and platelet count. 
Chemistry: 
BUN, creatinine, sodium, potassium, chloride, bicarbonate, 
phosphorus, magnesium, total calcium, albumin, LDH, 
CPK, fasting blood glucose, and fasting lipid panel. 
Liver function tests: 
ALT, AST, total bilirubin, ALP, and GGT. 
Pregnancy test and FSH: 
All women of childbearing potential (as defined in inclusion 
criteria) will have a serum pregnancy test at screening.  
Women who have had amenorrhea for > 12 months 
but < 2 years should have a screening FSH. 
 
These laboratory assessments will be analyzed at the study site’s local laboratory.  
Blood and tumor tissue samples for biomarker, pharmacogenomics sample, and PK 
samples will be sent to one or several Roche-designated central laboratories or to the 


 
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Sponsor for analysis.  Instruction manuals and supply kits will be provided for all central 
laboratory assessments.   
4.5.1.9 
Patient Reported Outcomes 
Following approval of v5 of the protocol, PRO data will no longer be collected.  
4.5.1.10 
Pharmacokinetic Assessments 
Plasma concentrations of vemurafenib and cobimetinib will be measured in a central 
laboratory using validated assays.  Venous blood samples will be collected according to 
the schedule of PK assessments (see Section 4.5.2.2 and Appendix 2) at the following 
timepoints: 
• 
1 − 4 hours after the first dose on Cycle 1, Day 1 
• 
Pre-dose on Cycle 1, Day 15 ± 3 days 
• 
2 − 4 hours post-dose on Cycle 1, Day 15 ± 3 days 
• 
Pre-dose on Cycle 2, Day 15 ± 3 days 
 
On the days of PK sample procurement, patients are not required to fast; however, the 
time of the last meal must be recorded in the eCRF. 
The procedures for the collection, handling, and shipping of PK samples can be found in 
the laboratory manual.  PK samples for analysis of vemurafenib concentration will be 
collected in sodium heparin tubes and will require 2 mL of venous blood at each 
timepoint.  PK samples for analysis of cobimetinib concentration will be collected in 
K2-EDTA tubes and will require 3 mL of venous blood at each timepoint. 
The total volume of blood collected for PK assessments will be approximately 16−20 mL 
during the entire study.  Unscheduled PK samples are not considered in this calculation 
(see Section 4.5.2.2). 
4.5.1.11 
Cardiac Evaluation – ECGs and Evaluation of Left Ventricular 
Function 
ECG 
Vemurafenib is associated with concentration-dependent QTc prolongation (see 
Section 4.4.5).  Cobimetinib, as either monotherapy or in combination with vemurafenib, 
is not associated with QTc prolongation (see cobimetinib IB).  All patients who continue 
to receive vemurafenib will undergo ECG monitoring in accordance with the vemurafenib 
IB (e.g., at Day 15, monthly during the first 3 months and then every 3 months thereafter 
or more frequently if clinically indicated).  ECGs should be conducted per local standard 
of care.  Central ECG reading will no longer be conducted.  
For patients who have discontinued vemurafenib but are continuing treatment with 
cobimetinib or placebo, ECG monitoring is not required unless clinically indicated. 


 
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Evaluation of Left Ventricular Function 
There is a potential for MEKi, including cobimetinib, to result in reductions in LVEF 
(Flaherty et al. 2012). 
In the Phase III study (GO28141), with active surveillance, reductions in LVEF were 
reported more frequently in patients treated with vemurafenib + cobimetinib  than 
vemurafenib + placebo (6.7% vs. 2.9%).  See Section 1.3.7.4 and the cobimetinib IB for 
further details. 
All patients will undergo evaluation of LVEF, either by echocardiography (ECHO) or 
multiple gated ejection acquisition scan (MUGA) at the following timepoints: 
• 
Screening 
• 
Cycle 2, Day 1 ± 1 week  
• 
On Day 1 of Cycles 5, 8, and 11 (every 3 treatment cycles) ± 2 weeks 
• 
On Day 1 of Cycles 15, 19, and 23 (every 4 treatment cycles) ± 2 weeks 
• 
On Day 1 of Cycles 29, 35, 41, 47, etc. (every 6 treatment cycles) ± 2 weeks 
• 
End-of-study-treatment visit  
 
Evaluation of LVEF does not need to be performed at end-of-study treatment visit if an 
evaluation has been performed within the last 12 weeks and there are no clinically 
significant findings and/or changes from baseline.  Any patient who develops clinical 
signs or symptoms suspicious of cardiac failure should undergo an LVEF assessment as 
clinically indicated until resolution. 
Evaluation of LVEF must be performed by the same method for each patient.  It is 
strongly encouraged that the same laboratory and operator perform ECHO for each 
individual patient.  
Investigators must be aware of local institution regulations regarding repeat MUGA 
scans.  The repeat administration of radioisotopes is limited in some nuclear medicine 
laboratories and some patients in this study could require monitoring on 4 occasions or 
more. 
For patients who cross over from placebo to cobimetinib treatment, the ECHO/MUGA 
schedule must begin again, with exams at the following timepoints: 
• 
Within 28 days of, but not after the first day of cross over 
• 
Start of second cycle after cross over, Day 1 ± 1 week  
• 
On Day 1 of Cycles 5, 8, and 11 after cross over (every three treatment cycles) 
± 2 weeks 
• 
On Day 1 of Cycles 15, 19, and 23 after cross over (every four treatment cycles) 
± 2 weeks 


 
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• 
On Day 1 of Cycles 29, 35, 41, 47 after cross over, etc. (every six treatment cycles) 
± 2 weeks 
• 
End-of-study-treatment visit 
 
4.5.1.12 
Exploratory Biomarker Assessments 
Patient specimens for dynamic (non-inherited) and genetic (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 or severity of adverse effects to combined BRAF and MEK 
inhibition.  This 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.  Additional markers might be evaluated if further scientific 
evidence provides justification.  The details of the biomarker analysis will be specified in 
a separate Biomarker Analysis Plan. 
• 
Identify biomarkers of response and resistance in clinical specimens collected at 
pretreatment (archival and/or baseline), during treatment (Cycle 2 Day 15), and at 
the end-of-study treatment (disease progression). Biomarker analysis may include:  
o Mutation and copy number changes in RAF/RAS/MEK, other oncogenes, 
and tumor suppressor genes by DNA sequencing 
o Levels of pErk, pS6, PTEN and RTKs, such as MET by 
immunohistochemistry 
o Infiltration of immune-cells, such as CD3/CD4/CD8 positive T-cells, in 
tumor environment by immunofluorescence staining 
o Expression of BRAF, PDGFR, IGF1R, and other components of 
melanoma signaling pathways by Fluigidm Melanoma Panel  
• 
Identify potential biomarkers in blood to monitor for melanoma progression.  
Biomarker analysis may include: 
o Circulating DNA that harbors the V600 mutation of BRAF  
• 
Characterization of SCC (cutaneous and non-cutaneous), or other non-cuSCC new 
primary neoplasms and normal skin.  Analysis may include: 
o HRAS/KRAS/NRAS, BRAF, TP53 mutations as well as other tumor 
specific mutations 
o ERK phosphorylation and proliferation 
o Additional markers dependent on the type of lesion or if new scientific 
evidence warrants 
 


 
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Biopsies of accessible melanoma lesions are mandatory upon patient’s consent to 
participate in the trial.  Tumor biopsies will be obtained at three timepoints: 
• 
Baseline sample:  within 28 days of Cycle 1, Day 1; either FFPE or fresh-frozen 
tumor biopsy (or both) may be provided 
o Baseline sample biopsies should be completed at least 48 hours before 
the initiation of study drug therapy on Cycle 1 Day 1.  Archival tissue may 
be submitted in place of newly obtained tumor tissue for the baseline 
sample biopsy.   
Note:  10–20 unstained FFPE slides will be accepted only if the tumor 
block cannot be provided. 
• 
On treatment cycle:  on Cycle 2, Day 15 (± 1 week); either FFPE or fresh-frozen 
tumor biopsy (or both) may be provided.  
• 
Disease progression sample:  at time of PD; either FFPE or fresh-frozen tumor 
biopsy (or both) may be provided.  
o The lesion must be a progressing lesion while the patient is still receiving 
study drugs or within 3 days after last study treatment. 
 
Excisional biopsies, punch biopsies, 14-gauge core needle biopsies are acceptable. 
FNA biopsies are not acceptable.   
• 
Plasma   
  
o Blood samples for biomarker analysis will be obtained on Day 1 of Cycles 
1, 3 and 5 and at the time of disease progression.  The following blood 
sample will be required at each timepoint: one 6-mL blood sample 
anticoagulated in EDTA (Schedule of Assessments, Appendix 1) 
 
The total blood loss for plasma biomarker assessments will be approximately 6 mL per 
study visit. 
• 
Whole blood  
  
o A mandatory blood sample (one 6-mL blood sample anticoagulated in 
EDTA) for genotyping analysis will be collected on Cycle 1 Day 1 
(Schedule of Assessments, Appendix 1). 
o If consent is obtained, an optional blood sample (one 6-mL blood sample 
anticoagulated in EDTA) for RCR will be collected on Cycle 1 Day 1 
(Schedule of Assessments, Appendix 1). 
 


 
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• 
Presumed or suspected SCC (cutaneous and non-cutaneous), new primary 
melanoma, other suspicious lesions, and normal skin 
o FFPE tissue or 10–20 unstained FFPE slides from a presumed or 
suspected SCC (cutaneous and non-cutaneous), new primary melanoma, 
or other suspicious lesion.  Blocks will be returned after analyses are 
complete. 
o A FFPE specimen containing normal skin (sun exposed if possible) from 
patients who develop cuSCC or new primary melanoma (only 1 specimen 
of normal skin is required from patients who develop multiple cuSCCs 
during study treatment).  Note:  normal skin biopsies should be collected 
at the time the cuSCC 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-mm 
to 4-mm punch biopsy device, which should not require suturing. 
o Biopsies of suspicious malignant lesions not thought to represent SCC or 
new primary melanoma (e.g., BCC) 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 4.5.1.14).  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 
A clinic visit should be scheduled any time there is a safety issue or any unscheduled 
assessments need to be performed. 
4.5.1.14 
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 in the future. 


 
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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 or Ethics 
Committee (IRB/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 
accordance with the IRB/EC-approved Informed Consent Form and applicable laws 
(e.g., health authority requirements). 
Optional Samples for RCR 
The following samples will be used for identification of dynamic (non-inherited) 
biomarkers: 
• 
Remaining blood and plasma samples 
• 
Remaining FFPE or FF tissue (with the exception of archival FFPE blocks, which 
will be returned to the sites) 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 K3-EDTA) at 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 


 
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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 
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. 


 
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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 his or her 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 GO28141 does not, by itself, constitute withdrawal of specimens from long 
term storage in the RCR.  Likewise, a patient's withdrawal from long term storage in the 
RCR does not constitute withdrawal from Study GO28141. 
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 
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.  All signed Informed 
Consent Forms 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.  Unless 
otherwise specified, screening and pretreatment tests and evaluations will be performed 
within 28 days of randomization.  Results of standard-of-care tests or examinations 
performed prior to obtaining informed consent and within 28 days prior to randomization 
may be used, and such tests do not need to be repeated for screening.  
Requirement for the cobas® 4800 BRAF V600 mutation test is detailed in Section 4.5.1.1.  
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the time the first additional screening assessment is performed after the cobas® 4800 
BRAF V600 mutation test result is available. 
For a complete description of study assessments, refer to Section 4.5.1 and Appendix 1. 
The following assessments will be performed at screening: 
• 
Informed consent  
• 
BRAFV600 mutation status of the primary tumor or metastatic site confirmed using the 
cobas® 4800 BRAF V600 mutation test. 
• 
Medical history and demographics 
• 
Concomitant medications 
• 
Complete physical examination, ECOG Performance Status, height, weight, and 
vital signs. 
• 
Visual and digital evaluation of the anus and anal canal. 
• 
All female patients will undergo pelvic examination including visual inspection of the 
uterine cervix and Pap smear at to monitor for cervical carcinoma. 
• 
Baseline dermatologic examination for cuSCC surveillance by a dermatologist or 
qualified equivalent medical specialist 
• 
Hematology, serum chemistries, including fasting blood glucose and lipid panel, 
LFTs  
• 
Serum pregnancy test, FSH, if applicable 
• 
Stage of melanoma according to the AJCC (v. 7.0) classification (Appendix 8), 
based on physical examination, imaging studies (contrast-enhanced CT or MRI of 
the chest, abdomen, and pelvis as well as the site of the primary tumor; contrast-
enhanced MRI of the brain [or CT if MRI is not generally available)]. 
• 
ECG and evaluation of left ventricular function with either ECHO or MUGA 
• 
Baseline complete ophthalmologic evaluation that includes visual acuity testing, 
intraocular pressure measurements by tonometry, slit lamp ophthalmoscopy, 
indirect ophthalmoscopy, and spectral domain optical coherence tomography 
(spectral domain OCT, if not available, may be substituted with time domain OCT). 
• 
Melanoma tumor tissue (archival or newly obtained tumor tissue) for exploratory 
biomarker assessments. 
• 
Cutaneous SCC tumor tissue for suspicious neoplasms 
 
The following assessments are required on Cycle 1, Day 1 (prior to administration of 
study treatment*): 
• 
Randomization with the IxRS (can be done up to 72 hours prior to Cycle 1 Day 1) 
• 
ECGs in accordance with the vemurafenib IB and conducted per local standard of 
care for patients receiving vemurafenib. See Section 4.5.1.4. 


 
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• 
Vital signs, weight, 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. 
• 
Hematology, serum chemistries, and LFTs 
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 for biomarker analysis 
• 
Blood for pharmacogenetic analysis 
• 
RCR DNA sample, an optional whole blood sample (6 mL in EDTA) for exploratory 
biomarker assessments. 
• 
Dispense diary for drug accountability 
 
*In addition, a blood sample for PK assessment will be taken at 1−4 hours after dose 
of study treatment. 
Please see Appendix 1 for the schedule of screening and pretreatment assessments. 
4.5.2.2 
Assessments during Study 
Assessments scheduled on the day of study drug administration should be performed 
prior to study drug dosing, unless otherwise specified.  Unless otherwise specified, 
assessments that are done every 2 weeks should be performed within a ± 2 days 
window. Assessments that are performed monthly should be performed within a window 
of ± 3 days.  
For a complete description of study assessments, refer to Section 4.5.1 and Appendix 1. 
The following assessments will be performed during the study: as indicated in the 
schedule of assessments (Appendix 1): 
• 
Interval medical history including documentation of new or worsening adverse 
events and concomitant medications. 
• 
ECOG Performance Status 
• 
Vital signs.  As part of the physical examination, a thorough head and neck 
evaluation to monitor for non-cutaneous SCC, consisting of visual inspection and 
palpation of the oral cavity, oropharynx and neck lymph node palpation, must be 
performed by the site investigator. 
• 
ECGs in accordance with the vemurafenib IB and conducted per local standard of 
care for patients receiving vemurafenib. See Section 4.5.1.4. 
• 
Hematology. 
• 
Serum chemistries and LFTs. 
• 
Evaluation of left ventricular function with either ECHO or MUGA. 
• 
Ophthalmologic evaluation.  See Section 4.5.1.7. 


 
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• 
Tumor assessments as clinically indicated    
• 
Dermatologic examination performed by a dermatologist, or qualified equivalent 
medical specialist, for surveillance of cuSCC, new primary melanoma, or other 
cutaneous neoplasms per local standard of care.  
• 
Biopsy of suspected SCC (cutaneous and non-cutaneous), or other new primary 
neoplasms (FFPE tissue blocks or 10–20 unstained tissue slides).  
• 
Melanoma tumor tissue biopsy, if clinically accessible. 
• 
PK assessments for vemurafenib and cobimetinib. 
• 
Blood samples for biomarker analysis. 
• 
Drug accountability. 
 
Please see Appendix 1 for the Schedule of Assessments performed during the treatment 
period. 
The Sponsor recommends that workup of any suspected case of pancreatitis should 
include serum amylase and lipase testing in addition to other appropriate testing 
(e.g., CT abdomen). 
4.5.2.3 
End-of-Study-Treatment Visit 
Patients may remain on study treatment until disease progression as assessed by the 
investigator, unacceptable toxicity, or study termination by the Sponsor. The following 
are required as part of the end-of-study treatment visit: 
• 
Interval medical history including documentation of new or worsening adverse 
events. 
• 
Concomitant medications 
• 
Physical examination (including HEENT) and vital signs. 
• 
Dermatologic examination for surveillance of cuSCC, new primary melanoma, or 
other cutaneous neoplasms, if one was not performed within the last 12 weeks. 
• 
Ophthalmologic evaluation, if one was not performed within the last 12 weeks. 
• 
Evaluation of left ventricular function if one was not performed within the last 
12 weeks. 
• 
Melanoma tumor tissue biopsy at time of melanoma progression, if clinically 
accessible. 
• 
Blood samples for biomarker 
• 
Drug accountability. 
 


 
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4.5.2.4 
Post-Study Treatment and Survival Follow-Up Assessments 
Please see Appendix 1 for the Schedule of Assessments performed during follow-up.  
Upon study treatment discontinuation or withdrawal from study treatment, patients are 
required to continue the following assessments as indicated in the Schedule of 
Assessments: 
• 
Physical examination and vital signs. 
• 
Dermatologic examination performed by a dermatologist, or qualified equivalent 
medical specialist, for surveillance of cuSCC, new primary melanoma, or other 
cutaneous neoplasms per local standard of care. 
• 
Anal examination (all patients) and gynecological examination (female patients only), 
including visual inspection of the uterine cervix and Pap smear per local standard of 
care. 
• 
CT/MRI of the chest to monitor for the occurrence of SCC per local standard of care. 
• 
Survival follow-up, including subsequent anti-cancer therapy information will be 
collected via telephone calls and/or clinic visits every 12 weeks until death. 
 
All patients will be followed for survival information unless a 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.   
4.5.2.5 
Adverse Event Follow Up  
Ongoing adverse events thought to be related to vemurafenib and/or cobimetinib will be 
followed until the event has resolved to baseline grade, is assessed by the investigator 
as stable, new subsequent 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 treatment, adverse events should be followed as outlined in 
Sections 5.5 and 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 
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• 
Investigator or Sponsor determines it is in the best interest of the patient 
• 
Patient non-compliance with the study and/or study procedures (e.g., dosing 
instructions, study visits) 
 
4.6.1.1 
Discontinuation from Study Treatment 
Patients must discontinue study treatment if they experience any of the following: 
• 
Disease progression per investigator assessment  
• 
Intolerance of study treatment despite undergoing protocol defined dose reduction 
• 
Pregnancy 
• 
Withdrawal of consent 
 
Patients who discontinue study drug for any reason will be asked to return to the clinic 
for end-of-study-treatment visit and undergo follow-up assessments (see 
Sections 4.5.2.3 and 4.5.2.4, respectively).  The primary reason for study drug 
discontinuation should be documented on the appropriate eCRF.  Patients who 
discontinue study drug will not be replaced. 
4.6.1.2 
Withdrawal from Study 
Every effort should be made to obtain information on patients who withdraw from the 
study.  The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF.  Patients will not be followed for any reason after consent has been 
withdrawn.  Patients who withdraw from the study will not be replaced. 
If lost to follow-up, the investigator should contact the patient or a responsible relative by 
telephone followed by registered mail to establish as completely as possible the reason 
for the withdrawal and survival status.  These steps for contacting patients will be 
recorded in the source document.  
If the reason for removal of a patient from the study is an adverse event, the principal 
specific event will be recorded on the eCRF.  The patient should be followed until the 
adverse event has resolved, if possible. 
4.6.1.3 
Withdrawal of Patients from the Roche Clinical Repository   
Please refer to Section 4.5.1.14. 
4.6.2 
Study and Site Discontinuation 
Roche 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.  
• 
All enrolled patients have discontinued study treatment. 
• 
Patient enrollment is unsatisfactory. 
 


 
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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 close a site at any time.  Reasons for closing 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 
 
5. 
ASSESSMENT OF SAFETY 
5.1 
SAFETY PLAN 
Cobimetinib for use with vemurafenib is approved in the United States, Canada, 
members of the European Union, and other countries.  The safety plan for patients in this 
study is based on clinical experience with cobimetinib in completed and ongoing studies.  
The anticipated important safety risks for cobimetinib are outlined below.  Please refer to 
the cobimetinib Investigator's Brochure for a complete summary of safety information.  
Several measures will be taken to ensure the safety of patients who participate in this 
study.  Eligibility criteria have been designed to exclude patients at higher risk for 
toxicities.  Patients will undergo safety monitoring during the study, including 
assessment of the nature, frequency, and severity of adverse events.  In addition, 
guidelines for managing adverse events, including criteria for dosage modification, and 
treatment interruption or discontinuation, are provided below.  There are management 
guidelines for specific toxicities of cobimetinib in Section 5.1.4.   
5.1.1 
Risks Associated with Vemurafenib 
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., γ glutamyltransferase, alkaline phosphatase, ALT, 
AST, and bilirubin).   
The majority of adverse events reported in conjunction with Phase I through 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 due to adverse events has been rare. 
Approximately 20% of vemurafenib recipients developed one or more localized 
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these were observed within the first 16 weeks of vemurafenib exposure and were not 
treatment limiting.  The risk for cutaneous squamous cell carcinoma will be mitigated 
through the use of a Risk Management Plan as outlined in Section 5.1.3.  This plan has 
been utilized across all clinical studies of vemurafenib to date. 
Analysis of ECG data from the Phase II, NP22657 study of vemurafenib in metastatic 
melanoma patients (Genentech, data on file) revealed a risk of QT interval prolongation 
without associated clinical symptomatology. 
Two cases of squamous cell carcinoma of the head and neck have been reported in 
2 patients treated with vemurafenib in excess of 300 days while enrolled on a clinical trial.  
In addition, two cases of adenomatous colonic polyps have been reported in patients 
who received vemurafenib for > 2 years. 
As of the second quarter of 2014, an adverse drug reaction of pancreatitis has been 
identified in patients being treated with vemurafenib.  Seventeen cases of pancreatitis 
with no strong risk factors or alternative explanations were reported.  Eight of the 
17 cases were assessed as likely associated with vemurafenib use based on event 
onset latency and rechallenge/dechallenge information.  The clinical presentation, 
including mild to moderate severity, was consistent with the clinical picture of 
drug-induced pancreatitis (Lankisch and Gottesleben 1995).   
The Sponsor recommends that serum amylase and lipase testing be conducted as part 
of the workup of any suspected case of pancreatitis in addition to other appropriate 
testing (e.g., computed tomography of the abdomen).  
An adverse drug reaction of acute kidney injury, including interstitial nephritis following 
vemurafenib administration, has been identified in patients being treated with 
vemurafenib.  The majority of these cases were characterized by mild to moderate 
increases in serum creatinine (some observed in the setting of dehydration events) with 
recovery after dose modification.  Approximately 2% of acute kidney injury cases were 
biopsy−proven interstitial nephritis, and approximately 3% of acute kidney injury cases 
were acute tubular injury/necrosis.  No fatal cases were related to acute kidney injury.   
Renal function should be monitored in patients undergoing vemurafenib treatment.  
Vemurafenib dose modification guidelines should be utilized when applicable, and it is 
recommended to routinely monitor serum creatinine levels in all patients undergoing 
vemurafenib therapy.  
5.1.2 
Risks Associated with Cobimetinib 
Information related to risks attributed to cobimetinib is based on safety data from this 
Phase III Study GO28141 (cobimetinib plus vemurafenib), Phase Ib Study NO25395 
(cobimetinib plus vemurafenib), and Phase I Study MEK4592g (cobimetinib 


 
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monotherapy).  For further information regarding clinical safety, please refer to the 
current cobimetinib Investigator’s Brochure. 
5.1.2.1 
Important Identified Risks Associated with Cobimetinib 
Hemorrhage 
Hemorrhage, including major hemorrhages defined as symptomatic bleeding in a 
critical area or organ, can occur with cobimetinib.  In clinical studies with cobimetinib, 
events of cerebral hemorrhage, gastrointestinal tract hemorrhage, reproductive tract 
hemorrhage, and hematuria, have been reported. 
In the Phase III study GO28141, Grade 1−4 hemorrhagic events were reported in 13.0% 
of patients treated with cobimetinib plus vemurafenib and in 7.3% of patients treated 
with placebo plus vemurafenib.  The majority of hemorrhagic events were Grade 1 or 2 
and non-serious.  Grade 3−4 hemorrhage events were reported in 1.2% of patients who 
received cobimetinib plus vemurafenib and 0.8% of patients who received placebo plus 
vemurafenib. 
Caution should be used in patients with additional risk factors for bleeding, such as 
brain metastases, and/or in patients who use concomitant medications that increase the 
risk of bleeding (including anti-platelet or anticoagulant therapy).  
Instructions and dose modifications for hemorrhage events are included in Table 10, in 
Section 5.1.5.3. 
Serous Retinopathy 
Serous retinopathy (fluid accumulation within the layers of the retina) has been observed 
in patients treated with MEK-inhibitors, including cobimetinib (Flaherty et al. 2012).  
Manifestations of serous retinopathy include visual disturbances, findings of 
retinal detachment, and retinopathy.  Serous retinopathy events may also be 
asymptomatic. 
Serous retinopathy has been characterized in the Phase III Study GO28141.  The study 
incorporated prospective serial ophthalmic examinations for all enrolled patients.  Serous 
retinopathy was reported more frequently in patients treated with cobimetinib plus 
vemurafenib than placebo plus vemurafenib (25.5% vs. 2.8%, respectively), and 
approximately half the events were asymptomatic Grade 1 events.  Few patients treated 
with cobimetinib plus vemurafenib experienced Grade ≥ 3 ocular events (2.8%); the 
majority of these were managed with dose modification of both cobimetinib and 
vemurafenib.  
To address serous retinopathy with cobimetinib treatment, all patients are required to 
undergo a baseline ophthalmologic examination to assess for history or evidence of 
retinal pathology that is considered to be a risk factor for or indicative of neurosensory 
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retinopathy of prematurity.  Patients will also undergo ophthalmologic examinations at 
specified timepoints throughout the study (see Appendix 1).  Details regarding baseline 
and subsequent ophthalmologic examinations are provided in Section 4.5.1.7.  
Guidelines for management of patients who develop Grade ≥ 2 visual disorders or 
retinopathy are provided in Table 10 in Section 5.1.5.3.  
Left Ventricular Dysfunction 
Decrease in left ventricular ejection fraction from baseline has been reported in patients 
receiving cobimetinib.  Left ventricular dysfunction may occur with signs and symptoms 
of cardiac failure, or reduction in left ventricular ejection fraction events may be 
asymptomatic. 
Left ventricular dysfunction has been characterized in the Phase III Study GO28141.  
The study incorporated prospective serial left ventricular ejection fraction evaluation in all 
patients.  With active surveillance, measured reductions in left ventricular ejection 
fraction were observed more frequently in patients treated with cobimetinib plus 
vemurafenib than placebo plus vemurafenib (26% vs. 19%, respectively, of Grade 2 or 3 
decrease).  Of the patients treated with cobimetinib plus vemurafenib, 2 patients (0.8%) 
had symptomatic reduction in left ventricular ejection fraction and the remaining patients 
were asymptomatic.  Most left ventricular ejection fraction reduction events in patients on 
cobimetinib plus vemurafenib (62%) improved or resolved with management according 
to the dose-modification guidelines (see Table 10 in Section 5.1.5.3).  
Rhabdomyolysis and CPK Elevations 
Elevations in CPK have been observed in patients who received cobimetinib 
monotherapy as well as when administered with other agents.  The majority of CPK 
elevations reported were asymptomatic, non-serious, and resolved with or without 
study drug interruption.  One event of rhabdomyolysis was reported in the Phase III 
study GO28141 (cobimetinib plus vemurafenib), and rhabdomyolysis has been reported 
in post-marketing experience.  
In Study GO28141, elevated CPK was reported as an adverse event more frequently in 
patients treated with cobimetinib plus vemurafenib (32.4% all grades, 11.3% Grade ≥ 3 
events) than placebo plus vemurafenib (8.1% all grades, 0% Grade ≥ 3 events).   
CPK will be monitored at baseline and monthly during treatment or as clinically 
indicated.  Instructions for dose modifications for elevated CPK and rhabdomyolysis are 
included in Table 10 in Section 5.1.5.3. 
Photosensitivity (when Administered with Vemurafenib) 
No evidence of phototoxicity has been observed with cobimetinib as a single agent. 
However, photosensitivity was observed on Study GO28141 with a higher frequency in 
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35%, respectively). The majority of events were Grades 1 or 2, with Grade ≥ 3 events 
occurring in 4% of patients in the cobimetinib plus vemurafenib arm versus 0% in the 
placebo plus vemurafenib arm.  Grade ≥ 3 photosensitivity events in the cobimetinib plus 
vemurafenib arm were treated with primary topical medication in conjunction with 
interruption of study agents.  Refer to Table 10 in Section 5.1.5.3 for photosensitivity 
management guidelines.  
Pneumonitis 
Events of pneumonitis have been reported in cobimetinib clinical studies.  Most reported 
events were considered non-serious and of low-severity grade.  In the Phase III study 
GO28141, pneumonitis events were reported more frequently in patients treated with 
cobimetinib plus vemurafenib than placebo plus vemurafenib (1.6% vs. 0.4%, all grades).  
There were no reported Grade ≥ 3 events in either study arm.  Serious events were 
reported in 2 patients (0.8%) treated with cobimetinib plus vemurafenib. 
5.1.2.2 
Potential Risks Associated with Cobimetinib 
Liver Laboratory Abnormalities and Severe Hepatotoxicity 
Liver laboratory test abnormalities, including increases in ALT, AST, and alkaline 
phosphatase, have been reported as adverse events and serious adverse events in 
patients treated with cobimetinib plus vemurafenib. 
In the Phase III Study GO28141, liver laboratory test abnormalities reported as Grade ≥ 3 
adverse events occurred more frequently in patients treated with cobimetinib plus 
vemurafenib than placebo plus vemurafenib (20.5% vs. 15.1%, respectively): 
Generally, elevations in liver laboratory tests were managed effectively with dose 
modification guidelines.  In both study arms, the majority of Grade ≥ 3 liver laboratory test 
abnormalities resolved. 
Impaired Female Fertility  
There is a potential for effects on fertility and embryo-fetal toxicity based on results from 
nonclinical studies.  
While no dedicated fertility studies have been conducted with cobimetinib in animals, 
degenerative changes observed in reproductive tissues included increased 
apoptosis/necrosis of corpora lutea and seminal vesicle, epididymal and vaginal 
epithelial cells in rats, and epididymal epithelial cells in dogs.  These changes were 
reversible upon discontinuation of cobimetinib administration. 
Teratogenicity and Development Toxicity 
In a dedicated nonclinical embryo-fetal toxicity study, cobimetinib produced fetal toxicity 
(resorptions and reductions in fetal weight), and teratogenicity (malformations of the 
great vessels and skull) at similar systemic exposures in rat to those observed in 
patients administered the 60 mg dose. 


 
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5.1.2.3 
Other Risks Associated with Cobimetinib 
Rash 
In the Phase III study GO28141, combined rash events of all types and grades were 
reported more frequently in patients treated with cobimetinib plus vemurafenib than 
placebo plus vemurafenib (71.7% vs. 66.7%, respectively), although Grade ≥ 3 events 
(approximately 16% of patients) and types of rash reported were similar between study 
arms.  Specific events in patients treated with cobimetinib plus vemurafenib included 
rash (39% all grades, 5.9% Grade ≥ 3, 1.6% serious adverse events) and rash 
maculo-papular (14.6% all grades, 6.3% Grade ≥ 3, 1.2% serious adverse events). 
Generally, Grade ≥ 3 rash events were effectively managed with dose modification 
guidelines.  In GO28141, approximately 90% of Grade ≥ 3 rash events resolved in both 
arms. 
Gastrointestinal Toxicity 
A range of gastrointestinal adverse events, including nausea, vomiting, and diarrhea, 
have been reported in all cobimetinib studies in adult cancer patients. 
In the Phase III study GO28141, diarrhea was the most common adverse event 
reported.  Diarrhea events of all severity grades were reported in 59.9% of patients and 
Grade 3 or 4 events were reported in 6.5% of patients treated with cobimetinib plus 
vemurafenib versus 30.9% and 0.8%, respectively, in the patients treated with placebo 
plus vemurafenib.  No Grade 5 events of diarrhea have been reported.  Serious adverse 
events of diarrhea were reported in 1.2% of patients treated with cobimetinib plus 
vemurafenib. 
Nausea and vomiting have been reported in association with cobimetinib.  Most nausea 
and vomiting events were considered non-serious and low-severity grade. In the 
Phase III Study GO28141, nausea and vomiting events were reported more frequently in 
the active cobimetinib arm than the control arm (nausea 39.0% vs. 23.8%; vomiting 
21.3% vs. 12.1%).  However, of patients treated with cobimetinib plus vemurafenib, few 
experienced Grade 3 events (nausea 0.8%, vomiting 1.2%). 
In the Phase I single-agent study (MEK4592g), all grades of nausea and vomiting were 
both reported as 33.9% with 0.9% reported for Grade ≥ 3 nausea and none reported for 
vomiting. 
The combination of diarrhea, nausea, and vomiting has the potential to contribute to 
clinically significant volume depletion/dehydration from the combination of fluid losses 
with decreased oral intake.  In the majority of cases, diarrhea has been effectively 
managed with antidiarrheal agents and supportive care.  Routine antiemetic prophylaxis 
is not recommended.  


 
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Hypersensitivity  
There have been few reports of hypersensitivity and/or anaphylaxis in clinical trials with 
patients who have been exposed to cobimetinib monotherapy or cobimetinib when used 
with other agents.  These have appeared to be isolated reports, and in some cases, 
occurred in patients with histories of drug allergies.  Thus, the relationship of cobimetinib 
to these events is unclear. 
In the Phase III Study GO28141, Grade 3 hypersensitivity events were reported in 
3 patients in the cobimetinib and vemurafenib arm compared with no such events in the 
placebo plus vemurafenib arm.  All events required hospitalization and treatment with 
steroids.  
Investigators should promptly evaluate and treat patients who are suspected of 
experiencing a hypersensitivity reaction. 
Please refer to the cobimetinib IB for additional safety information. 
5.1.3 
General Safety Mitigation Plan 
5.1.3.1 
Eligibility Criteria 
Eligibility criteria promulgated for this study will guard the safety of patients in this trial.  
The exclusion criteria for safety will include (but are not limited to) the following:  major 
surgical procedure or significant traumatic injury within 2 weeks prior to first dose of 
study drug treatment; pregnancy or breastfeeding; clinically significant cardiovascular 
disease; history of congenital long QT syndrome or QTc interval > 450 ms at baseline; 
inadequate bone marrow, hepatic, or renal function; and other clinically significant 
comorbid conditions. 
5.1.3.2 
Monitoring 
Safety will be evaluated in this study through the monitoring of all adverse events and 
targeted laboratory assessments according to NCI CTCAE v4.0.  Patients will be 
monitored every 2 weeks during the first 2 cycles, then prior to each subsequent cycle, 
and as necessary throughout the study.  All treatment-emergent adverse events and 
serious adverse events, whether or not deemed treatment related, will be followed until 
they resolve or become stabilized, 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 chemistries, liver function tests, and 
blood counts.  All serious adverse events and protocol-defined adverse events of special 
interest will be reported in an expedited fashion. 


 
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5.1.4 
Monitoring and Management of Specific Toxicities and 
Conditions that May Arise with Vemurafenib and/or 
Cobimetinib Treatment 
5.1.4.1 
Primary Cutaneous Squamous Cell Carcinoma and Other New 
Cutaneous Malignancies 
Complete evaluation of the skin by a dermatologist, or qualified equivalent medical 
specialist, will be conducted at baseline (up to 28 days prior to Cycle 1, Day 1), Cycle 2, 
Day 1 (± 1 week) of study treatment, every 3 treatment cycles (12 weeks ± 2 weeks) 
thereafter while receiving study treatment and at the end-of-study-treatment visit.  
Dermatologic examination does not need to be performed at end-of-study-treatment visit 
if the evaluation has been performed within the last 12 weeks.   
An unscheduled dermatology examination may be performed during treatment for 
investigation of any new skin lesions that are suspected of being cuSCC or new primary 
cutaneous neoplasm.   
The dermatologic evaluation will include: 
• 
Complete history of prior dermatologic medications and cuSCC risk factors 
(i.e., radiation therapy, sun exposure, immunosuppression, prior cuSCC, use of 
tanning beds, precursor lesions and phototherapy for psoriasis) 
• 
Skin examination for cuSCC, BCC, actinic keratosis, KA, and/or second primary 
melanoma.  
• 
Appropriately map any suspicious lesions that may represent cuSCC, BCC, actinic 
keratosis, KA, and/or second primary melanoma. 
• 
Biopsy and/or excision of any suspicious lesions identified at baseline and while on 
study. 
• 
Treatment of identified skin neoplasms or conditions per local standards of care. 
• 
Available specimen block/sections should be sent to a Roche-designated central 
pathology laboratory for confirmation of diagnosis and further molecular 
characterization. 
 
If a patient develops cuSCC either during or after withdrawal from the study, this 
information must be collected and reported as an 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 cutaneous neoplasm either during or after 
withdrawal from study, 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. 
5.1.4.2 
New Non-Cutaneous Primary Malignancies 
All new primary malignancies will be reported until 12 months after discontinuation of 
vemurafenib.  If a patient develops a new non-cutaneous, primary malignancy during or 
up to 12 months after discontinuation of vemurafenib, this event must be reported as a 


 
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serious adverse event to the Sponsor, whether it is deemed related or unrelated to study 
drug.  Thereafter, only new primary malignancies thought to be related to study 
treatment will be reported as serious adverse events. 
Any suspicious lesion identified must be biopsied/excised and a specimen 
(tissue block/sections) sent to a Roche-designated central pathology laboratory for 
pathological examination and further molecular characterization. 
Head and Neck Examination 
The complete physical examination performed at the beginning of every cycle should 
include examination of HEENT and neck (including lymph nodes) by the investigator to 
monitor for the occurrence of SCC in the upper aerodigestive tract. 
Lung Examination 
Patients will undergo CT/MRI of the chest to monitor for the occurrence of SCC while on 
study treatment and per local standard of care.  The chest CT/MRI scan performed as 
clinically indicated as part of the tumor assessment may be used for lung SCC 
surveillance while on study treatment.  
Anal Examination 
Visual inspection and digital examination of the anus and anal canal will be performed at 
screening, thereafter per local standard of care, and at other times as clinically indicated 
to monitor for anal SCC.  Colonoscopy, sigmoidoscopy, or anoscopy is not required but 
may be performed if clinically indicated. 
Gynecological Examination 
All female patients will undergo pelvic examination including visual inspection of the 
uterine cervix and Pap smear at screening, thereafter per local standard of care, and at 
other times as clinically indicated to monitor for the occurrence of cervical carcinoma.  
5.1.4.3 
Skin Toxicities Other than Neoplastic/Premalignant Lesions  
The skin toxicities other than neoplastic/premalignant lesions observed in patients 
treated with vemurafenib and/or include rash, pruritus, palmar-plantar 
erythrodysesthesia, dry skin, and exfoliation.  Of these, the most common has been rash 
(maculo-papular or acneiform), which has generally been manageable with supportive 
care.  Skin toxicities other than neoplastic/premalignant lesions, will be managed with 
supportive care according to institutional guidelines as well as by dose 
interruption/modification.  
Mild to severe photosensitivity has been reported in patients who received vemurafenib 
in clinical studies.  For managing photosensitivity, patients are advised to: 
• 
Avoid prolonged sun exposure while taking study treatment and for at least 5 days 
after discontinuation. 


 
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• 
Use broad-spectrum (UVA and UVB) sunscreen and lip balm (at least SPF > 30) to 
help protect against sunburn. 
 
5.1.4.4 
Ocular Toxicity 
All patients will undergo ophthalmologic examination at the following timepoints: 
• 
Screening 
• 
Cycle 2 Day 1 ± 1 week 
• 
On Day 1 of Cycles 5, 8, and 11 (every 3 treatment cycles) ± 2 weeks 
• 
On Day 1 of Cycles 15, 19, and 23 (every 4 treatment cycles) ± 2 weeks 
• 
On Day 1 of Cycles 19, 35, 41, 47, etc. (every 6 treatment cycles) ± 2 weeks 
 
For patients who cross over from placebo to cobimetinib treatment, the ophthalmologic 
examination schedule should begin again, with exams at the following timepoints: 
• 
Within 28 days of, but not after the first day of cross over 
• 
Start of second cycle after cross over, Day 1 ± 1 week  
• 
On Day 1 of Cycles 5, 8 and 11 after cross over (every three treatment cycles) 
± 2 weeks 
• 
On Day 1 of Cycles 15, 19, 23 after cross over (every four treatment cycles) 
± 2 weeks 
• 
On Day 1 of Cycles 29, 35, 41, 47 after cross over, etc. (every six treatment cycles) 
± 2 weeks 
• 
End-of-study-treatment visit 
 
Baseline and serial surveillance ophthalmologic examination will include visual acuity 
testing, intraocular pressure measurements by tonometry, slit lamp ophthalmoscopy, 
indirect ophthalmoscopy, and spectral domain OCT (spectral domain OCT, if not 
available, may be substituted with time-domain OCT). 
See Section 4.5.1.7. 
5.1.4.5 
Cardiac Toxicity 
ECG 
The following measures will be implemented to minimize the risk of ventricular 
arrhythmia in patients with metastatic melanoma treated in this study: 
• 
Patients with a baseline QTc > 450 ms or a history of congenital long QT syndrome 
are not eligible to participate in this study. 
• 
Concomitant medications known to prolong QTc interval should be avoided if 
possible. 
• 
ECG monitoring for patients who receive vemurafenib will be conducted in 
accordance with the vemurafenib IB.  Ongoing ECG monitoring is no longer required 
for patients who continue to receive only cobimetinib/placebo unless clinically 
indicated.  


 
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• 
Guidelines for interruption of treatment and dose reduction in the setting of QTc 
prolongation are described in Table 10. 
• 
Vemurafenib treatment should be permanently discontinued if the QTc interval 
increases to > 500 ms AND the increment from baseline exceeds 60 ms. 
 
Evaluation of Left Ventricular Function 
All patients will undergo evaluation of LVEF, either by ECHO or MUGA at the following 
timepoints: 
• 
Screening 
• 
Cycle 2, Day 1 ± 1 week  
• 
On Day 1 of Cycles 5, 8, and 11 (every 3 treatment cycles) ± 2 weeks 
• 
On Day 1 of Cycles 15, 19, and 23 (every 4 treatment cycles) ± 2 weeks 
• 
On Day 1 of Cycles 29, 35, 41, 47, etc. (every 6 treatment cycles) ± 2 weeks 
• 
End-of-study-treatment visit 
For patients who cross over from placebo to cobimetinib treatment, the ECHO/MUGA 
schedule must begin again, with exams at the following timepoints: 
• 
Within 28 days of, but not after the first day of cross over 
• 
Start of second cycle after cross over, Day 1 ± 1 week  
• 
On Day 1 of Cycles 5, 8, and 11 after cross over (every three treatment cycles) 
± 2 weeks 
• 
On Day 1 of Cycles 15, 19, and 23 after cross over (every four treatment cycles) 
± 2 weeks 
• 
On Day 1 of Cycles 29, 35, 41, 47 after cross over, etc. (every six treatment cycles) 
± 2 weeks 
• 
End-of-study-treatment visit 
 
See Section 4.5.1.11. 
Guidelines for interruption/dose modification in the setting of decreased LVEF are 
provided in Table 10. 
5.1.4.6 
Hepatic Toxicity 
Grade 4 elevations of serum γ glutamyltransferase and other less severe liver function 
abnormalities have been reported in patients treated with vemurafenib and cobimetinib.  
These have generally been managed with interruption of treatment and dose reduction.  
All patients will undergo liver function testing (AST, ALT, total bilirubin, ALP, and 
γ glutamyltransferase) at periodic intervals while on study treatment (see Appendix 1).  
Guidelines for interruption/dose modification in the setting of liver function abnormality 
are provided in Table 10.  


 
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5.1.5 
Management of Specific Adverse Events 
Dose levels for dose reductions are listed in Table 9.  
Table 9 
Dose Level Reductions  
Dose reduction 
Vemurafenib 
Cobimetinib 
1 dose level 
720 mg BID 
40 mg QD 
2 dose levels 
480 mg BID 
20 mg QD 
BID = twice daily; QD = once daily. 
 
Dose modifications, interruptions, and delays of vemurafenib and/or cobimetinib study 
treatment should be made on the basis of the guidelines provided in Table 10.  The dose 
modification guidelines are not intended to replace clinical judgment or dictate care of 
individual patients.  Dose reduction of each study drug is independent of the other study 
drug.  Dose re-escalation is not allowed. 
5.1.5.1 
Rash Management 
The appearance of rash must be differentiated as acneiform, non-acneiform or 
drug−induced photosensitive rash / sunburn. 
Prior to starting study treatment, patients must be advised to: 
• 
Avoid unnecessary or prolonged sun exposure while taking study treatment and for 
at least 5 days after discontinuation. 
• 
Use broad-spectrum (UVA and UVB) sunscreen and lip balm (at least SPF > 30) to 
help protect against sunburn. 
• 
Use thick, alcohol-free emollient cream (e.g. glycerine and cetomacrogol cream) on 
dry areas of the body. 
 
For Grade 1 to 2 rash, the following supportive measures may be considered: 
• 
For non-acneiform rash, mild strength topical steroid (e.g. hydrocortisone 1% 
cream). 
• 
For acneiform rash, doxycycline 100 mg BID or minocycline 100 mg BID for 1−2 
weeks. 
• 
For pruritic lesions, the cool compresses and oral/topical antihistamine agents 
• 
For photosensitive lesions / sunburn, use cool compresses and avoid further sun 
exposure. 
• 
For desquamation, thick emollients and mild soap are recommended. 
 
For Grade≥ 3 rash, see Table 10:  management of specific toxicities and dose 
modification guidelines. 


 
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5.1.5.2 
Diarrhea Management 
Rule out other or concomitant causes, including medications (e.g., stool softeners, 
laxatives, antacids), infection by Clostridium difficile, malabsorption/lactose intolerance, 
fecal impaction, and dietary supplements high in fiber. 
For Grade 1 to 2 diarrhea: 
• 
Dietary modifications:  
o Stop all lactose-containing products and eat small meals.  
o The BRAT (banana, rice, apples, toast) diet may be helpful.  
o Encourage adequate hydration. 
• 
Loperamide: 
o Suggested initial dose of 4 mg followed by 2 mg every 4 hours or after 
every unformed stool; up to a maximum of 16 mg/day. 
o Continue loperamide is suggested until diarrhea-free for 12 hours. 
o If Grade ≤ 2 diarrhea persists after 48 hours total treatment with 
loperamide, consider second-line agents (otreotide, budesonide, or 
tincture of opium). 
 
For Grade ≥ 3 diarrhea, see Table 10:  Management of Specific Toxicities and Dose 
Modification Guidelines. 


 
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5.1.5.3 
Management of Specific Toxicities and Dose Modification 
Guidelines 
Table 10 Management of Specific Toxicities and Dose Modification 
Guidelines  
Adverse Event 
Action 
A) Rash Grade ≥ 3 
The appearance of rash must be characterized as acneiform or 
non-acneiform. 
No change in vemurafenib and cobimetinib dosing will be 
implemented for Grade ≤ 2 rash; patients should receive maximal 
supportive care per institutional guidelines. 
Acneiform rash  
Hold cobimetinib dosing until Grade ≤ 2. 
Vemurafenib dosing may continue when cobimetinib is 
interrupted. 
Reduce cobimetinib by 1 dose level.  If after restarting at reduced 
dose, the patient experiences skin toxicity Grade ≥ 3, further 
reduce cobimetinib by another dose level.  Permanently 
discontinue cobimetinib if restarting after second dose reduction, 
the patient experiences skin toxicity Grade ≥ 3. 
Permanently discontinue cobimetinib  if rash  ≥ 3 persists 
for  > 28 days despite adequate supportive care. 
Non-acneiform or maculo-papular rash 
Delay vemurafenib dosing until Grade ≤ 2. 
Cobimetinib dosing may continue when vemurafenib is 
interrupted. 
For Grade 3 rash, reduce vemurafenib by 1 dose level.  If after 
restarting at reduced dose, the patient experiences skin toxicity 
Grade ≥ 3, further reduce vemurafenib by 1 dose level.  
Permanently discontinue vemurafenib if restarting after second 
dose reduction, the patient experiences recurrent skin toxicity 
Grade ≥ 3. 
For Grade 4 rash, reduce vemurafenib by 2 dose levels.  
Permanently discontinue vemurafenib if after restarting at 
reduced dose, the patient experiences skin toxicity Grade ≥ 3. 
 


 
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Table 10 Management of Specific Toxicities and Dose Modification 
Guidelines  (cont.)  
Adverse Event 
Action 
B) Photosensitivity Grade ≥ 3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a) Grade ≤ 2 photosensitivity should be managed with 
supportive care and treatment of both vemurafenib and 
cobimetinib may be continued.  
If Grade 2 photosensitivity does not resolve to Grade ≤ 1 after 
7 days or if photosensitivity worsens to Grade ≥ 3 despite best 
supportive care, then both vemurafenib and cobimetinib 
treatment must be interrupted until the photosensitivity 
resolves to a Grade ≤ 1. 
b) If resolution to Grade ≤ 1 occurs within 28 days, treatment 
may be re-initiated with vemurafenib dose reduced by 1 level 
and without change in cobimetinib dose. 
If the photosensitivity does not resolve to Grade ≤ 1 by 
28 days, then the therapy with vemurafenib and cobimetinib 
should be discontinued. 
c) If the photosensitivity recurs to Grade ≥ 3 with vemurafenib 
and cobimetinib, re-initiation despite prophylactic measures 
and dose reduction of vemurafenib, then both agents should 
be held until the photosensitivity resolves to Grade ≤ 1 or less.  
The dose of vemurafenib should be reduced by another dose 
level. 
d) If photosensitivity recurs a second time to Grade ≥ 3 despite 
prophylactic measures and the aforementioned 2 dose 
reductions of vemurafenib, vemurafenib should be 
discontinued.  The patient may continue on study treatment 
with cobimetinib/placebo alone. 
C) New skin lesion, suggestive 
of any cutaneous primary 
malignancy.  
 
Any cutaneous primary 
malignancy is considered a 
Grade 3 event in this study. 
a) Follow SCC Risk Management Plan detailed in protocol  
b) Interrupt vemurafenib and cobimetinib for 48 hours before 
and after excisional biopsy.  This period of interruption may be 
altered based upon experience in this study. 
c) If lesion is diagnosed as cuSCC, treatment may be 
re-instituted with vemurafenib and cobimetinib at pre-event 
dose levels after the lesion is excised.  If the lesion is not 
excised, vemurafenib treatment must be discontinued. 
d) If the lesion is not an SCC, then treatment with vemurafenib 
and cobimetinib may be restarted at the most recent dose 
level. 
D) Visual symptoms ≥ Grade 2 
NCI CTCAE v4.0 Eye Disorders – Other, specify: 
Grade 
Description 
1 
Asymptomatic or mild symptoms; clinical or 
diagnostic observations only; intervention not 
indicated 
2 
Moderate; minimal, local or noninvasive 
intervention indicated; limiting age appropriate 
instrumental ADL 


 
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Table 10 Management of Specific Toxicities and Dose Modification 
Guidelines  (cont.)  
Adverse Event 
Action 
3 
Severe or medically significant but not 
immediately sight threatening; hospitalization 
or prolongation of existing hospitalization 
indicated; disabling; limiting self-care ADL 
4 
Sight-threatening consequences; urgent 
intervention indicated; blindness (20/200 or 
worse) in the affected eye 
Interrupt cobimetinib and vemurafenib.   
Consult ophthalmology and undergo complete ophthalmologic 
examination, which includes visual acuity testing, intraocular 
pressure measurements by tonometry, slit-lamp 
ophthalmoscopy, indirect ophthalmoscopy, and spectral 
domain optical coherence tomography 
 
If retinal vein occlusion (RVO) is diagnosed, vemurafenib 
and cobimetinib dosing should be permanently discontinued 
and RVO treated per institutional guidelines. 
 
If neurosensory retinal detachment is diagnosed, 
cobimetinib dosing should be interrupted until symptoms 
improve to Grade 1.  Then cobimetinib should be dose 
reduced by 1 dose level when restarting.  If visual symptoms 
of Grade ≥ 2 recur despite 2 dose level reductions of 
cobimetinib, cobimetinib should be permanently discontinued. 
The patient may continue on study treatment with vemurafenib 
alone in the event that cobimetinib/placebo is discontinued. 
 
If uveitis/iritis is diagnosed, Grade ≤ 2 uveitis/iritis can be 
managed with ophthalmologic input using local non-invasive 
therapies and/or short courses of systemic therapy.  Dose 
reduction of study drugs is NOT required if uveitis/iritis is 
Grade ≤ 2.  For Grade ≥3 uveitis/iritis, vemurafenib should be 
reduced by 1 dose level. 
 
If RVO, neurosensory retinal detachment or uveitis/iritis are 
NOT identified:  
 
● and visual symptoms have not resolved to Grade 1 or less 
(with the continued use of local / non-invasive supportive care) 
within 28 days, permanent discontinuation of both study drugs 
should be considered. 
● and visual symptoms have resolved to Grade 1 or less (with 
the continued use of local / non-invasive supportive care) 
within 28 days, resume use of vemurafenib and cobimetinib at 
current doses.   


 
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Table 10 Management of Specific Toxicities and Dose Modification 
Guidelines  (cont.)  
Adverse Event 
Action 
● If visual symptoms of Grade ≥ 2 (despite the optimal use of 
local / non-invasive supportive care) recur, vemurafenib 
and/or cobimetinib should be dose reduced by 1 level, 
depending on which agent is implicated.  If visual symptoms of 
Grade ≥ 2 recurs despite 2 dose level reductions of both 
vemurafenib and cobimetinib, and maximal supportive care, 
vemurafenib and cobimetinib should be permanently 
discontinued.  
 
E) Diarrhea Grade >3 
a) No change in vemurafenib and cobimetinib dosing will be 
implemented for Grade ≤ 2 diarrhea; patients should receive 
maximal supportive care. 
b) If Grade ≥ 3 diarrhea occurs despite adequate supportive 
care, then both drugs should be held until the diarrhea has 
improved to Grade ≤ 1. 
• If this occurs within 28 days, vemurafenib and 
cobimetinib may be restarted with cobimetinib reduced 
by 1 dose level, with continued supportive care or 
prophylaxis. 
• If bowel movement characteristics have NOT improved 
to Grade ≤ 1 or baseline with maximal supportive care 
by 28 days, then both drugs should be discontinued. 
d) If Grade ≥ 3 diarrhea recurs despite supportive care and 
cobimetinib dose reduction, vemurafenib and cobimetinib 
should be held until the diarrhea resolves to Grade ≤ 1.  If this 
occurs within 28 days, then therapy may be re-initiated with 
vemurafenib reduced by 1 dose level.  The cobimetinib dose 
will be maintained at the previously reduced dose. 
e) If the diarrhea recurs at Grade ≥ 3 despite supportive care 
and dose reductions of 2 dose levels in both drugs (i.e., 
vemurafenib to 480 mg BID and cobimetinib to 20 mg QD), 
then both drugs should be permanently discontinued. 
F) Rhabdomyolysis or CPK 
elevations 
Rhabdomyolysis or symptomatic CPK elevations:  Interrupt 
cobimetinib treatment.  If severity is improved by at least on 
grade within 4 weeks, restart cobimetinib at a dose reduced 
by 20 mg, if clinically indicated.  Vemurafenib dosing can be 
continued when cobimetinib treatment is modified, if 
clinically indicated. 
If rhabdomyolysis or symptomatic CPK elevation do not 
improve within 4 weeks, permanently discontinue 
cobimetinib treatment. 
Asymptomatic CPK elevations:   
Grade ≤ 3:  cobimetinib dosing does not need to modified or 
interrupted to manage asymptomatic Grade ≤ 3 CPK 
elevations.   
Grade 4:  Interrupt cobimetinib treatment.  If improved to 


 
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Table 10 Management of Specific Toxicities and Dose Modification 
Guidelines  (cont.)  
Adverse Event 
Action 
Grade ≤ 3 within 4 weeks, restart cobimetinib at a dose 
reduced by 20 mg, if clinically indicated.  Vemurafenib 
dosing can be continued when cobimetinib treatment is 
modified, if clinically indicated.  If CPK elevations do not 
improve to Grade ≤ 3 within 4 weeks following dose 
interruption, permanently discontinue cobimetinib 
treatment. 
G) LFT elevations 
a) If Grade ≤ 2, continue current dose of vemurafenib and 
cobimetinib.  
b) If Grade 3, hold vemurafenib.  Continue current dose of 
cobimetinib. Upon resolution of LFT to Grade ≤ 1, resume 
vemurafenib at 1 lower dose level (e.g., 960 mg to 720 mg, or 
720 mg to 480 mg).  
c) If Grade 4, see Section J below. 
d) No dose modification is required for isolated GGT elevation 
in the absence of clinically significant elevation above baseline 
grade in AST, ALT, ALP, bilirubin or hepatic. 
H) QTcF interval prolongation 
on ECG Grade ≥ 3 
 
a) Rule out other risk factors for arrhythmia (e.g., myocardial 
ischemia); check for electrolyte disturbances (particularly 
potassium and magnesium levels) in all cases. 
b) Evaluate concomitant medications to determine if there is 
co-administration of drugs that prolongs QTc interval in all 
cases (e.g., 5-HT3 receptor antagonist anti-emetics; see 
Appendix 9). 
c) Interrupt dosing of vemurafenib ECG monitoring should be 
performed until QTc interval decreases below 500 ms. 
Electrolytes abnormalities should be corrected in all cases.  
Continue dosing with cobimetinib at the current dose if 
otherwise tolerated. 
d) Plan to seek a cardiologist consultation or advice. 
e) If QTc interval does not improve within 28 days after 
interruption of vemurafenib dosing, permanently discontinue 
vemurafenib; continue dosing with cobimetinib at the current 
dose. 
f) If QTc improves within 28 days, restart dosing of 
vemurafenib at 1 reduced dose level.  
g) Repeat 12-lead ECG monitoring at 2 weeks and 4 weeks of 
restarting vemurafenib at the lower dose.  Additional ECG 
monitoring will be performed at Day 15 of each subsequent 
Cycle for 3 cycles, and every 3 months thereafter.  
h) If second increase in QTc interval to > 500 ms occurs at the 
lower dose of vemurafenib, follow guidelines above, and 
reduce dose of   vemurafenib by an additional dose level. 
i) Permanently discontinue vemurafenib if after correction of 
associated risk factors and dose reductions, the QTc increase 
meets values of both > 500 ms and > 60 ms change from pre-
treatment values. 


 
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Table 10 Management of Specific Toxicities and Dose Modification 
Guidelines  (cont.)  
Adverse Event 
Action 
I) Reduction in LVEF 
NCI CTCAE v 4.0 EF decreased: 
 
Grade 
Description 
1 
- 
2 
Resting EF 50%−40%;  
10%−19% drop from baseline 
3 
Resting EF 39%−20%; 
 > 20% drop from baseline 
4 
Resting EF < 20% 
a) Asymptomatic decrease in LVEF 
See Appendix 5. 
All patients who require dose reduction of cobimetinib should 
have LVEF measurements at 2 weeks, 4 weeks, then every 6 
weeks for 12 weeks, and then per protocol. 
b) Symptomatic decrease in LVEF or symptomatic heart 
failure 
Cardiology consultation is strongly recommended. 
Hold cobimetinib.  Vemurafenib may be continued. 
Strong consideration should be given to permanently 
discontinuing cobimetinib if it is attributed to have caused the 
cardiac symptoms. 
If cardiac symptoms resolve completely within 28 days, and 
LVEF returns to LLN, reduce cobimetinib by 1 dose level.  The 
patient should have LVEF measurements at 2 weeks, 
4 weeks, then every 6 weeks for 12 weeks, and then per 
protocol. 
If cardiac symptoms resolve within 28 days, but LVEF is below 
LLN, see Appendix 5. 
If cobimetinib is permanently discontinued, patient may 
continue on vemurafenib. 


 
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Table 10 Management of Specific Toxicities and Dose Modification 
Guidelines  (cont.)  
Adverse Event 
Action 
J) Other Grade 4, 
non−hematologic adverse 
events related to study drug 
(except for GGT or CPK 
elevation) 
 
a) Interrupt dosing of vemurafenib and cobimetinib. 
b) If adverse event resolves to Grade ≤ 1 within 28 days, then 
restart dosing of vemurafenib and cobimetinib.  Vemurafenib 
should be decreased by 2 dose levels and cobimetinib by 1 
dose level.  
c) If the adverse event does not resolve to Grade ≤ 1 by 28 
days, discontinue study treatment. 
d) If the Grade 4 adverse event recurs (a second time), then 
both agents should be discontinued. 
Hemorrhage 
Grade 3 events: Interrupt cobimetinib treatment.  There are 
no data on the effectiveness of cobimetinib dose modification 
for hemorrhage events.  Clinical judgment should be applied 
when considering restarting cobimetinib treatment.  
Vemurafenib dosing can be continued when cobimetinib 
treatment is interrupted, if clinically indicated. 
Grade 4 events or cerebral hemorrhage (all grades):  
Interrupt cobimetinib treatment.  Permanently discontinue 
cobimetinib for hemorrhage events attributed to cobimetinib. 
ADL = activities of daily living; BID = twice daily; CPK = creatine phosphokinase; 
cuSCC = cutaneous squamous cell carcinoma; EF = ejection fraction; GGT = γ glutamyltransferase; 
LFT = liver function test; LLN = lower limit of normal; LVEF = left ventricular ejection fraction; NCI 
CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events; QD = once 
daily; QTc = corrected QT interval; RVO = retinal vein occlusion; SCC = squamous cell carcinoma 
 
 
5.2 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events 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. 


 
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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 
character, frequency, or severity of a known condition), except as described in 
Section 5.3.5.9 
• 
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: 
• 
Any non-cutaneous primary malignancy (related or unrelated to study treatment) 
that develop during or up to 12 months after study treatment completion must be 
reported as a serious adverse event 
• 
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) 
 


 
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The progression of underlying malignancy is not reported as an adverse event if it is 
clearly consistent with the suspected progression of the underlying cancer as defined by, 
or other criteria as determined by protocol; 
• 
Hospitalization due solely to the progression of underlying malignancy should NOT 
be reported as a serious adverse event. 
• 
Clinical symptoms of progression may be reported as adverse events if the 
symptom cannot be determined as exclusively due to the progression of the 
underlying malignancy or does not fit the expected pattern of progression 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 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 
criteria; see Section 5.3.3); the event itself may be of relatively minor medical 
significance (such as severe headache without any further findings). 
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/site to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions). 
5.2.3 
Adverse Events of Special Interest (Immediately Reportable to 
Roche) 
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 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: 
• 
Any retinal vein occlusion  
• 
Any retinal detachment, retinal pigment epithelium detachment, neurosensory retinal 
detachment or central serous chorioretinopathy 
• 
Grade ≥ 3 photosensitivity 
• 
Grade ≥ 3 rash 
• 
Grade ≥ 3 elevations of AST, ALT, serum bilirubin, γ glutamyltransferase, 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 
• 
Grade ≥ 3 QT interval prolongation 


 
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• 
Cardiac events/ Grade ≥ 2 LVEF reduction 
• 
Any cutaneous primary malignancy, including squamous cell carcinoma (SCC), 
keratoacanthoma (KA), basal cell carcinoma (BCC), new primary melanoma. 
• 
Suspected transmission of an infectious agent by the study drug, as defined below 
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product.  This term applies only 
when a contamination of the study drug is suspected. 
 
The occurrence of any cutaneous primary malignancy, including SCC, KA, BCC, new 
primary melanoma will be considered a Grade 3 adverse event in this study.  Any 
non−cutaneous primary malignancy will be reported as a serious adverse event (see 
Section 5.2.2). 
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 Sections 5.4−5.6.  For each 
adverse event recorded on the Adverse Event eCRF, the investigator will make an 
assessment of seriousness (see Section 5.2.2 for serious criteria), severity (see Section 
5.3.3), and causality (see 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 until 28 days after the last dose of study drug.  After this period, 
investigators should report any deaths, serious adverse events (including new primary 
cancers), or other adverse events of concern that are believed to be related to prior 
treatment with study drug (see Section 5.6).    


 
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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?”  
 
Adverse event reports will not be derived from PRO data by the Sponsor, and safety 
analyses will not be performed using PRO data.  However, if any PRO responses 
suggestive of a possible adverse event are identified during site review of the PRO data, 
the investigator will determine whether the criteria for an adverse event have been met 
and, if so, will document the event in the patient’s source document and report the event 
on the Adverse Event eCRF. 
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 11 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE. 
Table 11 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 GI 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 and ECG Findings  
Not every laboratory or ECG 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: 
• 
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) 
or a change in concomitant therapy 


 
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• 
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.,  ALP 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 × 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 × baseline value in combination with total 
bilirubin > 2 × ULN (of which 35% is direct bilirubin) 
• 
Treatment-emergent ALT or AST > 3 × 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 an adverse event of special interest (see Section 5.4.2). 
5.3.5.7 
Deaths 
For this protocol, mortality is an efficacy endpoint.  Deaths that occur during the 
protocol−specified adverse event reporting period (see Section 5.3.1) that are attributed 
by the investigator solely to progression of melanoma should be recorded only on the 
Study Completion/Early Discontinuation eCRF and do not need to be reported on the 
Adverse Events eCRF.  All other on-study 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 monitoring committee 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.  
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.  


 
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During the post-study survival follow up, deaths attributable to progression of melanoma 
should be recorded on the Survival eCRF. 
5.3.5.8 
Pre-Existing Medical Conditions 
A pre-existing 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.   
The following hospitalization scenarios are not considered to be serious adverse events: 
• 
Hospitalization for respite care 
• 
Hospitalization for a preexisting condition, provided that all of the following criteria 
are met: 
o The hospitalization was planned prior to the study or was scheduled 
during the study when elective procedure became necessary because of 
the expected normal progression of the disease 
o The patient has not suffered an adverse event 
• 
Hospitalization due solely to recurrence/progression of the underlying melanoma 
 
5.3.5.10 
Adverse Events Associated with an Overdose or Error in Drug 
Administration 
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 the Study Drug 
Administration eCRF.   
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). 


 
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5.3.5.11 
Patient-Reported Outcome Data 
Adverse event reports will not be derived from PRO data, and safety analyses will not be 
performed using PRO data.  However, if any patient 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 
documented in the patient’s source document and reported on the Adverse Event eCRF. 
5.4 
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR 
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug: 
• 
Serious adverse events 
• 
Adverse events of special interest 
• 
Pregnancies 
 
The investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 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 
Emergency Medical Contacts 
Medical Monitor Contact Information  
24 HOUR MEDICAL COVERAGE (Roche Emergency Medical Call Center Help 
Desk):  To reach the Roche Emergency Medical Call Center Help Desk please refer to 
your Regulatory binder for country-specific access numbers. 
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 


 
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medical translation service (if necessary), connect the investigator with a Roche Medical 
Monitor, and track all calls. The Emergency Medical Call Center Help Desk will be 
available 24 hours per day, 7 days per week.  Toll-free numbers for the Help Desk and 
Medical Monitor contact information will be distributed to all investigators (see "Protocol 
Administrative and Contact Information and List of Investigators").   
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest 
For reports of serious adverse events and adverse events of special interest, 
investigators should record all case details that can be gathered immediately (i.e., 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/ 
Adverse Event of Special Interest CRF and Fax Coversheet should be completed and 
faxed to Roche Safety Risk Management or its designee immediately (i.e., no more than 
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 during study treatment or within 6 months after the 
last dose of study drug.  All women of childbearing potential will have a serum 
pregnancy test at screening.  
A Pregnancy Report eCRF should be completed by the investigator immediately (i.e., no 
more than 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 
fax numbers provided to investigators (see "Protocol Administrative and Contact 
Information and List of Investigators"). 


 
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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 during study treatment or within 
6 months after the last dose of study drug.   
A Pregnancy Report eCRF should be completed by the investigator immediately (i.e., no 
more than 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 abortion associated with a pregnancy occurring during the study or within 6 months 
of the last dose of study drug should be classified as a serious adverse event 
(as the Sponsor considers abortions to be medically significant events), recorded on the 
Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no more than 
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 during the study or within 6 months of the last 
dose of study drug should be classified as a serious adverse event, recorded on the 
Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no more than 
24 hours after learning of the event; see Section 5.4.2). 


 
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5.4.4 
New Non-Cutaneous Primary Cancers 
In fulfillment of a post-marketing requirement as a condition of vemurafenib approval in 
the United States (for the treatment of locally-advanced Stage IIIC or metastatic 
melanoma), all non-melanoma, new non-cutaneous primary cancers will be reported to 
the U.S. FDA every 12 months after the first patient enrolls and for 12 months after the 
last patient has completed study treatment.   
5.5 
FOLLOW UP OF PATIENTS AFTER ADVERSE EVENTS 
5.5.1 
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, 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. 
5.5.2 
Sponsor Follow Up 
For serious adverse events, adverse events 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 TREATMENT ADVERSE EVENTS 
At the end-of-study-treatment visit and at the 4-week after end-of-study-treatment 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 special interest 
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. 


 
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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 and List of Investigators"). 
During survival follow-up, deaths attributed to progression of melanoma should be 
recorded only on the Survival eCRF. 
5.7 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES 
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against the cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation.   
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference documents: 
• 
Cobimetinib IB  
• 
Vemurafenib IB 
 
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 
6.1 
DETERMINATION OF SAMPLE SIZE 
6.1.1 
Progression-Free Survival 
The type 1 error (α) for the analysis of the primary endpoint of PFS is 0.05 (2-sided).   
Approximately 500 patients will be randomized to treatment.  The final analysis of the 
primary endpoint of PFS will take place when approximately 206 PFS events have 
occurred.  Statistical considerations are based on the following assumptions: 
• 
Stratified log-rank test at 0.05 significance level (2-sided) 
• 
6 months median PFS for the vemurafenib + placebo arm 
• 
11 months median PFS for the vemurafenib + cobimetinib arm 
• 
Accrual ramp-up time of 9 months to reach 65 patients per month thereafter for a 
total enrollment period of approximate 14 months 
• 
5% dropout rate 


 
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• 
No interim analysis of PFS 
 
A total of 206 PFS events provides > 95% power to detect an improvement in median 
PFS from 6 months in the vemurafenib + placebo arm to 11 months in the 
vemurafenib + cobimetinib arm (corresponding to a hazard ratio of 0.55, and the minimal 
detectable difference [MDD] is 0.76).   
6.1.2 
Overall Survival 
See Section 6.9.2 for a description of the planned interim analysis and final analysis of 
OS.  The type 1 error (α) for the analysis of the secondary endpoint of OS is 
0.05 (2-sided).   
The final analysis of OS will be performed after the occurrence of approximately 
250 deaths.  A total of 250 deaths provides approximately 80% power to detect an 
improvement in median OS from 15 months in the vemurafenib + placebo arm to 
21.4 months in the vemurafenib + cobimetinib arm (corresponding to a hazard ratio for 
death of 0.70) at an overall 2-sided 0.05 significance level. 
6.2 
SUMMARIES OF CONDUCT OF STUDY 
Enrollment, eligibility violations, and patient disposition will be summarized for 
randomized patients by treatment arm.  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 and disease 
characteristics (including disease stage and LDH) 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.  
6.4.1 
Primary Efficacy Analysis 
The primary analysis will be a comparison of PFS between the 2 treatment arms using a 
stratified log-rank test at an overall 0.05 significance level (2-sided).   
The statistical hypothesis of this study is as follows: 
H0: PFS(Arm A) = PFS(Arm B) 
H1: PFS(Arm A) ≠ PFS(Arm B) 
 


 
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where PFS(Arm A) represents the survival function of PFS in the vemurafenib + placebo  
arm and PFS(Arm B) represents the survival function of PFS in the 
vemurafenib + cobimetinib arm. 
PFS as assessed by Investigator will be the primary endpoint evaluated.  PFS is defined 
as the time between date of randomization and the date of first documented disease 
progression or death, whichever occurs first.  Disease progression will be determined 
based on investigator assessment using RECIST v1.1.  Data from patients who have not 
experienced disease progression or death will be censored at the last tumor assessment 
date.  Data from patients with no post-baseline tumor assessment will be censored at 
the randomization date.  The hazard ratio for PFS will be estimated using a stratified Cox 
model.  Two-sided 95% CIs for the hazard ratio will be provided.  The stratified analyses 
will incorporate 2 stratification factors:  geographic region (North America, Europe, 
Australia/New Zealand/others) and metastatic classification (unresectable Stage IIIc, 
M1a, and M1b; M1c).  Results from an unstratified log-rank test and the unstratified 
hazard ratio will also be presented.  Kaplan-Meier methodology will be used to estimate 
median PFS for each treatment arm, and the Kaplan-Meier curves will be provided.   
6.4.2 
Secondary Efficacy Analyses 
Secondary efficacy endpoints are OS, ORR, DOR, and PFS assessed by independent 
review.  
OS is defined from randomization until death from any cause.  For patients who are alive 
at the time of analysis data cutoff, OS time will be censored at the last date the patient 
was known to be alive.  Survival time for patients with no post-baseline survival 
information will be censored on the date of randomization.   
The final analysis of ORR will take place at the time of final analysis of PFS.  BORR will 
be assessed by the investigator according to the RECIST v1.1.  Confirmed ORR is 
defined as the total number of patients whose best overall response is CR or PR divided 
by the population evaluable for ORR.  Confirmation of response (partial response or 
complete response) will be done no earlier than 28 days. In the case of stable disease, 
measurements must have met the stable disease criteria at least once after study entry 
at a minimum interval not less than 6 weeks.  Treatment difference in BORR will be 
tested using a chi-square test with Schouten correction, and a 95% Hauck-Anderson CI 
will be calculated for the difference in BORRs between treatment groups.  In addition, a 
95% Clopper-Pearson CI will be calculated for the BORR.  
DOR is defined as the interval between the date of the earliest qualifying response and 
the date of progressive disease or death for any cause.  This will be calculated only for 
patients who had a confirmed overall response of CR or PR.  Median duration of 
response will be estimated using the Kaplan-Meier method, and the 95% CI will be 
calculated using the method of Brookmeyer and Crowley (1982). Since the 


 
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determination of DOR is based on a non-randomized subset of patients, formal 
hypothesis testing will not be performed on this endpoint. 
6.5 
SAFETY ANALYSES 
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 study treatment.   
Adverse events will be summarized using MedDRA by mapped term, appropriate 
thesaurus level, and toxicity grade. adverse events will be graded by the investigator 
using NCI CTCAE v4.  The following safety parameters will be summarized by treatment 
arm: 
• 
All adverse events 
• 
All adverse events leading to discontinuation of study treatment 
• 
All deaths 
• 
Serious adverse events 
• 
Adverse events of special interest (see Section 5.2.3 for a list of adverse events of 
special interest for this study) 
 
In addition, exposure to study treatment (vemurafenib, cobimetinib, placebo), 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). 
6.6 
PHARMACOKINETIC ANALYSES 
Summary statistics will be used as appropriate to perform the descriptive analysis of the 
plasma concentrations of vemurafenib and cobimetinib.  Cobimetinib and vemurafenib 
concentrations will be measured as shown in Appendix 2.  Cobimetinib and vemurafenib 
plasma concentration versus time data, together with information on dosing and patient 
characteristics, will be pooled and analyzed using a pop PK analysis approach.  
Nonlinear mixed-effect modeling will be used for the estimation of pop PK parameters for 
cobimetinib and vemurafenib.  Covariates such as patient demographics (e.g., age, sex, 
body size), total protein, serum albumin, liver function tests (e.g., AST, ALT, ALP), and 
serum creatinine will be tested for significance on PK parameters of interest.  The PK 
data in this study might be pooled with PK data from other studies.  
The PK data will be combined with the safety (e.g., QTc) and efficacy (e.g., PFS) data 
for exposure−response modeling as data permit.  PK and PK − pharmacodynamic 
analyses may be reported in separate stand-alone reports.  Additional analyses may be 
explored as warranted by the data. 


 
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6.7 
PATIENT-REPORTED OUTCOMES 
Quality of life, 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 (e.g., physical functioning, role 
functioning, emotional functioning, cognitive functioning, social functioning), as well as 
symptom scales, will be examined at baseline, and change from baseline for each 
timepoint by use of descriptive statistics. 
Repeated measures mixed-effects models will be the primary models for the formal 
comparison of the QLQ-C30 multiple-item subscale scores between treatment arms.  
Each model will have a term for intercept, a term for a linear time trend term (in weeks), 
a term for treatment group, and a term for treatment-by-time interaction.  Repeated 
measures over time will be accounted for by unstructured covariance structure (using 
the REPEATED statement in SAS® PROC MIXED). 
Health economic measures, as assessed by the EQ-5D, will be evaluated for patients 
with a baseline assessment and at least one post-baseline EQ-5D assessment that 
generate a score.  Scores at baseline and change from baseline scores for each 
timepoint will be quantified with descriptive statistics. 
Following approval of v5 of the protocol, PRO data will no longer be collected. 
6.8 
BIOMARKER 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 
6.9.1 
Interim Efficacy Analyses of Primary Endpoint 
No interim analyses of the primary endpoint (PFS) will be performed. 
6.9.2 
Analysis of Overall Survival 
The OS analyses plan for this study protocol (v5) and the statistical analysis plan (SAP) 
have been revised.  The study will incorporate 2 OS analyses (1 interim and 1 final 
analysis).  The first OS interim analysis was performed at the time of the primary PFS 
analysis (16 months after the first patient was randomized).  The originally planned final 
analysis for OS at 385 events is anticipated to occur in the second quarter of 2017.  
The rapid development of other potentially effective therapies for patients with metastatic 
melanoma provides more treatment options for patients following disease progression, 
which may potentially confound the OS benefit of vemurafenib + cobimetinib in future OS 
analyses. Therefore, in order to minimize this potential impact while maintaining a 
statistically robust evaluation of the OS benefit associated with the combination, the 
protocol-defined OS analyses have been revised.   


 
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The revised plan for OS analyses is to perform the final OS analysis at approximately 
250 deaths without further interim analyses.  The type 1 error rate would be strictly 
controlled at the 0.05 level by the continued use of the Lan-DeMets implementation of 
the O’Brien-Fleming use function as pre-specified in the original protocol and SAP.  
The final OS analysis will be performed after the occurrence of approximately 
250 deaths (projected to occur at approximately 31 months after the first patient was 
randomized).  The Lan-DeMets implementation of the O’Brien and Fleming use function 
will be used to control the overall type I error for the OS comparison at a 2-sided, 
0.05 significance level.  Table 12 summarizes the assumptions and characteristics of the 
interim and final analyses for OS. 
Table 12 Assumptions and Characteristics of the Interim and Final 
Analyses for Overall Survival 
Assumptions 
Findings 
HR targeted 
0.70 
Targeted median (vemurafenib + placebo) 
15 months 
Targeted median 
(vemurafenib + cobimetinib) 
21.4 months 
Projected enrollment period 
12.7 months 
First interim OS  
(to be performed at time of final PFS 
analysis)  
 
Estimated cutoff date a 
16 months after FPI 
Projected number of events (% of final 
events) 
85c (34%) 
Projected MDD b (p-value) 
0.45 (<0.000242) 
Final OS  
 
Number of events (% of final events) 
250 (100%) 
Estimated cutoff date a 
31 months after FPI 
Projected MDD b (p-value) 
0.78 (<0.0499) 
Power  
80% 
α level (2-sided) 
0.05 
FPI = first patient in; HR = hazard ratio; MDD = minimally detectable 
difference; PFS = progression free survival; OS = overall survival. 
a    Estimated data cutoff time from study enrollment date.  Analysis 
results will be available after data cleaning. 
b    The largest observed HR that is projected to be statistically significant. 
c    The actual number of events observed at the interim analysis in 
July 2014 
 


 
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7. 
DATA COLLECTION, MANAGEMENT, AND QUALITY 
ASSURANCE 
7.1 
DATA QUALITY ASSURANCE 
A contract research organization (CRO) and the Sponsor will be responsible for the data 
management of this study, including quality checking of the data.  Data obtained 
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.   
The Sponsor will perform oversight of the data management of this study.  The Sponsor 
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 the Sponsor, 
using the Sponsor’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 by the Sponsor and records retention for the study data 
will be consistent with the Sponsor’s standard procedures. 
ePRO data was collected using an electronic device provided by an ePRO vendor.  The 
device is designed for entry of data in a way that is attributable, secure, and accurate, in 
compliance with U.S. Food and Drug Administration (FDA) regulations for electronic 
records (21 CFR Part 11).  Only identified and trained users may view the data, and their 
actions become part of the audit trail.  The Sponsor will have view access only.  System 
backups for data stored by the Sponsor and records retention for the study data will be 
consistent with the Sponsor’s standard procedures. 
7.2 
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed using a Sponsor-designated EDC system.  Sites will receive 
training and have access to a manual for appropriate eCRF completion.  eCRFs will be 
submitted electronically to the Sponsor and should be handled in accordance with 
instructions from the Sponsor. 
All eCRFs should be completed by designated, trained site staff.  eCRFs must 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. 


 
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7.3 
ELECTRONIC PATIENT-REPORTED OUTCOME DATA  
Patients used an ePRO device to capture PRO data.  The data was transmitted via to a 
centralized database at the ePRO vendor.  The data can be reviewed by site staff via 
secure access to a method. 
Once the study is complete, the ePRO data, audit trail, and trial and system 
documentation will be archived.  The investigator will receive patient data for the site in 
both human- and machine-readable formats on an archival-quality compact disc that 
must be kept with the study records as source data.  Acknowledgement of receipt of the 
compact disc is required.  In addition, the Sponsor will receive all patient data in a 
machine-readable format on a compact disc. 
7.4 
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, patient-reported outcomes, 
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 7.6. 
To facilitate source data verification, the investigators and institutions must provide the 
Sponsor or designee 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. 
7.5 
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 


 
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accordance with health authority requirements pertaining to computerized systems used 
in clinical research.  An acceptable computerized data collection system allows 
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. 
7.6 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, ePRO data (if applicable), Informed Consent Forms, laboratory 
test results, and medication inventory records, must be retained by the Principal 
Investigator 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 the Sponsor.  Written 
notification should be provided to the Sponsor 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 EU/EEA will comply 
with the EU Clinical Trial Directive (2001/20/EC). 
8.2 
INFORMED CONSENT 
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Child’s Assent or Caregiver's Informed Consent Form, if applicable) will 
be provided to each site.  If applicable, it will be provided in a certified translation of the 
local language.  The Sponsor or its designee must review and approve any proposed 
deviations from the Sponsor'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 the 
Sponsor 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 


 
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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 storage 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 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 
the Sponsor 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 of 1996 (HIPAA).  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 Principal 
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.  


 
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The Principal 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 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 the Sponsor.  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 
The Sponsor 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 Sponsor 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, Sponsor 
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 OS analysis. 
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 


 
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amendments, Informed Consent Forms, and documentation of IRB/EC and 
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 the Sponsor or an authorized representative for 
inspection of study data, patients’ medical records, and eCRFs.  The investigator will 
permit national and local health authorities, Sponsor 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 Ltd and managed with the 
support of a CRO, which will provide clinical monitoring, sample management, and 
project management support.  Approximately 180 centers globally may participate in the 
study and will randomize approximately 500 patients.   
Randomization will occur through an IxRS.  Central facilities will be used for certain 
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. 
9.4 
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS 
The results of this study may be published or presented at scientific meetings.  If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the Sponsor 
prior to submission.  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. 
The Sponsor will comply with the requirements for publication of study results.  In 
accordance with standard editorial and ethical practice, the Sponsor 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 


 
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150 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor 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 the Sponsor, except where agreed otherwise. 
9.5 
PROTOCOL AMENDMENTS 
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements. 
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) 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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Aithal, GP, Watkins PB, Andrade RJ, et al. Case definition and phenotype 
standardization in drug-induced liver injury. Clin Pharmacol Ther 2011;89:806−15. 
Alam M, Ratner D. Cutaneous squamous-cell carcinoma. N Engl J Med 
2001;344(13):975−83.  
Ascierto P, Streicher HZ, Sznol M. Melanoma: A model for testing new agents in 
combination therapies. J Translational Med 2010;(8):38. 
Atefi M, von Euw E, Attar N, et al. Reversing melanoma cross-resistance to BRAF and 
MEK inhibitors by co-targeting the AKT/mTOR pathway. PLoS One 
2011;6(12):e28973.  
Australian Government Department of Health and Ageing. 
http://www.skincancer.gov.au/internet/skincancer/publishing.nsf/Content/fact-2 
(2008). 
Beeram M, Patnaik, Rowinsky EK. Raf: a strategic target for therapeutic development 
against Cancer. J Clin Oncol 2005;23:6771−90. 
Brookmeyer R, Crowley J. A confidence interval for the median survival time. 
Biometrics 1982;38:29−41. 
Callahan MK, Rampal R, Harding JJ, et al. Progression of RAS-mutant leukemia during 
RAF inhibitor treatment. N Engl J Med 2012;367:2316−21. 
Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in 
melanoma with BRAF V600E mutation. N Engl J Med 2011;364(26):2507−16.  
Curtin JA, Fridlyand J, Kageshita T, et al. Distinct sets of genetic alterations in 
melanoma. N Engl J Med 2005;353: 2135−47. 
Flaherty KT, Puzanov I, Kim KB, et al. Inhibition of mutated, activated BRAF in 
metastatic melanoma.  N Engl J Med 2010;363:809−19. 
Flaherty KT, Robert C, Hersey P, et al; METRIC Study Group. Improved survival with 
MEK inhibition in BRAF-mutated melanoma. N Engl J Med 2012;367:107−14. 
Gray-Schopfer V, Wellbrock C, Marais R. Melanoma biology and new targeted therapy. 
Nature 2007;445:851−7. 
Grey A, Cooper A, McNeil C, et al. Progression of KRAS mutant pancreatic 
adenocarcinoma during vemurafenib treatment in a patient with metastatic 
melanoma. Intern Med J 2014;44:597−600. 
Haass NK, Sproesser K, Nguyen TK, et al. The mitogen-activated protein/extracellular 
signal-regulated kinase kinase inhibitor AZD6244 (ARRY-142886) induces growth 
arrest in melanoma cells and tumor regression when combined with docetaxel. 
Clin Cancer Res 2008;14:230−9. 


 
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Harding JJ, Lacouture ME, Pulitzer M, et al. Hypersensitivity skin reactions in melanoma 
patients treated with vemurafenib after ipilimumab therapy J Clin Oncol 
2012:30(suppl; abstr 8515). 
Hingorani SR, Jacobetz MA, Robertson GP, et al. Integrating BRAF/MEK inhibitors in 
combination therapy for melanoma. Cancer Research 2003;63:5198−202. 
Infante JR, Fecher LA, Nallapareddy S, et al. Safety and efficacy results from the first-in-
human study of the oral MEK 1/2 inhibitor GSK1120212. J Clin Oncol 2010;28:15s, 
(suppl; abstr 2503). 
Johannessen CM, Boehm JS, Kim SY, et al. COT drives resistance to RAF inhibition 
through MAP kinase pathway reactivation. Nature 2010;468(7326):968-72. 
Lang J, Mackie RM. Prevalence of exon 15 BRAF mutations in primary melanoma of the 
superficial spreading, nodular, acral, and lentigo maligna subtypes. J Invest 
Dermatol 2005;125:575−9. 
Lankisch PG, Gottesleben DF. Drug induced acute pancreatitis: incidence and severity. 
M Gut 1995; 37: 565−7. 
Larkin J, Ascierto PA, Dréno B, et al. Combined vemurafenib and cobimetinib in 
BRAF-mutated melanoma. N Engl J Med 2014;371:1867−76.  
Lucas R. Global Burden of Disease of solar Ultraviolet Radiation, Environmental Burden 
of Disease Series, July 25, 2006; No. 13. News release, World Health 
Organization. 
Maldonado JL, Fridlyand J, Patel H, et al., Determinants of BRAF mutations in primary 
melanomas. J Natl Cancer Inst 2003;95:1878−90. 
National Cancer Institute. SEER Cancer Statstics Review, 1975 − 2009, Table 1.1. 
http://www.seer.cancer.gov/csr/1975_2009_pops09/results_single/ 
sect_01_table.01.pdf. Accessed 10 July 2012.  
Nazarian R, Shi H, Wang Q, et al. Melanomas acquire resistance to B-RAF(V600E) 
inhibition by RTK or N-RAS upregulation. Nature 2010;468(7326):973−7. 
O'Dwyer PJ, Catalano RB. Uridine diphosphate glucuronosyltransferase (UGT) 1A1 and 
irinotecan: practical pharmacogenomics arrives in cancer therapy. J Clin Oncol 
2006;24:4534−8. 
Paraiso KH, Fedorenko IV, Cantini LP, et al. Recovery of phospho-ERK activity allows 
melanoma cells to escape from BRAF inhibitor therapy. Br J Cancer 
2010;102(12):1724−30. 
Poulikakos PI, Persaud Y, Janakiraman M, et al. RAF inhibitor resistance is mediated by 
dimerization of aberrantly spliced BRAF(V600E). Nature 2011;480(7377):387−90.  
Ribas A, Hodi FS, Callahan M, et al. Correspondence: hepatotoxicity with combination of 
vemurafenib and ipilimumab. N Engl J Med 2012 368:1365−6. 


 
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Ries LAG, et al, eds. SEER Cancer Statistics Review, 1975-2000, Bethesda, MD: 
National Cancer Institute 2003:Table XVI-1-9. 
Sanger Institute. http://www.sanger.ac.uk/genetics/CGP/cosmic/. Accessed 10 July 2012. 
Shi H, Moriceau G, Kong X, et al. Melanoma whole-exome sequencing identifies 
(V600E) B-RAF amplification-mediated acquired B-RAF inhibitor resistance. Nat 
Commun 2012;3:724.  
Smalley KS, Hass NK, et al., Multiple signaling pathways must be targeted to overcome 
drug resistance in cell lines derived from melanoma metastases. Molec Cancer 
Therapy 2006;5:1136−44. 
Smalley KSM, Herlyn M, Flaherty KT. Targeting BRAF/MEK in melanoma: new hope or 
another false dawn? Expert Tev. Dermatol 2007;2:179−90. 
Solit DB, Garraway LA, Pratilas CA, et al. BRAF mutation predicts sensitivity to MEK 
inhibition. Nature 2006;(439):358−62. 
Sosman JA, Kim KB, Schuchter L, et al. Survival in BRAF V600-mutant advanced 
melanoma treated with vemurafenib. N Engl J Med. 2012;366(8):707−14. 
Su F, Bradley WD, Wang Q, et al. Resistance to selective BRAF inhibition can be 
mediated by modest upstream pathway activation. Cancer Res 2012;72(4):969−78. 
Sumimoto H, Miyagishi M, Miyoshi H, et al., Inhibition of growth and invasive ability of 
melanoma by invasion of mutated BRAF with lentivirus-mediated RNA interference. 
Oncogene 2004;(23):6031−9. 
SUNSMART Cancer Council. 
http://www.sunsmart.com.au/browse.asp?ContainerID=1752/ SUNSMART Victoria 
(2007). 
Villanueva J, Vultur A, Lee JT, et al. Acquired resistance to BRAF inhibitors mediated by 
a RAF kinase switch in melanoma can be overcome by cotargeting MEK and 
IGF-1R/PI3K. Cancer Cell 2010;18(6):683−95. 
Wagle N, Emery C, Berger MF, et al. Dissecting therapeutic resistance to RAF inhibition 
in melanoma by tumor genomic profiling. J Clin Oncol 2011;29(22):3085−96. 


 
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Appendix 1  Schedule of Assessments and Procedures 
Period 
Screening 
Study Treatment 
End-of-
study 
treatment
Follow-up after treatment 
discontinuation 
Cycle 
 
Cycle 1 
Cycle 
2 
Cycle 
3 
Cycle 
4 
Cycle 
5 
Cycle 
6 
Cycles 
7 +  
 
4 
wks
12 
wks
6 mths 
Day 
 
1 
15
1 
15
1 
15
1 
1 
1 
15 
1 
 
 
 
 
Informed 
consent1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor tissue 
for BRAFV600 
mutation 
testing1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization2 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
and 
demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Interval medical 
history 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
 
 
 
Physical exam 
including 
HEENT, vital 
signs, height, 
weight3 
X 
X 
X 
X 
X 
X 
 
X3 
X 
X 
 
X3  
 
X 
 
 
Anal and 
gynecological 
exam3A 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Appendix 1 Schedule of Assessments and Procedures (cont.) 
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155 
Period 
Screening 
Study Treatment 
End-of-
study 
treatment
Follow-up after treatment 
discontinuation 
Cycle 
 
Cycle 1 
Cycle 
2 
Cycle 
3 
Cycle 
4 
Cycle 
5 
Cycle 
6 
Cycles 
7 +  
 
4 
wks
12 
wks
6 mths 
Day 
 
1 
15
1 
15
1 
15
1 
1 
1 
15 
1 
 
 
 
 
ECOG 
Performance 
Status 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
 
 
 
 
12-lead ECG5 
X 
Per vemurafenib IB for patients receiving vemurafenib. If clinically 
indicated for patients receiving only cobimetinib/placebo 5 
 
 
 
 
ECHO or 
MUGA6 
X 
 
 
X 
 
 
 
 
X 
 
 
X6 
X6 
 
 
 
Hematology7 
X 
X 
 
X 
 
X 
 
X 
X 
X 
 
X 
 
 
 
 
Chemistry and 
LFTs8 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
 
 
Serum 
pregnancy 
tests9 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fasting blood 
glucose and 
lipid panel10 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT/MRI brain11 
X 
As clinically indicated 
 
 
 
 
Radiologic 
tumor 
assessment12 
X 
Per local standard of care12 
 
 
 
 
 


Appendix 1 Schedule of Assessments and Procedures (cont.) 
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156 
Period 
Screening 
Study Treatment 
End-of-
study 
treatment
Follow-up after treatment 
discontinuation 
Cycle 
 
Cycle 1 
Cycle 
2 
Cycle 
3 
Cycle 
4 
Cycle 
5 
Cycle 
6 
Cycles 
7 +  
 
4 
wks
12 
wks
6 mths 
Day 
 
1 
15
1 
15
1 
15
1 
1 
1 
15 
1 
 
 
 
 
Mandatory 
whole blood 
sample for 
genotyping 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK blood 
samples 13 
 
X 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Vemurafenib 
administration14 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Cobimetinib 
administration14 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Drug 
accountability15 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
 
 
 
Concomitant 
medications16 
X16 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
 
 
 
Adverse 
events17 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X17 
 
 
Survival 
assessment 
and 
subsequent 
anti-cancer 
therapy18 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X18 
→ 


Appendix 1 Schedule of Assessments and Procedures (cont.) 
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Period 
Screening 
Study Treatment 
End-of-
study 
treatment
Follow-up after treatment 
discontinuation 
Cycle 
 
Cycle 1 
Cycle 
2 
Cycle 
3 
Cycle 
4 
Cycle 
5 
Cycle 
6 
Cycles 
7 +  
 
4 
wks
12 
wks
6 mths 
Day 
 
1 
15
1 
15
1 
15
1 
1 
1 
15 
1 
 
 
 
 
Dermatologic 
exam19 
X 
 
 
X 
 
 
 
 
X 
 
 
X19 
X19 
 
 
 
Ophthalmologic 
exams20 
X 
 
 
X 
 
 
 
 
X 
 
 
X20 
X20 
 
 
 
Tumor biopsy 
for biomarker 
analyses21 
X 
 
 
 
X 
 
 
 
 
 
 
 
X21A 
 
 
 
Blood samples 
for biomarker22 
 
X 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
Cutaneous 
SCC tumor 
tissue or 
suspicious 
neoplasms23 
X 
→ 
→ 
→
→ 
→
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
CT/MRI of 
chest to 
monitor for 
SCC24 
 
Per local 
standard 
of care 
24 
 
 
 
 
 
 
 
 
 
 
 
 
 


Appendix 1 Schedule of Assessments and Procedures (cont.) 
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Protocol GO28141, Version 8 
158 
Period 
Screening 
Study Treatment 
End-of-
study 
treatment
Follow-up after treatment 
discontinuation 
Cycle 
 
Cycle 1 
Cycle 
2 
Cycle 
3 
Cycle 
4 
Cycle 
5 
Cycle 
6 
Cycles 
7 +  
 
4 
wks
12 
wks
6 mths 
Day 
 
1 
15
1 
15
1 
15
1 
1 
1 
15 
1 
 
 
 
 
Optional whole 
blood sample 
for RCR 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT = computerized tomography scan; ECG = electrocardiogram; ECHO = echocardiogram; HEENT = head, ears, eyes, nose and throat; LFT = 
liver function test; MRI = magnetic resonance imaging scan; MUGA = Multiple Gated Acquisition; RCR = Roche Clinical Repository; SCC = 
squamous cell carcinoma 
→ Assessment or procedure is performed throughout the study.  
 
Schedule of Assessments – Footnotes 
Notes:  Assessments scheduled on the day of study drug administration should be performed prior to study drug dosing, unless otherwise specified. 
Unless otherwise specified, assessments that are done every 2 weeks should be performed within a ± 2 days window. Assessments performed 
monthly, should be performed within a window of ± 3 days.  
A clinic visit should be scheduled any time there is a safety issue or any unscheduled assessments need to be performed. 
1. Informed consent must be obtained before any study specific screening assessments are performed. Screening assessments are to be 
performed within 28 days prior to Cycle 1 Day 1 unless otherwise noted. Assessments performed as standard of care before signed informed 
consent form but within the screening window may be used for screening. Screening exams for ECG, hematology, and chemistry must be 
performed within 14 days of first dose.  Melanoma tissue must be tested for BRAFV600 mutation using the cobas® 4800 BRAF V600 mutation may 
be performed at a Roche-designated Central Reference Laboratory or at a non-Roche-designated laboratory.  If a non-Roche-designated 
laboratory is used for BRAFV600 mutation testing, documentation of the test procedures and results must be included as source documentation.  
Testing requires an FFPE tumor block or 5 unstained sections.  BRAFV600 mutation testing must be performed prior to additional screening 
tests and requirements.  Standard-of-care tests or examinations may be performed concurrently with the BRAFV600 mutation testing. The 
28-day window (Day-28 to Day-1) for performing screening assessments opens at the time the first additional screening assessment is 
performed after the cobas® 4800 BRAF V600 mutation test result is available. 


Appendix 1 Schedule of Assessments and Procedures (cont.) 
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2. Randomization can be done up to 72 hours prior to Cycle 1 Day 1. Following approval of protocol v6, treatment assignment will be unblinded and 
patients who have been receiving vemurafenib plus placebo who provide consent may cross over to receive vemurafenib plus cobimetinib if this 
is considered by the physician to be in the patient’s best interest. 
3. Physical exam will be performed during screening and subsequently at each study visit.  After initial screening physical exam, a 
symptom-directed exam that contains an evaluation of the oral cavity, oropharynx, neck, lungs, heart, abdomen, and skin, will be performed.  
Patients will be asked about skin and vision changes at each symptom-directed physical exam.  Assessments must be done before study drug 
dosing, where applicable.  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.  Weight, and vital signs, which include temperature, heart rate, respiratory rate, and systolic and diastolic blood 
pressures while the patient is in a seated position, will be collected at each study visit that a physical exam is performed.  Blood pressure and 
heart rate measurements will be recorded after a 5-minute rest in a seated position.  Height will be collected only at screening/baseline.  
3A Visual inspection of the anus and digital examination of the anal canal will be performed at screening, thereafter per local standard of care for 
vemurafenib-treated patients, and at other times as clinically indicated to monitor for SCC. Colonoscopy, sigmoidoscopy, or anoscopy is not 
required but may be performed if clinically indicated. All female patients will undergo pelvic examination including visual inspection of the uterine 
cervix and Pap smear at screening, thereafter per local standard of care, and at other times as clinically indicated to monitor for cervical 
carcinoma. 
4. Following approval of v5 of the protocol, QoL assessments will no longer be conducted.  
5. ECG monitoring for patients receiving vemurafenib will be conducted in accordance with the vemurafenib IB. Ongoing ECG monitoring is no 
longer required for patients continuing to receive only cobimetinib/placebo unless clinically indicated.   
6. All patients will undergo evaluation of left ventricular function, either by ECHO or MUGA at the following timepoints: 
• Screening 
• Cycle 2, Day 1 ± 1 week  
• On Day 1 of Cycles 5, 8, and 11 (every 3 treatment cycles) ± 2 weeks 
• On Day 1 of Cycles 15, 19, 23 (every 4 treatment cycles) ± 2 weeks 
• On Day 1 of Cycles 29, 35, 41, 47 etc. (every 6 treatment cycles) ± 2 weeks 
• End-of-study-treatment visit   
    Evaluation of left ventricular function does not need to be performed at end-of-study-treatment visit if it has been performed within the last 
12 weeks. Any patient who develops clinical signs or symptoms suspicious of cardiac failure should undergo an LVEF assessment. Evaluation of 
left ventricular function must be performed by the same method for each patient. 
 For patients who cross over from placebo to cobimetinib treatment, the ECHO/MUGA schedule must begin again, with exams at the following 
timepoints: 
• 
Within 28 days of, but not after the first day of cross over 


Appendix 1 Schedule of Assessments and Procedures (cont.) 
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• Start of second cycle after cross over, Day 1 ± 1 week  
• On Day 1 of Cycles 5, 8, and 11 after cross over (every three treatment cycles) ± 2 weeks 
• On Day 1 of Cycles 15, 19, and 23 after cross over (every four treatment cycles) ± 2 weeks 
• On Day 1 of Cycles 29, 35, 41, 47 after cross over, etc. (every six treatment cycles) ± 2 weeks 
• End-of-study-treatment visit 
7. Hematology includes hemoglobin, hematocrit, WBC with differential (neutrophils, lymphocyte, monocyte, eosinophil and basophil counts, and 
other cells), and platelet count.  Screening hematology values must be obtained within 14 days of Cycle 1 Day 1.  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. 
8. Chemistry includes BUN, creatinine, sodium, potassium, chloride, bicarbonate, phosphorus, magnesium, total calcium, albumin, LDH, and CPK. 
LFTs include ALT, AST, total bilirubin, ALP, and GGT.  Screening chemistry values must be obtained within 14 days of Cycle 1 Day 1. 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. 
9. For women of childbearing potential, a serum pregnancy test is required at screening within 14 days prior to Cycle 1 Day 1.  Women who have 
had amenorrhea for > 12 months but < 2 years should have an FSH test at screening for eligibility purposes.  
10. This is performed only during screening. Both blood glucose and lipid panel must be obtained after at least an 8-hour fast. Lipid panel should 
include total cholesterol, low-density lipoprotein and triglycerides. 
11. All patients must have a screening brain CT or MRI to assess for brain metastasis, and subsequently only as clinically indicated.  
12. The frequency, method, and evaluation criteria for tumor assessments will be determined by the investigator per local clinical practice.  
Response may be assessed using RECIST v1.1. Assessments should include CT scans of the chest, abdomen and pelvis, with an evaluation of 
all known or suspected sites of disease, whenever possible. The same radiographic procedure used at screening should be used throughout the 
study.  
13.PK sample for analysis of vemurafenib concentration will be collected in sodium heparin tubes and will require 2mL of venous blood at each 
timepoint. PK sample for analysis of cobimetinib concentration will be collected in K2-EDTA tubes and will require 3mL of venous blood at each 
timepoint. The time and date of all PK samples must be documented. Plasma samples for vemurafenib and cobimetinib concentration 
measurement will be collected at the following time-points: 
• 1−4 hours after the first dose on Cycle 1, Day 1 
• Pre-dose on Cycle 1, Day 15 ± 3 days 
• 2−4 hours post-dose on Cycle 1, Day 15 ± 3 days 
• Pre-dose on Cycle 2, Day 15 ± 3 days 
14. For both investigational drugs, dosing will continue until disease progression, consent withdrawal, or unacceptable toxicity. Dispense a 
sufficient number of vemurafenib and cobimetinib to last until the next visit. Extra medications may be dispensed if there is a reasonable 
possibility that the patient’s next visit may be delayed (e.g., because of inclement weather or distance of patient’s home from study center).  


Appendix 1 Schedule of Assessments and Procedures (cont.) 
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161 
15. Provide a medication diary. Instruct patient to record the time and date they take each study drug dose in the diary and to return all unused 
capsules at each study visit to assess compliance. Collect and review medication diary, collect unused medications, and assess compliance at 
each subsequent visit. At least 7 days off cobimetinib are required prior to starting a new treatment cycle. 
16. Review and capture of all concomitant medications will be performed at each study visit. Concomitant medications are defined as any 
prescription medications, over-the-counter preparations and supplements used by a patient within 7 days prior to Cycle 1, Day 1 and continuing 
through the study completion visit.  
17. All adverse events and serious adverse events will be collected. All adverse events or serious adverse events occurring after study 
discontinuation will be recorded until 28 days after the last dose of study treatment or until initiation of another subsequent anti-cancer therapy, 
whichever occurs first. Any second non-cutaneous primary malignancy (related or unrelated to study treatment) that develop during or up to 
12 months after study treatment completion must be reported as a serious adverse event. 
18. Survival assessment will be used to collect overall survival during long-term follow-up; patient should be followed up every 12 weeks until 
death, withdrawal of consent, or loss to follow-up. Subsequent anti-cancer therapy information will be collected at the same time as survival 
assessment. 
19. Dermatology evaluation: Complete evaluation of the skin by a dermatologist, or qualified equivalent medical specialist, will be conducted at 
baseline (up to 28 days prior to Cycle 1, Day 1), Cycle 2, Day 1 (± 1 week), and per local standard of care thereafter while receiving study 
treatment and at the end-of-study-treatment visit. Dermatologic examination does not need to be performed at end-of-study-treatment visit if one 
has been performed within the last 12 weeks.  
20. All patients will undergo ophthalmologic examination at the following timepoints: 
• Screening 
• Cycle 2, Day 1 ± 1 week  
• On Day 1 of Cycles 5, 8 and 11 (every 3 treatment cycles) ± 2 weeks 
• On Day 1 of Cycles 15, 19, 23 (every 4 treatment cycles) ± 2 weeks 
• On Day 1 of Cycles 29, 35, 41, 47 etc. (every 6 treatment cycles) ± 2 weeks 
• End-of-study-treatment visit 
    Ophthalmologic examination does not need to be performed at end-of-study-treatment visit if one has been performed within the last 12 weeks. 
Baseline ophthalmologic examination evaluates for evidence of retinal pathology that is considered a risk factor for neurosensory retinal 
detachment, RVO, or neovascular macular degeneration. Risk factors for RVO include elevated serum cholesterol, hypertriglyceridemia, 
hyperglycemia, hypertension and glaucoma. Ophthalmologic examination will include visual acuity testing, intraocular pressure measurements 
by tonometry, slit lamp ophthalmoscopy, indirect ophthalmoscopy, and spectral domain optical coherence tomography (spectral domain OCT, if 
not available, may be substituted with time domain OCT). 


Appendix 1 Schedule of Assessments and Procedures (cont.) 
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Protocol GO28141, Version 8 
162 
 For patients who cross over from placebo to cobimetinib treatment, the ophthalmologic examination schedule should begin again, with exams at 
the following timepoints: 
• 
Within 28 days of, but not after the first day of cross over 
• Start of second cycle after cross over, Day 1 ± 1 week  
• On Day 1 of Cycles 5, 8 and 11 after cross over (every three treatment cycles) ± 2 weeks 
• On Day 1 of Cycles 15, 19, 23 after cross over (every four treatment cycles) ± 2 weeks 
• On Day 1 of Cycles 29, 35, 41, 47 after cross over, etc. (every six treatment cycles) ± 2 weeks 
• End-of-study-treatment visit 
 
21. Biopsies of accessible melanoma lesions are mandatory upon patient’s consent to participate in the trial. Either FFPE or fresh-frozen biopsies 
(or both) will be obtained at 3 timepoints: 
• Baseline sample: during screening within 28 days of Cycle 1 Day 1 
• On treatment cycle: on Cycle 2, Day 15 (± 1 week) 
• Disease progression sample: at time of progressive disease 
    Baseline sample biopsies should be completed at least 48 hours before the initiation of study drug therapy on Cycle 1 Day 1. Archival tissue 
may be submitted in place of newly obtained tumor tissue for the baseline sample biopsy. It is highly recommended that the biopsy at disease 
progression be collected within 3 days after last study treatment. Excisional biopsies, punch biopsies, 14-gauge core needle biopsies are 
acceptable. Fine needle aspiration (FNA) biopsies are not acceptable.   
21A. Biopsy will only be performed if patient has accessible lesion and disease progression.  
22. Blood samples for biomarker analysis will be obtained on Day 1 of Cycles 1, 3, and 5, and at the time of disease progression.  Blood sample 
required at each timepoint: one 6-mL blood sample anticoagulated in EDTA. 
23. If a patient develop any cutaneous lesion(s) suspicious for SCC or KA during the study, biopsy tissue and a paired normal skin biopsy must be 
obtained for central pathology review. Only one normal skin biopsy is required per patient, regardless of the number of SCC lesions identified 
and biopsied during the study. Any suspicious lesions (cutaneous or non-cutaneous) thought to be malignant must also be sent for central 
pathology review and may undergo molecular characterization. 
• 
Any second non-cutaneous primary malignancy (related or unrelated to study treatment) that develop during or up to 12 months after 
study treatment completion must be reported as a serious adverse event and tumor tissue sent for central pathology review.  
24. Patients will undergo CT/MRI of the chest to monitor for the occurrence of SCC while on study treatment and per local standard of care.  


 
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Appendix 2  Schedule of Pharmacokinetic Assessments 
Visit 
Timepoint 
Sample Type 
Cycle 1, Day 1 
1-4 hours after the first dose of 
vemurafenib and cobimetinib 
vemurafenib PK 
cobimetinib PK 
Cycle 1, Day 15 ± 
3 days 
Prior to doses of vemurafenib and 
cobimetinib 
vemurafenib PK 
cobimetinib PK 
Cycle 1, Day 15 ± 
3 days 
2-4 hours after the dose of vemurafenib 
and cobimetinib 
vemurafenib PK 
cobimetinib PK 
Cycle 2, Day 15 ± 
3 days 
Prior to doses of vemurafenib and 
cobimetinib 
vemurafenib PK 
cobimetinib PK 
PK = pharmacokinetic. 
 
 
 


 
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Appendix 3 New Response Evaluation Criteria in Solid Tumors 
–  
Version 1.1 – Excerpt From Original Publication with Addition of 
Supplementary Explanations  
MEASURABILITY OF TUMOR AT BASELINE 
DEFINITIONS  
At baseline, tumor lesions/lymph nodes will be categorized measurable or 
non-measurable as follows:  
MEASURABLE TUMOR LESIONS 
Tumor lesions must be accurately measured in at least one dimension (longest diameter 
in the plane of measurement is to be recorded) with a minimum size of:  
• 
10 mm by computed tomography (CT) scan (CT scan slice thickness no greater 
than 5 mm).  
• 
10 mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable).  
• 
20 mm by chest X-ray.  
• 
Malignant lymph nodes:  To be considered pathologically enlarged and measurable, 
a lymph node must be ≥ 15 mm in short axis when assessed by CT scan (CT scan 
slice thickness recommended to be no greater than 5 mm).  At baseline and in 
follow-up, only the short axis will be measured and followed.  See also section 
below on ‘Baseline documentation of target and non-target lesions’ for information 
on lymph node measurement.  
 
NON-MEASURABLE TUMOR LESIONS 
Non-measurable tumor lesions encompass small lesions (longest diameter < 10 mm or 
pathological lymph nodes with ≥ 10 to < 15 mm short axis) as well as truly 
non-measurable lesions.  Lesions considered truly non-measurable include:  
leptomeningeal disease, ascites, pleural or pericardial effusion, inﬂammatory breast 
disease, lymphangitic involvement of skin or lung, peritoneal spread, abdominal 
masses/abdominal organomegaly identiﬁed by physical exam that are not measurable 
by reproducible imaging techniques.  


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Special Considerations Regarding Lesion Measurability  
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment:  
Bone lesions: 
• 
Bone scan, positron emission tomography (PET) scan or X-rays are not considered 
adequate imaging techniques to measure bone lesions.  However, these techniques 
can be used to conﬁrm the presence or disappearance of bone lesions.  
• 
Lytic bone lesions or mixed lytic-blastic lesions, with identiﬁable soft tissue 
components, that can be evaluated by cross sectional imaging techniques, such as 
CT or magnetic resonance imaging (MRI) can be considered as measurable lesions 
if the soft tissue component meets the deﬁnition of measurability described above.  
• 
Blastic bone lesions are non-measurable.  
 
Cystic lesions: 
• 
Lesions that meet the criteria for radiographically deﬁned simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since 
they are, by deﬁnition, simple cysts.  
• 
‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the deﬁnition of measurability described above.  
However, if non-cystic lesions are present in the same patient, these are preferred 
for selection as target lesions.  
 
Lesions with prior local treatment:  
• 
Tumor lesions situated in a previously irradiated area, or in an area subjected to 
other loco-regional therapy, are usually not considered measurable unless there has 
been demonstrated progression in the lesion.  Study protocols should detail the 
conditions under which such lesions would be considered measurable.  
 
SPECIFICATIONS BY METHODS OF MEASUREMENTS  
MEASUREMENT OF LESIONS  
All measurements should be recorded in metric notation, using calipers if clinically 
assessed.  All baseline evaluations should be performed as close as possible to the 
treatment start and never more than 4 weeks before the beginning of the treatment.  
METHOD OF ASSESSMENT  
The same method of assessment and the same technique should be used to 
characterize each identiﬁed and reported lesion at baseline and during follow-up.  
Imaging-based evaluation should always be done rather than clinical examination unless 
the lesion(s) being followed cannot be imaged but are assessable by clinical exam.  


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Clinical lesions:  Clinical lesions will only be considered measurable when they are 
superﬁcial and ≥ 10 mm diameter as assessed using calipers (e.g. skin nodules).    As 
noted above, when lesions can be evaluated by both clinical exam and imaging, imaging 
evaluation should be undertaken since it is more objective and may also be reviewed at 
the end of the study.  
Chest X-ray:  Chest CT is preferred over chest X-ray, particularly when progression is an 
important endpoint, since CT is more sensitive than X-ray, particularly in identifying new 
lesions.  However, lesions on chest X-ray may be considered measurable if they are 
clearly deﬁned and surrounded by aerated lung.  Still, non-contrast CT is preferred over 
chest X-ray. 
CT, MRI:  CT is the best currently available and reproducible method to measure lesions 
selected for response assessment.  This guideline has deﬁned measurability of lesions 
on CT scan based on the assumption that CT slice thickness is 5 mm or less.  When CT 
scans have slice thickness greater than 5 mm, the minimum size for a measurable lesion 
should be twice the slice thickness.  MRI is also acceptable in certain situations (e.g., for 
body scans). 
If prior to enrolment it is known that a patient is not able to undergo CT scans with 
intravenous (IV) contrast due to allergy or renal insufficiency, the decision as to whether 
a non-contrast CT or MRI (with or without IV contrast) will be used to evaluate the 
patient at baseline and follow-up, should be guided by the tumor type under investigation 
and the anatomic location of the disease.  For patients who develop contraindications to 
contrast after baseline contrast CT is done, the decision as to whether non-contrast CT 
or MRI (enhanced or non-enhanced) will be performed, should also be based on the 
tumor type, anatomic location of the disease and should be optimized to allow for 
comparison to the prior studies if possible.  Each case should be discussed with the 
radiologist to determine if substitution of these other approaches is possible and, if not, 
the patient should be considered not evaluable from that point forward. 
Ultrasound:  Ultrasound is not useful in assessment of lesion size and should not be 
used as a method of measurement.  Ultrasound examinations cannot be reproduced in 
their entirety for independent review at a later date and, because they are operator 
dependent, it cannot be guaranteed that the same technique and measurements will be 
taken from one assessment to the next.  If new lesions are identiﬁed by ultrasound in the 
course of the study, conﬁrmation by CT or MRI is advised.  If there is concern about 
radiation exposure at CT, MRI may be used instead of CT in selected instances.   
Endoscopy, laparoscopy:  The utilization of these techniques for objective tumor 
evaluation is not advised.  However, they can be useful to conﬁrm complete pathological 


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response when biopsies are obtained or to determine relapse in trials where recurrence 
following complete response or surgical resection is an endpoint.  
Tumor markers:  Tumor markers alone cannot be used to assess objective tumor 
response.  If markers are initially above the upper normal limit, however, they must 
normalize for a patient to be considered in complete response.  Because tumor markers 
are disease speciﬁc, instructions for their measurement should be incorporated into 
protocols on a disease speciﬁc basis.  Speciﬁc guidelines for both CA-125 response 
(in recurrent ovarian cancer) and PSA response (in recurrent prostate cancer) have 
been published.  In addition, the Gynecologic Cancer Intergroup has developed CA-125 
progression criteria, which are to be integrated with objective tumor assessment for use 
in ﬁrst-line trials in ovarian cancer. 
Cytology, histology:  These techniques can be used to differentiate between partial 
response (PR) and complete response (CR) in rare cases if required by protocol 
(for example, residual lesions in tumor types such as germ cell tumors, where known 
residual benign tumors can remain).  When effusions are known to be a potential 
adverse effect of treatment (e.g., with certain taxane compounds or angiogenesis 
inhibitors), the cytological conﬁrmation of the neoplastic origin of any effusion that 
appears or worsens during treatment can be considered if the measurable tumor has 
met criteria for response or stable disease in order to differentiate between response 
(or stable disease) and progressive disease.  
TUMOR RESPONSE EVALUATION  
ASSESSMENT OF OVERALL TUMOR BURDEN AND MEASURABLE 
DISEASE  
To assess objective response or future progression, it is necessary to estimate the 
overall tumor burden at baseline and use this as a comparator for subsequent 
measurements.  Only patients with measurable disease at baseline should be included 
in protocols where objective tumor response is the primary endpoint.  Measurable 
disease is deﬁned by the presence of at least one measurable lesion (as detailed above 
in the section titled “Measurable Tumors at Baseline”).  In studies where the primary 
endpoint is tumor progression (either time to progression or proportion with progression 
at a ﬁxed date), the protocol must specify if entry is restricted to those with measurable 
disease or whether patients having non-measurable disease only are also eligible.  
Baseline Documentation of ‘Target’ and ‘Non-Target’ Lesions  
When more than one measurable lesion is present at baseline all lesions up to a 
maximum of ﬁve lesions total (and a maximum of two lesions per organ) representative 
of all involved organs should be identiﬁed as target lesions and will be recorded and 
measured at baseline. 


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This means in instances where patients have only one or two organ sites involved a 
maximum of two (one site) and four lesions (two sites), respectively, will be recorded.  
Other lesions in that organ will be recorded as non-measurable  
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter), be representative of all involved organs, but in addition should be those that 
lend themselves to reproducible repeated measurements.  It may be the case that, 
on occasion, the largest lesion does not lend itself to reproducible measurement in which 
circumstance the next largest lesion which can be measured reproducibly should be 
selected. 
Lymph nodes merit special mention since they are normal anatomical structures that 
may be visible by imaging even if not involved by tumor.  Pathological nodes which are 
deﬁned as measurable and may be identiﬁed as target lesions must meet the criterion of 
a short axis of ≥ 15 mm by CT scan.  Only the short axis of these nodes will contribute to 
the baseline sum.  The short axis of the node is the diameter normally used by 
radiologists to judge if a node is involved by solid tumor.  Nodal size is normally reported 
as two dimensions in the plane in which the image is obtained (for CT scan this is almost 
always the axial plane; for MRI the plane of acquisition may be axial, saggital or coronal).  
The smaller of these measures is the short axis.  For example, an abdominal node, 
which is reported as being 20 mm × 30 mm, has a short axis of 20 mm and qualiﬁes as a 
malignant, measurable node.  In this example, 20 mm should be recorded as the node 
measurement.  All other pathological nodes (those with short axis ≥ 10 mm but < 15 mm) 
should be considered non-target lesions.  Nodes that have a short axis < 10 mm are 
considered non-pathological and should not be recorded or followed.  
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum diameters.  If lymph 
nodes are to be included in the sum, then as noted above, only the short axis is added 
into the sum.  The baseline sum diameters will be used as reference to further 
characterize any objective tumor regression in the measurable dimension of the disease.  
All other lesions (or sites of disease) including pathological lymph nodes should be 
identiﬁed as non-target lesions and should also be recorded at baseline.  Measurements 
are not required and these lesions should be followed as ‘present’, ‘absent’, or in rare 
cases ‘unequivocal progression.’  In addition, it is possible to record multiple non-target 
lesions involving the same organ as a single item on the case report form (e.g., ‘multiple 
enlarged pelvic lymph nodes’ or ‘multiple liver metastases’).  


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RESPONSE CRITERIA  
This section provides the deﬁnitions of the criteria used to determine objective tumor 
response for target lesions.  
EVALUATION OF TARGET LESIONS  
• 
Complete Response (CR):  Disappearance of all target lesions.  Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis 
to < 10 mm. 
• 
Partial Response (PR):  At least a 30% decrease in the sum of diameters of target 
lesions, taking as reference the baseline sum diameters.  
• 
Progressive Disease (PD):  At least a 20% increase in the sum of diameters of 
target lesions, taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study).  In addition to the relative increase of 
20%, the sum must also demonstrate an absolute increase of at least 5 mm.  
(Note:  the appearance of one or more new lesions is also considered progression.) 
• 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study. 
 
Special Notes on the Assessment of Target Lesions 
Lymph nodes:  Lymph nodes identiﬁed as target lesions should always have the actual 
short axis measurement recorded (measured in the same anatomical plane as the 
baseline examination), even if the nodes regress to below 10 mm on study.  This means 
that when lymph nodes are included as target lesions, the ‘sum’ of lesions may not be 
zero even if complete response criteria are met, since a normal lymph node is deﬁned as 
having a short axis of < 10 mm.  Case report forms (CRFs) or other data collection 
methods may therefore be designed to have target nodal lesions recorded in a separate 
section where, in order to qualify for CR, each node must achieve a short axis < 10 mm.  
For PR, SD, and PD, the actual short axis measurement of the nodes is to be included in 
the sum of target lesions.  
Target lesions that become ‘too small to measure’:  while on study, all lesions (nodal and 
non-nodal) recorded at baseline should have their actual measurements recorded at 
each subsequent evaluation, even when very small (e.g., 2 mm).  However, sometimes 
lesions or lymph nodes which are recorded as target lesions at baseline become so faint 
on CT scan that the radiologist may not feel comfortable assigning an exact measure 
and may report them as being ‘too small to measure’.  When this occurs it is important 
that a value be recorded on the CRF: 
• 
If it is the opinion of the radiologist that the lesion has likely disappeared, the 
measurement should be recorded as 0 mm. 


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• 
If the lesion is believed to be present and is faintly seen but too small to measure, a 
default value of 5 mm should be assigned and BML (below measurable limit) should 
be ticked.  (Note:  It is less likely that this rule will be used for lymph nodes since 
they usually have a deﬁnable size when normal and are frequently surrounded by 
fat such as in the retroperitoneum; however, if a lymph node is believed to be 
present and is faintly seen but too small to measure, a default value of 5 mm should 
be assigned in this circumstance as well and BML should also be ticked).  
 
This default value is derived from the 5 mm CT slice thickness (but should not be 
changed with varying CT slice thickness).  The measurement of these lesions is 
potentially non-reproducible, therefore providing this default value will prevent false 
responses or progressions based upon measurement error. 
To reiterate, however, if the radiologist is able to provide an actual measure, that 
should be recorded, even if it is below 5 mm and in that case BML should not be 
ticked. (BML is equivalent to a less than sign <.) 
Lesions that split or coalesce on treatment: when non-nodal lesions ‘fragment’, 
the longest diameters of the fragmented portions should be added together to calculate 
the target lesion sum.  Similarly, as lesions coalesce, a plane between them may be 
maintained that would aid in obtaining maximal diameter measurements of each 
individual lesion.  If the lesions have truly coalesced such that they are no longer 
separable, the vector of the longest diameter in this instance should be the maximal 
longest diameter for the ‘coalesced lesion’.  
EVALUATION OF NON-TARGET LESIONS  
This section provides the deﬁnitions of the criteria used to determine the tumor response 
for the group of non-target lesions.  While some non-target lesions may actually be 
measurable, they need not be measured and instead should be assessed only 
qualitatively at the timepoints speciﬁed in the protocol.  
• 
Complete Response (CR):  Disappearance of all non-target lesions and 
normalization of tumor marker level.  All lymph nodes must be non-pathological in 
size (< 10 mm short axis). 
• 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits. 
• 
Progressive Disease (PD):  Unequivocal progression of existing non-target lesions. 
(Note: the appearance of one or more new lesions is also considered progression.) 
  


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Special Notes on Assessment of Progression of Non-Target Disease  
The concept of progression of non-target disease requires additional explanation as 
follows:  
• 
When the patient also has measurable disease:  in this setting, to achieve 
‘unequivocal progression’ on the basis of the non-target disease, there must be an 
overall level of substantial worsening in non-target disease in a magnitude that, 
even in presence of SD or PR in target disease, the overall tumor burden has 
increased sufficiently to merit discontinuation of therapy.  A modest ‘increase’ in the 
size of one or more non-target lesions is usually not sufficient to qualify for 
unequivocal progression status.  The designation of overall progression solely on 
the basis of change in non-target disease in the face of SD or PR of target disease 
will therefore be extremely rare.  
• 
When the patient has only non-measurable disease:  this circumstance arises in 
some Phase III trials when it is not a criterion of study entry to have measurable 
disease.  The same general concepts apply here as noted above; however, in this 
instance there is no measurable disease assessment to factor into the interpretation 
of an increase in non-measurable disease burden.  Because worsening in non-
target disease cannot be easily quantiﬁed (by deﬁnition:  if all lesions are truly non-
measurable) a useful test that can be applied when assessing patients for 
unequivocal progression is to consider if the increase in overall disease burden 
based on the change in non-measurable disease is comparable in magnitude to the 
increase that would be required to declare PD for measurable disease:  i.e., an 
increase in tumor burden representing an additional 73% increase in ‘volume’ 
(which is equivalent to a 20% increase diameter in a measurable lesion).  Examples 
include an increase in a pleural effusion from ‘trace’ to ‘large’, an increase in 
lymphangitic disease from localized to widespread, or may be described in protocols 
as ‘sufficient to require a change in therapy’.  If ‘unequivocal progression’ is seen, 
the patient should be considered to have had overall PD at that point.  While it 
would be ideal to have objective criteria to apply to non-measurable disease, the 
very nature of that disease makes it impossible to do so; therefore the increase 
must be substantial.  
 
NEW LESIONS  
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important.  There are no speciﬁc criteria for 
the identiﬁcation of new radiographic lesions; however, the ﬁnding of a new lesion 
should be unequivocal: i.e., not attributable to differences in scanning technique, change 
in imaging modality or ﬁndings thought to represent something other than tumor 
(for example, some ‘new’ bone lesions may be simply healing or ﬂare of pre-existing 
lesions).  


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This is particularly important when the patient’s baseline lesions show partial or 
complete response.  For example, necrosis of a liver lesion may be reported on a CT 
scan report as a ‘new’ cystic lesion, which it is not.  
A lesion identiﬁed on a follow-up study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression.  An example 
of this is the patient who has visceral disease at baseline and while on study has a brain 
CT or MRI ordered which reveals metastases.  The patient’s brain metastases are 
considered to be evidence of PD even if he/she did not have brain imaging at baseline 
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease.  If repeat scans conﬁrm 
there is deﬁnitely a new lesion, then progression should be declared using the date of 
the initial scan.  
EVALUATION OF BEST OVERALL RESPONSE  
The best overall response is the best response recorded from the start of the study 
treatment until the end of treatment taking into account any requirement for conﬁrmation.  
On occasion a response may not be documented until after the end of therapy so 
protocols should be clear if post-treatment assessments are to be considered in 
determination of best overall response.  Protocols must specify how any new therapy 
introduced before progression will affect best response designation.  
The patient’s best overall response assignment will depend on the ﬁndings of both target 
and non-target disease and will also take into consideration the appearance of new 
lesions.  
Furthermore, depending on the nature of the study and the protocol requirements, it may 
also require conﬁrmatory measurement.  Speciﬁcally, in non-randomized trials where 
response is the primary endpoint, conﬁrmation of PR or CR is needed to deem either 
one the ‘best overall response’.  This is described further below.  
Timepoint Response  
It is assumed that at each protocol speciﬁed timepoint, a response assessment occurs. 
Table 1 provides a summary of the overall response status calculation at each timepoint 
for patients who have measurable disease at baseline. 
 
 
 


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When patients have non-measurable (therefore non-target) disease only, Table 2 is to 
be used.  
 
 
 
 
MISSING ASSESSMENTS AND NOT-EVALUABLE DESIGNATION  
When no imaging/measurement is done at all at a particular timepoint, the patient is not 
evaluable at that timepoint.  If only a subset of lesion measurements are made at an 
assessment, usually the case is also considered not evaluable at that timepoint, unless a 
convincing argument can be made that the contribution of the individual missing lesion(s) 
would not change the assigned timepoint response.  This would be most likely to happen 
in the case of PD.  


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For example, if a patient had a baseline sum of 50 mm with three measured lesions and 
at follow-up only two lesions were assessed, but those gave a sum of 80 mm, the patient 
will have achieved PD status, regardless of the contribution of the missing lesion.  
If one or more target lesions were not assessed either because the scan was not done, 
or could not be assessed because of poor image quality or obstructed view, the 
Response for Target Lesions should be “Unable to Assess” since the patient is not 
evaluable.  Similarly, if one or more non-target lesions are indicated as ‘not assessed’, 
the response for non-target lesions should be “Unable to Assess” (except where there is 
clear progression).  Overall response would be “Unable to Assess” if either the target 
response or the non-target response is “Unable to Assess” (except where this is clear 
evidence of progression) as this equates with the case being not evaluable at that 
timepoint. 
BEST OVERALL RESPONSE: ALL TIMEPOINTS 
The best overall response will be determined by statistical programming once all the 
data for the patient is known. 
Reference:  Eisenhauer EA, Therasse P, Bogaerts J, et al, New response evaluation 
criteria in solid tumors: revised RECIST guideline (Version 1.1). Eur J Cancer 
2009;45:228-247. 
 


 
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Appendix 4 ECOG Performance Status 
Patients will be graded according to the ECOG Performance Status scale and criteria as 
described below: 
Grade 
ECOG 
 
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, office work.  
 
2 
 
Ambulatory and capable of all self-care but unable to carry out any work 
activities.  Up and about more than 50% of waking hours. 
 
3 
 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours. 
 
4 
 
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed 
or chair. 
 
5 
 
Dead 
As published in:  Oken, MM, Creech RH, Tormey DC, et al. Toxicity and Response Criteria of the 
Eastern Cooperative Oncology Group.  Am J Clin Oncol 1982;5:649-655. 
 
 


 
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Appendix 5 Guidelines for Management of Asymptomatic 
Reduction in Ejection Fraction 
 


 
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Appendix 6 ICH Guidelines for Clinical Safety Data Management, 
Definitions and Standards for Expedited Reporting, Topic E2 
A serious adverse event is any experience that suggests a significant hazard, 
contraindication, side effect or precaution.  It is any AE that at any dose fulfills at least 
one of the following criteria: 
• 
Is fatal; [results in death] [NOTE: death is an outcome, not an event] 
• 
Is life-threatening [NOTE: the term "life-threatening" refers to an event in which the 
patient was at immediate risk of death at the time of the event; it does not refer to an 
event which could hypothetically have caused a death had it been more severe]. 
• 
Required in-patient hospitalization or prolongation of existing hospitalization; 
• 
Results in persistent or significant disability/incapacity; 
• 
Is a congenital anomaly/birth defect; 
• 
Is medically significant or requires intervention to prevent one or other of the 
outcomes listed above 
  
Medical and scientific judgment should be exercised in deciding whether expedited 
reporting to the Sponsor is appropriate in other situations, such as important medical 
events that may not be immediately life-threatening or result in death or hospitalization 
but may jeopardize the patient or may require intervention to prevent one of the 
outcomes listed in the definitions above. These situations should also usually be 
considered serious. 
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse. 
An unexpected AE is one, the nature or severity of which is not consistent with the 
applicable product information. 
Causality is initially assessed by the investigator. For Serious Adverse Events, possible 
causes of the event are indicated by selecting one or more options.  (Check all that apply)  
• 
Pre-existing/Underlying disease − specify  
• 
Study treatment – specify the drug(s) related to the event 
• 
Other treatment (concomitant or previous) – specify 
• 
Protocol-related procedure 
• 
Other (e.g. accident, new or intercurrent illness) – specify 
 
The term severe is a measure of intensity, thus a severe AE is not necessarily serious. 
For example, nausea of several hours' duration may be rated as severe, but may not be 
clinically serious. 


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The term severe is a measure of intensity, thus a severe AE is not necessarily serious. 
For example, nausea of several hours' duration may be rated as severe, but may not be 
clinically serious. 
A serious adverse event occurring during the study or which comes to the attention of 
the investigator within 15 days after stopping the treatment or during the protocol-defined 
follow-up period, if this is longer, whether considered treatment-related or not, must be 
reported.  In addition, a serious adverse event that occurs after this time, if considered 
related to test “drug”, should be reported. 
Such preliminary reports will be followed by detailed descriptions later which will include 
copies of hospital case reports, autopsy reports and other documents when requested 
and applicable. 
For serious adverse events, the following must be assessed and recorded on the 
adverse events page of the eCRF: intensity, relationship to test substance, action taken, 
and outcome to date. 
The investigator must notify the Ethics Review Committee/Institutional Review Board of 
a serious adverse event in writing as soon as is practical and in accordance with 
international and local laws and regulations. 
ROCHE LOCAL COUNTRY CONTACT for serious adverse events: Local Monitor  
See attached Protocol Administrative and Contact Information & List of Investigators 
Form,[ gcp_for000227], for details of administrative and contact information. 
ROCHE HEADQUARTERS CONTACT for serious adverse events and other medical 
emergencies: Clinical Operations/Clinical Science 
See attached Protocol Administrative and Contact Information & List of Investigators 
form,[gcp_for000227], for details of administrative and contact information  
24 HOUR MEDICAL COVERAGE (Roche Emergency Medical Call Center Help 
Desk):  Within the US, weekends, holidays and after 5:00 pm, call: 1-866-286-9573 and 
ask for the physician on call.  From Australia, call 1-800-031-902 and ask for the 
physician on call. (Note, the number for Australia cannot be dialed from a mobile phone.) 
 


 
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Appendix 7 New York Heart Association Classification of 
Functional Cardiac Capacity 
Class 
 
I 
No limitation:  Ordinary physical activity does not cause undue fatigue, 
dyspnea, or palpitation. 
II 
Slight limitation of physical activity:  Such patients are comfortable at rest.  
Ordinary physical activity results in fatigue, palpitations, dyspnea, or 
angina. 
III 
Marked limitation of physical activity:  Although patients are comfortable at 
rest, less than ordinary physical activity will lead to symptoms. 
IV 
Inability to carry on physical activity without discomfort:  Symptoms of 
congestive heart failure are present even at rest.  With any physical 
activity, increased discomfort is experienced. 
From:  Criteria Committee, New York Heart Association, Inc. Diseases of the heart 
and blood vessels. Nomenclature and criteria for diagnosis. 6th ed. Boston, Little, 
Brown and Co, 1964:114. 


 
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Appendix 8 AJCC TNM Staging for Melanoma 
Tumor (T) classification 
TX 
Primary tumor cannot be assessed (e.g., shave biopsy, regressed primary) 
Tis 
Melanoma in situ 
< or = 1.0 mm 
a: without ulceration and level II/III* 
T1 
b: with ulceration or level IV or V* 
1.01-2.0 mm 
a: without ulceration 
T2 
b: with ulceration 
2.01-4.0 mm 
a: without ulceration 
T3 
b: with ulceration 
>4.0 mm 
a: without ulceration 
T4 
b: with ulceration 
Node (N) classification 
One lymph node 
a: micrometastases (clinically occult) 
N1 
b: macrometastases (clinically apparent) 
2-3 lymph nodes 
a: micrometastases 
b: macrometastases 
N2 
c: in-transit met(s)/satellite(s) without metastatic lymph nodes 
N3 
4 or more metastatic lymph nodes, or matted lymph nodes, or in-transit met(s)/satellite(s) 
with metastatic lymph node(s) 
Metastasis (M) classification 
M1a 
Distant skin, subcutaneous, or lymph node metastases, normal LDH 
M1b 
Lung metastases, normal LDH 
M1c 
All other visceral metastases, normal LDH 
Any distant metastases, elevated LDH 
* Clark's levels: level II: invades the papillary dermis; level III: invades to the papillary-reticular 
dermal interface; level IV: invades the reticular dermis; level V: invades subcutaneous tissue. 
 Micrometastases are diagnosed after elective or sentinel lymphadenectomy. 
 Macrometastases are defined as clinically detectable lymph node metastases confirmed by 
therapeutic lymphadenectomy or when any lymph node metastasis exhibits gross extracapsular 
extension. 
 


 
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Appendix 9 Medications Affecting QT Interval (Information 
Available on http://www.azcert.org) 
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  Cobas® 4800 BRAF V600 Mutation Test 
Information 
The cobas® 4800 BRAF V600 Mutation Test is a real-time polymerase chain reaction 
(PCR) test intended to be used to identify melanoma patients whose tumors carry the 
BRAFV600 mutation for treatment with vemurafenib monotherapy. Its primary use is the 
detection of the BRAFV600 mutation in DNA isolated from formalin-fixed, 
paraffin-embedded human melanoma and colorectal cancer (CRC) tumor tissue. 
A prototype version of this test, designed to run on the cobas® TaqMan® 48 Analyzer, 
was used to select melanoma and CRC patients for the Phase I extension cohorts. 
The cobas® 4800 System uses the same technology as that used in the cobas® 
TaqMan® 48 Analyzer. 
Analytical performance studies have been conducted to characterize the cobas® 
4800 BRAF V600 Mutation Assay for analytical sensitivity, limits of sample input, 
accuracy and reproducibility for detection of the BRAFV600 mutation in DNA from 
melanoma.  Based upon these studies, the cobas® 4800 BRAF V600 Mutation Assay 
has been approved by the US FDA for investigational use to select adult patients with 
metastatic melanoma for treatment with vemurafenib in the Phase II and Phase III 
clinical trials of vemurafenib in locally-advanced/unresectable or metastatic melanoma 
(Investigational Device Exemption G070126). 
Based on preliminary findings that the BRAF mutation is preserved in patients with 
tumors that escape vemurafenib-mediated suppression of the RAS/RAF pathways, 
BRAF mutation status will be confirmed retrospectively by the cobas® 4800 BRAF V600 
Mutation Assay in the proposed clinical trial of vemurafenib and cobimetinib combination, 
NO25395. 
Patients with a positive test for the mutation will be eligible for treatment in the clinical 
drug trial if they meet other eligibility criteria.