Conditions: Malignant Melanoma
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 131
Healthy volunteers: no

Brief summary:
This open-label, dose-escalation study of vemurafenib in combination with cobimetinib will evaluate the safety, tolerability and pharmacokinetics in participants with BRAFV600 mutation-positive metastatic melanoma. Participants with previously untreated, BRAFV600E mutation-positive, locally advanced/unresectable or metastatic melanoma or those who have progressed on vemurafenib monotherapy immediately prior to enrolling in this trial are eligible. Participants will be assigned to different cohorts with escalating oral doses of vemurafenib and cobimetinib. This study consists of 2 stages, Stage 1 (Dose Escalation Stage \[DES\] and Cohort Expansion Stage \[CES\]) and the anticipated time on study treatment is until disease progression, unacceptable toxicity or any other discontinuation criterion is met.

Detailed description:

Arms:
arm 1: Participants will receive oral 60 milligrams (mg) cobimetinib once daily (QD) on Days 1-14, followed by 14 days off on Days 15-28 (14/14 dosing schedule) and oral 720 mg vemurafenib twice daily (BID) on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met. arm 2: Participants will receive oral 60 mg cobimetinib QD on Days 1-21, followed by 7 days off on Days 22-28 (21/7 dosing schedule) and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met. arm 3: Participants will receive oral 60 mg cobimetinib QD on 21/7 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met. arm 4: Participants will receive oral 60 mg cobimetinib QD on Days 1-28 (28/0 dosing schedule) and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met. arm 5: Participants will receive oral 60 mg cobimetinib QD on 28/0 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met. arm 6: Participants will receive oral 80 mg cobimetinib QD on 14/14 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met. arm 7: Participants will receive oral 100 mg cobimetinib QD on 14/14 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met. arm 8: Participants will receive oral 60 mg cobimetinib QD on 14/14 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met. arm 9: Participants will receive oral 80 mg cobimetinib QD on 14/14 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met. arm 10: Participants will receive oral 60 mg cobimetinib QD on 21/7 dosing schedule, or oral 100 mg cobimetinib QD on 14/14 dosing schedule of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met. arm 11: Participants will receive oral 60 mg cobimetinib QD on 21/7 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met. arm 12: Participants will receive oral 60 mg cobimetinib QD on 21/7 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.

Interventions: intervention 1: Cobimetinib intervention 2: vemurafenib
Intervention descriptions: intervention 1: Participants will receive cobimetinib 60 to 100 mg at any of the 3 dosing schedules with or without vemurafenib in cycles of 28 days each until disease progression, unacceptable toxicity, or any other discontinuation criteria are met. intervention 2: Participants will receive vemurafenib 720 or 960 mg along with cobimetinib in cycles of 28 days each until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.

Protocol document:
Prot_SAP_000.pdf: 
Official Title: A PHASE IB, OPEN LABEL, DOSE-ESCALATION STUDY 
EVALUATING THE SAFETY, TOLERABILITY AND 
PHARMACOKINETICS OF VEMURAFENIB IN COMBINATION 
WITH GDC-0973 WHEN ADMINISTERED IN BRAFV600E
MUTATION–POSITIVE PATIENTS PREVIOUSLY TREATED 
(BUT WITHOUT PRIOR EXPOSURE TO BRAF OR MEK 
INHIBITOR THERAPY) OR PREVIOUSLY UNTREATED FOR 
LOCALLY ADVANCED/UNRESECTABLE OR METASTIC 
MELANOMA OR THOSE WHO HAVE PROGRESSED AFTER 
TREATMENT WITH VEMURAFENIB 
NCT Number:   NCT01271803 
Document Dates: PROTOCOL AND SAP 
Version A: 27 August 2010 
Version B: 30 September 2010 
Version C: 6 March 2011 
Version D: 13 July 2011 
Version E: 5 December 2011 
Version F: 12 July 2012 
Version G: 13 September 2013 
Version H: 2 April 2014 
Version I: 9 April 2015 
Version J: 7 October 2015 
Version K: 13 July 2016 
Version L: 20 October 2016 


Clinical Study Report: RO5185426 - F. Hoffmann-La Roche Ltd
Protocol NO25395     Report Number 1087965
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Title
20-Oct-2016 16:08:14
Date and Time (UTC)
Company Signatory
Approver's Name
Protocol NO25395 Version L: vemurafenib and cobimetinib - F. Hoffmann-La Roche Ltd
CONFIDENTIAL
1
PROTOCOL
TITLE: A PHASE IB, OPEN LABEL, DOSE-ESCALATION STUDY 
EVALUATING THE SAFETY, TOLERABILITY AND 
PHARMACOKINETICS OF VEMURAFENIB IN COMBINATION 
WITH GDC-0973 WHEN ADMINISTERED IN BRAFV600E
MUTATION–POSITIVE PATIENTS PREVIOUSLY TREATED (BUT 
WITHOUT PRIOR EXPOSURE TO BRAF OR MEK INHIBITOR 
THERAPY) OR PREVIOUSLY UNTREATED FOR LOCALLY 
ADVANCED/UNRESECTABLE OR METASTIC MELANOMA OR 
THOSE WHO HAVE PROGRESSED AFTER TREATMENT WITH 
VEMURAFENIB
PROTOCOL NUMBER:
NO25395
VERSION NUMBER:
L
EUDRACT NUMBER:
Not applicable
IND NUMBER:
109307
TEST PRODUCT:
Vemurafenib (RO5185426) and cobimetinib (GDC-0973; 
RO5514041)
MEDICAL MONITOR:
 M.D., Ph.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
DATE FINAL:
Version A:  27 August 2010
DATES AMENDED:
Version B:  30 September 2010
Version C:  6 March 2011
Version D:  13 July 2011
Version E:  5 December 2011
Version F:  12 July 2012
Version G:  13 September 2013
Version H:  2 April 2014
Version I:  9 April 2015
Version J:  7 October 2015
Version K:  13 July 2016
Version L:  See electronic date stamp below.
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, Switzerland. However, it may be 
implemented in individual countries by Roche’s local affiliates, including Genentech, Inc. in the United States.  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.


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PROTOCOL AMENDMENT, VERSION L:
RATIONALE
Protocol NO25395 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:

The Medical Monitor has been changed (global).

It has been clarified that changes as of Protocol Amendment K also apply to 
future amendments (global).

Information has been added to reflect rhabdomyolysis and CPK elevations
(Section 1.3.7.4) and hemorrhage (Section 1.3.7.1), and gastrointestinal toxicity 
(Section 1.3.7.8) associated with cobimetinib.  

Risks associated with vemurafenib have been updated (Section 3.10.1)

Section 3.10.2 has been updated to reflect standard cobimetinib safety language, 
including identified risks associated with cobimetinib (Section 3.10.2.1), potential 
risks associated with cobimetinib (Section 3.10.2.2), and other risks associated 
with cobimetinib (Section 3.10.2.3).

Language regarding impaired female fertility and developmental toxicity was 
clarified (Section 3.10.2.2). 

Survival will be followed every 12 weeks until death (Sections 3.11, 5, and 5.7).

A minor correction was made to Table 10 in Section 5.1.1. 

The dose modification table has been updated to add hemorrhage and update 
recommendations for rhabdomyolysis and CPK elevations (Table 12 in 
Section 6.1.1).

Language around treatment and follow-up of adverse events was clarified 
(Section 7.1.2). 

The outdated pregnant partner data release form number has been removed 
(Section 7.2.2).
Substantive new information appears in italics. This amendment represents cumulative 
changes to the original protocol.


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PROTOCOL AMENDMENT, VERSION L:
SUMMARY OF CHANGES
Global Changes
The Medical Monitor has changed.
It has been clarified that changes as of Protocol Amendment K also apply to future 
amendments. 
Protocol Synopsis
The synopsis has been updated to reflect the changes to the protocol.
Section 1.3.7.1:  Hemmorhage
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 12, in Section 6.1.1.
Section 1.3.7.4:  Rhabdomyoloysis and Increased CPK
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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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. 
Section 3.10.1:  Risks Associated with Vemurafenib
Other safety events for vemurafenib used in monotherapy include new primary 
malignancies such as cutaneous malignancies, non-cutaneous squamous cell 
carcinoma, and other malignancies; tumor promotion in BRAF wild-type 
malignancies; 
hypersensitivity 
reactions; 
hepatotoxicity; 
ophthalmologic 
reactions; embryo-fetal toxicity; radiation sensitization and radiation recall; and 
renal failure.  


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Section 3.10.2.1:  Identified Risks Associated with Cobimetinib
Hemorrhage
Hemorrhage, including major hemorrhages defined as symptomatic bleeding in a 
critical area or organ, can occur with Cotellic. 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 receiving cobimetinib plus vemurafenib and 0.8% of 
patients receiving placebo plus vemurafenib. 
Caution should be used in patients with additional risk factors for bleeding, such 
as brain metastases, and/or in patients that use concomitant medications that 
increase the risk of bleeding (including antiplatelet or anticoagulant therapy).
Instructions for Dose Modification for hemorrhage events are included in 
Table 12 in Section 6.1.1.
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 postmarketing 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 
Modification 
for 
elevated 
CPK 
and 
rhabdomyolysis are included in Table 12 in Section 6.1.1.


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Section 3.10.2.2:  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 with 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
Heading change only.
Teratogenicity and Developmental Toxicitiy
Heading change only.
Section 3.10.2.3:  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 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.


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Section 3.11:  End of Study
Upon study treatment discontinuation or withdrawal from study treatment, 
patients are required to continue the following assessments as indicated in the 
Schedule of Assessments:
•
A study completion visit will be performed 28 days after the last dose of study 
treatment for all patients. 

Survival will be collected via telephone calls and/or clinic visits every 
12 weeks until death, weithdrawal of consent of loss to follow-up.

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.  Survival 
follow-up can be conducted via telephone. 
A study completion visit will be performed 28 days after the last dose of study treatment 
for all patients.  Patients will continue to be followed every 12 weeks until 6 months after 
last study treatment for survival. Survival follow up can be conducted via telephone. 
Section 5:  Schedule of Assessments
The schedule of assessments has been updated to reflect the changes to the text.
Table 10:  Schedule of PK Sampling for Patients Previously Treated with 
Vemurafenib
Footnotes have been added to the table (correction).
Section 5.7:  Patients who have Discontinued Study Drug
All patients who discontinue vemurafenib and cobimetinib or cobimetinib monotherapy 
treatments will be followed for survival. Survival status will be assessed every 12 weeks 
until 6 months after last study treatment, withdrawal of consent, death, or loss to 
follow-up, whichever occurs first.  
Section 6.1.1:  Vemurafenib and Cobimetinib Dose Modification
Table 12
Vemurafenib and Cobimetinib Dose Modification Guidelines
The table has been updated for hemorrhage and rhabdomyolysis/CPK elevaations. 
Section 7.1.2:  Treatment and Follow-up of Adverse Events
Unrelated severe or life-threatening adverse events: Follow until one of the following 
occurs:

Resolved or improved to baseline


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
Intensity (severity) improved to Grade 2 or lower
Section 7.2.2:  Pregnancy
NOTE:  The investigator should fill out a Pregnancy Reporting Form, [SRD-0115311], 
only if the pregnant partner has signed a Pregnant Partner Data Release Form,
[gcp_for000186].
Sample Informed Consent Form
The sample informed consent form has been updated to reflect current safety information 
for cobimetinib. 


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Table of Contents
Page
Protocol Amendment Acceptance Form ............................................................20
Protocol Synopsis ..............................................................................................21
1. Background and Rationale ............................................................................30
1.1 Background ...........................................................................................30
1.1.1 Melanoma...........................................................................................30
1.2 Role of BRAF Kinase in Melanoma.......................................................30
1.2.1 Study Drug Vemurafenib (BRAF Inhibitor) .........................................30
1.2.2 Clinical Pharmacokinetics of Vemurafenib.........................................31
1.2.3 Clinical Safety of Vemurafenib ...........................................................31
1.2.3.1 Adverse Events and Dose‑Limiting Toxicities of 
Vemurafenib..........................................................................................32
1.2.3.2 Clinical Safety in Phase II Trial: NP22657 (BRIM-2).......................34
1.2.3.3 Clinical Safety in Phase III Trial: NO25026 (BRIM-3)......................35
1.2.3.4 Profile in Global Safety Study MO25515.........................................36
1.2.3.5 Deaths and Serious Adverse Events Associated with 
Vemurafenib..........................................................................................36
1.2.4 Adverse Events of Special Interest for Vemurafenib..........................37
1.2.4.1 Cutaneous Squamous Cell Carcinoma ...........................................37
1.2.4.2 Other Neoplasms ............................................................................37
1.2.4.3 QT Interval Prolongation .................................................................38
1.2.4.4 Liver Injury.......................................................................................38
1.2.5 Other Adverse Events of Clinical Significance ...................................39
1.2.5.1 Drug Reaction with Eosinophilia and Systemic Symptoms.............39
1.2.5.2 Neutropenia.....................................................................................39
1.2.5.3 Pancreatitis......................................................................................39
1.2.5.4 Panniculitis ......................................................................................39
1.2.5.5 Potentiation of Radiation Toxicity....................................................39
1.2.5.6 Ipilimumab and Vemurafenib...........................................................40
1.2.6 Clinical Efficacy of Vemurafenib.........................................................40
1.3 Role of MEK Kinase in Melanoma.........................................................41
1.3.1 Study Drug Cobimetinib (MEK Inhibitor) ............................................41
1.3.2 Nonclinical Studies with Cobimetinib..................................................42


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1.3.3 Nonclinical Metabolism and Pharmacokinetics of 
Cobimetinib...........................................................................................42
1.3.4 Nonclinical Safety of Cobimetinib.......................................................42
1.3.5 Clinical Pharmacokinetics of Cobimetinib ..........................................43
1.3.6 Clinical Experience of Cobimetinib Monotherapy: 
Study MEK4592g..................................................................................44
1.3.6.1 Dose-Limiting Toxicities ..................................................................45
1.3.6.2 Adverse Events ...............................................................................45
1.3.6.3 Grade ≥ 3 Adverse Events ..............................................................47
1.3.6.4 Serious Adverse Events..................................................................49
1.3.6.5 Deaths.............................................................................................49
1.3.6.6 Clinical Efficacy ...............................................................................50
1.3.7 Adverse Events Associated with Cobimetinib (GDC-0973)................50
1.3.7.1 Hemorrhage ....................................................................................50
1.3.7.2 Serous Retinopathy.........................................................................51
1.3.7.3 Left Ventricular Dysfunction ............................................................51
1.3.7.4 Rhabdomyolysis and Increased CPK..............................................51
1.3.7.5 Liver Laboratory Abnormalities........................................................52
1.3.7.6 Rash................................................................................................52
1.3.7.7 Photosensitivity ...............................................................................53
1.3.7.8 Gastrointestinal Toxicity ..................................................................53
1.4 Rationale for the Study..........................................................................53
2. Objectives ......................................................................................................57
2.1 Primary Objectives ................................................................................57
2.2 Exploratory Objectives ..........................................................................58
3. Study Design..................................................................................................59
3.1 Overview of Study Design.....................................................................59
3.1.1 Stage 1: Dose‑Escalation Cohort .......................................................59
3.1.2 Option to Receive Single‑Agent Cobimetinib .....................................67
3.1.3 Dose-Limiting Toxicity Assessment Window......................................68
3.1.4 Rules for Dose‑Escalation and Potential Dose De-
Escalation; Changes in Dose Scheduling following 
Dose‑Limiting Toxicity...........................................................................68
3.1.5 Definition of Dose-Limiting Toxicity ....................................................70
3.1.6 Dosing Beyond Cycle 1......................................................................71


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3.2 Stage 2: Cohort‑Expansion Stage.........................................................71
3.3 Rationale for Patient Selection..............................................................72
3.4 Rationale for Starting Dose and Schedule ............................................73
3.5 Rationale for Pharmacokinetic Evaluation Schedule.............................74
3.6 Rationale for Dosing Beyond Cycle 1....................................................75
3.7 Rationale for Collection of Patient Specimens for Molecular 
Analyses (Biopsies, Plasma, Blood) .....................................................75
3.8 Rationale for Evaluating FDG-PET Changes........................................76
3.9 Outcome Measures...............................................................................77
3.9.1 Safety Outcome Measures.................................................................77
3.9.2 Pharmacokinetic and Pharmacodynamic Outcome 
Measures ..............................................................................................77
3.9.3 Efficacy Outcome Measures ..............................................................77
3.9.4 Exploratory Outcome Measures.........................................................78
3.10 Safety Plan..........................................................................................78
3.10.1 Risks Associated with Vemurafenib .................................................78
3.10.2 Risks Associated with Cobimetinib...................................................79
3.10.2.1 Identified Risks Associated with Cobimetinib................................79
3.10.2.2 Potential Risks Associated with Cobimetinib.................................82
3.10.2.3 Other Risks Associated with Cobimetinib......................................82
3.10.3 General Plan to Manage Safety Concerns.......................................84
3.11 End of Study........................................................................................85
3.12 Number of Patients/Assignment to Treatment Groups........................85
3.13 Centers................................................................................................86
4. Study Population............................................................................................86
4.1 Overview ...............................................................................................86
4.2 Inclusion Criteria....................................................................................86
4.3 Exclusion Criteria ..................................................................................88
4.4 Concomitant Medication and Treatment ...............................................90
4.4.1 Concomitant Therapy.........................................................................90
4.4.2 Excluded Therapy and Food ..............................................................91
4.4.3 Medication Precautions in Case of Drug-Drug Interactions ...............91
4.4.4 Medications Affecting QT Interval ......................................................92
4.5 Criteria for Premature Withdrawal and Discontinuation ........................93
4.6 Withdrawal of Patients from the Roche Clinical Repository ..................94


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4.7 Replacement Policy (Ensuring Adequate Numbers of 
Evaluable Patients)...............................................................................94
4.7.1 For Patients........................................................................................94
4.7.2 For Centers ........................................................................................94
5. Schedule of Assessments and Procedures ...................................................95
5.1 Screening Examination and Eligibility Screening Form.......................102
5.2 Procedures for Enrollment of Eligible Patients....................................102
5.3 Clinical Assessments and Procedures................................................103
5.3.1 Screening and Pre‑Treatment Assessment .....................................103
5.3.2 Tumor Response Criteria .................................................................105
5.3.3 Performance Status..........................................................................106
5.3.4 Clinical Safety Assessments ............................................................106
5.3.4.1 Medical History..............................................................................106
5.3.4.2 Vital Signs and Oxygen Saturation................................................106
5.3.4.3 Physical and Symptom-Directed Examinations.............................106
5.3.4.4 Ophthalmologic Examinations.......................................................107
5.3.4.5 ECG...............................................................................................107
5.3.4.6 Dermatologic Evaluation, Surveillance of Second Primary 
Malignancies, and Risk Management Plan.........................................107
5.3.5 FDG-PET Imaging............................................................................109
5.4 Laboratory Assessments.....................................................................110
5.4.1 Laboratory Assessments List ...........................................................110
5.4.2 Assessments during Treatment........................................................110
5.4.3 Dose‑Escalation (Cohorts 1 Through 5), Dose-De-
Escalation, and Dose‑Expansion Cohorts ..........................................110
5.4.4 Study Completion/Early Termination Visit........................................111
5.4.5 Follow-Up Assessments...................................................................111
5.5 Pharmacokinetic Assessments ...........................................................111
5.5.1 Assay Methods.................................................................................112
5.6 Exploratory Molecular Assessments (Biomarker 
Assessments) .....................................................................................114
5.6.1 Plasma Samples ..............................................................................114
5.6.2 Whole Blood for Biomarker Analyses...............................................114
5.6.3 Tissue Samples................................................................................114
5.6.3.1 Tumor Tissue ................................................................................114


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5.6.3.2 Presumed or Suspected Squamous Cell Carcinoma, 
Second Primary Melanoma, and Normal Skin....................................116
5.6.4 Storage of Pharmacodynamic and Exploratory Biomarker 
Samples..............................................................................................117
5.7 Patients Who Have Discontinued Study Drug.....................................117
5.8 Dosing Beyond Progression................................................................117
6. Investigational Medicinal Product ................................................................118
6.1 Dose and Administration Schedule of Vemurafenib and 
Cobimetinib.........................................................................................118
6.1.1 Vemurafenib and Cobimetinib Dose Modification ............................119
6.2 Accountability and Patient Compliance for Investigational 
Medicinal Product ...............................................................................125
6.3 Formulation, Storage, Packaging, and Labeling .................................126
6.3.1 Vemurafenib.....................................................................................126
6.3.2 Cobimetinib ......................................................................................126
6.4 Blinding and Un-Blinding.....................................................................127
6.5 Accountability of Investigational Medicinal Product and 
Assessment of Compliance ................................................................127
6.5.1 Accountability of Investigational Medicinal Product..........................127
6.5.2 Assessment of Compliance..............................................................128
7. Safety Instructions and Guidance................................................................128
7.1 Adverse Events and Laboratory Abnormalities ...................................128
7.1.1 Clinical Adverse Events....................................................................128
7.1.1.1 Intensity.........................................................................................128
7.1.1.2 Drug-Adverse Event Relationship .................................................129
7.1.1.3 Serious Adverse Events (Immediately Reportable to 
Roche) ................................................................................................130
7.1.1.4 Adverse Events of Special Interest ...............................................130
7.1.1.5 Other Adverse Events Requiring Expedited Reporting .................130
7.1.1.6 Progression of Underlying Malignancy..........................................131
7.1.2 Treatment and Follow-Up of Adverse Events...................................131
7.1.3 Laboratory Test Abnormalities .........................................................132
7.1.3.1 Follow-Up of Abnormal Laboratory Test Values............................132
7.2 Handling of Safety Parameters ...........................................................132
7.2.1 Reporting of Serious Adverse Events (Immediately 
Reportable) .........................................................................................132


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7.2.2 Pregnancy ........................................................................................133
7.3 Warnings and Precautions ..................................................................134
7.3.1 Vemurafenib Warnings and Precautions..........................................134
7.3.2 Cobimetinib Warnings and Precautions ...........................................134
7.3.3 Other Precautions ............................................................................134
8. Statistical Considerations and Analytical Plan.............................................134
8.1 Primary and Secondary Study Variables.............................................134
8.1.1 Primary Variable...............................................................................134
8.1.2 Secondary Variables ........................................................................135
8.1.3 Safety ...............................................................................................135
8.2 Statistical and Analytical Methods.......................................................135
8.2.1 Statistical Model ...............................................................................135
8.2.2 Hypothesis Testing...........................................................................136
8.2.3 Analysis Populations ........................................................................136
8.2.4 Safety Data Analyses.......................................................................136
8.2.5 Exploratory Analyses........................................................................137
8.2.6 Determination of Maximal Tolerated Dose.......................................137
8.2.7 Other Analyses.................................................................................137
8.2.7.1 Pharmacokinetic Analysis .............................................................137
8.2.7.2 Exploratory Biomarker Analyses ...................................................137
8.3 Sample Size ........................................................................................138
9. Data Collection, Management, and Quality Assurance ...............................139
9.1 Assignment of Preferred Terms and Original Terminology .................139
10. Study Committees......................................................................................140
11. References.................................................................................................141
12. Ethical Aspects ..........................................................................................144
12.1 Local Regulations/Declaration of Helsinki.........................................144
12.2 Informed Consent..............................................................................144
12.2.1 Main Study Informed Consent........................................................144
12.2.2 Roche Clinical Repository Informed Consent.................................145
12.2.3 Death or Loss of Competence of Participant who has 
Donated a Specimen(s) That is Stored in the Roche Clinical 
Repository...........................................................................................146
12.3 Independent Ethics Committees (IEC)/Institutional Review 
Board (IRB).........................................................................................146


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12.4 Role of the Science and Ethics Advisory Group (SEAG) ..................147
12.5 Financial Disclosure ..........................................................................147
13. Conditions for Modifying the Protocol ........................................................147
14. Conditions for Terminating the Study ........................................................147
15. Study Documentation, CRFs and Record Keeping ...................................148
15.1 Investigator's Files / Retention of Documents ...................................148
15.2 Source Documents and Background Data........................................148
15.3 Audits and Inspections ......................................................................149
15.4 Case Report Forms or Electronic Case Report Forms......................149
16. Monitoring the Study..................................................................................149
17. Confidentiality of Trial Documents and Subject Records...........................150
18. Clinical Study Report (CSR) ......................................................................150
19. Publication of Data and Protection of Trade Secrets.................................150


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List of Tables
Page
Table 1 Study PLX06-02: Adverse Events Reported in Patients 
(≥10%) with Metastatic Melanoma ..............................................................33
Table 2 Summary of Overall Survival by Study .................................................41
Table 3 Treatment‑Emergent Adverse Events Regardless of 
Relationship to Study Drug That Occurred in 10% or More of 
Patients in Study MEK4592g.......................................................................46
Table 4 Grade ≥ 3 Treatment‑Emergent Adverse Events in Study 
MEK4592g...................................................................................................48
Table 5 Roadmap for Planned Dose Escalation................................................64
Table 6 Roadmap for Planned Dose-De-Escalation Cohorts in the 
Setting of Cohort 1 Failure ..........................................................................65
Table 7 Roadmap for Planned Dose De-Escalation Cohort in the 
Setting of Cohorts 1A, 1C, or 1D Failure.....................................................65
Table 8 Cohort Expansion for Patients Receiving Vemurafenib and 
Cobimetinib .................................................................................................71
Table 9 Schedule of Assessments (All Cohorts including Cobimetinib 
Monotherapy Cohort) ..................................................................................95
Table 10 Schedule of PK Sampling for Patients Previously Treated 
with Vemurafenib.......................................................................................113
Table 11 Schedule of PK Sampling for Patients Either Previously 
Treated (but without Prior Exposure to BRAF or MEK Inhibitor 
Therapy) or Previously Untreated for Locally 
Advanced/Unresectable or Metastatic Melanoma.....................................113
Table 12 Vemurafenib and Cobimetinib Dose Modification Guidelines...........120
Table 13 Properties of the Dose-Escalation Rules with Different 
Underlying Rates of DLT...........................................................................138
Table 14 Probability of Safety-Signal Detection with an Expansion 
Cohort of 20 Patients.................................................................................139


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List of Figures
Page
Figure 1: Potential Mechanisms of Resistance to BRAF Inhibitors in 
Melanoma Cells...........................................................................................55
Figure 2: Combination of Vemurafenib with a MEK Inhibitor 
(RO5068760) Demonstrates a Synergistic Anti-Proliferation Effect 
in the Acquired‑Resistance Melanoma Cell Model......................................56
Figure 3: Combination Study of Vemurafenib and the MEK Inhibitor 
RO5068760 in the BRAFV600E‑Expressing A375 Melanoma 
Xenograft Model..........................................................................................57
Figure 4: Dose‑Escalation Plan for the Combination of Vemurafenib 
and Cobimetinib Administered on a 14/14 Schedule ..................................61
Figure 5: Dose Escalation Scheme for the Combination of 
Vemurafenib and Cobimetinib Administered Either on a 21/7 Day 
or a Continuous Schedule...........................................................................62
Figure 6: Dosing Schema for Patients Receiving Vemurafenib and 
Cobimetinib .................................................................................................67
Figure 7: Dosing Schema for Patients Receiving Single‑Agent 
Cobimetinib .................................................................................................68


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List of Appendices
Page
Appendix 1: New Response Evaluation Criteria in Solid Tumors –  
Version 1.1–Excerpt from Original Publication with Addition of 
Supplementary Explanations (Eisenhauer et al. 2009) .............................152
Appendix 2: ECOG Performance Status .........................................................164
Appendix 3: ICH Guidelines for Clinical Safety Data Management, 
Definitions and Standards for Expedited Reporting, Topic E2 ..................165
Appendix 4: New York Heart Association Classification of Functional 
Cardiac Capacity.......................................................................................167
Appendix 5: AJCC TNM Staging for Melanoma ..............................................168
Appendix 6: Medications Affecting QT Interval (Information Available 
on http://www.azcert.org) ..........................................................................169
Appendix 7: Plasma Pharmacokinetic Sample Collection Schedule for 
Patients Previously Treated with Vemurafenib..........................................170
Appendix 8: Plasma Pharmacokinetic Sample Collection Schedule for 
Patients Either Previously Untreated or Treated (but without 
Exposure to BRAF or MEK Inhibitor Therapy) for Locally 
Advanced/Unresectable or Metastatic Melanoma.....................................172
Appendix 9: Cobas 4800 BRAF V600 Mutation Assay Information.................174
Appendix 10: Impact of Vemurafenib on Concomitant Medications ................175


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PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
A PHASE IB, OPEN LABEL, DOSE-ESCALATION 
STUDY EVALUATING THE SAFETY, 
TOLERABILITY AND PHARMACOKINETICS OF 
VEMURAFENIB IN COMBINATION WITH GDC-0973 
WHEN ADMINISTERED IN BRAFV600E
MUTATION-POSITIVE PATIENTS PREVIOUSLY 
TREATED (BUT WITHOUT PRIOR EXPOSURE TO 
BRAF OR MEK INHIBITOR THERAPY) OR 
PREVIOUSLY UNTREATED FOR LOCALLY
ADVANCED/UNRESECTABLE OR METASTIC 
MELANOMA OR THOSE WHO HAVE 
PROGRESSED AFTER TREATMENT WITH 
VEMURAFENIB
PROTOCOL NUMBER:
NO25395
VERSION NUMBER:
L
EUDRACT NUMBER:
Not applicable
IND NUMBER:
109307
TEST PRODUCT:
Vemurafenib (RO5185426) and cobimetinib 
(GDC-0973; RO5514041)
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 retain the signed original of this form for your study files.  Please return a copy as 
instructed by by your local study monitor.


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PROTOCOL SYNOPSIS
TITLE:
A PHASE IB, OPEN-LABEL, DOSE-ESCALATION STUDY 
EVALUATING THE SAFETY, TOLERABILITY AND 
PHARMACOKINETICS OF VEMURAFENIB IN COMBINATION 
WITH GDC-0973 WHEN ADMINISTERED IN BRAFV600E
MUTATION–POSITIVE PATIENTS PREVIOUSLY TREATED (BUT 
WITHOUT PRIOR EXPOSURE TO BRAF OR MEK INHIBITOR 
THERAPY) OR PREVIOUSLY UNTREATED FOR LOCALLY-
ADVANCED/UNRESECTABLE OR METASTATIC MELANOMA OR 
THOSE WHO HAVE PROGRESSED AFTER TREATMENT WITH 
VEMURAFENIB
PROTOCOL NUMBER:
NO25395
VERSION NUMBER:
L
EUDRACT NUMBER:
Not applicable
IND NUMBER:
109307
TEST PRODUCT:
Vemurafenib (RO5185426) and cobimetinib (GDC-0973; 
RO5514041)
PHASE:
Ib
INDICATION:
BRAFV600E-Positive Metastatic Melanoma
SPONSOR:
F. Hoffmann-La Roche Ltd
OBJECTIVES
PRIMARY OBJECTIVES
To evaluate the safety and tolerability of the vemurafenib and cobimetinib (GDC-0973/XL518) 
combination, and in doing so,

To identify the dose-limiting toxicities (DLTs) that determine the maximum-tolerated dose of the 
vemurafenib and cobimetinib combination

To identify a potential Phase II/III dose and schedule for the vemurafenib and cobimetinib 
combination

To characterize Day 1 and steady-state pharmacokinetics of cobimetinib when administered in 
combination with vemurafenib and to characterize the steady-state pharmacokinetics of vemurafenib 
administered alone and in combination with cobimetinib
Secondary Objectives

To assess the anti-tumor activity of the vemurafenib and cobimetinib combination

To assess the mechanisms of response and resistance to vemurafenib and cobimetinib combination 
therapy (including genetic alterations of RAS, RAF, and MEK)

To assess the BRAFV600E mutation status of patients who progressed on vemurafenib monotherapy

To identify factors that may pre-dispose patients to squamous cell carcinoma (SCC) development


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
To assess the pharmacodynamic (PD) effects of vemurafenib and cobimetinib when administered in 
combination, as measured by changes in fluorodeoxyglucosepositron emission tomography 
(FDG-PET)

To assess the PD effects of vemurafenib and cobimetinib when administered in combination, as 
measured by changes in molecular biomarkers in sequential paired biopsies

To assess the PD utility of FDG-PET and changes in molecular biomarkers in sequential paired 
biopsies in a subset of patients (up to n=20) treated with single-agent cobimetinib
STUDY DESIGN
This is an open-label, multicenter, Phase Ib, dose-escalation study designed to assess the safety, 
tolerability, and pharmacokinetics of continuous daily oral dosing of vemurafenib administered in 
combination with orally dosed cobimetinib administered daily for 14 consecutive days followed by 
14 days off (14/14), for 21 consecutive days followed by 7 days off (21/7), or as a continuous daily dose.
Patients with previously untreated, BRAFV600E mutation-positive, locally advanced/unresectable or 
metastatic melanoma OR those who have progressed on vemurafenib monotherapy immediately prior to 
enrolling in this trial are eligible. Patients in the former category who were previously treated must have 
had no prior exposure to any BRAF or MEK inhibitor therapy. Treatment will continue until disease 
progression, unacceptable toxicity, or any other discontinuation criterion is met (Section 4.5). 
Vemurafenib will be dosed daily, and cobimetinib will be dosed on a 14/14, 21/7, or a continuous 
schedule in a 28-day cycle. Alternate dosing regimens and schedules may be interrogated depending on 
the nature and timing of the toxicities encountered.
There are 2 stages to this study: a dose-escalation stage and a cohort-expansion stage. During the 
dose-escalation stage, 10 dose-escalation cohorts of 36 patients each will be enrolled in order to identify 
a safe and tolerable dose of each agent to be administered during the cohort-expansion stage, i.e., the 
potential recommended Phase II/III dose combination. Approximately 20 additional patients will be 
enrolled into each of (minimally) two expansion cohorts during the cohort-expansion stage. One cohort 
will consist of patients who have progressed on vemurafenib monotherapy immediately prior to enrolling 
in this trial, and the other will consist of previously untreated or treated patients without prior exposure to 
any BRAF or MEK inhibitor therapy. Therefore, approximately 130 patients (not including patients 
treated with cobimetinib monotherapy) will be enrolled in the trial at approximately 7–10 sites in total in 
the United States and Australia.
For a small subset of patients who have progressed on vemurafenib monotherapy immediately prior to 
enrollment in this trial (up to 20), there is also an option for treatment with single-agent cobimetinib at 
60 mg on a 21/7 schedule (see Section 3.1.2). The PD data obtained from this patient group will be 
reviewed with the vemurafenib plus cobimetinib combination PD data to enhance understanding of the 
combination PD data. 
Participation in this cohort is limited to patients meeting one of the following criteria. Patients previously 
treated with vemurafenib at a dose of:
1.
480 mg twice daily (bid) due to tolerability issues at higher doses and who progressed at this dose 
prior to enrolling in this study
2.
720 mg or 960 mg bid vemurafenib for whom a treatment slot does not exist in the 
currently enrolling dose escalation cohort(s), and who are not able to wait for the next 
available cohort to open
Note:  The total number of cobimetinib monotherapy patients who satisfy either criterion 1 or 2 above is 
limited to 20. 
See Section 3.1.1 for details on dose escalation for all cohorts.
OUTCOME MEASURES
SAFETY OUTCOME MEASURES

Incidence, nature, and intensity (severity) of adverse events and serious adverse events, graded 
according to the National Cancer Institute Common Terminology Criteria for Adverse Events v4.0

Incidence and nature of DLTs

Changes in vital signs, ECGs, and clinical laboratory results during the course of study 
(See Section 5.3).


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PHARMACOKINETIC OUTCOME MEASURES
The goal of pharmacokinetic (PK) sampling is to describe vemurafenib and cobimetinib 
pharmacokinetics when given in combination and in comparison with historic controls when the agents 
were given as monotherapy. The relationship between vemurafenib and cobimetinib concentrations and 
anti-tumor activity will also be described.
Vemurafenib and cobimetinib PK parameters will be determined in all patients who receive study 
treatment using non-compartmental analysis and/or population methods.
For both vemurafenib and cobimetinib, the following PK parameters will be estimated:

Total exposure (AUC0-last)

Maximal plasma concentration (Cmax)

Minimal plasma concentration (Cmin)

Other PK parameters may be determined after visual inspection of observed concentrationtime data.
Pharmacodynamic Outcome Measures

FDG-PET response rates based on modified definitions proposed by the European Organization for 
Research of Cancer and as assessed by an independent, blinded FDG-PET Image Reading Facility (As 
of Protocol Version K and future amendments, central collection of scans is no longer required.)  

Changes in effector molecules of the MAPK pathway that are directly or indirectly affected by BRAF 
and MEK inhibition (including but not limited to ERK and phosphorylated ERK and MEK) by 
immunohistochemistry using biopsies at baseline, between Days 1014 of Cycle 1,  and at disease 
progression (when available).
Efficacy Outcome Measures

Objective response (OR)

Progression-free survival 

Duration of response (DOR)

Overall survival
SAFETY PLAN
Measures will be taken to ensure the safety of patients participating in this trial, in particular, the use of 
stringent inclusion and exclusion criteria (Sections 4.2 and 4.3) and close monitoring of patients as 
indicated below and in Section 3.10.4.
Because this is the first time vemurafenib and cobimetinib will be administered to humans in 
combination, all patients will be monitored closely for toxicity. All adverse events will be recorded 
during the trial and for up to 28 days after the last dose of study treatment or until initiation of another 
anti-cancer therapy, whichever comes first. The potential safety issues anticipated in this trial, as well as 
measures intended to avoid or minimize such toxicities, are outlined in Section 3.10.
Safety monitoring by an independent Data Safety Monitoring Board has ceased following the results of 
the primary efficacy analysis of the Phase III study, GO28141. As with other vemurafenib studies, the 
risk for SCC will be mitigated by utilization of the Risk Management Plan (RMP) that is described in 
Section 5.3.4.6 of this protocol.
STUDY TREATMENT
Patients enrolled in a given cohort will receive vemurafenib and cobimetinib at a specified dose 
combination as described in Section 3. Vemurafenib will be dosed orally bid and cobimetinib will be 
dosed orally once daily. Study drug will be shipped in bulk to the study sites in bottles.
Patients in screening (written informed consent) for this study who were previously receiving 960 mg bid 
vemurafenib will be dose-reduced to 720 mg bid for 7–14 days prior to Cyle, 1 Day 1 in Cohorts 1, 1A, 2, 
2A, or 1C. Patients receiving 960 mg bid vemurafenib prior to screening initiation (written informed 
consent) and assigned to Cohorts 1B, 1D, 3, 4, or 5 will continue receiving 960 mg bid vemurafenib, 
assuming this dose has been adequately tolerated prior to starting the study. Patients in screening (written 


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informed consent) for this study who are treatment naïve to vemurafenib at the time of consent will only 
start vemurafenib on Cycle 1, Day 1 once they are deemed eligible for enrollment.
Vemurafenib will be dosed daily, and cobimetinib will be dosed on a 14/14, a 21/7, or a continuous daily 
schedule in a 28-day cycle. 
On study visit days, the daily doses of cobimetinib will be taken in the clinic after pre-dose assessments 
have been performed. After establishing patient eligibility for continued administration of study drugs, 
patients will be given a sufficient number of tablets and/or capsules to last until the next visit. In some 
cases, extra tablets and/or capsules may be dispensed if there is a reasonable possibility that the patient’s 
next visit may be delayed (e.g., due to inclement weather or distance of patient’s home from study 
center).
Cobimetinib should be taken at approximately the same time each day, preferably in the morning, and no 
later than 4 hours after the scheduled time. Each dose of cobimetinib should be taken with a glass of 
water. 
For vemurafenib, patients will receive study medication bottles, each containing tablets that are 240 mg 
each. The number of tablets for the morning and evening dose will depend on the cohort assignment, with 
at least 8 hours between doses. Each dose of vemurafenib should be taken with a glass of water. As soon 
as feasible after signing informed consent, patients previously treated with vemurafenib should continue 
vemurafenib treatment with study drug provided expressly for this particular study and discontinue their 
supply of study drug from the antecedent vemurafenib study.
Both cobimetinib and vemurafenib will be taken at the same time in the morning. 
On PK sample collection days, patients will be required to come into the clinic and have vemurafenib and 
cobimetinib administered as part of the scheduled study visit after pre-dose assessments have been 
performed. Vemurafenib and cobimetinib may be taken with or without food, including on PK sampling 
days. 
Patients will be instructed as to the number and strength of the tablets and capsules to take according to 
their assigned dose cohort. The cobimetinib tablets and capsules should never be opened or chewed or 
opened; the vemurafenib tablets should never be chewed.
If a dose is missed (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.
Patients will be asked to record the time and date they take each dose in a medication diary. Missed doses 
should be recorded in a patient diary.  Patients will be instructed to bring all unused study medication and 
their medication diaries to each study visit for assessments of compliance.
The protocol requires a study evaluation to occur on Day 1 of every cycle but allows a period 
of ± 3 days. Patients on the 14/14 and 21/7 dosing schedule of cobimetinib are required to have 
the minimum number of days per cycle without cobimetinib dosing 14 and 7 days, respectively. Patients 
are still expected to return for PK blood draws according to the schedule outlined in Tables 10 and 11. 
For example, if a patient on a 21/7 cobimetinib dosing schedule has a study evaluation 2 days earlier than 
the nominal study day, the patient cannot restart cobimetinib until he/she has had at least 7 days without 
cobimetinib dosing.
Dose modifications, interruptions, and delays of vemurafenib and/or cobimetinib study treatment during 
and after the DLT assessment window should be made on the basis of the guidelines provided in Table 12 
of the protocol. Recognizing that new knowledge will be acquired and unforeseen safety issues may arise 
in the course of the study, the guidelines are not exhaustive and do not represent the full spectrum of care 
or treatment options described. The dose modification guidelines are not intended to replace clinical 
judgment or dictate care of individual patients.
CONCOMITANT THERAPY AND CLINICAL PRACTICE
Concomitant therapy includes any prescription medications or over-the-counter preparations used by a 
patient within 7 days before screening through the study completion visit. Patients who use oral 
contraceptives, hormone-replacement therapy, or maintenance therapy should continue their use as 
outlined in the eligibility criteria (see Sections 4.2 and 4.3). Patients who experience toxicities may be 
treated symptomatically as clinically indicated. All concomitant medications should be recorded on the 
appropriate electronic Case Report Form.
Anti-emetics and anti-diarrheal medications should not be administered prophylactically before initial 
treatment with study drug. At the discretion of the investigator, prophylactic anti-emetic and 


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anti-diarrheal medication(s) may be used per standard clinical practice before subsequent doses of study 
drug.  
Hematopoietic growth factors (e.g., erythropoietin and granulocyte colony-stimulating factors) and pain 
medications administered as dictated by standard practice are acceptable while the patient is enrolled in 
the study. However, growth factors should not be administered prophylactically before initial treatment 
with study drug; nor should they be used during the DLT observation period.
STATISTICAL METHODS
No statistical model will be used in the efficacy analysis and no formal hypothesis testing is planned. 
Descriptive statistics will be used to summarize the clinical activity, pharmacokinetics, and PD effect of 
vemurafenib and cobimetinib as described in the section on study objectives. 
DLTs that occur in the first 28 days after initial dose of vemurafenib and cobimetinib will be used to 
determine the recommended dose. Subsequent DLTs will be reported and summarized as well.   
The safety and efficacy (e.g., OR rate, DOR) will be presented by dose cohort in the dose-escalation stage 
and treatment group (patients previously treated with vemurafenib; patients previously untreated or treated 
[but without prior exposure to any BRAF or MEK inhibitor therapy] for locally advanced/unresectable or 
metastatic disease) in the dose-expansion stage.  The final analysis will be performed on all patient data 
collected through the 28 days after last patient’s last dose of study drug or at least 12 months after last 
patient in, whichever occurs later.  Once all applicable patients complete 6 months SCC follow-up after
end of treatment, an additional analysis will be performed to summarize any SCC findings per the RMP. 
From protocol amendment j forward, following cessation of study drug, surveillance of SCC should be 
performed in accordance with the local standard of care.
SAFETY DATA ANALYSES
The treated population is defined as all patients who receive any amount of study medication. All safety 
analyses will use the treated population. Patients who enroll in the dose-escalation stage who complete 
the DLT assessment window (Day 28) or experience a DLT in the assessment window and are withdrawn 
from study will be evaluable for determination of the recommended dose.  
Safety will be assessed through summaries of DLTs, adverse events, changes in laboratory test results, 
changes in vital signs, and vemurafenib and cobimetinib exposures. Descriptive statistics will be used to 
summarize all safety data. Summary tables and listings will be presented by assigned dose cohort.
Adverse event data will be reported in listings and presented in frequency tables by MedDRA terms. All 
adverse events occurring on or after treatment on Cycle 1, Day 1 will be summarized. Summaries of 
adverse event by grade, seriousness, and relationship to study treatment will be presented, as well as 
summaries of adverse events leading to death or to premature withdrawal from study treatment. Serious 
adverse events, including deaths, will be listed separately and summarized.
Relevant laboratory and vital signs (temperature, heart rate and blood pressure) data will be presented 
using summary statistics.
Laboratory data will be presented as summary tables for worst toxicity grade compared with baseline 
using Standard Internationale units. Descriptive statistics will be used to summarize Eastern Cooperative 
Oncology Group performance status. Vital signs, ECGs, and ophthalmologic and dermatologic test results 
will be reported in the listings.
Exposure to study medication will be summarized by total duration of study medication, number of 
cycles started, and cumulative dose using descriptive statistics. Dose interruptions/modifications and their 
reasons will be presented.
PHARMACOKINETIC ANALYSES
Several PK parameters derived from the blood PK samples will be analyzed using descriptive statistics 
(means, standard deviations, coefficients of variation, median). They will include Cmax, Cmin, and AUC. 
Additional parameters such as apparent CL, volume of distribution, and t1/2 will be estimated if the 
concentration data are sufficient.
Estimation of the PK parameters will be performed using standard non-compartmental methods.  Actual 
sampling times will be used to calculate PK parameters.
Steady-state pharmacokinetics of vemurafenib and cobimetinib will be summarized descriptively. 
Relevant PK parameters will be correlated with dose, safety, or efficacy variables.


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DETERMINATION OF SAMPLE SIZE  
Design considerations were not made with regard to explicit power and type I errors but to obtain 
preliminary safety, PK, and PD information in this patient population. The number of patients expected to 
be treated with combination therapy in this two-stage study is approximately 130, assuming 
approximately 30–60 patients enroll in the dose-escalation stage, and at least 40 patients enroll in at least 
two expansion cohorts. 
The sample size for this trial is based upon the dose-escalation rules described in Table 13, which 
describe the properties of the dose-escalation rules with different underlying rates of DLT.
Patients who withdraw from the study prior to completing the DLT assessment window for reasons other 
than DLTs will be replaced.
An expansion cohort of approximately 20 patients treated at the recommend dose will provide a 
reasonable chance (87.8%) of observing at least one or more adverse events when the true frequency of the 
adverse event is 10% at a given dose level. Table 14 provides probabilities of seeing at least one adverse 
event among 20 patients for probabilities ranging from 0.001 to 0.20 (i.e., adverse event frequencies of 
0.1% to 20%). For example, if the true probability of an adverse event is 0.20 or greater, there is a more 
than a 98.8% chance of seeing at least one such event in an expansion cohort of 20 patients.
Preliminary evaluation of activity in the RAS/RAF-mutant population is an important study objective. 
With an expansion cohort of 20 patients RAS/RAF-mutant patients, if the true response rate is at least 
20%, the chance of seeing at least one response is >98.8%.


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GLOSSARY OF ABBREVIATIONS
14/14
14 days on/14 days off
21/7
21 days on/7 days off
AJCC
American Joint Committee on Cancer
ALP
alkaline phosphatase
AUC
area under the plasma concentrationtime curve
BCC
basal cell carcinoma
bid
twice daily
BORR
best overall response rate
CL
clearance
Cmax
maximum plasma concentration
Cmin
minimum plasma concentrations
CPK
creatine phosphokinase
CRC
colorectal cancer
CT
computed tomography
cuSCC
cutaneous squamous cell carcinoma
DDI
drugdrug interaction
DLT
dose-limiting toxicity
DOR
duration of response
DSMB
Data Safety Monitoring Board
EAP
expanded access protocol
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report Form
EORTC 
European Organization for Research of Cancer
ERK
extracellular signal-regulated kinase
FDG-PET
fluorodeoxyglucosepositron emission tomography
FFPE
formalin-fixed paraffin-embedded 
FNA
fine needle aspiration


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GLOSSARY OF ABBREVIATIONS
IB
Investigator Brochure
ICH
International Conference on Harmonisation
IHC
immunohistochemistry
IMP
Investigational Medicinal Product
IND
Investigational New Drug
IRF
Image Reading Facility
KA
keratoacanthoma
KM
Kaplan-Meier
LVEF
left ventricular ejection fraction
MAPK
mitogen-activated protein kinase
MBP
micro-precipitated bulk powder
MedDRA
Medical Dictionary for Regulatory Affairs
MEKi
MEK inhibitor
MTD
maximal tolerated dose 
NCI
National Cancer Institute
NCI CTCAE
National Cancer Institute Common Terminology Criteria 
for Adverse Events
NOAEL
no observed adverse effect level
OR
objective response
OS
overall survival
PD
pharmacodynamics
PFS
progression-free survival
Pgp
P-glycoprotein
PK
pharmacokinetic
pMEK
phosphorylation of MEK
PPI
proton-pump inhibitor
qd
once daily
RCR
Roche Clinical Repository


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GLOSSARY OF ABBREVIATIONS
RECIST
Response Evaluation Criteria in Solid Tumors
RMP
Risk Management Plan
RVO
retinal vein occlusion
SCC
squamous cell carcinoma
SD
stable disease
SNP
single nucleotide polymorphism
t1/2
terminal half-life 
TEN
toxic epidermal necrolysis
tmax
time to maximum plasma concentration 
ULN
upper limit of normal
WHO
World Health Organization


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PART I:
STUDY DESIGN AND CONDUCT
1.
BACKGROUND AND RATIONALE
1.1
Background
1.1.1
Melanoma
Approximately 160,000 new cases of melanoma are diagnosed globally each year [1]. 
According to a World Health Organization (WHO) report, about 48,000 melanoma 
related deaths occur worldwide every year [2]. 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 represents 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 now 1 in 14 for 
men and 1 in 24 for women [3, 4]. In the United States, it is estimated that over 
68,000 new melanoma cases will be diagnosed and over 8,000 patients will die from the 
disease during 2009. Further, incidence rates for melanoma have increased sharply by 
approximately 6% per year in the United States since the 1970s.
There are a limited number of treatments available for metastatic melanoma, and the 
response to available treatments to date has been extremely poor. 
1.2
Role of BRAF Kinase in Melanoma
Recent advances in the understanding of the biology of melanoma have resulted in 
identifying the role of BRAF kinase in melanoma. Mutated BRAF dimers constitutively 
activate the RAS-RAF pathway leading to the generation of transcriptional signalling 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., in superficial spreading and nodular melanomas) [5, 6, 7, 8]. 
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 over 90% of the V600 mutations are 
V600E (1799 T>A) [9]. 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 V600E, result in constitutive 
activation of the BRAF kinase. Most of the transforming activity of the BRAFV600E is 
thought to result through the constitutive activation of the mitogen-activated protein 
kinase (MAPK) pathway [10]. The therapeutic relevance of BRAF is supported by the 
demonstration that depletion of mRNA for oncogenic BRAF by siRNA leads to growth 
inhibition of melanoma cell lines in vitro [11, 12]. This has led to the development of 
agents that can inhibit BRAF kinase and tests to identify mutations [13, 14, 15].
The cobasBRAF V600 mutation assay and Sanger Sequencing techniques have been 
utilized to identify BRAFV600 mutation status in clinical trials.
1.2.1
Study Drug Vemurafenib (BRAF Inhibitor)
Vemurafenib (also known as RO5185426 and PLX4032) is a low molecular weight, 
orally available inhibitor of the oncogenic form of the BRAF serine-threonine kinase 


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commonly found in metastatic melanoma. It is a potent and highly selective inhibitor of 
V600E-mutant BRAF.
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, Canada, members of the European Union, and numerous other
countries worldwide.
1.2.2
Clinical Pharmacokinetics of Vemurafenib
Pharmacokinetic (PK) information is available for patients treated with 160 to 1120 mg 
twice daily (bid) of the optimized clinical formulation (also referred to as the 
micro-precipitated bulk powder [MBP] formulation).  The MBP formulation has been 
provided as 40-mg capsules (dry granulation method), 80 mg capsules (wet granulation 
method), and 120-mg capsules (roller compaction method) in the PLX06-02 Phase I trial, 
a dose-escalation study in patients with metastatic melanoma.
The vemurafenib MBP formulations were developed to increase bioavailability. 
Dose-proportional increases were seen in exposure with the 40-, 80-, and 120-mg 
capsules, particularly from 240 to 960 mg bid. There were some patients who were high 
and low exposure outliers.  The reason for this variability is currently unknown. 
Steady-state exposure is expected to be reached by 15 days and mean steady-state levels 
of vemurafenib (area under the concentrationtime curve [AUC024h]) ranged from 
428 µMh to 1800 µMh in the PLX06-02 Phase I trial.  The 960 mg bid dose of 
vemurafenib achieved mean steady-state exposures of 90 µM and 1800 µMh for 
maximum plasma concentration (Cmax) and AUC0-24h, respectively.  The mean effective 
half-life of vemurafenib across all dose cohorts was ~50 hours (range of 3080 hours).
Mean steady-state vemurafenib exposures (Cmax and AUC0-8h) achieved with 
the to-be-marketed 240-mg tablet formulation in the Phase II study, NP22657 
(n=60), were found to be 11% higher compared with the 120-mg capsule formulation 
(PLX06-02, n=30) in metastatic melanoma patients dosed with 960 mg bid. 
Additional information can be obtained from the vemurafenib IB.
1.2.3
Clinical Safety of Vemurafenib
Vemurafenib clinical safety 
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. 
o
Dose Escalation Phase: (patients with solid tumors); original formulation, 
n26, MBP formulation, n30. 
o
Treatment Extension Phase: Metastatic melanoma patients, n32, 
o
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


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
NO25026 (BRIM3), Phase III: clinical cutoff: 1 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 to-be-marketed (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 detailed 
information.
1.2.3.1
Adverse Events and Dose-Limiting Toxicities of Vemurafenib
The Phase I Study PLX06-02 showed that vemurafenib was generally well tolerated in 
patients in the dose-escalation and melanoma-extension cohort 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, dose-limiting toxicities (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.
Table 1 provides a summary of adverse events reported in 10% of patients with 
metastatic melanoma (n62) who received the MBP formulation of vemurafenib in the 
dose-escalation and treatment-extension cohorts of Study PLX06-02.


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Table 1
Study PLX06-02: Adverse Events Reported in Patients (10%) with 
Metastatic Melanomaa 
System Organ Class
Preferred Term
Overall 
AEs
n (%)
Related b
Any Grade
n (%)
Any 
Relationship
and 
Grade 3
n (%)
Related b
and 
Grade 3 
n (%)
Number of patients reporting AEs (n=62)c
62 (100)
58 (93.5)
37 (59.7)
25 (40.3)
Skin and subcutaneous tissue disorders
52 (83.9)
52 (83.9)
6 ( 9.7)
6 (9.7)
Rash
32 (51.6)
30 (48.4)
2 (3.2)
2 (3.2)
Photosensitivity
19 (30.6)
19 (30.6)
1 (1.6)
1 (1.6)
Pruritus
19 (30.6)
19 (30.6)
1 (1.6)
1 (1.6)
Alopecia
19 (30.6)
19 (30.6)
0
0
Palmar-plantar erythrodysaesthesia syndrome
9 (14.5)
9 (14.5)
2 (3.2)
2 (3.2)
Dry skin
10 (16.1)
10 (16.1)
0
0
Skin exfoliation
9 (14.5)
9 (14.5)
1 (1.6)
1 (1.6)
General disorders and administration site
48 (77.4)
31 (50.0)
8 (12.9)
5 (8.1)
Fatigue
31 (50.0)
20 (32.3)
4 (6.5)
4 (6.5)
Pyrexia
13 (21.0)
5 (8.1)
0
0
Edema peripheral
11 (17.7)
4 (6.5)
0
0
Musculoskeletal and connective tissue 
disorders
41 (66.1)
33 (53.2)
6 (9.7)
4 (6.5)
Arthralgia
28 (45.2)
26 (41.9)
2 (3.2)
2 (3.2)
Myalgia
11(17.7)
9 (14.5)
0
0
Pain in extremity
10 (16.1)
7 (11.3)
0
0
Gastrointestinal disorders
35 (56.5)
24 (38.7)
3 (4.8)
1 (1.6)
Nausea
23 (37.1)
16 (25.8)
1 (1.6)
1 (1.6)
Vomiting
14 (22.6)
7 (11.3)
0
0
Diarrhea
10 (16.1)
8 (12.9)
0
0
Constipation
12 (19.4)
3 (4.8)
0
0
Abdominal pain
8 (12.9)
2 (3.2)
1 (1.6)
0
Investigations
32 (51.6)
20 (32.3)
6 (9.7)
5 (8.1)
Alanine aminotransferase increased
8 (12.9)
8 (12.9)
2 (3.2)
2 (3.2)
Blood alkaline phosphatase increased
7 (11.3)
5 (8.1)
2 (3.2)
2 (3.2)
Aspartate amino transferase increased
7 (11.3)
6 (9.7)
1 (1.6)
1 (1.6)
Weight decreased
8(12.9)
3(4.8)
0
0
Metabolism and nutrition disorders
34 (54.8)
18 (29.0)
6 (9.7)
3 (4.8)
Anorexia
14 (22.6)
8 (12.9)
0
0
Hyperglycemia
13 (21.0)
4 (6.5)
1 (1.6)
1 (1.6)
a Includes 5 patients with solid tumors: thyroid cancer (n=3), rectal carcinoma (n=1), ovarian cancer (n=1).
b Considered possibly or probably related to study therapy.  
c One patient initiated treatment with crystalline formulation and subsequently transitioned to the MBP 
formulation after completing six cycles.


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Table 1
Study PLX06-02: Adverse Events Reported in Patients (10%) with 
Metastatic Melanomaa (cont.)
System Organ Class
Preferred Term
Overall 
AEs 
n (%)
Related b
Any Grade
n (%)
Any 
Relationship
and
Grade 3 n 
(%)
Related b
and 
Grade 3 
n (%)
Nervous system disorders
29 (46.8)
20 (32.3)
3 (4.8)
1 (1.6)
Headache
13 (21.0)
8 (12.9)
1 (1.6)
0
Dysgeusia
7 (11.3)
7 (11.3)
0
0
Neoplasms benign, malignant, and 
unspecified (incl cysts and polyps)
25 (40.3)
17 (27.4)
16 (25.8)
15 (24.2)
Squamous cell carcinoma
17 (27.4)
17 (27.4)
17 (27.4)
17 (27.4)
Injury, poisoning, and procedural 
complications
17 (27.4)
10 (16.1)
1 (1.6)
1 (1.6)
Sunburn
12 (19.4)
10 (16.1)
1 (1.6)
1 (1.6)
Respiratory, thoracic, and mediastinal 
disorders
20 (32.3)
6 (9.7)
2 (3.2)
1 (1.6)
Cough
7 (11.3)
3 (4.8)
0
0
Blood and lymphatic system disorders
16 (25.8)
7 (11.3)
3 (4.8)
1 (1.6)
Anemia
12 (19.4)
5 (8.1)
2 (3.2)
1 (1.6)
a  Includes 5 patients with solid tumors: thyroid cancer (n=3), rectal carcinoma (n=1), ovarian cancer (n=1).
b Considered possibly or probably related to study therapy. 
c  One patient initiated treatment with crystalline formulation and subsequently transitioned to the MBP 
formulation after completing six cycles.
Forty-four percent of the 62 patients who received the MBP formulation in the 
dose-escalation and the melanoma-extension cohort had their vemurafenib dose 
interrupted and/or dose reduced as a result of adverse events that included a broad range 
of adverse events and laboratory abnormalities (i.e., ALT, AST, alkaline phosphatase 
[ALP], and -glutamyl transpeptidase [GGT]), the majority of which were Grade 3 in 
intensity and resolved with no sequelae.
Three of 62 (4.8%) patients discontinued treatment as a result of adverse events 
(pancreatitis, hyperbilirubinemia with edema of the lower extremities, nausea, seizures 
related to brain metastasis and hemorrhagic cerebellar brain metastasis). The last two
adverse events were described by the investigator as unlikely to be related to treatment.
1.2.3.2
Clinical Safety in Phase II Trial: NP22657 (BRIM-2)
Study NP22657 (BRIM-2), 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 (AE). Treatment-related AEs occurred in 
130 (98%) patients. The majority of AEs were of mild or moderate intensity. The most 
commonly reported AEs (occurred 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%).


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The percentage of patients in NP22657 (BRIM2) with at least one Grade 3 adverse 
event was 73%. The percentage of patients with at least one Grade 3 treatment-related 
AE was 61%. The most commonly reported treatment-related Grade 3 AEs 
(incidence 5%) were: squamous cell carcinoma (SCC) of skin (23%), serum GGT 
increase (9%), basal cell carcinoma (7%), rash (7%), maculopapular rash (6%), and 
arthralgia (6%).
1.2.3.3
Clinical Safety in Phase III Trial: NO25026 (BRIM-3)
The percentages of patients with at least one AE in the vemurafenib and DTIC treatment 
groups were 99% and 91%, respectively. The majority of AEs were of mild or moderate 
intensity. The most commonly reported AEs (occurred in ≥30% of patients) in the 
vemurafenib group were in the system organ class of skin and subcutaneous tissue 
disorders (vemurafenib 93% vs. DTIC 23%), the most common of which were alopecia, 
rash, and photosensitivity. 
Other AEs that occurred in ≥10% of vemurafenib-treated patients and at an incidence 
more than twice that observed in the DTIC group included SCC of skin, skin papilloma, 
arthralgia, headache, dysgeusia, pyrexia, peripheral edema, pain in extremity, myalgia, 
decreased appetite, diarrhea, hyperkeratosis, seborrheic keratosis, and dry skin.
Among the 37 patients who switched from DTIC to vemurafenib, 32 patients (86%) had 
at least one AE, and 26 patients (70%) reported at least one treatment-related AE. The 
majority of AEs were of mild or moderate intensity. 
Grade 3 Adverse Events
Fifty-nine percent of patients in the vemurafenib arm and 33% of patients in the DTIC 
arm experienced one or more adverse event ≥ Grade 3 in intensity. The percentage of 
vemurafenib-treated patients with cutaneous SCC and keratoacanthoma (KA) were 
16% and 9%, respectively, compared with <1% and 0% for DTIC-treated patients 
(all cases of cutaneous squamous cell carcinoma [cuSCC] and KA were considered to be 
treatment related, Grade 3 intensity, and  serious). 
Other common Grade 3 AEs in the vemurafenib group included photosensitivity 
reaction (9%), rash (8%), maculopapular rash
(8%), and arthralgia (4%); the 
corresponding frequency of these AEs in the DTIC group were 0%, 0%, 0%, and <1%. 
Grade 4 Adverse Events
The overall incidence of Grade 4 AEs was lower in the vemurafenib group 
(13 patients [4%] with 14 AEs) than the dacarbazine group (22 patients [8%] with 
27 AEs). Grade 4 AEs in the vemurafenib group included: pulmonary embolism 
(3 patients), increased GGT (2 patients), increased blood CPK, increased blood bilirubin, 
increased lipase, ageusia, intraventricular hemorrhage, pneumonia, pneumothorax, 
respiratory distress, neutropenia (all in one patient each). Five vemurafenib patients had a 
total of six Grade 4 AEs that were considered by the investigator to be related to 
treatment (increased blood bilirubin, GGT increased [two patients], ageusia, increased 
CPK, and neutropenia).  One of the 37 crossover patients experienced a Grade 4 AE of 


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decreased neutrophil count after the date of crossover. It was judged by the investigator 
to be unrelated to treatment and non-serious.
Grade 5 Adverse Events
Grade 5 AEs were reported in 6 patients (2%) in the vemurafenib group at the time of the 
clinical cutoff (1 March 2011). Only one AE (intracranial tumor hemorrhage) was 
considered by the investigator to be treatment-related. Each of the other patients 
experienced the following Grade 5 AEs (all unrelated to study treatment): general 
physical health deterioration, cerebrovascular accident, pneumonia, aortic aneurysm 
rupture, and cardiac failure. 
1.2.3.4
Profile in Global Safety Study MO25515
In the MO25515 post-approval safety study (February 2012), out of the 2207 patients 
who received at least 1 dose of vemurafenib, 1913 (87%) have reported AEs, 78% of 
which were related to vemurafenib, with 32% of these Grade 3 adverse events and 2% 
Grade 4 adverse events. 
The most common adverse events (10%) of any grade were arthralgia (31.2%), rash 
(26.2%), fatigue (20.7%), alopecia (16.9%), nausea (15.8%), photosensitivity reaction 
(11.3%), dry skin (11%), pruritus (10.6%), hyperkeratosis (10.5%), and headache (10%); 
adverse events were similar irrespective of presence or absence of brain metastases and 
Eastern Cooperative Oncology Group (ECOG) performance status. The most common 
grade 3/4 adverse events (1%) were rash (2.6%), arthralgia (2.5%), fatigue (1.5%), 
anaemia (1.0%), and cuSCC/KA (4.7%/3.3%). Of 1282 patients (58%) who discontinued 
treatment, most withdrew due to progressive disease (42.8%) or death (6.7%) but 5.1% 
withdrew due to adverse events (most commonly general physical deterioration). Adverse 
events resulted in treatment interruption in 512 patients (23.2%).
In a setting representative of routine clinical practice, vemurafenib is well tolerated for 
the treatment of BRAF V600mutated metastatic melanoma, with a safety profile that 
resembles the safety profiles in the Phase I to III data.
1.2.3.5
Deaths and Serious Adverse Events Associated with 
Vemurafenib
Across all studies, the majority of reported deaths were attributed to progressive disease. 
In the pivotal, Phase III Study NO25026 (BRIM3), the percentage of patients who died 
was 19% in the vemurafenib group and 34% in the DTIC group. No patient died after 
crossing over from the DTIC group to the vemurafenib group as of the clinical cutoff date
(1 March 2011). In Studies NP22657 (BRIM2) and NP25163, the percentages of patients 
who died were 39% and 25%, respectively.
Across the NO25026 (BRIM3), NP22657 (BRIM2), and NP25163 studies, the most 
commonly reported vemurafenib-related SAE was cuSCC. 
In Study NO25026 (BRIM3), the percentage of patients who experienced one or more 
SAEs was 42% in the vemurafenib group and 18% in the DTIC group as of the clinical 
cutoff date. The percentage of patients who experienced one or more treatment-related 
SAEs was 31% and 5%, respectively. The most common treatment-related SAEs in the 


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vemurafenib group were cutaneous SCC (17%) and KA (9%). No other treatment-related 
SAE occurred in >1% of patients in either treatment group.
One notable treatment-related SAE occurred in a vemurafenib-treated patient after the 
1 March, 2011 clinical cutoff date. This patient developed toxic epidermal necrolysis 
(TEN). The event improved slightly after the patient was given treatment but was not 
resolved at last report. The patient was discharged from the hospital and permanently 
discontinued treatment with vemurafenib.
In Study NP22657 (BRIM2), the percentage of patients who experienced one or more 
SAEs was 53%. The most common treatment-related SAEs included SCC of the skin 
(23%), basal cell carcinoma (7%), KA (3%), elevated LFTs (2%), rash (2%), pyrexia 
(2%), and arthralgia (2%). 
In Study NP25163, the percentage of patients who experienced one or more SAEs was 
33%. The most common treatment-related SAE was cutaneous SCC (19%). A single case 
of irreversible retinal vein occlusion (RVO) was reported 
 in a patient who 
received vemurafenib 960 mg bid. 
1.2.4
Adverse Events of Special Interest for Vemurafenib
1.2.4.1
Cutaneous Squamous Cell Carcinoma 
In Studies NO25026, NP22657, and NP25163, 79 (23.5%), 34 (25.8%), and 10 (19.2%) 
patients developed cuSCC/KA), respectively, and most cuSCC/KA cases were 
keratoacanthomas, 58/79 (73.4%), 30/34 (88.2%), and 19/19 (100%), respectively.
Although all events of cuSCC were to be reported per protocol as serious cuSCC events 
were generally treated with local excision and were not vemurafenib dose limiting. A risk 
management plan, including regular dermatological examinations, head and neck 
examinations, and chest computed tomography (CT) scans, has been established to 
monitor and treat SCC in patients who receive vemurafenib and during prolonged 
follow-up (see Section 5.3.4.6).
1.2.4.2
Other Neoplasms
1.2.4.2.1
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 tonsilar SCC after receiving vemurafenib for 200 days. 
The patient had a 30 pack-year history of tobacco use. The patient’s biopsy tested 
strongly positive for p16 by immunohistochemistry (IHC), but no evidence of a RAS 
mutation or epidermal growth factor receptor amplification or mutation was present. 
A second case occurred in study NP25163 (PK/pharmacodynamics [PD] study). This 
patient had an invasive SCC of the tongue. He was previously treated for metastatic 
melanoma with ipilimumab, therapeutic vaccine (type not specified), and highdose 
interleukin-2, prior to enrollment on 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 papilloma virus genome. 


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Patients in clinical trials will undergo monitoring including head and neck examination 
(which will consist of at least a visual inspection of oral mucosa and lymph node 
palpation), chest CT, and in relevant cases anal examinations and pelvic examinations 
(for women).
1.2.4.2.2
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.
1.2.4.2.3
Progression of Cancers Associated with RAS Mutations
Based on its mechanism of action, vemurafenib may cause progression of cancers 
associated with RAS mutations. Reports of progression of NRAS-mutated chronic 
myelomonocytic leukemia [16] and KRAS-mutated pancreatic adenocarcinoma [17] have 
been published in peer-reviewed scientific journals. Vemurafenib should be used with 
caution in patients with a prior or concurrent cancer associated with RAS mutation. Full 
details are provided in the vemurafenib IB.
1.2.4.3
QT Interval Prolongation
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 at 960 mg bid did not appear to have a clinically meaningful effect on heart 
rate 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 QTcP values >500 msec 
(CTC Grade 3), while 49 (37.1%) and 6 (4.5%) of patients exhibited QTcP values
450 msec and > 480 msec, respectively. No patients had treatment-emergent QT 
(uncorrected) values > 500 msec. Maximal treatment-emergent individual QTcP changes 
from baseline of > 30 msec were observed in 58 (43.9%) patients, but only 1 patient 
(0.8%) exhibited a QTcP change from baseline of > 60 msec. 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% confidence interval 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 
15.1ms (upper boundary of the 2-sided 90% confidence interval of 17.7 ms) was detected 
at a pre-dose time point.
For a detailed summary of QTc interval prolongation among recipients of vemurafenib, 
see the vemurafenib IB.
1.2.4.4
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 


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[20].  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 outcomes of the 2 cases
of severe liver injury were reported as completely resolved with vemurafenib 
discontinuation.  The median time to onset of the adverse events was 44 days after initial 
dose.  The median ALT to 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.
1.2.5
Other Adverse Events of Clinical Significance
1.2.5.1
Drug Reaction with Eosinophilia and Systemic Symptoms 
As of 31 March 2013, 12 cases of drug reaction with eosinophilia and systemic 
symptoms syndrome have been observed with vemurafenib treatment, and no case was 
reported to result in death. The time to onset was 7 to 25 days. In the majority of patients 
(seven), vemurafenib was discontinued. Some patients (five) were treated with systemic 
steroids with corresponding improvement or resolution of symptoms. In addition, two 
patients with Grade 3 rash, who were treated with vemurafenib after ipilimumab, had 
biopsies that showed pathology consistent with drug hypersensitivity reaction [17]. Full 
details are provided in the vemurafenib IB. 
1.2.5.2
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.
1.2.5.3
Pancreatitis
Pancreatitis has been identified in patients being treated with vemurafenib. Seventeen 
cases of pancreatitis with no strong risk factors or alternative explanations have been
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 [18].
1.2.5.4
Panniculitis
Twenty-six cases of medically confirmed panniculitis cases, out of an estimated 
14,926 patients treated with vemurafenib, have been reported; 85% of the cases were 
assessed as causally associated with vemurafenib treatment. The majority of the cases are 
in females (n =21), and in most cases the latency was 10 to 20 days after the initial dose.
1.2.5.5
Potentiation of Radiation Toxicity
As of Q4 2014, an adverse drug reaction of potentiation of radiation treatment toxicity 
has been identified in patients treated with radiation either prior, during, or subsequent to 
vemurafenib treatment. This is based on 20 cases of radiation injuries, adjudicated as 
radiation recall (n8) and radiation sensitization (n12). The nature and severity of the 
events in all 20 cases were evaluated as worse than expected for the normal tissue 


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tolerance to therapeutic radiation with fatal outcome in 3 cases. The reaction was seen in 
the skin, esophagus, lung, liver, rectum, and urinary bladder. Vemurafenib should be used 
with caution when given concomitantly or sequentially with radiation treatment. Full 
details are provided in the vemurafenib IB.
1.2.5.6
Ipilimumab and Vemurafenib
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) [21]. All liver 
laboratory 
abnormalities 
were 
asymptomatic 
and 
reversible 
with 
permanent 
discontinuation of the study drugs or, in some cases, administration of corticosteroids. 
Based on these data, concurrent administration of ipilimumab and vemurafenib is not 
recommended outside of a clinical trial. Full details are provided in the vemurafenib IB. 
1.2.6
Clinical Efficacy of Vemurafenib
Clinical efficacy data to support the use of vemurafenib for the treatment of patients with 
BRAFV600 mutation-positive unresectable or metastatic melanoma is primarily based on 
results from the following studies: 

PLX06-02, Phase I: clinical cutoff: 3 June 2010. 
o
Dose escalation phase: (patients with solid tumors); original formulation, 
n=26, MBP formulation, n=30. 
o
Treatment-extension phase: Metastatic melanoma patients, n=32, 
o
Treatment-extension phase: Metastatic colorectal cancer patients, n=21.

NP22657 (BRIM2), Phase II: clinical cutoff: 31 January 2011; n=132, 

NO25026 (BRIM3), Phase III: clinical cutoff: 31 March 2011; vemurafenib 
n=337; dacarbazine (DTIC) n=338. 
In the Phase III Study NO25026 (BRIM3), after a median 6.21 months of follow-up in 
the vemurafenib arm, the Kaplan-Meier estimate of median survival among patients 
randomized to vemurafenib was not reached (95% CI: 9.59 months, not reached). Among
patients randomized to dacarbazine, after a median 4.46 months of follow-up, the KM 
estimate of median survival was 7.89 months (95% CI: 
7.26, 9.63 months). 
The Kaplan-Meier estimate of the 6-month survival rate among patients randomized to 
vemurafenib was 83% (95% CI:
79%, 87%) and among patients randomized to 
dacarbazine was 63% (95% CI: 
57%, 69%).  The hazard ratio for death was 
0.44 (95% CI: 
0.33, 0.59) in favor of vemurafenib. Treatment with vemurafenib 
demonstrated a clinically meaningful and statistically significant improvement in PFS 
compared with dacarbazine treatment (p<0.0001). There was a statistically significant 
improvement in BORR (confirmed) as assessed by the investigator with vemurafenib 
(48.4%; 95% CI: 41.6%, 55.2%) compared with dacarbazine (5.5%; 95% CI: 2.8%, 
9.3%, p <0.0001).
In the Phase II Study, NP22657 (BRIM2), after a median duration of follow-up of 
10.4 months, 
the 
primary 
endpoint 
of 
confirmed 
BORR 
was 
53% 
(95% CI: 44.2%, 61.8%). Secondary endpoints of median response duration was 


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6.7 months (95% CI: 5.6, 9.8), median OS had not been reached (95% CI: 11.2, not 
reached). Median PFS was 6.8 months (95% CI: 5.6, 8.1). 
In the Phase I Study, PLX06-02, patients in the melanoma extension cohort had a KM 
estimate of median survival of 384 days, median duration of response of 227 days 
(7.6 months), median PFS of 233 days (7.8 months), and a 1-year OS survival rate of 
55%.
Table 2 summarizes the efficacy data across the 3 studies (NO25026, NP22657 and 
PLX06-02).
Table 2
Summary of Overall Survival by Study
NO25026 a
NP22657 b
PLX06-02 c
DTIC
n = 338 (%)
Vemurafenib
n = 337 (%)
Vemurafenib
n = 132 (%)
Melanoma Ext
n = 32 (%)
Patients included in analysis
338 (100)
337 (100)
132 (100)
32 (100)
Patients with event
121 (35.8)
78 (23.1)
52 (39.4)
22 (68.8)
Patients without event
217 (64.2)
259 (76.9)
80 (60.8)
10 (31.3)
Hazard ratio (unstratified)
(95% CI)
0.44
(0.33, 0.59)


Time to event (months)
Median (KM)
(95% CI)
7.89
(7.26, 9.63)
Not reached
(9.59, not 
reached)
Not reached
(11.2, not 
reached)
384 days
(318, 795 days)
6-month survival rate (KM) 
(95% CI) 
63%
(57%, 69%)
83%
(79%, 87%)
77%
(70%, 85%)
87% 
(NA)
1-year survival rate (KM)
(95% CI)



55% 
(NA)
Duration of follow-up Median 
(mos)
Min–max
4.46
0.0–11.7
6.21
0.4–13.9
10.4
0.6 to 14.7
NA
NA
DTIC = dacarbazine; KM = Kaplan-Meier estimate; NA=not available.
a Clinical cutoff: 31 March 2011.
b Clinical cutoff: 31 January 2011.
c Clinical cutoff: 3 June 2010.
For further details please refer to the Investigator’s Brochure.
1.3
Role of MEK Kinase in Melanoma
The best characterized substrate of BRAF is MEK kinase. Phosphorylation of MEK 
(pMEK) by BRAF results in increased MEK catalytic activity. Cancer cells transformed 
by BRAFV600E are exceptionally sensitive to MEK inhibition in vitro. It has been reported 
that allosteric MEK inhibitors can result in G1 phase growth arrest in melanoma cells 
[24, 25, 26]. In vitro, MEK inhibitors reduce cell proliferation, soft agar colony 
formation, and matrigel invasion of BRAFV600E-mutant melanoma cells and are also 
effective against BRAFV600E melanoma xenografts, suggesting a potentially important 
role for MEK inhibitors in melanoma and other tumors harboring the BRAFV600E 
mutation [25]. 
1.3.1
Study Drug Cobimetinib (MEK Inhibitor)
Cobimetinib (GDC-0973/XL518) is a potent and highly selective inhibitor of MEK1/2, a 
central component of the RAS/RAF pathway.


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Cobimetinib in combination with 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, Canada, members of the European 
Union, and several other countries worldwide.
1.3.2
Nonclinical Studies with Cobimetinib
Cobimetinib inhibits proliferation of a variety of human tumor cell lines by inhibiting 
MEK1 and MEK2. In addition, Cinhibits extracellular signal-regulated kinase (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.
1.3.3
Nonclinical Metabolism and Pharmacokinetics of Cobimetinib
The pharmacokinetics of cobimetinib were characterized in multiple species including 
mice, rats, dogs, and monkeys; clearance (CL) of drug from plasma was moderate and 
volume of distribution was moderate to high. Plasma protein binding of cobimetinib
across nonclinical species ranged from 93% to 99%. Plasma protein binding in humans 
was 94.8% at 1 µM. The current understanding of cobimetinib with respect to pathways 
of elimination is limited, and metabolite identification studies are ongoing. Cobimetinib 
inhibits CYP2D6 and CYP3A4, with approximate IC50 values of 1.8 µM and 5.9 µM, 
respectively. Preliminary data suggest that cobimetinib is a substrate of CYP3A4; 
therefore, caution is recommended when administering cobimetinib with potent inhibitors 
or inducers of CYP3A4 or with drugs that are substrates of CYP2D6 or CYP3A4. 
Preliminary in silico assessment (SimCYP, Sheffied, United Kingdom) suggests that 
cobimetinib poses a low risk of causing a drug-drug interaction (DDI) or being subject to 
a DDI at doses up to 80 mg cobimetinib. Cobimetinib appears to be a substrate of P-
glycoprotein (Pgp).
1.3.4
Nonclinical Safety of Cobimetinib
The nonclinical toxicity of cobimetinib was characterized in single- and repeat-dose 
general toxicity studies in rats and dogs, in vitro genotoxicity studies, and in 
cardiovascular, neurobehavioral, and respiratory safety pharmacology studies.
Key findings from the 7- or 28-day GLP toxicity studies in rats and dogs, as well as the 
13-week study in rats and dogs, are summarized below and a more detailed description 
can be found in the cobimetinib (GDC-0973) IB.
Treatment-related findings in rats dosed daily at 3 mg/kg for 28 days were present only in 
the adrenal cortex, thymus, and bone marrow. All cobimetinibassociated microscopic 
changes appeared fully reversible (except in the mandibular lymph node). The mean 


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exposures in rats at STD10 of 3 mg/kg (Day 1) were 1.29 µMhr and 0.735 µMhr in 
female and male rats, respectively; on Day 28, the mean exposures at 3 mg/kg were 
1.72 µMhr and 0.940 µMhr in female and male rats, respectively. In dogs, repeat-dose 
toxicity associated with cobimetinib treatment was observed only in the 7-day, 
repeatdose range finding study at doses of 3 mg/kg administered daily for up to 
7 days and included findings suggestive of liver toxicity (increased ALT, AST, 
and alkaline 
phosphatase 
[ALP] 
values), 
gastrointestinal 
tract 
toxicity 
(macroscopic tissue discoloration), lymphoid tissue toxicity (decreased lymphocyte 
counts), and dehydration (increased RBC, hemoglobin, HCT, and BUN values). 
No significant toxicities were observed in a 28-day, repeat-dose toxicity study in dogs at 
doses up to 1 mg/kg. In the definitive 28-day, repeat-dose toxicity studies of cobimetinib
in rats and dogs, the no observed adverse effect level (NOAEL) in each species was 
determined to be 1 mg/kg once daily (qd). The mean exposures in dogs at 1 mg/kg 
(Day 1) were 4.02 µMhr and 5.89 µMhr in female and male dogs, respectively, and on 
Day 28, the mean exposures at 1 mg/kg were 6.89 µMhr and 11.6 µMhr in female and 
male dogs, respectively. 
No new cobimetinibrelated adverse events were observed in either rats or dogs in the 
13-week studies that were not already apparent in the shorter-term studies. 
Dogs appeared to be more sensitive to the adverse effects of cobimetinib, which could be 
explained by the higher exposures in dogs than in rats. The NOAEL was determined to be 
3 mg/kg in rats (Day 90 AUC: 2.20 µMhr and 1.31 µMhr in females and males, 
respectively) and 0.3 mg/kg in dog qd x 13 weeks (Day 90 AUC: 0.94 µMhr and 
1.37 µMhr in females and males respectively). Significant cobimetinibrelated adverse 
findings upon repeated administration up to 13 weeks were noted in the gastrointestinal 
tract, bone marrow, lymphoid tissues, adrenal gland, liver, kidney, and skin. Cobimetinib
caused a dose-related bone marrow and lymphoid depletion in dogs with correlative 
decrease in lymphocyte counts. Changes in erythrocytic parameters due to concurrent 
treatment-associated dehydration were associated with gastrointestinal and renal 
toxicities that were generally reversible upon discontinuation of cobimetinib
administration.
Administration of cobimetinib to conscious telemerized dogs at doses up to 3 mg/kg
resulted in no adverse effects on cardiovascular function (including QTc interval), 
although GDC-073 effectively inhibited hERGK plus channel activity in vitro 
(IC50 = 1 µM). Cobimetinib administration in rats resulted in no adverse effects on 
neurobehavioral or respiratory function.
For more details, please refer to the cobimetinib (GDC-0973) IB.
1.3.5
Clinical Pharmacokinetics of Cobimetinib
The key PK findings from the clinical studies conducted in patients and healthy subjects 
are summarized below.

Cobimetinib exposure (AUC at steady state and Cmax at steady state) was dose-
proportional across the dose range of 0.05 mg/kg (3.5 mg for a 70-kg adult) to 100 
mg (clinically relevant dose range) following oral administration. 


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
The absolute bioavailability was 46%, and the fraction absorbed was estimated to be 
88%, which indicates significant first pass metabolism. 

Cobimetinib binds to plasma proteins (95%) in a concentration-independent manner. 

Cobimetinib was extensively metabolized by CYP3A and UGT2B7 and eliminated in 
feces with minimal renal elimination. Cobimetinib was the predominant moiety in 
plasma as no metabolites were circulating at 10% of total radioactivity. 

Cobimetinib has a mean terminal elimination half-life (t1/2) of 43.6 hours. 

Cobimetinib does not alter the pharmacokinetics of midazolam (sensitive CYP3A 
substrate) or dextromethorphan (sensitive CYP2D6 substrate) in patients with cancer. 
Substrates of CYP3A and CYP2D6 can be co-administered with cobimetinib without 
any dose adjustment. 

Co-administration with a high-fat meal or the proton-pump inhibitor (PPI)
rabeprazole did not alter cobimetinib pharmacokinetics. Cobimetinib can therefore be 
administered without regard to food, PPIs, or other acid-reducing agents. 

Cobimetinib AUC increased by approximately 7-fold and Cmax by approximately 3-
fold when co-administered with a strong CYP3A inhibitor (itraconazole). Hence, 
concomitant administration of strong CYP3A inhibitors with cobimetinib is not 
recommended. 

Physiologically-based PK simulations indicate that weak inhibitors of CYP3A will 
not alter cobimetinib PK, while moderate inhibitors will increase cobimetinib AUC 
approximately 3- to 4-fold in the presence of moderate and strong inducers.
For more information, please refer to the cobimetinib (GDC-0973) IB.
1.3.6
Clinical Experience of Cobimetinib Monotherapy:
Study MEK4592g 
Study MEK4592g is a multicenter, Phase I, non-randomized, open-label, dose-escalation 
study. 
The study consisted of five treatment stages:

Stage I: Dose-escalation cohorts; patients were treated on a 21 days on, 7 days off 
(21/7) schedule to determine the maximal tolerated dose (MTD). The MTD for the 
21/7 schedule was found to be 60 mg.

Stage IA: Dose-escalation cohorts; patients were treated on a 14 days on, 14 days off 
(14/14) schedule to determine the MTD on an alternate dosing regimen. The MTD for 
the 14/14 schedule was found to be 100 mg. 

Stage II: Expansion cohort with the MTD determined in Stage I (60 mg qd 21/7) in 
approximately 20 patients using fluorodeoxyglucose Positron Emission Tomography 
(FDG-PET) scans of avid tumors that harbored a BRAF, NRAS, or KRAS mutation 
and with FDG-PETavid disease.

Stage IIA: Expansion cohort with the MTD determined in Stage IA (100 mg qd 
14/14) in approximately 20 patients with FDG-PETavid tumors that harbored a 
BRAF, NRAS, or KRAS mutation.

Stage III: A dedicated DDI study at the MTD determined in Stage I (60 mg qd 21/7) 
in approximately 20 patients with solid tumors. 


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The primary objectives of Stages I, IA, II, and IIA of this study were to evaluate the 
safety and tolerability of cobimetinib administered orally as repeated doses in patients 
with solid tumors and to determine the MTD of daily oral administration of cobimetinib 
in patients with solid tumors.  The primary objective of Stage III of this study was to 
evaluate the possible effect of cobimetinib on the pharmacokinetics of dextromethorphan 
and midazolam. Study MEK4592g has been completed; a total of 115 subjects were 
treated. 
1.3.6.1
Dose-Limiting Toxicities
Four DLTs were 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, two 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. 
1.3.6.2
Adverse Events 
An overview of treatment-emergent adverse events, regardless of relationship to study 
drug, with frequency 10% in all patients in Study MEK4592g is presented in Table 3.
All patients in Study MEK4592g experienced an adverse event. The most frequent 
adverse events were diarrhea (67.0%), fatigue (50.4%), rash (49.6%), nausea and
vomiting (33.9% each), and edema peripheral (28.7%). Other events that occurred 
in10% of patients included anemia, abdominal pain, constipation, hypokalemia, 
decreased appetite, headache, dizziness, back pain, increased AST, dermatitis acneiform, 
pruritus, and dry skin.
Among the patients who received cobimetinib 60 mg qd 21/7, the most frequent 
treatment-emergent adverse events were diarrhea (64.4%), rash (53.3%), fatigue (48.9%), 
nausea and edema peripheral (31.1% each), and vomiting (28.9%).


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Table 3
Treatment-Emergent Adverse Events Regardless of Relationship 
to Study Drug That Occurred in 10% or More of Patients in 
Study MEK4592g
MedDRA System Organ Class and Preferred Term
60 mg qd 21/7
n45
All Patients
n115
Patients with at least one AE, n (%)
45 (100)
115 (100)
Blood and lymphatic system disorders
  9
26
Anemia
8 (17.8)
21 (18.3)
Gastrointestinal disorders
43 
109
Diarrhea
29 (64.4)
77 (67.0)
Nausea
14 (31.1)
39 (33.9)
Vomiting
13 (28.9)
39 (33.9)
Abdominal pain
6 (13.3)
28 (24.3)
Constipation
10 (22.2)
24 (20.9)
Stomatitis
4   (8.9)
14 (12.2)
General disorders and administration site 
conditions
29
82
Fatigue
22 (48.9)
58 (50.4)
Edema peripheral
14 (31.1)
33 (28.7)
Infections and infestations
10
35
Urinary tract infection
5 (11.1)
14 (12.2)
Investigations
19 
36
Aspartate aminotransferase increased
5 (11.1)
12 (10.4)
Metabolism and nutrition disorders
25 
65
Decreased appetite
11 (24.4)
27 (23.5)
Dehydration
10 (22.2)
27 (23.5)
Hypokalaemia
5 (11.1)
14 (12.2)
Hyponatraemia
4 (8.9)
12 (10.4)
Musculoskeletal and connective tissue disorders
13
36
Back pain
5 (11.1)
13 (11.3)
Nervous system disorders
17 
42
Dizziness
7 (15.6)
21 (18.3)
Headache
3 (6.7)
14 (12.2)
Skin and subcutaneous tissue disorders
35 
84 
Rash
24 (53.3)
57 (49.6)
Dry skin
4 (8.9)
16 (13.9)
Dermatitis acneiform
8 (17.8)
13 (11.3)
Pruritus
4 (8.9)
13 (11.3)


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Table 3
Treatment-Emergent Adverse Events Regardless of Relationship 
to Study Drug That Occurred in 10% or More of Patients in 
Study MEK4592g (cont.)
60 mg qd 21/7: Patients who received the proposed cobimetinib commercial dosing regimen (60 mg qd 
21/7) (pool from Stages I, IA, II, IIA and III).
All Patients: Patients who received cobimetinib on all schedules and doses (pooled from Stage I, IA, II, 
IIA, and III).
Note: Event coding is from the MedDRA, v16.0. At each level of patient summarization, a patient is 
counted once if the patient experienced one or more events. Treatment emergent refers to adverse events 
with onset on or after the date of first dose of study drug.
Source: Modified from Study MEK4592g Summary of Clinical Safety
Data cutoff: 11 June 2013.
1.3.6.3
Grade3 Adverse Events
Table 4
summarizes the Grade
3 
treatment-emergent adverse 
events that 
affected2 patients of all patients in Study MEK4592g (n115) and of those who received 
cobimetinib 60 mg 21/7 (n45).
Among all cobimetinib-treated patients, 5 patients (4.3%) experienced a Grade 4 adverse 
event, and 53 patients (46.1%) experienced a Grade 3 adverse event. The most frequent 
Grade 3 and Grade 4 adverse events were hyponatremia (9.6%), fatigue (8.7%), anemia 
(7.8%), diarrhea, and hypokalemia (6.1% each). Grade 5 adverse events, which in Study 
MEK4592g included disease progression reported as an adverse event, are discussed 
separately below.


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Table 4
Grade 3 Treatment-Emergent Adverse Events in Study 
MEK4592g
MedDRA System Organ Class and Preferred Term
60 mg qd 21/7
n45
All Patients
n115
Patients with at least one Grade3 AE, n (%)
26 (57.8)
75 (65.2)
Blood and lymphatic system disorders
2
11
Anaemia
2   (4.4)
9   (7.8)
Leukopenia
1   (2.2)
2   (1.7)
Lymphopenia
1   (2.2)
2   (1.7)
Cardiac disorders
1
4
Cardio-respiratory arrest
0
2   (1.7)
Gastrointestinal disorders
9
26
Diarrhea
0
7   (6.1)
Abdominal pain
3   (6.7)
5   (4.3)
Gastrointestinal hemorrhage
0
2   (1.7)
Ileus
1   (2.2)
2   (1.7)
Intestinal obstruction
1   (2.2)
2   (1.7)
General disorders and administration site
conditions
6
13
Fatigue
6  (13.3)
10   (8.7)
Chest pain
0
2   (1.7)
Hepatobiliary disorders
1 
4 
Bile duct obstruction
0
3   (2.6)
Infections and infestations
2
6
Urinary tract infection
2   (4.4)
3   (2.6)
Pneumonia
0
2   (1.7)
Investigations
7
14
Aspartate aminotransferase increased
1   (2.2)
3   (2.6)
Blood creatine phosphokinase increased
2   (4.4)
3   (2.6)
Electrocardiogram QT prolonged
2   (4.4)
3   (2.6)
Gamma-glutamyltransferase increased
1   (2.2)
3   (2.6)
Alanine aminotransferase increased
0
2   (1.7)
Blood bilirubin increased
1   (2.2)
2   (1.7)
Blood lactate dehydrogenase increased
1   (2.2)
2   (1.7)
Metabolism and nutrition disorders
  7
21
Hyponatremia
4   (8.9)
11   (9.6)
Hypokalemia
2   (4.4)
7   (6.1)
Dehydration
2   (4.4)
5   (4.3)
Hypophosphatemia
0
3   (2.6)


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Table 4
Grade 3 Treatment-Emergent Adverse Events in Study 
MEK4592g (cont.)
MedDRA System Organ Class and Preferred Term
60 mg qd 21/7
n45
All Patients
n115
Neoplasms benign, malignant and unspecified 
(including cysts and polyps)
4
  7
Malignant neoplasm progression
1   (2.2)
2   (1.7%)
Nervous system disorders
1
  7
Syncope
0
5   (4.3%)
Respiratory, thoracic and mediastinal disorders
7
10
Respiratory arrest
3   (6.7)
3   (2.6%)
Skin and subcutaneous tissue disorders
2
8
Rash
0
5   (4.3%)
Vascular disorders
3 
10
Hypertension
2   (4.4)
4   (3.5%)
Deep vein thrombosis
1   (2.2)
3   (2.6%)
60 mg QD 21/7: Patients who received the proposed cobimetinib commercial dosing regimen (60 mg QD 
21/7) (pool from Stages I, IA, II, IIA and III).
All Patients: Patients who received cobimetinib on all schedules and doses (pooled from stage I, IA, II, IIA 
and III).
Note: Event coding is from the MedDRA, Version 16.0. At each level of patient summarization, a patient is 
counted once if the patient experienced one or more events. Treatment emergent refers to adverse events 
with onset on or after the date of first dose of study drug.
Source: Modified from Study MEK4592g Summary of Clinical Safety
Data cutoff: 11 June 2013.
1.3.6.4
Serious Adverse Events 
A total of 49 patients (42.6%) experienced a serious adverse event. The most common 
types of serious adverse events were gastrointestinal disorders (n 17), but there were no 
trends in specific preferred terms. The gastrointestinal serious adverse events, such as 
intestinal obstructions and gastrointestinal hemorrhages, occurred in patients with 
gastrointestinal malignancies. Serious adverse events reported for 2 patients among all 
patients in the study were anemia, bile duct obstruction, dehydration, syncope, and 
respiratory arrest (3 patients each [2.6%]).
1.3.6.5
Deaths 
Study MEK4592g accrued a patient population with metastatic or unresectable solid 
tumors for which standard curative or palliative measures did not exist or were no longer 
effective. In addition, in Study MEK4592g disease progression was reported as an 
adverse event (Grade 5) instead of an outcome measure.
As of the clinical data cutoff date (20 September 2013), a total of 29 patients (25.2%) had 
died, including 11 patients in the cobimetinib 60 mg qd 21/7 group.


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A total of 14 deaths were reported for patients treated in Stage I of the study. With the 
exception of 1 patient who died of cardiopulmonary arrest secondary to progressive
disease, all deaths in Stage I occurred because of progressive disease, and no death was 
considered by the investigator to be related to the study drug.
During Stages IA, II, and IIA of the study, 12 deaths were reported, all of which occurred
30 days after the last dose of study drug. Of these, 2 deaths were considered by the 
investigator to be possibly related to study drug. In both cases, the investigator 
considered the metastatic cancer to be a contributing etiologic factor to the patient’s 
death.
Three deaths were reported in Stage III of this study. None of the deaths were assessed by 
the investigator as treatment related. Other etiologic factors that contributed to the deaths 
included the patients’ underlying diseases and malignant tumor progression.
1.3.6.6
Clinical Efficacy 
Assessment of responses was an exploratory endpoint in Study MEK4592g. Best overall 
response was assessed for 74 of 97 patients in Stages I, IA, II and IIA of the study who 
had measurable lesions and at least 1 post-baseline tumor assessment. Overall, 6 patients 
(all of whom had melanoma; 6.2%) had a confirmed partial response, 28 patients (28.9%) 
had stable disease, and 40 patients (41.2%) had progressive disease. Twenty-three 
patients had non-measurable lesions or measurable lesions with no post-baseline tumor 
assessments.
In Stage III of Study MEK4592g, 18 patients were accrued. Best overall response was 
assessed for 14 of 18 patients in Stage III with measurable lesions and at least
1 post-baseline tumor assessment. Overall, 4 patients (22.2%) had stable disease as their 
best overall response, 8 patients (44.4%) had disease progression, and 2 patients (11.1%) 
had unconfirmed tumor response.
1.3.7
Adverse Events Associated with Cobimetinib (GDC-0973) 
Information related to cobimetinib-associated risks is presented below based mainly on 
review of data from the pivotal Phase III study, GO28141, following the primary efficacy 
analysis (data cutoff 9 May 2014) and study MEK4592g. Please refer to the cobimetinib 
IB for full details.
1.3.7.1
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.


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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 12, in Section 6.1.1.
1.3.7.2
Serous Retinopathy
Serous retinopathy (fluid accumulation within the layers of the retina) has been observed 
with MEKi, including cobimetinib. The majority of events in cobimetinib-treated patients 
were reported as chorioretinopathy or retinal detachment. In the Phase I single-agent 
study (MEK4592g), also with ocular examinations prescribed for patients reporting 
visual disturbance, 2.6% of patients (including 1 patient with a Grade 2 event that was 
not coded at the time of the data cutoff date) experienced serous retinopathy events, all of 
which were Grade 1 or 2.
In the Phase III study (GO28141), with prospective serial ocular examinations, serous 
retinopathy events were reported more frequently in patients treated with 
vemurafenibcobimetinib
than 
vemurafenibplacebo
(24% 
vs. 
2.1%), 
and 
approximately 50% were asymptomatic Grade 1 events. Few patients treated with 
vemurafenibcobimetinib experienced Grade3 ocular events (2.8%); the majority of 
these were managed with dose modification of both cobimetinib and vemurafenib, and all 
were resolved or resolving as of the data cutoff date. 
1.3.7.3
Left Ventricular Dysfunction
Left ventricular dysfunction may occur with signs and symptoms of cardiac failure, or 
reduction in left ventricular ejection fraction (LVEF) may be asymptomatic. Without 
active surveillance for reduction in LVEF, there were no events in this risk category 
reported in the Phase I single agent study (MEK4592g).
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%). 
Of 
the 
patients 
treated 
with 
vemurafenibcobimetinib, 2 patients (0.8%) had symptomatic reduction in LVEF and 
the remaining patients were asymptomatic. One patient in each arm (0.4% each) 
experienced serious events; these were symptomatic. Most events in patients treated with 
vemurafenibcobimetinib (88%) improved or resolved with management according to 
the dose modification guidelines. No Grade 4 or 5 events of reduction in LVEF have been 
reported in cobimetinib clinical studies as of the data cutoff dates. Reduction in LVEF 
has also been observed in patients treated with MEKi other than cobimetinib.
Investigators should monitor patients for clinical signs and symptoms of cardiac 
dysfunction. 
1.3.7.4
Rhabdomyolysis and Increased CPK
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 


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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 12, in Section 6.1.1.
1.3.7.5
Liver Laboratory Abnormalities
Liver laboratory test abnormalities, including elevations in AST and/or ALT, have been 
reported as adverse events and serious adverse events in patients treated with 
vemurafenibcobimetinib. In the Phase III study (GO28141), liver laboratory test 
abnormalities reported as Grade3 adverse events occurred more frequently in patients 
treated with vemurafenibcobimetinib than vemurafenibplacebo (20.5% vs. 15.1%).
Liver laboratory test abnormalities reported as Grade3 adverse events
at 
frequencies2% higher in patients treated with
vemurafenibcobimetinib
than 
vemurafenibplacebo included increased ALT (11.4% vs. 6.3%), increased AST (8.3% 
vs. 2.1%), and increased ALP (4.3% vs. 1.7%).
In Study MEK4592g, there were no reported adverse events or serious adverse events for 
clinically significant Grade 4 elevations in liver laboratory tests, and no patient 
experienced findings suggestive of drug-induced liver injury or liver failure.
Generally, elevations in liver laboratory tests were managed effectively with dose 
modification guidelines. In both study arms of GO28141, the majority of Grade3 liver 
laboratory test abnormalities resolved.
Refer to Section 6.1 for management of liver laboratory abnormalities.
1.3.7.6
Rash
Skin toxicities of rash have been reported in patients treated with cobimetinib as a single 
agent or in combination with other therapies. 
In the Phase III study (GO28141), combined rash events of all types and grades were 
reported more frequently in patients treated with vemurafenib cobimetinib than 
vemurafenib placebo (71.7% vs. 65.7%), although Grade 3 events (approximately 
16%) and types of rash reported were similar between study arms. Specific events in 
patients treated with vemurafenib cobimetinib included rash (39% all grades, 5.9% 
Grade 3, 1.6% serious events) and rash maculo-papular (14.6% all grades, 6.3% 
Grade 3, 1.2% serious events).
In the Phase I single-agent study (MEK4592g), reported rash events included rash (49.6%
all grades, 4.3% Grade3 events) and rash maculo-papular (1.7% all grades, 0.9% 
Grade3 events).
Refer to Section 6.1 for management of rash.


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1.3.7.7
Photosensitivity
Although no evidence of phototoxicity was observed with cobimetinib as a single agent, 
photosensitivity events, including photosensitivity reaction, solar dermatitis, and sunburn,
have been reported in cobimetinib clinical studies in combination with vemurafenib. 
In the Phase III study (GO28141), photosensitivity events were reported more frequently 
in patients treated with vemurafenibcobimetinib (41.3% all grades, 3.1% Grade3) 
than vemurafenibplacebo
(31.4% all grades, 1.6% Grade3). No serious 
photosensitivity events were reported in either study arm.
Refer to Section 6.1 for management of photosensitivity.
1.3.7.8
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. 
1.4
Rationale for the Study 
The rationale for the clinical investigation of the vemurafenib/cobimetinib drug 
combination is to simultaneously target BRAF and MEK in patients with previously 
untreated BRAFV600E mutation-positive, locally advanced/unresectable or metastatic 
melanoma, those previously treated but without prior exposure to any BRAF or MEK 
inhibitor (MEKi) therapy, OR those who have progressed after treatment with 
vemurafenib monotherapy, based on the following:


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
The overall clinical activity of vemurafenib in patients with BRAFV600E-positive 
metastatic melanoma

The ability of the MEK inhibitor cobimetinib to suppress pERK signaling when given 
as monotherapy and the potential to act additively or synergistically when given in 
combination with  vemurafenib

An expectation of a tolerable safety profile for the vemurafenib and cobimetinib
combination based upon xenograft BRAF inhibitor and MEKi combinations.

Potential safety benefit by decreasing the risk of developing SCC with vemurafenib 
monotherapy
A proportion of BRAFV600E-positive melanoma patients who responded to vemurafenib in 
the Phase I extension cohort, Phase II and III studies have subsequently progressed. 
The pattern of progression has been mixed or asynchronous, occurring in a subset of 
lesions (typically less than 30% of those targeted). The majority of progressing patients, 
approximately 70%, exhibited this pattern of asynchronous progression, suggesting that 
there may be some benefit to continuing treatment with vemurafenib.
The reason(s) for this pattern of mixed progression in BRAFV600E-positive patients treated 
with vemurafenib is unclear. No gatekeeper or activating BRAF mutations have been 
noted. Biopsies of progressing lesions demonstrate increased pERK, suggesting the 
possibility of reactivation of the RAS/RAFMEK/ERK pathway, in the presence of 
vemurafenib. This may be attributed to one of the following factors illustrated in 
Figure 1. 


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Figure 1: Potential Mechanisms of Resistance to BRAF Inhibitors in 
Melanoma Cells
RG7204 = vemurafenib.
Although the escape mechanism of RAS-RAF pathway suppression is unknown, the 
formation of BRAF-CRAF or CRAF-CRAF dimers and the reactivation of
MEK-mediated signaling are likely to be integral components of this process [27, 28, 29].
Combining the MEK inhibitor cobimetinib
with vemurafenib in patients with 
BRAFV600E-positive melanoma
who experience discordant/mixed progression on 
vemurafenib monotherapy may re-establish suppression of the RAS-RAF pathway in 
progressing lesions while maintaining pathway suppression in non-progressing lesions.
To date, assessments of the combination of vemurafenib with cobimetinib have not been 
conducted. However, nonclinical data from two studies provide proof-of-concept support 
for combining a BRAF inhibitor with a MEK inhibitor to suppress ERK signaling and 
restore sensitivity to BRAF inhibition.


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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 MEK inhibitor), and to RO5068760. The combination of BRAF inhibition by 
vemurafenib and MEK inhibition by RO5068760 (Figure 2) [30] abrogated the 
constitutive upregulation of ERK phosphorylation, inhibited cell cycle progression, and 
induced apoptosis in the resistant cells to a greater extent than either agent alone.
Figure 2: Combination of Vemurafenib with a MEK Inhibitor (RO5068760) 
Demonstrates a Synergistic Anti-Proliferation Effect in the 
Acquired-Resistance Melanoma Cell Model
RO5185426 = vemurafenib.
An in vivo efficacy study in nude mice bearing BRAFV600E-positive A375 melanoma 
xenograft tumors demonstrated synergistic anti-tumor activity when vemurafenib was 
combined with the MEK inhibitor RO5068760 (Figure 3). No toxicity was observed in 
the animal subjects treated during this xenograft study.
These in vivo and in vitro studies suggest that combined RAF/MEK pharmacologic 
inhibition of the BRAF pathway is more effective than either agent alone and may 
suppress the emergence of the pathway-specific resistance in tumors harboring the
BRAFV600E mutation. 
In light of the preclinical evidence suggesting additive or synergistic benefit from the 
combination of vemurafenib with cobimetinib, enrollment in the current study will also 
include patients with previously untreated, locally advanced/unresectable or metastatic 
melanoma, positive for the BRAFV600E mutation as well as those previously treated but 
without prior exposure to any BRAF or MEK inhibitor therapy.  


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Figure 3: Combination Study of Vemurafenib and the MEK Inhibitor 
RO5068760 in the BRAFV600E-Expressing A375 Melanoma 
Xenograft Model
RG7204 = vemurafenib.
Patients treated with vemurafenib have developed SCC, the majority of which are the KA 
subtype. The development of this adverse event of interest may be related to higher 
MAPK pathway signaling by the upregulation of pERK in the setting of mutant RAS 
(or upregulation of growth factor receptors). In addition to down regulating pERK 
signaling, thereby overcoming the tumor escape mechanism, the combination of 
vemurafenib and cobimetinib may have the potential to improve the safety profile of 
vemurafenib-treated patients by decreasing the incidence of SCC. 
2.
OBJECTIVES 
2.1
Primary Objectives
Study NO25395 will be conducted in previously untreated or previously treated patients 
with BRAFV600E mutation-positive, locally-advanced and unresectable or metastatic 
melanoma OR those who have progressed on treatment with vemurafenib monotherapy
immediately prior to enrollment in this trial. Patients in the former category who were 
previously treated must have had no prior exposure to any BRAF or MEK inhibitor 
therapy. See Section 4.2 for full inclusion criteria. The objectives of the trial are as 
follows. 


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Primary Objectives:
To evaluate the safety and tolerability of the vemurafenib and cobimetinib combination, 
and in doing so,

To identify the DLTs that determine the MTD of the vemurafenib and cobimetinib
combination

To identify a potential Phase II/III dose and schedule for the vemurafenib and 
cobimetinib combination

To characterize Day 1 and steady-state pharmacokinetics of cobimetinib when 
administered in combination with vemurafenib and to characterize the steady-state 
pharmacokinetics of vemurafenib administered alone and in combination with 
cobimetinib
Secondary Objectives:

To assess the anti-tumor activity of the vemurafenib and cobimetinib combination

To assess the mechanisms of response and resistance to vemurafenib and cobimetinib
combination therapy (including genetic alterations of RAS, RAF, and MEK)

To assess the BRAFV600E mutation status of patients who progressed on vemurafenib 
monotherapy

To identify factors that may pre-dispose patients to SCC development

To assess the PD effects of  vemurafenib and cobimetinib when administered in 
combination, as measured by changes in FDG-PET

To assess the PD effects of vemurafenib and cobimetinib when administered in 
combination, as measured by changes in molecular biomarkers in sequential paired 
biopsies

To assess the PD utility of FDG-PET and changes in molecular biomarkers in 
sequential paired biopsies in a subset of patients (up to n=20) treated with 
single-agent cobimetinib
2.2
Exploratory Objectives 
Roche is committed to the collection of biomarker samples in all clinical study protocols. 
The objective of biomarker profiling is to enable development of treatments specifically 
targeted for optimal patient benefit (personalized healthcare). Biomarker samples will be 
stored in the Roche Clinical Repository (RCR). RCR is a central facility for the long-term 
storage of human biological specimens including body fluids, solid tissues, and 
derivatives thereof (e.g., DNA, RNA proteins/ peptides). Specimens stored in the RCR 
will be used for any of the following:

Study the association of biomarkers with efficacy and/or adverse events associated 
with medicinal products

Increase our knowledge and understanding of disease biology

Develop biomarker or diagnostic assays; establish performance characteristics of 
these assays


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
To evaluate the relationship between anti-tumor activity and changes in PD 
biomarkers when study drugs are administered in combination at the recommended 
MTD dose and schedule
3.
STUDY DESIGN
3.1
Overview of Study Design
This is an open-label, multicenter, Phase Ib, dose-escalation study designed to assess the 
safety, tolerability, and pharmacokinetics of continuous daily oral dosing of vemurafenib 
administered in combination with orally dosed cobimetinib administered daily for 
14 consecutive days followed by 14 days off (14/14), for 21 consecutive days followed 
by 7 days off (21/7), or as a continuous daily dose. Patients with previously untreated, or 
treated
BRAFV600E
mutation-positive, locally advanced/unresectable or metastatic 
melanoma OR those who have progressed on vemurafenib monotherapy immediately 
prior to enrolling in this trial are eligible. Patients in the former category who were 
previously treated must have had no prior exposure to any BRAF or MEK inhibitor 
therapy. Treatment will continue until disease progression, unacceptable toxicity, or any 
other discontinuation criterion is met (Section 4.5). For a small subset of patients who 
have progressed on vemurafenib monotherapy immediately prior to enrollment in this 
trial (up to 20), there is also an option for treatment with single-agent cobimetinib at 
60 mg on a 21/7 schedule (see Section 3.1.2). The PD data obtained from this patient 
group will be reviewed with the vemurafenib plus cobimetinib combination PD data to 
enhance our understanding of the combination PD data. 
Vemurafenib will be dosed daily and cobimetinib will be dosed on a 14/14, a 21/7, or a 
continuous schedule in a 28-day cycle. Alternate dosing regimens and schedules may be 
interrogated depending on the nature and timing of the toxicities encountered.
There are two stages to this study: a dose-escalation stage and a cohort-expansion stage. 
During the dose-escalation stage, 10 dose-escalation cohorts of 36 patients each will be 
enrolled in order to identify a safe and tolerable dose of each agent to be administered 
during the cohort-expansion stage, i.e., the potential recommended Phase II/III dose
combination. Approximately 20 additional patients will be enrolled into each of 
(minimally) two expansion cohorts during the cohort-expansion stage. One cohort will 
consist of patients who have progressed on vemurafenib monotherapy immediately prior 
to enrolling in this trial, and the other will consist of previously untreated or treated 
patients without prior exposure to any BRAF or MEK inhibitor therapy.  Therefore, 
approximately 130
patients (not including patients treated with cobimetinib
monotherapy) will be enrolled in the trial at approximately 7-10 sites in total in the 
United States and Australia.
3.1.1
Stage 1: Dose-Escalation Cohort
The dose-escalation stage is designed to evaluate the safety, tolerability, MTD, 
pharmacokinetics, and any anti-tumor activity of vemurafenib when administered in 
combination with cobimetinib.


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Stage 1 will be conducted in previously untreated or treated patients with 
BRAFV600E-positive metastatic melanoma (unresectable Stage IIIc and Stage IV, 
according to the American Joint Committee on Cancer [AJCC] classification) OR those 
who have discordant/mixed progression on treatment with vemurafenib monotherapy in a 
previous clinical trial or postmarketing setting immediately preceding enrollment in this 
trial. Patients in the former category who were previously treated must have had no prior 
exposure to any BRAF or MEK inhibitor therapy. Please see Sections 4.2 and 4.3 for a 
detailed description of the eligibility criteria. Patients who have FDG-PET avid disease 
will undergo FDG-PET imaging as a PD biomarker and potential early readout of 
anti-tumor activity. 
a) Starting Doses and Overall Study Design
A 3+3 dose-escalation schema will be used. The starting dose of vemurafenib will be 
720 mg bid for 28 consecutive days of each 28-day cycle of combination dosing, which is 
one dose level below the single-agent MTD of 960 mg bid established in the vemurafenib 
Phase Ia trial (PLX06-02) and which is utilized in the dose-modification scheme in the 
Phase II and Phase III trials of vemurafenib. This dose level was selected in an attempt to 
maintain RAS/RAF/ERK pathway suppression in non-progressing melanoma lesions. 
The effectiveness of this dose is supported by data from the Phase I through III clinical
trials. In the Phase I trial, approximately 30% of patients have required dose reductions to 
720 mg bid, while continuing to show a response to vemurafenib monotherapy. 
The starting dose of cobimetinib will be 60 mg per day for 14 consecutive days of each 
28-day cycle of combination dosing, which is two dose levels below the single-agent 
MTD of 100 mg per day administered on this schedule as established in the cobimetinib
Phase Ia trial (Study MEK4592g). Dose escalation will proceed in increments, taking into 
account the safety and tolerability of the combination.
b) Dose Escalation
The dose-escalation schema and plan are detailed in Figure 4, Figure 5, and Table 5. 


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Figure 4: Dose-Escalation Plan for the Combination of Vemurafenib and 
Cobimetinib Administered on a 14/14 Schedule
* Simultaneous enrollment in Cohorts 1A (Figure 5), 2, and 3


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Figure 5: Dose Escalation Scheme for the Combination of Vemurafenib and 
Cobimetinib Administered Either on a 21/7 Day or a 
Continuous Schedule
* Declaration of Cohort 1A safety and tolerability will trigger enrollment in several cohorts: Cohort 1B 
(under Amendment D), Cohort 1C (pending approval of Amendment E), and Cohort 1A expansion 
cohorts of patients who progressed on vemurafenib immediately prior to enrolling this trial (n = 20) and 
previously untreated with vemurafenib or other BRAF or MEK inhibitor (n = 20); see Section 3.1.
If the Cohort 1 dose combination is safe and tolerable as per the rules for dose-limiting 
toxicity (Section 3.1.4), escalation will continue with simultaneous enrollment of 
Cohort 1A (Figure 5) when available, Cohort 2, and Cohort 3 (Figure 4). Cohort 2 will 
evaluate the combination of vemurafenib at a dose of 720 mg bid and cobimetinib at 
80 mg/day on a 14/14 day schedule, and Cohort 3 will evaluate the combination of 
vemurafenib at a dose of 960 mg bid and cobimetinib at 60 mg/day on a 14/14 day 
schedule. Cohort 2A (Figure 4) may be enrolled only if the dose combination tested in 
Cohort 2 is declared safe and tolerable. Enrollment in Cohort 4 may occur only if the dose 
combinations tested in both Cohorts 2 and 3 are declared safe and tolerable. Cohort 4 will 
evaluate the combination of vemurafenib at 960 mg bid and cobimetinib at 80 mg/day on 
a 14/14 day schedule. If the Cohort 4 combination is safe and tolerable, further escalation 
will occur with enrollment in Cohort 5. Cohort 5 will evaluate the combination of both 


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vemurafenib and cobimetinib at their monotherapy MTDs (960 mg bid and 100 mg/day, 
respectively, 14/14 day schedule,).
Cohort 1A (Figure 5) will test the safety and tolerability of vemurafenib at a dose of 
720 mg bid in combination with cobimetinib at 60 mg/day on a 21/7 day schedule. 
Cohorts 1B and 1C may enroll patients only after the Cohort 1A dose combination is 
declared safe and tolerable. Cohort 1B will test the safety and tolerability of vemurafenib 
at a dose of 960 mg bid in combination with cobimetinib at 60 mg/day on a 21/7 day 
schedule, and Cohort 1C will test the safety and tolerability of vemurafenib at a dose of 
720 mg bid and cobimetinib at 60 mg/day on a continuous schedule. After both Cohorts
1B and 1C are deemed to be acceptably safe and tolerable, Cohort 1D will open to 
evaluate the combination of vemurafenib at a dose of 960 mg bid and cobimetinib at 
60 mg/day on a continuous schedule.
There will be no intrapatient dose escalation during the DLT assessment window 
(Cycle 1, Days 128). After the DLT assessment window (Cycle 2 and beyond), patients 
without evidence of melanoma progression may receive cobimetinib at the highest cohort 
dose level for which there are at least 4 weeks of safety data demonstrating acceptable 
tolerability (i.e., no DLTs observed in a cohort of 3 evaluable patients or 1 DLT in a 
cohort of 6 evaluable patients).  In some cases, this may allow the skipping of more than 
one dose level.  For example, after Cohort 2A is determined to be safe and tolerable, 
patients in Cohort 2 may increase their daily dose of cobimetinib from 80 to 100 mg on a 
14/14 schedule, and patients in Cohort 1 may increase their daily dose of cobimetinib
from 60 to 100 mg on a 14/14 schedule. Patients that are beyond the Cycle 1 DLT 
assessment window are eligible for multiple, step-wise dose escalations (with agreement 
of the Sponsor’s Medical Monitor) although dose escalations for an individual patient 
may not continue once that patient develops cobimetinib–related Grade 3 toxicity. 
Intrapatient dose modification will be allowed in patients within a given cobimetinib
administration schedule once the next higher dose level(s) is deemed to be acceptably 
safe and tolerable. Patients treated on a 14/14 schedule cannot transition to a 21/7 or a 
continuous daily schedule.
In all such circumstances, the daily dose of vemurafenib may remain the same 
(at 720 or 960 mg bid) or increase from 720 to 960 mg bid, but only if the patient was 
tolerating 960 mg bid in a previous clinical study or postmarketing setting of 
vemurafenib monotherapy, immediately preceding enrollment in this trial. 
All intrapatient dose escalations must begin on Day 1 of the next treatment cycle.
Table 5 outlines the vemurafenib and cobimetinib dose and schedule combinations 
planned for Cohorts 1, 1A, 1B, 1C, 1D, 2, 2A, 3, 4, 5, and the cobimetinib monotherapy 
cohort. All cohorts except the cobimetinib monotherapy cohort will be open to patients 
who either have progressed on vemurafenib monotherapy or are previously untreated or 
treated (but without prior exposure to BRAF or MEK inhibitor therapy) for locally
advanced/unresectable or metastatic melanoma.


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Table 5
Roadmap for Planned Dose Escalation 
Cohort 
(Patient number)
VEMURAFENIB/
Cobimetinib dose, 
schedule
Eligible patients
Comments
1 (n=3-6)
720 mg bid/60 mg qd 14/14
Vemurafenib progressors, 
PTPs, and PUPs
After (if) cohort 1 dose 
combination is deemed 
safe, cohorts 1A, 2 and 3 
will open to new patients 
simultaneously
1A (n=3-6)*
720 mg bid/60 mg qd 21/7
Vemurafenib progressors, 
PTPs, and PUPs
1B (n=3-6)*
960 mg bid/60 mg qd 21/7
Vemurafenib progressors, 
PTPs, and PUPs
Cohort 1B may open to 
new patients only after 
Cohort 1A dose 
combination is deemed safe 
and tolerable
1C (n=3-6)†
720 mg bid/60 mg qd 28/0
Vemurafenib progressors, 
PTPs, and PUPs
Cohort 1C may open to 
new patients only after 
Cohort 1A dose 
combination is deemed safe 
and tolerable
1D (n=3-6))†
960 mg bid/60 mg qd 28/0
Vemurafenib progressors, 
PTPs, and PUPs
Cohort 1D may open to 
new patients only after 
Cohort 1B and 1C dose 
combinations are deemed 
safe and tolerable
2 (n=3-6)
720 mg bid/80 mg qd 14/14
Vemurafenib progressors, 
PTPs, and PUPs
2A (n=3-6)
720 mg bid/100 mg qd 
14/14
Vemurafenib progressors, 
PTPs, and PUPs
Cohort 2A may open to 
new patients only after 
Cohort 2 dose combination 
is deemed safe and 
tolerable
3 (n=3-6)
960 mg bid/60 mg qd 14/14
Vemurafenib progressors, 
PTPs, and PUPs
4 (n=3-6)
960 mg bid/80 mg qd 14/14
Vemurafenib progressors, 
PTPs, and PUPs
Cohort 4 will open to new 
patients only after both 
Cohorts 2 and 3 dose 
combinations are deemed 
safe and tolerable 
5 (n=3-6)
960 mg bid/100 mg qd 
14/14
Vemurafenib progressors, 
PTPs, and PUPs
Cobimetinib
monotherapy (up to 20)
60 mg qd 21/7
Vemurafenib IB progressors 
only
Abbreviations:  PTPs= patients previously treated for locally advanced/unresectable or metastatic melanoma but 
without prior exposure to any BRAF or MEK inhibitor therapy; PUPs = previously untreated patients with BRAFV600E
mutation-positive, locally advanced/unresectable or metastatic melanoma 
*New cohorts not represented in Amendment C.
†New cohorts not represented in Amendment D.
Dose De-Escalation
The dose-escalation plan for vemurafenib and cobimetinib combination therapy may not 
be tolerable. In this case, a dose de-escalation plan may be adopted at the discretion of the 
study Sponsor.
If the Cohort 1 dose combination is not tolerated, dose de-escalation for either 
vemurafenib or cobimetinib will occur. Dose de-escalation will occur with simultaneous 


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enrollment into Cohort -1 (in which only vemurafenib is de-escalated to a lower dose 
level of 480 mg bid) and Cohort -2 (in which only cobimetinib is de-escalated to a lower 
dose level of 40 mg on a 14/14 schedule). If Cohort -1 or Cohort -2 dose 
combinations are not tolerated, there may be one further dose de-escalation to Cohort 3 
(in which both vemurafenib and cobimetinib doses are decreased).
Table 6 Roadmap for Planned DoseDe-escalation Cohorts in the Setting 
of Cohort 1 Failure
Cohort
Vemurafenib
Cobimetinib (14/14 schedule)
–1
480 mg bid
60 mg qd
–2
720 mg bid
40 mg qd
–3
480 mg bid
40 mg qd
Table 6 outlines potential vemurafenib and cobimetinib dose combinations planned for 
Cohorts -1, -2, and -3 if needed. As described above, these potential cohorts would only be 
opened if dose de-escalation is needed because the Cohort 1 dose combination is not safe 
and tolerable.
If the Cohort 1A, 1B, 1C, or 1D dose combination is not tolerated, dose de-escalation for 
cobimetinib may occur at the Sponsor’s discretion. Table 7 outlines the vemurafenib and 
cobimetinib dose combination planned for Cohorts -1A, -1B, -1C, and -1D, if needed. 
These cohorts would only be opened if the dose combination tested in Cohort 1A, 1C,
and 1D are not deemed safe and tolerable.
Table 7
Roadmap for Planned Dose De-Escalation Cohort in the Setting of 
Cohorts 1A, 1C, or 1D Failure 
Cohort
Vemurafenib
Cobimetinib (21/7 
schedule)
Cobimetinib (28/0 
schedule)
-1A
720 mg bid
40 mg qd
NA
-1B
960 mg bid
40 mg qd
NA
-1C 
720 mg bid
NA
40 mg qd
-1D
960 mg bid
NA
40 mg qd
NA= not applicable.
Cohort Assignment
Patients eligible to participate in this protocol will have the ability to enroll in a single 
vemurafenib and cobimetinib combination cohort or in the cobimetinib monotherapy 
cohort.  Enrollment in the cobimetinib monotherapy cohort will be limited to 20 patients 
in total.  
See the guidance below.


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Dose-Escalation Cohorts 1, 1A, 1B, 1C, 1D, 2, 2A, 3, 4, and 5
Patients who progressed on vemurafenib monotherapy immediately preceding enrollment 
in this trial:
Patients who have tolerated 720 mg or 960 mg vemurafenib bid may be enrolled in 
Cohorts 1. Patients who are initiating study therapy and for whom a slot does not exist 
in the currently enrolling dose cohort have the option of receiving a previously cleared 
vemurafenib/ cobimetinib dose combination or waiting until a slot in the current or next 
dose-escalation cohort is available. Expansion of previously cleared cohorts should 
increase the accuracy of the safety assessment. Enrollment in a previously cleared cohort 
requires consent of the Medical Monitor as the priority for enrollment in this study is into 
advancing cohorts.  The size of a given cohort above the number required to assess safety 
may be limited by the Medical Monitor at any time during the study.
Patients whose vemurafenib dose was limited to 720 mg bid due to tolerability issues will 
not be allowed to receive dose combinations containing 960 mg bid of vemurafenib
(Cohorts 1B, 1D, and 35).
Patients previously treated with 960 mg bid of vemurafenib may enroll in cohorts where 
vemurafenib dosing is limited to 720 mg bid (Cohorts 1, 1A, 1C, 2, 2A). In these cases, 
patients must have their vemurafenib dose reduced to 720 mg bid for at least 1 week prior 
to starting the vemurafenib plus cobimetinib combination.
Previously untreated patients with locally advanced/unresectable or metastatic melanoma 
or those previously treated but without prior exposure to any BRAF or MEK inhibitor 
therapy:
This category of patients can enroll in all cohorts except the cobimetinib monotherapy 
cohort. Patients who are initiating study therapy and for whom a slot does not exist in the 
currently enrolling dose cohort have the option of receiving a previously cleared 
vemurafenib/ cobimetinib dose combination or waiting until a slot in the current or next 
dose-escalation cohort is available. Expansion of previously cleared cohorts should 
increase the accuracy of the safety assessment. Enrollment in a previously cleared cohort 
requires consent of the Medical Monitor, as the priority for enrollment in this study is 
into advancing cohorts.  The size of a given cohort above the number required to assess 
safety may be limited by the Medical Monitor at any time during the study.
De-Escalation Cohorts -1 to -3 and -1A, -1B, -1C, and -1D
Patients who previously tolerated 720 mg or 960 mg bid of vemurafenib must be dose 
reduced to the lower, cohort-specific vemurafenib dose for at least 1 week prior to 
starting the vemurafenib plus cobimetinib combination in Cohorts -1, -2, -3 and -1A, -1C,
and -1D.






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
The highest dose level(s) at which fewer than one-third of patients (e.g., 1 out of 6) 
experiences a DLT will be declared the MTD(s). If only 3 patients were initially 
evaluated at that dose level, an additional 3 patients will be enrolled to evaluate for 
DLTs at that dose level. It is possible that more than one MTD combination may be 
determined, e.g., if the dose combinations in Cohorts 2 and 3 are both deemed to be 
safe and tolerable and the dose combination in Cohort 4 is not; or if there are different 
MTDs for the combination of vemurafenib with cobimetinib dosed on a 14/14, 21/7,
or continuous daily schedule. In these cases, more than one combination MTD dose 
and schedule may be expanded.
A minimum of two expansion cohorts 
(n= 20 per cohort) will be enrolled (see below), one consisting of patients who have 
progressed on vemurafenib monotherapy immediately preceding enrollment in this 
trial and the other consisting of previously untreated patients with locally
advanced/unresectable or metastatic melanoma or those previously treated but 
without prior exposure to any BRAF or MEK inhibitor therapy. 

If the combination MTD is exceeded in Cohort 1 (in which cobimetinib is given on a 
14/14 schedule), further dose escalation will be discontinued, and instead, dose 
de-escalation with Cohort -1, -2 and Cohort -3 may occur (see Table 6). If the 
combination MTD is exceeded in Cohort 1A (in which cobimetinib is given on a 
21/7 schedule), dose de-escalation with Cohort -1A may occur. If the combination 
MTD is exceeded in Cohort 1B, 1C,
or 1D, dose de-escalation
in
Cohort -1B, -1C,or -1D, respectively, may occur (see Table 7).

After dosing has been completed in each cohort, data pertaining to dose-escalation 
decisions will be reviewed by a committee composed of the following Sponsor 
representatives: Roche/Genentech Medical Monitor, statistician, Roche/Genentech 
safety officer with consultation from the PK scientist and Global Studies Leader. 
Investigator input will be provided by the principal investigators.
This committee will review available relevant data on demographics, adverse events, 
laboratory assessments, 12-lead ECGs, and dose administration logs, as well as PK data. 
On the basis of a review of these data and in consultation with the participating 
investigators, a determination will be made as to whether dose escalation should 
continue, and if so, at what level and schedule. The selection of a recommended Phase II 
dose and schedule will depend upon results of the safety, activity, and PK evaluations 
from all patients treated in both the dose-escalation and cohort-expansion stages.
The overall vemurafenib and cobimetinib dose-escalation/de-escalation plan is depicted 
in Figure 4, Figure 5, Table 5, Table 6, and Table 7.
On the basis of a review of available safety and PK data during this and other studies 
with both agents, dose-escalation may be halted or modified by the Sponsor, in 
consultation with investigators as deemed appropriate for safety concerns.


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3.1.5
Definition of Dose-Limiting Toxicity
Adverse events will be graded according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events, Version 4.0 (NCI CTCAE v4.0). A copy of 
this grading scale will be provided to the study sites upon request or can be accessed at
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm
DLT definitions reflect the known and expected toxicities of vemurafenib and 
cobimetinib.
A DLT definition is defined as one of the following toxicities occurring during the DLT 
assessment window and considered by the investigator to be related to study treatment 
(per guidance in Section 7).

Grade 3 non-hematologic, non-hepatic organ toxicity, EXCLUDING the following:   
a) Grade 3 nausea or vomiting that resolves to Grade 1 within 7 days of 
appropriate supportive therapy
b) Grade 3 diarrhea that resolves to Grade 1 within 7 days with appropriate 
supportive therapy
c) Grade 3 rash that resolves to Grade 2 within 7 days with appropriate 
supportive therapy 
d) Grade 3 photosensitivity that resolves to Grade 2 within 7 days with appropriate 
supportive therapy
e) Grade 3 cuSCC that is subsequently resected 
f)
Grade 3 fatigue that resolves to Grade 2 within 7 days 
g) Grade 3 hyperuricemia that resolves to Grade 2 within 7 days
h) Grade 3 fever
i)
Grade 3 or 4 elevation of serum CPK levels, which is asymptomatic (i.e., not 
accompanied by signs, symptoms, or other laboratory abnormalities associated 
with rhabdomyolysis or myocardial injury), deemed by the investigator to be 
clinically insignificant and that returns to Grade 2 within 14 days of cobimetinib
treatment interruption.

Grade 3 febrile neutropenia

Grade 4 neutropenia (ANC <500/µl) 

Grade 4 thrombocytopenia 

Grade 4 anemia

Grade 3 total bilirubin, hepatic transaminase (ALT or AST), ALP, with the 
following exceptions: 
Patients with Grade 2 hepatic transaminase or ALP elevation at baseline as a 
result of metastases; for these patients, hepatic transaminase or ALP elevation 
10 x upper limits of normal (ULN) will be considered a DLT.
All DLTs will be reported by telephone to the Medical Monitor within 24 hours.


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3.1.6
Dosing beyond Cycle 1
Treatment will continue until disease progression, unacceptable toxicity, or any other 
discontinuation criterion is met (Section 4.5). There may be circumstances in which one 
of the study drugs is discontinued (e.g., as outlined in dose modification, Section 6.1). In 
the case of permanent cobimetinib discontinuation, patients previously treated with 
vemurafenib should come off the study. In the case of permanent
vemurafenib
discontinuation, it will be possible for the patient to continue treatment with single-agent 
cobimetinib until disease progression, unacceptable toxicity, or any other discontinuation 
criterion is met (see Section 4.5). In patients without prior treatment for locally advanced 
and unresectable or metastatic melanoma, permanent discontinuation of either drug while 
continuing the other will not be grounds for study discontinuation.
3.2
Stage 2: Cohort-Expansion Stage
After a cohort is declared safe and tolerable, cohort-expansion may be instituted for that 
specific cohort. For a given vemurafenib/ cobimetinib dose and schedule, a minimum of 
2 expansion cohorts will be enrolled, and each will consist of approximately 20 patients. 
Expansion Cohort 1 will be open to patients whose melanoma has progressed while on 
vemurafenib immediately preceding enrollment in this trial and Expansion Cohort 2 will 
enroll patients without prior treatment for locally advanced/unresectable or metastatic 
melanoma or those who are previously treated but without prior exposure to any BRAF 
or MEK inhibitor therapy. Expansion cohorts will allow for the gathering of additional 
safety and PK data and the opportunity to better describe the PD effects of the 
combination. The cobimetinib schedule(s) to be used in each expansion cohort 
(i.e., 14/14 vs. 21/7 vs. continuous daily schedule) will be based upon an evaluation of 
safety, activity, and PK results from all patients treated on these schedules during the 
dose-escalation stage. 
Results from the cohort-expansion stage will further inform our choice of the optimal 
dose and schedule of cobimetinib in combination with vemurafenib for further clinical 
testing (Table 8).
Table 8
Cohort Expansion for Patients Receiving Vemurafenib and 
Cobimetinib
Cohort (patient number)
Vemurafenib/Cobimetinib dose, 
schedule
Eligible patients
1 (n=20)
Combination MTD at one or 
more dose/schedule
Vemurafenib progressors only
2 (n=20)
Combination MTD at one or 
more dose/schedule
(PUPs and PTPs)
PTPs:  patients previously treated for locally advanced/unresectable or metastatic melanoma but without prior exposure 
to any BRAF or MEK inhibitor therapy.
PUPs:  patients previously untreated for locally advanced/unresectable or metastatic melanoma.
All patients, whether enrolled in the dose-escalation or expansion stage of the study, will 
be required to provide melanoma tumor biopsy samples at baseline (pre-treatment),
Day 14, and at disease progression for PD biomarker analyses. These lesions should have 
accessible melanoma tumors that may be biopsied with minimal risk and discomfort. In 
cases where there are no lesions amenable to biopsy, sample collection can be omitted. 
This should be discussed with the Medical Monitor.


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Patients in the expansion stage (Stage 2) of the study will undergo the same tumor, 
safety, PD marker, biomarker, and PK assessments as those enrolled in the 
dose-escalation cohorts. Note: PK assessments upon disease progression, at the time of 
DLT, and at the time of dose reduction/treatment interruption due to adverse events were 
no longer required as of protocol amendment j.
If the frequency of Grade 3 or 4 toxicities or other unacceptable chronic toxicities in the 
cohort-expansion stage suggests that the MTD has been exceeded at that dose level, any 
remaining accrual at that dose level will be halted. Consideration will then be given to 
enrolling expansion cohorts at a lower dose combination level.
As noted above, it is possible that more than one MTD combination will be defined, 
consisting of different dose combinations and/or schedules of 
vemurafenib and 
cobimetinib that are deemed safe and tolerable. If this occurs, it is possible that more than 
two expansion cohorts will be enrolled to gather additional safety, PK, and PD data at 
these MTD combinations and schedules.  
3.3
Rationale for Patient Selection
Patient with previously untreated, BRAFV600E mutation-positive, locally advanced and 
unresectable or metastatic melanoma OR those previously treated but without prior 
exposure to any BRAF or MEK inhibitor therapy are eligible. Additionally, those who 
exhibit documented evidence of asynchronous progression of melanoma during 
participation in a Phase I (PLX06-02, clinical pharmacology studies), Phase II (BRIM-2), 
or Phase III clinical trial of vemurafenib monotherapy (including the expanded access 
protocol) or while receiving vemurafenib in a postmarketing setting immediately prior to 
enrollment in this study will also be eligible. 
The BRAFV600E mutation status for eligible patients must have been determined using the 
cobas® diagnostic test.
Patients previously treated with vemurafenib
(either in a clinical
trial or 
postmarketing setting):
The majority of patients with metastatic melanoma treated in Phase I and II clinical trials 
of vemurafenib have had asynchronous progression, where progression occurs in a subset 
of lesions (i.e., less than 30% of those identified as target lesions). This pattern of 
discordant/mixed progression suggests that there may be a benefit to continuing treatment 
with vemurafenib to maintain disease control in the non-progressing lesions.
The reason for this pattern of mixed progression in patients treated with vemurafenib is 
unclear. Preliminary review of data from Study PLX06-02 suggests that progressing 
patients maintain their BRAF mutation. It is likely that as melanomas progress, the 
functional redundancy between the numerous signaling pathways present in the tumor 
allows the tumor to overcome previously effective pathway blockade [15]. 
Overexpression of CRAF is hypothesized to play a role in the escape of 
BRAFV600E-mutated tumors to vemurafenib treatment, for example.
In vitro and in vivo assessments of MEK inhibitors have shown that they can inhibit the 
growth of BRAFV600E-mutated melanomas. In fact, the presence of BRAF mutations 


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appears to predict for sensitivity to MEK inhibition [25, 31]. This sensitivity may result 
from the suppression of the RAF/MEK/ERK pathway.
The additional RAS/RAF/MEK/ERK pathway suppression from cobimetinib
in 
combination with vemurafenib may re-establish and enhance tumor control in the 
progressing lesions of patients experiencing discordant/mixed progression on treatment 
with vemurafenib.
Patients without prior treatment for locally advanced/unresectable or metastatic 
melanoma or those previously treated but without prior exposure to any BRAF or MEK
inhibitor therapy:
Inclusion of this category of patient will allow a more expedient assessment of the 
optimal dose(s) and schedule(s) for the vemurafenib/ cobimetinib combination as well as 
a preliminary assessment of the activity of this combination in relationship to that 
observed historically with vemurafenib monotherapy.
3.4
Rationale for Starting Dose and Schedule
The starting dose of vemurafenib in this Phase Ib study will be 720 mg bid for 
28 consecutive days of each 28-day cycle of combination dosing, which is one dose level 
below the single-agent MTD of 960 mg bid administered on this schedule as established 
in the vemurafenib Phase Ia trial (PLX06-02) and which has been utilized in all 
subsequent vemurafenib clinical trials. The 720 mg bid dose has been shown to be 
effective and tolerable in the subset of patients requiring dose reduction in the Phase I 
and II trials of vemurafenib. This dose should be adequate to maintain 
vemurafenib-mediated control of non-progressing lesions and, at the same time, allow for 
combination with cobimetinib. Patients in screening (written informed consent) for this 
study who were previously receiving 960 mg bid vemurafenib will be dose-reduced to 
720 mg bid for 714 days prior to Cycle 1, Day 1 in Cohorts 1, 1A, 2, 2A or 1C. 
Patients receiving 960 mg bid vemurafenib prior to screening initiation (written informed 
consent) and assigned to Cohorts 1B, 1D, 3, 4, or 5 will continue receiving 960 mg bid 
vemurafenib throughout the screening period, assuming this dose has been adequately 
tolerated prior to starting the study. Patients in screening for this study who are naïve to 
prior treatment with vemurafenib at the time of consent will only start vemurafenib on 
Cycle 1, Day 1 once they are deemed eligible for enrollment. As soon as feasible after 
signing informed consent, patients should initiate vemurafenib treatment with study drug 
provided expressly for this particular study and discontinue their supply of study drug 
from the antecedent vemurafenib clinical study or commercial source.  
The starting dose of cobimetinib in this Phase Ib trial will be 60 mg per day for 
14 consecutive days of each 28-day cycle of combination therapy, which is two dose 
levels below the single-agent MTD of 100 mg per day administered on this schedule. 
cobimetinib dosing will be investigated in the current study on a 14/14, a 21/7, and a 
continuous daily schedule as it is unclear whether a schedule that may deliver higher peak 
concentrations of cobimetinib
over a shorter treatment interval per cycle 
(i.e., the 14/14 schedule) will exhibit a better safety and tolerability profile than one 
associated with lower peak concentrations but longer duration of exposure per 
cycle (i.e., the 21/7 or continuous daily schedule). As noted, the safety and tolerability of 


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cobimetinib monotherapy on a 21/7 schedule (MTD–60 mg/day) has been established in 
the MEK 4592g study. 
Review of nonclinical and available clinical data for vemurafenib and cobimetinib
suggest that the risk for significant additive or overlapping toxicities or DDI potential is 
tolerable. In vivo combinations of vemurafenib and other MEK inhibitors or cobimetinib
and other BRAF inhibitors in xenograft models have not demonstrated toxicities that 
impacted dosing. Therefore, it is anticipated that 720 mg bid of vemurafenib dosed daily 
for 28 days in combination with 60 mg of cobimetinib dosed daily for 14 days of a 
28-day cycle are appropriate starting doses with which to evaluate this combination.
3.5
Rationale for Pharmacokinetic Evaluation Schedule
Vemurafenib and cobimetinib will be used in combination in metastatic melanoma 
patients for the first time in this study. 
Historical PK data are available for both compounds as monotherapies. Data from the 
combination of both drugs used in this study will be compared with these historical 
controls to monitor any unexpected changes in pharmacokinetics that may occur 
following the co-administration of both drugs. Currently, no major concerns have been 
identified for any PK interaction between vemurafenib and cobimetinib. In vitro 
experiments indicate that vemurafenib may be a weak substrate and moderate inhibitor of 
Pgp. Cobimetinib is a substrate of Pgp and combination therapy with vemurafenib may 
lead to an alteration of plasma exposures of cobimetinib. Additional nonclinical and 
clinical data regarding the metabolism of vemurafenib suggest that the drug may be a 
mild inducer of CYP3A4. Preliminary information suggests that CYP3A and UGT2B7 
are the enzymes responsible for cobimetinib metabolism. However, the fraction of 
cobimetinib metabolized by CYP3A is unknown. Thus, induction of CYP3A4 by 
vemurafenib may lead to decreased systemic exposures of cobimetinib. 
In vitro CYP inhibition studies suggest that cobimetinib has a moderate potential to 
interact with drugs that are substrates for CYP2D6 (IC50 1.8µM) or CYP3A 
(IC50 5.91.7 µM; Ki 7.6 µM).  It is unclear how cobimetinib may alter the 
pharmacokinetics of vemurafenib.
For patients who have progressed while receiving vemurafenib monotherapy immediately 
preceding enrollment in this trial only, an exposure time profile for vemurafenib will be 
taken at Day -1, spanning an 8-hour post-dose period to determine the exposure level of 
this drug prior to study start. Patients assigned to Cohorts 1, 1A, 2, 2A, and 1C who 
tolerated 960 mg bid vemurafenib prestudy will be dose reduced to 720 mg bid for at 
least 1 week prior to study start. 


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There will be no opportunity to evaluate the pharmacokinetics of cobimetinib
monotherapy in this study except in those patients who are treated in the cobimetinib
monotherapy arm. Cobimetinib will be combined with vemurafenib on Day 1, and for all 
patients, PK assessments will occur on Day 1 for cobimetinib (0, 0.5, 1, 2, 4, and 6 hours 
post-dose) and Day 14 (0, 0.5, 1, 2, 4, 6, and 8 hours post-dose) for both agents to 
characterize exposure for each drug after single dose and at steady state, respectively. A 
PK assessment will be made on Day 8 to characterize the approach to steady state. 
Additional PK samples will be collected during the 14-days off period for cobimetinib to 
evaluate the elimination properties (t1/2 clearance) of the drug in the presence of 
vemurafenib for those patients treated on a 14/14 schedule only.
Lastly, for both compounds, periodic steady-state PK samples will be collected in 
subsequent cycles to ensure patients are exposed to constant drug levels throughout the 
study. For additional information on PK sampling, refer to Table 10 and Table 11.
3.6
Rationale for Dosing beyond Cycle 1
The ethical conduct of studying cancer therapeutics requires that patients have the 
opportunity to continue study treatment for as long as the treatment is effective and 
tolerable. Therefore, patients enrolled in this study who comply with the requirements of 
the protocol and are tolerating study treatment may continue dosing until disease 
progression, unacceptable toxicity, or any other discontinuation criterion is met 
(Section 3.1.6).
3.7
Rationale for Collection of Patient Specimens for 
Molecular Analyses (Biopsies, Plasma, Blood)
Roche is committed to the collection of patient specimens in all clinical study protocols. 
The objective of molecular analyses (biomarker profiling) is to enable development of 
treatments specifically targeted for optimal patient benefit (personalized healthcare). 
The rationale of planned molecular analyses is explained below. However, 
since knowledge of the drug, the disease, new markers, and technologies are evolving, 
the definitive list of analyses may be modified based on new information as the 
information becomes available.
Investigation of Response/Resistance Markers
To identify causes for resistance, molecular analyses will be performed to investigate 
BRAF, CRAF, PTEN, RAS, and MEK, as well as further key pathway markers at the 
protein, mRNA, and genetic level.
As this study shall help to create new hypotheses of response/resistance mechanisms for 
this drug combination, genetic analyses of the whole genome of tumors is required and 
shall be performed if patient consents. These analyses allow us to identify mutations that 
have so far not been associated with drug resistance and help to answer the questions how 
to treat or further treat patients.
To assess mechanisms of response and resistance to the vemurafenib and cobimetinib
combination therapy, baseline (the post-progression biopsy sample from the previous 


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vemurafenib study may be substituted), Day 10 to 14, and disease progression biopsies 
from melanoma tumors will be analyzed for all patient cohorts, if available.
BRAFV600E mutation will be evaluated retrospectively on tumor biopsies collected during 
this study and in plasma. It has been shown that tumor-specific mutations can be 
identified in serum/plasma of patients. Analysis and correlation of plasma and biopsy will 
help to further evaluate the option of using plasma for the detection of tumor specific 
mutations.
BRAF mutations have remained stable in previous analyses of melanoma tumors over 
time (data on file). Therefore, BRAF mutation testing of tumor samples will not be 
prioritized.
Molecular Characterization of SCC or Other Suspicious Neoplasms
The objective of molecular analyses using SCC or other suspicious neoplasm specimens
is to further understand the mechanism and cause of SCC development in recipients of 
vemurafenib and to identify factors that may pre-dispose patients to develop 
drug-induced SCC (see Section 5.3.4.6). 
Lesions that are suspicious for malignancy other than SCC may be submitted at the 
discretion of the investigator.
Genetic analysis of RAS, p53, and RAF, as well as analyses of MAPK pathway protein 
activation, will be performed using specimens from SCC or suspicious neoplasms, as 
well as paired normal skin. Normal skin will be needed as a control in order to be able to 
explore differences in MAPK pathway activation.
Molecular Analyses to Investigate Drug Effects of Vemurafenib and 
Cobimetinib
In vitro experiments on BRAFV600E-positive melanoma cell lines have shown suppression 
of ERK and MEK phosphorylation in response to vemurafenib dosing. ERK and MEK 
phosphorylation will be investigated in melanoma tumor biopsies to assess the effect of 
the drug combination directly on the tumor. Other molecular analyses may be performed 
in light of emerging scientific information.
3.8
Rationale for Evaluating FDG-PET Changes
Serial FDG-PET scans are used routinely to monitor anti-tumor activity in patients with 
advanced cancer including metastatic melanoma. In addition, it is sometimes used as a 
non-invasive PD measure of drug activity. 
a) In this study, FDG-PET imaging will be used to provide a non-invasive measurement 
of drug activity and a potential early readout of anti-tumor activity in patients 
receiving the vemurafenib and cobimetinib combination or cobimetinib monotherapy. 
All patients in the study who have PET-avid disease at screening will be asked to 
undergo FDG-PET imaging at three additional timepoints during study treatment:

Steady state in Cycle 1 (between Days 1014)

Cycle 2, Day 147 days (coinciding with first CT/MRI response assessment)


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
Disease progression (for characterization of progression patterns; when available)
3.9
Outcome Measures
3.9.1
Safety Outcome Measures
Safety outcome measures for this study are as follows:

Incidence, nature, and intensity (severity) of adverse events and serious adverse 
events, graded according to NCI CTCAE v4.0

Incidence and nature of DLTs

Changes in vital signs, ECGs, and clinical laboratory results during the course of 
study (see Section 5.3).
3.9.2
Pharmacokinetic and Pharmacodynamic Outcome Measures
The goal of PK sampling is to describe vemurafenib and cobimetinib pharmacokinetics 
when given in combination and in comparison with historic controls when the agents 
were given as monotherapy. The relationship between vemurafenib and cobimetinib
concentrations and anti-tumor activity will also be described.
Vemurafenib and cobimetinib PK parameters will be determined in all patients who 
receive study treatment using non-compartmental analysis and/or population methods.
For both vemurafenib and cobimetinib, the following PK parameters will be estimated:

Total exposure (AUC0-last)

Maximal plasma concentration (Cmax)

Minimal plasma concentration (Cmin)

Other PK parameters may be determined after visual inspection of observed 
concentrationtime data.
The following PD outcome measures will be assessed:

FDG-PET response rates based on modified definitions proposed by the 
European Organization for Research of Cancer (EORTC; [32]) and as assessed by an 
independent, blinded FDG-PET Image Reading Facility (IRF)  

Changes in effector molecules of the MAPK pathway that are directly or indirectly 
affected by BRAF and MEK inhibition (including but not limited to ERK and 
phosphorylated ERK and MEK) by IHC using biopsies at baseline, between 
Days 1014 of Cycle 1, and at disease progression (when available).
3.9.3
Efficacy Outcome Measures
The following activity outcome measures will be assessed (see Section 5.3.2 for methods 
of assessments):

Objective response (OR)

PFS

DOR


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
OS
3.9.4
Exploratory Outcome Measures
To evaluate the relationship between anti-tumor activity (objective response rate, PFS, 
DOR, etc.) and changes in PD biomarkers or other genetic alterations when vemurafenib 
and cobimetinib are administered in combination.
3.10
Safety Plan
Measures will be taken to ensure the safety of patients participating in this trial, 
in particular, the use of stringent inclusion and exclusion criteria (Sections 4.2 and 4.3) 
and close monitoring of patients as indicated below and in Section 3.10. 
Because this is the first time vemurafenib and cobimetinib will be administered to 
humans in combination, all patients will be monitored closely for toxicity. All adverse 
events will be recorded during the trial and for up to 28 days after the last dose of study 
treatment or until initiation of another anti-cancer therapy, whichever comes first. The 
potential safety issues anticipated in this trial, as well as measures intended to avoid or 
minimize such toxicities, are outlined in the following sections.
As with other vemurafenib studies, the risk for SCC will be mitigated by utilization of the 
Risk Management Plan (RMP) that is described in Section 5.3.4.6 of this protocol.
3.10.1
Risks Associated with Vemurafenib
The toxicity profile for vemurafenib has been documented from safety data derived from 
seven studies of more than 600 treated patients with locally advanced unresectable or 
metastatic melanoma. The most common toxicities observed were rash, fatigue, 
arthralgia, myalgia, headache, nausea, photosensitivity, alopecia, and pruritus. The most 
common laboratory abnormalities reported as adverse events included elevations of liver 
function tests (i.e., GGT, ALP, ALT, AST, and bilirubin).  Other safety events for 
vemurafenib used in monotherapy include new primary malignancies such as 
cutaneous malignancies, non-cutaneous squamous cell carcinoma, and other 
malignancies; 
tumor 
promotion 
in 
BRAF 
wild-type 
malignancies; 
hypersensitivity 
reactions; 
hepatotoxicity; 
ophthalmologic 
reactions; 
embryo-fetal toxicity; radiation sensitization and radiation recall; and renal 
failure. Please refer the vemurafenib IB for additional safety information.
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 cuSCCs 
(mainly KA type).  The majority of these were observed within the first 16 weeks of 
vemurafenib exposure and were not treatment limiting.  The risk for cuSCC will be 
mitigated through the use of a Risk Management Plan as outlined in Section 5.3.4.6.  
This plan has been utilized across all clinical studies of vemurafenib to date.


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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 SCC 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, 2 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 
[18].  
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., CT 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 who are 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. 
Please refer the vemurafenib IB for additional safety information.
3.10.2
Risks Associated with Cobimetinib
3.10.2.1
Identified Risks Associated with Cobimetinib
Hemorrhage
Hemorrhage, including major hemorrhages defined as symptomatic bleeding in a 
critical area or organ, can occur with Cotellic. 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 


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events were Grade 1 or 2 and non-serious.  Grade 3-4 hemorrhage events were 
reported in 1.2% of patients receiving cobimetinib plus vemurafenib and 0.8% of 
patients receiving placebo plus vemurafenib. 
Caution should be used in patients with additional risk factors for bleeding, such 
as brain metastases, and/or in patients that use concomitant medications that 
increase the risk of bleeding (including antiplatelet or anticoagulant therapy).
Instructions for Dose Modification for hemorrhage events are included in 
Table 12 in Section 6.1.1.
Serous Retinopathy
Serous retinopathy (fluid accumulation within the layers of the retina) has been observed 
in patients treated with MEK inhibitors, including cobimetinib [33].  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 of the events were asymptomatic Grade 1 events. Few patients treated 
with cobimetinib plus vemurafenib experienced Grade3 ocular adverse 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 
retinal detachment, central serous chorioretinopathy, neovascular retinopathy, or 
retinopathy of prematurity. Patients will also undergo ophthalmologic examinations at 
specified timepoints throughout the study (see the schedule of assessments and 
procedures in Section 5).  Details regarding baseline and subsequent ophthalmologic 
examinations are provided in Section 5.3.4.4. 
Guidelines for management of patients who develop Grade2 visual disorders or 
retinopathy are provided in Section 6.1.1. 
Left Ventricular Dysfunction
Decreases in LVEF from baseline have been reported in patients receiving cobimetinib. 
Left ventricular dysfunction may occur with signs and symptoms of cardiac failure, or 
reduction in LVEF events may be asymptomatic.
Left ventricular dysfunction has been characterized in the Phase III Study GO28141, 
which incorporated prospective serial LVEF evaluation in all patients. With active 
surveillance, measured reductions in LVEF were observed more frequently in patients 
treated with cobimetinib plus vemurafenib than placebo plus vemurafenib (26% vs. 19%, 


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respectively, of Grade 2 or 3 decrease). Of the patients treated with cobimetinib plus 
vemurafenib, 2 patients (0.8%) had symptomatic reduction in LVEF, and the remaining 
patients were asymptomatic. Most LVEF reduction events in patients on cobimetinib plus 
vemurafenib (62%) improved or resolved with management according to the 
dose-modification guidelines (see Section 6.1.1). 
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 postmarketing 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 
Modification 
for 
elevated 
CPK 
and 
rhabdomyolysis are included in Table 12 in Section 6.1.1.
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 
the cobimetinib plus vemurafenib arm versus the placebo plus vemurafenib arm (46% vs. 
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 Section 6.1.1 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 adverse 
events were reported in 2 patients (0.8%) treated with cobimetinib plus vemurafenib.


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3.10.2.2
Potential Risks Associated with Cobimetinib
Liver Laboratory Abnormalities and Severe Hepatotoxicity
Liver laboratory test abnormalities, including increases in ALT, AST, and ALP, 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 Developmental Toxicitiy
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.
3.10.2.3
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.


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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% and vomiting 21.3% vs. 
12.1%, respectively). 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 
reported at rates of 33.9% with 0.9% reported for Grade3 nausea and no Grade3 
events 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. 
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.


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3.10.3
General Plan to Manage Safety Concerns
Eligibility Criteria
Eligibility criteria for this study were selected to guard the safety of patients in this trial. 
A number of exclusion criteria are specifically based on nonclinical and clinical safety 
data observed following exposure to cobimetinib and vemurafenib as single agents. 
The exclusion criteria for safety (see Section 4.3 for a complete list and description of 
exclusion criteria) include, but are not limited to, the following: history of prior 
significant toxicity from exposure to another RAF or MEK inhibitor requiring 
discontinuation of treatment; known brain metastases that are untreated, symptomatic, or 
require therapy to control symptoms; major surgical procedure or significant traumatic 
injury within 4 weeks prior to first dose of study drug treatment; pregnancy or lactation; 
clinically significant cardiovascular disease; history of congenital long QT syndrome or 
QTc 450 msec; inadequate bone marrow function; inadequate hepatic or renal function; 
uncontrolled ascites requiring weekly large volume paracentesis; and history of 
malabsorption or other clinically significant metabolic dysfunction; history of RVO; 
evidence of visible retinal pathology that is considered a risk factor for retinal vein 
thrombosis; factors predisposing to RVO including uncontrolled hypertension 
(Grade 2 at screening), diabetes (e.g., untreated or inadequately treated Grade 2 
glucose intolerance), hyperlipidemia (e.g., untreated or inadequately treated Grade 2 
hypercholesterolemia or hypertriglyceridemia) or hypercoagulable state; and evidence of 
intraocular pressure >21 mm Hg as measured by tonometry.
Monitoring
Safety will be evaluated in this study through the monitoring of all serious and 
non-serious adverse events, which are defined and graded according to NCI CTCAE 
v4.0. 
Patients will be monitored weekly for safety during the first 8 weeks and then every 
4 weeks starting with Cycle 3 and also as needed until 28 days after the last dose of study 
treatment or until initiation of other anti-cancer therapy, whichever occurs first. 
All unresolved adverse events and serious adverse events will be followed until the 
events are resolved or stabilized, the patient is lost to follow-up, or it has been determined 
that the study treatment or participation is not the cause of the adverse event or serious 
adverse event. Dermatologic, head and neck evaluations, and chest CT scans will be 
conducted according to the local standard of care after patient discontinues study 
treatment, withdraws consent, dies or is lost to follow-up, whichever occurs earliest. 
Please see Section 5.3.4.6. 
Definitions of DLTs have been designed to keep the degree and frequency of severe 
toxicity observed in this study within acceptable limits for Phase I trials in oncology.
General safety assessments will include serial interval histories, physical examinations, 
and specific laboratory studies, including serum chemistries and blood counts 
(see Section 5.3.4, Table 9 for the list and timing of study assessments).


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All serious adverse events, protocol-defined adverse events of special interest, DLTs, and 
Grade 3 and 4 adverse events during the DLT assessment window will be reported in an 
expedited fashion (see Section 7.1.1.4). In addition, the Medical Monitor and the 
investigators will review and evaluate observed adverse events on a regular basis. 
Patients who have an ongoing treatment-related adverse event upon study completion or 
at discontinuation from the study will be followed until the event has resolved to baseline 
grade, the event is assessed by the investigator as stable, new anti-tumor treatment is 
initiated, the patient is lost to follow-up, the patient withdraws consent, or it has been 
determined that study treatment or participation is not the cause of the adverse event. 
See Table 9 and Section 5.3.4 (Assessment of Safety) for complete details of the safety 
evaluation for this study.
3.11
End of Study 
Study treatment will be discontinued in patients who experience disease progression or 
unacceptable toxicity and are not eligible for single-agent cobimetinib treatment or are 
not compliant with the study protocol.
Upon study treatment discontinuation or withdrawal from study treatment, 
patients are required to continue the following assessments as indicated in the 
Schedule of Assessments:
•
A study completion visit will be performed 28 days after the last dose of study 
treatment for all patients. 

Survival will be collected via telephone calls and/or clinic visits every 
12 weeks until death, weithdrawal of consent of loss to follow-up.
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.  Survival 
follow-up can be conducted via telephone. 
3.12
Number of Patients/Assignment to Treatment Groups
It is estimated that approximately 3-6 patients per cohort will be enrolled during the 
dose-escalation stage. Additional patients may be enrolled in a previously cleared 
vemurafenib/cobimetinib
dose combination (Section 3.1.1). Approximately twenty 
patients who have progressed on vemurafenib monotherapy immediately preceding 
enrollment in this trial as well as approximately 20 patients previously untreated or 
treated (but without prior exposure to any BRAF or MEK inhibitor therapy) patients in 
each expansion cohort will be enrolled during the cohort-expansion stage.  
The single-agent cobimetinib cohort will enroll up to 20 patients who meet one of the 
following criteria:

Had previously tolerated only 480 mg bid on a prior study of  vemurafenib and had 
progressed at this dose


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
Had previously tolerated 720 mg bid or 960 mg bid of vemurafenib and for whom a 
treatment slot does not exist in the currently enrolling, dose escalation cohort(s) and 
who are unable to wait for the next available cohorts to open.
3.13
Centers
Approximately 7–10 centers from two countries (United States and Australia) will 
participate in this study.
4.
STUDY POPULATION
4.1
Overview
Patients with BRAFV600E mutation-positive melanoma who are previously untreated for 
locally advanced/unresectable or metastatic disease OR those previously treated but 
without prior exposure to any BRAF or MEK inhibitor therapy OR those who have 
progressed during treatment with vemurafenib monotherapy immediately prior to 
enrollment in this study will participate. Patients
who progress while on
vemurafenib may include those who participated in any of the current Phase I trials 
(including clinical pharmacology studies), the Phase II clinical trial (BRIM-2), the 
Phase III pivotal study (BRIM-3) and the Expanded Access Protocol (EAP) study OR
those who progress while receiving vemurafenib in a postmarketing setting. 
All eligible patients will have had their BRAFV600E mutation status confirmed using the 
cobastest prior to study enrollment.
4.2
Inclusion Criteria
A patient may be included if the answer to all of the following statements is “yes.”
Disease-Specific Inclusion Criteria:
1. Patients with histologically confirmed melanoma, either unresectable Stage IIIc or 
Stage IV metastatic melanoma, as defined by AJCC
2. Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 
(see Appendix 1)
3. ECOG performance status of 1 (see Appendix 2)
General Inclusion Criteria:
4. Male or female patient age 18 years
5. 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
6. Patients must 
a.) be previously untreated for locally advanced/unresectable or metastatic melanoma 
OR
b.) previously treated but without prior exposure to any BRAF or MEK inhibitor
therapy OR


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c.) progressed on vemurafenib while participating in a Phase I (including clinical 
pharmacology studies), II, or III clinical study or EAP immediately prior to 
enrollment in this study OR
d.) progressed on vemurafenib administered in a postmarketing setting immediately 
prior to enrollment in this study.
Note:  Participants in an antecedent vemurafenib clinical trial or those who progress 
while receiving the drug in a postmarketing setting should exhibit evidence of 
discordant/mixed progression and not have received intervening antimelanoma 
therapy except with vemurafenib. The presence of V600E mutation in melanoma 
tumor tissue must be documented using the cobas BRAFV600 mutation test in all 
patients.
7. Life expectancy 12 weeks
8. Patients must have fully recovered from the effects of any major surgery or 
significant traumatic injury within 14 days from the first dose of study treatment.
9. Adequate hematologic and end organ function, defined by the following laboratory
results obtained within 2 weeks prior to first dose of study drug treatment:    
o
ANC 1.5 X 109/L
o
Platelet count 100 X 109/L 
o
Hemoglobin 9 g/dL   
o
Albumin 2.5 g/dL 
o
Bilirubin 1.5 X ULN 
o
AST, ALT, and ALP 2.5 X ULN, with the following exceptions:
o
Patients with documented liver metastases: AST and /or ALT 5 X ULN
o
Patients with documented liver or bone metastases: ALP 5 X ULN
o
Serum creatinine 1.5 X ULN or creatinine clearance 50 ml/min on the 
basis of measured creatinine clearance from a 24-hour urine collection or the
Cockroft-Gault glomerular filtration rate estimation: (140-age) x (weight in 
kg) x (0.85 if female)
1. 72 x (serum creatinine in mg/dL)
10. INR and aPTT 1.5 X ULN
11. Female patients of childbearing potential and male patients with partners of 
childbearing potential must agree to always use an effective form(s) 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 hysterectomy who have had any evidence of menses in the past 12 months. 
In order to be considered NOT of childbearing potential, amenorrhea for a period 
of 12 months or longer must have occurred in the absence of chemotherapy, 
anti-estrogens, or ovarian suppression.

Effective forms of contraception includes surgical sterilization, a reliable barrier 
method with spermicide, birth control pills, or contraceptive hormone implants
12. Negative serum pregnancy test within 7 days prior to commencement of dosing 
in women of childbearing potential; women of non-childbearing potential may be 
included if they are either surgically sterile or have been naturally menopausal 


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for 1 year. Women of non-childbearing potential need not undergo the pregnancy 
test.
13. Absence of any psychological, familial, sociological, or geographical condition 
potentially hampering compliance with the study protocol and follow-up schedule; 
those conditions should be discussed with the patient before trial entry.
14. Consent to provide archival tissue (either a paraffin-embedded tissue block or up to 
15 unstained slides) for molecular analyses to investigate BRAF, CRAS, CRAF, 
PTEN, RAS, and MEK, as well as other pathway markers on the protein, epigenetic, 
and genetic level. See Table 9 for details.  
15. Consent to undergo tumor biopsies of accessible lesions for PD biomarker and 
molecular analyses including BRAF, CRAF, PTEN, RAS, and MEK, as well as other 
pathway markers on the protein, mRNA, and genetic level. See Table 9 for details. 
4.3
Exclusion Criteria
A patient will be excluded if the answer to any of the following statements is "yes."
Cancer-Related Exclusion Criteria:
1. History of prior significant toxicity from another RAF or MEK pathway inhibitor 
requiring discontinuation of treatment
2. Allergy or hypersensitivity to components of the cobimetinib or vemurafenib 
formulations
3. Palliative radiotherapy within 2 weeks prior to first dose of study drug treatment in 
Cycle 1, Day 1
4. Experimental therapy within 4 weeks prior to first dose of study drug treatment in 
Cycle 1, Day 1 except  vemurafenib
5. Major surgical procedure or significant traumatic injury within 14 days prior to first 
dose of study drug treatment in Cycle 1, Day 1 or anticipation of the need for major 
surgery during the course of study treatment
6. a) For patients who participated in an antecedent vemurafenib study or progressed 
while receiving vemurafenib in a postmarketing setting: administration of any 
systemic anti-melanoma therapy other than vemurafenib during the interval between 
documentation of progression coincident with their vemurafenib exposure and 
consideration for this study will render the patient ineligible.
b) For previously untreated patients: no prior systemic, anti-cancer therapy 
(e.g., biologic or other targeted therapy, chemotherapy or hormonal therapy) for 
unresectable, locally advanced or metastatic melanoma disease. Note: Prior treatment 
in the adjuvant setting for previously resected melanoma is allowed. 
c) For previously treated patients:  no prior exposure to any BRAF or MEK inhibitor 
therapy; prior treatment with systemic chemotherapy or ipilumumab is allowed.
7.
Active malignancy other than melanoma that could potentially interfere with 
interpretation of the PD or efficacy measures


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Exclusion Criteria Based on Organ Function
Ocular:
8.
Evidence of visible retinal pathology, as assessed by ophthalmologic examination,
that is considered a risk factor for retinal vein thrombosis
9.
Intraocular pressure > 21 mm Hg as measured by tonometry
10. History of RVO
11. Predisposing factors to RVO, including uncontrolled hypertension (Grade 2 at 
screening), uncontrolled diabetes (e.g., untreated or inadequately treated Grade 2 
glucose intolerance), uncontrolled hyperlipidemia (e.g., untreated or inadequately 
treated Grade 2 hypercholesterolemia or hypertriglyceridemia) or hypercoagulable 
state
Cardiac:
12. History of clinically significant cardiac or pulmonary dysfunction, including the 
following:

Grade 2 hypertension (treated or untreated) or unstable angina

Current Grade 2 dyspnea or hypoxia or need for supplemental oxygen

History of symptomatic congestive heart failure of New York Heart 
Association ≥Class II (see Appendix 4) or serious cardiac arrhythmia requiring 
treatment, with 
the 
exceptions of 
atrial fibrillation
and paroxysmal 
supraventricular tachycardia

History of myocardial infarction within 6 months prior to first dose of study drug 
treatment in Cycle 1

Current dyspnea at rest due to complications of advanced malignancy or any 
requirement for supplemental oxygen to perform activities of daily living
History of congenital long QT syndrome or QTc > 450 msec.
Central Nervous System:
13. Patients with active CNS lesions are excluded (i.e., those with radiographically 
unstable, symptomatic lesions). However, patients treated with stereotactic therapy 
or surgery are eligible if they remain without evidence of disease progression in the 
brain for 3 weeks. 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:
14. The patient has not recovered to Grade 1 from adverse events due to 
investigational or other agents administered more than 28 days prior to enrollment
except for alopecia.
15. Current severe, uncontrolled systemic disease (e.g., clinically significant 
cardiovascular, pulmonary or metabolic disease)
16. Inability or unwillingness to swallow pills


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17. History of malabsorption or other condition that would interfere with enteral 
absorption of study drug
18. History of clinically significant liver disease (including cirrhosis), current alcohol 
abuse, or known infection with HIV, hepatitis B virus, or hepatitis C virus
19. Any condition requiring therapeutic anticoagulation (e.g., for chronic atrial 
fibrillation) with either warfarin, or unfractionated heparin. Note: Patients receiving 
anticoagulation with low-molecular weight heparin, and low-dose aspirin are 
eligible, as long as INR and aPTT are ≤1.5X ULN
20. Use of thrombolytics to establish patency of obstructed indwelling venous catheters 
is allowed.
21. Prophylactic anticoagulation to maintain patency of venous access devices is allowed 
as long as INR and aPTT are 1.5 X ULN.
22. Active autoimmune disease (e.g., systemic lupus erythematosis, autoimmune 
vasculitis, inflammatory bowel disease)
23. Uncontrolled ascites requiring weekly large volume paracentesis for 3 consecutive 
weeks prior to enrollment
24. Pregnancy, lactation, or breast feeding
25. Unwillingness or inability to comply with study and follow-up procedures
26. No other history of or ongoing malignancy that would potentially interfere with the 
interpretation of the PD or efficacy assays
27. Need to take a concomitant medication, dietary supplement, or food that is prohibited 
during the study (as described in Sections 4.4.1 and 4.4.2)
4.4
Concomitant Medication and Treatment 
4.4.1
Concomitant Therapy
Concomitant therapy includes any prescription medications or over-the-counter 
preparations used by a patient within 7 days before screening through the study 
completion visit. Patients who use oral contraceptives, hormone-replacement therapy, or 
maintenance therapy should continue their use as outlined in the eligibility criteria 
(see Sections 4.2
and 4.3). Patients who experience toxicities may be treated
symptomatically as clinically indicated. All concomitant medications should be recorded 
on the appropriate electronic Case Report Form (eCRF).
Anti-emetics and anti-diarrheal medications should not be administered prophylactically 
before initial treatment with study drug. 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 drug.  
Hematopoietic growth factors (e.g., erythropoietin and granulocyte colony-stimulating 
factors) and pain medications administered as dictated by standard practice are acceptable 
while the patient is enrolled in the study. However, growth factors should not be 
administered prophylactically before initial treatment with study drug; nor should they be 
used during the DLT observation period.


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4.4.2
Excluded Therapy and Food
Use of the following foods and therapies is prohibited during the study (i.e., from 7 days 
before screening through the study completion visit):

Grapefruit juice

St. John’s wort or hyperforin

Any concomitant therapy intended for the treatment of cancer (approved by health 
authorities 
or 
experimental), 
including 
chemotherapy, 
radiation 
therapy, 
immunotherapy, hormonal therapy, biologic therapy, investigational agents, or herbal 
therapy; after Cycle 1, certain forms of radiation therapy may be considered for pain 
palliation if patients are deriving benefit. Study treatment may be suspended during 
radiation therapy with agreement by the Medical Monitor.

Warfarin, anti-thrombotic therapy (except low-molecular weight heparin), or 
anti-platelet drugs (except low-dose aspirin), prophylactic anticoagulation and/or 
local application of thrombolytics for patency of venous access devices are allowed as 
long as INR and aPTT are 1.5 ULN.

Quinidine or other anti-arrthymic agents

Chronic systemic corticosteroid use (10 mg of prednisone or equivalent dose of 
other anti-inflammatory corticosteroids for >7 days) or use of immunosuppressants. 
However, treatment with systemic corticosteroids during the course of the study for 
management of toxicity related to vemurafenib and /or cobimetinib (e.g., allergic 
rash) is allowed.
Patients who require the use of any of these agents will be discontinued from study 
treatment and followed for safety outcomes for 28 days after the last dose of study 
treatment or until initiation of another anti-cancer therapy, whichever comes first.
4.4.3
Medication Precautions in Case of DrugDrug Interactions
Vemurafenib: 
On the basis of nonclinical data, vemurafenib may have the potential to cause DDI with 
concomitant medications that are primarily eliminated by CYP2C9. Patients should be 
advised to consult with their physician before taking any of the listed medications:

Non-steriodal anti-inflammatory drugs (e.g., ibuprofen, diclofenac, meloxicam)

Oral hypoglycemic agents (e.g., tolbutamide, glipizide, glyburide, glimepiride)

Antihypertensives (e.g., losartan, irbesartan, torsemide)

Anticonvulsants (e.g., phenytoin)

Anticoagulants (e.g., warfarin)

Lipid-lowering drugs (e.g., fluvostatin)
In a CYP450 in vivo metabolism study (NP22676), vemurafenib inhibited CYP1A2 and 
induced CYP3A4 activity in melanoma patients by approximately 3-fold and 2-fold, 
respectively. If CYP1A2 substrates must be co-administered with vemurafenib, 
investigators should assess the safety risk associated with a potential increase in plasma 


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concentrations of CYP1A2 metabolized drugs. If CYP3A4 substrates must be 
co-administered with vemurafenib, investigators should monitor the signs of reduced 
benefit of CYP3A4 metabolized drugs due to a potential decrease in their plasma 
concentration. Doses of concomitant CYP1A2 and CYP3A4 drugs, but not the dose of 
vemurafenib, may be adjusted as necessary to alleviate the impact of drug interaction.
For CYP2C9, data suggested that the relatively strong nonclinical signal inhibition, 
(IC505.9 M in vitro in hepatic microsomes) did not translate to a DDI with this 
CYP450 isoform. However, vemurafenib was associated with a decrease in clearance of 
warfarin from plasma, and a 19% increase in the mean exposure (AUC) that did not fall 
outside of the equivalence boundary.
Little metabolism of vemurafenib (10%) was detected in nonclinical studies and in data 
from a human mass balance study with 14C- vemurafenib in patients with melanoma 
(Study NP25158). Nonclinical studies suggest that CYP3A4 metabolism and subsequent 
glucuronidation are responsible for the metabolism of vemurafenib. No clinical data are 
currently available evaluating the effects of CYP3A4 inducers or inhibitors on 
vemurafenib exposure.
Appendix 10 includes a non-exhaustive list of typical examples of CYP1A2, CYP3A4, 
and CYP2C9 substrates and CYP3A4 inducers and inhibitors. A more extensive list of 
medications 
can 
be 
found 
online 
at 
the 
following 
link:  
http://medicine.iupui.edu/clinpharm/ddis/Table.asp. For further information see the 
Investigator’s Brochure.
Cobimetinib:
On the basis of in vitro data showing that cobimetinib is metabolized by the hepatic 
cytochrome CYP3A4, the drugs listed below should be avoided.  If use of one of 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, troleandamycin, and voriconazole

Strong CYP3A4/5 inducers such as, but not limited to, rifampin, carbamazepine, 
rifapentine, phenytoin, and Phenobarbital
4.4.4
Medications Affecting QT Interval
Certain medications could affect the results of QT intervals on ECG measurements 
required in this study. Specifically, anti-emetics other than those belonging to the 
5-HT3 receptor antagonist class (i.e., granisetron, ondansetron, dolasetron, palanosetron) 
are preferred since the latter has the potential to prolong the QTc interval 
(see Section 3.10.1). We encourage and recommend that investigators avoid or take 
precautions in closely monitoring patients who are on medications or herbal and vitamin 
supplements that may increase QTc interval. Alternative treatment options for 
medications known to affect QT interval should be discussed with each patient prior to 


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their inclusion into this study. A complete list of medications that may cause QT interval 
prolongation is provided in Appendix 6. Please refer to http://www.azcert.org/ for 
additional information and references.
4.5
Criteria for Premature Withdrawal and Discontinuation
Patients have the right to withdraw from the study at any time for any reason.
In cases where the patient decides to prematurely discontinue study treatment 
(“refuses treatment”), he/she should be asked if he/she can still be contacted for further 
information. The outcome of that discussion should be documented in both the medical 
records and in the eCRF. 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. A complete final evaluation at the 
time of the patient’s withdrawal should be made with an explanation of why the patient is 
withdrawing from the study.
When applicable, patients should be informed of circumstances under which their 
participation may be terminated by the investigator without the patient’s consent. 
The investigator may withdraw patients from the study in the event of intercurrent illness, 
adverse events, treatment failure after a prescribed procedure, lack of compliance with 
the study and/or study procedures (e.g., dosing instructions, study visits), cure or any 
reason where it is felt by the investigator that it is in the best interest of the patient to be 
terminated from the study. Any administrative or other reasons for withdrawal must be 
documented and explained to the patient. Any patient who discontinues will be 
encouraged to return to the study center for a study completion visit. 
Additionally, patients must discontinue study treatment if they experience any of the 
following:

Disease progression per investigator assessment using RECIST v1.1

Intolerance of vemurafenib and cobimetinib combination therapy or cobimetinib 
monotherapy after discussion with the Medical Monitor

Pregnancy
Patients should return to the clinic for a study completion visit 28 days after study 
treatment discontinuation (see Section 5 for assessments that are to be performed at that 
visit). The primary reason for discontinuation must be recorded on the appropriate eCRF.
Study 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:

All enrolled patients have discontinued study treatment.

The incidence or intensity (severity) of adverse events in this or other studies 
indicates a potential health hazard to patients.


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Post-Trial Access
Roche does not intend to provide vemurafenib or cobimetinib or other interventions to 
patients after the conclusion of the study or any earlier withdrawal (see Section 3.11).
4.6
Withdrawal of Patients from the Roche Clinical Repository
Patients who give consent to long-term storage of biomarker specimens for further 
research in the RCR have the right to withdraw their consent to long-term storage of the 
samples at any time for any reason. If a patient wishes to withdraw his/her consent to the 
long-term storage of his/her specimen(s), the investigator must inform the Medical 
Monitor in writing of the patient’s wishes using the withdrawal form provided and enter 
the date of withdrawal in the patient’s eCRF. A patient withdrawal from the trial does not 
by itself constitute withdrawal from long-term storage of sample(s) in the RCR; likewise, 
withdrawal from the long-term storage of samples(s) in the RCR does not constitute a 
withdrawal from the main trial.
4.7
Replacement Policy (Ensuring Adequate Numbers of 
Evaluable Patients)
4.7.1
For Patients
No patient prematurely discontinued from the study for any reason, after having 
completed the first cycle (first 28 days on the study), will be replaced. Patients who 
discontinue study treatment or have missed 3 or more days in total of either study drug in 
the first 28-day cycle for reasons other than a DLT will be replaced.
4.7.2
For Centers
A center may be replaced or closed for the following administrative reasons:  
–
Poor protocol adherence


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5.
SCHEDULE OF ASSESSMENTS AND PROCEDURES
Table 9
Schedule of Assessments (All Cohorts Including Cobimetinib Monotherapy Cohort)
Screening
Period
(28 Days)
Combination (Vemurafenib and Cobimetinib) Treatment Period or 
Cobimetinib Monotherapy Treatment Period
Follow-Up after Study Treatment
Cycle
Cycle 1
Cycle 2
Cycle 3
Cycle 4+
Cycle Day
-28 to -1 
Days1
-1
1
2
8
14
15
22
1
8
15
22
1
8
15
22
1
8
15
22
Disease 
Progression/
Final Visit
28 Days 
Post- Dose
Every 
12 
Weeks
Informed consent1
x
Medical history 
and demographics
x
Tumor tissue for 
BRAFV600E
Mutation 
screening1
x
Physical exam2
x
x
x
x
x
x
x
x
x
x
x
Vital signs, height, 
weight3
x
x
x
x
x
x
x
x
x
x
x
ECOG status3
x
x
x
x
x
x
x
x
x
x
x
12-lead ECG4
x4
x4
x
x
x
x
x
x
x4
Ophthalmic
exams5
x
Hematology6
x
x
x
x
x
x
x
x
x
x
x
Chemistry7
x
x
x
x
x
x
x
x
x
x
x
Coagulation tests6
x
Pulse oximetry
x
Urinalysis8
x
Serum pregnancy 
tests9
x
x
x
x
x


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Table 9:
Schedule of Assessments (All Cohorts Including Cobimetinib Monotherapy Cohort) (Cont.)
Screening 
Period
(28 Days)
Combination (Vemurafenib and Cobimetinib) Treatment Period or 
Cobimetinib Monotherapy Treatment Period
Follow-Up after Study 
Treatment
Cycle
Cycle 1
Cycle 2
Cycle 3
Cycle 4+
Cycle Day
-28 to 
-1 Days1
-1
1
2
8
14
15
22
1
8
15
22
1
8
15
22
1
8
15
22
Disease 
Progression/
Final Visit
28 Days 
Post-
Dose
Every 
12 
Weeks
CT/MRI of the head10
x
Tumor assessment 
(CT/MRI)10
x
x
FDG-PET11
x11
x
x11
PK blood samples12
PLEASE REFER TO Table 10 and Table 11 FOR PK SAMPLING SCHEDULE
Vemurafenib 
administration13
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x x
x
x
Cobimetinib 
administration14
x
x
x
x
x14
x14
x
x
x14
x14
x
x
x14
x14
x x
x14
x14
Concomitant 
medications15
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Adverse events16
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Drug accountability
x
x
x
x
x
x
x
x
x
x
Survival assessment17
x
ASSESSMENTS FOR SCC RISK MANAGEMENT
Dermatology 
evaluation18
x
x
Head and neck SCC 
examination19
x
x
Chest CT for SCC 
RMP20
x
x
x


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Table 9:
Schedule of Assessments (All Cohorts Including Cobimetinib Monotherapy Cohort) (Cont.)
Screening 
Period
(28 Days)
Combination (Vemurafenib and Cobimetinib) Treatment Period or 
Cobimetinib Monotherapy Treatment Period
Follow-Up after Study 
Treatment
Cycle
Cycle 1
Cycle 2
Cycle 3
Cycle 4+
Cycle Day
-28 to -1 
Days1
-1
1
2
8
14
15
22
1
8
15
22
1
8
15
22
1
8
15
22
Disease 
Progression/
Final Visit
28 Days 
Post-
Dose
Every 12 
Weeks
ASSESSMENTS FOR BIOMARKERS
Tumor biopsy for 
biomarker analyses 21
x
x
x
Whole blood samples
for biomarker
x
Plasma for biomarker 
analysis
x
Squamous cell 
carcinoma tumor tissue 
or other suspicious 
malignant lesions and 
normal skin22
x
Ongoing throughout trial, according to local standard of care 
x
According to local 
standard of care
Schedule of Assessments – Footnotes
ECOGEastern Cooperative Oncology Group; INRinternational normalized ratio; PKpharmacokinetic; pretreatpretreatment period
Notes: Assessments scheduled on the day of study drug administration should be performed prior to study drug dosing, unless otherwise specified.


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Table 9:
Schedule of Assessments (All Cohorts Including Cobimetinib Monotherapy Cohort) (Cont.)
Unless otherwise specified, assessments that are done weekly, should be performed within a ± 1 day window except PK assessments. Those performed monthly, 
should be performed within a window of ± 3 days. Patients are NOT required to visit the clinics on Days 15, and 22 of Cycle 3, Cycle 4, and subsequent cycles if 
no assessments are scheduled on these days. In addition, 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 Day 1 of Cycle 1 unless otherwise noted. Assessments performed as standard of care within the screening window may be used for screening. 
Screening exams for ECG, hematology, chemistry, coagulation, urinalysis, and pulse oximetry must be performed within 14 days of first dose. Note:  All 
study patients who were not previously treated with vemurafenib must have melanoma tissue tested for BRAFV600 mutation using the cobas® 4800 BRAF 
V600 Mutation Test. Testing requires a formalin-fixed paraffin-embedded (FFPE) tumor block or unstained sections. A screening window of 42 days prior to 
Cycle 1, Day 1 will be allowed to test for the BRAFV600E mutation in patients without prior exposure to vemurafenib only. Other screening assessments can 
commence only after a positive test result is documented and a slot is available in an open cohort of either the dose-escalation or cohort-expansion phase. For 
patients without prior exposure to vemurafenib, the 28-day window (Day –28 to Day –1) for performing screening assessments begins at the time the first 
screening assessment is performed after documentation of BRAFV600E mutation–positive tumor tissue.
2.
Physical exam will be performed during screening and subsequently at each study visit. The frequency of each study visit should be performed in accordance 
with the local standard of care. After initial screening physical exam, a limited physical exam, a symptom-directed exam that contains an evaluation of the 
oropharynx, 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.
3.
ECOG, 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 when a physical exam is performed in accordance with standard of care. Height will be collected only at screening/baseline.
4.
Triplicate 12-lead ECG should be performed at screening (within 14 days); Day 1, Hour 0 (pre-vemurafenib dose);  Cycle 1, Day 1, Hour 4 
(4 hours post-cobimetinib dose); Day 2, Hour 0 (pre-dose); Day 14, Hour 0 (pre-dose) and Hours 2, 4, and 8 post-dose; Day 22, Hour 0 
(pre-vemurafenib dose); Cycle 2, Day 1; Cycle 3, Day 1; Cycle 4, Day 1. Following Cycle 4, the frequency of ECG monitoring should be performed in 
accordance with the local standard of care, and triplicate ECGs are not longer required. Triplicate 12-lead ECG monitoring should be performed more 
frequently if clinically indicated.  ECG on Day -1 is not required for previously treated (but without prior exposure to BRAF or MEK inhibitor therapy) or 
previously untreated for locally advanced/unresectable or metastatic melanoma patients. Follow the guidelines in Table 11 for ECG monitoring in the setting 
of vemurafenib interruption and dose reduction due to QTc interval prolongation.  For all ECGs, patients should be resting in a supine position for 10 
minutes prior to ECG collection
5.
Complete ophthalmologic exams will be performed at screening and subsequently as clinically indicated if a patient notes any visual disturbances. Complete 
ophthalmologic examination will be performed and interpreted by a qualified ophthalmologist, including visual acuity testing, intraocular pressure 
measurements by tonometry, slit-lamp ophthalmoscopy, indirect ophthalmoscopy, and spectral domain optical coherence tomography. Ophthalmologic 
examination may be performed up to 42 days prior to starting study treatment.


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Table 9:
Schedule of Assessments (All Cohorts Including Cobimetinib Monotherapy Cohort) (Cont.)
6.
Hematology includes hemoglobin, hematocrit, WBC count with differential (neutrophils, bands, eosinophils, basophils, lymphocytes, monocytes), and platelet 
count. Coagulation tests include INR and aPTT and are required only at screening. Frequency of hematology assessments after Cycle 4 should be performed 
in accordance with the local standard of care.
7.
Chemistry includes glucose, BUN, creatinine, sodium, potassium, chloride, magnesium, bicarbonate, phosphate, calcium, total protein, albumin, total bilirubin, 
direct bilirubin, ALP, LDH, CPK, uric acid, AST, and ALT.  Note:  Patients who exhibit CPK elevation coincident with cobimetinib treatment should have 
measurement of MB fraction, if there is a clinical suspicion of possible myocardial
injury or in the case of prolongation of the QTc interval. Frequency of chemistry asssessments after Cycle 4 should be performed in accordance with the local 
standard of care.
8.
Urinalysis is required only at screening and includes specific gravity, pH, glucose, protein ketones, blood, and microscopics (RBC, WBC, casts, and crystals).
9.
For women of childbearing potential, including premenopausal women who have had a tubal ligation, a serum pregnancy test is required at screening 
(within 7 days prior to C1D1) and should be performed in accordance with the local standard of care while the patient is receiving study treatment.
10. All patients must have a screening head CT and/or MRI to assess for brain metastasis, and subsequently only as clinically indicated. Radiographic tumor 
assessments (CT or MRI scans) will be obtained to assess extent of disease at the following timepoints: screening (any time within 28-day period of Cycle 1, 
Day 1) and thereafter tumor assessments should be performed in accordance with the local standard of care while the patient is receiving study treatment. If at 
any time during the treatment phase there is suspicion of disease progression based on clinical or laboratory findings before the next scheduled assessment, an 
unscheduled tumor assessment should be performed. If a PET scan is used for preliminary assessment of progressive disease or for SCC follow-up assessment, 
a corresponding CT scan is required to be completed. A documented standard-of-care tumor assessment performed within 28 days of Cycle 1, Day 1 may be 
used for the screening assessment (must contain a chest CT scan).
11. FDG-PET imaging will be done at screening (14 days prior to Cycle 1, Day 1). If the patient has FDG-PET avid disease, he/she will undergo subsequent 
FDG-PET imaging. This will be scheduled once during mid-Cycle 1 (anytime between Days 10 and 14) and once on Cycle 2, Day 14±7 days to coincide with 
the first CT/MRI response assessment. FDG-PET scan must be performed fasting (patients must not have consumed any food or glucose/sugar-containing 
fluid) at least 4 hours prior to FDG-PET scan.  Blood glucose level will be obtained immediately prior to FDG administration either by fingerstick test or by 
serum glucose assay on a blood sample obtained by venipuncture and processed in the local laboratory. 
12. PK samples should be obtained according to the schedule provided in Table 10 and Table 11 for patients who progressed while on vemurafenib immediately 
prior to enrollment in this study and those previously untreated or treated (but without prior exposure to any BRAF or MEK inhibitor therapy) for locally
advanced/unresectable or metastatic melanoma, respectively. Document date and time of all PK draws.
13. Patients who have progressed on vemurafenib will continue daily treatment with vemurafenib during the screening period pending cohort assignment. 
Confirm dose with study site monitor as a dose reduction may be required. During this study, patients will be treated with an oral dose of vemurafenib daily in 
a 28-day cycle. Patients available for enrollment in this study who were receiving 960 mg bid vemurafenib will be dose reduced to 720 mg bid for 714 days 
prior to enrollment in Cohorts 1, 1A, 2, 2A, and 1C. Patients assigned to Cohorts 1B, 1D, 3, 4, or 5 will continue receiving 960 mg bid vemurafenib
throughout the screening period, assuming this dose has been adequately tolerated prestudy.


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Table 9:
Schedule of Assessments (All Cohorts Including Cobimetinib Monotherapy Cohort) (Cont.)
14. Patients will receive cobimetinib on a 14-days on/14-days off schedule, on a 21-days on/7 days off schedule, or on a continuous schedule (qd) in a 
28-day cycle. For study evaluations performed earlier than the scheduled day, patients cannot restart cobimetinib until they have had the minimum number of 
days without cobimetinib dosing. For patients on the 14/14 and 21/7 dosing schedules of cobimetinib, the minimum numbers of days without cobimetinib are
14 and 7, respectively. For both investigational drugs, dosing will continue until disease progression, consent withdrawal, or unacceptable toxicity. Dispense a 
sufficient number of vemurafenib and cobimetinib capsules/tablets to last until the next visit and provide a medication diary. Extra capsules/tablets 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). Instruct patient to record the time and date they take each study drug dose in the diary and to return all unused capsules/tablets at each study 
visit to assess compliance. Collect and review medication diary, collect unused capsules/tablets, and assess compliance at each subsequent visit.
15. Review and capture of all concomitant medications will be performed at each study visit. Concomitant medications are defined as any prescription 
medications or over-the-counter preparations used by a patient within 7 days before screening and continuing through the study completion visit. 
16. After signing the informed consent, adverse events will be collected as detailed in Section 7.1.2. All adverse events will be recorded until 28 days after the 
last dose of study treatment or until initiation of another anti-cancer therapy, whichever occurs first.
17. During long-term follow-up, survival assessments should be performed every 12 weeks until death after last study treatment.
18. Dermatology evaluation: screening (up to 28 days prior to Cycle 1, Day 1), after 2230 days on study treatment (Cycle 2, Day 1); thereafter, dermatology 
evaluation should be performed in accordance with the local standard of care while the patient is receiving study treatment and after completion of study 
treatment. If patients develop SCC (cutaneous or non-cutaneous) or any primary neoplasms as per the RMP after withdrawal from study, this information 
must be collected and reported as a serious adverse event to the Sponsor whether deemed related or unrelated to study drug. Any other adverse events or 
serious adverse events occurring after study discontinuation will only be collected up to 28 days after the last dose of study medication or as per serious 
adverse event guidelines.
19. A head and neck exam for SCC (cutaneous or non-cutaneous) or any primary neoplasms risk management will be done by the treating physician at screening;
thereafter, head and neck exams should be performed in accordance with the local standard of care while the patient is receiving study treatment and after 
completion of study treatment.
20. The routinely scheduled radiologic assessment for tumor burden can be used as the chest CT for the Risk Management Plan of SCC (cutaneous or non-
cutaneous) or any primary neoplasms while the patient is on study drug. Following cessation of study drug, surveillance of SCC should be performed in 
accordance with the local standard of care.


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Table 9:
Schedule of Assessments (All Cohorts Including Cobimetinib Monotherapy Cohort) (Cont.)
21. For all patients—previously treated with vemurafenib and those either previously untreated or treated (but without prior exposure to any BRAF or MEK 
inhibitor therapy) for locally advanced/unresectable or metastatic melanoma—biopsies of accessible tissue are mandatory upon patient’s consent to participate 
in the trial. Fresh-frozen and paraffin-embedded tumor biopsy for molecular analyses will be obtained within 28 days of Cycle 1, Day 1 (unless progression 
biopsy tissue was submitted in previous study within 3 months of screening). Biopsies should be completed at least 48 hours before the initiation of study drug 
therapy on Cycle 1, Day 1. Biopsies (both formalin-fixed and fresh-frozen samples) will be collected at time of progressive disease. A biopsy of tumor tissue 
must be obtained during Cycle 1 while the patient is receiving cobimetinib; Day 10 to 14 is the required timing for this biopsy. It is highly recommended that 
the biopsy at disease progression be collected within 3 days after last study treatment. Lesions with the greatest change in dimensional size, based on interval 
evaluation, are the lesions to be biopsied. Excisional biopsies, punch biopsies, or multiple (2 or more), 14-gauge core needle biopsies are acceptable. Fine 
needle aspiration (FNA) biopsies will not be accepted.  
22. For patients who develop any cutaneous lesion(s) suspicious for squamous cell carcinoma (SCC) or keratoacanthoma (KA) during treatment with vemurafenib 
and/or cobimetinib, biopsy tissue and a paired normal skin biopsy must be obtained for biomarker analyses (mandatory sample). Only one normal skin biopsy 
is required per patient, regardless of the number of SCC lesions identified and biopsied during the study.  Suspicious lesions not thought to represent cutaneous 
SCC may also be sent for central pathological review at the discretion of the investigator and may undergo molecular characterization.


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5.1
Screening Examination and Eligibility Screening Form
All patients must provide written informed consent before any study-specific assessments 
or procedures are performed. 
A pre-screening log needs to be completed and sent to the study leader or 
Medical Monitor for attribution of the slot.
An Eligibility Screening Form documenting the investigator’s assessment of each 
screened patient with regard to the protocol’s inclusion and exclusion criteria is to be 
completed by the investigator. 
A screen failure log must be maintained by the investigator.
A screening examination should be performed between Day 28 and Day 1, except for 
ophthalmologic examination. The ophthalmologic examination may be performed up to 
42 days prior to starting study treatment. Patients who meet all the inclusion and 
exclusion criteria will be enrolled into the study treatment phase. All screening and 
baseline assessments are outlined in the Schedule of Assessments, Table 9.
For patients previously treated with vemurafenib, examinations and biopsies performed 
during the previous study of vemurafenib in which the patient was enrolled may be 
substituted for screening examinations and biopsies in this study, provided they were 
performed within 3 months of screening for the current study (see Section 5.3.1).
5.2
Procedures for Enrollment of Eligible Patients
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before the first dose of study treatment. Written informed consent 
for participation in the study must be obtained before performing any study-specific 
screening tests or evaluations. Informed Consent Forms for patients who are not 
subsequently enrolled will be maintained at the study site. 
All patients at all participating sites will be registered with the Sponsor/designee. 
Investigators will submit an Enrollment Form and the fully executed Eligibility Screening 
Form to the Sponsor/designee. The Principal Investigator will be notified of the 
enrollment/cohort assignment upon receipt. Assignment of a patient number and 
treatment doses for vemurafenib and cobimetinib will be generated and provided back to 
the investigator at the time of patient registration. 
Under no circumstance will patients who enroll in this study and have completed 
treatment as specified be permitted to re-enroll in the study with the exception of patients 
allowed to receive single-agent cobimetinib (after having failed the combination of 
vemurafenib and cobimetinib, with the Medical Monitor’s permission. Such patients are 
not required to undergo a second screening evaluation prior to initiation of cobimetinib
monotherapy.
Results of standard-of-care tests or examinations performed prior to obtaining informed 
consent and within the screening window may be used; such tests do not need to be 
repeated for screening. Screening local laboratory assessments performed 96 hours 
prior to Day 1 do not have to be repeated. 


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A patient Enrollment and Identification Code List must be maintained by the investigator.
5.3
Clinical Assessments and Procedures
All patients will be closely monitored for safety and tolerability during all cycles of 
therapy, at the study completion visit, and during the survival follow-up period. After 
signing the informed consent, adverse events will be collected as detailed in 
Section 7.2.1. Patients will be assessed for adverse events weekly during the first two 
cycles, prior to each subsequent cycle, and as necessary throughout the study. All adverse 
events will be recorded until 28 days after the last dose of study treatment or until 
initiation of another anti-cancer therapy, whichever occurs first. Dosing will occur only if 
the clinical assessment and local laboratory test values are acceptable. 
Visits are based on the 28-day cycle. If the timing of a protocol-mandated procedure 
coincides with a holiday and/or other scheduling conflict that precludes the visit, the visit 
should be scheduled on the date nearest to the date in question, which may be earlier or 
later.
5.3.1
Screening and Pre-Treatment Assessment
All study patients who were not previously treated with vemurafenib must have 
melanoma tissue tested for BRAFV600E mutation using the cobas® 4800 BRAF V600 
Mutation Test. Testing requires a formalin-fixed paraffin-embedded (FFPE) tumor block 
or unstained sections. A screening window of 42 days prior to Cycle 1, Day 1 will be 
allowed to test for the BRAFV600E mutation in patients without prior exposure to 
vemurafenib only. Other screening assessments can commence only after a positive test 
result is documented by the central reference laboratory and a slot is available in an open 
cohort of either the dose-escalation or cohort-expansion phase. For patients without prior 
exposure to vemurafenib, the 28-day window (Day –28 to Day –1) for performing 
screening assessments begins at the time the first screening assessment is performed
following documentation of BRAFV600E mutation–positive tumor tissue.
Any patient who has melanoma progression either on an antecedent clinical trial of 
vemurafenib monotherapy or while receiving the drug in a postmarketing setting
immediately prior to enrollment in this study should continue to receive vemurafenib 
during the screening evaluation until it has been determined that he/she is ineligible for 
the current study.  
Screening assessments will include a CT or MRI scan of the brain, chest, abdomen, and 
pelvis and all other known and suspected sites of disease. A bone scan should also be 
performed, if clinically indicated. Subsequent tumor assessments should include a CT or 
MRI of the chest, abdomen, and pelvis and all other sites of disease documented at 
baseline. The same imaging methods used at screening must be used throughout the study 
for each patient.
The following clinical assessments and procedures will be performed during the 
screening period after the written informed consent has been obtained (see Table 9).

Review of eligibility criteria

Medical, surgical, and cancer histories


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
Demographic data (sex, age, self-reported race/ethnicity)

Documentation of previous and current concomitant medications (prescribed and 
over-the-counter preparations)

Complete physical examination 

Height

Weight

Vital signs

Pulse oximetry, resting (14 days prior to Day 1 of Cycle 1)

ECOG performance status (see Appendix 2)

12-lead ECG (in triplicate), resting (14 days prior to Day 1 of Cycle 1 and also on 
Day 1)

Screening complete ophthalmologic examinations: Screening assessments must be 
performed and interpreted by a qualified ophthalmologist, including visual acuity 
testing, intraocular pressure measurements by tonometry, slit-lamp ophthalmoscopy, 
indirect ophthalmoscopy, and spectral domain optical coherence tomography.

Local laboratory assessments ( 14 days prior to Cycle 1, Day 1)
o
Hematology (hemoglobin, hematocrit, WBC count with differential [neutrophils, 
bands, eosinophils, basophils, lymphocytes, monocytes]) and platelet count 
o
Serum chemistries (glucose, BUN, creatinine, sodium, potassium, chloride, 
magnesium, bicarbonate, phosphate, calcium, total protein, albumin, total 
bilirubin, direct bilirubin, ALP, LDH, CPK, uric acid, AST, and ALT)
o
Coagulation (aPTT and INR)
o
Urinalysis
o
Serum pregnancy test (for women of childbearing potential, including 
premenopausal women who have had a tubal ligation) within 7 days prior to 
C1D1

PreFDG-PET blood glucose test:  Blood glucose levels will be obtained 
immediately prior to FDG administration either by fingerstick test or by serum 
glucose assay on a blood sample obtained by venipuncture and processed in the local 
laboratory. Patients should not have consumed food for 4 hours prior to this test. 

FDG-PET scan
The following procedures must be performed only after patient eligibility has been 
confirmed and informed consent has been obtained.

Thorough head and neck evaluation (completed by treating physician)

CT scan of chest (for SCC risk management; can use routinely scheduled radiologic 
assessment for tumor burden while patient is in the study)

Dermatology evaluation

Fresh-frozen and paraffin-embedded tumor biopsy for molecular analyses to 
investigate response or resistance, as well as pharmacodynamics (unless progression 
biopsy tissue was submitted in previous study within 3 months of screening). 

Plasma samples for molecular analyses 

Whole blood for molecular analyses including genetic analyses of germline mutations

Listed PK samples (see Table 10 and Table 11) 


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5.3.2
Tumor Response Criteria
Tumor response will be evaluated according to RECIST v1.1 (see Appendix 1).
Any evaluable and measurable disease must be documented at screening and re-assessed 
at each subsequent tumor evaluation. The frequency of post-baseline tumor assessments 
will be conducted in accordance to the local standard of care. At the investigator’s 
discretion, CT/MRI scans may be repeated at any time if progressive disease is suspected. 
In addition, an OR must be confirmed by repeat assessments 4 weeks after initial 
documentation. In the case of stable disease (SD), tumor measurements must have met 
the SD criteria at least once after study entry at a minimum interval of not fewer than 6 
weeks.
The extent of disease will be determined by reproducible radiographic techniques, either 
the CT or MRI scan. All known and suspected areas of disease will be evaluated as 
deemed appropriate by the investigator. If more than one method of assessment is used at 
screening, select the most accurate method according to RECIST v1.1 when recording 
data; in addition, this method should again be used in all subsequent evaluations. 
The preferred method for radiologic tumor response assessment(s) is a CT or MRI scan. 
PET scan is not adequate for RECIST response assessment. If a PET scan is used for 
determination of disease progression, then a corresponding CT and/or MRI scan is 
required. CT and/or MRI scans will be compared against PET scans.
The use of radiographic contrast (intravenous contrast) is required unless medically 
contraindicated (see Appendix 1). Tumor measurements should be made by the same 
investigator/radiologist for each patient during the study to the extent that this is feasible. 
The results of the second FDG-PET scan (performed 1014 days after the start of the 
cobimetinib and vemurafenib combination dosing in Cycle 1) will not be used to make 
response assessments.
Only superficial lesions (skin nodules, palpable lymph nodes/adenopathy) are considered 
to be measurable on physical examination. In the case of skin lesions, the use of color 
photography, including a ruler/calliper, must be used for documentation of response.
Tumor assessment scans may be assessed by an independent IRF. As of Protocol 
Version K and future amendments, central collection of scans is no longer required.
Scheduling of Tumor Assessments
Baseline total tumor burden must be assessed within 4 weeks before Cycle 1, Day 1. The 
frequency of post-baseline tumor assessments will be conducted in accordance to the 
local standard of care. If there is suspicion of disease progression based on clinical or 
laboratory findings before the next scheduled assessment, an unscheduled assessment 
should be performed. If an unscheduled evaluation shows clear evidence of progression 
by standard RECIST criteria and the patient is not a candidate for treatment beyond 
progression (see Section 5.8), the treatment will be discontinued and the patient will be 
defined as a treatment failure.


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5.3.3
Performance Status
Performance status will be measured using the ECOG Performance Status Scale 
(see Appendix 2). It is recommended, where possible, that a patient’s performance status 
be assessed by the same person throughout the study. Please refer to Table 9 for details 
on when ECOG performance statuses are collected.
Performance status will be assessed at multiple points throughout the trial (Table 9) to 
see if the performance status score changes. 
5.3.4
Clinical Safety Assessments
NCI CTCAE v4.0 will be used to characterize the toxicity profile of the study treatment. 
All patients will be assessed for adverse events. After signing the informed consent, 
adverse events will be collected as detailed in Section 7.2.1. Patients will be assessed for 
adverse events weekly during the first two cycles, prior to each subsequent cycle, and as 
necessary throughout the study. All adverse events will be recorded until 28 days after 
the last dose of study treatment or until initiation of another anti-cancer therapy, 
whichever occurs first. Prolonged follow-up is required for any occurrence of SCC as 
outlined in the RMP (Section 5.3.4.6). 
A complete medical history (including demographics) will be performed at screening.
A limited physical examination will be performed as indicated. Please refer to the 
Schedule of Assessments (Table 9) for specific details and timepoints pertaining to 
clinical assessments and procedures outlined below. 
5.3.4.1
Medical History
Medical history includes clinically significant diseases within the last 5 years, smoking 
history, prior cancer history, prior cancer therapies and procedures, and all medications 
used by the patient within 28 days before the screening visit (including prescription, 
over-the-counter, and herbal/homeopathic remedies and therapies).
5.3.4.2
Vital Signs and Oxygen Saturation
Vital signs will include measurements of heart rate, respiratory rate, and systolic and 
diastolic blood pressures while the patient is in a seated position and oral or tympanic 
temperature (C). Oxygen saturation will be assessed by pulse oximetry at rest.
5.3.4.3
Physical and Symptom-Directed Examinations
A complete physical examination should include the evaluation of head, eye, ear, nose 
and throat, cardiovascular, dermatological, musculoskeletal, respiratory, gastrointestinal, 
and neurological systems, weight, as well as height at screening. Changes from baseline 
abnormalities should be recorded at each subsequent physical examination. New or 
worsened abnormalities should be recorded as adverse events if appropriate.
As part of tumor assessments, physical examinations should include evaluation of the 
presence of enlarged lymph nodes, hepatomegaly, and splenomegaly. Some visits allow 
symptom-directed examination (physical examinations relevant to patient’s symptoms). 
As part of each symptom-directed examination in this study, patients will be asked about 
skin and vision changes.


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5.3.4.4
Ophthalmologic Examinations
All patients will have complete ophthalmologic examinations performed and interpreted 
by a qualified ophthalmologist, including visual acuity testing, intraocular pressure 
measurements by tonometry, slit-lamp ophthalmoscopy, indirect ophthalmoscopy, and 
spectral domain optical coherence tomography. These examinations will be performed at 
baseline and subsequently as clinically indicated, if patients note any visual disturbances. 
Changes from baseline findings should be recorded at each subsequent ophthalmologic 
examination. The ophthalmologic examination may be performed up to 42 days prior to 
starting study treatment.
5.3.4.5
ECG
Triplicate 12-lead ECG should be performed in all patients at following timepoints:

Screening

Day -1, Hour 0 (pre-vemurafenib dose)*
Day -1 ECG is not required for previously treated (but without prior exposure to 
BRAF or MEK inhibitor therapy) or previously untreated for locally 
advanced/unresectable or metastatic melanoma patients.

Cycle 1, Day 1, Hour 4 (4 hours postcobimetinib dose and ±1 hour)

Cycle 1, Day 2, Hour 0 (pre-dose)

Cycle 1, Day 14, Hour 0 (pre-dose) and Hours 2 (±15 minutes), 4 (±1 hour) and 8 (±1 
hour) post-dose

Cycle 1, Day 22, Hour 0 (pre-vemurafenib dose)

Cycle 2, Day 1

Cycle 3, Day 1

Cycle 4, Day 1
*Day -1 ECG is not required for Previously Treated (but without Prior Exposure to 
BRAF 
or 
MEK 
Inhibitor 
Therapy) 
or 
Previously 
Untreated 
for 
Locally 
Advanced/Unresectable or Metastatic Melanoma patients.
Following Cycle 4, ECG monitoring should be performed in accordance with the local 
standard of care, and triplicate ECGs are no longer required. As of Protocol Version K
and future amendments, central collection of ECGs is no longer required.
Additional ECGs should be performed when clinically indicated. To minimize postural 
variability, it is important that patients are resting and in a supine position 
for 10 minutes prior to each ECG assessment. Blood draws and other procedures 
should be avoided during the period immediately before ECG measurement, and activity 
should be controlled as much as possible to minimize variability due to the effects of 
physical stress. If QTc interval prolongation (>500 msec) is noted on ECG while on study 
treatment, please refer to the guidelines provided in Table 12 for modification of 
vemurafenib dosing and subsequent ECG monitoring.
5.3.4.6
Dermatologic Evaluation, Surveillance of Second Primary 
Malignancies, and Risk Management Plan 
Patients will be followed for SCCs (cutaneous and non-cutaneous) and development of 
any new primary malignancies according to the Risk Management Plan outlined below. 


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Dermatologic Evaluation
A dermatological evaluation performed by a dermatologist will be conducted pre-dose 
(up to 28 days prior to Cycle 1, Day 1), after 2230 days on study treatment 
(Cycle 2, Day 1); thereafter, dermatology evaluation should be performed in accordance 
with the local standard of care while patients are receiving study treatment and after 
completion of study treatment. During study treatment and up to 6 months after treatment 
completion, patients and investigators must record the occurrence of any new primary 
malignancy, including but not limited to squamous cell carcinomas (cutaneous or non-
cutaneous) according to NCI CTCAE v4.0. Patients should see their physicians as needed 
for any new skin lesions while on study drug. An unscheduled dermatology examination 
may be done during treatment as needed and if SCC or any second primary cutaneous 
malignancy is suspected.

A designated dermatologist will perform skin evaluations to monitor for SCC, BCC, 
actinic keratosis, and KA (Table 9). 

A complete history of prior dermatologic medications and SCC risk factors 
(i.e., radiation therapy, sun exposure, immunosuppression, prior SCC, use of tanning 
beds, precursor lesions and phototherapy for psoriasis) must be collected.

Any lesions suspected of representing a new SCC, BCC, new primary melanoma, 
actinic keratosis, or KA should be appropriately mapped and photographed 
(with images stored digitally and made available to the Sponsor upon request).

Any suspicious lesions not thought to represent SCC, BCC, new primary melanoma 
or keratoacanthoma identified either at baseline or while on study drug may be 
biopsied/excised and sent for pathological examination at the discretion of the 
investigator. Available specimen block/sections should also be sent to a designated 
central pathology laboratory for confirmation of diagnosis.

Available specimen block/sections of SCC or other suspicious lesions, should be sent 
to the designated central pathology laboratory for confirmation of diagnosis

Residual biopsy tissue (if available) will be analyzed for further molecular 
characterization.
Suspicious lesion submitted to central pathology must be accompanied by a biopsy of 
normal skin as reference for molecular characterization of the lesion. Only 
one normal skin sample is required per patient, regardless of the number of SCC 
lesions identified.

Actinic keratosis, KA, or other skin conditions identified by the dermatologist should 
be treated as per local standards of care.

If a patient develops SCC 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.

The occurrence of any skin changes, including rash and photosensitivity, should be 
reported to the study investigator, and patients will be referred to the dermatologist as 
required.


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Additional Assessments for Second Primary Malignancy Surveillance 
(Treating Physician or Other Qualified Physician):

A thorough examination of the head and neck must be performed by the treating 
physician at baseline for all patients enrolled; thereafter, head and neck exams should 
be performed in accordance with the local standard of care while the patient is 
receiving study treatment and after the completion of study treatment. 

The routinely scheduled chest CT/MRI scan performed as part of the assessment of 
tumor burden will be used as the chest CT for SCC surveillance while the patient is 
on study treatment. Following cessation of study drug, surveillance of SCC should be 
performed in accordance with the local standard of care. 
Patients who previously developed cuSCC and are already participating in a skin 
surveillance program must restart the process upon enrollment into this study with a 
dermatologic examination performed within 28 days prior to the initiation of therapy and 
after 2230 days on study treatment (Cycle 2, Day 1). Thereafter, dermatology evaluation 
should be performed in accordance with the local standard of care while the patient is 
receiving study treatment and after the completion of study treatment.
5.3.5
FDG-PET Imaging
Patients on this study are required to undergo FDG-PET imaging. 
FDG-PET imaging will be done at baseline (14 days prior to first dose of study 
treatment). If the patient has FDG-PET avid disease, he/she will undergo subsequent 
FDG-PET imaging.  This will be scheduled during Cycle 1 between Days 10 to 14 and 
Cycle 2, Day 147 days (coinciding with first CT/MRI response assessment). FDG-PET 
images should be obtained per procedures outlined in the separate imaging manual. 
FDG-PET scans will be assessed by an independent IRF.
Given the exploratory nature of FDG-PET changes at Cycle 1, Day 14 (e.g., FDG-PET 
flares), the results of this scan should not be utilized to determine a patient’s disease 
status during treatment with vemurafenib and cobimetinib.

PreFDG-PET blood glucose test
Blood glucose levels will be measured immediately prior to FDG administration 
either by fingerstick test or by serum glucose assay on a blood sample obtained by 
venipuncture and processed in the local laboratory. Patients should not have 
consumed food for 4 hours prior to this test.

FDG-PET scan
Follow-up FDG-PET scans should be performed at the above-mentioned timepoints 
only in patients who have FDG-PET avid disease at baseline (i.e., with one or more 
evaluable lesions detected on the baseline scan). Procedures for obtaining FDG-PET 
scans are described in detail in the imaging manual.


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5.4
Laboratory Assessments
A series of laboratory assessments will be made throughout the course of this study.  
These assessments are being performed to monitor patient safety.
Normal ranges for the study laboratory parameters, where available, must be supplied to 
Roche/designee before the study starts. 
The total volume of blood collected for safety laboratory assessments will be 
approximately 10 mL.
5.4.1
Laboratory Assessments List
The laboratory assessments listed will be performed at a local laboratory:

Hematology: WBC count, hemoglobin, hematocrit, platelet count, WBC differential 
count (neutrophils, bands, lymphocytes, eosinophils, basophils, and monocytes)

Serum chemistries: sodium, potassium, chloride, bicarbonate, glucose, BUN, 
creatinine, calcium, phosphate, magnesium, total and direct bilirubin, total protein, 
albumin, AST, ALT, LDH, ALP, CPK, and uric acid. Note: Patients who exhibit CPK 
elevation coincident with cobimetinib treatment should have measurement of MB 
fraction if there is a clinical suspicion of possible myocardial injury or in case of 
prolongation of the QTc interval.

Coagulation screening studies (aPTT, INR)

Urinalysis: specific gravity, pH, glucose, protein, blood, ketones, microscopics 
(RBC, WBC, casts and crystals)

Serum pregnancy test (for women of childbearing potential including premenopausal 
women who have had a tubal ligation)
5.4.2
Assessments during Treatment
For patients on the 14/14 and 21/7 dosing schedule of cobimetinib, the 
minimum numbers of days per cycle without cobimetinib dosing are 14 and 7, 
respectively.
Please see Table 9 for the Schedule of Assessments.
5.4.3
Dose-Escalation (Cohorts 1 through 5), DoseDe-escalation, 
and Dose-Expansion Cohorts
Day 1 is the day of the first combined administration of vemurafenib and cobimetinib.  
Patients in the dosede-escalation and dose-expansion cohorts will follow the same 
schedule of assessments and procedures as required for patients in the dose-escalation 
stage. 
Cobimetinib Monotherapy Cohort
Patients in this cohort will follow the same schedule of assessments and procedures as 
patients in the dose-escalation stage.


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5.4.4
Study Completion/Early Termination Visit
Patients who complete the study or discontinue early from the study will be asked to 
return to the clinic within 28 days after their last dose of  vemurafenib and/or cobimetinib
or before starting new non-protocol therapy (whichever is earlier) for a study completion 
visit. The visit at which a response assessment showed disease progression may be used 
as the study completion/early termination visit. The following assessments will be 
performed:

Concomitant medications

Adverse events
Please refer to Table 9 for assessments to be performed at the study completion or early 
termination visit.
5.4.5
Follow-Up Assessments
After the study completion visit, ongoing adverse events thought to be related to study 
treatment will be followed until the event has resolved to baseline grade, is assessed by 
the investigator as stable, new anti-tumor treatment is initiated, the patient is lost to 
follow-up, the patient withdraws consent, or it has been determined that study treatment 
or participation is not the cause of the adverse events.
After the study completion visit, investigators should report only serious adverse events 
that are deemed related to study treatment (See Section 7.2.1).
5.5
Pharmacokinetic Assessments 
Plasma samples for measurements of vemurafenib and cobimetinib concentrations and 
possible metabolites will be collected to characterize the pharmacokinetics of 
vemurafenib and cobimetinib.
For each PK blood sample collection, venous blood (2 mL in a heparin tube for 
vemurafenib and 3 mL in an EDTA tube for cobimetinib) will be collected to measure 
concentrations of vemurafenib and cobimetinib. When ECG recordings are obtained at 
the same visit, the collection of PK samples should be time-matched to the collection of 
ECG recordings (plasma samples collected after ECG recording) to investigate any 
potential relationship of systemic levels of vemurafenib and cobimetinib with ECG 
findings.
Plasma samples for the determination of vemurafenib and cobimetinib levels will be 
collected as outlined in Table 10 and Table 11 for patients who have progressed while 
receiving vemurafenib immediately prior to enrollment on this study and those either 
previously untreated or treated (but without prior exposure to any BRAF or MEK 
inhibitor therapy) for locally advanced/unresectable or metastatic melanoma, 
respectively. For cobimetinib, the sampling will allow determination of the total exposure 
(AUC0-24), Cmax, and Cmin. For vemurafenib, plasma exposures will be assessed before 
(for patients previously treated with vemurafenib only) and during (all patients) co-
administration with cobimetinib. Plasma concentrations will be compared with historical 
exposures observed in previous studies with vemurafenib. 


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Potential correlations of relevant PK parameters with dose, safety or efficacy outcomes, 
and other covariates will be explored.
Changes in PD markers will be listed by dose, exposure, cohort, mutation status, and 
response status. Additional PK and PD analyses will be conducted as appropriate.
5.5.1
Assay Methods
Concentrations of vemurafenib and cobimetinib will be determined in plasma using 
validated liquid chromatography tandem mass spectroscopy methods.


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Table 10 Schedule of PK Sampling for Patients Previously Treated with Vemurafenib a,b
Day of Assessment
-1
1
2
8
14
15
16
17
C2 D1
C2D8
C3D8
Time (hr)
0
2
4
6
8
0
0.5
1
2
4
6
0
0
0
0.5
1
2
4
6
8
0
0
0
0
0, 2hr 
post-
dose
0
Vemurafenib
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
xb
xb
x
x
Cobimetinib 14/14
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Cobimetinib 21/7
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Cobimetinib
continuous
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
a Vemurafenib plasma levels samples shall be collected on Days 16 and 17 of C1 only when cobimetinib is given on a 14/14 schedule.
b Patients on cobimetinib monotherapy will undergo PK sampling based on their assigned cobimetinib dosing schedule.
Table 11 Schedule of PK Sampling for Patients Either Previously Treated (but without Prior Exposure to BRAF or 
MEK Inhibitor Therapy) or Previously Untreated for Locally Advanced/Unresectable or Metastatic 
Melanoma a
Day of 
Assessment
1
2
8
14
15
16
17
C2 
D1
C2D8
C3D8
Time (hr)
0
0.5
1
2
4
6
0
0
0
0.5
1
2
4
6
8
0
0
0
0
0, 2hr 
post-
dose
0
Vemurafenib
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
xb
xb
x
x
Cobimetinib 14/14
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Cobimetinib 21/7
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Cobimetinib 
Continuous
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
a Vemurafenib plasma levels samples shall be collected on Days 16 and 17 of C1 only when cobimetinib is given on a 14/14 schedule.


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5.6
Exploratory Molecular Assessments (Biomarker 
Assessments)
Samples collected for PD and biomarker assessments will be analyzed with the objective 
of understanding mechanisms of action and pharmacodynamics and to identify 
biomarkers that are predictive of response to the vemurafenib and cobimetinib
combination or to cobimetinib alone or to explain mechanisms of resistance. Additional 
markers might be measured in case a strong scientific rationale for these analyses 
develops.
Specimens for dynamic (non-inherited) and genetic (inherited) biomarker discovery and 
validation will be collected from all patients participating in the trial. 
The total volume blood loss for plasma, serum, and whole blood biomarker assessments 
will be approximately 18 mL.
For all samples, dates of consent and specimen collection should be recorded on the 
eCRF. For sampling procedures, storage conditions and shipment instructions, see the 
Sample Handling and Logistics Manual.
5.6.1
Plasma Samples
Blood (two approximately 6.0-mL samples in EDTA) for plasma isolation will be 
obtained at baseline. These samples will be used for biomarker assays, which may 
include BRAF mutations and other candidate biomarkers (including somatic mutations of 
the tumor).
5.6.2
Whole Blood for Biomarker Analyses
A blood sample (approximately 6 mL in K3 EDTA) for biomarker analysis will be 
collected as described in the laboratory manual.
The following assessments may be performed on whole blood:

Analysis of new mutations (not described so far) detected in tumor tissue in order to 
verify the somatic nature of this mutation

Single nucleotide polymorphisms (SNPs) in case evidence develops that SNPs might 
be associated with safety, efficacy, or pharmacokinetics of vemurafenib
5.6.3
Tissue Samples
For all patients tumor biopsies of accessible tissue are required.  
5.6.3.1
Tumor Tissue
A final biopsy is requested at the time of progression. A lesion with the greatest change 
in dimension based on interval evaluation should be excised at time of progressive 
disease. As stated above, the scheduling of this tumor biopsy should not interfere with the 
scheduling of the FDG-PET scan.
Tumor biopsies will be obtained from patients with accessible progressing tumors at 
baseline following the patient’s consent to participate in the trial. Failure to obtain 


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sufficient tumor sample after making best efforts to biopsy the tumor will not be 
considered a protocol deviation. If a biopsy at progression was submitted to Roche from 
an antecedent vemurafenib study within 3 months of enrollment, no baseline biopsy is 
required. For previously untreated patients only, the diagnostic tumor specimen may be 
substituted as baseline tumor sample.
If archival tumor tissue was not collected during the previous trial, or was inadequate for 
testing, then archival tumor tissue (formalin-fixed paraffin-embedded archival block or 
20 unstained slides) may also be requested. Fine needle aspiration (FNA) biopsies are not 
acceptable.
In addition to the biopsies noted above, patients will be required to provide tumor 
biopsies approximately 1014 days after the start of dosing with vemurafenib and 
cobimetinib in Cycle 1. The patient must be taking cobimetinib at the time of the 
Day 1014 biopsy.
Scheduling of the tumor biopsy should not interfere with the scheduling of the first, 
post-baseline FDG-PET scan. The FDG-PET scan should not occur within 1 week 
following a study-mandated biopsy unless the biopsy is obtained from a site that is not a 
region of interest on the FDG-PET. Ideally, tumor biopsies at screening and during 
Days 10 to 14 of Cycle 1 should be performed after the mandated PET scans.
See the guidance below regarding the logistics for tumor biopsy and FDG-PET scanning 
in the case of multiple or single lesions.

Multiple lesions: The tumor biopsy will be obtained from a lesion other than the 
one of interest being scanned for FDG-PET and should be obtained 14 hours after 
study drug dosing in Week 2 of Cycle 1, either before or after the scan. 

Single lesion: For patients with only one lesion for both the FDG-PET and the tumor 
biopsy, the timing of the FDG-PET scan is more important and the biopsy should be 
obtained after the second FDG-PET scan. The second FDG-PET scan 
(performed 10 to 14 days after start of dosing with vemurafenib and cobimetinib
in Cycle 1) will be completed first (approximately 1–4 hours after dosing) and the 
tumor biopsy will then be obtained.
Formalin-fixed tumor tissue embedded in paraffin blocks (FFPE biopsy) and, if feasible, 
fresh-frozen tumor tissue will be collected at baseline, between Days 10 and 14, and at 
disease progression. The biopsy at disease progression should be taken from an enlarging 
lesion. Biopsies at progression should be obtained within 3 days of study drug 
discontinuation (i.e., continue study treatment for several days beyond documentation of 
progression, if necessary, in order to coordinate the timing of biopsy to occur within 
3 days of study drug discontinuation). 
Biopsies will be collected and immediately transferred into provided vials filled with 
formalin. The biopsies will then be fixed for 242 hours, transferred into 70% ethanol, 
and then (in ethanol) shipped to a central pathology laboratory for paraffin embedding. In 
cases where a reasonable-sized biopsy (e.g., excisional biopsy, 5-mm punch or more than 


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one 14-gauge core biopsy) can be collected with formalin fixation, every effort should 
also be made to collect a fresh-frozen biopsy. 
Fresh-frozen tumor (baseline, between Days 10 and 14, and at disease progression) may 
be used for whole genome analysis; other techniques such as reverse phase protein array 
or mRNA quantitation may also be performed.  
FFPE tumor from baseline and disease progression biopsies will be used to perform the 
following assessments:

IHC for molecules known to be relevant for activity of the MAPK pathway (ERK and 
MEK protein phosphorylation)

IHC for molecules potentially related to response/resistance including BRAF, CRAF, 
and PTEN

BRAF mutations (including V600E) and other somatic mutations affecting PI3K, 
RAS, RAF, and ERK
The following assessments are planned using the FFPE biopsy taken under treatment 
(Days 1014):

IHC for molecules that are potential PD biomarkers for vemurafenib and cobimetinib
(e.g., ERK and MEK phosphorylation).
5.6.3.2
Presumed or Suspected Squamous Cell Carcinoma,
Second Primary Melanoma, and Normal Skin
Formalin-fixed tissue embedded in paraffin blocks will be collected from patients who 
develop lesions presumed or suspected to be SCC or second primary melanomas during 
screening, the treatment period, and during follow-up. Tumor blocks will be returned 
after biomarker analyses have been performed. Unstained slides are acceptable if, despite 
all efforts, tumor blocks cannot be sent. Biopsies of suspicious malignant lesions not 
thought to represent SCC or second primary melanoma may be submitted at the 
discretion of the investigator.
Normal skin punch biopsies will be obtained under local anesthesia from all patients who 
develop SCC. Skin biopsies should be collected at the time the SCC lesion is excised in 
an area of normal skin (with hair follicles present) to the level of subcutaneous tissue. 
These samples may be obtained by using a 3- to 4-mm punch biopsy device, which 
should not require suturing. The skin biopsies will be formalin fixed on site and will be 
shipped in 70% ethanol.
FFPE samples from paired biopsies of SCC (or suspicious neoplasms) and normal skin 
will be used to perform immunohistochemical analyses of pathway markers 
(pERK, pMEK, p53), as well as somatic mutation analyses (including mutations of RAS, 
RAF, CDKN2A, and p53).


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5.6.4
Storage of Pharmacodynamic and Exploratory Biomarker 
Samples
All PD and exploratory biomarker samples (plasma and/or tissue) will be stored for up to 
5 years after completion of the study. Patients will have the option to consent that 
samples remaining after the protocol-defined analyses can be stored up to 15 years in 
the RCR.
If the patient consents to long-term storage, the RCR specimens will be destroyed no later 
than 15 years after the final freeze of the respective clinical database unless regulatory 
authorities require that specimens be maintained for a longer period. The implementation 
and use of the RCR specimens is governed by the RCR policy to ensure the appropriate 
use of specimens. If no consent has been given for long-term storage, all samples will be 
destroyed no later than 5 years after the initial freeze of the respective clinical database 
unless regulatory authorities require that specimens be maintained for a longer period.
The specimens in RCR will also be made available for future biomarker research towards 
further understanding of vemurafenib and cobimetinib treatment of advanced metastatic 
melanoma, related diseases, and adverse events and for the development of potential 
associated diagnostic assays.
Plasma and tumor specimens will be single coded as for all other clinical samples 
(labeled and tracked using the patient’s study identification number).
5.7
Patients Who Have Discontinued Study Drug
All patients who discontinue vemurafenib and cobimetinib or cobimetinib monotherapy 
treatments will be followed for survival. Survival status will be assessed every 12 weeks 
until withdrawal of consent, death, or loss to follow-up, whichever occurs first.
5.8
Dosing beyond Progression
Dosing beyond progression is not recommended. Only under special circumstances when 
it is felt that the patient may clinically benefit by continued therapy should dosing beyond 
progression be considered.  If it is judged by the investigator, in consultation with the 
Sponsor, that it is in the best interest of the patient, the patient may continue dosing of 
both vemurafenib and cobimetinib at the current dose or on cobimetinib alone. All 
patients who continue cobimetinib monotherapy dosing beyond progression will be dosed 
at 60 mg daily on a 21/7 schedule and will continue to be followed in their previously 
assigned cohort. Patients, who prior to progression could only tolerate a dose of 
cobimetinib below 60 mg daily, may continue dosing at their previously tolerated dose 
and schedule.
Special circumstances can be defined by, for example, cystic lesions, mixed responses, 
and new brain metastases that are treatable during the study with stereotactic radiotherapy 
or surgery but that do not require whole brain radiotherapy. If brain metastases are to be 
treated with stereotactic radiotherapy/gamma knife, vemurafenib and cobimetinib should 
be held 1 day prior to the procedure and may resume 1 day after the procedure is 
completed.


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Patients who receive study therapy beyond progression must continue to undergo study 
visits, laboratory assessments and safety assessments and tumor assessments as specified 
in Sections 5.3 and 5.4. Tumor assessment scans collected post-progression will not be 
sent to ICON and the tumor assessment forms in the eCRF does not need to be 
completed.
Patients who receive study therapy beyond progression may stop study therapy anytime 
the investigator judges that the patient is no longer benefiting from the study therapy. 
Patients are required to stop study therapy if continued disease progression is documented
in subsequent tumor assessments.
6.
INVESTIGATIONAL MEDICINAL PRODUCT
This is an open-label study. Assignment of patients to specific dose cohorts will be 
tracked manually by the Sponsor. Study drug assignment will be handled manually by the 
Sponsor. 
6.1
Dose and Administration Schedule of Vemurafenib and 
Cobimetinib
Patients enrolled in a given cohort will receive vemurafenib and cobimetinib at a 
specified dose combination as described in Section 3. Vemurafenib will be dosed orally 
bid and cobimetinib will be dosed orally qd.
Patients in screening (written informed consent) for this study who were previously 
receiving 960 mg bid vemurafenib will be dose-reduced to 720 mg bid for 7–14 days 
prior to Cycle, 1 Day 1 in Cohorts 1, 1A, 2, 2A, or 1C. Patients receiving 960 mg bid 
vemurafenib prior to screening initiation (written informed consent) and assigned to 
Cohorts 1B, 1D, 3, 4, or 5 will continue receiving 960 mg bid vemurafenib, assuming this 
dose has been adequately tolerated prior to starting the study. Patients in screening 
(written informed consent) for this study who are treatment naive to vemurafenib at the 
time of consent will only start vemurafenib on Cycle 1, Day 1 once they are deemed 
eligible for enrollment.
Vemurafenib will be dosed daily and cobimetinib will be dosed on a 14/14 schedule, a 
21/7 schedule, or a continuous daily schedule in a 28-day cycle. 
On study visit days, the daily doses of cobimetinib will be taken in the clinic after 
pre-dose assessments have been performed. After establishing patient eligibility for 
continued administration of study drugs, patients will be given a sufficient number of 
tablets and/or capsules to last until the next visit. In some cases, extra tablets and/or 
capsules may be dispensed if there is a reasonable possibility that the patient’s next visit 
may be delayed (e.g., due to inclement weather or distance of patient’s home from study 
center).
Cobimetinib should be taken at approximately the same time each day, preferably in the 
morning, and no later than 4 hours after the scheduled time. Each dose of cobimetinib 
should be taken with a glass of water. 
For vemurafenib, patients will receive study medication bottles, each containing tablets 
that are 240 mg each. The number of tablets for the morning and evening dose will 


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depend on the cohort assignment, with at least 8 hours between doses. Each dose of 
vemurafenib should be taken with a glass of water. As soon as feasible after signing 
informed consent, patients previously treated with vemurafenib should continue 
vemurafenib treatment with study drug provided expressly for this particular study and 
discontinue their supply of drug derived either from their antecedent vemurafenib study
or a pharmacy.
Both cobimetinib and vemurafenib will be taken at the same time in the morning. 
On PK sample collection days, patients will be required to come into the clinic and have 
vemurafenib and cobimetinib administered as part of the scheduled study visit after 
pre-dose assessments have been performed. Vemurafenib and cobimetinib may be taken 
with or without food, including on PK sampling days.
Patients will be instructed as to the number and strength of the tablets and/or capsules to 
take according to their assigned dose cohort. The cobimetinib and vemurafenib tablets 
and/or capsules should never be chewed or opened.
If a dose is missed (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.
Patients will be asked to record the time and date they take each dose in a medication 
diary. Missed doses should be recorded in a patient diary. Patients will be instructed to 
bring all unused study medication and their medication diaries to each study visit for 
assessments of compliance.
The protocol requires a study evaluation to occur on Day 1 of every cycle but allows a 
period of ± 3 days. Patients on the 14/14 and 21/7 dosing schedule of cobimetinib are 
required to have the minimum number of days per cycle without cobimetinib dosing 
14 and 7 days, respectively. Patients are still expected to return for PK blood draws 
according to the schedule outlined in Table 10 and Table 11. For example, if a patient on 
a 21/7 cobimetinib dosing schedule has a study evaluation 2 days earlier than the nominal 
study day, the patient cannot restart cobimetinib until he/she has had at least 7 days
without cobimetinib dosing.
6.1.1
Vemurafenib and Cobimetinib Dose Modification
Dose modifications, interruptions, and delays of vemurafenib and/or cobimetinib study 
treatment during and after the DLT assessment window should be made on the basis of 
the guidelines provided in Table 12. Recognizing that new knowledge will be acquired 
and unforeseen safety issues may arise in the course of the study, the guidelines are not 
exhaustive and do not represent the full spectrum of care or treatment options described. 
The dose modification guidelines are not intended to replace clinical judgment or dictate 
care of individual patients. 


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Table 12 Vemurafenib and Cobimetinib Dose Modification Guidelines
Adverse Event
Action
A) Rash/desquamation:    
Grade 3
a) The appearance of rash must be characterized as acneiform or 
non-acneiform.
b) Acneiform rash 

Initiate supportive measures per site guidelines.
Delay cobimetinib dosing until Grade ≤2.
Vemurafenib dosing may continue when cobimetinib is interrupted.
Reduce cobimetinib by one dose level (e.g., 60 to 40 mg at assigned 
dosing schedule). If after restarting at reduced dose, the patient 
experiences skin toxicity grade ≥3, further reduce cobimetinib by 
another dose level (e.g., 40 to 20mg at assigned dosing schedule). 
Permanently discontinue cobimetinib if restarting after second dose 
reduction, the patient experiences skin toxicity grade ≥ 3.
If rash Grade3 persists for 28 days despite adequate supportive 
care, cobimetinib may be resumed if in the investigator’s judgement, 
the benefit-risk of treatment remains favorable.
c) Non-acneiform, maculo-papular rash
Initiate supportive measures per site guidelines.
Delay vemurafenib dosing until Grade≤2.
Cobimetinib dosing may continue when vemurafenib is interrupted.
For Grade 3 rash, reduce vemurafenib by one dose level (e.g., 960 to 
720 mg or 720 to 480 mg). 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 skin 
toxicity Grade ≥ 3.
For Grade 4 rash, reduce vemurafenib by two dose levels 
(e.g., 960 to 480 mg or 720 to 240 mg). Permanently discontinue 
vemurafenib
if after restarting at reduced dose, the patient 
experiences skin toxicity Grade ≥ 3.


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Table 12
Vemurafenib and Cobimetinib Dose Modification Guidelines
(Cont.)
Adverse Event
Action
B) Photosensitivity:
Grade 3
a) In cases of Grade 2 photosensitivity, treatment with vemurafenib and 
cobimetinib may be continued for up to 1 week with the initiation of 
supportive measures. If the photosensitivity does not resolve to 
Grade
1 during this time or if the photosensitivity worsens to 
Grade 3, then both vemurafenib and cobimetinib treatment must be 
interrupted until the photosensitivity resolves to a Grade 1. If this 
occurs within 28 days, treatment may be re-initiated with vemurafenib 
dose reduced by one level (e.g., 720 to 480 mg).
b) 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 the dose 
reduction of vemurafenib, then both agents should be held until the 
photosensitivity resolves to Grade 1 or less.  Cobimetinib should be 
dose reduced by one level when treatment is re-initiated (e.g., 80 to 
60 mg on a 14/14 day schedule; from 60 to 40 mg on a 21/7 or a 
continuous schedule).  The dose of vemurafenib should be maintained at 
the previously reduced dose.
d) If photosensitivity recurs a second time to Grade 3 despite 
prophylactic measures and the aforementioned dose reductions of 
vemurafenib and cobimetinib, either one or both study treatments may 
resume if in the investigator’s judgement, the benefit-risk of treatment 
remains favorable.
C) New skin lesion, suggestive 
of SCC; SCC is considered a 
Grade 3 event in NCI CTCAE 
v4.0
a) Follow SCC Risk Management Plan detailed in protocol 
(Section 5.3.4.6)
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 SCC, 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 may be 
resumed if in the investigator’s judgement, the benefit-risk of treatment 
remains favorable.
d) If the lesion is not an SCC, then treatment with vemurafenib and 
cobimetinib may be restarted at the most recent dose level.


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Table 12
Vemurafenib and Cobimetinib Dose Modification Guidelines 
(Cont.)
Adverse Event
Action
D) Ocular toxicity or visual 
symptoms
Grade 2
a) For any treatment-emergent Grade 2 visual symptoms or ocular 
toxicity, cobimetinib and  vemurafenib must be interrupted pending 
diagnostic 
evaluation, 
including 
a 
complete 
ophthalmologic 
examination performed and interpreted by a qualified ophthalmologist, 
visual acuity testing, intraocular pressure measurements by tonometry, 
slit-lamp ophthalmoscopy, indirect ophthalmoscopy, and
spectral 
domain optical coherence tomography.
b) If RVO is diagnosed, vemurafenib and cobimetinib dosing should be 
permanently discontinued and the RVO treated per institutional 
guidelines.
c) If RVO is not present, but the visual symptoms are not completely 
resolved by 28 days, either one or both study treatments may resume if 
in the investigator’s judgement, the benefit-risk of treatment remains 
favorable.
d) If visual symptoms have completely resolved and findings consistent 
with RVO or neurosensory retinal detachment are not present, the 
patient may resume use of vemurafenib and cobimetinib with 
cobimetinib dose reduced by one level (e.g., 80 to 60 mg on a 14/14 day 
schedule; 60 to 40 mg on a 21/7 or a continuous schedule).
e) If ocular toxicity of Grade 2 recurs a second time, both 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 per institutional guidelines.
b) If Grade 3 diarrhea occurs despite 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 dose reduced by one level (e.g., 80 to 60 mg
on a 14/14 day schedule; 60 to 40 mg on a 21/7 or a continuous
schedule).
c) If the diarrhea is not completely resolved by 28 days, then either one 
or both study treatments may resume if in the investigator’s judgement, 
the benefit-risk of treatment remains favorable.
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 dose 
reduced by one level (e.g., 720 to 480 mg). The cobimetinib dose may 
be maintained at the previously reduced dose.
e) If the diarrhea recurs at Grade 3 despite supportive care and dose 
reductions in both drugs, then either one or both study treatments may 
resume if in the investigator’s judgement, the benefit-risk of treatment 
remains favorable.


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Table 12
Vemurafenib and Cobimetinib Dose Modification Guidelines
(Cont.)
Adverse Event
Action
F) Rhabdomyolysis or 
symptomatic CPK 
elevations
a) 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.
b) If rhabdomyolysis or symptomatic CPK elevation do not 
improve within 4 weeks, permanently discontinue cobimetinib 
treatment.
G) Asymptomatic CPK 
elevations  
a) Grade 3: cobimetinib dosing does not need to modified or 
interrupted to manage asymptomatic Grade 3 CPK elevations.  
b) Grade 4:  Interrupt cobimetinib treatment.  If improved to 
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.
H) Liver function test (LFT)
elevations
a) If Grade 1 or 2, continue current dose of vemurafenib and 
cobimetinib. 
b) If Grade 3 or 4, hold vemurafenib. Continue current dose of 
cobimetinib. Upon resolution of LFT to Grade ≤ 1, resume 
vemurafenib at one lower dose level (e.g., 960 to 720 mg, or 720 to 
480 mg). 
c) If Grade 3 or 4, LFT elevation recurs after one dose reduction, 
vemurafenib may be reduced by another dose level (e.g., 720 to 480 to 
240 mg). Permanently discontinue vemurafenib if Grade 4 LFT 
elevation recurs when vemurafenib is at a dose of 240 mg bid and 
continue current dose of cobimetinib.


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Table 12
Vemurafenib and Cobimetinib Dose Modification Guidelines 
(Cont.)
Adverse Event
Action
I) QTc interval prolongation 
on ECG  
On-study QTc interval  prolongation to 500 ms but 60 ms 
increment compared with baseline OR prolongation of QTc interval to 
≥60 ms compared with baseline (regardless of absolute QTc):
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 6.
c) Interrupt dosing of vemurafenib and perform ECG and electrolyte 
monitoring weekly during period of vemurafenib interruption until 
QTc improves and electrolytes are corrected in all cases; continue 
dosing with cobimetinib at the current dose if otherwise tolerated.
d) 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.
e) If QTc improves within 28 days, restart dosing of   vemurafenib at 
one reduced dose level (e.g., 960 to 720 mg bid). 
f) Repeat 12-lead ECG monitoring at Week 2 and Week 4 of the new, 
lower vemurafenib dose, at Day 1 of each subsequent Cycle3, and 
every 3 months thereafter. 
g) If second increase in QTc interval to 500 ms occurs at the lower 
dose of   vemurafenib, follow Guidelines a through c above, reduce 
dose of   vemurafenib by 1 more dose level (e.g., 720 to 480 mg bid), 
and follow Guidelines d and e.
On-study QTc interval prolongation to 500ms AND 60 ms  
increment compared with baseline:
a) Patient may continue cobimetinib at his/her current dose level.
Vemurafenib treatment may resume if in the investigator’s judgement, 
the benefit-risk of treatment remains favorable.
J) 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.


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Table 12
Vemurafenib and Cobimetinib Dose Modification Guidelines
(Cont.)
Adverse Event
Action
K) Other Grade 4, 
non-hematologic adverse 
events related to study drug
a) Interrupt dosing of vemurafenib and cobimetinib.
b) If adverse event resolves to Grade 1 within 28 days, then 
(at investigator discretion) restart dosing of vemurafenib and 
cobimetinib. Both should be decreased by one dose level of the 
pre-event dose (e.g., 960 to 720 mg for vemurafenib; 80 to 60 mg for 
cobimetinib on a 14/14 day schedule).
c) If the adverse event does not resolve to Grade 1 within 28 days, 
discontinue study treatment.
d) If the adverse event recurs after 1 dose reduction, either one or both 
study treatments may resume if in the investigator’s judgement, the 
benefit-risk of treatment remains favorable.
bidtwice daily; LFTliver function test; QTccorrected QT interval; RVOretinal vein occlusion; 
SCCsquamous cell carcinoma.
6.2
Accountability and Patient Compliance for Investigational 
Medicinal Product 
The investigator is responsible for the control of drugs under investigation. 
Adequate records for the receipts (e.g., Drug Receipt Record) and disposition 
(e.g., Drug Dispensing Log) of the study drug must be maintained.  Patients will be asked 
to return all used and unused drug supply containers at the end of the treatment as a 
measure of compliance.
Accountability and patient compliance will be assessed by maintaining adequate 
“drug dispensing” and return records.
Accurate records must be kept for each study drug provided by the Sponsor. 
These records must contain the following information.

Documentation of drug shipments received from the Sponsor (date received 
and quantity

Disposition of unused study drug not dispensed to patient
A Drug Dispensing Log must be kept current and should contain the following 
information:

The identification of the patient to whom the study medication was dispensed

The date(s) and quantity of the study medication dispensed to the patient.

The date(s) and quantity of the study medication returned by the patient.
All records and drug supplies must be available for inspection by the study monitor at 
every monitoring visit.


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All study drug required for completion of this study will be provided by Sponsor. The 
recipient will acknowledge receipt of the drug by returning the appropriate 
documentation form indicating shipment content and condition. Damaged supplies will 
be replaced.
Study drug will either be disposed of at the study site according to study site’s 
institutional standard operating procedures or returned to Roche and/Genentech with the 
appropriate documentation, as determined by the study site. If the study site chooses to 
destroy the study drug, the method of destruction must be documented.
Roche and/or Genentech must evaluate and approve the study site’s drug destruction 
standard operating procedure prior to the initiation of drug destruction by the study site.
6.3
Formulation, Storage, Packaging, and Labeling
Study drug packaging will be overseen by the Roche clinical trial supplies department 
and bear a label with the identification required by local law, the protocol number, drug 
identification, and dosage.
The packaging and labeling of the study medication will be in accordance with Roche 
standards and local regulations.
The study drug must be stored according to the details on the product label.  The drug 
label indicates the storage temperature.
Local packaging in some countries may be different.
Upon arrival of investigational products at the site, site personnel should check them for 
damage and verify proper identity, quantity, integrity of seals, and temperature conditions 
and report any deviations or product complaints to the study monitor upon discovery.
6.3.1
Vemurafenib
Vemurafenib is supplied in 240-mg film-coated tablets packed in bottles for oral 
administration. For additional batch specific instructions and information for vemurafenib 
film-coated tablets, see the packaging.
Vemurafenib will be stored at the clinical site under the recommended storage conditions 
of “Do Not Store above 25°C” as indicated on the study drug label.  Patients will be 
requested to store the vemurafenib at the recommended storage conditions noted on the 
label, out of the reach of children or other co-inhabitants.
Vemurafenib will be labeled in compliance with Good Manufacturing Procedures.  
The drug label will include the contents, protocol number, batch number, and storage 
conditions, as well as any required statements that the drug is “For Investigational Use 
Only.”
6.3.2
Cobimetinib
Cobimetinib will be supplied in two forms: capsules and tablets.
While supplies last, cobimetinib will be supplied as 5-mg, 25-mg, and 100-mg capsules 
that are differentiated by color. 
The 5-mg capsules are light blue (Size 1), the 


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25-mg capsules are orange (Size 1), and the 100-mg capsules are flesh colored (Size 0).
The capsule formulation contains no excipients other than the hard gelatin capsule.
The capsules should be stored at the clinical site under recommended storage conditions:  
15C30°C/59F86°F, as indicated on the study drug label.
After the capsule supplies are used up or have expired, cobimetinib will be administered 
in tablet format.  The tablet formulation of cobimetinib (GDC-0973) will be a 20-mg 
filmcoated, immediate-release tablet. The tablet formulation consists of the cobimetinib 
and the following inactive ingredients: microcrystalline cellulose, lactose monohydrate, 
croscarmellose sodium, magnesium stearate (non-bovine), and Opadry White film coat.
All excipients used in the tablet formulation are compendial (USP/NF and/or EP) grade 
with the exception of the film coating. The tablet coating consists of polyvinyl alcohol 
part hydrolyzed, titanium dioxide, polyethylene glycol 3350, and talc. The ingredients in 
the film coating are compendial. The tablets should not be stored above 25°C (77°F). 
The tablet/capsule dose administered to each patient will be based on cohort assignment.   
Doses will be administered at the clinical site for the initial dose and on subsequent 
dosing days that coincide with clinical site visits. Patients will be given instructions for 
self-administration on dosing days that do not coincide with clinical site visits. Any 
unused study drug must be returned to the study site for disposal. Patients will be asked 
to store the cobimetinib at the recommended storage conditions noted on the label, out of 
reach of children or other co-inhabitants.
Cobimetinib 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.
For further details, see the cobimetinib (GDC-0973) IB.
6.4
Blinding and Un-blinding
This is not applicable as this study is open-labeled.
6.5
Accountability of Investigational Medicinal Product and 
Assessment of Compliance
6.5.1
Accountability of Investigational Medicinal Product
All records and drug supplies must be available for inspection by the study monitor at 
every monitoring visit.
Patients will be asked to return all used and unused drug supply containers at the end of 
the treatment as a measure of compliance.  All supplies, including partially used or empty 
containers and copies of the dispensing and inventory logs, must be returned to the 
Roche/Genentech monitor at the end of the study, unless alternate destruction has been 


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authorized by Roche/Genentech or required by local or institutional regulations 
(Section 6.5.2).
6.5.2
Assessment of Compliance
Patient compliance will be assessed by maintaining adequate study drug dispensing 
records. The investigator is responsible for ensuring that dosing is administered in 
compliance with the protocol.  Delegation of this task must be clearly documented and 
approved by the investigator.
Destruction of the Investigational Medicinal Product (IMP) 
Local or institutional regulations may require immediate destruction of unused IMP for 
safety reasons, e.g., cytotoxicity.  In these cases, it may be acceptable for investigational 
site staff to destroy dispensed IMP before a monitoring inspection, provided that source 
document verification is performed on the remaining inventory and reconciled against the 
documentation of quantity shipped, dispensed, returned, and destroyed. Written 
authorization must be obtained from the Sponsor at study start up before destruction.
Written documentation of destruction must contain the following:

Identity (batch numbers or patient numbers) of investigational product(s) destroyed

Quantity of investigational product(s) destroyed

Date of destruction (date discarded in designated hazardous container for destruction)

Method of destruction (the site must provide the Sponsor with documentation of its 
institutional policy and procedures for handling and disposing of hazardous drugs)

Name and signature of responsible person who discarded the investigational product 
in a hazardous container for destruction
7.
SAFETY INSTRUCTIONS AND GUIDANCE
7.1
Adverse Events and Laboratory Abnormalities
7.1.1
Clinical Adverse Events
According to the International Conference of Harmonization (ICH), an adverse event is 
any untoward medical occurrence in a patient or clinical investigation patient 
administered a pharmaceutical product and that does not necessarily have a causal 
relationship with this treatment.  An adverse event can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or 
not considered related to the medicinal (investigational) product.  Preexisting conditions 
that worsen during a study are to be reported as adverse events.
7.1.1.1
Intensity 
Intensity of all adverse events will be graded according to the NCI CTCAE v4.0 on a 
5-point scale (Grade 1 to 5) and reported in detail on the eCRF. 


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Adverse events not listed on the CTCAE should be graded as follows:  
CTC Gradea,b
Equivalent to:
Definition
Grade 1
Mild
Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated
Grade 2
Moderate
Moderate; minimal, local or noninvasive intervention indicated; 
limiting age-appropriate instrumental ADLc
Grade 3
Severe
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self care ADLd
Grade 4
Life threatening/ 
disabling
Life-threatening consequences; urgent intervention indicated
Grade 5e
Death 
Death related to AE
a Semi-colon indicates ‘or’ within the description of the grade; a single dash (-) indicates a grade is not 
available.
b Not all grades are appropriate for all AEs. Therefore, some AEs are listed with fewer than five options for 
grade selection.
c  Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc.
d
Self-care ADL refers to bathing, dressing, and undressing, feeding self, using the toilet, taking 
medications, and not being bedridden.
e  Grade 5 (death) is not appropriate for some AEs and therefore is not an option.
7.1.1.2
DrugAdverse Event Relationship
The causality relationship of study drug to the adverse event will be assessed by the 
investigator as either:
Yes or No
If there is a reasonable suspected causal relationship to the study medication, i.e., there 
are facts (evidence) or arguments to suggest a causal relationship, drugevent 
relationship should be assessed as Yes.
The following criteria should be considered in order to assess the relationship as Yes:

Reasonable temporal association with drug administration

It may or may not have been produced by the patient’s clinical state, environmental or 
toxic factors, or other modes of therapy administered to the patient.

Known response pattern to suspected drug

Disappears or decreases on cessation or reduction in dose

Reappears on rechallenge
The following criteria should be considered in order to assess the relationship as No:

It does not follow a reasonable temporal sequence from administration of the drug.

It may readily have been produced by the patient’s clinical state, environmental or 
toxic factors, or other modes of therapy administered to the patient.

It does not follow a known pattern of response to the suspected drug.

It does not reappear or worsen when the drug is re-administered.


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7.1.1.3
Serious Adverse Events (Immediately Reportable to Roche)
A serious adverse event is any experience that suggests a significant hazard, 
contraindication, side effect, or precaution.  It is any adverse event that at any dose fulfils 
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 that could hypothetically have caused a death had it been more severe.)

Requires 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
**The term sudden death should be used only when the cause is of a cardiac origin 
as per standard definition.  The terms death and sudden death are clearly distinct 
and must not be used interchangeably.
The study will comply with all local regulatory requirements and adhere to the full 
requirements of the ICH Guideline for Clinical Safety Data Management, Definitions 
and Standards for Expedited Reporting, Topic E2 (see Appendix 3).
7.1.1.4
Adverse Events of Special Interest
The following events are adverse events of special interest and will need to be reported to 
the Sponsor expeditiously (see Section 7.2.1 for instructions on expedited reporting), 
irrespective of regulatory seriousness criteria:

Grade 1 retinal vein occlusion

Grade 2 visual disturbances

cuSCC of any grade

Grade ≥3 QTc interval prolongation

Grade ≥3 photosensitivity

Grade 4 elevations in liver function tests (serum ALT, AST and/or bilirubin)
7.1.1.5
Other Adverse Events Requiring Expedited Reporting
The following events are adverse events that will need to be reported to the Sponsor 
expeditiously, irrespective of regulatory seriousness criteria:

Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy’s 
law:
o
Treatment-emergent ALT or AST3baseline value in combination with total 
bilirubin2ULN (of which 35% is direct bilirubin)


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o
Treatment-emergent ALT or AST3baseline value in combination with clinical 
jaundice.

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.
7.1.1.6
Progression of Underlying Malignancy
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 
RECIST criteria 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.
Symptomatic deterioration may occur in some patients.  In this situation, progression is 
evident in the patient’s clinical symptoms but is not supported by the tumor 
measurements.  Or, the disease progression is so evident that the investigator may elect 
not to perform further disease assessments.  In such cases, the determination of clinical 
progression is based on symptomatic deterioration.  These determinations should be a 
rare exception as every effort should be made to document the objective progression of 
underlying malignancy.
If there is any uncertainty about an adverse event being due only to the disease under 
study, it should be reported as an adverse event or serious adverse event.
7.1.2
Treatment and Follow-Up of Adverse Events 
After the discontinuation of therapy with vemurafenib and/or cobimetinib, continue 
following up of adverse events as follows:
Related adverse events: Follow until one of the following occurs:

Resolved or improved to baseline

Relationship is reassessed as unrelated

Death

Start of new anti-cancer regimen 

Investigator confirms no further improvement can be expected 

Clinical or safety data will no longer be collected; or final database closure
Unrelated severe or life-threatening adverse events: Follow until one of the following 
occurs:

Resolved or improved to baseline


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
Intensity (severity) improved to Grade 2 or lower

Death

Start of new anti-cancer regimen 

Investigator confirms that no further improvement can be expected 

Clinical or safety data will no longer be collected; or final database closure
Unrelated Grade 1 or Grade 2 adverse events: Follow as clinically indicated.
The final outcome of each adverse event must be recorded on the eCRF 
7.1.3
Laboratory Test Abnormalities
Laboratory test results will be recorded on the laboratory results eform of the eCRF or 
appear on electronically produced laboratory reports submitted directly from the central 
laboratory, if applicable. 
Any laboratory result abnormality fulfilling the criteria for a serious adverse event should 
be reported as such, in addition to being recorded as an adverse event in the eCRF.
Any treatment-emergent abnormal laboratory result that is clinically significant, 
i.e., meeting one or more of the following conditions, should be recorded as a single 
diagnosis on the adverse event page in the eCRF:

Accompanied by clinical symptoms

Leading to a change in study medication (e.g., dose modification, interruption, or 
permanent discontinuation)

Requiring a change in concomitant therapy (e.g., addition of, interruption of, 
discontinuation of, or any other change in a concomitant medication, therapy, 
or treatment)
This applies to any protocol and non-protocolspecified safety and efficacy laboratory 
result from tests performed after the first dose of study medication that falls outside the 
laboratory reference range and meets the clinical significance criteria.
7.1.3.1
Follow-Up of Abnormal Laboratory Test Values
In the event of medically significant unexplained abnormal laboratory test values, the 
tests should be repeated and followed-up until they have returned to the normal range 
and/or an adequate explanation of the abnormality is found.  If a clear explanation is 
established, it should be recorded on the eCRF. 
7.2
Handling of Safety Parameters
7.2.1
Reporting of Serious Adverse Events (Immediately Reportable)
Investigators will seek information on adverse events at each patient contact.
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). The 


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exception to this is if the patient is on commercial Zelboraf (vemurafenib) during 
this time; in such cases, adverse events are to be reported to Roche, and spontaneous 
reporting criteria will apply.
After initiation of study drug any clinical adverse event or abnormal laboratory test 
value that is serious and that occurs during the course of the study (as defined in 
Section 7.1.1.3) must be reported to Roche immediately (i.e., no more than 24 hours after 
learning of an event). The investigator must complete the SAE Reporting Form 
[SRD-0115310] and forward it to the person in charge of processing the serious adverse 
events at Roche (SAE Responsible).
Related serious adverse events MUST be collected and reported regardless of the time 
elapsed from the last study drug administration, even if the study has been closed.
Unrelated serious adverse events must be collected and reported during the study and for 
up to 28 days after the last dose of study medication.
Diagnosis versus Signs and Symptoms
If known, a diagnosis should be recorded on the SAE Reporting Form [SRD-0115310] 
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 as an adverse 
event or serious adverse event. If a diagnosis is subsequently established, it should be 
reported as follow-up information.
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. For example, if severe 
diarrhea is known to have resulted in dehydration, it is sufficient to record only diarrhea 
as an adverse event or serious adverse event. 
However, medically significant adverse events occurring secondary to an initiating event 
that are separated in time should be recorded as independent events. For example, if a 
severe gastrointestinal hemorrhage leads to renal failure, both events should be recorded 
separately.
For the purposes of this study, the following will not be considered a serious adverse 
event:

Elective hospitalizations or surgical procedures that are a result of a patient’s 
preexisting condition(s) that have not worsened since receiving trial medication; 
examples may include, but are not limited to, cholecystectomy for gallstones, joint 
replacement surgery, and diagnostic testing. Such events should still be recorded as 
medical procedures in the eCRF.
7.2.2
Pregnancy 
A female patient must be instructed to stop taking the test “drug” and immediately inform 
the investigator if she becomes pregnant during the study.  The investigator should report 


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all pregnancies within 24 hours to the Sponsor using the Clinical Trial Pregnancy 
Reporting Form, [SRD-0115311] for any pregnancies that occur within 6 months of last 
dose of study treatment.  The investigator should counsel the patient and discuss the risks 
of continuing with the pregnancy and the possible effects on the fetus.  Monitoring of the 
patient should continue until conclusion of the pregnancy.  
Pregnancy occurring in the partner of a male patient participating in the study should be 
reported to the investigator and the Sponsor. The partner should be counseled, the risks of 
continuing the pregnancy discussed, as well as the possible effects on the fetus. 
Monitoring of the patient should continue until conclusion of the pregnancy. 
NOTE:  The investigator should fill out a Pregnancy Reporting Form, [SRD-0115311], 
only if the pregnant partner has signed a Pregnant Partner Data Release Form.
7.3
Warnings and Precautions 
7.3.1
Vemurafenib Warnings and Precautions
Investigators and patients should be aware of the risks of photosensitivity reactions, 
cutaneous neoplasms, non-cutaneous neoplasms, potentiation of radiation toxicities, 
hypersensitivity reactions, severe dermatologic reactions, liver injury, QTc interval 
prolongation, and potential DDIs during treatment with vemurafenib. For details 
pertaining to these risks, please refer to Section 1.2.4 and Section 1.2.5.  
7.3.2
Cobimetinib Warnings and Precautions
Investigators and patients should be aware of the risks of serous retinopathy and left 
ventricular dysfunction during treatment with cobimetinib. For details pertaining to the 
risk of serous retinopathy and left ventricular dysfunction, please refer to Section 1.3.7.2
and Section 1.3.7.3, respectively, for details pertaining to these risks.
7.3.3
Other Precautions
Given the biopsy requirements in this study, risks such as infection of the surgical site, 
excessive bleeding, or injury to adjacent tissues should be considered for patients who 
undergo tumor tissue biopsies.
8.
STATISTICAL CONSIDERATIONS AND ANALYTICAL PLAN
8.1
Primary and Secondary Study Variables
8.1.1
Primary Variable
This study is designed to evaluate the safety and tolerability of vemurafenib and 
Cobimetinib when administered in combination in patients with previously untreated or 
treated (but without prior exposure to any BRAF or MEK inhibitor therapy), BRAFV600E 
mutation-positive, locally advanced/unresectable or metastatic melanoma as well as those 
who have progressed after treatment with vemurafenib immediately prior to enrollment 
on this study and to identify a recommended dose and schedule for the combination of 
vemurafenib and cobimetinib for further clinical testing. Safety and tolerability will be 
described through DLTs and MTDs for vemurafenib and cobimetinib.


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8.1.2
Secondary Variables
Evidence of objective tumor response following vemurafenib and cobimetinib treatment 
or cobimetinib monotherapy will be documented and summarized. Potential alterations in 
the RAS/RAF/MEK pathway (such as RAS, RAF, and MEK mutations) will be assessed 
to identify potential tumor response and resistance mechanisms. BRAFV600E mutation 
status of progressing patients will be assessed as well. Predisposing factors for SCC 
development will be analyzed using specimens from SCC or suspicious neoplasms, 
as well as paired normal skin. 
The steady-state pharmacokinetics of vemurafenib and cobimetinib will be characterized. 
PD effects of vemurafenib and cobimetinib combination therapy and cobimetinib 
monotherapy (up to 12 patients) will be measured by changes in FDG-PET and changes 
in biomarkers from pre- and during-treatment samples.
Secondary efficacy endpoints include the following:
OR is defined as a complete or a partial response confirmed ≥ 4 weeks after initial 
documentation on the basis of investigator assessment using the RECIST v1.1 criteria.
DOR is defined as the interval (days) 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 an OR. Patients with no documented progression after a complete or 
partial response will be censored at the date of the last evaluable tumor assessment.
PFS is defined as the interval (days) between the start date of treatment and the date of 
progression or death for any cause, whichever comes first. Patients who have neither 
progressed nor died will be censored on the date of last evaluable tumor assessment. 
Patients who had no post-baseline assessments and did not have an event will be censored 
at Day 1. PFS will be calculated on the basis of investigator assessment according to 
RECIST v1.1.
OS is defined as the interval between the start date of treatment and the date of death for 
any cause.  
Tumor assessment scans may be assessed by an independent IRF.
8.1.3
Safety
Safety of the treatment will be evaluated by adverse events, laboratory tests, vital signs, 
ECGs, performance status, and ophthalmic and dermatological evaluations.
All patients who received any amount of treatment will be included in the safety 
evaluation.
8.2
Statistical and Analytical Methods
8.2.1
Statistical Model  
No statistical model will be used in the efficacy analysis and no formal hypothesis testing 
is planned. Descriptive statistics will be used to summarize the clinical activity, 
pharmacokinetics, and PD effect of vemurafenib and cobimetinib as described in the 
section on study objectives.  


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DLTs that occur in the first 28 days after initial dose of vemurafenib and cobimetinib will 
be used to determine the recommended dose.  Subsequent DLTs will be reported and 
summarized as well.   
The safety and efficacy (e.g., ORR, duration of response) will be presented by assigned 
dose cohort in the dose escalation stage and treatment group (patients previously treated 
with vemurafenib; patients previously untreated or treated [but without prior exposure 
to any BRAF or MEK inhibitor therapy]
for locally
advanced/unresectable or 
metastatic disease) in the dose expansion stage.  The final analysis will be performed on 
all patient data collected through the 28 days after last patient’s last dose of study drug or 
at least 12 months after last patient in, whichever occurs later.
For all patients who
completed 6 months SCC follow-up after end of treatment prior to protocol amendment j, 
an additional analysis will be performed to summarize any SCC findings per the RMP.
8.2.2
Hypothesis Testing
Descriptive statistical analyses will be performed for all analyses. Any statistical testing 
performed will be exploratory in nature and will be used to demonstrate the mechanism 
of action of vemurafenib and cobimetinib. 
8.2.3
Analysis Populations
The treated population is defined as all patients who receive any amount of study 
medication. All safety analyses will use the treated population. Patients who enroll in the 
dose escalation stage who complete the DLT assessment window (Day 28) or experience 
a DLT in the assessment window and are withdrawn from study will be evaluable for 
determination of the recommended dose.  
8.2.4
Safety Data Analyses
Safety will be assessed through summaries of DLTs, adverse events, changes in 
laboratory test results, changes in vital signs, and vemurafenib and cobimetinib 
exposures. Descriptive statistics will be used to summarize all safety data. Summary 
tables and listings will be presented by assigned dose cohort.
Adverse event data will be reported in listings and presented in frequency tables by 
Medical Dictionary for Regulatory Affairs (MedDRA) terms. All adverse events 
occurring on or after treatment on Cycle 1, Day 1 will be summarized. Summaries of 
adverse event by grade, seriousness, and relationship to study treatment will be presented, 
as well as summaries of adverse events leading to death or to premature withdrawal from 
study treatment. Serious adverse events, including deaths, will be listed separately and 
summarized.
Relevant laboratory and vital signs (temperature, heart rate, and blood pressure) data will 
be presented using summary statistics.
Laboratory data will be presented as summary tables for worst toxicity grade compared 
with baseline using Standard Internationale units. Descriptive statistics will be used to 
summarize ECOG performance status. Vital signs, ECGs, and ophthalmologic and 
dermatologic test results will be reported in the listings.


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Exposure to study medication will be summarized by total duration of study medication, 
number of cycles started, and cumulative dose using descriptive statistics. 
Dose interruptions/modifications and their reasons will be presented.
8.2.5
Exploratory Analyses
Pharmacogenetic Analysis
In order to explore the potential role of polymorphisms in drug metabolism enzyme and 
gene transporters in the PK disposition and safety profile of vemurafenib and 
cobimetinib, gene mutations may be assayed using multiplex PCR, allele-specific PCR, 
direct sequencing, or other appropriate methods. PK parameters, including 
dose-normalized AUC and Cmax, would be compared between genotypes and, where 
possible, predicted phenotypes.
8.2.6
Determination of Maximal Tolerated Dose
Patients who withdraw from the study or who miss more than the allowed number of 
vemurafenib or cobimetinib doses prior to Cycle 1, Day 28 for reasons other than a DLT 
will be considered unevaluable for DLTs and will not be included in the determination of 
the MTD of the vemurafenib and cobimetinib combination. The MTD of the vemurafenib 
and cobimetinib combination will be determined according to the rules described in 
Section 3.1.4. In the event dose escalation does not continue until the MTD can be 
determined (e.g., because of PK futility), the MTD will be reported as “undetermined.” 
8.2.7
Other Analyses
8.2.7.1
Pharmacokinetic Analysis 
Several PK parameters derived from the blood PK samples will be analyzed using 
descriptive statistics (means, standard deviations, coefficients of variation, median).  
They will include Cmax, Cmin, and AUC. Additional parameters such as apparent CL, 
volume of distribution, and t1/2 will be estimated if the concentration data are sufficient.
Estimation of the PK parameters will be performed using standard non-compartmental 
methods.  Actual sampling times will be used to calculate PK parameters.
Steady-state pharmacokinetics of vemurafenib and cobimetinib will be summarized 
descriptively. Relevant PK parameters will be correlated with dose, safety, or efficacy 
variables.
8.2.7.2
Exploratory Biomarker Analyses
The aim of exploratory biomarker analyses is to explore the potential to predict efficacy 
(response, PFS, and survival) and/or toxicities by each marker separately and/or by 
suitable combinations.
Given the explorative nature of these analyses, no fixed analysis schedule can be 
specified. Exploratory analyses of individual biomarkers and combinations of markers 
will be conducted using appropriate statistical methods in a data-dependent way. 
The results might generate hypotheses on how biomarker observation could predict for 
benefit. Validation of the hypotheses will require a new set of independent data.


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Additional biomarker data may become available from other studies prior to finalizing 
this study. Testing of biomarkers to support or confirm results from other studies will be 
specified in an analysis plan prior to closing this study.
FDG-PET response as defined by the EORTC will be used as a potential early readout of 
anti-tumor activity.
8.3
Sample Size
Design considerations were not made with regard to explicit power and type I errors but 
to obtain preliminary safety, PK, and PD information in this patient population. 
The number of patients expected to be treated with combination therapy in this two-stage 
study is approximately 130, assuming approximately 30–60 patients enroll in the 
dose-escalation stage (i.e., 10 dose cohorts) and at least 40 patients enroll in at least two 
expansion cohorts (one consisting of patients previously treated with vemurafenib, the 
other consisting of patients previously treated [but without prior exposure to BRAF or 
MEK inhibitor therapy] or previously untreated for locally advanced/unresectable or 
metastatic melanoma). This estimate does not include up to 20 patients who may enroll in
the cobimetinib monotherapy cohort. 
The sample size for this trial is based upon the dose-escalation rules described in 
Table 13, which describes the properties of the dose-escalation rules with different 
underlying rates of DLT.
Patients who withdraw from the study prior to completing the DLT assessment window 
for reasons other than DLTs will be replaced.
Table 13 Properties of the Dose-Escalation Rules with Different Underlying 
Rates of DLT
Underlying Rates of 
Dose-Limiting Toxicity
Probability of Enrolling an 
Additional 3 Patients
Probability that the Dose Is 
Determined to be Tolerated
0.10
0.24
0.91
0.20
0.38
0.71
0.33
0.44
0.43
0.40
0.43
0.31
0.50
0.38
0.17
0.60
0.29
0.08




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10.
STUDY COMMITTEES
A Data Safety Monitoring Board (DSMB) has been utilized to ensure patient safety and 
will consist of external clinicians who are experts in the disease area and 1 external 
statistician.  The DSMB reviewed available safety data approximately every 3 months. 
The DSMB had the option to change the data review schedule as deemed needed.  Details 
of the DSMB’s responsibilities and logistics were outlined in the charter. Safety 
monitoring by an independent DSMB has ceased following the results of the primary 
efficacy analysis of the Phase III study, GO28141.


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11.
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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.
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Lucas, R. Global Burden of Disease of solar Ultraviolet Radiation, 
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Cancer Council Victoria (2007).
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Beeram M, Patnaik, et al., Raf: a strategic target for therapeutic development 
against Cancer. J Clin Oncol 2005; (23):677190.
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Maldonado JL, Fridlyand J, Patel H, et al., Determinants of BRAF mutations 
in primary melanomas. J Natl Cancer Inst 2003; (95): 187890.
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Lang J, Mackie RM, Prevalence of exon 15 BRAF mutations in primary 
melanoma of the superficial spreading, nodular, acral, and lentigo maligna 
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Curtin JA, Fridlyand J, Kageshita T, et al. Distinct sets of genetic alterations 
in melanoma. N Engl J Med. 2005; (353): 2135-47.
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http://www.sanger.ac.uk/genetics/CGP/cosmic/.
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Gray-Schopfer V, Wellbrock C and Marais R.Melanoma biology and new 
targeted therapy. Nature, 2007; (445):8517.
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Hingorani SR, Jacobetz MA, et al, Integrating BRAF/MEK inhibitors in 
combination therapy for melanoma. Cancer Research, 2003; (63):51985202
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Sumimoto H, Miyagishi M, Miyoshi H, et al., Inhibition of growth and 
invasive ability of melanoma by invasion of mutated BRAF with lentivirus-
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Smalley KSM, Herlyn M, et al., Targeting BRAF/MEK in melanoma: new 
hope or another false dawn? Expert Tev. Dermatol., 2007;(2):17990.
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Ascierto P, Streicher HZ, and Sznol M. Melanoma: A model for testing new 
agents in combination therapies. J of Translational Med., 2010;(8):38.
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Flaherty KT, Puzanov I. Kim KB et al. Inhibition of mutated, activated BRAF 
in metastatic melanoma.  N Engl J Med 2010; (363):809:819.
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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.


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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.
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Lankisch PG, Gottesleben DF. Drug induced acute pancreatitis: incidence and 
severity. M Gut 1995; 37: 5657.
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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 30, 2012 (suppl; abstr 8515).
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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 
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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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Chapman PB, Hauschild A, et al. Improved survival with vemurafenib in 
melanoma with BRAF V600E mutation. N Engl J Med. (2011), 364, 250716.
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Murad, A, et al., Cutaneous Squamous Cell Carcinoma., New Engl. J Med., 
(2001), 13, 975983.
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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.
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Solit DB, Garraway LA, et al., BRAF mutation predicts sensitivity to MEK 
inhibition. Nature, 2006; (439):35862.
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Haass NK, Sproesser K, 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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Poulikos IP, Zhnag C, Bollag G, et al Raf inhibitors transactivate RAF dimers 
and ERK signaling in cells with wild-type BRAF. Nature, 2010; 
(464):42730.
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Hatzivassiliou G, Song K, Yen I, et al., Raf inhibitors prime wild-type RAF 
to activate the MAPK pathway and enhance growth. Nature., 2010;(464): 431.
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Heidorn SJ, Milagre C, Whittaker S, et al. Kinase-dead BRAF and oncogenic 
RAS cooperate to drive tumor progression through CRAF , Cell, (2010), 140, 
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30.
Daouti S, Higgins B, et al., Preclinical in vivo evaluation of efficacy, 
pharmacokinetics, and pharmacodynamics of a novel MEK1/2 kinase 
inhibitor RO5068760 in multiple tumor models. Mol. Cancer Ther. (2010), 9, 
13444.
31.
Leboeuf R, Baumgartner JE, et al, BRAF V600E mutation is associated with 
preferential sensitivity to MEK inhibition in thyroid cancer cell lines. (2008), 
J Clin, Endocrinol. and Metab. 93, 21942201.
32.
Young H, Baum R, et al,. Measurement of clinical and subclinical tumor 
response using [18F]-flurodeoxyglucose and positron emission tomography: 
review. Eur.J Cancer. (1999), 35, 177382.
33.
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.
34.
Lynch TJ Jr, Kim ES, et al Epidermal growth factor receptor inhibitor-
associated cutaneous toxicities: an evolving paradigm in clinical management. 
Oncologist, (2007), 12, 61021.


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PART II:
ETHICS AND GENERAL STUDY ADMINISTRATION
12.
ETHICAL ASPECTS
12.1
Local Regulations/Declaration of Helsinki
The investigator will ensure that this study is conducted in full conformance with the 
principles of the “Declaration of Helsinki” or with the laws and regulations of the country 
in which the research is conducted, whichever affords the greater protection to the 
individual.  The study must fully adhere to the principles outlined in “Guideline for Good 
Clinical Practice” ICH Tripartite Guideline [January 1997] or with local law if it affords 
greater protection to the subject. For studies conducted in the USA or under US IND, 
the investigator will additionally ensure adherence to the basic principles of “Good 
Clinical Practice” as outlined in the current version of 21 CFR, subchapter D, part 312, 
“Responsibilities 
of 
Sponsors 
and 
Investigators”, 
part 
50, 
“Protection 
of 
Human Subjects”, and part 56, “Institutional Review Boards”.
In other countries where “Guideline for Good Clinical Practice” exists, Roche and the 
investigators will strictly ensure adherence to the stated provisions.
Patients who comply with the requirements of the protocol, are tolerating study treatment, 
and have not developed disease progression may be offered dosing beyond Cycle 1 at the 
investigator’s discretion after a careful assessment and thorough discussion of the 
potential risks and benefits of continued treatment with the patient. Such patients may 
have the option to continue RO8155426 in combination with cobimetinib for up to 1 year 
as long as the above-mentioned conditions are met. If the study is terminated 
(see Section 4.7), however, study drugs may not be offered after study termination.
12.2
Informed Consent 
Written Informed Consent from Subjects:
12.2.1
Main Study Informed Consent
It is the responsibility of the investigator, or a person designated by the investigator 
[if acceptable by local regulations], to obtain signed informed consent from each 
subject prior to participating in this study after adequate explanation of the aims, 
methods, anticipated benefits, and potential hazards of the study. 
The investigator or designee must also explain that the subjects are completely free to 
refuse to enter the study or to withdraw from it at any time, for any reason.  
The Case Report Forms (CRFs) for this study contain a section for documenting subject 
informed consent, and this must be completed appropriately.  If new safety information 
results in significant changes in the risk/benefit assessment, the consent form should be 
reviewed and updated if necessary. All subjects (including those already being treated) 
should be informed of the new information, given a copy of the revised form and give 
their consent to continue in the study.


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For the subject not qualified or incapable of giving legal consent, written consent must be 
obtained from the legally acceptable representative.  In the case where both the subject 
and his/her legally acceptable representative are unable to read, an impartial witness 
should be present during the entire informed consent discussion.  After the subject and 
representative have orally consented to participation in the trial, the witness’ signature on 
the form will attest that the information in the consent form was accurately explained and 
understood.  
For US-IND studies: In a life-threatening situation where a subject is unconscious or 
otherwise unable to communicate, the emergency is such that there is not enough time to 
obtain consent from the subject's legally acceptable representative, and there is no other 
or better treatment available, it is permissible to treat the subject under protocol with 
consent of both the investigator and another physician not involved in the study, with 
appropriate documentation submitted to the IRB within 5 days. If this collaboration is not 
immediately possible, there must be a written evaluation by a physician independent of 
the study and the appropriate documentation be submitted to the IRB within 5 days of 
treating the subject.    In addition, the subject or his/her legally acceptable representative 
should be informed about the trial as soon as possible and consent to continue, giving 
written consent as described above.
For non-US-IND studies: In a life-threatening situation where a subject is unconscious 
or otherwise unable to communicate, the emergency is such that there is not enough time 
to obtain consent from the subject's legally acceptable representative, and there is no 
other or better treatment available, it is permissible to treat the subject under protocol 
with consent of the investigator, with appropriate documentation that the IEC had 
approved the procedures used to enroll subjects in such situations.  In addition, 
the subject or his/her legally acceptable representative should be informed about the trial 
as soon as possible and consent to continue, giving written consent as described above.
12.2.2
Roche Clinical Repository Informed Consent
It is the responsibility of the investigator, or a person designated by the investigator 
(if acceptable under local regulations), to obtain written informed consent from each 
individual who has consented to have their samples stored long term for future research 
in the RCR after adequate explanation of the aims, methods, objectives and potential 
hazards. Subjects must receive an explanation that they are completely free to refuse long 
term storage of their samples for future research and may withdraw his/her sample at any 
time and for any reason during the 15 year storage period of the specimen(s). 
The Informed Consent for an optional long term storage of specimen(s) donation will be 
incorporated as a specific section into the main Clinical Trial [or Experimental Research 
study] Informed Consent Form (ICF). A second, separate, specific signature consenting 
to long term storage will be required to document the study participant’s agreement to 
provide an optional specimen for long-term storage of their samples for future research; 
if the participant declines, he/ she will check a “no” box in the appropriate section and 
not provide a second signature.
The CRF for the associated clinical study contains a page for documenting subject 
informed consent to the RCR, and this must be completed appropriately.


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12.2.3
Death or Loss of Competence of Participant who has Donated 
a Specimen(s) that is Stored in the Roche Clinical Repository
In case the Informed Consent Form and/or the Study Protocol do not provide any specific 
provisions for death or loss of competence, specimen and data will continue to be used as 
part of RCR research.
In the event of the death of a participant of a Roche Clinical Trial or Experimental 
Medicine Research study or if a participant is legally incompetent at the time of the 
specimen and data procurement, or becomes legally incompetent thereafter, applicable 
provisions as stated for such situations in the respective Informed Consent Form and/or 
the Study Protocol shall become effective and be followed accordingly.
Additional procurement of assent from legally incompetent persons and minors shall take 
place according to local laws and international best practice, as it applies to the specific
case 
12.3
Independent Ethics Committees (IEC)/Institutional Review 
Board (IRB) 
The protocol, informed consent and any accompanying material provided to the subject 
in the U.S. will be submitted by the investigator to an IRB for review.  For EEA member 
states, the sponsor will submit to the Competent Authority and IEC, the protocol and any 
accompanying material provided to the subject.  In both the US and EEA member states, 
the accompanying material may include subject information sheets, descriptions of the 
study used to obtain informed consent and terms of any compensation given to the 
subject as well as advertisements for the trial.
An approval letter or certificate (specifying the protocol number and title) from the 
IEC/IRB must be obtained before study initiation by the investigator specifying the date 
on which the committee met and granted the approval.  This applies whenever subsequent
amendments/modifications are made to the protocol.
Any modifications made to the protocol, informed consent or material provided to the 
subject after receipt of the IEC/IRB approval must also be submitted by the investigator 
in the U.S. and by the Sponsor in the EEA member states in accordance with local 
procedures and regulatory requirements.
When no local review board exists, the investigator is expected to submit the protocol to 
a regional committee.  If no regional committee exists, Roche will assist the investigator 
in submitting the protocol to the European Ethics Review Committee.
Long term storage of samples in the RCR is contingent on review and approval of the 
exploratory biomarker assessments and written informed consent by an appropriate 
regulatory body (depending on the country where the study is performed) and a site’s 
Institutional Review Board (IRB) / Ethics Committee (EC). If a regulatory authority or 
site’s IRB/EC do not approve the long term storage of samples for the exploratory 
assessments, the section on biomarker sampling will only be applicable for 5 year storage 
of samples.


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Roche shall also submit an Annual Safety Report once a year to the IEC and Competent 
Authorities (CAs) according to local regulatory requirements and timelines of each 
country participating in the study.  In the U.S. Roche submits an IND Annual Report to 
the FDA according to local regulatory requirements and timelines.
12.4
Role of the Science and Ethics Advisory Group (SEAG)
A Science and Ethics Advisory Group consisting of experts in the fields of biology, 
ethics, sociology and law will advise Roche regarding the use of specimens stored in the 
RCR and on the scientific and ethical aspects of handling genetic information. The SEAG 
is independent of Roche.
12.5
Financial Disclosure
The investigator(s) will provide the Sponsor with sufficient accurate financial 
information (PD35) to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities.  
The investigator is responsible to promptly update any information provided to the 
Sponsor if relevant changes occur in the course of the investigation and for 1 year 
following the completion of the study (last patient, last visit).
13.
CONDITIONS FOR MODIFYING THE PROTOCOL
Requests from investigators to modify the protocol to ongoing studies will be considered 
only by consultation between an appropriate representative of the sponsor and the 
investigator [investigator representative[s] in the case of a multicenter trial].  Protocol 
modifications must be prepared by a representative of the sponsor and initially reviewed 
and approved by the Clinical Science Leader/Clinical Pharmacologist and Biostatistician.
All protocol modifications must be submitted to the appropriate Independent Ethics 
Committee or Institutional Review Board for information and approval in accordance 
with local requirements, and to Regulatory Agencies if required. Approval must be 
obtained before any changes can be implemented, except for changes necessary to 
eliminate an immediate hazard to trial subjects, or when the change[s] involves only 
logistical or administrative aspects of the trial [e.g. change in monitor[s], change of 
telephone number[s].
14.
CONDITIONS FOR TERMINATING THE STUDY
Both the sponsor and the investigator reserve the right to terminate the study at any time.  
Should this be necessary, both parties will arrange the procedures on an individual study 
basis after review and consultation.  In terminating the study, Roche and the investigator 
will assure that adequate consideration is given to the protection of the patient’s interests. 
The appropriate Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
and Regulatory Agencies should be informed accordingly.


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15.
STUDY DOCUMENTATION, CRFS AND RECORD KEEPING
15.1
Investigator's Files / Retention of Documents
The Investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented and the study data to be subsequently verified. 
These documents
should be classified into two different separate categories: 
1) Investigator's Study File, and 2) subject clinical source documents.
The Investigator's Study File will contain the protocol/amendments, eCRF and schedule 
of assessments, Independent Ethics Committee/Institutional Review Board and 
governmental approval with correspondence, sample informed consent, drug records, 
staff 
curriculum 
vitae 
and 
authorization 
forms 
and 
other 
appropriate 
documents/correspondence, etc. In addition at the end of the study the investigator will 
receive the subject data, which includes an audit trail containing a complete record of all 
changes to data, query resolution correspondence and reasons for changes, in human 
readable format on CD which also has to be kept with the Investigator’s Study File.
Subject clinical source documents [usually defined by the project in advance to record 
key efficacy/safety parameters independent of the eCRFs] would include subject 
hospital/clinic records, physician's and nurse's notes, appointment book, original 
laboratory reports, ECG, electroencephalogram, X-ray, pathology and special assessment 
reports, signed informed consent forms, consultant letters, and subject screening and 
enrollment logs. The Investigator must keep the two categories of documents as 
described above (including the archival CD) on file for at least 15 years after completion 
or discontinuation of the study. After that period of time the documents may be 
destroyed, subject to local regulations.
Should the Investigator wish to assign the study records to another party or move them to 
another location, Roche must be notified in advance.
If the Investigator can not guarantee this archiving requirement at the investigational site 
for any or all of the documents, special arrangements must be made between the 
Investigator and Roche to store these in a sealed container[s] outside of the site so that 
they can be returned sealed to the Investigator in case of a regulatory audit. Where source 
documents are required for the continued care of the subject, appropriate copies should be 
made for storing outside of the site.
ICH GCP guidelines require that Investigators maintain information in the study subject’s 
records which corroborate data collected on the eCRF(s).  Completed eCRF will be 
forwarded to Roche.
15.2
Source Documents and Background Data
The investigator shall supply the sponsor on request with any required background data 
from the study documentation or clinic records. This is particularly important when errors 
in data transcription are suspected. In case of special problems and/or governmental 
queries or requests for audit inspections, it is also necessary to have access to the 
complete study records, provided that subject confidentiality is protected.


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15.3
Audits and Inspections
The investigator should understand that source documents for this trial should be made 
available to appropriately qualified personnel from the Roche Pharma Development 
Quality Assurance Unit or its designees, or to health authority inspectors after appropriate 
notification. The verification of the CRF data must be by direct inspection of source 
documents.
15.4
Case Report Forms or Electronic Case Report Forms  
Data for this study will be captured directly onto the electronic case report form (eCRF) 
after logging onto the secure InForm database which is web based. An audit trail will 
maintain a record of initial entries and changes made; reasons for change; time and date 
of entry; and user name of person authorizing entry or change. 
For each subject enrolled, an eCRF must be completed and electronically signed by the 
principal investigator or authorized delegate from the study staff. This also applies to 
records for those subjects who fail to complete the study [even during a 
pre-randomization screening period if an eCRF was initiated]. If a subject withdraws 
from the study, the reason must be noted on the eCRF. If a subject is withdrawn from the 
study because of a treatment-limiting AE, thorough efforts should be made to clearly 
document the outcome.
The investigator should ensure the accuracy, completeness and timeliness of the data 
reported to the sponsor in the eCRFs and in all required reports.
16.
MONITORING THE STUDY
It is understood that the responsible Roche monitor [or designee] will contact and visit 
the investigator regularly and will be allowed, on request, to inspect the various records 
of the trial [CRFs and other pertinent data] provided that subject confidentiality is 
maintained in accord with local requirements.
It will be the monitor's responsibility to inspect the CRFs at regular intervals throughout 
the study, to verify the adherence to the protocol and the completeness, consistency and 
accuracy of the data being entered on them. The monitor must verify that the subject 
received the dose and schedule of study drugs assigned. The monitor should have access 
to laboratory test reports and other subject records needed to verify the entries on the 
CRF. The investigator [or deputy] agrees to cooperate with the monitor to ensure that any 
problems detected in the course of these monitoring visits are resolved.
Roche Clinical Repository specimens will at all times be tracked in a manner consistent 
with Good Clinical Practice, by a quality controlled, auditable and validated Laboratory 
Information Management System, to ensure compliance with data confidentiality as well 
as adherence to authorized use of specimens as specified in the study protocol and ICF, 
respectively. Roche monitors and auditors will have direct access to appropriate parts of 
records relating to subjects participating in this study for the purposes of verifying the 
data provided to Roche. The site will permit monitoring, audits, Institutional Review 
Board/Independent Ethics Committee (IRB/IEC) review, and regulatory inspections by 
providing direct access to source data and documents related to the RCR Research 
Project.


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17.
CONFIDENTIALITY OF TRIAL DOCUMENTS AND SUBJECT 
RECORDS
The investigator must assure that subjects’ anonymity will be maintained and that their 
identities are protected from unauthorized parties. On CRFs or other documents 
submitted to the sponsor, subjects should not be identified by their names, but by an 
identification code. The investigator should keep a subject enrollment log showing codes, 
names and addresses.
The investigator should maintain documents not for submission to Roche, e.g., Roche 
already maintains rigorous confidentiality standards for clinical studies by “coding” 
(i.e. assigning a unique subject ID number at the investigator site) all subjects enrolled in 
Roche clinical studies.  This means that subject names are not included in data sets that 
are transmitted to any Roche location. Given the sensitive nature of genetic data, Roche 
has implemented a number of additional processes to assure subject confidentiality.  
All specimens taken for inherited genetic research that will be stored in the RCR 
(see Section 5.5.1) undergo a second level of “coding”. At Roche, the specimen is 
transferred to a new tube and labeled with a new random number. This is referred to as 
“Double Coding (De-Identification)”. Data generated following the use of these 
specimens and all clinical data transferred from the clinical study database and 
considered relevant, will also be labeled with this same code. The “linking key” between 
the participant’s identification number and this new independent code will be stored in a 
secure database system. Access to the table linking the participant identification number 
to the specimen code will be strictly limited and monitored by audit trial. Legitimate 
operational reasons for accessing the “linking key” will be documented in a standard 
operating procedure. Access to the “linking key” for any other reason will require written 
approval from the Governance Committee responsible for the specimen(s).
18.
CLINICAL STUDY REPORT (CSR)
A clinical study report has been written and distributed to Health Authorities as required 
by applicable regulatory requirements.  
19.
PUBLICATION OF DATA AND PROTECTION OF TRADE SECRETS
Roche will comply with the requirements for publication of study results.
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 Roche 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.  
In accordance with standard editorial and ethical practice, Roche will generally support 
publication of multicenter trials only in their entirety and not as individual center data. In 
this case, a coordinating investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors (ICMJE) authorship requirements.  Any formal 
publication of the study in which input of Roche personnel exceeded that of conventional 


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monitoring will be considered as a joint publication by the investigator and the 
appropriate Roche personnel. 
Data derived from RCR specimen analysis on individual subjects will not be provided to 
study investigators, except where explicitly stipulated in a study protocol (e.g. if the 
result is an enrollment criterion). Exceptions may be granted (e.g. if biomarker data 
would be linked to safety issues). 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 will become and remain the exclusive and unburdened property of 
Roche, except where agreed otherwise. 


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Appendix 1:
New Response Evaluation Criteria in Solid Tumors –
Version 1.1–Excerpt From Original Publication with Addition 
of Supplementary Explanations (Eisenhauer et al. 2009)
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 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. 
Special Considerations Regarding Lesion Measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment: 
Bone lesions:
Bone scan, 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. 


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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 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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Supplementary Explanations (Eisenhauer et al. 2009) (Cont.)
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). For the 
case of skin lesions, documentation by color photography including a ruler to estimate the 
size of the lesion is suggested. 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 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. 


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Endoscopy, laparoscopy: The utilization of these techniques for objective tumor 
evaluation is not advised. However, they can be useful to conﬁrm complete pathological 
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 CA125 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 PR and 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 Section. 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. 


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Appendix 1: New Response Evaluation Criteria in Solid Tumors –
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Supplementary Explanations (Eisenhauer et al. 2009) (Cont.)
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.
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 which 
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 x 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. 


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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’). 
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 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. 


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Supplementary Explanations (Eisenhauer et al. 2009) (Cont.)
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 assign(Cohorts 1C and 1D)ing 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 case report form:
If it is the opinion of the radiologist that the lesion has likely disappeared, the 
measurement should be recorded as 0 mm.
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. 


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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). 
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. 


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Appendix 1: New Response Evaluation Criteria in Solid Tumors –
Version 1.1–Excerpt From Original Publication with Addition of 
Supplementary Explanations (Eisenhauer et al. 2009) (Cont.)
When the patient has only non-measurable disease: this circumstance arises in some 
Phase 3 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). 
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. 


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Appendix 1: New Response Evaluation Criteria in Solid Tumors –
Version 1.1–Excerpt From Original Publication with Addition of 
Supplementary Explanations (Eisenhauer et al. 2009) (Cont.)
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. 
(18)F-Fluorodeoxyglucose Positron Emission Tomography (FDG-PET)
While FDG-PET response assessments need additional study, it is sometimes reasonable 
to incorporate the use of FDG-PET scanning to complement CT scanning in assessment 
of progression (particularly possible ‘new’ disease). New lesions on the basis of 
FDG-PET imaging can be identiﬁed according to the following algorithm: 
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion. 
No FDG-PET at baseline and a positive FDG-PET at follow-up:
o
If the positive FDG-PET at follow-up corresponds to a new site of disease 
conﬁrmed by CT, this is PD.
o
If the positive FDG-PET at follow-up is not conﬁrmed as a new site of disease on 
CT, additional follow-up CT scans are needed to determine if there is truly 
progression occurring at that site (if so, the date of PD will be the date of the 
initial abnormal FDG-PET scan).
o
If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease 
on CT that is not progressing on the basis of the anatomic images, this is not PD. 
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. 


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Appendix 1: New Response Evaluation Criteria in Solid Tumors –
Version 1.1–Excerpt From Original Publication with Addition of 
Supplementary Explanations (Eisenhauer et al. 2009) (Cont.)
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 time point, a response assessment occurs. 
Table 1 provides a summary of the overall response status calculation at each time point 
for patients who have measurable disease at baseline.
When patients have non-measurable (therefore non-target) disease only, Table 2 is to be 
used. 


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Appendix 1: New Response Evaluation Criteria in Solid Tumors –
Version 1.1–Excerpt From Original Publication with Addition of 
Supplementary Explanations (Eisenhauer et al. 2009) (Cont.)
Missing Assessments and Not-Evaluable Designation 
When no imaging/measurement is done at all at a particular time point, the patient is not 
evaluable at that time point. If only a subset of lesion measurements are made at an 
assessment, usually the case is also considered not evaluable at that time point, unless a 
convincing argument can be made that the contribution of the individual missing lesion(s) 
would not change the assigned time point response. This would be most likely to happen 
in the case of PD. 
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 time point.
Best Overall Response: All Timepoints
The best overall response will be determined by statistical programming once all the data 
for the patient is known.


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Appendix 2:
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 Am. J. Clin. Oncol.:  Oken, M.M.,  Creech, R.H.,  Tormey, D.C.,  Horton, J.,  Davis, 
T.E.,  McFadden, E.T.,  Carbone, P.P.: Toxicity and Response Criteria of the Eastern Cooperative 
Oncology Group.  Am J Clin Oncol 5: 649–655, 1982.


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Appendix 3:
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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Appendix 4:
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 5:
AJCC TNM Staging for Melanoma
Tumor (T) classification
TX
Primary tumor cannot be assessed (e.g., shave biopsy, regressed primary)
Tis
Melanoma in situ
T1
< or = 1.0 mm
a: without ulceration and level II/III*
b: with ulceration or level IV or V*
T2
1.01-2.0 mm
a: without ulceration
b: with ulceration
T3
2.01-4.0 mm
a: without ulceration
b: with ulceration
T4
>4.0 mm
a: without ulceration
b: with ulceration
Node (N) classification
N1
One lymph node
a: micrometastases (clinically occult)
b: macrometastases (clinically apparent)
N2
2-3 lymph nodes
a: micrometastases
b: macrometastases
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 6:
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 7:
Plasma Pharmacokinetic Sample Collection Schedule for 
Patients Previously Treated with Vemurafenib a,b
Study Visit
Time
Event
Cycle 1, Day -1
0-4 hours before vemurafenib AM dose. Record exact 
time of vemurafenib dose administration
Plasma sample for 
vemurafenib
2 hours (15 minutes) after vemurafenib morning 
dose
Plasma sample for 
vemurafenib
4 hours (30 min) after vemurafenib morning dose
Plasma sample for 
vemurafenib
6 hours (1 hour) after vemurafenib morning dose
Plasma sample for 
vemurafenib
8 hours (1 hour) after vemurafenib morning dose
Plasma sample for 
vemurafenib
Cycle 1, Day 1
0-4 hours before cobimetinib dose. Record exact time
of cobimetinib dose administration
Plasma sample for 
cobimetinib and 
vemurafenib
0.5 hour (10 minutes) after cobimetinib dose
Plasma sample for 
cobimetinib
1 hour (15 minutes) after cobimetinib dose
Plasma sample for 
cobimetinib
2 hours (15 minutes) after cobimetinib dose
Plasma sample for 
cobimetinib
4 hours (1 hour) after cobimetinib dose
Plasma sample for 
cobimetinib
6 hours (1 hour) after cobimetinib dose
Plasma sample for 
cobimetinib
Cycle 1, Day 2
0-2 hours before the second cobimetinib
dose 
(24 hours from first dose of cobimetinib) Record exact 
time of cobimetinib dosing 
Plasma sample for 
cobimetinib and
vemurafenib
Cycle 1, Day 8
0-4 hours before cobimetinib and vemurafenib dose. 
Record exact time of dosing
Plasma sample for 
cobimetinib and
vemurafenib
Cycle 1, Day 14
0-4 hours before cobimetinib and vemurafenib dose. 
Record exact time of dosing
Plasma sample for 
cobimetinib and
vemurafenib
0.5 hour (10 minutes) after cobimetinib dose
Plasma sample for 
cobimetinib and 
vemurafenib
1 hour (15 minutes) after cobimetinib dose
Plasma sample for 
cobimetinib and
vemurafenib


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Appendix 7: Plasma Pharmacokinetic Sample Collection Schedule for 
Patients Previously Treated with Vemurafenib a,b (Cont.)
Study Visit
Time
Event
2 hours (15 minutes) after cobimetinib dose
Plasma sample for cobimetinib
and vemurafenib
4 hours (1 hour) after cobimetinib dose
Plasma sample for cobimetinib 
and  vemurafenib
6 hours (1 hour) after cobimetinib dose
Plasma sample for cobimetinib 
and vemurafenib
8 hours (1 hour) after cobimetinib dose
Plasma sample for cobimetinib 
and vemurafenib
Cycle 
1, 
Day 15
0-2 hours before vemurafenib dose 
Plasma sample for cobimetinib 
and vemurafenib
Cycle 
1, 
Day 16a
0-2 hours before vemurafenib dose (48 hours from 
Day 14 dose of cobimetinib)
Plasma sample for cobimetinib 
and vemurafenib
Cycle 
1, 
Day 17a
0-2 hours before vemurafenib dose (72 hours from 
Day 14 dose of cobimetinib)
Plasma sample for cobimetinib 
and vemurafenib
Cycle 
2, 
Day 1
0-4 hours before cobimetinib dose
Record exact time of cobimetinib dosing.
Plasma sample for cobimetinib
Cycle 
2, 
Day 8
0-4 hours before cobimetinib dose
Record exact time of cobimetinib dosing.
Plasma sample for cobimetinib 
and vemurafenib
Cycle 
2, 
Day 8
2-4 hours after cobimetinib dose
Record exact time of cobimetinib dosing for Day 8 of 
Cycle 2.
Plasma sample for cobimetinib 
and vemurafenib
Cycle 
3, 
Day 8
0-4 hours before cobimetinib dose
Record exact time of cobimetinib dosing.
Plasma sample for cobimetinib 
and vemurafenib
a Vemurafenib plasma levels samples shall be collected on Days 16 and 17 of C1 only when cobimetinib
is given on a 14/14 schedule
b Patients on cobimetinib monotherapy will undergo PK sampling based on their assigned cobimetinib
dosing schedule. 


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Appendix 8:
Plasma Pharmacokinetic Sample Collection Schedule for 
Patients Either Previously Untreated or Treated (but without 
Exposure to BRAF or MEK Inhibitor Therapy) for Locally
Advanced/Unresectable or Metastatic Melanomaa
Study Visit
Time
Event
Cycle 1, Day 1
0-2 hours before cobimetinib and vemurafenib 
AM dose. Record exact time of cobimetinib and 
vemurafenib dose administration. 
Plasma sample for cobimetinib and 
vemurafenib
0.5 hour (10 minutes) after morning dose
Plasma sample for cobimetinib and 
vemurafenib
1 hour (15 minutes) after morning dose
Plasma sample for cobimetinib and 
vemurafenib
2 hours (15 minutes) after morning dose
Plasma sample for cobimetinib and 
vemurafenib
4 hours (1 hour) after morning dose
Plasma sample for cobimetinib and 
vemurafenib
6 hours (1 hour) after morning dose
Plasma sample for cobimetinib and 
vemurafenib
Cycle 1, Day 2
0-2 hours before the second cobimetinib dose 
(24 hours from first dose of cobimetinib) Record 
exact time of cobimetinib dosing
Plasma sample for cobimetinib and 
vemurafenib
Cycle 1, Day 8
0-4 hours before cobimetinib and vemurafenib 
dose.
Record exact time of dosing
Plasma sample for cobimetinib and 
vemurafenib
Cycle 1, Day 14
0-4 hours before cobimetinib and vemurafenib 
dose.
Record exact time of dosing
Plasma sample for cobimetinib and 
vemurafenib
0.5 hour (10 minutes) after morning dose of 
vemurafenib and cobimetinib
Plasma sample for cobimetinib and
vemurafenib
1 hour (15 minutes) after morning dose of 
vemurafenib and cobimetinib
Plasma sample for cobimetinib and 
vemurafenib
2 hours (15 minutes) after morning dose of 
vemurafenib and cobimetinib
Plasma sample for cobimetinib and 
vemurafenib
4 hours (1 hour) after morning dose of 
vemurafenib and cobimetinib
Plasma sample for cobimetinib and 
vemurafenib


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Appendix 8: Plasma Pharmacokinetic Sample Collection Schedule for 
Patients Either Previously Untreated or Treated (but without Exposure to 
BRAF and MEK Inhibitor Therapy for Locally Advanced/Unresectable or 
Metastatic Melanoma (Cont.) a
Study Visit
Time
Event
6 hours (1 hour) after morning dose of 
vemurafenib and cobimetinib
Plasma sample for cobimetinib and 
vemurafenib
8 hours (1 hour) after morning dose of 
vemurafenib and cobimetinib
Plasma sample for cobimetinib and 
vemurafenib
Cycle 1, Day 15
0-2 hours before cobimetinib dose (24 hours 
from Day 14 dose of cobimetinib)
Plasma sample for cobimetinib and 
vemurafenib
Cycle 1, Day 16a
0-2 hours before vemurafenib dose (48 hours 
from Day 14 dose of cobimetinib)
Plasma sample for cobimetinib and  
vemurafenib
Cycle 1, Day 17b
0-2 hours before vemurafenib dose (72 hours 
from Day 14 dose of cobimetinib)
Plasma sample for cobimetinib and  
vemurafenib
Cycle 2, Day 1
0-4 hours before cobimetinib dose
Record exact time of cobimetinib dosing.
Plasma sample for cobimetinib
Cycle 2, Day 8
0-4 hours before cobimetinib dose
Record exact time of cobimetinib dosing for 
Day 7 and Day 8 of Cycle 2.
Plasma sample for cobimetinib and 
vemurafenib
Cycle 2, Day 8
2-4 hours after cobimetinib dose 
Record exact time of cobimetinib dosing for 
Day 8 of Cycle 2.
Plasma sample for cobimetinib and 
vemurafenib
Cycle 3, Day 8
0-2 hours before cobimetinib dose Record 
exact time of cobimetinib dosing for Day 7 
and Day 8 of Cycle 2.
Plasma sample for cobimetinib and 
vemurafenib
a Vemurafenib plasma levels samples shall be collected on Days 16 and 17 of Cycle 1 only when 
cobimetinib is given on a 14/14 schedule.


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Appendix 9:
Cobas® 4800 BRAF V600 Mutation Assay Information
The cobas® 4800 BRAF V600 Mutation Assay is a real-time polymerase chain reaction 
(PCR) test intended to be used to identify melanoma patients whose tumors carry the 
BRAFV600E mutation for treatment with vemurafenib monotherapy. Its primary use is the 
detection of the BRAFV600E
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 1 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 BRAFV600E 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 2 and Phase 3 clinical 
trials of vemurafenib in locally-advanced/uresectable 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. 


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Appendix 10: Impact of Vemurafenib on Concomitant Medications


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Appendix 10:
Impact of Vemurafenib on Concomitant Medications (Cont.)


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Protocol NO25395     Report Number 1087965
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Protocol NO25395 Version L: vemurafenib and cobimetinib - F. Hoffmann-La Roche Ltd
CONFIDENTIAL
177
Appendix 10:
Impact of Vemurafenib on Concomitant Medications (Cont.)
1 Exposure of these drugs may be increased following vemurafenib treatment. 
2 Exposure of these drugs may be decreased following vemurafenib treatment.