Clinical trial NCT02639546
Conditions: Solid Tumors
Sponsor: Hoffmann-La Roche
Start date: 2016-05-20; Completion date: 2021-07-21
Enrollment: 56 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This open-label, dose-escalation study is designed to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of cobimetinib in pediatric and young adult participants with solid tumors with known or potential kinase pathway activation for which standard therapy has proven to be ineffective or intolerable or for which no curative standard-of-care treatment options exist. The study will be conducted in two stages: a dose-escalation stage and an expansion stage at the recommended dose.

Detailed description:

Arms: arm 1: Dose-Escalation: Participants received 0.6 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle. arm 2: Dose-Escalation: Participants received 0.8 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle. arm 3: Dose-Escalation: Participants received 1 milligram per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle. arm 4: Dose-Escalation: Participants received 0.6 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle. arm 5: Dose-Escalation: Participants received 0.8 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle. arm 6: Dose-Escalation: Participants received 1 milligram per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle. arm 7: Dose-Escalation: Participants received 1.33 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle. arm 8: Dose-Expansion: Participants received 1 milligram per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.
Interventions: intervention 1: Cobimetinib
Intervention descriptions: intervention 1: Cobimetinib tablet or suspension will be administered as per the schedule described in arm description.

Protocol documents:
Prot_SAP_000.pdf: 
 
Official Title: A Phase I/II, Multicenter, Open-Label, Dose-Escalation Study of the 
Safety and Pharmacokinetics of Cobimetinib in Pediatric and Young 
Adult Patients With Previously Treated Solid Tumors 
NCT Number: NCT02639546 
Document Date: Protocol Version 11: 11-April-2019 
 
 
 




Cobimetinib—F. Hoffmann-La Roche Ltd
2/Protocol GO29665, Version 11
PROTOCOL AMENDMENT, VERSION 11:
RATIONALE
Protocol GO29665 has been amended primarily to reduce the frequency of tumor 
assessments (i.e. MRI scans) and ophthalmologic examinations (i.e. optical coherence 
tomography [OCT]) for patients with indolent tumor types (Low-Grade Glioma, Plexiform 
Neurofibroma) who have received long-term study therapy.  Changes to the protocol, 
along with a rationale for each change, are summarized below:

Section 4.5.5 and Appendix 1 have been updated to reduce the frequency of tumor 
assessments for patients who have completed at least 12 cycles of cobimetinib 
therapy and who do not meet criteria for progressive disease to reduce the burden 
of undergoing regular imaging studies (including radiation exposure in those 
patients followed by CT scan).

Plasma samples collection (Appendix 1) has been updated to align with the new 
tumor assessments schedule (amended to reduce frequency, as stated in bullet 
above). 

Section 4.5.6 and Appendix 1 have been updated to reduce the frequency of 
ophthalmologic examinations for patients who have completed 6 cycles of 
cobimetinib therapy and who have not developed retinal pathology or other Adverse 
Events (AEs) involving the retina because retinopathy events typically occur very 
early in the treatment course of cobimetinib. As noted in the Investigator’s Brochure, 
the median time to initial onset of serous retinopathy was 1 month (range: 
09 months), so patients who are tolerating study drug without retinal AEs require 
less frequent evaluation.

Section 5.2.3 has been updated to exclude epistaxis grade 1 (defined by National 
Cancer Institute Common Terminology Criteria for Adverse Events [CTCAE v4.0]
criteria as “Mild symptoms; intervention not indicated”) from the AESI (Adverse 
Event Special of Interest) reporting requirement for hemorrhage events. Minor 
nosebleeds that do not require medical intervention are common in children and are 
not consistent with the common understanding of the term 'hemorrhage' that would 
warrant expedited reporting to the Sponsor. Grade 1 epistaxis will still be reportable 
as an AE.

Appendix 1 (Schedule of Assessments) and footnote f have been updated to clarify
blood sample collection requirement for patients who consented to the optional on-
study biopsy for exploratory research.

Corrections of typographical errors have been made to Appendix 10 dosing tables: 
Dose level 31mg/kg, suspension (4.8 mg/mL) and Dose Level 1 (Minus 
One)0.45 mg/kg/day, Suspension (4.8 mg/mL).

Language has been updated to indicate that Visual Acuity should be reported in
Snellen units (Section 4.5.6).
Additionally, standard protocol updates were made to update or clarify reporting of 
adverse events (Sections 5.3.5.7, 5.3.5.10, and 5.4.3.3), protocol deviations processes


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(Section 9.2), and to align with Roche standard operating procedures and policies
(Sections 4.5.9, 4.5.11.6, 7.5, and 8.1).  Furthermore, minor changes have been made 
to improve clarity and consistency. Substantive new information appears in italics. This 
amendment represents cumulative changes to the original protocol.


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TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 11
PROTOCOL SYNOPSIS .................................................................................... 12
1.
BACKGROUND .......................................................................................... 24
1.1
RAS/RAF/MEK/ERK Pathway and Cancer............................ 24
1.2
Background on Cobimetinib................................................... 27
1.2.1
Nonclinical Studies with Cobimetinib ..................................... 27
1.2.2
Clinical Studies with Cobimetinib........................................... 29
1.2.2.1
Clinical Pharmacokinetics...................................................... 29
1.2.2.2
Clinical Safety........................................................................ 29
1.2.2.3
Clinical Efficacy ..................................................................... 30
1.2.2.4
Approved Indications ............................................................. 30
1.3
Study Rationale and Benefit-Risk Assessment...................... 31
1.3.1
Rationale for Inclusion of Patients with Brain 
Tumors .................................................................................. 31
2.
OBJECTIVES.............................................................................................. 32
2.1
Safety Objective .................................................................... 32
2.2
Pharmacokinetic Objective .................................................... 32
2.3
Efficacy Objective .................................................................. 32
2.4
Dose-Finding Objective ......................................................... 32
2.5
Exploratory Objectives........................................................... 33
3.
STUDY DESIGN......................................................................................... 33
3.1
Description of Study .............................................................. 33
3.1.1
Dose-Escalation Stage .......................................................... 34
3.1.1.1
Definition of Dose-Limiting Toxicity........................................ 36
3.1.1.2
Dose-Escalation Rules .......................................................... 38
3.1.2
Expansion Stage ................................................................... 41
3.1.3
Internal Monitoring Committee and Scientific 
Oversight Committee............................................................. 43
3.2
End of Study.......................................................................... 44
3.3
Rationale for Study Design.................................................... 45


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3.3.1
Rationale for Cobimetinib Dose and Schedule ...................... 45
3.3.1.1
Rationale for Tablet and Suspension Dosing 
Strategy ................................................................................. 45
3.3.2
Rationale for Patient Population ............................................ 46
3.3.3
Rationale for Biomarker Assessments................................... 47
3.4
Outcome Measures ............................................................... 47
3.4.1
Safety Outcome Measures .................................................... 47
3.4.2
Pharmacokinetic Outcome Measure...................................... 48
3.4.3
Efficacy Outcome Measures.................................................. 48
3.4.4
Exploratory Outcome Measures ............................................ 48
4.
MATERIALS AND METHODS .................................................................... 49
4.1
Patients.................................................................................. 49
4.1.1
Inclusion Criteria.................................................................... 49
4.1.2
Exclusion Criteria................................................................... 52
4.2
Method of Treatment Assignment and Blinding..................... 54
4.3
Study Treatment.................................................................... 54
4.3.1
Formulation, Packaging, and Handling.................................. 54
4.3.1.1
Cobimetinib Tablet Formulation............................................. 55
4.3.1.2
Cobimetinib Suspension Formulation .................................... 55
4.3.2
Dosage, Administration, and Compliance.............................. 55
4.3.3
Investigational Medicinal Product Accountability ................... 57
4.3.4
Post-Trial Access to Cobimetinib........................................... 57
4.4
Concomitant Therapy and Food ............................................ 58
4.4.1
Permitted Therapy................................................................. 58
4.4.2
Prohibited Therapy ................................................................ 59
4.4.3
Prohibited Food and Supplements ........................................ 60
4.5
Study Assessments ............................................................... 60
4.5.1
Informed Consent Forms and Screening Log........................ 60
4.5.2
Medical History and Demographic Data ................................ 61
4.5.3
Physical Examinations and Assessments.............................. 61
4.5.4
Vital Signs.............................................................................. 61
4.5.5
Tumor and Response Evaluations......................................... 62
4.5.6
Ophthalmologic Examinations ............................................... 63


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4.5.7
Cardiac Function Monitoring.................................................. 63
4.5.8
Dermatologic Examinations................................................... 63
4.5.9
Laboratory, Biomarker, and Other Biological 
Samples................................................................................. 64
4.5.10
Acceptability Survey .............................................................. 66
4.5.11
Samples for Roche Clinical Repository.................................. 66
4.5.11.1
Overview of the Roche Clinical Repository............................ 66
4.5.11.2
Approval by the Institutional Review Board or 
Ethics Committee .................................................................. 67
4.5.11.3
Sample Collection.................................................................. 67
4.5.11.4
Confidentiality........................................................................ 68
4.5.11.5
Consent to Participate in the Roche Clinical 
Repository ............................................................................. 68
4.5.11.6
Withdrawal from the Roche Clinical Repository..................... 68
4.5.11.7
Monitoring and Oversight....................................................... 69
4.6
Patient, Treatment, Study, and Site 
Discontinuation...................................................................... 69
4.6.1
Patient Discontinuation.......................................................... 69
4.6.2
Study Drug Discontinuation ................................................... 70
4.6.3
Study and Site Discontinuation.............................................. 71
5.
ASSESSMENT OF SAFETY....................................................................... 71
5.1
Safety Plan ............................................................................ 71
5.1.1
Management of Specific Adverse Events .............................. 72
5.1.2
Risks Associated with Cobimetinib........................................ 76
5.1.2.1
Important Identified Risks Associated with 
Cobimetinib............................................................................ 76
5.1.2.2
Potential Risks Associated with Cobimetinib ......................... 80
5.1.2.3
Other Risks Associated with Cobimetinib .............................. 81
5.2
Safety Parameters and Definitions ........................................ 83
5.2.1
Adverse Events ..................................................................... 84
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 84
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................... 85


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5.2.4
Dose-Limiting Toxicities (Immediately Reportable 
to the Sponsor)...................................................................... 85
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 86
5.3.1
Adverse Event Reporting Period ........................................... 86
5.3.2
Eliciting Adverse Event Information....................................... 86
5.3.3
Assessment of Severity of Adverse Events ........................... 86
5.3.4
Assessment of Causality of Adverse Events ......................... 87
5.3.5
Procedures for Recording Adverse Events............................ 88
5.3.5.1
Diagnosis versus Signs and Symptoms................................. 88
5.3.5.2
Adverse Events That Are Secondary to Other 
Events.................................................................................... 89
5.3.5.3
Persistent or Recurrent Adverse Events................................ 89
5.3.5.4
Abnormal Laboratory Values ................................................. 90
5.3.5.5
Abnormal Vital Sign Values ................................................... 90
5.3.5.6
Abnormal Liver Function Tests.............................................. 91
5.3.5.7
Deaths ................................................................................... 91
5.3.5.8
Preexisting Medical Conditions.............................................. 92
5.3.5.9
Lack of Efficacy or Worsening of Cancer............................... 92
5.3.5.10
Hospitalization or Prolonged Hospitalization.......................... 92
5.3.5.11
Adverse Events Associated with an Overdose or 
Error in Drug Administration .................................................. 93
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 93
5.4.1
Emergency Medical Contacts................................................ 94
5.4.2
Reporting Requirements for Serious Adverse 
Events, Adverse Events of Special Interest, and 
Dose-Limiting Toxicities......................................................... 94
5.4.2.1
Events That Occur prior to Study Drug Initiation.................... 94
5.4.2.2
Events That Occur after Study Drug Initiation........................ 94
5.4.3
Reporting Requirements for Pregnancies.............................. 95
5.4.3.1
Pregnancies in Female Patients............................................ 95
5.4.3.2
Pregnancies in Female Partners of Male Patients................. 95
5.4.3.3
Abortions ............................................................................... 95
5.4.3.4
Congenital Anomalies/Birth Defects ...................................... 96


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5.5
Follow-Up of Patients after Adverse Events .......................... 96
5.5.1
Investigator Follow-Up........................................................... 96
5.5.2
Sponsor Follow-Up ................................................................ 96
5.6
Post-Study Adverse Events................................................... 96
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees................................................................. 97
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 97
6.1
Determination of Sample Size ............................................... 97
6.2
Summaries of Conduct of Study............................................ 98
6.3
Safety Analyses..................................................................... 98
6.4
Pharmacokinetic Analyses..................................................... 99
6.5
Efficacy Analyses .................................................................. 99
6.5.1
Primary Efficacy Endpoints.................................................... 99
6.5.2
Secondary Efficacy Endpoints............................................. 100
6.6
Exploratory Analyses........................................................... 100
6.6.1
Biomarker Analyses............................................................. 100
6.6.2
Acceptability Survey ............................................................ 101
6.7
Interim Analyses .................................................................. 101
6.7.1
Planned Interim Analyses.................................................... 101
6.7.2
Optional Interim Analyses.................................................... 101
7.
DATA COLLECTION AND MANAGEMENT ............................................. 101
7.1
Data Quality Assurance....................................................... 101
7.2
Electronic Case Report Forms............................................. 102
7.3
Source Data Documentation................................................ 102
7.4
Use of Computerized Systems ............................................ 103
7.5
Retention of Records........................................................... 103
8.
ETHICAL CONSIDERATIONS.................................................................. 103
8.1
Compliance with Laws and Regulations .............................. 103
8.2
Informed Consent................................................................ 104
8.3
Institutional Review Board or Ethics Committee.................. 104
8.4
Confidentiality...................................................................... 105
8.5
Financial Disclosure ............................................................ 105


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9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 106
9.1
Study Documentation .......................................................... 106
9.2
Protocol Deviations.............................................................. 106
9.3
Site Inspections ................................................................... 106
9.4
Administrative Structure....................................................... 106
9.5
Publication of Data and Protection of Trade 
Secrets ................................................................................ 107
9.6
Protocol Amendments ......................................................... 108
10. REFERENCES ......................................................................................... 109
LIST OF TABLES
Table 1
Dose Determination for the Next Patient in Rolling 6 Design...... 40
Table 2
Guidelines for Management of Specific Adverse Events ............ 73
Table 3
Guidelines for Management of Asymptomatic Reduction in 
Left Ventricular Ejection Fraction ................................................ 79
Table 4
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................... 87
Table 5
Causal Attribution Guidance ....................................................... 88
Table 6
Sample Size and Responder Requirements for Initial 
Response Assessment ............................................................... 98
LIST OF FIGURES
Figure 1
Study Schema:  Dose-Escalation Stage ..................................... 36
Figure 2
Study Schema:  Expansion Stage............................................... 43
LIST OF APPENDICES
Appendix 1
Schedule of Assessments......................................................... 114
Appendix 2
Schedule of Pharmacokinetic and Pharmacodynamic 
Assessments............................................................................. 119
Appendix 3
Modified International Neuroblastoma Response Criteria......... 120
Appendix 4
Response Assessment in Neuro-Oncology Criteria for 
High-Grade Glioma................................................................... 124


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Appendix 5
Response Assessment in Neuro-Oncology Criteria for 
Low-Grade Glioma.................................................................... 126
Appendix 6
Response Evaluation Criteria in Solid Tumors:  Modified 
Excerpt from Original Publication.............................................. 128
Appendix 7
Lansky Performance Status Scale (Patients 16 Years of 
Age) .......................................................................................... 140
Appendix 8
Karnofsky Performance Status Scale (Patients ≥16 Years of 
Age) .......................................................................................... 141
Appendix 9
Acceptability Survey for Patients............................................... 142
Appendix 10
Dosing Tables for Cobimetinib.................................................. 145
Appendix 11
List of Moderate and Strong CYP3A Inducers and Inhibitors 
That Are to Be Excluded in Dose Escalation Patients When 
Determining MTD...................................................................... 155


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PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
A PHASE I/II, MULTICENTER, OPEN-LABEL, 
DOSE-ESCALATION STUDY OF THE SAFETY AND 
PHARMACOKINETICS OF COBIMETINIB IN PEDIATRIC 
AND YOUNG ADULT PATIENTS WITH PREVIOUSLY
TREATED SOLID TUMORS
PROTOCOL NUMBER:
GO29665
VERSION NUMBER:
11
EUDRACT NUMBER:
2014-004685-25
IND NUMBER:
124,530
TEST PRODUCT:
Cobimetinib (RO5514041)
MEDICAL MONITOR:
, M.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
I agree to conduct the study in accordance with the current protocol.
Principal Investigator’s Name  (print)
Principal Investigator’s Signature
Date
Please retain the signed original of this form for your study files.  Please return a copy as 
instructed by your local study monitor.


Cobimetinib—F. Hoffmann-La Roche Ltd
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PROTOCOL SYNOPSIS
TITLE:
A PHASE I/II, MULTICENTER, OPEN-LABEL, DOSE-ESCALATION 
STUDY OF THE SAFETY AND PHARMACOKINETICS OF 
COBIMETINIB IN PEDIATRIC AND YOUNG ADULT PATIENTS 
WITH PREVIOUSLY TREATED SOLID TUMORS
PROTOCOL NUMBER:
GO29665
VERSION NUMBER:
11
EUDRACT NUMBER:
2014-004685-25
IND NUMBER:
124,530
TEST PRODUCT:
Cobimetinib (RO5514041)
PHASE:
Phase I/II
INDICATION:
Solid tumors
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives
Safety (Primary) Objective
The primary objective for this study is as follows:

To evaluate the safety and tolerability of cobimetinib in children and young adults, including 
estimation of the maximum-tolerated dose (MTD) or the maximum-administered dose (MAD) 
and characterization of dose-limiting toxicities (DLTs)
Pharmacokinetic Objective
The pharmacokinetic (PK) objective for this study is as follows:

To characterize the pharmacokinetics of cobimetinib in children and young adults
Efficacy Objective
The efficacy objective for this study is as follows:

To evaluate the anticancer activity of cobimetinib in children and young adults with solid or 
brain tumors, as measured by objective response rate (ORR), progression-free survival 
(PFS), duration of objective response (DOR), and overall survival (OS)
Dose-Finding Objective
An additional objective for this study is as follows:

To identify recommended Phase II doses for cobimetinib tablet and suspension 
formulations in pediatric patients on the basis of safety, PK, and efficacy outcome measures
Exploratory Objectives
The exploratory objectives for this study are as follows:

To explore the relationship between cobimetinib exposure and changes in levels of
pharmacodynamic (PD) biomarkers in children and young adults


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
To explore non-inherited biomarkers that may be predictive of response to cobimetinib 
(i.e., predictive biomarkers), may be associated with progression to a more severe disease 
state (i.e., prognostic biomarkers), acquired resistance to cobimetinib, or susceptibility to 
developing adverse events, may provide evidence of cobimetinib activity, or may increase 
the knowledge and understanding of disease biology

To explore inherited biomarkers (i.e., variants in germline DNA) that may be predictive of 
response to cobimetinib (i.e., predictive biomarkers), may be associated with progression to 
a more severe disease state (i.e., prognostic biomarkers), acquired resistance to 
cobimetinib, or susceptibility to developing adverse events, or may increase the knowledge 
and understanding of disease biology

To explore potential relationships between PK parameters for cobimetinib and other 
outcome measures (such as safety or efficacy outcome measures)

To evaluate tumor characteristics before and after treatment on the basis of available 
magnetic resonance imaging (MRI) and positron emission tomography (PET) scans

To evaluate specific aspects of the acceptability of the cobimetinib formulations
Study Design
Description of Study
Study Design
This is a Phase I/II, multicenter, open-label, dose-escalation study designed to evaluate the 
safety, tolerability, pharmacokinetics, and preliminary efficacy of cobimetinib in pediatric and 
young adult patients with solid tumors with known or potential RAS/RAF/MEK/ERK pathway 
activation for which standard therapy has proven to be ineffective (i.e., relapsed or refractory 
tumors) or intolerable or for which no curative standard-of-care treatment options exist.
Patients will be enrolled via an interactive web response system in two stages:  a 
dose-escalation stage and an expansion stage at the recommended dose.  During the 
dose-escalation stage, cohorts of 36 pediatric patients (age 6 months to 18 years) will be 
evaluated at escalating dose levels to determine the MTD or MAD of cobimetinib in pediatric 
patients with advanced solid tumors.  The MTD or MAD of each cobimetinib formulation (tablet 
and suspension) will be determined in separate dose escalations.  Once the MTD or MAD has 
been established, pediatric patients (age 6 months to 18 years) will be enrolled in the 
expansion stage and treated at the recommended dose, which will be at or below the MTD or 
MAD, as determined by the Sponsor; adult patients 18 years of age with pediatric tumor types 
can be enrolled on this study but only during the expansion stage; these adult patients will be 
treated at the adult flat dose.  Approximately 70 patients are expected be enrolled in the 
dose-escalation and initial expansion stages of this study, at approximately 30 investigative 
sites in Europe and North America.  If an efficacy signal is observed during the first expansion 
step for the initial response assessment, up to an additional 30 patients per cohort may be 
enrolled in the second expansion step for the additional response assessment.
Safety Assessment
All patients will be closely monitored for adverse events throughout the study and for at least 
30 days after the last dose of study treatment.  Adverse events will be graded according to the 
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), 
version 4.0.  Other safety assessments include echocardiograms, ophthalmologic examinations, 
and dermatologic examinations.
Pharmacokinetic Assessment
To characterize the PK properties of cobimetinib, blood samples will be taken at defined 
timepoints after dosing.
Efficacy Assessment
Tumor assessments will be performed in the final week of every other cycle, starting with 
Cycle 2.  Response will be determined by the investigator using the modified International 
Neuroblastoma Response Criteria (mINRC) for patients with neuroblastoma, Response 
Assessment in Neuro-Oncology (RANO) criteria for patients with high-grade glioma (HGG),
Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 for patients with other tumors and 


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Response Assessment in Neuro-Oncology for Low Grade Glioma (RANO) criteria for patients 
with low-grade glioma (LGG) in the expansion stage in addition to RECIST v1.1.
Study Drug Dosing
Patients in both dose-escalation and expansion stages will receive cobimetinib orally on Days 
121 of each 28-day treatment cycle (21/7 dosing schedule) until the occurrence of disease 
progression as determined by the investigator, death, unacceptable toxicity, or patient or 
investigator decision to discontinue treatment.  
Cohorts of 36 pediatric patients each will be treated at escalating doses of cobimetinib 
according to a rolling 6 design.  The first patient at each dose level must complete at least 
5 days of treatment (Days 15 of Cycle 1) without a DLT before subsequent patients can be 
treated at the same dose level.
The DLT assessment window is defined as Days 128 of Cycle 1.  Adverse events identified as 
DLTs will be reported to the Sponsor within 24 hours.
Two formulations will be available for the protocol:  a tablet (20 mg) and a suspension 
(4.8 mg/mL).  An MTD or MAD will initially be determined for tablets in patients 6 years and 
above.  Once the MTD or MAD is identified for tablets, enrollment of patients using the 
suspension will commence following review of relevant data from the tablet dose escalation.  
The starting dose for the suspension will be a minimum of one dose level below the MTD or 
MAD of the tablets.  Additional dose escalation with the suspension may proceed according to 
the dose-escalation rules until an MTD or MAD is identified for the suspension.  On the basis of 
an ongoing review of safety data and available PK data, increases in dose level or continued 
enrollment for either formulation may be halted by the Sponsor as deemed appropriate.
Patients who discontinue from the study prior to completing the DLT assessment window for 
reasons other than a DLT will be considered non-evaluable for dose-escalation decisions and 
MTD or MAD assessments.  These patients will be replaced at that same dose level unless 
there are 3 or more patients already treated and all were evaluated with no DLT at that level.  
Patients who miss five or more doses (i.e., 18% of the cumulative dose) during the DLT 
assessment window for reasons other than toxicity will also be replaced.  Patients who ingest 
moderate or strong CYP3A inducers or inhibitors, ingest prohibited foods/supplements, or 
receive supportive care during the DLT assessment window that confounds the evaluation of 
DLTs (not including supportive care described below as part of the DLT definition) may be 
replaced at the discretion of the Medical Monitor.
Patients who experience a DLT during the assessment window (first 28 days) may not 
subsequently continue drug at full dose, even if the drug is withheld until resolution of the toxic 
event.  The investigator should use guidance (and if guidance is not specified, investigator 
discretion) to determine whether the patient should permanently discontinue study drug or 
withhold study drug until toxicity resolves to Grade 1 or lower, then resume study drug at a dose 
corresponding to a reduction of one dose level.
After the MTD or MAD has been determined for a formulation, pediatric and young adult 
patients will be enrolled in tumor type cohorts to obtain additional safety, tolerability, and PK 
data, as well as any preliminary evidence of anti-cancer activity.  Pediatric (18 years of age) 
patients will be treated at or below the formulation-specific MTD or MAD identified in the 
dose-escalation stage of this study.  Young adult patients (18 years of age) will be treated at 
the recommended adult dose.  
The Sponsor reserves the right to determine whether enrollment into the expansion stage using 
tablets will proceed concurrently with or subsequent to dose-escalation for suspension.  
Enrollment in expansion cohorts may commence after internal monitoring committee (IMC) has 
reviewed PK and safety data obtained in the dose escalation phase.
Each tumor type will be considered a distinct tumor type cohort.  Different tumor type cohorts 
may not all enroll simultaneously.  Tumor type cohorts will be chosen after IMC review, prior to 
inclusion in the expansion stage of the study.  Chosen tumor type cohorts for the expansion 
stage may also include subgroups of tumor types included in the dose-escalation stage, with 
inclusion based on confirmed (rather than expected) RAS/RAF/MEK/ERK-pathway activation 
(based on local testing of sample from time of diagnosis or any subsequent timepoint prior to 
enrollment) with approval of medical monitor).  Two phases of response assessment are 
planned for the expansion stage:  an initial response assessment and an additional response 


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assessment.  An initial response assessment will be performed after a minimum of 10 patients, 
treated at the recommended dose for expansion stage, have been enrolled in a tumor type 
cohort and followed for approximately 12 months, to determine whether to expand the cohort for 
additional response assessment.  
Cohort expansion will be started once a pre-established number of responses for that tumor 
type are confirmed.  A decision to pursue additional enrollment in a tumor type cohort may be 
approved by the Sponsor or Medical Monitor before the initial response assessment. Cohort 
expansion, including the number of patients needed for the additional response assessment, 
will take into account practical considerations (e.g., enrollment feasibility), nonclinical findings, 
biomarker analysis, safety profiles, and any other relevant information.
If the frequency of Grade 3 or 4 toxicities or other unacceptable toxicities at the initial dose level 
in the expansion stage suggest that this dose is intolerable, accrual at that dose level will be 
halted.  Consideration will then be given to enrolling patients at a lower dose level.
The Sponsor may decide to stop enrollment of patients 18 years of age at any time during the 
study to ensure adequate enrollment of patients 18 years of age.  To meet study completion 
criteria below, the Sponsor may restrict enrollment of patients 10 years of age if too few 
patients 10 years of age are being enrolled.
The Sponsor intends to stop study enrollment once all of the following criteria are met:

The dose-escalation phase of both tablet and suspension formulations are complete

At least 20 patients 18 years of age have been treated with study drug

At least one tumor type cohort has completed response assessment (either initial response 
assessment or additional response assessment)

At least 10 patients 10 years of age have been treated with study drug
Enrollment in a tumor type cohort will be stopped if any one of the following criteria is met: 

The number of patients needed for initial response assessment is reached and the number 
of responders does not meet the requirement for tumor type cohort expansion

The number of patients needed for additional response assessment is reached

The Sponsor has stopped the study
Some exceptions may apply to these general stopping rules, including but not limited to the 
following:

Enrollment in the study may be stopped if enrollment has been open for more than 2 years 
and at least 20 patients have been treated with the study drug. 

Enrollment in a given tumor type cohort may be extended by the Sponsor if there is strong 
evidence of a positive efficacy signal in a slow enrolling and rare tumor type cohort, thus 
allowing for additional data to be collected.
Number of Patients
Approximately 70 patients are expected be enrolled in the dose-escalation and initial expansion 
stages of this study, at approximately 30 investigative sites in Europe and North America. If an 
efficacy signal is observed during the first expansion step for the initial response assessment, 
up to an additional 30 patients per cohort may be enrolled in the second expansion step for the 
additional response assessment.
Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed Informed Consent Form

Signed Child's Informed Assent, when appropriate as determined by patient's age and 
individual site and country standards

For dose-escalation stage, tablets:  Age at study entry 6 years to 18 years


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
For dose-escalation stage, suspension: age at study entry 6 months to 18 years
Patients 1 year of age will not be enrolled until 6 patients 1 year to 18 years of 
age have received at least one cycle of therapy with suspension and until safety and 
PK assessment of these patients has been conducted.

For expansion stage:  Age at study entry 6 months (6 years if suspension is not 
available) to 30 years
Patients 6 months to 1 year of age may not be enrolled until 6 patients 1 year to 
18 years of age have received at least one cycle of therapy with suspension in the
dose-escalation phase and until safety and PK assessment of these patients has been 
conducted.
In exceptional cases of relapsed pediatric tumors in patients 30 years of age, the 
Sponsor will consider waiving the age requirement with approval of the Medical 
Monitor.  This waiver is restricted to patients with pediatric-specific diseases 
(e.g., neuroblastoma) for whom clinical trials are unlikely to be available, and will not 
be extended to patients with tumors that typically occur both in children and adults 
(e.g., HGG).  The Sponsor may decide to stop enrollment of patients 18 years of age 
at any time during the study to ensure adequate enrollment of patients 18 years 
of age. 

Able to comply with the requirements of the study protocol, in the investigator’s judgment

Tumors for which prior treatment has proven to be ineffective (i.e., relapsed or refractory) 
or intolerable, or for which no standard therapy exists.

Tumors with known or expected RAS/RAF/MEK/ERK pathway involvement.  Diagnosis 
MUST be one of the following tumor types:
Central nervous system gliomas, including high- and low-grade gliomas, and diffuse 
intrinsic pontine glioma (DIPG)
For initial expansion stage, evidence of RAS/RAF/MEK/ERK-pathway activation is 
required (based on local testing of sample from time of diagnosis or any 
subsequent timepoint prior to enrollment) and must be approved by medical 
monitor for inclusion.
Embryonal rhabdomyosarcoma and other non-rhabdomyosarcoma soft tissue 
sarcomas
Neuroblastoma
Melanoma
Malignant peripheral nerve sheath tumor
Rhabdoid tumors, including atypical teratoid/rhabdoid tumor
Tumors from the following groups that, in the judgment of the investigator, are life 
threatening, resulting in severe symptoms (including severe pain), or are in close 
proximity to vital structures:
Neurofibromatosis 1 (NF1)-associated tumors (including plexiform neurofibroma)
Schwannoma
Any solid tumor or brain tumor that occurs in a patient with another RASopathy 
(such as Noonan syndrome)
Any solid or brain tumor that has been molecularly profiled and shown to have 
RAS/RAF/MEK/ERK pathway activation, with approval of the Medical Monitor.

Tumor diagnosis must be histologically or cytologically confirmed either at the time of 
diagnosis or at the time of relapse, except in the following scenario:
DIPG and optic pathway gliomas do not require histologic confirmation if radiographic 
findings are sufficient to make diagnosis and institutional standard of care does not 
mandate biopsy for diagnosis.

Current disease state for which there is no known curative therapy or therapy proven to 
prolong survival with an acceptable quality of life


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
Disease that is measurable as defined by mINRC, RANO criteria for HGG, RANO 
criteria for LGG, or RECIST v1.1 (as appropriate) or evaluable by nuclear medicine 
techniques, immunocytochemistry techniques, tumor markers, or other reliable 
measures

Availability of tumor tissue at study enrollment is mandatory.  Archival tumor tissue block 
or 15 freshly cut, unstained, serial slides available for submission, and/or willingness to 
undergo a core or excisional biopsy prior to enrollment are acceptable.  Fine-needle 
aspiration, brush biopsy, and lavage samples are not acceptable.
For patients submitting archival tissue, a minimum of 15 slides are required.  Patients 
with fewer than 15 slides available may be eligible for study entry following approval of 
the Medical Monitor.  

Lansky Performance Status or Karnofsky Performance Status 50%

Life expectancy 3 months, in the investigator's judgment

For female patients of childbearing potential:  agreement to remain abstinent (refrain 
from heterosexual intercourse) or use contraceptive measures, and agreement to refrain 
from donating eggs, as defined below:
Female patients must remain abstinent or use single or combined contraceptive 
methods that result in a failure rate of 1% per year during the treatment period and 
for at least 3 months after the last dose of study drug.  Female patients must refrain 
from donating eggs during this same period.
True abstinence is only acceptable if it is in line with the preferred and usual lifestyle of 
the patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, or 
postovulation methods) and withdrawal are not acceptable methods of contraception.
Examples of contraceptive methods with a failure rate of 1% per year include, 
hormonal implants, established, proper use of combined oral or injected hormonal 
contraceptives, and certain intrauterine devices.  Alternatively, two methods (e.g., two 
barrier methods such as a condom and a cervical cap) may be combined to achieve a 
failure rate of 1% per year.  Barrier methods must always be supplemented with the 
use of a spermicide.

For male patients with a female partner of childbearing potential or a pregnant female 
partner:  Agreement to remain abstinent or use a condom during the treatment period 
and for at least 3 months after the last dose of study drug
True abstinence is only acceptable if it is in line with the preferred and usual lifestyle of 
the patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, or 
postovulation methods) and withdrawal are not acceptable methods of contraception.

For male patients:  agreement to refrain from donating sperm during the treatment 
period and for at least 3 months after the last dose of study drug

Adequate hematologic and end organ function, defined by the following laboratory 
results obtained within 28 days prior to initiation of study drug:
ANC 0.75109/L (unsupported)
Platelet count 75109/L (unsupported)
Hemoglobin 8 g/dL (transfusion is acceptable to meet this criterion)
Bilirubin 1.5the upper limit of normal (ULN) for age
AST and ALT 2.5ULN for age
Serum creatinine 1.5ULN for age or creatinine clearance (or radioisotope 
glomerular filtration rate) 70 mL/min/1.73 m2


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
Fractional shortening (FS) 30% and left ventricular ejection fraction (LVEF) 50% at 
baseline, as determined by echocardiography or multigated acquisition scan within 28 days 
prior to initiation of study drug
Depending on institutional standard, either FS or LVEF is adequate for enrollment if 
only one value is measured; if both values are measured, then both values must meet 
criteria above.

Body weight must be20 kg if suspension is not available
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Pregnant or lactating, or intending to become pregnant during the study
Females of childbearing potential must have a negative serum pregnancy test result 
within 1 week prior to initiation of study drug.

Prior treatment with cobimetinib or other MEK inhibitor (prior sorafenib use is permissible)

Treatment with high-dose chemotherapy and stem-cell rescue (autologous stem cell 
transplant) within 3 months prior to initiation of study drug

Treatment with chemotherapy (other than high-dose chemotherapy as described above) or 
differentiation therapy (such as retinoic acid) or immunotherapy (such as anti-GD2 antibody 
treatment) within 4 weeks prior to initiation of study drug or, if treatment included 
nitrosoureas, within 6 weeks prior to initiation of study drug.  This requirement may be 
waived at the investigator’s request if the patient has recovered from therapeutic toxicity to 
the degree specified in the protocol, with approval of the Medical Monitor.

Treatment with thoracic or mediastinal radiotherapy within 6 weeks prior to initiation of study 
drug

Treatment with hormonal therapy (except hormone replacement therapy or oral 
contraceptives), immunotherapy, biologic therapy, or herbal cancer therapy within 4 weeks 
or 5 half-lives, whichever is shorter, prior to initiation of study drug

Treatment with a long-acting hematopoietic growth factor within 2 weeks prior to initiation of 
study drug or a short-acting hematopoietic growth factor within 1 week prior to initiation of 
study drug

Treatment with investigational therapy (with the exception of cancer therapies as described 
above) within 4 weeks prior to initiation of study drug

Requirement for initiation of corticosteroids or an increase in the dose of corticosteroids 
within 1 week prior to initiation of study drug

Treatment with St. John's wort or hyperforin or drugs that are strong inhibitors or inducers of 
CYP3A within 1 week prior to initiation of study drug

Ingestion of grapefruit juice within 1 week prior to initiation of study drug

Any toxicity (excluding alopecia and ototoxicity) from prior treatment that has not resolved to 
Grade1 (per NCI CTCAE v4.0) at screening except as otherwise permitted in the 
inclusion/exclusion criteria

Major surgical procedure or significant traumatic injury within 4 weeks prior to initiation of 
study drug, or anticipation of need for major surgical procedure during the course of the 
study
Placement of a vascular access device or minor surgery is permitted if the site has 
healed prior to initiation of study drug.

Known active infection (excluding fungal infection of the nail beds) within 28 days prior to 
initiation of study drug that has not completely resolved

History of Grade2 CNS hemorrhage 

History of CNS hemorrhage within 28 days of study entry.  This criterion may be waived at 
the investigator’s request if the CNS hemorrhage was asymptomatic, with approval of the 
Medical Monitor.


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
For brain tumor patients, use of anticoagulants within 1 week of study drug initiation.

History or evidence of retinal pathology on ophthalmologic examination that is considered to 
be a risk factor for or indicative of neurosensory retinal detachment, central serous 
chorioretinopathy, neovascular retinopathy, or retinopathy of prematurity

Known hypersensitivity to any component of the study drug

Inability to swallow oral medications

Impaired gastrointestinal absorption

Prior allogenic bone marrow transplantation or prior solid organ transplantation

Any other disease, metabolic or psychological dysfunction, physical examination finding, or 
clinical laboratory finding giving reasonable suspicion of a disease or condition that 
contraindicates use of an investigational drug or places the patient at unacceptable risk 
from treatment complications

Current drug or alcohol use or dependence that would interfere with adherence to study 
requirements, in the opinion of the investigator
Length of Study
The study will run for approximately 7 years, from screening of the first patient until last patient, 
last visit (LPLV).
End of Study
The end of this study is defined as the date when the LPLV occurs, or 5 years after the last 
patient is enrolled, whichever occurs first.  The Sponsor reserves the right to present interim 
data to health authorities for compliance purposes.
For an individual patient the completion of the study (i.e., the last visit) will occur when the 
patient withdraws consent, has completed follow-up, has been lost to follow-up, dies, or when 
the trial is stopped.
Outcome Measures
Safety Outcome Measures
The safety outcome measures for this study are as follows:

Incidence and nature of DLTs

Nature, frequency, severity, and timing of adverse events, including serious adverse 
events and adverse events of special interest

Changes in vital signs, physical findings, and clinical laboratory results during and 
following cobimetinib administration

Growth patterns (relative to age-specific standards for height and weight) accounting for 
baseline growth of the patient

Development patterns (relative to onset of menarche [for females] and pubertal changes) 
accounting for baseline development of the patient
Pharmacokinetic Outcome Measure
The PK outcome measure for this study is as follows: 

To characterize cobimetinib PK in pediatric patients, the following PK parameters 
following single and multiple doses will be estimated:  maximum plasma concentration 
observed, time to maximum concentration), total exposure (area under the 
concentrationtime curve from 0 to 24 hours [AUC0-24]), and apparent clearance 


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Efficacy Outcome Measures
The co-primary efficacy outcome measures for this study are as follows:

ORR, defined as the percentage of patients with a complete or partial response for patients 
with measurable disease or neuroblastoma patients with evaluable disease at baseline, or a 
complete response for patients with nonmeasurable but evaluable disease at baseline 
(except neuroblastoma patients), on two consecutive occasions 4 weeks apart, as 
determined by the investigator using mINRC for patients with neuroblastoma, RANO criteria 
for patients with HGG, for  the RANO criteria for patients with LGG, and RECIST v1.1 for 
patients with other tumors

PFS, defined as the time from initiation of study drug to the first documented occurrence of 
disease progression, as determined by the investigator using mINRC for patients with 
neuroblastoma, RANO criteria for patients with HGG, RECIST v1.1 for patients with other 
tumors and RANO criteria for patients with LGG in the expansion stage in addition to 
RECIST v1.1, or death from any cause, whichever occurs first
The secondary efficacy outcome measures for this study are as follows:

DOR, defined as the time from the first tumor assessment that supports the patient’s 
objective response to the time of disease progression, as determined by the investigator 
using mINRC for patients with neuroblastoma, RANO criteria for patients with HGG, 
RECIST v1.1 for patients with other tumors, and RANO criteria for patients with LGG in the 
expansion stage in addition to RECIST v1.1, or death from any cause, whichever occurs 
first

OS, defined as the time from initiation of study drug to death from any cause
Exploratory Outcome Measures
The exploratory outcome measures for this study are as follows:

Levels of potential PD biomarkers (potentially including, but not limited to, p-MEK, p-ERK, 
and Ki67) measured in tumor tissue collected at baseline, on treatment, and at the time of 
disease progression

Correlation between non-inherited and inherited biomarkers in plasma (potentially including,
but not limited to BRAF mutations, BRAF fusions, RAS mutations, and NF1 alterations) with 
safety, PK, or efficacy outcome measures

To explore potential relationships between cobimetinib pharmacokinetics and other 
outcome measures (such as safety or efficacy outcome measures)

ORR for LGG by RECIST, defined as the percentage of patients with measurable disease 
who have a complete or partial response, on two consecutive occasions 4 weeks apart, as 
determined by the investigator using RECIST v1.1

Exploratory ORR for LGG by RANO, defined as the percentage of patients with measurable 
disease who have a complete, partial or minor response  on two consecutive occasions 
4 weeks apart, as determined by the investigator using RANO criteria for LGG

Diffusion activity in tumors before and after cobimetinib treatment, as demonstrated on 
available MRI scans

Metabolic activity in tumors before and after cobimetinib treatment, as demonstrated on 
available PET scans

Acceptability Survey
Investigational Medicinal Products
The test product (investigational drug) for this study is cobimetinib available as 20 mg tablets or 
suspension (4.8 mg/mL).
Cobimetinib will be taken orally once daily on Days 121 of each 28-day treatment cycle
(21/7 dosing schedule) until the occurrence of disease progression as determined by the 
investigator, death, unacceptable toxicity, or patient or investigator decision to discontinue 
treatment.  Patients will be assigned to dose levels in the order in which they are enrolled.  The 


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starting dose for tablets will be 0.6 mg/kg in the dose-escalation stage.  Pediatric patients 
(18 years of age) enrolled in the expansion stage will be treated at or below the MTD or MAD, 
as determined by the Sponsor.  Adult patients (18 years of age) enrolled in the expansion 
stage will be treated with the adult recommended dose of 60 mg daily.  Cobimetinib should be 
taken at approximately the same time each day, no earlier than 1 hour before and no later than 
4 hours after the usual dosing time.
Patients under 6 years of age or weighing 20 kg are only eligible to receive the drug in 
suspension.  
Any overdose or incorrect administration of study drug should be noted on the Study Drug 
Administration electronic Case Report Form (eCRF).  Adverse events associated with an 
overdose or incorrect administration of study drug should be recorded on the Adverse Event 
eCRF.
Statistical Methods
Primary Analysis
Safety analyses will be performed on the safety-evaluable population, which is defined as 
patients who receive any amount of study drug.  Subgroup safety analyses by tumor type cohort 
will also be conducted as appropriate.
Study treatment exposure (such as treatment duration, total dose received, and number of 
cycles and dose modifications) will be summarized with descriptive statistics.
All adverse events, serious adverse events, adverse events leading to death, DLTs, adverse 
events of special interest, and adverse events leading to study treatment discontinuation, that 
occur on or after the first dose of study treatment (i.e., treatmentemergent adverse events), will 
be summarized by mapped term, appropriate thesaurus level, and toxicity grade.  For events of 
varying severity, the highest grade will be used in the summaries.  Deaths and cause of death 
will be summarized.
Laboratory toxicities will be summarized by NCI CTCAE grade.
Determination of Sample Size  
For the dose-escalation stage, the sample size is based on the dose-escalation rules described 
in the study design section of this document.  Explicit power and Type I error considerations 
were not factored into the design, as the dose-escalation stage was designed to obtain 
preliminary safety and PK information for the study drug.  
To make a preliminary assessment of the efficacy of the study drug, two phases of response 
assessment are planned for the expansion stage:  an initial response assessment and an 
additional response assessment.  Taking into account historical control ORRs for each pediatric 
tumor type, the minimum number of patients in the initial response assessment and the 
minimum number of responders needed for advancement to the additional response 
assessment were calculated. The selection of tumor type cohorts for additional response 
assessment, as well as the number of patients needed for the additional response assessment, 
will also take into account practical considerations (e.g., enrollment feasibility), biomarker 
analysis, safety profiles, and any other relevant information.  Similar consideration will be given 
to other rare pediatric tumor types that are enrolled in the study and not included in the body of 
the protocol.  No formal hypothesis testing is planned in this study.
Interim Analyses
Interim efficacy analyses will be conducted whenever a tumor type cohort has enrolled the 
10 patients required for initial response assessment and patients have been followed for 
approximately 12 months.  After a minimum of 20 patients have completed Cycle 1, an interim 
PK and safety analysis will be conducted.
Given the hypothesis-generating nature of this study, the Sponsor may choose to conduct 
additional interim efficacy analyses.  The decision to conduct an optional interim analysis and 
the timing of the analysis will be documented in the Sponsor’s trial master file prior to the 
conduct of the interim analysis.  The interim analysis will be performed and interpreted by 
Sponsor study team personnel.


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
ATRT
atypical teratoid/rhabdoid tumor
AUC
area under the concentration–time curve
AUC0-24
area under the concentration-time curve from 0 to 24 hours
AYA
adolescent and young adult
BCC
basal cell carcinoma
CL/F
apparent clearance
Cmax
maximum plasma concentration observed
CMN
congenital melanocytic nevi
CSCR
central serous chorioretinopathy
CT
computed tomography
DIPG
diffuse intrinsic pontine glioma
DLT
dose-limiting toxicity
DOR
duration of objective response
EC
Ethics Committee
eCRF
electronic Case Report Form
EDC
electronic data capture
FDA
U.S. Food and Drug Administration
FFPE
formalin-fixed paraffin-embedded
FS
fractional shortening
HGG
high-grade glioma
HIPAA
Health Insurance Portability and Accountability Act
ICH
International Conference for Harmonisation
IMC
Internal Monitoring Committee
IMP
investigational medicinal product
IND
Investigational New Drug
INRC
International Neuroblastoma Response Criteria
IRB
Institutional Review Board
IWRS
interactive web response system
LGG
low-grade glioma
LPLV
last patient, last visit
LVEF
left ventricular ejection fraction
MAD
maximum administered dose
MIBG
metaiodobenzylguanidine
mINRC
Modified International Neuroblastoma Response Criteria
MRI
magnetic resonance imaging


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Abbreviation
Definition
MTD
maximum tolerated dose
MUGA
multigated acquisition scan
NCI CTCAE
National Cancer Institute Common Terminology Criteria for 
Adverse Events
NF1
Neurofibromatosis 1
NF2
Neurofibromatosis 2
OCT
optical coherence tomography
ORR
objective response rate
OS
overall survival
PD
pharmacodynamics
PET
positron emission tomography
PFS
progression-free survival
P-gp
P-glycoprotein
PK
pharmacokinetic
RANO
Response Assessment in Neuro-Oncology
RCR
Roche Clinical Repository
RECIST
Response Evaluation Criteria in Solid Tumors
SCC
squamous cell carcinoma
SOC
Scientific Oversight Committee
T1/2
half-life
Tmax
time to maximum concentration
ULN
upper limit of normal


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1.
BACKGROUND
1.1
RAS/RAF/MEK/ERK PATHWAY AND CANCER
The MAPK signaling cascade transduces multiple proliferative and differentiating signals 
within tumor cells.  The ERK/MAPK pathway, one of four major mammalian MAPK 
pathway modules, plays a major role in the mediation of cell growth and differentiation in 
response to numerous extracellular signals (Johnson and Lapadat 2002; 
Roberts and Der 2007).  Ras-GTP activates RAF kinases, which in turn activate the 
MEK/ERK cascade and subsequent cellular proliferation (Downward 2003; 
Roberts and Der 2007).  To regulate cellular proliferation, activated ERKs translocate to 
the nucleus and regulate gene expression through the activation of several key 
transcription factors.  Abnormal regulation of the RAS/RAF/MEK/ERK pathway 
contributes to uncontrolled proliferation, invasion, metastasis, and angiogenesis as well 
as diminished apoptosis.
RAS/RAF/MEK/ERK pathway activation can be induced directly via gain-of-function 
mutations or indirectly via induction of growth factor signaling.  An advantage of targeting 
MEK is that the RAS/RAF/MEK/ERK pathway is a convergence point where a number of 
upstream signaling pathways can be blocked with the inhibition of MEK.  MEK inhibitors 
differ from most other kinase inhibitors in that they do not compete with ATP binding, 
which confers a high specificity.  Inhibitors of MEK are expected to be efficacious in 
tumors that are highly dependent on proliferative signals from the RAS/RAF/MEK/ERK 
signaling pathway.  To illustrate this concept, malignant melanoma frequently carries a 
BRAFV600E mutation, which leads to a constitutively active form of BRAF that 
subsequently leads to downstream MEK/ERK phosphorylation and activation.  Early 
clinical trials have demonstrated significant clinical responses to MEK inhibitors, both 
alone (see Section 1.2.2.3) and in combination with direct BRAF inhibitors.
Pediatric solid and brain tumor entities with evidence of RAS/RAF/MEK/ERK 
involvement and preclinical evidence of MEK inhibitor activity include:

Low-grade glioma:  RAS/RAF/MEK/ERK activation is universal in pediatric 
low-grade glioma.  MEK/ERK phosphorylation is mediated in the majority of 
pediatric low-grade gliomas via a 7q34 duplication, which encodes a constitutively 
active KIAA1549-BRAF fusion protein (Forshew et al. 2009; Jacob et al. 2009; 
Sievert et al. 2009).  Pediatric astrocytomas with this mutation demonstrate in vitro
resistance to BRAF inhibitors due to paradoxical activation of wild-type BRAF still 
present within the tumor (Sievert et al. 2013), which suggests that this class of 
patients requires downstream pathway targeting.  Subsequent sequencing has 
demonstrated alternate activating RAS/RAF/MEK/ERK pathway mutations in tumors 
without the KIAA1549-BRAF fusion protein (Zhang et al. 2013).  A murine xenograft 
of BRAFV600E-mutant low-grade astrocytoma cell line, BT-40, has demonstrated 
complete regression to targeted MEK inhibitor therapy with selumetinib (AZD6244; 
Kolb et al. 2010), suggesting the possibility that downstream pathway targeting may 
be viable for a variety of BRAF-mediated low-grade gliomas.  


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
High-grade glioma (HGG): Pediatric HGGs carry BRAFV600E mutations in 
approximately 10%20% of cases (Schindler et al. 2011), and activating tyrosine 
kinase mutations leading to RAS activation are present in up to 68% of HGGs, 
including diffuse intrinsic pontine glioma (DIPG; Wu et al. 2014). In vitro 
administration of MEK inhibitors PD0325901 and selumetinib to glioblastoma cell 
lines demonstrated universal inhibition of ERK phosphorylation as well as growth 
inhibition in neurofibromatosis 1 (NF1)-mutant cell lines LN229 and U373 
(See et al. 2012).  Significant (p<0.001) delay in tumor growth and prolongation in 
event-free survival was observed with selumetinib therapy in two of four murine 
glioblastoma xenografts (Kolb et al. 2010).  Case reports have indicated significant 
clinical response in patients, including complete remission, of HGGs to vemurafenib 
monotherapy (Bautista et al. 2014; Robinson et al. 2014). 

Rhabdomyosarcoma:  Whole exome sequencing of 147 rhabdomyosarcoma 
samples demonstrated frequent occurrence of tumors with a mutation leading to 
RAS/RAF/MEK/ERK pathway activation, typically in embryonal rhabdomyosarcoma 
(ERMS) without presence of PAX fusion genes.  Specifically, activating mutations in 
NRAS, KRAS, HRAS, and upstream RAS-effectors NF1 and FGF4 collectively 
occurred in 24% of rhabdomyosarcoma and 37% of PAX fusion negative tumors 
(Shern et al. 2014).  Xenografts of embryonal rhabdomyosarcoma cell line RD, 
which carries an activating Q61H NRAS mutation, demonstrated approximately 50% 
reduction in growth rate compared to control when treated with U0126, a specific 
MEK inhibitor, with demonstrable reduction of downstream ERK phosphorylation.  
Growth arrest and abrogation of ERK phosphorylation was similarly observed in 
vitro in ERMS cell line TE671 (Marampon et al. 2009).  In vitro synergistic effect of 
selumetinib on human cell line viability was also observed when given in 
combination with a PI3K inhibitor (Renshaw et al. 2013).

Non-rhabdomyosarcoma soft tissue sarcomas:  Data are limited regarding 
RAS/RAF/MEK/ERK pathway in other pediatric soft tissue sarcomas.  Adult patient 
myxofibrosarcoma and pleomorphic liposarcoma samples demonstrate a 
Ras-activating NF1 deletion in approximately 10% of cases (Barretina et al. 2010).  
Murine soft tissue sarcomas induced by targeted NF1 deletion experience delay in 
tumor growth with targeted MEK inhibition (Dodd et al. 2013), suggesting that MEK 
inhibitors are candidate agents for other pediatric soft tissue sarcomas.

Neuroblastoma:  Loss-of-function germline and somatic mutations in NF1 are 
associated with poor outcomes in neuroblastoma, which are mediated by 
RAS/RAF/MEK/ERK pathway activation that results in retinoic acid resistance 
(Hölzel et al. 2010).  Whole genome sequencing of paired diagnostic and relapse 
specimens demonstrated clonal evolution with appearance of novel 
RAS/RAF/MEK/ERK pathway mutations in 18 of 23 of samples (78%).  In vitro and 
in vivo exposure of cell lines to MEK inhibitors (including cobimetinib, in in vitro 
models) showed differential response depending on presence and type of RAS 
mutation, with oncogenic RAS mutations rendering cell lines most sensitive to MEK 
inhibition (Eleveld et al. 2015).  Neuroblastoma RAS/RAF/MEK/ERK pathway
activation can also result from NF1 downregulation by an 
ubiquitin-proteasome-dependent pathway (Han et al. 2011).  Administration of a 


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MEK inhibitor to cell lines in vitro restores retinoic acid sensitivity, which is indicative 
of the targetability of this pathway in neuroblastoma (Hölzel et al. 2010).  
Administration of the MEK inhibitor trametinib to two neuroblastoma cell lines with 
NRAS Q61K mutations resulted in pronounced in vitro response (Vujic et al. 2015).

Melanoma and congenital melanocytic nevi (CMN):  Adult melanoma is commonly 
characterized by presence of constitutively active BRAFV600E and is highly 
responsive to MEK inhibition (see cobimetinib Investigator’s Brochure).  Pediatric 
conventional melanomas (those that arise from ultraviolet exposure) carry activating 
BRAF mutations at high frequency (11 of 13 cases; Lu et al. 2014).  Pediatric 
melanoma can also arise from CMN, severe cutaneous lesions that can cover up to 
80% of the body surface area and are characterized by activating NRAS Q61 
mutations (Lu et al. 2014; Kinsler et al. 2013).  The presence of CMN can also lead 
to neurocutaneous melanosis, a syndrome of neurologic abnormalities triggered by 
infiltrates of melanocytes that contain the same NRAS mutation seen in cutaneous 
lesions (Kinsler et al. 2013). 

Rhabdoid tumors/atypical teratoid/rhabdoid tumor (ATRT):  Rhabdoid tumors, 
including ATRT of the brain, are rare poorly differentiated tumors induced by biallelic 
inactivating mutations of INI1 (SMARCB1), a chromatin regulator.  Prognosis is 
dismal, with a median survival of12 months from diagnosis (Strother 2005).  
Tumors can arise from transformed malignant brain tumors, and BRAFV600E can 
be present in rhabdoid/ATRT with comorbid INI1 loss.  High levels of KRAS 
expression in ATRTs have been observed irrespective of pathway mutation status, 
with intermediate- or high-level downstream expression of pERK observed in 
approximately one-third of ATRTs.  This observation led to in vitro experiments 
demonstrating blockade of ERK activation, suppression of cell growth, induction of 
apoptosis, and decreased cell cycle progression in vitro in pERK-expressing ATRT 
tumor cell lines treated with selumetinib (Weingart et al. 2015).  Mice xenografted 
with the rhabdoid tumor cell line BT-29 demonstrated nearly doubled (p0.001) 
event-free survival when treated with selumetinib relative to control 
(Kolb et al. 2010). 

NF1-related tumors and malignant peripheral nerve sheath tumor:  NF1 is an 
autosomal dominant genetic disorder characterized by mutations in NF1, loss of 
which results in increased RAS/RAF/MEK/ERK pathway activation.  Patients with 
this disorder are susceptible to development of a spectrum of benign and malignant 
tumors, including plexiform neurofibroma and malignant peripheral nerve sheath 
tumor.  Targeting the RAS/RAF/MEK/ERK pathway with MEK inhibition effectively 
treats in vivo models of NF1-associated disease.  The MEK inhibitor PD0325901 
suppressed growth of murine neurofibromas, induced by enforced loss of NF1 in 
Schwann cells.  In addition to inhibiting cell growth via decreased ERK 
phosphorylation in vitro, PD0325901 also diminished tumor growth and prolonged 
survival of mice xenografted with patient-derived MPNST cells (Jessen et al. 2013).

Neurofibromatosis 2 (NF2)-related tumors:  Although not classically considered a 
RASopathy, NF2 is caused by a loss-of-function mutation in the gene encoding 
Merlin, which normally inhibits RAS activation by decoupling RAS from growth factor 
signaling (Morrison et al. 2007).  NF2 leads to development of Schwannomas 


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(malignant tumors typically of the eighth cranial nerve), and accumulation of multiple 
tumors in patients is typically fatal.  Schwannoma cell cultures show decreased 
proliferation and increased apoptosis after in vitro exposure to a MEK inhibitor 
(Neff et al. 2012).

Solid tumors arising in a RASopathy (Rauen 2013):  In addition to NF1, other 
genetic disorders have mutations in genes that lead to activation of the 
RAS/RAF/MEK/ERK pathway.  Collectively these are referred to as RASopathies, 
many of which predispose patients to cancer.  An example is Noonan syndrome, 
which is characterized by activating mutations in RAS pathway genes including 
PTPN11, KRAS, NRAS, SHOC2, SOS1, and RAF1.  Children with Noonan 
syndrome who go on to develop cancer most commonly present with hematologic 
malignancies but solid tumors occur sporadically, including neuroblastoma, gliomas, 
and hepatoblastoma (Jongmans et al. 2011). 
1.2
BACKGROUND ON COBIMETINIB
Cobimetinib is a potent and highly selective small molecule inhibitor of MEK, a key 
component of the RAS/RAF/MEK/ERK pathway. 
1.2.1
Nonclinical Studies with Cobimetinib
Cobimetinib inhibited proliferation of a variety of human tumor cell lines via inhibition of 
MEK.  In addition, cobimetinib inhibited ERK phosphorylation in xenograft tumor models 
(breast, lung, colon, and melanoma) and stimulated apoptosis.  Cobimetinib 
accumulated in tumor xenografts and remained at high concentrations in the tumor after 
plasma concentrations had declined.  The activity of cobimetinib to inhibit ERK1 
phosphorylation was more closely correlated with its concentration in tumor tissue than 
in plasma.  In general, there was good correlation between reduced ERK1 
phosphorylation and efficacy in tumor xenograft models.  Tumor regression was 
observed in several human tumor xenograft models in a dose dependent fashion with up 
to 100% regression at the highest doses tested.  The models studied included colorectal 
cancer, malignant melanoma, breast carcinoma, and anaplastic lung carcinoma.
The pharmacologic and pharmacokinetic (PK) properties of cobimetinib were 
characterized in a series of nonclinical studies.  In addition, the nonclinical toxicity of 
cobimetinib was characterized in single-dose and repeat-dose general toxicity studies in 
rats and dogs; in vitro genotoxicity studies; rat embryo lethality/teratogenicity studies; a 
rat juvenile toxicity study; and cardiovascular, neurobehavioral, and respiratory safety 
pharmacology studies.  The toxicity profile, including target organs and tolerability, was 
similar in juvenile and adult rats.  These studies are summarized in the cobimetinib 
Investigator's Brochure.


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Like other MEK inhibitors, cobimetinib has a cytotoxic effect in vitro on pediatric cancer 
cell lines.  To date, 36 cell lines derived from pediatric solid and brain tumors and 
22 cell lines from pediatric leukemia and lymphoma have been evaluated for cellular 
viability and IC50 calculation.  Major findings include the following: 

Of 18 neuroblastoma cell lines evaluated at doses up to 10 M, six (33%) cell lines 
(CHP-212, NB(TU)1-10, SK-N-AS, BE(2)-M17, KP-N-SI9s, and SK-N-DZ) had IC50
less than 0.3 µM.  Of these six lines, two had NRAS Q61K mutations and one had 
KRAS G12A mutation.

Pediatric melanoma cell lines with known BRAFV600E mutations were susceptible to 
low concentrations of cobimetinib, with IC50 levels of 0.015 µM or less.

Of the 58 cell lines assessed, 18 cell lines exhibited RAS/RAF/MEK/ERK pathway 
activation as defined by oncogenic mutations in NRAS, KRAS, HRAS, or BRAF, by 
FLT3 internal tandem duplication, or by NF1 homozygous deletion.  Of the 18 cell 
lines with known RAS/RAF/MEK/ERK activation, 9 (50%) cell lines showed 
sensitivity to cobimetinib with an IC50 of 0.3 M, whereas only 4 (10%) of 40 cell 
lines without these mutations showed sensitivity at this level.

Responses were observed in cell lines with activating RAS mutations from diseases 
that do not ordinarily carry RAS mutations.  The osteosarcoma cell line 143B, a cell 
line transformed by murine sarcoma virus encoding a homolog of human KRAS, 
demonstrated IC50 of 0.351 M, but significantly less effect was noted in other 
osteosarcoma lines.  The medulloblastoma cell line ONS-76 with an activating 
NRAS Q61R mutation (Gajjar et al. 2014; Barretina et al. 2012) responded to 
cobimetinib with IC50of 0.074 M.
Several MEK-inhibitors have shown efficacy in in vivo mouse models of pediatric 
cancers (see Section 1.1).  Additionally, cobimetinib has now been evaluated in a 
neuroblastoma murine xenograft model.  Xenografts were derived from SK-N-AS cells, a 
neuroblastoma cell line with an NRAS Q61K mutation.  Cobimetinib was orally 
administered at multiple doses (1, 3, 5, and 7.5 mg/kg).  At the highest tested dose, 
cobimetinib inhibited tumor growth by 49% (as measured by area under the 
concentration-time curve [AUC]/day) relative to vehicle, and the time to progression (to 
five times the initial tumor size) increased from 6.5 days to 11.5 days.  ERK 
phosphorylation was reduced in murine tumors after cobimetinib dose administration; an 
effect was observed within 2 hours after cobimetinib dosing, and maximal effect was 
observed at 8 hours post-dosing (Genentech, Inc., unpublished results).
In summary, inhibition of the RAS/RAF/MEK/ERK pathway has been observed with 
several MEK small molecule inhibitors including cobimetinib.  This activity was observed 
across a spectrum of pediatric tumors in vitro, mainly in RAS pathway activated tumor 
types, and in vivo in a RAS-mutant neuroblastoma xenograft model.


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1.2.2
Clinical Studies with Cobimetinib
As of September 2017, cobimetinib has been administered alone or used with other 
agents in 21 clinical or clinical pharmacology trials in adults, and under two single-center, 
investigator-initiated, single-patient, compassionate-use trials (see the cobimetinib 
Investigator’s Brochure for details).
1.2.2.1
Clinical Pharmacokinetics
Clinical PK data from studies conducted in adults indicate that cobimetinib has a 
moderate rate of absorption, with time to maximum concentration (Tmax) ranging from 
1 hour to 6 hours across all doses.  Cobimetinib has linear pharmacokinectics in the 
dose range of 0.05 mg/kg to 100 mg.  On the basis of the mean terminal half-life (T1/2) of 
approximately 43.6 hours, a 2- to 3-fold accumulation is expected with daily oral dosing, 
and steady-state exposures should be achieved in 810 days.  Cobimetinib has minimal 
renal elimination and is mainly metabolized.
In vitro data indicate that cobimetinib is a substrate of CYP3A4 and UGT2B7, both of 
which are expressed before or soon after birth.
Detailed information on the clinical PK of cobimetinib is provided in the cobimetinib 
Investigator's Brochure.
1.2.2.2
Clinical Safety
Clinical safety data from patients treated with cobimetinib as a single agent are derived 
from Study MEK4592g, a Phase I, multicenter, non-randomized, open-label, 
dose-escalation study that evaluated the safety and PK of oral cobimetinib administered 
daily in adult patients with solid tumors.  The study tested multiple doses, two 
formulations, and two dosing schedules.  Fifty-six patients received cobimetinib for 
21 days followed by no treatment for 7 days (21/7 dosing schedule) at one of the 
following doses:  0.05, 0.10, or 0.20 mg/kg in a liquid formulation or 10, 20, 40, 60, or 
80 mg in a capsule formulation.  Forty-one patients received cobimetinib for 14 days 
followed by no treatment for 14 days (14/14 dosing schedule) at one of the following 
doses:  60, 80, 100, or 125 mg in a capsule formulation.
The maximum-tolerated dose (MTD) and the recommended dose for Phase II was 
60 mg for the 21/7 dosing schedule and 100 mg for the 14/14 dosing schedule.  The 
most frequent adverse events attributed to cobimetinib were diarrhea, rash, fatigue, and 
edema for patients on the 21/7 dosing schedule and diarrhea, rash, fatigue, vomiting, 
nausea, edema, eye disorders (including blurred vision), and abdominal pain for patients 
on the 14/14 dosing schedule.
An additional cohort of 18 adult patients was enrolled at 60 mg on the 21/7 dosing 
schedule to evaluate the effect of cobimetinib on the PK of midazolam and 
dextromethorphan, sensitive substrates of CYP3A4 and CYP2D6, respectively.  There 
was no clinically meaningful difference in the PK of midazolam or dextromethorphan.  


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Thus, cobimetinib does not cause any inhibition or induction of CYP3A4 or cause any 
inhibition of CYP2D6.
Refer to the cobimetinib Investigator's Brochure for additional details on the clinical 
safety of cobimetinib, given alone or in combination with other agents to patients or 
healthy subjects.
1.2.2.3
Clinical Efficacy
Clinical efficacy data from patients treated with cobimetinib as a single agent are derived 
from Study MEK4592g.
As of 25 May 2012, best overall tumor response per Response Evaluation Criteria in 
Solid Tumors (RECIST), Version 1.1, had been assessed for 74 of 97 patients with 
advanced solid malignancies treated with cobimetinib alone who had measurable lesions 
and at least one post-baseline tumor assessment.  Overall, 6 patients (6.2%) (all of 
whom had melanoma) had a confirmed partial response, 28 patients (28.9%) had stable 
disease, and 40 patients (41.2%) had disease progression. 
Among the 18 patients treated with cobimetinib who received doses of midazolam and 
dextromethorphan to evaluate drug-drug interaction, 4 patients had stable disease, 
8 patients had disease progression, 2 patients had an unconfirmed response, and 
4 patients discontinued prior to overall response assessment.
Three patients (1 patient with prolonged stable disease and 2 patients with a confirmed 
partial response) were ongoing in the study at the time of database lock (25 May 2012):  
a patient with carcinoid tumor in the small bowel (1369 days on study) and 2 patients 
with melanoma (753 days and 546 days on study).
Refer to the cobimetinib Investigator's Brochure for additional details on the clinical 
efficacy of cobimetinib, given alone or in combination with other agents.
1.2.2.4
Approved Indications
Cobimetinib is approved for use in the United States, European Union, and other regions 
for use in adults in combination with Zelboraf(vemurafenib) for the treatment of adults 
with unresectable or metastatic melanoma with a BRAF V600 mutation.  The largest 
study evaluating safety and efficacy of cobimetinib to date is the Study GO28141, a 
Phase III, randomized, double-blind, placebo-controlled study of vemurafenib plus 
placebo versus vemurafenib plus cobimetinib in previously untreated BRAF V600 
mutation-positive patients with unresectable locally advanced or metastatic melanoma.  
Refer to the Investigator’s Brochure for results of this study.  


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1.3
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT
Pediatric cancer that is recurrent or refractory represents an area of high unmet medical 
need.  Despite the progress made after 40 years of clinical research using combinations 
of chemotherapy, radiotherapy, and surgery, disease survival and overall survival (OS) 
rates have not significantly improved for children with relapsed or refractory tumors.
Cobimetinib is a potent and highly selective inhibitor of MEK, a central component of the 
RAS/RAF/MEK/ERK pathway that has been implicated in the pathogenesis of a number 
of pediatric tumor types.  Molecularly targeted agents like cobimetinib can potentially 
provide a measure of benefit while reducing the negative impact on quality of life that is 
associated with cytotoxic chemotherapy.
In nonclinical studies, cobimetinib inhibited proliferation of a variety of human tumor cell 
lines.  In addition, cobimetinib inhibited ERK phosphorylation in xenograft tumor models 
(breast, lung, colon, and melanoma) and stimulated apoptosis.  Tumor regression was 
observed in several human tumor xenograft models.
In Study MEK4592g, a Phase I study of single-agent cobimetinib in adult patients with 
solid tumors (n97), adverse events observed were generally tolerable and manageable, 
especially when compared with those associated with cytotoxic agents, such as 
alkylating agents.  Treatmentrelated adverse events included diarrhea, rash, fatigue, 
vomiting, nausea, edema, eye disorders, and abdominal pain.
Among 74 evaluable patients in Study MEK4592g, 6 patients (6.2%) (all of whom had 
melanoma) had a confirmed partial response, 28 patients (28.9%) had stable disease, 
and 40 patients (41.2%) had disease progression.
Because of the critical biological pathway targeted by cobimetinib, the spectrum of 
activity of this drug may include diverse pediatric tumor types.  This study will evaluate 
the safety, tolerability, PK, and preliminary efficacy of cobimetinib in pediatric and young 
adult patients with solid tumors for which prior treatment has proven to be ineffective 
(i.e., relapsed or refractory) or intolerable.  A recommended dose will be identified in the 
dose-escalation stage of the study.  Additional patients will be enrolled and treated at the 
recommended dose in the expansion stage.
Understanding the activity of cobimetinib as a single agent in the pediatric relapsed or 
refractory setting may allow for the addition of this drug to regimens currently available to 
treat newly diagnosed malignancies in pediatric patients.
1.3.1
Rationale for Inclusion of Patients with Brain Tumors
Preclinical studies of cobimetinib in normal mice demonstrated low concentrations of 
drug and a lack of pERK inhibition in brain tissue (Choo et al. 2012).  Cobimetinib is a 
substrate of the efflux transporter P-glycoprotein (P-gp), and knockout mice lacking P-gp 
achieve high concentrations of cobimetinib in the brain, indicating that low brain 


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concentrations of cobimetinib are mediated by drug efflux (Choo et al. 2014).  Preclinical 
animal model brain concentrations of small molecule P-gp substrates do not necessarily 
predict clinical outcomes; for instance, vemurafenib demonstrates clinical intracranial 
anti-tumor efficacy despite brain:plasma concentration ratio of less than 1% in mice 
(Dummer et al. 2014, Mittapalli et al. 2012, Robinson et al. 2014).  Drug efflux in this 
situation is likely reduced by blood-brain or blood-tumor barrier compromise, especially 
following the standard chemoradiotherapy and surgery approach taken in first-line 
treatment of this disease (Choo et al. 2014, Holdhoff et al. 2011).  Thus, children with 
brain tumors with RAS/RAF/MEK/ERK activation may have clinical responses to 
cobimetinib and will be eligible for enrollment in this study.
2.
OBJECTIVES
This study will evaluate the safety, tolerability, PK, and preliminary efficacy of orally 
administered cobimetinib in pediatric (6 months of age) and young adult (30 years of 
age) patients with solid tumors for which prior treatment has proven to be ineffective 
(i.e., relapsed or refractory) or intolerable.  Specific objectives for the study are outlined 
below.
2.1
SAFETY OBJECTIVE
The primary objective for this study is as follows:

To evaluate the safety and tolerability of cobimetinib in children and young adults, 
including estimation of the MTD or the maximum administered dose (MAD) and 
characterization of dose-limiting toxicities (DLTs)
2.2
PHARMACOKINETIC OBJECTIVE
The PK objective for this study is as follows:

To characterize the PK of cobimetinib in children and young adults
2.3
EFFICACY OBJECTIVE
The efficacy objective for this study is as follows:

To evaluate the anticancer activity of cobimetinib in children and young adults with 
solid or brain tumors, as measured by objective response rate (ORR), 
progression-free survival (PFS), duration of objective response (DOR), and OS
2.4
DOSE-FINDING OBJECTIVE
An additional objective for this study is as follows:

To identify recommended Phase II doses for cobimetinib tablet and suspension 
formulations in pediatric patients on the basis of safety, PK, and efficacy outcome 
measures (see Section 3.4)


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2.5
EXPLORATORY OBJECTIVES
The exploratory objectives for this study are as follows:

To explore the relationship between cobimetinib exposure and changes in levels of 
pharmacodynamic (PD) biomarkers in children and young adults

To explore non-inherited biomarkers that may be predictive of response to 
cobimetinib (i.e., predictive biomarkers), may be associated with progression to a 
more severe disease state (i.e., prognostic biomarkers), acquired resistance to 
cobimetinib, or susceptibility to developing adverse events, may provide evidence of 
cobimetinib activity, or may increase the knowledge and understanding of disease 
biology

To explore inherited biomarkers (i.e., variants in germline DNA) that may be 
predictive of response to cobimetinib (i.e., predictive biomarkers), may be 
associated with progression to a more severe disease state (i.e., prognostic 
biomarkers), acquired resistance to cobimetinib, or susceptibility to developing 
adverse events, or may increase the knowledge and understanding of disease 
biology

To explore potential relationships between PK parameters for cobimetinib and other 
outcome measures (such as safety or efficacy outcome measures)

To evaluate tumor characteristics before and after treatment on the basis of 
available magnetic resonance imaging (MRI) and positron emission tomography 
(PET) scans

To evaluate specific aspects of the acceptability of the cobimetinib formulations
3.
STUDY DESIGN
3.1
DESCRIPTION OF STUDY
This is a Phase I/II, multicenter, open-label, dose-escalation study designed to evaluate 
the safety, tolerability, PK, and preliminary efficacy of cobimetinib in pediatric and young 
adult patients with solid tumors with known or potential RAS/RAF/MEK/ERK pathway 
activation for which standard therapy has proven to be ineffective (i.e., relapsed or 
refractory tumors) or intolerable or for which no curative standard-of-care treatment 
options exist.  
Patients will be enrolled via an interactive web response system (IWRS) in two stages:  
a dose-escalation stage and an expansion stage at the recommended dose.  During the 
dose-escalation stage, cohorts of 36 pediatric patients (age 6 months to 18 years) 
will be evaluated at escalating dose levels to determine the MTD or MAD of cobimetinib 
in pediatric patients with advanced solid tumors. The MTD or MAD of each cobimetinib 
formulation (tablet and suspension) will be determined in separate dose escalations (as 
described in Section 3.1.1).  Once the MTD or MAD has been established, pediatric 
patients (age 6 months to 18 years) will be enrolled in the expansion stage and 
treated at the recommended dose, which will be at or below the MTD or MAD, as 
determined by the Sponsor; adult patients 18 years of age with pediatric tumor types 


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can be enrolled on this study but only during the expansion stage; these adult patients 
will be treated at the adult flat dose (see Section 3.1.2).  Approximately 70 patients are 
expected be enrolled in the dose-escalation and initial expansion stages of this study, at 
approximately 30 investigative sites in Europe and North America. If an efficacy signal is 
observed during the first expansion step for the initial response assessment, up to an 
additional 30 patients per cohort may be enrolled in the second expansion step for the 
additional response assessment.
All patients will be closely monitored for adverse events throughout the study and for at 
least 30 days after the last dose of study treatment (see Section 5.3.1).  Adverse events 
will be graded according to the National Cancer Institute Common Terminology Criteria 
for Adverse Events (NCI CTCAE), v4.0.  Other safety assessments include 
echocardiograms, ophthalmologic examinations, and dermatologic examinations.
To characterize the PK properties of cobimetinib, blood samples will be taken at defined 
timepoints after dosing (see Appendix 2).
Tumor assessments will be performed in the final week of every other cycle, starting with 
Cycle 2 (see Section 4.5.5 for more information).  Response will be determined by the 
investigator using the modified International Neuroblastoma Response Criteria (mINRC) 
for patients with neuroblastoma (see Appendix 3), Response Assessment in 
Neuro-Oncology (RANO) criteria for patients with HGG (see Appendix 4), RECIST v1.1 
(see Appendix 6) for patients with other tumors, and RANO criteria for patients with low-
grade glioma (LGG; see Appendix 5) in the expansion stage in addition to RECIST v1.1 .
Patients in both dose-escalation and expansion stages will receive cobimetinib orally 
according to the guidance provided in Appendix 10 on Days 121 of each 28-day 
treatment cycle (21/7 dosing schedule) until the occurrence of disease progression as 
determined by the investigator, death, unacceptable toxicity, or patient or investigator 
decision to discontinue treatment.  
The schedule of assessments is provided in Appendix 1 and the schedule of PK and PD 
assessments is provided in Appendix 2.
3.1.1
Dose-Escalation Stage
Cohorts of 36 pediatric patients each will be treated at escalating doses of cobimetinib 
in accordance with the dose-escalation rules described below.  The first patient at each 
dose level must complete at least 5 days of treatment (Days 15 of Cycle 1) without a 
DLT (as defined in Section 3.1.1.1) before subsequent patients can be treated at the 
same dose level.
The DLT assessment window is defined as Days 128 of Cycle 1.  Adverse events 
identified as DLTs, as defined below (see Section 3.1.1.1), will be reported to the 
Sponsor within 24 hours (see Section 5.4.2).


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Two formulations will be available for the protocol:  a tablet (20 mg) and a suspension 
(4.8 mg/mL).  An MTD or MAD will initially be determined for tablets in patients 6 years 
and above.  Once the MTD or MAD is identified for tablets, enrollment of patients using 
the suspension will commence following review of relevant data from the tablet dose 
escalation. The starting dose for the suspension will be a minimum of one dose level 
below the MTD or MAD of the tablets (see Section 3.1.1.2 for age requirements for 
suspension).  Additional dose escalation with the suspension may proceed according to 
the dose escalation rules (Section 3.1.1.2) until an MTD or MAD is identified for the 
suspension.  On the basis of an ongoing review of safety data and available PK data, 
increases in dose level or continued enrollment for either formulation may be halted by 
the Sponsor as deemed appropriate.
Patients who discontinue from the study prior to completing the DLT assessment window 
for reasons other than a DLT will be considered non-evaluable for dose-escalation 
decisions and MTD or MAD assessments.  These patients will be replaced at that same 
dose level unless there are 3 or more patients already treated and all were evaluated 
with no DLT at that level.  Patients who miss five or more doses (i.e., 18% of the 
cumulative dose) during the DLT assessment window for reasons other than toxicity will 
also be replaced.  Patients who ingest moderate or strong CYP3A inducers or inhibitors 
(defined in Appendix 11), ingest prohibited foods/supplements (defined in Section 4.4.3), 
or receive supportive care during the DLT assessment window that confounds the 
evaluation of DLTs (not including supportive care described below as part of the DLT 
definition) may be replaced at the discretion of the Medical Monitor.
Patients who experience a DLT during the assessment window (first 28 days) may not 
subsequently continue drug at full dose, even if the drug is withheld until resolution of the 
toxic event.  The investigator should use guidance in Section 5.1.1 and Table 2 (and if 
guidance is not specified, investigator discretion) to determine whether the patient 
should permanently discontinue study drug or withhold study drug until toxicity resolves 
to Grade 1 or lower, then resume study drug at a dose corresponding to a reduction of 
one dose level.
A study schema for the dose-escalation stage is displayed in Figure 1.


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Figure 1
Study Schema:  Dose-Escalation Stage
1.33
Additional 
cohorts as 
necessary
Cobimetinib Dose Level
(mg/kg)
Cohort 4
(36 patients)
1.0
Cohort 3 
(36 patients)
0.8
Tablet dose escalation: Pediatric patients 
(6 years to 18 years of age) with 
previously treated solid tumors monitored for 
adverse events during DLT assessment 
window (Days 128 of Cycle 1).  The first
patient at each dose level must complete 
Days 15 without a DLT before subsequent 
patients will be treated at same dose level.
Cohort 2 
(36 patients)
0.6
Cohort 1 
(36 patients)
0.45
Cohort 2 
(36 patients)
Study start
DLT dose-limiting toxicity.
Note:  All patients will receive cobimetinib orally once daily on Days 121 of each 28-day 
cycle.  Dose escalation for suspension will proceed in the same way after MTD of tablets 
has been established, starting at one dose level below the determined MTD or MAD of the 
tablets, and allowing for enrollment of patients 6 months to 6 years of age as permitted in 
Section 3.1.1.2.
3.1.1.1
Definition of Dose-Limiting Toxicity
Any one of the following events will be considered a DLT if it occurs during the DLT 
assessment window and is assessed by the investigator to be related or possibly related 
to cobimetinib (rules for attributing causality are defined in Section 5.3.4):

Grade 4 neutropenia (ANC 0.5109/L) lasting 7 days 

Grade 4 neutropenia with documented infection

Febrile neutropenia, defined as ANC500/mm3 with a single temperature of
38.3C (101F) or a sustained temperature of38C (100.4F) for more than 
1 hour

Grade 4 (i.e., life threatening) anemia of any duration


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
Grade 4 thrombocytopenia lasting 48 hours or any thrombocytopenia requiring a 
platelet transfusion, with the following exception:
For patients who have undergone autologous stem cell transplant or 
131I-metaiodobenzylguanidine (MIBG) therapy, Grade 4 thrombocytopenia 
lasting 7 days or any thrombocytopenia requiring a platelet transfusion on 
two or more separate dates will be considered a DLT.

Grade 3 thrombocytopenia with bleeding

Elevation of serum hepatic transaminase (ALT or AST) 5the upper limit of normal 
(ULN)
For patients with elevated hepatic transaminase levels at baseline as 
a result of liver metastases, hepatic transaminase 5baseline and 
10baseline for 3 days, or any hepatic transaminase 10baseline, will 
be considered a DLT.

Elevation of serum bilirubin 3ULN

For patients reliably able to report visual symptoms:  Grade 2 visual disturbance 
that does not resolve to Grade 1 within 72 hours after interruption of cobimetinib 
treatment

Retinal pathology of any grade, or Grade 2 uveitis or iritis

Grade 2 hemorrhage of any type

Intracranial hemorrhage of any grade

Grade 4 CPK elevation 

Rhabdomyolysis of any grade
o
Rhabdomyolysis includes elevations of CPK in conjunction with either clinical 
features (such as muscle pain, signs of renal failure, dark red or brown urine) 
or with laboratory evidence of renal insufficiency (including Grade 2 or higher 
increased creatinine or creatinine clearance [or radioisotope glomerular 
filtration rate]70 mL/min/1.73 m2), or investigator judgment that a clinical 
scenario is consistent with rhabdomyolysis.

Grade 2 ventricular dysfunction or symptomatic congestive heart failure

Reduction in left ventricular ejection fraction (LVEF) below 50% (or shortening 
fraction below 28%) AND either symptomatic heart failure or a10% relative 
reduction from baseline measurement
Note:  The relative reduction must be 10% of baseline function, not an 
absolute decrease of 10 percentage points. 

Grade 4 (i.e., life threatening) vomiting or diarrhea of any duration


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
Grade 3 non-hematologic, non-hepatic, non-ocular adverse event, with the 
following exceptions, which will not be considered DLTs:
Grade 3 diarrhea or rash that resolves to Grade 2 within 7 days after 
interruption of cobimetinib treatment.
Grade 3 fever.
Grade 3 mucositis or stomatitis that resolves to Grade 2 within 3 days.
Grade 3 nausea or vomiting that responds to standard-of-care therapy 
within 3 days.
Grade 3 fatigue lasting 3 days.
Grade 3 laboratory abnormalities that are asymptomatic and considered by 
the investigator not to be clinically significant.
3.1.1.2
Dose-Escalation Rules
The starting dose of cobimetinib for tablets will be 0.6 mg/kg, administered to patients in 
the first cohort by mouth once daily on Days 121 of each 28-day treatment cycle.  The 
dose will be increased by up to approximately 33% of the preceding dose level for each 
successive cohort, until an MTD or MAD is determined.  The following doses will be 
considered:
Dose Level
Cobimetinib Dose a
-1 
1 (starting dose)
0.45 mg/kg
0.6 mg/kg
2
0.8 mg/kg
3
1.0 mg/kg
4 
1.33 mg/kg
5 or more
TBD
TBDto be determined.
a See Appendix 10 for calculated doses per weight for each formulation.
Intrapatient dose escalation is not allowed except in the following instance:  once an
MTD/MAD has been established, any patient still being treated at a dose lower than the 
recommended dose for expansion stage will be dose-escalated to the recommended 
dose at the start of the next cycle of therapy, unless prior dose reductions or treatment 
interruptions due to therapeutic toxicity have occurred in that patient.
Because maturity of CYP3A4 enzymes does not occur until 1 year of age (see 
Section 3.3.1), patients 1 year of age will not be eligible for enrollment until a safety 
and PK assessment of the first 6 patients treated with suspension for at least one cycle 
of therapy has been conducted.


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Relevant demographic, adverse event, laboratory, dose administration, and all available 
PK data will be reviewed prior to dose-escalation decisions and prior to initiation of 
suspension dose escalation, which will be made by the Medical Monitor in consultation 
with the Principal Investigators and the Internal Monitoring Committee (IMC).  
In order to minimize safety risks during dose escalation but to ensure optimal access for 
children to the trial, dose escalation will commence according to the rolling 6 design.  In 
this design, up to a maximum of 6 patients can be enrolled concomitantly at the same 
dose level.  The dose level allocated to a new patient is based on the number of patients 
currently enrolled and evaluated, the number of patients experiencing DLT, and the 
number of patients whose evaluation is pending at the time of new patient entry.  De-
escalation occurs when two or more DLTs occur at a dose level, whereas escalation can 
be performed when 3/3, 4/4, 5/5, 5/6, or 6/6 patients are evaluated without a DLT.  
Otherwise, patients can be included at the same level up to a total of 6 patients per dose 
level.  Dose escalation will proceed according to the rules shown in Table 1 (adapted 
from Doussau et al. 2012 and Skolnik et al. 2008).


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Table 1
Dose Determination for the Next Patient in Rolling 6 Design
Number of 
Patients 
Enrolled
Number of 
Patients with 
DLTs
Number of 
Patients 
without DLT
Number of 
Patients with 
Data Pending
Enrolling 
Dose Level 
(MTD Not 
Exceeded)
Enrolling 
Dose Level 
(MTD 
Previously 
Exceeded)
2
0,1
Any
Any
Same
2
2
0
0
Dose 
decrease
3
0
0,1,2
3,2,1
Same
3
0
3
0
Dose increase
3
1
0,1,2
2,1,0
Same
3
2
Any
Any
Dose 
decrease
4
0
0,1,2,3
4,3,2,1
Same
Same
4
0
4
0
Dose increase
Same
4
1
0,1,2,3
3,2,1,0
Same
Same
4
2
Any
Any
Dose 
decrease
Dose 
decrease
5
0
0,1,2,3,4
5,4,3,2,1
Same
Same
5
0
5
0
Dose increase
Same
5
1
0,1,2,3,4
4,3,2,1,0
Same
Same
5
2
Any
Any
Dose 
decrease
Dose 
decrease
6
0
0,1,2,3,4
6,5,4,3,2
Suspend
Suspend
6
0
5,6
1,0
Dose increase
MTD
6
1
0,1,2,3,4
5,4,3,2,1
Suspend
Suspend
6
1
5
0
Dose increase
MTD
6
2
Any
Any
Dose 
decrease
Dose 
decrease
MTDmaximum tolerated dose.
Notes:  Samenext patient would be treated at the same dose.
Dose increasenext patient would be treated at a higher dose.
Dose decreasenext patient would be treated at a lower dose. 
Suspendenrollment will be suspended until enough patients have been evaluated.


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Dose escalation will proceed according to Table 1 and in accordance with the rules listed 
below.

If 2 or more of the first 6 DLT-evaluable patients in a cohort experience a DLT, the 
MTD will have been exceeded; subsequent patients must be treated at a lower dose 
level.

If the dose level at which the MTD is exceeded is 25% higher than the preceding 
dose level, an intermediate dose level may also be evaluated.  Otherwise, the 
highest dose at which fewer than 2 of 6 DLT-evaluable patients (i.e., 33%) 
experience a DLT will be declared the MTD.

If the MTD is not exceeded at any dose level, the highest dose administered in this 
study will be declared the MAD.
Enrollment in the dose-escalation stage for a particular formulation will be stopped if at
least 6 DLT-evaluable patients are treated at that formulation’s MTD or MAD.
On the basis of an ongoing review of real-time safety data and available PK data, 
increases in dose level may be halted by the Sponsor as deemed appropriate. 
3.1.2
Expansion Stage
After the MTD or MAD has been determined for a formulation, pediatric and young adult 
patients will be enrolled in tumor type cohorts to obtain additional safety, tolerability, and 
PK data, as well as any preliminary evidence of anti-cancer activity.  Pediatric 
(18 years of age) patients will be treated at or below the formulation-specific MTD or 
MAD identified in the dose-escalation stage of this study.  Young adult patients 
(18 years of age) will be treated at the recommended adult dose (see Section 4.3.2).  
The Sponsor reserves the right to determine which formulation(s) will be taken forward 
into the expansion stage and whether enrollment into the expansion stage using tablets
(if applicable) will proceed concurrently with or subsequent to dose-escalation for 
suspension. Enrollment in expansion cohorts may commence after the IMC has 
reviewed PK and safety data obtained in the dose escalation phase (see Section 3.1.3).
Each tumor type will be considered a distinct tumor type cohort. Different tumor type 
cohorts may not all enroll simultaneously. Tumor type cohorts will be chosen after IMC 
review, prior to inclusion in the expansion stage of the study. Chosen tumor type 
cohorts for the expansion stage may also include subgroups of tumor types included in 
the dose-escalation stage, with inclusion based on confirmed (rather than expected) 
RAS/RAF/MEK/ERK-pathway activation (based on local testing of sample from time of 
diagnosis or any subsequent timepoint prior to enrollment) with approval of medical 
monitor). Two phases of response assessment are planned for the expansion stage:  an 
initial response assessment and an additional response assessment (as defined in 
Table 6 in Section 6.1).  An initial response assessment will be performed after a 
minimum of 10 patients, treated at the recommended dose for expansion stage, have 


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been enrolled in a tumor type cohort and followed for approximately 12 months, to
determine whether to expand the cohort for additional response assessment.  For 
purposes of initial response assessment, patients “treated at the recommended dose for 
expansion stage” includes those patients who initiate therapy at the eventual 
recommended dose for expansion, whether they are treated during the dose escalation 
stage or during the expansion stage.  Patients who are dose-reduced from the 
recommended dose due to therapeutic toxicity will still be included for response 
assessment.  Patients in dose-escalation who are treated below the recommended dose 
for expansion, and subsequently dose-escalated to the recommended dose, will not be 
included for response assessment.
Cohort expansion will be started once a pre-established number of responses for that 
tumor type are confirmed (per Table 6).  A decision to pursue additional enrollment in a 
tumor type cohort may be approved by the Sponsor or Medical Monitor before the initial 
response assessment. Cohort expansion, including the number of patients needed for 
the additional response assessment, will take into account practical considerations 
(e.g., enrollment feasibility), preclinical findings, biomarker analysis, safety profiles, and 
any other relevant information.  A study schema for the expansion stage is displayed in 
Figure 2.
If the frequency of Grade 3 or 4 toxicities or other unacceptable toxicities at the initial 
dose level in the expansion stage suggest that this dose is intolerable, accrual at that 
dose level will be halted.  Consideration will then be given to enrolling patients at a lower 
dose level.
The Sponsor may decide to stop enrollment of patients 18 years of age at any time 
during the study to ensure adequate enrollment of patients 18 years of age.  To meet 
study completion criteria below, the Sponsor may restrict enrollment of patients 
10 years of age if too few patients 10 years of age have been enrolled.
The Sponsor intends to stop study enrollment once all of the following criteria are met:

The dose-escalation phase of both tablet and suspension formulations are complete

At least 20 patients 18 years of age have been treated with study drug

At least one tumor type cohort has completed response assessment (either initial 
response assessment or additional response assessment)

At least 10 patients 10 years of age have been treated with study drug
Enrollment in a tumor type cohort will be stopped if any one of the following criteria is 
met: 

The number of patients needed for initial response assessment is reached and the 
number of responders does not meet the requirement for tumor type cohort 
expansion




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completion of the dose-escalation stage.  The IMC will include Sponsor representatives 
from Clinical Science, Biostatistics, Safety Science, and Clinical Pharmacology.  IMC 
members should not have regular contact with the sites as part of their responsibilities. 
In addition to the ongoing assessment of the incidence and nature of DLTs, adverse 
events (particularly Grades 3), serious adverse events, deaths, and laboratory 
abnormalities by the investigator and the Medical Monitor, the IMC will review all 
necessary cumulative data at regular intervals during the study (including prior to 
suspension dose escalation and prior to initiation of expansion cohorts). Ad hoc 
meetings may be called in addition to scheduled meetings, as necessary, to obtain IMC 
recommendations on management of any new safety issues. 
A Scientific Oversight Committee (SOC), which will consist of experts external to the 
Sponsor (including at least two members not involved in study activities), will also be 
established for this study.  The SOC will enhance safety monitoring and leverage 
external experts’ scientific expertise by providing advice on data interpretation.  The 
SOC will function as a consultative body to the Sponsor, providing individual expert 
opinions.  
Specific operational details, such as committee composition, frequency and timing of 
meetings, and member roles and responsibilities, will be detailed in an IMC and SOC 
Charter.
3.2
END OF STUDY
The end of this study is defined as the date when the last patient, last visit (LPLV) occurs, 
or 5 years after the last patient is enrolled, whichever occurs first.  The Sponsor reserves 
the right to present interim data to health authorities for compliance purposes. 
For an individual patient the completion of the study (i.e., the last visit) will occur when 
the patient withdraws consent, has completed follow-up, has been lost to follow-up, dies, 
or when the trial is stopped.
The primary analysis will be conducted after the enrollment has been completed and all 
enrolled patients have been followed for at least 12 months.  Clinical Study Report (CSR) 
will be submitted to health authorities. 


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3.3
RATIONALE FOR STUDY DESIGN
3.3.1
Rationale for Cobimetinib Dose and Schedule
Cobimetinib will be administered by mouth once daily on Days 121 of each 28-day 
treatment cycle.  The traditional starting point for pediatric oncology Phase I studies of 
cytotoxic agents is 80% of the adult dose (Lee et al. 2005) and for targeted agents 
according to the toxicity profile 80%100% of the adult dose appears safe 
(Paoletti et al. 2013).  In the dose-escalation stage, the first cohort of 3 patients treated 
with tablets will receive cobimetinib at a dose of 0.6 mg/kg, or approximately 80% of the 
adult Phase III dose.  
The mean elimination T1/2 of most substrates approaches adult levels at 26 months of 
age.  In vitro data suggest that, although liver enzymes in general have not matured fully, 
a significant amount and activity of enzymes are present at this age (Bartelink et al. 
2006).  In vitro data indicate that cobimetinib is a substrate of CYP3A4 and UGT2B7, 
both of which are expressed before or soon after birth.  The activity of both CYP3A4 and 
UGT2B7 reaches 100% of adult activity by 1 year of age (Kearns et al. 2003).  Given the 
maturation profile of the two enzymes principally involved in cobimetinib metabolism, 
significant differences in cobimetinib metabolism are not expected to be observed 
among pediatric patients, even those as young as 6 months of age. Per Section 3.1.1.2,
patients 1 year of age will not be eligible for enrollment until a safety and PK 
assessment of the first 6 patients treated with suspension for at least one cycle of 
therapy has been conducted and until all available pediatric data from tablet and 
suspension cohorts has been reviewed by the IMC.
If a drug is mainly metabolized by UGT or CYP2D6, the plasma clearance seems to be 
correlated with body weight (Bartelink et al. 2006).  Thus, doses in this study will be 
based on patient body weight.
3.3.1.1
Rationale for Tablet and Suspension Dosing Strategy
Cobimetinib has good solubility in water (0.74 mg/mL, at 37C).  A mass balance study 
in humans has shown that the fraction of dose absorbed is 0.88, indicating high fraction 
absorbed and hence permeability.  Given the high solubility and permeability of 
cobimetinib, differences due to formulation change are not anticipated.  During 
development of cobimetinib in adult populations, it was seen that different formulations 
provided comparable exposures (see cobimetinib Investigator’s Brochure), and that 
cobimetinib absorption was not dissolution-rate limited.  Hence, the suspension is 
expected to provide similar exposures as would be obtained upon administration of the 
tablet, and therefore equivalent doses administered to pediatric patients will provide 
comparable exposures. As bioequivalence has not been directly proven between the 
existing tablet and powder for suspension formulations in a relative bioavailability study, 
the Sponsor will initiate dose escalation for the suspension at least one dose level below 
that of the tablet MTD/MAD to ensure study drug administration via suspension does not 
result in overexposure or excessive toxicity.


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Both tablet and suspension formulations are being utilized to ensure adequate 
age-appropriate dosing for the study.  Enrollment to receive the tablet will be restricted to 
patients 6 years of age due to the size of the tablet.  Enrollment to receive the tablet 
will further be restricted to patients weighing 20 kg, because tablet dosing (defined in 
Appendix 10) in patients 20 kg could potentially cause excessive variation in 
cumulative administered dose per kilogram (10%) within a dose level cohort.  
To ensure that patients treated with tablets receive a cumulative dose most closely 
approximating their body weight, patients will be assigned a cumulative weekly dose in 
20-mg increments, with distribution of tablets as evenly as possible throughout the week.  
For example, if a patient’s dose is 60 mg in a week, the dosing would be 20 mg on 
Days 1, 3, and 5 of that week.  Given the T1/2 of cobimetinib (approximately 2 days), the 
intermittent dosing of cobimetinib is not expected to result in significant fluctuations in 
the average cobimetinib concentrations, and steady state exposures will be achieved 
approximately 10 days after start of dosing.
3.3.2
Rationale for Patient Population
The late-phase program of cobimetinib in adults is focused on indications with limited 
existence in children, thus significantly reducing the population of pediatric patients
potentially able to receive the drug.  Given the occurrence of alterations in the 
RAS/RAF/MEK/ERK pathway in a large range of pediatric malignancies, the pursuit of a 
broad mechanism-of-actionderived approach to include pediatric tumors may maximize 
the opportunity to determine which pediatric patients may benefit from treatment with 
cobimetinib.  Importantly, the safety of cobimetinib as a single agent must be 
demonstrated and toxicity must be analyzed to provide treating physicians with clear 
guidance for administration of cobimetinib and monitoring of patients in the pediatric 
setting.  With this in mind, the trial will draw from a broad spectrum of pediatric tumor 
types, each of which has evidence of growth promotion through the RAS/RAF/MEK/ERK 
pathway either in nonclinical model systems or retrospective clinical tumor analyses.
The Sponsor expects that the majority of enrolled patients will be 18 years of age.  
Patients even as young as 6 months of age may experience tumor types such as 
neuroblastoma for which cobimetinib is a rational potential therapy, and these patients 
will be included in the trial upon availability of a suspension formulation. However, there 
may be young adult patients with "pediatric-type" tumors who are treated in pediatric 
oncology facilities.  In a specific analysis of adolescent and young adult (AYA) patients in 
the United States, limited clinical trial participation correlated with the relative lack of 
improvement in survival prolongation and cancer death rates (Bleyer et al. 2006).  The 
lower participation of AYAs in clinical trials has created significant knowledge gaps with 
respect to cancer biology, treatment, and other factors affecting the survival of AYAs 
with cancer.  As part of the Sponsor's commitment to the development of personalized 
medicine, AYAs up to 30 years of age (and in exceptional cases of relapsed pediatric 
tumors, beyond 30 years of age) will be included in the expansion stage of the study.


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3.3.3
Rationale for Biomarker Assessments
The Sponsor is committed to the collection of biomarker samples in all clinical studies.  
The objective of biomarker profiling is to enable development of treatments specifically 
targeted for optimum patient benefit.  The rationale for the planned biomarker analyses 
is explained below.  However, because the body of knowledge of potential new 
biomarkers is evolving, the definitive list of analyses may be modified on the basis of 
new information.
This study will explore biomarkers associated with response to MEK inhibition in archival 
or fresh tumor tissue specimens obtained at baseline.
Given the genetic heterogeneity of the patients who will enroll in this study, the 
magnitude of response to MEK inhibition may be different in certain pediatric tumors.  To 
identify candidate predictive biomarkers, molecular analyses of tumor tissue and plasma 
may include assessment of genetic and activation status of the targeted 
RAS/RAF/MEK/ERK pathway, potential escape mechanisms such as receptor tyrosine 
kinases and PI3K/PTEN pathways, and components of the tumor stroma (e.g., tumor 
infiltrating lymphocytes).  These analyses may be conducted at the DNA, RNA, protein, 
and cell levels.  In addition, expression of pathway-relevant prognostic biomarkers and 
alternative drug targets may be explored.  These analyses are essential for the 
identification of patients who will benefit the most from cobimetinib.
It has been shown that tumor-specific mutations can be identified in plasma (‘circulating 
tumor DNA).  Assessment of RNA and DNA may be evaluated in tumor tissue collected 
at baseline and plasma collected at baseline and during the study.  Analysis and 
correlation of mutations in tumor tissue and plasma will help to further evaluate the 
option of using plasma for the detection of tumor-specific mutations.
3.4
OUTCOME MEASURES 
3.4.1
Safety Outcome Measures
The safety outcome measures for this study are as follows:

Incidence and nature of DLTs

Nature, frequency, severity, and timing of adverse events, including serious adverse 
events and adverse events of special interest

Changes in vital signs, physical findings, and clinical laboratory results during and 
following cobimetinib administration

Growth patterns (relative to age-specific standards for height and weight) 
accounting for baseline growth of the patient

Development patterns (relative to onset of menarche [for females] and pubertal 
changes) accounting for baseline development of the patient


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3.4.2
Pharmacokinetic Outcome Measure
The PK outcome measure for this study is as follows:

To characterize cobimetinib PK in pediatric patients, the following PK parameters 
following single and multiple doses will be estimated:  maximum plasma 
concentration observed (Cmax), Tmax, total exposure (area under the 
concentrationtime curve from 0 to 24 hours [AUC0-24]), and apparent clearance 
(CL/F). 
3.4.3
Efficacy Outcome Measures
The co-primary efficacy outcome measures for this study are as follows:

ORR, defined as the percentage of patients with a complete or partial response for 
patients with measurable disease or neuroblastoma patients with evaluable disease 
at baseline, or a complete response for patients with nonmeasurable but evaluable 
disease at baseline (except neuroblastoma patients), on two consecutive occasions 
4 weeks apart, as determined by the investigator using mINRC for patients with 
neuroblastoma (see Appendix 3), RANO criteria for patients with HGG (see 
Appendix 4; Wen et al. 2012), for the RANO criteria for patients with LGG (see 
Appendix 5) and RECIST v1.1 for patients with other tumors (see Appendix 6).

PFS, defined as the time from initiation of study drug to the first documented 
occurrence of disease progression, as determined by the investigator using mINRC 
for patients with neuroblastoma (see Appendix 3), RANO criteria for patients with 
HGG (see Appendix 4; Wen et al. 2012), RECIST v1.1 for patients with other tumors 
(see Appendix 6), and RANO criteria for patients with LGG (see Appendix 5) in the 
expansion stage in addition to RECIST v1.1, or death from any cause, whichever 
occurs first
The secondary efficacy outcome measures for this study are as follows:

DOR, defined as the time from the first tumor assessment that supports the patient’s 
objective response to the time of disease progression, as determined by the 
investigator using mINRC for patients with neuroblastoma (see Appendix 3), RANO 
criteria for patients with HGG (see Appendix 4; Wen et al. 2012), RECIST v1.1 for 
patients with other tumors (see Appendix 6), and RANO criteria for patients with 
LGG (see Appendix 5) in the expansion stage in addition to RECIST v1.1. , or death 
from any cause, whichever occurs first

OS, defined as the time from initiation of study drug to death from any cause
3.4.4
Exploratory Outcome Measures
The exploratory outcome measures for this study are as follows:

Levels of potential PD biomarkers (potentially including, but not limited to, p-MEK, 
p-ERK, and Ki67) measured in tumor tissue collected at baseline, on treatment, and 
at the time of disease progression


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
Correlation between non-inherited and inherited biomarkers in plasma (potentially
including, but not limited to, BRAF mutations, BRAF fusions, RAS mutations, and 
NF1 alterations) with safety, PK, or efficacy outcome measures

To explore potential relationships between cobimetinib PK and other outcome 
measures (such as safety or efficacy outcome measures)

ORR for LGG, defined as the percentage of patients with measurable disease who 
have a complete or partial response  on two consecutive occasions 4 weeks apart, 
as determined by the investigator using RECIST v1.1

Modified ORR for LGG, defined as the percentage of patients with measurable 
disease who have a complete, partial, or minor response  on two consecutive 
occasions 4 weeks apart, as determined by the investigator using the RANO 
criteria for LGG (see Appendix 5).

Diffusion activity in tumors before and after cobimetinib treatment, as demonstrated 
on available MRI scans

Metabolic activity in tumors before and after cobimetinib treatment, as demonstrated 
on available PET scans

Acceptability survey
4.
MATERIALS AND METHODS
4.1
PATIENTS
This study will enroll approximately 70 pediatric or young adult patients with solid tumors
with known or expected RAS/RAF/MEK/ERK pathway activation for which prior 
treatment has proven to be ineffective (i.e., relapsed or refractory) or intolerable.
4.1.1
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed Informed Consent Form

Signed Child's Informed Assent, when appropriate as determined by patient's age 
and individual site and country standards

For dose-escalation stage, tablets:  Age at study entry 6 years to 18 years

For dose-escalation stage, suspension: age at study entry 6 months to 18 years
Patients 1 year of age will not be enrolled until 6 patients 1 year to 
18 years of age have received at least one cycle of therapy with suspension 
and until safety and PK assessment of these patients has been conducted.


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
For expansion stage:  Age at study entry 6 months (6 years if suspension is not 
available) to 30 years
Patients 6 months to 1 year of age may not be enrolled until 6 patients 
1 year to 18 years of age have received at least one cycle of therapy with 
suspension in the dose-escalation phase and until safety and PK assessment 
of these patients has been conducted).
In exceptional cases of relapsed pediatric tumors in patients 30 years of age, 
the Sponsor will consider waiving the age requirement with approval of the 
Medical Monitor.  This waiver is restricted to patients with pediatric-specific 
diseases (e.g., neuroblastoma) for whom clinical trials are unlikely to be 
available, and will not be extended to patients with tumors that typically occur 
both in children and adults (e.g., HGG).  The Sponsor may decide to stop 
enrollment of patients 18 years of age at any time during the study to ensure 
adequate enrollment of patients 18 years of age. 

Able to comply with the requirements of the study protocol, in the investigator’s 
judgment

Tumors for which prior treatment has proven to be ineffective (i.e., relapsed or 
refractory) or intolerable, or for which no standard therapy exists.  

Tumors with known or expected RAS/RAF/MEK/ERK pathway involvement. 
Diagnosis MUST be one of the following tumor types:
Central nervous system gliomas, including high- and low-grade gliomas, and 
DIPG
For initial expansion stage, evidence of RAS/RAF/MEK/ERK-pathway 
activation is required (based on local testing of sample from time of 
diagnosis or any subsequent timepoint prior to enrollment) and must be 
approved by medical monitor for inclusion.
Embryonal rhabdomyosarcoma and other non-rhabdomyosarcoma soft tissue 
sarcomas
Neuroblastoma
Melanoma
Malignant peripheral nerve sheath tumor 
Rhabdoid tumors, including ATRT
Tumors from the following groups that in the judgment of the investigator, are 
life threatening, resulting in severe symptoms (including severe pain), or are in 
close proximity to vital structures:
NF1-associated tumors (including plexiform neurofibroma)
Schwannoma
Any solid tumor or brain tumor that occurs in a patient with another 
RASopathy (such as Noonan syndrome)


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Any solid or brain tumor that has been molecularly profiled and shown to have 
RAS/RAF/MEK/ERK pathway activation, with approval of the Medical Monitor. 

Tumor diagnosis must be histologically or cytologically confirmed either at time of 
diagnosis or at time of relapse, except in the following scenario:
DIPG and optic pathway gliomas do not require histologic confirmation if 
radiographic findings are sufficient to make diagnosis and institutional standard 
of care does not mandate biopsy for diagnosis.

Current disease state for which there is no known curative therapy or therapy 
proven to prolong survival with an acceptable quality of life

Disease that is measurable as defined by mINRC, RANO criteria for HGG, RANO 
criteria for LGG, or RECIST v1.1 (as appropriate) or evaluable by nuclear medicine 
techniques, immunocytochemistry techniques, tumor markers, or other reliable 
measures

Availability of tumor tissue at study enrollment is mandatory.  Archival tumor tissue 
block or 15 freshly cut, unstained, serial slides available for submission, and/or 
willingness to undergo a core or excisional biopsy prior to enrollment are acceptable.  
Fine-needle aspiration, brush biopsy, and lavage samples are not acceptable.
For patients submitting archival tissue, a minimum of 15 slides are required.  
Patients with fewer than 15 slides available may be eligible for study entry 
following approval of the Medical Monitor.  See Section 4.5.9 for detailed tissue 
requirements.

Lansky Performance Status or Karnofsky Performance Status (see Appendix 7 and 
Appendix 8, respectively) 50%

Life expectancy 3 months, in the investigator's judgment

For female patients of childbearing potential:  agreement to remain abstinent (refrain 
from heterosexual intercourse) or use contraceptive measures, and agreement to 
refrain from donating eggs, as defined below:
Female patients must remain abstinent or use single or combined contraceptive 
methods that result in a failure rate of 1% per year during the treatment period 
and for at least 3 months after the last dose of study drug.  Female patients
must refrain from donating eggs during this same period.
True abstinence is only acceptable if it is in line with the preferred and usual 
lifestyle of the patient.  Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, or postovulation methods) and withdrawal are not acceptable 
methods of contraception.
Examples of contraceptive methods with a failure rate of 1% per year include, 
hormonal implants, established, proper use of combined oral or injected 
hormonal contraceptives, and certain intrauterine devices.  Alternatively, two 
methods (e.g., two barrier methods such as a condom and a cervical cap) may 
be combined to achieve a failure rate of 1% per year.  Barrier methods must 
always be supplemented with the use of a spermicide.


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
For male patients with a female partner of childbearing potential or a pregnant 
female partner:  Agreement to remain abstinent or use a condom during the 
treatment period and for at least 3 months after the last dose of study drug
True abstinence is only acceptable if it is in line with the preferred and usual 
lifestyle of the patient.  Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, or postovulation methods) and withdrawal are not acceptable 
methods of contraception.

For male patients:  agreement to refrain from donating sperm during the treatment 
period and for at least 3 months after the last dose of study drug

Adequate hematologic and end organ function, defined by the following laboratory 
results obtained within 28 days prior to initiation of study drug:
ANC 0.75109/L (unsupported)
Platelet count 75109/L (unsupported)
Hemoglobin 8 g/dL (transfusion is acceptable to meet this criterion)
Bilirubin 1.5ULN for age
AST and ALT 2.5ULN for age
Serum creatinine 1.5ULN for age or creatinine clearance (or radioisotope 
glomerular filtration rate) 70 mL/min/1.73 m2

Fractional shortening (FS) 30% and LVEF 50% at baseline, as determined by 
echocardiography or multigated acquisition scan (MUGA) within 28 days prior to 
initiation of study drug
Depending on institutional standard, either FS or LVEF is adequate for 
enrollment if only one value is measured; if both values are measured, then 
both values must meet criteria above.

Body weight must be 20 kg if suspension is not available
4.1.2
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Pregnant or lactating, or intending to become pregnant during the study
Females of childbearing potential must have a negative serum pregnancy test 
result within 1 week prior to initiation of study drug.

Prior treatment with cobimetinib or other MEK inhibitor.  Prior sorafenib use is 
permissible.

Treatment with high-dose chemotherapy and stem-cell rescue (autologous stem cell 
transplant) within 3 months prior to initiation of study drug


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
Treatment with chemotherapy (other than high-dose chemotherapy as described 
above) or differentiation therapy (such as retinoic acid) or immunotherapy (such as 
anti-GD2 antibody treatment) within 4 weeks prior to initiation of study drug or, if 
treatment included nitrosoureas, within 6 weeks prior to initiation of study drug.  This 
requirement may be waived at the investigator’s request if the patient has recovered 
from therapeutic toxicity to the degree specified in the protocol, with approval of the 
Medical Monitor.

Treatment with thoracic or mediastinal radiotherapy within 6 weeks prior to initiation 
of study drug

Treatment with hormonal therapy (except hormone replacement therapy or oral 
contraceptives), immunotherapy, biologic therapy, or herbal cancer therapy within 
4 weeks or 5 half-lives, whichever is shorter, prior to initiation of study drug

Treatment with a long-acting hematopoietic growth factor within 2 weeks prior to 
initiation of study drug or a short-acting hematopoietic growth factor within 1 week 
prior to initiation of study drug

Treatment with investigational therapy (with the exception of cancer therapies as 
described above) within 4 weeks prior to initiation of study drug

Requirement for initiation of corticosteroids or an increase in the dose of 
corticosteroids within 1 week prior to initiation of study drug

Treatment with St. John's wort or hyperforin or drugs that are strong inhibitors or 
inducers of CYP3A (refer to Section 4.4.2) within 1 week prior to initiation of study 
drug

Ingestion of grapefruit juice within 1 week prior to initiation of study drug

Any toxicity from prior treatment that has not resolved to Grade 1 (per 
NCI CTCAE v4.0) at screening, except 
Alopecia
Ototoxicity
Parameters otherwise permitted in the inclusion/exclusion criteria (such as 
hematologic, biochemical, or performance status criteria)

Major surgical procedure or significant traumatic injury within 4 weeks prior to 
initiation of study drug, or anticipation of need for major surgical procedure during 
the course of the study
Placement of a vascular access device or minor surgery is permitted if the site 
has healed prior to initiation of study drug.

Known active infection (excluding fungal infection of the nail beds) within 28 days 
prior to initiation of study drug that has not completely resolved

History of Grade ≥ 2 CNS hemorrhage. 

History of CNS hemorrhage within 28 days of study entry. This criterion may be 
waived at the investigator’s request if the CNS hemorrhage was asymptomatic, with 
approval of the Medical Monitor.


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
For brain tumor patients, use of anticoagulants within 1 week of study drug initiation

History or evidence of retinal pathology on ophthalmologic examination that is 
considered to be a risk factor for or indicative of neurosensory retinal detachment, 
central serous chorioretinopathy (CSCR), neovascular retinopathy, or retinopathy of 
prematurity

Known hypersensitivity to any component of the study drug

Inability to swallow oral medications

Impaired gastrointestinal absorption

Prior allogenic bone marrow transplantation or prior solid organ transplantation

Any other disease, metabolic or psychological dysfunction, physical examination 
finding, or clinical laboratory finding giving reasonable suspicion of a disease or 
condition that contraindicates use of an investigational drug or places the patient at 
unacceptable risk from treatment complications

Current drug or alcohol use or dependence that would interfere with adherence to 
study requirements, in the opinion of the investigator
4.2
METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
This is an open-label study.  Patients will be assigned to dose levels in the order in 
which they are enrolled.
4.3
STUDY TREATMENT 
4.3.1
Formulation, Packaging, and Handling
Cobimetinib packaging will be overseen by the Roche clinical trial supplies department 
and will 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.
Cobimetinib will be stored at the clinical site under the required storage conditions as 
indicated on the study drug labels.  Patients or their caregivers will be asked to store 
cobimetinib at the required storage conditions noted in Section 4.3.1.1 and 
Section 4.3.1.2, out of the reach of children or other co-inhabitants.


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4.3.1.1
Cobimetinib Tablet Formulation
The 20 mg cobimetinib drug product is a film-coated, white, round, immediate-release 
tablet approximately 6.6 mm in diameter.  Cobimetinib will be packaged in bottles.
The inactive ingredients in cobimetinib are as follows:  lactose monohydrate, 
microcrystalline cellulose, croscarmellose sodium, and magnesium stearate for the tablet 
core.  The tablet coating consists of polyvinyl alcohol-part hydrolyzed, titanium dioxide, 
polyethylene glycol 3350 and talc.
Cobimetinib tablets should not be stored above 25°C (77°F).  If study drug is stored 
outside of the permitted temperature ranges, quarantine the affected supply and contact 
the Medical Monitor.
4.3.1.2
Cobimetinib Suspension Formulation
Cobimetinib powder for oral suspension formulation will be supplied by the Sponsor as a 
white to off-white dry powder in an amber glass bottle for reconstitution by the 
institutional pharmacist with 50 mL of drinkable water.  This will result in a 4.8 mg/mL 
suspension.  The suspension is flavored with strawberry flavor.  Accurate dosing of 
patients will be ensured by a press-in-bottle adapter in combination with the use of an 
oral dispenser.  For further information on the formulation, the exact reconstitution 
procedure, and handling of cobimetinib powder for oral suspension, see the pharmacy 
manual.
Cobimetinib suspension should be stored at 2°C to 8C (36F to 46F).  If study drug is 
stored outside of the permitted temperature ranges, quarantine the affected supply and 
contact the Medical Monitor.
4.3.2
Dosage, Administration, and Compliance
Cobimetinib will be taken orally once daily on Days 121 of each 28-day treatment cycle
(21/7 dosing schedule) according to the guidance provided in Appendix 10 until the 
occurrence of disease progression as determined by the investigator, death, 
unacceptable toxicity, or patient or investigator decision to discontinue treatment.  The 
starting dose for tablets will be 0.6 mg/kg in the dose-escalation stage.  Possible 
subsequent doses are listed in Section 3.1.1.2.  Pediatric patients (18 years of age) 
enrolled in the expansion stage will be treated at or below the MTD or MAD, as 
determined by the Sponsor.  Adult patients (18 years of age) enrolled in the expansion 
stage will be treated with the adult recommended dose of 60 mg daily. In case a 
de-escalation is required in these adult patients, please refer to Section 5.1.1. Patients 
who reach 18 years of age after starting study therapy will remain on weight-based 
dosing.  Patients will be weighed at the beginning of each cycle. In Cycle 1, weight 
recorded during the screening period is acceptable.  For subsequent cycles, weight must 
be recorded within 3 days prior to the Day 1 dose, and the dose will be adjusted as 
needed.  No patients will be treated with cobimetinib on Days 2228 of each cycle.


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Patients under 6 years of age or weighing 20 kg are only eligible to receive the drug in 
suspension (see Section 3.3.1.1 for rationale).  Once the suspension is available, the 
Sponsor will determine whether tablets will remain available to sites based on the 
observed safety profile and PK of the two formulations, as well as operational feasibility 
of providing two formulations.  If a patient is eligible for treatment with either tablet or 
suspension formulation, and both formulations are available, the investigator will 
determine the most appropriate formulation for the patient and enroll the patient into 
study accordingly. However, patients may not switch formulations after the start of 
therapy unless safety differences between the two formulations mandate a change for all 
patients on the study.
For patients who receive tablets, cobimetinib will be administered on Days 1-21 of each 
cycle as whole 20-mg tablets.  For pediatric patients, a cumulative weekly dose (rounded 
to nearest 20 mg) based on weight and dose level will be determined, and daily dose in 
whole tablets will be extrapolated from this dose.  Investigators must not calculate the 
dose on their own but must use the dosing charts in Appendix 10 to determine the 
correct dose amount and frequency based on dose level and patient weight. 
For patients who receive suspension, cobimetinib will be administered using either a 
3-mL or a 10-mL oral dispenser.  The patient will take the same dose on Days 121 of 
each cycle.  Investigators must not calculate the dose on their own but must use the 
dosing charts in Appendix 10 to determine the correct dose amount based on dose level 
and patient weight.  Note that cobimetinib should not be administered through a 
nasogastric tube on this study, given that the adsorptive properties of nasogastric tubes 
for cobimetinib are unknown.
Cobimetinib should be taken at approximately the same time each day, no earlier than 
1 hour before and no later than 4 hours after the usual dosing time.  On study visit days, 
the dose of cobimetinib will be taken in the clinic, after pretreatment assessments have 
been performed.
Patients or their caregivers must record the time and date they take each dose of 
cobimetinib in a medication diary.   Cobimetinib can be administered at the same time as 
food, or on an empty stomach.  However, suspension cobimetinib should only be 
administered with the supplied oral dispenser(s) and should not be mixed into food, milk, 
or juice.  Tablets may not be crushed or cut.  Missed doses should also be recorded.  
Patients and their caregivers will be instructed to bring all unused study drug and the 
study drug diary to each study visit for assessments of compliance.  
If a dose of cobimetinib is missed (i.e., not taken within 4 hours after the scheduled 
dosing time), the patient should resume dosing with the next scheduled dose.  Missed or 
vomited doses will not be made up.


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If cobimetinib treatment has been interrupted for more than 28 days for whatever reason 
(including adverse events), the patient will be considered to have discontinued from 
study drug and will enter the treatment follow-up period.
Guidelines for dosage modification and treatment interruption or discontinuation are 
provided in Table 2.
Any overdose or incorrect administration of study drug should be noted on the Study 
Drug Administration electronic Case Report Form (eCRF).  Adverse events associated 
with an overdose or incorrect administration of study drug should be recorded on the 
Adverse Event eCRF.
4.3.3
Investigational Medicinal Product Accountability
The investigational medicinal product (IMP) required for completion of this study 
(i.e., cobimetinib) will be provided by the Sponsor.  The study site will acknowledge 
receipt of IMP and use the IWRS to confirm the shipment condition and content.  Any 
damaged shipments will be replaced.
IMP will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure or returned to the Sponsor with the appropriate 
documentation.  The site's method of IMP destruction must be agreed to by the Sponsor.  
The site must obtain written authorization from the Sponsor before any IMP is destroyed, 
and IMP destruction must be documented on the appropriate form.
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by
the study site should be recorded on the drug accountability log and IWRS.
4.3.4
Post-Trial Access to Cobimetinib
The Sponsor will offer post-trial access to the study drug (cobimetinib) free of charge to 
eligible patients in accordance with the Roche Global Policy on Continued Access to 
Investigational Medicinal Product, as outlined below.
A patient will be eligible to receive study drug after the end of the study if all of the 
following conditions are met:

The patient has a life-threatening or severe medical condition and requires 
continued study drug treatment for his or her well-being 

There are no appropriate alternative treatments available to the patient

The patient and his or her doctor comply with and satisfy any legal or regulatory 
requirements that apply to them


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A patient will not be eligible to receive study drug after the end of the study if any of the 
following conditions are met:

The study drug is commercially marketed in the patient's country and is reasonably 
accessible to the patient (e.g., is covered by the patient's insurance or wouldn't 
otherwise create a financial hardship for the patient)

The Sponsor has discontinued development of the study drug or data suggest that 
the study drug is not effective for solid tumors

The Sponsor has reasonable safety concerns regarding the study drug as treatment 
for solid tumors

Provision of study drug is not permitted under the laws and regulations of the 
patient's country
The Roche Global Policy on Continued Access to Investigational Medicinal Product is
available at the following Web site:
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf
4.4
CONCOMITANT THERAPY AND FOOD
4.4.1
Permitted Therapy 
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter 
drugs, herbal or homeopathic remedies, nutritional supplements) used by a patient from 
7 days prior to initiation of study drug until 30 days after the last dose of study drug.  
All such medications should be reported to the investigator and recorded on the 
Concomitant Medications eCRF.
Patients who use oral contraceptives, hormone-replacement therapy, or other 
maintenance therapy should continue their use.
Palliative radiotherapy may be given to patients for uncontrollable pain or imminent 
threat to a vital organ and must be approved by the Medical Monitor.  If thoracic or 
mediastinal palliative radiotherapy is required, however, patients must permanently 
discontinue cobimetinib due to the known risk of pneumonitis as an adverse drug 
reaction to cobimetinib (see Investigator Brochure).  Patients who undergo palliative 
radiation may not be evaluable for response by tumor assessments but will be assessed 
for progressive disease. 
Pain medications may be administered according to local standard practice guidelines 
while the patient is in the study.
Anti-emetics and anti-diarrheal medications should not be administered prophylactically 
before the initial dose of cobimetinib or at any time during the DLT assessment window 
(Days 128 of therapy) for patients in the dose escalation stage, as this may confound 
DLT analysis.  However, anti-emetics and anti-diarrheal medications may be 
administered during the DLT assessment window if a patient develops active symptoms 


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necessitating such therapy in the investigator’s judgment.  At the discretion of the 
investigator, prophylactic anti-emetic or anti-diarrheal medications may otherwise be 
used per standard clinical practice before subsequent doses of cobimetinib.  
Hematopoietic growth factors should not be administered prophylactically before the 
initial dose of cobimetinib or at any time during the DLT assessment window for patients 
(Days 128 of therapy) in the dose escalation stage, as this may confound DLT analysis.  
Hematopoietic growth factors may otherwise be administered according to local 
guidelines if indicated during the course of the study, after discussion with the Medical 
Monitor.
Case report forms will document use of prophylactic anti-emetics, anti-diarrheal 
medications, and hematopoietic growth factors.
4.4.2
Prohibited Therapy
Use of the following therapies is prohibited during the study:

Any concomitant therapy intended for the treatment of solid tumors, either approved 
by health authorities or experimental, including chemotherapy, radiotherapy (except 
as noted in Permitted Therapy, Section 4.4.1), hormonal therapy, immunotherapy, 
biologic therapy, or herbal therapy

Traditional herbal or homeopathic or natural medicines
Ingredients for such medicines have not been fully studied, and their use may 
result in unanticipated drug-drug interactions that may cause or confound 
assessment of toxicity.
Patients who require the use of any of these agents will be discontinued from study drug 
and followed for safety outcomes for 30 days after the last dose of study drug or until 
initiation of another subsequent anti-cancer therapy, whichever comes first.  These 
patients will also continue to be followed for survival.
In vitro data demonstrates that cobimetinib is metabolized by CYP3A4.  A clinical 
drug-drug interaction study with a strong CYP3A inhibitor showed a 6.6-fold increase in 
cobimetinib AUC.  Thus, it is likely that exposures of cobimetinib will be significantly 
lowered in the presence of strong CYP3A inducers.  The medications listed below
should be avoided.  If use of one of these medications is necessary, the risks and 
benefits should be discussed with the Medical Monitor prior to concomitant 
administration with cobimetinib.

Strong CYP3A inducers, including but not limited to rifampin, carbamazepine, 
rifapentine, phenytoin, phenobarbital, and St. John’s wort or hyperforin

Strong CYP3A inhibitors, including but not limited to atazanavir, clarithromycin, 
erythromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, 
saquinavir, telithromycin, troleandomycin, and voriconazole


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
Strong and moderate CYP3A inducers and inhibitors (as defined in Appendix 11) 
are prohibited for patients in the dose escalation stage during the DLT assessment 
window
Outside the DLT assessment window in the dose escalation stage, moderate CYP3A 
inhibitors and inducers are to be used with caution while strong CYP3A inducers and 
inhibitors should be avoided.  
Caution should be use with concomitant medications that increase the risk of bleeding 
(including antiplatelet or anticoagulant therapy).
The above lists of medications are not necessarily comprehensive.  Thus, the 
investigator should consult the prescribing information for any concomitant medication.  
In addition, the investigator should contact the Medical Monitor if questions arise 
regarding medications not listed above.
4.4.3
Prohibited Food and Supplements
Given the significant effect of CYP3A inducers and inhibitors on cobimetinib metabolism 
(described in Section 5.2 of the Investigator’s Brochure), use of the following foods is 
prohibited during the study and for at least 7 days prior to the initiation of study treatment, 
unless otherwise specified below:

St. John’s wort or hyperforin (potent CYP3A inducer)

Grapefruit juice (potent CYP3A enzyme inhibitors)
Ingestions of prohibited foods and supplements will render the patient non-evaluable for 
DLTs and may warrant removal from protocol therapy.  Such ingestions must be 
reported to the Medical Monitor for determination of whether study drug may be 
continued. Patients who are discontinued from study treatment for this reason will be 
followed for safety outcome for 4 weeks after the last dose of study treatment or until 
initiation of another subsequent anti-cancer therapy, whichever comes first.  These 
patients will also continue to be followed for survival.
4.5
STUDY ASSESSMENTS
Please see Appendix 1 and Appendix 2 for the schedules of assessments and schedule 
of PK assessments performed during the study.
4.5.1
Informed Consent Forms and Screening Log
Written informed consent for participation in the study must be obtained before any 
study-specific screening tests or evaluations are performed from the patient or 
parent/legal guardian.  Informed Consent Forms and Child's Informed Assent Forms for 
enrolled patients and for patients who are not subsequently enrolled will be maintained 
at the study site.


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All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before enrollment.  The investigator will maintain a screening log to 
record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
4.5.2
Medical History and Demographic Data
Medical history includes clinically significant diseases, major surgeries, cancer history 
(including prior cancer therapies and procedures), menstrual history, fertility history, and 
puberty history.  In addition, all medications (e.g., prescription drugs, over-the-counter 
drugs, herbal or homeopathic remedies, nutritional supplements) used by the patient 
within 7 days prior to initiation of study drug will be recorded.
Demographic data will include age, sex, and self-reported race/ethnicity where permitted 
by health authorities.
4.5.3
Physical Examinations and Assessments
A complete physical examination should include an evaluation of the head, eyes, ears, 
nose, and throat, and the cardiovascular, dermatological, musculoskeletal, respiratory, 
gastrointestinal, genitourinary, and neurological systems.  Any abnormality identified at 
baseline should be recorded on the General Medical History and Baseline Conditions 
eCRF. 
At subsequent visits (or as clinically indicated), changes from baseline abnormalities 
should be recorded in the source documents.  New or worsened clinically significant 
abnormalities should be recorded as adverse events on the Adverse Event eCRF.
When age appropriate, patients will be asked specifically about vision changes as part of 
each physical examination in addition to interval medical history.
During the treatment period, weight will be measured within 3 days prior to Day 1 dose 
of each cycle.  During the follow-up period, weight should be measured every 3 months 
for the first 2 years, every 6 months during the third year, and yearly thereafter until end 
of study (Section 3.2).
During the treatment period, height, head circumference (until 3 years of age), and 
Tanner stage should be measured every four cycles (approximately every 3 months).  
During the follow-up period, height, head circumference, and Tanner stage should be 
measured every 3 months for the first 2 years, every 6 months during the third year, and 
yearly thereafter until end of study (Section 3.2).  Tanner staging and height should be 
performed until the patient has reached Tanner Stage V.
4.5.4
Vital Signs
Vital signs will include measurements of respiratory rate, pulse rate, systolic and 
diastolic blood pressures, oxygen saturation, and temperature.


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4.5.5
Tumor and Response Evaluations
All known sites of disease must be documented at screening and re-assessed at each 
subsequent tumor evaluation.  Full baseline tumor assessments should be performed
within 28 days prior to initiation of study drug (Day 1 of Cycle 1).  Baseline assessments 
will consist of the entire diagnostic workup consistent with the response evaluation 
system used for the specific tumor type.  Tumor assessments must be performed during 
the last week of the even-numbered cycles (i.e., at the end of Cycles 2, 4, 6, 8, etc., prior 
to the start of treatment in the next cycle).  For patients who have not met study criteria 
for progressive disease after 12 cycles, subsequent response assessments should be 
conducted at Cycles 16, 20, 24, and every 6 cycles thereafter.  At the investigator’s 
discretion, tumor assessments may be repeated at any time if disease progression is 
suspected.
Response will be assessed by the investigator on the basis of physical examinations, 
computed tomography (CT) scans or MRI scans and additional 123I-MIBG imaging for 
neuroblastoma patients.  The following response assessment systems will be used 
mINRC, RANO criteria for HGG, RANO criteria for LGG, or RECIST v1.1, as appropriate 
for the patient’s diagnosis.  CT or MRI scans should evaluate neck, chest, abdomen, and 
pelvic region if clinically indicated.  MIBG scanning should be used for response 
assessments in neuroblastoma patients, if positive at baseline.  PET scans may be 
performed at the discretion of the treating physician.  
Any objective response must be confirmed by repeat assessments 4 weeks after initial 
documentation.  The same radiographic procedure used to assess disease sites at 
screening should be used throughout the study (e.g., the same contrast protocol for CT 
scans).  To the extent that is feasible, assessments should be performed by the same 
evaluator to ensure internal consistency across visits.
Patients with neuroblastoma must have a MIBG scan and bilateral bone marrow 
aspirates and biopsies done for disease evaluation.  If the enrollment bone marrow 
aspirates and biopsies are negative for disease, subsequent bone marrow aspirates and 
biopsies are not needed.  Patients with neuroblastoma should also have urine 
catecholamines (including homovanillic acid and vanillylmandelic acid) sent at screening 
and with all responses assessments.  
Patients without neuroblastoma who have a clinical suspicion of bone marrow 
involvement should also have bilateral bone marrow aspirates and biopsies performed at 
screening.  Those with positive bone marrow involvement at screening should then have 
bilateral bone marrow aspirates and biopsies done with each disease reassessment until 
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4.5.6
Ophthalmologic Examinations
All patients will undergo ophthalmologic examinations, performed by a qualified 
ophthalmologist, at specified timepoints throughout the study (see Appendix 1). For 
patients who have completed 6 cycles of cobimetinib therapy and who have not 
developed serous retinopathy, retinal detachment, or other adverse events involving the 
retina, ophthalmologic evaluations will be performed at Cycles 8, 10, 12, 16, 20, 24, 
and every 6 cycles thereafter.
Patients will be evaluated at screening for history or evidence of retinal pathology that is 
considered to be a risk factor for or indicative of neurosensory retinal detachment, CSCR, 
neovascular retinopathy, or retinopathy of prematurity.
Ophthalmologic examinations will include age-specific visual acuity testing (which 
should be reported in Snellen units), intraocular pressure measurements, slit-lamp 
ophthalmoscopy, and spectral domain optical coherence tomography (OCT) at baseline, 
the beginning of every cycle, study drug discontinuation, and at other timepoints 
identified in the protocol.  Indirect ophthalmoscopy and color fundus photography will be 
required only at baseline and at study drug discontinuation.  If spectral domain OCT is 
not available, time domain OCT may be performed.  In patients who are unable to 
successfully complete OCT scans due to underlying visual impairment from non-retinal 
causes (such as brain tumor), color fundus photography and indirect ophthalmoscopy 
should be performed instead of OCT at each scheduled ophthalmologic evaluation.  
Additionally, fluorescein angiography will be performed for identified OCT serous fluid 
accumulation or edema and thereafter based upon clinical findings.  Binocular indirect 
ophthalmoscopy will be performed any time fluorescein angiography is performed.  
Fluorescein angiography may be deferred if patients have known contrast allergies or 
abnormal renal function, at the discretion of the investigator.  Providers should be 
advised that patients 3 years of age are likely to require examination under anesthesia 
for successful evaluation. 
4.5.7
Cardiac Function Monitoring
Cardiac echocardiograms or MUGA will be performed during screening to assess 
baseline cardiac function and at regular intervals beginning with the visit at Cycle 2.  
These exams will be repeated every third cycle thereafter (i.e., Cycles 5, 8, 11, etc.) and 
at the end of study visit.
4.5.8
Dermatologic Examinations
Full-body dermatologic examinations should be performed at regular intervals as 
outlined in the schedule of assessments (see Appendix 1).  A dermatologist should be 
consulted for patients who develop Grade 3 skin disorders or any grade rash with 
concurrent signs or symptoms strongly suggestive of a severe Type I hypersensitivity or 
anaphylactic or anaphylactoid reaction, with painful desquamation or mucosal 


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involvement suggestive of Stevens-Johnson syndrome or toxic epidermal necrolysis, or 
with other life-threatening complications.
4.5.9
Laboratory, Biomarker, and Other Biological Samples
Assessments that require blood, draws should be monitored closely to ensure that no 
more than 2.5% of the total blood volume is taken at one time or that no more than 5% 
of the total blood volume is taken over a 30-day period (total blood volume is defined as 
80 mL/kg).  Institutions should use micro sampling systems to minimize the amount of 
blood drawn when able.  In situations where the total amount will exceed the amount 
stated above, clinical laboratory assessments should be prioritized.  Any remaining 
blood should be sent for PK analysis followed by biomarker and PD analyses.
Samples for the following laboratory tests will be sent to the study site's local laboratory 
for analysis:

Hematology (WBC count, hemoglobin, platelet count, 3-cell differential count 
[absolute neutrophils, monocytes, and lymphocytes])

Serum chemistry (sodium, potassium, magnesium, chloride, bicarbonate (or total 
carbon dioxide), glucose, BUN or urea, creatinine, total protein, albumin, 
phosphorus, calcium, total bilirubin [if abnormal, fractionate sample for direct and 
indirect], alkaline phosphatase, CPK, ALT, AST, uric acid, LDH)

Urinalysis (specific gravity, glucose, protein, blood) in children 3 years of age. 
Creatinine clearance as clinically indicated (If radioisotope glomerular filtration 
rate is routinely performed at the institution to measure patients’ creatinine 
clearance, this test can be used to assess renal function at screening, per the 
eligibility criteria.  Otherwise, serum creatinine is sufficient to document renal 
function at screening).

Pregnancy test
All post-menarcheal females will undergo pregnancy tests within 1 week prior to 
the start of each treatment cycle.  A serum pregnancy test must be performed 
at screening (prior to Cycle 1).  Urine or serum pregnancy tests will be 
performed prior to all subsequent cycles.

Coagulation (INR, aPTT, PT)
Samples for the following research laboratory tests will be sent to one or several central 
laboratories for analysis:

Plasma samples for PK analysis (see Central Laboratory Manual)
The following samples will be sent to a central laboratory, the Sponsor, or a designee for 
analysis:

Plasma samples for exploratory research on candidate biomarkers, including but not 
limited to BRAF mutations, BRAF fusions, RAS mutations, NF1, and other candidate 
biomarkers (including somatic mutations of the tumor)


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
Availability of tumor tissue at study enrollment is mandatory.  Archival and/or fresh 
primary tumor tissue samples are required for exploratory research on candidate 
biomarkers, including but not limited to p-MEK, p-ERK, Ki67, BRAF mutations, 
BRAF fusions, RAS mutations, and NF1.
Submission of bone biopsy specimens is strongly discouraged due to 
complications in the assessment of such tissue, but they may be submitted if no 
other tissue is available.
For patients with archival samples:  Representative formalin-fixed 
paraffin-embedded (FFPE) tumor specimens in paraffin blocks or at least 
15 freshly cut, unstained, serial slides (blocks preferred), with an associated 
pathology report, are required for study entry.  The specimen should be of good 
tissue quality and to have sufficient viable tumor content as determined by the 
institutional pathologist.  Patients with fewer than 15 slides available may be 
eligible for study entry following discussion with the Medical Monitor.  The tumor 
specimen and associated pathology report must be confirmed to be available 
prior to patient participation in any study-specific screening procedures and 
must be shipped within 30 days of first dosing. 

Patients will be encouraged to submit all available FFPE tumor specimens from 
prior surgeries and biopsies performed as part of routine medical care.  If a patient 
has multiple archival specimens available but only wishes to submit one sample, the 
specimen obtained closest to the start of treatment should be used, with the 
exception that non-bone specimens are preferred over bone biopsy specimens.
Archival tumor blocks will be returned to the sites at the end of the study or 
upon site request.

Patients without archival samples must be willing to undergo a core or excisional 
biopsy prior to enrollment.  Fine-needle aspiration, brush biopsy, and lavage 
samples are not acceptable.  

A whole blood sample for molecular analysis of mutations and single-nucleotide 
polymorphisms (SNPs) is required ONLY for patients who consent to submitting 
optional on-study tissue (tissue submission described in Section 4.5.10).  This 
sample may be used for the analysis of novel mutations detected in tumor tissue in 
order to verify the somatic nature of this mutation and SNPs that might be 
associated with safety, efficacy, or PK of the drug. This sample is not collected if 
patients have not consented to the optional on-study biopsy.  
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.


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These samples will be destroyed when the final clinical study report has been completed, 
with the following exception:

Any remaining samples collected for PK analysis, biomarker assays, and ATA 
assays may be used for exploratory biomarker profiling, identification, and PD assay 
development purposes and for additional safety assessments (e.g., ATA assay) as 
appropriate. The remainder of samples obtained for study-related procedures will 
be destroyed no later than 5 years after the date of final closure of the clinical 
database unless the patient gives specific consent for the remainder of the samples 
to be stored for optional exploratory research.  If the patient provides consent for 
optional exploratory research, the samples will be destroyed no later than 15 years 
after the date of final closure of the clinical database.
When a patient withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the patient specifically requests that the 
samples be destroyed or local laws require destruction of the samples.  However, if 
samples have been tested prior to withdrawal, results from those tests will remain as 
part of the overall research data.
4.5.10
Acceptability Survey
To better understand the acceptability of the cobimetinib formulations, a survey will be 
administered immediately following administration of cobimetinib on Day 8 of Cycle 1. It 
would be advisable that patients rinse their mouths prior to taking the medication and 
complete the survey before any rinsing or water.  
For patients who have not yet developed the cognitive ability to provide detailed 
feedback on the acceptability of a medication, the parent or guardian will complete the 
Acceptability Survey based on their observation of their child’s reaction and facial 
expression following the medication intake.  Patients able to provide feedback will 
complete the survey with reading support from their parents or the clinical staff as 
needed.  Study staff and patient’s caregiver possibly present during the assessment 
should remain neutral.  If a patient is having difficulty with selecting a score, patients 
may be asked the interview question first and then redirected to complete the 
assessment score. Parents or caregivers will be asked about their ease of experience of 
administering the suspension at home.
The survey will document specific aspects of the acceptability of each of the cobimetinib 
formulations, including swallowability and palatability (Kozarewicz 2014).  The survey is 
required regardless of whether the patient is taking tablets or suspension.
4.5.11
Samples for Roche Clinical Repository
4.5.11.1
Overview of the Roche Clinical Repository
The Roche Clinical Repository (RCR) is a centrally administered group of facilities used 
for the long-term storage of human biologic specimens, including body fluids, solid 
tissues, and derivatives thereof (e.g., DNA, RNA, proteins, peptides).  The collection and 


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analysis of RCR specimens will facilitate the rational design of new pharmaceutical 
agents and the development of diagnostic tests, which may allow for individualized drug 
therapy for patients in the future.
Specimens for the RCR will be collected from patients who give specific consent to 
participate in this optional research.  RCR specimens will be used to achieve the 
following objectives:

To study the association of biomarkers with efficacy, adverse events, or disease 
progression

To increase knowledge and understanding of disease biology

To study drug response, including drug effects and the processes of drug absorption 
and disposition

To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays
4.5.11.2
Approval by the Institutional Review Board or Ethics 
Committee
Collection and submission of biological samples to the RCR is contingent upon the 
review and approval of the exploratory research and the RCR portion of the Informed 
Consent Form by each site's Institutional Review Board (IRB) or Ethics Committee (EC) 
and, if applicable, an appropriate regulatory body.  If a site has not been granted 
approval for RCR sampling, this section of the protocol (Section 4.5.11) will not be 
applicable at that site.
4.5.11.3
Sample Collection
The following samples will be collected for research purposes, including but not limited 
to research on dynamic (non-inherited) biomarkers related to cobimetinib or solid tumors:

Fresh tissue from on-study biopsies and residual tissue from non-study related 
procedures, from the primary tumor location, metastatic site, or site of local 
recurrence or advancement will be collected for analyses that may include DNA or 
RNA extraction.  Samples should be obtained at the following timepoints:  prior to 
drug initiation; during the week before Cycle 3 of drug; and at the time of disease 
progression (if applicable).  Patients may choose to consent to any or all of these 
timepoints.
For fresh tissue biopsies, a minimum of three fresh tissue cores should be 
acquired using an 18-gauge needle.  If not feasible, one or two cores may be 
acceptable after discussion with the Medical Monitor.
Patients consenting to the optional on-study biopsies will also be required to provide a 
mandatory whole blood sample listed under the main informed consent form.
For all samples, dates of consent should be recorded on the associated RCR page of 
the eCRF.  For sampling procedures, storage conditions, and shipment instructions, see 
the laboratory manual.  


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RCR specimens will be destroyed no later than 15 years after the date of final closure of 
the associated clinical database.  The RCR storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements).
The dynamic biomarker specimens will be subject to the confidentiality standards 
described in Section 8.4. 
4.5.11.4
Confidentiality
Data generated from RCR specimens must be available for inspection upon request by 
representatives of national and local health authorities, and Roche monitors, 
representatives, and collaborators, as appropriate.
Patient medical information associated with RCR specimens is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.
Data derived from RCR specimen analysis on individual patients will generally not be 
provided to study investigators unless a request for research use is granted.  The 
aggregate results of any research conducted using RCR specimens will be available in 
accordance with the effective Roche policy on study data publication.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RCR data will become and remain the exclusive and unburdened property 
of Roche, except where agreed otherwise.
4.5.11.5
Consent to Participate in the Roche Clinical Repository
The Informed Consent Form will contain a separate section that addresses participation 
in the RCR.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the RCR.  Patients will be 
told that they are free to refuse to participate and may withdraw their specimens at any 
time and for any reason during the storage period.  A separate, specific signature will be 
required to document a patient's agreement to provide optional RCR specimens.  
Patients who decline to participate will not provide a separate signature.
The investigator should document whether or not the patient has given consent to 
participate by completing the RCR Research Sample Informed Consent eCRF.
In the event of an RCR participant's death or loss of competence, the participant's 
specimens and data will continue to be used as part of the RCR research.
4.5.11.6
Withdrawal from the Roche Clinical Repository
Patients who give consent to provide RCR specimens have the right to withdraw their 
specimens from the RCR at any time for any reason. After withdrawal of consent, any 


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remaining samples will be destroyed or will no longer be linked to the patient. However, 
if RBR samples have been tested prior to withdrawal of consent, results from those tests 
will remain as part of the overall research data.  If a patient wishes to withdraw consent 
to the testing of his or her specimens, the investigator must inform the Medical Monitor in 
writing of the patient's wishes through use of the RCR Subject Withdrawal Form and, if 
the trial is ongoing, must enter the date of withdrawal on the RCR Research Sample 
Withdrawal of Informed Consent eCRF.  If a patient wishes to withdraw consent to the 
testing of his or her RCR samples after closure of the site, the investigator must inform 
the Sponsor by emailing the study number and patient number to the following email 
address:
global rcr-withdrawal@roche.com
A patient's withdrawal from Study GO29665 does not, by itself, constitute withdrawal of 
specimens from the RCR.  Likewise, a patient's withdrawal from the RCR does not 
constitute withdrawal from Study GO29665.
4.5.11.7
Monitoring and Oversight
RCR specimens will be tracked in a manner consistent with Good Clinical Practice by a 
quality-controlled, auditable, and appropriately validated laboratory information 
management system, to ensure compliance with data confidentiality as well as 
adherence to authorized use of specimens as specified in this protocol and in the 
Informed Consent Form.  Roche monitors and auditors will have direct access to 
appropriate parts of records relating to patient participation in the RCR for the purposes 
of verifying the data provided to Roche.  The site will permit monitoring, audits, IRB/EC 
review, and health authority inspections by providing direct access to source data and 
documents related to the RCR samples.
4.6
PATIENT, TREATMENT, STUDY, AND SITE DISCONTINUATION
4.6.1
Patient Discontinuation
Patients have the right to voluntarily withdraw from the study (or be withdrawn by their 
parents or caregivers, if the patient is a minor) at any time for any reason.  In addition, 
the investigator has the right to withdraw a patient from the study at any time.  Reasons 
for withdrawal from the study may include, but are not limited to, the following:

Patient withdrawal of consent (or withdrawal of consent by their parents or 
caregivers, if the patient is a minor) at any time

Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient’s safety if he or she continues in the study

Investigator or Sponsor determines it is in the best interest of the patient

Patient non-compliance with the study procedures (e.g., dosing instructions, study 
visits)


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Every effort should be made to obtain information on patients who withdraw from the 
study.  The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF.  However, patients will not be followed for any reason after consent 
has been withdrawn.  Patients in the dose-escalation stage who discontinue from the 
study prior to completing the DLT assessment window for reasons other than a DLT will 
be replaced except as noted in Section 3.1.1.  Patients in the expansion stage who 
discontinue from the study will not be replaced.
4.6.2
Study Drug Discontinuation
Patients must discontinue study drug if they experience any of the following:

Disease progression as determined by the investigator using mINRC, RANO criteria 
for HGG, RANO criteria for LGG, or RECIST v1.1, as appropriate.  In cases where 
any doubt regarding disease progression exists, the patient should remain under 
close observation (e.g., every 4 weeks) and further radiographic assessments 
should be performed to document either stability or progression. If subsequent 
evaluations confirm that the patient is experiencing progression, the date of 
progressive disease should be the time at which the potential progression was first 
noted. Should such uncertainty occur during the treatment period, the patient may 
continue with the study treatment until the next scheduled efficacy assessment.

Unacceptable toxicity despite per-protocol dose reductions or treatment 
interruptions

Pregnancy

Withdrawal of consent
Patients who discontinue study drug for any reason will be asked to return to the clinic 
for a study drug discontinuation visit and undergo follow-up assessments (see the 
schedule of assessments in Appendix 1).  If treatment with another anti-cancer treatment 
is scheduled to begin less than 30 days after the last dose of cobimetinib, assessments 
at this visit should be performed before the patient starts the other treatment, if possible.  
Patients who discontinue for reasons other than progressive disease should continue 
follow-up assessments, including tumor assessments, using the same schedule of 
assessments as on treatment until radiographic documentation of progressive disease, 
start of another treatment, or withdrawal of consent.  The primary reason for study drug 
discontinuation should be documented on the appropriate eCRF.  Patients in the 
dose-escalation stage who discontinue study drug prior to completing the DLT 
assessment window for reasons other than a DLT will be replaced except as noted in 
Section 3.1.1.  Patients in the expansion stage who discontinue study drug will not be 
replaced.


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4.6.3
Study and Site Discontinuation
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following:

The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients.

Patient enrollment is unsatisfactory.
The Sponsor will notify the investigator if the study is discontinued.  
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following:

Excessively slow recruitment

Poor protocol adherence

Inaccurate or incomplete data recording

Non-compliance with the International Conference on Harmonisation (ICH) guideline 
for Good Clinical Practice

No study activity (i.e., all patients have completed and all obligations have been 
fulfilled)
5.
ASSESSMENT OF SAFETY
5.1
SAFETY PLAN
The safety plan for patients in this study is based on clinical experience with cobimetinib 
in completed and ongoing studies.  The anticipated important safety risks of cobimetinib 
are outlined below.  Please refer to the cobimetinib Investigator's Brochure for a 
complete summary of safety information.
Several measures will be taken to ensure the safety of patients participating in this trial.  
Eligibility criteria have been designed to exclude patients at higher risk for toxicities (see 
Section 4.1).  In addition, patients will undergo safety monitoring during the study as 
described in Section 4.5, Section 5, and the schedule of assessments (see Appendix 1).  
An Internal Monitoring Committee and an Scientific Oversight Committee will monitor 
patient safety throughout the study.  The Internal Monitoring Committee will provide a 
recommendation on the dose to be taken forward into the expansion stage after 
completion of the dose-escalation stage (see Section 3.1.3 for details).
Finally, guidelines for managing adverse events, including criteria for dosage 
modification and treatment interruption or discontinuation, have been provided (see 
Section 5.1.1).  These guidelines apply to patients in the dose-escalation and expansion 
stages.  However, the guidelines are not intended to replace clinical judgment or dictate 
care of individual patients.


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5.1.1
Management of Specific Adverse Events
Guidelines for managing specific adverse events are provided in Table 2.  Asymptomatic 
declines in left ventricular ejection fraction should be managed according to the 
algorithm presented in Table 3 in Section 5.1.2.1.
If dose reduction is indicated for an individual patient, the dose should be reduced to the
next lower dose level, with dose defined in Appendix 10. The dose regimen of adult 
patients (18 years of age) treated with the adult-recommended daily dose of 60 mg will 
be reduced by one 20 mg tablet (i.e., from 60 mg to 40 mg). If the patient is treated at 
the lowest defined dose level, the dose should be reduced by 25%.  Note that the need 
for dose reduction below the minimum doses for administration in this study (specified in 
Appendix 10) is considered unacceptable toxicity and requires study drug 
discontinuation. For patients taking tablets, study drug should be discontinued if 
required weekly dose after reduction is 60 mg/week.  For patients taking suspension, 
study drug should be discontinued if required dose after reduction is 4.8 mg (1 mL) 
daily.  Dose re-escalation is not allowed.


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Table 2
Guidelines for Management of Specific Adverse Events
Event
Action to Be Taken
Grade 2 diarrhea
Grade 3 diarrhea

If Grade 3 diarrhea occurs despite adequate supportive 
care, do not administer cobimetinib until recovery to 
Grade 1.

Following recovery, resume cobimetinib at a dose
corresponding to a reduction of one dose level.

If patient experiences two episodes of Grade 3 diarrhea
despite adequate supportive care, discontinue cobimetinib 
permanently.
Grade 2 diarrhea

If Grade 2 diarrhea persists for 10 days despite adequate 
supportive care, do not administer cobimetinib until recovery 
to Grade 1.

Following recovery, resume cobimetinib at a reduced dose 
after consulting with the Medical Monitor.
Any rash with concurrent 
signs or symptoms 
strongly suggestive of a 
severe Type I 
hypersensitivity or 
anaphylactic or 
anaphylactoid reaction, 
with painful desquamation 
or mucosal involvement 
suggestive of 
Stevens-Johnson 
syndrome or toxic 
epidermal necrolysis, or 
with other life-threatening 
complications

Discontinue cobimetinib permanently.

Immediately consult a dermatologist.
Skin lesion suspicious for 
SCC/BCC

Do not administer cobimetinib.

Immediately consult a dermatologist.

Biopsy suspicious lesions.  If lesion is benign, resume 
cobimetinib; if lesion consistent with SCC or BCC, do not 
resume cobimetinib.


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Table 2
Guidelines for Management of Specific Adverse Events (cont.)
Event
Action to Be Taken
Grade 3 rash that does 
not meet above criteria

Consult a dermatologist.

Do not administer cobimetinib until recovery to Grade 2.

Following recovery, resume cobimetinib at a dose 
corresponding to a reduction of one dose level.

If patient experiences two episodes of Grade 3 rash, 
discontinue cobimetinib.

If Grade 3 rash persists for 10 days despite adequate 
supportive care, discontinue cobimetinib permanently.
Retinopathy or Grade 2 
visual disorders

Do not administer cobimetinib.

Consult ophthalmologist, who should perform complete 
ophthalmologic examination that includes visual acuity 
testing, IOP measurements by tonometry, slit-lamp 
ophthalmoscopy, indirect ophthalmoscopy with dilation, 
and SD-OCT.

Resume cobimetinib if no evidence of retinopathy and 
either visual disorder has recovered to Grade 1 or visual 
disorder is attributable to underlying disease (i.e., optic 
glioma).
Diagnosis of serous retinopathy

Do not administer cobimetinib until retinopathy has 
resolved (or in patients who were symptomatic at 
presentation, recovered to Grade 1).

When retinopathy resolves, resume cobimetinib at the 
next lower dose per the dose-escalation scheme, or if 
at or below lowest dose level, reduce dose by 25% 
(Section 3.1.1.2).

If retinopathy recurs, discontinue cobimetinib 
permanently.
Diagnosis of retinal vein occlusion or Grade 3retinal 
detachment

Permanently discontinue cobimetinib
Grade 3 ALT or AST 
elevations
ALT or AST elevation of 5ULN

Do not administer cobimetinib until recovery to 3ULN.

Following recovery, resume cobimetinib at a dose
corresponding to a reduction of one dose level.
ALT or AST 3ULN in combination with total bilirubin 
2ULN or clinical jaundice

Discontinue cobimetinib permanently.


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Table 2
Guidelines for Management of Specific Adverse Events (cont.)
Event
Action to Be Taken
Grade 3 rash that does 
not meet above criteria

Consult a dermatologist.

Do not administer cobimetinib until recovery to Grade 2.

Following recovery, resume cobimetinib at a dose 
corresponding to a reduction of one dose level.

If patient experiences two episodes of Grade 3 rash, 
discontinue cobimetinib.

If Grade 3 rash persists for 10 days despite adequate 
supportive care, discontinue cobimetinib permanently.
Left ventricular 
dysfunction
Symptomatic congestive 
heart failure

Discontinue cobimetinib permanently.
Asymptomatic LVEF 
decrease

Consult algorithm Table 3 in Section 5.1.2.1.

Patients who require dose reduction should have LVEF 
measurements at 2, 4, 10, and 16 weeks after diagnosis or 
as clinically indicated.
Cerebral hemorrhage       
(all grades)

Permanently discontinue cobimetinib.
Grade 2 hemorrhage 
(excluding cerebral 
hemorrhage)

Interrupt cobimetinib treatment until recovery to Grade 1, 
then contact Medical Monitor prior to restarting. Do not 
resume cobimetinib without approval of Medical 
Monitor and careful benefit-risk assessment.

There are no data on the effectiveness of cobimetinib dose 
modification for hemorrhage events. Clinical judgment 
should be applied when considering 
restarting cobimetinib treatment.
Grade 3 hemorrhage

Permanently discontinue cobimetinib.
Rhabdomyolysis and CPK 
elevations
Rhabdomyolysis or 
symptomatic CPK 
elevations

Interrupt cobimetinib treatment.  If severity is improved by 
at least one grade (note rhabdomyolysis can be graded 
using the scale provided in Table 4 in Section 5.3.3) within 
4 weeks, restart cobimetinib at a dose corresponding to a 
reduction of one dose level, if clinically indicated. 
If rhabdomyolysis or symptomatic CPK elevations do not 
improve within 4 weeks, permanently discontinue 
cobimetinib treatment.


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Table 2
Guidelines for Management of Specific Adverse Events (cont.)
Event
Action to Be Taken
Asymptomatic CPK 
elevations:

Grade 3: cobimetinib dosing does not need to be 
modified or interrupted to manage asymptomatic 
Grade 3 CPK elevations.

Grade 4: Interrupt cobimetinib treatment.  If improved to 
Grade 3 within 4 weeks, restart cobimetinib at a dose 
corresponding to a reduction of one dose level, if clinically 
indicated.  If CPK elevations do not improve to Grade 3 
within 4 weeks following dose interruption, permanently 
discontinue cobimetinib treatment.
Other Grade 3
non-hematologic toxicities
or Grade 4 hematologic
toxicities considered to be
related to cobimetinib

Do not administer cobimetinib until recovery to Grade 1.

Following recovery, resume cobimetinib at a dose 
corresponding to a reduction of one dose level.

If patient experiences two episodes of the toxicity, 
discontinue cobimetinib permanently.

If toxicity persists for 14 days despite adequate 
supportive care, discontinue cobimetinib permanently.
BCCbasal cell carcinoma; IOPintraocular pressure; LVEFleft ventricular ejection fraction; 
SCCsquamous cell carcinoma; SD-OCTspectral domain optical coherence tomography; 
ULNupper limit of normal.
5.1.2
Risks Associated with Cobimetinib
Information related to risks attributed to cobimetinib is based on safety data from this 
Phase III Study GO28141 (cobimetinib plus vemurafenib), Phase Ib Study NO25395 
(cobimetinib plus vemurafenib), and Phase I Study MEK4592g (cobimetinib 
monotherapy).  For further information regarding clinical safety, please refer to the 
current cobimetinib Investigator’s Brochure.
5.1.2.1
Important Identified Risks Associated with Cobimetinib
Hemorrhage Events
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% of patients treated with cobimetinib plus vemurafenib, and in 7.3% of patients 
treated with placebo plus vemurafenib.  Higher frequencies in the cobimetinib plus 
vemurafenib arm were observed for cerebral hemorrhage (1% vs. 0%). The majority of 
hemorrhagic  events were Grade 1 or 2 and non-serious.  Grade 3 and 4 hemorrhage 
events were reported in 1.2% of patients receiving cobimetinib plus vemurafenib and 
0.8% of patients receiving placebo plus vemurafenib.


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Serious and severe bleeding has been reported in both the clinical-trial and 
postmarketing setting. These events occurred in patients with additional risk factors for 
bleeding, such as central nervous system metastasis, and/or in patients who use 
concomitant medications that increased the risk of bleeding (including antiplatelet or 
anticoagulant therapy). Intracerebral events were predominantly associated with brain 
metastases in patients on therapy with cobimetinib and vemurafenib for metastatic 
melanoma.
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 2 in 
Section 5.1.1.
Any Grade 2 hemorrhagic event will be considered a dose-limiting toxicity on this 
study, except intracranial hemorrhagic events, which are considered a dose-limiting 
toxicity regardless of their grading. For Grade 2 extracranial hemorrhagic events, 
investigator should not administer study drug until toxicity resolves to Grade 1.  Dose 
reductions or discontinuations should be implemented per Table 2 in Section 5.1.2.  For 
hemorrhagic events of Grade 3, or for any intracranial hemorrhage, study drug should 
be permanently discontinued.
Ocular Toxicity (Serous Retinopathy)
Serous retinopathy (fluid accumulation within the layers of the retina is a known adverse 
drug reaction for cobimetinib (Infante et al. 2012; Schoenberger et al. 2013; 
Larkin et al. 2014).  Manifestations of serous retinopathy include visual disturbances, 
findings of retinal detachment, and retinopathy.  Serous retinopathy events may also be 
asymptomatic.  In Study MEK4592g, visual disturbances associated with accumulation 
of fluid between the layers of the retina were reported as related to cobimetinib.  In some 
cases, patients had subretinal fluid observed incidentally on ophthalmologic examination 
without visual symptoms.  Some patients have been able to resume cobimetinib at the 
same dose or at a reduced dose.  One dose-limiting toxicity of Grade 3 blurred vision 
was reported at 125 mg, and all other visual disturbances (including blurred vision and 
seeing flashing lights) were Grade 1 or 2.  Serous retinopathy has been characterized in 
the Phase III Study GO28141.  The study incorporated prospective serial ophthalmic 
examinations for all enrolled patients.  Serous retinopathy was reported more frequently 
in patients treated with cobimetinib plus vemurafenib than placebo plus vemurafenib 
(25.5% vs. 2.8%, respectively), and approximately half the events were asymptomatic 
Grade 1 events.  Few patients treated with cobimetinib plus vemurafenib experienced 
Grade 3 ocular events (2.8%); the majority of these were managed with dose 
modification of both cobimetinib and vemurafenib. 


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To address potential ocular toxicity, 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 Appendix 1).  Details regarding baseline and subsequent 
ophthalmologic examinations are provided in Section 4.5.6.  
Guidelines for management of patients who develop Grade 2 visual disorders or 
retinopathy are provided in Table 2 in Section 5.1.1.
Cardiac Toxicity
Decrease in cardiac function has been identified as an adverse event that falls under 
“Warnings and Precautions” for adult use of cobimetinib.  Study GO28141 demonstrated 
a decrease in cardiac function in 7% of cobimetinib plus vemurafenib-treated patients 
versus 3% of vemurafenib-treated patients.  Most cases were asymptomatic.  Symptoms 
consistently improved following treatment discontinuation, treatment interruption, or dose 
reduction in the cobimetinib arm, while improvement was inconsistent in the vemurafenib 
arm.  There has been no in vitro or nonclinical evidence of decreased cardiac function 
with cobimetinib administration.  
As there is no biomarker that can accurately identify early decreased cardiac function in 
children, cardiac function will be assessed through echocardiograms performed at 
specified timepoints throughout the study (see Appendix 1).  This is particularly 
important in pediatric patients who have been treated with an anthracycline analogue, 
and even more so in pediatric patients who have had chest radiotherapy in addition to 
anthracycline treatment, both of which increase the risk of cardiac dysfunction.
Guidelines for the management of symptomatic reduction in left ventricular ejection 
fraction are provided in Table 3.


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Table 3
Guidelines for Management of Asymptomatic Reduction in Left 
Ventricular Ejection Fraction
Patient
LVEF Value
Recommended 
Cobimetinib Dose 
Modification
LVEF Value Following
Treatment Break
Recommended 
Cobimetinib Daily Dose
Asymptomatic
50%
(or 40%49%
and 10%
absolute
decrease from
baseline)
Continue at
current dose
N/A
N/A
< 40%
(or 40%49%
and 10%
absolute
decrease from
baseline)
Interrupt treatment
for 2 weeks
10% absolute
decrease from
baseline
1st occurrence: reduce by 
1 dose level
2nd occurrence: reduce by 
additional dose level
3rd occurrence:
permanent discontinuation
40%
(or 10% absolute
decrease from
baseline)
Permanent discontinuation
LVEFleft ventricular ejection fraction; FSfractional shortening. 
Note:  Investigators may substitute FS for LVEF in algorithm above as follows:

FS28% equivalent to LVEF 50%

FS 25%27.9% equivalent to LVEF 40%49%

FS25% equivalent to LVEF40%
Patients who require dose reduction should have LVEF measurements at 2, 4, 10, and 16 weeks 
after diagnosis.  Patients with symptomatic heart failure must discontinue study drug.
Rhabdomyolysis and CPK Elevations
Elevations in CPK have been observed in patients who received cobimetinib 
monotherapy as well as when combined 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).  


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CPK will be monitored at baseline, on Cycle 1 Days, 1, 8, 15, and 21; then on Day 1 of 
each subsequent cycle (monthly), and at study drug discontinuation as indicated in 
Appendix 1, or as clinically indicated.   Instructions for dose modification for elevated 
CPK and rhabdomyolysis are included in Table 2 in Section 5.1.1.
Photosensitivity
No evidence of phototoxicity has been observed with cobimetinib as a single agent.  
However, photosensitivity was observed on the GO28141 trial with a higher frequency in 
the cobimetinib plus vemurafenib arm vs. 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.  There were no apparent trends in the time of onset of 
Grade 3 events.  Grade 3 photosensitivity events in the cobimetinib plus vemurafenib 
arm were treated with primary topical medication in conjunction with interruption of study 
agents.  Grade3 photosensitivity on this trial will be treated as any other Grade 3 
non-hematologic toxicity as outlined in Table 2 in Section 5.1.1.
Pneumonitis
Events of pneumonitis have been reported in cobimetinib clinical studies. Most reported 
events were considered non-serious and low-severity grade.  In the Phase III 
Study GO28141, pneumonitis events were reported more frequently in patients treated
with cobimetinib plus vemurafenib than placebo plus vemurafenib (1.6% vs. 0.4%, all 
grades).  There were no reported Grade 3 events in either study arm.  Serious events 
were reported in 2 patients (0.8%) treated with cobimetinib plus vemurafenib.  
Pneumonitis is an expected adverse drug reaction for cobimetinib.
5.1.2.2
Potential Risks Associated with Cobimetinib
Liver Laboratory Abnormalities and Severe Hepatotoxicity
Liver laboratory abnormalities can occur when cobimetinib is used with vemurafenib, and 
when vemurafenib is used as a single agent.
Liver laboratory test abnormalities, including increases in ALT, AST, and alkaline 
phosphatase, have been reported as adverse events and serious adverse events in 
patients treated with cobimetinib plus vemurafenib.
In the Phase III Study GO28141, liver laboratory test abnormalities reported as 
Grade 3 adverse events occurred more frequently in patients treated with cobimetinib 
plus vemurafenib than placebo plus vemurafenib (20.5% vs. 15.1%, respectively). 
Generally, elevations in liver laboratory tests were managed effectively with dose 
modification guidelines.  In both study arms, the majority of Grade 3 liver laboratory 
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No Grade 3 liver laboratory test elevations were reported in the cobimetinib 
monotherapy Study MEK4952g, with the exception of 1 case of Grade 3 bilirubin 
increase.
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, seminal vesicle and 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 Toxicity
In a dedicated 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 to those observed in adult patients administered 
the 60 mg dose.
See Section 4.1.1 for contraceptive requirements for study.
5.1.2.3
Other Risks Associated with Cobimetinib
Skin Toxicity
Skin rash, including erythema and maculopapules, is a known and expected 
dose-limiting toxicity of MEK inhibitors (LoRusso et al. 2007; Adjei et al. 2008; LoRusso 
et al. 2010) and can be monitored and managed clinically.  Skin toxicities of rash, 
including dermatitis acneiform, rash pruritic, rash generalize, dermatitis, exfoliative rash, 
rash erythematous, and rash maculopapular, were reported frequently in studies where 
cobimetinib was used as a single agent or in combination with other drugs.  
In Study MEK4592g with use of cobimetinib as a single agent, the incidence of rash 
regardless of attribution was reported to be 52.6%.
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 
maculopapular (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 Study GO28141, approximately 90% of Grade 3 rash events resolved in 
both arms.


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Patients will undergo dermatologic examinations at specified timepoints throughout the 
study (see Appendix 1).  Patients who develop mild to moderate skin toxicity may be 
treated with concomitant medications (e.g., topical agents or oral antibiotics) at the 
discretion of the investigator.  Skin toxicity should be managed according to institutional 
guidelines.
Guidelines for management of patients who develop Grade 3 rash are provided in 
Table 2 in Section 5.1.1. 
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, a randomized, placebo-controlled trial comparing 
cobimetinib plus vemurafenib versus placebo plus vemurafenib in adult patients with 
advanced BRAF V600-mutated melanoma, 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% 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 cobimetinib plus vemurafenib arm than the placebo plus vemurafenib 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 
reported as 33.9% for both, 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. 
Patients and their parents should be instructed to promptly contact the investigators if 
the patient develops diarrhea.  Investigators should treat diarrhea and intervene 
promptly for patients who appear to be at increased risk of development of significant 


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dehydration, electrolyte imbalances, and/or multi-organ failure.  Patients should receive 
maximum supportive care per institutional guidelines.
Guidelines for management of patients who develop Grade 2 diarrhea are provided in 
Table 2 in Section 5.1.1.
Cutaneous Squamous Cell and Basal Cell Carcinoma
Cutaneous squamous cell carcinoma has been reported at high frequency with use of 
BRAF inhibitors, including vemurafenib, but co-administration of cobimetinib with 
vemurafenib was associated with lower frequency of squamous cell carcinoma on the 
GO28141 trial (3% in cobimetinib/vemurafenib-treated patients vs. 11% in 
placebo/vemurafenib-treated patients).  Basal cell carcinoma  occurred at higher 
frequency on the GO28141 trial in the cobimetinib/vemurafenib arm compared to 
placebo/vemurafenib arm (4% vs. 2%, respectively).  Specific management of lesions 
suspicious for cutaneous squamous cell carcinoma or basal cell carcinoma is outlined in 
Table 2 in Section 5.1.1.
Hypersensitivity
There have been few reports of hypersensitivity and/or anaphylaxis in clinical trials with 
patients who have been exposed to cobimetinib as monotherapy or when used with 
other agents.  These have appeared to be isolated reports, and in some cases, occurred 
in patients with histories of drug allergies.  Therefore, 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.
5.2
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing 
protocol-specified safety laboratory assessments, measuring protocol-specified vital 
signs, and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study.
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4.


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5.2.1
Adverse Events
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product

Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition), except as described in 
Section 5.3.5.9

Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline

Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug

Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies)
5.2.2
Serious Adverse Events (Immediately Reportable to the 
Sponsor)
A serious adverse event is any adverse event that meets any of the following criteria:

Is fatal (i.e., the adverse event actually causes or leads to death)

Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death)
This does not include any adverse event that, had it occurred in a more severe 
form or was allowed to continue, might have caused death.

Requires or prolongs inpatient hospitalization (see Section 5.3.5.10)

Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient’s ability to conduct normal life 
functions)

Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug

Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above)
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to NCI CTCAE 


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criteria; see Section 5.3.3); the event itself may be of relatively minor medical 
significance (such as severe headache without any further findings).
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF.
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions).
5.2.3
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor)
Adverse events of special interest, regardless of seriousness, are required to be 
reported by the investigator to the Sponsor immediately (i.e., no more than 24 hours 
after learning of the event; see Section 5.4.2 for reporting instructions).  Adverse events 
of special interest for this study include the following:

Retinal detachment, retinal pigment epithelium detachment, neurosensory retinal 
detachment, serous retinopathy, or CSCR

Any grade retinal vein occlusion

Rhabdomyolysis or Grade 3 CPK elevation

Any grade hemorrhage event (except Grade 1 epistaxis per CTCAE v4.0 criteria)

Any grade cerebral hemorrhage

Any new malignancy, including cutaneous squamous cell and basal cell carcinoma

Grade 3 rash

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 (as defined in Section 5.3.5.6)

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.

Symptomatic heart failure or Grade 2 LVEF reduction
5.2.4
Dose-Limiting Toxicities (Immediately Reportable to the 
Sponsor)
During the DLT assessment window, adverse events identified as DLTs, as defined in 
Section 3.1.1.1, are required to be reported by the investigator to the Sponsor 


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immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions).
5.3
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Sections 5.45.6.
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4).  
5.3.1
Adverse Event Reporting Period
Investigators will seek information on adverse events at each patient contact.  
All adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient’s medical record and on the Adverse Event eCRF.
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures, such as biopsies, discontinuation of medications) should be reported 
(see Section 5.4.2 for instructions for reporting serious adverse events).
After initiation of study drug, all adverse events will be reported until 30 days after the 
last dose of study drug.  After this period, the investigator should report any serious 
adverse events that are believed to be related to prior study drug treatment (see 
Section 5.6).
5.3.2
Eliciting Adverse Event Information
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following:
"How have you felt since your last clinic visit?"
"Have you had any new or changed health problems since you were last here?" 
5.3.3
Assessment of Severity of Adverse Events
The adverse event severity grading scale for the NCI CTCAE (v4.0) will be used for 
assessing adverse event severity.  Table 4 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE.


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Table 4
Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE
Grade
Severity
1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated
2
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a
3
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting age-appropriate self-care activities of daily living b,c
4
Life-threatening consequences or urgent intervention indicated d
5
Death related to adverse event d
NCI CTCAENational Cancer Institute Common Terminology Criteria for Adverse Events.
Note:  Based on the most recent version of NCI CTCAE (v4.0), which can be found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm
a Instrumental activities of daily living for adults refer to preparing meals, shopping for groceries 
or clothes, using the telephone, managing money, etc. Age appropriate developmental 
milestones, however, should be taken into account when assessing instrumental activities of 
pediatric patients.
b Examples of self-care activities for adults daily living include bathing, dressing and 
undressing, feeding oneself, using the toilet, and taking medications, as performed by 
patients who are not bedridden. Age-appropriate developmental milestones, however, 
should be taken into account when assessing self-care activities of pediatric patients.
c If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section 5.4.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.2.2.
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4.2 for 
reporting instructions), per the definition of serious adverse event in Section 5.2.2.
5.3.4
Assessment of Causality of Adverse Events
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether or 
not an adverse event is considered to be related to the study drug, indicating "yes" or 
"no" accordingly.  The following guidance should be taken into consideration (see also 
Table 5):

Temporal relationship of event onset to the initiation of study drug

Course of the event, considering especially the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable)

Known association of the event with the study drug or with similar treatments

Known association of the event with the disease under study


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
Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event

Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event
Table 5
Causal Attribution Guidance
Is the adverse event suspected to be caused by the study drug on the basis of facts, evidence, 
science-based rationales, and clinical judgment?
YES
There is a plausible temporal relationship between the onset of the adverse event and 
administration of the study drug, and the adverse event cannot be readily explained by 
the patient's clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to the study drug; and/or the 
adverse event abates or resolves upon discontinuation of the study drug or dose 
reduction and, if applicable, reappears upon re-challenge.
NO
An adverse event will be considered related, unless it fulfills the criteria specified below.  
Evidence exists that the adverse event has an etiology other than the study drug 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, or 
concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of the study drug (e.g., cancer diagnosed 2 days after first 
dose of study drug).
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy.
5.3.5
Procedures for Recording Adverse Events
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations.
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF.
5.3.5.1
Diagnosis versus Signs and Symptoms
A diagnosis (if known) should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases).  However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the Adverse Event 
eCRF.  If a diagnosis is subsequently established, all previously reported adverse events 
based on signs and symptoms should be nullified and replaced by one adverse event 
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis.


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5.3.5.2
Adverse Events That Are Secondary to Other Events
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example:

If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF.

If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF.

If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF.

If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF.

If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF.
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated.
5.3.5.3
Persistent or Recurrent Adverse Events
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  Details regarding any increases or decreases in severity will be captured on the 
Adverse Event Intensity or Grade Changes eCRF.  If the event becomes serious, it 
should be reported to the Sponsor immediately (i.e., no more than 24 hours after 
learning that the event became serious; see Section 5.4.2 for reporting instructions).  
The Adverse Event eCRF should be updated by changing the event from "non-serious" 
to "serious," providing the date that the event became serious, and completing all data 
fields related to serious adverse events.
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF.


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5.3.5.4
Abnormal Laboratory Values
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy

Is clinically significant in the investigator’s judgment 
Note:  For oncology trials, certain abnormal values may not qualify as adverse 
events.
It is the investigator’s responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event.
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5 ULN associated with cholestasis), only the 
diagnosis (i.e., cholestasis) should be recorded on the Adverse Event eCRF.
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating if the test result is above or below the normal range (e.g., "elevated 
potassium," as opposed to "abnormal potassium").  If the laboratory abnormality can be 
characterized by a precise clinical term per standard definitions, the clinical term should 
be recorded as the adverse event.  For example, an elevated serum potassium level of 
7.0 mEq/L should be recorded as "hyperkalemia."
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.3 for 
details on recording persistent adverse events).
5.3.5.5
Abnormal Vital Sign Values
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must 
be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention or a change in concomitant therapy

Is clinically significant in the investigator’s judgment 


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It is the investigator’s responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event.
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF.
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.3 for 
details on recording persistent adverse events).
5.3.5.6
Abnormal Liver Function Tests
The finding of an elevated ALT or AST (3ULN) in combination with either an elevated 
total bilirubin (2ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury (as 
defined by Hy's law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following:

Treatment-emergent ALT or AST 3 ULN in combination with total bilirubin 
2ULN

Treatment-emergent ALT or AST 3 ULN in combination with clinical jaundice
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.1) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest (see 
Section 5.4.2).
5.3.5.7
Deaths
For this protocol, mortality is an efficacy endpoint.  Deaths that occur during the 
protocolspecified adverse event reporting period (see Section 5.3.1) that are attributed 
by the investigator solely to progression of underlying disease should be recorded only 
on the Study Discontinuation eCRF.  All other on-study deaths, regardless of relationship 
to study drug, must be recorded on the Adverse Event eCRF and immediately reported 
to the Sponsor (see Section 5.4.2).
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death. The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death").


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During survival follow-up, deaths attributed to progression of underlying disease should 
be recorded only on the Study Discontinuation eCRF. 
5.3.5.8
Preexisting Medical Conditions
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF.
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches").
5.3.5.9
Lack of Efficacy or Worsening of Cancer
Events that are clearly consistent with the expected pattern of disease evolution should 
not be recorded as adverse events.  These data will be captured as efficacy assessment 
data only.  In most cases, the expected pattern of progression will be based on mINRC, 
RANO criteria for HGG, RANO criteria for LGG, or RECIST v1.1, as appropriate.  In rare 
cases, the determination of clinical progression will be based on symptomatic 
deterioration.  However, every effort should be made to document progression through
use of objective criteria.  If there is any uncertainty as to whether an event is due to 
disease progression, it should be reported as an adverse event.
5.3.5.10
Hospitalization or Prolonged Hospitalization
Any adverse event that results in hospitalization (i.e., in-patient admission to a hospital) 
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as outlined 
below.  
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event:

Hospitalization for respite care

Hospitalization for a preexisting condition, provided that all of the following criteria 
are met:
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of underlying disease
The patient has not experienced an adverse event

Hospitalization due solely to progression of underlying disease


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An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead:

Hospitalization for an adverse event that would ordinarily have been treated in an 
outpatient setting had an outpatient clinic been available
5.3.5.11
Adverse Events Associated with an Overdose or Error in Drug 
Administration
An overdose is the accidental or intentional use of a drug in an amount higher than the 
dose being studied.  An overdose or incorrect administration of study treatment is not 
itself an adverse event, but it may result in an adverse event.  All adverse events 
associated with an overdose or incorrect administration of study drug should be 
recorded on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria, the event should be reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2).
No safety data related to overdosing of cobimetinib are available.
5.4
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug:

Serious adverse events (see Section 5.4.2 for further details)

Adverse events of special interest, regardless of seriousness (see Section 5.4.2 for 
further details)

DLTs (immediate reporting during the DLT assessment window; see Section 5.4.2
for further details)

Pregnancies (see Section 5.4.3 for further details)
The investigator must report new significant follow-up information for these events to the
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information).  New significant information includes the following:

New signs or symptoms or a change in the diagnosis

Significant new diagnostic test results

Change in causality based on new information

Change in the event’s outcome, including recovery

Additional narrative information on the clinical course of the event


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Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC.
5.4.1
Emergency Medical Contacts
Medical Monitor Contact Information 
Medical Monitor:
, M.D.
Telephone No.:
Alternate Telephone:
To ensure the safety of study patients, an Emergency Medical Call Center Help Desk will
access the Roche Medical Emergency List, escalate emergency medical calls, provide 
medical translation service (if necessary), connect the investigator with a Roche Medical 
Monitor, and track all calls.  The Emergency Medical Call Center Help Desk will be 
available 24 hours per day, 7 days per week.  Toll-free numbers for the Help Desk, as 
well as Medical Monitor contact information, will be distributed to all investigators. 
5.4.2
Reporting Requirements for Serious Adverse Events, Adverse 
Events of Special Interest, and Dose-Limiting Toxicities
5.4.2.1
Events That Occur prior to Study Drug Initiation
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.  
The Serious Adverse Event/Adverse Event of Special Interest Reporting Form provided 
to investigators should be completed and submitted to the Sponsor or its designee 
immediately (i.e., no more than 24 hours after learning of the event), either by faxing or 
by scanning and emailing the form using the fax number or email address provided to 
investigators.
5.4.2.2
Events That Occur after Study Drug Initiation
After initiation of study drug, serious adverse events and adverse events of special 
interest will be reported until 30 days after the last dose of study drug.  DLTs will be 
reported during the DLT assessment window.  Investigators should record all case 
details that can be gathered immediately (i.e., within 24 hours after learning of the event) 
on the Adverse Event eCRF and submit the report via the electronic data capture (EDC) 
system.  A report will be generated and sent to Roche Safety Risk Management by the 
EDC system.
In the event that the EDC system is unavailable, the Serious Adverse Event/Adverse 
Event of Special Interest Reporting Form provided to investigators should be completed 
and submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours 
after learning of the event), either by faxing or by scanning and emailing the form using 
the fax number or email address provided to investigators.  Once the EDC system is 
available, all information will need to be entered and submitted via the EDC system.  
Instructions for reporting post-study adverse events are provided in Section 5.6.


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5.4.3
Reporting Requirements for Pregnancies
5.4.3.1
Pregnancies in Female Patients
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 3 months after the last 
dose of study drug.  The Clinical Trial Pregnancy Reporting Form provided to 
investigators should be completed and submitted to the Sponsor or its designee 
immediately (i.e., no more than 24 hours after learning of the pregnancy), either by 
faxing or by scanning and emailing the form using the fax number or email address 
provided to investigators.   Pregnancy should not be recorded on the Adverse Event 
eCRF.  The investigator should discontinue study drug and counsel the patient, 
discussing the risks of the pregnancy and the possible effects on the fetus.  Monitoring 
of the patient should continue until conclusion of the pregnancy.  Any serious adverse 
events associated with the pregnancy (e.g., an event in the fetus, an event in the mother 
during or after the pregnancy, or a congenital anomaly/birth defect in the child) should be 
reported on the Adverse Event eCRF.  In addition, the investigator will submit a Clinical 
Trial Pregnancy Reporting Form when updated information on the course and outcome 
of the pregnancy becomes available.
5.4.3.2
Pregnancies in Female Partners of Male Patients
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or within 3 
months after the last dose of study drug.  The Clinical Trial Pregnancy Reporting Form 
provided to investigators should be completed and submitted to the Sponsor or its 
designee immediately (i.e., no more than 24 hours after learning of the pregnancy), 
either by faxing or by scanning and emailing the form using the fax number or email 
address provided to investigators.  Attempts should be made to collect and report details 
of the course and outcome of any pregnancy in the partner of a male patient exposed to 
study drug.  When permitted by the site, the pregnant partner would need to sign an 
Authorization for Use and Disclosure of Pregnancy Health Information to allow for 
follow-up on her pregnancy.  If the authorization has been signed, the investigator 
should update the Clinical Trial Pregnancy Reporting Form with additional information on 
the course and outcome of the pregnancy.  An investigator who is contacted by the male 
patient or his pregnant partner may provide information on the risks of the pregnancy 
and the possible effects on the fetus, to support an informed decision in cooperation with 
the treating physician and/or obstetrician.  In addition, the investigator will submit a 
Clinical Trial Pregnancy Reporting Form when updated information on the course and 
outcome of the pregnancy becomes available.
5.4.3.3
Abortions
A spontaneous abortion should be classified as a serious adverse event (as the Sponsor 
considers abortions to be medically significant), recorded on the Adverse Event eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5.4.2).  


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If a therapeutic or elective abortion was performed because of an underlying maternal 
or embryofetal toxicity, the toxicity should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2).  A therapeutic or 
elective abortion performed for reasons other than an underlying maternal or 
embryofetal toxicity is not considered an adverse event.
All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form. 
5.4.3.4
Congenital Anomalies/Birth Defects
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug or the female partner of a male patient exposed to study drug should be classified 
as a serious adverse event, recorded on the Adverse Event eCRF, and reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2).
5.5
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS
5.5.1
Investigator Follow-Up
The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the patient is lost to 
follow-up, or the patient withdraws consent.  Every effort should be made to follow all 
serious adverse events considered to be related to study drug or trial-related procedures 
until a final outcome can be reported.
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification.
All pregnancies reported during the study should be followed until pregnancy outcome.  
Follow reporting instructions provided in Section 5.4.3.1.
5.5.2
Sponsor Follow-Up
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, electronic mail, and/or a 
monitoring visit to obtain additional case details and outcome information (e.g., from 
hospital discharge summaries, consultant reports, autopsy reports) in order to perform 
an independent medical assessment of the reported case.
5.6
POST-STUDY ADVERSE EVENTS
The Sponsor should be notified if the investigator becomes aware of any serious 
adverse event that occurs after the end of the adverse event reporting period (defined as 
30 days after the last dose of study drug), if the event is believed to be related to prior 
study drug treatment.  


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The investigator should report these events directly to the Sponsor or its designee, using 
the Adverse Event eCRF via the electronica data capture (EDC) system, unless EDC is 
no longer available; in which case, they should be faxing or by scanning and emailing 
the Serious Adverse Event/Adverse Event of Special Interest Reporting Form using the 
fax number or email address provided to investigators.
5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation.
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference document:

Cobimetinib Investigator's Brochure
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document.
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed.
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
This is a Phase I/II, multicenter, open-label, dose-escalation, study designed to evaluate 
the safety, tolerability, PK, and preliminary efficacy of cobimetinib in pediatric and young 
adult patients with solid tumors for which prior treatment has proven to be ineffective (i.e., 
relapsed or refractory) or intolerable.  The primary analysis will be conducted after 
enrollment has been completed and all enrolled patients have been followed for at least 
12 months.
6.1
DETERMINATION OF SAMPLE SIZE
For the dose-escalation stage, the sample size is based on the dose-escalation rules 
described in the study design section of this document.  Explicit power and Type I error 
considerations were not factored into the design, as the dose-escalation stage was 
designed to obtain preliminary safety and PK information for the study drug.  
To make a preliminary assessment of the efficacy of the study drug, two phases of 
response assessment are planned for the expansion stage:  an initial response 
assessment and an additional response assessment.  Taking into account historical 
control ORRs for each pediatric tumor type, the minimum number of patients in the initial 


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response assessment and the minimum number of responders needed for advancement 
to the additional response assessment were calculated and are presented by tumor type 
in Table 6.  The selection of tumor type cohorts for additional response assessment, as 
well as the number of patients needed for the additional response assessment, will also 
take into account practical considerations (e.g., enrollment feasibility), biomarker 
analysis, safety profiles, and any other relevant information.  Similar consideration will be 
given to other rare pediatric tumor types that are enrolled in the study and not included in 
Table 6.  No formal hypothesis testing is planned in this study.
Table 6
Sample Size and Responder Requirements for Initial Response 
Assessment
Tumor Type
(relapsed/refractory)
Historical Control 
Overall Response 
Rate (%)
Initial Response Assessment
Minimum No. of 
Patients Enrolled
Minimum No. of Responders 
Needed for Tumor Type
Cohort Expansion
Melanoma
20%
10
3
Neuroblastoma
18%
10
3
Rhabdomyosarcoma
10%
10
2
Non-rhabdomyosarcoma 
soft tissue sarcoma
10%
10
2
High-grade glioma a
12%
10
2
Low-grade glioma b
20%
10
3
a
Gururangan et al. 2010; Warren et al. 2012; Fouladi et al. 2013; MacDonald et al. 2013.
b
Packer et al. 2009; Bouffet et al. 2012; Yalon et al. 2013.
Overall, approximately 70 patients will be enrolled in the study. 
6.2
SUMMARIES OF CONDUCT OF STUDY
Patient enrollment will be tabulated by study site.  Patient disposition and reasons for 
discontinuations will be summarized for all enrolled patients.  In addition, major protocol 
deviations will be summarized. 
Patient demographics and baseline characteristics, including age, sex, race, medical 
history, and prior cancer treatment, will be summarized overall and by tumor type cohort.  
Descriptive statistics (mean, median, standard deviation, 25 h percentile, 75th percentile, 
and range) will be presented for continuous variables, and proportions will be presented 
for categorical variables.
6.3
SAFETY ANALYSES
Safety analyses will be performed on the safety-evaluable population, which is defined 
as patients who receive any amount of study drug.  Subgroup safety analyses by tumor 
type cohort will also be conducted as appropriate.


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Study treatment exposure (such as treatment duration, total dose received, and number 
of cycles and dose modifications) will be summarized with descriptive statistics.
All adverse events, serious adverse events, adverse events leading to death, DLTs, 
adverse events of special interest, and adverse events leading to study treatment 
discontinuation, that occur on or after the first dose of study treatment 
(i.e., treatmentemergent adverse events), will be summarized by mapped term, 
appropriate thesaurus level, and toxicity grade.  For events of varying severity, the 
highest grade will be used in the summaries.  Deaths and cause of death will be 
summarized.
Laboratory toxicities will be summarized by NCI CTCAE grade.
6.4
PHARMACOKINETIC ANALYSES
Plasma samples for determination of cobimetinib concentration will be collected prior to 
dosing and at 2, 4, 6, and 24 hours after dosing on Days 1 and 21 of Cycle 1, and within 
4 hours prior to dosing on Day 1 of Cycle 2.  The sampling will allow determination of 
the total exposure (AUC0-24 after a single dose and at steady state), Cmax, Tmax, and 
accumulation ratio.  Mean and individual concentration-time graphs will be plotted, and 
PK parameters will be reported using descriptive statistics (e.g., mean, standard 
deviation, coefficient of variation, median, minimum, and maximum).  Other PK 
parameters such as steady-state concentration, steady-state concentration at the end of 
a dosing interval, CL/F, and t1/2 may be determined as data allow. After a minimum of 
20 patients have completed Cycle 1, an interim PK and safety analysis will be conducted.
In addition, cobimetinib plasma concentrationtime data, together with information on 
dosing and patient characteristics, will be pooled and analyzed using a population PK 
analysis approach.
Additional analyses may be conducted as warranted by the data.
6.5
EFFICACY ANALYSES
All efficacy analyses will be performed on safety-evaluable population, which is defined 
as patients who receive any amount of study drug. 
6.5.1
Primary Efficacy Endpoints
The co-primary endpoints for efficacy are ORR and PFS. 
An objective response is defined as a complete or partial response on two consecutive 
occasions 4 weeks apart, as determined by the investigator using mINRC for patients 
with neuroblastoma, RANO criteria for patients with HGG, RANO criteria for patients with 
LGG, and RECIST v1.1 for patients with other tumors.  ORR is the percentage of 
patients who are determined to have an objective response.  Patients with no post-
baseline tumor assessments will be counted as non-responders.  ORR and 


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corresponding 95% exact confidence interval (CI), using the Blyth-Still-Casella method, 
will be summarized overall and by tumor type cohort.
PFS is defined as the time from initiation of study drug to the first documented 
occurrence of disease progression, as determined by the investigator, or death from any 
cause, whichever occurs first.  Data for patients without disease progression or death 
will be censored at the date of the last tumor assessment at which the patient was 
known to be progression-free or, if no tumor assessment is performed after the baseline 
visit, at the date of initiation of study drug.  The Kaplan-Meier approach will be used to 
estimate median PFS.  The 95% CI of the median PFS will be estimated using 
Brookmeyer and Crowley method.  Subgroup analysis of PFS by tumor type cohort will 
be conducted as appropriate.
6.5.2
Secondary Efficacy Endpoints
The secondary efficacy endpoints are DOR and OS. 
For patients who achieve an objective response, DOR is defined as the time from the 
first tumor assessment that supports the patient’s objective response to the time of 
disease progression, as determined by the investigator, or death from any cause, 
whichever occurs first. Data for patients without disease progression or death will be 
censored at the date of the last tumor assessment at which the patient was known to be 
progression-free or, if no tumor assessment is performed after the baseline visit, at the 
date of initiation of study drug. The Kaplan-Meier approach will be used to estimate 
median DOR.  The 95% CI of the median DOR will be estimated using Brookmeyer and 
Crowley method.  Subgroup analysis of DOR by tumor type cohort will be conducted as 
appropriate.
OS is defined as the time from initiation of study drug to death from any cause.  Patients 
who are alive at the data cutoff date will be censored at the date the patient was last 
known to be alive.  The Kaplan-Meier approach will be used to estimate median OS.  
The 95% CI of the median OS will be estimated using Brookmeyer and Crowley method.  
Subgroup analysis of OS by tumor type cohort will be conducted as appropriate.
6.6
EXPLORATORY ANALYSES
6.6.1
Biomarker Analyses
Levels of potential PD biomarkers (including but not limited to p-MEK, p-ERK, and Ki67) 
will be measured in tumor tissue collected at baseline, on treatment, and at the time of 
disease progression.  These samples will be analyzed for changes in biomarker levels in 
response to exposure to cobimetinib.
Plasma and archival tumor tissue samples will be collected at baseline and analyzed for 
non-inherited and inherited biomarkers (including but not limited to BRAF mutations, 
BRAF fusions, RAS mutations, and NF1 mutations) that may be correlated with 


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response or resistance to MEK inhibition or with severity of adverse effects associated 
with MEK inhibition.
A modified ORR will be used for LGG and is defined as the percentage of patients 
with measurable disease who have a complete, partial, or minor response on two 
consecutive occasions 4 weeks apart, as determined by the investigator using RANO 
criteria for LGG.
ORR for LGG will also be assessed using RECIST v1.1 and is defined as the 
percentage of patients with measurable disease who have a complete or partial 
response for on two consecutive occasions 4 weeks apart, as determined by the 
investigator.
Diffusion activity and metabolic activity before and after cobimetinib treatment will be 
analyzed in available tumor MRI scans and PET scans, respectively.
6.6.2
Acceptability Survey
Analyses will be descriptive, enumerating the number of patients that selected each 
answer choice. Analyses will be conducted separately for patients receiving suspension 
and patients receiving tablets.
6.7
INTERIM ANALYSES
6.7.1
Planned Interim Analyses
Interim efficacy analyses will be conducted whenever a tumor type cohort has enrolled 
the 10 patients required for initial response assessment and patients have been followed 
for approximately 12 months. 
6.7.2
Optional Interim Analyses
Given the hypothesis-generating nature of this study, the Sponsor may choose to 
conduct additional interim efficacy analyses.  The decision to conduct an optional interim 
analysis and the timing of the analysis will be documented in the Sponsor’s trial master 
file prior to the conduct of the interim analysis.  The interim analysis will be performed 
and interpreted by Sponsor study team personnel.
7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
The Sponsor will be responsible for the data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC through use of 
eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 
discrepant data, the Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system.  


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The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  Central laboratory data and IWRS data 
will be sent directly to the Sponsor, using the Sponsor’s standard procedures to handle 
and process the electronic transfer of these data.
eCRFs and correction documentation will be maintained in the EDC system’s audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor’s standard procedures.
7.2
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor.
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee.
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required.
7.3
SOURCE DATA DOCUMENTATION
Study monitors will perform ongoing source data verification to confirm that critical 
protocol data (i.e., source data) entered into the eCRFs by authorized site personnel are 
accurate, complete, and verifiable from source documents. 
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, evaluation checklists, pharmacy 
dispensing records, recorded data from automated instruments, copies of transcriptions 
that are certified after verification as being accurate and complete, microfiche, 
photographic negatives, microfilm or magnetic media, X-rays, patient files, and records 
kept at pharmacies, laboratories, and medico-technical departments involved in a clinical 
trial.
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data.
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.5.


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To facilitate source data verification, the investigators and institutions must provide the 
Sponsor or its representatives direct access to applicable source documents and reports 
for trial-related monitoring, Sponsor audits, and IRB/EC review.  The study site must also 
allow inspection by applicable health authorities.
7.4
USE OF COMPUTERIZED SYSTEMS
When clinical observations are entered directly into a study site’s computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  
An acceptable computerized data collection system allows preservation of the original 
entry of data.  If original data are modified, the system should maintain a viewable audit 
trail that shows the original data as well as the reason for the change, name of the 
person making the change, and date of the change.
7.5
RETENTION OF RECORDS
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, Informed Consent Forms, laboratory test results, and medication 
inventory records, must be retained by the Principal Investigator for at least 15 years 
after completion or discontinuation of the study, or for the length of time required by 
relevant national or local health authorities, whichever is longer.  After that period of time, 
the documents may be destroyed, subject to local regulations.  
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location.
Roche will retain study data for 25 years after the final Clinical Study Report has been 
completed or for the length of time required by relevant national or local health 
authorities, whichever is longer.
8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the applicable laws 
and regulations of the country in which the research is conducted, whichever affords the
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a U.S. 
Investigational New Drug Application (IND) will comply with U.S. Food and Drug 
Administration (FDA) regulations and applicable local, state, and federal laws.  Studies 
conducted in the European Union or European Economic Area will comply with the E.U. 
Clinical Trial Directive (2001/20/EC) and applicable local, regional, and national laws.


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8.2
INFORMED CONSENT
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Child’s Informed Assent Form or Caregiver's Informed Consent Form, if 
applicable) will be provided to each site.  If applicable, it will be provided in a certified 
translation of the local language.  The Sponsor or its designee must review and approve 
any proposed deviations from the Sponsor's sample Informed Consent Forms or any 
alternate consent forms proposed by the site (collectively, the "Consent Forms") before 
IRB/EC submission.  The final IRB/ECapproved Consent Forms must be provided to 
the Sponsor for health authority submission purposes according to local requirements.
The Consent Forms must be signed and dated by the patient and/or the patient’s legally 
authorized representative(s) before his or her participation in the study.  The case history 
or clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study.
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes.
Patients and/or the patient’s legally authorized representative(s) must be re-consented 
to the most current version of the Consent Forms (or to a significant new 
information/findings addendum in accordance with applicable laws and IRB/EC policy) 
during their participation in the study.  For any updated or revised Consent Forms, the 
case history or clinical records for each patient shall document the informed consent 
process and that written informed consent was obtained using the updated/revised 
Consent Forms for continued participation in the study.
A copy of each signed Consent Form must be provided to the patient or the patient’s 
legally authorized representative(s).  All signed and dated Consent Forms must remain 
in each patient’s study file or in the site file and must be available for verification by study 
monitors at any time.
For sites in the United States, each Consent Form may also include patient authorization 
to allow use and disclosure of personal health information in compliance with the U.S. 
Health Insurance Portability and Accountability Act of 1996 (HIPAA).  If the site utilizes a 
separate Authorization Form for patient authorization for use and disclosure of personal 
health information under the HIPAA regulations, the review, approval, and other 
processes outlined above apply except that IRB review and approval may not be 
required per study site policies.
8.3
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 


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Investigator and reviewed and approved by the IRB/EC before the study is initiated.  In 
addition, any patient recruitment materials must be approved by the IRB/EC. 
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC.  Investigators are also responsible 
for promptly informing the IRB/EC of any protocol amendments (see Section 9.6).
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site’s study file. 
8.4
CONFIDENTIALITY
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location.
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.
Medical information may be given to a patient’s personal physician or other appropriate
medical personnel responsible for the patient’s welfare, for treatment purposes.
Data generated by this study must be available for inspection upon request by 
representatives of the FDA and other national and local health authorities, Sponsor 
monitors, representatives, and collaborators, and the IRB/EC for each study site, as 
appropriate.
8.5
FINANCIAL DISCLOSURE
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (i.e., LPLV).


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9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION
9.1
STUDY DOCUMENTATION
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including but not limited to the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes to 
data.
9.2
PROTOCOL DEVIATIONS
The investigator should document and explain any protocol deviations.  The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities. As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed.
9.3
SITE INSPECTIONS
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients’ medical records, and eCRFs.  The investigator will 
permit national and local health authorities, Sponsor monitors, representatives, and 
collaborators, and the IRBs/ECs to inspect facilities and records relevant to this study.
9.4
ADMINISTRATIVE STRUCTURE
This study will be sponsored by Roche and managed with the support of a contract 
research organization, which will provide clinical monitoring, sample management, and 
project management support.  Approximately 70 patients are expected be enrolled in this 
study, at approximately 30 investigative sites in Europe and North America. If an 
efficacy signal is observed during the first expansion step for the initial response 
assessment, up to an additional 30 patients per cohort may be enrolled in the second 
expansion step for the additional response assessment.  Patients will be enrolled 
through the study groups Innovative Therapies for Children with Cancer (ITCC) and 
Pediatric Oncology Experimental Therapeutics Investigators’ Consortium (POETIC).  
Patients will be enrolled using an IWRS.
Central facilities will be used for certain study assessments (i.e., PK and biomarker 
analyses).  Accredited local laboratories will be used for routine monitoring; local 
laboratory ranges will be obtained.  An IMC will monitor patient safety throughout the 


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study and provide a recommendation on the dose to be taken forward into the expansion 
stage after completion of the dose-escalation stage.  
9.5
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, both at scientific 
congresses and in peer-reviewed journals. The Sponsor will comply with all 
requirements for publication of study results.  For more information, refer to the Roche 
Global Policy on Sharing of Clinical Trials Data at the following Web site:
http://www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.
pdf
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective clinical study report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound.
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator.
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise.


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9.6
PROTOCOL AMENDMENTS
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements.
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information).


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10.
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2009;19:44958.
Sievert AJ, Lang SS, Boucher KL, et al. Paradoxical activation and RAF inhibitor 
resistance of BRAF protein kinase fusions characterizing pediatric astrocytomas. 
Proc Natl Acad Sci USA, 2013;110:595762. 


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Skolnik JM, Barrett JS, Jayaraman B, et al. Shortening the timeline of pediatric phase I 
trials: The rolling six design. J Clin Oncol 2008;26(2):190195.
Strother D. Atypical teratoid rhabdoid tumors of childhood: diagnosis, treatment and 
challenges. Expert Rev Anticancer Therapy 2005;5:90715.
Vujic I, Sanlorenzo M, Posch C, et al. Metformin and trametinib have synergistic effects 
on cell viability and tumor growth in NRAS mutant cancer. Oncotarget 
2015;6(2):969-978.
Warren KE, Gururangan S, Geyer JR, et al. A Phase II study of O6-benzylguanine and 
temozolomide in pediatric patients with recurrent or progressive high grade 
gliomas and brainstem gliomas: a pediatric brain tumor consortium study. 
J Neurooncol 2012;106:6439.
Weingart MF, Roth JJ, Hutt-Cabezas M, et al. Disrupting LIN28 in atypical teratoid 
rhabdoid tumors reveals the importance of the mitogen activated protein kinase 
pathway as a therapeutic target. Oncotarget 2015;6(5):316577.
Wen PY, Macdonald DR, Reardon DA, et al. Updated response assessment criteria for 
high-grade gliomas: Response assessment in neuro-oncology working group. J 
Clin Oncol 2012;28:196372.
Wu G, Diaz AK, Paugh BS, et al.; St. Jude Children's Research Hospital-Washington 
University Pediatric Cancer Genome, P. The genomic landscape of diffuse intrinsic 
pontine glioma and pediatric non-brainstem high-grade glioma. Nat Genet 
2014;46:44450.
Yalon M, Rood B, MacDonald TJ, et al. A feasibility and efficacy study of rapamycin and 
erlotinib for recurrent pediatric low-grade glioma. Pediatr Blood Cancer 
2013;60:716.
Zhang J, Wu G, Miller CP, et al.; St. Jude Children's Research Hospital-Washington 
University Pediatric Cancer Genome, P. Whole-genome sequencing identifies 
genetic alterations in pediatric low-grade gliomas. Nat Genet 2013;45:60212.






Appendix 1
Schedule of Assessments (cont.)
Cobimetinib—F. Hoffmann-La Roche Ltd
116/Protocol GO29665, Version 11
Assessments shaded in gray should be performed as scheduled, but the associated data do not need to be recorded on the eCRF (except in the 
case of an adverse event or a pregnancy).
a Results of standard-of-care tests or examinations performed prior to obtaining informed consent and within 28 days prior to Day 1 of Cycle 1 
may be used; such tests do not need to be repeated for screening.  
b Patients who discontinue study drug will return to the clinic for a study drug discontinuation visit 30 (3) days after the last dose of study drug.  
If treatment with another anti-cancer treatment is scheduled to begin less than 30 days after the last dose of cobimetinib, assessments at this 
visit should be performed before the patient starts the other treatment, if possible.
c Long term follow-up information will be collected every 3 months during the first 2 years (Years 1 and 2), every 6 months during Year 3, and 
yearly until study termination by Sponsor, death, loss to follow-up, or withdrawal of consent, whichever occurs first.  Timing of visits will be 
determined by date of study drug discontinuation.  More information is required for some patients as noted in Section 4.6.2.
d Informed consent must be documented before any study-specific screening procedure is performed.
e A tumor specimen and associated pathology report must be confirmed to be available prior to patient participation in any study-specific 
screening procedures and must be shipped within 30 days of first dosing.  Specimens must be adequate for biomarker testing even though the 
results will not be used to determine eligibility.  See Section 4.5.9 for details on sample collection.
f
Medical history includes clinically significant diseases, major surgeries, cancer history (including prior cancer therapies and procedures), 
menstrual history, fertility history, and puberty history.  Demographic data will include age, sex, and self-reported race/ethnicity.
g All females of childbearing potential will undergo pregnancy tests within 1 week prior to the start of each treatment cycle.  A serum pregnancy 
test must be performed at screening (prior to Cycle 1).  Urine or serum pregnancy tests will be performed prior to all subsequent cycles.
h Includes respiratory rate, pulse rate, systolic and diastolic blood pressures, oxygen saturation, and temperature.  Record abnormalities 
observed at baseline on the General Medical History and Baseline Conditions eCRF.  At subsequent visits, record abnormalities on the 
Adverse Event eCRF.
i
Assessments performed within 96 hours prior to Day 1 of Cycle 1 do not need to be repeated on Day 1.
j
Includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatological, musculoskeletal, respiratory, 
gastrointestinal, genitourinary, and neurological systems.  When age appropriate, patients will be asked specifically about vision changes.  
Record abnormalities observed at baseline on the General Medical History and Baseline Conditions eCRF.  At subsequent visits, record new or 
worsened clinically significant abnormalities on the Adverse Event eCRF.
k  In Cycle 1, weight recorded during the screening period is acceptable.  For subsequent cycles, weight must be recorded within 3 days prior to 
Day 1 dose.
l
See Section 4.5.3 for required assessments, depending on age and Tanner stage.


Appendix 1
Schedule of Assessments (cont.)
Cobimetinib—F. Hoffmann-La Roche Ltd
117/Protocol GO29665, Version 11
m Perform Lansky Performance Status for patients 16 years of age (Appendix 7) and Karnofsky Performance Status for patients 16 years of 
age (Appendix 8).
n Hematology includes WBC count, hemoglobin, platelet count, 3-cell differential count (absolute neutrophils, monocytes, and lymphocytes).
o Screening laboratory assessments should be obtained within 14 days prior to Day 1 of Cycle 1.
p Chemistry includes sodium, potassium, magnesium, chloride, bicarbonate (or total carbon dioxide), glucose, BUN or urea, creatinine, 
total protein, albumin, phosphorus, calcium, total bilirubin (if abnormal, fractionate sample for direct and indirect), alkaline phosphatase, CPK, 
ALT, AST, uric acid, LDH.
q Urinalysis includes specific gravity, glucose, protein, and blood in patients 3 years of age.  If radioisotope glomerular filtration rate is routinely 
performed at the institution to measure patients’ creatinine clearance, this test can be used to assess renal function at screening.  Otherwise, 
serum creatinine is sufficient to document renal function at screening. 
r
The same radiographic procedure used to assess disease sites at screening should be used throughout the study (e.g., the same contrast 
protocol for CT scans).  To the extent that is feasible, assessments should be performed by the same evaluator to ensure internal consistency 
across visits.  Urine catecholamine levels (homovanillic acid, vanillylmandelic acid) are required for patients with neuroblastoma at the time of 
tumor evaluation.  See Section 4.5.5 for detailed information on tumor and response evaluations.
s Tumor assessments must be performed during the last week of the even-numbered cycles (i.e., at the end of Cycles 2, 4, 6, 8, etc., prior to the 
start of treatment in the next cycle).  For patients who have not met study criteria for progressive disease after 12 cycles, tumor assessments 
must be performed at the end of even-numbered cycles for the first 12 cycles, then cycles 16, 20, 24, and every 6 cycles thereafter.  At the 
investigator’s discretion, tumor assessments may be repeated at any time if disease progression is suspected.  An objective response should
be confirmed by repeat assessments 4 weeks after initial documentation.  
t
Plasma samples for biomarkers should be collected on Day 1 of Cycle 1 and during the last week of the even-numbered cycles (i.e., at the end 
of Cycles 2, 4, 6, 8, etc., prior to the start of treatment in the next cycle) and at the time of disease progression 3 days.  After the first 12 
cycles of treatment, plasma for biomarkers should be collected every 4 cycles of treatment (at end of Cycles: 16, 20, 24) and every 6 cycles 
thereafter.
u Ensure that samples are obtained prior to receipt of study drug.
v See Appendix 2 for detailed schedule. The PK sampling at Cycle 1 Day 22 should occur 24 hours after the last dose intake of the Cycle 1 
Day 21 visit.
w Includes any medication (e.g., prescription drugs, over-the-counter drugs, herbal or homeopathic remedies, nutritional supplements) used by a 
patient from 7 days prior to initiation of study drug until 30 days after the last dose of study drug.
x Patients will take cobimetinib orally according to the instructions in Appendix 10 on Days 121 of each 28-day treatment cycle until disease 


Appendix 1
Schedule of Assessments (cont.)
Cobimetinib—F. Hoffmann-La Roche Ltd
118/Protocol GO29665, Version 11
progression as determined by the investigator, death, unacceptable toxicity, or patient or investigator decision to discontinue treatment.  
Patients will be weighed at the beginning of each cycle, and the dose will be adjusted as needed.
y Performed immediately after dosing (Appendix 9).
z Echocardiograms should be performed at Cycle 2 and every third cycle thereafter (i.e., Cycles 5, 8, 11, etc.)
aa Ophthalmologic examinations will include age-specific visual acuity testing (should be reported in Snellen units), intraocular pressure 
measurements, slit-lamp ophthalmoscopy, and spectral domain OCT at all scheduled timepoints.  Indirect ophthalmoscopy and color fundus 
photography will be performed at screening and (if performed) at study drug discontinuation.  If spectral domain OCT is not available, 
time-domain OCT may be performed.  In patients who are unable to successfully complete OCT scans due to underlying visual impairment 
from non-retinal causes (such as brain tumor), color fundus photography and indirect ophthalmoscopy should be performed instead of OCT at 
each scheduled ophthalmologic evaluation.  Fluorescein angiography will be performed for identified OCT serous fluid accumulation or edema 
and thereafter based upon clinical findings.  Binocular indirect ophthalmoscopy will be performed any time fluorescein angiography is 
performed.
bb During treatment, ophthalmologic examinations should be performed on Cycle 1 Days 8 and 15 and at the start of every subsequent cycle; for 
patients who have completed 6 cycles of cobimetinib therapy and who have not developed serous retinopathy, retinal detachment, or other 
adverse events involving the retina, ophthalmologic evaluations will be performed at Cycles 8, 10, 12, 16, 20, 24, and every 6 cycles 
thereafter.
cc Ophthalmologic examination is not required if performed within the previous 12 weeks and there were no clinically significant findings or 
changes identified in the prior examination. 
dd During treatment, dermatologic examinations will be performed at Cycle 2 and every third cycle thereafter (i.e., Cycles 5, 8, 11, etc.).
ee Optional RCR tumor tissue samples will be collected prior to drug initiation, during the last week of Cycle 2 (i.e., prior to the start of treatment in 
Cycle 3) and at the time of disease progression or treatment discontinuation.  Samples may be collected at the time of scheduled tumor 
assessments.  
ff Blood sample is required for exploratory research for patients who consented to the optional on-study biopsy.


Cobimetinib—F. Hoffmann-La Roche Ltd
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Appendix 2
Schedule of Pharmacokinetic and Pharmacodynamic 
Assessments
Visit
Timepoint
Sample Type
Cycle 1, Day 1
Prior to the dose
Plasma PK sample for cobimetinib 
+ Plasma PD biomarker sample
2 hr (30 min) after the dose
Plasma PK sample for cobimetinib
4 hr (30 min) after the dose
Plasma PK sample for cobimetinib
6 hr (30 min) after the dose
Plasma PK sample for cobimetinib
24 hr (1 hr) after the dose, prior 
to dose on Day 2 of Cycle 1
Plasma PK sample for cobimetinib
Cycle 1, Day 21
Prior to the dose
Plasma PK sample for cobimetinib
2 hr (30 min) after the dose
Plasma PK sample for cobimetinib
4 hr (30 min) after the dose
Plasma PK sample for cobimetinib
6 hr (30 min) after the dose
Plasma PK sample for cobimetinib
24 hr (1 hr) after the dose
Plasma PK sample for cobimetinib
Cycle 2, Day 1
Prior to the dose (within 4 hr prior) Plasma PK sample for cobimetinib
Cycle 2 (and every 
2 cycles 
thereafter), 
Days 2228
Samples should be collected on 
the day of scheduled tumor 
assessments.
Plasma PD biomarker sample
Study drug 
discontinuation
Any time during visit
Plasma PD biomarker sample
hrhour; minminute; PDpharmacodynamics; PKpharmacokinetic.
Note:  Except for Day 1 of Cycle 1, all other study visits and assessments during the 
treatment period should be performed within 3 days of the scheduled date.


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Appendix 3
Modified International Neuroblastoma Response Criteria
Below response assessment is modified from the original INRC publication in 1993.
DEFINITION OF MEASURABLE (EVALUABLE) DISEASE ON CT/MRI SCAN
The presence of at least one lesion that can be accurately measured in at least one 
dimension with the longest diameter at least 20 mm.  With a spiral computed 
tomography (CT) scan, lesions must be at least 10 mm.  The investigator will identify up 
to 10 measurable target lesions to be followed for response.  Note that bone lesions will 
be considered as non-target lesions for evaluation of CT/magnetic resonance imaging 
(MRI) response since they will be evaluated with MIBG scans.
Malignant Lymph Nodes.  To be considered pathologically enlarged and measurable, a 
lymph node must be 15 mm in the short axis when assessed by CT scan (CT scan 
slice thickness recommended to be 5 mm).  At baseline and in follow-up, only the short 
axis will be measured and followed.  Serial measurements of lesions are to be done with 
CT or MRI.  The same method of assessment used to characterize each identified and 
reported lesion at baseline should be used during follow-up.
RESPONSE CRITERIA FOR MEASURABLE DISEASE ON CT/MRI SCAN
The sum of the longest diameter (LD) for all target lesions will be calculated and 
reported as the disease measurement.  The response of the CT/MRI lesions will be 
defined as outlined below:

Complete response (CR):  Disappearance of all target and non-target CT/MRI 
lesions

Very good partial response (VGPR):  Greater than 90% decrease of the disease 
measurement for CT/MRI lesions, taking as reference the disease measurement 
done to confirm measurable disease at study entry; non-target CT/MRI lesions 
stable to smaller in size

Partial response (PR):  At least a 30% decrease in the disease measurement for 
CT/MRI lesions, taking as reference the disease measurement done to confirm 
measurable disease at study entry; non-target CT/MRI lesions stable to smaller in 
size

Progressive disease (PD):  At least a 20% increase in the disease measurement, 
taking as reference the smallest disease measurement since the treatment started, 
or a new site of tumor; non-target CT/MRI lesions stable, smaller, or increased in 
size

Stable disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD taking as reference the smallest disease measurement 
since the treatment started; no new sites of disease


Appendix 3
International Neuroblastoma Response Criteria (cont.)
Cobimetinib—F. Hoffmann-La Roche Ltd
121/Protocol GO29665, Version 11
RESPONSE CRITERIA FOR MORPHOLOGIC BONE MARROW DISEASE
Only those patients with morphologic evidence of neuroblastoma by routine H and E 
staining (neuron-specific enolase [NSE] staining only is not evaluable) will be evaluable 
to assess bone marrow response.

CR:  No tumor cells detectable by routine morphology on two subsequent bilateral 
bone marrow aspirates and biopsies done at least 3 weeks apart after study entry.

PD:  Tumor seen on morphology on two consecutive bone marrows done at least 
3 weeks apart in patients who had no tumor in bone marrow at study entry
Patient may be declared to have PD in bone marrow after only one diagnostic 
bone marrow at the discretion of the treating physician
Patients who enter study with bone marrow tumor by morphology will be 
considered to have PD if there is a minimum of 25% tumor in the marrow by 
morphology and a doubling in the amount of tumor in the marrow compared 
with the level present at study entry.  For example, a patient entering with 5% 
tumor in marrow by morphology must increase to 25% tumor to have PD; a 
patient entering with 30% tumor must increase to 60% tumor.

SD:  Persistence of an amount of tumor in the bone marrow by morphology that 
does not meet criteria for either CR or PD
Patients who clear morphologic tumor but have immunocytologic tumor will be 
called SD. 
RESPONSE CRITERIA FOR MIBG-POSITIVE LESIONS
All patients with known MIBG-avid lesions will be evaluable for MIBG response following 
the first course of therapy.  The following criteria will be used to report MIBG response:

CR:  Complete resolution of all MIBG-positive lesions

PR:  Resolution of at least one MIBG-positive lesion, with persistence of other MIBG 
positive lesions

SD:  No change in MIBG scan in number of positive lesions (includes patients who 
have same number of positive lesions but decreased intensity)

PD:  Development of new MIBG-positive lesions 


Appendix 3
International Neuroblastoma Response Criteria (cont.)
Cobimetinib—F. Hoffmann-La Roche Ltd
122/Protocol GO29665, Version 11
DEFINITION OF OVERALL RESPONSE FOR EACH PATIENT WITH 
NEUROBLASTOMA
The International Neuroblastoma Response Criteria were developed to define responses 
in patients being treated with frontline therapy from diagnosis.1  These criteria were 
utilized as a basis for the following response criteria, which integrate response at all sites 
defined as measurable in this study, including CT/MRI lesions that meet RECIST, MIBG-
positive lesions, and bone marrow disease.  These criteria will be used to define the 
overall response for each patient. 

CR:  Disappearance of all target lesions; no evidence of tumor at any site (chest, 
abdomen, liver, bone, bone marrow, nodes, etc.); homovanillic acid (HVA) and 
vanillylmandelic acid (VMA) normal

VGPR:  Greater than 90% decrease of the disease measurement for CT/MRI target 
lesions, taking as reference the disease measurement done to confirm measurable 
disease in target lesions at study entry; all preexisting bone lesions with CR by 
MIBG; MIBG scan can be SD or CR in soft tissue lesions corresponding to lesions 
on CT/MRI; CR in bone marrow; no new sites of tumor; HVA/VMA normal

PR:  At least a 30% decrease in the disease measurement for CT/MRI target lesions, 
taking as reference the disease measurement done to confirm measurable disease 
in target lesions at study entry; bone marrow with CR; MIBG with either PR or CR in 
bone lesions; MIBG may be SD or CR in soft tissue lesions corresponding to lesions 
on CT/MRI; HVA/VMA may still be elevated. 

PD:  Any one of the following:
At least a 20% increase in the disease measurement for CT/MRI target lesions, 
taking as reference the smallest disease measurement recorded since the start 
of treatment
Appearance of one or more new lesions or new sites of tumor
PD as defined above for either bone marrow or MIBG lesions

SD:  Stable disease by either CT/MRI lesion, bone marrow, or MIBG criteria; no new 
lesions; no new sites of disease
The overall response as assessed at any particular timepoint based on the various 
disease sites is summarized in the table below. 
                                           
1 Brodeur GM, Pritchard J, Berthold F, et al. Revisions of the international criteria for 
neuroblastoma diagnosis, staging, and response to treatment. J Clin Oncol 1993;11:146677.


Appendix 3
International Neuroblastoma Response Criteria (cont.)
Cobimetinib—F. Hoffmann-La Roche Ltd
123/Protocol GO29665, Version 11
Table 1
Overall Response at Any Timepoint
CT/MRI Lesions
MIBG Lesions
Bone Marrow
Catechols
Overall 
Response
PD
Any
Any
Any
PD
Any
PD
Any
Any
PD
Any
Any
PD
Any
PD
CR
CR
CR
Normal
CR
VGPR
CR in bone 
lesions ; May have 
SD/CR in soft 
tissue sites 
corresponding to 
lesions on CT/MRI
CR
Normal
VGPR
PR
PR/CR in bone 
lesions; May have 
SD/CR in soft 
tissue sites 
corresponding to 
lesions on CT/MRI
CR
Any
PR
SD
SD
SD
Any
SD
SD/PR/VGPR/CR
SD
SD/CR
Any
SD
SD/PR/VGPR/CR
SD/PR/CR
SD
Any
SD
CRcomplete response; CTcomputed tomography; MIBG metaiodobenzylguanidine; 
MRImagnetic resonance imaging; PDprogressive disease; PRpartial response; SDstable 
disease; VGPRvery good partial response.


Cobimetinib—F. Hoffmann-La Roche Ltd
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Appendix 4
Response Assessment in Neuro-Oncology Criteria
for High-Grade Glioma
Response 
Criteria
Complete 
response
Requires all of the following:

Complete disappearance of all enhancing measurable and nonmeasurable 
disease sustained for at least 4 weeks

No new lesions 

Stable or improved non-enhancing (T2/FLAIR) lesions

Patients must be off corticosteroids (or on physiological replacement doses 
only)

Clinical status is stable or improved
Partial 
response
Requires all of the following:

50% decrease compared with baseline in the sum of products of 
perpendicular diameters of all measurable enhancing lesions sustained for at 
least 4 weeks

No progression of nonmeasurable T1 enhancing disease

No new lesions

Stable or improved non-enhancing (T2/FLAIR) lesions on the same or lower 
dose of corticosteroids compared to baseline

Clinical status is stable or improved
Note:  Patients with nonmeasurable disease only cannot have a partial response; 
the best response possible is stable disease
Stable 
disease
Requires all of the following:

Patient does not qualify for complete response, partial response, or progression

Stable non-enhancing (T2/FLAIR) lesions on same or lower dose of 
corticosteroids compared to baseline 

Clinical status is stable or improved
Note:  In the event that the corticosteroid dose was increased for new symptoms 
and signs without confirmation of disease progression on neuroimaging, and 
subsequent follow-up imaging shows that this increase in corticosteroids was 
required because of disease progression, the last scan considered to show stable 
disease will be the scan obtained when the corticosteroid dose was equivalent to 
the baseline dose.


Appendix 4
Response Assessment in Neuro-Oncology Criteria
for High-Grade Glioma (cont.)
Cobimetinib—F. Hoffmann-La Roche Ltd
125/Protocol GO29665, Version 11
Response 
Criteria
Progression
Defined by any of the following:

25% increase in sum of the products of perpendicular diameters of enhancing 
lesions compared with the smallest  tumor measurement obtained either at 
baseline (of no decrease) or best response, on a stable or increasing dose of 
corticosteroids

Significant increase in T2/FLAIR non-enhancing lesions on stable or increasing 
doses of steroids compared with baseline scan or best response after initiation 
of therapy, not caused by comorbid events (e.g., radiation therapy, 
demyelination, ischemic injury, seizures, postoperative changes, or other 
treatment effects)

Presence of any new lesions

Clear clinical deterioration not attributable to other causes apart from the tumor 
(e.g., seizures, medication adverse effects, complications of therapy, 
cerebrovascular events, infection, and so on) or decreases in corticosteroid 
dose

Failure to return for evaluation due to death or deteriorating condition

Clear progression of nonmeasurable disease
FLAIRfluid-attenuated inversion recovery.
Note:  Adapted from Wen PY, Macdonald DR, Reardon DA, et al. Updated response assessment 
criteria for high-grade gliomas: Response assessment in neuro-oncology working group. J Clin 
Oncol 2012;28:196372.


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Appendix 5
Response Assessment in Neuro-Oncology Criteria
for Low-Grade Glioma 
Response 
Criteria
Complete 
response
Requires all of the following criteria compared with the baseline scan:

Complete disappearance of the lesion on T2 or FLAIR imaging (if enhancement 
had been present, it must have resolved completely)

No new lesions, no new T2 or FLAIR abnormalities apart from those consistent 
with radiation effects, and no new or increased enhancement

Patients must be off corticosteroids or only on physiological replacement doses

Patients should be stable or improved clinically
Partial 
response
Requires all of the following criteria compared with the baseline scan:

50% decrease in the product of perpendicular diameters of the lesion on T2 or 
FLAIR imaging sustained for at least 4 weeks compared with baseline

No new lesions, no new T2 or FLAIR abnormalities apart from those consistent 
with radiation effects, and no new or increased enhancement

Patients should be on a corticosteroid dose that should not be greater than the 
dose at time of baseline scan and should be stable or improved clinically
Minor 
response
Requires the following criteria compared with baseline:

A decrease of the area of non-enhancing lesion on T2 or FLAIR magnetic 
resonance imaging between 25% and 50% compared with baseline

No new lesions, no new T2 or FLAIR abnormalities apart from those consistent 
with radiation effect, and no new or increased enhancement

Patients should be on a corticosteroid dose that should not be greater than the 
dose at time of baseline scan and should be stable or improved clinically
Stable 
disease
Is present if the changes do not qualify for complete, partial, or minor response, or 
progression and requires:

Stable area of non-enhancing abnormalities on T2 or FLAIR imaging

No new lesions, no new T2 or FLAIR abnormalities apart from those consistent 
with radiation effect, and no new or increased enhancement

Patients should be on a corticosteroid dose that should not be greater than the 
dose at time of baseline scan and should be stable or improved clinically


Appendix 5
Response Assessment in Neuro-Oncology Criteria
for Low-Grade Glioma (cont.)
Cobimetinib—F. Hoffmann-La Roche Ltd
127/Protocol GO29665, Version 11
Response 
Criteria
Progression
Defined by any of the following:

Development of new lesions or increase of enhancement (radiological evidence 
of malignant transformation)

A 25% increase of the T2 or FLAIR non-enhancing lesion on stable or 
increasing doses of corticosteroids compared with baseline scan or best 
response after initiation of therapy, not attributable to radiation effect or to 
comorbid events

Definite clinical deterioration not attributable to other causes apart from the 
tumor or decrease in corticosteroid dose

Failure to return for evaluation because of death or deteriorating condition, 
unless caused by documented non-related disorders
FLAIR fluid-attenuated inversion recovery; RANO=Response Assessment in Neuro-Oncology.
Note:  Adapted from Wen PY, Macdonald DR, Reardon DA, et al. Updated response assessment 
criteria for high-grade gliomas: Response assessment in neuro-oncology working group. J Clin 
Oncol 2012;28:196372.


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Appendix 6
Response Evaluation Criteria in Solid Tumors: 
Modified Excerpt from Original Publication
Selected sections from the Response Evaluation Criteria in Solid Tumors (RECIST), 
Version 1.1,2 are presented below, with slight modifications and the addition of 
explanatory text as needed for clarity.3
MEASURABILITY OF TUMOR AT BASELINE
DEFINITIONS
At baseline, tumor lesions/lymph nodes will be categorized as measurable or 
non-measurable as described below.
Measurable Tumor Lesions
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 
as follows: 

10 mm by computed tomography (CT) or magnetic resonance imaging (MRI) scan 
(CT/MRI scan slice thickness/interval no greater than 5 mm)

10-mm caliper measurement by clinical examination (lesions that 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 the short axis when assessed by CT scan (CT scan 
slice thickness recommended to be no greater than 5 mm).  At baseline and follow-up, 
only the short axis will be measured and followed.  See also notes 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 short axis 10 but 15 mm) 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, and abdominal 
                                           
2 Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumors: 
revised RECIST guideline (Version 1.1). Eur J Cancer 2009;45:228–47.
3 For consistency within this document, the section numbers and cross-references to other 
sections within the article have been deleted and minor formatting changes have been made.


Appendix 6
Response Evaluation Criteria in Solid Tumors: 
Modified Excerpt from Original Publication (cont.)
Cobimetinib—F. Hoffmann-La Roche Ltd
129/Protocol GO29665, Version 11
mass/abdominal organomegaly identified by physical examination that is 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, as outlined below.
Bone Lesions:

Bone scan, PET scan, or plain films are not considered adequate imaging 
techniques for measuring bone lesions.  However, these techniques can be used to 
confirm the presence or disappearance of bone lesions.

Lytic bone lesions or mixed lytic–blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross-sectional imaging techniques such as 
CT or 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.
TARGET LESIONS:  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.


Appendix 6
Response Evaluation Criteria in Solid Tumors: 
Modified Excerpt from Original Publication (cont.)
Cobimetinib—F. Hoffmann-La Roche Ltd
130/Protocol GO29665, Version 11
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 the study.  
Imaging-based evaluation should always be the preferred option.
Clinical Lesions.  Clinical lesions will only be considered measurable when they are 
superficial and 10 mm in 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.
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.
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. 
If prior to enrollment it is known that a patient is unable to undergo CT scans with 
intravenous (IV) contrast because of allergy or renal insufficiency, the decision as to 
whether a non-contrast CT or MRI (without IV contrast) will be used to evaluate the 
patient at baseline and during the study 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 and the anatomic location of the disease, and should 
be optimized to allow for comparison with 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.  Care must be taken in measurement of target lesions on a different modality 
and interpretation of non-target disease or new lesions, since the same lesion may 
appear to have a different size using a new modality.
Ultrasound.  Ultrasound is not useful in assessment of lesion size and should not be 
used as a method of measurement.


Appendix 6
Response Evaluation Criteria in Solid Tumors: 
Modified Excerpt from Original Publication (cont.)
Cobimetinib—F. Hoffmann-La Roche Ltd
131/Protocol GO29665, Version 11
Endoscopy, Laparoscopy, Tumor Markers, Cytology, Histology.  The utilization of 
these techniques for objective tumor evaluation cannot generally be advised.
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.  Measurable disease is defined by the presence of at least one 
measurable lesion, as detailed above.
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 that, for instances in which patients have only one or 
two organ sites involved, a maximum of two lesions (one site) and four lesions (two 
sites), respectively, will be recorded.  Other lesions (albeit measurable) in those organs 
will be recorded as non-measurable lesions (even if the size is 10 mm by CT scan).  
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter) and be representative of all involved organs, but in addition should 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 that can be measured reproducibly should be 
selected.
Lymph nodes merit special mention since they are normal anatomical structures that 
may be visible by imaging even if not involved by tumor.  As noted above, pathological 
nodes that 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 this is 
almost always the axial plane; for MRI the plane of acquisition may be axial, sagittal, or 
coronal).  The smaller of these measures is the short axis.  For example, an abdominal 
node that is reported as being 20 mm30 mm has a short axis of 20 mm and qualifies 
as a malignant, measurable node.  In this example, 20 mm should be recorded as the 
node measurement.  All other pathological nodes (those with short axis 10 mm but


Appendix 6
Response Evaluation Criteria in Solid Tumors: 
Modified Excerpt from Original Publication (cont.)
Cobimetinib—F. Hoffmann-La Roche Ltd
132/Protocol GO29665, Version 11
15 mm) should be considered non-target lesions.  Nodes that have a short axis of 
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 of 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 of diameters will be used as a reference to further 
characterize any objective tumor regression in the measurable dimension of the disease.
All other lesions (or sites of disease), including pathological lymph nodes, should be 
identified as non-target lesions and should also be recorded at baseline.  Measurements 
are not required and these lesions should be followed as “present,” “absent,” or in rare 
cases “unequivocal progression.”
In addition, it is possible to record multiple non-target lesions involving the same organ 
as a single item on the Case Report Form (CRF) (e.g., “multiple enlarged pelvic lymph 
nodes” or “multiple liver metastases”).
RESPONSE CRITERIA
Evaluation of Target Lesions
This section provides the definitions of the criteria used to determine objective tumor 
response for 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 of 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 (nadir), including baseline
In addition to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm.
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 on study


Appendix 6
Response Evaluation Criteria in Solid Tumors: 
Modified Excerpt from Original Publication (cont.)
Cobimetinib—F. Hoffmann-La Roche Ltd
133/Protocol GO29665, Version 11
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 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 CR criteria are met, since a normal lymph node is defined as having a short axis 
of 10 mm.
Target Lesions That Become Too Small to Measure.  During the 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 that are recorded as target lesions at baseline 
become so faint on CT scan that the radiologist may not feel comfortable assigning an 
exact measure and may report them as being too small to measure.  When this occurs, it 
is important that a value be recorded on the CRF, as follows:

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 below measurable limit (BML) 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).
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.
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 maximum 
longest diameter for the coalesced lesion.


Appendix 6
Response Evaluation Criteria in Solid Tumors: 
Modified Excerpt from Original Publication (cont.)
Cobimetinib—F. Hoffmann-La Roche Ltd
134/Protocol GO29665, Version 11
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.

CR:  Disappearance of all non-target lesions and (if applicable) 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 lesions and/or 
(if applicable) maintenance of tumor marker level above the normal limits

PD:  Unequivocal progression of existing non-target lesions
The appearance of one or more new lesions is also considered progression.
Special Notes on Assessment of Progression of Non-Target Disease
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 the 
presence of SD or PR in target disease, the overall tumor burden has increased 
sufficiently to merit discontinuation of therapy.  A modest increase in the size of one or 
more non-target lesions is usually not sufficient to qualify for unequivocal progression 
status.  The designation of overall progression solely on the basis of change in non-
target disease in the face of SD or PR of target disease will therefore be extremely rare.
When the Patient Has Only Non-Measurable Disease.  This circumstance arises in 
some Phase III trials when it is not a criterion of study entry to have measurable disease.  
The same general concepts apply here as noted above; however, in this instance there 
is no measurable disease assessment to factor into the interpretation of an increase in 
non-measurable disease burden.  Because worsening in non-target disease cannot be 
easily quantified (by definition:  if all lesions are truly non-measurable), a useful test that 
can be applied when assessing patients for unequivocal progression is to consider if the 
increase in overall disease burden based on the change in non-measurable disease is 
comparable in magnitude to the increase that would be required to declare PD for 
measurable disease, that is, an increase in tumor burden representing an additional 73% 
increase in volume (which is equivalent to a 20% increase in diameter in a measurable 
lesion).  Examples include an increase in a pleural effusion from “trace” to “large” or 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 


Appendix 6
Response Evaluation Criteria in Solid Tumors: 
Modified Excerpt from Original Publication (cont.)
Cobimetinib—F. Hoffmann-La Roche Ltd
135/Protocol GO29665, Version 11
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, that is, 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 preexisting 
lesions).  This is particularly important when the patient’s baseline lesions show PR or 
CR.  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 during the study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression.
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease.  If repeat scans confirm 
there is definitely a new lesion, then progression should be declared using the date of 
the initial scan.
EVALUATION OF RESPONSE
Timepoint Response (Overall Response)
It is assumed that at each protocol-specified timepoint, a response assessment occurs.  
Table 1 provides a summary of the overall response status calculation at each timepoint 
for patients who have measurable disease at baseline.
When patients have non-measurable (therefore non-target) disease only, Table 2 is to 
be used.


Appendix 6
Response Evaluation Criteria in Solid Tumors: 
Modified Excerpt from Original Publication (cont.)
Cobimetinib—F. Hoffmann-La Roche Ltd
136/Protocol GO29665, Version 11
Table 1
Timepoint Response:  Patients with Target Lesions (with or 
without Non-Target Lesions)
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all 
evaluated
No
PR
SD
Non-PD or not all 
evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or no
PD
Any
PD
Yes or no
PD
Any
Any
Yes
PD
CRcomplete response; NEnot evaluable; PDprogressive disease; PRpartial response; 
SDstable disease.
Table 2
Timepoint Response:  Patients with Non-Target Lesions Only
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PD a
Not all evaluated
No
NE
Unequivocal PD
Yes or no
PD
Any
Yes
PD
CRcomplete response; NEnot evaluable; PDprogressive disease.
a “Non-CR/non-PD” is preferred over “stable disease” for non-target disease since stable 
disease is increasingly used as an endpoint for assessment of efficacy in some trials; thus, 
assigning “stable disease” when no lesions can be measured is not advised.


Appendix 6
Response Evaluation Criteria in Solid Tumors: 
Modified Excerpt from Original Publication (cont.)
Cobimetinib—F. Hoffmann-La Roche Ltd
137/Protocol GO29665, Version 11
Missing Assessments and Not-Evaluable Designation
When no imaging/measurement is done at all at a particular timepoint, the patient is not 
evaluable at that timepoint (Table 3).  If only a subset of lesion measurements are made 
at an assessment, usually the case is also considered not evaluable at that timepoint, 
unless a convincing argument can be made that the contribution of the individual missing 
lesion(s) would not change the assigned timepoint response.  This would be most likely 
to happen in the case of PD.  For example, if a patient had a baseline sum of 50 mm 
with three measured lesions and during the study 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 the scan 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 not assessed, the response 
for non-target lesions should be “unable to assess” except where there is clear 
progression.  Overall response would be “unable to assess” if either the target response 
or the non-target response is “unable to assess” except where this is clear evidence of 
progression, as this equates with the case being not evaluable at that timepoint.


Appendix 6
Response Evaluation Criteria in Solid Tumors: 
Modified Excerpt from Original Publication (cont.)
Cobimetinib—F. Hoffmann-La Roche Ltd
138/Protocol GO29665, Version 11
Table 3
Best Overall Response When Confirmation Is Required
Overall Response at First 
Timepoint
Overall Response at 
Subsequent Timepoint
Best Overall Response
CR
CR
CR
CR
PR
SD, PD, or PR a
CR
SD
SD, provided minimum 
duration for SD was met; 
otherwise, PD
CR
PD
SD, provided minimum 
duration for SD was met; 
otherwise, PD
CR
NE
SD, provided minimum 
duration for SD was met; 
otherwise, NE
PR
CR
PR
PR
PR
PR
PR
SD
SD
PR
PD
SD, provided minimum 
duration for SD was met; 
otherwise, PD
PR
NE
SD, provided minimum 
duration for SD was met; 
otherwise, NE
NE
NE
NE
CRcomplete response; NEnot evaluable; PDprogressive disease; PRpartial response; 
SDstable disease.
a If a CR is truly met at the first timepoint, any disease seen at a subsequent timepoint, even 
disease meeting PR criteria relative to baseline, qualifies as PD at that point (since disease 
must have reappeared after CR).  Best response would depend on whether the minimum 
duration for SD was met.  However, sometimes CR may be claimed when subsequent scans 
suggest small lesions were likely still present and in fact the patient had PR, not CR, at the first 
timepoint.  Under these circumstances, the original CR should be changed to PR and the best 
response is PR.


Appendix 6
Response Evaluation Criteria in Solid Tumors: 
Modified Excerpt from Original Publication (cont.)
Cobimetinib—F. Hoffmann-La Roche Ltd
139/Protocol GO29665, Version 11
Special Notes on Response Assessment
When nodal disease is included in the sum of target lesions and the nodes decrease to 
“normal” size (10 mm), they may still have a measurement reported on scans.  This 
measurement should be recorded even though the nodes are normal in order not to 
overstate progression should it be based on increase in size of the nodes.  As noted 
earlier, this means that patients with CR may not have a total sum of “zero” on the CRF.
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.”  Every effort should be made to document objective 
progression even after discontinuation of treatment.  Symptomatic deterioration is not a 
descriptor of an objective response; it is a reason for stopping study therapy.  The 
objective response status of such patients is to be determined by evaluation of target 
and non-target disease as shown in Tables 1–3.
For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic 
changes or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment.  If at the next scheduled assessment, progression is confirmed, the date of 
progression should be the earlier date when progression was suspected.
In studies for which patients with advanced disease are eligible (i.e., primary disease still 
or partially present), the primary tumor should also be captured as a target or non-target 
lesion, as appropriate.  This is to avoid an incorrect assessment of CR if the primary 
tumor is still present but not evaluated as a target or non-target lesion.


Cobimetinib—F. Hoffmann-La Roche Ltd
140/Protocol GO29665, Version 11
Appendix 7
Lansky Performance Status Scale (Patients 16 Years of Age)
Score
Description
100
Fully active; normal
90
Minor restrictions in physically strenuous activity
80
Active but tires more quickly
70
Both greater restriction of and less time spent in play activity
60
Up and around, but minimal active play; keeps busy with 
quieter activities
50
Gets dressed, but lies around much of the day; no active play; 
able to participate in all quiet play and activities
40
Mostly in bed; participates in quiet activities
30
In bed; needs assistance even for quiet play
20
Often sleeping; play entirely limited to very passive activities
10
No play; does not get out of bed


Cobimetinib—F. Hoffmann-La Roche Ltd
141/Protocol GO29665, Version 11
Appendix 8
Karnofsky Performance Status Scale (Patients≥16 Years of Age)
Score
Description
100
Normal; no complaints; no evidence of disease
90
Able to carry on normal activity; minor signs or symptoms of 
disease
80
Normal activity with effort; some signs or symptoms of disease
70
Cares for self; unable to carry on normal activity or do active 
work
60
Requires occasional assistance, but is able to care for most of 
his/her needs
50
Requires considerable assistance and frequent medical care
40
Disabled; requires special care and assistance
30
Severely disabled; hospitalization indicated; death not 
imminent
20
Very sick; hospitalization indicated; death not imminent
10
Moribund; fatal processes progressing rapidly


Cobimetinib—F. Hoffmann-La Roche Ltd
142/Protocol GO29665, Version 11
Appendix 9
Acceptability Survey for Patients
Instructions: Please answer the questions below to help us understand your 
experience with the study medication (cobimetinib).  For questions with a face, indicate 
which of the faces best matches how you felt about the medication.
For children who cannot read yet, parents or caregiver, please help us understand 
your child’s experience with the medication.  Invite your child to look at the cartoon, ask 
him or her the questions, and record his or her answer.  If your child cannot answer the 
question, please leave the question blank.
For children who cannot answer for themselves, parents or caregiver, please go 
directly to questions 7 and 8.
1.
How much did you like the taste of the medication?





Really Bad
Bad
Not sure
Good
Really Good
2.
What was the taste of the medication?
Bitter          
Sweet
         
Sour             
Salty        
3.
How much did you like the feeling of the medication in your mouth?





Really Bad
Bad
Not sure
Good
Really Good


Appendix 9
Acceptability Survey for Patients (cont.)
Cobimetinib—F. Hoffmann-La Roche Ltd
143/Protocol GO29665, Version 11
4.
How difficult was it to swallow the medication?





Really Bad
Bad
Not sure
Good
Really Good
5.
After the medication was not in your mouth anymore, could you still taste the 
medication?
Yes
No
6.
What was the taste you had in your mouth after the medication was gone?
Bitter          
Sweet
         
Sour             
Salty        
For parent or caregiver of children who cannot answer for themselves:
7.
At any time did you have a problem in giving the medication to your child because 
he or she refused to take it? 
Yes
No
8.
At any time did you have a problem in giving the planned dose of the medication to 
your child because he or she threw it up? 
Yes
No


Appendix 9
Acceptability Survey for Patients (cont.)
Cobimetinib—F. Hoffmann-La Roche Ltd
144/Protocol GO29665, Version 11
Additional questions for participants receiving the SUSPENSION:
Instructions:  Please answer the questions below to help us understand your 
experience giving the study medication (cobimetinib) at home. 
9.
Which size medication dispenser (syringe) did you use to administer the medication?
3-mL
10-mL
10. How many times did you have to fill the medication dispenser (syringe) to administer 
the prescribed dose of the medication?
Once
More than once
11. How easy or difficult was it to fill the medication dispenser (syringe) from the bottle?
Very easy
Somewhat easy
Somewhat difficult
Very difficult
Thank You


Cobimetinib—F. Hoffmann-La Roche Ltd
145/Protocol GO29665, Version 11
Appendix 10
Dosing Tables for Cobimetinib
DOSE LEVEL 10.6 MG/KG/DAY, 20 MG TABLETS
Cumulative weekly dose4.2 mg/kg/week
Doses to be administered on Days 121 of cycle; do not administer on Days 2228.
Weight (kg)
Daily Dose for 7 days
Cumulative Weekly Dose 
(mg/wk)
20.021.4
1 tab 4 d/wk, 0 tab 3 d/wk
80
21.526.1
1 tab 5 d/wk, 0 tab 2 d/wk
100
26.230.9
1 tab 6 d/wk, 0 tab 1 d/wk
120
31.035.7
1 tab daily
140
35.840.4
2 tab 1 d/wk, 1 tab 6 d/wk
160
40.545.2
2 tab 2 d/wk, 1 tab 5 d/wk
180
45.350.0
2 tab 3 d/wk, 1 tab 4 d/wk
200
50.154.7
2 tab 4 d/wk, 1 tab 3 d/wk
220
54.859.5
2 tab 5 d/wk, 1 tab 2 d/wk
240
59.664.2
2 tab 6 d/wk, 1 tab 1 d/wk
260
64.369.0
2 tab daily
280
69.173.8
3 tab 1 d/wk, 2 tab 6 d/wk
300
73.978.5
3 tab 2 d/wk, 2 tab 5 d/wk
320
78.683.3
3 tab 3 d/wk, 2 tab 4 d/wk
340
83.488.0
3 tab 4 d/wk, 2 tab 3 d/wk
360
88.192.8
3 tab 5 d/wk, 2 tab 2 d/wk
380
92.997.6
3 tab 6 d/wk, 2 tab 1 d/wk
400
97.7102.3
3 tab daily
420
102.4107.1
4 tab 1 d/wk, 3 tab 6 d/wk
440
107.2111.9
4 tab 2 d/wk, 3 tab 5 d/wk
460
112.0116.6
4 tab 3 d/wk, 3 tab 4 d/wk
480
116.7121.4
4 tab 4 d/wk, 3 tab 3 d/wk
500
121.5126.1
4 tab 5 d/wk, 3 tab 2 d/wk
520
126.2130.9
4 tab 6 d/wk, 3 tab 1 d/wk
540
131.0135.7
4 tab daily
560
135.7
Contact Medical Monitor


Appendix 10
Dosing Tables for Cobimetinib (cont.)
Cobimetinib—F. Hoffmann-La Roche Ltd
146/Protocol GO29665, Version 11
DOSE LEVEL 0.6 MG/KG/DAY, SUSPENSION (4.8 MG/ML)
Doses to be administered on Days 121 of cycle; do not administer on Days 2228.
Weight (kg)
Daily Dose 
(mL)
Cumulative 
Weekly 
Dose (mg)
Weight (kg)
Daily Dose 
(mL)
Cumulative 
Weekly Dose 
(mg)
7.6
Call Medical Monitor
38.041.9
5
168.0
7.68.3
1.0
33.6
42.045.9
5.5
184.8
8.49.1
1.1
37.0
46.049.9
6
201.6
9.29.9
1.2
40.3
50.053.9
6.5
218.4
10.010.7
1.3
43.7
54.057.9
7
235.2
10.811.5
1.4
47.0
58.061.9
7.5
252.0
11.612.3
1.5
50.4
62.065.9
8
268.8
12.413.1
1.6
53.8
66.069.9
8.5
285.6
13.213.9
1.7
57.1
70.073.9
9
302.4
14.014.7
1.8
60.5
74.077.9
9.5
319.2
14.815.5
1.9
63.8
78.081.9
10
336.0
15.616.7
2.0
67.2
82.085.9
10.5
352.8
16.818.3
2.2
73.9
86.089.9
11
369.6
18.419.9
2.4
80.6
90.093.9
11.5
386.4
20.021.5
2.6
87.4
94.097.9
12
403.2
21.623.1
2.8
94.1
98.0101.9
12.5
420.0
23.225.9
3.0
100.8
102.0105.9
13
436.8
26.029.9
3.5
117.6
106.0109.9
13.5
453.6
30.033.9
4
134.4
110.0113.9
14
470.4
34.037.9
4.5
151.2
114.0117.9
14.5
487.2
118.0121.9
15
504.0
122.0125.9
15.5
520.8
126.0129.9
16
537.6
130.0133.9
16.5
554.4
133.9
Call Medical Monitor


Appendix 10
Dosing Tables for Cobimetinib (cont.)
Cobimetinib—F. Hoffmann-La Roche Ltd
147/Protocol GO29665, Version 11
DOSE LEVEL 20.8 MG/KG/DAY, 20 MG TABLETS
Cumulative weekly dose5.6 mg/kg/week (wk).
Doses to be administered on Days 121 of cycle; do not administer on Days 2228.
Weight (kg)
Daily Dose for 7 days
Cumulative Weekly Dose
(mg/wk)
20.023.2
1 tablet (tab) 6 d/wk, 0 tab 1 d/wk
120
23.326.7
1 tab daily
140
26.830.3
2 tab 1 d/wk, 1 tab 6 d/wk
160
30.433.9
2 tab 2 d/wk, 1 tab 5 d/wk
180
34.037.5
2 tab 3 d/wk, 1 tab 4 d/wk
200
37.641.0
2 tab 4 d/wk, 1 tab 3 d/wk
220
41.144.6
2 tab 5 d/wk, 1 tab 2 d/wk
240
44.748.2
2 tab 6 d/wk, 1 tab 1 d/wk
260
48.351.7
2 tab daily
280
51.855.3
3 tab 1 d/wk, 2 tab 6 d/wk
300
55.458.9
3 tab 2 d/wk, 2 tab 5 d/wk
320
59.062.5
3 tab 3 d/wk, 2 tab 4 d/wk
340
62.666.0
3 tab 4 d/wk, 2 tab 3 d/wk
360
66.169.6
3 tab 5 d/wk, 2 tab 2 d/wk
380
69.773.2
3 tab 6 d/wk, 2 tab 1 d/wk
400
73.376.7
3 tab daily
420
76.880.3
4 tab 1 d/wk, 3 tab 6 d/wk
440
80.483.9
4 tab 2 d/wk, 3 tab 5 d/wk
460
84.087.5
4 tab 3 d/wk, 3 tab 4 d/wk
480
87.691.0
4 tab 4 d/wk, 3 tab 3 d/wk
500
91.194.6
4 tab 5 d/wk, 3 tab 2 d/wk
520
94.798.2
4 tab 6 d/wk, 3 tab 1 d/wk
540
98.3101.7
4 tab daily
560
101.8105.3
5 tab 1 d/wk, 4 tab 6 d/wk
580
105.4108.9
5 tab 2 d/wk, 4 tab 5 d/wk
600
109.0112.5
5 tab 3 d/wk, 4 tab 4 d/wk
620
112.6116.0
5 tab 4 d/wk, 4 tab 3 d/wk
640
116.1119.6
5 tab 5 d/wk, 4 tab 2 d/wk
660
119.7123.2
5 tab 6 d/wk, 4 tab 1 d/wk
680
123.3126.7
5 tab daily
700
126.8
Contact Medical Monitor


Appendix 10
Dosing Tables for Cobimetinib (cont.)
Cobimetinib—F. Hoffmann-La Roche Ltd
148/Protocol GO29665, Version 11
DOSE LEVEL 20.8 MG/KG/DAY, SUSPENSION (4.8 MG/ML)
Doses to be administered on Days 121 of cycle; do not administer on Days 2228.
Weight (kg)
Daily Dose 
(mL)
Cumulative 
Weekly 
Dose (mg)
Weight (kg)
Daily Dose 
(mL)
Cumulative 
Weekly Dose 
(mg)
5.7
Call Medical Monitor
34.537.4
6 
201.6
5.76.2
1.0
33.6
37.540.4
6.5
218.4
6.36.8
1.1
37.0
40.543.4
7
235.2
6.97.4
1.2
40.3
43.546.4
7.5
252.0
7.58.0
1.3
43.7
46.549.4
8
268.8
8.18.6
1.4
47.0
49.552.4
8.5
285.6
8.79.2
1.5
50.4
52.555.4
9
302.4
9.39.8
1.6
53.8
55.558.4
9.5
319.2
9.910.4
1.7
57.1
58.561.4
10
336.0
10.511.0
1.8
60.5
61.564.4
10.5
352.8
11.111.6
1.9
63.8
64.567.4
11
369.6
11.712.5
2.0
67.2
67.570.4
11.5
386.4
12.613.7
2.2
73.9
70.573.4
12
403.2
13.814.9
2.4
80.6
73.576.4
12.5
420.0
15.016.1
2.6
87.4
76.579.4
13
436.8
16.217.3
2.8
94.1
79.582.4
13.5
453.6
17.419.4
3.0
100.8
82.585.4
14
470.4
19.5-22.4
3.5
117.6
85.588.4
14.5
487.2
22.525.4
4
134.4
88.591.4
15
504.0
25.528.4
4.5
151.2
91.594.4
15.5
520.8
28.531.4
5
168.0
94.597.4
16
537.6
31.534.4
5.5
184.8
97.5100.4
16.5
554.4
100.5103.4
17
571.2
103.5106.4
17.5
588.0
106.5109.4
18
604.8
109.5112.4
18.5
621.6
112.4
Call Medical Monitor


Appendix 10
Dosing Tables for Cobimetinib (cont.)
Cobimetinib—F. Hoffmann-La Roche Ltd
149/Protocol GO29665, Version 11
DOSE LEVEL 31 MG/KG/DAY, 20 MG TABLETS
Cumulative weekly dose7 mg/kg/week
Doses to be administered on Days 121 of cycle; do not administer on Days 2228.
Weight (kg)
Daily Dose for 7 days
Cumulative Weekly Dose (mg/wk)
20.021.4
1 tab daily
140
21.524.2
2 tab 1 d/wk, 1 tab 6 d/wk
160
24.327.1
2 tab 2 d/wk, 1 tab 5 d/wk
180
27.230.0
2 tab 3 d/wk, 1 tab 4 d/wk
200
30.132.8
2 tab 4 d/wk, 1 tab 3 d/wk
220
32.935.7
2 tab 5 d/wk, 1 tab 2 d/wk
240
35.838.5
2 tab 6 d/wk, 1 tab 1 d/wk
260
38.641.4
2 tab daily
280
41.544.2
3 tab 1 d/wk, 2 tab 6 d/wk
300
44.347.1
3 tab 2 d/wk, 2 tab 5 d/wk
320
47.250.0
3 tab 3 d/wk, 2 tab 4 d/wk
340
50.152.8
3 tab 4 d/wk, 2 tab 3 d/wk
360
52.955.7
3 tab 5 d/wk, 2 tab 2 d/wk
380
55.858.5
3 tab 6 d/wk, 2 tab 1 d/wk
400
58.661.4 a
3 tab daily
420
61.564.2
4 tab 1 d/wk, 3 tab 6 d/wk
440
64.367.1
4 tab 2 d/wk, 3 tab 5 d/wk
460
67.270.0
4 tab 3 d/wk, 3 tab 4 d/wk
480
70.172.8
4 tab 4 d/wk, 3 tab 3 d/wk
500
72.975.7
4 tab 5 d/wk, 3 tab 2 d/wk
520
75.878.5
4 tab 6 d/wk, 3 tab 1 d/wk
540
78.681.4
4 tab daily
560
81.584.2
5 tab 1 d/wk, 4 tab 6 d/wk
580
84.387.1
5 tab 2 d/wk, 4 tab 5 d/wk
600
87.290.0
5 tab 3 d/wk, 4 tab 4 d/wk
620
90.192.8
5 tab 4 d/wk, 4 tab 3 d/wk
640
92.995.7
5 tab 5 d/wk, 4 tab 2 d/wk
660
95.898.5
5 tab 6 d/wk, 4 tab 1 d/wk
680
98.6101.4
5 tab daily
700
101.5104.2
6 tab 1 d/wk, 5 tab 6 d/wk
720
104.3107.1
6 tab 2 d/wk, 5 tab 5 d/wk
740
107.2110.0
6 tab 3 d/wk, 5 tab 4 d/wk
760
110.1112.8
6 tab 4 d/wk, 5 tab 3 d/wk
780
112.9115.7
6 tab 5 d/wk, 5 tab 2 d/wk
800
115.8118.5
6 tab 6 d/wk, 5 tab 1 d/wk
820 
118.6121.4
6 tab daily
840 
a For patients 60 kg, contact Medical Monitor.


Appendix 10
Dosing Tables for Cobimetinib (cont.)
Cobimetinib—F. Hoffmann-La Roche Ltd
150/Protocol GO29665, Version 11
DOSE LEVEL 31 MG/KG/DAY, SUSPENSION (4.8 MG/ML)
Doses to be administered on Days 121 of cycle; do not administer on Days 2228.
Weight (kg)
Daily Dose 
(mL)
Cumulative 
Weekly Dose 
(mg)
Weight (kg)
Daily Dose 
(mL)
Cumulative 
Weekly Dose 
(mg)
4.6
Call Medical Monitor
44.446.7
9.5
319.2
4.65.0
1.0
33.6
46.849.1
10
336.0
5.15.5
1.1
37.0
49.251.5
10.5
352.8
5.65.9
1.2
40.3
51.653.9
11
369.6
6.06.4
1.3
43.7
54.056.3
11.5
386.4
6.56.9
1.4
47.0
56.458.7
12
403.2
7.07.4
1.5
50.4
58.861.1a
12.5
420.0
7.57.9
1.6
53.8
61.263.5
13
436.8
8.08.3
1.7
57.1
63.665.9
13.5
453.6
8.48.8
1.8
60.5
66.068.3
14
470.4
8.99.3
1.9
63.8
68.470.7
14.5
487.2
9.410.0
2.0
67.2
70.873.1
15
504.0
10.111.0
2.2
73.9
73.275.5
15.5
520.8
11.111.9
2.4
80.6
75.677.9
16
537.6
12.012.9
2.6
87.4
78.080.3
16.5
554.4
13.013.9
2.8
94.1
80.482.7
17
571.2
14.015.5
3.0
100.8
82.885.1
17.5
588.0
15. 617.9
3.5
117.6
85.287.5
18
604.8
18.020.3
4
134.4
87.689.9
18.5
621.6
20.422.7
4.5
151.2
90.092.3
19
638.4
22.825.1
5
168.0
92.494.7
19.5
655.2
25.227.5
5.5
184.8
94.897.1
20
672.0
27. 629.9
6
201.6
97.299.5
20.5
688.8
30.032.3
6.5
218.4
99.6101.9
21
705.6
32.434.7
7
235.2
102.0104.3
21.5
722.4
34.837.1
7.5
252.0
104.4106.7
22
739.2
37.239.5
8
268.8
106.8109.1
22.5
756.0
39. 641.9
8.5
285.6
109.2111.5
23
772.8
42.044.3
9
302.4
111.6113.9
23.5
789.6
114.0116.3
24
806.4
a For patients 60 kg, contact Medical Monitor.


Appendix 10
Dosing Tables for Cobimetinib (cont.)
Cobimetinib—F. Hoffmann-La Roche Ltd
151/Protocol GO29665, Version 11
DOSE LEVEL 41.33 MG/KG/DAY, 20 MG TABLETS
Cumulative weekly dose9.31 mg/kg/week
Doses to be administered on Days 121 of cycle; do not administer on Days 2228.
Weight (kg)
Daily Dose for 7 days
Cumulative Weekly Dose
(mg/wk)
20.020.4
2 tab 2 d/wk, 1 tab 5 d/wk
180
20.522.5
2 tab 3 d/wk, 1 tab 4 d/wk
200
22.624.7
2 tab 4 d/wk, 1 tab 3 d/wk
220
24.826.8
2 tab 5 d/wk, 1 tab 2 d/wk
240
26.929.0
2 tab 6 d/wk, 1 tab 1 d/wk
260
29.131.1
2 tab daily
280
31.233.2
3 tab 1 d/wk, 2 tab 6 d/wk
300
33.335.4
3 tab 2 d/wk, 2 tab 5 d/wk
320
35.537.5
3 tab 3 d/wk, 2 tab 4 d/wk
340
37.639.7
3 tab 4 d/wk, 2 tab 3 d/wk
360
39.841.8
3 tab 5 d/wk, 2 tab 2 d/wk
380
41.944.0
3 tab 6 d/wk, 2 tab 1 d/wk
400
44.146.1
3 tab daily
420
46.248.3
4 tab 1 d/wk, 3 tab 6 d/wk
440
48.450.4
4 tab 2 d/wk, 3 tab 5 d/wk
460
50.552.6
4 tab 3 d/wk, 3 tab 4 d/wk
480
52.754.7
4 tab 4 d/wk, 3 tab 3 d/wk
500
54.856.9
4 tab 5 d/wk, 3 tab 2 d/wk
520
57.059.0
4 tab 6 d/wk, 3 tab 1 d/wk
540
59.161.2a
4 tab daily
560
61.363.3
5 tab 1 d/wk, 4 tab 6 d/wk
580
63.465.5
5 tab 2 d/wk, 4 tab 5 d/wk
600
65.667.6
5 tab 3 d/wk, 4 tab 4 d/wk
620
67.769.8
5 tab 4 d/wk, 4 tab 3 d/wk
640
69.971.9
5 tab 5 d/wk, 4 tab 2 d/wk
660
72.074.1
5 tab 6 d/wk, 4 tab 1 d/wk
680
74.276.2
5 tab daily
700
76.378.4
6 tab 1 d/wk, 5 tab 6 d/wk
720
78.580.5
6 tab 2 d/wk, 5 tab 5 d/wk
740
80.682.7
6 tab 3 d/wk, 5 tab 4 d/wk
760
82.884.8
6 tab 4 d/wk, 5 tab 3 d/wk
780
84.987.0
6 tab 5 d/wk, 5 tab 2 d/wk
800
87.189.1
6 tab 6 d/wk, 5 tab 1 d/wk
820
89.291.2
6 tab daily
840
a For patients >60 kg, contact Medical Monitor.


Appendix 10
Dosing Tables for Cobimetinib (cont.)
Cobimetinib—F. Hoffmann-La Roche Ltd
152/Protocol GO29665, Version 11
DOSE LEVEL 41.33 MG/KG/DAY, SUSPENSION (4.8 MG/ML)
Doses to be administered on Days 121 of cycle; do not administer on Days 2228.
Weight (kg)
Daily Dose 
(mL)
Cumulative 
Weekly 
Dose (mg)
Weight (kg)
Daily Dose 
(mL)
Cumulative 
Weekly Dose 
(mg)
4.9
Call Medical Monitor
37.038.7
10.5
352.8
4.95.2
1.4
47.0
38.840.6
11
369.6
5.35.5
1.5
50.4
40.742.4
11.5
386.4
5.65.9
1.6
53.8
42.544.2
12
403.2
6.06.3
1.7
57.1
44.346.0
12.5
420.0
6.46.6
1.8
60.5
46.147.8
13
436.8
6.77.0
1.9
63.8
47.949.6
13.5
453.6
7.17.5
2.0
67.2
49.751.4
14
470.4
7.68.3
2.2
73.9
51.653.2
14.5
487.2
8.49.0
2.4
80.6
53.255.0
15
504.0
9.19.7
2.6
87.4
55.156.8
15.5
520.8
9.810.4
2.8
94.1
56.958.6
16
537.6
10.511.7
3.0
100.8
58.760.4 a
16.5
554.4
11.813.5
3.5
117.6
60.562.2
17
571.2
13.615.3
4
134.4
62.364.0
17.5
588.0
15.417.1
4.5
151.2
64.165.8
18
604.8
17.218.9
5
168.0
65.967.6
18.5
621.6
19.020.7
5.5
184.8
67.769.4
19
638.4
20.822.5
6
201.6
69.571.2
19.5
655.2
22.624.3
6.5
218.4
71.373.0
20
672.0
24.426.1
7
235.2
73.174.8
20.5
688.8
26.227.9
7.5
252.0
74.976.6
21
705.6
28.029.7
8
268.8
76.778.4
21.5
722.4
29.831.5
8.5
285.6
78.580.3
22
739.2
31.633.3
9
302.4
80.482.1
22.5
756.0
33.435.1
9.5
319.2
82.283.9
23
772.8
35.236.9
10
336.0
84.085.7
23.5
789.6
85.887.5
24
806.4
a For patients >60 kg, contact Medical Monitor.


Appendix 10
Dosing Tables for Cobimetinib (cont.)
Cobimetinib—F. Hoffmann-La Roche Ltd
153/Protocol GO29665, Version 11
DOSE LEVEL 1 (MINUS ONE)0.45 MG/KG/DAY, 20 MG TABLETS
Cumulative weekly dose4.2 mg/kg/week
Doses to be administered on Days 121 of cycle; do not administer on Days 2228.
Weight (kg)
Daily Dose for 7 days
Cumulative Weekly Dose
(mg/wk)
2022.2
1 tab 3 d/wk, 0 tab 4 d/wk
60
22.328.5
1 tab 4 d/wk, 0 tab 3 d/wk
80
28.634.9
1 tab 5 d/wk, 0 tab 2 d/wk
100
35.041.2
1 tab 6 d/wk, 0 tab 1 d/wk
120
41.347.6
1 tab daily
140
47.753.9
2 tab 1 d/wk, 1 tab 6 d/wk
160
54.060.3
2 tab 2 d/wk, 1 tab 5 d/wk
180
60.4-66.6
2 tab 3 d/wk, 1 tab 4 d/wk
200
66.773.0
2 tab 4 d/wk, 1 tab 3 d/wk
220
73.179.3
2 tab 5 d/wk, 1 tab 2 d/wk
240
79.485.7
2 tab 6 d/wk, 1 tab 1 d/wk
260
85.892.0
2 tab daily
280
92.198.4
3 tab 1 d/wk, 2 tab 6 d/wk
300
98.5104.7
3 tab 2 d/wk, 2 tab 5 d/wk
320
104.8111.1
3 tab 3 d/wk, 2 tab 4 d/wk
340
111.2117.4
3 tab 4 d/wk, 2 tab 3 d/wk
360
117.5123.8
3 tab 5 d/wk, 2 tab 2 d/wk
380
123.9130.1
3 tab 6 d/wk, 2 tab 1 d/wk
400
130.2136.5
3 tab daily
420
136.5
Contact Medical Monitor


Appendix 10
Dosing Tables for Cobimetinib (cont.)
Cobimetinib—F. Hoffmann-La Roche Ltd
154/Protocol GO29665, Version 11
DOSE LEVEL 1 (MINUS ONE)0.45 MG/KG/DAY, SUSPENSIN (4.8 MG/ML)
Doses to be administered on Days 121 of cycle; do not administer on Days 2228.
Weight (kg)
Daily Dose 
(mL)
Cumulative 
Weekly 
Dose (mg)
Weight (kg)
Daily Dose 
(mL)
Cumulative 
Weekly Dose 
(mg)
10.2
Call Medical Monitor
50.755.9
5
168.0
10.211.1
1.0
33.6
56.061.3
5.5
184.8
11.212.2
1.1
37.0
61.466.6
6
201.6
12.313.3
1.2
40.3
66.771.9
6.5
218.4
13.414.3
1.3
43.7
72.077.3
7
235.2
14.415.4
1.4
47.0
77.482.6
7.5
252.0
15.516.5
1.5
50.4
82.787.9
8
268.8
16.617.5
1.6
53.8
88.093.3
8.5
285.6
17.618.6
1.7
57.1
93.498.6
9
302.4
18.719.7
1.8
60.5
98.7103.9
9.5
319.2
19.820.7
1.9
63.8
104.0109.3
10
336.0
20.822.3
2.0
67.2
109.4114.6
10.5
352.8
22.424.5
2.2
73.9
114.7119.9
11
369.6
24.626.6
2.4
80.6
120.0125.3
11.5
386.4
26.728.7
2.6
87.4
125.4130.6
12
403.2
28.830.9
2.8
94.1
>130.6
Call Medical Monitor
31.034.6
3.0
100.8
34.739.9
3.5
117.6
40.045.3
4
134.4
45.450.6
4.5
151.2


Cobimetinib—F. Hoffmann-La Roche Ltd
155/Protocol GO29665, Version 11
Appendix 11
List of Moderate and Strong CYP3A Inducers and Inhibitors That 
Are to Be Excluded in Dose Escalation Patients When 
Determining MTD
Based on in vitro studies, cobimetinib is a substrate of CYP3A.  Cobimetinib exposures 
were significantly increased in presence of a strong CYP3A inhibitor (itraconazole) in 
healthy subjects. Hence, strong and moderate inhibitors or inducers of CYP3A are 
excluded in this study.
CYP3A STRONG INHIBITORS
Diltiazem 
Clarithromycin 
Dronedarone 
Conivaptan 
Erythromycin 
Indinavir 
Fluconazole 
Ketoconazole 
Fosamprenavir 
Nefazodone 
Grapefruit Juice 
Posaconazole 
Imatinib 
Ritonavir 
Verapamil 
Telaprevir 
Diltiazem 
Voriconazole 
Aprepitant 
CYP3A STRONG INDUCERS
Ciprofloxacin 
Carbamazepine
Diltiazem 
Phenobarbital 
Erythromycin 
Phenytoin 
Fosamprenavir 
Rifampin 
Imatinib 
St. John's Wort 
CYP3A MODERATE INHIBITORS
CYP3A MODERATE INDUCERS
Aprepitant 
Bosentan 
Atazanavir 
Efavirenz 
Ciprofloxacin 
Etravirine 
Darunavir 
Modafinil