Phase II Open-label Global Study to Evaluate the Effect of Dabrafenib in Combination With Trametinib in Children and Adolescent Patients With BRAF V600 Mutation Positive Low Grade Glioma (LGG) or Relapsed or Refractory High Grade Glioma (HGG)
Phase: PHASE2
Conditions: Diffuse Astrocytoma, Anaplastic Astrocytoma, Astrocytoma, Oligodendroglioma, Childhood, Anaplastic Oligodendroglioma, Glioblastoma, Pilocytic Astrocytoma, Giant Cell Astrocytoma, Pleomorphic Xanthoastrocytoma, Anaplastic Pleomorphic Xanthoastrocytoma, Angiocentric Glioma, Chordoid Glioma of Third Ventricle, Gangliocytoma, Ganglioglioma, Anaplastic Ganglioglioma, Dysplastic Gangliocytoma of Cerebrellum, Desmoplastic Infantile Astrocytoma and Ganglioglioma, Papillary Glioneuronal Tumor, Rosette-forming Glioneurona Tumor, Central Neurocytoma, Extraventricular Neurocytoma, Cerebellar Iponeurocytoma
Sponsor: Novartis Pharmaceuticals

Clinical Development
Dabrafenib (DRB436), Trametinib (TMT212)
Oncology Clinical Protocol CDRB436G2201 / NCT02684058
Phase II open-label global study to evaluate the effect of 
dabrafenib in combination with trametinib in children and 
adolescent patients with BRAF V600 mutation positive Low 
Grade Glioma (LGG) or relapsed or refractory High Grade 
Glioma (HGG)
Document type
Amended Protocol Version
EUDRACT number
2015-004015-20
Version number
v05 (Clean)
Development phase
II
Document status
Final
Release date
12-Dec-2019
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis
Template version 6-Apr-2017

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Table of contents
Table of contents .................................................................................................................2
List of figures ......................................................................................................................6
List of tables ........................................................................................................................6
List of abbreviations............................................................................................................9
Glossary of terms...............................................................................................................12
Protocol summary:.............................................................................................................14
Amendment 5 (26-Nov-2019)...........................................................................................21
Amendment 3 (07-Aug-2018)...........................................................................................24
Amendment 2 (23-Feb-2018)............................................................................................24
Amendment 1 (07-Jun-2017) ............................................................................................24
1
Background........................................................................................................................26
1.1
Overview of disease pathogenesis, epidemiology and current treatment..............26
1.1.1
Pathogenesis..........................................................................................26
1.1.2
Epidemiology........................................................................................26
1.1.3
Current Treatments and Unmet Medical Need .....................................27
1.2
Introduction to investigational treatment(s) and other study treatment(s).............30
1.2.1
Overview of Dabrafenib........................................................................30
1.2.2
Overview of Trametinib........................................................................36
1.2.3
Overview of dabrafenib and trametinib combination therapy ..............42
1.2.4
Overview of carboplatin and vincristine chemotherapy .......................43
2
Rationale............................................................................................................................43
2.1
Study rationale and purpose...................................................................................43
2.2
Rationale for the study design ...............................................................................45
2.3
Rationale for dose and regimen selection..............................................................47
2.4
Rationale for choice of combination drugs............................................................48
2.5
Rationale for choice of comparators drugs............................................................48
2.6
Risks and benefits..................................................................................................49
3
Objectives and endpoints...................................................................................................50
4
Study design ......................................................................................................................54
4.1
Description of study design ...................................................................................54
4.1.1
Screening...............................................................................................57
4.1.2
Treatment ..............................................................................................58
4.1.3
Post Treatment Follow up.....................................................................60
4.1.4
Survival follow-up ................................................................................60
4.2
Timing of interim analyses and design adaptations...............................................60

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4.3
Definition of end of study......................................................................................61
4.4
Early study termination..........................................................................................61
5
Population..........................................................................................................................61
5.1
Patient population..................................................................................................61
5.2
Inclusion criteria ....................................................................................................62
5.3
Exclusion criteria...................................................................................................63
6
Treatment...........................................................................................................................65
6.1
Study treatment......................................................................................................65
6.1.1
Dabrafenib and Trametinib Dosing regimen.........................................65
6.1.2
Carboplatin and Vincristine Dosing Regimen ......................................70
6.1.3
Ancillary treatments..............................................................................71
6.1.4
Rescue medication ................................................................................72
6.1.5
Guidelines for continuation of treatment ..............................................72
6.1.6
Treatment duration................................................................................72
6.2
Dose escalation guidelines.....................................................................................72
6.3
Dose modifications................................................................................................73
6.3.1
Dose modification and dose delay ........................................................73
6.4
Concomitant medications ......................................................................................93
6.4.1
Permitted concomitant therapy .............................................................93
6.4.2
Permitted concomitant therapy requiring caution and/or action...........94
6.4.3
Prohibited concomitant therapy ............................................................95
6.5
Patient numbering, treatment assignment or randomization .................................96
6.5.1
Patient numbering .................................................................................96
6.5.2
Treatment assignment or randomization...............................................96
6.5.3
Treatment blinding................................................................................96
6.6
Study drug preparation and dispensation...............................................................97
6.6.1
Study treatment packaging and labeling ...............................................97
6.6.2
Drug supply and storage........................................................................98
6.6.3
Study drug compliance and accountability ...........................................98
6.6.4
Disposal and destruction .......................................................................98
7
Visit schedule and assessments .........................................................................................98
7.1
Study flow and visit schedule................................................................................98
7.1.1
Molecular pre-screening......................................................................117
7.1.2
Screening.............................................................................................117
7.1.3
Treatment period.................................................................................119
7.1.4
Discontinuation of study treatment .....................................................120

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7.1.5
Withdrawal of consent ........................................................................120
7.1.6
Follow up for safety evaluations.........................................................121
7.1.7
Lost to follow-up.................................................................................122
7.2
Assessment types.................................................................................................122
7.2.1
Efficacy assessments...........................................................................122
7.2.2
Safety and tolerability assessments.....................................................124
7.2.3
Pharmacokinetics ................................................................................130
132
7.2.5
Resource utilization.............................................................................134
7.2.6
Patient reported outcomes (LGG cohort only)....................................134
7.2.7
Acceptability and Palatability Questionnaires ....................................134
8
Safety monitoring and reporting......................................................................................135
8.1
Adverse events.....................................................................................................135
8.1.1
Definitions and reporting ....................................................................135
8.1.2
Laboratory test abnormalities..............................................................136
8.1.3
Adverse events of special interest.......................................................136
8.2
Serious adverse events.........................................................................................137
8.2.1
Definitions...........................................................................................137
8.2.2
Reporting.............................................................................................138
8.3
Emergency unblinding of treatment assignment .................................................139
8.4
Pregnancies..........................................................................................................139
8.5
Warnings and precautions....................................................................................139
8.6
Data Monitoring Committee................................................................................139
8.7
Steering Committee .............................................................................................140
9
Data collection and management.....................................................................................140
9.1
Data confidentiality .............................................................................................140
9.2
Site monitoring ....................................................................................................141
9.3
Data collection.....................................................................................................141
9.4
Database management and quality control..........................................................142
10 Statistical methods and data analysis ..............................................................................142
10.1
Analysis sets ........................................................................................................143
10.1.1
Full Analysis Set .................................................................................143
10.1.2
Safety set .............................................................................................143
10.1.3
Per-Protocol Set ..................................................................................143
10.1.4
Dose-determining analysis set.............................................................143
10.1.5
Pharmacokinetic analysis set...............................................................143

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10.1.6
Other analysis sets...............................................................................144
10.2
Patient demographics/other baseline characteristics ...........................................144
10.3
Treatments (study treatment, concomitant therapies, compliance) .....................144
10.4
Primary objective.................................................................................................145
10.4.1
Variable...............................................................................................145
10.4.2
Statistical hypothesis, model, and method of analysis........................145
10.4.3
Handling of missing values/censoring/discontinuations.....................146
10.4.4
Supportive and sensitivity analyses ....................................................146
10.5
Secondary objectives ...........................................................................................147
10.5.1
Safety objectives .................................................................................149
10.5.2
Pharmacokinetics ................................................................................151
153
10.5.4
Resource utilization.............................................................................154
10.5.5
Patient-reported outcomes...................................................................155
155
10.7
Interim analysis....................................................................................................155
10.7.1
HGG Cohort........................................................................................155
10.7.2
LGG Cohort ........................................................................................157
10.8
Sample size calculation........................................................................................157
10.8.1
HGG Cohort........................................................................................157
10.8.2
LGG Cohort ........................................................................................159
10.9
Power for analysis of key secondary variables....................................................160
11 Ethical considerations and administrative procedures ....................................................160
11.1
Regulatory and ethical compliance......................................................................160
11.2
Responsibilities of the investigator and IRB/IEC/REB.......................................160
11.3
Informed consent procedures...............................................................................160
11.4
Discontinuation of the study................................................................................161
11.5
Publication of study protocol and results.............................................................161
11.6
Study documentation, record keeping and retention of documents.....................162
11.7
Confidentiality of study documents and patient records .....................................162
11.8
Audits and inspections.........................................................................................163
11.9
Financial disclosures............................................................................................163
12 Protocol adherence ..........................................................................................................163
12.1
Amendments to the protocol................................................................................163
13 References (available upon request)................................................................................164
14 Appendices ......................................................................................................................168

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14.1
Appendix 1 – Concomitant medications..............................................................168
14.2
Appendix 2 – Performance Status Criteria..........................................................170
14.3
Appendix 3 – Response Assessment in Neuro-oncology (RANO) Criteria........171
14.4
Appendix 4 – WHO (2016) Grading of Tumors of the CNS ..............................174
175
List of figures
Figure 4-1
Study Design for HGG Cohort..............................................................55
Figure 4-2
Study Design for LGG Cohort..............................................................57
List of tables
Table 1-1
Efficacy Outcomes in Trials for Relapsed, Refractory Pediatric 
HGG......................................................................................................28
Table 1-2
Median Steady-State Dabrafenib AUC (ng*h/mL) (day 15) by 
Dose and Age Cohorts ..........................................................................36
Table 1-3
Geometric mean Steady-State Dabrafenib AUC(ng*h/mL) (day 15) 
by Age groups for Part 2 .......................................................................36
Table 1-4
Median trametinib PK (day 15) by age groups.....................................41
Table 3-1
Objectives and related endpoints ..........................................................51
Table 6-1
Dose and treatment schedule for dabrafenib (DRB436) capsules for 
patients less than 12 years of age (5.25 mg/kg/day) .............................66
Table 6-2
Dose and treatment schedule for dabrafenib (DRB436) capsules for 
patients greater or equal 12 years of age (4.5 mg/kg/day) ....................66
Table 6-3
Dose and treatment schedule for dabrafenib (DRB436) dispersible 
tablets for patients less than 12 years of age (5.25mg/kg/day) .............66
Table 6-4
Dose and treatment schedule for dabrafenib (DRB436) dispersible 
tablet for patients greater than or equal 12 years of age (4.5 
mg/kg/day) ............................................................................................67
Table 6-5
Dose and treatment schedule for trametinib (TMT212) oral 
solution for patients less than 6 years old (0.032 mg/kg/day)...............67
Table 6-6
Dose and treatment schedule for trametinib (TMT212) oral 
solution for patients greater or equal to 6 years old (0.025 
mg/kg/day) ............................................................................................68
Table 6-7
Dose and treatment schedule for trametinib (TMT212) tablets for 
patients less than 6 years and weight greater or equal 26kg (0.032 
mg/kg/day) ............................................................................................68

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Table 6-8
Dose and treatment schedule for trametinib (TMT212) tablets for 
patients greater or equal to 6 and weight greater or equal 33kg 
(0.025 mg/kg/day).................................................................................68
Table 6-9
Induction therapy ..................................................................................71
Table 6-10
Maintenance therapy.............................................................................71
Table 6-11
General guidelines for dose modification for adverse events 
considered related to dabrafenib and trametinib combination 
treatment................................................................................................73
Table 6-12
Dose Modification for trametinib (TMT212) oral solution for 
patients greater or equal to 6 years old..................................................74
Table 6-13
Dose Modification for trametinib (TMT212) for oral solution for 
patients less than 6 years old.................................................................75
Table 6-14
Dose Modification for dabrafenib (DRB436) dispersible tablet for 
patients less than 12 years of age ..........................................................75
Table 6-15
Dose Modification for dabrafenib (DRB436) dispersible tablet for 
patients greater or equal 12 years of age...............................................75
Table 6-16
Mandatory dose modification and recommended clinical 
management for pyrexia syndrome suspected to be related to 
dabrafenib and/or trametinib treatment.................................................77
Table 6-17
Mandatory dose modifications and recommended clinical 
management guidelines for renal function alterations ..........................78
Table 6-18
Mandatory dose modifications and recommended clinical 
management guidelines for pneumonitis ..............................................80
Table 6-19
Mandatory dose modification and recommended clinical 
management for visual changes and/or ophthalmic examination 
findings suspected to be related to trametinib treatment.......................81
Table 6-20
Mandatory dose modification and recommended clinical 
management for retinal pigment epithelial detachments (RPED) 
suspected to be related to trametinib treatment.....................................82
Table 6-21
Mandatory dose modification and recommended clinical 
management for uveitis, including iritis suspected to be related to 
dabrafenib treatment..............................................................................82
Table 6-22
Withholding and Stopping Criteria for QTc-Prolongation ...................84
Table 6-23
Mandatory dose modification and recommended clinical 
management for LVEF suspected to be related to dabrafenib and/or 
trametinib treatment ..............................................................................85
Table 6-24
Mandatory dose modifications and recommended clinical 
management guidelines for rash............................................................86
Table 6-25
Mandatory dose modification and recommended clinical 
management for hypertension...............................................................88
Table 6-26
Packaging and labeling .........................................................................97

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Table 7-1
Visit evaluation schedule for HGG and LGG dabrafenib and 
trametinib treatment arm.....................................................................100
Table 7-2
Visit evaluation schedule for LGG crossover patients........................107
Table 7-3
Visit evaluation schedule for LGG chemotherapy arm.......................111
Table 7-4
Imaging Assessment Collection Plan..................................................123
Table 7-5
Central Clinical laboratory parameters collection plan.......................127
Table 7-6
Full Pharmacokinetic blood collection log – HGG cohort and 
subset of LGG cohort..........................................................................131
Table 7-7
Sparse Pharmacokinetic blood collection log for subset of LGG 
cohort...................................................................................................131
133
Table 10-1
Non-compartmental pharmacokinetic parameters ..............................152
Table 10-2
Predictive probability of the lower bound of 95% CI exceeding 
20% at the primary analysis under different interim results ...............156
Table 10-3
Exact Binomial 95 and 80 percent Confidence Intervals Around 
Potential Observed ORRs for N=40....................................................158
Table 10-4
Operating Characteristics with regard to the 95% CI excluding 
20% response rate ...............................................................................158
Table 10-5
Operating Characteristics with regard to the 95% and 80% CIs 
excluding 32% response rate...............................................................159
Table 10-6
Power scenarios under different true ORR in BRAF V600 mutant ....160
Table 14-1
List of medications to be used with caution during study drug 
treatment..............................................................................................168
Table 14-2
List of prohibited medications during study drug treatment...............169

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List of abbreviations
ADL
Activities of daily living
AE
Adverse event
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase/glutamic pyruvic transaminase/GPT
AST
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT
AUC
Area under the curve 
b.i.d.
bis in diem/twice a day
BAL
Bronchoalveolar lavage
BCC
Basal cell carcinoma
Cavg
Average concentration
CBDCA
Carboplatin
CBR
Clinical benefit rate
 
Cmax
The observed maximum (peak) plasma concentration after drug administration
CHMP
Committee for Medicinal Products for Human Use
CI
Confidence interval 
CMO&PS
Chief Medical Office and Patient Safety
CMV
Cytomegalovirus
CNS
Central nervous system
COG
CR
Children’s Oncology Group
Complete response
CRF
Case report/record form; the term CRF can be applied to either EDC or paper
CRO
Contract research organization
CRP
C reactive protein 
CSF
Cerebrospinal fluid
CSP
Clinical study protocol 
CSR
Clinical study report
CSR 
addendum
An addendum to Clinical Study Report (CSR) that captures all the additional information that is 
not included in the CSR
CTCAE
Common terminology criteria for adverse event 
DILI
Drug-induced liver injury
DLT
DMC
Dose limiting toxicity
Data monitoring committee
DOR
Duration of response
DRESS
Drug reaction with eosinophilia and systemic symptoms
EBV
EEA
Epstein-Barr virus
European Economic Area
ECG
Electrocardiogram
eCRF
Electronic case report forms for EDC
ECHO
Echocardiogram
EDC
Electronic data capture
EMA
EU
The European Medicines Agency
European Union
eSAE
Electronic serious adverse event 
FAS
FFPE
Full analysis set 
Formalin-fixed, paraffin-embedded
FDA
Food and Drug Administration
GBM
GDPR
Glioblastoma multiforme
General Data Protection Regulation

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HBV
Hepatitis B Virus 
HCV
Hepatitis C Virus 
HGG
High Grade Glioma 
HPMC
Hydroxypropylmethyl cellulose 
HSV
Herpes simplex virus
i.v.
intravenous(ly)
IB
Investigator’s brochure
ICF
Informed consent form 
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
INR
International normalized ratio 
IRB
Institutional Review Board
IRT
Interactive Response Technology that includes Interactive Voice Response System and 
Interactive Web Response System
IUD
Intrauterine device
IUS
Intrauterine system
Kg
Kilogram 
LCH
Langerhans Cell Histiocytosis
LFT
Liver function test
LGG
Low Grade Glioma
MAP
Master analysis plan documents project standards in the statistical methods which will be used 
within the individual clinical trial RAP documentation
MRI
Magnetic resonance imaging 
MTD
Maximum tolerated dose
NGS
Next-generation sequencing
NSCLC
Non-small cell lung cancer
q.d.
omnia die/once a day
ORR
Overall response rate 
OS
Overall survival 
PAS
Pharmacokinetic analysis set 
PD
Progression of disease 
PFS
Progression free survival
PHI
Protected Health Information
PK
Pharmacokinetics 
p.o.
per os/by mouth/orally
POS
Probability of success
PPS
Per-protocol set 
PR
Partial Response
PRO
Patient reported outcomes
PTC
Papillary Thyroid Cancer
PXA
Pleomorphic Xanthoastrocytoma 
QT
Q to T interval (ECG)
QTcF
QT interval corrected using Fridericia method 
RANO
Response Assessment in Neuro-Oncology Criteria
RAP
The Report and Analysis Plan (RAP) is a regulatory document which provides evidence of 
preplanned analyses
REB
Research Ethics Board
RP2D
RPED
Recommended phase two dose
Retinal pigment epithelial detachment
RoW
Rest of world
RR
Response rate

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R Value
ALT/ALP in x ULN
RVO
Retinal vein occlusion
SAE
Serious adverse event
SC
Steering committee 
SCAR
Severe cutaneous adverse reactions
SIADH
Syndrome of inappropriate antidiuretic hormone secretion 
SmPC
Summary of product characteristics
SOC
Standard of care
SOP
Standard operating procedure
TBIL
Total bilirubin
TTR
Time to response
ULN
Upper limit of normal 
VCR
Vincristine
WBC
White blood cells 
WHO
World Health Organization

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Glossary of terms
Assessment
A procedure used to generate data required by the study
Biologic Samples
A biological specimen including, for example, blood (plasma, serum), saliva, 
tissue, urine, stool, etc. taken from a study patient 
Control drug
A study treatment used as a comparator to reduce assessment bias, preserve 
blinding of investigational drug, assess internal study validity, and/or evaluate 
comparative effects of the investigational drug
Cohort
A group of newly enrolled patients treated at a specific dose and regimen (i.e. 
treatment group) at the same time
Cycles
Number and timing or recommended repetitions of therapy are usually expressed 
as number of days (e.g.: q28 days)
Dose level
The dose of drug given to the patient (total daily or weekly etc.) 
Enrollment
Point/time of patient entry into the study; the point at which informed consent must 
be obtained (i.e. prior to starting any of the procedures described in the protocol)
Investigational drug
The study treatment whose properties are being tested in the study; this definition 
is consistent with US CFR 21 Section 312.3 and is synonymous with 
“investigational new drug.”
Investigational treatment
Drug whose properties are being tested in the study as well as their associated 
placebo and active treatment controls (when applicable). This also includes 
approved drugs used outside of their indication/approved dosage, or that are 
tested in a fixed combination. Investigational treatment generally does not include 
other study treatments administered as concomitant background therapy required 
or allowed by the protocol when used in within approved indication/dosage
Medication number
A unique identifier on the label of each study treatment package which is linked to 
one of the treatment groups of a study
Other study treatment
Any drug administered to the patient as part of the required study procedures that 
was not included in the investigational treatment
Subject Number (Subject 
No.)
A unique identifying number assigned to each patient who enrolls in the study
Period
A subdivision of the study timeline; divides stages into smaller functional segments 
such as screening, baseline, titration, washout, etc.
Personal Data
Subject information collected by the Investigator that is transferred to Novartis for 
the purpose of the clinical trial.  This data includes subject identifier information, 
study information and biological samples.
Randomization number
A unique treatment identification code assigned to each randomized patient, 
corresponding to a specific treatment arm assignment
Stage related to study 
timeline
A major subdivision of the study timeline; begins and ends with major study 
milestones such as enrollment, randomization, completion of treatment, etc.
Stage in cancer
The extent of a cancer in the body. Staging is usually based on the size of the 
tumor, whether lymph nodes contain cancer, and whether the cancer has spread 
from the original site to other parts of the body
Stop study participation
Point/time at which the patient came in for a final evaluation visit or when study 
treatment was discontinued and post treatment follow-up is complete, whichever is 
later
Study treatment
Includes any drug or combination of drugs in any study arm administered to the 
patient (subject) as part of the required study procedures, including placebo and 
active drug run-ins.
In specific examples, it is important to judge investigational treatment component 
relationship relative to a study treatment combination; study treatment in this case 
refers to the investigational and non-investigational treatments in combination.
Study treatment 
discontinuation
Point/time when patient permanently stops taking study treatment for any reason
Supportive treatment
Refers to any treatment required by the exposure to a study treatment, e.g. 
premedication of vitamin supplementation and corticosteroid for pemetrexed 
disodium.

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Treatment group
A treatment group defines the dose and regimen or the combination, and may 
consist of 1 or more cohorts. Cohorts are not expanded, new cohorts are enrolled.
Variable
Identifier used in the data analysis; derived directly or indirectly from data collected 
using specified assessments at specified timepoints
Withdrawal of study 
consent
Withdrawal of consent from study occurs only when a patient does not want to 
participate in the study any longer, and does not allow any further collection of 
personal data

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Protocol summary: 
Title
Phase II open-label global study to evaluate the effect of dabrafenib in 
combination with trametinib in children and adolescent patients with BRAF V600 
mutation positive Low Grade Glioma (LGG) or relapsed or refractory High Grade 
Glioma (HGG)
Brief title
Study of efficacy and safety of dabrafenib in combination with trametinib in 
pediatric patients with BRAF V600 mutation positive LGG or relapsed or refractory 
HGG tumors
Sponsor and Clinical 
Phase
Novartis
Phase II
Investigation type
Drug
Study type
Interventional 
Purpose and rationale
Relapsed, refractory or resistant pediatric HGG lacks a standard of care. Multiple 
chemotherapies and targeted agents have been studied in this setting but none 
have demonstrated activity. Targeted agents in this disease setting have shown a 
lack of efficacy. 
Preliminary results from [BRF116013, CDRB436A2102, data cut off of 12-Sept-
2017] showed that 14 of 31 patients (45%) with relapsed or refractory BRAF V600 
mutant HGG had central independent radiologic review confirmed responses (CRs 
+ PRs) following dabrafenib monotherapy. These results indicate that dabrafenib 
may offer improvement in treatment outcome for these patients. For this reason, 
the historical response rate (RR) in BRAF V600 mutant pediatric relapsed 
refractory HGG may be higher than that observed in unselected populations, 
where the RR is less than 12%.
Pediatric patients with BRAF V600 mutant LGG that is progressing following 
optimal surgical resection often require systemic treatment. The standard of care 
in this setting has been a regimen of carboplatin and vincristine, which may not be 
as effective in patients whose tumor harbors the BRAF V600 mutation, with lower 
response rate, PFS and OS than those without this mutation. Furthermore, in 
patients with BRAF V600 mutant LGG who have failed prior systemic 
chemotherapy, independently confirmed response of dabrafenib monotherapy 
exceeds historical expectations for this subgroup of patients.
The combination of dabrafenib with trametinib in adults with BRAF V600 mutant 
melanoma, non-small cell lung cancer (NSCLC) and other tumors have resulted in 
improved efficacy over dabrafenib monotherapy and suggests that greater efficacy 
may also be seen in the pediatric patients with a BRAF V600 mutant malignancy.
Given the high unmet medical need in pediatric HGG and LGG, the encouraging 
efficacy of dabrafenib monotherapy in pediatric patients with BRAF V600 mutant 
HGG and LGG, and the improved efficacy seen in adult cancer studies upon the 
addition of trametinib to dabrafenib, this study aims to demonstrate the 
effectiveness of dabrafenib with trametinib in pediatric patients with BRAF V600 
mutant LGG and relapsed refractory HGG.
Primary Objective(s) 
The primary objective of the HGG cohort is to evaluate the anti-tumor activity of 
dabrafenib in combination with trametinib, as measured by overall response rate 
(ORR) by central independent assessment using the RANO criteria.
The primary objective of the LGG cohort is to compare the anti-tumor activity of 
dabrafenib in combination with trametinib to the combination of carboplatin and 
vincristine, as measured by overall response rate (ORR) by central independent
assessment using the RANO criteria.
Secondary Objectives
HGG Cohort:
1. Evaluate ORR by investigator assessment
2. Evaluate duration of response (DOR) by investigator and central independent 
assessment
3. Evaluate progression free survival (PFS) by investigator and central 
independent assessment
4. Evaluate time to response (TTR) by investigator and central independent 
assessment

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5. Evaluate clinical benefit rate (CBR) by investigator and central independent 
assessment
6. Evaluate overall survival (OS)
7. Evaluate the safety and tolerability profile of dabrafenib in combination with 
trametinib in the study population
8. Evaluate the palatability of dabrafenib oral suspension and trametinib oral 
solution
9. Characterize the pharmacokinetics of dabrafenib, its metabolites and trametinib 
in the study population
LGG Cohort:
10.Evaluate ORR of dabrafenib in combination with trametinib versus carboplatin 
with vincristine, as measured by investigator assessment.
11.Evaluate the DOR of dabrafenib in combination with trametinib versus 
carboplatin with vincristine by both investigator and independent assessment.
12.Evaluate PFS of dabrafenib in combination with trametinib versus carboplatin 
with vincristine, as measured by both investigator and independent 
assessment.
13.Evaluate TTR of dabrafenib in combination with trametinib versus carboplatin 
with vincristine, as measured by both investigator and independent 
assessment.
14.Evaluate CBR of dabrafenib in combination with trametinib versus carboplatin 
with vincristine, as measured by both investigator and central independent 
assessment.
15.Evaluate the overall survival of dabrafenib in combination with trametinib 
versus carboplatin with vincristine.
16.Evaluate the safety and tolerability of dabrafenib in combination with trametinib 
versus carboplatin with vincristine.
17.Evaluate the palatability of dabrafenib oral suspension and trametinib oral 
solution
18.Characterize the pharmacokinetics of dabrafenib, its metabolites and trametinib 
in the study population.
19.Assess patient reported outcomes of dabrafenib in combination with trametinib 
versus carboplatin with vincristine.
Study design
CDRB436G2201 combines two pediatric glioma cohorts into a single multi-center, 
global, open-label, phase II study. The HGG cohort is a single arm part evaluating 
the effect of dabrafenib in combination with trametinib in children and adolescent 
patients with BRAF V600 mutation positive relapsed, refractory HGG. 
Approximately 40 patients will be enrolled to receive oral dabrafenib twice daily 
and trametinib once daily based on weight, age and appropriate dose level. 
The LGG cohort is a randomized part comparing the anti-tumor activity of 
dabrafenib in combination with trametinib to the combination of carboplatin and 
vincristine in children and adolescents with BRAF V600 mutation positive LGG. 
Approximately 102 patients will be randomized in a 2:1 ratio to either dabrafenib 
plus trametinib or carboplatin with vincristine. For the LGG cohort, patients 
randomized to carboplatin with vincristine control arm will be allowed to crossover 
to receive dabrafenib in combination with trametinib treatment after centrally 
confirmed and RANO-defined disease progression.
All patients will be followed for survival for at least 2 years after the last patient first
study treatment (except if consent is withdrawn, patient death, lost to follow-up or 
study is discontinued). An interim analysis for futility for the HGG cohort will be 
implemented to allow possible termination of recruitment into the HGG cohort in 
the event that there is insufficient efficacy. An independent DMC will be instituted 
to review safety data during the study for all patients in LGG and HGG cohorts.  
For full details of study design refer to Section 4.
Population
This study will be conducted in two cohorts of pediatric patients, HGG cohort and 
LGG cohort.

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For the HGG cohort, approximately 40 male or female children or adolescent 
patients between ≥12 months and <18 years of age with BRAF V600 mutation 
positive, refractory or relapsed HGG after having received at least one previous 
standard therapy will be enrolled. 
For the LGG cohort, approximately 102 male or female children or adolescent 
patients between ≥12 months and <18 years of age with BRAF V600 mutation 
positive LGG with progressive disease following surgical excision, or non-surgical 
candidates with necessity to begin first systemic treatment because of a risk of 
neurological impairment with progression.
Inclusion criteria
Key Inclusion criteria:
-
Male or female ≥12 months and <18 years of age.  Patient must weigh ≥7 kg at 
the time of enrollment.
-
Locally determined HGG or LGG as defined by WHO histological classification 
system, revised 2016. 

For HGG cohort only: locally confirmed histologic diagnosis of High 
Grade Glioma (Grade III or IV), including anaplastic pleomorphic 
xanthoastrocytoma (aPXA) and anaplastic ganglioglioma. 

For LGG cohort only: locally confirmed histologic diagnosis of Low Grade 
Glioma (Grade I or II).
-
HGG cohort: Relapsed, progressed, or failed to respond to frontline therapy. 
-
LGG cohort: Patients with progressive disease following surgical excision, or 
non-surgical candidates with necessity to begin systemic treatment because of 
a risk of neurological impairment with progression.
-
BRAF V600 mutation-positive tumor assessed locally, or at a Novartis 
designated central reference laboratory if local BRAF V600 testing is 
unavailable. 
-
Locally determined and centrally confirmed measurable disease with minimal 
bi-perpendicular diameter that must be at least twice the imaging slice 
thickness to be used for efficacy assessments.
-
Tumor tissue must be provided for central confirmatory testing of BRAF
mutational status (LGG and HGG cohorts), and for HGG histopathology (HGG 
cohort only).
-
Karnofsky/Lansky performance score of ≥50%.
-
Adequate bone marrow function per central or local lab in the absence of 
growth factor support.
-
Adequate renal function, liver function, and cardiac function.
-
If receiving glucocorticoids, patient must be on a stable or weaning dose for at 
least 7 days prior to first dose of study treatment.

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Exclusion criteria
Key Exclusion criteria:
-
Malignancy OTHER than BRAF V600 mutant HGG or LGG.
-
Previous treatment with dabrafenib or another RAF inhibitor, trametinib or 
another MEK inhibitor, or an ERK inhibitor.
-
HGG patients: Cancer therapy (chemotherapy with delayed toxicity, 
immunotherapy, biologic therapy, vaccine therapy) or investigational drugs 
within 3 weeks preceding the first dose of study treatment. LGG patients: Any 
systemic anticancer therapy (chemotherapy, immunotherapy, biologic therapy 
or vaccine therapy) or investigational drugs prior to enrollment. 
-
HGG patients: Radiotherapy to CNS glioma lesions within 3 months prior to first 
dose of study treatment, unless there is clear evidence of radiologic 
progression outside of the field of radiation. LGG patients: Radiotherapy to 
CNS glioma lesions at any point prior to enrollment. 
-
History of malignancy with confirmed activating RAS mutation or with BRAF
fusion such as BRF-KIAA1549. 
-
Current use of a prohibited medication or herbal preparation or requires any of 
these medications during the study. See Section 6.4 for details. 
-
Unresolved toxicity greater than NCI CTCAE v 4.03 grade 2 from previous anti-
cancer therapy, including major surgery, except those that in the opinion of the 
investigator are not clinically relevant given the known safety/toxicity profile of 
the study treatment (e.g., alopecia and/or peripheral neuropathy related to 
platinum or vinca alkaloid based chemotherapy).
-
History of allergic reactions attributed to compounds of similar chemical or 
biologic composition to dabrafenib, trametinib and their excipients. For LGG 
patients only: history of allergic reactions or contraindications to the use of 
carboplatin or vincristine (refer to local product label or SmPC)
-
Autologous or allogeneic stem cell transplant within 3 months prior to the first 
dose of study treatment [NOTE: patients with evidence of active graft versus 
host disease are excluded regardless of elapsed time].
-
History or current diagnosis of cardiac disease indicating significant risk of 
safety for patients participating in the study such as uncontrolled or significant 
cardiac disease.
-
Uncontrolled medical conditions (e.g., diabetes mellitus, hypertension, liver 
disease or uncontrolled infection), psychological, familial, sociological, or 
geographical conditions that do not permit compliance with the protocol; or 
unwillingness or inability to follow the procedures required in the protocol.
-
Presence of active GI disease or other condition (e.g., small bowel or large 
bowel resection) that will interfere significantly with the absorption of drugs. 
-
A history of Hepatitis B Virus or Hepatitis C Virus infection (patients with 
laboratory evidence of cleared Hepatitis B Virus and/or Hepatitis C Virus may 
be enrolled).
-
Women of child-bearing potential, defined as all women physiologically capable 
of becoming pregnant (e.g. are menstruating), unless they are using highly 
effective methods of contraception during dosing of study treatment and for 16
weeks after stopping study medication with trametinib monotherapy or 
dabrafenib in combination with trametinib, and 2 weeks after stopping treatment 
with dabrafenib monotherapy, whichever is longer. Note: Hormonal-based 
methods are not permitted as a method of contraception due to potential drug-
drug interactions with dabrafenib.
-
Women who are pregnant or actively breast feeding.
-
Sexually active males (including those that have had a vasectomy) unless they 
use a condom during intercourse while on study and for 16 weeks after 
stopping study treatment, and agree not to father a child during this period.
-
A history or current evidence of retinal vein occlusion (RVO) or central serous 
retinopathy. See Section 5.3 for details

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Investigational and 
reference therapy
Dabrafenib (DRB436) oral administration, twice daily based on weight, age and
appropriate dose level. Trametinib (TMT212) oral administration, once daily based 
on weight and/or age. See dosing regimen in Section 6.1.1.
LGG patients randomized to receive carboplatin plus vincristine are administered 
one course of induction (10 weeks of chemotherapy with 2 weeks of rest) followed 
by 8 cycles of maintenance chemotherapy. Each maintenance cycle is 6 weeks. 
See dosing regimen in Section 6.1.2
Efficacy assessments
HGG and LGG cohorts: Brain MRI every 8 weeks during the first 56 weeks and 
every 16 weeks thereafter while on treatment, during post-treatment follow-up, and 
at any time there is suspicion of clinical disease progression. Partial Response 
(PR) and Complete Response (CR) must be confirmed by repeat assessments 
performed ≥4 weeks after the criteria for response are first met.
Tumor evaluation by RANO criteria as assessed by local investigator and central 
independent assessment.
Safety assessments
HGG and LGG cohorts:
Medical history
Physical examination, vital signs, height and weight, 
Performance status
Laboratory evaluations (hematology, clinical chemistry and urinalysis)
Monthly pregnancy testing for women of childbearing potential
Cardiac assessment, including ECG and cardiac imaging
 
Dermatology evaluation
Ophthalmologic exam
 
Adverse events, the severity, the seriousness, the relationship to study drug, and 
AEs of special interest
Other assessments
HGG and LGG cohorts:
Pharmacokinetics (PK) blood collection to summarize exposure (dabrafenib, 
dabrafenib metabolites and trametinib) 
 
Taste questionnaires for dabrafenib oral suspension and trametinib oral solution.
Tumor samples for confirmatory testing of HGG histopathology (HGG patients 
only)
Tumor samples for confirmatory testing of BRAF mutational status for both LGG 
and HGG patients. 
 
Survival status follow-up 
LGG cohort only:
Patient reported outcomes on PROMIS Parent Proxy Global 7+2 Health 
questionnaire 

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Data analysis
Data analysis to address the primary objective:
The primary analysis will be performed on the full analysis set (FAS). For HGG 
cohort, point estimate and the exact binomial confidence intervals (CIs) of ORR by 
central independent assessment will be provided. The lower bound of the CIs will 
be used to provide evidence that the true ORR is greater than a certain specific 
response rate. For LGG cohort, the ORR by central independent assessment of 
the two treatment groups will be compared using Mantel Haenszel chi-square test 
at one-sided 2.5% level of significance. ORR will be summarized using descriptive 
statistics by treatment arm along with two-sided exact binomial 95% CIs (Clopper 
and Pearson 1934).
Data analysis to address secondary objectives:
ORR per investigator assessment for HGG cohort and LGG cohort will also be 
analyzed.
TTR, DOR, CBR and PFS will be analyzed as per investigator and independent 
assessment. Confirmation of response is required for all response endpoints, as 
per RANO.
DOR, PFS and OS will be described using Kaplan-Meier methods and appropriate 
summary statistics.
Efficacy: The efficacy analysis will be performed on all patients who receive at 
least one dose of study treatment. Sensitivity analysis on the primary and 
secondary efficacy endpoints will be performed on the evaluable set of patients.
Safety:
The assessment of safety will be based mainly on the frequency of adverse events 
and on the number of laboratory values that fall outside of pre-determined ranges. 
Other safety data (e.g. vital signs, ECG, ECHO) will be considered as required. 
The safety summary tables will include only assessments collected no later than 
30 days after study treatment discontinuation, unless otherwise specified. The 
safety analysis will be performed on patients receiving at least one dose of study 
treatment.
The palatability of dabrafenib oral suspension and trametinib oral solution will be 
evaluated.
The patient reported outcome for the LGG cohort will be summarized.
Interim analysis:
An interim analysis for futility will be implemented to allow possible termination of 
recruitment of the HGG cohort in the event that there is insufficient efficacy. The 
patients for inclusion in the formal interim analysis for futility will be determined 
shortly after 16 HGG patients in the FAS have been enrolled. The analysis will be 
conducted when this initial group of patients to be included in the analysis have all 
had at least 20 weeks of follow-up or have withdrawn early. If the observed ORR 
assessed by central independent assessment is ≤ 25% there may be a 
consideration to stop the enrollment into the HGG cohort due to insufficient 
efficacy. The final decision on whether to stop enrollment into this cohort will also 
take into account all available study information at the IA cut-off including safety 
data and all efficacy endpoints. Any decision to halt further enrollment into the 
HGG cohort will not impact the treatment options for patients already enrolled into 
this cohort. HGG patients deriving benefit as per investigator discretion may 
continue receiving dabrafenib plus trametinib treatment on study.
In addition, an additional interim analysis of key safety and PK data of the 
adolescent patients in the HGG cohort may be performed to support a health 
authority request for data in adolescent patients.
Sample size for HGG cohort:
Approximately 40 patients will be enrolled in HGG cohort if the study is not 
stopped for futility at the time of IA. 

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With a total of 40 patients and with 16 patients included in the futility interim 
analysis and when the true ORR is ≤ 20%:

the probability of meeting the futility consideration criteria at IA is > 79%, 

the probability of the 95% CI excluding 20% at the primary analysis is < 1.6%,

and the probabilities of the 95% CI and the 80% CI excluding 32% at the 
primary analysis are both < 0.1% respectively.
With a total of 40 patients and with 16 patients included in the futility interim 
analysis and if the true ORR is 55% or higher, then:

the probability of meeting the futility consideration criteria at IA is < 2%, 

the probabilities of the 95% CI excluding 20% and the 80% CI excluding 32% 
at the primary analysis are both > 90% respectively, 

and the probability that the 95% CI excludes 32% is > 78%.
Sample size for LGG cohort:
For LGG cohort, to detect a 30% improvement in ORR based on central independent 
assessment response of 50% in the dabrafenib in combination with trametinib arm 
vs 20% in the carboplatin plus vincristine arm with at least 80% power, 102 patients 
are required to be randomized in the two treatment arms in a 2:1 ratio using a
Maentel-Haenszel chi-squared test, and one-sided alpha = 2.5%.
Key words
High grade glioma, HGG, Low grade glioma, LGG, BRAF, DRB436, dabrafenib,
TMT212, trametinib, carboplatin and vincristine, children, adolescent

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Amendment 5 (26-Nov-2019)
As of 26-Nov-2019, twenty six (26) patients have been enrolled and treated in the HGG cohort 
of CDRB436G2201 and forty four (44) patients have been randomized in the LGG cohort of 
CDRB436G2201.
Amendment Rationale
The main purpose of this amendment is (1) to add dose modification requirements for cases of 
severe cutaneous adverse reactions (SCARs) which have been reported during treatment with 
dabrafenib in combination with trametinib outside this clinical study, and (2) to change the duration 
of male and female contraception following the last dose of dabrafenib from 4 weeks to 2 weeks
and following the last dose of trametinib from 6 months to 16 weeks. 
These changes were made in order to align with updated information available in dabrafenib and 
trametinib Investigator’s Brochure Edition 11.
Further, inclusion criterion 3 was clarified as local histological diagnosis of HGG is sufficient for 
the study entry and criteria for patients with Gilbert’s syndrome were established for inclusion 
criterion 11.
Other clarifications and corrections are also applied throughout the protocol.
Changes to the protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions.
Updated Section 4.1.2.2: Section has been corrected to clarify that for LGG patient, Day 1 of 
crossover therapy must occur within 90 days from the date of the first centrally confirmed 
progression.  
Updated Section 5.2: Inclusion criterion 3 has been clarified by removing mention of central 
confirmation of histopathology as this is not required for eligibility, inclusion criterion 11 has 
been modified to allow specific laboratory criteria for enrollment of patientswith Gilbert’s
syndrome. Exclusion criteria 14 and 17 have been modified to reflect the modified 
contraception requirements.
Updated Section 6.3.1.11: Management of severe skin cutaneous adverse reactions has been 
modified in line with DRB436 Investigator Brochure 11 and provide guidance on SCAR event 
management.
Section 8.4: wording regarding the duration of reporting period for pregnancy after patient 
discontinued treatment has been modified to 16 weeks after stopping treatment with trametinib 
monotherapy or dabrafenib in combination with trametinib, and 2 weeks after stopping 
treatment with dabrafenib monotherapy, whichever is longer.  

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Institutional Review Board (IRB)/Independent Ethics Committee (IEC)/Research 
Ethics Board (REB)
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs)/Research Ethics Board (REB) and Health 
Authorities.
The changes described in this amended protocol require IRB/IEC/REB approval prior to 
implementation.
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.
Summary of previous amendment
Amendment 4 (11-Mar-2019)
As of 28-Feb-2019, fifteen (15) patients have been enrolled and treated in the HGG cohort of 
CDRB436G2201 and fourteen (14) patients have been randomized in the LGG cohort of 
CDRB436G2201. 
Amendment rationale
The purpose of this amendment is to add an additional interim analysis of key safety and 
pharmacokinetics (PK) data of the adolescent patients (ages ≥12 to <18 years) in the HGG 
cohort to support a health authority request in the1st half of 2019 for data in adolescent patients. 
In addition, exclusion criteria #18 was added to exclude patients with history or current 
evidence of retinal vein occlusion and central serous retinopathy.  This exclusion criteria is 
standard language for all studies with trametinib and was inadvertently omitted from previous 
versions of CDRB436G2201. 
Also, optional cerebrospinal fluid (CSF) collection was removed.  Based on experience to date, 
CSF samples are expected to be very limited (1/30 patients provide a sample).  Hence, the value 
of the analyses is limited.  
Other clarifications and corrections are also applied throughout the protocol. 
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions.

Updated protocol summary table to match changes throughout protocol

Updated Table 3-1 to remove optional CSF sample collection

Updated Figures 4-1 and 4-2 to reflect that trametinib dosing is age and weight based

Updated Section 4.1.2 to reference Visit Evaluation Schedule Table 7-3 created for the 
chemotherapy arm

Updated Section 4.2 to include an additional interim analysis in the HGG cohort to 
support a health authority request

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
Updated Section 5.2

Inclusion criterion #5: Removed CLIA-approved laboratory (US only) or local 
equivalent, removed requirement for molecular testing for BRAF V600 confirmation 

Updated Section 5.3

Added Exclusion criterion #18: To exclude patients with history or current evidence of 
retinal vein occlusion (RVO) or central serous retinopathy

Exclusion criterion #14: Added the option to use hormonal IUD or IUS in addition to 
non-hormonal IUD or IUS as a form of birth control. Removed the term “Hormonal-
based methods” from the note. 

Updated Table 6-16 for pyrexia dose modifications to indicate that patients and parents 
should be re-educated about pyrexia syndrome

Changed “renal toxicity” to nephrotoxicity in Section 6.1.2.1 to be consistent with 
language in Section 6.3.1.16

Corrected reference to RPED dose modiciation table in Table 6-19

Clarified in Section 6.3.1.16 that the induction cycle of chemotherapy should only be 
modified in the event of grade 3 neurotoxicity, grade 2 nephrotoxicity, grade 4 
hematologic toxicity, or disease progression.

Updated Section 6.4.2.1 to clarify that anti-cancer surgery is allowed in HGG patients 
once investigator has declared progressive disease. 

Updated Section 6.4.3 to remove the reference to dabrafenib concentrations as the 
prohibited concomitant therapy is for vincristine.  

Updated Tables 7-1 and 7-2 to remove optional CSF sample collection, remove reference 
to chemotherapy patients as this was moved to Tablet 7-3 for clarity

Added Table 7-3 in Section 7.1 for LGG chemotherapy patients. Updated protocol 
throughout with Table 7-3 reference. 

Updated table number throughout Section 7

Updated Section 7.1.2 to remove exclusion of immunohistochemistry testing for local 
testing for BRAF V600 confirmation. 
. 

Updated Table 7-7 and Section 7.2.4.3 to remove the optional CSF sample collection

Updated Section 8.1.3 to combine Cutaneous squamous cell carcinoma (cuSCC), 
keratoacanthomas, noncutaneous treatment emergent malignancies (excluding cuSCC 
keratoacanthomas and BCC) and new primary malignant melanoma into one Adverse 
Event of Special Interest of “New primary/secondary malignancy” 

Updated Section 10.5.3.1 to remove optional CSF sample collection 

Updated Section 10.7.1 to include an additional interim analysis in the HGG cohort to 
support a health authority request

Updated Table 14-2 to remove oxcarbazepine from list of prohibited medications during 
study treatment

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Amendment 3 (07-Aug-2018)
Protocol amendment 3 changed the age range of patients eligible to enroll in the study from ≥6 
to <18 years of age to ≥12 months to <18 years of age. This change was possible as the 
recommended dose for the combination of dabrafenib with trametinib for patients between 12 
months and 6 years of age has been determined. 
The inclusion and exclusion criteria were also updated to clarify the eligible population for the 
LGG cohort as patients with BRAF V600 mutant LGG, who either have progressive disease 
following surgical excision, or non-surgical candidates with necessity to begin first systemic 
treatment because of a risk of neurological impairment with progression. Further, the exclusion 
criteria specified that LGG patients who have had any prior systemic anticancer therapy or 
antitumor radiotherapy are excluded.
In addition, the primary endpoint for the High Grade Glioma cohort was changed from 
investigator assessment of Overall Response Rate (ORR) to central independent review of ORR. 
This change may lessen the potential for bias that may be introduced due to investigator 
assessment in a single arm trial. Investigator assessment of ORR has therefore been added as a 
secondary endpoint. 
Amendment 2 (23-Feb-2018)
Protocol amendment 2 added a new cohort of BRAF V600 mutant Low Grade Glioma children 
and adolescent patients whose tumor is unresectable and require systemic treatment.  
Additionally the amendment also added a pediatric formulation of dabrafenib as a dispersible 
tablet. 
The LGG cohort was added to enroll approximately 102 pediatric patients with BRAF V600 
mutant low grade glioma, randomized 2:1 dabrafenib with trametinib versus carboplatin plus 
vincristine, with overall response rate (PR+CR) as primary endpoint. 
In addition, taste questionnaires for trametinib and dabrafenib pediatric formulations were 
implemented for all patients who receive the trametinib oral solution and/or dabrafenib oral 
suspension.  The PROMIS Patient Reported Outcome questionnaire was added for the LGG 
cohort of patients. Sparse PK collection was included for a subset of LGG patients.  The specific 
RANO criteria for LGG were added into Appendix 2. 
Amendment 1 (07-Jun-2017)
Protocol amendment 1 revised the investigational treatment regimen from dabrafenib 
monotherapy to include trametinib with dabrafenib for children and adolescents with BRAF
V600 mutation positive relapsed or refractory HGG. Guidance provided to the sponsor by the 
FDA and CHMP, in addition to updated efficacy data from the ongoing dabrafenib monotherapy 
study [BRF116013, CDRB436A2102] supported the use of combination treatment in pediatric 
glioma clinical studies. Safety related changes were also implemented to include:

Requirement to obtain informed consent/assent for patients who continue treatment 
beyond progression per RANO criteria.

Added ophthalmic examinations to follow any visual changes in patients receiving 
trametinib and dabrafenib combination therapy.

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
Updated dose modification guidance for combination treatment.

Revised cardiac toxicity monitoring and the conditions for re-starting study treatment per 
FDA advice.
 

Updated the adverse events of special interest pertaining to dabrafenib and trametinib

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1
Background
1.1
Overview of disease pathogenesis, epidemiology and current 
treatment
1.1.1
Pathogenesis
High grade glioma (HGG) typically arises from cells within the glial lineage and are classified 
by the World Health Organization (WHO) as either grade III or IV meaning that they are highly 
aggressive tumors with characteristic pathological findings (Louis 2007). HGG include a 
variety of heterogeneous lesions with differing histologies, the most common being anaplastic 
astrocytoma (WHO Grade III) and glioblastoma multiforme (GBM; WHO grade IV). There are 
also less frequently occurring pediatric HGGs of grade III (anaplastic oligodendroglioma, 
anaplastic 
oligoastrocytoma, 
anaplastic 
ganglioglioma, 
anaplastic 
pleomorphic 
xanthoastrocytoma, and anaplastic pilocytic astrocytoma) and grade IV (giant cell glioblastoma, 
epitheloid glioblastoma and gliosarcoma).
Low grade glioma (LGG) also represents a diverse group of histologically distinct tumor types, 
including pilocytic astrocytoma, ganglioglioma, pilomyxoid astrocytoma, pleomorphic 
xanthoastrocytoma and others. They are distinguished historically from HGG generally by their 
lower apparent mitotic rates (Louis 2016, Lassaletta 2017). 
1.1.2
Epidemiology
HGGs are rare tumors in the pediatric population, and comprise approximately 8–12% of all 
primary, pediatric central nervous system (CNS) tumors (Bondy 2008; Broniscer 2006).  
Among patients 0–19 years old in the USA, the overall total incidence of HGGs (including 
anaplastic astrocytoma, anaplastic oligodendroglioma, glioblastoma, mixed glioma, and 
malignant glioma) was approximately 0.85 per 100,000 (CBTRUS 2012). Similar incidence 
estimates for pediatric HGG have been reported from the German Childhood Cancer Registry 
(Kaatsch 2001). Thus, approximately 350-400 new cases of pediatric HGG are diagnosed in 
Europe yearly (EMA 2011). Grade III tumors are believed to have a more favorable natural 
history than grade IV tumors but the impact of tumor grade on prognosis is relatively minor. 
Thus for the purposes of clinical trials there has been expert consensus that grade III and IV 
tumors should be studied together (EMA 2011).
Although LGGs are also rare pediatric tumor types, they are approximately 2 times as common 
(incidence 1.68 cases per 100,000) as HGG (CBTRUS 2015).  This is a heterogeneous group 
of tumors in children with different locations, histologic subtypes, ages at presentation, and 
clinical behavior.  Pilocytic astrocytoma is the most common histologic subtype.  Evolving 
molecular characterization of this group of tumors reveals most will have only a small number 
of mutations, and these mutations often converge on the activation of the RAS/MAPK pathway 
(Lassaletta 2017).

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1.1.3
Current Treatments and Unmet Medical Need
1.1.3.1
High Grade Glioma
Current therapies for children with HGGs are limited. The current standard of care for newly 
diagnosed children is gross total surgical resection, followed by focal irradiation to the tumor 
bed plus additional chemotherapy (MacDonald 2011). Independent of other known prognostic 
factors such as age, tumor location and histology, the extent of surgical resection is one of the 
strongest predictors of survival in children with HGG (Finlay 1995; Jones 2012). Given the 
infiltrative nature of HGGs, there is high likelihood of local recurrence. Thus for older children 
(>3 years of age), adjuvant radiotherapy to the tumor bed and surrounding margin has become 
a standard. Multi-agent chemotherapy is routinely used in conjunction with radiotherapy to treat 
children with newly diagnosed HGGs. However, while a number of trials have explored the use 
of varying agents and schedules, the toxicity is burdensome, results are contradictory and the 
exact role of chemotherapy and the true survival benefit are disputed (Fangusaro 2012; 
Broniscer 2004; Finlay 2005; EMA 2011). Among younger patients (<3 years of age), 
radiotherapy is generally not used due to its substantial neurocognitive toxicity. These patients 
are often treated with radiation sparing approaches such as chemotherapy alone (Broniscer 
2004).  Multiple trials have also been conducted in pediatric patients with HGGs utilizing 
biologic agents in combination with focal radiotherapy, but none have demonstrated a benefit 
in overall survival (OS) (MacDonald 2011).
Long-term outcomes for patients with pediatric HGGs are poor despite aggressive 
multimodality therapy and improvements in neurosurgery, radiotherapy, and chemotherapy. 
After a new diagnosis of HGG, the median duration of survival is approximately 18-24 months 
in children (Qaddoumi 2009; EMA 2011). Five-year survival outcomes range from 10 to 35% 
with the large majority of children ultimately succumbing to their disease (Broniscer 2004; 
Finlay 2005; Broniscer 2006; Cohen 2011; Wolff 2010). The majority of patients do develop 
recurrent disease and in these cases the therapeutic options are limited, with very few treatment 
options providing clinically meaningful responses. Temozolomide is most often used in the 
recurrent disease setting. However, in 5 trials evaluating temozolomide monotherapy or 
temozolomide-based combinations, the RR in recurrent or refractory, pediatric HGG ranged 
from 0-12% (Lashford 2002; Nicholson 2007; Ruggiero 2006; Warren 2012; Hummel 2013). 
A variety of targeted agents have also been evaluated in this patient population and response 
rates have been noted to be less than 10%. Given the lack of clinically meaningful activity, there 
have been no targeted agents that have been approved for patients with pediatric HGG. Due to 
the lack of an efficacious standard of care, participation in clinical trials is highly encouraged 
for these patients. 
One approach to recurrent disease has been the use of high dose chemotherapy followed by 
autologous hematopoietic stem cell rescue. This is still considered very controversial, but there 
may be a role for this strategy in a specific group of children (Guruangan 1998; Finlay 2008; 
Massimino 2010). The limitations of this strategy are significant treatment-related morbidity, 
and the fact that despite these risks, a minority of patients with HGG have long term survival. 
Studies of rational chemotherapy combinations and targeted agents in this disease setting have 
also failed to show clinical activity in pediatric HGG patients and emphasise the poor outcomes 
for this patient population. Given that refractory or recurrent pediatric HGG is a rare tumor type, 

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there is no robust and reliable prospective study to describe the natural history in a large 
population. 
A comprehensive literature review was performed by GSK/Novartis for trials that treated a 
minimum of 5 pediatric patients with recurrent or refractory HGG (Table 1-1). Trials that 
included myeloablative therapy with stem cell rescue were excluded from this review. Trials 
that did not specify low vs. high grade glioma were also excluded. Limitations of all the trials 
were limited sample size, non-randomized design, limited efficacy endpoints (response but no 
duration of response or time to event endpoint data) and a likely selection bias. It is also unclear 
how these results apply to pediatric HGG patients harbouring a BRAF V600 mutation as the 
predictive and prognostic effect of this mutation in this particular disease is unknown. These 
data demonstrate that for both chemotherapy and/or targeted agents, the response rate to second 
line therapy is typically <10%. To supplement the limited data available in the literature, GSK 
has sought the insight of clinicians with expertise in pediatric neuro-oncology. These 
consultants estimate that pediatric HGG patients who have failed frontline therapy have 
response rate of 10-12% to second line temozolomide therapy. Given the low response rates, 
they felt that there is no true standard of care in this setting.
Table 1-1
Efficacy Outcomes in Trials for Relapsed, Refractory Pediatric HGG
Agent
n
RR (%)
mPFS (m)
6m PFS (%)
OS (m)
Reference
Irinotecan
5e
3 (60)
NR
NR
NR
Turner 2002
Paclitaxel
13e
1 (8)
NR
NR
NR
Hurwitz 2001
Carboplatin
15e
0 (0)
NR
NR
NR
Gaynon 1990
Etoposide
14e
3 (21)
NR
NR
NR
Chamberlain 1997
Erlotinib
29
0 (0)
1.5
34
4.1
Geoerger 2011
Nimotuzumab
46
4 (9)
NR
NR
4.4
Bode 2007
Imatinib
40
0 (0)
NR
17.9-18.2b
NR
Pollack 2007
Bevacizumab + 
Irinotecan
15
0 (0)
4.2
41.8
Guruangan 2010
Cilengitide
24
0 (0)
0.92c
NR
NR
MacDonald 2013
Temsirolimus
6
0 (0)
2a
38%a,d
NR
Geoerger 2012
Tipifarnib
31
1 (3)
NR
NR
NR
Fouladi 2007
Temozolomide
25
3 (12)
NR
NR
4.7
Lashford 2002
Temozolomide
23
1 (4)
NR
NR
NR
Nicholson 2007
Temozolomide
24
0 (0)
3
NR
NR
Ruggiero 2006
O6-
Benzylguanine 
+Temozolomide
25
1 (4)
1.7
16
NR
Warren 2012
Temozolomide 
+Vorinostat
7
0 (0)
NR
NR
NR
Hummel 2013
Lobradimil + 
carboplatin
9
0 (0)
2.6c
NR
NR
Warren 2006
Poly-ICLC
12
1 (8)
NR
NR
NR
Hartman 2014
a.
Includes patients with HGG and diffuse pontine intrinsic glioma
b.
Six month event free survival
c.
Median time to progression
d.
mPFS at 12 weeks
e.
Trial accrued patients with refractory brain tumors of various types. The results reported are those for 
recurrent, pediatric HGG

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The European Medicines Agency (EMA) hosted a pediatric research expert meeting in 2011 
that focused on current pediatric HGG treatment modalities and research. The outcomes 
highlighted the inadequacy of current treatment options, and suggested that pediatric patients 
with relapsed, refractory, and or resistant HGGs should consider experimental treatments 
available in clinical trials. The committee minutes indicate agreement that outcomes in pediatric 
patients with HGG are generally very unfavourable with the different multi-agent chemotherapy 
regimens in current use, often with burdensome toxicity and limited benefit. For children, only 
one anticancer substance, temozolomide, is currently authorized in some jurisdictions (i.e.
European Union, EU) specifically for HGG (for use in relapsed or progressive disease). 
Although it is used in children based on adult efficacy data, its benefit in children is considered 
modest at best. Overall, the treatment of children with HGG reflects a significant unmet need, 
with almost no improvement in survival outcomes in recent years (EMA 2011).
The role of BRAF V600 mutation in the clinical behaviour of pediatric HGG has been studied 
in a large retrospective analysis of patients with available tumor tissue and known clinical 
course (Korsunov 2015).  Of the 202 patients with histological classification of pediatric HGG, 
21 of the tumors were BRAF V600 mutant. Using the pattern of DNA methylation to further 
characterize these tumors, forty of the 202 tumors were identified to have a ‘low grade glioma’ 
methylation signature and an improved clinical outcome (PFS, OS).  Seventeen of the 21 BRAF
V600 mutant tumors were also classified as ‘low grade glioma methylation signature’ and thus 
associated with a more favourable prognosis. A univariate evaluation of the patient specific data 
from this report reveals no apparent difference in PFS for tumors with BRAF V600 mutation 
relative to BRAF wildtype, while the OS of patients with the mutation appears favourable. The 
public data from this analysis does not include information on response to standard treatment 
in the second line setting. Nonetheless, the data do suggest that pediatric patients with BRAF
V600 mutant HGG may be more likely respond to conventional therapy in the second line 
setting, as their time to first progression is similar to patients with BRAF V600 wild type tumors, 
yet their OS is distinctly longer. In a recent analysis of anaplastic ganglioglioma, a subtype of 
HGG, in both pediatric and adult patients, the BRAF V600 mutation does not appear to have 
prognostic significance, while other histologic and molecular features were identified with 
potential prognostic significance (Zanello 2016). The BRAF V600 mutation was detected in 4 
of 5 (80%) of the pediatric tumor specimens and 9 of 18 adult tumor specimens (50%).  
This study will evaluate the ORR (CR+PR) in patients with relapsed or refractory BRAF V600 
mutant HGG.
1.1.3.2
Low Grade Glioma
Unlike patients with HGG, patients with LGG typically have a more protracted natural history.  
For unselected pediatric patients with LGG who could not be cured by surgical resection and 
enrolled into studies of cytotoxic chemotherapy, the 5 year PFS was 46% and OS was 89% 
(Gnekow 2017).  Treatment goals generally are to prolong overall and progression free survival 
while minimizing morbidity of treatment. Surgical removal, when practical, is often the 
treatment of choice. The extent of resection is predictive of progression free interval. Most 
patients will eventually experience progression of their disease and require post-surgical 
therapy.  Because of the typical young age of pediatric LGG patients, and the potential for long 
term neurocognitive effects of radiotherapy, post-surgical therapy often includes chemotherapy 

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with carboplatin and vincristine.  In one large study, the ORR (CR+PR) by central review was 
35% (Ater 2012) in unselected patients with LGG requiring post-operative systemic therapy 
with carboplatin and vincristine.
The BRAF V600 mutation is identified in about 17% of pediatric LGG tumors (Lassaletta 2017). 
The role of BRAF V600 mutation in the clinical course of pediatric LGG has recently been 
described. First, patients with LGG who have progressed to secondary HGG (sHGG) are more 
likely to have had BRAF V600 mutation in their LGG at initial diagnosis (Mistry 2015), and 
thus suggestive of a poor prognosis.  More recently, the molecular profile of archived diagnostic 
tumor tissues has been coupled with clinical outcomes of patients treated with standard of care.  
This analysis revealed that those patients whose tumor harbored the BRAF V600 mutation had 
worse PFS and OS (Lassaleta 2017) than those with tumors with wild type sequence at BRAF
V600. This research also revealed a lower ORR for these patients when treated with 
chemotherapy with apparent 11% PR+CR rate.  In both analyses, there was evidence of poorer 
outcomes when deletion of CDKN2A was coupled with the BRAF V600 mutation (Mistry 2015,
Lassaletta 2017, Jones 2017)).
Pediatric patients with LGG harboring a BRAF V600 mutation have a poorer prognosis than 
those without this mutation, and require improved treatment options.
1.2
Introduction to investigational treatment(s) and other study 
treatment(s)
1.2.1
Overview of Dabrafenib
Dabrafenib is a potent and selective inhibitor of BRAF kinase (a member of the RAF kinases) 
with a mode of action consistent with adenosine triphosphate-competitive inhibition. 
Dabrafenib suppresses ERK [pERK] that is downstream of BRAF in the MAPK pathway and 
demonstrated anti-proliferative activity against multiple BRAF V600 mutation-positive tumor 
cell lines, and tumor regression in BRAF mutation positive xenograft models, and has 
demonstrated significant anti-tumor efficacy in BRAF V600-mutation positive tumors, 
including melanoma, and non-small cell lung cancer.
Dabrafenib (Tafinlar®) was first approved by the FDA on 29 May 2013 as a single-agent oral 
treatment for unresectable or metastatic melanoma in adult patients with the BRAF V600E 
mutation. Tafinlar® is currently also approved in the, EU, Switzerland, Canada, Australia and 
multiple other countries for the treatment of adult patients with unresectable or metastatic 
melanoma with a BRAF V600 mutation. Prior to initiation of dabrafenib patients must have 
confirmation of tumor BRAF V600 mutation. These approvals include the following limitation 
of use: dabrafenib is not indicated for the treatment of wild-type BRAF melanoma. The 
recommended dose of dabrafenib is 150 mg (two 75 mg capsules) BID (corresponding to a total 
daily dose of 300 mg). Dabrafenib in combination with trametinib is also approved in the US 
and EU for the treatment of patients with advanced non-small cell lung cancer (NSCLC) with 
a BRAF V600 mutation.
1.2.1.1
Non-clinical experience
The toxicologic effects following administration of dabrafenib to rats, mice and/or dogs were 
noted in skin, heart, vasculature, testes, epithelium, hematologic/lymphoid tissues, liver, 

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gastrointestinal and respiratory tract.  The principal dose-limiting toxicity in animals was 
adverse gastrointestinal effects, which can be clinically monitored.  Aside from mild to 
moderate increases in heart rate, there were no significant findings in safety pharmacology 
studies in animals evaluating the cardiovascular and respiratory systems and in a general 
behavioral study conducted with dabrafenib. In a dabrafenib and trametinib 4-week 
combination study in dogs, there were no significant new findings or exacerbations of toxicities 
previously observed with either agent alone. Details of non-clinical experience can be found in 
the [Dabrafenib Investigators Brochure].
In support of clinical development in pediatric cancer patients, toxicity studies in juvenile rats 
with dabrafenib were conducted. These studies included an oral tolerability/dose range juvenile 
toxicity study, a GLP juvenile toxicity study, and an oral investigative renal study. Key findings 
from these studies are presented below. No further nonclinical studies are planned.
Renal Effects 
Renal toxicity was observed primarily in pre-weaning juvenile rats (PND 7-21) which was not 
previously observed in adult rats, dogs or mice. Renal findings were partially reversible 
following a 6-week off-drug period and were consistent with an obstructive nephropathy 
characterised by tubular deposits, increased incidence of cortical cysts and tubular basophilia 
with reversible increases in serum urea and/or creatinine concentrations. The renal tubular 
deposits were found to contain calcium, phosphate, potassium and lipids; dabrafenib-related 
material was not present in the deposits. These effects were seen in juvenile rats at a renal 
functional maturity stage similar to a 6 to 12 month old human, suggesting a higher risk for 
tubular injury for human infants <1 years of age. Monitoring for potential renal effects will be 
performed in pediatric patients by monitoring of serum creatinine evaluations and urinalysis.  
Patients in clinical studies [BRF116013, CDRB436A2102] (Phase I/IIa) and [BRF116536, 
CDRB436G2201] (Phase II) must be ≥1 year old to participate.
Constitutional and Developmental Effects 
In juvenile rat toxicity studies of dabrafenib monotherapy, there were dose-dependent decreases 
in body weight and/or gain, food consumption and long bone growth. These changes in bone 
growth were likely related to overall growth of the animal and not due to a bone specific effect 
of dabrafenib. Pediatric patients will be monitored for potential effects on body weight and 
growth through physical examination including routine monitoring of height and weight.
Fertility In testes 
Testicular toxicity in the seminiferous tubules was observed with evidence of partial recovery 
after a 12-week recovery period in rats, suggesting a potential human risk for impaired 
spermatogenesis, which may be irreversible. 
Non-clinical pharmacokinetics and metabolism
Dabrafenib induces CYP3A4- and CYP2C9- mediated metabolism and may induce other 
enzymes including CYP2B6, CYP2C8, CYP2C19 and UDP glucuronosyltransferases (UGT). 
Dabrafenib may also induce transporters (e.g. P-glycoprotein (P-gp)). In human hepatocytes, 
dabrafenib produced dose-dependent increases in CYP2B6 and CYP3A4 mRNA levels up to 

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32 times the control levels and was shown to be an inducer of CYP3A4 and CYP2C9 in vivo. 
Human liver microsome studies suggest that CYP2C8 and CYP3A4 are the primary CYP 
enzymes involved in the oxidative metabolism of dabrafenib in vitro while its metabolites
hydroxy-dabrafenib and desmethyl-dabrafenib are CYP3A4 substrates.
Dabrafenib is a highly permeable molecule which distributes widely into tissues and is mostly 
eliminated by 3 days post administration. No brain penetration of drug-related material was 
observed after a single dose in rats and pigs (repeat dose studies were not conducted in these 
species); however, following repeat dosing in mice, low levels of dabrafenib may reside in the 
cerebro spinal fluid.
For more details please refer to the latest [Dabrafenib Investigator Brochure].
1.2.1.2
Clinical experience
As of 22 June 2017, approximately 10,000 patients, primarily with BRAF V600-mutated cancer,
have received dabrafenib alone or in combination with trametinib across the clinical 
development program. Cumulative postmarketing exposure to dabrafenib through 31 March 
2015 is estimated to be 3,546.16 patient-years. The estimated exposure from June 2015 to June 
2016 was approximately 5204.45 patient-years [Dabrafenib Investigator Brochure].
Updated safety data from an integrated safety population (N=586) receiving 150 mg BID 
showed that 97% had experienced AEs, the most common (≥20%) being hyperkeratosis, 
headache, pyrexia, arthralgia, fatigue, nausea, alopecia, skin papilloma, and rash.  A total of 
174 (30%) patients experienced serious adverse events (SAE), and 114 (19%) patients had 
treatment-related SAEs. The proportion of patients who experienced AEs leading to 
discontinuation of study treatment was low (3%).
In the pivotal Phase III study [BRF113683, BREAK-3, CDRB436A2301], dabrafenib was 
associated with a 70% reduction in the risk of progression or death compared with dacarbazine 
with a hazard ratio (HR) of 0.30 (95% CI: 0.18, 0.51; p<0.0001) in patients with BRAF V600E 
mutation positive melanoma and no brain metastases (Hauschild 2012). Dabrafenib provided a 
clear and meaningful benefit in patients with BRAF V600E mutation-positive melanoma with 
brain metastases as demonstrated by overall intracranial response rate (OIRR) over 30% and 
median OS exceeding 7 months in study [BRF113929, BREAK-MB].  Patients with BRAF
V600E mutation positive melanoma also benefit from dabrafenib treatment, with a confirmed 
response rate of 13% and the median duration of response of 5.3 months [BRF113710, BREAK-
2, CDRB436A2201]. For the latest summarized efficacy results for these studies, please refer 
to the Dabrafenib approved local prescribing information and [Dabrafenib Investigator 
Brochure].
1.2.1.2.1 Dabrafenib pediatric experience
A Phase I clinical trial of dabrafenib is ongoing in children with BRAF V600 mutant solid 
tumors [BRF116013, CDRB436A2102].
Eighty patients have been enrolled into study [BRF116013, CDRB436A2102] beginning in 
April 2013 through the interim data cut off 12-Sept-2017; 27 into part 1 dose finding across 4 
dose levels, and 53 into part 2 (disease specific cohort expansions) at the recommended phase 
2 dose.  Thirty-two patients with relapsed refractory LGG, 31 with relapsed refractory HGG, 

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13 with advanced Langerhans Cell Histiocytosis (LCH) and 4 other solid tumor patients were
enrolled into the various parts of the study.
Part 1 patients had a median age of 8 years, while part 2 patients had a median age of 11 years.
All were previously treated for their tumor. Similar to the experience in adults, a maximally 
tolerated dose was not identified in this study.  Based on the doses in part 1 that achieved target 
exposures (median AUCs 0-12 hours > 4000 ng*hr/mL, parent molecule), there are currently 
separate phase II dose recommendations for those under 12 years of age (5.25mg/kg/day), and 
those 12 and older (4.5mg/kg/day). 
At the time of interim data cutoff, 45 of the 80 patients remained on study (56%), with 35 still 
on protocol therapy (44%).  
Efficacy for glioma patients was determined using RANO criteria by investigators, as well as 
by an independent pediatric neuro-radiologist. Independent expert histopathology review of 
tumor specimens from the patients enrolled with presumed HGG was performed in all cases 
where tissue was available. Safety monitoring included standard clinical trial methods, as well 
as routine echocardiograms and dermatologic exams.
Efficacy Results
High Grade Glioma
Of the 31 enrolled HGG patients, 10 (32%) had investigator confirmed responses (CR + PR)
following dabrafenib monotherapy. Independent radiologic determination of RANO response 
identified 14 patients (45%) with confirmed responses (CR+PR).  Median duration of treatment 
was 24 weeks, and median duration of response was 33 weeks.  Independent histopathology 
revealed that 7 of the 31 patients (23%) had grade 1 or 2 gliomas in the submitted tumor 
specimen. Four additional patients did not have sufficient tissue submitted to make any 
determination of glioma grade. The therapy has been generally well tolerated and adverse events 
easily managed.  
Low Grade Glioma
At the time of interim analysis, 32 pediatric patients with relapsed, refractory or progressive 
LGG with BRAF V600 mutations were enrolled into [BRF116013, CDRB436A2102]. Of these,
there was one independently confirmed CR, and 13 PRs for an ORR of 14/32 or 44%. In 
addition, 11 patients had independently confirmed SD.  Median duration of treatment was 24 
months.  Median duration of independently confirmed response was 110 weeks.
Langerhans Cell Histiocytosis
At the time of interim analysis, 13 pediatric patients with previously treated severe LCH and 
BRAF V600 mutations were enrolled into [BRF116013, CDRB436A2102]. Investigator 
assessed responses were 5 complete resolutions, and 5 regressions.  Median duration of 
treatment was 76 weeks.  Nine patients remain in response.
Other solid tumors
Four patients with other solid tumors and BRAF V600 mutations were enrolled; three 
discontinued within 16 weeks of enrollment (2 with Neuroblastoma, another with a sarcoma).  

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One patient with BRAF V600 mutant papillary thyroid cancer has stable disease and continues 
therapy at almost 4 years.
Safety Results
Adverse events
The four most common AEs occurring in pediatric patients with advanced BRAF V600 mutation 
positive solid tumors treated with dabrafenib were pyrexia, vomiting, fatigue and rash. 
Serious Adverse Events 
As of the clinical cut-off date for [BRF116013, CDRB436A2102], a single fatal SAE of 
depressed level of consciousness was reported in one subject at 5.25 mg/kg/day dose in Part 1.
This event was associated with disease progression, and was considered not related to study 
drug.
At the time of the interim analysis, 31 of the 80 enrolled patients (39%) were reported to have
SAEs. The most common SAEs were pyrexia (11), pneumonia (4) and headache (4); all other 
SAEs occurred in one or two patients.
Dose limiting toxicity
There was one patient with LGG (10 years old at 4.5 mg/kg/d dose) who experienced a dose 
limiting toxicity (DLT) of Grade 3 maculopapular rash with onset on day 1 of dosing. After 
protocol specified dose interruption, the patient was able to resume treatment at 3.75 mg/kg/day 
and continues on treatment beyond one year, with tolerable skin toxicity of grade ≤2. 
Dose modifications
Forty four of the 80 patients (55%) had at least one dose interruption due to AEs while on study.  
Discontinuations for toxicity
At the time of interim analysis, 6 patients had been withdrawn from study for toxicity.  
Safety Conclusions
Based on the interim analysis of the dabrafenib monotherapy study, the toxicity profile observed 
in pediatric patients is generally similar to that observed in the adult patient experience. Both 
populations experienced frequent rash, pyrexia, fatigue, arthralgia and headache. The frequency 
of rash and related adverse events may be higher in this pediatric population than in adults.  
There were three patients (4%) with grade 3 rash in the pediatric study, while there were no 
patients with Grade ≥3 rash in the integrated safety population (n=586) in adults.  Rash 
management guidelines suggested in the protocol were followed for patients with rash as they 
remained on therapy. There were no cases of cutaneous SCC observed in these pediatric patients.
The most common AEs according to the system organ class was skin. Adequate exposures were 
obtained without reaching a maximally tolerated dose. 

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1.2.1.3
Pharmacokinetics - Dabrafenib
In adults following oral administration of dabrafenib HPMC capsules, the plasma 
concentrations of dabrafenib peaked approximately 2 hours post-dose and decreased thereafter 
following a bi-exponential decline. The terminal half-life (t1/2) is 8.4 hours, mainly due to a 
prolonged terminal phase after oral administration. The t1/2 following IV microdose is 2.6 
hours.
Increases in maximum observed concentration (Cmax) and area under the concentration time 
curve (AUC) were generally dose-proportional with single doses and less than dose 
proportional after repeat BID dosing. Following administration of 150 mg BID, the AUC on 
Day 18 was 27% lower than on Day 1. Following administration of 150 mg BID (HPMC 
capsules), the geometric mean Cmax, AUC(0-τ) and predose concentration (Cτ) were 1478 
ng/mL, 4341 ng*hr/mL and 26.1 ng/mL, respectively. Interpatient variability was 37- 38% for 
Cmax and AUC(0-τ) and 119% for Cτ. Administration of dabrafenib with food reduced the 
bioavailability (Cmax and AUC decreased by 51 % and 31 % respectively) and delayed the 
absorption of dabrafenib capsules when compared to the fasted state. Dabrafenib should be 
taken either at least one hour before, or at least two hours after a meal.
The relative bioavailability of single dose dabrafenib was slightly lower (AUC decreased by 
20%) when administered as an oral suspension (dispersible tablets) compared to HPMC 
capsules. This difference in AUC is not considered clinically relevant based on the exposure-
response relationship in adult melanoma and therefore no dose adjustment will be made for the 
dispersible tablets in this study.
Results of a population pharmacokinetic analysis in adults indicated that body weight is a 
significant predictor of oral clearance and apparent volume of distribution for dabrafenib, with 
higher weight being associated with higher clearance and lower plasma concentrations; 
however this does not appear to have a clinically relevant effect on exposure. The range of body 
weights of patients included in the population PK analysis was 36 to 150 kg. Dabrafenib 
apparent oral clearance and apparent volume of distribution were predicted in a typical adult 
patient with low (50 kg) or high (140 kg) body weight and were shown to be within 20% of the 
value of a typical 80 kg patient. This difference was not considered clinically relevant.
Studies demonstrated that the oxidative metabolism of dabrafenib is primarily mediated by 
CYP2C8 and CYP3A4. Dabrafenib is metabolized sequentially to three known metabolites: 
hydroxy-dabrafenib (GSK2285403, M7), carboxy-dabrafenib (GSK2298683, M4), and 
desmethyl-dabrafenib (GSK2167542, M8). Plasma concentrations of hydroxy-dabrafenib peak 
at about 4 hours post-dose, and exposure of the metabolite is similar to that of parent with a 
metabolite:parent AUC ratio of 0.9, with a similar half-life (9.7 hrs). Carboxy- and desmethyl-
dabrafenib accumulates with repeat dosing due to their long half-life (21-22 hrs). Metabolite to 
parent AUC ratios after repeat-dose administration of dabrafenib 150 mg BID are 11.2 and 0.7 
for carboxy-, and desmethyl-dabrafenib, respectively. The preclinical activities of dabrafenib 3 
metabolites have been characterized in multiple studies and compared to dabrafenib. Based on 
exposure, relative potency, and pharmacokinetic properties, both hydroxy- and desmethyl-
dabrafenib are likely to contribute to the clinical activity of dabrafenib; while the activity of 
carboxy-dabrafenib is not likely to be significant.

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Preliminary pharmacokinetic results from study BRF116013 (CDRB436A2102) in pediatric 
patients are summarized in Table 1-2 as doses of 3, 3.75, 4.5 and 5.25 mg/kg/day (divided into 
two daily doses) based on the data cut-off date of 7 March 2015.
Results from Table 1-2 show that median plasma AUC achieved its target (between 95%CI: 
3599, 5235 ng*h/mL, which is from the adult Phase III study BRF113683) in older pediatric 
patients (> 12 years) at 4.5 mg/kg/day dose level. In younger patients (≤ 12 years), target median 
was achieved at 5.25 mg/kg/day, while the median observed at 4.5 mg/kg/day was below the 
target. These results were used to determine the recommended part 2 dose (s) in BRF116013.
Since Part 2 dose selection, an interim analysis was performed based on a data cut-off of 01-
April-2016. Results from Table 1-3 show that for patients 6 years and greater  after 
administration of the dosing regimen selected in Part 1: the geometric mean AUC(0-tau) in Part 
2 are within the exposure range associated with efficacy in adults when given as monotherapy 
(BRF113683) and in combination therapy with trametinib (BRF113220 and MEK115306). 
Table 1-2
Median Steady-State Dabrafenib AUC (ng*h/mL) (day 15) by Dose and 
Age Cohorts
Age cohort
Dabrafenib dose cohort (total daily dose)
3 mg/kg/day
3.75 mg/kg/day
4.5 mg/kg/day
5.25 
mg/kg/day
All AUC, ng*h/mL (n)
2911 (3)
3389 (10)
3903 (9)
4384 (5)
≤ 12 years
2269 (2)
2928 (4)
3592 (6)
4384 (5)
>12 years
6604 (1)
3850 (6)
5285 (3)
NA
Table 1-3
Geometric mean Steady-State Dabrafenib AUC(ng*h/mL) (day 15) by 
Age groups for Part 2
Age Range
Dose 
N
AUC(0-tau)* (ng*hr/mL)
12-17 years
4.5 mg/kg/day
15
3979
6-<12 years
5.25 mg/kg/day
8
3972
In study [MEK116540, CTMT212X2101], four pediatric patients were dosed with the 
recommended dabrafenib doses from study BRF116013 and the recommended dose for 
trametinib (from Part A MEK116540) in combination. Preliminary PK was available in 3 
subjects; dabrafenib Day 15 AUC(0-tau) values (3490, 4339, 3570 ng*hr/mL) were within the 
range observed in the pediatric patients from the dabrafenib monotherapy study BRF116013.
1.2.2
Overview of Trametinib
Trametinib (GSK1120212/TMT212) is a MEK1 and MEK2 inhibitor with selective anti-
proliferative activity towards BRAF and RAS mutant cancer cell lines and hematopoietic cancer 
cells from acute myeloid leukemia (AML) and chronic myeloid leukemia (CML) origins. 
Trametinib inhibited the proliferation of most BRAF mutant melanoma cell lines tested (22 of 
25) and it effectively inhibited the growth of BRAF mutant melanoma xenografts in vivo alone 
or in combination with dabrafenib. Trametinib inhibits ERK phosphorylation leading to G1 cell 
cycle arrest and tumor xenograft growth inhibition in vivo following oral dosing. The effects of 
trametinib in combination with dabrafenib and other anticancer agents have also been studied 
in a variety of human cancer cell lines and in vivo models.

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Trametinib is being developed for the treatment of a variety of cancers and is currently approved:

In the United States, EU, and other countries as a monotherapy and in combination with 
dabrafenib for the treatment of subjects with unresectable or metastatic melanoma with a 
BRAF V600 mutation 

In the United States and other countries in combination with dabrafenib for the adjuvant 
treatment of patients with melanoma with a BRAF V600 mutation and involvement of 
lymph node(s), following complete resection

In the United States, and EU in combination with dabrafenib for the treatment of patients 
with advanced non-small cell lung cancer (NSCLC) with a BRAF V600 mutation 

In the United States in combination with dabrafenib for the treatment of patients with 
locally advanced or metastatic anaplastic thyroid cancer with BRAF V600E mutation and 
with no satisfactory locoregional treatment options
Please refer to local labeling for further details on approved indications.
1.2.2.1
Non-clinical experience
The nonclinical toxicology findings associated with trametinib administration to mice, rats and 
dogs are consistent with pharmacologically mediated changes as a result of MEK1/MEK2 
inhibition and disruption of mitogen-activated protein kinase (MAPK) signaling pathways. 
Trametinib caused adverse effects in a variety of tissues and systems (skin, gastrointestinal tract, 
phosphate homeostasis, liver, ovary, bone and hematological tissues). The majority of the 
findings in mice and dogs appeared to be related to effects within the gastrointestinal tract. In 
rats, tolerability was more dependent on changes occurring in skin over time and its effect on 
impaired barrier function. These findings may be related to those seen in the clinic in the form 
of skin rashes and diarrhea. Rats were more sensitive to trametinib, with liver, phosphate 
homeostasis, soft tissue mineralization, bone, hematopoietic and ovary effects. In a dabrafenib 
and trametinib 4 week combination study in dogs, there were no significant new findings or 
exacerbations of toxicities previously observed with either agent alone.
Trametinib may impair female fertility based on the reduction of corpora lutea in rats. There 
were no effects on male reproductive organs in toxicology studies in rats or dogs, indicating 
that trametinib is unlikely to affect male fertility. In embryo fetal development studies, maternal 
toxicity and developmental toxicity, including total loss of pregnancy and post-implantation 
loss, were observed in rats and/or rabbits. 
The principal effects of trametinib in juvenile rats were on growth (bodyweight and long bone 
length) and in bone, phosphate homeostasis, eye, skin, liver, heart and female reproductive 
system effects, consisting of a delay in a physical landmark of sexual maturity and mammary 
gland development, lower corpora lutea and lower ovarian weights. With the exception of 
corneal mineralization/dystrophy and increased heart weight, similar effects have been 
observed in adult animals given trametinib. 
The genotoxicity assessments conducted indicate that trametinib does not present a genotoxic 
hazard to humans.
Trametinib was phototoxic in the in vitro mouse fibroblast 3T3-Neutral Red Uptake (3T3-NRU) 
assay at significantly higher concentrations than clinical exposures.

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The principal dose limiting nonclinical toxicology findings associated with trametinib treatment 
were either directly or indirectly associated with its pharmacologic activity. Administration of 
trametinib to mice, rats and dogs produced dose-dependent effects related to inhibition of cell 
proliferation in tissues with high proliferative rates including hematopoietic, gastrointestinal 
and integument systems. These findings are associated with inhibitory pharmacology due to the 
role of the MAPK pathway in cellular proliferation (Sebolt-Leopold 2000). In mice, rats and 
dogs, these effects generally occurred at or below the exposures achieved at the oral therapeutic 
dose of 2 mg/day in cancer patients. Other findings include effects on phosphate homeostasis 
and soft tissue mineralization, liver, bone, ovary and the developing embryo or fetus.
1.2.2.2
Clinical experience
As of 22-Jun-2017, approximately 1632 patients have been treated with trametinib
monotherapy across 25 clinical studies.
Data from a Phase I, II and III studies indicate substantial clinical activity of trametinib in 
unresectable, BRAF mutation positive melanoma. Efficacy results from the pivotal Phase III 
study MEK114267 (CTMT212A2301) (melanoma) study and the supporting studies 
MEK113583 (melanoma), MEK111054 (solid tumors or lymphoma), and MEK114653 
(NSCLC) indicated:

Substantial evidence of effectiveness in unresectable BRAF V600 mutation positive 
melanoma as evidenced by prolongation of progression-free survival (PFS) and overall 
survival (OS). Updated long term results from MEK114267 (CTMT212A2301) study also 
consolidated the OS benefit of trametinib treatment over chemotherapy in this patient 
population.

The clinical activity of trametinib observed in melanoma subjects whose tumors harbor 
BRAF V600K mutations is comparable to the activity seen in BRAF V600E mutations. 

The efficacy of trametinib in melanoma was evident across all demographic (i.e., age, 
gender) and prognostic factors (i.e., tumor stage, Eastern Cooperative Oncology Group 
Performance Status [ECOG PS], lactate dehydrogenase (LDH) levels, history of brain 
metastases).
In the 11 monotherapy studies of trametinib for which data are available, 50% to 100% of all 
subjects in any dose group had at least 1 AE, and 0% to 70% of all subjects in any dose group 
had at least 1 serious adverse event (SAE). Of the studies with discontinuations or withdrawals, 
3% to 26% of subjects receiving trametinib permanently discontinued study treatment or 
withdrew due to AEs.
In the 2.0 mg dose group across all completed monotherapy studies with AEs, the most common 
AEs were rash, diarrhea, fatigue, edema peripheral, nausea, dermatitis acneiform, vomiting, 
constipation, anemia, pruritus, alopecia, hypertension, decreased appetite, dyspnea and dry skin.
For more details please refer to the latest [Trametinib Investigator Brochure].
1.2.2.2.1 Trametinib pediatric experience
Study [MEK116540, CTMT212X2101] is an ongoing study of trametinib monotherapy, 
including dose finding, age specific cohort expansions, disease specific cohort expansions, as 

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well as combination dabrafenib and trametinib dose finding and disease specific cohort 
expansions.
The recommended phase 2 dose (RP2D) for trametinib monotherapy is 0.025 mg/kg/day (not 
to exceed adult dose) for patients 6 years old and above and is equivalent to the 2 mg/day dose 
for an average 80 kg adult. This dose was the highest tolerated dose tested in this age group, 
with 0.04mg/kg/day dosing resulting in unacceptable skin toxicity across each age category.  
Twelve patients under 6 years of age were treated with an intermediate dose of 0.032 mg/kg/day 
to determine tolerability and in an effort to achieve suitable exposures in this age group.  
Preliminary data are available.  During the 28 day dose limiting toxicity (DLT) period, there 
were no DLTs, no dose adjustments, and no SAEs.  Interruption of dosing due to adverse events 
occurred in 2 patients, each after about 25 weeks of treatment. 
The RP2D for the combination of dabrafenib with trametinib is 100% of dabrafenib with 100% 
of trametinib.  Evaluation of the combination in patients under 6 years of age (N=3, July 2018) 
reveals that 100% of each monotherapy dose is tolerated, with no DLTs, dose adjustments, nor 
SAEs reported in this group.
Results from an interim analysis with data cutoff date of 19-Sept-2017 are available.  From 
January 2015 to the data cutoff date, 90 patients have enrolled into this multipart study. Forty 
patients enrolled into part A across 4 trametinib monotherapy dose levels. Thirty eight patients 
enrolled into part B disease specific cohorts (Part B1, Neuroblastoma; part B2, LGG with fusion; 
Part B3, NF1 with plexiform neurofibromas (NF1 with PN); and part B4, solid tumors with 
BRAF V600 mutation – all of which had LGG) and were treated with the RP2D of trametinib 
monotherapy.  In addition, 12 patients were enrolled into two dose level cohorts of combination 
therapy, dabrafenib (50% of RP2D (n=3) or 100% of RP2D (n=9)) combined with trametinib
(100% of RP2D). Across parts A and B, there were 26 patients with NF1 and PN, 23 patients 
known to have LGG with BRAF fusion, 12 known to have LGG with BRAF V600 mutation, 
and 9 with neuroblastoma.  All were previously treated for their tumor. At the time of interim 
data cutoff, 55 of the 90 patients (61%) were still on protocol therapy.
Efficacy for glioma patients was determined using RANO criteria by investigators, as well as 
by an independent pediatric neuro-radiologist. Efficacy for NF1 patients with PN was reported 
by investigators as RECIST, the volumetric approach, or both. Independent determination of 
efficacy using the volumetric approach was also reported. Safety monitoring included standard 
clinical trial methods, as well as routine echocardiograms, ophthalmologic exams, and 
dermatologic exams.
Neurofibromatosis 1 with plexiform neurofibromas (NF1 with PN)
There were 26 patients with NF1 with PN enrolled into several dose levels in part A and at 
RP2D in part B. Independent response determination using the volumetric approach yielded 12 
partial responses (46%), 9 SD and 1 PD, and 4 unknown or too soon to determine.  At the time 
of data cutoff, 20 of 27 patients remained on treatment with a median duration of 61 weeks. 
Low Grade Glioma with BRAF fusion
There were 23 patients with LGG and a known fusion involving the BRAF gene, across parts A 
and B. At data cutoff, 15 (65%) patients remained on treatment with minimum follow up of at 

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least one year.  Independent response determination was performed using RANO. One patient 
(4%) had confirmed PR as best response, 18 (78%) had stable disease and four were not 
evaluable.  None had a best response of progressive disease.  
Low Grade Glioma with BRAF V600 mutation
There were 12 patients with LGG and known BRAF V600 mutation, across parts A and B.  
Independent response determination was performed using RANO. Two patients (17%) had 
confirmed PR as best response, 6 (50%) had SD, while 4 (33%) had PD within 16 weeks’ time.
Neuroblastoma
There were 9 patients with neuroblastoma enrolled.  One has remained on treatment beyond 
one year; the others have withdrawn from treatment within three months’ time.
Trametinib monotherapy
Adverse events occurring at the RP2D can be described among the 38 patients from part B 
disease cohort expansion. The median duration of treatment is 55 weeks with 26 (68%) still on 
treatment.  The most common AEs experienced with trametinib monotherapy from part B on 
this study have been diarrhea 53%, dry skin 42%, pyrexia 40%, anemia (37%), vomiting (34%), 
alopecia (32%), and paronychia (32%).  Treatment related AEs leading to discontinuation 
occurred in 5 (13%) patients; 14 (37%) patients required some dose adjustment or interruption 
for AEs.  Five patients experienced at least one treatment related serious adverse event, with no 
event reported more than once.  There were no on-study deaths. Adverse events of special 
interest were collected, regardless of study drug relationship. Thirty-one (82%) patients had 
skin related toxicity, 20 (53%) had diarrhea, 15 (40%) had pyrexia, 13 (34%) had hepatic events, 
12 (32%) had hypersensitivity, and 11 (29%) had bleeding events.  4 (11%) patients had ocular 
events. All but 2 events were grade 2 or less (one each of hepatic disorder, hypersensitivity).
Safety conclusions
The safety of trametinib monotherapy has previously been described in the adult population, 
and in pediatric patients in the ongoing study [MEK116540, CTMT212X2101].  Most patients 
experienced skin related toxicity, as well as diarrhea, pyrexia, anemia, vomiting, and alopecia.  
Thirty-seven percent required some form of dose adjustment or interruption due to toxicity.  
Most patients remain on treatment more than one year since starting therapy.  Treatment with 
trametinib monotherapy is manageable following protocol described treatment and dose 
modification for toxicity.
1.2.2.3
Pharmacokinetics - Trametinib 
Trametinib pharmacokinetic (PK) parameters in adults were determined after single and repeat 
dose oral administration. Trametinib was absorbed rapidly, requiring 1.5 hr to reach the 
maximum concentration (Tmax) after single oral administration under fasting conditions
[MEK113709]. The absolute oral bioavailability of a single trametinib 2 mg tablet is moderate 
to high (72%) relative to a co-administered intravenous microdose
[MEK116540, 
CTMT212X2101]. Single-dose administration of trametinib with a high-fat, high-calorie meal 
resulted in a 70% decrease in maximum observed concentration (Cmax) and a 10% decrease in 

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area under the concentration-time curve from time zero (pre-dose) extrapolated to infinity 
[AUC(0-∞)] compared to fasted conditions [MEK113709]. 
Following repeat-dosing, the mean area under the concentration-time curve over the dosing 
interval (AUC0-∞) and Cmax increased in a dose proportional manner. Trametinib accumulates 
with repeat dosing, with a mean accumulation ratio at the recommended dose of 2 mg once 
daily of 5.97. Terminal half-life is 5.3 days, determined after single dose administration. Steady 
state is achieved by Day 15, with little difference in pre-dose (trough) concentration at the end 
of the dosing interval (Cτ), Cmax and AUC from time zero (pre-dose) to 24 hr AUC(0-24h)
between Day 15 and Day 21. In adults receiving trametinib 2 mg daily for 15 days (n=13) the 
geometric mean AUC(0-24h) (coefficient of variation [CV] %) was 370 (22%) ng*hr/mL, 
Cmax 22.2 (28%) ng/mL, Tmax 1.75 hr (range 1-3 hr), and Cτ12.1 (19%) ng/mL (Infante, 2012).
The oral liquid formulation (0.05 mg/mL) had similar bioavailability to the trametinib tablet 
formulation. Single dose administration of trametinib as a 2 mg oral solution compared to the 
oral tablet resulted in a 12%, 10 % and 71% increase in AUC(0-∞), AUC(0-last) and Cmax, 
respectively.
A population PK model was developed with data (n=493) combined from the FTIH study 
[MEK111054], and the Phase II and III studies in subjects with BRAF V600 mutation positive 
melanoma [MEK113583] and [MEK114267, CTMT212A2301]. Trametinib CL/F was 
estimated as 5.07 L/hr and was dependent on gender and weight. Although smaller female 
subjects will tend to have higher exposure than heavier male subjects, no dosage adjustment is 
warranted in this population.
In adults, administration of trametinib and dabrafenib in combination had no clinically relevant 
effect on the exposure of trametinib or of dabrafenib relative to single agent administration.
Preliminary trametinib PK results for the selected dose of 0.025 mg/kg/day from study 
[MEK116540, CTMT212X2101] are summarized in Table 1-4. The summary includes 6
patients with available Day 15 PK who received the combination treatment. For patients aged 
6 to 17 years, the median trametinib average concentration (Cavg) value was similar to that 
achieved in adults with melanoma that were treated with 150 mg dabrafenib BID in combination 
with trametinib 2mg QD (BRF113220 median= 13.4 ng/ml). Median Ctrough was also 
consistent between patients aged 6 to 17 years and adults in [BRF113220] (10.1 ng/mL). In 
study [BRF113220], an increase in confirmed response rate was noted in subjects that received 
dabrafenib in combination with 2mg trametinib as compared to combination with 1 mg
trametinib. 
Preliminary trametinib PK results for the selected dose of 0.032 mg/kg/day for subjects less 
than 6 years old from study [MEK116540, CTMT212X2101] are summarized in Table 1-4. The 
summary includes 3 patients with available Day 15 PK who received the combination treatment. 
Cavg for this age group was similar to that achieved in adults with melanoma at the 
recommended combination regimen [BRF113220].
Table 1-4
Median trametinib PK (day 15) by age groups
Age Range
Dose
(mg/kg/day)
N
Ctrough 
(ng/mL)
Cavg 
(ng/mL)
12-17 years
0.025
14
9.9
13.5

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Age Range
Dose
(mg/kg/day)
N
Ctrough 
(ng/mL)
Cavg 
(ng/mL)
6-<12 years
0.025
16
12.0
16.3
6-17 years
0.025
30
11.7
16.3
< 6 years
0.032
3
7.91
12.5
1.2.3
Overview of dabrafenib and trametinib combination therapy
The safety of dabrafenib and trametinib combination therapy has been evaluated in multiple 
studies of adults treated with dabrafenib 150 mg orally twice daily and trametinib 2 mg orally 
once daily. The most common adverse reactions (>20%) for dabrafenib and trametinib 
combination therapy include pyrexia, fatigue, nausea, headache, chills, diarrhea, rash, arthralgia, 
hypertension, vomiting and cough. Increased risks of intracranial and gastrointestinal 
hemorrhage are notable concerns for the combination treatment compared to dabrafenib 
monotherapy; confounding factors in these cases include brain metastasis and anticoagulant 
therapy. The safety profile of the combination of dabrafenib and trametinib in adults generally 
reflects the safety profiles of the individual agents, with adverse events that are manageable 
with appropriate intervention. Pyrexia remains the most common AE for the combination and 
hyperproliferative skin lesions including cuSCC are reduced for the combination when 
compared to dabrafenib monotherapy. 
Based on efficacy data for adults with BRAF V600 mutant metastatic melanoma or BRAF V600 
mutant NSCLC, the concomitant and more complete inhibition of the MAPK pathway at the 
level of the BRAF- and MEK- kinases provides greater anti-tumor effect than administration of 
dabrafenib alone. Additionally the combination prevents the paradoxical activation of the 
MAPK pathway in BRAF wild-type cells resulting in lower incidence of cuSCC.
Preliminary data from [MEK116540, CTMT212X2101] are available for pediatric patients
treated with the combination of dabrafenib and trametinib.  The combination was tolerated when 
dosed at 100% of recommended pediatric phase 2 dose of each agent.
1.2.3.1
Safety of dabrafenib with trametinib
Twelve patients were treated in part C dose exploration for combination therapy of dabrafenib 
with trametinib, 3 at 50% dabrafenib, and 9 at full dose dabrafenib.  Each received full dose 
trametinib.
All twelve patients had BRAF V600 mutant LGG.  Two (17%) had independently confirmed 
PR as best response, 8 (67%) had SD, and 2 (17%) had PD as best response. Eight (67%) remain 
on treatment, with median treatment duration at 41 weeks at the time of interim analysis.
The most common AEs reported, regardless of causal relationship were rash (67%), pyrexia 
(58%), diarrhea, fatigue, headache, and vomiting (each 42%). Two patients had a total of 5 
possibly related SAEs, both with ejection fraction decrease (17%) and one each with nausea, 
vomiting, and pyrexia (8%).  Dose interruptions for toxicity were required for 8 (67%) patients.  
There have been no deaths in this group.
No dose limiting toxicities were observed.  Evaluation of combination therapy in patients under 
6 years of age also demonstrates tolerability at the 100% dose of trametinib (0.032 mg/kg/day) 
together with 100% dabrafenib dose (5.25 mg/kg/day divided into two equal doses per day).

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1.2.4
Overview of carboplatin and vincristine chemotherapy
The carboplatin with vincristine chemotherapy regimen has been employed in the systemic 
treatment of pediatric patients with LGG for several decades, and continues to serve as the 
standard of care treatment in several large studies (Ater 2012, Gnekow 2017).
There are multiple treatment schedules or regimens for administering carboplatin with 
vincristine in this setting of first systemic therapy for patients with LGG.  The most widely 
utilized are those employed in the COGA9952 protocol (Ater 2012) and the SIOP-LGG-2004 
protocol (Gnekow 2017). For CDRB436G2201, the treatment regimen from COGA9952 will 
be used for those patients assigned to chemotherapy treatment in the LGG cohort.
The treatment regimen is described in detail in Section 6.1.2, and consists of 10 weeks of 
induction therapy, followed by 8 cycles of maintenance therapy. 
2
Rationale
2.1
Study rationale and purpose
The RAS/RAF/MEK/ERK pathway is a critical proliferation pathway in many human cancers. 
This pathway can be constitutively activated by alterations in specific proteins, including BRAF, 
which phosphorylates MEK on two regulatory serine residues. 
Dabrafenib is a potent and selective inhibitor of BRAF kinase activity. Excluding RAF enzymes, 
dabrafenib demonstrated IC50 values <100 nM against only 8 kinases from ~300 protein and 
lipid kinases tested.  In addition, dabrafenib suppresses phosphorylated ERK [pERK]) that is 
downstream of BRAF in the MAPK pathway and demonstrated anti-proliferative activity 
against multiple BRAF mutation positive tumor cell lines, and tumor regression in BRAF
mutation positive xenograft models.
When present, the BRAF V600 mutation appears to result in constitutive activation of the BRAF
enzyme in cancer cells regardless of tumor context, and as such, BRAF V600 mutations may be 
relevant drivers of tumor progression in other settings, including childhood cancers.  Reports 
citing the frequencies of BRAF mutations in childhood cancers are currently limited in the 
scientific literature. However, to date, BRAF V600E mutations have been positively identified 
in >10% of patients with certain types of gliomas (both low- and high-grade tumors) (Dougherty 
2010; MacConaill 2009; Schiffman 2010; Janeway 2013; Jones 2012).
Relapsed, refractory or resistant pediatric HGG lacks a standard of care. BRAF V600 mutant, 
recurrent or refractory, pediatric HGG is a rare tumor type with a dismal prognosis. Multiple 
chemotherapies and targeted agents have been studied in this setting but none have 
demonstrated clinical activity. Temozolomide has demonstrated poor expected ORR in this 
setting. The most relevant historical efficacy data for pediatric patients with relapsed, refractory, 
or progressed HGG may come from the literature (Lashford 2002). The observed response rate 
of 12% (4 PRs in 33 temozolomide treated pediatric patients) is low and is generally consistent 
with other similar studies. A more recent study of bevacizumab and irinotecan, conducted based
on demonstrated efficacy in treating adults with recurrent HGG, failed to show efficacy in 
pediatric patients with second line HGG (Gururangan 2010). Other targeted agents have also 
been studied in this disease setting but have shown a lack of efficacy (Jones 2012).  Preliminary 

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results from [BRF116013, CDRB436A2102] showed that 6 of 19 patients (31.5%) with
relapsed or refractory BRAF V600 mutant HGG and measurable disease had investigator 
confirmed responses (CRs+PRs) following dabrafenib monotherapy. These results indicate that 
dabrafenib may offer improvement in treatment outcome for these patients.
The prognostic role of BRAF V600 mutation in pediatric HGG is unclear, but available data 
suggest that BRAF V600 mutation may be prognostically favourable in pediatric HGG. For this 
reason, the historical RR in BRAF V600 mutant pediatric relapsed refractory HGG may be 
higher than that observed in unselected populations, where the RR is less than 12%. The 
combination of dabrafenib with trametinib in adults with BRAF V600 mutant melanoma,
NSCLC and other tumors have resulted in improved efficacy over dabrafenib monotherapy and 
suggests that greater efficacy may also be seen in the pediatric setting such as patients with 
relapsed refractory BRAF V600 mutant HGG. Given the high unmet medical need in pediatric 
HGG, the encouraging efficacy of dabrafenib monotherapy in pediatric patients with BRAF
V600 mutant HGG, and the improved efficacy seen in adult cancer studies upon the addition of 
trametinib to dabrafenib, the HGG cohort portion of this study aims to demonstrate the 
effectiveness of dabrafenib with trametinib in pediatric patients with BRAF V600 mutant 
relapsed refractory HGG. 
Recent analysis of tumor tissue and clinical outcomes has revealed that patients with BRAF
V600 mutant LGG represent a subgroup of patients with LGG who have a significantly worse 
prognosis, with lower ORR, shorter PFS and shorter OS (Lassaletta 2017).  While unselected 
patients with LGG requiring systemic therapy typically are adequately treated with standard of 
care chemotherapy, this group of patients with BRAF V600 mutant LGG has a need for 
improved treatment options over standard cytotoxic chemotherapy. The observed activity of 
dabrafenib monotherapy in patients with BRAF V600 mutant LGG that had failed their first 
systemic anticancer therapy (CR+PR 44%) [BRF11603, CDRB436A2102] exceeds historical 
expectations (11%) (Lassaletta 2017) for this subgroup of patients, and suggests a role for 
dabrafenib treatment in this disease. 
The LGG cohort portion of this trial will compare the relative clinical benefit of combination 
targeted therapy of dabrafenib and trametinib to carboplatin with vincristine chemotherapy. 
The decision to use systemic therapy for pediatric patients with LGG can be complex.  
Treatment is reserved for those patients who are deemed to require therapy for their disease, 
having had optimal surgical resection, where further surgical treatment would result in 
unacceptable neurologic toxicity and who will have further neurologic deterioration due to their 
disease.
Carboplatin with vincristine chemotherapy has been employed in the systemic treatment of 
pediatric patients with LGG for several decades, and has served as the standard of care treatment 
in several large studies. Toxicity in treatment with carboplatin and vincristine includes 
hematologic suppression, peripheral neurotoxicity, and significant hypersensitivity reactions. 
Median progression free survival in unselected patients undergoing their first systemic 
chemotherapy with carboplatin with vincristine was about 5 years (Ater 2012).Response rate 
(CR+PR) at the end of chemotherapy was 35% in this study.

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2.2
Rationale for the study design
CDRB436G2201 combines two pediatric glioma cohorts into a single multi-center, open-label, 
phase II study. 
The HGG cohort is a single arm study that will evaluate the effect of dabrafenib in combination 
with trametinib in children and adolescent patients with BRAF V600 mutation positive relapsed 
or refractory HGG tumors. Eligible patients must have received at least one prior standard 
therapy. Approximately 40 patients will be enrolled and treatment will continue until disease 
progression or patients are no longer receiving clinical benefit in the opinion of the investigator, 
death, or unacceptable toxicity. Patients will be followed from the first dose of study treatment 
for both efficacy and safety. Patients must have local and centrally confirmed measurable 
disease for enrolment, and efficacy will be determined using the RANO criteria by independent 
expert pediatric neuro-radiologists. After discontinuation of the study treatment, patients will 
remain on the study for follow-up assessments and collection of information on subsequent anti-
cancer treatments and survival. 
A single arm design is used in the HGG cohort for the following reasons:
1. There is no standard of care comparator available in this patient population. 
2. There is no non-standard therapy available that would offer equipoise to dabrafenib or 
dabrafenib in combination with trametinib in this setting.
3. A non-randomized approach is suitable as the study aims to demonstrate a large treatment 
effect. 
4. It is infeasible to conduct a larger statistically robust randomized controlled trial in such a 
rare tumor population.
Eligible patients must have tumors harboring the BRAF V600 mutation, as the antitumor effect 
of dabrafenib is limited to tumors with this mutation. Approximately 10% of pediatric HGGs 
will have this mutation. This enrichment of the trial population limits the participation of 
patients with BRAF V600 wild type tumors who would not be expected to respond to dabrafenib 
therapy and thus allows those patients to promptly seek alternative treatments that might be 
more beneficial to them.
Tumor response is the primary endpoint, representing an objective measurement of clinically 
relevant antitumor effect that can be ascertained in a uniform and reliable fashion. Response 
assessment will be performed using the RANO criteria. ORR is a direct measure of therapeutic 
effect and is not affected by disease natural history. ORR can also be determined relatively 
rapidly and thus early futility declared. There are extensive historical ORR data for a variety of 
salvage therapies in this patient population, including cytotoxic chemotherapies and targeted 
agents. These studies can serve as indirect comparators for the proposed study. 
BRAF V600 mutation status, tumor histopathology and grade III/IV will be centrally confirmed 
for all enrolled patients. ORR will be determined by investigator and also be assessed through
independent central review. Independent assessment of ORR will be the primary endpoint.
Central review of tumor histopathology is intended to assure consistent application of the WHO
2016 glioma classification scale. Together, these measures should allow for more reliable 
comparison to historical studies conducted to similarly rigorous standards. 

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Trametinib is added to dabrafenib in this setting in an effort to further improve the response 
rates, as well as the duration of responses that might result from targeted therapy in this 
population. Formulations of both dabrafenib and trametinib to be used in this study will be those 
already commercially available or very similar to formulations intended to be marketed in the 
future, pending successful clinical results.
The LGG cohort is a randomized comparison of dabrafenib with trametinib versus 
chemotherapy in the treatment of chemotherapy naïve patients with BRAF V600 mutant LGG 
whose tumor is unresectable and who require treatment. Eligible patients will have locally 
determined BRAF V600 mutant LGG with both local and centrally confirmed measurable 
disease. Approximately 102 patients will be randomized in a 2:1 ratio to either dabrafenib with 
trametinib or carboplatin with vincristine chemotherapy. Treatment with carboplatin plus 
vincristine will continue until completion of the prescribed chemotherapy regimen. Treatment
with dabrafenib plus trametinib will continue until disease progression or patients are no longer 
receiving clinical benefit in the opinion of the investigator, death, or unacceptable toxicity. After 
discontinuation of the study treatment, patients will remain on the study for follow-up 
assessments and collection of information on subsequent anti-cancer treatments and survival. 
A randomized comparison of the safety and efficacy of experimental targeted therapy to that of 
cytotoxic chemotherapy will provide substantial evidence upon which to base future treatment 
recommendations for this and closely related patient populations. Safety and efficacy data are 
becoming available from ongoing non-randomized clinical studies using dabrafenib with 
trametinib in pediatric patients with BRAF V600 mutant tumors.  While these data are valuable, 
the interpretation of results obtained from a non-randomized study in a molecularly defined 
subset of patients can be significantly constrained by the lack of available robust historical 
datasets upon which to compare. For example, the assumptions of relative clinical efficacy used 
to design the LGG cohort of this study are taken from a relatively small number of patients with 
molecularly selected tumors who were treated with targeted therapy for the experimental arm, 
and taken from a retrospective analysis of clinical outcomes database where there was also 
sufficient clinical tumor material available to allow molecular profiling (Lassaletta 2017) for 
the chemotherapy arm. While the data are encouraging and supportive of further exploration of 
targeted therapy in this patient subset, the data may not be sufficient to establish future treatment 
recommendations for this and closely related patient populations.  Through the use of a 
randomized comparison, the LGG cohort portion of this trial aims to prove the relative clinical 
benefit of combination targeted therapy of dabrafenib with trametinib as compared to standard 
of care cytotoxic chemotherapy. 
The primary endpoint for the LGG cohort of this study is ORR by RANO criteria as determined 
by blinded independent expert pediatric neuroradiologist central review. This independent 
reviewer will not have access to clinical data prior to making radiologic determination of 
response. This approach reduces the potential for bias regarding the treatment assignment to 
interfere with objective determination of response.
To avoid introduction of bias into the determination of progression free survival, frequent tumor 
assessments are scheduled during the first 12 months.
The study design assures a determination of clinical activity for the LGG cohort in a reasonable 
time frame. The overall sample size is sufficient to demonstrate the superiority of the 

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experimental arm over the standard chemotherapeutic arm under the assumptions of this trial 
using the response rate (CR+PR) as the primary endpoint. Additionally, the study design will 
allow for a description of the important endpoint of progression free survival in this indolent 
disease at a later time point, to supplement the ORR results. Randomization will be in a 2:1 
ratio, favoring targeted therapy, reducing the number of patients assigned to cytotoxic 
chemotherapy. Patients randomized to the chemotherapy arm will have the opportunity to 
receive experimental therapy of dabrafenib in combination with trametinib at the time of 
centrally confirmed progression of their disease on study. 
It is not feasible to blind this study for multiple reasons. The two treatment arms are very distinct 
in the route of administration, the schedule for administration, and the clinically obvious 
toxicity profiles. The necessary supportive care will also vary depending on treatment 
assignment.
2.3
Rationale for dose and regimen selection
The combination dose regimen rationale for this study was based on safety, tolerability and PK.
In Study [BRF116013, CDRB436A2102] the recommended dabrafenib monotherapy doses 
were determined based on PK as an MTD was not determined. Dabrafenib exposure associated 
with efficacy in adult studies has been well demonstrated, while an MTD has not been 
determined. The geometric mean (95% CI) dabrafenib AUC(0-12) after administration of 150
mg BID in the Phase III study [BRF113683, CDRB436A2301] (patients with BRAF mutant 
metastatic melanoma) was 4341 (3599, 5235) ng*h/mL. Therefore the exposure target range of 
~4000-5500 ng*h/mL was applied in the dose-escalation part of the pediatric Phase I study 
[BRF116013, CDRB436A2102]. 
Based on the preliminary PK data, the following doses were determined:

< 12 years old patients: 5.25 mg/kg/day dabrafenib administered orally, divided into two 
equal doses

≥12 years old patients: 4.5 mg/kg/day dabrafenib administered orally, divided into two 
equal doses
In Study [MEK116540, CTMT212X2101], three dose levels were initially tested for trametinib: 
0.0125, 0.025 and 0.04 mg/kg/day. Since the dose regimen of 0.04 mg/kg/day resulted in dose 
limiting toxicities, 0.025 mg/kg/day was selected as the recommended trametinib dose for 
patients 6 years of age and older, based on safety and tolerability. An intermediate dose of 0.032 
mg/kg/day trametinib was studied in patients under 6 years of age and was well tolerated and is 
the recommended trametinib dose for patients under 6 years of age.  
In Part C of MEK114560 the combination regimen was tested using a dose escalation scheme 
for dabrafenib: trametinib 0.025 mg/kg/day with half the recommended dabrafenib dose from 
study [BRF116013, CDRB436A2102] (dose level 1) and with 100% of the recommended 
dabrafenib dose from [BRF116013, CDRB436A2102] (dose level 2). The combination regimen 
was safe and tolerated at both dose levels.  For patients under 6 years of age a higher dose of 
0.032 mg/kg/day for trametinib in combination with 5.25 mg/kg/day dabrafenib was evaluated 
with the aim of achieving higher exposure levels than those observed at the trametinib 0.025 
mg/kg/day dose in this age group.This higher dose was safe and tolerated based on data from
three patients in Part C that received the combination regimen. 

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Based on PK data from [BRF116013, CDRB436A2102] and [MEK116540, CTMT212X2101]
at the recommended dabrafenib doses for patients ≥6 years; dabrafenib AUC(0-tau) on Day 15 
was within the exposure values associated with efficacy in adults (Section 1.2.2.1). 
Based on preliminary PK data from [MEK116540, CTMT212X2101] at the recommended
trametinib dose (0.025 mg/kg/day) for patients ≥6 years: the trametinib Cavg was greater than
10 ng/mL for 90% of patients and at the recommended dose (0.032 mg/kg/day) for patients < 6
years: the trametinib Cavg was greater than 10 ng/mL for 2 out of 3 patients (Section 1.2.2.3). 
This target concentration has been associated with higher response rate in adults receiving 
combination therapy.
Overall the PK of dabrafenib and trametinib are within the exposure ranges associated with 
efficacy in adults and the combination regimen has a manageable safety profile. Collectively 
these data support the selected dabrafenib and trametinib dose(s) for children and adolescents. 
The recommended combination dosing regimen for children and adolescents are:

Trametinib

< 6 years old: 0.032 mg/kg/day

≥6 years old: 0.025 mg/kg/day

Dabrafenib

< 12 years old: 5.25 mg/kg/day, divided into two equal doses

≥12 years old: 4.5 mg/kg/day, divided into two equal doses
Patients enrolled in this study will receive dabrafenib twice daily and trametinib once daily. The 
total daily dose of dabrafenib will not exceed 300 mg (150 mg BID) and for trametinib will not 
exceed 2 mg. Treatment will continue until disease progression or patients are no longer 
receiving clinical benefit as determined by the investigator, death or unacceptable toxicity.
2.4
Rationale for choice of combination drugs 
Not applicable.
2.5
Rationale for choice of comparators drugs
Carboplatin with vincristine chemotherapy has been employed in the systemic treatment of 
pediatric patients with LGG for several decades, and has served as the standard of care treatment 
in several large studies (Ater 2012, Gnekow 2017)
There are multiple treatment schedules or regimens for administering carboplatin with 
vincristine in this setting of first systemic therapy for patients with LGG.  The most widely 
utilized are those employed in the COGA9952 protocol (Ater 2012) and the SIOP-LGG-2004 
protocol (Gnekow 2017). For this current study, the treatment regimen from COGA9952 will 
be used for those patients assigned to chemotherapy in the LGG cohort. The treatment regimen 
includes 10 weeks of induction therapy, followed by 8 cycles of consolidation therapy.
There have been no randomized comparisons of these regimens, but they are considered 
comparable in overall outcomes.  The chosen regimen is slightly shorter in duration. This 
schedule was selected with guidance from the protocol steering committee as one that is well 
recognized and has a good benefit risk profile for this patient population.

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2.6
Risks and benefits 
Potential Risks
Based on the interim analysis of the 65 pediatric patients enrolled across four dose levels
[BRF113773, CDRB436A2101], the toxicity profile of dabrafenib is generally similar to that 
observed in the adult patient experience. Both populations experienced frequent rash, pyrexia, 
fatigue, arthralgia and headache. The frequency of rash and similar adverse events may be 
higher in this pediatric population than in adults. In contrast, there were no cases of cutaneous 
SCC observed in these pediatric patients. The most common adverse events (AEs) were in the 
Skin body system. Adequate exposures were obtained without reaching a maximally tolerated 
dose. 
Results from the ongoing [MEK116540, CTMT212X2101] study are preliminary.  Dose 
limiting toxicity was predominantly skin toxicity (rash, folliculitis). In adults in the 2.0 mg dose 
group across all completed monotherapy trametinib studies, the most common AEs were rash, 
diarrhea, fatigue, edema peripheral, nausea, dermatitis acneiform, vomiting, constipation, 
anemia, pruritus, alopecia, hypertension, decreased appetite, dyspnea and dry skin.
The combination treatment of pediatric patients at full recommended monotherapy dose of 
dabrafenib and trametinib was tested in a small (less than 10) number of patients. No DLTs 
were observed.  In adults, the safety of dabrafenib and trametinib combination therapy has been 
evaluated in multiple studies of adults treated with dabrafenib 150 mg orally twice daily and 
trametinib 2 mg orally once daily. The most common adverse reactions (>20%) for dabrafenib 
and trametinib combination therapy include pyrexia, fatigue, nausea, headache, chills, diarrhoea, 
rash, arthralgia, hypertension, vomiting and cough. The safety profile of the combination of 
dabrafenib and trametinib in adults generally reflects the safety profiles of the individual agents, 
with adverse events that are manageable with appropriate intervention. Pyrexia remains the 
most common AE for the combination and hyperproliferative skin lesions including cuSCC are 
reduced for the combination therapy when compared to dabrafenib monotherapy. 
The safety experience in the pediatric population is described in more detail in the latest 
[Investigator Brochure].
Potential Benefits
Relapsed or refractory pediatric HGG is associated with very unfortunate outcomes using 
conventional therapy, with expectations of less than 12% RR and a median survival of 5 months
for unselected patients. Interim analysis of [BRF116013, CDRB436A2102] includes
independently confirmed response rate of 45% (10/22) and manageable safety profile for 
dabrafenib monotherapy. The combination of dabrafenib with trametinib has been studied in 
adult patients with BRAF V600 mutant metastatic melanoma or NSCLC and has shown greater 
efficacy than with dabrafenib alone.  
Pediatric patients with BRAF V600 mutant LGG who progress following optimal surgical 
resection often require systemic treatment. The standard of care in this setting has been a 
regimen of carboplatin and vincristine.  Recent analysis of paired tumor molecular profiles and 
patient outcomes reveals that this standard of care may not be as effective as previously noted
in patients whose tumor carries the BRAF V600 mutation, with lower response rate, PFS and 

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OS than those without this mutation. Furthermore, in patients with BRAF V600 mutant LGG 
who have failed prior systemic chemotherapy, independently confirmed response rate (RANO, 
CR+PR) of dabrafenib monotherapy (44%) [BFR116013, CDRB436A2102] exceeds historical 
expectations (11%) (Lassaletta 2017) for this subgroup of patients. Thus, it is possible that this 
apparent improved outcome in relapsed or refractory LGG may also be seen in patients with 
BRAF V600 mutant LGG experiencing their first post-surgical progression. For the reasons 
stated previously, the addition of trametinib to dabrafenib is predicted to further improve the 
outcomes for LGG patients. Patients randomized to the chemotherapy treatment arm of the LGG 
cohort will benefit from the treatment approach that has been utilized for many years, but will 
also have the opportunity to cross over to the experimental therapy upon reaching the centrally 
confirmed progression of disease endpoint. Patients with LGG often receive substantial benefit 
from subsequent treatments, suggesting that those patients who do cross over as part of their 
study treatment, may experience benefit from that therapy. 
Overall Conclusion 
Overall, these results suggest that dabrafenib monotherapy represents a potentially favorable 
benefit risk to pediatric patients with BRAF V600 mutant relapsed refractory or progressive 
HGG and LGG, and that the addition of trametinib to this treatment may result in even greater 
response rates, with possible longer duration of responses, while maintaining a tolerable risk 
profile. For patients in the LGG cohort, a recognized standard of care treatment regimen of 
carboplatin and vincristine (Ater, 2012) will be utilized, together with the option to cross over 
to treatment with dabrafenib plus trametinib at the time of centrally confirmed disease 
progression on study. The study is designed in such a way as to reduce the overall sample size, 
including the number of patients randomized into the chemotherapy treatment arm of the LGG 
cohort, while providing a reasonable expectation of meaningful results to guide future treatment 
decisions in this molecularly selected patient populations.  Risks will also be minimized by 
compliance with the eligibility criteria and study procedures as well as close clinical monitoring, 
and interim analysis to determine early stopping for futility if sufficient clinical activity is not 
demonstrated for the HGG cohort. An independent Data Monitoring Committee (DMC) will be 
constituted and will be responsible for monitoring and reviewing clinical data for safety during 
the study. Recommended guidelines for prophylactic or supportive management of study drug 
induced adverse events are provided in Section 6.3. There may be unforeseen risks which could 
be serious. Refer to the latest [Investigator's Brochure].
3
Objectives and endpoints
Objectives and related endpoints are described in Table 3-1 below.

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Table 3-1
Objectives and related endpoints
Objective
Endpoint
Analysis
Primary
Refer to Section 10.4
HGG Cohort:
Evaluate the anti-tumor activity of dabrafenib in combination with 
trametinib, as measured by overall response rate (ORR) by 
central independent assessment using the RANO criteria.
ORR, proportion of patients with a best overall confirmed Complete 
Response (CR) or Partial Response (PR) by independent 
assessment per RANO criteria.
LGG Cohort:
Compare the anti-tumor activity of dabrafenib in combination 
with trametinib versus carboplatin with vincristine, as measured 
by overall response rate (ORR) by central independent 
assessment using the RANO criteria.
ORR, proportion of patients with a best overall confirmed Complete 
Response (CR) or Partial Response (PR) by blinded independent 
review per RANO criteria.
Secondary
Refer to Section 10.5.1
HGG Cohort:
1.
Evaluate ORR by investigator assessment  
2.
Evaluate duration of response (DOR) by investigator and 
central independent assessment
3.
Evaluate progression free survival (PFS) by investigator and 
central independent assessment
4.
Evaluate time to response (TTR) by investigator and central 
independent assessment
5.
Evaluate clinical benefit rate (CBR) by investigator and 
central independent assessment
6.
Evaluate overall survival (OS)
7.
Evaluate the safety and tolerability profile of dabrafenib in 
combination with trametinib in children and adolescents
8.
Evaluate the palatability of dabrafenib oral suspension and 
trametinib oral solution
9.
Characterize the pharmacokinetics of dabrafenib, its 
metabolites and trametinib in the study population 
1.
ORR by investigator assessment per RANO criteria
2.
DOR, calculated as the time from the date of the first 
documented confirmed response (CR or PR) to the first 
documented progression or death due to any cause, as 
assessed separately by investigator and central independent 
reviewer per RANO criteria.
3.
PFS, defined as time from first dose of study treatment to 
progression or death due to any cause, as assessed separately 
by central independent reviewer and investigator per RANO 
criteria 
4.
TTR, calculated as the time from the start date of study 
treatment to first documented confirmed response CR or PR 
(which must be confirmed subsequently) as assessed 
separately by investigator and independent central reviewer per 
RANO criteria
5.
CBR is the proportion of patients with a best overall response of 
CR or PR, or an overall lesion response of SD which lasts for a 
minimum time duration of at least 24 weeks, as assessed 
separately by investigator and central independent reviewer per 
RANO criteria.

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Objective
Endpoint
Analysis
6.
OS, defined as the time from first dose of study treatment to 
death due to any cause
7.
Incidence of adverse events and serious adverse events, 
changes in laboratory results, vital signs, ECG and ECHO.
8.
Palatability questionnaire data
9.
Plasma concentration-time profiles of dabrafenib, its 
metabolites and trametinib and PK parameters
Secondary 
Refer to Section 10.5.1
LGG Cohort:
10. Evaluate ORR of dabrafenib in combination with trametinib 
versus carboplatin with vincristine, as measured by 
investigator assessment.   
11. Evaluate the DOR of dabrafenib in combination with 
trametinib versus carboplatin with vincristine by both 
investigator and central independent assessment.
12. Evaluate PFS of dabrafenib in combination with trametinib 
versus carboplatin with vincristine, as measured by both 
investigator and central independent assessment.
13. Evaluate TTR of dabrafenib in combination with trametinib 
versus carboplatin with vincristine, as measured by both 
investigator and central independent assessment.
14. Evaluate CBR of dabrafenib in combination with trametinib 
versus carboplatin with vincristine, as measured by both 
investigator and central independent assessment
15. Evaluate OS of dabrafenib in combination with trametinib 
versus carboplatin with vincristine.
16. Evaluate 2-year OS estimate of dabrafenib in combination 
with trametinib versus carboplatin with vincristine.
17. Evaluate the safety and tolerability of dabrafenib in 
combination with trametinib versus carboplatin with 
vincristine =.
18. Evaluate the palatability of dabrafenib and trametinib 
19. Characterize the pharmacokinetics of dabrafenib, its 
metabolites and trametinib in the study population
10. ORR by investigator assessment per RANO criteria.
11. DOR, calculated as the time from the date of the first 
documented confirmed response (CR or PR) to the first 
documented progression or death due to any cause, as 
assessed separately by investigator and central independent 
reviewer per RANO criteria.
12. PFS, defined as time from date of randomization to progression 
or death due to any cause, as assessed separately by central 
independent reviewer and investigator per RANO criteria
13. TTR, calculated as the time from the date of randomization to 
first documented confirmed response CR or PR (which must be 
confirmed subsequently) as assessed separately by 
investigator and independent central reviewer per RANO 
criteria
14. CBR is the proportion of patients with a best overall response of 
CR or PR, or an overall lesion response of SD which lasts for a 
minimum time duration of at least 24 weeks, as assessed 
separately by investigator and central independent reviewer per 
RANO criteria.
15. OS, defined as the time from date of randomization to death 
due to any cause.
16. 2-year OS estimate
17. Incidence of adverse events and serious adverse events, 
changes in laboratory results, vital signs, ECG and ECHO.
18. Palatability questionnaire data

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Objective
Endpoint
Analysis
20. Assess patient reported outcomes of dabrafenib in 
combination with trametinib versus carboplatin with 
vincristine
19. Plasma concentration-time profiles of dabrafenib, its 
metabolites and trametinib and PK parameters
20. Change from baseline in PROMIS Parent Proxy scale - Global 
Health 7+2

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4
Study design
4.1
Description of study design
High Grade Glioma (HGG) Cohort
The HGG cohort is a multi-center, single arm, open-label part of this phase II study conducted 
in children and adolescent patients with BRAF mutation positive, refractory or relapsed HGG 
tumors after having received at least one previous standard therapy. 
Approximately 40 patients will be enrolled to receive dabrafenib and trametinib. 
The primary objective is to evaluate the anti-tumor activity of dabrafenib in combination with 
trametinib, as measured by ORR to study treatment by central independent assessment using 
RANO criteria in the Full Analysis Set (FAS) population. ORR as assessed by investigator, 
DOR, PFS, TTR, and CBR assessed by investigator and independent central review, OS, 
palatability and the safety and tolerability profile of dabrafenib and trametinib are secondary 
endpoints. 
A Steering Committee (SC) will be established, composed of investigators and Novartis 
personnel participating in the trial, to ensure transparent management of the study according to 
the protocol through recommending and approving modifications as outlined in Section 8.7.
A Data Monitoring Committee (DMC) will also be established for the study. The DMC will 
function independently of all other individuals associated with the conduct of this clinical trial, 
including the site investigators participating in the study. The DMC will be responsible to 
review study data from the HGG and LGG cohorts approximately every 6 months during the 
conduct of the study as outlined in Section 8.6. 
Patients in the HGG cohort may continue to receive the assigned study treatment until disease 
progression by RANO criteria or loss of clinical benefit as determined by the investigator, 
unacceptable toxicity, start of a new anti-neoplastic therapy, discontinuation at the discretion of 
the investigator or patient/legal guardian, lost to follow-up, death, or study termination by the 
sponsor.
HGG patients who have disease progression by RANO criteria may continue study treatment if 
the investigator determines that patient has clear evidence of clinical benefit from study 
treatment, continuing study treatment may be in the best interest for the patient, and the 
patient/legal guardian is willing to continue on study treatment and sign the Informed Consent 
for treatment beyond progression. The decision to continue study treatment after PD must be 
documented in the patient records and eCRF after every tumor evaluation. In this case, the 
patient will continue assessments as defined in Section 7. An End of Treatment visit will be 
performed when patients permanently discontinue study treatment. 
Patients who discontinue the study treatment without disease progression by RANO criteria 
will continue tumor assessment and safety evaluation as part of the post treatment follow-up 
outlined in Section 7, until central independently confirmed disease progression by RANO 
criteria or death irrespective of start of new anti-neoplastic therapy. 

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Patients who discontinue study treatment and efficacy follow-up, and have completed the post-
treatment skin examination will enter the post treatment survival follow-up during which 
survival data is collected every 3 months. During the survival follow-up, subsequent anti-
neoplastic therapies initiated after study treatment discontinuation will be collected. 
All patients will be followed for survival for at least 2 years after the last patient first study
treatment (except if consent is withdrawn, death, or patient is lost to follow-up or study 
discontinuation). 
An interim analysis for futility will be implemented to allow possible termination of recruitment 
of the HGG cohort in the event that there is insufficient efficacy. The patients for inclusion in 
the formal interim analysis for futility will be determined shortly after 16 HGG patients in the 
FAS have been enrolled. The interim analysis will be conducted when this initial group of 
patients in the HGG cohort included in the analysis have all had at least 20 weeks of follow-up 
or have withdrawn early. If the observed ORR in the HGG cohort assessed by central 
independent reviewer is ≤ 25%, there may be a consideration to stop the HGG cohort due to 
insufficient efficacy. The final decision on whether to stop enrollment in the HGG cohort will 
take into account all available study information at the IA cut-off including safety data and all
efficacy endpoints. Any decision to halt further enrollment into the HGG cohort will not impact 
the treatment options for patients already enrolled into this cohort. HGG patients deriving 
benefit as per investigator discretion may continue receiving dabrafenib plus trametinib 
treatment on study.
The primary analysis of the HGG cohort will be conducted based on the all treated patients 
when all HGG patients have either completed at least 32 weeks of treatment or have 
discontinued earlier. In order to evaluate response against the efficacy seen in existing Standard 
of Care (SOC) and to provide evidence that trametinib contributes to the effect of the 
combination therapy for the HGG cohort, the point estimate and exact binomial confidence 
intervals (CIs) of ORR will be provided. The lower bound of the CIs will be used to provide 
evidence that the true ORR is greater than a certain specific response rate.
Figure 4-1
Study Design for HGG Cohort

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Low Grade Glioma (LGG) Cohort
The LGG cohort is a multi-center, randomized, open-label part of this phase II study conducted 
in children and adolescent patients with BRAF mutation positive, with progressing LGG whose 
tumor is unresectable and who require treatment.
Approximately 102 patients will be randomized in a 2:1 ratio to either dabrafenib plus
trametinib or carboplatin with vincristine.
The primary objective is to compare the anti-tumor activity of dabrafenib in combination with 
trametinib versus carboplatin with vincristine, as measured by ORR by central independent 
assessment using RANO criteria in the Full Analysis Set (FAS) population. Secondary 
endpoints include ORR as assessed through investigator assessment, DOR, PFS, TTR, and CBR
assessed by both investigator and independent central review and OS. Patient reported outcomes 
from the PROMIS questionnaire, palatability, and the safety and tolerability profile of 
dabrafenib and trametinib are additional secondary endpoints. 
A Steering Committee (SC) composed of investigators and Novartis personnel participating in 
the trial will ensure transparent management of the study according to the protocol through 
recommending and approving modifications as outlined in Section 8.7.
A Data Monitoring Committee (DMC) will be established for the study. The DMC will function 
independently of all other individuals associated with the conduct of this clinical trial, including 
the site investigators participating in the study. The DMC will be responsible to review data
from the HGG and LGG cohorts approximately every 6 months during the conduct of the study 
as outlined in Section 8.6.
LGG patients receiving carboplatin with vincristine treatment will follow the regimen in 
Section 6.1.2 in conjunction with institutional practice. Duration of treatment should continue 
for the prescribed number of cycles as tolerated, or until unacceptable toxicity, start of a new 
anti-neoplastic therapy, discontinuation at the discretion of the investigator or patient/legal 
guardian, lost to follow-up, death, study termination by the sponsor, or until disease progression. 
See Section 6.3.1.16 for dose modifications and management guidelines or carboplatin with 
vincristine. Patients randomized to the carboplatin with vincristine treatment arm will only be 
allowed to cross over to receive dabrafenib in combination with trametinib after centrally 
confirmed RANO-defined disease progression. Crossover will be allowed during the treatment 
period or the post-treatment period.
LGG patients on dabrafenib with trametinib treatment may continue to receive the assigned 
study treatment until disease progression by RANO criteria or loss of clinical benefit as 
determined by the investigator, unacceptable toxicity, start of a new anti-neoplastic therapy, 
discontinuation at the discretion of the investigator or patient/legal guardian, lost to follow-up, 
death, or study termination by the sponsor.  
LGG patients receiving dabrafenib with trametinib who have disease progression by RANO 
criteria may continue study treatment if the investigator determines that patient has clear 
evidence of clinical benefit from study treatment, continuing study treatment may be in the best 
interest for the patient, and the patient/legal guardian is willing to continue on study treatment 
and sign the Informed Consent for treatment beyond progression. The decision to continue study 
treatment after PD must be documented in the patient records and eCRF after every tumor 

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evaluation. In this case, the patient will continue assessments as defined in Section 7. An End 
of Treatment visit will be performed when patients permanently discontinue study treatment.  
Patients who discontinue dabrafenib with trametinib treatment or complete carboplatin with 
vincristine treatment without disease progression by RANO criteria will continue tumor 
assessment as part of the post treatment follow-up outlined in Section 7 until central 
independently confirmed disease progression by RANO criteria or death irrespective of start of 
new anti-neoplastic therapy. 
Patients who discontinue study treatment and efficacy follow-up, and have completed the post-
treatment skin examination will enter the post treatment follow-up period during which survival 
will be collected every 3 months. During the survival follow-up, subsequent anti-neoplastic 
therapies initiated after study treatment discontinuation and response to those treatments will 
be collected. 
All patients will be followed for survival for at least 2 years after the last patient first study 
treatment (except if consent is withdrawn, death, or patient is lost to follow-up or study 
discontinuation). 
No formal interim analysis is planned for the LGG cohort.
The primary analysis will be conducted based on all treated patients when all patients have 
either completed at least 32 weeks of treatment or have discontinued earlier. 
Figure 4-2
Study Design for LGG Cohort 
4.1.1
Screening 
Pediatric patients for both cohorts will be screened for eligibility during the 28 days 
immediately prior to starting study treatment on Day 1. During this time, the inclusion and 
exclusion criteria will be assessed and all screening procedures will be performed. Results of 
all screening evaluations must be reviewed by the investigator or his/her designee prior to 
enrollment of each patient into the study to ensure all criteria have been met.  

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Eligible patients may only be included in the study after the patient or parental/legal guardian 
provides written (witnessed, where required by law or regulation) informed consent. In cases 
where the patient’s representative gives consent, the patient should be informed about the study 
to the extent possible given his/her understanding. If the patient is capable of doing so, he/she 
should indicate assent by personally signing and dating the written informed consent document 
or a separate assent form. 
As part of the screening, all patients must have available tumor samples (either formalin-fixed, 
paraffin-embedded [FFPE] blocks or slides) for central confirmation of BRAF V600 mutation 
(HGG and LGG), and for patients enrolled into the HGG cohort, for independent confirmation 
of HGG histopathology by an independent neuropathologist. The sample should be the best 
representation of the tumor and submitted for central confirmation approximately within one 
month of enrollment onto the study. Eligibility will be assessed based on local results of 
histology and BRAF V600 mutation. 
Central confirmation of baseline measurable disease by an independent radiologist will be 
required before enrollment. 
Following the completion of screening procedures and verifying patient eligibility based on 
assessments, the patient will be enrolled via the Interactive Response Technology (IRT) system. 
Please refer to and comply with detailed guidelines in the IRT manual. IRT systems will confirm 
the inclusion of eligible patients. 
4.1.2
Treatment 
The study treatment phase begins on Day 1 with the first administration of study treatment. In 
the HGG cohort, all patients will receive dabrafenib in combination with trametinib. In the LGG 
cohort, patients will be randomized 2:1 to receive dabrafenib in combination with trametinib or 
carboplatin with vincristine. 
All patients who receive dabrafenib with trametinib will take dabrafenib twice daily and 
trametinib once daily until no longer receiving clinical benefit as determined by the investigator, 
disease progression, death, unacceptable toxicity that precludes further treatment, start of new 
anticancer therapy, or study is terminated by Sponsor. 
Patients enrolled into the LGG cohort and randomized in the control arm will be administered 
carboplatin with vincristine, according to the regimen defined in Section 6.1.2. Treatment 
should continue for the prescribed number of cycles, as tolerated, or until unacceptable toxicity, 
start of a new anti-neoplastic therapy, discontinuation at the discretion of the investigator or 
patient/legal guardian, lost to follow-up, death, study is terminated by the sponsor or until 
disease progression. Patients randomized to the control arm are expected to follow protocol 
specified evaluations according to Table 7-3, including efficacy and safety assessments. 
Patients in both cohorts will be assessed at screening (within 28 days before initiation of study 
treatment) and every 8 weeks for the first year on treatment, and every 16 weeks thereafter for 
efficacy using RANO criteria. All radiological scans will be collected for independent central 
review. 
In the HGG cohort, clinical response will be monitored during the study to enable early stopping 
for futility if sufficient clinical activity is not demonstrated. After the first 16 patients have been 

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enrolled, have completed at least 20 weeks of treatment or have discontinued treatment earlier, 
an interim analysis will be conducted in order to determine whether the futility criteria have
been met. 
Safety assessments (collection of AEs, concomitant medications, laboratory parameters, 
dermatologic skin evaluations, and ophthalmologic exams) will be conducted on a continuous 
basis during the treatment phase according to Table 7-1, Table 7-2 for LGG crossover patients
or Table 7-3. 
 
 
4.1.2.1
Treatment after Progression of Disease
Patients receiving dabrafenib with trametinib are permitted to continue treatment beyond 
investigator-assessed, RANO-defined PD, as long as they meet the following criteria:

Investigator assessed clear evidence of clinical benefit 

Tolerance of study treatment

Continuation of study treatment is in the best interest of the patient as determined by the 
Investigator

Patient/legal guardian is willing to continue on the study and sign Informed Consent for 
treatment beyond progression
If the Principal Investigator determines that all above criteria are met, the patient may continue 
dabrafenib with trametinib treatment on study and follow all study related procedures, including 
tumor assessments, as scheduled in Table 7-1. After each tumor assessment, the Principal 
investigator must confirm if the patient is still benefitting from study treatment, and document 
this in patient medical records and the eCRF.
4.1.2.2
Crossover and Continuation of Treatment (LGG Cohort)
For the LGG cohort, patients randomized to the carboplatin with vincristine treatment arm will 
be allowed to crossover to receive dabrafenib in combination with trametinib treatment after 
centrally confirmed and RANO-defined disease progression. Patients who cross over are 
expected to continue to undergo protocol specified evaluations according to Table 7-2, 
including efficacy and safety assessments.
LGG patients who crossover to receive dabrafenib in combination with trametinib must 
continue to meet the inclusion criteria for cardiac function, be willing to follow all contraception 
guidance, and cannot meet the exclusion criteria for allergy to dabrafenib, trametinib, or their 
excipients. Measurable disease is not mandatory but a new baseline tumor evaluation must be 
established within 28 days of starting dabrafenib in combination with trametinib crossover 
treatment. Day 1 of crossover therapy must occur within 90 days from the date of the first 
centrally confirmed progression. After the final PFS analysis and assuming significant 
favorable ORR and favorable PFS for the experimental therapy, patients randomized to 
carboplatin plus vincristine arm with persistent stable disease and deemed suitable for further 
systemic therapy for their disease may be allowed to crossover to receive dabrafenib in 
combination with trametinib.

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PRO, taste questionnaires and pharmacokinetic samples will not be obtained on those patients 
who cross over to receive dabrafenib plus trametinib therapy. 
4.1.3
Post Treatment Follow up
After discontinuation of study treatment, all patients will be followed for safety for at least 30 
days after the last dose of study treatment except in the case of death, loss to follow-up or 
withdrawal of consent. All patients who discontinue study treatment for reasons other than 
disease progression, death, lost to follow up, or withdrawal of consent will move into Post 
Treatment Follow Up phase. 
Tumor evaluations during this period will continue as per Table 7-1, Table 7-2 or Table 7-3
until central independently confirmed disease progression by RANO criteria, withdrawal of 
consent by patient or a parental/legal guardian to tumor status follow-up, or lost to follow-up. 
Patients who start a new anti-cancer therapy prior to disease progression will continue tumor 
evaluations following the same above schedule until radiographic evidence of disease 
progression is centrally confirmed.
Skin examinations should be performed at 3 and 6 months after the last dose of study treatment
or until the start of a new anti-cancer therapy. Safety assessments including physical exams and 
growth/developmental follow up will continue according to Table 7-1, Table 7-2 or Table 7-3
and Section 7.1.6.
Patients who discontinue study treatment due to disease progression by RANO criteria that has 
been confirmed by central independent assessment, and begin new anti-cancer therapy at EOT 
will enter Survival follow-up outlined in Section 4.1.4.
4.1.4
Survival follow-up
All patients will be followed for survival once they discontinue study treatment and complete 
protocol required efficacy assessments, and the required skin evaluation per Table 7-1, Table 
7-2 for LGG crossover patients or Table 7-3. Survival follow-up assessments will be done every 
12 weeks or earlier if a survival update is required to meet safety or regulatory needs. Survival 
information can be obtained by clinical visits or telephone calls until death, the patient is lost to 
follow-up, the patient/legal guardian withdraws consent or study discontinuation. 
4.2
Timing of interim analyses and design adaptations
An interim analysis for futility will be implemented to allow possible termination of recruitment 
in the HGG cohort in the event that there is insufficient efficacy. The patients for inclusion in 
the formal interim analysis for futility will be made shortly after 16 patients in the FAS have 
been enrolled. The interim analysis will be conducted when this initial group of patients to be 
included in the analysis have all had at least 20 weeks of follow-up or have withdrawn early. If 
the observed ORR assessed by central independent reviewer is ≤ 25%, there may be a 
consideration to stop the HGG cohort due to insufficient efficacy. The final decision on whether 
to stop the HGG cohort will also take into account all available study information at the IA cut-
off including safety data and all efficacy endpoints. If enrollment into the HGG cohort is 
stopped early, patients on study continuing to derive benefit from dabrafenib plus trametinib 

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may continue to receive treatment on this study or may be transferred to another study where 
drug will be provided. 
The statistical considerations for the interim analysis can be found in Section 10.7.
In addition, an interim analysis of key safety and PK data of the adolescent patients in the HGG 
cohort may be performed to support a health authority request for data in adolescent patients. 
There is no intent to declare efficacy or futility based on this interim analysis.
No formal interim analysis is planned for the LGG cohort. 
4.3
Definition of end of study
The end of study will occur when all patients have had at least two years of follow-up i.e. 2 
years after last patient first treatment, or if the study is terminated early. At the end of the study, 
patients continuing to derive benefit from dabrafenib plus trametinib study treatment may be 
transferred to another clinical study where study drug will be provided to ongoing patients. 
Long term effects on patients who have received dabrafenib and trametinib may be assessed in 
a separate protocol.  
4.4
Early study termination
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
the patients should be seen as soon as possible and the same assessments should be performed 
as described in Section 7.1.4 and Section 7.1.5 for a discontinued or withdrawn patient. The 
investigator may be informed of additional procedures to be followed in order to ensure that 
adequate consideration is given to the protection of the patient’s interests. The investigator will 
be responsible for informing IRBs and/or ECs of the early termination of the trial.
If the study is terminated early for any reason, patients continuing to derive benefit from 
dabrafenib plus trametinib treatment may be transferred to another study where study drug will 
be provided. 
5
Population
5.1
Patient population
This study will be conducted in two cohorts: HGG and LGG pediatric patient cohorts. 
For the HGG cohort, the patient population is children and adolescent patients with BRAF V600 
mutation positive, refractory or relapsed HGG tumors after having received at least one previous 
standard therapy.
For the LGG cohort, the patient population is children and adolescent patients with BRAF V600 
mutant LGG with progressive disease following surgical excision, or non-surgical candidates 
with necessity to begin first systemic treatment because of a risk of neurological impairment 
with progression
Patients enrolled in this study are not permitted to participate in additional parallel 
investigational drug or device studies. 

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The investigator or designee must ensure that only patients who meet all the following inclusion 
and none of the exclusion criteria are offered treatment in the study.
5.2
Inclusion criteria
Patients eligible for inclusion in this study have to meet all of the following criteria:
1. Male or female between ≥12 months and <18 years of age at the time of signing the 
informed consent form. Patients under 6 years old must weigh at least 7 kg at the time of 
enrollment.  Patients over 6 years old must weigh at least 10 kg at the time of enrollment.
2. For HGG cohort only: Relapsed, progressed, or failed to respond to frontline therapy. 
Frontline therapy is presumed to be optimal surgical approach (biopsy or resection) with 
radiation and/or chemotherapy.
For LGG cohort only: Patients with progressive disease following surgical excision, or 
non-surgical candidates with necessity to begin first systemic treatment because of a risk 
of neurological impairment with progression. 
3. Locally determined HGG or LGG as defined by WHO histological classification system, 
revised 2016 (Appendix 4). For HGG cohort only: Locally confirmed histologic 
diagnosis of High Grade Glioma (Grade III or IV glioma), including anaplastic 
pleomorphic xanthoastrocytoma (aPXA) and anaplastic gangliogliomas.
For LGG cohort only: Locally confirmed histologic diagnosis of Low Grade Glioma 
(Grade I or II)
4. Locally determined and centrally confirmed measurable disease with minimal bi-
perpendicular diameter that must be at least twice the imaging slice thickness to be used 
for efficacy assessments. (Both local and centrally confirmed results must show 
measurable disease to meet eligibility)
5. BRAF V600 mutation-positive tumor as assessed locally, or at a Novartis designated 
central reference laboratory if local BRAF V600 testing is unavailable.
6. Tumor tissue must be available and subsequently provided to Novartis for central 
confirmatory testing of BRAF mutational status (HGG and LGG cohort), and for HGG 
histopathology (HGG cohort).
7. Performance score of ≥50% according to the Karnofsky/Lansky performance status scale.
8. Females of child-bearing potential must be willing to practice acceptable methods of birth 
control.  Additionally, females of childbearing potential must have a negative serum 
pregnancy test within 28 days prior to day 1.
9. Must have adequate bone marrow function per central or local lab in the absence of 
growth factor support and is defined as:

Absolute neutrophil count (ANC) ≥1000/µL;

Platelets ≥75,000/µL and transfusion independent, defined as not receiving platelet 
transfusions within a 7 day period prior to meeting this enrollment criteria. Note for 
LGG patients only, platelets ≥100,000/µL prior to Day 1 dosing.

Hemoglobin ≥8.0 g/dL (may receive red blood cell transfusions)
10. Adequate renal function defined as:

Calculated eGFR (Schwartz formula) or radioisotope GFR ≥90 mL/min/1.73 m2; or

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
A serum creatinine within the testing lab reference range (for age/gender, if available)
11. Adequate liver function defined as:

Total Bilirubin (sum of direct and indirect) ≤ 1.5 x upper limit of normal (ULN) for 
age except for subjects with Gilbertsyndrome who may only be included if the total 
bilirubin is ≤3.0 x ULN or direct bilirubin ≤1.5 x ULN

AST and ALT ≤2.5 x ULN
12. Adequate cardiac function defined as:

LVEF greater than or equal to institutional LLN by ECHO (while not receiving 
medications for cardiac function)

Corrected QT (QTcF) interval ≤480 msecs.
13. If receiving glucocorticoids, patient must be on a stable or weaning dose for at least 7 days
prior to the first dose of study treatment. 
14. Written informed consent/assent must be obtained prior to any protocol specific screening 
procedures being performed.
5.3
Exclusion criteria
Patients eligible for this study must not meet any of the following criteria:
1. Malignancy OTHER than BRAF V600 mutant HGG or LGG.
2. Previous treatment with dabrafenib or another RAF inhibitor, trametinib or another MEK 
inhibitor, or ERK inhibitor.
3. HGG patients: Cancer therapy (chemotherapy with delayed toxicity, immunotherapy, 
biologic therapy, vaccine therapy) or investigational drugs within 3 weeks preceding the 
first dose of study treatment.  LGG patients: Any systemic anticancer therapy 
(chemotherapy, immunotherapy, biologic therapy, or vaccine therapy) or investigational 
drugs prior to enrollment.
4. HGG patients: Radiotherapy to CNS glioma lesions within 3 months prior to first dose of 
study treatment, unless there is clear evidence of radiologic progression outside of the 
field of radiation. LGG patients: Radiotherapy to CNS glioma lesions at any point prior to 
enrollment. 
5. History of malignancy with confirmed activating RAS mutation or with BRAF fusion such 
as BRF-KIAA1549 or with known diagnosis of NF1. Note: Prospective RAS testing is not 
required. However, if the results of previous RAS testing are known, they must be used in 
assessing eligibility. 
6. Current use of a prohibited medication or herbal preparation or requires any of these 
medications during the study. See Section 6.4 for details. 
7. Unresolved toxicity greater than NCI CTCAE v 4.03 grade 2 from previous anti-cancer 
therapy, including major surgery, except those that in the opinion of the investigator are 
not clinically relevant given the known safety/toxicity profile of the study treatment (e.g., 
alopecia and/or peripheral neuropathy related to platinum or vinca alkaloid based 
chemotherapy).
8. History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to dabrafenib, trametinib and their excipients. For LGG patients only: history 

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of allergic reactions or contraindications to the use of carboplatin or vincristine (refer to 
local product label or SmPC). 
9. Autologous or allogeneic stem cell transplant within 3 months prior to the first dose of 
study treatment [NOTE:  patients with evidence of active graft versus host disease are 
excluded regardless of elapsed time].
10. History or current diagnosis of cardiac disease indicating significant risk of safety for 
patients participating in the study such as uncontrolled or significant cardiac disease, 
including any of the following:

recent myocardial infarction (within last 6 months), 

uncontrolled congestive heart failure, 

unstable angina (within last 6 months),

clinically significant (symptomatic) or known, uncontrolled cardiac arrhythmias (e.g., 
sustained ventricular tachycardia, and clinically significant second or third degree AV 
block without a pacemaker) except sinus arrhythmia within the past 24 weeks prior to 
the first dose of study treatment 

coronary angioplasty or stenting (within last 6 months)

intra-cardiac defibrillators

abnormal cardiac valve morphology (≥grade 2) documented by echocardiogram 
(patients with grade 1 abnormalities [i.e. mild regurgitation/stenosis] can be enrolled 
on study.  Patients with moderate valvular thickening should NOT be enrolled.
11. Uncontrolled medical conditions (e.g., diabetes mellitus, hypertension, liver disease or 
uncontrolled infection), psychological, familial, sociological, or geographical conditions 
that do not permit compliance with the protocol; or unwillingness or inability to follow the 
procedures required in the protocol
12. Presence of active GI disease or other condition (e.g., small bowel or large bowel 
resection) that will interfere significantly with the absorption of drugs.
13. A history of Hepatitis B Virus, or Hepatitis C Virus infection (patients with laboratory 
evidence of cleared Hepatitis B Virus and/or Hepatitis C Virus may be enrolled).
14. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant (e.g. are menstruating), unless they are using highly effective methods 
of contraception during dosing of study treatment and for 16 weeks after stopping study 
medication with trametinib monotherapy or dabrafenib in combination with trametinib, 
and 2 weeks after stopping treatment with dabrafenib monotherapy, whichever is longer. 
Effective contraception methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the 
patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception 

Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy, or bilateral tubal ligation or tubal occlusion at least 
six weeks before taking study treatment. In case of oophorectomy alone, only when 
the reproductive status of the woman has been confirmed by follow up hormone level 
assessment is she considered not of child bearing potential.

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
Male sterilization (at least 6 months prior to screening). For female patients on the 
study, the vasectomized male partner should be the sole partner for that patient.

Placement of a hormonal or non-hormonal intrauterine device (IUD) or intrauterine 
system (IUS) with a documented failure rate of less than 1% per year.
Note: Oral contraceptives are not permitted as a method of contraception due to potential drug-
drug interactions with dabrafenib.  
15. Pregnant females as determined by positive human chorionic gonadotropin (hCG) test at 
screening or prior to dosing.
16. Lactating females who are actively breast feeding.
17. Sexually active males (including those that have had a vasectomy) unless they use a 
condom during intercourse while on study and for 16 weeks after stopping study 
treatment, and agree not to father a child during this period.
18. A history or current evidence of retina vein occlusion (RVO) or central serous retinopathy.
6
Treatment
6.1
Study treatment
In this study, the term “study treatment or drug” refers to Novartis study drug dabrafenib 
(DRB436) with trametinib (TMT212) or carboplatin and vincristine. 
Refer to Section 6.1.1.1 for dabrafenib (DRB436) and trametinib (TMT212) dosing instructions.
Refer to Section 6.1.2 for carboplatin and vincristine dosing instructions.
All dosages prescribed and dispensed to the patient and all dose changes during the study must 
be recorded on the Dosage Administration Record eCRF.
6.1.1
Dabrafenib and Trametinib Dosing regimen
Dabrafenib (DRB436) will be administered orally, twice daily based on weight, age and the 
appropriate dose level. Trametinib (TMT212) will be administered orally, once daily in 
combination with the first daily dose of dabrafenib based on weight. A dosing nomogram based 
on weight and/or age will be used to prescribe dabrafenib (DRB436) and trametinib (TMT212)
to minimize inter-patient dosing variability. Dabrafenib is available as capsules and as 
dispersible tablets for oral suspension (Table 6-1, Table 6-2, Table 6-3 and Table 6-4) and 
trametinib is available as tablets and as a powder in bottle for oral solution (Table 6-5, Table 6-
6, Table 6-7 and Table 6-8).
Dabrafenib Dosing Tables 

Patients <12 years old and ≥16 kg may be administered either the dabrafenib capsules 
(Table 6-1) or dabrafenib dispersible tablets for oral suspension (Table 6-3)

Patients ≥12 years old and ≥19 kg may be administered either the dabrafenib capsules 
(Table 6-2) or dabrafenib dispersible tablets for oral suspension (Table 6-4)

Patients <12 years old and <16 kg must be administered dabrafenib dispersible tablets for 
oral suspension (Table 6-3)

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
Patients ≥12 years old and <19 kg must be administered dabrafenib dispersible tablets for 
oral suspension (Table 6-4)
Table 6-1
Dose and treatment schedule for dabrafenib (DRB436) capsules for 
patients less than 12 years of age (5.25 mg/kg/day)
Table 6-2
Dose and treatment schedule for dabrafenib (DRB436) capsules for 
patients greater or equal 12 years of age (4.5 mg/kg/day)
Table 6-3
Dose and treatment schedule for dabrafenib (DRB436) dispersible 
tablets for patients less than 12 years of age (5.25mg/kg/day)
Weight
Dose
Frequency and/or 
Regimen
Total Daily Dose
Pharmaceutical form and route of 
administration
16-23.5 kg
50 mg 
b.i.d
100 mg
Capsules for oral administration
23.6-33.5 kg
75 mg 
b.i.d
150 mg
Capsules for oral administration
33.6-42.5 kg
100 mg
b.i.d
200 mg
Capsules for oral administration
42.6-52.5 kg
125 mg
b.i.d
250 mg
Capsules for oral administration
≥52.6 kg
150 mg
b.i.d
300 mg
Capsules for oral administration
Weight
Dose
Frequency and/or 
Regimen
Total Daily 
Dose
Pharmaceutical form and route of 
administration
19-27.5 kg
50 mg 
b.i.d
100 mg
Capsules  for oral administration
27.6-38.5 kg
75 mg 
b.i.d
150 mg
Capsules  for oral administration
38.6-50.5 kg
100 mg
b.i.d
200 mg
Capsules  for oral administration
50.6-61.5 kg
125 mg
b.i.d
250 mg
Capsules  for oral administration
≥61.6 kg
150 mg
b.i.d
300 mg
Capsules  for oral administration
Weight (kg)
Dose
Frequency 
and/or 
Regimen
Total Daily Dose
Pharmaceutical form and route of 
administration
7-9.5
20 mg
b.i.d
40 mg
Dispersible tablet for oral suspension
9.6-13.5
30 mg
b.i.d
60 mg
Dispersible tablet for oral suspension
13.6-17.5
40 mg 
b.i.d
80 mg
Dispersible tablet for oral suspension
17.6-20.5
50 mg
b.i.d
100 mg
Dispersible tablet for oral suspension
20.6-24.5
60 mg
b.i.d
120 mg
Dispersible tablet for oral suspension
24.6-28.5
70 mg
b.i.d
140 mg
Dispersible tablet for oral suspension
28.6-32.5
80 mg
b.i.d
160 mg
Dispersible tablet for oral suspension
32.6-36.5
90 mg
b.i.d
180 mg
Dispersible tablet for oral suspension
36.6-40.5
100 mg
b.i.d.
200 mg
Dispersible tablet for oral suspension
40.6-43.5
110 mg
b.i.d
220 mg
Dispersible tablet for oral suspension
43.6-47.5
120 mg
b.i.d
240 mg
Dispersible tablet for oral suspension
47.6-51.5
130 mg
b.i.d
260 mg
Dispersible tablet for oral suspension
51.6-55.5
140 mg
b.i.d.
280 mg
Dispersible tablet for oral suspension
≥55.6 kg
150 mg
b.i.d
300 mg
Dispersible tablet for oral suspension

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Table 6-4
Dose and treatment schedule for dabrafenib (DRB436) dispersible 
tablet for patients greater than or equal 12 years of age (4.5 
mg/kg/day)
Trametinib Dosing Tables

Patients <6 years old and <26 kg must be administered the trametinib oral solution (Table 
6-5)

Patients <6 years old and ≥26 kg may be administered either the trametinib oral solution 
(Table 6-5) or trametinib tablets (Table 6-7)

Patients ≥6 years old and ≥10 kg < 33 kg must be administered the trametinib oral 
solution (Table 6-6)

Patients ≥6 years old and ≥33 kg may be administered either the trametinib oral solution 
(Table 6-6) or the trametinib tablets (Table 6-8)
Table 6-5
Dose and treatment schedule for trametinib (TMT212) oral solution for 
patients less than 6 years old (0.032 mg/kg/day)
Weight (kg)
Dose
Frequency 
and/or 
Regimen
Total Daily Dose
Pharmaceutical form and route of 
administration
10-11.5
20 mg
b.i.d
40 mg
Dispersible tablet for oral suspension
11.6-17.5
30 mg
b.i.d
60 mg
Dispersible tablet for oral suspension
17.6-20.5
40 mg
b.i.d
80 mg
Dispersible tablet for oral suspension
20.6-24.5
50 mg
b.i.d
100  mg
Dispersible tablet for oral suspension
24.6-28.5
60 mg
b.i.d
120 mg
Dispersible tablet for oral suspension
28.6-32.5
70 mg
b.i.d
140 mg
Dispersible tablet for oral suspension
32.6-36.5
80 mg
b.i.d
160 mg
Dispersible tablet for oral suspension
36.6-40.5
90 mg
b.i.d
180 mg
Dispersible tablet for oral suspension
40.6-43.5
100 mg
b.i.d
200 mg
Dispersible tablet for oral suspension
43.6-47.5
110  mg
b.i.d
220 mg
Dispersible tablet for oral suspension
47.6-51.5
120 mg
b.i.d
240 mg
Dispersible tablet for oral suspension
51.6-55.5
130 mg
b.i.d
260 mg
Dispersible tablet for oral suspension
55.6-64.5
140 mg
b.i.d
280 mg
Dispersible tablet for oral suspension
≥64.6 
150 mg
b.i.d
300 mg
Dispersible tablet for oral suspension
Weight
(kg)
Dose
Frequency and/or 
Regimen
Total Daily 
Dose
Pharmaceutical form and route 
of administration
mL
mg
7-9.9
5
0.25
q.d
0.25
Solution  for oral administration
10-12.5
7.5
0.375
q.d
0.375
Solution  for oral administration
12.6-16.5
10
0.5
q.d
0.5
Solution  for oral administration
16.6-24.5
12.5
0.625
q.d
0.625
Solution  for oral administration
24.6-35
17.5
0.875
q.d
0.875
Solution  for oral administration
35.1-45
25
1.25
q.d
1.25
Solution  for oral administration
45.1-55
30
1.5
q.d
1.5
Solution  for oral administration
≥55.1
40
2
q.d
2
Solution  for oral administration

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Table 6-6
Dose and treatment schedule for trametinib (TMT212) oral solution for 
patients greater or equal to 6 years old (0.025 mg/kg/day)
Table 6-7
Dose and treatment schedule for trametinib (TMT212) tablets for 
patients less than 6 years and weight greater or equal 26kg (0.032 
mg/kg/day)
Table 6-8
Dose and treatment schedule for trametinib (TMT212) tablets for
patients greater or equal to 6 and weight greater or equal 33kg (0.025 
mg/kg/day)
The investigator or responsible site personnel should instruct the patient and guardians to take 
the study drug as per protocol (promote compliance).
If a patient’s weight changes by more than the allowed institutional standard (or 10% if no 
institutional standard), the patient’s administered dose may be adjusted based on the current 
weight of the patient using protocol Table 6-1 through Table 6-8.
If a patient has increased in weight and is tolerating the current dose administered, the protocol 
dosing Table 6-1 through Table 6-8 should be consulted to determine if a higher dose should 
be given.  Otherwise, it is optional to consider if a higher dose should be administered.
If the patient has decreased in weight, they may continue on the current administered dose if it 
is tolerated. However, if the current administered dose is not tolerated, then the protocol dosing 
Table 6-1 through Table 6-8 should be consulted to determine if a lower dose should be given.  
Otherwise, it is optional to consider if a lower dose should be administered.
Weight
(kg)
Dose
Frequency and/or 
Regimen
Total Daily 
Dose
Pharmaceutical form and route of 
administration
mL
mg
10-12.5
5
0.25
q.d
0.25
Solution  for oral administration
12.6-16.5
7.5
0.375
q.d
0.375
Solution  for oral administration
16.6-24.5
10
0.5
q.d
0.5
Solution  for oral administration
24.6-35
15
0.75
q.d
0.75
Solution  for oral administration
35.1-45
20
1.0
q.d
1.0
Solution  for oral administration
45.1-55
25
1.25
q.d
1.25
Solution  for oral administration
55.1-68
30
1.5
q.d
1.5
Solution  for oral administration
68.1-72
35
1.75
q.d
1.75
Solution  for oral administration
>72
40
2
q.d
2
Solution  for oral administration
Weight
Dose
Frequency 
and/or Regimen
Total Daily 
Dose
Pharmaceutical form and route of 
administration
26-39.5
2 X 0.5 mg
q.d
1 mg
Tablets  for oral administration
39.6-54.5 kg
3 X 0.5 mg
q.d
1.5 mg 
Tablets  for oral administration
≥54.6 kg
1 X 2 mg
q.d
2 mg
Tablets  for oral administration
Weight
Dose
Frequency 
and/or Regimen
Total Daily 
Dose
Pharmaceutical form and route of 
administration
33-49.5 kg
2 X 0.5 mg
q.d
1 mg
Tablets  for oral administration
49.6-69.5 kg
3 X 0.5 mg
q.d
1.5 mg 
Tablets  for oral administration
≥69.6 kg
1 X 2 mg
q.d
2 mg
Tablets  for oral administration

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If a patient’s weight should fall below the lowest weight specified in Table 6-1 through Table 
6-8, and per investigator the patient requires a lower administered dose (i.e., not tolerating 
current dose) then the dose specified in dose modification Table 6-12 through Table 6-15 should 
be utilized.
6.1.1.1
Dabrafenib (DRB436) and trametinib (TMT212) dosing
Study medications should be taken as follows:

Dabrafenib will be administered twice daily per the dosing regimen shown in Table 6-1, 
Table 6-2, Table 6-3 and Table 6-4.

Trametinib will be administered once daily per the dosing regimen shown in Table 6-5, 
Table 6-6, Table 6-7 and Table 6-8.

Trametinib should be taken in combination with dabrafenib once daily, preferably in the 
morning. 

Dabrafenib capsules and trametinib tablets should be taken with approximately 120-240 
mL of water.

Trametinib pediatric oral solution formulation will be administered with a graduated 
syringe. Please refer to the trametinib oral solution Instructions for Use. 

Dabrafenib pediatric oral suspension formulation administration will be administered 
using dosing cup and/or graduated syringe. Please refer to dabrafenib oral suspension 
Instructions for Use.

Refer to the dabrafenib and trametinib Instructions for Use documents if enteral feeding 
tubes are required for administering pediatric oral solutions. 

Patients less than 12 years of age who weigh less than 16 kg must be administered the
dabrafenib dispersible tablets for oral suspension.

Patients equal to or greater than 12 years of age who weigh less than 19 kg must be 
administered the dabrafenib dispersible tablets for oral suspension. 

Patients less than 6 years old who weigh less than 26 kg must be administered the 
trametinib oral solution.

Patients older than 6 years old must weigh at least 33 kg to be administered the trametinib 
tablets. 

Patients should be encouraged to take dabrafenib at approximately 12 hour intervals and at 
similar times each day.

Study treatment should be administered under fasting conditions, at least 1 hour before or 
2 hours after a meal.

If it is not possible for a patient to tolerate the fasting conditions noted above, study 
treatment may be administered with a small non-fat meal (e.g. small amount of apple 
juice/sauce, a piece of dry toast).  Patients and their guardians should be advised to avoid 
administering study drug with milk or high-fat, high-calorie foods.  

Patients who are being breastfed may continue to be breastfed on demand. If the patient is 
breastfed during collection of PK samples the time of breastfeeding should be recorded as 
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
If a patient vomits after taking study drug, the patient should be instructed not to retake the 
dose and wait for the next scheduled dose.  

If a patient misses a dabrafenib dose, they should be instructed not to double the next 
regularly scheduled dose.  However, patients may take the missed dose immediately if the 
next scheduled dose is at least 6 hours later. Patients may then take the next dose at the 
scheduled time. 

If a patient misses a trametinib dose, they should be instructed not to double the next 
regularly scheduled dose. However, patients may take the missed dose immediately if the 
next scheduled dose is at least 12 hours later. Patients may then take the next dose at the
scheduled time.

The total daily dose of dabrafenib will not exceed 300 mg (150 mg BID).

The total daily dose of trametinib will not exceed 2 mg. 
6.1.1.2
Additional dosing guidelines for pharmacokinetic sampling/chemistry 
panel collection
PK samples will be collected on all HGG patients and LGG patients randomized to receive 
dabrafenib with trametinib treatment. PK samples will not be collected from the LGG patients 
randomized to receive carboplatin with vincristine, even after crossover from carboplatin with
vincristine to dabrafenib plus trametinib. 
On days with PK, the following additional guidelines must be followed:

On protocol visit days when PK blood collection is scheduled at the clinic, patients must 
take study treatment in the clinic under the supervision of the Investigator or designee.  On 
all other days, patients may take dabrafenib and trametinib at home.

Post-dose PK samples should be collected after dosing of the study treatment in the 
morning (AM). PK sample collection will be performed according to Table 7-5 and Table 
7-6.
6.1.2
Carboplatin and Vincristine Dosing Regimen
Carboplatin and vincristine will be supplied locally as commercially available and labelled 
accordingly to comply with legal requirements of each country. Carboplatin and vincristine will 
be administered as one course of induction (10 weeks of chemotherapy with 2 weeks of rest), 
followed by 8 cycles of maintenance chemotherapy. Each maintenance cycle is 6 weeks. 
Maintenance cycles are only given following sufficient recovery of hematologic parameters.  
Chemotherapy administration should follow the guidelines below and as per local product 
labels or SmPC. Please consult local product labels and institutional standards for duration of 
infusion and flush requirements when administering carboplatin and vincristine. 
Local safety laboratory testing to confirm hematologic parameters may be conducted per 
institutional practice during induction and maintenance phases of chemotherapy prior to dosing
when central labs are not scheduled per protocol or when central lab results will not be available 
prior to dosing. Results will be collected in the eCRF. 

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6.1.2.1
Induction Therapy
Prior to induction, central or local lab results must be assessed to confirm ANC ≥1000/µL and 
platelet count ≥100,000/µL.
Induction will consist of 10 weeks of therapy followed by 2 weeks without chemotherapy.  
Induction should only be interrupted in the event of grade 3 neurotoxicity, grade 2 
nephrotoxicity, grade 4 hematologic toxicity, or disease progression. See Section 6.3.1.16 for 
dose modification guidelines. 
Carboplatin (CBDCA): 175 mg/m2 as weekly IV infusion over 60 minutes on weeks 1 to 4, and 
on weeks 7 to 10, on the same day as VCR dosing
Vincristine (VCR): 1.5 mg/m2 as weekly IV bolus infusion (0.05 mg/kg if child is <12 kg) 
(maximum dose of 2.0 mg) for 10 weeks. 
Table 6-9
Induction therapy
Week 
1
Week 
2
Week 
3
Week 
4
Week 
5
Week 
6
Week 
7
Week 
8
Week 
9
Week 
10
Week 
11
Week 
12
VCR
CBDC
A
VCR
CBDC
A
VCR
CBDC
A
VCR
CBDC
A
VCR
VCR
VCR
CBD
CA
VCR
CBDC
A
VCR
CBDC
A
VCR
CBDC
A
Rest
Rest
6.1.2.2
Maintenance Therapy 
Following induction therapy and two weeks of rest, maintenance therapy should begin if 
peripheral counts recover to ANC ≥1,000/µL and platelet count ≥100,000/µL. Repeat blood 
counts every 7 days until counts are adequate. Recovery of peripheral counts is required prior 
to starting each maintenance cycle. Local laboratory results may be used prior to dosing if a 
central lab is not scheduled per protocol or when central lab results will not available in time 
for a scheduled cycle. Results will be collected in the eCRF.
Each maintenance cycle will be 6 weeks in duration and consists of 4 weekly doses of 
carboplatin, and three weekly doses of vincristine given concomitantly with the first 3 weeks 
of carboplatin, followed by two weeks of rest. Maintenance will continue for a total of 8 cycles. 
See Section 6.3.1.16 for dose modification guidelines. 
Carboplatin (CBDCA): 175 mg/m2 as weekly IV infusion over 60 minutes on weeks 1 to 4 of 
each cycle.
Vincristine (VCR): 1.5 mg/m2 as weekly IV bolus infusion (0.05 mg/kg if child is <12 kg) 
(maximum dose of 2.0 mg) on weeks 1 to 3 of each cycle, on the same day as CBDCA dosing.
Table 6-10
Maintenance therapy
Week 1
Week 2
Week 3
Week 4
Week 5
Week 6
VCR
CBDCA
VCR
CBDCA
VCR
CBDCA
CBDCA
Rest
Rest
6.1.3
Ancillary treatments 
Not applicable

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6.1.4
Rescue medication 
Not applicable
6.1.5
Guidelines for continuation of treatment 
For guidelines for continuation of treatment, refer to Section 6.3.
6.1.6
Treatment duration
Dabrafenib with trametinib:
Patients will receive dabrafenib in combination with trametinib until disease progression or loss 
of clinical benefit as determined by the investigator, death, unacceptable toxicity, withdrawal 
of consent or if the investigator judges that further therapy is no longer in the best interest of 
the patient, or early termination of the study by the sponsor. 
Patients who have disease progression (as defined by RANO) may continue on study treatment 
if the investigator determines that the patient has clear evidence of clinical benefit from study 
treatment, continuing study drug may be in the best interest for the patient, and the patient/legal 
guardian is willing to continue on study drug and sign Informed Consent for treatment beyond 
progression. If the patient is continuing on study treatment, then all study procedures including 
tumor assessments must be followed as scheduled (Table 7-1 or Table 7-2). In addition, after 
each tumor assessment, the investigator must confirm and document in patient medical records 
and the eCRF that the patient is still benefitting from study treatment and therefore can continue 
receiving study treatment. 
Carboplatin with vincristine for LGG Cohort only:
Duration of treatment should continue for the prescribed number of cycles, as tolerated or until 
unacceptable toxicity, start of a new anti-neoplastic therapy, discontinuation at the discretion of 
the investigator or patient/legal guardian, lost to follow-up, death, study is terminated by the 
sponsor or until disease progression. 
Carboplatin should always be given in a setting with rapid access to pediatric advanced life-
supporting support capability. See Section 6.3.1.16.5 for additional guidelines for the 
management of allergic reactions. Patients who develop an intolerable allergic reaction to 
carboplatin should be managed per institutional standards. Only after centrally confirmed 
RANO-defined disease progression will patients randomized to carboplatin with vincristine 
treatment will be allowed to crossover to receive dabrafenib in combination with trametinib 
treatment.
6.2
Dose escalation guidelines
Not applicable. 

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6.3
Dose modifications 
6.3.1
Dose modification and dose delay
For patients who do not tolerate the protocol-specified dosing schedule, dosing interruptions or 
modifications are mandated in order to allow patients to continue the study treatment. 
General guidelines regarding management and dose reduction for adverse events that are 
considered by the investigator to be related to study treatment and for which specific guidelines 
do not apply are provided in Table 6-11. These guidelines are intended primarily for toxicities 
not easily managed with routine supportive care. For example, alopecia is not an indication for 
dose modification, nor is grade 2 nausea and vomiting that can be easily managed with anti-
emetics. Refer to Section 6.3.1.16 for general guidelines for dose modifications for carboplatin 
and vincristine.
Table 6-11
General guidelines for dose modification for adverse events 
considered related to dabrafenib and trametinib combination 
treatment
Grade
Recommended adverse event 
management guidelines
Mandatory dose modification 
requirements
Grade 1 or Grade 2 
tolerable

Monitor closely.

Provide supportive care according 
to institutional standards.

Continue dabrafenib and trametinib at 
the same dose level.
Grade 2 intolerable or
Grade 3

Monitor closely.

Provide supportive care according 
to institutional standards.

Interrupt dabrafenib and trametinib 
(except for cuSCC, keratoacanthoma, 
new primary melanoma, and basal cell 
carcinoma).
-
When toxicity resolves to ≤ Grade 
1 or baseline, restart dabrafenib 
and trametinib reduced by one 
dose level.

If the Grade 2 (intolerable) or Grade 3 
toxicity recurs, interrupt dabrafenib 
and trametinib.
-
When toxicity resolves to Grade 1 
or baseline, restart dabrafenib 
and trametinib reduced by 
another dose level. Re-escalation 
of the patient’s dose is 
recommended if criteria in 
Section 6.3.1 are met.
Grade 4

Monitor closely.

Provide supportive care according 
to institutional standards.

Interrupt dabrafenib and trametinib.

Restart with dabrafenib and trametinib 
reduced by one dose level once 
toxicity resolves to ≤ Grade 1 or 
baseline or permanently discontinue 
dabrafenib and trametinib at the 
discretion of investigator.
These are general guidelines and investigators should always use clinical judgment in adverse 
event management for any individual patient. Some toxicities may require hospitalization for 
stabilization, additional work-up, and consultation with a specialist before treatment can be 
restarted. Investigators should always err on the side of caution in these settings if treatment

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related toxicity is a possibility. All dose modifications are based on the worst preceding toxicity 
using Common Terminology Criteria for Adverse Events (CTCAE) Version v4.03.
If treatment related toxicities occur that are specific to combination treatment of dabrafenib and 
trametinib, then both treatments should be simultaneously dose reduced, interrupted or 
discontinued with the exception shown below:
Exception where dose modifications are necessary for only dabrafenib:

Uncomplicated pyrexia (Table 6-16)

Uveitis (Table 6-21)
Exception where dose modifications are necessary for only trametinib:

Retinal vein occlusions (RVO) (Table 6-19) and retinal pigment epithelial detachment 
(RPED) Table 6-20)

Left ventricular ejection fraction (LVEF) reduction (Table 6-23)
If the patient requires a dose interruption of > 28 days (greater than 6 weeks for uveitis, iritis, 
see Table 6-21) from the previous dose for persistent grade 2 or greater dabrafenib and/or 
trametinib treatment related toxicity, then the patient must be discontinued from study treatment. 
Up to two dose reductions will be allowed.
Dose reductions will occur in increments of 50 mg from the total daily dose for dabrafenib 
capsules and in increments of 0.5 mg from the total daily dose for trametinib tablets. If a patient 
is receiving trametinib 0.05 mg/mL oral solution, dose modification guidelines in Table 6-12
and Table 6-13 should be followed. If patient is receiving dabrafenib dispersible tablet, dose 
modification guidelines in Table 6-14 and Table 6-15 should be followed. If more than two 
dose reductions are needed, the patient must be discontinued from study treatment. Patients who 
discontinue study treatment due to adverse event will be followed until resolution or 
stabilization of the event. All dose changes and the reason for dose interruption must be 
recorded on the Dosage Administration Record eCRF.
Table 6-12
Dose Modification for trametinib (TMT212) oral solution for patients 
greater or equal to 6 years old
Dose: 0.025 mg/kg/day
Dose Level 1: ~30% reduction
Dose Level 2: ~30% reduction
Weight
(kg)
Dose
Dose Reduction 
Level 1
Dose reduction
Level 2
mL
mg
mL
mg
mL
mg
10-12.5
5
0.25
3.5
0.175
2.5
0.1225
12.6-16.5
7.5
0.375
5
0.25
3.5
0.175
16.6-24.5
10
0.5
7
0.35
5
0.25
24.6-35
15
0.75
10
0.5
7
0.35
35.1-45
20
1.0
14
0.7
10
0.5
45.1-55
25
1.25
17.5
0.875
12
0.6
55.1-68
30
1.5
20
1
14
0.7
68.1-72
35
1.75
25
1.25
17.5
0.875
>72
40
2
28
1.4
20
1

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Table 6-13
Dose Modification for trametinib (TMT212) for oral solution for 
patients less than 6 years old
Dose: 0.032 mg/kg/day
Dose Level 1: ~0.025 mg/kg/day
Dose Level 2: ~ 30% reduction
Table 6-14
Dose Modification for dabrafenib (DRB436) dispersible tablet for 
patients less than 12 years of age
Weight (kg)
Dose (b.i.d)
Dose Reduction Level 1
(b.i.d)
Dose Reduction Level 2 (b.i.d)
7-9.5
20 mg
10 mg
0 mg
9.6-13.5
30 mg
20 mg
10 mg
13.6-17.5
40 mg 
30 mg
20 mg
17.6-20.5
50 mg
40 mg
30 mg
20.6-24.5
60 mg
50 mg
40 mg
24.6-28.5
70 mg
60 mg
50 mg
28.6-32.5
80 mg
70 mg
60 mg
32.6-36.5
90 mg
80 mg
70 mg
36.6-40.5
100 mg
90 mg
80 mg
40.6-43.5
110 mg
100 mg
90 mg
43.6-47.5
120 mg
110  mg
100  mg
47.6-51.5
130 mg
120 mg
110 mg
51.6-55.5
140 mg
130 mg
120 mg
≥55.6 kg
150 mg
140 mg
130 mg
Dose: 5.25 mg/kg/day
Dose level 1: 4.5 mg/kg/day
Dose level 2: 3.75 mg/kg/day
Table 6-15
Dose Modification for dabrafenib (DRB436) dispersible tablet for 
patients greater or equal 12 years of age
Weight
(kg)
Dose
Dose Reduction 
Level 1
Dose reduction
Level 2
mL
mg
mL
mg
mL
mg
7-9.9
5
0.25
3.5
0.175
2.5
0.1225
10-12.5
7.5
0.375
5
0.25
3.5
0.175
12.6-16.5
10
0.5
7.5
0.375
5
0.25
16.6-24.5
12.5
0.625
10
0.5
7
0.35
24.6-35
17.5
0.875
15
0.75
10
0.5
35.1-45
25
1.25
20
1
14
0.7
45.1-55
30
1.5
25
1.25
17.5
0.875
≥55.1
40
2
30
1.5
20
1
Weight
Dose (b.i.d)
Dose Reduction Level 1 
(b.i.d)
Dose Reduction Level 2 (b.i.d)
10-11.5
20 mg
10 mg
0 mg
11.6-17.5
30 mg
20 mg
10 mg
17.6-20.5
40 mg
30 mg
20 mg
20.6-24.5
50 mg
40 mg
30 mg

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If a patient’s dose of dabrafenib and trametinib has been reduced per the dose modification 
instructions, dose re-escalation may be considered provided the following criteria are met:

A period of 4 weeks of treatment have passed since restarting dosing at the lower dose 
level and treatment has been well tolerated

Patient is deriving clinical benefit
Dose re-escalation follows the same dosing steps as de-escalation, in increments of 50 mg 
from the total daily dose for dabrafenib capsules and in increments of 0.5 mg from the total 
daily dose for trametinib tablets. Patients receiving trametinib 0.05 mg/mL oral solution are to 
follow Table 6-12 and Table 6-13 for dose re-escalation. Patients receiving dabrafenib 
dispersible tablet are to follow Table 6-14 and Table 6-15 for dose re-escalation. The 
dabrafenib dose must not exceed 150 mg twice daily (300 mg total daily dose). The trametinib 
dose must not exceed 2 mg once daily. 
The following sections address the specific instructions for mandatory dose modifications and 
recommended management for AEs considered suspected to be related to study treatment. 
6.3.1.1
Pyrexia
Episodes of pyrexia syndrome have been observed in patients receiving dabrafenib 
monotherapy or in combination with trametinib. The pyrexia syndrome is defined as treatment-
related fever (≥38°C) or chills/rigors/night sweats or flu-like symptoms. In a minority of cases 
pyrexia was accompanied by symptoms such as severe chills/rigors, dehydration, and 
hypotension, dizziness or weakness and required hospitalization. The incidence and severity of 
pyrexia syndrome are increased when dabrafenib is used in combination with trametinib 
compared to dabrafenib monotherapy. 
Patients and guardians must be instructed on the importance of immediately reporting febrile 
episodes. Dabrafenib and trametinib must be interrupted promptly and anti-pyretics
(acetominophen, ibuprofen, similar) started at the very first symptom of pyrexia or its associated 
prodrome (chills or rigors or night sweats or flu-like symptoms). Adequate hydration status 
should be maintained.  Dabrafenib and trametinib should be restarted upon improvement of 
symptoms of at least 24 hours, and at the same dose.
24.6-28.5
60 mg
50 mg
40 mg
28.6-32.5
70 mg
60 mg
50 mg
32.6-36.5
80 mg
70 mg
50 mg
36.6-40.5
90 mg
80 mg
60 mg
40.6-43.5
100 mg
90 mg
60 mg
43.6-47.5
110  mg
100 mg
70 mg
47.6-51.5
120 mg
110 mg
80 mg
51.6-55.5
130 mg
120 mg
80 mg
55.6-64.5
140 mg
130 mg
100 mg
≥64.6
150 mg
140 mg
110 mg
Dose: 4.5 mg/kg/day
Dose level 1: 3.75 mg/kg/day
Dose level 2: 3.00 mg/kg/day

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In the event of recurring pyrexia events despite the use of antipyretics and drug interruption,
the use of oral corticosteroids may be considered when restarting dabrafenib and trametinib. In 
patients experiencing pyrexia associated with rigors, severe chills, dehydration or hypotension, 
serum creatinine increase and other evidence of renal function decrease should be monitored 
carefully during and following severe events of pyrexia.
Pyrexia accompanied by hypotension, dehydration requiring intravenous fluids, renal 
insufficiency and/or severe (≥ Grade 3) rigors/chills in the absence of an obvious infectious 
cause are to be reported as a SAE.
Guidelines for dose modification and management for pyrexia syndrome considered to be 
related to dabrafenib are provided in Table 6-16.
Table 6-16
Mandatory dose modification and recommended clinical management 
for pyrexia syndrome suspected to be related to dabrafenib and/or 
trametinib treatment
Pyrexia
Occurrence
Recommended adverse event management
guidelines
Mandatory dose modification 
requirements
1st occurrence and 
subsequent 
occurrences

Re-educate patient/family about pyrexia 
syndrome and immediately interrupt 
dabrafenib and trametinib at the very first 
symptom of pyrexia or its associated 
prodrome (chills or rigors or night sweats 
or flu-like symptoms).

Clinical evaluation for infection and 
hypersensitivitya

Laboratory work-upa

Administer anti-pyretic treatment with non-
steroidal anti-inflammatory drugs (NSAID) 
and/or paracetamolb

Oral hydration should be encouraged in 
patients without evidence of dehydration.  
Intravenous hydration is recommended in 
patients experiencing pyrexia complicated 
by dehydration/hypotension.

For recurring pyrexia events despite the 
use of anti-pyretics and dose interruption, 
consider oral corticosteroids (i.e. 
prednisone 10mg or pediatric equivalent, 
or more) for at least 5 days or as clinically 
indicated.  

Optimize oral corticosteroid dose as 
clinically indicated for recalcitrant pyrexia

Dabrafenib and trametinib must 
be interrupted promptly at the 
very first symptom of pyrexia or its 
associated prodrome (chills, 
rigors, night sweats or flu-like 
symptoms) Adequate hydration 
status should be maintained.  
Dabrafenib and trametinib should 
be restarted upon improvement of 
symptoms of at least 24 hours, at 
the same dose

If pyrexia cannot be managed 
with interruption, dose reduction 
must be considered if clinically 
indicated.
a.
For patients experiencing pyrexia, a clinical evaluation and laboratory work-up is mandatory for each 
event; thorough clinical examination for signs and symptoms of infection or hypersensitivity is required; 
laboratory work-up should include full-blood-count, electrolytes, creatinine, blood urea nitrogen (BUN), C-
reactive protein (CRP), liver transaminases, blood culture, and urine culture.
b.
Anti- pyretic treatment should be started immediately at the first occurrence and prophylactic anti-pyretic 
treatment is recommended. Anti-pyretic treatment may include acetaminophen, ibuprofen, or suitable anti-
pyretic medication according to institutional standards. Prophylactic anti-pyretic treatment is recommended 
to be discontinued after three days in the absence of pyrexia.

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6.3.1.2
Renal Insufficiency
Cases of renal insufficiency have occurred in adult patients receiving dabrafenib and the 
combination of dabrafenib and trametinib. Prior to start of study treatment, concomitant 
medications must be reviewed for the potential risk of inducing nephrotoxicity and concomitant 
medications may be modified if clinically possible. 
Guidelines regarding management and dose reduction for renal insufficiency considered to be 
related to study treatment by the investigator are provided Table 6-17.
Table 6-17
Mandatory dose modifications and recommended clinical 
management guidelines for renal function alterations
NCI-CTCAE v4.03
Grade
Recommended adverse event 
management guidelines
Mandatory dose modification 
requirements
Grade 1 (Creatinine > ULN to 
≤ 1.5× ULN)

Monitor creatinine weekly

If creatinine return to baseline 
resume routine creatinine 
monitoring per protocol

Promote hydration and cessation 
of nephrotoxic drugs.

Continue dabrafenib and 
trametinib at the same dose.
Grade 2 (Creatinine > 1.5× to 
≤ 3× ULN

Monitor creatinine every 2 to 3 
days

Consult with specialist and 
consider renal biopsy 

Promote hydration and cessation 
of nephrotoxic drugs.
1st occurrence

Interrupt dabrafenib and 
trametinib until ≤ Grade 1 or 
baseline and then reinstate 
dabrafenib and trametinib at the 
same dose.
2nd occurrence:

Interrupt dabrafenib and 
trametinib until ≤ Grade 1 or 
baseline. Once recovered, reduce 
dabrafenib and trametinib to the 
next dose level. Re-escalation of 
the patient’s dose is 
recommended if criteria in Section 
6.3.1 are met.
3rd occurrence:

Interrupt dabrafenib and 
trametinib until ≤ Grade 1 or 
baseline. Once recovered, reduce 
dabrafenib and trametinib to the 
next dose level. Re-escalation of 
the patient’s dose is 
recommended if criteria in Section 
6.3.1 are met.
4th occurrence

Permanently discontinue 
dabrafenib and trametinib.
Grade 3 (Creatinine > 3.0 to < 
6×ULN)

Monitor creatinine every 1 to 2 
days.

Consult with nephrologist. 

Promote hydration and cessation 
of nephrotoxic drugs.
1st occurrence:

Interrupt dabrafenib and 
trametinib until ≤ Grade 1 or 
baseline and then reduce 
dabrafenib and trametinib to the 
next lower. Re-escalation of the 

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NCI-CTCAE v4.03
Grade
Recommended adverse event 
management guidelines
Mandatory dose modification 
requirements
patient’s dose is recommended if 
criteria in Section 6.3.1 are met.
2nd occurrence:

Interrupt dabrafenib and 
trametinib until ≤ Grade 1 or 
baseline and then reduce 
dabrafenib and trametinib to the 
next lower dose. Re-escalation of 
the subject’s dose is 
recommended if criteria in Section 
6.3.1 are met.
3rd occurrence:

Interrupt dabrafenib and 
trametinib until ≤ Grade 1 or 
baseline and then reduce 
dabrafenib and trametinib to the 
next lower dose, if available as 
dose level -2. If already at dose 
level -2 at time of occurrence, 
permanently discontinue 
dabrafenib and trametinib. Re-
escalation of the patient’s dose is 
recommended if criteria in Section 
6.3.1 are met.
4th occurrence:

Permanently discontinue 
dabrafenib and trametinib.
Grade 4: Creatinine > 6× ULN

Monitor creatinine daily.

Consult with specialist and 
recommend renal biopsy. 

Promote hydration and cessation 
of nephrotoxic drugs.

Permanently discontinue 
dabrafenib and trametinib.
6.3.1.3
Pneumonitis
Pneumonitis has been observed in patients receiving trametinib in combination with dabrafenib. 
Guidelines for dose modification and management of pneumonitis considered to be related to 
study treatment by the investigator are provided in Table 6-18.

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Table 6-18
Mandatory dose modifications and recommended clinical 
management guidelines for pneumonitis
Pneumonitis (NCI-CTCAE v4.03)
Grade
Recommended adverse event 
management guidelines
Mandatory dose modification 
requirements
Grade 1: Radiographic 
changes only-
Asymptomatic

CT scan (high-resolution with 
lung windows) recommended, 
with serial imaging to monitor for 
resolution or progression- re-
image at least every 3 weeks

Monitor for symptoms every 2-3 
days - Clinical evaluation and 
laboratory work-up for infection

Monitoring of oxygenation via 
pulse oximetry recommended

Consultation of pulmonologist 
recommended.

Continue dabrafenib and trametinib 
at the same dose.
Grade 2: Symptomatic
medical intervention 
indicated; limits 
instrumental Activities of 
Daily Living (ADLs)

CT scan (high-resolution with 
lung windows)

Monitor symptoms daily, 
consider hospitalization

Clinical evaluation and 
laboratory work up for infection

Consult pulmonologist

Pulmonary function tests if 
normal at baseline, repeat every 
8 weeks

Bronchoscopy with biopsy 
and/or bronchoscopic alveolar 
lavage (BAL) recommended

Symptomatic therapy including 
corticosteroids if clinically 
indicated (systemic 
corticosteroids at a dose of 1 to 
2 mg/kg/day prednisone or 
equivalent as clinically 
indicated).
1st occurrence:

Interrupt trametinib until recovery to 
≤ Grade 1 or baseline. Dabrafenib 
may continue at the same dose.

Once recovered, reduce 
trametinib to the next lower 
dose. Re-escalation of the 
patient’s dose is recommended 
if criteria in Section 6.3.1 are 
met.

If no recovery to ≤ Grade 1 
within 4 weeks, permanently 
discontinue trametinib. 
Dabrafenib may continue.

If worsens treat as Grade 3 or 
4.
Grade 3: Severe 
symptoms; limits self-care 
ADLs; oxygen indicated

CT scan (high-resolution with 
lung windows)

Clinical evaluation and 
laboratory work-up for infection

Consult pulmonologist

Pulmonary function tests-if < 
normal, repeat every 8 weeks 
until ≥ normal

Bronchoscopy with biopsy 
and/or BAL if possible

Treat with intravenous steroids 
(methylprednisolone 125 mg or 
equivalent) as indicated. When 
symptoms improve to ≤ Grade 
1, a high dose oral steroid 
(prednisone 1 to 2 mg/kg/day or 
dexamethasone 4 mg every 4 
hours or equivalent).

Interrupt trametinib until recovery to 
Grade ≤1 or baseline. Dabrafenib 
may continue.

Once recovered, trametinib 
may be restarted at the next 
lower dose. Re-escalation of 
the patient’s dose is 
recommended if criteria in 
Section 6.3.1 are met.

If no recovery to Grade ≤ 1 or 
baseline within 4 weeks, 
permanently discontinue 
trametinib. Dabrafenib may 
continue.

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Pneumonitis (NCI-CTCAE v4.03)
Grade
Recommended adverse event 
management guidelines
Mandatory dose modification 
requirements

If IV steroids followed by high 
dose oral steroids does not 
reduce initial symptoms within 
48 to 72 hours, consider non-
corticosteroid 
immunosuppressive medication 
Grade 4: Life- threatening 
respiratory compromise

Same as Grade 3

Same as Grade 3
6.3.1.4
Dose modification and management guideline for visual changes
suspected to be related to dabrafenib and/or trametinib treatment
Episodes of visual changes have been observed in patients receiving trametinib, dabrafenib, and 
combination therapy. An ophthalmologist is to be consulted if changes in vision develop.  
However, if the visual changes are clearly unrelated to study treatment (e.g., allergic 
conjunctivitis), then monitor closely as it may be reasonable to defer ophthalmic examination.
Special attention should be given to retinal findings (e.g., retinal pigment epithelial detachment 
(RPED) or retinovascular abnormalities (i.e., branch or central retinal vein occlusions (RVO). 
Treatment emergent cases of RVO and RPED are to be reported as SAEs. 
Guidelines for dose modifications and management for visual changes and/or ophthalmic 
examination findings considered to be related to study treatment are provided in Table 6-19 and
Table 6-20.
Treatment with dabrafenib has been associated with the development of uveitis, including iritis.  
Monitor patients for visual signs and symptoms (such as, change in vision, photophobia and 
eye pain) during therapy. Guidelines for dose modifications and management for uveitis, 
including iritis considered to be related to study treatment are provided in Table 6-21.
Table 6-19
Mandatory dose modification and recommended clinical management 
for visual changes and/or ophthalmic examination findings suspected 
to be related to trametinib treatment 
Visual changes (Eye disorders – Other, CTCAE Version 4.03, retinal, and similar)
Grade
Recommended adverse event 
management guidelines
Mandatory dose modification requirements
Grade 1
If visual changes 
are clearly 
unrelated to study 
treatment (e.g. 
allergic 
conjunctivitis), 
monitor closely but 
ophthalmic 
examination is not 
required 
Initiate local therapy and consult 
ophthalmologist within 7 days of 
onset.

If dilated fundus examination cannot be 
performed within 7 days of onset, interrupt 
trametinib until RPED and RVO can be 
excluded by retina specialist/ophthalmologist. 
Continue dabrafenib.
If RPED and RVO excluded, continue (or restart) 
trametinib at same dose level

If RPED suspected or diagnosed: see RPED 
dose modification Table 6-20; report as SAE 
if diagnosed.

If RVO diagnosed: Permanently discontinue 
trametinib and report as SAE.

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Visual changes (Eye disorders – Other, CTCAE Version 4.03, retinal, and similar)
Grade
Recommended adverse event 
management guidelines
Mandatory dose modification requirements
Grade 2 and Grade 
3

Initiate local therapy and consult 
ophthalmologist immediately
Interrupt trametinib. Dabrafenib may be continued 
at the current dose.

If RPED and RVO excluded, restart trametinib 
at same dose level. 

If RPED diagnosed, see RPED dose 
modification in Table 6-20; report as SAE.

If RVO diagnosed: Permanently discontinue 
trametinib and report as SAE.
Grade 4

Initiate local therapy and consult 
ophthalmologist immediately

Interrupt trametinib. Dabrafenib may be 
continued at the same dose.

If RPED and RVO excluded, consider 
restarting trametinib at the same or reduced 
dose level. 

If RVO diagnosed, permanently 
discontinue trametinib and report as SAE.
Table 6-20
Mandatory dose modification and recommended clinical management 
for retinal pigment epithelial detachments (RPED) suspected to be 
related to trametinib treatment
Retinal pigment epithelial detachments (RPED)
Grade
Recommended adverse event 
management guidelines
Mandatory dose modification 
requirements

Grade 1 (Asymptomatic; 
clinical or diagnostic 
observations only)

If RPED worsens follow 
instructions below.

Continue treatment with retinal 
evaluation monthly until 
resolution.

Grade 2-3 RPED 
(Symptomatic with mild to 
moderate decrease in 
visual acuity).

Retinal evaluation monthly.

Interrupt trametinib.

If improved to ≤ Grade 1, restart 
trametinib at a lower dose.
Table 6-21
Mandatory dose modification and recommended clinical management 
for uveitis, including iritis suspected to be related to dabrafenib 
treatment
Grade
Recommended adverse event 
management guidelines
Mandatory dose modification requirements
Grade 1 
Initiate local therapy and consult 
ophthalmologist immediately

Continue dabrafenib and trametinib

If no response to local treatment within 7 days, 
interrupt dabrafenib.  Once uveitis resolves, 
restart dabrafenib

Continue trametinib
Grade 2, 3 or 4
Initiate local therapy and consult 
ophthalmologist immediately 

Interrupt dabrafenib

If ≥ grade 2 uveitis (including iritis and iridocylitis)
lasts >6 weeks on local treatment and 
dabrafenib has not been restarted, permanently 
discontinue dabrafenib

Continue trametinib 

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6.3.1.5
Dose modification and management guideline for new malignancies
suspected to be related to dabrafenib and/or trametinib treatment
New Malignancies: Cutaneous and Non-cutaneous
6.3.1.5.1 Cutaneous malignancies
Cutaneous squamous cell carcinoma (CuSCC), keratoacanthomas (KA) and new primary 
melanomas have been observed in patients treated with dabrafenib and dabrafenib/trametinib 
combination therapy. These treatment-related lesions should be surgically removed according 
to institutional practices. Dose modification or interruption of study treatment is not required 
for cuSCC, KA, or new primary melanoma, however cuSCC and new primary melanoma are 
to be reported as a SAE. In addition, a biopsy of the lesion should be taken, where possible, and 
submitted for further analyses and a summary of the results submitted to Novartis. Patients 
should be instructed to immediately inform their physician if new lesions develop. Skin 
examinations are to be performed prior to initiation of study treatment and throughout therapy 
as detailed in the Visit Evaluation Schedule (Table 7-1, Table 7-2 for LGG crossover patients
or Table 7-3). Monitoring will occur at 3 and 6 months following discontinuation of study 
treatment or until initiation of another anti-neoplastic therapy. Monitoring of the skin can be 
performed by a qualified local physician at the discretion of the investigator during non-clinic 
visits. If possible, the same local physician should perform each exam throughout the study to 
ensure consistency between evaluations. 
6.3.1.5.2 Non-Cutaneous Malignancies
In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling in 
BRAF wild type cells with RAS mutations when exposed to BRAF inhibitors, which may lead 
to increased risk of non-cutaneous malignancies in patients treated with dabrafenib.  Cases of 
RAS-driven malignancies have been seen with BRAF inhibitors.  Consider the benefits and risks 
before continuing treatment with dabrafenib in patients with a non-cutaneous malignancy that 
has a RAS mutation. No dose modification of trametinib is required when taken in combination 
with dabrafenib.
New non-cutaneous malignancies are to be reported as a SAE. A biopsy of the new malignancy 
should be taken, where possible, and submitted for further analyses including RAS mutation 
status with the results provided to Novartis. 
 
 
 
Patients should be monitored for secondary malignancy as clinically appropriate. This may 
include review of signs and symptoms and physical exam.  If there is clinical concern or 
possible increased risk for the development of an occult secondary malignancy, additional 
imaging such as whole-body MRI may be appropriate. Following discontinuation of dabrafenib, 
monitoring for non-cutaneous secondary/recurrent malignancies should continue for up to 6 
months or until initiation of another anti-neoplastic therapy.

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6.3.1.6
Dose modification and management guideline for hyperglycemia
Hyperglycemia requiring an increase in the dose of, or initiation of insulin or oral therapy can 
occur with dabrafenib. Monitor serum glucose levels as clinically appropriate during treatment 
with dabrafenib in patients with pre-existing diabetes or hyperglycemia.
Advise patients to report symptoms of severe hyperglycemia such as excessive thirst or any 
increase in the volume or frequency of urination.
6.3.1.7
Guidelines for prolonged QTc
Guidelines for dose modification and stopping criteria due to QTc-prolongation are provided in 
Table 6-22.
If ECG results demonstrate a prolonged QT interval (QTcF ≥501 msec), obtain two or more 
additional ECGs over a brief period, and then use the average QTc values of the three ECGs to 
determine if study treatment should be interrupted or discontinued. If the QTc prolongation 
resolves to Grade 1 or baseline, the patient may resume study treatment if the investigator 
determines that the patient may benefit from further treatment. This determination must be 
documented by the investigator in the patient’s medical record.
Table 6-22
Withholding and Stopping Criteria for QTc-Prolongation
QTc Prolongation
Action and Dose Modifications
QTcF ≥501 msec
Based on average QTc value of 
triplicate ECGs

Assess the quality of the ECG recording and the QT value and repeat 
if needed

Interrupt dabrafenib and trametinib (study treatments) until QTcF 
prolongation resolves to Grade 1 or baseline

Test serum potassium, calcium, phosphorus and magnesium. If 
abnormal, correct per routine clinical practice to within normal limits.

Review concomitant medication associated with QT prolongation, 
including drugs with a “known”, “possible” or “conditional risk of 
Torsade de pointes” and drugs with the potential to increase the risk of 
study drug exposure related to QT prolongation

If event resolves to grade 1 or baseline, patient may restart study 
treatments at current dose level if patient may benefit from further 
treatment 

If event does not resolve within 28 days, permanently discontinue 
study treatments.  Consider evaluation with cardiologist.

If event recurs, permanently discontinue study treatments.  Consider 
evaluation with cardiologist.
Abbreviations:  ECG = electrocardiogram; msec = milliseconds; QTcF = QT duration corrected for heart rate by 
Fredericia formula.
6.3.1.8
Left Ventricular Ejection Fraction Stopping Criteria
Decreases of the left-ventricular-ejection-fraction (LVEF) have been observed in patients
receiving trametinib monotherapy and in combination with dabrafenib. Therefore, ECHOs must 
be performed to assess cardiac ejection fraction in regular intervals as outlined in the Visit 
Evaluation Schedule (Table 7-1, Table 7-2 for LGG crossover patients, Table 7-3). Dose 
modification guidance and stopping criteria for LVEF decrease are provided in Table 6-23. 
ECHO to be performed at baseline and at follow up visit(s).

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Table 6-23
Mandatory dose modification and recommended clinical management 
for LVEF suspected to be related to dabrafenib and/or trametinib 
treatment
Left Ventricular Ejection Fraction decrease (NCI-CTCAE v4.03)
LVEF-drop (%) &
clinical symptoms
Recommended adverse event 
management guidelines
Mandatory dose modification 
requirements
Asymptomatic:
Absolute decrease of >10% in 
LVEF compared to baseline 
and ejection fraction below 
the institution’s LLN

Closely monitoring LVEF via 
ECHO, repeat ECHO within 2 
weeks*.

If the LVEF recovers within 4 
weeks (defined as LVEF ≥LLN 
and absolute decrease ≤10% 
compared to baseline)

Repeat ECHO 2, 4, 8 and 12 
weeks after re-start; continue 
in intervals of 12 weeks 
thereafter.

If repeat LVEF does not recover 
within 4 weeks.

Consult with cardiologist

Repeat ECHO after 2, 4, 8, 
12, and 16 weeks or until 
resolution

Report as SAE.

Interrupt trametinib.

If the LVEF recovers, restart 
trametinib reduced by one 
dose level and continue 
dabrafenib at the same dose 
level.

More than two occurrence, 
permanently discontinue 
trametinib.

Permanently discontinue 
trametinib if repeat LVEF does 
not recover within 4 weeks.
Symptomatic:
Resting LVEF 39-20%
or >20% absolute reduction 
from baseline
resting LVEF <20%

Consult with cardiologist.

Repeat ECHO after 2, 4, 8, 12, 
and 16 weeks or until resolution.

Report as SAE.

Permanently discontinue 
trametinib.

Interrupt dabrafenib

Restart dabrafenib if LVEF 
recovers including resolution of 
symptoms.
* If ECHO does not show LVEF recovery after 2 weeks, repeat ECHO 2 weeks later.
6.3.1.9
Cardiac valvular toxicity stopping criteria
Grade 2: Patients who have an asymptomatic, moderate regurgitation or stenosis by ECHO 
(Grade 2 mitral/tricuspid/aortic valvular toxicity) should temporarily discontinue dabrafenib 
and trametinib and have a repeat evaluation by ECHO within 1 week. ECHO should be repeated 
every 1-2 weeks for 4 weeks or until valve recovery to baseline.

If the valve recovers to baseline any time during the next 4 weeks, the patient may be 
restarted at a reduced dose(s). For such patients, monitoring of the valve via ECHO will 
then be performed 2 and 4 weeks after re-challenge, and every 4 weeks thereafter for 12 
weeks and then per protocol.

If repeat ECHO does not reveal valve recovery to baseline within 4 weeks, then the patient 
should permanently discontinue dabrafenib and trametinib.  The valve should continue to 
be monitored via ECHO every 4 weeks for 16 weeks or until resolution.
Grade 3: Patients with a Grade 3 valvular toxicity (symptomatic, severe regurgitation/stenosis 
by imaging, with symptoms controlled by medical intervention) must discontinue dabrafenib
and trametinib. Valvular toxicity should continue to be monitored every 4 weeks for 16 weeks 
or until resolution. If recovery occurs (return to baseline via imaging AND symptom resolution) 
within 4 weeks and the patient is receiving unequivocal clinical benefit from the study treatment 

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as per documented investigator assessment, the patient may restart dabrafenib and trametinib at 
a reduced dose.
Grade 4: Patients with a Grade 4 valvular toxicity [life-threatening consequences; urgent 
intervention indicated (e.g., valve replacement, valvuloplasty)] must permanently discontinue
dabrafenib and trametinib.
6.3.1.10 Dose modification and management guideline for skin rash
Guidelines for dose modification and management of skin rash considered to be related to study 
treatment by the investigator are provided in Table 6-24.
Table 6-24
Mandatory dose modifications and recommended clinical 
management guidelines for rash
Rash Events (NCI-CTCAE v4.03)
Grade
Recommended adverse event 
management guidelines
Mandatory dose modification 
requirements
Grade 1: Rash covering < 
10% body surface area

Initiate prophylactic and symptomatic 
treatment measures.

Consider use of topical corticosteroids 
or urea containing creams in 
combination with oral antipruritics or 
moderate strength topical steroid 
(hydrocortisone 2.5% cream or 
fluticasone propionate 0.5% cream)

Reassess after 2 weeks

Continue dabrafenib and 
trametinib at the same dose.
Grade 2: 10-30% of body 
surface area

If tolerable, as per Grade 1

If intolerable, initiate systemic steroids 
(0.5 to 1 mg/kg/day prednisone or 
equivalents)

If symptoms persist or recur consider 
skin biopsy.

If tolerable, continue 
dabrafenib and trametinib at 
the same dose.

If intolerable:
1st occurrence

Interrupt dabrafenib and 
trametinib until ≤ Grade 1, and 
reduce dabrafenib and 
trametinib to the next dose 
level. Re-escalation of the 
patient’s dose is 
recommended if criteria in
Section 6.3.1 are met.
Grade 3: More than 30% of 
body surface area

Obtain a skin biopsy and dermatology 
consult.

Initiate therapy with high dose steroids 
(1 to 2 mg/kg/day prednisone or 
equivalents)
1st occurrence

Interrupt dabrafenib and 
trametinib until ≤ Grade 1, and 
reduce dabrafenib and 
trametinib to the next dose 
level. Re-escalation of the 
patient’s dose is 
recommended if criteria in
Section 6.3.1 are met.
2nd occurrence

Interrupt dabrafenib and 
trametinib until ≤ Grade 1 or 
baseline. Once recovered, 
reduce dabrafenib and 
trametinib to the next dose 
level. Re-escalation of the 

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Rash Events (NCI-CTCAE v4.03)
Grade
Recommended adverse event 
management guidelines
Mandatory dose modification 
requirements
patient’s dose is 
recommended if criteria in 
Section 6.3.1 are met.
3rd occurrence

Interrupt dabrafenib and 
trametinib until ≤ Grade 1 or 
baseline. Once recovered, 
reduce dabrafenib and 
trametinib to the next dose 
level, if available as dose level 
-2. If already at dose level -2 at 
time of occurrence, 
permanently discontinue 
dabrafenib and trametinib. Re-
escalation of the patient’s dose 
is recommended if criteria in 
Section 6.3.1 are met.
4th occurrence

Permanently discontinue 
dabrafenib and trametinib.
Grade 4: Life-threatening

Same as Grade 3

Permanently discontinue 
dabrafenib and trametinib.
6.3.1.11 Management of Severe cutaneous adverse reactions (SCAR)
Cases of severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome, 
and drug reaction with eosinophilia and systemic symptoms (DRESS), which can be life-
threatening or fatal, have been reported during treatment with dabrafenib in combination with 
trametinib. Before initiating treatment, patients should be advised of the signs and symptoms 
and monitored closely for skin reactions. If signs and symptoms suggestive of SCARs appear, 
dabrafenib and trametinib should be permanently discontinued..
6.3.1.12 Management Guidelines for Additional AEs

Palmar Plantar Erythrodysesthesia (PPES) – Measures for PPES should include:

Lifestyle modification:  avoidance of hot water, traumatic activity, constrictive 
footwear, or excessive friction on the skin and the use of thick cotton socks and 
gloves, and shoes with padded insoles

Symptomatic treatments:  apply moisturizing creams frequently, topical keratolytics 
(e.g. urea 20-40 % cream, salicylic acid 6%, tazarotene 0.1% cream, fluorouracil 5% 
cream), clobetasol propionate 0.05% ointment for erythematous areas, topical 
lidocaine 2%, and / or systemic pain medication such as nonsteroidal anti-
inflammatory drugs, codeine, and pregabalin for pain.

Dose modification may also be required (refer to Table 6-9)

Pancreatitis – In the event of abdominal pain or suspected pancreatitis, amylase and 
lipase laboratory samples should be collected for confirmation of the diagnosis. If 
pancreatitis is suspected, dabrafenib should be held until recovery.  Trametinib dosing 

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may continue.  Patients should be closely monitored when re-starting dabrafenib after an 
episode of pancreatitis
6.3.1.13 Dose modification and management guideline for hypertension
suspected to be related to dabrafenib and/or trametinib treatment
Increases in blood pressure have been observed in patients receiving trametinib. For adequate 
monitoring and management of hypertension, all blood pressure assessments should be 
performed under the following optimal conditions:

the patient has been seated with back support, ensuring that legs are uncrossed and flat on 
the floor

the patient is relaxed comfortably for at least 5 minutes

restrictive clothing has been removed from the cuff area and the right cuff size has been 
selected

the patient’s arm is supported so that the middle of the cuff is at heart level

the patient remains quiet during the measurement.
In patients with an initial blood pressure reading within the hypertensive range, a second reading 
should be taken at least 1 minute later, with the 2 readings averaged to obtain a final blood 
pressure measurement. The averaged value should be recorded in the eCRF.
Persistent hypertension is defined as an increase of systolic or diastolic blood pressure (SBP, 
DBP) > 95th percentile for age in three consecutive visits with blood pressure assessments from 
two readings collected as described above. Visits to monitor increased blood pressure can be 
scheduled independently from the protocol visits outlined in Table 7-1, Table 7-2 for LGG 
crossover patients or Table 7-3. Ideally, subsequent blood pressure assessments should be 
performed within one week.
Asymptomatic hypertension is defined as an increase of SBP or DBP >95th percentile in the 
absence of headache, light-headedness, vertigo, tinnitus, episodes of fainting or other symptoms 
indicative of hypertension.
For patients experiencing an increase in systolic and/or diastolic blood pressure that is persistent 
and may be associated with the study treatment, recommendations for dose modifications and 
management of hypertension are described below in Table 6-25.
Table 6-25
Mandatory dose modification and recommended clinical management 
for hypertension
Hypertension (NCI-CTCAE 4.03)
Severity
Recommended adverse event 
management guidelines
Mandatory dose modification 
requirements
(Scenario A)

Asymptomatic and 
persistenta increase of 
SBP or DBP >95th
percentile 

Clinically significant 
increase in DBP of 20 
mmHg (but still below 100 
mmHg).

Adjust current or initiate new 
antihypertensive medication.

Titrate antihypertensive 
medication(s) during the next 2 
weeks as indicated to achieve well-
controlledb BP

If BP is not well controlled within 2 
weeks, recommended to refer to a 
specialist and go to scenario (B).

Continue dabrafenib and 
trametinib at the same dose.

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Hypertension (NCI-CTCAE 4.03)
Severity
Recommended adverse event 
management guidelines
Mandatory dose modification 
requirements
(Scenario B)

Asymptomatic increase of 
SBP or DBP >99th
percentile, or
Failure to achieve well-
controlled BP within 2 weeks 
in Scenario A

Adjust current or initiate new 
antihypertensive medication(s).

Titrate antihypertensive 
medication(s) during the next 2 
weeks as indicated to achieve well-
controlled BP.

Interrupt dabrafenib and 
trametinib if clinically 
indicated.

Once BP is well controlled, 
restart dabrafenib and 
trametinib reduced by one 
dose level.

Symptomaticc
hypertension or

Persistent increase in 
SBP or DBP >99th
percentile, despite 
antihypertensive 
medication and dose 
reduction of study 
treatment.

Adjust current or initiate new 
antihypertensive medication(s)

Titrate antihypertensive medication 
during the next 2 weeks as 
indicated to achieve well-controlled 
BP.

Referral to a specialist for further 
evaluation and follow-up is 
recommended.

Interrupt dabrafenib and 
trametinib.

Once BP is well controlled, 
restart dabrafenib and 
trametinib reduced by one 
dose level.

Refractory hypertension 
unresponsive to above 
interventions or 
hypertensive crisis.

Continue follow-up per protocol.

Permanently discontinue 
dabrafenib and trametinib.
a.
Hypertension detected in two separate readings during up to three consecutive visits.
b.
Well-controlled blood pressure defined as SBP and DBP ≤95th percentile in two separate readings during 
up to three consecutive visits.
c.
Symptomatic hypertension defined as hypertension aggravated by symptoms (e.g., headache, light-
headedness, vertigo, tinnitus, episodes of fainting) that resolve after the blood pressure is controlled within 
the normal range.
6.3.1.14 Dose modification and management guideline for hemorrhage
Hemorrhage, including major hemorrhage defined as symptomatic bleeding in a critical area or 
organ, can occur when dabrafenib is administered with trametinib. Permanently discontinue 
dabrafenib and trametinib for all Grade 4 hemorrhagic events and for any persistent Grade 3 
hemorrhagic events. Withhold dabrafenib and trametinib for Grade 3 hemorrhagic events; if 
improved, resume at the next lower dose level. 
6.3.1.15 Dose modification and management guideline for thromboembolic 
events
Advise patients to immediately seek medical care if they develop symptoms of DVT or 
pulmonary embolism (PE), such as shortness of breath, chest pain, or arm or leg swelling. If 
any signs or symptoms of venous thromboembolism are present, the patient will undergo 
specific laboratory and medical imaging assessments to confirm. The medical imaging 
assessment(s) selected will depend on the anatomic site or organ of involvement. If the 
diagnosis is confirmed, appropriate medical care according to standard local clinical practice 
should be initiated immediately. 
Permanently discontinue trametinib for life threatening PE. Withhold trametinib for 
uncomplicated venous thromboembolism for up to 3 weeks; if improved, trametinib may be 
resumed at a lower dose level.  Dabrafenib dosing may continue.

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6.3.1.16 Dose modification and management guidelines for carboplatin with 
vincristine treatment
The induction cycle should only be interrupted in the event of grade 3 neurotoxicity, grade 2 
nephrotoxicity, grade 4 hematologic toxicity, or disease progression.
6.3.1.16.1
Myelosuppression
To begin induction or each cycle of maintenance chemotherapy:

ANC should be ≥1000/µL and platelet count ≥100,000/µL
If ANC <1,000/µL or platelet count <100,000/µL:

hold administration and repeat counts every 7 days.
Each cycle of induction or maintenance chemotherapy should begin at full dose, unless delays 
have been required because of myelosuppression during the previous two successive cycles. If 
this has occurred, then begin the next cycle with 75% of full dose carboplatin.
During induction or maintenance:

If ANC falls <500/µL and/or platelet count <50,000/µL, hold chemotherapy administration 
and repeat counts every 7 days until they recover to an ANC of ≥1000/µL and platelet count 
of ≥100,000/µL.

Resume at 75% of full dose carboplatin when these levels are reached. The 75% reduced 
dose should continue for the remainder of Induction or Maintenance.
However, if a patient is dose reduced during Induction, they can start the first maintenance cycle 
at 100% dosing. Those patients who are dose reduced during maintenance, should continue at 
the dose reduction throughout the remainder of all maintenance cycles.
Once induction or maintenance has started, vincristine should not be held due to 
Myelosuppression.
6.3.1.16.2
Nephrotoxicity
If creatinine is greater than upper limit of normal for the patient’s age, a creatinine clearance or 
GFR must be determined.  If the creatinine clearance is <75% of normal for the patient’s age, 
then the carboplatin dose should be held until creatinine clearance recovers to 75% of normal. 
Carboplatin dose should then be reduced by 25%. 
6.3.1.16.3
Hepatotoxicity
If Grade 3-4 hepatotoxicity develops during maintenance, hold chemotherapy until toxicity is 
less than Grade 2.  If the etiology of the toxicity is unexplained, then the dose of vincristine and 
carboplatin should be reduced by 25%. 

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6.3.1.16.4
Neurotoxicity
Seizures
For seizure due to vincristine, hold one dose, then resume at 1.0 mg/m2 (1.5 mg max) while on 
anticonvulsants. If seizures do not recur, escalate to full dose. For seizures not associated with 
vincristine, place patient on anticonvulsants after appropriate neurological evaluations, and 
proceed with chemotherapy at full doses.
Encephalopathy
Neither carboplatin nor vincristine commonly cause encephalopathy. Therefore the patient must 
be carefully assessed for other causes including hydrocephalus, shunt malfunction, over-
hydration, too rapid withdrawal of steroids, syndrome of inappropriate antidiuretic hormone 
secretion (SIADH), hypothalamic dysfunction, hemorrhage, anticonvulsant toxicity, etc. If a 
correctable cause cannot be identified, delay therapy up to 2 weeks and proceed only if patient 
has improved substantially.  Proceed with 20% reduction of both carboplatin and vincristine.
Peripheral neuropathy
For peripheral neuropathy from vincristine including weakness, paresthesia, ileus requiring IV 
therapy, stridor or ptosis or visual change, hold vincristine until symptoms are markedly 
improved. Resume at 66% dose or 1.0 mg/m2 (1.5 mg max). Escalate to full dose as tolerated. 
For jaw pain, constipation, mild foot drop, do not modify dose unless causing significant patient 
discomfort. Then the vincristine may be reduced to 80% or 1.2 mg/m2 (1.5 m2) and escalate as 
tolerated. 
6.3.1.16.5
Allergic reactions
Allergic reactions may occur in 10 to 30% of children receiving frequent carboplatin. These 
reactions can include facial flushing, urticaria, agitation, abdominal pain, edema, and 
sometimes bronchospasm leading to hypoxia and even respiratory arrest.  
Patients receiving carboplatin should be monitored by an experienced nurse throughout the 
infusion and for 1 hour after.  
Patients with any respiratory compromise as a result of carboplatin therapy should not receive 
carboplatin again and will be discontinued from the study.  They will continue into post-
treatment follow up.
Patients with mild or questionable reactions without respiratory compromise may continue on 
therapy with pre-treatment as per below. 
Carboplatin allergies should be documented as an adverse event in the eCRF.
Carboplatin should always be given in a setting with rapid access to pediatric advanced life-
supporting support capability.  
Consideration should be given to provide effective measures to prevent any recurrences of 
allergic reactions.  

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The following are offered as a supplement to institutional practice.  If an allergic reaction occurs 
it should be treated as for any other drug reactions as follows:
1. Stop the carboplatin infusion
2. Rapid assessment and management of the airway
3. If airway compromise or acute bronchospasm, give Epinephrine 0.01 ml/kg (maximum 
0.5 mL) of 1:1000 solution SQ and repeat in 20 minutes if necessary.
4. Albuterol inhaled can be used to treat resistant bronchospasm.
5. Diphenhydramine 1-2 mg/kg slow IV will help shorten the duration of the reaction, but 
does not have an immediate effect.
6. Glucocorticoids may have no effect for 6 to 12 hours, but may help prevent relapse of 
severe reactions. 
7. Patients with mild to moderate reactions (urticaria or mild bronchospasm) should be 
observed for a minimum of 6 hours. Those with moderate to severe reactions may relapse 
and should be observed in the hospital at least overnight. 
8. Prevention of recurrence:
a. Children with respiratory compromise should no longer receive carboplatin and are 
discontinued from the study.
b. Children with mild or questionable reactions can continue carboplatin with close 
monitoring and pre-treatment with steroids and diphenhydramine. For optimal effect, 
give Prednisone 1 mg/kg q6 hours PO or Prednisolone 1 mg/kg IV q6 hours for 3 to 4 
doses prior to carboplatin, with the last dose one hour before carboplatin. Also give 
diphenhydramine 1 mg/kg IV or PO one hour before carboplatin. All carboplatin 
should be given in a monitored setting with resuscitation drugs and equipment readily 
available. A guideline for desensitization and continuation of treatment if a patient’s 
tumor is responding well to carboplatin treatment has been published (Broom 1996).
6.3.1.17 Follow up on potential drug-induced liver injury (DILI) cases
Patients with transaminase increase combined with total bilirubin (TBIL) increase may be 
indicative of potential DILI, and have to be considered as clinically important events. 
The threshold for potential DILI may depend on the patient’s baseline AST/ALT and TBIL 
value; patients meeting any of the following criteria will require further follow-up as outlined 
below:

For patients with normal ALT and AST and TBIL value at baseline: AST or ALT > 3.0 x 
ULN combined with TBIL > 2.0 x ULN 

For patients with elevated AST or ALT or TBIL value at baseline: [AST or ALT > 2 x 
baseline AND > 3.0 x ULN] OR [AST or ALT > 8.0 x ULN], combined with [TBIL > 2 x 
baseline (if elevated at baseline) AND > 2.0 x ULN]
Medical review needs to ensure that liver test elevations are not caused by cholestasis, defined 
as ALP elevation > 2.0 x ULN with R value < 2 in patients without bone metastasis, or elevation 
of ALP liver fraction in patients with bone metastasis.

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Note: (The R value is calculated by dividing the ALT by the ALP, using multiples of the ULN 
for both values. It denotes the relative pattern of ALT and/or ALP elevation is due to cholestatic
(R ≤2), hepatocellular (R ≥5), or mixed (R > 2 and < 5) liver injury).
In the absence of cholestasis, these patients should be immediately discontinued from study 
drug treatment, and repeat LFT testing as soon as possible, preferably within 48 hours from the 
awareness of the abnormal results. The evaluation should include laboratory tests, detailed 
history, physical assessment and the possibility of liver metastasis or new liver lesions, 
obstructions/compressions, etc. 

Laboratory tests should include ALT, AST, albumin, creatine kinase, total bilirubin, direct 
and indirect bilirubin, GGT, prothrombin time (PT)/INR and alkaline phosphatase. 

A detailed history, including relevant information, such as review of ethanol, concomitant 
medications, herbal remedies, supplement consumption, history of any pre-existing liver 
conditions or risk factors, should be collected.

Further testing for acute hepatitis A, B, C or E infection and liver imaging (e.g. biliary 
tract) may be warranted. 

Obtain PK sample, as close as possible to last dose of study drug.

Additional testing for other hepatotropic viral infection (CMV, EBV or HSV), 
autoimmune hepatitis or liver biopsy may be considered as clinically indicated or after 
consultation with specialist/hepatologist. 
All cases confirmed on repeat testing meeting the laboratory criteria defined above, with no 
other alternative cause for LFT abnormalities identified should be considered as “medically 
significant”, thus, met the definition of SAE (Section 8.2.1) and reported as SAE using the term 
“potential drug-induced liver injury”. All events should be followed up with the outcome clearly
documented.
6.4
Concomitant medications
6.4.1
Permitted concomitant therapy
The investigator must be informed as soon as possible about any medication taken from the 
time of screening until the end of post treatment follow up. Any concomitant medication(s), 
including dietary supplements, taken during the study will be recorded in the Concomitant 
Medications eCRF. The minimum requirement is that drug name, dose, and the dates of 
administration are to be recorded. Additionally, a complete list of all prior surgical procedures 
will be recorded on the Medical History eCRF.  
Patients should receive full supportive care during the study, including transfusions of blood 
and blood products, and treatment with antibiotics, anti-emetics, anti-diarrheals, and analgesics, 
and other care as deemed appropriate, and in accordance with their institutional guidelines. Use 
of anticoagulants such as warfarin is permitted, however, caution should be exercised and 
additional International Normalized Ratio (INR) monitoring is recommended when dabrafenib 
is used concomitantly with warfarin. 

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6.4.2
Permitted concomitant therapy requiring caution and/or action 
The following medications should be used with caution as their concentrations may be altered 
by dabrafenib or they may alter dabrafenib concentrations:

Drugs that are moderate inhibitors or inducers of CYP3A and CYP2C8 as they may alter 
concentrations of dabrafenib.

Dabrafenib has been shown to induce CYP3A4 and CYP2C9 in vivo using midazolam 
(CYP3A4 substrate) and S-warfarin (CYP2C9 substrate).  Dabrafenib is an in vitro 
inducer of CYP2B6 and other enzymes such as CYP2C8, CYP2C19, UDP-glucuronyl 
transferases. Transporters may also be affected.  Co-administration of dabrafenib and 
medications which are affected by the induction of these enzymes (including warfarin) 
and transporters may result in loss of efficacy.  If co-administration of these medications 
is necessary, investigators should monitor patients for loss of efficacy or consider 
substitutions of these medications. A partial list of these medications is provided in 
Appendix 1.

Warfarin exposure has been shown to decrease (37% decrease) due to dabrafenib-
mediated enzyme induction. Conversely, if dabrafenib dosing is reduced, interrupted, or 
discontinued, warfarin exposure may be increased. Thus, warfarin dosing may need to be 
adjusted based on PT/INR during and after treatment with dabrafenib. Prophylactic low 
dose warfarin may be given to maintain central catheter patency. 

The renal effects of nephrotoxic compounds (e.g. aminoglycosides) may be potentiated by 
carboplatin and should be used with caution.
6.4.2.1
Anti-cancer Surgery
For patients enrolled in the HGG cohort, anti-cancer surgery is allowed for patients enrolled on 
the study after at least 8 months on treatment or after radiologic progression of disease has been 
confirmed by investigator. Study treatment may be taken up to two days prior to surgery as 
deemed appropriate by the investigator. If the investigator determines that further treatment 
with dabrafenib and trametinib may be clinically beneficial to the patient, study treatment may 
be resumed when the surgical wound is stable, the patient is able to take oral medications and 
at least 3 days after surgery.  Prior to anti-cancer surgery, investigators are required to complete 
a RANO evaluation.
For patients enrolled into the LGG cohort, elective anti-cancer surgery should not be performed 
prior to either centrally confirmed radiologic progression of disease or at least a total of 36 
months of treatment plus follow-up, whichever comes first. Elective anti-cancer surgery prior 
to documented radiologic progression does not qualify a patient for cross over therapy within 
this protocol.  Study treatment may be taken up to one day prior to surgery as deemed 
appropriate by the investigator. If the investigator determines that further treatment with 
dabrafenib and trametinib may be clinically beneficial to the patient, study treatment may be 
resumed when the patient has recovered sufficiently to consume a semi-solid diet. Prior to anti-
cancer surgery, investigators are required to complete a RANO evaluation.

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6.4.2.2
Radiotherapy
Radiation skin injury has been reported with concurrent use of dabrafenib and radiation. To 
reduce this risk, it is recommended that dabrafenib be held for at least 3 days before and after 
fractionated radiotherapy and at least 1 day before and after stereostatic radiotherapy (Anker 
2016). These recommendations can be modified based on the physician’s assessment of the risk 
of radiation skin injury. Prior to starting radiotherapy, investigators are required to complete a 
RANO evaluation.
Elective anti-cancer radiotherapy should not be performed prior to the either documented 
radiologic progression of disease or at least a total of 36 months of treatment and follow-up, 
whichever comes first.  Elective anti-cancer radiotherapy prior to documented radiologic 
progression does not qualify a patient for cross over therapy (LGG cohort) within this protocol.
6.4.3
Prohibited concomitant therapy
The use of certain medications and illicit drugs within 28 days or 5 half-lives, whichever is 
shorter, prior to the first dose of study drug and for the duration of the study will not be allowed. 
The following medications or non-drug therapies are also prohibited while on treatment in this 
study:

Other anti-cancer therapies (except for anti-cancer surgery according to Section 6.4.2.1
and radiotherapy in Section 6.4.2.2);

Other investigational drugs;

Antiretroviral drugs;

Herbal remedies (e.g., St. John’s wort);

Dabrafenib is metabolized primarily by Cytochrome P450 (CYP) 2C8 and CYP3A4.  Co-
administration of dabrafenib with ketoconazole, a CYP3A4 inhibitor, or with gemfibrozil, 
a CYP2C8 inhibitor, resulted in increases in dabrafenib AUC of 71% and 47%, 
respectively. Drugs that are strong inhibitors or inducers of CYP3A and CYP2C8 
(Appendix 1) may only be used under special circumstances (e.g. as a single use for a 
procedure) while treatment with study drug is interrupted as they may alter dabrafenib 
concentrations; consider therapeutic substitutions for these medications. The list may be 
modified based on emerging data. 

Vincristine is a substrate for CYP3A. Drugs that are strong inhibitors or inducers of 
CYP3A (Appendix 1) may only be used under special circumstances (e.g. as a single use 
for a procedure) while treatment with study drug is interrupted, consider therapeutic 
substitutions for these medications.

Vincristine is also a substrate for P-glycoprotein (P-gp). The concomitant use of potent P-
pg inhibitors or inducers should be avoided.  

Simultaneous administration of phenytoin and vincristine have been reported to reduce 
blood levels of phenytoin and to increase seizure activity.

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6.5
Patient numbering, treatment assignment or randomization
6.5.1
Patient numbering
Each patient is identified in the study by a Subject Number (Subject No.), that is assigned when 
the patient is first enrolled for screening and is retained as the primary identifier for the patient 
throughout his/her entire participation in the trial. The Subject No. consists of the Center 
Number (Center No.) (as assigned by Novartis to the investigative site) with a sequential patient 
number suffixed to it, so that each patient is numbered uniquely across the entire database. Upon 
signing the informed consent form, the patient is assigned to the next sequential Subject No. 
available to the investigator through the Oracle Clinical RDC interface.
The investigator or designated staff will contact the IRT and provide the requested identifying 
information for the patient to register them into the IRT. Once assigned, the Subject No. must 
not be reused for any other patient and the Subject No. for that individual must not be changed, 
even if the patient is re-screened. If the patient fails to start treatment or is not randomized (LGG 
cohort) for any reason, the reason will be entered into the Screening Disposition page.
IRT must be notified within 2 days that the patient did not receive study drug or was not 
randomized (for LGG cohort).
6.5.2
Treatment assignment or randomization
HGG Cohort
All patients will receive the same treatment in the HGG cohort. 
LGG Cohort
Patients in the LGG cohort will be randomized in a 2:1 ratio to dabrafenib with trametinib or 
carboplatin with vincristine. 
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from patients and investigator staff. A patient 
randomization list will be produced by the Interactive Response Technology (IRT) provider 
using a validated system that automates the random assignment of patient numbers to 
randomization numbers. These randomization numbers are linked to the different treatment 
arms, which in turn are linked to medication numbers.
The investigator or his/her delegate will log on to the IRT and confirm that the LGG patient 
fulfills all the inclusion/exclusion criteria. The IRT will assign a randomization number to the 
LGG patient, which will be used to link the patient to a treatment arm and will specify a unique 
medication number for the first package of study treatment to be dispensed to the patient. 
6.5.3
Treatment blinding
All patients in the HGG cohort receive the same treatment therefore blinding is not applicable.
The LGG cohort is open label. Sponsor statisticians and statistical programmers will remain 
blinded to the identity of the treatment from the time of randomization until database lock for 
the LGG cohort only. Dummy randomization codes will be employed, with the actual 

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randomization codes kept strictly confidential until the time of database lock and treatment 
unblinding. However, independent statistician(s) and programmer(s) who will perform analyses 
for the DMC will have access to the randomization codes.
6.6
Study drug preparation and dispensation
Patients and/or caregivers will be provided with an adequate supply of study drugs for self-
administration at home, including instructions for administration, until at least their next 
scheduled study visit.
The investigator or responsible site personnel must instruct the patient or caregiver to take the 
study drugs as per protocol. The study drugs will be dispensed to the patient by authorized site 
personnel only. All dosages prescribed to the patient and all dose changes during the study must 
be recorded on the Dosage Administration Record eCRF.
Drug accountability must be performed on a regular basis. Patients will be instructed to return 
unused study drugs to the site at each visit. The site personnel will ensure that the appropriate 
dose of each study drug is provided at each visit. 
Responsible site personnel will identify the study treatment package(s) to dispense by the 
medication(s) assigned by the IRT to the patient. Site personnel will add the patient number on 
the label. If the label has 2-parts (base plus tear-off label), immediately before dispensing the 
package to the patient, site personnel will detach the outer part of the label from the package 
and affix it to the patient’s source document.
6.6.1
Study treatment packaging and labeling
Study treatment, dabrafenib (DRB436) and trametinib (TMT212), will be provided as global 
clinical open-labelled supply or commercially sourced supply. Global supplies will be packed 
and labeled under the responsibility of Novartis Drug Supply Management. Commercially 
sourced supplies will be packed and labeled as per local regulations.
Dabrafenib and trametinib in different formulations and strengths can be used once a protocol 
amendment with additional formulation description is approved.
Study treatment labels will comply with the legal requirements of each country and will include 
storage conditions, and Novartis Drug Supply Management supplied treatment will also contain 
a unique medication number (corresponding to study treatment and strength).  
Table 6-26
Packaging and labeling
Study treatments
Packaging
Labeling 
DRB436 50mg
Capsules in bottles
DRB436 50mg HPMC
DRB436 75mg
Capsules in bottles
DRB436 75mg HPMC
DRB436 10mg 
Dispersible tablets in bottles
DRB436 10mg
TMT212 0.5 mg
Tablets in bottles
TMT212 0.5 mg FCT
TMT212 2.0 mg
Tablets in bottles 
TMT212 2.0 mg FCT
TMT212 PIB 5mg
Powder in bottle
TMT212 PIB 5mg FMI
Carboplatin 175 mg/m2
Refer to local product information
Refer to local product information
Vincristine 1.5 mg/m2
Refer to local product information
Refer to local product information

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6.6.2
Drug supply and storage
Study treatments must be received by designated personnel at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and designated 
site personnel have access. Upon receipt, the study treatment should be stored according to the 
instructions specified on the drug labels and in the [Investigator’s Brochure]. 
6.6.3
Study drug compliance and accountability
6.6.3.1
Study drug compliance
Compliance will be assessed by the investigator and/or study personnel at each patient visit and 
information provided by the patient and/or caregiver will be captured in the Drug 
Accountability Form. This information must be captured in the source document at each patient 
visit.
On PK sampling days, compliance will be assured by administrations of the study treatment 
under the supervision of investigator or his/her designee, and will be verified by determinations 
of dabrafenib and trametinib in plasma.
6.6.3.2
Study drug accountability
The investigator or designee must maintain an accurate record of the shipment and dispensing 
of study treatment in a drug accountability log. Drug accountability will be noted by the field 
monitor during site visits and at the completion of the study. Patients will be asked to return all 
unused study treatment and packaging on a regular basis, at the end of the study or at the time 
of study treatment discontinuation.
At study close-out, and, as appropriate during the course of the study, the investigator will return 
all used and unused study treatment, packaging, drug labels, and a copy of the completed drug 
accountability log to the Novartis monitor or to the Novartis address provided in the investigator 
folder at each site.
6.6.3.3
Handling of other study treatment
Not applicable.
6.6.4
Disposal and destruction
The study drug supply can be destroyed at the local Novartis facility, Drug Supply group or 
third party, as appropriate. Study drug destruction at the investigational site will only be 
permitted if authorized by Novartis in a prior agreement and if permitted by local regulations. 
7
Visit schedule and assessments
7.1
Study flow and visit schedule
Table 7-1 is the visit evaluation schedule for all HGG patients and LGG patients randomized to 
the dabrafenib and trametinib treatment arm. Table 7-2 is the visit evaluation schedule for LGG 
patients crossed over to dabrafenib plus trametinib treatment. Table 7-3 is the visit evaluation 

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schedule for LGG patients randomized to the chemotherapy treatment arm. These tables list all 
of the assessments and indicates with an “X”, the visits when they are performed. All data 
obtained from these assessments must be supported in the patient’s source documentation. The 
table indicates which assessments produce data to be entered into the database (D) or remain in 
source documents only (S) (“Category” column).
Screening assessments must occur within 28 days of Week 1 (Day 1), as per Table 7-1.  A urine 
pregnancy test must be completed on Day 1 and confirmed negative prior to dosing.
For Visits on Weeks 1 through 5, there is a general ±2 day visit window.  For all subsequent 
visits, there is a general ±7 day visit window, except during the post-treatment follow which is 
every 16 weeks with ±14 day visit window.

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Protocol No. CDRB436G2201
Table 7-1
Visit evaluation schedule for HGG and LGG dabrafenib and trametinib treatment arm
Screening 
period
Treatment Period 
Post Treatment Period
Category
Protocol Section
Screening
Weekly 
Assessments 
(Weeks 1 to 5) 
± 2 day visit 
window
Every 8 Week Assessments
(Weeks 8 to 56)
±7 day visit window
Every 16 
weeks
±7 day visit 
window
End of treatment (EoT)
Within 30 days after last dose
Post Treatment Follow up
Every 16 weeks ±14 day visit 
window
Survival follow up
Every 3 months
Week 
-28 to -1
1
2
3
4
5
8
16
24
32
40
48
56
72, 
88-n
Obtain Informed 
Consent/Assent
D
7.1.2
X
Obtain Informed 
Consent/Assent for 
post-progression 
treatment on 
dabrafenib with 
trametinib
D
7.1.3.1
X – at the time of Treatment after Progression of Disease
Local determination 
of BRAF V600  
D
5.2, 7.1.2
X
Tumor tissue for 
histopathology (HGG 
only) and BRAF
central test 
confirmation (both 
HGG and LGG, 
paraffin block or 
slides)
D
7.2.4
X
IRT Registration 
(after ICF signature)
S
7.1.2.1
X

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Protocol No. CDRB436G2201
Screening 
period
Treatment Period 
Post Treatment Period
Category
Protocol Section
Screening
Weekly 
Assessments 
(Weeks 1 to 5) 
± 2 day visit 
window
Every 8 Week Assessments
(Weeks 8 to 56)
±7 day visit window
Every 16 
weeks
±7 day visit 
window
End of treatment (EoT)
Within 30 days after last dose
Post Treatment Follow up
Every 16 weeks ±14 day visit 
window
Survival follow up
Every 3 months
Week 
-28 to -1
1
2
3
4
5
8
16
24
32
40
48
56
72, 
88-n
Eligibility checklist 
(within IRT)
S
7.1.2.1
X
IRT Randomization 
(LGG cohort only)
D
6.5.2
X
Patient History
Demography
D
7.1.2.3
X
Inclusion/exclusion 
criteria
D
5.2, 5.3
X
Medical History 
D
7.1.2.3
X
Seizure history
D
7.2.2.2
X
Diagnosis and extent 
of cancer
D
7.1.2.3
X
Prior antineoplastic 
therapy
D
7.1.2.3
X
Prior/concomitant 
medications and non-
drug therapies
D
7.1.2.3
X
X – Continuous
Prior surgical 
procedures
D
7.1.2.3
X
Physical exam
Physical examination
S
7.2.2.1
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X

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Protocol No. CDRB436G2201
Screening 
period
Treatment Period 
Post Treatment Period
Category
Protocol Section
Screening
Weekly 
Assessments 
(Weeks 1 to 5) 
± 2 day visit 
window
Every 8 Week Assessments
(Weeks 8 to 56)
±7 day visit window
Every 16 
weeks
±7 day visit 
window
End of treatment (EoT)
Within 30 days after last dose
Post Treatment Follow up
Every 16 weeks ±14 day visit 
window
Survival follow up
Every 3 months
Week 
-28 to -1
1
2
3
4
5
8
16
24
32
40
48
56
72, 
88-n
Performance status 
(Karnofsky/Lansky)
D
7.2.2.5
X
X
X
X
X
X
X
X
X
X
X
X
X
Height 
D
7.2.2.4
X
X
X
X
X
X
X
X
X
X
X
X
Weight
D
7.2.2.4
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs
D
7.2.2.3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory assessments
Hematology
D
7.2.2.8.1
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistry
D
7.2.2.8.2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hepatitis testing for 
clearance (only for 
positive history)
D
7.2.2.8.5
X
Urinalysis
D
7.2.2.8.3
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy test, 
serum (as applicable)
D
7.2.2.8.4
X
Pregnancy test, urine 
(as applicable)
D
7.2.2.8.4
X – Day 1 and Monthly thereafter
X

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Protocol No. CDRB436G2201
Screening 
period
Treatment Period 
Post Treatment Period
Category
Protocol Section
Screening
Weekly 
Assessments 
(Weeks 1 to 5) 
± 2 day visit 
window
Every 8 Week Assessments
(Weeks 8 to 56)
±7 day visit window
Every 16 
weeks
±7 day visit 
window
End of treatment (EoT)
Within 30 days after last dose
Post Treatment Follow up
Every 16 weeks ±14 day visit 
window
Survival follow up
Every 3 months
Week 
-28 to -1
1
2
3
4
5
8
16
24
32
40
48
56
72, 
88-n
Imaging
Tumor evaluation
D
7.2.1
X
X
X
X
X
X
X
X
X
X
X - until PD 
or off 
study.
Treatment after 
Progression of 
Disease on 
dabrafenib with 
trametinib
D
7.1.3.1
X - See Section 7.1.3.1 for details
Safety
Adverse events 
 
D
8.1
X – Continuous
Dermatological 
Evaluation 
D
7.2.2.6
X
X
X - Monthly (local qualified physician assessment for 
non-clinic visits)
X  – At EOT, 3 and 6 
months after the last dose of 
study treatment or until start 
of new antineoplastic 
therapy initiated 
ECG
D
7.2.2.10.1
X
X
X
X
X
X
X

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Protocol No. CDRB436G2201
Screening 
period
Treatment Period 
Post Treatment Period
Category
Protocol Section
Screening
Weekly 
Assessments 
(Weeks 1 to 5) 
± 2 day visit 
window
Every 8 Week Assessments
(Weeks 8 to 56)
±7 day visit window
Every 16 
weeks
±7 day visit 
window
End of treatment (EoT)
Within 30 days after last dose
Post Treatment Follow up
Every 16 weeks ±14 day visit 
window
Survival follow up
Every 3 months
Week 
-28 to -1
1
2
3
4
5
8
16
24
32
40
48
56
72, 
88-n
Cardiac imaging/ 
ECHO
D
7.2.2.10.2
X
X
X
X
X
X
X
Ophthalmic 
examination
D
7.2.2.7
X
X
X
X
X
X
X
Study drug administration
DRB436 
administration
D
6.1
X - Continuous b.i.d daily dosing
TMT212 
administration
D
6.1
X – Continuous q.d. daily dosing
Pharmacokinetics
Full PK sampling 
DRB436 
D
7.2.3
X
X
X
Full PK sampling 
TMT212
D
7.2.3
X
X
X
Sparse PK sampling 
DRB436 (subset of 
LGG patients)
D
7.2.3
X
X
Sparse PK sampling 
TMT212 (subset of 
LGG patients)
D
7.2.3
X
X
Meal record
D
7.2.3.3
X
X
X

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Protocol No. CDRB436G2201
Screening 
period
Treatment Period 
Post Treatment Period
Category
Protocol Section
Screening
Weekly 
Assessments 
(Weeks 1 to 5) 
± 2 day visit 
window
Every 8 Week Assessments
(Weeks 8 to 56)
±7 day visit window
Every 16 
weeks
±7 day visit 
window
End of treatment (EoT)
Within 30 days after last dose
Post Treatment Follow up
Every 16 weeks ±14 day visit 
window
Survival follow up
Every 3 months
Week 
-28 to -1
1
2
3
4
5
8
16
24
32
40
48
56
72, 
88-n
Patient Reported Outcomes
Parent Proxy Global 
7+2 Health (LGG 
cohort only)
D
7.2.6
X
X
X
X
X
X
X
X
X
X
X
X
Acceptability/Palatabi
lity Questionnaire –
Dabrafenib
D
7.2.7
X
X
Acceptability/Palatabi
lity Questionnaire –
Trametinib 
D
7.2.7
X
X
Study Completion
End of Phase 
Disposition
D
7.1.4
X
X
X

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Protocol No. CDRB436G2201
Screening 
period
Treatment Period 
Post Treatment Period
Category
Protocol Section
Screening
Weekly 
Assessments 
(Weeks 1 to 5) 
± 2 day visit 
window
Every 8 Week Assessments
(Weeks 8 to 56)
±7 day visit window
Every 16 
weeks
±7 day visit 
window
End of treatment (EoT)
Within 30 days after last dose
Post Treatment Follow up
Every 16 weeks ±14 day visit 
window
Survival follow up
Every 3 months
Week 
-28 to -1
1
2
3
4
5
8
16
24
32
40
48
56
72, 
88-n
Antineoplastic 
therapies since 
discontinuation of 
study treatment
D
7.1.6.1
X
X
X
Survival Follow-up
D
7.1.6.2
X

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Protocol No. CDRB436G2201
Table 7-2
Visit evaluation schedule for LGG crossover patients
Crossover Treatment Period for LGG patients 
Crossover Post Treatment 
Period
Category
Protocol Section
Pre-Treatment
Weekly Assessments 
(Weeks 1 to 5) ± 2 day 
visit window
Every 8 Week Assessments
(Weeks 8 to 56)
±7 day visit window
Every 16 
weeks
±7 day 
visit 
window
End of treatment (EoT)
Within 30 days after last dose
Post Treatment Follow up
Every 16 weeks ±14 day visit 
window
Survival follow up
Every 3 months
Week 
-28 to -1
1
2
3
4
5
8
1
6
2
4
3
2
4
0
4
8
56
72, 
88-n
Obtain Informed 
Consent/Assent for 
post-progression 
treatment on 
dabrafenib with 
trametinib
D
7.1.3.1
X – at the time of Treatment after Progression of Disease on dabrafenib 
with trametinib
Concomitant 
medications and non-
drug therapies
D
7.1.2.3
X – Continuous
Physical exam
Physical examination
S
7.2.2.1
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Performance status 
(Karnofsky/Lansky)
D
7.2.2.5
X
X
X
X
X
X
X
X
X
X
X
X
Height 
D
7.2.2.4
X
X
X
X
X
X
X
X
X
X
X
Weight
D
7.2.2.4
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs
D
7.2.2.3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X

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Protocol No. CDRB436G2201
Crossover Treatment Period for LGG patients 
Crossover Post Treatment 
Period
Category
Protocol Section
Pre-Treatment
Weekly Assessments 
(Weeks 1 to 5) ± 2 day 
visit window
Every 8 Week Assessments
(Weeks 8 to 56)
±7 day visit window
Every 16 
weeks
±7 day 
visit 
window
End of treatment (EoT)
Within 30 days after last dose
Post Treatment Follow up
Every 16 weeks ±14 day visit 
window
Survival follow up
Every 3 months
Week 
-28 to -1
1
2
3
4
5
8
1
6
2
4
3
2
4
0
4
8
56
72, 
88-n
Laboratory assessments
Hematology
D
7.2.2.8.
1
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistry
D
7.2.2.8.
2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis
D
7.2.2.8.
3
X
X
X
X
X
X
X
X
X
X
X
Pregnancy test, serum 
(as applicable)
D
7.2.2.8.
4
X
Pregnancy test, urine 
(as applicable)
D
7.2.2.8.
4
X – Day 1 and Monthly thereafter
X
Imaging
Tumor evaluation
D
7.2.1
X
X
X
X
X
X
X
X
X
X
X - until 
PD or off 
study
Treatment after 
Progression of Disease 
on dabrafenib with 
trametinib
D
7.1.3.1
X - See Section 7.1.3.1 for details

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Protocol Amended Version 05 
Protocol No. CDRB436G2201
Crossover Treatment Period for LGG patients 
Crossover Post Treatment 
Period
Category
Protocol Section
Pre-Treatment
Weekly Assessments 
(Weeks 1 to 5) ± 2 day 
visit window
Every 8 Week Assessments
(Weeks 8 to 56)
±7 day visit window
Every 16 
weeks
±7 day 
visit 
window
End of treatment (EoT)
Within 30 days after last dose
Post Treatment Follow up
Every 16 weeks ±14 day visit 
window
Survival follow up
Every 3 months
Week 
-28 to -1
1
2
3
4
5
8
1
6
2
4
3
2
4
0
4
8
56
72, 
88-n
Safety
Adverse events 
 
D
8.1
X – Continuous
Dermatological 
Evaluation
D
7.2.2.6
X
X - Monthly (local qualified physician assessment 
for non-clinic visits)
X  – At EOT, 3 and 6 
months after the last 
dose of study 
treatment or until start 
of new antineoplastic 
therapy initiated 
ECG
D
7.2.2.1
0.1
X
X
X
X
X
X
X
Cardiac imaging/ 
ECHO
D
7.2.2.1
0.2
X
X
X
X
X
X
X
Ophthalmic 
examination
D
7.2.2.7
X
X
X
X
X
X
Study drug administration
DRB436 administration
D
6.1
X - Continuous b.i.d daily dosing
TMT212 administration
D
6.1
X – Continuous q.d. daily dosing

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Protocol Amended Version 05 
Protocol No. CDRB436G2201
Crossover Treatment Period for LGG patients 
Crossover Post Treatment 
Period
Category
Protocol Section
Pre-Treatment
Weekly Assessments 
(Weeks 1 to 5) ± 2 day 
visit window
Every 8 Week Assessments
(Weeks 8 to 56)
±7 day visit window
Every 16 
weeks
±7 day 
visit 
window
End of treatment (EoT)
Within 30 days after last dose
Post Treatment Follow up
Every 16 weeks ±14 day visit 
window
Survival follow up
Every 3 months
Week 
-28 to -1
1
2
3
4
5
8
1
6
2
4
3
2
4
0
4
8
56
72, 
88-n
Study Completion
End of Phase 
Disposition
D
7.1.4
X
X
Antineoplastic 
therapies since 
discontinuation of 
study treatment
D
7.1.6.1
X
X
X
Survival Follow-up
D
7.1.6.2
X

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Protocol Amended Version 05 
Protocol No. CDRB436G2201
Table 7-3
Visit evaluation schedule for LGG chemotherapy arm
Screening 
period
Treatment Period for Induction and Maintenance phases for LGG 
chemotherapy
Post Treatment Period
Category
Protocol Section
Screening
Weekly 
Assessments 
(Weeks 1 to 5) 
± 2 day visit 
window
Every 8 Week Assessments
(Weeks 8 to 56)
±7 day visit window
End of treatment 
(EoT)
Within 30 days 
after last dose
Post Treatment 
Follow up
Every 16 weeks 
±14 day visit 
window
Survival follow up
Every 3 months
Week 
-28 to -1
1
2
3
4
5
8
16
24
32
40
48
56
Obtain Informed 
Consent/Assent
D
7.1.2
X
IRT Registration 
(after ICF signature)
S
7.1.2.1
X
Eligibility checklist 
(within IRT)
S
7.1.2.1
X
IRT Randomization 
D
6.5.2
X
Patient History
Demography
D
7.1.2.3
X
Inclusion/exclusion 
criteria
D
5.2, 5.3
X
Medical History 
D
7.1.2.3
X
Seizure history
D
7.2.2.2
X

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Protocol Amended Version 05 
Protocol No. CDRB436G2201
Screening 
period
Treatment Period for Induction and Maintenance phases for LGG 
chemotherapy
Post Treatment Period
Category
Protocol Section
Screening
Weekly 
Assessments 
(Weeks 1 to 5) 
± 2 day visit 
window
Every 8 Week Assessments
(Weeks 8 to 56)
±7 day visit window
End of treatment 
(EoT)
Within 30 days 
after last dose
Post Treatment 
Follow up
Every 16 weeks 
±14 day visit 
window
Survival follow up
Every 3 months
Week 
-28 to -1
1
2
3
4
5
8
16
24
32
40
48
56
Diagnosis and extent 
of cancer
D
7.1.2.3
X
Prior antineoplastic 
therapy
D
7.1.2.3
X
Prior/concomitant 
medications and non-
drug therapies
D
7.1.2.3
X
X – Continuous
Prior surgical 
procedures
D
7.1.2.3
X
Physical exam
Physical examination
S
7.2.2.1
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Performance status 
(Karnofsky/Lansky)
D
7.2.2.5
X
X
X
X
X
X
X
X
X
X
X
X
Height 
D
7.2.2.4
X
X
X
X
X
X
X
X
X
X
X
Weight
D
7.2.2.4
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs
D
7.2.2.3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory assessments
Hematology
D
7.2.2.8.1
X
X
X
X
X
X
X
X
X
X
X
X
X
X

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Protocol Amended Version 05 
Protocol No. CDRB436G2201
Screening 
period
Treatment Period for Induction and Maintenance phases for LGG 
chemotherapy
Post Treatment Period
Category
Protocol Section
Screening
Weekly 
Assessments 
(Weeks 1 to 5) 
± 2 day visit 
window
Every 8 Week Assessments
(Weeks 8 to 56)
±7 day visit window
End of treatment 
(EoT)
Within 30 days 
after last dose
Post Treatment 
Follow up
Every 16 weeks 
±14 day visit 
window
Survival follow up
Every 3 months
Week 
-28 to -1
1
2
3
4
5
8
16
24
32
40
48
56
Chemistry
D
7.2.2.8.2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Local laboratory tests
D
7.2.2.8
X – Weekly or as needed per local practice throughout carboplatin with 
vincristine treatment 
Hepatitis testing for 
clearance (only for 
positive history)
D
7.2.2.8.5
X
Urinalysis
D
7.2.2.8.3
X
X
X
X
X
X
X
X
X
X
X
Pregnancy test, 
serum (as applicable)
D
7.2.2.8.4
X
Pregnancy test, urine 
(as applicable)
D
7.2.2.8.4
X – Day 1 and  Monthly thereafter
X
Imaging
Tumor evaluation
D
7.2.1
X
X
X
X
X
X
X
X
X
X - until PD 
or off study.
Safety
Adverse events 
 
D
8.1
X – Continuous

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Protocol Amended Version 05 
Protocol No. CDRB436G2201
Screening 
period
Treatment Period for Induction and Maintenance phases for LGG 
chemotherapy
Post Treatment Period
Category
Protocol Section
Screening
Weekly 
Assessments 
(Weeks 1 to 5) 
± 2 day visit 
window
Every 8 Week Assessments
(Weeks 8 to 56)
±7 day visit window
End of treatment 
(EoT)
Within 30 days 
after last dose
Post Treatment 
Follow up
Every 16 weeks 
±14 day visit 
window
Survival follow up
Every 3 months
Week 
-28 to -1
1
2
3
4
5
8
16
24
32
40
48
56
Dermatological 
Evaluation 
D
7.2.2.6
X
X
X - Monthly (local qualified physician assessment for non-
clinic visits)
X  – At EOT, 3 and 6 
months after the last dose 
of study treatment or until 
start of new antineoplastic 
therapy initiated 
ECG
D
7.2.2.10.
1
X
X
X
X
X
X
X
Cardiac imaging/ 
ECHO
D
7.2.2.10.
2
X
X
X
X
X
X
X
Ophthalmic 
examination
D
7.2.2.7
X
X
X
X
X
X
X
Study drug administration
Carboplatin
D
6.1.2
Weeks 1 – 4
Weeks 7 - 10
Weeks 13 - 16
Weeks 19 - 22
Weeks 25 - 28
Weeks 31 - 34
Weeks 37 - 40
Weeks 43 - 46
Weeks 49 - 52
Weeks 55 - 58
Vincristine
D
6.1.2
Weeks 1 - 10
Weeks 13 - 15

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Protocol Amended Version 05 
Protocol No. CDRB436G2201
Screening 
period
Treatment Period for Induction and Maintenance phases for LGG 
chemotherapy
Post Treatment Period
Category
Protocol Section
Screening
Weekly 
Assessments 
(Weeks 1 to 5) 
± 2 day visit 
window
Every 8 Week Assessments
(Weeks 8 to 56)
±7 day visit window
End of treatment 
(EoT)
Within 30 days 
after last dose
Post Treatment 
Follow up
Every 16 weeks 
±14 day visit 
window
Survival follow up
Every 3 months
Week 
-28 to -1
1
2
3
4
5
8
16
24
32
40
48
56
Weeks 19 - 21
Weeks 25 - 27
Weeks 31 - 33
Weeks 37 - 39
Weeks 43 - 45
Weeks 49 - 51
Weeks 55 - 57
Patient Reported Outcomes
Parent Proxy Global 
7+2 Health 
D
7.2.6
X
X
X
X
X
X
X
X
X
X
X
Study Completion

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Screening 
period
Treatment Period for Induction and Maintenance phases for LGG 
chemotherapy
Post Treatment Period
Category
Protocol Section
Screening
Weekly 
Assessments 
(Weeks 1 to 5) 
± 2 day visit 
window
Every 8 Week Assessments
(Weeks 8 to 56)
±7 day visit window
End of treatment 
(EoT)
Within 30 days 
after last dose
Post Treatment 
Follow up
Every 16 weeks 
±14 day visit 
window
Survival follow up
Every 3 months
Week 
-28 to -1
1
2
3
4
5
8
16
24
32
40
48
56
End of Phase 
Disposition
D
7.1.4
X
X
X
Antineoplastic 
therapies since 
discontinuation of 
study treatment
D
7.1.6.1
X
X
X
Survival Follow-up
D
7.1.6.2
X

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7.1.1
Molecular pre-screening 
There is no molecular pre-screening for this study. 
7.1.2
Screening
Written informed consent/assent must be obtained prior to any screening procedures. The 
window for screening each patient will be up to 28 days before the first dose, including a serum 
pregnancy test for women of childbearing potential. A urine pregnancy test must conducted and 
confirmed negative on Day 1 before dosing. Adverse events will also be recorded at this visit. 
Screening assessments to confirm eligibility should be performed as per the schedule of 
assessments (Table 7-1, Table 7-2, Table 7-3). 
Local BRAF V600 mutation result may be used to qualify patients for enrollment, as part of the 
study inclusion criteria listed in Section 5.2. The CRF page for method of local BRAF V600 
mutation testing, including the methodology used for local assessment, must be completed for 
patients whose tumor sample was tested by a local institutional assay. BRAF V600 mutation 
result must be locally documented prior to Day 1 (HGG cohort) or randomization (LGG cohort). 
The BRAF V600 mutation status will be assessed using a validated tissue-based test. Molecular-
based BRAF V600 testing should be used where available and is strongly preferred over non-
molecular methods, e.g. immunohistochemistry. Liquid biopsy-based BRAF V600 results 
cannot be used to enroll patients. BRAF V600 mutation results will be subjected to retrospective 
central confirmation by a Novartis designated laboratory. For the retrospective central 
confirmation all subjects will be required to provide a tumor tissue sample at screening prior to 
study treatment, as either a tumor block or a minimum of 20 FFPE slides (see Table 7-8). Central 
confirmation of BRAF V600 mutation status is not required for enrollment, if local test results 
are positive for BRAF V600 mutation. Patients will not be excluded if central testing is later 
found to be discordant or uninformative (e.g. inadequate sample).
For patients who do not have a BRAF V600 mutation result documented locally, a tumor sample 
must be submitted for central testing of BRAF mutation status during screening. The minimum 
requirements for this sample are listed in Table 7-8.
A patient who has a laboratory test result(s) that does not satisfy the entrance criteria may have 
the test(s) repeated within the screening window (within 28 days from the first dose). In this 
case, the patient will not be required to sign another ICF, and the original patient ID number 
assigned will be used. In the event that the laboratory test(s) cannot be performed within 28
days of the original screening visit, or the re-test(s) do not meet the entrance criteria, or
eligibility criteria have changed and are not met anymore, the patient is considered a screen 
failure.
A new ICF/assent will need to be signed if the investigator chooses to re-screen the patient after 
a patient has screen failed, however the patient ID number will remain the same. All required 
screening activities must be performed when the patient is re-screened for participation in the 
study. 

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7.1.2.1
Eligibility screening 
Following registering in the IRT for screening, patient eligibility will be checked once all 
screening procedures are completed. The key eligibility check will be embedded in the IRT 
system. Please refer and comply with detailed guidelines in the IRT manual.
7.1.2.2
Information to be collected on screening failures
Patient who signed an Informed Consent Form but failed to be started on treatment for any 
reason will be considered a screen failure. 
The demographic information, informed consent/assent, Inclusion/Exclusion and Screening 
Phase Disposition pages must be completed for screen failure patients. No other data will be 
entered into the clinical database for patients who are screen failures, unless the patient 
experienced a Serious Adverse Event during the Screening Phase (see Section 8 for SAE 
reporting details). 
7.1.2.3
Patient demographics and other baseline characteristics
The data that will be collected on patient characteristics at screening includes:

Demography (Year of birth, calculated age, sex, childbearing status, race, ethnicity)

Histologically confirmed diagnosis of High Grade Glioma (Grade III or IV glioma) or 
Low Grade Glioma (Grade I or II glioma), as defined by WHO histological classification 
system, 2016.

Medical history (e.g., important medical, surgical, and allergic conditions from the 
patient’s medical history which could have an impact on the patient’s evaluation) / current 
medical conditions (e.g., all relevant current medical conditions which are present at the 
time of signing informed consent/assent). Frequency of seizures prior to the first day of 
dosing should be assessed and recorded on the Medical History eCRF. For LGG patients, 
the indication to treatment must be reported which may include clinical and/or 
neurological symptoms. Ongoing medical conditions, symptoms and disease which are 
recorded on the Medical History eCRF should include the toxicity grade.

All prior antineoplastic therapies including surgical interventions and chemo-, biologic-, 
immunologic- and radiation-therapies provided as treatment for cancer prior to the 
administration of study drug.

All medications and significant non-drug therapies taken within 30 days before the first 
dose is administered. They must be recorded on the Prior and Concomitant medication or 
Surgical and medical procedures eCRF page and updated on a continual basis if there are 
any new changes to the medications.
Furthermore the following assessments will be performed:
 

Central confirmation of HGG histopathology (HGG cohort only) and BRAF V600 
mutation (HGG and LGG cohorts) (Tumor tissue required)

Radiological assessments (e.g. MRI) to confirm measurable disease per RANO response 
criteria (locally determined and central confirmation required before enrollment)

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
Vital signs

Height, weight

Physical examination

Performance status (Karnofsky/Lansky)

Laboratory evaluations (hematology, chemistry, urinalysis)

Pregnancy testing (for menstruating females and women of childbearing potential)

Hepatitis testing (for patients with a history of hepatitis)

ECG

ECHO

Ophthalmology exam 

Dermatological exam
7.1.3
Treatment period
Following completion of screening procedures and verifying patient eligibility, patients will 
complete registration in IRT and start study treatment. HGG patients and LGG patients 
randomized to dabrafenib with trametinib will have weekly visits for the first 5 weeks, followed 
by visits every 8 weeks until the end of the first year; subsequent visits will occur every 16 
weeks. LGG patients randomized to chemotherapy will follow the same visit schedule for 
protocol assessments, but will be required to return to the clinical site for additional 
chemotherapy dosing visits per Section 6.1.2.
For details of assessments, refer to Table 7-1, Table 7-2 for LGG crossover patients and Table 
7-3.
Concomitant medication, adverse events and SAE monitoring will be continuous throughout 
the trial.
Patients will be treated with study treatment until disease progression, unacceptable toxicity, 
death or discontinuation from the study treatment due to any other reason. 
7.1.3.1
Treatment after Progression of Disease
Patients will be permitted to continue dabrafenib with trametinib beyond investigator-assessed, 
RANO-defined PD, as long as they meet the following criteria:

Investigator assessed clear evidence of clinical benefit 

Tolerance of study drug

Continuation of study treatment is in the best interest of the patient as determined by the 
Investigator

Patient/legal guardian is willing to continue on the study and signed ICF for treatment 
beyond progression
If the Investigator determines that all above criteria are met, the patient may continue study 
treatment and follow all study related procedures, including tumor assessments, as scheduled 
in Table 7-1, Table 7-2 for LGG crossover patients and Table 7-3. After each tumor assessment, 

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the investigator must confirm if the patient is still benefitting from study treatment, and 
document this in the patient’s chart and the appropriate CRF pages.
7.1.4
Discontinuation of study treatment
Patients may voluntarily discontinue from the study for any reason at any time. If a patient
decides to discontinue from the investigational treatment, the investigator should make a  
reasonable effort (e.g. telephone, e-mail, letter) to understand the primary reason for this
decision and record this information in the patient’s chart and on the appropriate CRF pages. 
They may be considered withdrawn if they state an intention to withdraw, fail to return for visits,
or become lost to follow-up for any other reason.
For patients who discontinue treatment for reasons other than documented disease progression, 
death, lost to follow-up, or withdrawal of consent/assent, tumor assessments must continue to 
be performed every 16 weeks until documented disease progression, death, lost to follow-up, 
or withdrawal of consent/assent.
Patients must be discontinued under the following circumstances:

Pregnancy

Study Terminated by Sponsor

Patient/guardian decision

Physician decision (investigator may discontinue study treatment for a given patient if,
he/she believes that continuation would be detrimental to the patient’s well-being)

Any other protocol deviation that results in a significant risk to the patient’s safety
Patients who discontinue study treatment should NOT be considered withdrawn from the
study. They should return for the assessments indicated in Section 7.2.1. If they fail to return
for these assessments for unknown reasons, every effort (e.g. telephone, email, letter) should
be made to contact them as specified in Section 7.1.7. The investigator must also contact the
IRT to register the patient’s discontinuation from the study.
In some circumstances patients may be allowed to continue to receive study treatment beyond 
disease progression as per RANO criteria (Section 7.1.3.1). These patients will continue 
assessments as outlined in Table 7-1, Table 7-2 for LGG crossover patients or Table 7-3, and 
will complete the End of Treatment visit only after permanent discontinuation of study 
treatment.
7.1.4.1
Replacement policy
Patients will not be replaced on study. 
However, if a patient is considered as non-evaluable for the per-protocol set (PPS), enrollment 
of a new patient will be considered if there is less than the required number of evaluable patients. 
7.1.5
Withdrawal of consent
Patients/legal guardian may voluntarily withdraw assent/consent to participate in the study for
any reason at any time. Withdrawal of assent/consent occurs only when a patient/legal 
guardian:

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
Does not want to participate in the study any longer, and

Does not allow further collection of personal data.
If a patient/legal guardian withdraws assent/consent, the investigator should make a reasonable 
effort (e.g. telephone, e-mail, letter) to understand the primary reason for the patient/legal 
guardian decision to withdraw his/her consent and record this information.
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing.
Further attempts to contact the patient/legal guardian are not allowed unless safety findings 
require communicating or follow-up.
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the patient’s study withdrawal should be made as detailed in the 
assessment table. 
Novartis will continue to keep and use collected study information (including any data resulting 
from the analysis of a patient’s samples until their time of withdrawal) according to applicable 
law.
For US and Japan: All biological samples not yet analyzed at the time of withdrawal may still 
be used for further testing/analysis in accordance with the terms of this protocol and of the 
informed consent form. 
For EU and RoW: All biological samples not yet analyzed at the time of withdrawal will no 
longer be used, unless permitted by applicable law. They will be stored according to applicable 
legal requirements.
7.1.6
Follow up for safety evaluations
All patients must have safety evaluations for at least 30 days after the last dose of study 
treatment as per Table 7-1, Table 7-2 for LGG crossover patients, or Table 7-3. Data collected 
should be added to the Adverse Events eCRF and the Concomitant Medications eCRF.
7.1.6.1
Post treatment follow up
After discontinuation of study treatment, all patients will be followed for safety for at least 30 
days after the last dose of study treatment except in the case of death, loss to follow-up or 
withdrawal of consent/assent. All patients who discontinue study treatment for reasons other 
than disease progression, death, lost to follow up, or withdrawal of consent/assent will move 
into Post Treatment Follow Up phase. 
Tumor evaluations during this period will continue as per Table 7-1, Table 7-2 or Table 7-3
until central independently confirmed disease progression by RANO criteria, withdrawal of 
assent/consent by patient/guardian to tumor status follow-up, or lost to follow-up. Patients who
start a new anti-cancer therapy prior to disease progression will continue tumor evaluations 
following the same above schedule until radiographic evidence of disease progression is 
centrally confirmed.
Skin examinations should be performed at 3 and 6 months after the last dose of study drug or 
until the start of a new anti-cancer therapy. Safety assessments including physical exams and 

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growth/developmental follow up will continue according to Table 7-1, Table 7-2 or Table 7-3
and Section 7.1.6.
Patients who discontinue study treatment due to disease progression by RANO criteria that has 
been confirmed by central independent assessment, and begin new anti-cancer therapy at EOT 
will enter Survival follow-up period.
7.1.6.2
Survival follow-up
All patients will be followed for survival once they discontinue study treatment and complete 
protocol required efficacy assessments, and the required skin evaluation per Table 7-1, Table 
7-2 for LGG crossover patients or Table 7-3. Survival follow-up assessments will be done every 
12 weeks or earlier if a survival update is required to meet safety or regulatory needs. Survival 
information can be obtained by clinical visits or telephone calls until death, the patient is lost to 
follow-up, the patient/legal guardian withdraws assent/consent or study discontinuation.
7.1.7
Lost to follow-up
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to withdraw consent/assent, the investigator should show "due diligence" by
contacting the patient, family or family physician as agreed in the informed consent/assent and
by documenting in the source documents steps taken to contact the patient, e.g. dates of
telephone calls, registered letters, etc. A patient should not be considered lost to follow-up until
due diligence has been completed. Patients lost to follow up should be recorded as such on the
appropriate Disposition CRF.
7.2
Assessment types
7.2.1
Efficacy assessments
Tumor response will be assessed locally and centrally based on the Response Assessment in 
Neuro-Oncology (RANO) criteria for solid tumors (Wen, 2010). The imaging assessment 
collection plan is presented in Table 7-4. Details of the central review process will be described 
in the independent review charter by the assigned imaging vendor.
Imaging data will be centrally collected and checked for quality by an imaging vendor 
designated by Novartis. The decision regarding patient management will remain with the local 
investigator.
Information regarding prior interventions (e.g. radiotherapy), pre-existing radiographic findings 
that mimic metastatic disease at baseline/screening, prior and on-study interventions, and 
cytology results should be transmitted to the imaging vendor for review by an independent
medical radiologist. Sites must ensure the data transmitted is consistent with the data entered in 
the clinical database.
For patients who discontinue treatment for reasons other than documented disease progression, 
death, lost to follow-up, or withdrawal of consent/assent, tumor assessments must continue to 
be performed every 16 weeks until documented disease progression, death, lost to follow-up, 
or withdrawal of consent/assent.

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Table 7-4
Imaging Assessment Collection Plan
Procedure a
Screening
During Treatment/Follow-up
End of Treatment
Tumor evaluation 
Brain MRI
Mandated

Every 8 weeks (+/- 7 days) during the 
first 56 weeks.

Every 16 weeks (+/- 7 days) thereafter 
while on treatment as well as during 
post-treatment follow up.

PR and CR must be confirmed by 
repeat assessments performed ≥4 
weeks after the criteria for response are 
first met.

At any time there is suspicion of clinical 
disease progression.
Mandated
MRI Spine
As clinically indicated per investigator discretion
a Refer to Section 7.2.1.1
7.2.1.1
Baseline imaging assessments
Imaging assessments will be performed at screening/baseline within 28 days of start of 
treatment (Day -28 to Day -1).
Any imaging assessments already completed during the regular work-up of the patient within 
28 days prior to start of treatment, including before signing the study ICF, can be considered as 
the baseline images for this study. The following assessments are required at screening/baseline:

Brain MRI - Contrast enhanced brain MRI is preferred. However, if MRI contrast is 
contraindicated, CT with or without contrast is allowed, but highly discouraged.

MRI spine may be obtained if clinically indicated according to investigator discretion
Required conditions for baseline tumor assessment

During screening, patients must have locally determined and centrally confirmed 
measurable disease at least twice the imaging slice thickness to be used for efficacy 
assessment

Patients with only non-measurable lesions are not eligible

Any potentially measurable lesion that has been previously treated with radiotherapy 
should be considered as a non-measurable lesion. However, if a lesion previously treated 
with radiotherapy has clearly progressed since more than 3 weeks from the radiotherapy, it 
can be considered as a measurable lesion.
Since measurable disease is an eligibility requirement, study sites should send the baseline 
imaging scans and any required vendor forms to the imaging CRO immediately following scan 
acquisition during screening. Rapid image transmission to the imaging CRO may be 
accomplished by transferring the images electronically. The baseline imaging will undergo 
expedited central review and the results of the central review will be communicated to the site. 
If the central review determines measurable disease, then the patient can be enrolled in the study. 
If the central review does not determine measurable disease, the patient should not be enrolled 
in the study; additional follow-up can be requested.

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7.2.1.2
Post-baseline imaging assessments
Imaging assessments as described in Table 7-4 should be performed at the time points specified 
using the same imaging modality used at baseline, irrespective of study treatment interruption 
or actual dosing (see Table 7-1, Table 7-2 for LGG crossover patients or Table 7-3). Imaging 
assessments for response evaluation will be performed every 8 weeks (+/- 7 days) during the 
first year, subsequently every 16 weeks (+/- 7 days) thereafter until disease progression, death, 
lost to follow-up or withdrawal of consent/assent. Imaging assessments should be scheduled 
using the enrollment date as the reference date (not the previous tumor assessment), and should 
be respected regardless of whether study treatment is temporarily withheld or unscheduled 
assessments performed.
Local imaging results are to be used for treatment decisions by the investigator.
Additional imaging assessments may be performed at any time during the study at the 
investigator’s discretion to support the efficacy evaluations for a patient, as necessary. Clinical 
suspicion of disease progression at any time requires a physical examination and imaging 
assessments to be performed promptly rather than waiting for the next scheduled imaging 
assessment. Partial Response (PR) and Complete Response (CR) must be confirmed by repeat 
assessments performed ≥4 weeks after the criteria for response are first met.
MRI spine may be obtained during study treatment if clinically indicated according to the 
discretion of the investigator.
Each lesion that is identified at baseline must be followed by the same method and when 
possible, the same local radiologist/physician throughout the study so that the comparison is 
consistent. If an off-schedule imaging assessment is performed because progression is 
suspected, subsequent imaging assessments should be performed in accordance with the 
original imaging schedule.
All study imaging (including any off-schedule imaging studies) should be submitted to the 
designated imaging vendor for quality control and central review. 
7.2.2
Safety and tolerability assessments
Safety will be monitored by the assessments described below as well as collecting of the adverse 
events at every visit (see Table 7-1, Table 7-2 for LGG crossover patients or Table 7-3). For 
details on AE collection and reporting, refer to Section 8.
For LGG patients randomized to carboplatin and vincristine, investigators should follow local
institutional and local SmPC guidelines for any additional safety monitoring that may be 
required during administration of carboplatin and vincristine. This includes audiometry testing 
on patients where there is suspicion of hearing loss or when it is institutional practice to conduct 
such testing during administration of carboplatin.  Events of hearing loss should be reported as 
Adverse Events and recorded on the electronic case report form (eCRF).
Significant findings that were present prior to the signing of informed consent/assent must be 
included in the Medical History page on the patient’s eCRF. Significant new findings that begin 
or worsen after informed consent/assent must be recorded on the Adverse Event page of the 
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7.2.2.1
Physical examination
A complete physical examination will include the examination of general appearance, 
assessment of the skin, neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, 
back, lymph nodes, extremities, vascular and neurological. If indicated based on medical history 
and/or symptoms, rectal, external genitalia, breast, and pelvic exams will be performed.  
A short physical exam will include the examination of general appearance, assessment of the 
skin, lungs, cardiovascular system, abdomen (liver and spleen), and neurological exam as 
clinically indicated. A short physical exam will be at all visits starting from Week 8. 
 
For the assessment schedule refer to the Visit Evaluation Schedule (Table 7-1, Table 7-2 for 
LGG crossover patients or Table 7-3).
7.2.2.3
Vital signs
Vital signs include blood pressure, body temperature, pulse measurements. Vital signs should 
be taken before any study medication is given on each assessment day (i.e. pre-dose).
Blood pressure will be taken:

After the patient has been sitting for five minutes. The appropriate cuff size is used to 
ensure accurate measurement.

Measurements will be taken per local practice.
If the blood pressure reading is outside the age appropriate normal ranges, repeat the 
measurement, waiting 1-2 minutes between readings, to verify the initial reading. Repeat 
measurements will be documented in the patient’s eCRF. 
For the assessment schedule refer to the Visit Evaluation Schedule (Table 7-1, Table 7-2 for 
LGG crossover patients or Table 7-3).
7.2.2.4
Height and weight
Height in centimeters (cm) will be measured as a requirement to monitor growth, and body 
weight (to the nearest 0.1 kilogram [kg] in indoor clothing, but without shoes) will be measured 
where indicated in the Visit Evaluation Schedule (Table 7-1, Table 7-2 for LGG crossover 
patients or Table 7-3).  

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7.2.2.5
Performance status
The performance status will be assessed according to Karnofsky for patients >16 years of age 
or Lansky for patients ≤16 years of age at screening (see Appendix 2). Performance status will 
be assessed according the scheduled assessment in Visit Evaluation Schedule (Table 7-1, Table 
7-2 for LGG crossover patients or Table 7-3).
7.2.2.6
Dermatological Evaluation
Skin examination should be performed prior to initiation of study treatment, and during the 
study on a monthly basis throughout therapy and at End of Treatment. After discontinuation of 
study treatment, skin examinations should be performed at 3 and 6 months after the last dose of 
study treatment or until the start of a new anti-neoplastic therapy according to the Visit 
Evaluation Schedule (Table 7-1, Table 7-2 for LGG crossover patients or Table 7-3).
Monitoring of the skin can be performed by a qualified local physician at the discretion of the 
investigator during non-clinic visits. If possible, the same local physician should perform each 
exam throughout the study to ensure consistency between evaluations. 
7.2.2.7
Ophthalmologic exam
Patients are required to have standard age-appropriate ophthalmologist examinations performed 
by an ophthalmologist according to the schedule of assessments in Visit Evaluation Schedule 
(Table 7-1, Table 7-2 for LGG crossover patients or Table 7-3). Based on the investigator’s 
discretion, the examination may include best corrected visual acuity, tonometry, slit lamp 
biomicroscopic examination, visual field examination, dilated indirect fundoscopy with special 
attention to retinal abnormalities, and optical coherence tomography. During the study, 
ophthalmologic exams may be repeated as clinically warranted. If any changes are noted during 
the required age-appropriate exam, or otherwise clinically indicated, a detailed ophthalmologic 
exam is mandatory (with sedation if necessary).
7.2.2.8
Laboratory evaluations
A central laboratory will be used for analysis of all specimens collected. Details on the 
collections, shipment of samples and reporting of results by the central laboratory are provided 
to investigators in the laboratory manual.
Central laboratory results should be used to determine study eligibility, however if there is an 
immediate need to determine study eligibility and commence treatment on study, then local lab 
result may be used for assessment of eligibility. In this case, central laboratory samples should 
still be collected for evaluation. Sites do not need to wait for the results of centrally-analyzed 
laboratory assessments when an immediate clinical decision needs to be made, and in those 
cases locally unscheduled testing may be performed. 
For LGG patients receiving carboplatin plus vincristine, local laboratory results can be used as 
required during chemotherapy when a central lab is not scheduled per Visit Evaluation Schedule 
(Table 7-1, Table 7-2 or Table 7-3) or when central lab results will not be received in time for 
dosing. Novartis must be provided with a copy of the local laboratory’s certification (if 
applicable), and a tabulation of the normal ranges and units of each parameter collected in the 
eCRF. Any changes regarding normal ranges and units for laboratory values assessed during 

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the study must be reported via an updated tabulation indicating the new effective date. 
Additionally, if at any time a patient has laboratory parameters obtained from a different 
(outside) laboratory, Novartis must be provided with a copy of the certification and a tabulation 
of the normal ranges and units for this laboratory as well. The investigator is responsible for 
reviewing all laboratory reports for patients in the study and evaluating any abnormalities for 
clinical significance.
At any time during the study, abnormal laboratory parameters which are clinically relevant and 
require an action to be taken with study treatment (e.g., require dose modification and/or 
interruption of study treatment, or require therapeutic intervention), whether specifically 
requested in the protocol or not, will be recorded on the AE eCRF page. Laboratory data will 
be summarized using the Common Terminology Criteria for Adverse events (CTCAE) version 
4.03. Additional analyses are left to the discretion of the investigator. The frequency of the 
assessments is indicated in the Visit Evaluation Schedule (Table 7-1, Table 7-2 for LGG 
crossover patients or Table 7-3). 
Table 7-5
Central Clinical laboratory parameters collection plan
Test Category
Test Name
Hematology
Hemoglobin, Platelets, White blood cells, WBC Morphology with Differential (Basophils, 
Eosinophils, Lymphocytes, Monocytes, Neutrophils, Bands, other)
Chemistry
Albumin, Alkaline phosphatase, ALT (SGPT), AST (SGOT), Calcium,  Creatinine, 
Magnesium, Sodium, Potassium, glucose (non-fasting), Phosphate, Total bilirubin, direct 
bilirubin, Total protein, Blood Urea Nitrogen (BUN) or Urea
Urinalysis
Macroscopic Panel (Dipstick) (Color, Bilirubin, Blood, Glucose, Ketones,  Nitrite, pH, 
Protein, Specific Gravity, Urobilinogen)
If there are any significant findings on the dipstick then a microscopic evaluation should be 
measured: Microscopic Panel (Red Blood Cells and White Blood Cell sediments, Casts, 
Crystals, Bacteria, Epithelial cells)
Hepatitis 
For patients with a history of chronic HBV and/or HCV: Viral hepatitis serology, Hepatitis B 
surface antigen and Hepatitis B core antibody (IgM) and/or Hepatitis C RNA
Additional tests
Serum pregnancy test at screening (females of childbearing potential). 
Urine pregnancy test on Day 1, monthly throughout the study and at EOT (females of 
childbearing potential)
7.2.2.8.1 Hematology
Hematology tests are to be performed by the central laboratory according to the Visit Schedule 
outlined in the Visit Evaluation Schedule (Table 7-1, Table 7-2 for LGG crossover patients or 
Table 7-3). The hematology panel is listed in Table 7-5.
7.2.2.8.2 Clinical chemistry
Blood chemistry assessments are to be performed by the central laboratory according to the 
Visit Schedule outlined the Visit Evaluation Schedule (Table 7-1, Table 7-2 for LGG crossover 
patients or Table 7-3). The clinical chemistry panel includes items listed in Table 7-5.

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7.2.2.8.3 Urinalysis
Urinalysis includes items listed in Table 7-5 and will be performed according to the Visit 
Evaluation Schedule (Table 7-1, Table 7-2 for LGG crossover patients or Table 7-3). Any
significant findings on dipstick will be followed up with a microscopic evaluation.
7.2.2.8.4 Pregnancy and assessments of female fertility
The need for a screening pregnancy test depends on whether the female patient is of 
childbearing potential or non-childbearing potential. 
Females of child-bearing potential are defined as all females physiologically capable of 
becoming pregnant. This includes female pediatric patients who are menarchal or who become 
menarchal during the study. All menarchal females and their parents/caregivers should be 
informed about the potential risks of pregnancy and the need to prevent pregnancy during the 
study. It is important to be sensitive in introducing this issue, as understanding and 
comprehension of puberty, sexual activity, pregnancy and contraception is influenced by age, 
as well as factors as precocity, socio (educational) economic and familial background. These 
discussions with the patient and her parents/caregivers are therefore best performed by 
investigators familiar with the pediatric patient and her family and should be guided by 
requirements of the local regulatory authorities. These discussions should take into account the 
socio-economic, cultural factors and religious beliefs of the participant and her family. The 
investigator should also discuss the management of the pregnancy test results with the patient 
and her parents/caregivers. The privacy of patient should be considered in accordance with the 
local law and ethics.
All women of child bearing potential must undergo a serum pregnancy test at screening (Day -
28 to Day -1). On Day 1 and monthly thereafter a urine pregnancy test will be performed as per 
the Visit Evaluation Schedule (Table 7-1, Table 7-2 for LGG crossover patients or Table 7-3).
On Day 1, the urine pregnancy test must be confirmed negative before dosing. 
Urine pregnancy test kits will be provided to patients for administering the test at home using 
the kit provided. For all urine pregnancy tests performed at home, the site personnel will follow-
up with the patient to collect the date and test results and document the information in the 
patient’s source document and entered in the clinical database. If local requirements dictate 
otherwise, local regulations should be followed. 
Patients with a positive pregnancy test result during screening must be excluded from the study. 
In case of pregnancy during study participation, the patient must permanently stop study 
treatment immediately, and the pregnancy must be reported on the Clinical Trial Pregnancy 
Form. If a positive pregnancy test is performed in between study visits, the patient must 
immediately notify the investigator. 
7.2.2.8.5 Hepatitis screen
Patients with medical history of Hepatitis B or C may be enrolled in the study if there is 
laboratory evidence of cleared HBV and/or HCV at screening. 

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7.2.2.10 Cardiac assessments 
7.2.2.10.1
Electrocardiogram (ECG)
Standard 12-lead ECG should be performed according to the Visit Evaluation Schedule (Table 
7-1, Table 7-2 for LGG crossover patients or Table 7-3). ECGs will be collected as single 
measurements in the supine position.  
If an abnormal ECG is obtained at any time, patient’s electrolytes must be reviewed and repeat 
ECG measurements must be done after correction of electrolyte abnormalities. In the event that 
a QTcF value of ≥ 501 ms is observed, obtain two or more additional ECGs over a brief period, 
and then use the average QTc values of the three ECGs to determine if study treatments should 
be interrupted or discontinued as per Section 6.3.1.7. 
An ECG may be repeated at the discretion of the investigator at any time during the study and 
as clinically indicated.
Interpretation of the tracing must be made by a qualified physician and documented on the ECG 
eCRF page. Clinically significant abnormalities present when the patient signed informed 
consent/assent should be reported on the Medical History eCRF page. Clinically significant 
findings must be discussed with Novartis prior to enrolling the patient in the study. New or 
worsened clinically significant findings occurring after informed consent/assent must be 
recorded on the Adverse Events CRF page.
Two copies of the ECG tracing should be obtained at the time of the ECG, to be kept in the 
source documents and in the study file at the study site for retrospective collection by the 
sponsor if necessary. Each ECG tracing should be labeled with the study number, patient initials 
(where regulations permit), patient number, and date. 
7.2.2.10.2
Cardiac imaging - Echocardiogram
Echocardiogram will be performed according to the Visit Evaluation Schedule (Table 7-1,
Table 7-2 for LGG crossover patients or Table 7-3).
Cardiology consultations should be performed on patients who experience >10% absolute 
decrease in LVEF from baseline and whose cardiac ejection fraction is less than the institution’s 
LLN. 
Copies of all ECHOs are to be kept in the source documents at the study site for retrospective 
collection by the sponsor if necessary. 

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7.2.3
Pharmacokinetics
Pharmacokinetic blood samples will be collected for the analysis of plasma concentrations of 
dabrafenib,
its 
metabolites 
hydroxy-dabrafenib, carboxy-dabrafenib, and desmethyl-
dabrafenib (GSK2285403, GSK2298683 and GSK2167542, respectively), and trametinib.
Full PK blood samples will be collected as described in Table 7-6 for all patients in the HGG 
cohort and the first 20 LGG patients randomized to dabrafenib plus trametinib treatment. For 
the remaining LGG patients on dabrafenib plus trametinib treatment, sparse PK blood samples 
will be collected as described in Table 7-7. An unscheduled PK blood sample may be collected 
at any time for measurement of plasma drug concentrations if clinically indicated or at the 
Investigator’s discretion.  PK samples will not be collected from LGG patients after they 
crossover from carboplatin with vincristine treatment.
The date and exact time of dosing, as well as the date and actual time of blood sampling must 
be recorded on the appropriate eCRF pages. Any sampling problems (e.g., patient took study 
drug before blood sample, scheduled sampling time is missed, sample is not drawn according 
to the schedule) should be noted as a comment on the eCRF.
If vomiting occurs during the course of treatment, no re-dosing of the patient is allowed, and 
medication should resume at the next scheduled dose. The occurrence and frequency of any 
vomiting must be noted in the adverse events section of the eCRF. In addition, the date and 
exact time of vomiting should only be recorded if it occurs within 4 hours of dosing on the days 
of full PK sampling. If a vomiting episode occurs within the first 4 hours post-dosing during 
the day of the last dose prior to trough PK samples the exact time (whenever possible) must be 
noted on the PK Dose and Administration Record eCRF.
Concentrations of dabrafenib, its metabolites and trametinib will be summarized; a detailed 
description of the planned PK analyses is given in Section 10.5.2.
7.2.3.1
Pharmacokinetic blood collection and handling
Blood samples will be taken either by direct venipuncture or through an indwelling cannula 
(e.g., inserted in a forearm vein, or central venous line). 
At the specified time points described in Table 7-6 and Table 7-7, one single 1 mL blood draw 
will be collected into a tube containing EDTA and gently inverted several times to thoroughly 
mix the anticoagulant. The blood tube will be centrifuged to separate plasma and transferred 
into separate pre-labeled tubes for dabrafenib. Plasma samples will be stored frozen in an 
upright position until shipment.
Refer to the [CDRB436G2201 Laboratory Manual] for detailed instructions for the collection, 
handling, and shipment of PK samples.

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Table 7-6
Full Pharmacokinetic blood collection log – HGG cohort and subset of 
LGG cohort
Week
Day
Scheduled 
timepoint
Dose 
reference ID 
Dabrafenib* 
Dose 
reference ID 
Trametinib*
PK 
Sampl
e No*
Sample volume [mL]
Patient
s 
<10kg
Patients 
≥10kg and 
<25kg
Patients 
≥25kg
1
1
Post-dose 0.5 
hr ±5mins
101
201
101
N/A
1 mL
1 mL
Post-dose 2 hr
±5mins
101
201
102
N/A
1 mL
1 mL
Post-dose 4 hr
±20mins
101
201
103
N/A
1 mL
1 mL
3
1
Pre-dosea
-30mins
102
12b
202       14b
104
1 mL
1 mL
1 mL
Post-dose 0.5 
hr
±5mins
102
202
105
N/A
N/A
1 mL
Post-dose 1 hr
±5mins
102
202
106
N/A
1 mL
1 mL
Post-dose 2 
hrs
±5mins
102
202
107
1 mL
1 mL
1 mL
Post-dose 3
hrs
±20mins
102
202
108
N/A
1 mL
1 mL
Post-dose 4 
hrs
±20mins
102
202
109
1 mL
1 mL
1 mL
Post-dose 6 
hrs
±20mins
102
202
110
N/A
N/A
1 mL
Post-dose 8 
hrs
±20mins
102
202
111
N/A
1 mL
1 mL
4
1
Pre-dosea
-30mins
103
13b
203      15b
112
1 mL
1 mL
1 mL
Unscheduled PK Samplec
---
16d
17d
1001+
1 mL
1 mL
1 mL
a Pre-dose PK samples will be collected immediately prior to the start of study drug administration. 
b The first Dose Reference ID (DRID no.) is for current dose, while the second DRID no. is for the last dose the 
patient received prior to the collection of the PK sample.
c Unscheduled PK samples will be uniquely, sequentially numbered 1001, 1002, etc.
d Last dose the patient received prior to the collection of the unscheduled PK
Note: *DRID and sample numbers implemented in the above table are for Novartis internal reference. 
Table 7-7
Sparse Pharmacokinetic blood collection log for subset of LGG cohort
Week
Day
Scheduled 
timepoint
Dose 
reference ID 
Dabrafenib* 
Dose 
reference ID 
Trametinib*
PK 
Sampl
e No*
Sample volume [mL]
Patient
s 
<10kg
Patients 
≥10kg and 
<25kg
Patients 
≥25kg
3
1
Pre-dosea
-30mins
301
21b
401       23b
201
1 mL
1 mL
1 mL
Post-dosee 1-
3 hr
301
401
202
N/A
N/A
1 mL

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Week
Day
Scheduled 
timepoint
Dose 
reference ID 
Dabrafenib* 
Dose 
reference ID 
Trametinib*
PK 
Sampl
e No*
Sample volume [mL]
Patient
s 
<10kg
Patients 
≥10kg and 
<25kg
Patients 
≥25kg
Post-dosef 5-
10 hr
301
401
203
N/A
1 mL
1 mL
4
1
Pre-dosea
-30mins
302
22b
402      24b
204
1 mL
1 mL
1 mL
Unscheduled PK Samplec
---
25d
26d
2001+
1 mL
1 mL
1 mL
a Pre-dose PK samples will be collected immediately prior to the start of study drug administration. 
b The first Dose Reference ID (DRID no.) is for current dose, while the second DRID no. is for the last dose the 
patient received prior to the collection of the PK sample.
c Unscheduled PK samples will be uniquely, sequentially numbered 2001, 2002, etc. 
d Last dose the patient received prior to the collection of the unscheduled PK
e PK samples can be collected anytime between 1-3 hours after the morning dose
f PK samples can be collected anytime between 5-10 hours after the morning dose
Note: *DRID and sample numbers implemented in the above table are for Novartis internal reference. 
7.2.3.2
Analytical method
Plasma concentrations of dabrafenib and its metabolites hydroxy-dabrafenib (GSK2285403), 
carboxy-dabrafenib (GSK2298683), and desmethyl-dabrafenib (GSK2167542) and trametinib
will be measured using validated liquid chromatography/mass spectrometry/ mass spectrometry
(LC/MS/MS) methods. The lower limit of quantification (LLOQ) for dabrafenib, hydroxy-
dabrafenib and desmethyl-dabrafenib is 1 ng/mL and 0.25 ng/mL for trametinib for a 50 L 
aliquot of human plasma. The LLOQ for carboxy-dabrafenib is 5 ng/mL for a 25 L aliquot of 
human plasma. Concentrations below the LLOQ will be treated as zero.
 
 
 
7.2.3.3
Meal record
Meal records must be kept for all patients on PK days as indicated in Table 7-1. The date, start 
and end time, and percentage consumed for all meals on PK days must be recorded in the CRFs. 

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Other assessments
No additional tests will be performed on patients entered into this study.
7.2.5
Resource utilization
Not applicable.
7.2.6
Patient reported outcomes (LGG cohort only)
Patient reported outcomes (PRO) will be assessed using the PROMIS Parent Proxy Global 
Health 7+2 for LGG patients. The PRO will measure the patient’s overall evaluation of his or 
her physical, mental, and social health. PRO data will be collected using an electronic tablet 
device and administered in the patient’s local language. Patients should be given the 
questionnaire to be completed before any clinical assessments are performed. Site personnel 
must review the questionnaire for completeness, and document patient’s refusal to complete all 
or any part of the questionnaire. Completed questionnaire and any unsolicited comments written 
by the patient should be reviewed and assessed by the investigator for responses which may 
indicate potential AEs or SAEs. If AEs or SAEs are confirmed, investigators should not 
encourage the patient to change responses reported in the completed questionnaire. 
Investigators must follow reporting instructions outlined in Section 8. Questionnaires are 
administered according to the Table 7-1 and Table 7-3 until the patient disease progression per 
RANO criteria. 
7.2.7
Acceptability and Palatability Questionnaires
All patients who receive the dabrafenib oral suspension and/or trametinib oral solution will 
complete the respective questionnaire to evaluate the palatability and acceptability/tolerability
of the pediatric formulations. The dabrafenib oral suspension and trametinib oral solution 
questionnaires must be completed after the dosing of dabrafenib with trametinib according to
Table 7-1. 

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8
Safety monitoring and reporting
8.1
Adverse events
8.1.1
Definitions and reporting
An adverse event is defined as the appearance of (or worsening of any pre-existing) undesirable 
sign(s), symptom(s), or medical condition(s) that occur after patient’s signed informed 
consent/assent has been obtained.
Abnormal laboratory values or test results occurring after informed consent constitute adverse 
events only if they induce clinical signs or symptoms, are considered clinically significant, 
require therapy (e.g., hematologic abnormality that requires transfusion or hematological stem 
cell support), or require changes in study medication(s).
Adverse events that begin or worsen after informed consent should be recorded in the Adverse 
Events CRF. Conditions that were already present at the time of informed consent should be 
recorded in the Medical History page of the patient’s eCRF. Adverse event monitoring should 
be continued for at least 30 days following the last dose of study treatment. Adverse events 
(including lab abnormalities that constitute AEs) should be described using a diagnosis 
whenever possible, rather than individual underlying signs and symptoms. When a clear 
diagnosis cannot be identified, each sign or symptom should be reported as a separate Adverse 
Event.
Adverse events will be assessed and graded according to the Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.03. Grade 1 to 5 will be used to characterize the severity 
of the Adverse Event.
If CTCAE grading does not exist for an adverse event, the severity of mild, moderate, severe, 
and life-threatening, death related to the AE corresponding respectively to Grades 1 - 5, will be 
used. Information about any deaths (related to an Adverse Event or not) will also be collected 
though a Death form.
The occurrence of adverse events should be sought by non-directive questioning of the patient 
(subject) during the screening process after signing informed consent/assent and at each visit 
during the study. Adverse events also may be detected when they are volunteered by the patient 
(subject) during the screening process or between visits, or through physical examination, 
laboratory test, or other assessments. As far as possible, each adverse event should be evaluated 
to determine:
1. The severity grade (CTCAE Grade 1-5)
2. Its duration (Start and end dates) 
3. Its relationship to the study treatment (Reasonable possibility that AE is related: No,
Yes, investigational treatment, Yes, the study treatment (non-investigational), Yes, both 
and/or indistinguishable)
4. Action taken with respect to study or investigational treatment (none, dose adjusted, 
temporarily interrupted, permanently discontinued, unknown, not applicable, 
investigational treatment resumed)

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5. Whether medication or therapy was given (no concomitant medication/non-drug therapy, 
concomitant medication/non-drug therapy)
6. Outcome (not recovered/not resolved, recovered/resolved, recovering/resolving, 
recovered/resolved with sequelae, fatal, unknown) 
7. Whether it is serious, where a serious adverse event (SAE) is defined as in Section 8.2.1
and which seriousness criteria have been met
All adverse events should be treated appropriately. If a concomitant medication or non-drug 
therapy is given, this action should be recorded on the Adverse Event eCRF.
Once an adverse event is detected, it should be followed until its resolution or until it is judged 
to be permanent, and assessment should be made at each visit (or more frequently, if necessary) 
of any changes in severity, the suspected relationship to the study treatment, the interventions 
required to treat it, and the outcome.
Progression of malignancy (including fatal outcomes), if documented by use of appropriate 
method (as per RANO criteria) should not be reported as a serious adverse event.
Adverse events separate from the progression of malignancy (example, deep vein thrombosis 
at the time of progression or hemoptysis concurrent with finding of disease progression) will 
be reported as per usual guidelines used for such events with proper attribution regarding 
relatedness to the drug.
8.1.2
Laboratory test abnormalities
8.1.2.1
Definitions and reporting
Laboratory abnormalities that constitute an Adverse event in their own right (are considered 
clinically significant, induce clinical signs or symptoms, require concomitant therapy or require 
changes in study treatment), should be recorded on the Adverse Events eCRF. Whenever 
possible, a diagnosis, rather than a symptom should be provided (e.g. anemia instead of low 
hemoglobin). Laboratory abnormalities that meet the criteria for Adverse Events should be 
followed until they have returned to normal or an adequate explanation of the abnormality is 
found. When an abnormal laboratory or test result corresponds to a sign/symptom of an already 
reported adverse event, it is not necessary to separately record the lab/test result as an additional 
event.
Laboratory abnormalities, that do not meet the definition of an adverse event, should not be 
reported as adverse events. A Grade 3 or 4 event (severe) as per CTCAE does not automatically 
indicate a SAE unless it meets the definition of serious as defined below and/or as per 
investigator’s discretion. A dose hold or medication for the lab abnormality may be required by 
the protocol in which case the lab abnormality would still, by definition, be an adverse event 
and must be reported as such.
8.1.3
Adverse events of special interest 
Adverse events of special interest (AESI) are defined as events (serious or non-serious) which 
are ones of scientific and medical concern specific to the sponsor’s product or program, for 
which ongoing monitoring and rapid communication by the investigator to the sponsor may be 

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appropriate. Such events may require further investigation in order to characterize and 
understand them.
Adverse events of special interest are defined on the basis of an ongoing review of the safety 
data. AESIs are discussed in detail in the Investigator Brochure. 
Dabrafenib and trametinib events of special interest include:

Skin related toxicities

Ocular events

Cardiac related events

Hepatic disorders

Pneumonitis/interstitial lung disease

Bleeding events

Hypertension

Complicated pyrexia and/or grade 3 and grade 4

Pre-Renal and intrinsic renal failure

Uveitis

New primary/secondary malignancy

Hypersensitivity

Hyperglycemia

Deep venous thrombosis/pulmonary embolism

Pancreatitis

Neutropenia
Potential emergent new AEs will be monitored during the course of the study. 
8.1.3.1
Definitions and reporting
Refer to Section 8.1.1. 
8.2
Serious adverse events
8.2.1
Definitions
Serious adverse event (SAE) is defined as one of the following:

Is fatal or life-threatening

Results in persistent or significant disability/incapacity

Constitutes a congenital anomaly/birth defect

Is medically significant, i.e., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above

Requires inpatient hospitalization or prolongation of existing hospitalization, 

Note that hospitalizations for the following reasons should not be reported as serious 
adverse events:

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
Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 

Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed 
consent/assent

Social reasons and respite care in the absence of any deterioration in the patient’s 
general condition

Note that treatment on an emergency outpatient basis that does not result in hospital 
admission and involves an event not fulfilling any of the definitions of a SAE given above 
is not a serious adverse event
8.2.2
Reporting
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has provided informed consent/assent and until at least 30 days after the patient has 
stopped study treatment must be reported to Novartis within 24 hours of learning of its 
occurrence.
Any additional information for the SAE including complications, progression of the initial SAE, 
and recurrent episodes must be reported as follow-up to the original episode within 24 hours of 
the investigator receiving the follow-up information. An SAE occurring at a different time 
interval or otherwise considered completely unrelated to a previously reported one should be 
reported separately as a new event.
Any SAEs experienced after the 30 day safety evaluation follow-up period should only be 
reported to Novartis if the investigator suspects a causal relationship to the study treatment.  
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess and record the relationship of each SAE to each 
specific study treatment (if there is more than one study treatment), complete the SAE Report 
Form in English, and submit the completed form within 24 hours to Novartis. Detailed 
instructions regarding the SAE submission process and requirements for signatures are to be 
found in the investigator folder provided to each site.
Follow-up information is submitted in the same way as the original SAE Report.  Each re-
occurrence, complication, or progression of the original event should be reported as a follow-
up to that event regardless of when it occurs. The follow-up information should describe 
whether the event has resolved or continues, if and how it was treated, and whether the patient 
continued or withdrew from study participation.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the Novartis study treatment, an oncology Novartis 
Chief Medical office and Patient Safety (CMO&PS) department associate may urgently require 
further information from the investigator for Health Authority reporting. Novartis may need to 
issue an Investigator Notification (IN), to inform all investigators involved in any study with 
the same drug that this SAE has been reported. Suspected Unexpected Serious Adverse 
Reactions (SUSARs) will be collected and reported to the competent authorities and relevant 

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ethics committees in accordance with Directive 2001/20/EC or as per national regulatory 
requirements in participating countries.
8.3
Emergency unblinding of treatment assignment
Since this study is an open-label study, there is no need for treatment unblinding instructions or 
unblinding codes. 
8.4
Pregnancies
To ensure patient safety, each pregnancy occurring after signing the informed consent/assent 
and 16 weeks after stopping treatment with trametinib monotherapy or dabrafenib in 
combination with trametinib, and 2 weeks after stopping treatment with dabrafenib 
monotherapy, whichever is longer must be reported to Novartis within 24 hours of learning of 
its occurrence. The pregnancy should be followed up to determine outcome, including 
spontaneous or voluntary termination, details of the birth, and the presence or absence of any 
birth defects, congenital abnormalities, or maternal and/or newborn complications.
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the oncology Novartis Chief Medical office and Patient Safety (CMO&PS). 
Pregnancy follow-up should be recorded on the same form and should include an assessment 
of the possible relationship to the Novartis study treatment of any pregnancy outcome. Any 
SAE experienced during pregnancy must be reported on the SAE Report Form.
Pregnancy outcomes should be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother.
8.5
Warnings and precautions
No evidence available at the time of the approval of this study protocol indicated that special 
warnings or precautions were appropriate, other than those noted in the provided Investigator 
Brochure. Additional safety information collected between IB updates will be communicated 
in the form of Investigator Notifications. This additional safety information, if any, will be 
included in the patient informed consent/assent and should be discussed with the patient during 
the study as needed.
8.6
Data Monitoring Committee 
A data monitoring committee (DMC) will independently monitor the safety of patients enrolled 
in this study. The DMC will function independently of all other individuals associated with the 
conduct of this clinical trial, including the site investigators participating in the study. The DMC 
will be constituted prior to the randomization of the first patient into the LGG cohort. The DMC 
will be responsible to review safety data from the HGG and LGG cohorts approximately every 
6 months for the first two years, and then, if agreed by DMC members, to provide such data 
every 12 months thereafter from start of enrollment. This includes but does not limit the role of 
the DMC to evaluate these data and to provide recommendations to the sponsor to continue,
modify or stop the study early.

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It is expected that the DMC will consist at a minimum of two physicians with appropriate 
disease area qualifications and one statistician. There will be a meeting with the DMC 
describing their roles and responsibilities and discussing potential data format and process 
issues prior to the finalization of DMC charter and the statistical analysis plan.
8.7
Steering Committee
A steering committee (SC) will be established comprising of investigators participating in the 
trial prior to initiation of the trial. 
The SC will ensure transparent management of the study, both HGG and LGG cohorts,
according to the protocol through recommending and approving modifications as circumstances 
require. The SC will review protocol amendments as appropriate. Together with the clinical 
trial team, the SC will also develop recommendations for publications of study results including 
authorship rules. The details of the role of the Steering Committee will be defined in a Steering 
Committee charter.
9
Data collection and management
9.1
Data confidentiality
Information about study patients will be kept confidential and managed under the applicable 
laws and regulations. Those regulations require a signed patient authorization informing the 
patient of the following:

What protected health information (PHI) will be collected from patients in this study

Who will have access to that information and why

Who will use or disclose that information

The rights of a research patient to revoke their authorization for use of their PHI.
In the event that a patient revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of patient 
authorization. For patients that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect follow-up safety information (e.g. has the patient 
experienced any new or worsened AEs) at the end of their scheduled study period.
The data collection system for this study uses built-in security features to encrypt all data for 
transmission in both directions, preventing unauthorized access to confidential participant 
information. Access to the system will be controlled by a sequence of individually assigned 
user identification codes and passwords, made available only to authorized personnel who have 
completed prerequisite training.
Prior to entering key sensitive personally identifiable information (Patient Initials and exact 
Date of Birth), the system will prompt site to verify that this data is allowed to be collected. If 
the site indicates that country rules or ethics committee standards do not permit collection of 
these items, the system will not solicit Patient Initials. Year of birth will be solicited (in the 
place of exact date of birth) to establish that the patient satisfies protocol age requirements and 
to enable appropriate age-related normal ranges to be used in assessing laboratory test results.

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9.2
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, Novartis 
personnel will review the protocol and eCRFs with the investigators and their staff. During the 
study, the field monitor will visit the site regularly to check the completeness of patient records, 
the accuracy of entries on the eCRFs, the adherence to the protocol to Good Clinical Practice, 
the progress of enrollment, and to ensure that study treatment is being stored, dispensed, and 
accounted for according to specifications. Key study personnel must be available to assist the 
field monitor during these visits.
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information recorded on eCRFs must be traceable to source documents in the 
patient's file. The investigator must also keep the original signed informed consent/assent form 
(a signed copy is given to the patient/legal guardian).
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the eCRF entries. Novartis monitoring standards require full verification for 
the presence of informed consent/assent, adherence to the inclusion/exclusion criteria and 
documentation of SAEs. Additional checks of the consistency of the source data with the CRFs 
are performed according to the study-specific monitoring plan.
9.3
Data collection
Electronic Data Capture (EDC) is used for this study. The designated investigator staff will 
enter the data required by the protocol into the Electronic Case Report Forms (eCRF). The 
eCRFs have been built using fully validated secure web-enabled software that conforms to 21 
CFR Part 11 requirements, Investigator site staff will not be given access to the EDC system 
until they have been trained. Automatic validation programs check for data discrepancies in the 
eCRFs and, allow modification or verification of the entered data by the investigator staff.
The Principal Investigator is responsible for assuring that the data entered into eCRF is complete, 
accurate, and that entry and updates are performed in a timely manner.
Pharmacokinetic (PK) 
 will be collected in this study. 
Designated investigator staff will enter the required information onto the PK 
 
sample collection eCRFs. 
 
 The field monitor will 
review the relevant eCRFs for accuracy and completeness and will work with the site staff to 
adjust any discrepancies as required. The field monitor will also review requisition forms for 
completeness. 
Radiological scans used for tumor assessments will be centrally collected and reviewed.
Data entered into IRT will be transferred electronically to Novartis as described in the Data 
Transfer Specifications for designated IRT vendor. 

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9.4
Database management and quality control
Novartis personnel will review the data in the eCRFs entered by investigational staff for 
completeness and accuracy. Electronic data queries stating the nature of the problem and 
requesting clarification will be created for discrepancies and missing values and sent to the 
investigational site via the EDC system. Designated investigator site staff is required to respond 
promptly to queries and to make any necessary changes to the data.
Concomitant treatments and prior medications entered into the database will be coded using the 
WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical classification 
system. Medical history/current medical conditions and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology.
Samples and/or data will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO). Data that will be processed centrally include:

IRT data including information regarding screening, drug assignment and discontinuation

Central imaging review (i.e. MRI scans)

Centrally analyzed laboratory data including clinical, PK, 
 and safety 
parameters
Data about all study treatments dispensed to the patient and all IRT assigned dosage changes 
will be tracked using an Interactive Response Technology. The system will be supplied by a 
vendor(s), who will also manage the database. The data will be sent electronically to Novartis 
personnel (or designated CRO).
At the conclusion of the study, the occurrence of any protocol violations will be determined. 
After these actions have been completed and the data has been verified to be complete and 
accurate, the database will be declared locked and made available for data analysis. 
Authorization is required prior to making any database changes to locked data, by joint written 
agreement between the Global Head of Biostatistics and Data Management and the Global Head 
of Clinical Development.
After database lock, the investigator will receive a CD-ROM or paper copies of the patient data 
for archiving at the investigational site.
10
Statistical methods and data analysis
The data from all participating centers in this protocol will be combined. 
The data for the HGG and LGG cohorts will be analyzed independently with timing of analyses 
based on specific independent criteria for each cohort outlined in this protocol. 
Note that there may be a need to support the initial submission of an indication based on the 
primary analysis data with safety and PK interim data from both cohorts. Thus the initial 
planning of the primary analysis for a specific cohort should anticipate that a safety interim or 
update analysis of the other cohort may also be required.
The primary endpoint for the HGG cohort will be analyzed at the time of the interim analysis 
and the study may be stopped for futility according to the criteria described in the Interim 
Analysis Section (Section 10.7). If the HGG cohort is not stopped at interim analysis then the 

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primary analysis of the HGG cohort will be conducted at the time when all treated patients  have 
either completed at least 32 weeks of treatment or have discontinued earlier. These data will be 
summarized in the primary Clinical Study Report (CSR). The final analysis of the HGG cohort
will be conducted at the end of the study as specified in Section 4.3. All available data from all
HGG cohort patients up to the end of study cutoff date will be analyzed.
The primary analysis for the LGG cohort will be conducted when all treated patients have either 
completed at least 32 weeks of treatment or have discontinued earlier. These data will be 
summarized in the primary CSR. 
The final analysis of LGG cohort will be conducted at the end of the study as specified in 
Section 4.3. All available data from all LGG cohort patients up to the end of study cutoff date 
will be analyzed.
All data will be summarized by treatment group and included in listings.
10.1
Analysis sets
10.1.1
Full Analysis Set
The Full Analysis Set (FAS) for the HGG cohort will include all patients to whom study 
treatment has been assigned and who receive at least one dose of study treatment.
For the LGG cohort the FAS comprises all patients to whom study treatment has been assigned 
by randomization regardless of whether or not treatment was administered. According to the 
intent to treat principle, patients will be analyzed according to the treatment they have been 
assigned to during the randomization procedure.
10.1.2
Safety set
The Safety Set for both HGG and LGG cohort include all patients who received at least one 
dose of study treatment.
For the LGG cohort, patients will be analyzed according to the study treatment received, where 
treatment received is defined as the randomized treatment if the patient took at least one dose 
of that treatment or the first treatment received if the randomized treatment was never received.
10.1.3
Per-Protocol Set
Not applicable.
10.1.4
Dose-determining analysis set
Not applicable. 
10.1.5
Pharmacokinetic analysis set
The pharmacokinetic analysis set (PAS) for both HGG and LGG cohort consists of all patients 
who receive at least one (full or partial) dose of dabrafenib or trametinib and provide at least 
one evaluable pharmacokinetic (PK) blood sample. 
The definition of an evaluable PK blood sample will be further specified in the SAP.

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10.1.6
Other analysis sets
10.1.6.1 Evaluable set
The Evaluable Set (ES) consists of all evaluable patients in the FAS who have centrally 
confirmed measurable disease, positive BRAF V600 mutation, an adequate tumor assessment 
at baseline, and a follow-up tumor assessment at least 8 weeks after starting treatment (unless 
disease progression is observed before that time) or have discontinued for any reason. For the 
HGG cohort, the evaluable set also requires that the patient’s tumor is centrally confirmed by 
histopathology to be HGG.
The evaluable set will be used for sensitivity analyses.
10.2
Patient demographics/other baseline characteristics
For each cohort, demographic and other baseline data including disease characteristics will be 
summarized descriptively by treatment group based on the FAS. Categorical data will be 
presented as frequencies and percentages. For continuous data, mean, standard deviation, 
median, 25th and 75th percentiles, minimum, and maximum will be presented.
Relevant medical histories and current medical at baseline will be summarized separately by 
system organ class and preferred term.
10.3
Treatments (study treatment, concomitant therapies, 
compliance)
The safety set will be used for the analyses below for each cohort. Categorical data will be 
summarized as frequencies and percentages. For continuous data, mean, standard deviation, 
median, 25th and 75th percentiles, minimum, and maximum will be presented.
For the dabrafenib plus trametinib combination in each cohort the duration of exposure in weeks 
to dabrafenib and trametinib as well as the dose intensity (computed as the ratio of actual 
cumulative dose received and actual duration of exposure) and the relative dose intensity 
(computed as the ratio of dose intensity and planned dose intensity) will be summarized 
separately for dabrafenib and trametinib by means of descriptive statistics using the safety set. 
The duration of exposure will also be presented for the study treatment of dabrafenib in 
combination with trametinib. 
For the carboplatin with vincristine control arm in the LGG cohort duration of exposure will be 
analyzed similarly.
The number of patients with dose adjustments (reductions, interruption, or permanent 
discontinuation) and the reasons will be summarized by treatment group (with the individual 
drugs also summarized separately) and all dosing data will be listed.
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed and summarized according to the Anatomical Therapeutic 
Chemical (ATC) classification system by treatment group. 

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10.4
Primary objective
HGG Cohort:
The primary objective of the HGG cohort is to evaluate the anti-tumor activity of dabrafenib in 
combination with trametinib, as measured by overall response rate (ORR) by central 
independent review assessment using RANO criteria.
LGG Cohort:
The primary objective of the HGG cohort is to compare the anti-tumor activity of dabrafenib in 
combination with trametinib versus carboplatin with vincristine, as measured by overall 
response rate (ORR) by independent review assessment using RANO criteria.
10.4.1
Variable
For the HGG cohort, the primary variable used to evaluate the anti-tumor activity of dabrafenib
in combination with trametinib is the overall response rate (ORR), defined as the proportion of 
patients with a best overall confirmed Complete Response (CR) or Partial Response (PR) as 
assessed per Response Assessment in Neuro-Oncology (RANO) criteria by the independent 
reviewer. 
For the LGG cohort, the primary variable used to evaluate the anti-tumor activity of dabrafenib 
in combination with trametinib versus carboplatin with vincristine is the overall response rate 
(ORR), defined as the proportion of patients with a best overall confirmed Complete Response 
(CR) or Partial Response (PR) as assessed per Response Assessment in Neuro-Oncology 
(RANO) criteria by the independent reviewer. 
10.4.2
Statistical hypothesis, model, and method of analysis
The primary analysis in the HGG cohort will be performed on the FAS. Point estimate and the 
exact binomial confidence intervals (CIs) (Clopper and Pearson 1934) of ORR will be provided.
The lower bound of the CIs will be used to provide evidence that the true ORR is greater than 
a certain specific response rate.
The 95% CI, via the lower limit, is used to establish the levels of response which are exceeded 
by taking the combination therapy according to a robust standard of evidence (i.e. one-sided 
alpha=0.025). For example, out of 40 patients who have been enrolled and have completed at 
least 32 weeks of treatment or have discontinued treatment earlier, if 14 responses (35%) are 
observed then the corresponding 95% CI will exclude 20% which is greater, than the typical 
standard of care response rate previously observed (Lashford 2002; Nicholson 2007; Ruggiero 
2006; Warren 2012; Hummel 2013). 
With respect to the HGG cohort, the study also aims to provide evidence that trametinib gives 
added value to the dabrafenib and trametinib combination over and above dabrafenib 
monotherapy treatment. Since a lower standard of evidence is usually required to show such 
added value the lower limit of an 80% CI is used to identify the response rates which will be 
exceeded by taking the combination therapy based on a reduced level of evidence (one-sided 
alpha of 0.1). For example, if 18 responses (45%) out of the 40 patients are observed then the 
lower bound of 80% CI will exclude 32%, which is the response rate of dabrafenib monotherapy 

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observed from the study [BFR116013, CDRB436A2102]. In addition, the 95% CI can also be 
used to provide more robust evidence of the added benefit of trametinib. For example, if 20 
responses (50%) are observed, then the lower bound of 95% CI will also exclude 32%. 
LGG Cohort
The primary efficacy analysis in the LGG cohort is the comparison of ORR based on 
independent review assessment between the two treatment arms. The following statistical 
hypothesis will be tested: 
H: 		
 ≤		 vs. H: 		
 > 		
where 		
 is the ORR in the Trametinib plus Dabrafenib arm and 		 is the ORR in the 
carboplatin with vincristine arm. The analysis to test these hypotheses and compare the two 
treatment groups will consist of a Mantel Haenszel chi-square test at one-sided 2.5% level of 
significance. 
The primary efficacy analysis will be performed on the FAS.
ORR will be summarized using descriptive statistics (N, %) by treatment arm along with two-
sided exact binomial 95% CIs (Clopper and Pearson 1934).
10.4.3
Handling of missing values/censoring/discontinuations
Patients with unknown or missing best overall response (BOR) will be counted as failures. If 
there is no baseline tumor assessment, all post-baseline overall lesion responses are expected to 
be ‘Unknown’. If no valid post-baseline tumor assessments are available, the best overall 
response must be “Unknown” unless progression is reported. For the computation of ORR, 
these patients will be included in the FAS and will be counted as ‘failures’.
10.4.4
Supportive and sensitivity analyses
The following supportive and sensitivity analyses will be performed for the HGG and LGG 
cohorts as appropriate.
The primary analysis on the FAS will be repeated on the evaluable set. The analyses of ORR, 
DOR, and PFS will be repeated based on radiological response assessed by independent review 
by only incorporating the radiographic data in the FAS. In addition, ORR, DOR and PFS will 
be evaluated using a ITT approach i.e including all response assessments irrespective of new 
anti-neoplastic therapy using the FAS. 
If the primary efficacy analysis shows that the 95% CI of ORR excludes 20% for HGG and 
statistically significant for LGG, the following subgroups may be considered:
The primary efficacy endpoint ORR and secondary endpoint DOR by investigator and central 
independent assessments may be summarized by risk categories such as that determined by 
methylation analysis based on FAS and Evaluable set. The risk categories will be specified in 
a later SAP amendment prior to database lock 
.
The SAP will pre-specify analyses that will be conducted using crossover data, if applicable.
PPD

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Additional supportive 
 analyses may be conducted to support the primary 
objective of the HGG and LGG cohorts if appropriate, and the details of these analyses will be 
defined in the SAP.
10.5
Secondary objectives
HGG Cohort
With respect to the HGG cohort, the secondary objectives are to evaluate the overall response 
rate (ORR) by investigator assessment, duration of response (DOR), time to response (TTR), 
clinical benefit rate (CBR), progression-free survival (PFS) by both investigator assessment and 
central independent assessment, as well as overall survival (OS), and safety. 
LGG Cohort
With respect to the LGG cohort the secondary objectives related to efficacy in this study are to 
compare the two treatment groups with respect to the overall response rate (ORR) by 
investigator assessment, duration of response (DOR), time to response (TTR), clinical benefit 
rate (CBR), and progression-free survival (PFS) by both investigator assessment and central 
independent assessment as well as overall survival (OS), safety, and patient reported outcome 
(PRO). 
All secondary efficacy analyses will be performed based on the FAS and will be repeated for 
the Evaluable set. All secondary endpoints will be listed and summarized separately for each 
cohort by treatment group. 
For the LGG cohort, a hierarchical approach will be taken to control for the overall type-I error 
rate for testing of multiple endpoints: PFS will be formally tested only if the primary endpoint 
ORR is statistically significant and then OS will be formally tested if PFS is also significant. No 
other multiplicity adjustments are planned for secondary endpoints testing.
ORR by investigator assessment (HGG Cohort)
For the HGG cohort, the evaluation of ORR will be repeated by investigator assessment as per 
RANO criteria. ORR will be summarized using descriptive statistics (N, %) along with 2-sided 
exact 95% confidence intervals (CIs) (Clopper and Pearson 1934). 80% confidence intervals
will also be provided for the HGG cohort.
ORR by investigator assessment (LGG Cohort)
For the LGG Cohort the evaluation of ORR will be repeated by investigator assessment
assessment as per RANO criteria.
The Cochrane-Mantel-Haenszel chi-square test will be used to compare ORR between the two 
treatment groups, at the one-sided 2.5% level of significance.
Duration of response
Among patients with a confirmed response (PR or CR) per RANO, duration of response (DOR) 
is defined as the time from first documented response (PR or CR) to the date of first documented 
disease progression or death due to any cause. DOR will be listed by patient and may be 

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described using Kaplan-Meier curves and relevant statistics if appropriate. Only the subset of 
patients who show a confirmed complete or partial tumor response will be included. Censoring 
rules for DOR will be outlined in detail in the SAP. DOR will be analyzed as per investigator 
assessment and as per central independent assessment, separately.
Progression free survival
Progression-free survival (PFS) is defined as the time from the date of first dose of study 
treatment (for HGG cohort) or date of randomization (for LGG cohort) to the date of first 
documented disease progression per RANO criteria or death due to any cause.
A patient who has not progressed or died or has received any further anticancer therapy at the 
analysis cut-off date, PFS will be censored at the time of the last adequate tumor evaluation 
before the cut-off date or before the start of the new anticancer therapy date, whichever is earlier. 
By default, if disease progression or death is documented after one single missing tumor 
evaluation, the actual event date of disease progression/death will be used for the PFS event 
date. If disease progression or death is documented after two or more missing tumor evaluations, 
the PFS time of these patients will be censored at the date of the last adequate tumor evaluation 
without PD. Censoring rules for PFS will be described in detail in the SAP.
PFS assessed by the investigators and the central independent reviewers will be described using 
Kaplan-Meier methods and appropriate summary statistics. 
For the LGG cohort the hazard ratio for PFS will be calculated, along with its 95% confidence 
interval, using a Cox model. A log-rank test at the one-sided 2.5% level of significance will be 
used to compare the two treatment groups.
PFS estimates (and 95% CIs) for both cohorts will be provided for key timepoints (i.e. 12, 24, 
36 months).
Time to response (TTR)
Time to response (CR or PR) is the time from start date of study treatment (for HGG cohort) or 
date of randomization (for LGG cohort) to first documented response of CR or PR (which must 
be confirmed subsequently) according to RANO criteria. All patients in the FAS will be 
included in the time to response calculations. Patients without a confirmed CR or PR will be 
censored at the study-maximum follow-up time (i.e., LPLV-FPFV) for patients with a PFS 
event (i.e., disease progression or death due to any cause), or at the date of the last adequate 
tumor assessment for patients without a PFS event. TTR will be listed and summarized by 
treatment group.
The distribution of time to response will be estimated using the Kaplan-Meier method and the 
median time to response will be presented along with 95% confidence interval only if a 
sufficient number of responses is observed. A responders-only analysis will also be performed 
in this case.
TTR will be analyzed using investigator and independent reviewer assessments separately.

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Clinical Benefit Rate 
Clinical benefit rate (CBR) is defined as the proportion of patients with a best overall response 
of CR or PR, or an overall lesion response of SD which lasts for a minimum time duration of at 
least 24 weeks. A patient will be considered to have SD for 24 weeks or longer if a SD response 
is recorded at 23 weeks or later (i.e >= 161 days) from randomization, allowing for the ±1 week 
visit window for tumor assessments.
For the HGG cohort, CBR will be summarized using descriptive statistics (N, %) along with 2-
sided exact 95% confidence intervals (CIs) (Clopper and Pearson 1934). 
For the LGG Cohort, CBR will be summarized by treatment group along with 2-sided exact 95% 
confidence intervals (CIs). Cochrane-Mantel-Haenszel chi-square test will be used to compare 
CBR between the two treatment groups, at the one-sided 2.5% level of significance.
Overall survival
Overall survival (OS) is defined as the time from the date of first dose of study treatment (for 
HGG cohort) or date of randomization (for LGG cohort) to the date of death due to any cause. 
OS time for patients who are alive at the end of the study or are lost to follow-up will be 
censored at the date of last contact.
OS will be described using Kaplan-Meier methods and appropriate summary statistics.
For the LGG cohort, the hazard ratio for OS will be calculated, along with its 95% confidence 
interval, using a Cox model. A log-rank test at the one-sided 2.5% level of significance will be 
used to compare the two treatment groups.
In addition, 2-year OS estimate with corresponding 95% CIs will be provided by treatment 
groups.
10.5.1
Safety objectives
Safety will be assessed separately for the HGG and LGG cohorts. For the LGG cohort the data 
will be analyzed by treatment arm. 
10.5.1.1 Analysis set and grouping for the analyses
For all safety analyses in both cohorts, the safety set will be used. All listings and tables will be 
presented by all patients.
The overall observation period will be divided into three mutually exclusive segments:
1. Pre-treatment period: from day of patient’s informed consent to the day before first dose 
of study medication
2. On-treatment period: from day of first dose of study medication to 30 days after last dose 
of study medication
3. Post-treatment period: starting at day 31 after last dose of study medication.
The safety summary tables will include only data collected during the on-treatment period. 
However, all safety data will be listed with data collected during the pre-treatment and post-
treatment period flagged.

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10.5.1.2 Adverse events (AEs)
Summary tables for adverse events (AEs) will include only AEs that started or worsened during 
the on-treatment period, the treatment-emergent AEs.
The incidence of treatment-emergent AEs (new or worsening from baseline) will be 
summarized by system organ class and/ or preferred term, severity (based on CTCAE grades), 
type of AE, and relation to study treatment. 
Serious adverse events (SAE), non-serious adverse events and adverse events of special interest
(AESI) during the on-treatment period will be tabulated.
All deaths (on-treatment and post-treatment) will be summarized.
All AEs, deaths and serious adverse events (including those from the pre and post-treatment 
periods) will be listed and those collected during the pre-treatment and post-treatment period 
will be flagged. A listing of all grouping levels down to the MedDRA preferred terms used to 
define each AESI will be generated.
10.5.1.3 Laboratory abnormalities
Grading of laboratory values will be assigned programmatically as per NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03. The calculation of CTCAE 
grades will be based on the observed laboratory values only, clinical assessments will not be 
taken into account.
CTCAE Grade 0 will be assigned for all non-missing values not graded as 1 or higher. Grade 5 
will not be used.
For laboratory tests where grades are not defined by CTCAE v4.03, results will be categorized 
as low/normal/high based on laboratory normal ranges.
The following summaries will be generated separately for hematology, and biochemistry tests:

Listing of all laboratory data with values flagged to show the corresponding CTCAE 
v4.03 grades if applicable and the classifications relative to the laboratory normal ranges
For laboratory tests where grades are defined by CTCAE v4.03

Worst post-baseline CTCAE grade (regardless of the baseline status). Each patient will be 
counted only once for the worst grade observed post-baseline.

Shift tables using CTCAE v4.03 grades to compare baseline to the worst on-treatment 
value
For laboratory tests where grades are not defined by CTCAE y4.03,

Shift tables using the low/normal/high/ (low and high) classification to compare baseline 
to the worst on-treatment value.
A listing of laboratory values will be provided by laboratory test, patient, and study day. A 
separate listing will display notable laboratory abnormalities (i.e., newly occurring CTCAE 
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10.5.1.4 Other safety data
ECG
12-lead ECGs including PR, QRS, QT, QTcF, and RR intervals will be obtained for each patient 
during the study. ECG data will be read and interpreted locally. 
Categorical analysis of QT/QTc interval data based on the number of patients meeting or 
exceeding predefined limits in terms of absolute QT/QTc intervals or changes from baseline 
will be presented.  In addition, a listing of these patients will be produced.
Vital signs
Data on vital signs will be tabulated and listed, notable values will be flagged.
Data from other tests (including ECHO, performance status, dermatological evaluation,
 
) will be listed and summarized using descriptive statistics as 
appropriate. Notable values may be flagged. Notable/Abnormal values for safety data will be 
further specified in the SAP and will be used for shift tables. Any other information collected 
will be listed as appropriate.
Analyses will be performed on the safety set for both study cohorts.
10.5.1.5 Supportive analyses for secondary objectives
Not applicable.
10.5.1.6 Tolerability
Tolerability will be summarized in terms of dose reductions or drug interruption due to an AE.
10.5.1.7 Palatability
Data on palatability assessments (bitterness, sweetness, texture and overall taste) will be 
summarized and listed. 
10.5.2
Pharmacokinetics
The PAS will be used in all pharmacokinetic data analysis and PK summary statistics for each
cohort.
10.5.2.1 Non-compartmental Analysis
On Day 15 PK parameters for dabrafenib, its metabolites and trametinib will be calculated with 
standard non-compartmental methods using Phoenix WinNonlin (Pharsight, Mountain View, 
California in US). The PK parameters listed in Table 10-1 will be estimated and reported, when 
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Table 10-1
Non-compartmental pharmacokinetic parameters
AUClast
The AUC from time zero to the last measurable concentration sampling time (tlast) (ng*h/mL)
AUCtau
The AUC calculated to the end of a dosing interval (tau) at steady-state (ng*h/mL); tau= 12 hrs
Cmax
The maximum (peak) observed plasma, blood, serum, or other body fluid drug concentration after 
single dose administration (ng/mL)
Tmax
The time to reach maximum (peak) plasma, blood, serum, or other body fluid drug concentration 
after single dose administration (h)
Ctrough
Measured concentration at the end of a dosing interval at steady state (taken directly before next 
administration) (ng/mL)The trough (predose) plasma concentration determined directly from the 
raw concentration-time data
10.5.2.2 Basic table, figure and listing
Validity of PK samples will be confirmed by checking sampling time window, steady state 
condition and occurrence of vomiting with respect to time of dose. Only confirmed PK 
concentrations will be used in the analyses.
Summary statistics of plasma concentration of dabrafenib, its relevant metabolites and 
trametinib will be reported by visit and actual leading dose (i.e. the dose taken on the day prior 
to the PK sampling day) for all patients that provided at least one evaluable PK sample. 
Summary statistics include n, arithmetic mean, median, SD, geometric mean, coefficient of 
variation (CV) (%) and geometric CV (%), minimum and maximum. Zero concentrations will 
not be included in the geometric mean calculation Graphical presentation will be provided on 
mean concentration at each scheduled time point for PK sub-population where the full PK 
profile is available.
10.5.2.3 Data handling principles
Plasma concentration values below the lower limit of quantification (LLOQ) will be set to zero 
by the bioanalyst, and will be displayed as zero in the listings and flagged. Values below the 
LLOQ will be treated as zero in any calculations of summary statistics, and treated as missing 
for the calculation of the geometric means and their CV%. Any missing pharmacokinetic 
parameters or concentrations will not be imputed.
 
 
 
 
 
 

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10.5.4
Resource utilization 
Not applicable.

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10.5.5
Patient-reported outcomes
Patient reported outcome (PRO) will only be evaluated in the LGG cohort. One PRO
questionnaire will be used: the PROMIS Parent Proxy Global Health 7+2. The 7+2 item parent 
proxy pediatric global health measure include a one global health score plus a single score from 
pain and a score from fatigue interference item which are scored independently. These two 
items are administered but do not contribute to the global health score. Rather, they are “signal” 
items that provide initial score estimates for pain interference and fatigue. Scoring of PRO data 
and methods for handling of missing items or missing assessments will be according to the 
scoring manual and user guide for each respective patient questionnaire. No imputation 
procedures will be applied for missing items or missing assessments. Descriptive statistics will 
be used to summarize the scored scales of PROMIS Parent Proxy Global Health 7+2 at each 
scheduled assessment time point for each treatment group. Additionally, change from baseline 
in the scale at the time of each assessment will be summarized. Subjects with an evaluable 
baseline score and at least one evaluable post baseline score during the treatment period will be 
included in the change from baseline analyses. In addition, a repeated measures model for 
longitudinal data will be used to estimate differences in PROMIS Parent Proxy Global Health 
7+2 scores between treatment groups. The number of subjects completing each questionnaire 
and the number of missing or incomplete assessments will be summarized by treatment group 
for each scheduled assessment time point. No formal statistical tests will be performed for PRO 
data and hence no multiplicity adjustment will be applied. The FAS will be used for analyzing 
PRO data.
10.7
Interim analysis
10.7.1
HGG Cohort
An interim analysis for futility (HGG cohort only) will be implemented to allow possible 
termination of recruitment and the study in the event that there is insufficient efficacy. The 
patients for inclusion in the formal interim analysis for futility will be made shortly after 16 
patients in the FAS have been enrolled. The interim analysis will be conducted when this initial 
group of patients to be included in the analysis have all had at least 20 weeks of follow-up or 
have withdrawn early. However, any decision to stop or continue the study will be made based 
on all data available at the IA cut-off taking the futility analysis into account.

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The futility criteria will be considered met if the observed overall response rate (ORR) assessed 
by independent reviewer is less than or equal to 25% which is considered a threshold for clinical 
relevance. This will trigger consideration for stopping the study taking account of all available 
data and not just the response data required for determination of futility. 
The choice of futility threshold has also taken account of operating characteristics which 
suggest that the chance of the futility criteria being met is high if the true underlying response 
rate is in a low range (e.g. <=20%); whereas if the true rate is considerably higher, as expected, 
then there is a very low chance of declaring futility at the IA. Full details of the futility criteria 
and operating characteristics are provided below in Table 10-2 and Table 10-4. 
Futility criteria 
Given the data observed in the IA, the probability of the lower bound of 95% CI at the primary 
analysis exceeding a certain response rate (i.e. 20%) conditional on the observed number of 
responders observed at the IA can be calculated. The conditional probability can be calculated 
using beta-binomial distribution (posterior predictive distribution). Let Y represent the number 
of responders from m future patients at the primary analysis and x is the number of responders 
among n patients at the interim analysis. The (posterior) predictive distribution of Y conditioned 
on the observed data at the interim analysis (x responders out of n patients) is a beta-binomial 
distribution described by
where a minimally informative unimodal Beta distribution B(a0, b0) (Neuenschwander et al 
2008) is used with mean equal to 20%,  i.e., the prior distribution will be Beta (0.25, 1) for the 
POS calculations at the interim analysis.
Table 10-2 shows the predictive probabilities that the 95% CI excludes 20% at the primary 
analysis under different interim results. For example, with 16 patients at IA, if 4 responses are 
observed (i.e. 25% response rate), the probability of the 95% CI excluding 20% at the primary 
analysis is 13.7%.
Table 10-2
Predictive probability of the lower bound of 95% CI exceeding 20% at 
the primary analysis under different interim results
# of responses
Observed response rate at 
IA given n=16 (%)
Predictive probability that the 95% CI excludes 
20% at the primary analysis (%)a
1
6.3
< 0.1
2
12.5
0.5
3
18.8
3.5
4
25.0
13.7
5
31.3
34.4
6
37.5
61.0
7
43.8
83.1
8
50.0
94.9
9
56.3
99.0
aThe predictive probabilities are calculated from a beta-binomial distribution.

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In addition to the interim futility analysis described above if the LGG primary analysis is 
subsequently reported prior to the HGG primary analysis then an update/interim analysis of 
HGG safety data only may be required to support the LGG submission.
Also, an additional interim analysis of key safety and PK data of the adolescent patients in the 
HGG cohort may be performed to support a heath authority request for data in adolescent 
patients. There will be no efficacy or futility conclusion drawn based on this interim analysis.
10.7.2
LGG Cohort
No formal interim analysis is planned for the LGG cohort. The primary analysis will be 
performed after all patients have completed Week 32 or discontinued prior to Week 32. A final 
analysis will be performed after all patients have been on the study for at least two years (or 
otherwise discontinued from the study). Formal testing of the primary endpoint with full alpha 
will be performed at the primary analysis.
10.8
Sample size calculation
10.8.1
HGG Cohort
Based on the exact binomial distribution, approximately 40 patients will be enrolled if the study 
is not stopped for futility at the time of the interim analysis. 
The exact 95% and 80% CIs for potential observed ORR for 40 patients are shown in Table 10-
3.
The 95% CI, via the lower limit, is used to establish the levels of response which are exceeded 
by taking the combination therapy according to a robust standard of evidence (i.e. one-sided 
alpha=0.025). 
Due to the uncertainties regarding the historical control data there is no specific “success” 
threshold level that we can apply that the lower limit should be greater than  to give robust 
evidence that dabrafenib and trametinib combination therapy is better than historical control; 
however, the study sample size gives reasonable operating characteristics for an illustrative 
threshold historical level of 20%, which is higher than the range expected based on the 
information given in the literature (Section 1.1.3).  
The study also aims to provide evidence that trametinib gives added value to the dabrafenib and 
trametinib combination over and above dabrafenib monotherapy treatment. Since a lower 
standard of evidence is usually required to show such added value, the lower limit of an 80% 
CI is used to identify the response rates which will be exceeded by taking the combination 
therapy based on a reduced level of evidence (one-sided alpha of 0.1). Again it is difficult to 
ascertain a definitive  threshold for “success” for evaluation in these circumstances but the 
number of patients in this trial give reasonable operating characteristics for an illustrative 
threshold level of 32%, which is the response rate observed in dabrafenib monotherapy patients 
in the study [BRF116013, CDRB436A2102] although based on limited data. Note that the 95% 
CIs can also be used to provide more robust evidence of the benefit of trametinib by looking at 
the lower limit compared to possible levels of dabrafenib monotherapy response.

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Table 10-3
Exact Binomial 95 and 80 percent Confidence Intervals Around 
Potential Observed ORRs for N=40
Number of responders
Observed ORR (%)
95% exact CI (%)
80% exact CI (%)
12
30.0
16.6, 46.5
20.5, 41.2
13
32.5
18.6, 49.1
22.7, 43.8
14
35.0
20.6, 51.7
24.9, 46.3
15
37.5
22.7, 54.2
27.1, 48.9
16
40.0
24.9, 56.7
29.4, 51.4
17
42.5
27.0, 59.1
31.7, 53.9
18
45.0
29.3, 61.5
34.1, 56.3
19
47.5
31.5, 63.9
36.4, 58.8
20
50.0
33.8, 66.2
38.8, 61.2
21
52.5
36.1, 68.5
41.2, 63.6
22
55.0
38.5, 70.7
43.7, 65.9
For example, out of the 40 patients, with 14 responses (35%), the lower bound of 95% CI would 
be higher than 20%; with 18 responses (45%), the 80% CI would be higher than 32%; and with 
20 responses (50%), the 95% CI would be higher than 32%.
Table 10-4 and Table 10-5 show the operating characteristics under different true ORR with 
respect to different criteria. The tables show probability of meeting the futility consideration 
criteria (less than 5 responders out of 16 patients), probability of the confidence interval 
excluding the target response rate at the primary analysis, and probability that the futility criteria 
is not met at IA but the confidence interval does not exclude the target response rate at the 
primary analysis.
At this sample size, when the true ORR is ≤20%, 

the probability of meeting the futility consideration criteria at interim analysis is > 79%,

the probability of the 95% CI excluding 20% at the primary analysis is >1.6%, 

and the probabilities of the 95% CI and the 80% CI excluding 32% at the primary analysis 
are both < 0.1% respectively. 
Within 40 patients, if the true ORR is 55% or higher, then 

the probability of meeting the futility consideration criteria at IA is < 2%, 

the probabilities of the 95% CI excluding 20% and the 80% CI excluding 32% at the 
primary analysis are both > 90% respectively, 

and the probability that the 95% CI excludes 32% is > 78%.
Table 10-4
Operating Characteristics with regard to the 95% CI excluding 20% 
response rate
True 
ORR (%)
Probability to 
meet futility 
consideration 
criteria at IA (%)
Probability that the futility 
consideration criteria is not 
met at IA and the 95% CI 
excludes 20% at primary 
analysis (%)
Probability that the futility consideration 
criteria is not met at IA and the 95% CI 
does not exclude 20% at primary analysis
(%) 
20
79.8
1.6
18.6
25
63.0
8.5
28.4
30
45.0
25.2
29.8
35
28.9
49.1
22.0

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True 
ORR (%)
Probability to 
meet futility 
consideration 
criteria at IA (%)
Probability that the futility 
consideration criteria is not 
met at IA and the 95% CI 
excludes 20% at primary 
analysis (%)
Probability that the futility consideration 
criteria is not met at IA and the 95% CI 
does not exclude 20% at primary analysis
(%) 
40
16.7
71.7
11.6
45
8.5
87.1
4.4
50
3.8
95.0
1.2
55
1.5
98.3
0.2
60
0.5
99.5
< 0.1
The probabilities are calculated based on the exact binomial distribution.
Table 10-5
Operating Characteristics with regard to the 95% and 80% CIs 
excluding 32% response rate
True ORR 
(%)
Probability to 
meet futility 
consideration 
criteria at IA 
(%)
Probability that 
the futility 
consideration 
criteria is not 
met at IA and 
the 95% CI 
excludes 32% 
at primary 
analysis (%)
Probability that 
the futility 
consideration 
criteria is not 
met at IA and 
the 95% CI does 
not exclude 32% 
at primary 
analysis (%)
Probability that 
the futility 
consideration 
criteria is not 
met at IA and 
the 80% CI 
excludes 32%
at primary 
analysis (%)
Probability that 
the futility 
consideration 
criteria is not 
met at IA and 
the 80% CI 
does not 
exclude 32% at 
primary 
analysis (%)
20
79.8
< 0.1
20.2
< 0.1
20.1
25
63.0
0.1
36.9
0.5
36.5
30
45.0
0.6
54.4
3.1
51.9
35
28.9
3.6
67.5
12.1
59.0
40
16.7
12.9
70.5
30.5
52.9
45
8.5
31.4
60.1
55.2
36.3
50
3.8
56.0
40.1
77.6
18.5
55
1.5
78.5
20.0
91.7
6.8
60
0.5
92.4
7.1
97.8
1.7
The probabilities are calculated based on the exact binomial distribution.
10.8.2
LGG Cohort
To detect a 30% improvement in ORR based on central independent assessed response of 50% 
in the dabrafenib plus trametinib arm vs 20% in the carboplatin with vincristine arm (Lassaletta 
2017) with at least 80% power, 102 patients are required to be randomized in the two treatment 
arms in a 2:1 ratio based on using a Maentel-Haenszel chi-squared test and one-sided alpha = 
2.5%.
Based on the following assumptions i.e 102 patients, 2:1 randomization ratio based on Maentel-
Haenszel chi-squared test and one sided alpha of 2.5%, the study power scenarios under 
different true ORR are shown in Table 10-6.

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Table 10-6
Power scenarios under different true ORR in BRAF V600 mutant
LGGTrue ORR % (carboplatin with 
vincristine arm vs. dabrafenib plus 
trametinib )
Power (%)
20% vs. 55%
90%
20% vs. 50%
80%
20% vs. 45%
67%
15% vs. 50%
90%
25% vs. 50%
66%
10.9
Power for analysis of key secondary variables
Not applicable.
11
Ethical considerations and administrative procedures
11.1
Regulatory and ethical compliance
This clinical study was designed, shall be implemented and reported in accordance with the 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC and US Code of Federal Regulations 
Title 21), and with the ethical principles laid down in the Declaration of Helsinki.
11.2
Responsibilities of the investigator and IRB/IEC/REB
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Independent Ethics Committee/Research 
Ethics Board (IRB/IEC/REB) before study start. Prior to study start, the investigator is required 
to sign a protocol signature page confirming his/her agreement to conduct the study in 
accordance with these documents and all of the instructions and procedures found in this 
protocol and to give access to all relevant data and records to Novartis monitors, auditors, 
Novartis Clinical Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs/REBs and regulatory authorities as required.
11.3
Informed consent procedures
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC/REB-approved informed consent (if applicable, or, if 
incapable of doing so, after such consent has been provided by a legally acceptable 
representative of the patient. In cases where the patient’s representative gives consent, the 
patient should be informed about the study to the extent possible given his/her understanding. 
If the patient is capable of doing so, he/she should indicate assent by personally signing and 
dating the written informed consent document or a separate assent form).
Informed consent must be obtained before conducting any study-specific procedures (i.e. all of 
the procedures described in the protocol). The process of obtaining informed consent should be 
documented in the patient source documents. The date when a patient’s Informed Consent was 
actually obtained will be captured in their CRFs.

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Novartis will provide to investigators, in a separate document, a proposed informed consent 
form (ICF) that is considered appropriate for this study and complies with the ICH GCP 
guideline and regulatory requirements. Any changes to this ICF suggested by the investigator 
must be agreed to by Novartis before submission to the IRB/IEC/REB, and a copy of the 
approved version must be provided to the Novartis monitor after IRB/IEC/REB approval.
Women of child bearing potential should be informed that taking the study medication may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree that 
in order to participate in the study they must adhere to the contraception requirement for the 
duration of the study. If there is any question that the patient will not reliably comply, they 
should not be entered in the study.
Additional consent form
Not applicable.
11.4
Discontinuation of the study
Novartis reserves the right to discontinue this study under the conditions specified in the clinical 
study agreement. Specific conditions for terminating the study are outlined in 
Section 4.4.
11.5
Publication of study protocol and results
Novartis is committed to the following high ethical standards for reporting study results for its 
innovative medicines, including the timely communication and publication of clinical trial 
results, whatever their outcome. Novartis assures that the key design elements of this protocol 
will be posted on the publicly accessible database, e.g. clinicaltrials.gov, before study start. In 
addition, results of interventional clinical trials in adult patients are posted on 
www.novartisclinicaltrials.com, a publicly accessible database of clinical study results within 
1 year of study completion (i.e., LPLV), those for interventional clinical trials involving 
pediatric patients within 6 months of study completion.
Novartis follows the ICMJE authorship guidelines (.icmje.org) and other specific guidelines of 
the journal or congress to which the publication will be submitted. Authors will not receive 
remuneration for their writing of a publication, either directly from Novartis or through the 
professional medical writing agency. Author(s) may be requested to present poster or oral 
presentation at scientific congress; however, there will be no honorarium provided for such 
presentations.
As part of its commitment to full transparent in publications, Novartis supports the full 
disclosure of all funding sources for the study and publications, as well as any actual and 
potential conflicts of interest of financial and non-financial nature by all authors, including 
medical writing/editorial support, if applicable. 
For the Novartis Guidelines for the Publication of Results from Novartis-sponsored Research, 
please refer to .novartis.com. 

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11.6
Study documentation, record keeping and retention of 
documents
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with Section 4.9 of the ICH E6 GCP, and regulatory and institutional requirements 
for the protection of confidentiality of patients. As part of participating in a Novartis-sponsored 
study, each site will permit authorized representatives of the sponsor(s) and regulatory agencies 
to examine (and when required by applicable law, to copy) clinical records for the purposes of 
quality assurance reviews, audits and evaluation of the study safety and progress.
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Examples 
of these original documents and data records include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, patients’ diaries or evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, and patient files and records kept 
at the pharmacy, at the laboratories, and medico-technical departments involved in the clinical 
trial.
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site Principal Investigator. The study case report form (CRF) is the primary data collection 
instrument for the study. The investigator should ensure the accuracy, completeness, legibility, 
and timeliness of the data reported in the CRFs and all other required reports. Data reported on 
the CRF, that are derived from source documents, should be consistent with the source 
documents or the discrepancies should be explained. All data requested on the CRF must be 
recorded. Any missing data must be explained. Any change or correction to a paper CRF should 
be dated, initialed, and explained (if necessary) and should not obscure the original entry. For 
electronic CRFs an audit trail will be maintained by the system. The investigator should retain 
records of the changes and corrections to paper CRFs.
The investigator/institution should maintain the trial documents as specified in Essential 
Documents for the Conduct of a Clinical Trial (ICH E6 Section 8) and as required by applicable 
regulations and/or guidelines. The investigator/institution should take measures to prevent 
accidental or premature destruction of these documents.
Essential documents (written and electronic) should be retained for a period of not less than 
fifteen (15) years from the completion of the Clinical Trial unless Sponsor provides written 
permission to dispose of them or, requires their retention for an additional period of time 
because of applicable laws, regulations and/or guidelines.
11.7
Confidentiality of study documents and patient records
The investigator must ensure anonymity of the patients; patients must not be identified by names 
in any documents submitted to Novartis. Signed informed consent forms and patient enrollment 
log must be kept strictly confidential to enable patient identification at the site.

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11.8
Audits and inspections
Source data/documents must be available to inspections by Novartis or designee or Health 
Authorities.
11.9
Financial disclosures
Financial disclosures should be provided by study personnel who are directly involved in the 
treatment or evaluation of patients at the site - prior to study start.
12
Protocol adherence
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact Novartis or its agents, if any, monitoring the study 
to request approval of a protocol deviation, as no authorized deviations are permitted. If the 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC/REB it cannot be implemented. All significant protocol 
deviations will be recorded and reported in the CSR.
12.1
Amendments to the protocol
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, Health Authorities where required, and the IRB/IEC/REB. Only 
amendments that are required for patient safety may be implemented prior to IRB/IEC/REB 
approval. Notwithstanding the need for approval of formal protocol amendments, the 
investigator is expected to take any immediate action required for the safety of any patient 
included in this study, even if this action represents a deviation from the protocol. In such cases, 
Novartis should be notified of this action and the IRB/IEC at the study site should be informed 
according to local regulations (e.g. UK requires the notification of urgent safety measures 
within 3 days) but not later than 10 working days.

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13
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14
Appendices
14.1
Appendix 1 – Concomitant medications
Table 14-1
List of medications to be used with caution during study drug 
treatment
USE WITH CAUTION:  Moderate  inhibitors of CYP3A, or CYP2C8 since concentrations of 
dabrafenib or vincristine may be increased
Class/Therapeutic Area
Moderate CYP3A and CYP2C8 Inhibitors
Antiarrhythmics
Diltiazem, verapamil
Antibiotic
Erythromycin
Antifungal
Fluconazole
Miscellaneous
Aprepitant
USE WITH CAUTION: Co-administration of these drugs with study treatment may result in loss of 
efficacy.  Monitor patients for loss of efficacy or substitute with another medication.
Class/Therapeutic Area
CYP3A4, CYP2B6, CYP2C8, CYP2C9, CYP2C19 or Transporter 
Substrates that May be Affected by Induction 
Analgesics
Alfentanil, buprenorphine, celecoxib, codeine, fentanyl, methadone, 
oxycodone
Antiarrhythmics
Disopyramide, dronedarone, mexiletine, propafenone, quinidine
Antibiotics
Chloramphenicol, doxycycline, erythromycin, moxifloxacin 
Anticoagulants/ Antiplatelets
Cilostazole, warfarin
Anticonvulsants
Divalproex, lamotrigine, valproate, zonisamide
Antidepressants and 
Antipsychotics
Aripiprazole, bupropion, buspirone, desipramine, haloperidol, mirtazapine, 
pimozide, quetiapine, trazodone, amitriptyline, clomipramine, imipramine
Antidiabetics
Glyburide, saxagliptin, tolbutamide, nateglinide, pioglitazone, repaglinide, 
rosiglitazone
Antifungals
Caspofungin, fluconazole, terbinafine
Antihistamines
Astemizole, chlorpheniramine, ebastine
Antihypertensives
Amlodipine, diltiazem, felodipine, nifedipine, nilvadipine, nisoldipine, 
verapamil
Antimigraine Agents
Diergotamine, eletriptan, ergotamine
Corticosteroids
Dexamethasone, methylprednisolone, oral budesonide
Erectile Dysfunction Agents
Sildenafil, tadalafil, vardenafil
HMG-CoA Reductase 
Inhibitors
Atorvastatin, lovastatin, simvastatin, rosuvastatin, pravastatin
Hypnotics and Sedatives
Alprazolam, brotizolam, diazepam, estazolam, midazolam, triazolam, 
zolpidem, zopiclone
Immunosuppressants
Everolimus, sirolimus, tacrolimus
Miscellaneous
Aprepitant, cisapride, darifenacin, digoxin, disopyramide, leflunomide, 
methohexital, oral contraceptives, quinine, ranitidine, solifenacin, 
sulfasalazine, tramadol, tolvaptan, chloroquine, zopiclone
Selective Aldosterone 
Blockers
Eplerenone
Abbreviations: CYP = cytochrome P450; HMG-CoA = 3-hydroxy-3-methylglutaryl-coenzyme A.

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Table 14-2
List of prohibited medications during study drug treatment
PROHIBITED – strong inducers of CYP3A or CYP2C8, since concentrations of dabrafenib or vincristine
may be decreased
Class/Therapeutic Area
Drugs/Agents
Antibiotics
Rifamycin class agents (e.g.,  rifampin, rifabutin, rifapentine), 
Anticonvulsant
Carbamazepine, phenobarbital, phenytoin, s-mephenytoin 
Miscellaneous
bosentan,
PROHIBITED – Strong inhibitors of CYP3A, or CYP2C8 since concentrations of dabrafenib or 
vincristine may be increased
Class/Therapeutic Area
Drugs/Agents
Antibiotics
Clarithromycin, telithromycin, troleandomycin
Antidepressant
Nefazodone
Antifungals
Itraconazole, ketoconazole, posaconazole, voriconazole
Hyperlipidemia
Gemfibrozil
Anti-retroviral
Ritonavir, Saquinavir, Atazanavir
Miscellaneous
Conivaptan 

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14.2
Appendix 2 – Performance Status Criteria
PERFORMANCE STATUS CRITERIA
Karnofsky and Lansky performance scores are intended to be in multiples of 10
Karnofsky (age ≥16 years of age)
Lansky (age <16 years)
Score
Description
Score
Description
100
Normal, no complaints no evidence of 
disease.
100
Fully active, normal.
90
Able to carry on normal activity, minor 
signs of symptoms of disease.
90
Minor restrictions in physically strenuous activity.
80
Normal activity with effort, some signs of 
symptoms of disease.
80
Active, but tires quickly.
70
Cares for self, unable to carry on normal 
activity or do active work.
70
Both greater restriction of and less time spent in 
play activity.
60
Requires occasional assistance, but is 
able to care for most of his/her needs.
60
Up and around, but minimal active play, keeps 
busy with quieter activities.
50
Requires considerable assistance and 
frequent medical care.
50
Gets dressed, but lies around much of the day; 
no active play, able to participate in all quiet play 
and activities.
40
Disabled, requires special care and 
assistance.
40
Mostly in bed, participates in quiet activities.
30
Severely disabled, hospitalization 
indicated.  Death not imminent.
30
In bed, needs assistance even for quiet play.
20
Very sick, hospitalization indicated.  
Death not imminent.
20
Often sleeping; play entirely limited to very 
passive activities.
10
Moribund, fatal processes progressing 
rapidly.
10
No play, does not get out of bed.

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14.3
Appendix 3 – Response Assessment in Neuro-oncology (RANO) 
Criteria
Anti-tumor activity will be assessed based on clinical evidence and the Response Assessment 
in Neuro-Oncology (RANO) criteria for solid tumors (Wen 2010, Wen 2017).
All measureable and nonmeasureable lesions should be assessed using the same techniques as 
at baseline.  Ideally, patients should be imaged on the same MRI scanner, or at least with the 
same magnet strength, for the duration of the study to reduce difficulties in interpreting changes.  
The RANO criteria for assessment of LGG differs from that for HGG primarily in that LGG 
assessments utilize T2/FLAIR imaging while HGG assessments utilize Gadolinium enhanced 
imaging.  For purposes of this protocol, the minor response category will not be used for 
description of LGG response assessments.
Measurable disease is defined as bidimensionally contrast enhancing (HGG) or T2/FLAIR 
(LGG) lesions with clearly defined margins by MRI scan, with two perpendicular diameters of 
at least twice the thickness of the imaging slices with 0-mm skip. In the event there are interslice 
gaps, this also needs to be considered in determining the size of measurable lesions at baseline. 
Measurement of tumor around a cyst or surgical cavity represents a particularly difficult 
challenge. In general, such lesions should be considered nonmeasurable unless there is a nodular 
component of at least twice the slice thickness. The cystic or surgical cavity should not be 
measured in determining response. 
Nonmeasurable disease is defined as either unidimensionally measurable lesions, masses with 
margins not clearly defined, or lesions with maximal perpendicular diameters less than twice 
the slice thickness. 
Radiographic response should be determined in comparison to the tumor measurements 
obtained at pretreatment baseline for determination of response.  The smallest tumor 
measurements at either pretreatment baseline or after initiation of therapy should be used for 
determination of progression.  
Response definitions for HGG:

Complete response (CR): Complete disappearance of all enhancing measureable and 
nonmeasureable disease on contrast enhanced MRI scan sustained for at least 4 weeks, no 
new lesions, and stable or improved nonenhancing (T2/FLAIR) lesions. In addition, 
patient must be off steroids or only on physiologic replacement doses.  In the absence of a 
confirming scan 4 weeks later, this response will be considered only stable disease.

Partial response (PR): Greater than or equal to a 50% reduction, compared to baseline, in 
the sum of products of the perpendicular diameters for all measurable lesions for at least 4 
weeks, no progression of nonmeasureable disease, no new lesions, and stable or improved 
nonenhancing (T2/FLAIR) lesions.  In addition, patient must be on a corticosteroid dose 
not greater than the dose at the time of baseline scan and be stable or improving clinically.  
In the absence of a confirming scan 4 weeks later, this response will be considered only 
stable disease.

Progressive Disease (PD): Greater than or equal to a 25% increase in sum of the products 
of perpendicular diameters of enhancing lesions (compared with baseline if no decrease) 
on stable or increasing doses of corticosteroids, OR a significant increase in T2/FLAIR 

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nonenhancing lesions on stable or increasing doses of corticosteroids compared with 
baseline scan or best response after initiation of therapy, not due to comorbid events, OR 
the appearance of any new lesions, OR clear progression of nonmeasurable lesions, OR 
definite clinical deterioration not attributable to other causes apart from tumor, or to 
decrease in corticosteroid dose.  Failure to return for evaluation as a result of death or 
deteriorating condition should also be considered as progression. 

Stable disease: If patient does not qualify for CR, PR, or PD and has stable nonenhancing 
(T2/FLAIR) lesions on same or lower doses of corticosteroids compared with baseline 
scan and clinically stable status.  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 corticosteroid dose 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.
Response definitions for LGG:

Complete response (CR): Complete disappearance of all measureable and nonmeasureable 
disease on MRI scan sustained for at least 4 weeks, and no new lesions. In addition, 
patient must be off steroids or only on physiologic replacement doses.  In the absence of a 
confirming scan 4 weeks later, this response will be considered only stable disease.

Partial response (PR): Greater than or equal to a 50% reduction, compared to baseline, in 
the sum of products of the perpendicular diameters for all measurable lesions for at least 4 
weeks, no progression of nonmeasureable disease, and no new lesions.  In addition, patient 
must be on a corticosteroid dose not greater than the dose at the time of baseline scan and 
be stable or improving clinically.  In the absence of a confirming scan 4 weeks later, this 
response will be considered only stable disease.

Progressive Disease (PD): Greater than or equal to a 25% increase in sum of the products 
of perpendicular diameters of measurable lesions (compared with baseline if no decrease) 
on stable or increasing doses of corticosteroids compared with baseline scan or best 
response after initiation of therapy, not due to comorbid events, OR the appearance of any 
new lesions, OR clear progression of nonmeasurable lesions, OR definite clinical 
deterioration not attributable to other causes apart from tumor, or to decrease in 
corticosteroid dose.  Failure to return for evaluation as a result of death or deteriorating 
condition should also be considered as progression. 

Stable disease: If patient does not qualify for CR, PR, or PD and has stable lesions on 
same or lower doses of corticosteroids compared with baseline scan and clinically stable 
status.  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 corticosteroid dose 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.

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Increase in corticosteroid dose alone, in the absence of clinical deterioration related to tumor, 
will not be used as a determinant of progression. Patients with stable imaging studies whose 
corticosteroid dose was increased for reasons other than clinical deterioration related to tumor 
do not qualify for stable disease or progression. They should be observed closely. If their 
corticosteroid dose can be reduced back to baseline, they will be considered as having stable 
disease; if further clinical deterioration related to tumor becomes apparent, they will be 
considered to have progression. The date of progression should be the first time point at which 
corticosteroid increase was necessary.
The definition of clinical deterioration is left to the discretion of the treating physician, but it is 
recommended that a decline in the KPS from 100 or 90 to 70 or less, a decline in KPS of at least 
20 from 80 or less, or a decline in KPS from any baseline to 50 or less, for at least 7 days, be 
considered neurologic deterioration unless attributable to comorbid events or changes in 
corticosteroid dose. Similarly, a decline in the Eastern Cooperative Oncology Group and WHO 
performance scores from 0 or 1 to 2 or 2 to 3 would be considered neurologic deterioration.  
In general, if there is doubt about whether the lesion has progressed, continued treatment and 
close follow-up evaluation will help clarify whether there is true progression.  If there is 
uncertainty regarding whether there is progression, the patient may continue on treatment and 
remain under close observation (e.g., evaluated at 4-week intervals). If subsequent evaluations 
suggest that the patient is in fact experiencing progression, then the date of progression should 
be the time point at which this issue was first raised.

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14.4
Appendix 4 – WHO (2016) Grading of Tumors of the CNS 

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