Conditions: Cancer
Keywords: v600-mutation neuroblastoma Trametinib pediatrics Langerhans Cell Histiocytosis low grade glioma plexiform neurofibromas
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 139
Healthy volunteers: no

Brief summary:
This was a 4-part (Part A, Part B, Part C and Part D), Phase I/IIa, multi-center, open label, study in pediatric subjects with refractory or recurrent tumors.

Part A was a repeat dose, dose escalation and expansion phase that identified the recommended phase II dose (RP2D) of trametinib monotherapy. Part B evaluated the preliminary activity of trametinib monotherapy in 4 disease-specific cohorts of subjects. Part C was aimed to determine the safety, tolerability and preliminary activity of the RP2D of trametinib in combination with a limited dose escalation of dabrafenib. Part D evaluated the preliminary activity of trametinib in combination with dabrafenib in 2 disease-specific cohorts of subjects.

The overall goal of this trial was to efficiently establish safe, pharmacologically relevant dose of trametinib monotherapy and trametinib in combination with dabrafenib in infants, children and adolescents and determine preliminary activity of trametinib monotherapy and trametinib in combination with dabrafenib in selected recurrent, refractory or unresectable childhood tumors.

Detailed description:
This was a 4-part (Part A, Part B, Part C and Part D), Phase I/IIa, multi-center, open label, study in pediatric subjects with refractory or recurrent tumors.

Part A was a repeat dose, dose escalation and expansion phase that identified the recommended phase II dose (RP2D) of trametinib monotherapy using a 3 + 3 dose- escalation procedure. The starting dose level of trametinib was 0.0125 mg/kg/day, the second dose level was 0.025 mg/kg/day and the third dose level was 0.040 mg/kg/day. Additionally, in Part A extension an intermediate trametinib dose level of 0.032 mg/kg/day was assessed in subjects under 6 years of age. In all cohorts, the total daily trametinib dose was not to exceed the adult dose (2 mg) in any subject.

Part B evaluated the preliminary activity of trametinib monotherapy in 4 disease-specific cohorts of subjects:

B1: Refractory or relapsed neuroblastoma B2: Recurrent or unresectable low grade glioma (LGG) with BRAF tandem duplication with fusion (glioma fusion) B3: Neurofibromatosis Type -1 associated plexiform neurofibromas (NF-1 with PN) that are unresectable and medically significant B4: BRAF V600 mutant tumors In Part B it was used the RP2D of trametinib (0.025 mg/kg/day) determined in Part A.

Part C was a 3+3 study design to determine the safety, tolerability and preliminary activity of the RP2D of trametinib in combination with a limited dose escalation of dabrafenib. The trametinib dose administered in Part C was based on the trametinib monotherapy RP2D from Part A (0.025 mg/kg/day). For the evaluation of combination therapy in this study, the starting dose of dabrafenib was 50% of the monotherapy RP2D established in a separate study: 2.63 mg/kg/day (\<12 years old subjects) and 2.25 mg/kg/day (≥12 years old subjects). The second dose level of dabrafenib was 100% of the monotherapy RP2D: 5.25 mg/kg/day (\<12 years old subjects) and 4.5 mg/kg/day (≥12 years old subjects).

Additionally, in Part C extension, the trametinib dose determined from Part A extension (0.032 mg/kg/day) with 100% pediatric RP2D of dabrafenib (5.25 mg/kg/day) was assessed in subjects under 6 years of age.

In all cohorts, the total daily trametinib dose was not to exceed the adult dose (2 mg) in any subject and the total daily dabrafenib dose was not to exceed the adult dose (300 mg) in any subject.

Part D evaluated the preliminary activity of trametinib in combination with dabrafenib in two disease-specific cohorts of subjects diagnosed with low grade glioma (LGG) and Langerhans cell histiocytosis (LCH).

In Part D it was used the RP2D of the combination treatment determined in Part C (0.025 mg/kg/day trametinib and the 100% RP2D of dabrafenib) in subjects 6 years to \< 18 years of age. Additionally, once Part C extension had defined the trametinib RP2D for subjects under 6 years of age, this dose was used for the remaining subjects enrolled in Part D (0.032 mg/kg/day trametinib and the 100% RP2D of dabrafenib).

The overall goal of this trial was to efficiently establish safe, pharmacologically relevant dose of trametinib monotherapy and trametinib in combination with dabrafenib in infants, children and adolescents and determine preliminary activity of trametinib monotherapy and trametinib in combination with dabrafenib in selected recurrent, refractory or unresectable childhood tumors.

Arms:
arm 1: Participants treated with trametinib 0.0125 mg/kg/day arm 2: Participants treated with trametinib 0.025 mg/kg/day arm 3: Participants under 6 years of age treated with trametinib 0.032 mg/kg/day arm 4: Participants treated with trametinib 0.04 mg/kg/day arm 5: Participants with refractory or relapsed neuroblastoma treated with trametinib 0.025 mg/kg/day arm 6: Participants with refractory or relapsed neuroblastoma treated with trametinib 0.025 mg/kg/day arm 7: Participants with neurofibromatosis Type -1 associated plexiform neurofibromas (NF-1 with PN) treated with trametinib 0.025 mg/kg/day arm 8: Participants with BRAF V600 mutant solid tumors treated with trametinib 0.025 mg/kg/day arm 9: Participants treated with a combination therapy of trametinib (0.025 mg/kg/day) plus 50% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (2.63 mg/kg/day for \<12 years old subjects and 2.25 mg/kg/day for ≥12 years old subjects) arm 10: Participants treated with a combination therapy of trametinib (0.025 mg/kg/day) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for \<12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects) arm 11: Participants under 6 years of age treated with a combination therapy of trametinib (0.032 mg/kg/day) with 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day) arm 12: Participants with low grade glioma (LGG) treated with a combination therapy of trametinib (0.032 mg/kg/day for \< 6 years old subjects and 0.025 mg/kg/day for ≥ 6 years old subjects) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for \<12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects) arm 13: Participants with Langerhans cell histiocytosis (LCH) treated with a combination therapy of trametinib (0.032 mg/kg/day for \< 6 years old subjects and 0.025 mg/kg/day for ≥ 6 years old subjects) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for \<12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects)

Interventions: intervention 1: Trametinib intervention 2: Dabrafenib
Intervention descriptions: intervention 1: Trametinib was administered orally, once daily. It was available in tablets (0.125 mg, 0.5 mg, 2 mg dose) as well as in powder form for oral solution (0.05 mg/mL dose). intervention 2: Dabrafenib was administered orally, twice daily. The daily dose was divided into two equal doses. It was available in capsules (50 mg and 75 mg), dispersible tablets (10 mg) and powder for oral suspension (10 mg/mL dose).

Protocol document:
Prot_000.pdf: 


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Table of contents
Table of contents .................................................................................................................2
List of figures ......................................................................................................................8
List of tables ........................................................................................................................8
List of Abbreviations.........................................................................................................10
Amendment 9 (21-Aug-2020)...........................................................................................14
Amendment 8 (23-Jan-2020).............................................................................................16
Amendment 7 (04-Apr-2019)............................................................................................18
Amendment 6 (17-Sep-2018)............................................................................................19
Sponsor Information Page.................................................................................................28
Protocol Synopsis ..............................................................................................................29
1
Introduction .......................................................................................................................35
1.1
Background............................................................................................................35
1.2
Trametinib..............................................................................................................35
1.2.1
Pharmacokinetics of Trametinib in Humans.........................................36
1.2.2
Clinical Safety and Efficacy of Trametinib ..........................................36
1.2.3
Trametinib Preclinical Juvenile Toxicity..............................................37
1.2.4
Trametinib Pediatric Experience...........................................................38
1.2.5
Trametinib Pharmacokinetic/Pharmacodynamics Relationships..........38
1.3
Dabrafenib .............................................................................................................38
1.3.1
Pharmacokinetics of Dabrafenib in Humans.........................................38
1.3.2
Clinical Safety and Efficacy of Dabrafenib ..........................................39
1.3.3
Dabrafenib Preclinical Juvenile Toxicity..............................................40
1.3.4
Dabrafenib Pediatric Experience...........................................................40
1.4
Combination of Trametinib and Dabrafenib..........................................................44
1.5
Rationale for BRAF and MEK inhibitors in Pediatric Cancers.............................46
1.6
Malignant Solid Tumors in Infants, Children, and Adolescents ...........................47
1.6.1
Low-grade glioma.................................................................................47
1.6.2
Neurofibromatosis Type-1 Related Plexiform Neurofibromas.............48
1.6.3
Langerhans Cell Histiocytosis (LCH)...................................................48
1.6.4
V600 Mutations in Childhood Cancer ..................................................49
1.7
Summary of Risk Management .............................................................................50
1.7.1
Predicted Toxicities for Trametinib ......................................................50
1.7.2
Predicted Toxicities for Combination of Trametinib and 
Dabrafenib.............................................................................................51
2
Objective(s), Endpoint(s) and Hypothesis(es)...................................................................53


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3
Investigational Plan ...........................................................................................................55
3.1
Discussion of Study Design...................................................................................55
3.2
Part A: Trametinib Dose-Determination ...............................................................57
3.2.1
Trametinib Dose Levels........................................................................57
3.2.2
Trametinib Dose Escalation..................................................................58
3.2.3
Dose Limiting Toxicity Definitions......................................................59
3.2.4
Part A: Age Group Expansion...............................................................60
3.2.5
Definition of Recommended Phase 2 Dose (RP2D) of Trametinib......62
3.2.6
Part A Extension: Intermediate Trametinib Dose Exploration .............62
3.3
Part B:  Tumor-Specific Expansion.......................................................................63
3.4
Part C: Trametinib in Combination with Dabrafenib ............................................63
3.4.1
Part C Extension: Intermediate Trametinib Dose Exploration with 
Dabrafenib.............................................................................................64
3.5
Part D: Tumor-Specific Expansion of Trametinib in Combination with 
Dabrafenib .............................................................................................................65
3.6
Criteria for Continuing in the Study......................................................................65
3.7
Intra-subject Dose-Escalation................................................................................66
3.7.1
Part A: Intra-subject Dose Escalation ...................................................66
3.7.2
Part B Intra-subject Dose Escalation.....................................................67
3.7.3
Part C Intra-subject Dose Escalation.....................................................67
3.7.4
Part D Intra-subject Dose Escalation ....................................................67
3.8
Study Schematics...................................................................................................68
3.9
Rationale................................................................................................................70
3.9.1
Rationale for Study ...............................................................................70
3.9.2
Rationale for Populations......................................................................70
3.9.3
Rationale for Dose.................................................................................71
3.9.4
Rationale for Endpoints.........................................................................73
3.10
Study Treatment.....................................................................................................74
3.10.1
Treatment Assignment ..........................................................................74
3.11
Dosage and Administration of Study Treatments..................................................74
3.11.1
Trametinib.............................................................................................74
3.11.2
Dabrafenib.............................................................................................75
3.11.3
Meals and Dietary Restrictions.............................................................76
3.11.4
Blinding.................................................................................................76
3.12
Safety Management Guidelines.............................................................................76
3.12.1
Liver Chemistry Stopping Criteria........................................................76


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3.12.2
QTc Stopping Criteria...........................................................................79
3.12.3
Left Ventricular Ejection Fraction (LVEF) and Valvular Toxicity 
Stopping Criteria...................................................................................79
3.13
Dose Delay and Modification for Events Considered Related to Trametinib.......81
3.13.1
Dose Delay and Modification for Events Considered Related to 
Trametinib and/or Dabrafenib...............................................................81
3.13.2
Guidelines and Dose Modifications for Trametinib Events of 
Special Interest......................................................................................83
3.13.3
Management of Rash.............................................................................83
3.13.4
Diarrhea.................................................................................................85
3.13.5
Hypertension .........................................................................................86
3.13.6
Visual Changes......................................................................................88
3.13.7
Pneumonitis...........................................................................................90
3.14
Dose Delay and Modification for Events Considered Related to Dabrafenib.......91
3.15
Guidelines for Dose Modifications and Toxicity Management for 
Combination Therapy............................................................................................92
3.15.1
Pyrexia...................................................................................................92
3.15.2
Renal insufficiency................................................................................94
3.15.3
Malignancies .........................................................................................95
3.15.4
Prolonged QTc ......................................................................................96
4
Investigational Product(s)..................................................................................................96
4.1
Description of Investigational Products.................................................................96
4.1.1
Trametinib.............................................................................................96
4.1.2
Dabrafenib.............................................................................................97
4.2
Preparation/Handling/Storage of Investigational Products ...................................98
4.2.1
Trametinib.............................................................................................98
4.2.2
Dabrafenib.............................................................................................98
4.3
Product Accountability..........................................................................................99
4.4
Treatment Compliance...........................................................................................99
4.5
Treatment of Investigational Product Overdose..................................................100
5
Study Population .............................................................................................................100
5.1
Number of Subjects .............................................................................................100
5.2
Subject Selection Criteria ....................................................................................100
5.2.1
Inclusion Criteria.................................................................................100
5.2.2
Exclusion Criteria (All Parts)..............................................................107
6
Completion or Withdrawal of Subjects ...........................................................................109


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6.1
Screen and Baseline Failures...............................................................................109
6.2
Subject Completion Criteria ................................................................................109
6.3
Permanent Discontinuation from Study Treatment .............................................109
6.4
Subject Visits and Lost to follow-up Criteria......................................................110
6.5
Study Completion................................................................................................110
6.6
Treatment after the End of the Study...................................................................110
6.7
Withdrawal of Consent........................................................................................111
7
Study Assessments and Procedures.................................................................................112
7.1
Time and Events Tables.......................................................................................112
7.2
Demographic/Medical History and Baseline Assessments .................................123
7.3
Safety Evaluations ...............................................................................................123
7.3.1
Physical Examinations ........................................................................123
7.3.2
Ophthalmology Examination ..............................................................124
7.3.3
Performance Status..............................................................................124
7.3.4
Vital Signs...........................................................................................124
7.3.5
Electrocardiogram...............................................................................124
7.3.6
Echocardiogram ..................................................................................124
7.3.7
Laboratory Assessments......................................................................125
7.3.8
Pregnancy Testing and Reporting .......................................................127
7.4
Pharmacokinetics.................................................................................................127
7.4.1
Blood Sample Collection for Pharmacokinetics .................................128
7.4.2
Pharmacokinetic Sample Analysis......................................................128
7.5
Translational Research.........................................................................................129
7.5.1
Tumor Tissue for Mutation Testing....................................................129
7.5.2
Tumor Tissue for Pharmacodynamic Testing.....................................130
130
131
7.6
Evaluation of Anti-Cancer Activity.....................................................................131
7.6.1
MRI and/or CT Scan...........................................................................134
7.6.2
Tumor Marker(s).................................................................................134
8
Adverse Events and Serious Adverse Events..................................................................134
8.1
Definition of an AE .............................................................................................134
8.2
Definition of a SAE .............................................................................................135
8.3
Laboratory and Other Safety Assessment Abnormalities Reported as AEs and 
SAEs ....................................................................................................................136
8.3.1
Cardiovascular Events.........................................................................136


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8.4
Time Period and Frequency of Detecting AEs and SAEs ...................................137
8.4.1
Method of Detecting AEs and SAEs...................................................137
8.4.2
Prompt Reporting of SAEs and Other Events to Novartis..................138
8.4.3
Regulatory reporting requirements for SAEs......................................139
9
Concomitant Medications and Non-Drug Therapies.......................................................139
9.1
Permitted Medication(s) ......................................................................................139
9.2
Prohibited Medications........................................................................................140
9.2.1
Prohibited Medications: Parts A & B  (Trametinib)...........................140
9.2.2
Prohibited Medications: Parts C & D (Dabrafenib)............................140
9.3
Medications to be Used with Caution; Parts C & D (Dabrafenib) ......................140
10 Lifestyle and/or Dietary Restrictions...............................................................................142
10.1
Contraception.......................................................................................................142
10.1.1
Female Subjects ..................................................................................142
10.1.2
Male Subjects......................................................................................143
10.2
Lactation Restrictions..........................................................................................143
11 Data Management............................................................................................................143
12 Data Analysis and Statistical Considerations..................................................................144
12.1
Hypotheses...........................................................................................................144
12.1.1
Part A: Dose-Escalation Phase............................................................144
12.1.2
Part B: Expansion Cohort....................................................................144
12.1.3
Part C: Combination Cohort................................................................144
12.1.4
Part D: Expansion Cohort with Combination Therapy.......................144
12.2
Sample Size Determination .................................................................................144
12.2.1
Part A: Dose-Escalation Phase............................................................144
12.2.2
Part B: Expansion Cohort....................................................................145
12.2.3
Part C: Combination Cohort................................................................146
12.2.4
Part D: Expansion Cohort with Combination Therapy.......................146
12.3
Data Analysis Considerations..............................................................................147
12.3.1
Analysis Populations...........................................................................147
12.4
Interim Analysis...................................................................................................148
12.4.1
Part A: Dose-Escalation......................................................................148
12.4.2
Part B: Expansion Cohort....................................................................148
12.4.3
Part C: Combination Cohort................................................................148
12.4.4
Part D: Expansion Cohort with Combination Therapy.......................148
12.4.5
Additional Interim Analyses ...............................................................149


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12.5
Key Elements of Analysis Plan ...........................................................................149
12.5.1
Anti-Cancer Activity Analyses ...........................................................149
12.5.2
Safety Analyses...................................................................................149
12.5.3
Pharmacokinetic Analyses ..................................................................150
13 Study Conduct Considerations ........................................................................................152
13.1
Posting of Information on Clinicaltrials.gov .......................................................152
13.2
Regulatory and Ethical Considerations, Including the Informed Consent 
Process .................................................................................................................152
13.3
Urgent Safety Measures.......................................................................................152
13.4
Quality Control (Study Monitoring)....................................................................152
13.5
Quality Assurance................................................................................................153
13.6
Study and Site Closure.........................................................................................153
13.7
Records Retention................................................................................................153
13.8
Provision of Study Results to Investigators, Posting of Information on 
Publicly Available Clinical Trials Registers and Publication..............................154
14 References .......................................................................................................................155
15 Appendices ......................................................................................................................162
15.1
Appendix 1:  Karnofsky and Lansky Performance Scores..................................162
15.2
Appendix 2:  Dosing Nomograms .......................................................................163
15.3
Appendix 3:  Response Criteria for Solid Tumors (Not Neuroblastoma or PNs 
or Glioma)............................................................................................................174
15.4
Appendix 4:  Response Criteria for Neuroblastoma............................................176
15.5
Appendix 5: Response Assessment in Neuro-oncology (RANO) Criteria 
(Glioma Subjects)................................................................................................180
15.5.1
Response assessment in neuro-oncology (RANO) criteria for low-
grade gliomas (LGG) (RANO-LGG)..................................................182
15.6
Appendix 6: Response Criteria for PNs...............................................................186
15.7
Appendix 7: Definition of disease state, response criteria and response 
definition for LCH ...............................................................................................188
15.8
Appendix 8:  Blood Pressure Levels for Children by Age and Height 
Percentile .............................................................................................................190
15.9
Appendix 9:  Dose Escalation based on PK criteria............................................193
15.10 Appendix 10:  Guidelines for additional dermatological monitoring while on 
therapy and after IP discontinuation....................................................................194
15.11 Appendix 11:  Protocol Amendment Changes (Amendments 1- 4)....................195


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List of figures
Figure 1-1
Duration of Study Treatment (as of 7th March 2015)............................41
Figure 3-1
Trametinib Dose Escalation (Part A) ....................................................68
Figure 3-2
Trametinib Disease Specific Expansion (Part B)..................................68
Figure 3-3
Trametinib in Combination with Dabrafenib (Part C)..........................69
Figure 3-4
Tumor-Specific Expansion of Trametinib in Combination with 
Dabrafenib (Part D)...............................................................................69
Figure 3-5
Additional Dose Exploration (Part A Extension and Part C 
Extension) .............................................................................................70
Figure 3-6
Algorithm For Management of Study Drug(s)-Related 
Hypertension .........................................................................................87
List of tables
Table 1-1
Patient Numbers Enrolled at Each Dose: Extent of exposure...............41
Table 2-1
Objective(s), Endpoint(s) and Hypothesis(es) ......................................53
Table 3-1
Trametinib Dose Levels for Part A .......................................................58
Table 3-2
Dose Escalation Procedure....................................................................58
Table 3-3
Median trametinib PK (Day 15) by age groups ....................................72
Table 3-4
Recommended dabrafenib dose levels..................................................73
Table 3-5
Mandatory dose modification and required clinical management for 
LVEF.....................................................................................................79
Table 3-6
Dose Delay and Modification for General Events Considered 
Related to Trametinib and/or Dabrafenib .............................................81
Table 3-6a
Dose Modification for dabrafenib (DRB436) dispersible tablet for 
patients less than 12 years of age ..........................................................82
Table 3-6b
Dose Modification for dabrafenib (DRB436) dispersible tablet for 
patients greater or equal 12 years of age...............................................82
Table 3-7
Mandatory dose modifications and recommended clinical 
management guidelines for rash............................................................84
Table 3-8
Loperamide Dosing for Study Treatment Related Diarrhea .................86
Table 3-9
Mandatory dose modification and required clinical management for 
visual changes and/or ophthalmic examination findings ......................89
Table 3-10
Mandatory dose modification and required clinical management for 
retinal pigment epithelial detachments (RPED)....................................89
Table 3-11
Mandatory dose modifications and recommended clinical 
management guidelines for pneumonitis ..............................................90
Table 3-12
Mandatory dose modification and recommended clinical 
management for pyrexia a, b...................................................................93


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Table 3-13
Mandatory dose modifications and required clinical management 
guidelines for renal function alterations................................................94
Table 4-1
Investigational Product - Trametinib ....................................................96
Table 4-2
Investigational Product - Dabrafenib ....................................................97
Table 7-1
Time and Events, Treatment Phase:  Screening through Day 28........113
Table 7-2
Trametinib Monotherapy PK Sampling: Time and Events for Parts 
A, A extension and B on Day 15 and Day 22.....................................117
Table 7-3
Trametinib and Dabrafenib Combination PK Sampling: Time and 
Events for Parts C, C extension and D on Day 1, Day 15 and Day 
22.........................................................................................................117
Table 7-4
Time and Events, Treatment Phase, Week 9 to Final Visit ................118
Table 7-5
Time and Events, Part B Clinical Activity Assessments, Week 9 to 
Final Visit............................................................................................121
Table 7-6
List of Clinical Laboratory Tests ........................................................126
Table 7-7
List of Samples for Translational Research ........................................129
Table 7-8
Efficacy Assessment Methods and Measurement Modalities.............132
Table 8-1
Reporting of SAEs and Other Events to Novartis...............................138
Table 9-1
Prohibited Medications; Parts C and D (Dabrafenib) .........................140
Table 9-2
Medications to be used with Caution; Parts C and D (Dabrafenib)....141
Table 12-1
Statistical Basis for Phase I Dose Escalation in a 3+3 Scheme ..........145
Table 12-2
Exact Binomial Probabilities of Observing 0 and 1 (or more) 
Responses in 10 Subjects ....................................................................145
Table 12-3
Exact Binomial 95% Confidence Intervals Around Potential 
Observed Objective Responses Rates for 10 Subjects........................145
Table 12-4
Exact Binomial Probabilities of Observing less than 6 and at least 6 
Responses in 20 Subjects ....................................................................146
Table 12-5
Exact Binomial Probabilities of Observing less than 3 and at least 3
Responses in 10 Subjects ....................................................................147
Table 12-6
Exact Binomial 95% Confidence Intervals around Potential 
Observed Objective Responses Rates for 20 Subjects........................147


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List of Abbreviations
ADL
Activities of daily living
AE(s)
Adverse Event(s)
AKT
Serine/threonine kinase AKT (protein kinase B)
ALK
Anaplastic Lymphoma Kinase
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
ANC
Absolute neutrophil count
AST
Aspartate aminotransferase
ATP
Adenosine triphosphate
ATRX
ATP-dependent transcriptional regulating X-linked helicase
AUC
Area under the concentration-time curve
AUC(0-)
Area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite 
time
AUC(0-last)
Area under the concentration-time curve until the last measurable plasma concentration time 
point
AUC(0-t)
Area under the concentration-time curve over a period of time (t)
AUC(0-)
Area under the concentration-time curve over the dosing interval
-HCG
Beta-Human Chorionic Gonadotropin
BAL
Bronchioalveolar lavage
BCR/ABL
Breakpoint cluster region/Abelson murine leukemia virus oncogene homolog 1 gene fusion 
(Philadelphia chromosome translocation)
BID
Twice daily
BM
Bone marrow
BRAF/BRAF
B-Raf serine/threonine-protein kinase/proto-oncogene encoding B-Raf
BRAT
Bananas, rice, apples, toast (diet)
BSA
Body surface area
BUN
Blood urea nitrogen
CAP
College of American Pathologist
CBC
Complete blood count
CDC
Centers for Disease Control and Prevention
CENP-E
Centromere-associated protein –E
CI
Confidence Interval
CL/F
Apparent clearance following oral dosing
CLIA
Clinical Laboratory Improvement Amendments
Cmax
Maximum observed concentration
Cmin
Minimum observed concentration
CNS
Central nervous system
CO2
Carbon dioxide
CPK
Creatine phosphokinase
CR
Complete response/ Complete remission
CSF
Cerebrospinal fluid
CT
Computed tomography
C
(trough) concentration


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cuSCC
Cutaneous Squamous Cell Carcinoma
CV
Coefficient of variation
DICOM
Digital Imaging and Communications in Medicine
dL
Deciliter
DLT
Dose Limiting Toxicity
DMPK
Drug Metabolism and Pharmacokinetics
DSS
Disease-specific survival
ECG(s)
Electrocardiogram(s)
ECHO
Echocardiogram
eCRF
Electronic case report form
ERK
Extracellular signal-regulated kinase
FDA
Food and Drug Administration
FGF
Fibroblast growth factor
FGFR
Fibroblast growth factor receptor
FLT3
Feline McDonough stain (Fms)-like tyrosine kinase 3
FSH
Follicle Stimulating Hormone
FSEIR
Fast spin echo-inversion recovery
FTIH
First time in human
G
CTCAE Grade 
G6PD
Glucose 6 Phosphate Dehydrogenase Deficiency
GAP
GTPase activating protein
GCP
Good Clinical Practice
GCPH
Global Clinical Program Head
GDP
Guanosine diphosphate
GFR
Glomerular filtration rate
GGT
Gamma glutamyltransferase
gIC50
Concentration causing 50% growth inhibition
GLP
Good Laboratory Practice
GLS
Geometric least square
GM-CSF
Granulocyte-macrophage colony-stimulating factor
GSK
GlaxoSmithKline
GTP
Guanosine-5'-triphosphate
GVHD
Graft versus host disease
HAs
Health Authorities
HBV
Hepatitis B Virus
HCV
Hepatitis C Virus
H&E
Hematoxylin and Eosin
HgF
Fetal Hemoglobin
HGF
Hepatocyte Growth Factor
h/hr
Hour(s)
HIV
Human Immunodeficiency Virus
HPLC
High Performance Liquid Chromatograhy
HPMC
Hydroxypropyl Methylcellulose


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HR
Hazard Ratio
HVA/VMA
Homovanillic Acid / Vanillylmandelic Acid (ratio)
123I
Iodine-123 (radioisotope)
IB
Investigator’s Brochure
IC50
Half maximal inhibitory concentration
ICH
International Conference on Harmonization
IDSL
International Data Standards Library
IEC
Independent Ethics Committee
Ig
Immunoglobulin
IND
Investigational New Drug
INR
International normalized ratio
IP
Investigational Product
IR
Incomplete Response
IRB
Institutional Review Board
IU
International Unit
ka
Absorption rate constant
kg
Kilogram
KRAS/KRAS
Kirsten rat sarcoma virus homolog/oncogene encoding KRAS
L
Liter
LCH
Langerhans Cell Histiocytosis
LDH
Lactate Dehydrogenase
LGG
Low Grade Glioma
LLN
Lower limit of normal
LS
Least squares
LSLV
Last subject’s last visit
LVEF
Left Ventricular Ejection Fraction
MAPK
Mitogen-activated protein kinase
MCH
Mean corpuscular hemoglobin
MCHC
Mean corpuscular hemoglobin concentration
MCV
Mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
MEK
MAPK/ERK kinase
mg
Milligram(s)
MIBG
Meta-iodobenzylguanidine
µl/ mcL
Microliter(s)
mm
Millimeter(s)
MPNST
Malignant peripheral nerve sheath tumors
MRI
Magnetic resonance imaging
MSDS
Material Safety Data Sheet
msec
Millisecond(s)
MTD
Maximum tolerated dose
mTOR
Mammalian target of rapamycin serine/threonine protein kinase
MYNC
Proto-oncogene of the transcription factor MYC
NCI
National Cancer Institute


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NCI-CTCAE
National Cancer Institute-Common Terminology Criteria for Adverse Events
NF-1
Neurofibromatosis Type-1
NF-1 with PN
Neurofibromatosis Type-1 associated plexiform neurofibromas
ng
Nanogram(s)
NIH
National Institutes of Health
NRAS/NRAS
Neuroblastoma RAS virus homolog/oncogene encoding NRAS
NSAIDs
Nonsteroidal anti-inflammatory drugs
NYHA
New York Heart Association
OIRR
Overall intracranial response rate
OS
Overall Survival
OTC
Over the counter
PD
Pharmacodynamic or Progressive Disease
PET
Positron emission tomography
PFS
Progression-free survival
pg
Picogram(s)
PI
Principal Investigator
PI3K
Phosphatidylinositide 3-kinase(s)
PK
Pharmacokinetic
pmol
Picomolar
PN
Plexiform Neurofibroma
PO
Orally administered
POB
Pediatric Oncology Branch
PP
Polypropylene
PPES
Palmar Plantar Erythrodysaethesia Syndrome
PR
Partial Response or P wave interval
PT
Prothrombin time
PTC
Papillary Thyroid Carcinoma
PTEN
Phosphatase and tensin homolog
PTPN11/
PTPN11
Protein-tyrosine phosphatase non-receptor type 11/gene encoding PTPN11
QTc
Corrected QT interval duration
QTcB
QT interval corrected for heart rate by Bazett’s formula
RAF
Serine/threonine-specific protein kinase Raf (Rapidly accelerated fibrosarcoma)
RANO
Response Assessment in Neuro-Oncology
RAP
Reporting and Analysis Plan
RAS/RAS
Ras (Rat sarcoma) proto-oncogene product/oncogene encoding RAS
RBC
Red blood cell(s)
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
Ribonucleic acid
RP2D
Recommended phase 2 dose
RPED
Retinal pigment epithelium detachment
RR
Response Rate
RVO
Retinal vein occlusion
SAE(s)
Serious adverse event(s)


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SCARs
Severe cutaneous adverse reactions
SD
Stable Disease
SEER
Surveillance, Epidemiology and End Results
SPF
Skin protection factor
SPM
Study Procedures Manual
t½
Half-Life
TARGET
Therapeutically Applicable Research to Generate Effective Treatments
Tmax
Time of occurrence of Cmax
U/L
Units/Liter
ULN
Upper limit of normal
UK
United Kingdom
US/USA
United States/United States of America
Vc/F
Central volume of distribution
VEGFR
Vascular endothelial growth factor receptor
V/F
Volume of distribution
XRT
X-Ray Therapy
WBC
White blood cell(s)
WHO
World Health Organization
Amendment 9 (21-Aug-2020)
Amendment Rationale
As of 17-Jul-2020, 139 patients have received study treatment in 5 countries. Parts A, B, C and 
D have enrolled 50, 41, 18 and 30 patients, respectively.  All cohorts have completed enrollment 
and are now closed. 80 patients in parts A, B, C and D have discontinued study treatment and 
13 have enrolled into the CDRB436G2401 Rollover and Follow-up study.
The purpose of this amendment is to add updated RANO criteria specifically for low grade 
glioma (RANO-LGG; Wen 2017) as the basis for independent review. These more recent 
RANO-LGG criteria allow for the identification of measurable target lesions in patients with 
LGG that may not be gadolinium enhancing and are best seen by T2/FLAIR imaging sequences. 
These updated RANO - LGG criteria will be utilized in supplemental independent RANO 
response determination for those patients with LGG.  Note that the independent response 
determinations that were originally intended to be applied using the older RANO criteria will 
be retained for analysis purposes.  Also note that the response category of ‘minor response’ will 
not be used in this trial.
In addition, the contraception information has been updated following results from a trametinib 
PK study which showed that no loss of efficacy of combined hormonal contraceptives 
(norethindrone and ethinyl estradiol) is expected when coadministered with trametinib 
monotherapy.
Changes in the protocol:


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Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strikethrough red font for deletions and red underline for insertions:

List of Abbreviations table: updated to include LGG and RANO

Removal of named contact details and integrated signature pages in alignment with 
current Novartis template and standards.

Section 10.1.1: Updated highly contraceptive methods for female subjects on trametinib 
monotherapy.

Appendix 15.5.1: added updated RANO criteria for LGG patients (RANO-LGG) and 
removed the minor response category in the “Response assessment of target lesions” 
table as it is not used in this clinical trial.  
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC 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.


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Amendment 8 (23-Jan-2020)
Amendment Rationale
As of 21-Nov-2019, 138 patients have received study treatment in 5 countries. Parts A, B, C 
and D have enrolled 50, 41, 18 and 29 patients, respectively. Currently, the only cohorts open 
to enrollment are: C (BRAF V600 melanoma), and D2 (LCH). All other cohorts have completed 
enrollment and are now closed. 71 patients in Parts A, B, C and D have discontinued study 
treatment.
The main purpose of this amendment is 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. This change was made in 
order to align with updated information available in dabrafenib and trametinib Investigator’s 
Brochure Edition 11.
The definition of ‘Study Completion’ has also been amended, reducing the minimum treatment 
duration from 12 months to 6 months. The primary analysis for safety and efficacy (response 
rate) will not be impacted, but this change allows for an earlier  final analysis of this study.  
Longer term follow-up of study subjects will be available through the rollover follow-up study 
[CDRB436G2401]. 
Dabrafenib powder for oral suspension (150 mg stickpack, 10 mg/mL in oral suspension), and 
trametinib 0.125 mg tablets have been removed, as the manufacturing of these formulations has 
been discontinued, and they are no longer in use in CTMT212X2101.  Patients have changed 
to dabrafenib 10 mg dispersible tablets and trametinib 0.5 mg and 2 mg tablets.
The contraception requirement post end of treatment, for patients on dabrafenib monotherapy 
has been updated to 2 weeks, in line with the latest Investigator Brochure.
Changes in the protocol:
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strikethrough red font for deletions and red underline for insertions:

Section 3.13.1: Added dose modification requirements for patients taking solid dosage
forms of dabrafenib and trametinib.

Section 3.13.3.3: Added dose modification requirements for cases of SCARs, which have
been reported during treatment with dabrafenib in combination with trametinib. If signs
and symptoms suggestive of SCARs appear, dabrafenib and trametinib should be
permanently discontinued.

Section 6.5: Reduced the minimum on-study duration from 12 months to 6 months.

Multiple sections: Removal of references to dabrafenib powder for oral suspension (150
mg stickpack, 10 mg/mL for oral suspension), and trametinib 0.125 mg tablets.

Section 10.1.1: Reduced contraception requirement for subjects on dabrafenib
monotherapy from 4 to 2 weeks.

Update to contact details and integrated signature pages.


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IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC 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.


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Amendment 7 (04-Apr-2019)
Amendment Rationale
As of 06-Feb-2019, 133 patients have received study treatment in 5 countries. Parts A, B, C and 
D have enrolled 50, 39, 18 and 26 patients, respectively. Currently, the only cohorts open to 
enrollment are: B1 (neuroblastoma), C (BRAF V600 melanoma), and D2 (LCH). All other 
cohorts have completed enrollment and are now closed. 59 patients in Part 1 or 2 have 
discontinued study treatment. The purpose of this amendment is to add additional interim 
analyses of data to support health authority requests/publication requests.
Changes in the protocol:
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strikethrough red font for deletions and red underline for insertions:

Section 6.3 : Removal of the requirement for patients to discontinue study treatment, 
where a >28 day delay has been due to administrative/scheduling reasons

Section 9.2.2 : Table 9-1 updated to remove oxcarbazepine from list of prohibited 
medications during study treatment. Based on review of the literature, oxcarbazepine is 
not a strong CYP3A4 inducer, but more as a moderate inducer. Therefore, significant 
drug-drug interaction risk between oxcarbazepine and the investigated drug is considered 
relatively low. 

Section 10.1.1 : Minor update to the language for female contraception to remove the term 
‘hormonal methods’ from the sentence to clarify that oral contraceptives  are not 
considered as highly effective methods of contraception due to potential drug-drug 
interactions with dabrafenib.  

Section 12.4: Updated to include additional interim analyses to support health authority 
requests or publication requests.

Section 14: Added two references to confirm that oxcarbazepine is not a strong CYP3A4 
inducer.
IRBs/IECs
The changes described in this amended protocol are considered to be non-substantial.


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Amendment 6 (17-Sep-2018)
Amendment Rationale
Study CTMT212X2101 has enrolled 128 patients and additionally has completed enrollment in 
Cohort C Extension (total 6 patients) as well as Cohort D1 LGG (total 20 patients) according 
to the current protocol. Due to the completion of enrollment in Cohort C Extension, RP2D/MTD 
has been declared for combination therapy of trametinib and dabrafenib in patients under 6 
years of age. 
The purpose of this amendment is:
1. Addition of a new pediatric formulation dosage form of dabrafenib 10mg as dispersible 
tablets.
2. Update the withdrawal of consent language to align with the new Global Data Protection 
Requirements.
Changes in the protocol:
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strikethrough red font for deletions and red underline for insertions:

Update Sponsor Information Page to correct current study team

Protocol Synopsis table updated to reflect language in protocol

Section 1.2.2: minor update to include current program data

Section 1.3.1: Addition of PK data of Dabrafenib dispersible tablet formulation

Section 1.4: Addition of Trametinib in text referring to Investigator Brochure

Section 3.1, 3.11.2, 3.13, 4.1.2, 4.2.2, 4.3: Addition of Dabrafenib dispersible tablet 
language

Section 6.7: Withdrawal of consent wording added to align with new Global Data 
Protection Requirements

Section 10.1: Updated program standard language regarding contraceptive methods

Appendix 2: Dosing nomogram updated for dispersible tablet formulation.
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC 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.


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Amendment 5 (8-Mar-2017)
Amendment rationale
Amendment 5 incorporates two major changes to this ongoing study.
1. Two new specific BRAFV600 mutant disease cohorts (LGG and LCH) are added for 
study of combination therapy of dabrafenib and trametinib to obtain preliminary efficacy 
information in these diseases, as well as additional safety, tolerability and PK data for the 
combination.  The added cohorts in Part D are part of an agreement with the US Food and 
Drug Administration (FDA).
2. Two current dose escalation portions of the protocol (Part A and Part C) are extended to 
allow additional dose exploration of trametinib in patients under 6 years of age in an effort 
to obtain target exposure comparable to adults in this age group.
As of 8-Mar-17:

A total of 86 patients have received study treatment in five countries and twenty one 
patients have discontinued study treatment.

In Part A (dose escalation and age expansion with trametinib monotherapy) of the study, a 
total of 38 patients have been treated with trametinib monotherapy at 0.0125, 0.025 or 
0.04mg/kg/day dose in the dose escalation and age expansion cohorts. The trametinib dose 
of 0.04mg/kg/day was not tolerable and has shown to exceed the maximum tolerable dose 
(MTD). The 0.025mg/kg/day trametinib is tolerable and has been declared the 
recommended phase 2 dose (RP2D) for patients aged 1 month to <18 years. 
Results from completed and ongoing cohorts (Parts A, B and C) of this trial have shown that 
the 0.025 mg/kg/day dose level also achieved target exposures that are associated with the 
recommended efficacious adult dose for melanoma treatment, in most patients older than 6 
years of age.  However, patients under the age of 6 are less likely to achieve the target exposure 
when dosed at 0.025 mg/kg/day than are the older patients. The exposure-efficacy relationship 
for trametinib when combined with dabrafenib in adult melanoma patients demonstrates an 
apparent threshold effect and provides further rationale to optimize trametinib exposures in 
pediatric patients. Therefore, Part A extension has been added to test the intermediate trametinib 
dose level of 0.032 mg/kg/day in patients under 6 years of age for safety, tolerability and 
pharmacokinetics. 

In Part B (disease expansion with trametinib monotherapy) of the study, a total of 36 
patients have been treated with trametinib monotherapy at the RP2D of 0.025mg/kg/day in 
four disease expansion cohorts. Planned enrollment is ongoing in this part. No specific 
changes to this part have been made in this amendment.

In Part C (dose escalation with trametinib and dabrafenib combination therapy) of the 
study, a total of 12 patients have been treated with a fixed trametinib dose at 
0.025mg/kg/day and dose escalated with dabrafenib first at 50% pediatric RP2D dose and 
then with 100% pediatric RP2D. It has been found that 100% pediatric RP2D of 
dabrafenib in combination with trametinib is safe and well tolerated for patients 12 months 
to < 18 years. Based on the trametinib exposure results seen and as explained above, 
trametinib dose of 0.025mg/kg/day and dabrafenib dose of 100% pediatric RP2D has been 


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declared combination RP2D for patients aged 6 years to <18 years only. Part C extension 
has been added to assess the trametinib dose determined from Part A extension with 100% 
pediatric RP2D of dabrafenib in patients under 6 years of age. 
This amendment also adds Part D to test trametinib and dabrafenib combination in two BRAF 
V600 mutant disease expansion cohorts in pediatric patients with relapsed or refractory low 
grade glioma (LGG) and relapsed or refractory Langerhans Cell Histiocytosis (LCH). The 
preliminary efficacy observed in patients with BRAF V600 mutant relapsed or refractory LGG 
or LCH in the ongoing dabrafenib monotherapy study [CDRB436A2102] is favorable. In adult 
patients, the combination of dabrafenib with trametinib has demonstrated improved therapeutic 
benefit in BRAF V600 mutant metastatic melanoma and NSCLC, and a similar improved 
benefit may also be anticipated in these two pediatric populations. Investigation of combination 
therapy in these two pediatric populations may contribute to improved treatment options for 
these molecularly defined subsets of patients.
Additional changes were made to the overall protocol.  

Trametinib and dabrafenib dosing were clarified or updated for intra-subject dose 
escalations in all study parts, maximum total daily dose and dose reduction schemes.

Consuming grapefruit, Seville orange and pommello juices concomitantly with study 
treatment is now allowed. Grapefruit only affects CYP3A substrate drugs with low oral 
bioavailability. Based on dabrafenib’s high oral bioavailability of ~95%, the risk of 
grapefruit having an effect on dabrafenib exposure is little to none. The safety monitoring 
and management sections have been revised to clarify the procedures that are 
recommended or mandatory and to clarify which study drug(s) are to be dose modified in 
the management of adverse events. 

Dose modification guidance for uveitis and grade 2 diarrhea was added. 

Study completion period was changed from 6 months to 12 months due to slow 
progression of studied disease.

Palatability questionnaire requirement was clarified and indicated to be required for both 
trametinib and dabrafenib.

Details on the dermatological follow-up requirement for patients in France that was 
implemented in amendment 3 was added.Imaging scans from the most recent prior 
chemotherapy will be collected from patients with LGG. 

PK sampling has been simplified for patients on combination therapy in Parts C and D.

Allowable female contraceptive methods updated to reflect current list of highly effective 
method of contraception per Clinical Trial Facilitation Group (CTFG) guidelines and due 
to possible drug-drug interaction of hormone based contraceptives with dabrafenib.

Male patients are now required to use condom to avoid unnecessary exposure of 
trametinib and/or dabrafenib to the fetus.

Data analysis and statistical consideration updated to clarify and reflect current analysis 
plan.

Two interim analyses are added and planned for decision making of future development 
options.


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
PK parameters updated to include analysis of dabrafenib metabolites and to exclude 
parameters that are not calculable based on PK sample collection schedule.

Additional information was added to provide clarity on assessment procedures and timing. 

Editorial changes and text corrections were made for clarification, where required, and to 
align with Novartis terminology and procedures.  
Details of the specific changes made in each section of the protocol are described below in 
Changes to the Protocol section.
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.

Revision Chronology for Protocol Amendment 3 was corrected to reflect no change to the 
HbA1c monitoring schedule

Protocol synopsis: Section was updated to align with changes made in the protocol body.

Section 1.4: Added study background at time of Protocol Amendment 5 

Section 2: Updated objectives and endpoints for combination treatment.    

Section 2, Section 12.5.3.1: Certain PK parameters were removed because based on the 
current PK sample collected, it may not be possible to estimate these parameters.

Section 3.1, Section 3.2.1, Section 3.2.6, Section 3.4, Section 3.4.1, Section 3.5, Section 
3.8, Section 3.9.3.1, Section 3.9.3.2, Section 3.9.4, Section 5.1, Section 5.2.1.1, Section 
7.1, Section 15.2: Added or modified language related to adding Part A extension and Part 
C extension for evaluating an additional trametinib dose level (0.032 mg/kg/day) in 
monotherapy and in combination treatment with dabrafenib

Section 3.1, Section 3.5, Section 3.6, Section 3.8, Section 3.9.3.3, Section 3.9.4, Section 
3.10.1, Section 5.1, Section 5.2.1, Section 5.2.1.1, Section 5.2.1.5, Section 7.1, Section 
7.4.1, Section 7.5, Section 7.5.1.2, Section 9.2, Section 12.1.4, Section 12.2.4, Section 
12.4.4: Added or modified language related to adding disease expansion cohorts in 
combination treatment in Part D 

Section 3.1, Section 12.4.2, Section 12.4.4: Added language on 2 interim analyses

Section 3.2.3: Text modified to clarify the definition of DLT population 

Section 3.3: Text was added to clarify that safety and tolerability is also evaluated in this 
part of the study and to clarify the tumor tissue requirement.

Section 3.7: Updated to provide additional details on intra-subject dose escalations for 
Parts B and C and to add Part D intra-subject dose escalation details

Section 3.9.2: Updated to provide rationale for Part C and Part D

Section 3.9.4: Clarified rationale for endpoints in Part B

Section 3.10.1: Text updated to provide clarity on randomization number assignment

Section 3.11.1: Text added to provide maximum total daily dose of trametinib allowed in 
the study


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
Section 3.11.2: Text added to provide maximum total daily dose of dabrafenib allowed in 
the study

Section 3.11.3: Language was updated to specify that fasting requirements apply for both 
trametinib and dabrafenib. Restriction related to grapefruit juice and other citrus products 
was removed due to minimal/no effect on dabrafenib exposure.

Section 3.12, Section 3.13, Section 3.15: The tables in these sections were updated to 
provide clarity on the safety monitoring and management procedures that are 
recommended or mandatory in the management of adverse events. The adverse event 
management guidelines remains largely the same as protocol amendment 4. 

Section 3.12.1.2: Text added to indicate blood samples are to be sent to the central lab for 
testing related to liver events.

Section 3.13.4: Added dose discontinuation requirement for grade 2 diarrhea lasting >7 
days 

Section 3.14: Added dose modification guidance for persistent ≥ grade 2 uveitis

Section 3.15 and Section 15.2 (Appendix 2): Modified to provide clarity on dose reduction 
scheme for dabrafenib and updated the dosing nomograms and instructions.

Section 4.1.2: Text added to indicate that Novartis will provide dabrafenib

Section 5.2.1.3: Text was clarified on the tissue submission requirement in Part B4

Section 5.2.2: Clarified exclusion criterion for prior treatments 

Section 6.3: Text deleted to align with current dose modification guidelines. Updated 
adverse event and safety event follow-up period to 30 days to align with program 
standard. 

Section 6.5: Definition for study completion period has been changed from 6 months to 12 
months.

Section 6.5 and Section 6.6: The GSK rollover study numbers have been removed due to 
the change in sponsorship. New Novartis numbers will be assigned at a later time.

Section 7: Corrected the blood volume collected over the study duration to align with the 
Time and Events table

Section 7.1: Tables in this section were updated to provide clarity on the assessments, in 
particular the efficacy assessment for the various disease types, and to correct 
typographical errors. Simplified the PK collection schedule for patients on combination 
treatment.

Section 7.1 and Section 7.2: Added details on collection of scans from the most recent 
prior chemotherapy for patients with LGG. 

Section 7.1, Section 7.3.7: Clarified palatability questionnaires are required for both 
trametinib and dabrafenib for patients on combination treatment

Section 7.1, Section 15.10: Added details on dermatological follow-up requirement for 
patients in France, which were implemented in protocol amendment 3

Section 7.3.1: Clarified the timing of baseline plain radiographs

Section 7.3.4: Clarified details of baseline vital signs measurement requirement


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
Section 7.3.6: Text added to clarify when the collected ECHO scans will be analyzed

Section 7.3.7: Text added to reduce HbA1c assessment to baseline 

Section 7.4, Section 12.5.3: Text added to indicate dabrafenib metabolite levels will be 
analyzed.

Section 7.4.1: Text added to compile all  additional PK sample collection for certain 
adverse events as indicated in other sections.

Section 7.4.2: Updated language regarding analytical procedure

Section 7.5: Table in this section has been updated to provide updated plans for 
translational research

Section 5.2.1.3, Section 5.2.1.4, Section 7.5.1.2: Updated to allow CLIA equivalent lab for 
analysis

Section 7.6: Table added to clearly and concisely provide disease response assessment 
methodologies and assessment modalities for each of the possible disease types to be 
enrolled in this study. 

Section 8.3.1: Added symptomatic LVEF decrease as an event to be recorded on the 
specific cardiovascular eCRF and reinforced SAE reporting requirement, if applicable. 

Section 8.4.2: Table in this section was updated to provide clarity on reporting timeframes 
and tools on SAEs, DLTs and certain AEs 

Section 10.1.1: Updated allowed female contraceptive methods to reflect current list of 
highly effective method of contraception per Clinical Trial Facilitation Group (CTFG) 
guidelines. Double barrier method and hormone based contraception methods are now 
excluded.    

Section 10.1.2: Added  male contraception requirements for trametinib monotherapy and 
combination therapy with dabrafenib 

Section 12.1.2: Section was modified for providing additional clarity on analysis plan in 
Part B

Section 12.2.2: Updated to provide confidence intervals around potential observed 
objective responses

Section 12.3.1: Updated to provide clarity on analysis populations

Section 12.5.1: Clarified how anti-cancer activity analyses, including investigator and 
independent review data, will be performed. 

Section 12.5.2: Text was modified to indicate that safety analysis will be based on Safety 
Population

Section 12.5.2.1 and Section 15.5.2.2: Text modified to indicate that additional details are 
provided in the SAP

Section 12.5.2.3: Text modified to reflect planned analyses for laboratory data

Section 12.5.3.2: Text added to align with objective added in Section 2

Section 14: Two references were added

Section 15.3: Title was updated to indicate this assessment methodology is not indicated 
for glioma patients


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
Section 15.4: Text was added to clarify requirement for Overall Best Response 
Assessment for Neuroblastoma

Section 15.6: Appendix 6 was updated to clarify MRI submission requirements for PNs 
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC 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.


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Amendment 4
Amendment rationale 
Subsequent to the acquisition of GlaxoSmithKline (GSK) compound GSK1120212 and 
GSK2118436 by Novartis, the purpose of this protocol Amendment 4 is to:

Delete or replace references to GlaxoSmithKline or its staff with that of Novartis and its 
authorized agents to align with the change of sponsorship;

Make administrative changes to align with Novartis processes and procedures;
As of 02-Aug-16:

64 patients have received study treatment in 5 countries; 

10 patients have completed or discontinued study treatment.
The changes described in this amended protocol require Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) approval prior to implementation. 
A copy of this amended protocol will be sent to the IRBs/IECs and Health Authorities (HAs).
The changes herein affect the Informed Consent and all sites are required to update and submit 
for approval, a revised Informed Consent that takes into account the change of study 
sponsorship described in the protocol amendment.
Upon approval of this amendment, patients who have already been enrolled in the study will 
sign a new informed consent form indicating Novartis is the new study sponsor and continue 
the appropriate visit schedule.


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Amendments 1 to 3
Amendment rationale and summary of changes for previous amendments 1 to 3 are provided 
below in Revision Chronology section and also in Appendix 11 as tracked changes. 
Revision Chronology


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Sponsor Information Page
Clinical Study Identifier:
MEK116540 (CTMT212X2101)
Sponsor Contact Information
Novartis Pharmaceuticals Corporation
In some countries, the clinical trial sponsor may be the local Novartis and its authorized agents. 
Where applicable, the details of the Sponsor and contact person will be provided to the relevant 
regulatory authority as part of the clinical trial submission.
Sponsor Serious Adverse Events (SAE) Contact Information: 
For study conduct questions not related to study subject safety, the first line of contact should 
be with the designated local country company contact.  In the event that the designated company 
contact is not available please contact the Medical Lead. Please refer to the Study Procedures 
Manual (SPM) for further details.
             
If you have any questions regarding the protocol, please contact your local Novartis office.
Regulatory Agency Identifying Number(s):
Compound Number
IND Number
EudraCT Number
GSK1120212 (trametinib)
GSK2118436 (dabrafenib)
119,309
2013-003596-35




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Secondary Endpoint(s):
● C(trough), AUC(0-t), AUC(0-), apparent clearance following oral dosing 
(CL/F), maximum observed concentration (Cmax), time of occurrence of Cmax 
(tmax) and half-life (t½) of trametinib, as appropriate
● AEs; ECG; changes in laboratory values and vital signs
● Tumor response to trametinib monotherapy and trametinib in combination with 
dabrafenib by investigator assessment as defined in Appendix 3 through 
Appendix 7.
● CL/F, volume of distribution (V/F), absorption rate (ka), and coefficients for 
significant covariates
● C(trough), AUC(0-t), AUC(0-), apparent clearance following oral dosing 
(CL/F), Cmax, tmax, and Cavg of trametinib and dabrafenib when administered 
in combination, if the data permit
Hypothesis: 
● Infants, children and adolescents will tolerate doses of trametinib alone or in 
combination with dabrafenib that achieve steady state trough concentrations 
associated with clinical benefit in adults.
Study design
This is a 4-part (Part A, Part B, Part C and Part D), Phase I/IIa, multi-center, 
open label, study in pediatric subjects with refractory or recurrent tumors.
Part A will be a pharmacokinetically driven limited dose escalation in subjects 
and will include an expansion for safety, tolerability, and pharmacokinetics (PK) 
in three age ranges (1 month to <2years, 2 to ≤12 years, and over 12 years of 
age).  The primary goal of Part A is to establish the toxicity profile, PK, and 
recommended Phase 2 dose (RP2D) of trametinib in each age cohort.  
Approximately 18 subjects will be accrued to the dose escalation phase and 18 
subjects to the age expansion phase. 
Part A will be extended to include an age-specific trametinib dose (0.032 
mg/kg/day) exploration in up to 12 subjects aged 1 month to < 6 years old. 
Part B will be a tumor cohort expansion part of the study to further evaluate the 
safety, tolerability, and preliminary clinical activity of trametinib in tumor-specific 
pediatric populations.  Disease cohorts are selected based on current data of 
proto-oncogene RAS (Ras)/ mitogen-activated protein kinase (MAPK) activation 
in childhood solid tumors.  At least forty subjects are planned for Part B, 10 
subjects in each of 4 disease cohorts.
● Refractory or relapsed neuroblastoma 
● Recurrent or unresectable low grade gliomas associated with BRAF tandem 
duplication with fusion, or NF1 subjects with gliomas, not suitable for the NF1 
with PN cohort
● Neurofibromatosis Type -1 associated plexiform neurofibromas that are 
unresectable and medically significant. 
● BRAF V600 mutant tumors
Part C is a limited dose escalation part of the study evaluating the combination 
of trametinib with dabrafenib in children and adolescents with recurrent, 
refractory or unresectable BRAF V600 mutated tumors.  This part of the study 
will enroll approximately 18 subjects (including up to 6 adolescent subjects with 
BRAF V600 mutant metastatic melanoma)and will not open to accrual until the 
dose of dabrafenib in children is established in study BRF116013, the dose of 
trametinib is established in Part A and review of the available safety and PK 
data of trametinib and dabrafenib monotherapy in children is completed.  
Amendment 3 provides the updated safety data and dabrafenib dosing in 
children. Parts B and C may be open to accrual simultaneously. Patients who 
have had prior dabrafenib therapy may enroll in part C if they have had prior 
benefit to dabrafenib monotherapy, as determined by the investigator.
Part C will be extended to include an age-specific dose exploration in up to 6 
subjects aged 12 months to < 6 years old. If the trametinib dose of  0.032 


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mg/kg/day is tolerated in Part A extension, a combination of trametinib 
0.032mg/kg/day and the full dabrafenib RP2D will be tested in this cohort.
Part D will be a tumor cohort expansion part of the study to further evaluate the 
safety, tolerability, and preliminary clinical activity of the combination of 
trametinib and dabrafenib at the recommended phase 2 combination dose in 
tumor-specific pediatric populations listed below. 
● BRAF V600-mutant, relapsed or refractory low grade glioma (LGG)
● BRAF V600-mutant, relapsed or refractory  Langerhans cell histiocytosis 
(LCH)
Approximately 20 subjects with LGG and 10 subjects with LCH will be enrolled.
Subjects may not enroll in more than one part of the study. Subjects will receive 
study treatment until disease progression, death or unacceptable toxicity. 
All parts of the study will use trametinib tablet strengths (0.5, and 2 mg tablets) 
for children who are able to reliably swallow tablets.  In addition, an oral solution 
formulation (0.05 mg/mL) is available.  Doses will be calculated using body 
weight and prescribed using a dosing nomogram. Rules for dose modifications 
in response to toxicity are provided in the protocol.
For Parts C and D of the study, dabrafenib capsules (50, 75 mg) or 10mg 
dispersible tablets will be used.
Number of 
subjects
Approximately 142 subjects will be enrolled in the study (approximately 48 
subjects in Part A, 40 subjects in Part B, 24 subjects in Part C and 
approximately 30 subjects in Part D).
Inclusion / 
Exclusion 
criteria
General Inclusion Criteria for All Parts (for complete details and further 
eligibility criteria for specific parts please see full protocol):
1. Written informed consent – a signed informed consent and/or assent (as age 
appropriate) for study participation including pharmacokinetics sampling will be 
obtained according to institutional guidelines;
2. Male or female between one month and < 18 years of age (inclusive) at the
time of signing the informed consent form
3. Part C and Part D subjects between 12 months and <18 years of age, 
inclusive;
4. Part A subjects < 2 years of age will not be included in the initial dose 
escalation 
5. Must have a disease that is relapsed/refractory to all potentially curative 
standard treatment regimens or must have a current disease for which there is 
no known curative therapy, or therapy proven to prolong survival with an 
acceptable quality of life. 
6. Prior therapy: The subject’s disease (i.e. cancer, NF-1 with Plexiform 
Neurofibromas, or Langerhans Cell Histiocytosis [LCH]) must have relapsed 
after or failed to respond to frontline curative therapy or there must not be other 
potentially curative treatment options available.  Curative therapy may include 
surgery, radiation therapy, chemotherapy, or any combination of these 
modalities.  Subjects must have recovered to grade ≤1 from the acute toxic 
effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to 
enrollment.
7. Performance score of ≥50% according to the Karnofsky/Lansky performance 
status scale (Yates, 1980).
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 7 days prior to enrollment;
9. Must have adequate multi organ function.
10. In France, subjects will be eligible for inclusion in this study only if either 
affiliated to or a beneficiary of a social security category.


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General Exclusion Criteria for All Parts:
1. Lactating or pregnant female.
2. History of another malignancy including resected non-melanomatous skin 
cancer.
3. Subjects with Neurofibromatosis Type-1 (NF-1) associated optic pathway 
tumors are excluded if they are actively receiving therapy for the optic pathway 
tumor or do not meet criteria for Plexiform Neurofibroma or malignant solid 
tumor.
4. Subjects with a history of NF-1 related cerebral vascular anomaly (such as 
Moyamoya).
5. Subjects with NF-1 actively receiving therapy for the optic pathway tumor
6. Subjects with NF-1 and only Plexiform Neurofibroma (PN) lesions that cannot 
be evaluated by volumetric analysis.
7. Any serious and/or unstable pre-existing medical, psychiatric disorder or other 
conditions that could interfere with subject’s safety, obtaining informed consent 
or compliance to the study procedures.
8. Any prohibited medication(s) as described in Section 9.2.
9. Any medications for treatment of left ventricular systolic dysfunction
10. Part B cohorts 1, 2 and 3: Previous treatment with dabrafenib, trametinib or 
another MEK inhibitor (exception: prior treatment with sorafenib is permitted). 
Patients who have had prior dabrafenib therapy may enroll into cohort B4.  
Patients who have had prior dabrafenib therapy and had benefit from that 
therapy  as determined by the investigator, are allowed in Part C or Part D 
11. Administration of an investigational study treatment within 30 days preceding 
the first dose of study treatment(s) in this study.
12. Have a known hypersensitivity reaction or idiosyncrasy to drugs chemically 
related to study treatment or excipients that contraindicate their participation.
13. Current active liver or biliary disease (with the exception of Gilbert's 
syndrome or asymptomatic gallstones, or liver metastases).
14. History of hepatic sinusoid obstructive syndrome (Venoocculsive disease) 
within the prior 3 months.
15. History of heparin-induced thrombocytopenia.
16. History of interstitial lung disease or pneumonitis.
17. History of or current evidence of retinal vein occlusion (RVO) 
18. For subjects with solid tumors that are not primary central nervous system 
(CNS) tumors or NF-1 associated plexiform neurofibromas, subjects with 
symptomatic or untreated leptomeningeal or brain metastases or spinal cord 
compression are excluded.
19. A history of known Human Immunodeficiency Virus (HIV), Hepatitis B Virus 
(HBV), or Hepatitis C Virus (HCV) infection. 
20. Unresolved toxicity of National Cancer Institute Common Terminology 
Criteria for Adverse Events, version 4.0 (NCI CTCAE v4.0) [NCI, 2009] Grade 2 
or higher from previous anti-cancer therapy, except alopecia.
21. Presence of active gastrointestinal disease or other condition that will 
interfere significantly with the absorption of drugs.  If clarification is needed as to 
whether a condition will significantly affect absorption of drugs, contact the 
Medical Lead for guidance to enrol the subject.
22. A history or evidence of cardiovascular risk (as detailed in protocol Section 
5.2.2)
Study treatment 
dose / route / 
regimen
Trametinib is administered orally once daily under fasting conditions, either 1 hr 
before or 2 hr after a meal.  The starting dose of trametinib (0.0125 mg/kg) is 
50% of the recommended fixed dose in adults (2 mg once daily) based on an 80 
kg adult. A dosing nomogram based on weight and dose level will be used to 
prescribe trametinib to minimize inter-subject dosing variability. Dabrafenib is 
administered orally twice daily either 1 hr before or 2 hr after a meal.  Subjects 
should be encouraged to take their doses at approximate 12 hr intervals and at 
similar times every day.  When taken together, trametinib should be taken 
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for trametinib, dabrafenib and its metabolites will be calculated with standard 
non-compartmental methods. All trametinib and dabrafenib concentration-time 
data may be combined and included in a population PK analysis that will 
examine the influence of demographics (especially age and weight) on the PK of 
study treatment.
Complete details will be provided in the Statistical Analysis Plan (SAP).


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1
Introduction
1.1
Background
The Ras/Raf/MEK/ERK or the mitogen-activated protein kinase (MAPK) pathway is a critical 
signal transduction cascade implicated in normal growth and the uncontrolled proliferation of 
many human cancers.  Under normal physiological conditions, signal transduction through the 
MAP kinase pathway is tightly regulated through multiple negative feedback mechanisms 
(Niault 2010).  However, in cancer cells, this regulation is frequently disrupted most 
prominently through somatic mutations of cell-surface receptors, or mutations of Ras- as well 
as the down-stream serine/threonine kinase B-Raf (BRAF) constitutively activating the 
downstream kinases MEK1 and MEK2.  Activating mutations in RAS or BRAF occur in 
approximately 30 % of human cancers.  Activation of the MEK/ERK pathway has been 
implicated in childhood cancer including neuroblastoma (Wu 2009, Castelletti 2010), Wilms 
tumor (Timofeeva 2006, Hu 2011), soft tissue sarcoma (Tatevossian 2010, Dodd 2013), 
osteosarcoma (Tatevossian 2010), gliomas (Zebisch 2007), acute leukemia (Sasaki 2011, 
Steelman 2011) and juvenile myelomonocytic leukemia (Chang 2013).  In addition Ras 
pathway activation is well described in malignant and non-malignant tumors associated with 
Neurofibromatosis Type-1 (NF-1) (Jessen 2013) because wildtype neurofibromin encodes a 
GTPase activating protein which hydrolyzes active Ras-GTP to the inactive Ras-GDP.
Complex signal transduction pathway feedback and development of resistance to monotherapy 
necessitate testing of combination therapies that target multiple points the signal transduction 
cascade (Montagut 2009, Akinleye 2013).  Combinations of BRAF, MEK, and PI3K/mTOR 
inhibitors may overcome acquired resistance (Greger 2012), however, cross resistance can 
develop to combined BRAF/MEK inhibition (Gowrishankar 2012).
1.2
Trametinib
Trametinib is a reversible, highly selective allosteric inhibitor of MEK1/MEK2 activation and 
kinase activity.  Trametinib interferes with cellular signal-transduction and inhibits proliferation 
by inducing cell apoptosis in tumor cell lines in vitro and human tumor xenografts in mice.  
Analysis of >300 solid cancer cell lines demonstrated that 80% of B-RAF mutant and 72% of 
RAS mutant cell lines were sensitive (half maximal inhibitory concentration [IC50] <50 nM) to 
trametinib, while only 28% of cell lines with wildtype RAS and RAF were sensitive, suggesting 
that Ras and Raf mutational status may be predictors of sensitivity.  Twenty-two out of 25 
melanoma cell lines were sensitive to trametinib.  The three melanoma cell lines that did not 
respond to trametinib had IC50s >1 μM.  In vitro and in vivo studies of trametinib in 
neuroblastoma, malignant peripheral nerve sheath tumor (MPNST), NF-1 associated plexiform 
neurofibromas (PNs) are ongoing.
Please refer to the most current version of the trametinib Investigator’s Brochure (IB) for the 
updated safety information and additional details.


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1.2.1
Pharmacokinetics of Trametinib in Humans
Trametinib pharmacokinetic (PK) parameters 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.  The absolute 
oral bioavailability of a single trametinib 2 mg tablet is moderate to high (72%) relative to a co-
administered intravenous microdose.  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 area under the concentration-time curve from time zero (pre-dose) 
extrapolated to infinity [AUC(0-)] compared to fasted conditions.
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 (C), Cmax and area under the concentration-time curve 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 (Coefficient of variation [CV] %) AUC(0-
24h) was 370 (22%) ng•hr/mL, Cmax 22.2 (28%) ng/mL, Tmax 1.75hr (range 1-3hr), and C
12.1 (19%) ng/mL. (Infante, 2012).  It is important to note that the 95% confidence interval (CI) 
associated with the adult mean of C12.1 ng/mL was 10.86 to 13.4 ng/mL. The lower bound 
of the 95% CI (approximately 10 ng/mL) of the adult mean Cwill be utilized to guide the 
recommended Phase 2 dose in the current study.
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.
In the adult population PK model, trametinib CL/F was estimated as 5.07 L/hr and was 
dependent on gender and weight.  The typical CL/F of trametinib in male subjects was 24% 
higher than that observed in female subjects. The effect of body weight at the minimum and 
maximum weight observed was within 16% of the typical CL/F value. Although smaller female 
subjects will tend to have higher exposure than heavier male subjects, no dosage adjustment is 
warranted in this population.
1.2.2
Clinical Safety and Efficacy of Trametinib
Based on the adverse events (AEs) observed in the dose escalation phase of the early phase 
trials in adults, the Maximum Tolerated Dose (MTD) of trametinib was 3 mg once daily, and 
the recommended Phase II dose of trametinib was 2 mg once daily. Across clinical multiple 
studies in more than 500 subjects, adverse events have been reported by 50% to 100% of 
subjects, with the most common being rash, diarrhea, fatigue, edema peripheral, nausea, 
dermatitis acneiform, vomiting, constipation, anemia, pruritus, alopecia, hypertension, 
decreased appetite, dyspnea and dry skin.  In these studies up to 32% of subjects reported serious 
AEs (SAEs), and up to 13% permanently discontinued study treatment due to AEs.


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Rash, diarrhea, visual disorders, hepatic disorders, cardiac-related AEs,hypertension, bleeding 
events, edema and pneumonitis are considered AEs of special interest for trametinib because 
they are either known class effects (i.e., were observed with other MEK inhibitors) or 
potentially life-threatening.  Please refer to the trametinib IB for the most current safety 
information and additional details.
Data from Phase I, II and III studies indicate substantial clinical activity of trametinib in 
unresectable, BRAF mutation positive melanoma (Gilmartin 2011, Infante 2012, Falchook 
2012a, Falchook 2012b).  The pivotal Phase III study, MEK114267 (METRIC), showed 
significant improvement in 6 month overall survival (OS, 81% vs 67%, P=0.01) and 
progression-free survival (PFS, 4.8 months versus 1.5 months, P<0.001) in favor of trametinib 
over standard dacarbazine or paclitaxel chemotherapy in the treatment of patients with advanced 
or metastatic BRAF V600E/K mutation positive melanoma (Flaherty 2012, Sausville 2012).
Trametinib (MEKINIST®) was approved by the Food and Drug Administration (FDA) on 29 
May 2013 as a single-agent oral treatment for unresectable or metastatic melanoma in adult 
patients with the BRAF V600E or V600K mutation.
1.2.3
Trametinib Preclinical Juvenile Toxicity
In juvenile rat toxicity studies, there were dose-dependent effects on growth (body weight and 
long bone length), bone (physeal thickening), increased serum phosphorus, eye (corneal 
mineralization/dystrophy), skin, liver, heart (increased heart weight) 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.  All of the female 
reproductive effects were reversible.  With the exception of the heart and eye findings, similar 
effects have been observed in adult animals given trametinib.
In bone, physeal thickening was reversible following a recovery period and may be associated 
with inhibition of MEK-dependent fibroblast growth factor (FGF) signaling, as similar effects 
have been observed in rats given a small molecule inhibitor of FGF receptor (FGFR) tyrosine 
kinase (Brown 2005) or in FGFR-3-deficient mice (Deng 1996).  Unlike in adults, where bone 
growth has completed and the physeal plates have closed, children (2 to 11 years of age) and 
adolescents (12 to <18 years of age) may represent sensitive populations to chronic MEK 
inhibitor treatment and may demonstrate growth velocity impairment.
Gonadal maturation and development is a potentially sensitive process in children who have yet 
to reach sexual maturity.  In female rats given trametinib at subclinical exposures, ovarian 
function perturbations were observed, including increases in cystic follicles and decreases in 
cystic corpora lutea.  Pharmacologic inhibition of MEK activity in ovarian granulosa cell 
cultures blocked ovulatory gene expression, follistatin signaling and granulosa cell survival 
(Shiota 2003, Kihara 2006 and Sriraman 2008), indicating a potential role of MEK in 
folliculogenesis.  In juvenile rats, similar ovarian findings occurred, as well as delays in onset 
of physical hallmarks of sexual maturity and mammary gland development. Therefore, onset of 
female reproductive maturation is a concern in pediatric populations receiving trametinib.


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1.2.4
Trametinib Pediatric Experience
Prior to the initiation of this trial, no subject under the age of 18 has received trametinib 
monotherapy in a GSK or Novartis sponsored clinical trial.
1.2.5
Trametinib Pharmacokinetic/Pharmacodynamics Relationships
Repeat administration of trametinib doses of 0.5 mg, 1 mg, and 2 mg once daily in adults 
resulted in dose-dependent modulations in tumor biomarkers.  Higher doses resulted in greater 
inhibition of phosphorylated ERK (pERK), Ki67 and increases in p27, confirming inhibition of 
the MAPK/ERK pathway.  In adults with solid tumors, paired tumor biopsies were obtained at 
baseline and on day 15 of trametinib administration.  Pathway modulation was dose dependent 
in subjects with BRAF, NRAS mutant melanoma.  For all subjects receiving trametinib 2 mg 
daily the median change was 30% inhibition of pERK, 54% inhibition of Ki67, and 83% 
increase in p27.  In the melanoma subgroup at this dose, median change was 62% inhibition of 
pERK, 83% inhibition of Ki67, and 171% increase in p27.  Day 15 trametinib Cwas 9.51-18.2 
ng/mL (Infante 2012).
An exposure-response analysis was conducted using data from the first time in human (FTIH) 
study (Study MEK111054) to determine the relationship between the independently manually-
read corrected QT interval duration (QTc) and plasma concentrations of trametinib using a non-
linear mixed effects model.  The electrocardiogram (ECG) data obtained in Part 1 of the study 
were matched to trametinib concentration and used in these analyses.  Data were available in 
50 subjects with a total of 498 matched QTc values.  Trametinib showed no apparent potential 
to alter the QTc interval.  At the mean Cmax value observed at the recommended dose of 2 mg 
once daily, median (90% confidence interval [CI]) increase in QTc is 2.2 msec (0.2, 4.0).
1.3
Dabrafenib
Dabrafenib (GSK2118436) is a potent and selective inhibitor of BRAF kinase activity with a 
mechanism of action consistent with adenosine triphosphate (ATP)-competitive inhibition.  
Dabrafenib has demonstrated suppression of a downstream pharmacodynamic (PD) biomarker 
pERK in tumor cell lines, demonstrated anti-proliferative activity against multiple BRAF 
mutation-positive tumor cell lines, achieved biomarker suppression and tumor regression in 
BRAF mutant xenograft models, and has demonstrated significant anti-tumor efficacy in BRAF 
V600-mutation positive melanoma.
Please refer to the most current version of the dabrafenib Investigator Brochure for the most 
current safety information and additional details.
1.3.1
Pharmacokinetics of Dabrafenib in Humans
Following single-dose oral administration of dabrafenib in hydroxypropyl methylcellulose 
(HPMC) capsules, plasma concentrations peaked approximately 2.0 hr post-dose and decreased 
thereafter following a bi-exponential decline.  Median terminal half-life in adults is 
approximately 8 hr after a single dose.  Increases in maximum observed concentration (Cmax) 
and area under the concentration-time curve (AUC) were generally dose-proportional following 
single doses up to 300 mg (gelatin capsules), but less than proportional to dose following repeat 


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dosing.  There was no accumulation with repeat daily dosing, with a steady state/single-dose 
AUC ratio of 0.65 following administration of dabrafenib 150 mg twice daily (BID) HPMC 
capsules.  The decrease in exposure noted with repeat dosing of dabrafenib was likely due to 
induction of its own metabolism.
Oral absorption of dabrafenib HPMC capsule is nearly complete, with a geometric least square 
(GLS) mean (90% confidence interval [CI]) absolute bioavailability of 94.5% (81.3, 109.7).  
Administration of dabrafenib HPMC capsules with a high-fat, high-calorie meal resulted in a 
decrease in the rate and extent of absorption with fed:fasted ratios (90% CI) for Cmax and area 
under the concentration-time curve from time zero (AUC(0-∞)) of 0.49 (0.35, 0.69) and 0.69 
(0.57, 0.85), respectively.
Treatment with dabrafenib dispersible tablets resulted in a decrease of AUC and Cmax by 20% 
and 49%, respectively relative to administration of HPMC dabrafenib capsules. Tmax was 
comparable between the two formulations.. 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. Cmax is not associated with 
response. 
In the adult population PK model for dabrafenib, body weight also impacted oral volume of 
distribution (Vc/F) and distributional clearance (Q/F).  The difference between female and male 
subjects (9%) and between subjects with low (50 kg) or high (140 kg) body weight relative to 
a typical body weight of 80 kg (<20%) was not considered clinically relevant.
1.3.2
Clinical Safety and Efficacy of Dabrafenib
As of 22 June 2015, approximately 2,000 patients with various cancers have received 
dabrafenib for up to 6 years and approximately 3,200 subjects have received trametinib in 
combination with dabrafenib for up to 5 years in Novartis-sponsored ongoing or completed 
studies and compassionate care programs.  Cumulative postmarketing exposure to dabrafenib 
through 31 March 2015 is estimated to be 3,546.16 patient-years.
Integrated safety data from subjects (N=586) receiving 150 mg BID showed that 97% had 
experienced AEs, the most common (≥20%) being hyperkeratosis (32%), headache (30%), 
pyrexia (30%), arthralgia (29%), fatigue (26%), nausea (25%), alopecia (23%), skin papilloma 
(21%), and rash (20%).  A total of 174 (30%) subjects experienced any serious adverse event 
(SAE), and 114 (19%) subjects had treatment-related SAEs.  The proportion of subjects who 
experienced AEs leading to discontinuation of study treatment was low (3%).
In the pivotal Phase III study BRF113683 (BREAK-3), 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 subjects with BRAF V600E mutation positive 
melanoma and no brain metastases (Hauschild 2012).  Dabrafenib provided a clear and 
meaningful benefit in subjects 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).  Subjects 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).


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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.
1.3.3
Dabrafenib Preclinical Juvenile Toxicity
In juvenile rat toxicity studies, there were dose-dependent decreases in body weight and/or gain, 
food consumption and long bone growth.  In testes, there were similar effects (testicular 
degeneration/atrophy and tubular dilation) in juvenile animals as seen in adults.
In juvenile rat studies, dose-dependent effects on kidney (tubular deposits with secondary 
changes, increased incidence of cortical cysts and tubular basophilia, tubular dilation and 
reversible increases in serum urea and/or creatinine concentrations) were observed.  Renal 
toxicity has not been observed in adult rats, dogs or mice given dabrafenib for up to 3 months.  
The spectrum of renal changes noted in juvenile rats suggests obstructive injury.  In general, 
renal toxicity was observed with greater incidence and severity in juvenile rats where dosing 
was initiated pre-weaning compared to post-weaning.  When dosing of dabrafenib was initiated 
post-weaning (postnatal day 22), there was no progression in the severity of renal findings nor 
were there any secondary changes.  The observation of greater renal toxicity in rats < 22 days 
old suggests a higher risk for tubular injury for human infants <1 years of age based on 
comparison of renal maturation rates, and a correspondingly lower risk for patients between 1 
and 4 years of age.
1.3.4
Dabrafenib Pediatric Experience
A Phase 1 clinical trial of dabrafenib is ongoing in children with solid tumors (BRF116013).
1.3.4.1
Background data from part 1 of study BRF116013
Twenty seven subjects were enrolled, with a median age of 9.0 years, ranging from 11 months 
-17 years old; 56% were male.  Most subjects (89%) were caucasian. Most subjects (21 subjects, 
78%) had measurable disease at baseline per the investigator, and all were previously treated 
for this tumor. Dose escalation was pharmacokinetically driven, to achieve exposures 
(measured as AUC 0-12) in pediatric patients that is similar to that seen in adults treated at 
recommended doses. Note that an MTD has not been determined in adults.
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 (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). The doses will be 
further defined based on modelling and simulation of all available data at the time of finalizing 
the protocol. 
An interim data cut from this ongoing study was made 7 March 2015, and resultant tables and 
listing prepared for the 27 patients enrolled into part 1. Twenty-one of these 27 patients were 
continuing to receive dabrafenib at the time of the data cut off.




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had CRs, 2 had PRs and 4 of the eight patients were on study treatment for 9 months or more. 
This is shown graphically in Figure 1-1 above.
These results compare very favorably to the historical data where paediatric patients with 
relapsed, refractory or progressive HGG are expected to have a less than 10% RR and a median 
survival of 5 months, using conventional therapy.
LGG
Fifteen pediatric patients with relapsed, refractory or progressive LGG with BRAFV600 
mutations were enrolled into the dose finding portion of BRF116013.  Of these 15 patients, 5 
had partial responses (33%), 7 had stable disease (47%), one had progressive disease and two 
were not yet evaluable for response.  
LCH
Two pediatric patients with previously treated severe LCH and BRAFV600 mutations were 
enrolled into BRF116013.  Both achieved complete responses as assessed by the investigator.
Other
Two patients with other solid tumors and BRAFV600 mutations were enrolled; neither had a 
response to dabrafenib therapy.
Safety Results
Adverse events
All subjects reported at least one AE.  The most common (>30%) AEs were pyrexia, fatigue, 
vomiting, headache, and nausea. There were nine subjects (33%) with AEs of maximal grade 
3, and 2 subjects with maximal grade 4 (intracranial hemorrhage, hypotension). No grade 3 
event occurred in >2 subjects. The most common body system impacted by AEs was skin (93% 
all grades, including 7% G2 and 7% G3 with multiple terms for rash most common), general 
disorders (81% all grades, including 33% G2, with pyrexia and fatigue most common), and 
metabolic (74% all grades, including 15% G2 and 11% G3, various electrolyte abnormalities).
Serious Adverse Events 
Nine subjects (33%) reported 22 SAEs during this time period, all resolved.  Three subjects had 
related SAEs, one with rash, one with arthralgia, and one with pyrexia followed by DIC, 
hypotension, and increased INR.  All three remain on study as of July, 2015.
Dose limiting toxicity
There was one subject with low grade glioma 
years old at 4.5 mg/kg/d dose) who 
experienced a DLT of Grade 3 maculopapular rash with onset on day 1 of dosing.  After protocol 
specified dose interruption, the subject 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. 


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Dose modifications
Eleven of the 27 subjects had at least one dose interruption while on study, mostly for rash 
and/or pyrexia, and followed protocol guidelines.  Two subjects required dose reductions for 
toxicity, per protocol.
Discontinuations for toxicity
There were no subjects prematurely withdrawn from study for toxicity in part 1.  However, 
through 7 March 2015, one subject in part 2 of the study was withdrawn for painful rash related 
to study drug, noted in the first week of study start, with recurrence upon re-challenge. The 
patient was aged 
years, with a primary diagnosis of grade I Pilocytic Astrocytoma. An AE 
of grade 2 Erythema Nodosum resulted in study withdrawal. 
Deaths
There were no deaths on study treatment.
Laboratory data
Review of laboratory data reveals no apparent safety signals.  In most cases, it was possible to 
grade the laboratory data in this interim data analysis using local normal ranges. There were 
two events of G3 elevated hemoglobin and one event of G3 hypokalemia during viral upper 
respiratory tract infection. There was one patient with G2 hypokalemia and all other graded 
laboratory values were G1 or less.
Safety Conclusions
Based on preliminary data, the toxicity profile observed in these initial 27 paediatric subjects is 
generally similar to that observed in the adult subject experience.  Both populations experienced 
frequent rash, pyrexia, fatigue, arthralgia and headache (m2.7.4 Section 2.1.1, common adverse 
events).  The frequency of rash and similar adverse events may be higher in this paediatric 
population than in adults.  There were two subjects (7%) with grade 3 Rash in the paediatric 
population while there is less than 1% rate in adults.  Rash management guidelines suggested 
in the protocol were followed for subjects with rash as they remained on therapy.  In contrast, 
there were no cases of cutaneous SCC observed in these paediatric subjects and fewer paediatric 
subjects have discontinued treatment due to toxicity (0 of 27 in part 1) than adult subjects.  The 
most common AEs were in the Skin body system.  There was one dose limiting toxicity, a G3 
Rash, although higher doses were later shown to be tolerable in this age group.  There were no 
discontinuations due to toxicity.  Adequate exposures were obtained without reaching a 
maximally tolerated dose. 
Overall Conclusion 
Overall, these results suggest that dabrafenib monotherapy represents a potentially favorable 
benefit risk to pediatric patients < 18 years old with BRAFV600 mutant relapsed refractory or 
progressive gliomas including HGG.


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1.4
Combination of Trametinib and Dabrafenib
Please refer to the most current version of the dabrafenib and trametinib Investigator Brochure 
for the most current safety information and additional details.  Data summarizing the clinical 
safety profile for dabrafenib 150 mg BID in combination with trametinib 2 mg QD in adult 
patients with BRAF V600 mutation-positive unresectable or metastatic melanoma were pooled 
from two large randomized Phase III studies (N=559). The Phase III data are supported by data 
from the Phase II Study BRF113220 Part C (150/2 combination therapy group, n=55) , 
providing a total of over 600 subjects on randomized combination treatment. The safety profile 
of the combination of dabrafenib and trametinib generally reflect AEs of the individual agents. 
The AE profile for combination therapy in both Phase III studies, including SAEs and AEs 
leading to dose modifications, were similar, indicating that the pooled data is a reliable 
representation of the combination therapy safety profile. The incidence of discontinuations and 
temporary dose modifications to manage AEs was higher for subjects on the combination 
therapy (discontinuations, 12%; dose reductions, 31%; dose interruptions, 55%) compared to 
dabrafenib monotherapy (discontinuations, 7%; dose reductions, 14%; dose interruptions, 37%) 
but similar to vemurafenib (discontinuations, 12%; dose reductions, 39%; dose interruptions, 
56%). The intended dosing in subjects receiving combination therapy was not compromised.
The most common SAE reported for combination therapy was pyrexia, followed by ejection 
fraction decreased and chills. Discontinuations due to pyrexia and ejection fraction decreased 
each occurred in 3% of subjects in the combination therapy group. 
There were 8 fatal AEs reported for combination therapy; 6 of the 8 fatal SAEs were intracranial 
hemorrhages. The presence of various confounding factors in 5 of the 6 subjects with 
intracranial hemorrhage makes the evaluation of causality difficult; contribution of the 
combination therapy cannot be ruled out.
The rate of permanent discontinuation due to AEs for combination therapy was 12%. Dose 
reductions due to AEs were required in approximately one-third of subjects receiving 
combination therapy (31%). Dose interruptions due to AEs were required in more than one-half 
of subjects receiving combination therapy (55%). The most frequently occurring AEs requiring 
dose modifications were those where management guidance was provided in the protocols. AEs 
of special interest were identified based on the clinical significance, frequency and the potential 
association with the mode of action of BRAF and MEK inhibitors.
Pyrexia occurred at increased frequency and severity for combination therapy subjects as 
compared to either monotherapy arm. Approximately 60% of the dose interruptions and 50% 
of the dose reductions in the combination therapy group were due to AEs of pyrexia. With 
appropriate management and dose modifications, most patients were able to continue on 
treatment.
Bleeding events occurred at a similar frequency on combination therapy compared to 
dabrafenib monotherapy, and at a higher frequency compared to vemurafenib monotherapy. 
The majority of bleeding events for all treatments were Grade 1, and resolved without dose 
modification. There were 6 fatal intracranial hemorrhages for combination treatment. Bleeding 
in other critical sites (e.g., gastrointestinal, pulmonary, genitourinary) have also occurred, none 
of which were fatal.


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Ejection fraction decreased occurred in 7% of subjects for combination therapy and the majority 
of the LVEF decreases that met interruption criteria were asymptomatic and resolved. Most 
subjects who were re-challenged were able to continue on treatment without further dose 
modification. These findings suggest that by regular, longitudinal monitoring with appropriate 
dose modification, more severe sequelae may be prevented.
Hyperproliferative skin lesions, including keratoacanthoma and cuSCC, occurred at a reduced 
frequency and with a prolonged latency in subjects receiving this combination regimen as 
compared to BRAF inhibitors as monotherapy; substantiating the non-clinical hypothesis that 
addition of trametinib abrogates an important safety concern resulting from the paradoxical 
activation of the MAP kinase pathway exerted by BRAF-inhibitors.
Other treatment-emergent malignancies (for example pancreatic  and colorectal) were reported 
at rates of 1% for combination treatment, which is not higher than what would be expected in 
the population, and comparable to that observed with monotherapy. 
Other adverse events of special interest such as renal insufficiency and pancreatitis for 
dabrafenib, and skin-related toxicities, ocular events, pneumonitis, and diarrhea for trametinib, 
appeared at a frequency and/or severity consistent with the known AE profiles of either 
dabrafenib or trametinib monotherapy.
The safety profile for dabrafenib + trametinib combination therapy in adult subjects with 
unresectable/metastatic melanoma has been established and is well-characterized with 
consistent results across two randomized Phase III studies, with 33% of subjects receiving >12 
months of combination treatment. There were no new or unexpected safety concerns compared 
to those observed in the Study BRF113220 Part C combination group. In addition, no new or 
unexpected safety concerns have been identified for subjects on combination treatment in 
studies with prolonged additional follow-up (an additional 17 months for MEK115306; an 
additional 20 months for BRF113220 Part C. The safety profile of the combination generally 
reflects the safety profiles of the individual agents.
The combination regimen of dabrafenib at the recommended dose of 150 mg BID and 
trametinib at the recommended dose of 2 mg QD has an acceptable safety profile in adult 
patients with unresectable or metastatic BRAF V600 mutation positive melanoma, with 
toxicities that are manageable with appropriate intervention. Administration of dabrafenib and 
trametinib in combination had no clinically relevant effect on the exposure of trametinib or of 
dabrafenib relative to administration of either compound alone.
In adults, data from phase I/II and phase III studies of the combination of these two agents 
demonstrate that both agents can be delivered together at their full recommended monotherapy 
doses, and that generally the observed AE profile represents the profiles of each individual agent.  
Some events were higher in the combination arms than in dabrafenib alone arms, including 
pyrexia, diarrhea, chills, vomiting and hypertension.  Some events were lower in the 
combination arms than in the dabrafenib arms, including cuSCC alopecia, hyperkeratosis, PPES 
and skin papilloma. Bleeding events overall were similar in dabrafenib monotherapy and 
combination arms, although there were 6 fatal intracranial hemorrhage events out of 559 adult 
subjects treated in the combination therapy arms versus none in the 211 adult subjects on 
dabrafenib monotherapy.  These events of intracranial hemorrhage were generally confounded 


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and were considered not related to treatment by the treating physicians but were more frequent 
in the combination therapy arms.
The combination therapy in the pediatric population may result in a higher frequency and 
severity of pyrexia as compared to dabrafenib monotherapy, including pyrexia requiring dose 
interruption and the use of antipyretics, as well as increased rates of chills, diarrhea, vomiting, 
and edema peripheral. The combination may result in a lower rate of hyperkeratosis, skin 
papilloma, alopecia, palmar plantar erythrodysesthesia syndrome (PPES), and palmoplantar 
keratoderma as compared to dabrafenib monotherapy.
The efficacy of the combination of dabrafenib plus trametinib in the treatment of adults with 
BRAFV600 mutant advanced melanoma has been shown to be superior to that of dabrafenib 
alone. Similarly, the combination of dabrafenib and trametinib appears superior to that of 
dabrafenib alone in the treatment of adult subjects with BRAFV600 mutant NSCLC.  Current 
clinical trial data on dabrafenib monotherapy in the treatment of pediatric subjects with 
BRAFV600 mutant solid tumors suggests clinically relevant efficacy that compares favorably 
with the current standard of care available for the various diseases that have been studied. 
Nonetheless, there may be an opportunity for further improvement in efficacy with combination 
therapy, perhaps manifest as higher response rates, and/or responses of longer duration.
This is the first clinical study of trametinib and dabrafenib combination in pediatric patients.  
At the time of Amendment 5 release, preliminary data supports RP2D of 100% dabrafenib and 
100% trametinib for combination therapy in patients 6 years of age and older. In patients less 
than 6 years of age, an additional dose level of trametinib will be evaluated as monotherapy and 
if tolerated, as combination therapy. Based on the results of these evaluations, combination 
therapy RP2D will be established in this age cohort
1.5
Rationale for BRAF and MEK inhibitors in Pediatric Cancers
Given the central role of MAPK signaling in cell proliferation, growth, and adhesion, and 
available evidence of enhanced MAPK activity in many human cancers, it is hypothesized that 
the MEK inhibitor trametinib may confer beneficial effects against the pediatric cancers 
including:

Relapsed or refractory neuroblastoma

Recurrent or unresectable low grade gliomas with BRAF tandem duplication with fusion

Neurofibromatosis (NF)-related PNs.

BRAF V600 mutant tumors 

Langerhans cell histiocytosis with MAP2K1 mutation
The safety and activity of the combination of dabrafenib with trametinib in adults with BRAF 
V600 mutation positive melanoma has been demonstrated.  Once the doses of dabrafenib and 
trametinib monotherapy are determined in children and adolescents, a treatment arm to evaluate 
the safety of dabrafenib in combination with trametinib in children and adolescents will be 
opened.


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1.6
Malignant Solid Tumors in Infants, Children, and Adolescents
Survival rates for childhood cancer, primarily leukemia and lymphoma, continue to improve.  
However, the 5 year survival for children and adolescents with solid tumors except 
neuroblastoma has not changed in the past 20 years and improvement in survival for children 
with brain tumors has not improved significantly in the past 15 years (Smith 2010). The 
Ras/MEK/ERK pathway has been evaluated in a number of pediatric solid tumors.
Neuroblastoma is a neoplasm of the sympathetic nervous system. It is the most common extra-
cranial malignant tumor of childhood, and the most common solid tumor of infancy. Ten to 20% 
of children and adolescents with high risk neuroblastoma have disease that is refractory to 
primary therapy, an additional 50%  will relapse after intensive multimodality therapy (Park 
2010, Cheung 2013, Maris 2010). The National Cancer Institute (NCI) Therapeutically 
Applicable Research to Generate Effective Treatments (TARGET) initiative has demonstrated 
that somatic mutations in neuroblastoma including anaplastic lymphoma kinase (ALK) (9.2%), 
Protein-tyrosine phosphatase non-receptor type 11 (PTPN11) (2.9%), adenosine triphosphate 
(ATP)-dependent transcriptional regulating X-linked helicase (ATRX) (2.5%, 7.1% with focal 
deletion), proto-oncogene for transcription factor MYC (MYNC) (1.7%) and NRAS (0.83%) 
are rare.  However, multiple lines of evidence indicate that MEK/ERK activation and signaling 
are critical to neuroblastoma cell survival (Hsu 2013, Martinez 2012).  In pre-clinical 
neuroblastoma models and other cell lines, MEK 1/2 inhibition was synergistic with inhibition 
of centromere-associated protein –E (CENP-E) (Mayes 2013).
1.6.1
Low-grade glioma
In children with low grade gliomas, gross total resection is curative.  For patients who do not 
achieve a gross total resection, observation or adjuvant chemotherapy is considered.  Radiation 
therapy is typically reserved for salvage treatment. In young children, chemotherapy (typically 
vincristine combined with carboplatin) can be used to delay radiotherapy to decrease risk of 
neurocognitive damage.  With this current treatment paradigm, progression-free survival in 
children with low grade glioma is 80-90% at 10 years.  For patients who have recurrent tumor, 
radiation therapy is considered.  For children who have received radiation and chemotherapy, 
younger children for whom the risk of radiation therapy remains high, and children with 
relapsed/recurrent low-grade gliomas, new therapeutic approaches are needed.
MAPK pathway deregulation occurs in low grade gliomas (Tatevossian 2010).  Constitutively 
active Braf signaling has been identified in >50% of pilocytic astrocytoma, as a result of the 
tandem duplication of chromosome 7q34.  This caused an oncogenic gene fusion of BRAF and 
KIAA1549 (Pfister 2008, Forshew 2009, Jacob 2009, Jones 2009, Korshunov 2009, Horbinski 
2010, Schiffman 2010).  Due to the loss of the N-terminal autoregulatory domain, the BRAF-
KIAA1549 gene fusion product has increased Braf kinase activity resulting in a wild-type Braf 
sequence with catalytic activity similar to BRAF V600 sequence mutations.  This fusion product 
has also been identified in >80% of cerebellar pilocytic astrocytoma specifically (Jacob 2009, 
Jones 2009, Horbinski 2010).  Cells expressing the KIAA1549-BRAF fusion kinase have a 
paradoxical activation of MAPK signaling that may decrease the effectiveness of specific V600
BRAF inhibitors in these tumors (Sievert 2013).


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1.6.2
Neurofibromatosis Type-1 Related Plexiform Neurofibromas
Neurofibromatosis Type-1 is an autosomal dominant, multisystem, tumor predisposition 
syndrome (Evans 2006, Boyd 2009, Williams 2009). Patients with NF-1 have an increased 
susceptibility to the development of a number of tumors including: PNs, astrocytomas 
(particularly optic pathway), and MPNST (Benesch 2010). The incidence of NF-1 is 
approximately 1 in 3,000 (Poyhonen 2000, Lammert 2005, Boyd 2009). At least 30% of patients 
with NF-1 suffer from PNs, which are benign tumors that originate from peripheral nerves and 
can arise in various parts of the body (Friedrich 2005). These tumors are often present at birth 
and can progress rapidly during the first years of life.  PNs can cause facial disfigurement, 
functional deficits, and severe clinical complications following resection (Friedrich 2005).
The NF-1 gene, located on chromosome 17q11.2, encodes the tumor suppressor neurofibromin 
(Boyd 2009, Wetmore 2010).  Neurofibromin functions as a GTPase activating protein (GAP) 
for Ras by accelerating the conversion of active Ras-GTP to inactive Ras-Guanosine 
diphosphate (GDP), thereby converting Ras from its active to inactive conformation. Loss of 
NF-1 function leads to loss of neurofibromin activity, leading to Ras being locked in its active 
confirmation, which stimulates MEK, and then ERK activity (Boyd 2009).
1.6.3
Langerhans Cell Histiocytosis (LCH)
LCH is a rare proliferative disorder of unknown etiology that primarily affects children.  It is 
distinguished by the clonal proliferation of pathologic histiocytes with the morphologic 
characteristics of Langerhans cells.  Langerhans cells are bone-marrow derived dendritic cells, 
characterized by the expression of CD1a, S100 and the production of Birbeck granules.  The 
pathogenesis of LCH is poorly understood.  Clinical manifestations are related to the pattern of 
infiltration or organ involvement (Stockschlaeder 2006, Arico 1998).  The clinical presentation 
is heterogeneous, can involve single or multiple organs, and can be associated with varying, 
often unpredictable outcomes ranging from spontaneous regression to multiple episodes of 
reactivation, long term debilitating sequelae, rapid progression, and death. 
Patients with localized (single system) disease in ‘low risk’ organs typically have good 
prognosis and may require minimal treatment (for example, isolated bone lesion).  On the other 
hand, multisystem disease, especially disease involving key ‘high risk’ organs (hematopoietic, 
spleen, liver, lung), carries higher risk of poor outcomes and recurrent events (reactivation 
disease) after initial therapy. 
LCH occurs at an estimated rate of 2 to 10 per million children/adolescents under the age of 15 
years (NCI 2012, Stalemark 2008), as compared to approximately 1 to 2 cases per million in 
adults.  Approximately 76% of cases occur in children less than 10 years old.  Risk of morbidity 
and mortality increases substantially when multifocal or multi-organ disease is present (Satter 
2008).
In a recent report, which is also the first to show activation of any oncogenic signalling pathway 
in LCH, BRAF V600E mutations were identified in nearly 60% of a cohort of archival lesion 
samples obtained from children and adults with LCH (Badalian-Very 2010).  The identification 
of BRAF V600E mutations in LCH has been confirmed in a recently published second report 
(Satoh 2012).


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Mutational analysis of BRAF V600 wild type LCH tumors has very recently revealed a second 
pathway activating alteration, MAP2K1 (Brown 2014).  Of the roughly half of LCH specimens 
lacking the BRAF V600E mutation, half (about 25% overall) were found to have activation 
mutations of MAP2K1. This finding reinforces the important role of this pathway in the genesis 
of LCH and related diseases, and provides a rationale for additional investigation of inhibition 
of this pathway at more downstream positions, including that provided by inhibitors of MEK1/2.
1.6.4
V600 Mutations in Childhood Cancer
1.6.4.1
High Grade Gliomas
BRAF V600E point mutants have been reported to occur in up to 30% of high-grade 
astrocytomas (Schiffman 2010, Basto 2005).  The frequency of BRAF activating mutations may 
be more common in pediatric astrocytomas than in adult tumors (Knobbe 2004).  Similar to 
adults, high-grade gliomas in children have poor outcomes overall.  However, in children the 
extent of surgical resection is of prognostic significance with a benefit being derived from near 
total (>90%) resection.  Focal radiation and adjuvant temozolomide demonstrate an overall one-
year survival of approximately 68% and a one-year event-free survival of 31% and 36% for 
anaplastic astrocytoma (World Health Organization [WHO] Grade III) and glioblastoma (WHO 
Grade IV), respectively (Cohen 2011).
BRAF V600E point mutants have been reported to occur in approximately 50-60% of 
gangliogliomas (MacConaill 2009, Dougherty 2010), approximately 2-12% of pilocytic 
astrocytomas (Forshew 2009, Pfister 2008, MacConaill 2009, Qaddoumi 2009, Jacob 2009, 
Dias-Santagata 2011), and in as many as 30% of high-grade astrocytomas (Schiffman 2010, 
Basto 2005).
1.6.4.2
Melanoma
Melanoma in children is rare (Lange 2007).  Histopathologically, adult and pediatric 
melanoma appears to be similar.  In 2013, it was estimated that approximately 337 new cases 
are expected to be diagnosed among those aged 0-18 years in the United States (SEER 2013, 
US Census 2008).  Of all patients with melanoma diagnosed before 19 years of age, 6.8% of 
male patients and 4.6% of female patients had an initial diagnosis of stage IIIC and IV 
melanoma.  The frequency of BRAF mutations in melanoma has been reported to be 
approximately 50% (range: 27% to 70%) (Garnett 2004, Chapman 2011).
1.6.4.3
Papillary Thyroid Carcinoma (PTC)
Thyroid nodules are rare in childhood and adolescence; however, they are more frequently 
malignant than in adults (approximately 20% of cases) (Corrias 2010).  Pediatric Papillary 
Thyroid Carcinoma (PTC) usually presents at an advanced stage, but has a 5-year survival rate 
of >99% (SEER 2013, Hay 2010).  At presentation, 70% of patients typically have regional 
nodal involvement, and 10 to 20% may have distant metastasis, with the most common site of 
metastases being the lungs (Alessandri 2000).


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BRAF V600E activating mutations are common in adult PTC, reported at a rate of 
approximately 50% (Nikiforova 2009, Melck 2010).  BRAF V600E mutations were identified 
in approximately 20% of cases in patients aged <20 years (Rosenbaum 2005, Kumagai 2004).
1.7
Summary of Risk Management
1.7.1
Predicted Toxicities for Trametinib
The data and guidance presented in this section are derived from all of the available safety 
information at the time of compilation; this includes pre-clinical safety data and data available 
from the clinical study program. Updated safety information may be found in the most recent 
IB for trametinib and local prescribing information for trametinib.
Ocular effects: Visual impairments, including chorioretinopathy, retinal pigment epithelium 
detachment (RPED), and retinal vein occlusion (RVO), were reported with trametinib. Cases 
of ocular toxicities were reported with other MEK inhibitors in clinical development. Subjects 
with a history of RVO should not receive trametinib.  
Comprehensive stopping criteria, dose modifications, and ocular effects management 
guidelines are incorporated in this protocol.
Cardiovascular effects: Left ventricular dysfunction was reported with trametinib as well as 
with other MEK inhibitors in clinical development.  Adult subjects with a history or evidence 
of cardiovascular risk including current ≥ Class II congestive heart failure as defined by New 
York Heart Association are not being enrolled in current studies.  Subjects must also have a 
normal left ventricular ejection fraction (LVEF) on screening assessment.  Comprehensive 
stopping criteria, dose modifications, and left ventricular dysfunction management guidelines 
are provided in in Section 3.12.3. 
Rash: In clinical studies with trametinib, rash has been observed in about 60% of subjects. The 
majority of these AEs was Grade 1 or 2 and did not require any dose interruptions or dose 
reductions. Rash management guidelines are provided in Section 3.13.3.
Renal impairment:  No dosage adjustment is required in subjects with mild or moderate renal 
impairment.  Mild or moderate renal impairment had no significant effect on the PK of 
trametinib.  There are no data with trametinib in subjects with severe renal impairment.  
Eligibility criteria for this study will include normal age adjusted creatinine or creatinine 
clearance greater than 60 ml/min per 1.73 m2 for all infants, children and adolescents.
Hepatic impairment:  No dosage adjustment is required in subjects with mild hepatic 
impairment.  In a population PK analysis, trametinib oral clearance and thus exposure was not 
significantly different in subjects with mild hepatic impairment compared to subjects with 
normal hepatic function.  There are no clinical data in subjects with moderate or severe hepatic 
impairment.  Trametinib should be used with caution in subjects with moderate or severe 
hepatic impairment.
Reproductive Effects: Trametinib may impair female fertility in humans, as in repeat-dose 
studies, increases in cystic follicles and decreases in corpora lutea were observed in female rats 
at exposures below the human clinical exposure based on AUC. However, in animal repeat dose 


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toxicity studies, there were no treatment effects observed in male reproductive tissues.  
Developmental toxicity was observed in animals at sub-clinical exposures and consisted of 
decreased fetal weights, increased post-implantation loss, increased abortions and increased 
incidence of incomplete ossification and skeletal malformations.
There are no adequate and well-controlled studies of trametinib in pregnant women.  Therefore, 
the compound must not be administered to pregnant women or nursing mothers.  Women of 
childbearing potential should use effective methods of contraception during therapy and for 4 
months following discontinuation.  Pregnant women are excluded from this study, and periodic 
pregnancy tests will be performed on women of childbearing potential to confirm continued 
eligibility.  Women who are breast-feeding are also excluded; although it is not known whether 
trametinib is excreted in human milk a risk to the nursing infant has not been discharged.
1.7.2
Predicted Toxicities for Combination of Trametinib and Dabrafenib
The assessment of the risk for the combination of trametinib and dabrafenib, and suggestions 
for management of risk, are based on clinical data from the concluded and ongoing combination 
studies in adults.  Additional information may be found in the IB for trametinib and dabrafenib.
Pyrexia: Pyrexia was reported in clinical trials with dabrafenib monotherapy and in 
combination with trametinib. In dabrafenib monotherapy clinical studies, pyrexia was one of 
the most frequently occurring AEs in up to 27% of subjects across all dabrafenib studies. Most 
of the pyrexia events (64%) were considered to be related to study treatment. The incidence and 
severity of pyrexia are increased when dabrafenib is used in combination with trametinib. In 
patients who received the combination dose of dabrafenib 150 mg twice daily and trametinib 2 
mg once daily and developed pyrexia, approximately half of the first occurrences of pyrexia 
happened within the first month of therapy. About one-third of the patients receiving 
combination therapy who experienced pyrexia had 3 or more events. Pyrexia may be 
accompanied by severe rigors, dehydration and hypotension which in some cases can lead to 
acute renal insufficiency.
Serious non-infectious febrile events have been observed. These events responded well to dose 
interruption and/or dose reduction and supportive care in clinical trials. Subjects should be 
evaluated for signs and symptoms of infection and work up considered as clinically indicated.  
Dabrafenib must be held for fever of 38.5C or higher, and blood samples for an absolute 
neutrophil count (ANC) and serum creatinine must be drawn in the setting of fever.  Trametinib 
can be continued in subjects receiving combination therapy.  
Dermatological Effects
Cutaneous Squamous cell carcinoma (cuSCC): In vitro experiments have demonstrated a 
paradoxical activation of MAP-kinase signaling in keratinocytes and potentially other cells 
harboring a wild-type BRAF kinase but a mutated RAS kinase upon exposure to a BRAF 
inhibitor. This paradoxical MAP-kinase pathway activation is potentially associated with a 
higher risk for the development of squamous cell carcinoma induction.
Cases of cuSCC (which include those classified as keratoacanthoma or mixed keratoacanthoma 
subtype) have been reported in patients treated with dabrafenib in combination with trametinib. 


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In patients who received the combination dose of dabrafenib in combination with trametinib, 
cutaneous SCC (including keratoacanthoma [KA]) occurred in a lower percentage of subjects 
and events occurred later than with dabrafenib monotherapy, with the median time to onset of 
the first occurrence of 20 to 32 weeks as compared to approximately 8 weeks with dabrafenib 
monotherapy. Most patients on combination therapy who developed cuSCC continued on 
dabrafenib treatment without dose modification. Skin examination should be performed prior 
to initiation of dabrafenib and during treatment with dabrafenib, every 2 months throughout 
therapy. An additional examination should be considered 2 to 3 months after discontinuation of 
dabrafenib or until initiation of another anti-neoplastic therapy. Cases of cuSCC should be 
managed by dermatological excision and dabrafenib treatment should be continued without any 
dose adjustment. Patients should be instructed to immediately inform their physician if new 
skin lesions develop.
New primary melanoma: New primary melanomas have been reported in patients treated with 
dabrafenib. These were identified within the first 5 months of therapy and did not require 
treatment modification other than excision. Monitoring for skin lesions should occur as 
described for cuSCC.
Rash: Skin-related toxicities, primarily rash (maculopapular type rash with dabrafenib and 
acneiform-type rash with trametinib) have been reported with both trametinib and dabrafenib 
monotherapies. The incidence of skin-related events reported with the combination regimen 
appears to be lower than what has been observed following trametinib monotherapy. Rash 
management guidelines are provided in Section 3.13.3.
Hemorrhage: Major hemorrhagic events including fatal events can occur in patients receiving 
dabrafenib in combination with trametinib. Monitor for signs and symptoms of bleeding.
Venous Thromboembolism: Deep vein thrombosis and pulmonary embolism can occur in 
patients receiving dabrafenib in combination with trametinib.
Interstitial lung disease (ILD)/Pneumonitis: 
Pneumonitis has been observed in subjects receiving trametinib and trametinib in combination 
with dabrafenib.  To reduce the risk of pneumonitis, subjects will be monitored closely for 
symptoms, evaluated with imaging and functional tests if clinically indicated. No modification 
of dabrafenib is required when taken in combination with trametinib.
Pancreatitis – Pancreatitis has been observed in subjects receiving dabrafenib and dabrafenib 
in combination with trametinib. Subjects will be monitored for abdominal pain or suspected 
pancreatitis, amylase and lipase laboratory samples should be collected for confirmation of the 
diagnosis.
Hyperglycemia: Hyperglycemia requiring an increase in the dose of, or initiation of insulin or 
oral therapy can occur with dabrafenib. Serum glucose levels will be monitored as clinically 
appropriate during treatment with dabrafenib in subjects with pre-existing diabetes or 
hyperglycemia. 
Hepatic Events:


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Hepatic adverse events have been reported in clinical trials with trametinib as monotherapy and 
in combination with dabrafenib. 
Ocular effects: Both trametinib and dabrafenib have been associated with ocular toxicities 
which appear to be class effects, including papilledema, RPED, and RVO associated with 
trametinib, uveitis and iritis associated with dabrafenib. Please refer to Section 1.7.1 and Section 
3.13.5.
Decreased LVEF:  Left ventricular dysfunction was reported with trametinib as well as with 
other MEK inhibitors in clinical development. Please refer to Section 1.7.1 and Section 3.12.3.1. 
Non-cutaneous secondary/recurrent malignancy: In vitro experiments have demonstrated 
paradoxical activation of MAP-kinase signaling in BRAF wild type cells with RAS mutations 
which are 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 including dabrafenib, and with dabrafenib/trametinib combination 
therapy. Patients should be monitored as clinically appropriate.
Reproductive Effects: Dabrafenib may impair male and female fertility as adverse effects on 
male and female reproductive organs have been seen in animals given dabrafenib. In repeat 
dose studies, testicular degeneration/depletion was seen in rats and dogs (≥ 0.2 times the human 
clinical exposure based on AUC). Testicular changes in rat and dog were still present following 
a 4-week recovery period. Male subjects should be informed of the potential risk for impaired 
spermatogenesis, which may be irreversible.  In combined female fertility, early embryonic and 
embryofetal development studies in rats, numbers of ovarian corpora lutea were reduced in 
pregnant females at 300 mg/kg/day (approximately 3 times human clinical exposure based on 
AUC), but there were no effects on estrous cycle, mating or fertility indices. Developmental 
toxicity including embryo-lethality and ventricular septal defects were seen at 300 mg/kg/day, 
and delayed skeletal development and reduced fetal body weight at ≥20 mg/kg/day (≥0.5 times 
human clinical exposure based on AUC).  There are no adequate and well-controlled studies of 
dabrafenib in pregnant women.
2
Objective(s), Endpoint(s) and Hypothesis(es)
Table 2-1
Objective(s), Endpoint(s) and Hypothesis(es)
Objective
Endpoint
Hypothesis(es)
Primary
To determine the safe and tolerable 
trametinib dose(s) for chronic dosing in 
pediatric subjects (infants, children, and 
adolescents) that achieves similar 
exposures (C) to the recommended 
adult dose
Adverse Events (AEs); ECG; ECHO; 
changes in laboratory values and vital 
signs.  Steady state Cof trametinib
Infants, children and 
adolescents will tolerate 
doses of trametinib that 
achieve steady state
trough concentrations 
associated with clinical 
benefit in adults 
Secondary
To characterize the pharmacokinetics of 
trametinib 
C(trough), AUC(0-t), AUC(0-), 
apparent clearance following oral 


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Objective
Endpoint
Hypothesis(es)
dosing (CL/F) Cmax, tmax and Cavg, 
as appropriate  
To characterize the safety and 
tolerability of trametinib 
AEs; ECG; changes in laboratory 
values and vital signs
To assess any preliminary anti-tumor 
activity of trametinib
Tumor response to trametinib as 
defined in Appendix 3 through 
Appendix 7 will be assessed by 
investigator assessment.
To determine the effect of covariates 
such as age and weight on the 
pharmacokinetics of trametinib using a 
population pharmacokinetics approach
CL/F, volume of distribution (V/F), 
absorption rate (ka), and coefficients 
for significant covariates
To characterize the pharmacokinetics of 
trametinib and dabrafenib when 
administered in combination
C(trough), AUC(0-t), AUC(0-), 
apparent clearance following oral 
dosing (CL/F) Cmax, tmax and Cavg 
of trametinib and dabrafenib when 
administered in combination, if the 
data permit
To characterize the safety and 
tolerability of trametinib and dabrafenib 
when administered in combination
Adverse Events (AEs); ECG; ECHO; 
changes in laboratory values and vital 
signs.
To determine the safe and tolerable 
dabrafenib dose(s) when administered 
in combination with the recommended 
trametinib dose for chronic continuous 
daily dosing in pediatric subjects 
(infants, children and adolescents) that 
achieves similar exposures  to the 
recommended adult dose
Adverse Events (AEs); ECG; ECHO; 
changes in laboratory values and vital 
signs.  Steady state Cof trametinib; 
steady state AUC(0-12) of dabrafenib
To assess any preliminary anti-tumor 
activity of trametinib and dabrafenib 
when administered in combination
Tumor response to dabrafenib and  
trametinib combination as defined in 
Appendix 3 through Appendix 7 by 
investigator assessment.
To determine the acceptability and 
palatability of trametinib and dabrafenib 
in pediatric subjects
Palatability questionnaire data


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3
Investigational Plan
3.1
Discussion of Study Design
This is a 4-part (Part A, Part B, Part C, and Part D), Phase I/IIa, multi-center, open label study 
in pediatric subjects with refractory or recurrent tumors likely to have pathway activation and 
thus more likely to benefit from therapy.  The overall goal of this trial is to efficiently establish 
safe, pharmacologically relevant dose of trametinib in infants, children and adolescents and 
determine preliminary activity of trametinib monotherapy in selected recurrent, refractory or 
unresectable childhood tumors.  In addition, Part C and Part D of the study are designed to 
establish the safety, tolerability and activity of trametinib in combination with dabrafenib in 
children and adolescents with recurrent, refractory or unresectable BRAFV600E mutated 
tumors.

Part A will be a pharmacokinetically driven limited dose escalation in subjects with an 
expansion for safety, tolerability, and PK in three age ranges (1 month to <2years, 2 to
≤12 years, and over 12 years of age).  The primary goal of Part A is to establish the 
toxicity profile, PK, and recommended Phase 2 dose (RP2D) of trametinib in each age 
cohort.  Approximately 18 subjects will be accrued to the dose escalation phase and 18 
subjects to the age expansion phase (subjects less than 2 years of age will not be included 
in the initial dose escalation until the age specific cohorts are opened). 

Part A extension will be an age-specific dose exploration in up to 12 subjects aged 1 
month to < 6 years old. Preliminary PK analysis of pediatric patients in this current study 
suggests that for patients < 6 years old, an intermediate dose (i.e., 0.032 mg/kg/day) may 
increase the proportion of these patients who achieves exposures similar to adults. The 
goal of this additional dose exploration is to establish the safety, tolerability, PK and 
further refine the RP2D of trametinib in this younger age cohort. Part B will be an 
expansion study to further evaluate the safety, tolerability, and preliminary clinical activity 
of trametinib in tumor-specific pediatric populations.  Disease cohorts are selected based 
on current data of Ras/MAPK activation in childhood solid tumors.  Forty subjects are 
planned for Part B, 10 subjects in each of 4 disease cohorts. Part B will use the dose 
determined in Part A. 

B1: Refractory or relapsed neuroblastoma 

B2: Recurrent or unresectable low grade gliomas with BRAF tandem duplication with 
fusion

B3: Neurofibromatosis Type -1 associated plexiform neurofibromas (NF-1 with PN) 
that are unresectable and medically significant.

B4: BRAF V600 mutant tumors.

Part C will be a limited dose escalation of the combination of trametinib in combination 
with dabrafenib in children and adolescents with recurrent, refractory or unresectable 
BRAF V600 mutated tumors.  This part of the study will establish the RP2D of dabrafenib 
and trametinib when given in combination in children and adolescents. This part of the 
study, with a planned enrollment of up to 18 subjects with up to 6 adolescent subjects with 
BRAF V600 mutant metastatic melanoma, will not open until the dose of dabrafenib in 
children is established in study BRF116013, the dose of trametinib monotherapy is 




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Two interim analyses (IAs) are planned for decision making of future development options and 
the data may be used for publication. No decision regarding the conduct of this study will be 
made at IAs. The first IA will be performed after all subjects in Cohort B3 (NF-1 with PN) have 
been enrolled and have completed at least three post baseline tumor assessments or have 
discontinued treatment earlier. The second IA will be performed after all subjects have been 
enrolled in cohort D1 (LGG) and have completed at least 12 months of treatment or have 
discontinued treatment earlier. At the time of each IA, the data from other disease cohorts and 
study parts will also be analyzed. Safety and tolerability will be monitored closely on a 
continuing basis.
Final analysis will be performed at the time of study completion (see Section 6.5).
Supplementary study conduct information not mandated to be present in this protocol is 
provided in the accompanying Study Procedures Manual (SPM).  The SPM provides site 
personnel with administrative and detailed technical information that does not impact subject 
safety.
3.2
Part A: Trametinib Dose-Determination
Part A is a repeat dose, dose escalation monotherapy study that will identify the RP2D on the 
continuous dosing schedule using a 3 + 3 dose-escalation procedure.  The goal of the study is 
to find a RP2D based on PK criteria (PK target dose), defined as achieving in children a steady 
state (Day 15) mean trough concentration (C) of trametinib that is equivalent to a mean steady 
state (Day 15) trough concentration of 10 ng/mL trametinib observed in adults at the 
recommended dose of 2 mg once daily.
During dose escalation, children will be closely monitored for drug-related toxicity. If MTD is 
determined, the RP2D will be defined by the MTD rather than by PK criteria.
3.2.1
Trametinib Dose Levels
The starting dose of trametinib (0.0125 mg/kg/day) is 50% of the recommended fixed dose in 
adults (2 mg once daily) based on an 80 kg adult (Table 3-1).  In adults (n=2) after 15 days of 
continuous trametinib dosing (1 mg administered orally [PO] daily), the individual steady state 
Cwas 8.44 and 19.1 ng/mL.  The lowest trough concentration associated with an objective 
response in adults with melanoma was approximately 7 ng/mL; one complete response (1 mg 
dose) and one partial response (0.5 mg dose) were observed out of 12 subjects with Cof 7 
ng/mL.
The second dose level (0.025 mg/kg/day) is equivalent to the recommended dose in adults (2 
mg PO daily).  In adults (n=13) receiving this dose, the Day 15 mean steady state Cwas 12.1 
ng/mL (range 8.26-16.9; 95% CI=10.86-13.4).  In adults trametinib 2 mg PO daily on a 
continuous schedule is not associated with dose limiting toxicity and PK-PD modelling in adults 
with melanoma predict that 79% of subjects would exceed the mean target trough concentration 
over the entire dosing interval.
The third dose level (0.040 mg/kg/day) is equivalent to the MTD in adults (3 mg PO daily).


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In the absence of establishing a pediatric MTD, if the PK target (Day 15 C≥10 ng/ml) is not 
achieved at the maximum dose level of 0.04 mg/kg/day, safety and PK data will be examined 
to consider amending the protocol for inclusion of additional higher dose levels.
Table 3-1
Trametinib Dose Levels for Part A
Trametinib Oral Dosing
Dose Level 1 – Starting Dose
0.0125 mg/kg/day
Dose Level 2
0.025 mg/kg/day 
Dose Level 3
0.04 mg/kg/day
Additional Dose Levels
Protocol amendment to explore additional dose according to 
observed PK values relative to target concentrations 
3.2.2
Trametinib Dose Escalation
Subjects enrolled at each dose cohort will be observed for DLT during the first 28 days.
Dose escalation will occur according to Table 3-2 and will be determined by both toxicity and 
observed PK values.
DLT Criteria for Escalation:

Escalation may occur once the initial 3 subjects on Dose Level 1 or Dose Level 2 meet all 
of the following criteria: 

have completed the first 28 days, and

have completed PK sampling on Day 15, and

are evaluable for toxicity (received at least 75% of prescribed (21/28) doses), and

have not experienced DLT attributable to trametinib in the first 28 days

If one of the initial 3 subjects in the dose cohort experiences a DLT in the determinative 
period, the cohort will be expanded to 6 subjects.  Dose escalation may occur once all 6 
subjects at the current dose level meet all of the following criteria:

have completed the first 28 days, and

have completed PK sampling on Day 15, and 

are evaluable for toxicity (received at least 75% of prescribed (21/28) doses), and

no more than one subject (≤1/6) experienced a DLT attributable to trametinib during 
the first 28 days

If 2 or more of the initial 3-6 subjects enrolled at a dose level experience DLT, accrual 
will be suspended and the MTD will have been exceeded.
Table 3-2
Dose Escalation Procedure
Number of Subjects with DLT
Action
0 out of 3 subjects
Escalate to next dose level
1 out of 3 subjects
Accrue 3 additional evaluable subjects at current dose level for a total 
of 6 evaluable subjects
1 out of 6 subjects
Escalate to the next dose level
2 or more subjects in a dosing cohort 
(up to 6 subjects)
MTD has been exceeded.  Expand prior dose level to at least 6 
subjects 


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PK Criteria for Escalation:
Detailed PK sampling will be required on Day 15 for trametinib (see Section 7.4.1). Subjects 
who have a day 15 trametinib C<10 ng/mL will be considered to have failed to reach the PK 
target.  If more than 1 out of 3 to 6 patients at a dose level have failed to reach the PK target, 
and MTD criteria have not been met, dose escalation will continue.  The Day 15 trametinib Cτ 
of all subjects in a dose level cohort will be compared to the target C(10 ng/mL) in adults who 
were treated with the recommended dose in adults.  In the absence of an MTD, the RP2D will 
be the PK target dose defined as the dose that meets the PK criteria for adequate exposure (Day 
15 trametinib C≥10 ng/mL in at least 80% of subjects in a cohort of at least 6 subjects (i.e.; 
5/6 subjects) treated at that dose level (Appendix 9).
3.2.3
Dose Limiting Toxicity Definitions
The DLT evaluable population is defined as those subjects participating in dose determining 
portion of the study (Part A and 3+3 design portions of Part A extension, Part C and Part C 
extension)  fulfilling the ‘All Treated’ population criteria and having received at least 21 doses 
in the first 28 days to enable an appropriate evaluation of study treatment related DLTs.  
Subjects who are either withdrawn or dose reduced due to toxicity during the first 28 days will 
be included in the DLT evaluable population. Patients enrolled for only PK characterization 
(Part A extension, Part C, or Part C extension) or for the melanoma cohort in Part C will not be 
observed for DLTs.
If a subject is withdrawn before completing at least 75% of doses (at least 21 doses during the 
first 28 days of study treatment), for any reason other than toxicity, the subject will be replaced 
with the next available subject if escalation or de-escalation rules have not been fulfilled.
An AE will be considered a DLT if it is considered by the investigator to be at least possibly 
related to study treatment, meets any of the criteria listed in Section 3.2.3.1 or Section 3.2.3.2
and occurred during the first 28 days of treatment in the dose determining portion of the study 
(Part A and 3+3 design portions of Part A extension, Part C and Part C extension). DLTs will 
be reported to Novartis using the procedures outlined for reporting of SAEs and other events 
(Section 8.4.2).
3.2.3.1
Non-Hematological Dose Limiting Toxicity 

Any Grade 4 non-hematological toxicity with the exception of

Grade 4 fever/pyrexia that resolves to grade <2 within 72 hr with supportive care 
(anti-pyretics)

Any Grade 3 non-hematological toxicity with the specific exclusion of:

Grade 3 nausea and vomiting of less than 3 days duration,

Grade 3 fever or infection of less than 7 days duration,

Grade 3 hypophosphatemia, hypokalemia, hypocalcemia or hypomagnesemia 
responsive to oral supplements within 7 days,

Dose limiting hypertension will be considered as the following:

Grade 4 hypertension


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
Any Grade 2 non-hematological toxicity that persists for greater than or equal to 7 days 
and is considered medically significant or sufficiently intolerable by subjects that it 
requires treatment interruption.

Grade 2 allergic reactions that necessitate discontinuation of study treatment will not 
be considered a dose-limiting toxicity

Grade 2 left ventricular ejection fraction decrease (see Section 3.12.3.1)

Grade 2 cardiac valvular toxicity (mitral/aortic/tricuspid) (see Section 3.12.3.2)

Grade 2 diarrhea (see Section 3.13.4)

Grade 2 pneumonitis (see Section 3.13.7)

Treatment interruption longer than 14 days due to delayed recovery from toxicity will be 
dose limiting.  Treatment delays for non-hematological toxicity (Section 3.6) that exceed 
28 days meet the criteria for permanent discontinuation of study treatment (Section 6.3).
3.2.3.2
Hematological Dose Limiting Toxicity

Any hematologic toxicity requiring treatment interruption for greater than 14 days or 
requires a dose reduction.  Treatment delays for hematological toxicity (Section 3.6) that 
exceed 28 days meet the criteria for permanent discontinuation of study treatment (Section 
6.3).

Grade 4 neutropenia on 2 consecutive measurements at least 72 hr apart (continue study 
treatment for first measurement of Grade 4 neutropenia, recheck within 72 hr, if Grade 4 
neutropenia confirmed then hold study treatment and declare as DLT)

Grade 4 thrombocytopenia or Grade 3 thrombocytopenia requiring platelet transfusion 
(exception: prophylactic platelet transfusions for platelet count ≥25,000 administered prior 
to procedures will not be considered dose limiting)

Grade 4 anemia 

Grade 3 or 4 hemolysis 

Grade ≥3 leukopenia is not a dose-limiting toxicity in the absence of dose-limiting 
neutropenia (see above).

Grade ≥3 lymphopenia will not be considered dose limiting.

Grade ≥3 decrease in hemoglobin that can be corrected to at least 8.0 g/dL (Grade 2) by 
transfusion of red blood cells is not a dose-limiting toxicity
Maximum Tolerated Dose
The MTD is the highest dose at which no more than 1 out of 6 subjects (or < 33%) experience 
DLT during the first 28 days of therapy.  If 2 or more subjects in a dosing cohort of 3-6 subjects 
(or ≥ 33%) experience DLT, the MTD has been exceeded.
3.2.4
Part A: Age Group Expansion
Following the initial 3+3 dose escalation (Section 3.2.2), the dose will be confirmed and 
evaluated in the following specific age groups (age on day of consent):

Infants and toddlers (age 1 month to <2 years).


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
Children (age 2 to ≤12 years).

Adolescents (age >12 years to <18 years).
Note: For the purposes of this study, age 12 is considered to be the day of a subject’s 12th
birthday. The day after the 12th birthday, a subject is considered to be greater than 12 years.
Approximately 4 to 6 subjects may be enrolled in each age group and treated at the dose 
determined in the 3+3 escalation. Subjects in the age expansion cohorts will continue to be 
monitored for DLTs and PK as described for the initial dose escalation in Part A. The goal of 
the age expansion cohorts is to confirm the RP2D for each age group.
If the criteria for MTD are not met, and less than 80% of subjects in any age group (out of all 
subjects treated at that dose in that age group) achieve trametinib C≥10 ng/mL, subjects in 
that age cohort may not be enrolled on Parts B or C until the study sponsor and study team 
review all available safety and PK data.
Effect of sample size and PK sampling scheme on characterization of trametinib PK 
A modeling and simulation exercise was undertaken to assess the effect of sample size (N=4 
versus N=5 versus N=6 patients) and PK sampling scheme (5 versus 8 PK samples per patient) 
needed to estimate with adequate precision trametinib clearance (CL/F) and central volume of 
distribution (Vc/F) in pediatric patients.  Two hundred studies each were simulated in 4 different 
age groups (i.e. 1 month-12 months, >12 months to < 2years, 2-12 years and >12 to <18 years) 
with varying body weight ranges and PK sampling schemes.  As trametinib is metabolized 
predominantly via deacetylation (non-CYP450 mediated) alone or with mono-oxygenation or 
in combination with glucuronidation biotransformation pathways, a maturation factor (applied 
to lowest age group) in addition to allometric scaling was utilized to predict trametinib 
exposures in pediatric patients.  The 60 and 140% CIs around the adult mean CL/F and Vc/F 
parameters from the final population PK model developed in BRAF-mutation melanoma were 
calculated and considered the pre-specified “goal posts” for comparison to the pediatric data.  
Results of this analysis suggest that for all three sample sizes evaluated (i.e.  N=4 versus N=5 
versus N=6 patients) with either 5 or 8 PK samples per patient, 80% of the pediatric data for 
CL/F fell within the adult pre-specified “goal-posts”.  These results suggest that the study would 
have 80% power to meet the 60 to 140% criterion for CL/F in all age groups to be studied with 
either PK sampling scheme.  However, for Vc/F, regardless of sample size or PK sampling 
scheme, the study would not be adequately powered in each age group to be studied.  Given the 
long elimination half-life of trametinib (~ 5 days), this is likely due to the limited PK sampling 
schemes utilized as input into the model.  In spite of these results for pediatric Vc/F, possible 
dose adjustments in the pediatric population would most likely be based on CL/F.   Therefore, 
PK sampling schemes of 8 PK samples per patient (i.e. ≥10 kg and above) and 5 PK samples 
per patient (<10 kg) for sample sizes between N=4-6 patients were incorporated into Part A of 
the pediatric protocol for trametinib.
DLT and MTD monitoring during expanded age cohorts
In any age cohort of 4 to 6 subjects, if the MTD is exceeded (≥2 subjects experience DLT in 
the first 28 days in that age cohort), accrual in all age cohorts will be suspended until all subjects 


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are fully evaluable for toxicity during the first 28 days and the sponsor and study team review 
safety data for all age cohorts.

If ≥33% of all enrolled subjects, regardless of age, have had a DLT during the first 
28 days, all additional subjects, regardless of age, will be enrolled at a lower dose level.  If 
this review occurs at Dose Level 1, accrual will be suspended to all subjects until review 
of safety and PK data are complete.

If <33% of all enrolled subjects, regardless of age, experience a DLT during the first 
28 days, then dose reduction will occur only in the age group where a DLT was reported.  
Up to 6 additional subjects in that age group will be accrued and treated at a lower dose 
level.  If this review occurs at Dose Level 1, accrual will be suspended to subjects in that 
age group until review of safety and PK data are complete.
Determination of the RP2D for each age group is independent of the other age groups. After the 
RP2D for any age group has been determined, enrollment into Parts B and C for that age range 
may begin even if dose determination is still ongoing in a different age group.
3.2.5
Definition of Recommended Phase 2 Dose (RP2D) of Trametinib
The RP2D is established by age groups (1 mo-<2 years, 2 years to ≤12 years, >12 years of age) 
as the dose level at which <33% of subjects in the age group experience DLT and >80% of 
subjects in the age group have trametinib C≥10 ng/mL.
3.2.6
Part A Extension: Intermediate Trametinib Dose Exploration
Preliminary trametinib PK analysis of 52 patients at the 0.025 mg/kg/day dose level from Parts 
A, B and C of this study (data cut-off 31-Oct-2016) indicated that the median trametinib Cwas 
8.2 ng/mL (< 10 ng/mL) in patients < 6 years old, whereas the median trametinib Cwas 11.7 
ng/mL in patients 6 years of age and older. A dose of 0.04 mg/kg/day exceeded the MTD and 
was not well tolerated across age categories. An intermediate dose of 0.032 mg/kg/day will be 
explored in patients under 6 years of age in an effort to achieve a Csimilar to that achieved in 
adults (> 10 ng/mL) without exceeding the MTD in this age group. This is the only additional 
dose level intended for this age group. Using the DLT definition provided in Section 3.2.3 RP2D 
will be declared based on safety and tolerability. The 0.032 mg/kg/day dose may replace the 
previously determined RP2D of 0.025 mg/kg/day for trametinib monotherapy for patients under 
6 years of age. 

Initially, three patients will be enrolled at the intermediate dose level (0.032 mg/kg/day) 
and observed for DLT (dose determining cohort).  

If 0 DLTs are noted, then 0.032 mg/kg/day will be declared the new trametinib 
monotherapy RP2D for patients under 6 years of age, and 9 more patients enrolled to 
further characterize the PK of this dose in this age group.  

If 1 DLT is observed in the initial 3 patients, then three additional patients will be enrolled 
into the dose determining cohort.  If no additional DLTs are observed (i.e., a total of 1 
DLT in first 6 patients), then 0.032mg/kg/day will be declared the RP2D for trametinib 
monotherapy for patients under 6 years of age, and 6 more patients will be enrolled to 
further characterize the PK of this dose in this age group.  


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
If 2 or more DLTs are observed in the first 3 (or 6) patients in the dose determining 
cohort, no further patients will be enrolled at that dose and 0.032 mg/kg/day will have 
exceeded the MTD, and 0.025 mg/kg/day will be confirmed as the RP2D for trametinib 
monotherapy in this age group.
PK samples will be collected on Day 15 and Day 22.
3.3
Part B:  Tumor-Specific Expansion
Part B will evaluate the safety, tolerability, and preliminary activity of trametinib monotherapy 
in 4 disease-specific cohorts of subjects.  Each cohort will enroll at least 10 response-evaluable 
subjects (evaluable for response is defined as a subject with a pre-dose and at least 1 post–dose 
disease assessment or clinical assessment of progression of disease). 
PK samples will be collected on Day 15 only.
Archived or fresh tumor tissue to confirm BRAF V600 (cohort B4) 
 
 is required from all subjects at screening, unless the patient is specifically 
exempt from the requirement for histologic confirmation (e.g. NF-1, some brainstem gliomas 
(refer to inclusion criteria)).  If tissue is unavailable, from non-exempt patients, then enrollment 
is not permitted.
Blood samples for clinical laboratory tests will be collected throughout the study, and safety, 
tolerability and clinical activity assessments will be conducted according to the Time and 
Events Tables (Section 7.1).
Trametinib will be continued until disease progression, until subjects are no longer obtaining 
clinical benefit from continued treatment, until they develop an unacceptable toxicity, or until 
they withdraw consent, begin a new anti-cancer therapy, or the Sponsor terminates the study.  
At the end of treatment, a final study visit will occur.  Additional details on subject completion 
are provided in Section 6.2.
3.4
Part C: Trametinib in Combination with Dabrafenib
Part C will be a 3+3 study design to determine the safety, tolerability and preliminary activity 
of the RP2D of trametinib in combination with a limited dose escalation of dabrafenib (50% of 
pediatric RP2D and 100% RP2D).  Part C will enroll up to 24 subjects aged 1 to <18 years with 
recurrent or refractory malignant solid tumors harboring a V600 mutation.
Amendment 3 provides information from the pediatric Phase 1 study of dabrafenib 
(BRF116013), which has established the recommended dabrafenib dose in children and 
provides relevant safety information for dabrafenib monotherapy in children and 
dabrafenib/trametinib combination therapy in adults. Once Part A of this study has been 
completed for at least one of the three age specific cohorts, enrollment into Part C will 
commence. Enrollment for Part C will close upon enrollment of 18 non melanoma pediatric 
patients and up to 6 BRAF V600 mutant melanoma patients or 36 months from the time Part C 
was opened for enrollment, whichever should come first. 
PK samples will be collected on Day1, Day 15, and Day 22.


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Blood samples for clinical laboratory tests will be collected throughout the study, and safety, 
tolerability and clinical activity assessments will be conducted according to the Time and 
Events Tables (Section 7.1).
Study treatment will be continued until disease progression, until subjects are no longer 
obtaining clinical benefit from continued treatment, until they develop an unacceptable toxicity, 
or until they withdraw consent, begin a new anti-cancer therapy, or the Sponsor terminates the 
study.  At the end of treatment, a final study visit will occur.  Additional details on subject 
completion are provided in Section 6.2.
3.4.1
Part C Extension: Intermediate Trametinib Dose Exploration with 
Dabrafenib
A total of 6 patients under 6 years of age will be enrolled in this extension part.
If the trametinib dose of  0.032 mg/kg/day is tolerated in Part A extension, a combination of 
trametinib 0.032mg/kg/day and full dabrafenib RP2D will be tested in this extension part in a 
3+3 study design to determine the RP2D of trametinib in combination with dabrafenib for 
patients < 6 years of age. 

Initially three patients will be enrolled at trametinib 0.032 mg/kg/day and full dabrafenib 
RP2D and observed for DLT (dose determining cohort).  

If 0 DLTs are noted, then 0.032/mg/kg/day will be declared the new trametinib RP2D in 
combination with dabrafenib (full RP2D) for patients under 6 years of age, and 3 more 
patients will be enrolled to further characterize the PK of this dose in this age group.  

If 1 DLT is observed in the initial 3 patients, then 3 additional patients will be enrolled 
into the dose determining cohort.  

If no additional DLTs are observed (i.e., a total of 1 DLT in 6 patients), then 
0.032/mg/kg/day will be declared the trametinib RP2D in combination with 
dabrafenib (full RP2D) for patients under 6 years of age.  

If 2 or more DLTs are observed in these 6 patients, 0.032 mg/kg/day will have 
exceeded the MTD, and 0.025 mg/kg/day will be confirmed as the trametinib RP2D 
in combination with dabrafenib (full RP2D) for this age group. 

If 2 or more DLTs are observed in the initial 3 patients, 0.032 mg/kg/day will have 
exceeded the MTD, and 0.025 mg/kg/day will be confirmed as the trametinib RP2D in 
combination with dabrafenib for this age group. The remaining three patients allocated for 
this part will be enrolled  at trametinib 0.025 mg/kg/day and full dabrafenib RP2D to 
further characterize the PK. 
If the trametinib dose of  0.032 mg/kg/day is not tolerated in Part A extension, 0.025 mg/kg/day 
will be confirmed as RP2D for trametinib monotherapy and for use in combination with 
dabrafenib in this age group. The 6 patients allocated for this extension part will be enrolled  at 
trametinib RP2D (0.025 mg/kg/day) and full dabrafenib RP2D to further characterize the PK in 
this age group. 
PK samples will be collected on Day 1, Day 15, and Day 22.


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3.5
Part D: Tumor-Specific Expansion of Trametinib in Combination 
with Dabrafenib
Part D will evaluate the safety, tolerability, and preliminary activity of the combination of 
trametinib and dabrafenib in 2 disease-specific cohorts in patients from 12 months to less than 
18 years of age. BRAF V600-mutant LGG cohort will enroll approximately 20 subjects and 
BRAF V600-mutant LCH cohort will enroll approximately 10 subjects. 
At the time of Amendment 5 release, RP2D of trametinib and dabrafenib combination has been 
established in Part C in children and adolescents ages 6 years to <18 years. Patients who are 6 
to < 18 years old will start enrolling in Part D in parallel with the testing of the additional dose 
level of trametinib in Part A extension, (patients aged 1 month to < 6 years) and then in Part C 
extension, (patients aged 12 months to <6 years). Once the RP2D of trametinib and dabrafenib 
combination is determined for patients <6 years in Part C extension (or in Part A extension), 
Part D will start enrolling patients aged 12 months to <6 years. 
Archived or fresh tumor tissue to confirm BRAF V600 is required from all subjects at screening. 
If tissue is unavailable, then enrollment is not permitted.
PK samples will be collected on Day 1, Day 15, and Day 22.
Blood samples for clinical laboratory tests will be collected throughout the study, and safety, 
tolerability and clinical activity assessments will be conducted according to the Time and 
Events Tables (Section 7.1).
Study treatment will be continued until disease progression, until subjects are no longer 
obtaining clinical benefit from continued treatment, until they develop an unacceptable toxicity, 
or until they withdraw consent, begin a new anti-cancer therapy, or the Sponsor terminates the 
study.  At the end of treatment, a final study visit will occur. Additional details on subject 
completion are provided in Section 6.2.
3.6
Criteria for Continuing in the Study
For subjects enrolled on Part A, Part B, Part C, and Part D, the following criteria must be met 
to advance beyond the first 28 days:

Subjects have not met discontinuation of treatment criteria (Section 6.3)

No evidence of progressive disease (See Section 7.6) defined as no clinical evidence of 
progression for assessments that do not require imaging/disease assessment or no evidence 
of radiographic or histologic/morphologic progression if disease assessment included 
imaging (solid tumor) 
Patients will be permitted to continue study treatment beyond initial Investigator-assessed 
disease progression, 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.  For this determination, the investigator should consider all relevant 
data, such as:


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
Absence of symptoms and signs of progressive disease 

No decline in performance status 

Absence of rapid progression of disease or of progressive tumor at critical 
anatomic sites (e.g., cord compression) that would require urgent medical 
intervention. 

Patient/guardian is willing to continue on the study
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 the appropriate Time and Events Tables (Section 7.1 table.

After each tumor assessment, the investigator must confirm if the patient is still 
benefitting from study treatment, and document this in patient medical records. Toxicity 
resolved to baseline or grade ≤ 2 with specific exception of:

Specific criteria for Ejection Fraction Results (Section 3.12.3).

For subjects in Part B who are not evaluable for hematological toxicity due to 
marginal bone marrow function from disease infiltration or prior therapy, the 
following hematologic criteria must be met:

Absolute neutrophil count > 500 cell/L,

Platelet count > 25,000/L (without transfusion in ≥ 7 days),

No life threatening consequences of anemia (no grade 4 anemia per NCI-CTCAE 
v4.03) (NCI 2009).
3.7
Intra-subject Dose-Escalation
3.7.1
Part A: Intra-subject Dose Escalation
For subjects enrolled on Part A, an individual subject’s dose level may be increased up to the 
RP2D in the appropriate age cohort if the subject has (all of the following must be true):

completed at least 56 days of treatment,

Cis less than 10 ng/mL,

not experienced a drug related toxicity greater than Grade 2,

met criteria for continuation of study treatment (Section 3.6),

approval was obtained from a Medical Lead.
Subjects who meet criteria for intrasubject dose escalation will repeat evaluations for the first 
28 days (See Section 3.2.2), including Day 15 PK.
No subject may dose escalate beyond the RP2D or currently evaluated dose for their age group.  
No subject may have the dose of trametinib escalated above 0.04 mg/kg/day.
For individual subjects who meet criteria for intrasubject dose escalation, data from the 
escalated dose will not contribute to the definition of MTD or to establishing the recommended 
dose but will be summarized in the study toxicity data reporting.  Data from subjects who are 
able to increase their dose may be incorporated into PK-PD modelling.


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3.7.2
Part B Intra-subject Dose Escalation
For subjects ages below 6 years enrolled in Part B at 0.025 mg/kg/day dose level, an individual 
subject’s trametinib dose level may be increased up to 0.032 mg/kg/day if this dose is found to 
be tolerated in Part A extension and if the subject has (all of the following must be true):

completed at least 56 days of treatment,

not experienced a drug related toxicity greater than Grade 2,

met criteria for continuation of study treatment (Section 3.6),
Subjects who meet criteria for intra-subject dose escalation and receive the higher dose may 
continue to follow the time and event table using the originally assigned study day 1
Subjects may be allowed to re-escalate following dose reduction for AE upon resolution of AE. 
Please follow guidelines in Section 3.13.
3.7.3
Part C Intra-subject Dose Escalation
For subjects ages below 6 years enrolled in Part C at 0.025mg/kg/day trametinib dose, an 
individual subject’s trametinib dose level may be increased up to 0.032 mg/kg/day if this dose 
is found to be tolerated in Part C extension and if the subject has (all of the following must be 
true):

completed at least 56 days of treatment,

not experienced a drug related toxicity greater than Grade 2,

met criteria for continuation of study treatment (Section 3.6),
For subjects enrolled in Part C at Dose Level 1, an individual subject’s dabrafenib dose may be 
increased to Dose Level 2 (full dabrafenib RP2D) if the subject has (all of the following must 
be true):

completed at least 56 days of treatment,

not experienced a drug related toxicity greater than Grade 2,

met criteria for continuation of study treatment (Section 3.6),
Subjects who meet criteria for intra-subject dose escalation and receive the higher dose may 
continue to follow the time and event table using the originally assigned study day 1
Subjects may be allowed to re-escalate following dose reduction for AE upon resolution of AE. 
Please follow guidelines in Section 3.13, Section 3.14 and Section 3.15.
3.7.4
Part D Intra-subject Dose Escalation
Subjects may be allowed to re-escalate following dose reduction for AE upon resolution of AE. 
Please follow guidelines in Section 3.13, Section 3.14 and Section 3.15. 


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3.8
Study Schematics
Figure 3-1
Trametinib Dose Escalation (Part A)
Figure 3-2
Trametinib Disease Specific Expansion (Part B)
Note: A minimum of four subjects age younger than 6 years old is required in each of the four groups.


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Figure 3-3
Trametinib in Combination with Dabrafenib (Part C)
Figure 3-4
Tumor-Specific Expansion of Trametinib in Combination with 
Dabrafenib (Part D)


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Figure 3-5
Additional Dose Exploration (Part A Extension and Part C Extension)
*Note:  Part D design for 6 years to <18 years old patients is provided in Figure 3-4
3.9
Rationale
3.9.1
Rationale for Study
Despite the advances made over the past 30 years in the treatment of pediatric cancer, there 
remain important subpopulations within this group of patients for whom efficacious therapies 
have yet to be discovered.  Specifically, pediatric patients with recurrent high grade gliomas, 
and patients with metastatic or recurrent solid tumors, continue to have a poor prognosis and 
lower rates of long-term survival than patients with localized or non-recurrent disease.  Use of 
second- and third-line cytotoxic chemotherapies, even in dose-intensive regimens, has yet to 
yield significant impact on progression-free survival or overall survival. Therefore development 
of new therapeutic options for pediatric cancer patients is needed.
3.9.2
Rationale for Populations
Trametinib is FDA approved for the treatment of adults with BRAF V600 mutant-positive 
malignant melanoma that is unresponsive to standard therapies or for which there was no 
approved or curative therapy.  Preliminary data from ongoing studies of trametinib in adult 
subjects with other advanced solid tumors (e.g., pancreatic cancer) as well as results from other 
MEK inhibitor clinical programs, suggest that trametinib may have beneficial effects in tumour 


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types beyond melanoma.  Trametinib is being proposed for study in pediatric subjects with 
advanced solid tumors, with a focus on those that have been reported in the medical literature 
to potentially involve activation of the RAS/RAF signalling pathway.  These include tumors 
positive for BRAF V600 mutation, BRAF gene duplication (e.g., juvenile pilocytic astrocytoma, 
low grade gliomas); NF-1 related PN; and neuroblastoma.
Part A and B of this study will focus on development of trametinib monotherapy in infants, 
children and adolescents with advanced or relapsed/recurrent solid tumour types that may 
involve activation of the RAS/RAF/MEK signalling pathway.
A concurrent study of dabrafenib in pediatric subjects with BRAF V600 mutation positive 
tumors is ongoing.  Recent data from adult studies indicate that the combination of trametinib 
with dabrafenib is well tolerated and may provide more benefit to subjects with BRAF V600 
mutation in tumors.  Therefore, subjects with BRAF V600 mutation in tumors may be enrolled .
Part C and D of this study will focus on development of trametinib and dabrafenib combination 
therapy in children and adolescents with BRAF V600 mutation positive tumors.
3.9.3
Rationale for Dose
3.9.3.1
Trametinib
The targeted dose and schedule of trametinib is based on the adult clinical dose and schedule
required to achieve therapeutic benefit in BRAF mutant melanoma.  In adults, the mean (range) 
AUC(0-τ) following repeat dosing of 1 and 2 mg once daily was 175 ng•hr/mL (107-243 
ng•hr/mL) and 360 ng•hr/mL (204-536ng•hr/mL), respectively.  The mean (range) C
following repeat dosing of both the 1 and 2 mg once daily doses were 13.8 (n=2, 8.44 and 19.1 
ng/mL) and 12.1 ng/mL (n=13, 8.3-16.9 ng/mL, CV=19%, 95%CI=10.86-13.4), respectively. 
The lowest Cconcentration associated with an objective response was approximately 7 ng/mL, 
where 1 complete response (CR) (1 mg dose) and 1 partial response (PR) (0.5 mg dose) were 
observed of 12 subjects with Cof 7 ng/mL.
Given the safety and tolerability observed at the adult dose of 2 mg once daily and the variability 
associated with the mean adult trough concentration (95%CI=10.86-13.4), therapeutic benefit 
in pediatric subjects may be achieved by attaining trough concentration at steady state (day 15 
C≥ 10 ng/mL) that is similar to those achieved in adults at the recommended dose. In the 
absence of DLT,  if the PK exposure (C) is significantly lower than those achieved in adults, 
higher doses for subsequent cohorts may be modified in a protocol amendment in order to 
achieve PK target during dose escalation.
The starting dose in the pediatric population will be based on 1 mg as given to average 80 kg 
adult subject (0.0125 mg/kg) which is 50% of the recommended and FDA approved dose in 
adults.  Steady state trough concentration (Cycle 1 Day 15 C(trough) data for trametinib from 
adults will be compared to PK data in the pediatric subjects and will guide pediatric dose 
recommendations.  Exposure and Day 15 Cwill be assessed in-stream during the study.  PK 
sampling at day 15, modelling and simulation will allow prediction of trametinib dosage 
regimens for children that will deliver target trametinib steady-state concentrations and 
exposure similar to adults.


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Three dose levels are planned in pediatric subjects.  In the absence of DLT, if the PK exposure 
is significantly lower than those achieved in adults,, higher doses for subsequent cohorts may 
be modified in a protocol amendment in order to achieve PK target during dose escalation.
Since the approval and implementation of Amendment 3, the dose of 0.04 mg/kg/day was found 
to result in DLTs and 0.025 mg/kg/day was established as the RP2D of trametinib in Parts B 
and C based on safety and tolerability. Based on preliminary trametinib PK analysis in patients 
at the selected dose of 0.025 mg/kg in Parts A, B and C (data cut-off 31-Oct-2016), the median 
trametinib Cwas 8.2 ng/mL in patients < 6 years (Table 3-3). Due to this trend of lower 
trametinib exposure in patients < 6 years, an intermediate dose of 0.032 mg/kg/day may achieve 
exposures that are similar to those in adults. This dose will be explored as single agent first. If 
safety and tolerability permit, this dose will be tested in combination with dabrafenib. 
Table 3-3
Median trametinib PK (Day 15) by age groups  
Age Range
Dose (mg/kg)
N
Ctrough (ng/mL)
< 6 years
0.025
22
8.2
6-17 years
0.025
30
11.7
Age-related anatomical and physiological changes occur in the first 6 months to 24 months that 
may affect drug absorption and disposition.  This study will evaluate appropriateness of weight 
based dosing across three age groups; those less than 2 years of age, those 2 years of age to 12 
years of age (inclusive), and those over 12 years of age up to  <18 years of age.
3.9.3.2
Starting dose for Part C, Trametinib in Combination with Dabrafenib
In adults the recommended dose of trametinib in combination with dabrafenib is the full adult 
monotherapy dose of each: trametinib 2 mg PO daily and dabrafenib 150 mg PO twice daily.  
In the context of this clinical trial, the trametinib dose administered in Part C will be the 
trametinib monotherapy RP2D from Part A. The monotherapy RP2D of dabrafenib in children 
was established on a separate trial (BRF116013).  The following RP2D doses were determined 
for dabrafenib:

< 12 years old subjects: 5.25 mg/kg/day dabrafenib administered orally, divided into two 
equal doses 

≥ 12 years old subjects: 4.5 mg/kg/day dabrafenib administered orally, divided into two 
equal doses
For the evaluation of combination therapy on this trial, the starting dose of dabrafenib (Dose 
Level 1) will be 50% of the RP2D, divided into two equal doses. If tolerated a single dose 
escalation to the full dabrafenib RP2D (Dose Level 2) will be evaluated. If dose levels proposed 
are not well tolerated, intermediate dose levels of dabrafenib and/or trametinib may be evaluated 
if warranted.


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Table 3-4
Recommended dabrafenib dose levels
Dose Level
Dabrafenib
Trametinib
< 12 years
≥ 12 years
All ages
1 (Starting dose)
2.63 mg/kg/d
2.25 mg/kg/d
RP2D
2
5.25 mg/kg/d
4.5 mg/kg/d
RP2D
The RP2D for trametinib monotherapy determined in Part A extension for patients aged 1 month 
to < 6 years (either 0.025 mg/kg/day or 0.032mg/kg/day) along with full dabrafenib RP2D will 
be the starting dose for Part C extension patients (aged 12 months to <6 years).
3.9.3.3
Starting dose for Part D, Trametinib in Combination with Dabrafenib
Based on safety, tolerability and PK, the dose of trametinib and dabrafenib in patients 6 years 
to <18 years will be the RP2D (0.025mg/kg/day trametinib and full RP2D of dabrafenib) 
already determined from Part C. For patients <6 years old, the trametinib dose will be 
determined from Part C extension (or Part A extension) and will be either 0.025 mg/kg/day or 
0.032 mg/kg/day. The selected dose of trametinib will then be combined with the full RP2D of 
dabrafenib (100% of monotherapy dose) in patients under 6 years of age, just as in other age 
groups.  Patients who are 6 to < 18 years old will start enrolling in Part D in parallel with the 
testing of the additional dose level of trametinib in Part A extension, (patients aged 1 month to 
< 6 years) and then in Part C extension, (patients aged 12 months to <6 years).
The safety of the combination of trametinib and full dose dabrafenib has been confirmed in 
adults and pediatrics.  Similar to other age groups, the dose of 0.025 mg/kg/day trametinib was 
tolerated with full dose dabrafenib (5.25 mg/kg/day) in patients under 6 years of age in Part C. 
The dose of 0.032 mg/kg/day trametinib will be brought forward into Part D for patients under 
6 years of age only if it is shown to be safe when given as monotherapy in Part A extension and 
as combination therapy in Part C extension.
3.9.4
Rationale for Endpoints
This study will be the first administration of trametinib to pediatric subjects.  Safety parameters 
will be carefully and systematically monitored.
Part A: The expectation is that a PK endpoint will help define a dose that will provide an 
efficacious exposure in pediatric subjects without the need to reach maximum toxicity levels. 
In the absence of DLT in this pediatric study, a PK target endpoint will be used as the primary 
endpoint for dose determination.  In adults, there is minimal intersubject variability in the steady 
state C(CV 19%, 95%CI=10.86-13.4), and responses were observed at exposures as low as 
C= 7 ng/mL in subjects with melanoma, while efficacy has been clearly identified at known 
plasma levels of study drug (≥10 ng/mL trough) which were well tolerated. However, safety 
will be carefully reviewed and DLT definitions are incorporated in the protocol should safety 
in pediatric subjects differ from those in adult subjects following treatment with trametinib.
Part A extension: Based on preliminary PK data from Parts A, B and C, there was a trend for 
lower trametinib exposure in patients < 6 years old. An intermediate dose that is between the 
RP2D established in Part A and the higher dose that exceeded MTD will be explored. Safety, 
tolerability and PK are the primary endpoints of this part of the study. 


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Part B: The RP2D established in Part A and verified by age cohorts (1 month to <2 years, 2 
years to ≤12 years and >12 years) will be administered in Part B.  Safety, tolerability and 
preliminary activity assessed by investigator are the primary endpoints of this part of the study..
Part C: Subjects will be monitored for DLT and toxicity using the same DLT criteria as in Part 
A. Safety, tolerability and preliminary activity are the primary endpoints of this part of the study.  
In the absence of DLT, dose escalation will not exceed the trametinib monotherapy RP2D in 
combination with the dabrafenib monotherapy RP2D.
Part C extension: If Part A extension indicates trametinib 0.032mg/kg/day is tolerated in 
patients < 6 years old, the same trametinib dose will be explored in Part C extension with full 
dabrafenib RP2D. Safety, tolerability and PK are the primary endpoints of this part of the study. 
Part D: Safety and tolerability are the primary endpoints of this part of the study.
3.10
Study Treatment
3.10.1
Treatment Assignment
Subjects will be identified by a unique subject number that will remain consistent for the 
duration of the study.  Each site will be given a subject number range.  These ranges and details 
regarding assignment of subject numbers can be found in the SPM.
Treatment will not be randomized; nonetheless, each subject will be assigned a randomization 
number as described in SPM.
At the time of enrollment, subjects will be assigned to one part of the study designated Part A 
or Part B or Part C or Part D.  Individual subjects will participate in the specified part of the 
study, however, data analysis may combine parts of the study. For example, all subjects treated 
at the trametinib RP2D dose in Part A will contribute to age expansion in Part A of the study. 
Response evaluations in subjects in Part A of the study at the RP2D will be considered in 
analysis of Part B for specific disease cohorts.
3.11
Dosage and Administration of Study Treatments
3.11.1
Trametinib
Please note that study drug dispensed to subjects in the original container should not be 
repackaged without explicit permission from the Sponsor. Trametinib is administered orally 
once daily under fasting conditions, either 1 hr before or 2 hr after a meal.  Subjects should be 
encouraged to take trametinib approximately 24 hours apart at the same time each day. Dose 
levels are provided in Section 3.2.1.
Ideally, patients will take the trametinib study drug in the morning up through the PK day.  After 
the PK day, the patient may change to evening dosing, if they prefer.  If the patient is on an 
evening dosing regimen as they enter the PK testing period, the evening dose prior to the PK 
day SHOULD BE taken by the patient.  In all cases, the timing of the dose prior to the PK 
sampling must be maintained and recorded accurately.


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For trametinib tablets, it is recommended that subjects drink approximately 4 to 6 mL of 
water/kg body weight with each dose.
Trametinib pediatric oral solution formulation will be administered with a graduated syringe.  
It is recommended that subjects drink 4 to 6 mL of water/kg body weight following dosing.
A dosing nomogram (see Appendix 2) based on weight and dose level will be used to prescribe 
trametinib to minimize inter-subject dosing variability.  If a subject vomits after taking study 
medication, the subject should be instructed not to retake the dose and should take the next 
scheduled dose.  If a subject misses a dose, subject should not double the next regularly 
scheduled dose.  However, subject can take the missed dose immediately if the next scheduled 
dose is at least 12 hr later.  Subject should take the next dose at its usual time.
The total daily trametinib dose should not exceed the adult dose (2mg) in any subject.
Refer to Section 3.13, Section 3.14 and Section 3.15 for dose modifications for toxicity.
3.11.2
Dabrafenib
Please note that study drug dispensed to subjects in the original container and should not be 
repackaged without explicit permission from the Sponsor.
Capsules:  Dabrafenib capsules will be supplied by Novartis (for subjects able to reliably and 
consistently swallow capsules). For capsule administration, only 50 mg and 75 mg dose 
strengths are available. Therefore, the dose recommendations by weight range are within 20% 
of the ideal dose. The same dosing recommendation was applied to the suspension nomograms, 
at the same weight ranges that overlap with the capsule nomograms.
.
Dispersible tablets: Dabrafenib will be supplied by Novartis as dispersible tablets. The tablets 
will be  dispersed  with a specified volume of water at the time of use to form a suspension. 
Administration will be performed using a dosing cup / PP oral liquid dispenser.
Detailed instructions for the dispersion  of the tablets and dosing will be provided in the SPM.
Dabrafenib (applicable for all formulations) will be administered orally, twice daily based on 
weight at the appropriate study dose level. A dosing nomogram (Appendix 2, also in the SPM) 
based on weight and dose level will be used to prescribe dabrafenib to minimize inter-subject 
dosing variability. 
The total daily dabrafenib dose should not exceed the adult dose (300mg) in any subject.
Dabrafenib capsules will be taken with approximately 1 ounce (30 mLs) of water for every 10 
pounds of body weight, twice a day. Subjects should be encouraged to take their doses at 
approximate 12 hour intervals and at similar times every day.
If a subject vomits after taking study medication, the subject should be instructed not to retake 
the dose and should take the next scheduled dose.
If a subject misses a dose, subject should not double the next regularly scheduled dose. However, 
subject can take the missed dose immediately if the next scheduled dose is at least 6 hours 
later. Subject should take the next dose at its usual time. 


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Children younger than 6 years and subjects, regardless of age, with a risk of choking when 
swallowing capsules will be required to use the dispersible tablet formulation.
3.11.3
Meals and Dietary Restrictions
All subjects will fast except for water ad libitum for 2 hr prior and 1 hr following administration 
of trametinib and/or dabrafenib in either formulations.  Data from the adult trametinib food 
effect study (MEK113709) demonstrated that administration of trametinib with a high-fat, high-
calorie meal resulted in an approximate 70% decrease in Cmax and 10-24% decrease in AUC 
compared to administration under fasting conditions.  Data from the adult dabrafenib food effect 
study (BRF113468) demonstrated that administration of dabrafenib following a high-fat, high-
calorie meal resulted in an approximate 30% decrease in exposure and 50% decrease in Cmax 
compared to administration under fasting conditions.

If it is not possible for a subject to tolerate the fasting conditions noted above, trametinib 
and/or dabrafenib can be administered with a small non-fat meal (e.g., small amount of 
apple juice/sauce, a piece of dry toast). Children that are breastfeeding may continue to 
breast feed on demand.  If child is breast fed during collection of PK samples the time of 
breastfeeding should be recorded.

Avoid administration with high-fat or high calorie food or beverages, examples milk, 
beverages containing dairy products or high protein beverages or supplements for 2 hr 
prior and 1 hr following administration of trametinib and/or dabrafenib in either 
formulation.
3.11.4
Blinding
This is an open-label study.
3.12
Safety Management Guidelines
3.12.1
Liver Chemistry Stopping Criteria
Liver chemistry threshold stopping criteria have been designed to assure subject safety and to 
evaluate liver event etiology during administration of study treatment(s) and the follow-up 
period.  Upper limit of normal (ULN) for ALT in this study will be 45 U/L. Study treatment(s) 
will be stopped if any of the following liver chemistry stopping criteria is/are met:
1. ALT 3 times upper limit of normal (ULN) and bilirubin 2 times ULN (or ALT 3 times 
ULN and international normalization ratio [INR] >1.5)

NOTE: Serum bilirubin fractionation should be performed if testing is available.  If 
fractionation is unavailable, urinary bilirubin is to be measured via dipstick (a 
measurement of direct bilirubin, which would suggest liver injury).
2. ALT 5 times ULN.
3. ALT 3 times ULN if associated with the appearance or worsening of rash or hepatitis 
symptoms (fatigue, nausea, vomiting, right upper quadrant pain or tenderness, or jaundice) 
or hypersensitivity (such as fever, rash or eosinophilia).
4. ALT 3 times ULN persists for 4 weeks.


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5. ALT 3 times ULN and cannot be monitored weekly for 4 weeks.
Subjects with ALT 3 times ULN and <5 times ULN and bilirubin <2 times ULN, who do not 
exhibit hepatitis symptoms or rash, can continue study treatment(s) as long as they can be 
monitored weekly for 4 weeks.  See following section for details on weekly follow-up 
procedures for these subjects.
3.12.1.1 Liver Chemistry Follow-up Procedures
The procedures listed below are to be followed if a subject meets the liver chemistry stopping 
criteria 1 through 5 defined in Section 3.12.1:

Immediately discontinue study treatment(s).

Notify the Medical Lead within 24 hr of learning of the abnormality to confirm the 
subject’s study treatment(s) cessation and follow-up.

Complete the “Safety Follow-Up Procedures” listed below.

Complete the liver event electronic case report forms (eCRFs).  If the event also meets the 
criteria of a SAE (see Section 8.2), the SAE data collection tool will be completed 
separately with the relevant details.

Upon completion of the safety follow-up permanently withdraw the subject from the study 
and do not rechallenge with study treatment(s).
Safety Follow-Up Procedures for subjects with ALT 3 times ULN:

Monitor subjects weekly until liver chemistries (ALT, aspartate aminotransferase [AST], 
alkaline phosphatase [ALP], and bilirubin) resolve, stabilize or return to within baseline 
values.
Safety Follow-Up Procedures for subjects meeting stopping criterion 1 (ALT 3 times 
ULN and bilirubin 2 times ULN [or ALT 3 times ULN and INR >1.5]):

This event is considered an SAE (see Section 8.2).  Serum bilirubin fractionation should 
be performed if testing is available.  If fractionation is unavailable, urinary bilirubin is to 
be measured via dipstick (a measurement of direct bilirubin, which would suggest liver 
injury).

Make every reasonable attempt to have subjects return to the clinic within 24 hr for repeat 
liver chemistries, additional testing, and close monitoring (with specialist or hepatology 
consultation recommended).

Monitor subjects twice weekly until liver chemistries (ALT, AST, ALP, bilirubin) resolve, 
stabilize or return to within baseline values.

In addition, every attempt should be made to carry out the liver event follow-up 
assessments described in Section 3.12.1.2.
3.12.1.2 Liver Chemistry Testing Procedures
For subjects meeting any of the liver chemistry stopping criteria in Section 3.12.1, make every 
attempt to carry out the liver event follow-up assessments described below. Laboratory tests for 


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liver events will be performed at the central laboratory.  Additional information can be found 
in the  lab manual and SPM.

Viral hepatitis serology, including:

Hepatitis A IgM antibody

Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM)

Hepatitis C RNA

Cytomegalovirus IgM antibody

Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, then obtain 
heterophile antibody or monospot testing)

Blood sample for pharmacokinetic (PK) analysis, obtained within 20 days of the last dose 
of study treatment(s). Record the date and time of the PK blood sample draw and the date 
and time of the last dose of study treatment(s) prior the blood sample draw on the eCRF.  
If the date or time of the last dose is unclear, provide the subject’s best approximation.  If 
the date or time of the last dose cannot be approximated, or if a PK sample cannot be 
collected within the 20-day period following the last dose, do not obtain a PK sample.  
Instructions for sample handling and shipping are found in the Study Procedures Manual 
(SPM).

Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH).

Fractionate bilirubin, if total bilirubin ≥2 X upper limit of normal (ULN).

Obtain a complete blood count (CBC) with differential to assess eosinophilia.

Record the appearance or worsening of clinical symptoms indicative of hepatitis or 
hypersensitivity, such as fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever, rash or eosinophilia as relevant on the AE eCRF.

Record the use of concomitant medications, including acetaminophen, herbal remedies or 
any other over the counter (OTC) medications, or any putative hepatotoxins, on the 
concomitant medication eCRF.

Record alcohol use on the liver event alcohol intake eCRF.
Every attempt should be made to obtain the following assessments for subjects with ALT ≥3 X 
ULN and bilirubin ≥2X ULN (>35% direct). These assessments are optional for other abnormal 
liver chemistries:

Anti-nuclear antibody, anti-smooth muscle antibody, and Type 1 anti-liver kidney 
microsomal antibodies.

Liver imaging (ultrasound, MRI or CT) to evaluate liver disease.

Liver Imaging and/or Liver Biopsy eCRFs are also to be completed if these tests are 
performed.

Serum acetaminophen adduct High Performance Liquid Chromatography (HPLC) assay 
(quantifies potential acetaminophen contribution to liver injury in subjects with definite or 
likely acetaminophen use in the preceding week (James 2009).


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3.12.2
QTc Stopping Criteria
QTc-Prolongationa
Required adverse event 
management guidelines
Mandatory dose modification 
requirements
● QTc ≥501 msec 
● Test serum potassium, calcium, phosphorus 
and magnesium. If abnormal, correct per 
routine clinical practice to within normal limits.
● Review concomitant medication usage for 
agents that prolong QTc.
● Consider evaluation with cardiologist 
(recommended).
● Interrupt all study treatments (trametinib and 
dabrafenib) until QTc prolongation resolves to 
grade 1 or baseline
● If event resolves to grade 1 or baseline, 
restart study treatment at current dose level
● If event does not resolve, permanently 
discontinue study treatments.  
● If event recurs, permanently discontinue 
study treatments.  
a. Based on average QTc value of triplicate ECGs.  For example, if an ECG demonstrates a prolonged QT 
interval, obtain two or more ECGs over a brief period, and then use the averaged QTc values of the three 
ECGs.
Every attempt should be made to obtain a blood sample to test serum potassium, calcium, 
phosphorus and magnesium levels. If any of these are below the lower limits of normal, correct 
with supplements to within normal limits.
A review of concomitant medication usage for any medications that may prolong QTc should 
also be performed.
3.12.3
Left Ventricular Ejection Fraction (LVEF) and Valvular Toxicity 
Stopping Criteria
3.12.3.1 LVEF Stopping Criteria
Decreases of the left-ventricular-ejection-fraction (LVEF) have been observed in subjects 
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 Time and 
Events Table (Section 7.1). Dose modification guidance and stopping criteria for LVEF 
decrease are provided inTable 3-5.
ECHO should be performed at baseline and at follow up visit(s).  Electronic copies of all ECHO 
scans will be collected by Novartis for review.  Instructions for submission of ECHO scans are 
provided in the Study Procedures Manual (SPM).
Table 3-5
Mandatory dose modification and required clinical management for 
LVEF 
LVEF-drop (%) &
clinical symptoms
Required 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
● Report as SAE.
● Closely monitoring LVEF via ECHO, 
repeat ECHO within 2 weeks. If ECHO 
does not show LVEF recovery after 2 
weeks, repeat ECHO 2 weeks later
● 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.
Interrupt trametinib (on combination therapy dabrafenib may 
continue) 
If the LVEF recovers within 4 weeks, 
● restart treatment with trametinib dose reduced to levels 
indicated in Appendix 2, dose reduction column and continue 
dabrafenib at the same dose level.
● If the event recurs at the reduced dose level, permanently 
discontinue trametinib. On combination therapy dabrafenib 
may continue


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LVEF-drop (%) &
clinical symptoms
Required adverse event 
management guidelines
Mandatory dose modification requirements
● If repeat LVEF does not recover 
within 4 weeks.
● Consult with cardiologist
(recommended)
● Repeat ECHO after 2, 4, 8, 12, 
and 16 weeks or until resolution
● If the event recurs after the subject re-escalated to 
previous dose level, Interrupt trametinib (on combination 
therapy dabrafenib may continue) and manage as first event. 
Note: To restart trametinib, LVEF must return to ≤10% 
decrease compared to original baseline
● If more than two occurrence, permanently discontinue 
trametinib. On combination therapy dabrafenib may continue
If LVEF does not recover within 4 weeks
● Permanently discontinue trametinib, (on combination 
therapy dabrafenib may continue)
Symptomatic:
Resting LVEF ≤39%
or >20% absolute 
reduction from baseline
● Report as SAE.
● Consult with cardiologist 
(recommended)
● Repeat ECHO after 2, 4, 8, 12, and 
16 weeks or until resolution
● Permanently discontinue trametinib. 
● Interrupt dabrafenib
● Restart dabrafenib if LVEF recovers including resolution of 
symptoms.
3.12.3.2 Cardiac Valvular Toxicity Stopping Criteria
Subjects who have a new asymptomatic, moderate regurgitation or stenosis by echocardiogram 
(ECHO) (Grade 2 mitral/tricuspid/aortic valvular toxicity per National Cancer Institute-
Common Toxicity Criteria for Adverse Events [NCI-CTCAE], version 4.03) should 
temporarily discontinue study treatment (both trametinib and dabrafenib if on combination 
therapy) and have a repeat evaluation by ECHO within 1 week.  ECHO should be repeated 
every 1 to 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 subject may be 
restarted on study treatment at a reduced dose(s) (see Appendix 2 dosing nomogram 
“Dose Reduction” columns for trametinib and dabrafenib).  For such subjects, monitoring 
of the valve via ECHO will then be performed 2 and 4 weeks after rechallenge, and every 
4 weeks thereafter for 16 weeks and then per protocol.

If repeat ECHO does not reveal valve recovery to baseline within 4 weeks, then the 
subject should permanently discontinue study treatment (both trametinib and dabrafenib if 
on combination therapy).  The valve should continue to be monitored via ECHO every 4 
weeks for 16 weeks or until resolution.
Subjects with a Grade 3 or 4 (symptomatic, severe regurgitation/stenosis by imaging with 
symptoms controlled by medical intervention) valvular toxicity must discontinue study 
treatment (both trametinib and dabrafenib if on combination therapy).  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, the subject may 
restart study treatment at a reduced dose (see Appendix 2 dosing nomogram “Dose Reduction” 
columns for trametinib and dabrafenib).
ECHO must be performed at baseline and at the final study visit.  Copies of all ECHO(s) and 
cardiology consultations performed on subjects who experience valvular toxicity will be 


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required by Novartis for review.  Instructions for submitting qualifying ECHOs are provided in 
the Study Procedures Manual (SPM).
3.13
Dose Delay and Modification for Events Considered Related to 
Trametinib
A maximum of one trametinib dose reduction is allowed.  If a second dose level reduction is 
required, treatment will be permanently discontinued.
Trametinib dose modification guidelines are outlined in Table 3-6 for clinically significant 
toxicities with exception for following events of special interest: 

rash (Section 3.13.3) 

diarrhea (Section 3.13.4) 

ejection fraction changes (Section 3.12.3.1) 

hypertension (Section 3.13.5)

prolonged QTc (Section 3.12.1)

pneumonitis (Section 3.13.5)

visual changes (Section 3.13.5) 

liver chemistry elevation (Section 3.12.1) 
For these refer to the relevant sections for dose modification guidelines for adverse events of 
special interest as stated above.
If treatment related toxicities occur when dabrafenib is used in combination with trametinib 
then both treatments should be simultaneously dose reduced, interrupted or discontinued with 
the exceptions described below.
3.13.1
Dose Delay and Modification for Events Considered Related to 
Trametinib and/or Dabrafenib
Table 3-6
Dose Delay and Modification for General Events Considered Related 
to Trametinib and/or Dabrafenib
CTCAE 
Grade
Recommended adverse event management 
guidelines
Mandatory dose modification requirements
Grade 1 
and 
tolerable 
Grade 2 
● Monitor closely
● Provide supporting care according to institutional 
standards
● Continue study drug(s) at current dose level
Intolerable 
Grade 2 
and 
Grade 3 
● Monitor closely.
● Provide supportive care according to institutional 
standards.
● Interrupt study drug(s) (except for cuSCC, 
keratoacanthoma, new primary melanoma, and basal cell 
carcinoma)
● When toxicity resolves to Grade 1 or baseline, restart 
study drug(s) at reduced levels (see Appendix 2 dosing 
nomogram “Dose Reduction” columns for trametinib and 
dabrafenib)
● If the Grade 2 (intolerable) or Grade 3 toxicity recurs 
while at reduced dose, discontinue study treatment(s) 
● If the Grade 2 (intolerable) or Grade 3 toxicity recurs 
while after re-escalating to previous dose,


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CTCAE 
Grade
Recommended adverse event management 
guidelines
Mandatory dose modification requirements
● Interrupt dabrafenib and trametinib.
● When toxicity resolves to Grade 1 or baseline, 
restart study drug(s) reduced levels (see Appendix 2 
dosing nomogram “Dose Reduction” columns for 
trametinib and dabrafenib)
Grade 4 
● Monitor closely.
● Provide supportive care according to institutional 
standards.
● Interrupt study drug (s)
● Once toxicity resolves to ≤ Grade 1 or baseline , 
restart study drug(s) at reduced levels (see Appendix 2 
dosing nomogram “Dose Reduction” columns for 
trametinib and dabrafenib)
● or permanently discontinue study drug (s) at the 
discretion of investigator
Table 3-6a
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 3-6b
Dose Modification for dabrafenib (DRB436) dispersible tablet for 
patients greater or equal 12 years of age
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
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


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For subjects treated with solid dosage forms, 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. See also Appendix 2.
3.13.2
Guidelines and Dose Modifications for Trametinib Events of Special 
Interest
The severity of adverse events (AEs) will be graded utilizing the NCI-CTCAE v4.03 (NCI 
2009). Guidelines for dose modifications and interruptions for management of common 
toxicities associated with trametinib are provided in this section. 
3.13.3
Management of Rash
Rash is a frequent AE observed in subjects receiving trametinib and dabrafenib (see the 
Investigator’s Brochure for more information). A proactive approach is recommended. 
Encourage subjects to avoid unnecessary exposure to sunlight and encourage use of sunscreens 
and sunblock (see Section 3.13.3.1). If subjects develop rash, verify treatment intervention and 
consider recommended steps outlined under Section 3.13.3.2 and Table 3-7.
3.13.3.1 Prophylactic Treatment
The following management should be considered (see Table 3-7).  The prophylactic regimen 
should be based on the investigator’s experience. 
1. Broad-spectrum sunscreen (containing titanium dioxide or zinc oxide) with a skin 
protection factor (SPF) ≥15 at least twice daily.
2. Thick, alcohol-free emollient cream (e.g., glycerine and cetomacrogol cream) on dry areas 
of the body at least twice daily.
3. Mild strength topical steroid (e.g., hydrocortisone 1% cream) and topical antibiotics (e.g 
clindamycin) applied at least twice daily starting on Day 1 of study treatment, to body 
areas such as face, chest and upper back with escalation to higher strength and/or oral 
steroid as detailed below.
4. Offer doxycycline or minocycline for 2 to 3 weeks of study treatment administration.  
May dose per institutional guidelines or substitute similar antibiotic.  Consider topical 
antibiotics if oral doxycycline or minocycline is not feasible or tolerable.
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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
Doxycycline:

No dosing recommendations for children < 8 years of age

Children < 45 kg:  2.2 mg/kg/dose PO twice daily 

Children ≥ 45 kg: 100 mg PO twice daily

Minocycline:

No dosing recommendations for children < 8 years of age

Children < 45 kg: 2 mg/kg/dose PO twice daily

Children ≥ 45 kg: 100 mg PO twice daily
3.13.3.2 Reactive Management
It is strongly recommended that subjects who develop rash/skin toxicities receive evaluations 
for management of the specific side effect.

For pruritic lesions, the use of cool compresses and oral antihistamine agents may be 
helpful.

For fissuring, the use of Monsel’s solution, silver nitrate or zinc oxide cream is advised.

For desquamation, thick emollients and mild soap are recommended.

For paronychia, antiseptic bath and local potent corticosteroids in addition to oral 
antibiotics are recommended, and if no improvement is seen, a dermatology or surgery 
consultation is recommended.

For infected lesions, bacterial and fungal culturing followed by the appropriate culture-
driven systemic or topical antibiotics is indicated.
Table 3-7
Mandatory dose modifications and recommended clinical 
management guidelines for rash 
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 study drug(s) 
● If rash does not recover to baseline within 2 weeks despite 
best supportive care, reduce study drug (s) dose (see 
Appendix 2 dosing nomogram “Dose Reduction” columns for 
trametinib and dabrafenib)
Grade 2 (10-
30% of body 
surface area)
If tolerable, as per Grade 1:
● Initiate prophylactic and symptomatic 
treatment measures for first 6 weeks of 
study treatment
● Use moderate strength topical steroid 
(hydrocortisone 2.5% cream or fluticasone 
prioprionate 0.5% cream)
● Reassess after 2 weeks.
● Reduce study drug (s) dose (see Appendix 2 dosing 
nomogram “Dose Reduction” columns for trametinib and 
dabrafenib)
● If rash recovers to ≤Grade 1 within 2 weeks, increase 
dose to previous dose level
● If no recovery to ≤Grade 1 within 2 weeks, interrupt study 
drug(s) until recovery to ≤grade 1, restart study drug (s) at 
reduced dose (see Appendix 2 dosing nomogram “Dose 
Reduction” columns for trametinib and dabrafenib)
Grade 3 
(More than 
Use moderate strength topical steroids 
( PLUS consider a brief period of oral high 
● Interrupt study drug(s) until rash recovers to Grade ≤1
● Restart with study drug(s) at reduced dose level (see 


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CTCAE v4.03 
Grade
Recommended adverse event 
management guidelines
Mandatory dose modification requirements
30% of body 
surface area or 
Life-
threatening)
dose steroid such as methylprednisolone)
Consult dermatologist   
Appendix 2 dosing nomogram “Dose Reduction” columns for 
trametinib and dabrafenib) 
● Escalation of study drug (s) to previous dose level 
may be considered if no rash is evident 4 weeks after 
restarting study treatment 
● If no recovery to grade ≤2 within 4 weeks, permanently 
discontinue study drug(s).
NOTE: suspected cases of SCAR require permanent 
discontinuation of study treatment, see section 3.13.3.3
3.13.3.3 Severe Cutaneous Adverse Reaction(s)
Cases of 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. 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.
3.13.4
Diarrhea
Etiology and attribution.  Consider evaluation for an alternative etiology for diarrhea as 
clinically indicated.  These include medications (e.g., stool softeners, laxatives, antacids, etc.), 
infection by C. difficile or Candida species, partial bowel obstruction, malabsorption/lactose 
intolerance, fecal impaction, or diets high in fiber or lactose.
For Grade ≤ 2 diarrhea:

Dietary modifications may include: stop all lactose-containing products and eat small 
meals.  A bananas, rice, apples, toast (BRAT) diet can be helpful.

Encourage oral hydration according to institutional weight oral hydration guidelines as 
clinically appropriate.

For subjects ≥ 2 years of age, consider administration loperamide (Table 3-8) with 
dosing per institutional guidelines or as suggested below.  Loperamide is not 
recommended for children < 2 years of age.  Continuation of loperamide is suggested 
until the subject is diarrhea-free for at least 12 hr.

If diarrhea resolves to grade≤ 1 within 72 hr of anti-diarrheal measures or supportive care 
measures, continue study treatment without interruption or dose reduction.

If grade 2 diarrhea persists after 72 hr total treatment with loperamide or supportive 
measures in children <2 years, hold study treatment and consider start of second-line 
agents (octreotide) as clinically indicated.  If diarrhea resolves to grade ≤1 or baseline 
within 7 days resume study treatment(s) with dose reduction (Appendix 2).  If grade  2 
diarrhea does not resolve in ≤ 7 days without study treatment, discontinue protocol 
therapy.


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Table 3-8
Loperamide Dosing for Study Treatment Related Diarrhea
Age
Weight
Initial Dose (start 
after first loose 
bowel movement)
Subsequent Doses
Maximum 
daily dose
>2 to ≤ 12 
years
<13 kg
0.5 mg
0.5 mg every 3 hr while awake, 
every 4 hr during sleep
4 mg/day
13 to < 20 kg
1 mg
1 mg every 4 hr
6 mg/day
20 to < 30 kg
2 mg
1 mg every 3 hr while awake, 
every 4 hr during sleep
8 mg/day
30 to < 43 kg
2 mg
1 mg every 2 hr while awake, 
every 4 hr during sleep
12 mg/day
≥ 13 years
≥ 43 kg
4 mg
2 mg every 2 hr
16 mg/day
For Grade 3 to 4 diarrhea:

Hold study treatment until symptoms resolve to Grade 1 or baseline then may resume 
study treatment(s) with a dose reduction (Appendix 2).

If loperamide has not been initiated, initiate loperamide immediately if age > 2years, using 
institutional or protocol guidelines for dosing 

For dehydration, use intravenous fluids as appropriate; if severe dehydration, consider 
administration of octreotide.

If grade > 2 diarrhea does not resolve in ≤ 7 days without study treatment, discontinue 
protocol therapy.
3.13.5
Hypertension
The algorithm in Figure 3-6 will be used to grade and manage trametinib and dabrafenib related 
hypertension. Should initiation of anti-hypertensive therapy be required, single agent therapy 
(commonly including the calcium channel blockers amlodipine or nifedipine,) should be started 
and the blood pressure should be monitored at least twice weekly until BP is within the 95th 
percentile for age, height, and gender per Section 3.12.3.2.
If patient is already on an anti-hypertensive medication at study enrollment, then their anti-
hypertensive therapy should be adjusted (by either adjusting the dose of their current anti-
hypertensive medication or by adding another anti-hypertensive agent) according to the 
algorithm in Section 3.13.5.1.
See requirements for Baseline blood pressure measurements in Section 7.3.4.
3.13.5.1 Management of Hypertension

The upper limit of normal (ULN) is defined as a BP equal to the 95th percentile for age, 
height, and gender (Appendix 7).

The NCI CTCAE will be utilized to determine the grade of hypertension for reporting 
purposes.

Elevated BP measurements should be repeated on the same day to confirm the elevation. 
Patients with an elevated BP should have BP measurements performed at least twice 
weekly until BP is ≤ ULN.


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
The algorithm below will be used to manage study drug(s) related hypertension.

Hypertension should be managed with appropriate anti-hypertensive agent(s) as clinically 
indicated. It is strongly recommended that nephrology or cardiology be consulted in the 
evaluation and management of hypertension.
Figure 3-6
Algorithm For Management of Study Drug(s)-Related Hypertension
Arm 1 of algorithm:

If blood pressure (BP) ≤ 95%ile for age, height, and gender: continue study drug(s) at the 
same dose.
Arm 2 of algorithm:

If BP ≤ 10 mm Hg above the ULN: continue study drug(s)  at the same dose and recheck 
the BP within 72 hours.

If the BP is ≤ ULN on recheck, continue study drug(s) at the same dose.

If the BP remains above the ULN on recheck, then start/adjust antihypertensive 
therapy and follow Arm 3 of the algorithm from the point that anti-hypertensive 
therapy is started/adjusted.
Arm 3 of algorithm:


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If BP is 11 to 25 mm Hg above the ULN on ≥ 2 of 3 measurements or > 35 mmHg above 
baseline on ≥ 2 of 3 measurements, start/adjust anti-hypertensive therapy and continue 
study drug(s) at the same dose. Monitor BP at least twice weekly.

If the BP returns to ≤ ULN within 14 days, continue study drug(s)  at the same dose 
and continue anti-hypertensive therapy.

If the BP remains elevated ≥25 mm Hg above the ULN or > 35 mm Hg above 
baseline for more than 14 days after the institution/adjustment of anti-hypertensive 
therapy, hold study drug(s), monitor BP at least every 3 days, and follow Arm 4 of 
the algorithm from the point that trametinib is held. The anti-hypertensive therapy 
should be continued until the BP is less than the ULN.

If the BP returns to ≤ ULN within 14 days, restart sudy drug (s) at a reduced dose.

If the BP remains > ULN for more than 14 days, patient must be removed from protocol 
therapy.

If the BP increases to > 25 mm Hg above the ULN despite anti-hypertensive therapy, 
hold study drug(s), but continue the anti-hypertensive agent(s). Monitor the BP as 
clinically indicated and follow Arm 4 of the algorithm from the point that study 
drug(s) is held.

If the BP is ULN within 14 days, study drug (s) may be restarted at a reduced dose 

If the BP is > ULN for > 14 days, the patient must be removed from protocol therapy 
(Section 6.3)
Arm 4 of algorithm:

If BP is > 25 mm Hg above the ULN hold study drug (s), monitor BP, and 
administer/adjust anti-hypertensive therapy as clinically indicated.

If the BP returns to ≤ ULN within 14 days, study drug(s) may be restarted at a
reduced dose.

If the BP is > ULN for >14 days, the patient must be removed from protocol therapy 
(Section 6.3).
Arm 5 of algorithm:

If the participant develops Grade 4 hypertension, discontinue study drug(s), monitor BP 
and administer anti-hypertensive therapy as clinically indicated. The patient is Off 
Protocol Therapy (Section 6.3).
3.13.6
Visual Changes
Episodes of visual changes have been observed in subjects receiving trametinib, and ocular 
adverse events are known to be related to trametinib.  An ophthalmologist should 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)).  For events of visual changes (regardless of severity) for which 


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an ophthalmic examination is conducted, a blood sample for PK analysis must be drawn as 
close as possible to the time of the event (Section 7.1 for PK sample volume).
Guidelines regarding management and dose reduction for visual changes considered to be 
related to study treatment are provided in Table 3-9.
Table 3-9
Mandatory dose modification and required clinical management for 
visual changes and/or ophthalmic examination findings
CTCAE v4.03 
Grade*
Required adverse event 
management guidelines
Mandatory dose modification requirements
Grade 1
● Consult ophthalmologist within 7 days 
of onset
● If visual changes are clearly unrelated 
to study treatment (e.g., allergic 
conjunctivitis), monitor closely but 
ophthalmic examination is not required.
● Report as SAE if RPED or RVO 
diagnosed  
● 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. On combination 
therapy dabrafenib may continue.  
● If RPED and RVO excluded, continue (or restart) trametinib at 
same dose level
● If RPED suspected or diagnosed: see RPED dose 
modification Table 3-10 below
● If RVO diagnosed:  Permanently discontinue trametinib (on 
combination therapy dabrafenib may continue) 
Grade 2 and 
Grade 3
● Consult ophthalmologist immediately 
● Report as SAE if RPED or RVO 
diagnosed  
● Interrupt trametinib. On combination therapy, dabrafenib may 
be continued at the same dose.
● If RPED and RVO excluded, restart trametinib at same dose 
level
● If RPED diagnosed, see RPED dose modification Table 3-10
below 
● If RVO diagnosed: Permanently discontinue trametinib (on 
combination therapy dabrafenib may continue) 
● Permanently discontinue dabrafenib for ≥ Grade 2 uveitis 
(including iritis and iridocyclitis) of > 6 weeks duration.
Grade 4
● Consult ophthalmologist immediately 
● Report as SAE if RPED or RVO 
diagnosed  
● Interrupt trametinib. On combination therapy, dabrafenib may 
be continued at the same dose.
● If RPED and RVO excluded, may consider restarting 
trametinib at same or reduced dose 
● If RPED or RVO diagnosed, permanently discontinue 
trametinib (on combination therapy dabrafenib may continue).
* Refers to NCI-CTCAE v4.03 ‘Eye disorders – Other, specify
Table 3-10
Mandatory dose modification and required clinical management for 
retinal pigment epithelial detachments (RPED)
CTCAE v4.03 Grade*
Required adverse event 
management guidelines
Mandatory dose modification 
requirements
Grade 1 RPED 
(Asymptomatic; clinical or
diagnostic observations 
only)
● If RPED worsens follow 
instructions below.
Continue treatment with retinal evaluation 
monthly until resolution. 


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Grade 2-3 RPED 
(Symptomatic with
mild to moderate decrease 
in visual acuity; limiting 
instrumental ADL)
●Retinal evaluation monthly.
● Interrupt trametinib (on combination 
therapy dabrafenib may continue)
If improved to ≤ Grade 1, restart trametinib 
at lower dose (Appendix 2, dose reduction 
column) 
* Refers to CTCAE Version 4.0 ‘Retinopathy’
3.13.7
Pneumonitis
Pneumonitis has been observed in subjects receiving trametinib.  To reduce the risk of 
pneumonitis, subjects will be monitored closely for symptoms, evaluated with imaging and 
functional tests if clinically indicated.  Dose modification and supportive care guidelines for 
pneumonitis are described in Table 3-11.
Table 3-11
Mandatory dose modifications and recommended clinical 
management guidelines for pneumonitis 
CTCAE v4.03 
Grade
Recommended adverse event 
management guidelines
Mandatory dose modification 
requirements
Grade 1
● CT scan (high-resolution with lung windows) 
● Clinical evaluation and laboratory work-up for 
infection
● Monitoring of oxygenation via pulse-oximetry 
● Consultation with pulmonologist 
● Continue study treatment (s) at current dose
Grade 2
● CT scan (high-resolution with lung windows)
● Clinical evaluation and laboratory work-up for 
infection
● Consult pulmonologist
● If feasible, pulmonary function tests -if <normal, 
repeat every 8 weeks until ≥normal
● Bronchoscopy with biopsy and/or BAL 
● Symptomatic therapy including corticosteroids if 
clinically indicated
● Interrupt trametinib until recovery to grade ≤1 (on 
combination therapy, dabrafenib may continue)
● Restart treatment with reduced trametinib dose 
level  (Appendix 2, dose reduction column)
● Escalation to previous dose level after 4 weeks if 
a period of 4 weeks of treatment have passed since 
restarting dosing at the lower dose level and there 
is no recurrence of the AE
● If no recovery to grade ≤1 within 4 weeks, 
permanently discontinue trametinib (on combination 
therapy, dabrafenib may continue)
Grade 3
● CT scan (high-resolution with lung windows)
● Clinical evaluation and laboratory work-up for 
infection
● Consult pulmonologist
● If feasible, pulmonary function tests-if <normal, 
repeat every 8 weeks until ≥normal
● Bronchoscopy with biopsy and/or BAL if possible
● Symptomatic therapy including corticosteroids as 
clinically indicated
● Interrupt trametinib until recovery to grade ≤1 (on 
combination therapy, dabrafenib may continue)
● When recovered to grade ≤1, treatment with 
trametinib may be restarted at reduced dose  
(Appendix 2, dose reduction column)
● If no recovery to grade ≤1 within 4 weeks, 
permanently discontinue trametinib (on combination 
therapy, dabrafenib may continue )
Grade 4
● Same as grade 3
● Permanently discontinue trametinib (on 
combination therapy, dabrafenib may continue)
Abbreviations: BAL= bronchioalveolar lavage; CT = computed tomography; CTCAE = Common Terminology 
Criteria for Adverse Events


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3.14
Dose Delay and Modification for Events Considered Related to 
Dabrafenib
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 3-6. 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.  
These are general guidelines and investigators should always use clinical judgment in 
determining dose adjustments for any individual patient.  Some toxicities may require 
hospitalization for stabilization, additional work-up, and consultation with a specialist before 
treatment can be restarted.  Specific adverse events and recommended management include:

Palmar Plantar Erythrodysaethesia Syndrome (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 (See Section 3.15).

Pancreatitis – In the event of abdominal pain or suspected pancreatitis, amylase and 
lipase laboratory samples should be collected for confirmation of the diagnosis. Patients 
should be closely monitored when re-starting dabrafenib after an episode of pancreatitis.

Uveitis - 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. Permanently discontinue dabrafenib for 
persistent ≥ grade 2 uveitis (including iritis and iridocyclitis) of > 6 week duration. No 
dose modification of trametinib is required when taken in combination with dabrafenib. 
See Section 3.13.5.

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 subjects 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.
Investigators should always err on the side of caution in these settings if treatment-related 
toxicity is a possibility. 
Please refer to Table 3-6 for general dose modification guidelines for trametinib and dabrafenib.


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When an individual’s adverse reactions are under effective management, dose re-escalation 
following the same dosing steps as de-escalation may be considered. The dabrafenib dose 
should not exceed 150 mg twice daily.
3.15
Guidelines for Dose Modifications and Toxicity Management for 
Combination Therapy
If treatment related toxicities occur when dabrafenib is used in combination with trametinib 
then both treatments should be simultaneously dose reduced, interrupted or discontinued with 
the exception shown below:

Dose modification is necessary for only dabrafenib

Mild to moderate pyrexia (Section 3.15.1)

Uveitis (Section 3.13.5 and Section 3.14)

Dose modifications are necessary for only trametinib:

Retinal vein occlusions (RVO) and retinal pigment epithelial detachment (RPED) 
(Section 3.13.5)

Left ventricular ejection fraction (LVEF) reduction (asymptomatic, Section 3.12.3.1)

Pneumonitis and interstitial lung disease (ILD) (grade 4, Section 3.13.7)
The severity of adverse events (AEs) will be graded utilizing the NCI-CTCAE v4.03 (NCI 
2009). Guidelines for dose modifications and interruptions for management of common 
toxicities associated with dabrafenib are provided in this section. 
Trametinib dose reduction for patients enrolled in all parts of the study should follow dose 
reduction column in the trametinib dosing nomogram in Appendix 2. 
Dabrafenib dose reduction should follow the dose reduction column in the dabrafenib dosing 
nomogram in Appendix 2 provided for patients enrolled in Part C and Part D, as described 
below

Dabrafenib dose modification levels in Part C

If a subject is dosed at Dose Level 1, and requires dose reduction, treatment must be 
discontinued

If a subject is dosed at Dose Level 2, and requires dose reduction, follow the dose 
reduction column in dosing nomogram

Dabrafenib dose modification levels in Part D. 

Follow dose reduction column in dosing nomogram
Nomograms for each dosing level are provided in Appendix 2.
If a second dose reduction is required, the treatment should be discontinued.
3.15.1
Pyrexia
Pyrexia has been observed in adult subjects receiving dabrafenib. In a minority of cases pyrexia 
was accompanied by symptoms such as severe chills/rigors, dehydration, and hypotension, 
which in some cases can lead to acute renal insufficiency.  Serious non-infectious febrile events 
have been observed and typically occurred within the first month of therapy.


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Subjects should be instructed on the importance of immediately reporting febrile episodes.  
Therapy with dabrafenib should be interrupted if the patient’s temperature is ≥38.5ºC or 101.3○
Fahrenheit.  In the event of a fever, the subject should be instructed to take anti-pyretics (e.g. 
ibuprofen or acetaminophen/paracetamol as appropriate to control fever). The use of oral 
corticosteroids should be considered in those instances in which anti-pyretics are insufficient.  
Monitor serum creatinine and other evidence of renal function during and following severe 
events of pyrexia.
Guidelines regarding management and dose reduction for pyrexia considered to be related to 
dabrafenib are provided in Table 3-12.
Table 3-12
Mandatory dose modification and recommended clinical management 
for pyrexia a, b
Occurrence
Recommended adverse event 
management guidelines
Mandatory dose modification 
requirements
Any
● Clinical evaluation for infection and 
hypersensitivityc
● Laboratory work-upc
● Hydration as requiredd
● See relevant row below
1st Eventb:
● Administer anti-pyretic treatmente as clinically 
indicatedf
● Interrupt dabrafenib
● Trametinib may continue (Interrupt trametinib 
for fever higher than 40°C (104°F))
● Once pyrexia resolves to baseline (<38.5°C 
(101.3°F)) , restart dabrafenib at the same 
dose level (for pyrexia of 38.5°C (101.3°F) to 
40°C (104°F)) or at the lower dose level 
(Appendix 2, dose reduction column) (for 
pyrexia > 40°C (104°F)) and restart trametinib 
(if applicable)
● If fever was associated with dehydration, 
hypotension, rigors or chills, or renal failure, 
interrupt dabrafenib and trametinibg
2nd Event f
● Same as for 1st event, and
● Consider oral corticosteroids (i.e. 
prednisone 10mg) for at least 5 days or as 
clinically indicatedg
● Same as first event
Subsequent Events: 
Within 3 days of onset of pyrexia:
● Optimize oral corticosteroid dose as clinically 
indicated for recalcitrant pyrexiaf
● If corticosteroids have been tapered and 
pyrexia recurs, restart steroids
● Interrupt dabrafenib
● Trametinib may continue (Interrupt trametinib 
for fever higher than 40°C (104°F))
● Once pyrexia resolves to baseline, restart 
dabrafenib at lower dose (appendix 2, dose 
reduction column) and restart trametinib (if 
applicable).
● Re-escalation of dabrafenib is allowed if no 
episode of pyrexia is observed in the 4 weeks 
subsequent to dose reduction.  
BUN = blood urea nitrogen; CRP = C-reactive protein
a.
Pyrexia is defined as a body temperature equal to or above 38.5○Celsius or 101.3○Fahrenheit. 
b.
For subjects experiencing pyrexia complicated by rigors, severe chills, etc., a clinical evaluation 
and laboratory work-up is mandatory for each event; anti-pyretic treatment should be started 
immediately at the first occurrence and prophylactic anti-pyretic treatment is recommended.
c.
Thorough clinical examination for signs and symptoms of infection or hypersensitivity is required; 
laboratory work up should include full blood count, electrolytes, creatinine, BUN, CRP, and liver 
function tests, blood culture and urine culture.


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d.
Oral hydration should be encouraged in subjects without evidence of dehydration.  Intravenous 
hydration is recommended in subjects experiencing pyrexia complicated by 
dehydration/hypotension.
e.
Anti-pyretic treatment may include acetaminophen (paracetamol), ibuprofen, or suitable anti-pyretic 
medication according to institutional standards. Prophylactic anti-pyretic treatment may be 
discontinued after three days in the absence of pyrexia
f.
In subjects experiencing pyrexia complicated by rigors, severe chills, etc., which cannot be 
controlled with anti-pyretic medication, oral corticosteroids should be started at the 2nd event and
doses should be gradually increased for subsequent events.
g.
Dabrafenib should be reduced by one dose level (Appendix 2, dose reduction column) at discretion 
of the investigator if pyrexia is accompanied by severe rigors which cannot be managed by best 
supportive care, including increasing doses of oral steroids.  
3.15.2
Renal insufficiency
Cases of renal insufficiency have occurred in adult subjects receiving dabrafenib.  Prior to start 
of study treatment, concomitant medications should be reviewed for the potential risk of 
inducing nephrotoxicity and concomitant medications should 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 in Table 3-13.
For the purposes of this guideline, increases from baseline should have at least the following 
absolute increase to qualify for the noted percent increase in this guideline. The normal serum 
creatinine values anticipated for young patients on this protocol are near the reporting limits of 
the laboratory analysis, and are thus subject to variability in reported results and high calculated 
percent changes.  The absolute increase values are intended to alleviate dosing changes due to 
spuriously high calculations for percentage change.
For a 25% increase – that must also be at least a 0.10mg/dL absolute increase
For a 50% increase – that must also be at least a 0.20 mg/dL absolute increase
For a 100% increase – that must also be at least a 0.40 mg/dL absolute increase
Table 3-13
Mandatory dose modifications and required clinical management 
guidelines for renal function alterations
For subjects 
with creatinine 
rise  ≥50% from 
baseline :
Required adverse event management 
guidelines
Mandatory dose modification 
requirements
1 st  occurrence
● If patient has fever: treat pyrexia as per Table 
3-12 (please note NSAIDs can induce renal 
insufficiency, especially in patients with 
dehydration); consider IV hydration
● Pediatric nephrology consult is recommended
● Re-check within 24 hours
● If creatinine rise is < 25% from baseline:
● Monitor creatinine weekly for 4 
weeks to ensure levels remain within 25% of 
baseline 
● If creatinine rise is ≥ 25% but < 50% from 
baseline:
● Monitor creatinine at least twice 
● If creatinine rise is < 25% from baseline:
● Continue dabrafenib and trametinib at 
current dose
● If creatinine rise is ≥ 25% but < 50% from 
baseline:
● Continue dabrafenib and trametinib at 
current dose


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For subjects 
with creatinine 
rise  ≥50% from 
baseline :
Required adverse event management 
guidelines
Mandatory dose modification 
requirements
weekly, can decrease frequency if creatinine 
rise < 25% from baseline
● Avoid nephrotoxic agents
● If creatinine rise is ≥ 50% but < 100% from 
baseline:
● Monitor creatinine at least twice 
weekly
● Avoid nephrotoxic agents
● If creatinine rise is ≥ 50% but < 100% 
from baseline:
● Interrupt dabrafenib and trametinib
● May restart dabrafenib at reduced 
dose and trametinib at reduced dose if 
creatinine rise returns to < 25% from 
baseline (see Appendix 2 dosing 
nomogram “Dose Reduction” columns for 
trametinib and dabrafenib)
● If creatinine rise is ≥ 100% from baseline:
● Permanently discontinue dabrafenib 
and trametinib
2nd occurrence
See guidance for first occurrence
● Permanently discontinue dabrafenib and 
continue trametinib
3.15.3
Malignancies
Cutaneous Squamous Cell Carcinomas (CuSCC)
Cases of cuSCC (which include those classified as keratoacanthoma or mixed keratoacanthoma 
subtype) have been observed in subjects treated with dabrafenib.  Approximately 70% of events 
occurred within the first 12 weeks of treatment with a median time to onset of 8 weeks.  These 
should be surgically removed according to institutional practices.  Dose modification or 
interruption of study treatment is not required for cuSCC or KA, however cuSCC should be 
reported as an SAE. In addition, a biopsy of the lesion should be taken, where possible, and a 
summary of the results submitted to the Sponsor. 
Patients should be instructed to immediately inform their physician if new lesions develop.  Skin 
examination should be performed prior to initiation of dabrafenib and during treatment with 
dabrafenib, every 2 months throughout therapy.  Monitoring of the skin should continue every 
2 to 3 months for 6 months following discontinuation of dabrafenib or until initiation of another 
anti-neoplastic therapy.
New Primary Melanoma
New primary melanomas have been reported in patients treated with dabrafenib.  These were 
identified primarily within the first 5 months of therapy and did not require treatment 
modification other than excision.  Monitoring for skin lesions should occur as described for 
cuSCC.
Non-Cutaneous Malignancies
In vitro experiments have demonstrated paradoxical activation of MAP-kinase signalling 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 


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RAS-driven malignancies have been seen with BRAF inhibitors.  Patients should be monitored 
as clinically 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.
New non-cutaneous malignancies should be reported as a SAE. A biopsy of the new malignancy 
should be taken, where possible, and submitted for further analyses with the results provided to 
Novartis.  Testing of these biopsies may include analysis of genomic alterations, which include 
but not limited to DNA, RNA and protein analysis of these biopsy specimens, and would 
analyze the biological pathways known to be associated with, and relevant to, BRAF-mutant 
tumor activation.  For any new non-cutaneous maligancy every effort should be made to identify 
the RAS mutation status and submit the results to Novartis.
Refer to Appendix 10 for French country specific dermatological follow up. 
3.15.4
Prolonged QTc
Guidelines for dose modification and stopping criteria due to QTC-prolongation are provided 
in Section 3.12.1.
4
Investigational Product(s)
The term ‘study treatment’ is used throughout the protocol to describe any combination of 
investigational product(s) (IP) received by the subject as per the protocol design.  Study 
treatment may therefore refer to the individual study treatment or the combination of those study 
treatments.
4.1
Description of Investigational Products
4.1.1
Trametinib
Table 4-1
Investigational Product - Trametinib
Product name:
Trametinib tablet
Trametinib powder for oral solution
Formulation 
description:
The drug substance is blended with inert 
ingredients (mannitol, sodium lauryl 
sulfate, colloidal silicon dioxide, 
microcrystalline cellulose, hypromellose, 
croscarmellose sodium, and magnesium 
stearate) and compressed into tablets.
The tablets are then coated with a pink 
opaque film (Opadry pink, a titanium 
dioxide-based formulation with iron oxide 
as colorant).
The drug substance is blended with inert 
ingredients (β-cyclodextrin 
sulfobutylether, citric acid monohydrate, 
sodium phosphate dibasic anhydrous, 
sucralose, methylparaben, potassium 
sorbate, strawberry flavor) filled into 
amber glass bottle with child resistant 
cap. The powder in bottle is reconstituted 
with 90 mL of Purified or Sterilized Water 
to obtain the dosing solution and a 
syringe adapter is inserted into the bottle 
to facilitate the withdrawal of the solution.
Dosage form:
Tablets
Powder for Oral Solution


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Product name:
Trametinib tablet
Trametinib powder for oral solution
Unit dose 
strength(s)/Dosage 
level(s):
0.5mg, 2mg
0.05mg/mL
Physical description:
0.5mg: yellow, modified oval 
4.85x8.86 mm tablet
2mg:pink, round 7.5mm tablet
Powder: White to slight white powder
Solution : Clear, colorless solution with 
strawberry flavor
Route/
Administration:
Oral
Oral
Dosing instructions:
Trametinib should be taken orally, with 
approximately 4-6 mL/kg of water, 1 hr 
before or 2 hr after a meal.
A graduated syringe is used to withdraw 
the volume and administered orally 1 hr 
before or 2 hr after a meal.
Subjects will drink approximately 
4-6 mL/kg of water following 
administration of oral dosing.
Manufacturer/
source of 
procurement:
Novartis
Novartis
Trametinib will be provided to sites by Novartis.  The contents of the label will be in accordance 
with all applicable regulatory requirements.
4.1.2
Dabrafenib
Table 4-2
Investigational Product - Dabrafenib
Formulation 
description:
Dabrafenib capsules
Dabrafenib  Dispersible 
Tablets for oral 
suspension
Dosage form:
Capsule
Dispersible Tablet
Unit dose strengths:
50 mg and 75 mg
10mg
Route/ Frequency:
Oral / BID 
Oral / BID
Physical description:
50 mg: opaque capsules composed 
of a dark red body and cap, each 
printed with one thick black line and 
one thin black line
75 mg: opaque capsules composed 
of pink body and cap, each printed 
with one thick black line and one 
thin black line
White to slightly-yellow 
round
biconvex, beveled edge 
tablet with debossment 
“8” on one side and no 
debossment on the
other
Manufacturer/
source of 
procurement:
Novartis
Novartis
Method for 
individualizing 
dosage:
Unit dose capsules
Administered using 
dosing cup / PP oral 
iquid dispenser
Dabrafenib will be provided to sites by Novartis.  The contents of the label will be in accordance 
with all applicable regulatory requirements.


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4.2
Preparation/Handling/Storage of Investigational Products
4.2.1
Trametinib
Preparation
A description of the methods and materials required for reconstitution of trametinib Powder for 
Oral Solution is provided in the SPM.
No special preparation of trametinib tablets is required.
Handling
Under normal conditions of handling and administration, IP is not expected to pose significant 
safety risks to site staff.  A Material Safety Data Sheet (MSDS) describing the occupational 
hazards and recommended handling precautions will be provided to site staff if required by 
local laws or will otherwise be available from Novartis upon request.
Take adequate precautions to avoid direct eye or skin contact and the generation of aerosols or 
mists.  In the case of unintentional occupational exposure notify the study monitor, the Medical 
Lead and/or the study manager.  Refer to the SPM for detailed procedures for the disposal and/or 
return of unused study treatment(s).
Storage
Trametinib must be stored in a secure area under the appropriate physical conditions for the 
product.  Access to and administration of the trametinib will be limited to the investigator and 
authorized site staff.  Trametinib must be dispensed or administered only to subjects enrolled 
in the study and in accordance with the protocol.
Trametinib tablets should be refrigerated at 2 to 8oC (36 to 46oF), protected from light and 
moisture.  Trametinib powder for oral solution should be refrigerated at 2 to 8oC (36 to 46oF), 
protected from light and moisture.  Store the solution at room temperature up to 25C (77F) 
and protect from light.  The solution can be used for up to 35 days after reconstitution.  
Maintenance of a temperature log (manual or automated) is required.
4.2.2
Dabrafenib
Preparation
No special preparation of study treatment is required for dabrafenib HPMC capsules.
Dabrafenib dispersible tablets will be dispersed  with a specified volume of water at the time of 
use to form a suspension. Detailed instructions for the  dispersion of the tablets and dosing will 
be provided in the SPM.
Study treatment must be dispensed or administered according to procedures described herein. 
Only subjects enrolled in the study may receive study treatment. Only authorized site staff may 
prepare and supply [administration will be performed by caretakers] study treatment. 
Patients less than 12 years of age, who weigh less than 16 kg must use dabrafenib dispersible 
tablets for oral suspension. Patients greater than or equal to 12 years of age, who weigh less 
than 19 kg must use dabrafenib dispersible tablets for oral suspension


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Handling
Investigational product is not expected to pose significant occupational safety risk to site staff 
under normal conditions of use and administration. Take adequate precautions to avoid direct 
eye or skin contact and the generation of aerosols or mists. Notify the monitor of any 
unintentional occupational exposure. A Material Safety Data Sheet (MSDS)/equivalent 
document describing occupational hazards and recommended handling precautions either will 
be provided to the investigator, where this is required by local laws, or is available upon request 
from Novartis.
However, precautions are to be taken to avoid direct skin contact, eye contact, and generating 
aerosols or mists. In the case of unintentional occupational exposure notify the monitor, Medical 
Lead and/or study manager.
Storage
All study treatment must be stored in a secure area with access limited to the investigator and 
authorized site staff.
Dabrafenib capsules are to be stored at room temperature up to 30C. Maintenance of a 
temperature log (manual or automated) is required.
Dabrafenib dispersible tablets are to be  stored at up to 25C. Maintenance of a temperature 
log (manual or automated) is required.
4.3
Product Accountability
In accordance with local regulatory requirements, the investigator, designated site staff, or head 
of the medical institution (where applicable) must document the amount of IP dispensed and/or 
administered to study subjects, the amount returned by study subjects, and the amount received 
from and returned to Novartis, when applicable.
The required accountability units for this study will be bottle for trametinib powder for oral 
solution and tablet for trametinib tablets.  For dabrafenib the required accountability units will 
be tablet for dabrafenib dispersible tablets, and capsule for dabrafenib capsules.  Discrepancies 
are to be reconciled or resolved.  Procedures for final disposition of unused study treatment are 
listed in the SPM.
Product accountability records must be maintained throughout the course of the study.  Refer 
to the SPM for further detailed instructions on product accountability.
4.4
Treatment Compliance
If subjects are dosed at the study site, they will receive study treatment directly from the 
investigator or designee, under medical supervision.  The date and time of each dose 
administered in the clinic will be recorded in the source documents.  The dose of study treatment 
and study participant identification will be confirmed at the time of dosing by a member of the 
study site staff other than the person administering the study treatment(s).
When subjects self-administer study treatment(s) at home, compliance with trametinib and 
dabrafenib dosing will be assessed through querying the subject during the site visits and 


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documented in the source documents and eCRF.  A record of the number of tablets, capsules, 
or powder dispensed to and taken by each subject must be maintained and reconciled with study 
treatment and compliance records.  Treatment start and stop dates, including dates for treatment 
delays and/or dose reductions will also be recorded in the eCRF.
4.5
Treatment of Investigational Product Overdose
In the event of an overdose (defined as administration of more than the protocol-specified dose) 
of study treatment, the investigator should:

contact institutional Principal Investigator (PI) and treating physician immediately to 
discuss plan for holding study treatment, monitoring for toxicity, or resuming protocol 
therapy;

contact the Medical Lead immediately to discuss dosing and monitoring plan;

closely monitor the subject for adverse events (AEs)/ SAEs and laboratory abnormalities 
until resolved to baseline or at least 30 days;

if possible, obtain a plasma sample for PK analysis within 3 days from the date of the last 
dose of study treatment if requested by the Medical Lead (determined on a case-by-case 
basis);

document the quantity of the excess dose as well as the duration of the overdosing in the 
eCRF.
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Medical Lead based on the clinical evaluation of the subject.
5
Study Population
5.1
Number of Subjects
Approximately 142 subjects will be enrolled in the study (approximately 48 subjects in Part A, 
at least 40 subjects in Part B, 24 subjects in Part C and approximately 30 subjects in Part D)  In 
Part A during the age expansion cohort, every attempt will be made to enroll 4-6 subjects in 
each age group. In Part A extension, up to 12 subjects under 6 years of age may be enrolled. In 
Part B a minimum of 10 subjects will be enrolled in each group with at least 4 in each cohort 
under the age of 6.  In Part C, no specific age expansion is planned and will be extended with 6 
subjects under 6 years of age to further test the selected trametinib dose in combination with 
dabrafenib. In Part D, approximately 30 subjects will be enrolled. Every attempt will be made 
to enroll at least 4 children under the age of 12 in Part C or Part D.
5.2
Subject Selection Criteria
5.2.1
Inclusion Criteria
Specific information regarding warnings, precautions, contraindications, adverse events (AEs), 
and other pertinent information on the study treatment that may impact subject eligibility is 
provided in the most recent version of the trametinib Investigator Brochure and dabrafenib 
Investigator Brochure.


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Deviations from inclusion criteria are not allowed because they can potentially jeopardize the 
scientific integrity of the study, regulatory acceptability or subject safety.  Therefore, adherence 
to the criteria as specified in the protocol is essential.
Subjects eligible for enrollment in any part (Part A, Part B, Part C or Part D) of the study must 
meet all of the following criteria in Section 5.2.1.1; in addition, Part (A, B,  C or D) Specific 
Criteria (Section 5.2.1.2 to Section 5.2.1.5) must be met.
5.2.1.1
General Eligibility Criteria (All Parts)
1. Written informed consent – a signed informed consent and/or assent (as age appropriate) 
for study participation including pharmacokinetics sampling will be obtained according to 
institutional guidelines.
2. Male or female between one month and < 18 years of age (inclusive) at the time of signing 
the informed consent form (Part C and Part D between 12 months and < 18 years of age, 
inclusive; Part A extension between 1 month and <6 years of age, inclusive; Part C 
extension between 12 months and <6 years of age, inclusive.
3. Must have a disease that is relapsed/refractory to all potentially curative standard 
treatment regimens or must have a current disease for which there is no known curative 
therapy, or therapy proven to prolong survival with an acceptable quality of life 
4. Prior therapy: The subject’s disease (i.e. cancer, NF-1 with PN, or LCH) must have 
relapsed after or failed to respond to frontline curative therapy or there must not be other 
potentially curative treatment options available.  Curative therapy may include surgery, 
radiation therapy, chemotherapy, or any combination of these modalities.  All subjects 
must have recovered to grade ≤1 from the acute toxic effects of all prior chemotherapy, 
immunotherapy, or radiotherapy prior to enrollment.

Myelosuppressive chemotherapy: The last dose of all myelosuppressive anticancer 
drugs must be at least 21 days prior to enrollment.  

Differentiating Agents/ Biologic response modifiers (small molecules, antibodies, 
viral therapies) (anti-cancer agent):  The last dose of all biologic agents for the 
treatment of the subject’s cancer (such as retinoids) must be at least 7 days prior to 
study entry.  The last dose of monoclonal antibodies, immunotherapy, or viral therapy 
must be at least 30 days prior to enrollment.

Non-myelosuppressive anticancer agents: (antiangiogenic agents, tyrosine kinase 
inhibitors):  The last dose of non-investigational agent that is not cytotoxic must be at 
least 2 weeks prior to enrollment.

Investigational agent: The last dose of all investigational agents must be at least 30 
days prior to study entry.

Radiation therapy: The last dose of radiation (including therapeutic Iodine-131-meta-
iodobenzylguanidine [MIBG]) to more than 25% of marrow containing bones (pelvis, 
spine, skull) must be at least 28 days prior to enrollment.  The last dose of all other 
local palliative (limited port) radiation must be at least 14 days prior to enrollment.

Stem Cell Transplantation or Infusion.  Subjects must be at least 2 months post-
autologous transplant or stem cell infusion and must have recovered from toxicities.  


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Subjects must be at least 6 months post- allogeneic transplant, must have recovered 
from toxicities, and must have no evidence of active graft-versus-host disease.  
Subjects must also have been off of immunosuppressive treatment at least 30 days.

Number of prior treatment regimens: No limitation on the number of prior systemic or 
local treatment modalities that the subject may have received prior to study entry.

Colony stimulating factors: The last dose of colony stimulating factors, such as 
filgrastim, sargramostim, and epoetin, must be at least 48 hr prior to study entry, and 
the last dose of long-acting colony stimulating factors, such as pegfilgrastim, must be 
at least 10 days prior to study entry.

Corticosteroids in subjects with solid tumors are permitted if the dose of 
corticosteroids is stable or decreasing for at least 7 days prior to enrollment.  .
5. Performance score of ≥50% according to the Karnofsky/Lansky performance status scale 
(Yates 1980, Appendix 1).
6. Females of child-bearing potential must be willing to practice acceptable methods of birth 
control (see Section 10.1).  Additionally, females of childbearing potential must have a 
negative serum pregnancy test within 7 days prior to start of study drugs, throughout 
treatment period and for 4 months after last dose of study drugs.
7. Must have adequate organ function as defined by the following values:

Renal function:  24 hr creatinine clearance (revised Schwartz formula), or 
radioisotope glomerular filtration rate (GFR) ≥ 60 mL/min/1.73 m2; or a serum 
creatinine  ≤ ULN for age and gender as defined in the following table:
Age
(Years)
Upper Limit of Normal Serum Creatinine (mg/dl)
Male
Female
Less than  6 months 
0.4
0.4
6 months to less than 1 year
0.5
0.5
1 year to less than 2 years
0.6
0.6
2 to less than 6 years
0.8
0.8
6 to less than 10 years
1
1
10 to less than 13 years
1.2
1.2
13 years to less than 16 years
1.5
1.4
Greater than 16 years
1.7
1.4
The threshold creatinine values in this table were derived from the Schwartz formula for estimating GFR 
(Schwartz 1985) utilizing child length and stature data published by the Centers for Disease Control and 
Prevention (CDC).

Liver function defined as:

Bilirubin (sum of conjugated + unconjugated) ≤ 1.5 x ULN for age

ALT 2.5 x ULN; for the purposes of enrollment and toxicity monitoring the 
ULN for ALT will be 45 U/L.

Cardiac function defined as: 

Corrected QT (QTcB) interval <480 msec

LVEF ≥LLN by ECHO


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8. Able to swallow and retain enterally (PO or nasogastric or gastric tube) administered 
medication and does not have any clinically significant gastrointestinal abnormalities that 
may alter absorption such as malabsorption syndrome or major resection of the stomach or 
bowels.
9. Adequate Blood Pressure Control defined as:
10. Blood pressure ≤ the 95th percentile for age, height, and gender) measured as described in 
Section 7.3.4. 
11. French subjects: In France, a subject will be eligible for inclusion in this study only if 
either affiliated to or a beneficiary of a social security category.
5.2.1.2
Specific Eligibility Criteria, Part A
Subjects must meet General Eligibility Criteria. The specific eligibility criteria listed here will 
apply to subjects enrolling to Part A.
1. For the initial dose escalation to identify the maximum tolerable or PK target dose, age 
between 2 years and < 18 years (inclusive) at the time of signing the informed consent 
form. Children < 2 years of age will be enrolled once the age specific expansion cohorts 
are open.
2. Histologically confirmed solid tumors, which may include but are not limited to 
rhabdomyosarcoma and other soft tissue sarcomas, Ewing sarcoma family of tumors, 
osteosarcoma, neuroblastoma, Wilms’ tumor, hepatic tumors, germ cell tumors, primary 
brain tumors, NF-1 associated plexiform neurofibromas, and Langerhans Cell histocytosis 
(LCH).  In subjects with brain stem gliomas the requirement for histological confirmation 
can be waived if a biopsy was not performed.  For plexiform neurofibromas, histologic 
confirmation of tumor is not necessary in the presence of consistent clinical and 
radiological findings, but should be considered if malignant degeneration of a PN is 
clinically suspected. 
3. Measurable or evaluable tumors.  Subjects with neuroblastoma that is only detectable by 
MIBG scan are eligible.  Subjects with neuroblastoma that is only detected by bone 
marrow aspirate/biopsy or elevated homovanillic acid / vanillylmandelic acid 
(HVA/VMA) are not eligible. 
4. Adequate bone marrow function defined as:

Absolute neutrophil count (ANC) ≥1000/µL;

Hemoglobin ≥8.0 g/dL (may receive red blood cell transfusions)Platelets ≥75,000/µL 
(transfusion independent, defined as not receiving platelet transfusions within a 7 day 
period prior to enrollment)
5.2.1.3
Specific Eligibility Criteria, Part B
Subjects must meet General Eligibility Criteria. The specific eligibility criteria listed here will 
apply to subjects enrolling to different cohorts of Part B.
1. Tumor tissue (archived or fresh) is required and must be available to be shipped to 
Novartis or site specific laboratory except in subjects where tumor biopsy is not possible.
2. Solid Tumor Cohort (B1) Specific Criteria:


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
Histologically confirmed neuroblastoma which have been associated with 
MAPK/RAS/MEK activation.  Histological confirmation may be at diagnosis or 
recurrence.  Laboratory documentation of pathway activation is not required; 
however, archival tissue is requested at the time of enrollment.

Measurable or evaluable tumors.  Subjects with neuroblastoma that is only detectable 
by MIBG scan are eligible if they have at least one lesion that can be assessed using 
the Curie scale.  Subjects with neuroblastoma that is only detected by bone marrow 
aspirate/biopsy or elevated HVA/VMA are not eligible.

If neuroblastoma subjects have only one MIBG positive lesion and that lesion was 
radiated (external beam or systemic radiolabeled 131I-MIBG), a biopsy must be done 
at least 28 days after radiation was completed and must show viable neuroblastoma

Hematological Toxicity Evaluable Subjects (at least 6 of cohort of 10) must have 
adequate bone marrow function defined as:

Absolute neutrophil count (ANC) ≥1000/µL;

Hemoglobin ≥8.0 g/dL (may receive red blood cell transfusions)

Platelets ≥75,000/µL (transfusion independent, defined as not receiving platelet 
transfusions within a 7 day period prior to enrollment)

Hematological Toxicity Inevaluable Subjects (up to 4 in a cohort of 10) must have 
adequate bone marrow function defined as:

Absolute neutrophil count (ANC) >500/µL;

Hemoglobin ≥8.0 g/dL (may receive red blood cell transfusions)

Platelets >25,000/µL (transfusion independent, defined as not receiving platelet 
transfusions within a 7 day period prior to enrollment)
3. BRAF Fusion Cohort (B2) Specific Criteria:

Relapsed or refractory gliomas or other primary brain tumors with BRAF 
fusion/duplication (documented in Clinical Laboratory Improvement Amendments 
(CLIA) certified or equivalent laboratory) or NF1 subjects with gliomas who are not 
suitable for the NF1 with PN cohort.  

Adequate hematologic function defined as:

Absolute neutrophil count (ANC) ≥1000/µL;

Hemoglobin ≥8.0 g/dL (may receive red blood cell transfusions)

Platelets ≥75,000/µL (transfusion independent, defined as not receiving platelet 
transfusions within a 7 day period prior to enrollment)
4. NF-1 Plexiform Neurofibroma Cohort (B3) Specific Criteria

Subjects with NF-1 must have a PN(s) that are progressive OR are cause of 
significant morbidity, such as (but not limited to) head and neck lesions that could 
compromise the airway or great vessels, brachial or lumbar plexus lesions that could 
cause nerve compression and loss of function, lesions that could result in major 
deformity (e.g., orbital lesions) or are significantly disfiguring, lesions of the 
extremity that cause limb hypertrophy or loss of function, and painful lesions.  
Subjects with paraspinal PN will be eligible for this trial. Histologic confirmation of 


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tumor is not necessary in the presence of consistent clinical and radiographic findings, 
but should be considered if malignant degeneration of a PN is clinically suspected.

A PN is defined as a neurofibroma that has grown along the length of a nerve and 
may involve multiple fascicles and branches.  A spinal PN involves two or more 
levels with connection between the levels or extending laterally along the nerve.

For subjects enrolled for tumor progression, progression is defined as: 

Presence of new PN on MRI documented by comparison with prior MRI), OR

A measurable increase in PN size (≥ 20% increase in the volume, or a ≥ 13% 
increase in the product of the two longest perpendicular diameters, or a ≥ 6% 
increase in the longest diameter) documented by comparison of two scans (MRI) 
in the time period of approximately one year or less prior to evaluation for this 
study.

For subjects enrolled for a “major deformity” or “significantly disfiguring” tumor, 
eligible tumors will be limited to tumors of the head & neck or those on other areas of 
the body that are unable to be concealed by standard garments.  

All subjects must have either the clinical diagnosis of NF-1 using the National 
Institutes of Health (NIH) Consensus Conference criteria or have a constitutional NF-
1 mutation documented in a CLIA/College of American Pathologist (CAP) certified 
lab.

Subjects must have measurable PN(s) amenable to volumetric MRI analysis. For the 
purpose of this study, the target lesion must be seen on at least 3 consecutive MRI 
slices and the field of view must contain the entire tumor of interest.  Tumors must be 
at least 3 mL in volume (most PNs 3 cm in longest diameter will meet this criteria).  If 
the tumor is <3 cm in longest diameter, the subject may still be eligible.  Central 
review of the MRI of the target PN is required prior to enrollment to ensure that the 
tumor is measurable and amenable to volumetric analysis.  After consenting, please 
follow instructions in Appendix 6 or the SPM for central review of MRI.  Central 
review will take 3-7 days (please plan accordingly).

Adequate hematologic function defined as:

Absolute neutrophil count (ANC) ≥1000/µL;

Hemoglobin ≥8.0 g/dL (may receive red blood cell transfusions)

Platelets ≥75,000/µL (transfusion independent, defined as not receiving platelet 
transfusions within a 7 day period prior to enrollment)

Subjects with NF-1 and PN will only be eligible if complete tumor resection is not 
feasible, or if a subject with a surgical option refuses surgery.

Since there is no standard effective chemotherapy for subjects with NF-1 and PN, 
subjects may be treated on this trial without having received prior medical 
therapy directed at their PN.

Must not have received myelosuppressive chemotherapy within prior 4 weeks.

Must be at least 2 weeks since undergoing major surgery and must be recovered 
from effects of surgery.


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
Subjects who have received previous investigational agents or biologic therapy, 
such as tipifarnib, pirfenidone, Peg-Intron, sorefenib, imatinib or vascular 
endothelial growth factor receptor (VEGFR) or MEK inhibitors are eligible for 
enrolment if general eligibility criteria are met.

Subjects who have received therapy for PN that included other MAPK/MEK 
/RAS inhibitors are eligible for this study.
5. BRAF V600 mutant solid tumors Cohort (B4) Specific Criteria:

Male or female ≥12 months and <18 years of age at the time of signing the informed 
consent form;

BRAF V600 mutation-positive tumor as confirmed in a CLIA-approved laboratory or 
equivalent. Subjects may be enrolled based on local test results.  Note: all subjects 
must provide archival or fresh tumor tissue at screening for central confirmation of 
local test derived BRAF V600 mutation status.

Recurrent disease, refractory disease, or progressive disease after having received at 
least one standard therapy for their disease;

NOTE: Subjects with metastatic (and surgically unresectable) melanoma can be 
enrolled for first-line treatment; Melanoma subjects with CNS involvement may be 
enrolled.

Measurable or evaluable tumors.

Adequate hematologic function defined as:

Absolute neutrophil count (ANC) ≥1000/µL;

Hemoglobin ≥8.0 g/dL (may receive red blood cell transfusions)

Platelets ≥75,000/µL (transfusion independent, defined as not receiving platelet 
transfusions within a 7 day period prior to enrollment)
5.2.1.4
Specific Eligibility Criteria, Part C
Subjects must meet General Eligibility Criteria.
1. Tumors that have been documented by CLIA or equivalent certified laboratory test to 
harbor BRAF V600 mutation at diagnosis or relapse.
2. Subjects may be enrolled based on local test results.  Note: all subjects must provide 
archival or fresh tumor tissue at screening for central confirmation of local test derived 
BRAF V600 mutation status.
3. Measurable or evaluable disease.
4. Adequate bone marrow function defined as:

Absolute neutrophil count (ANC) ≥1000/µL;

Hemoglobin ≥8.0 g/dL (may receive red blood cell transfusions);

Platelets ≥75,000/µL (transfusion independent, defined as not receiving platelet 
transfusions within a 7 day period prior to enrollment).


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
PT/INR and PTT 1.3 x ULN; subjects receiving anticoagulation treatment may be 
allowed to participate with INR established within the therapeutic range prior to 
starting study medication
5.2.1.5
Specific Eligibility Criteria, Part D
Subjects must meet General Eligibility Criteria.
1. Measurable or evaluable disease.
2. Recurrent or refractory BRAF mutant LGG or LCH tumors
3. BRAF V600 mutation confirmed in a CLIA-approved laboratory or equivalent. Subjects 
may be enrolled based on local test results.  Note: all subjects must provide archival or 
fresh tumor tissue at screening for central confirmation of local test derived BRAF V600
mutation status.
4. Adequate bone marrow function defined as:

Absolute neutrophil count (ANC) ≥1000/µL;

Hemoglobin ≥8.0 g/dL (may receive red blood cell transfusions);

Platelets ≥75,000/µL (transfusion independent, defined as not receiving platelet 
transfusions within a 7 day period prior to enrollment).

PT/INR and PTT 1.3 x ULN; subjects receiving anticoagulation treatment may be 
allowed to participate with INR established within the therapeutic range prior to 
starting study medication
5.2.2
Exclusion Criteria (All Parts)
Deviations from exclusion criteria are not allowed because they can potentially jeopardize the 
scientific integrity of the study, regulatory acceptability or subject safety.  Therefore, adherence 
to the criteria as specified in the protocol is essential.
Subjects meeting any of the following criteria must not be enrolled in the study:
1. Lactating or pregnant female.
2. History of another malignancy including resected non-melanomatous skin cancer.
3. Subjects with NF-1 associated optic pathway tumors are excluded if they are actively 
receiving therapy for the optic pathway tumor or do not meet criteria for PN or malignant 
solid tumor
4. Subjects with a history of NF-1 related cerebral vascular anomaly (such as Moyamoya) 
5. Subjects with NF-1 actively receiving therapy for the optic pathway tumor.
6. Subjects with NF-1 and only PN lesions that cannot be evaluated by volumetric analysis 
(only applicable to Part B).
7. Any serious and/or unstable pre-existing medical, psychiatric disorder or other conditions 
that could interfere with subject’s safety, obtaining informed consent or compliance to the 
study procedures.
8. Any prohibited medication(s), currently used or expected to be required, as described in 
Section 9.2.
9. Any medications for treatment of left ventricular systolic dysfunction


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10. Part B, C and D:  Previous treatment with dabrafenib or any BRAF inhibitor, trametinib or 
another MEK inhibitor, or an ERK inhibitor (exception: prior treatment with sorafenib is 
permitted).  Patients who have received prior dabrafenib or another BRAF inhibitor may 
enrol into Part B4.  Patients who have had prior dabrafenib or BRAF inhibitor therapy 
may enroll in part C or Part D if they have had prior benefit to dabrafenib or BRAF 
inhibitor monotherapy, as determined by the investigator. (Note: Subjects enrolled in Parts 
A or B are not eligible to participate in Parts C or D)
11. Administration of an investigational study treatment within 30 days preceding the first 
dose of study treatment(s) in this study.
12. Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs 
chemically related to study treatment or excipients that contraindicate their participation.
13. Current active liver or biliary disease (with the exception of Gilbert's syndrome or 
asymptomatic gallstones, or liver metastases).
14. History of hepatic sinusoid obstructive syndrome (venoocculsive disease) within the prior 
3 months.
15. History of heparin-induced thrombocytopenia.
16. History of interstitial lung disease or pneumonitis.
17. History or current evidence  RVO 
18. For subjects with solid tumors that are not primary CNS tumors or NF-1 associated 
plexiform neurofibromas, subjects with symptomatic or untreated leptomeningeal or brain 
metastases or spinal cord compression are excluded.
NOTE: Subjects previously treated for these conditions that have had stable CNS disease 
(verified with consecutive imaging studies) for >3 months, are asymptomatic and are not 
currently taking corticosteroids, or are on stable dose or decreasing of corticosteroids for at least 
7 days prior to enrolment are permitted.
19. A history of known Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection. 
Subjects with laboratory evidence of cleared HBV and HCV infection may be enrolled.
20. Unresolved toxicity of National Cancer Institute Common Terminology Criteria for 
Adverse Events, version 4.03 (NCI CTCAE v4.03) (NCI 2009) Grade 2 or higher from 
previous anti-cancer therapy, except alopecia.
21. Presence of active gastrointestinal disease or other condition that will interfere 
significantly with the absorption of drugs.  If clarification is needed as to whether a 
condition will significantly affect absorption of drugs, contact the Novartis Medical Lead 
for guidance to enrol the subject.
22. A history or evidence of cardiovascular risk including any of the following:

A QT interval corrected for heart rate using the Bazett’s formula (QTcB) 480 msec;

A history or evidence of current clinically significant uncontrolled arrhythmias; 
Clarification: Subjects with atrial fibrillation controlled for >30 days prior to dosing 
are eligible.

A history of acute coronary syndromes (including myocardial infarction or unstable 
angina), coronary angioplasty, or stenting within 6 months prior to randomization.


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
A history or evidence of current Class II congestive heart failure as defined by the 
New York Heart Association (NYHA) guidelines;

Patients with intra-cardiac defibrillators;

Abnormal cardiac valve morphology (≥grade 2) documented by echocardiogram 
(subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be entered 
on study).  Subjects with moderate valvular thickening should not be entered on 
study.  Subjects with prosthetic valves can be considered eligible provided they meet 
the criteria as stated above.

Treatment refractory hypertension defined as a blood pressure of systolic> 140 mmHg 
and/or diastolic > 90 mm Hg (or above 95th age-specific percentile as listed in 
Appendix 8), which cannot be controlled by anti-hypertensive therapy;
6
Completion or Withdrawal of Subjects
6.1
Screen and Baseline Failures
Data for screen and baseline failures will be collected in source documentation at the site but 
will not be transmitted to Novartis.
6.2
Subject Completion Criteria
A subject will be considered to have completed the study if they discontinued study treatment 
for reasons listed in Section 6.2 and completed a post-treatment follow-up visit or has died 
while receiving study treatment.
6.3
Permanent Discontinuation from Study Treatment
Subjects will receive study treatment until disease progression, death or unacceptable toxicity, 
including meeting stopping criteria for liver chemistry defined in Section 3.12.1.  In addition, 
study treatment may be permanently discontinued for any of the following reasons:

serious deviation(s) from the protocol that result in a significant risk to the patient’s 
safety;

subject becomes pregnant;

request of the subject or proxy (withdrawal of consent by subject or proxy);

investigator’s discretion;

a dose delay due to study treatment related toxicity of >28 days;

intercurrent illness that prevents further administration of study treatment(s);

subject is lost to follow-up;

sponsor terminates the study.
The primary reason study treatment was permanently discontinued must be documented in the 
subject’s medical records and eCRF.
If the subject voluntarily discontinues from treatment due to toxicity, ‘AE’ will be recorded as 
the primary reason for permanently discontinuation on the eCRF.


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Once a subject has permanently discontinued from study treatment, the subject will not be 
allowed to be retreated. All subjects who discontinue from study treatment will have safety 
assessments at the time of discontinuation and during post-study treatment follow-up as 
specified in Time and Events Table (see Section 7.1).
Adverse Events must be followed for a minimum of 30 days after the last dose. If it is not 
practical for the subject to return to the clinic, this data may be collected via telephone from the 
parent/caregiver/subject (as appropriate). 
The discontinuation related safety assessments (same assessments as Final visit in the Time and 
Events Table) may be completed at any time from the last dose to 30 days after the last dose.  
Ongoing toxicities should be followed to resolution if at all possible. If the decision to 
discontinue the patient occurs at a regularly scheduled visit, that visit may become the EOT 
visit rather than having the patient return for an additional visit.
6.4
Subject Visits and Lost to follow-up Criteria
Should a subject fail to attend the clinic for a required study visit, the site should attempt to 
contact the subject and re-schedule the missed visit as soon as possible.  The site should also 
counsel the subject on the importance of maintaining the assigned visit schedule and ascertain 
whether or not the subject wishes to and/or should continue in the study based on previous non-
compliance.
In cases where the subject does not return for the rescheduled visit or cannot be reached to 
reschedule the missed visit, the site should make every effort to regain contact with the subject 
(3 telephone calls and if necessary a certified letter to the subject’s last known mailing address) 
so that they can be appropriately withdrawn from the study.  These contact attempts should be 
documented in the subject’s medical record.
Should the subject continue to be unreachable, then and only then will he/she be considered to 
have withdrawn from the study with a primary reason of “Lost to Follow-up”.  For all other 
subjects withdrawing from the study, an alternative reason for discontinuation should be
recorded in the eCRF.
6.5
Study Completion
The study will be considered completed when the last subject enrolled (without disease 
progression or withdraw from the study for another reason) has been in the study for a minimum 
of 6 months AND, for those subjects still benefiting from treatment, the rollover protocols are 
open to enroll pediatric subjects.  For subjects entering the rollover study, data from the final 
study visit may be used for the transition visit into the rollover study
Per the EU Clinical Trial Directive, the end of the study is defined as the last subject’s last visit.
6.6
Treatment after the End of the Study
The investigator is responsible for ensuring that consideration has been given for the post-study 
care of the subject’s medical condition whether or not Novartis is providing specific post-study 
treatment.


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After study participation in the current study is completed or terminated, subjects may either:
1. Transition to the rollover study if eligible and continue receiving treatment with trametinib
or trametinib and dabrafenib
OR
2. Complete a follow-up visit after the last dose of study treatment(s) if the subject:

chooses not to enter the roll-over study, or

is withdrawn due to an AE considered related to study treatment, or

is considered ineligible to enter the rollover study.
Subjects who discontinued treatment with trametinib or dabrafenib will be offered Follow-Up 
from Novartis consisting of a visit every 3 months (±15 days) for a period of 2 years.  At each 
visit, the following assessments will be performed:  

Brief history and physical exam (a brief physical examination will include 
assessments of the skin, lungs, cardiovascular system, and abdomen (liver and spleen) 
[and neurological exam as clinically indicated]; brief physical exam to also include 
dermatologic evaluation, growth, and sexual maturation);

History to review development;

History of new malignancies or secondary malignancies, or other significant changes.
Subjects who discontinued dabrafenib treatment will be followed every 3 months for 2 years to 
monitor for the occurrence of cuSCC and monitored for up to 2 years for non-cutaneous 
malignancy. 
6.7
Withdrawal of Consent
Subjects may voluntarily withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent occurs only when a subject:

Does not want to participate in the study anymore, and 

Does not allow further collection of personal data. 

In this situation, the investigator should make a reasonable effort (e.g. telephone, e-
mail, letter) to understand the primary reason for the subject’s 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 subject 
are not allowed unless safety findings require further communication or follow-up.

All efforts should be made to complete the assessments prior to study withdrawal. A 
final evaluation at the time of the subject’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 subject’s samples until their time of withdrawal) according to applicable 
law.


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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
Study Assessments and Procedures
A signed, written informed consent form must be obtained from the subject prior to any study-
specific procedures or assessments being performed.
The timing of each assessment is listed in the Time and Events Table (Section 7.1).  The timing 
and number of the planned study assessments may be altered during the course of the study 
based on newly available data (e.g., to obtain data closer to the time of peak plasma 
concentrations) to ensure appropriate monitoring for the following assessments: safety, PK, 
PD
 or other assessments.  The institutional review board (IRB) or independent 
ethics committee (IEC) will be informed of any safety issues that require alteration of the safety
monitoring scheme.  No more than 10 mL of blood will be collected at baseline, up to 30 mL 
for safety and 10-22 mL for PK in the first month (depending on weight), then 6 mL every 4 
weeks for the first year, decreasing to every 12 weeks after the first year.
Whenever vital signs, 12-lead ECGs and blood draws are scheduled for the same nominal time, 
the timing of the assessments should allow the blood draw to occur at the exact nominal time.  
Detailed procedures for obtaining each assessment are provided in the SPM.
7.1
Time and Events Tables
This section consists of the Time and Events Tables to describe assessment windows and 
sequencing of study-specific assessments and procedures.


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Table 7-1
Time and Events, Treatment Phase:  Screening through Day 28
All subjects (unless specified) 
screening- day 28 
STUDY PHASE
SCREEN
TREATMENT DAYS 1 through 28
VISIT
Screen
Pre-dose
Day 1, 
Week 1
Pre-
dose
Day 8,
Week 2
Pre-
dose 
Day 15, 
Week 3
Pre-
dose 
Day 22, 
Week 4
Pre-
dose 
Day 28, 
Week 5
VISIT WINDOW (days)
-14
N/A
2
2
2
2
Baseline Assessments
Informed consent/assent
X
Tumor biopsy or bone marrow 
aspirate, Part A
Optional fresh biopsy or bone marrow aspirate.
X
Archived tumor biopsy or bone 
marrow aspirate, Part B1, B2, 
and B3
Archived tissue at screening is required and must be 
available to be shipped to Novartis; if not available fresh 
biopsy is acceptable. RAS mutation status does not have 
to be done within 14 days prior to dosing.
X
Tumor tissue for V600 testing 
for those subjects enrolled in 
Part B4, Part C and Part D, 
BRAFV600 mutation as per a local result is required for 
enrolment in the study; the local testing will be subject to 
subsequent confirmation by centralized testing.  Central 
confirmation can be from archival tissue or if no archival 
tissue is available, from fresh biopsy.  Central 
confirmation not required within 14 days prior to dosing.
X
Demographic data
Record date of birth, gender, race and ethnicity
X
Register subject
Using an interactive voice response system
X
X
Height and Weight/
Measurements in metric scale.
X
X 
X
Tanner Stage
X
X
Serum pregnancy test
In all menstruating females and according to applicable 
local requirements and/or regulations, a serum pregnancy 
test is required at screening (within 7 days of 
administration of the first dose of study medication).  If 
performed within 7 days of first dose of study drug, does 
not need to be repeated on Day 1 (pre-dose)
X
X
X
Disease characteristics
Record date of diagnosis, primary tumor type, histology, 
stage, etc.
X


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All subjects (unless specified) 
screening- day 28 
STUDY PHASE
SCREEN
TREATMENT DAYS 1 through 28
VISIT
Screen
Pre-dose
Day 1, 
Week 1
Pre-
dose
Day 8,
Week 2
Pre-
dose 
Day 15, 
Week 3
Pre-
dose 
Day 22, 
Week 4
Pre-
dose 
Day 28, 
Week 5
VISIT WINDOW (days)
-14
N/A
2
2
2
2
Prior anti-cancer therapy & 
radiation
X
Prior major surgical procedures
X
Past and current medical 
conditions
Medical history will be assessed as related to the eligibility criteria 
listed in Section 5.2.1.  Cardiovascular medical history/risk factors will 
also be assessed at baseline
X
Safety/Tolerability 
Assessments
Physical examination
Assessment of the head, eyes, ears, nose, throat, skin, 
thyroid, neurological, lungs, cardiovascular, abdomen 
(liver and spleen), lymph nodes and extremities 
X
X
X
X
X
X
Dermatologic skin assessment
Performed by the investigator (or dermatologist, at the 
discretion of the investigator).  If possible, the same 
physician should perform each exam throughout the 
study.  Photographs of suspect lesions at baseline are 
recommended with photographs and/or biopsies of any 
new or changing lesions recommended at subsequent on-
study visits. For subjects enrolled in France, see Appendix 
10 for additional follow up. 
X
X
Plain Radiograph of Wrist or 
Tibial Growth Plate
This procedure scheduled for Day 1 can be done anytime 
between screening and Day 1
X
Ophthalmologic examination
Performed by ophthalmologist. See Section 7.3.2 for 
details.
X
X
ECG
Two copies of the ECG tracing should be obtained at the 
time of the ECG, one to be kept in the study file for 
retrospective collection by the sponsor if necessary.  ECG 
data should be reviewed by personnel with experience in 
this study population (e.g., pediatric cardiologist).
X


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All subjects (unless specified) 
screening- day 28 
STUDY PHASE
SCREEN
TREATMENT DAYS 1 through 28
VISIT
Screen
Pre-dose
Day 1, 
Week 1
Pre-
dose
Day 8,
Week 2
Pre-
dose 
Day 15, 
Week 3
Pre-
dose 
Day 22, 
Week 4
Pre-
dose 
Day 28, 
Week 5
VISIT WINDOW (days)
-14
N/A
2
2
2
2
Echocardiogram (ECHO) 
Copies of all ECHOs performed on subjects will be sent to 
the study sponsor during the study (Additional details in 
the SPM).
X
X
Vital signs
Blood pressure (at baseline, 3 serial blood pressures; 
separated by at least 5 minutes see Section 7.3.4; for all 
other visits, one measure), body temperature, pulse rate, 
respirations
X
X
X
X
X
X
Urinalysis
Routine Urinalysis (See Table 3-5)
X
Concomitant medications
See Section 9 for list of prohibited and cautionary 
medications.
X
X
X
X
X
X
Adverse events
Adverse event assessment should be continuous
X
X
X
X
X
Palatability questionnaire 
(subjects receiving oral liquid 
formulation)
To be completed after the first dose of study drug and no 
later than Day 8 (3 days). See Section 7.3.7 for details. 
Separate questionnaires are to be used for trametinib and 
dabrafenib in Part C and part D
X
Blood Sampling
Chemistry
Evaluations performed by a local laboratory. Not required 
on Day 1 if screening assessments were within 72 hr of 
first dose.
X
X
X
X
X
X
Hematology
Evaluations performed by a local laboratory. Not required
on Day 1 if screening assessments were within 72 hr of 
first dose.
X
X
X
X
X
X
PK sampling
For Part A and Part A extension, trametinib PK sampling 
is required to be drawn on Day 15 and Day 22. For Part B, 
trametinib PK sampling is required to be drawn on Day 15 
only. For Part C, Part C extension and Part D, trametinib, 
dabrafenib and dabrafenib metabolites PK sampling is 
required to be drawn on Study Day 1, Day 15 and Day 22. 
X (Parts 
C and D)
X (All 
Parts)
X (Parts 
A, C and 
D)


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All subjects (unless specified) 
screening- day 28 
STUDY PHASE
SCREEN
TREATMENT DAYS 1 through 28
VISIT
Screen
Pre-dose
Day 1, 
Week 1
Pre-
dose
Day 8,
Week 2
Pre-
dose 
Day 15, 
Week 3
Pre-
dose 
Day 22, 
Week 4
Pre-
dose 
Day 28, 
Week 5
VISIT WINDOW (days)
-14
N/A
2
2
2
2
There is no visit window around these samples. For 
details, see Table 7-2 and Table 7-3 for PK schedules
Clinical Activity
Target and non-target lesion 
assessment
Must be identified at time of screening scan.
X
Brain MRI (glioma subjects 
ONLY)
May use brain MRI obtained within 35 days of the first 
dose.  CT with contrast allowed only if brain MRI is 
contraindicated.
X
Performance status 
(Karnofsky/Lansky)
See Appendix 1
X
X
X
X
X
X
MRI with volumetric assessment 
for Plexiform Neurofibromas
NF-1 PN Cohort Only. May be performed up to 4 weeks 
prior to enrollment, and requires central review (see 
Section 5.2.1.3)
X (Part 
B)
Tumor biopsy 
Optional fresh biopsy 
X
X
Study Medication
Dispense oral study medication 
and assess compliance
Dispense study medication with instructions.  Record 
dose reductions, dose interruptions/delays, and/or dose 
escalations.
X
X
Collection of Scans obtained 
prior to study
For patients with a diagnosis of 
LGG only (enrolled in all parts)
Collection of efficacy assessments (imaging scans, 
primarily MRI), if available from the most recent prior 
chemotherapy regimen to include the baseline 
assessment and a time point closest to 6 months following 
initiation of that therapy. 
This should be collected within 1 month of the patient enrolling in the 
study, or within 1 month of this amendment being approved, whichever 
is the later.
MRI = magnetic resonance imaging; ECG = electrocardiogram; ECHO = echocardiogram; PK = pharmacokinetic


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Table 7-2
Trametinib Monotherapy PK Sampling: Time and Events for Parts A, A extension and B on Day 15 and Day 22
Day 15 (Parts A, A extension and B)
Day 22 (Part A and Part A 
extension only)
Hr
0
1
2
4
7
10
24
0
COLLECTION WINDOW
-30 min
5 min
5 min
20  min
20 min
2 hr
20 min
-30 min
Subjects ≥ 25 kg
PK (2 mL sample)
X
X
X
X
X
X
X
X
Subjects <25 and ≥ 10 kg
PK (2 mL samples)
X
X
X
X
X
X
X
X
Subjects  < 10 kg
PK (2 mL samples)
X
X
X
X
X
Table 7-3
Trametinib and Dabrafenib Combination PK Sampling: Time and Events for Parts C, C extension and D on Day 1, 
Day 15 and Day 22
Day 1
Day 15
Day 22
Hr
0.5
2
4
0
0.5
1
2
3
4
6
8
0
COLLECTION WINDOW
5 
min
5 
min
20 
min
-30 
min
5 
min
5 
min
5 
min
20 
min
20 
min
20 
min
20 
min
-30
min
Subjects ≥ 25 kg
Trametinib, dabrafenib and dabrafenib 
metabolites PK (1 mL sample)
X
X
X
X
X
X
X
X
X
X
X
X
Subjects <25 and ≥ 10 kg
Trametinib, dabrafenib and dabrafenib 
metabolites PK (1 mL sample)
X
X
X
X
X
X
X
X
X
X
Subjects  < 10 kg
Trametinib, dabrafenib and dabrafenib 
metabolites PK (1 mL sample)
X
X
X
X
Plasma concentrations of trametinib, dabrafenib and dabrafenib metabolites will be measured in the 1 mL blood sample.
.


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Table 7-4
Time and Events, Treatment Phase, Week 9 to Final Visit
(All subjects unless specified)
week 9- final visit:
STUDY PHASE
TREATMENT WEEK 9+
Visit
Week 9
Week 13
Week 17
Week 21
Week 25
Weeks 25+ 
(after 6 
months)
Weeks 49+ 
(after 1 
year)
Final Visit
VISIT WINDOW (days)
3
7
7
7
7
7
7
Safety Assessments
Brief Physical examination
Will include height and weight, and assessments of 
the skin, lungs, cardiovascular system, and abdomen 
(liver and spleen) [and neurological exam as clinically 
indicated]
X
X
X
X
X
Every 4 
weeks
Every 12 
weeks
X
Dermatologic skin assessment
Performed by the investigator (or dermatologist, at the 
discretion of the investigator).  If possible, the same 
physician should perform each exam for the duration 
of the study to ensure consistency between 
evaluations.  Photographs of suspect lesions at 
baseline are recommended with photographs and/or 
biopsies of any new or changing lesions 
recommended at subsequent on-study visits.
X
X
X
X
X
Every 4 
weeks
Every 12 
weeks
X
Plain radiograph of wrist or tibial growth 
plate
Only in subjects with open growth plates at screening
X
X
Every 24 
weeks (6 
months) 
Every 48 
weeks (12 
months)
X
Tanner Stage
X
Every 24 
weeks (6 
months) 
Every 24 
weeks
X
Urine Pregnancy test
For menstruating females and as required per local 
applicable regulations
X
X
X
X
X
Every 4 
weeks
Every 12 
weeks
X
Vital signs
Blood pressure, body temperature, pulse rate, 
respirations
X
X
X
X
X
Every 4 
weeks
Every 12 
weeks
X
Ophthalmologic examination
Performed by ophthalmologist. See Section 7.3.2 for 
details.
X
X
Every 12 
weeks
Every 12 
weeks


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(All subjects unless specified)
week 9- final visit:
STUDY PHASE
TREATMENT WEEK 9+
Visit
Week 9
Week 13
Week 17
Week 21
Week 25
Weeks 25+ 
(after 6 
months)
Weeks 49+ 
(after 1 
year)
Final Visit
VISIT WINDOW (days)
3
7
7
7
7
7
7
ECG
Two copies of the ECG tracing should be obtained at 
the time of the ECG, one to be kept in the study file for 
retrospective collection by the sponsor if necessary.  
ECG data should be reviewed by personnel with 
experience in this study population 
X
X
X
Every 12 
weeks
Every 12 
weeks
X
Echocardiogram (ECHO)
Copies of all ECHOs will be collected and sent to the 
study sponsor during the study.  An ECHO does not 
need to be performed at study discontinuation unless 
one was not performed within the previous 8 weeks.
X
X
Every 12 
weeks
Every 12 
weeks
X
Concomitant medications
See Protocol Section 9 for list of prohibited and 
cautionary medications.
X
X
X
X
X
X
X
X
Adverse events
Adverse event assessment should be continuous
X
X
X
X
X
X
X
X
Urinalysis
Routine Urinalysis (See Table 7-6)
X
X
X
X
X
Every 4 
weeks
Every 12 
weeks
X
Blood Sampling
Chemistry
Evaluations performed by a local laboratory
X
X
X
X
X
Every 4 
weeks
Every 12 
weeks
X
Hematology
Evaluations performed by a local laboratory
X
X
X
X
X
Every 
4weeks
Every 12 
weeks
X


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(All subjects unless specified)
week 9- final visit:
STUDY PHASE
TREATMENT WEEK 9+
Visit
Week 9
Week 13
Week 17
Week 21
Week 25
Weeks 25+ 
(after 6 
months)
Weeks 49+ 
(after 1 
year)
Final Visit
VISIT WINDOW (days)
3
7
7
7
7
7
7
Clinical Activity 
Assessments
Part A, Part C and Part D only; for Part B please see Table 7-5
Target and non-target lesion assessment
Target and non-target lesions identified at time of 
screening scan must be re-assessed at each 
restaging scan.  If the last radiographic assessment 
was more than 12 weeks prior to subject 
discontinuation from study and progressive disease 
has not been documented, a disease assessment 
should be obtained at the time of study 
discontinuation. 
For disease specific assessment modality, see
Section 7.6
X
X
X
Every 12 
weeks
Every 12 
weeks (or 
more 
frequently 
per local 
standard 
of care)
X
Response (all subjects except LCH 
subjects)
Complete response/partial response confirmation 
assessments may take place at Week 13 if initial 
response was seen at the Week 9 scan.  Initial 
response (complete response/partial response) that is 
observed at Week 17 or after should be confirmed not 
less than 4 and not more than 8 weeks after the initial 
response.
For disease specific assessment methodology, refer 
to Section 7.6 and Appendix 3 to Appendix 7
X
X
X 
Every 12 
weeks
Every 12 
weeks
X
Response (LCH subjects only)
For disease specific assessment methodology, refer 
to Appendix 7
X
X
Every 12 
weeks
Every 12 
weeks
X
Performance status (Karnofsky/Lansky)
See Appendix 1
X
X
X
X
Every 12 
weeks
Every 12 
weeks
X
Tumor Biopsy
Optional fresh biopsy
Upon disease progression


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(All subjects unless specified)
week 9- final visit:
STUDY PHASE
TREATMENT WEEK 9+
Visit
Week 9
Week 13
Week 17
Week 21
Week 25
Weeks 25+ 
(after 6 
months)
Weeks 49+ 
(after 1 
year)
Final Visit
VISIT WINDOW (days)
3
7
7
7
7
7
7
Study Medication
Dispense oral study medication and 
assess compliance
Dispense a 4 week supply of the study medication 
with instructions.  Record dose reductions, dose 
interruptions/delays, and/or dose escalations.
X
X
X
X
X
Every 4 
weeks
Every 4-
12 weeks
Post Treatment Follow-up – See Section 6.6
MRI = magnetic resonance imaging; ECG = electrocardiogram; ECHO = echocardiogram
Table 7-5
Time and Events, Part B Clinical Activity Assessments, Week 9 to Final Visit
Additional  events Part B  week 9- final Visit: STUDY PHASE
TREATMENT WEEK 4+
Visit
Week 
9
Week 
13
Week 
17
Week 
21
Week 
25
Weeks 25+ 
(after 6 months)
Weeks 49+ 
(after 1 year)
Final 
Visit
VISIT WINDOW (days)
3
7
7
7
7
7
7
Clinical Activity 
 Assessments
Solid Tumor Cohort B1, BRAF Fusion Cohort B2, and BRAF V600 Mutant Solid Tumor Cohort B4
Target and non-target 
lesion assessment
Target and non-target lesions identified at 
time of screening scan must be re-
assessed at each restaging scan.  If the 
last radiographic assessment was more 
than 12 weeks prior to subject 
discontinuation from study and 
progressive disease has not been 
documented, a disease assessment 
should be obtained at the time of study 
discontinuation
For disease specific assessment modality, 
see Section 7.6
X
X
X
Every 12 weeks
Every 12 
weeks (or 
more 
frequently per 
local standard 
of care)
X


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Additional  events Part B  week 9- final Visit: STUDY PHASE
TREATMENT WEEK 4+
Visit
Week 
9
Week 
13
Week 
17
Week 
21
Week 
25
Weeks 25+ 
(after 6 months)
Weeks 49+ 
(after 1 year)
Final 
Visit
VISIT WINDOW (days)
3
7
7
7
7
7
7
Response
Complete response/partial response 
confirmation assessments may take place 
at Week 13 if initial response was seen at 
the Week 9 scan.  Initial response 
(complete response/partial response) that 
is observed at Week 17 or after should be 
confirmed not less than 4 and not more 
than 8 weeks after the initial response.
For disease specific assessment 
methodology,  refer to Section 7.6 and 
Appendices 3-7
X
X
X
Every 12 weeks
Every 12 
weeks
X
Performance status 
(Karnofsky/Lansky)
See Appendix 1
X
X
X
X
Every 12 weeks
Every 12 
weeks
X
Tumor Biopsy
Optional fresh biopsy
Upon disease progression
NF-1 Plexiform Neurofibroma Cohort B3
MRI with volumetric 
assessment and/or 
RECIST 1.1
Visit window of  2 weeks is allowed, 
central review required for baseline scan 
(Section 7.6.1)
X
Week 33, 49 
Week 73, 97 
Then every 24 
weeks
X
Response for NF-1
For disease specific assessment 
methodology,  refer to Section 7.6 and 
Appendices 3-7
X
Week 33, 49 
Week 73, 97 
Then every 24 
weeks
X
Tumor tissue
Optional fresh biopsy
Upon disease progression


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7.2
Demographic/Medical History and Baseline Assessments
The following demographic parameters will be captured during Screening: date of birth, gender, 
race and ethnicity.
Medical/medication history assessed as related to the eligibility criteria listed in Section 5.2.
Baseline (Screening) assessments are detailed in the Time and Events Table Section 7.1.
Procedures conducted as part of the subject’s routine clinical management (e.g., blood count, 
imaging study) and obtained prior to signing of informed consent may be utilized for Screening 
or baseline purposes provided the procedure meets the protocol-defined criteria and has been 
performed in the timeframe of the study.
Additional historic data will be collected, if available, on patients with a diagnosis of LGG 
enrolled in all study parts.  The additional data will consist of efficacy assessments (imaging 
scans, primarily MRI) from the most recent prior chemotherapy regimen to include the baseline 
assessment (scan taken just before the initiation of the prior chemotherapy) and a time point 
closest to 6 months following initiation of that therapy.
7.3
Safety Evaluations
Planned time points for all safety assessments are provided in the Time and Events Table 
(Section 7.1).
7.3.1
Physical Examinations
A complete physical examination will include assessments of the head, neck, eyes, ears, nose, 
mouth, throat, skin, thyroid, neurological, lungs, cardiovascular, abdomen (liver and spleen), 
lymph nodes and extremities.  Height and weight will also be measured and recorded. Sexual 
maturation will be assessed using Tanner staging.
A brief physical examination will include assessments of the head, neck, eyes, skin, lungs, 
cardiovascular system, and abdomen (liver and spleen).
A full body dermatological examination will be performed by a dermatologist (or suitably 
qualified physician) to identify abnormal skin lesions.  All findings will be photographed and 
identified during screening.  Brief skin examinations will be performed as indicated in the Time 
and Events Table or more frequently as necessitated.  Wherever possible, the same physician 
should perform these examinations.  Follow-up skin examinations by a referral dermatologist 
should be conducted if clinically indicated.
Plain radiographs of the wrist or tibial growth plates (following institutional practice) are 
required in children with open growth plates at Day 1. Radiograph can be performed anytime 
between screening and Day 1.


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7.3.2
Ophthalmology Examination
An age-appropriate ophthalmologic examination should be performed by an ophthalmologist at 
screening and at the timepoints specified in the Time and Events Tables (Section 7.1).
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).
7.3.3
Performance Status
The performance status will be assessed using Karnofsky and Lansky Scales (Appendix 1) as 
specified in the Time and Events Table (Section 7.1).
7.3.4
Vital Signs
Vital sign measurements will include systolic and diastolic blood pressure, temperature, 
respiration rate and pulse rate.  Vital signs should be measured after resting for at least 5 minutes 
in a semi-supine position.  Vital signs will be measured more frequently if warranted by clinical 
condition of the subject.  On days where vital signs are measured multiple times, temperature 
does not need to be repeated unless clinically indicated.  Refer to the SPM for details regarding 
measurement of vital signs. Baseline blood pressure measurement should be performed in 
triplicate and for all other occasions, measurement should be performed once.
Baseline blood pressure (BP) is defined as the blood pressure obtained at the examination used 
for study enrollment. This baseline BP should be obtained as follows:
1. Obtain 3 serial blood pressures from the same extremity with the patient in the same 
position that are separated by at least 5 minutes. Avoid using the lower extremity if 
possible.
2. Average the systolic blood pressure from the 2nd and 3rd measurements.
3. Average the diastolic blood pressure from the 2nd and 3rd measurements.
4. The baseline BP is the average of the systolic and average of the diastolic measurements.
7.3.5
Electrocardiogram
Single 12-lead ECGs will be obtained at designated time points during the study using an ECG 
machine that automatically calculates the heart rate and measures PR interval, QRS, QT, and 
corrected QT (QTc) intervals.  At each assessment a 12-lead ECG will be performed by 
qualified personnel at the site after the subject has at least a 10 minute rest.
The QT interval should be corrected for heart rate by Bazett’s formula (QTcB).  Refer to Section 
3.12.1 for QTc stopping criteria.  Additional QTc readings may be performed if necessary.  
Refer to the SPM for details regarding ECG procedures.
7.3.6
Echocardiogram
The ECHOs will be performed to assess cardiac ejection fraction and cardiac valve morphology 
for the purpose of study eligibility and during the study as specified in the Time and Events 


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Table (Section 7.1).  Additional ECHO assessments may be performed if clinically warranted.  
The evaluation of the echocardiographer should include an evaluation for LVEF and both right 
and left-sided valvular lesions.
Copies of all study ECHOs performed will be required to be provided to the sponsor. The 
ECHOs will not be reviewed in a real-time basis by the sponsor, but rather held for review at a 
future time point if a cardiac safety signal is identified.
7.3.7
Laboratory Assessments
All protocol required laboratory assessments, as defined in Table 7-6, should be performed 
according to the Time and Events Table (Section 7.1).  Details for the preparation and shipment 
of samples will be provided in the SPM.
Prior to administration of the first dose of study treatment, results of laboratory assessments 
should be reviewed.  Any laboratory test with a value outside the normal range may be repeated 
(prior to the first dose) at the discretion of the investigator.
If additional non-protocol specified laboratory assessments are performed at the institution’s 
local laboratory and result in a change in subject management or are considered clinical 
significant by the investigator (for example SAE or AE or dose modification) the results must 
be recorded in the subject’s CRF.  Refer to the SPM for appropriate processing and handling of 
samples to avoid duplicate and/or additional blood draws.
All laboratory tests with values that are significantly abnormal (Grade ≥3) during participation 
in the study or within 30 days after the last dose of study treatment should be repeated until the 
values return to normal or baseline.  If such values do not return to normal within a period 
judged reasonable by the investigator, the etiology should be identified and the sponsor notified.
Hematology, clinical chemistry, urinalysis and additional parameters to be tested are listed 
below:


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Table 7-6
List of Clinical Laboratory Tests
Hematology
Platelet Count 
RBC Indices:
Automated WBC Differential:
Red blood cell (RBC) Count
MCV
Neutrophils
White blood cell (WBC) Count 
(absolute) 
MCH
Lymphocytes
Hemoglobin
MCHC
Monocytes
Hematocrit
Eosinophils
HbA1c  at baseline (screening) only
Basophils
Clinical Chemistry
Blood urea nitrogen 
(BUN)
Potassium
Aspartate aminotransferase 
(AST)
Total and direct bilirubin (Bilirubin 
fractionation recommended if 
total bilirubin is >2x the upper 
limit of normal)
Creatinine
Chloride
Alanine aminotransferase (ALT)
Total Protein
Glucose (recheck 
fasting if 
>160 mg/dL)
Total carbon 
dioxide (CO2)
Gamma glutamyl transferase 
(GGT)
Albumin
Sodium
Calcium
Alkaline phosphatase (ALP)
Magnesium
Phosphate
Routine Urinalysis
Specific gravity
pH, glucose, protein, blood and ketones by dipstick
Microscopic examination (if blood or protein is abnormal)
Other screening tests
Serum pregnancy test
HVA/VMA in random or 24 hr urine for subjects with neuroblastoma
In the event of abdominal pain or suspected pancreatitis, amylase and lipase laboratory samples should be 
collected.
RBC = Red Blood Cell; WBC = White Blood Cell; MCV = Mean Corpuscular Volume; MCH = Mean 
Corpuscular Hemoglobin:  MCHC = Mean Corpuscular Hemoglobin Concentration; HVA/VMA = 
Homovanillic Acid / Vanillylmandelic Acid (ratio); CSF = Cerebrospinal fluid.
Palatability
For subjects ≥12 years of age who receive the dabrafenib suspension or trametinib oral solution, 
the subject will complete a form (for each drug separately if enrolled in Parts C and D) to 
evaluate the various properties of the suspension (e.g., bitterness, sweetness, appearance, 
texture and overall taste).  If the subject ≥12 years of age needs assistance completing the 
questionnaire(s), his/her caregiver (e.g. parent or guardian) will be requested to evaluate the 
suspension with the child based on verbal and non-verbal feedback.  For subjects <12 years of 
age who receive the suspension, their caregiver (e.g. parent or guardian) will be requested to 
evaluate the suspension with the child based on verbal and non-verbal feedback.   
Questionnaires for trametinib and dabrafenib are provided in the SPM.  The questionnaire (s) 
may be completed after the first dose of study drug (s) and must be completed no later than Day 
8 (±3 days). 


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7.3.8
Pregnancy Testing and Reporting
The need for a screening pregnancy test depends on whether a female subject is of childbearing 
potential or non-childbearing potential.
If a female subject is of childbearing potential, she must have a serum -Human Chorionic 
Gonadotropin (-HCG) pregnancy test performed within 7 days prior to the first dose of study 
treatment(s).  Subjects with a positive pregnancy test result must be excluded from the study.  
Subjects with a negative pregnancy test result must agree to use an effective contraception 
method as described below during the study until 4 months following the last dose of study 
treatment(s).
Any pregnancy that occurs during study participation must be reported using a clinical trial 
pregnancy form.  To ensure subject safety, each pregnancy must be reported to Novartis within 
24 hours of learning of its occurrence.  The pregnancy must be followed up to determine 
outcome (including premature termination) and status of mother and child.  Pregnancy 
complications and elective terminations for medical reasons must be reported as an AE or SAE.  
Spontaneous abortions must be reported as an SAE.
Any SAE occurring in association with a pregnancy brought to the investigator’s attention after 
the subject has completed the study and considered by the investigator as possibly related to the 
study treatment(s), must be promptly reported to Novartis.
In addition, the investigator must attempt to collect pregnancy information on any female 
partners of male study subjects who become pregnant while the subject is enrolled in the study.  
Pregnancy information must be reported to Novartis as described above.
7.4
Pharmacokinetics
PK parameters for study treatment (trametinib,dabrafenib and its metabolites) for subjects in 
whom the full blood sampling scheme will be used will be calculated with standard non-
compartmental methods.  The PK parameters calculated with non-compartmental methods 
include: AUC(0-t), Cmax, Tmax, Cτ, CL/F, and AUC (0-τ) (where τ = 24 hr for trametinib and 
12 hr for dabrafenib).  For subjects in whom the sparse blood sample collection scheme will be 
used, AUC(0-τ) and the average steady-state concentration may be estimated with a population 
PK model.  Final PK parameters will be summarized and will be compared to historical adult 
data.
All trametinib and dabrafenib concentration-time data may be combined and included in a 
population PK analysis that will examine the influence of demographics (especially age and 
weight) on the PK of study treatment.  Trametinib and dabrafenib PK parameters estimated in 
the population PK analysis may include: apparent clearance following oral dosing (CL/F), 
volume of distribution (V/F), and absorption rate (ka) (trametinib only).  Data may be pooled 
with trametinib and/or dabrafenib PK data from all parts of this study and with adult data.










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Table 7-8
Efficacy Assessment Methods and Measurement Modalities
Disease
Required Response Assessment
Required Response Measurement Modality
Glioma
Response assessed using RANO criteria provided in Appendix 5 by the treating 
institutions at each response assessment time points listed in Time and Events Table 
(Section 7.1)
Brain MRI is required at all assessment time points. If a 
brain MRI is contraindicated, a CT scan with contrast is 
allowed
NF-1 with PN
For all subjects with NF-1 with PN enrolled in Part A, Part A extension and Part B3, 
RECIST 1.1 based assessment is required by the treating institution. However, if the 
institution’s standard practice uses volumetric assessment (by Dombi et al in Appendix 
6), both assessments are required.
For all subjects with NF-1 with PN enrolled in Part A, Part 
A extension and Part B3, MRI scans that are amenable to 
volumetric MRI analysis is required at each response 
assessment time points listed in Time and Events Table 
(Section 7.1) For Part B3 patients, screening MRI must be 
centrally reviewed for eligibility prior enrollment
LCH
Response assessed by the treating institutions at each response assessment time 
points listed in Time and Events Table (Section 7.1) using RECIST 1.1 and the method 
provided by Histiocyte Society Evaluations and Treatment Guidelines, April 2009 as 
outlined in Appendix 7. 
LCH scores described (Donadieu 2004) as outlined in Appendix 7 is also required to be 
completed by the treating institution
CT Chest, Abdomen and Pelvis (CAP) scan and a brain 
MRI with and without contrast is required at each 
response assessment time points listed in Time and 
Events Table (Section 7.1)
Other tests required for LCH scoring system such as 
blood tests (see Appendix 7) at each response 
assessment time points listed in Time and Events Table
Neuroblastoma
Patients with neuroblastoma will be evaluated by multiple methodologies by the treating 
institution. The number of assessments will depend on factors such a presence of MIBG 
lesions, bone marrow involvement etc. at the time of screening. Please refer to 
Appendix 4.
1. If subject has measurable disease as a component of their disease burden, response 
criteria should be assessed according to RECIST v1.1, as well as evaluable disease 
assessments below as appropriate, to determine overall response.
2. Subjects who had a positive MIBG scan at the start of therapy will be evaluated by 
response criteria for neuroblastoma subjects with MIBG positive lesions and report the 
scores for the 9 anatomic regions for the Curie scale, in addition to other assessments if 
applicable.
3. Subjects who had a positive finding in bone marrow at the start of therapy will be 
evaluated by the treating institution using the response criteria for neuroblastoma 
subjects with bone marrow involvement provided in Appendix 4 in addition to other 
assessments if applicable
MRI or CT scan, MIBG scan, bone marrow biopsy and 
urine catecholamine levels are mandatory at screening. 
Each individual scan or test should be performed at 
subsequent visits if positive at screening.


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Disease
Required Response Assessment
Required Response Measurement Modality
Melanoma and 
other solid tumors
These patients must be assessed using RECIST 1.1 criteria provided in Appendix 3 by 
the treating institutions at each response assessment time points listed in Time and 
Events Table (Section 7.1)
Melanoma patients: chest, abdomen and pelvis CT or MRI 
(with contrast enhancement) is required. Brain CT or MRI 
is required for subjects with brain metastasis or if clinically 
indicated and CT or MRI of other metastatic sites (e.g., 
neck).
Other solid tumors not listed above: CT Chest, Abdomen 
and Pelvis (CAP) scan required.


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7.6.1
MRI and/or CT Scan
Magnetic resonance imaging (MRI) will be performed at Screening and at scheduled visits 
during the study (see Time and Events Table Section 7.1) for subjects with primary brain tumors 
and subjects with PN.  If a brain MRI is contraindicated, a CT scan with contrast is allowed 
(except for PN subjects in Part B where MRIs are required).  Whichever modality is used at 
screening should be consistently performed during the study.
Scans for neurofibroma will be centrally collected and reviewed.  Instructions for image 
acquisition are included in Appendix 6 and the SPM.
7.6.2
Tumor Marker(s)
For subjects whose disease may be followed by well-characterized tumor markers, such as urine 
HVA/VMA in neuroblastoma, disease assessments should include results of tumor marker 
measurements.
Tumor marker values will be recorded in the eCRF.
8
Adverse Events and Serious Adverse Events
The investigator or site staff will be responsible for detecting, documenting and reporting events 
that meet the definition of an AE or SAE as outlined in Section 8.1 and Section 8.2, respectively.
8.1
Definition of an AE
Any untoward medical occurrence in a subject or clinical investigation subject, temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product.
Note: An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the 
use of a medicinal product.  For marketed medicinal products, this also includes failure to 
produce expected benefits, abuse, or misuse.  Examples of events meeting the definition of an 
AE include:

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or grade of the condition

New conditions detected or diagnosed after study treatment administration even though it 
may have been present prior to the start of the study

Signs, symptoms, or the clinical sequelae of a suspected interaction

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study treatment 
or a concomitant medication (overdose per se will not be reported as an AE/ SAE).
“Lack of efficacy” or “failure of expected pharmacological action” per se is not to be reported 
as an AE or SAE.  However, any signs and symptoms and/or clinical sequelae resulting from 
“lack of efficacy” will be reported as an AE or SAE, if they fulfill the definition of an AE or 
SAE.


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Events that do not meet the definition of an AE include:

Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition that leads to 
the procedure is an AE.

Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or
detected at the start of the study that do not worsen.

The disease/disorder being studied, or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the subject’s 
condition.
8.2
Definition of a SAE
An SAE is any untoward medical occurrence that, at any dose:
a. Results in death
b. Is life-threatening
NOTE:  The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
subject was at risk of death at the time of the event.  It does not refer to an event, which 
hypothetically might have caused death, if it were more severe.
c. Requires hospitalization or prolongation of existing hospitalization
NOTE:  In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation and/or 
treatment that would not have been appropriate in the physician’s office or out-subject setting.  
Complications that occur during hospitalization are AEs.  If a complication prolongs 
hospitalization or fulfills any other serious criteria, the event is serious.  When in doubt as to 
whether “hospitalization” occurred or was necessary, the AE should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE.
d. Results in disability/incapacity, or
NOTE:  The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.  This definition is not intended to include experiences of relatively minor 
medical significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g., sprained ankle) which may interfere or prevent everyday life 
functions but do not constitute a substantial disruption.
e. Is a congenital anomaly/birth defect.
f.
Medical or scientific judgment should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
subject or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition.  These should also be considered serious.  
Examples of such events are invasive or malignant cancers, intensive treatment in an 


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emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions 
that do not result in hospitalization, or development of drug dependency or drug abuse.
g. Protocol-Specific SAEs:

All events of possible study treatment-induced liver injury with hyperbilirubinemia 
defined as alanine aminotransferase (ALT) 3 times ULN and bilirubin ≥2 times 
ULN (>35% direct) (or ALT ≥3 times ULN and international normalization ratio 
(INR) >1.5, if INR is measured) or termed ‘Hy’s Law’ events (INR measurement is
not required and the threshold value stated will not apply to subjects receiving 
anticoagulants).
NOTE:  Bilirubin fractionation is performed if testing is available.  If testing is not available, 
record presence of detectable urinary bilirubin on dipstick indicating direct bilirubin elevations 
and suggesting liver injury.  If testing is unavailable and a subject meets the criterion of total 
bilirubin ≥2 times ULN, then the event is still reported as a SAE.  If INR is obtained, include 
values on the SAE form.  INR elevations >1.5 suggest severe liver injury.

Any new primary malignancy with a histology different from the primary tumor.

LVEF that meets stopping criteria.

RPED or RVO.
8.3
Laboratory and Other Safety Assessment Abnormalities 
Reported as AEs and SAEs
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis), or other 
safety assessments (e.g., ECGs, radiological scans, vital signs measurements) including those 
that worsen from baseline, and events felt to be clinically significant in the medical and 
scientific judgment of the investigator are to be recorded as an AE or SAE, in accordance with 
the definitions provided.
In addition, an associated AE or SAE is to be recorded for any laboratory test result or other 
safety assessment that led to an intervention, including permanent discontinuation of study 
treatment, dose reduction, and/or dose interruption/delay.
However, any clinically significant safety assessments that are associated with the underlying 
disease, unless judged by the investigator to be more severe than expected for the subject's 
condition, are not to be reported as AEs or SAEs.
8.3.1
Cardiovascular Events
Investigators will be required to fill out event specific data collection tools for the following 
AEs and SAEs:

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension


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
Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularisation

Symptomatic LVEF decrease
This information should be recorded in the specific cardiovascular eCRF within one week of 
when the AE/SAE(s) are first reported. Any events meeting the definition of SAE should also 
follow the SAE reporting requirements (Section 8.4.2).
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as SAEs
An event which is part of the natural course of the disease under study (i.e., disease progression 
or hospitalization due to disease progression) does not need to be reported as an SAE.  Death 
due to disease under study is to be recorded on the Death eCRF.  However, if the underlying 
disease (i.e., progression) is greater than that which would normally be expected for the subject, 
or if the investigator considers that there was a causal relationship between treatment with study 
treatment(s) or protocol design or procedures and the disease progression, then this must be 
reported as a SAE.
8.4
Time Period and Frequency of Detecting AEs and SAEs
The investigator or site staff is responsible for detecting, documenting and reporting events that 
meet the definition of an AE or SAE.
AEs will be collected from the time the first dose of study treatment is administered until 30 
days following discontinuation of study treatment regardless of initiation of a new cancer 
therapy or transfer to hospice.
From the time a subject consents to participate in and completes the study (See Section 6), all 
SAEs assessed as related to study participation (e.g., protocol-mandated procedures, invasive 
tests, or change in existing therapy), will be reported promptly to Novartis, as indicated in Table 
8-1.
After discontinuation of study treatment, the investigator will monitor all AEs/SAEs that are 
ongoing until resolution or stabilization of the event or until the subject is lost to follow-up.  At 
any time after 30 days the investigator may report any AE that they believe possibly related to 
study treatment.
8.4.1
Method of Detecting AEs and SAEs
Care must be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the subject is the preferred method to inquire about AE 
occurrence. Appropriate questions include:
“How are you feeling?” or for pediatric studies, “How does your child seem to feel?”


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“Have you had any (other) medical problems since your last visit/contact?” or for pediatric 
studies, “Has your child had any (other) medical problems or seem to act differently in any way 
since his/her last visit/contact?”
“Have you taken any new medicines, other than those provided in this study, since your last 
visit/contact?” or for pediatric studies, ”Has your child needed to take any medicines, other than 
those provided in this study, since his/her last visit/contact?”
8.4.2
Prompt Reporting of SAEs and Other Events to Novartis
SAEs, DLTs, pregnancies, and grade ≥ 3 liver function abnormalities, discontinuation of 
protocol therapy for toxicity, and any grade 5 events that are not related to underlying disease 
meeting pre-defined criteria will be reported promptly by the investigator to Novartis as 
described in Table 8-1 once the investigator determines the event meets the protocol definition 
for that event.
Table 8-1
Reporting of SAEs and Other Events to Novartis
Initial Reports
Follow-up Information on a 
Previous Report
Type of Event
Time Frame
Documents
Time Frame
Documents
All SAEs 
24 hr
SAE data collection tool
24 hr
Updated SAE data 
collection tool 
DLTsd
24 hr
Email to Sponsor
24 hr
Email to Sponsor
“CV events” and/or 
“death” d
To be completed 
within one week 
CV events” and/or “death” data 
eCRFs 
To be 
completed 
within one 
week 
Updated “CV 
events” and/or 
“death” data 
eCRFs
Pregnancy
24 hours
Pregnancy Notification Form
2 Weeks
Pregnancy 
Follow-up Form
Liver chemistry abnormalities:
ALT 3 times ULN and 
bilirubin 2 times ULN 
(>35% direct) (or ALT 
3 times ULN and INR 
>1.5, if INR is 
measured)c
24 hra
SAE data collection tool;
Liver Event eCRF and liver 
imaging and/or biopsy eCRFs 
if applicableb
24 hr
Updated SAE data 
collection tool.  
Updated Liver 
Event eCRFb
ALT 5 times ULN; ALT 
3 times ULN with 
hepatitis or rash or 3 
times ULN 4 weeks
24 hra
Liver Event eCRFb
24 hr
Updated Liver 
Event eCRFb
ALT 3 times ULN and 
<5 times ULN and 
bilirubin <2 times ULN
24 hra
Liver Event eCRF does not 
need to be completed unless 
elevations persist for 4 weeks 
or subject cannot be monitored 
weekly for 4 weeksb
a.
Novartis to be notified at onset of liver chemistry elevations to discuss subject safety.
b. Liver event documents should be completed as soon as possible.


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c.
INR measurement is not required; if measured, the threshold value stated will not apply to 
subjects receiving anticoagulants.
d. If a DLT or “CV event” should also meet the definition of a SAE, the site should also 
follow the SAE reporting requirements.
Methods for detecting, recording, evaluating, and following up on AEs and serious adverse 
events (SAEs) are provided in the SPM.
8.4.3
Regulatory reporting requirements for SAEs
Prompt notification of SAEs by the investigator to Novartis is essential so that legal obligations 
and ethical responsibilities towards the safety of subjects are met.
Novartis has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation.  Novartis will 
comply with country specific regulatory requirements relating to safety reporting to the 
regulatory authority, IRB/IEC and investigators.
Investigator safety reports are prepared for suspected unexpected serious adverse reactions 
according to local regulatory requirements and Novartis policy and are forwarded to 
investigators as necessary.
An investigator who receives an investigator safety report describing a SAE(s) or other specific 
safety information (e.g., summary or listing of SAEs) from Novartis will file it with the IB and 
will notify the IRB/IEC, if appropriate according to local requirements.
9
Concomitant Medications and Non-Drug Therapies
Subjects will be instructed to inform the investigator prior to starting any new medications from 
the time of first dose of study treatment until the end of the study (Final Study Visit).  Any 
concomitant medication(s), including non-prescription medication(s) and herbal product(s), 
taken during the study will be recorded in the eCRF.  Additionally, a complete list of all prior 
anti-cancer therapies will be recorded in the eCRF.
If future changes are made to the list of permitted/prohibited medications, formal 
documentation will be provided by Novartis and stored in the study file.  Any such changes will 
be communicated to the investigative sites in the form of a letter.
9.1
Permitted Medication(s)
Subjects should receive full supportive care during the study, including transfusion of blood 
and blood products, and treatment with antibiotics, antiemetics, antidiarrheals, and analgesics, 
as appropriate. 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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9.2
Prohibited Medications
9.2.1
Prohibited Medications: Parts A & B  (Trametinib)
There are no prohibited medications while on treatment in Part A and Part B of this study.
9.2.2
Prohibited Medications: Parts C & D (Dabrafenib)
The following medications or non-drug therapies are prohibited while on treatment in Parts C 
& D of this study:

Other anti-cancer therapies;

Other investigational drugs;

Antiretroviral drugs (Note: Subjects with known human immunodeficiency virus (HIV) 
are ineligible for study participation);

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 inhibition, 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 
(see list in Table 9-1) 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.  
Approval by the Medical Lead is required in these situations.  The list may be modified 
based on emerging data.  Refer to the SPM for the most current list.
Table 9-1
Prohibited Medications; Parts C and D (Dabrafenib)
PROHIBITED – strong inducers of CYP3A or CYP2C8, since concentrations of dabrafenib 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 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 
9.3
Medications to be Used with Caution; Parts C & D (Dabrafenib)
The following medications should be used with caution in Parts C and D of this study as their 
concentrations may be altered by dabrafenib or they may alter dabrafenib concentrations:


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
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 subjects for loss of efficacy or consider 
substitutions of these medications.  A partial list of these medications is provided in Table 
9-2 and in the SPM.

Therapeutic level dosing of warfarin can be used with approval by the Medical Lead and 
close monitoring of Prothrombin Time/International Normalized Ratio (PT/INR) by the 
site.  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.

Dabrafenib solubility is pH-dependent with decreased solubility at higher pH.  Drugs such 
as proton pump inhibitors that inhibit gastric acid secretion to elevate gastric pH may 
decrease the solubility of dabrafenib and reduce its bioavailability.  No clinical study has 
been conducted to evaluate the effect of pH on dabrafenib PK.  In an ad-hoc analysis, no 
differences in Cmax and AUC were noted between subjects who reported taking pH-
elevating products relative to other subjects.  Due to the theoretical risk that pH-elevating 
agents may decrease oral bioavailability and exposure to dabrafenib, these medicinal 
products that increase gastric pH should be used with caution when administered with 
dabrafenib.
Table 9-2
Medications to be used with Caution; Parts C and D (Dabrafenib)
USE WITH CAUTION:  Moderate  inhibitors of CYP3A, or CYP2C8 since concentrations of 
dabrafenib 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 subjects 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


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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
USE WITH CAUTION: Co-administration of drugs that increase gastric pH should be used with 
caution when administered with dabrafenib as exposure to dabrafenib may be decreased
pH altering agents
dexlansoprazole. esomeprazole, famotidine, ilaprazole, lansoprazole, 
omeprazole, pantoprazole, rabeprazole, ranitidine
Abbreviations: CYP = cytochrome P450; HMG-CoA = 3-hydroxy-3-methylglutaryl-coenzyme A.
Questions regarding concomitant medications should be directed to the Medical Lead for 
clarification.
10
Lifestyle and/or Dietary Restrictions
10.1
Contraception
10.1.1
Female Subjects
Women of childbearing potential, defined as all women physiologically capable of becoming 
pregnant, must use highly effective methods of contraception during dosing and for 16 weeks 
after stopping treatment with trametinib or 2 weeks after stopping treatment with dabrafenib 
whichever is longer. Highly effective contraception methods include:
a. Total abstinence (when this is in line with the preferred and usual lifestyle of the subject). 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) 
and withdrawal are not acceptable methods of contraception.
b. Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy, or tubal ligation 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 levelassessment.


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c. Sterilization (at least 6 months prior to screening) for male partners. The vasectomized 
male partner should be the sole partner for that subject.
d. Trametinib in combination with dabrafenib only: 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.
e. Trametinib monotherapy only: Use of oral (estrogen and progesterone), injected or 
implanted combined hormonal methods of contraception or placement of an intrauterine 
device (IUD) or intrauterine system (IUS), or other forms of hormonal contraception that 
have comparable efficacy (failure rate <1%), for example hormone vaginal ring or 
transdermal hormone contraception.
Notes:

Double-barrier contraception: condom and occlusive cap (diaphragm or cervical/vault 
caps) with a vaginal spermicidal agent (foam/gel/cream/suppository) are not considered 
highly effective methods of contraception per Clinical Trial Facilitation Group (CTFG) 
guidelines (Clinical Trial Facilitation Group 2014).

Oral contraceptives are not considered as highly effective methods of contraception for 
patients taking dabrafenib, due to potential drug-drug interactions with dabrafenib.

Women are considered post-menopausal and not of child bearing potential if they have
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile 
(i.e. age appropriate, history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy), total hysterectomy, or tubal ligation at least
six weeks ago. In the 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.
10.1.2
Male Subjects
Male patients (including those that have had a vascetomy) must use a condom during 
intercourse while taking trametinib and/or dabrafenib and not to father a child during the study 
and for the period of 16 weeks following stopping of study treatment.
10.2
Lactation Restrictions
Female subjects who are lactating must discontinue nursing prior to the first dose of study 
treatment and must refrain from nursing throughout the treatment period.
11
Data Management
For this study subject data will be entered into the eCRF, transmitted electronically to the 
sponsor or designee and be combined with data provided from other sources in a validated data 
system.
Management of clinical data will be performed in accordance with applicable standards and 
data cleaning procedures to ensure the integrity of the data, e.g., resolving errors and 
inconsistencies in the data.  Adverse events and concomitant medications terms will be coded 


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using the Medical Dictionary for Regulatory Activities (MedDRA) and a custom drug 
dictionary.
In all cases, subject initials will not be collected or transmitted to Novartis according to Novartis 
policy.
12
Data Analysis and Statistical Considerations
12.1
Hypotheses
12.1.1
Part A: Dose-Escalation Phase
No formal statistical hypotheses are being tested.  Analysis of the data obtained from this 
portion of the study will be focused on comparison between dose cohorts and only descriptive 
methods will be utilized.
12.1.2
Part B: Expansion Cohort
No formal statistical hypotheses are being tested.  Analysis of the data obtained from this 
portion of the study will be focused on evaluating the safety profile, PK/PD relationship, and 
anti-cancer activity of trametinib for each disease cohort and only descriptive methods will be 
used in analysis of the data obtained from this study.  The range of response rate and the 
corresponding exact binomial 95%  CI is provided in Section 12.2.2, if any objective response 
is observed in the Expansion Cohort.
12.1.3
Part C: Combination Cohort
No formal statistical hypotheses are being tested.  Analysis of the data obtained from this 
portion of the study will be focused on comparison between dose cohorts and only descriptive 
methods will be utilized.
12.1.4
Part D: Expansion Cohort with Combination Therapy
No formal statistical hypotheses are being tested.  Analysis of the data obtained from this 
portion of the study will be focused on evaluating the safety profile, PK/PD relationship, and 
anti-cancer activity of trametinib in combination with dabrafenib for each disease cohort and 
only descriptive methods will be used in analysis of the data obtained from this study.  The 
range of response rate and the corresponding exact binomial 95%  CI is provided in Section 
12.2.4, if any objective response is observed in the Expansion Cohort.
12.2
Sample Size Determination
12.2.1
Part A: Dose-Escalation Phase
The total number of subjects to be enrolled in Part A will depend on the number of subjects 
needed to characterize individual dose cohorts.  The sample size is not driven by statistical 
considerations.  However, it is anticipated that approximately 48 subjects will be enrolled.


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Given true incidence rates of DLTs, the associated probability of escalating to the next dose 
level in a 3+3 scheme are provided for reference below in Table 12-1.
Table 12-1
Statistical Basis for Phase I Dose Escalation in a 3+3 Scheme
True incidence of dose-limiting toxicity
10%
20%
30%
40%
50%
60%
Probability of escalating the dose
0.91
0.71
0.49
0.31
0.17
0.08
12.2.2
Part B: Expansion Cohort
The sample size for Part B is based on feasibility, practicality, and what would be sufficient for 
the characterization of the safety of trametinib and the plasma PK for the populations enrolled.  
Each of the 4 expansion cohorts will enroll at least 10 evaluable subjects, 5 subjects in each 
cohort will be under the age of 6 years.  Therefore, it is estimated that at least 40 subjects will 
be enrolled into Part B.
If less than 1 response is observed after 10 subjects complete the study, the treatment could be 
considered to have insufficient clinical activity in that cohort.  The estimated sample size (n=10) 
for the Part B expansion cohorts was further evaluated using exact binominal distribution 
probabilities, and the details are provided in Table 12-2.  For example, if zero responses are 
observed among 10 subjects in a cohort [if the response rate (RR)=5%], the chance of declaring 
the cohort as having insufficient clinical activity after 10 subjects is 60%.  If the true RR=15% 
for trametinib in unresectable low grade gliomas subjects, the chance of declaring the cohort as 
having insufficient clinical activity after 10 subjects is approximately 20%. Table 12-4 provides 
the corresponding 95% CIs around potential observed objective response rates given N=10 
subjects.
Table 12-2
Exact Binomial Probabilities of Observing 0 and 1 (or more) 
Responses in 10 Subjects
True RR
Probability of Observing 0 
responses in 10 Subjects
Probability of Observing ≥1 
Responses in 10 Subjects
5%
0.60
0.40
10%
0.35
0.65
15%
0.20
0.80
20%
0.11
0.89
25%
0.056
0.94
30%
0.028
0.97
Table 12-3
Exact Binomial 95% Confidence Intervals Around Potential Observed 
Objective Responses Rates for 10 Subjects
Observed Objective Response Rate
Exact 95% Confidence Interval (%) (N=10)
10%
0.3, 44.5
20%
2.5, 55.6
30%
6.7, 65.2
40%
12.2, 73.8
50%
18.7, 81.3
60%
26.2, 87.8


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Observed Objective Response Rate
Exact 95% Confidence Interval (%) (N=10)
70%
34.8, 93.3
12.2.3
Part C: Combination Cohort
The total number of subjects to be enrolled in Part C will depend on the number of subjects 
needed to characterize individual dose cohorts.  The sample size is not driven by statistical 
considerations.  However, it is anticipated that approximately 18 subjects will be enrolled.
12.2.4
Part D: Expansion Cohort with Combination Therapy
The sample size for Part D is based on feasibility, practicality, and what would be sufficient for 
the characterization of the safety and preliminary anti-tumor activity of trametinib/ dabrafenib 
combination and the plasma PK for the populations enrolled. Similar patient populations have 
been enrolled into the dabrafenib monotherapy phase 1 study, BRF116013 (see Section 1.3.4.1
of this protocol) where it has been shown that it is more practical to enroll patients with LGG 
than those with LCH.  Thus, approximately 20 subjects with LGG and approximately 10 
subjects with LCH will be enrolled. Overall approximately 30 subjects will be enrolled into Part 
D.
The estimated sample size for the LGG and LCH cohorts in Part D is further evaluated using 
exact binominal distribution probabilities, and the details are provided in Table 12-4 and Table 
12-5. For example, if the true RR=20% for trametinib and dabrafenib combination, the 
probability of observing < 6 responses out of 20 LGG subjects (observed response rate < 30%) 
is approximately 80%, and the probability of observing < 3 responses out of 10 LCH subjects 
(observed response rate < 30%) is approximately 68%.  If the true RR=50%, the probability of 
observing at least 6 responses is > 97% given 20 LGG subjects, and the probability of observing 
at least 3 responses is > 94% given 10 LCH subjects. Table 12-6 provides the corresponding 
95% CIs around potential observed objective response rates given N=20 subjects. The 
corresponding 95% CIs for potential observed response rates given N=10 is shown in Table 12-
3.
Table 12-4
Exact Binomial Probabilities of Observing less than 6 and at least 6 
Responses in 20 Subjects
True RR
Probability of Observing < 6 
responses in 20 Subjects
Probability of Observing ≥ 6 
Responses in 20 Subjects
20%
0.80
0.20
25%
0.62
0.38
30%
0.42
0.58
35%
0.25
0.75
40%
0.13
0.87
45%
0.06
0.94
50%
0.02
0.98
55%
0.01
0.99


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Table 12-5
Exact Binomial Probabilities of Observing less than 3 and at least 3 
Responses in 10 Subjects
True RR
Probability of Observing < 3 
responses in 10 Subjects
Probability of Observing ≥ 3 
Responses in 10 Subjects
20%
0.68
0.32
25%
0.53
0.47
30%
0.38
0.62
35%
0.26
0.74
40%
0.17
0.83
45%
0.10
0.90
50%
0.05
0.95
55%
0.03
0.97
Table 12-6
Exact Binomial 95% Confidence Intervals around Potential Observed 
Objective Responses Rates for 20 Subjects
Observed Objective Response Rate
Exact 95% Confidence Interval (%) (N=20)
20%
5.7, 43.7
30%
11.9, 54.3
40%
19.1, 63.9
50%
27.2, 72.8
60%
36.1, 80.9
70%
45.7, 88.1
80%
56.3, 94.3
12.3
Data Analysis Considerations
12.3.1
Analysis Populations
The All Treated Population is defined as all subjects who receive at least one dose of study 
treatment.  
This analysis population will be used for summaries of demographic/baseline characteristics 
and evaluation of anti-cancer activity. 
The Safety Population consists of all subjects who receive at least one dose of study treatment. 
Safety will be evaluated based on this analysis population.
The ‘DLT Evaluable’ population is defined as those subjects participating in dose determining 
portion of the study (Part A and 3+3 design portions of Part A extension, Part C and Part C 
extension) fulfilling the ‘All Treated’ population criteria and having received an adequate 
treatment for the first 28 days to enable an appropriate evaluation of study drug related DLTs.  
Adequate exposure during the first 28 days will be defined as having received >75% of planned 
study treatment doses, exclusive of missed doses due to treatment-related toxicity.  Any subject 
in the ‘All Treated’ population who experiences a DLT, as defined in Section 3.2.3, will also 
be included in the DLT evaluable population regardless of exposure.
The PK Population will consist of all subjects from the All Treated Population for whom a PK 
sample is obtained and analyzed.




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12.4.5
Additional Interim Analyses
Additional interim analyses may be performed to support any health authority or publication 
requests as and when needed.  No efficacy or futility conclusions will be drawn based on these 
interim analyses.
12.5
Key Elements of Analysis Plan
Data will be listed and summarized according to Novartis reporting standards, where applicable.  
Complete details will be documented in the SAP.  Any deviations from, or additions to, the 
original analysis plan described in this protocol will be documented in the SAP and final study 
report.
As it is anticipated that accrual will be spread thinly across centers and summaries of data by 
center would be unlikely to be information, data from all participating centers will be pooled 
prior to analysis.
All data up to the time of study completion/withdrawal from study will be included in the 
analysis, regardless of duration of treatment.
As the duration of treatment for a given subject will depend on efficacy and tolerability, the 
duration of follow-up will vary between subjects.  Consequently there will be no imputation for 
missing data.
Demographic and baseline characteristics will be summarized.
Subjects who are intra-subject dose escalated will be summarized in the dose level to which 
they were initially assigned.
12.5.1
Anti-Cancer Activity Analyses
The All Treated Population will be used for anti-cancer activity analyses.  Since this is a Phase 
I study, anti-cancer activity will be evaluated by investigator assessment based on clinical 
evidence and response criteria provided in Appendix 3 through Appendix 7.  If data warrant, 
the response data will be summarized by disease cohort and by dose level.  Anti-cancer activity 
analyses will also be performed based on Response-Evaluable population as sensitivity analysis.
In a supportive analysis, for LGG and NF-1 patients, anti-cancer activity will also be evaluated 
by independent review assessment based on clinical evidence and response criteria provided in 
Appendix 5 and 6 respectively.
Correlation analysis will be conducted to explore any relationship between the subject’s PK or 
PD evaluations and tumor response based on disease specific response criteria provided in 
Appendix 3 through Appendix 7.
Full details will be specified in the SAP. 
12.5.2
Safety Analyses
The Safety Population will be used for the analysis of safety data.  All serially collected safety 
endpoints (e.g., laboratory tests, vital signs, ECGs) will be summarized according to the 
scheduled, nominal visit at which they were collected and across all on-treatment time points 


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using a “worst-case” analysis.  Complete details of the safety analyses will be provided in the 
SAP.
12.5.2.1 Extent of Exposure
The number of subjects administered study treatment will be summarized according to the 
duration of therapy. Further details will be provided in the SAP.
12.5.2.2 Adverse Events
Adverse events (AEs) will be coded using the standard MedDRA and grouped by system organ 
class.  Adverse events (AEs) will be graded by the investigator according to the NCI-CTCAE 
v4.03 (NCI 2009).
Events will be summarized by frequency and proportion of total subjects, by system organ class 
and preferred term.  Separate summaries will be given for all AEs, treatment-related AEs, SAEs 
and AEs leading to discontinuation of study treatment.  AEs, if listed in the NCI-CTCAE v4.03 
(NCI 2009) will be summarized by the maximum grade.  Otherwise, the AEs will be 
summarized by maximum intensity.
Characteristics (e.g., number of occurrences, action taken, grade, etc) of the following AEs of 
special interest will be summarized separately: rash, diarrhea.
The incidence of deaths and the primary cause of death will be summarized.
Dose-limiting toxicities (DLTs) will be listed for each subject and summarized by dose cohort 
according to  Novartis standards. Further details will be provided in the SAP.
12.5.2.3 Clinical Laboratory Evaluations
Hematology, clinical chemistry and urinalysis data will be summarized using frequencies and 
proportions according to NCI-CTCAE v4.03 (NCI 2009) 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 and will be summarized using proportions. Further details will be 
provided in the SAP.
12.5.2.4 Other Safety Measures
Data for vital signs, ECGs, and ECHOs will be summarized based on predetermined criteria 
identified to be of potential clinical interest.  Further details will be provided in the SAP.
12.5.3
Pharmacokinetic Analyses
PK parameters for study treatment (trametinib, dabrafenib and its metabolites) for subjects in 
whom the full blood sampling scheme will be used will be calculated with standard non-
compartmental methods.  The PK parameters calculated with non-compartmental methods 
include; AUC(0-t), Cmax, Tmax, C, CL/F, and AUC(0-) (where = 24 hr for trametinib and 
12 hr for dabrafenib).  For subjects in whom the sparse blood sample collection scheme will be 
used, AUC(0-) and the average steady-state concentration will be estimated with a population 




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13
Study Conduct Considerations
13.1
Posting of Information on Clinicaltrials.gov
Study information from this protocol will be posted on clinicaltrials.gov before enrollment of 
subjects begins.
13.2
Regulatory and Ethical Considerations, Including the Informed 
Consent Process
Prior to initiation of a study site, Novartis will obtain approval from the appropriate regulatory 
agency to conduct the study in accordance with International Conference on Harmonization 
Good Clinical Practice (ICH GCP) and applicable country-specific regulatory requirements.
The study will be conducted in accordance with all applicable regulatory requirements.
The study will be conducted in accordance with ICH GCP, all applicable subject privacy 
requirements, and the ethical principles that are outlined in the Declaration of Helsinki 2008, 
including, but not limited to:

IRB/IEC review and approval of study protocol and any subsequent amendments.

Subject informed consent/assent.

Investigator reporting requirements.
Novartis will provide full details of the above procedures, either verbally, in writing, or both.
Written informed consent and assent when applicable must be obtained from each subject or 
their legally authorized representative prior to participation in the study.
13.3
Urgent Safety Measures
If an event occurs that is related to the conduct of the study or the development of the IP, and 
this new event is likely to affect the study of subjects, the Sponsor, and the investigator will 
take appropriate urgent safety measures to protect subjects against any immediate hazard.
The Sponsor will work with the investigator to ensure the IRB/IEC is notified.
13.4
Quality Control (Study Monitoring)
In accordance with applicable regulations, Good Clinical Practice (GCP) and Novartis 
personnel (or designated Clinical Research Organization [CRO]) will contact the site prior to 
the start of the study to review with the site staff the protocol, study requirements, and their 
responsibilities to satisfy regulatory, ethical, and Novartis requirements.  When reviewing data 
collection procedures, the discussion will include identification, agreement and documentation 
of data items for which the eCRF will serve as the source document.
The investigator and the head of the medical institution (where applicable) agrees to allow the 
monitor direct access to all relevant documents and to allocate their time and the time to their 
staff to monitor to discuss findings and any issues.
Novartis (or designated CRO) personnel will monitor the study to ensure that the:


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
Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
13.5
Quality Assurance
To ensure compliance with ICH GCP and all applicable regulatory requirements, Novartis may 
conduct quality assurance audits of the site.  Regulatory agencies may conduct a regulatory 
inspection at any time during or after completion of the study.  In the event of an audit or 
inspection, the investigator (and institution) must agree to grant the auditor(s) and inspector(s) 
direct access to all relevant documents and to allocate their time and the time of their staff to 
discuss any findings/relevant issues.
13.6
Study and Site Closure
The end of the study will be defined as the date of the last visit of the last subject enrolled.
Upon completion or termination of the study, Novartis personnel (or designated CRO) will 
conduct site closure activities with the investigator or site staff (as appropriate), in accordance 
with applicable regulations, ICH GCP, and Novartis Standard Operating Procedures.
Novartis reserves the right to temporarily suspend or terminate a study cohort or the entire study 
at any time for reasons including (but not limited to) safety issues, ethical issues, or severe 
noncompliance.  If Novartis determines that such action is required, Novartis will discuss the 
reasons for taking such action with the investigator or head of the medical institution (where 
applicable).  When feasible, Novartis will provide advance notice to the investigator or head of 
the medical institution of the impending action.
If a study is suspended or terminated for safety reasons, Novartis will promptly inform all 
investigators, heads of the medical institutions (where applicable),and/or institutions 
conducting the study.  Novartis will also promptly inform the relevant regulatory authorities of 
the suspension/termination along with the reasons for such action.  Where required by 
applicable regulations, the investigator or head of the medical institution must inform the 
IRB/IEC promptly and provide the reason(s) for the suspension/termination.
Novartis may also close study sites which fail to recruit subjects within a predefined timeframe.
13.7
Records Retention
Following closure of the study, the investigator or head of the medical institution (where 
applicable) must maintain all site study records (except for those required by local regulations 
to be maintained elsewhere) in a safe and secure location.  The records must be easily accessible 
when needed (e.g., for a Novartis audit or regulatory inspection) and must be available for 
review in conjunction with assessment of the facility, supporting systems, and relevant site staff.
Where permitted by local laws/regulations or institutional policy, some or all of the records may 
be maintained in a format other than hard copy (e.g., microfiche, scanned, electronic); however, 
caution must be exercised before such action is taken.  The investigator must ensure that all 
reproductions are legible and are a true and accurate copy of the original.  In addition, they must 


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meet accessibility and retrieval standards, including regeneration of a hard copy, if required.  
The investigator must also ensure that an acceptable back-up of the reproductions exists and 
that there is an acceptable quality control procedure in place for creating the reproductions.
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 the 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.
The investigator must notify Novartis of any changes in the archival arrangements, including, 
but not limited to archival of records at an off-site facility or transfer of ownership of the records 
in the event that the investigator is no longer associated with the site.
13.8
Provision of Study Results to Investigators, Posting of 
Information on Publicly Available Clinical Trials Registers and 
Publication
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report.  The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the opportunity 
to review the complete study results at a Novartis site or other mutually-agreeable location.
Novartis will also provide the investigator with the full summary of the study results.  The 
investigator is encouraged to share the summary results with the study subjects, as appropriate.
Novartis will provide the investigator with the randomization codes for their site only after 
completion of the full statistical analysis and the clinical study report.
Novartis aims to post a results summary to the Novartis Clinical Trial Results website 
(novartisclinicaltrials.com) and other publicly available registers no later than twelve (12) 
months after the last subject’s last visit (LSLV). In addition, upon study completion and 
finalization of study report, Novaris aims to submit results of the study for publication. When 
publication is not feasible, please refer to the Novartis Clinical Trial Results website 
(novartisclinicaltrials.com) for a summary of the trial results.


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15
Appendices
15.1
Appendix 1:  Karnofsky and Lansky Performance Scores
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.
Reference
Yates JW, Chalmer B, McKegney FP. Evaluation of patients with advanced cancer using the 
Karnofsky performance status. Cancer. 1980; 45(8): 2220-4.














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Dose and treatment schedule for trametinib tablets for subjects less than 6 years 
and weight greater or equal to 26kg (0.032 mg/kg/day)
Weight
Dose
Frequency 
and/or Regimen
Total Daily Dose
Pharmaceutical 
form and route of 
administration
26-39.5
2 × 0.5 mg
q.d
1 mg
Tablets for oral 
administration
39.6-54.5 kg
3 × 0.5 mg
q.d
1.5 mg
Tablets for oral 
administration
≥ 54.6 kg
1 × 2 mg
q.d
2 mg
Tablets for oral 
administration
Dose and treatment schedule for trametinib tablets for subjects greater or equal 
to 6 years and weight greater or equal to 33kg (0.025 mg/kg/day)
Weight
Dose
Frequency 
and/or Regimen
Total Daily Dose
Pharmaceutical 
form and route of 
administration
33-49.5 kg
2 × 0.5 mg
q.d
1 mg
Tablets for oral 
administration
49.6-69.5 kg
3 × 0.5 mg
q.d
1.5 mg
Tablets for oral 
administration
≥ 69.6 kg
1 × 2 mg
q.d
2 mg
Tablets for oral 
administration


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Dosing Nomogram – Dabrafenib
1. If a patient’s current weight is not a whole number, it should be rounded to its 
nearest whole number (eg. 12.1 - 12.4 kg is rounded down to 12 and 12.5 – 12.9 
is rounded up to 13)
2. Age for daily dose determination in any period during the study is based on the 
age at enrolment and will remain constant throughout the study.
3. Children < 6 years-old and subjects, regardless of age, with a risk of choking 
when swallowing capsules will be required to use the dispersible tablet 
formulation.
4. The investigator or responsible site personnel should instruct the patient and 
guardians to take or administer the study drug as per protocol (to promote 
compliance).  






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Dose and treatment schedule for dabrafenib (DRB436) 10mg dispersible tablet for patients 
greater than or equal 12 years of age (4.5 mg/kg/day)
Please note that the new formulation (DT) applies to only the recommended doses, as the dose-
escalation part of the study is already completed. 
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
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


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15.3
Appendix 3:  Response Criteria for Solid Tumors (Not 
Neuroblastoma or PNs or Glioma)
RECIST v1.1 (Eisenhauer 2009) will be used for response evaluation for subjects with solid 
tumors except neuroblastoma, primary central nervous system tumors, or PN(s).
Subjects with solid tumors may have measurable or evaluable lesions.  Measureable lesions are 
defined as target or non-target lesions.  Details of RECIST v1.1 can be found at 
ctep.cancer.gov/protocolDevelopment/default.htm#protocol_development.
Response Criteria
Evaluation of Target Lesions
Complete 
Response (CR)
Disappearance of all target lesions.  Any pathological lymph nodes (whether target or 
non-target) must have reduction in short axis to <10 mm.
Partial Response 
(PR)
At least a 30% decrease in the sum of the diameters of target lesions, taking as 
reference the baseline sum diameters
Progressive 
Disease (PD)
At least a 20% increase in the sum of the diameters of target lesions, taking as 
reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study).  In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm.  (Note:  the appearance of one or 
more new lesions is also considered progressions).
Stable Disease 
(SD)
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, 
taking as reference the smallest sum diameters while on study.
Evaluation of Non-Target Lesions
Complete 
Response (CR):
Disappearance of all non-target lesions and normalization of tumor marker level.  All 
lymph nodes must be non-pathological in size (<10 mm short axis)
Note:  If tumor markers are initially above the upper normal limit, they must normalize for a subject to be 
considered in complete clinical response.
Non-CR/Non-PD:
Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker 
level above the normal limits
Progressive 
Disease (PD):
Appearance of one or more new lesions and/or unequivocal progression of existing 
non-target lesions.  Unequivocal progression should not normally trump target lesion 
status.  It must be representative of overall disease status change, not a single lesion 
increase.
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should be 
confirmed at a later time by the review panel (or Principal Investigator).
Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started).  The subject's best response assignment 
will depend on the achievement of both measurement and confirmation criteria.


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For Subjects with Measurable Disease (i.e., Target Disease)
Target Lesions
Non-Target 
Lesions
New 
Lesions
Overall 
Response
Best Overall Response 
when Confirmation is 
Required1
CR
CR
No
CR
4 wks.  Confirmation2
CR
Non-CR/Non-PD
No
PR
4 wks.  Confirmation2
CR
Not evaluated
No
PR
PR
Non-CR/Non-
PD/not evaluated
No
PR
SD
Non-CR/Non-
PD/not evaluated
No
SD
Documented at least once 
4 wks.  from baseline2
PD
Any
Yes or 
No
PD
no prior SD, PR or CR
Any
PD3
Yes or 
No
PD
Any
Any
Yes
PD
1. See RECIST v1.1 manuscript for further details on what is evidence of a new lesion 
(Eisenhauer, 2009)
2. Only for non-randomized trials with response as primary endpoint.
3. In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression.
Note: Subjects with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.”  Every effort should be made to document the objective 
progression even after discontinuation of treatment.
For Subjects with Non-Measurable Disease (i.e., Non-Target Disease)
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PD1
Not all evaluated
No
not evaluated
Unequivocal PD
Yes or No
PD
Any
Yes
PD
1. Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised




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morphological evidence of tumor cells in bone marrow biopsy or aspiration is present 
at enrollment, no tumor cells can be detected by routine morphology on two subsequent 
bilateral bone marrow aspirates and biopsies done at least 21 days apart to be considered 
a Complete Response.

Partial Response: Relative score ≤ 0.2 (lesions almost disappeared) to ≤ 0.5 (lesions 
strongly reduced).

Stable Disease: Relative score > 0.5 (lesions weakly but significantly reduced) to 1.0 
(lesions not reduced).

Progressive Disease: New lesions on MIBG scan.
Response Criteria for Neuroblastoma Subjects with Bone Marrow Involvement
Bone marrow obtained within 28 days (or less if specified by the protocol) prior to study 
enrollment with tumor cells seen on routine morphology (not by immunohistochemical staining 
only) of bilateral aspirate or biopsy on one bone marrow sample.
Bone Marrow responses are determined by Haematoxylin and Eosin (H&E) staining of bilateral 
bone marrow biopsies and aspirates.

Complete Response: No tumor cells detectable by routine morphology on 2 
consecutive bilateral bone marrow aspirates and biopsies performed at least 21 
days apart.  Normalization of urinary catecholamines or other tumor markers if 
elevated at study enrollment.

Progressive Disease: In subjects who enroll with neuroblastoma in bone 
marrow by morphology have progressive disease if there is a doubling in the 
amount of tumor in the marrow AND a minimum of 25% tumor in bone marrow 
by morphology.  (For example, a subject entering with 5% tumor in marrow by 
morphology must increase to ≥ 25% tumor to have progressive disease; a 
subject entering with 30% tumor must increase to > 60%).
In subjects who enroll without evidence of neuroblastoma in bone marrow will be 
defined as progressive disease if tumor is detected in 2 consecutive bone marrow 
biopsies or aspirations done at least 21 days apart.

Stable Disease: Persistence of tumor in bone marrow that does not meet the criteria 
for either complete response or progressive disease.
Overall Best Response Assessment:
Each subject will be classified according to his “best response” for the purposes of analysis of 
treatment effect.  Best response (chart below) is determined from the sequence of the overall 
response assessments as described above.
Overall Response Evaluation for Subjects Enrolled with Measureable Disease by CT/MRI
CT/MRI
MIBG
Bone Scan/ 
PET-CT if performed
Bone Marrow
Catechol
Overall
PD
Any
Any
Any
Any
PD
Any
PD
Any
Any
Any
PD
Any
Any
PD
Any
Any
PD


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CT/MRI
MIBG
Bone Scan/ 
PET-CT if performed
Bone Marrow
Catechol
Overall
Any
Any
Any
PD
Any
PD
SD
CR/PR/SD
Non-PD
Non-PD
Any
SD
PR
CR/PR
Non-PD
Non-PD
Any
PR
CR/PR
PR
Non-PD
Non-PD
Any
PR
CR
CR
Non-PD
Non-PD
Elevated
PR
CR
CR
CR
CR
Normal
CR*
CT = Computerized Tomography; MRI = Magnetic Resonance Imaging; MIBG = Meta-
iodobenzylguanidine (scan); PET = Positron Emission Tomography PD = Progressive Disease; SD = 
Stable Disease; PR = Partial Response; CR = Complete Response.
* If one or more assessments are missing, response will be considered PR
Overall Response Evaluation for Subjects Enrolled with MIBG Positive Disease without 
Measureable Disease by CT/MRI
Since subjects may be enrolled without disease measurable by CT/MRI, any new or newly 
identified lesion by CT/MRI that occurs during therapy would be considered PD.
MIBG
CT/MRI
Bone Scan/
PET-CT if performed
Bone 
Marrow
HVA/VMA
Overall
PD
Any
Any
Any
Any
PD
Any
New Lesion
Any
Any
Any
PD
Any
Any
PD
Any
Any
PD
Any
Any
Any
PD
Any
PD
SD
No New Lesion
Non-PD
Non-PD
Any
SD
PR
No New Lesion
Non-PD
Non-PD
Any
PR
CR
No New Lesion
Non-PD
Non-PD
Elevated
PR
CR
No New Lesion
CR
CR
Normal
CR*
CT = Computerized Tomography; MRI = Magnetic Resonance Imaging; MIBG = 
Meta-iodobenzylguanidine (scan); PET = Positron Emission Tomography PD = 
Progressive Disease; SD = Stable Disease; PR = Partial Response; CR = Complete 
Response.
* If one or more assessments are missing, response will be considered PR
References:
Ady N, Zucker JM, Asselain B, et al., A new 123I-MIBG whole body scan scoring method--
application to the prediction of the response of metastases to induction chemotherapy in stage 
IV neuroblastoma. Eur J Cancer. 1995; 31A(2): 256-61.
Decarolis B, Schneider C, Hero B, et al., Iodine-123 Metaiodobenzyguanidine Scintigraphy 
Scoring Allows Predication of Outcome in Patients with Stage 4 Neuroblastoma: Results of 
the Cologne Interscore Comparison Study. J Clin Oncol 2013; 31: 944-951
Fox E, Mosse YP, Meany HM, et al., Time to Disease Progression in Children with Relapsed 
or Refractory Neuroblastoma Treated with ABT-751: A Report from the Children’s Oncology 
Group (ANBL0621).  Pediatr Blood Cancer 2014; 61: 990-996.


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Yanik GA, Parisi MT, Shulkin BL, et al., Semiquantitative mIGB Scoring as a Prognostic 
Indicator in Patients with Stage 4 Neuroblastoma: A Report from the Children’s Oncology 
Group. J Nucl Med 2013; 54: 541-548


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15.5
Appendix 5: Response Assessment in Neuro-oncology (RANO) 
Criteria (Glioma Subjects)
Anti-tumor activity will be assessed based on clinical evidence and the Response Assessment 
in Neuro-Oncology (RANO) criteria for solid tumors (Wen 2010).
NOTE: As part of Protocol Amendment V09, the revised RANO criteria for LGG (RANO-
LGG; Wen 2017) will be used for central independent review. This review is in addition to 
the previously performed review using RANO (2010)  These criteria are noted in section 
15.5.1.  )
All measureable and nonmeasureable lesions should be assessed using the same techniques as 
at baseline.  Ideally, subjects 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.
Measurable disease is defined as bidimensionally contrast enhancing lesions with clearly 
defined margins by CT or MRI scan, with two perpendicular diameters of at least 10 mm, visible 
on two or more axial slices that are preferably, at most, 5 mm apart with 0-mm skip. As with 
RECIST version 1.1, in the event the MRI is performed with thicker slices, the size of a 
measurable lesion at baseline should be two times the slice thickness. 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 measuring ≥10 mm in diameter. 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 10 mm. 
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.  

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, 
subject 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, subject 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) 


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on stable or increasing doses of corticosteroids, OR a significant increase in T2/FLAIR 
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 subject 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.
Increase in corticosteroid dose alone, in the absence of clinical deterioration related to tumor, 
will not be used as a determinant of progression. Subjects 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.  
Subjects with nonmeasurable enhancing disease whose lesions have significantly increased in 
size and become measurable (minimal bidirectional diameter of ≥ 10 mm and visible on at least 
two axial slices that are preferably, at most, 5 mm apart with 0-mm skip) will also be considered 
to have experienced progression. The transition from a nonmeasurable lesion to a measurable 
lesion resulting in progression can theoretically occur with relatively small increases in tumor 
size (e.g., a 9 X 9mm lesion [nonmeasurable] increasing to a 10 X 11mm lesion [measurable]). 
Ideally, the change should be significant (>5 mm increase in maximal diameter or ≥ 25% 
increase in sum of the products of perpendicular diameters of enhancing lesions).  
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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15.5.1
Response assessment in neuro-oncology (RANO) criteria for low-
grade gliomas (LGG) (RANO-LGG)
During the course of the trial, revised RANO criteria specific for LGG have become available 
(RANO-LGG; Wen, 2017). These criteria will also be used for central independent, review per 
Protocol Amendment v09.This review is in addition to the previously performed review using 
RANO (2010). 
According the updated RANO-LGG criteria, the definition of measurable disease is modified. 
Measurable disease is defined as bidimensionally visible lesions on T2 weighted fluid-
attenuated inversion recovery (FLAIR) scans with clearly defined margins, with two 
perpendicular diameters of at least 10 mm (or at least two slice thicknesses with no gaps 
between slices), visible on two or more axial slices that are preferably, at most, 5 mm apart with 
0 mm skip.
Non-measurable disease includes all other lesions, including:

unidimensionally measurable lesions

lesions with maximal perpendicular diameter that is both < 10mm and less than two 
slice thicknesses with no gaps between slices

lesions with borders that cannot be reproducibly measured

dural, bony skull metastases

cystic or necrotic lesions (without a nodular component)

other measurable lesions that cannot be considered as target lesions
Lesions composed of a tumor around a cyst or a surgical cavity are considered non-measurable 
unless there is a nodular component that measures 10 mm or more in 2 perpendicular diameters. 
The cystic or surgical cavity should not be measured for the determination of a response. Non-
measurable lesions should all be followed as non-target lesions.
Target lesions should be assessed quantitatively at each of the time points specified in the 
protocol.
The updated response criteria for LGG are defined in the following tables. Please note that the 
minor response category is not used in this clinical trial.  Patients meeting criteria for minor 
response will be considered to have stable disease for the purposes of this trial.
Response assessment of target lesions
Response Criteria
Evaluation of target lesions
Complete 
response (CR)
Complete disappearance of all measurable lesions on T2/FLAIR images 
sustained for at least 4 weeks.* No new or increased enhancement on T1 
images.
Partial response 
(PR)
≥ 50% decrease, compared with baseline, in the sum of products of 
perpendicular diameters of all measurable lesions on T2/FLAIR sustained for 
at least 4 weeks.* No new or increased enhancement on T1 images.


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Response Criteria
Evaluation of target lesions
Progressive 
disease (PD)
≥25% increase in sum of the products of perpendicular diameters of 
measurable lesions on T2/FLAIR images compared to nadir. Increased 
enhancement on T1 images showing evidence of malignant transformation.
Stable disease 
(SD)
Neither sufficient shrinkage to qualify for partial response nor sufficient 
increase to qualify for progressive disease. No new or increased 
enhancement on T1 images.
Not Evaluable (NE)  Not evaluable will be used in exceptional cases where one or more 
measurable lesions cannot be assessed or have been assessed using a 
different method than baseline, in absence of progressive disease 
documentation
* In the absence of a confirming scan 4 weeks later, this scan will be considered only stable 
disease.
Response assessment of non-target lesions
Response Criteria
Evaluation of non-target lesions
Complete response 
(CR)
Complete disappearance of all non-measurable lesions on T2/FLAIR. No 
new or increased enhancement on T1 images.
NonCR/NonPD
Persistence of one or more non-measurable lesions on T2/FLAIR. No new 
or increased enhancement on T1 images.
Progressive disease 
(PD)
Significant and unequivocal increase of the non-measurable lesions on 
T2/FLAIR or increase of enhancement on T1 images
Not Evaluable (NE)  
Not evaluable will be used in exceptional cases where one or more non-
measurable lesions cannot be assessed or have been assessed using a 
different method than baseline, in absence of progressive disease 
documentation
A lesion not present at baseline and appearing at any follow-up evaluation timepoint (TP) is 
considered a New Lesion. 
The Investigator/local reader will characterize each new lesion as either equivocal or 
unequivocal (progressive disease). If unsure of a new lesion, the Investigator/local reader will 
mark it as equivocal and assess at the next timepoint if the lesion is present. Appearance of an 
equivocal new lesion does not lead to a determination of PD. If repeat scans confirm the lesion 
is unequivocal, progression should be retrospectively assigned back to the first observation of 
the lesion. 
The evaluation of overall lesion response at each assessment is a composite of the target lesion 
response, non-target lesion response, the presence of new lesions, corticosteroid use relative to 
baseline, and clinical status as assessed by investigator and supported by the ECOG/Karnofsky 
Performance Scale as shown below:


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Overall lesion response at each assessment (measurable and non-measurable disease at 
baseline)
Criterion 
Complete 
Response 
Partial 
Response 
Stable 
Disease 
Progressive 
Disease 
T2/FLAIR (target 
lesions)
None 
≥50% decrease 
in SPPD 
compared to 
baseline
<50% 
decrease
Compared 
to baseline 
but <25% 
increase  in 
SPPD 
compared 
to Nadir
≥25% 
increase in 
SPPD 
compared to 
Nadir**
T2/FLAIR (non-
target lesions)
None
Stable or 
improved
Stable or 
improved 
Unequivocal 
PD**
T1 gadolinium 
enhancing 
disease 
Stable or 
improved
Stable or 
improved
Stable or 
improved
Unequivocal 
increase**
New Lesions 
None
None 
None 
Present*
Corticosteroids 
compared to 
baseline
None
Stable or 
decreased
Stable or 
decreased
NA***
Clinical Status  
compared to 
baseline
Stable or 
improved
Stable or 
improved
Stable or 
improved
Worsened**
Requirement for 
Response
All 
All 
All 
Any**
Complete Response (CR):
All of the following criteria must be met:
a. Complete disappearance of the lesion of T2 or FLAIR imaging. . In the absence of a 
confirming scan at least 4 weeks later, this scan will be considered only stable disease.
b. No new lesions, no new T2 or FLAIR abnormalities apart from those consistent with 
radiation effects, and no new or increased size of enhancement
c. Participants must be on no steroids or on physiologic replacement doses only.
d. Stable or improved clinically, for clinical signs and symptoms present at baseline and 
recorded to be disease related
Partial Response (PR):
All of the following criteria must be met:
a. Greater than or equal to 50% in the product of perpendicular diameters of the lesion on T2 
or FLAIR imaging sustained for at least 4 weeks compared with baseline.


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b. No new lesions, no new T2 or FLAIR abnormalities apart from those consistent with 
radiation effects, and no new or increased size of enhancement
c. Patients should be on a corticosteroid dose that should not be greater than the dose at time 
of baseline scan, and should be stable or improved clinically.
Stable Disease (SD):
All of the following criteria must be met:
a. Does not qualify for CR, PR, MR or progression.
b. Stable area of non-enhancing abnormalities on T2 or FLAIR imaging
c. No new lesions, no new T2 or FLAIR abnormalities apart from those consistent with 
radiation effects, and no new or increased size of enhancement
d. Patients should be on a corticosteroid dose that should not be greater than the dose at time 
of baseline scan, and should be stable or improved clinically.
Progressive Disease (PD):
a. A 25% increase of the T2 or FLAIR non-enhancing lesion on stable or increasing doses of 
corticosteroids compared with nadir, not attributable to radiation effect or to comorbid 
events
b. Significant and unequivocal increase of the non-measurable lesions on T2/FLAIR
c. Development of new lesions or increased size of enhancement
d. Definite clinical deterioration not attributable to other causes apart from the tumor, or 
decrease in corticosteroid dose
e. Failure to return for evaluation because of death or deteriorating condition, unless caused 
by documented non-related disorders.
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.
Response Status Unknown: Not Evaluable (NE):
a. Progressive disease has not been documented and one or more target or non-target lesions 
have not been assessed.
b. Change in method or technique for assessing target and non-target lesions as that used at 
baseline regardless of the justification of the change;  e.g. if a participant develops a 
contraindication to MRI intravenous (IV) contrast media during the trial, a non-contrast 
MRI of the brain can be used (if possible); the participants response should only be recorded 
as not evaluable or progressive disease.


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15.6
Appendix 6: Response Criteria for PNs
Prior to starting treatment on this study all known measurable tumors should be imaged with 
MRI to obtain a baseline.  Tumor spread in subjects with NF-1 can be very extensive, and may 
not allow for all lesions to be followed using 3D-MRI.  The goal will therefore be to use 3D-
MRI only to follow the inoperable PN (a maximum of three lesions), which will be defined as 
index lesion(s).
Pre-study radiographic evaluation:
1. Identify and select the inoperable PN (a maximum of three lesions) for 3-D MRI 
evaluation based on prior imaging studies.  Should there be more than 3 inoperable PN, 
the three most clinically relevant PN will be followed by 3-D MRI analysis.
2. Perform 3-D MRI sequences on the selected index lesions as outlined in the MRI 
acquisition protocols below.
3. In addition, if possible, perform MRI of all additional measurable PN.
4. Send baseline MRI for central review prior to enrolment (for Part B3 patients).
In Study Part B, central review of the MRI of the target PN is required prior to enrollment to 
ensure that the tumor is measurable and amenable to volumetric analysis.
On study radiographic evaluation:
Unless clinically indicated otherwise obtain MRI of the index lesions only as outlined in the 
MRI acquisition protocol below prior to cycles 4, 8, 12, and then after every 6 cycles as long as 
the subject remains on study.
MRI protocols:
Depending on the location of the index lesions the Spine, Head/Neck or Trunk/Extremities 
protocols outlined in the SPM and imaging guidelines will be used.
Participating institutions may modify the MRI sequences to optimize differentiation of tumor 
and surrounding tissue.  Modifications should be documented in the MRI protocols, and the 
same imaging protocol, and, if possible, the same MRI scanner, should be used for all 
subsequent MRI studies.  Every attempt should be made to image the entire progressive PN.    
All MRI data will be analyzed.  The MRI data from each scan will be processed to assess the 
volume of the index PN(s).  Each subject’s volumetric measurement obtained from the initial 
MRI will serve as the baseline against which to assess incremental changes in volume that occur 
during the subsequent intervals.    . All MRI studies requested per protocol will be submitted to 
the imaging vendor via the instructions provided in the SPM.
Response Criteria for NF-1 Associated PNs (Dombi 2013):
Response is assessed at the time that follow-up MRI scans are performed as outlined in Section 
7.1.  For the purpose of determining the level of response, measurements from the follow-up 
scans are compared to the tumor size in the pretreatment MRI scan using 3D data analysis.

Complete Response (CR): A complete resolution of the target plexiform neurofibroma 
for ≥ 4 weeks


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
Partial Response (PR): A ≥20% reduction in the volume of the target plexiform 
neurofibroma lesion for ≥4 weeks. 

Stable Disease (SD): A <20% increase, and < 20% decrease in the volume of the target 
plexiform neurofibroma lesion for ≥4 weeks. 

Progressive Disease (PD): A ≥20% increase in the volume (by 3D-MRI) of the target 
plexiform neurofibroma compared to the pretreatment volume.

The appearance of new discrete subcutaneous neurofibromas does not qualify 
for disease progression. 
Worsening of existing symptoms or the appearance of new symptoms that persist for more than 
7 days and that are felt to be definitely related to the plexiform neurofibroma should be 
evaluated by repeating the MRI.  Subjects should not be classified as having progressive disease 
solely on the basis of new or increased symptoms.


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15.7
Appendix 7: Definition of disease state, response criteria and 
response definition for LCH
Adapted from Histiocyte Society Evaluations and Treatment Guidelines, April 2009.
Definition of Disease State
NON ACTIVE DISEASE 
(NAD) 
no evidence of disease 
resolution of all signs or symptoms 
ACTIVE DISEASE
regressive disease 
regression of signs or symptoms, no new lesions*
stable disease 
persistence of signs of symptoms, no new lesions 
progressive disease 
progression of signs or symptoms and/or 
appearance of new lesions**
*Plus partial or complete response by RECIST (Eisenhauer 2009); and/or pulmonary criteria if applicable
*/** Isolated pulmonary LCH: improvement in lung function is >10% increase in baseline FEV1 or DLCO at 
time of disease assessment.  Disease progression is >15% decline from baseline FEV1 or DLCO or FVC 
OR progression of symptoms (dyspnea, cough, constitutional symptoms) that cannot be explained by 
diagnoses other than pulmonary LCH (infection, heart disease, and/or other clinical issues excluded by 
careful clinical evaluation and testing)
** Isolated bone disease: progression is defined as appearance of new bone lesions or lesions in other 
organs
Response Criteria
BETTER
Complete Resolution
NAD
Regression
AD Better
INTERMEDIATE
Mixed
New lesions in one site, regression in another site
Stable
Unchanged
WORSE
Progression
Response Definition for Efficacy
3 Month Assessment
6 Month Assessment and beyond
(performance relative to 3 month assessment)
Response
NAD or AD Better
Mixed
Stable 
NAD or AD Better or Stable 
NAD or AD Better
NAD or AD Better
Failure
NAD or AD Better
NAD or AD Better
Mixed or Stable a
Progression
Mixed 
Progression
Mixed or Stable a or Progression
N/A
NAD = Non Active Disease
AD = Active Disease
Stable = Unchanged
Mixed = New lesions in one site, regression in another site
a. Subjects who are assessed only as stable at the 3 and 6 month assessment are not considered a 
treatment response; however, they may be considered for continued treatment 
LCH Scoring System (Donadieu 2004)
Variable
Modality
Score
Bone (a)
Pain
No Pain
1
0
Bone (b)
Compressing other organs (orbit or spine)
No compression
2
0
Fever (>38.5C)
Yes
No
1
0


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Variable
Modality
Score
Lung: iconography
Pneumothorax
Interstitial lesion on chest x-ray or lung CT
Normal chest x-ray or lung CT
2
1
0
Lung: function
Mechanical ventilation or PFT >50%
Supplemental oxygen or PFT between 50 and 80%
No dysfunction, no cyanosis, no supplemental oxygen
5
2
0
Skin: area
25%
5-25%
Below 5%
2
1
0
Soft tissue tumor 
(including CNS)
5 cm maximum diameter
2-5 cm maximum diameter
0-2 cm maximum diameter
2
1
0
Nodes (>2 cm)
Yes
No
1
0
Liver
Below umbilicus
Enlarged, above umbilicus
Not enlarged
2
1
0
Spleen
Below umbilicus
Enlarged, above umbilicus
Not enlarged
2
1
0
Liver (enzymes)
>10 ULN
3-10 ULN
<3 ULN
2
1
0
Liver (gamma GT)
>10 ULN
3-10 ULN
<3 ULN
2
1
0
Albumin
Perfusion required in past week
No perfusion but <30 g/L
>30 g/L
3
1
0
Platelet: requirements in 
past week
More than two transfusions
1 or 2 transfusions
Low platelet count, no transfusion
Normal count
4
3
2
0
Red cells: requirements 
in past week
More than 2 U
1 or 2 U
Hgb below 10 g/dL, no transfusion
No transfusion
4
3
1
0


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15.8
Appendix 8:  Blood Pressure Levels for Children by Age and Height Percentile
Blood pressure (BP) levels for BOYS
Systolic Blood Pressure, mm Hg
Diastolic Blood Pressure, mm Hg
Age
BP
Percentile of Height
Percentile of Height
(years)
Percentile
5th
10th
25th
50th
75th
90th
95th
5th
10th
25th
50th
75th
90th
95th
1
95th
98
99
101
103
104
106
106
54
54
55
56
57
58
58
2
95th
101
102
104
106
108
109
110
59
59
60
61
62
63
63
3
95th
104
105
107
109
110
112
113
63
63
64
65
66
67
67
4
95th
106
107
109
111
112
114
115
66
67
68
69
70
71
71
5
95th
108
109
110
112
114
115
116
69
70
71
72
73
74
74
6
95th
109
110
112
114
115
117
117
72
72
73
74
75
76
76
7
95th
110
111
113
115
117
118
119
74
74
75
76
77
78
78
8
95th
111
112
114
116
118
119
120
75
76
77
78
79
79
80
9
95th
113
114
116
118
119
121
121
76
77
78
79
80
81
81
10
95th
115
116
117
119
121
122
123
77
78
79
80
81
81
82
11
95th
117
118
119
121
123
124
125
78
78
79
80
81
82
82
12
95th
119
120
122
123
125
127
127
78
79
80
81
82
82
83
13
95th
121
122
124
126
128
129
130
79
79
80
81
82
83
83
14
95th
124
125
127
128
130
132
132
80
80
81
82
83
84
84
15
95th
126
127
129
131
133
134
135
81
81
82
83
84
85
85
16
95th
129
130
132
134
135
137
137
82
83
83
84
85
86
87
17
95th
131
132
134
136
138
139
140
84
85
86
87
87
88
89
Instructions for using this BP Chart:
1.
Measure the patient’s blood pressure using an appropriate size cuff.
2.
Select appropriate chart for a female or male patient.
3.
Using the “age” row and “height” column determine if the BP is within the ULN.
4.
See Section 3.2.3.1 for definition of dose limiting hypertension, Section 3.13.5 for management and grading of hypertension, and Section 3.13.5
for medical treatment of trametinib related hypertension. 


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This table was taken from “The Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and 
Adolescents” PEDIATRICS Vol. 114 No. 2 August 2004, pp. 555-576.
Blood pressure (BP) for GIRLS
Systolic Blood Pressure, mm Hg
Diastolic Blood Pressure, mm Hg
Age
BP
Percentile of Height
Percentile of Height
(years)
Percentile
5th
10th
25th
50th
75th
90th
95th
5th
10th
25th
50th
75th
90th
95th
1
95th
100
101
102
104
105
106
107
56
57
57
58
59
59
60
2
95th
102
103
104
105
107
108
109
61
62
62
63
64
65
65
3
95th
104
104
105
107
108
109
110
65
66
66
67
68
68
69
4
95th
105
106
107
108
110
111
112
68
68
69
70
71
71
72
5
95th
107
107
108
110
111
112
113
70
71
71
72
73
73
74
6
95th
108
109
110
111
113
114
115
72
72
73
74
74
75
76
7
95th
110
111
112
113
115
116
116
73
74
74
75
76
76
77
8
95th
112
112
114
115
116
118
118
75
75
75
76
77
78
78
9
95th
114
114
115
117
118
119
120
76
76
76
77
78
79
79
10
95th
116
116
117
119
120
121
122
77
77
77
78
79
80
80
11
95th
118
118
119
121
122
123
124
78
78
78
79
80
81
81
12
95th
119
120
121
123
124
125
126
79
79
79
80
81
82
82
13
95th
121
122
123
124
126
127
128
80
80
80
81
82
83
83
14
95th
123
123
125
126
127
129
129
81
81
81
82
83
84
84
15
95th
124
125
126
127
129
130
131
82
82
82
83
84
85
85
16
95th
125
126
127
128
130
131
132
82
82
83
84
85
85
86
17
95th
125
126
127
129
130
131
132
82
83
83
84
85
85
86
Instructions for using this BP Chart:
1.
Measure the patient’s blood pressure using an appropriate size cuff.
2.
Select appropriate chart for a female or male patient.
3.
Using the “age” row and “height” column determine if the BP is within the ULN.
4.
See Section 3.2.3.1 for definition of dose limiting hypertension, Section 3.13.5 for management and grading of hypertension, and Section 3.13.5
for medical treatment of pazopanib related hypertension.


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This table was taken from “The Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and 
Adolescents” PEDIATRICS Vol. 114 No. 2 August 2004, pp. 555-576.


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Appendix 9:  Dose Escalation based on PK criteria
Number of 
Subjects with DLT
Number of subjects 
failing PK criteria
Action
0 out of 3
0 out of 3
Accrue 3 additional evaluable subjects at current dose level 
for a total of 6 evaluable subjects
0 out of 3
One or more
Escalate to next dose level
1 out of 3
0,1,2,or 3
Accrue 3 additional evaluable subjects at current dose level 
for a total of 6 evaluable subjects
0 or 1 out of 6
0 or 1 out of 6
Select dose as PK Target dose
0 or 1 out of 6
2 or more out of 6
Escalate to the next dose level
2 or more 
MTD has been exceeded.  Expand prior dose level to at least 
6 subjects 


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Appendix 10:  Guidelines for additional dermatological 
monitoring while on therapy and after IP discontinuation
This Section applies to subjects enrolled in France only.
Cutaneous Squamous Cell Carcinoma (cuSCC) and New primary melanoma 
Dermatological examinations should be performed prior to initiation of study treatment, 
monthly during treatment, and monthly for 6 months following discontinuation of dabrafenib 
or until initiation of another anti-neoplastic therapy, whichever comes first. Subjects should be 
instructed to immediately inform their physician if new lesions develop. Any cuSCC or new 
primary melanoma should be reported as a protocol specific SAE and treated according to 
standard clinical practice.
Non-cutaneous secondary/recurrent malignancy
Prior to initiation of study treatment subjects should undergo a head and neck examination with 
minimally visual inspection of oral mucosa and lymph node palpation, as well as chest/abdomen 
Computed Tomography (CT) scan. During treatment subjects should be monitored as clinically 
appropriate which may include a head and neck examination every 3 months and a 
chest/abdomen CT scan every 6 months. Anal examinations and pelvic examinations are 
recommended before the start of and at the end of treatment or when considered clinically 
indicated. Complete blood cell counts should be performed as clinically indicated. 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, 
whichever comes first. Any noncutaneous secondary/recurrent malignancy should be reported 
as a protocol-specific SAE and treated according to standard clinical practice.


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Appendix 11:  Protocol Amendment Changes (Amendments 1- 4)
Amendment 1
Where the Amendment Applies
Amendment 1 applies to all sites and is submitted prior to initiation of the study.
Summary of Amendment Changes with Rationale
This amendment was made in response to FDA comments, as well as review from various 
clinical sites. An internal GSK decision was made to not include patients with leukemia 
therefore, all references to leukemia were deleted from the protocol. Clarifications were made 
to the dosing nomogram, response criteria for glioma subjects, age limit for subjects enrolled 
to dose escalation cohorts, disease status at screening, testing of BRAF mutation status, DLT 
criteria and reporting. Bone marrow assessments and Tanner staging were added to the Time 
and Events schedule, and the PK sampling schedule was modified. 
 
Protocol synopsis
Study Rationale PREVIOUS TEXT:
Specifically, pediatric patients with recurrent high grade gliomas, and patients with metastatic 
or recurrent solid tumors, or relapsed leukemia continue to have a poor prognosis and lower 
rates of long-term survival than patients with localized or non-recurrent disease. Use of 
second- and third-line cytotoxic chemotherapies, even in dose-intensive regimens, has yet to 
yield significant impact on progression-free survival or overall survival. Therefore 
development of new therapeutic options for pediatric cancer patients is needed.
Study Rationale REVISED TEXT:
Specifically, pediatric patients with recurrent high grade gliomas, and patients with metastatic 
or recurrent solid tumors or relapsed leukemia, continue to have a poor prognosis and lower 
rates of long term survival than patients with localized or non recurrent disease.  Use of second-
and third-line cytotoxic chemotherapies, even in dose-intensive regimens, has yet to yield 
significant impact on progression-free survival or overall survival. Increased understanding 
of the molecular mechanisms of pediatric tumors allows for rationale investigation of 
agents targeting these mechanisms. Therefore Development of new therapeutic options for 
pediatric cancer patients is needed and clinical testing of targeted approaches may provide these 
options.
PREVIOUS TEXT




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
Recurrent or refractory leukemia including juvenile 
myelomonocytic leukemia (JMML)
Part C is a limited dose escalation part of the study evaluating the 
combination of trametinib with dabrafenib in children and adolescents 
with recurrent, refractory or unresectable BRAF V600 mutated 
tumors.  This part of the study will enroll approximately 18 subjects 
and will not open to accrual until the dose of dabrafenib in children is 
established in study BRF116013, the dose trametinib is established in 
Part A and review of the available safety and PK data of trametinib 
and dabrafenib monotherapy in children is completed.  Part C will 
require an amendment to this study prior to enrollment to include 
updated safety data and dabrafenib dosing in children.  Part B and C 
may be open to accrual simultaneously.
REVISED TEXT:
STUDY DESIGN

Refractory or relapsed neuroblastoma solid tumors with MAPK 
pathway activation including but not limited to neuroblastoma, 
rhabdomyosarcoma, malignant peripheral nerve sheath tumors.

Recurrent or unresectable low grade gliomas with 
serine/threonine kinase B Raf (BRAF tandem 
duplication with fusion (without BRAF V600E 
mutations).

Neurofibromatosis Type -1 associated plexiform neurofibromas 
that are unresectable and medically significant. 

Recurrent or refractory leukemia including juvenile 
myelomonocytic leukemia (JMML)

BRAF V600 mutant tumors
Part C is a limited dose escalation part of the study evaluating the 
combination of trametinib with dabrafenib in children and adolescents 
with recurrent, refractory or unresectable BRAF V600 mutated 
tumors.  This part of the study will enroll approximately 18 subjects 
and will not open to accrual until the dose of dabrafenib in children is 
established in study BRF116013, the dose trametinib is 
established in Part A and review of the available safety and PK 
data of trametinib and dabrafenib monotherapy in children is 
completed.  Part C will require an amendment to this study prior to 
enrollment to include updated safety data and dabrafenib dosing in 
children.  Part B and C may be open to accrual simultaneously.


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PREVIOUS TEXT:
INCLUSION/
EXCLUSION CRITERIA
General Inclusion Criteria for All Parts (for complete details and 
further eligibility criteria for specific parts please see full protocol):
1.
Male or female between one month and < 18 years of age 
(inclusive) at the time of signing the informed consent form
2.
Part C between 12 months and <18 years of age, inclusive;
5.
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 7 days prior to enrollment;
General Exclusion Criteria for All Parts:
17. History or Current evidence / risk of retinal vein occlusion 
(RVO) or retinal pigment epithelium detachment (RPED):

History of RVO or RPED, or predisposing factors to RVO or 
RPED (e.g., uncontrolled glaucoma or ocular hypertension, 
uncontrolled systemic disease(s) such as hypertension, 
diabetes mellitus, or history of hyperviscosity or 
hypercoagulability syndromes).

Visible retinal pathology as assessed by ophthalmic exam 
performed within 1 month of enrollment that is considered a 
risk factor for RVO or RPED such as:

Evidence of new optic disc cupping

Evidence of new visual field defects

Intraocular pressure >21mm Hg
19. A history of known Human Immunodeficiency Virus (HIV), 
Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection. 
Subjects with laboratory evidence of cleared HBV and HCV 
infection may be enrolled.


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REVISED TEXT:
INCLUSION/
EXCLUSION CRITERIA
General Inclusion Criteria for All Parts (for complete details and 
further eligibility criteria for specific parts please see full protocol):
1.
Male or female between one month and < 18 years of age 
(inclusive) at the time of signing the informed consent form
2.
Part C between 12 months and <18 years of age, inclusive;
3.
(added text) Part A subjects < 2 years of age will not be 
include in the initial dose escalation 
5.
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 714 days prior to enrollment;
General Exclusion Criteria for All Parts:
17. History or Current evidence / risk of retinal vein occlusion (RVO) 
or retinal pigment epithelium detachment (RPED):

History of RVO or RPED, or predisposing factors to 
RVO or RPED (e.g., uncontrolled glaucoma or ocular 
hypertension, uncontrolled systemic disease(s) such 
as hypertension, diabetes mellitus, or history of 
hyperviscosity or hypercoagulability syndromes).

Visible retinal pathology as assessed by ophthalmic exam 
performed within 1 month of enrollment that is considered a 
risk factor for RVO or RPED such as:

Evidence of new optic disc cupping

Evidence of new visual field defects

Intraocular pressure >21mm Hg
19. A history of known Human Immunodeficiency Virus (HIV), 
Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection. 
Subjects with laboratory evidence of cleared HBV and HCV 
infection may be enrolled.
PREVIOUS TEXT, 1st paragraph, last sentence:
STUDY TREATMENT 
DOSE/ROUTE/
REGIMEN
When taken together, trametinib should be taken with the morning 
dose of dabrafenib.
REVISED TEXT, 1st paragraph, last sentence:




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The safety and activity of the combination of dabrafenib with trametinib in adults with BRAF 
V600 mutation positive melanoma has been demonstrated.  Once the dose of dabrafenib is 
determined in children and adolescents, a treatment arm to evaluate the safety of dabrafenib in 
combination with trametinib in children and adolescents will be opened.
Section 1.5 Rationale for BRAF and MEK inhibitors in Pediatric Cancers 
REVISED TEXT

Relapsed or refractory neuroblastoma

Recurrent or unresectable low grade gliomas with BRAF tandem duplication with fusion

Neurofibromatosis (NF)-related PNs.

BRAF V600 mutant tumors 
The safety and activity of the combination of dabrafenib with trametinib in adults with BRAF 
V600 mutation positive melanoma has been demonstrated.  Once the doses of dabrafenib 
and trametinib monotherapy are determined in children and adolescents, a treatment arm to 
evaluate the safety of dabrafenib in combination with trametinib in children and adolescents 
will be opened.
Section 1.6 Malignant Solid Tumors in Infants, Children, and Adolescents 
DELETED TEXT
Rhabdomyosarcoma is the most common malignant soft tissue tumor in children.  Alveolar 
rhabdomyosarcoma frequently harbor chromosomal rearrangements.  Recent investigations 
indicate that 20% of embryonal rhabdomyosarcomas have somatic NRAS mutations and 
dysregulation of RAS signaling may contribute to pathogenesis of this cancer [Martinelli, 
2009].  Concomitant activation of Ras/MEK/ERK and PI3K/protein kinase B (AKT)/mTOR 
in rhabdomyosarcoma may require combination therapy [Guenther, 2013].
Malignant peripheral nerve sheath tumors are rare malignant tumors that can be sporadic or 
associated with NF 1 [Stucky, 2011].  Malignant peripheral nerve sheath tumors comprise 
approximately 3 10% of all soft tissue sarcomas [Zou, 2009] and develop in the cells 
surrounding the peripheral nerves.  MPNSTs generally occur in adulthood (between 20 and 50 
years), but approximately 10 20% of cases have been reported to occur in the first 2 decades 
of life [Minovi, 2007; Ferrari, 2007a; Ferrari, 2007b].  The incidence of MPNST in NF 1 
patients may be as high as 8% to 12% [Zou, 2009].  In a recent analysis, disease specific 
survival (DSS) was similar in patients with NF 1 related MPNST and sporadic MPNST.  
Subjects in this retrospective analysis had newly diagnosed high grade MPNST (n=105) and 
70% had negative margins after primary resection.  The 3 year DSS was 64% and median 
DSS was 8 years [LaFemina, 2013].  Prognosis is poor for patients with unresectable, 
metastatic or recurrent MPNST (< 10 20% 5 year OS).  MPNST is considered to be a sarcoma 
with complex genetic alterations [Yang, 2013].  NF 1 associated MPNST have been 
associated with molecular heterogeneity among tumors as well as intra tumor molecular 
heterogeneity [Thomas, 2012].  In addition, studies in animal models indicate that other 
sarcomas with NF 1 deletions may be sensitive to MEK inhibition by direct effects on 
proliferation of tumor cells and indirectly by changes in the tumor microenvironment [Dodd, 
2013].


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Section 1.7 Relapsed or Recurrent Leukemia including JMML in Infants, 
Children and Adolescents was DELETED; all subsequent sections numbering 
was updated.
Previously Section 1.9.1 Predicted Toxicities for Trametinib, PREVIOUS TEXT
Ocular effects:  Visual impairments, including chorioretinopathy, retinal pigment epithelium 
detachment (RPED), and retinal vein occlusion (RVO), were reported with trametinib.  Cases 
of ocular toxicities were reported with other MEK inhibitors in clinical development.  
Subjects with a history of RVO or risk factors of RVO, should not receive trametinib.  
Subjects with the following visible retinal pathology as assessed by ophthalmic exam that is 
considered a risk factor for RVO should not receive trametinib:
Evidence of optic disc cupping.

Evidence of new visual field defects on perimetry.

Intraocular pressure > 21 mm Hg as measured by tonography.
Section 1.8.1 Predicted Toxicities for Trametinib, REVISED TEXT
Ocular effects:  Visual impairments, including chorioretinopathy, retinal pigment epithelium 
detachment (RPED), and retinal vein occlusion (RVO), were reported with trametinib.  Cases 
of ocular toxicities were reported with other MEK inhibitors in clinical development. 
Subjects with a history of RVO or risk factors of RVO, should not receive trametinib.  
Subjects with the following visible retinal pathology as assessed by ophthalmic exam that is 
considered a risk factor for RVO should not receive trametinib:
Evidence of optic disc cupping.

Evidence of new visual field defects on perimetry.

Intraocular pressure > 21 mm Hg as measured by tonography.


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Previously Section 1.9.2 Predicted Toxicities for Combination of Trametinib and 
Dabrafenib; ADDED TEXT
Hemorrhage: Major hemorrhagic events can occur in patients receiving dabrafenib in 
combination with trametinib. Monitor for signs and symptoms of bleeding. 
Venous Thromboembolism: Deep vein thrombosis and pulmonary embolism can occur in 
patients receiving dabrafenib in combination with trametinib.
Interstitial lung disease (ILD)/Pneumonitis: 
Pneumonitis has been observed in subjects receiving trametinib.  To reduce the risk of 
pneumonitis, subjects will be monitored closely for symptoms, evaluated with imaging and 
functional tests if clinically indicated.
Pancreatitis – Pancreatitis has been observed in subjects receiving dabrafenib. Subjects will 
be monitored for abdominal pain or suspected pancreatitis, amylase and lipase laboratory 
samples should be collected for confirmation of the diagnosis. 
Hyperglycemia: Hyperglycemia requiring an increase in the dose of, or initiation of insulin or 
oral therapy can occur with dabrafenib. Serum glucose levels will be monitored as clinically 
appropriate during treatment with dabrafenib in subjects with pre-existing diabetes or 
hyperglycemia. 
Hepatic Events:
Hepatic adverse events have been reported in clinical trials with trametinib as monotherapy 
and in combination with dabrafenib. 
Ocular effects: Both trametinib and dabrafenib have been associated with ocular toxicities 
which appear to be class effects, including papilledema, RPED, and RVO, uveitis and iritis 
associated with trametinib, and uveitis (including chorioretinitis, choroiditis, retinitis, vitritis, 
cyclitis, iridocyclitis, iritis, and uveitis) associated with dabrafenib. Please refer to Section 
1.8.1 and Section 3.13.3.
Section 2 Objectives, Endpoints, Hypothesis(es) PREVIOUS TEXT
Objective
Endpoint
Hypothesis(es)
Primary
To determine the safe and tolerable 
trametinib dose(s) alone or in 
combination with dabrafenib for 
chronic dosing in pediatric subjects 
(infants, children, and adolescents) 
that achieves similar exposures (C) 
to the recommended adult dose
Adverse Events (AEs); ECG; 
ECHO; changes in laboratory 
values and vital signs.  Steady 
state Cof trametinib
Infants, children and 
adolescents will tolerate 
doses of trametinib 
alone or in combination 
with dabrafenib that 
achieve steady state 
trough concentrations 
associated with clinical 
benefit in adults 




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Section 3.1 Discussion of Study Design, PREVIOUS TEXT

Part A will be a pharmacokinetically driven limited dose escalation study in subjects with 
an expansion for safety, tolerability, and PK in three age ranges (1 month to <2years, 2 to 
≤12 years, and over 12 years of age).  The primary goal of Part A is to establish the 
toxicity profile, PK, and recommended Phase 2 dose (RP2D) of trametinib in each age 
cohort.  Approximately 18 subjects will be accrued to the dose escalation phase and 18 
subjects to the age expansion phase. 

Part B will be an expansion study to further evaluate the safety, tolerability, and 
preliminary clinical activity of trametinib in tumor-specific pediatric populations.  Disease 
cohorts are selected based on current data of Ras/MAPK activation in childhood solid 
tumors.  Forty subjects are planned for Part B, 10 subjects in each of 4 disease cohorts.
–
Refractory or relapsed solid tumors with Ras/MAPK pathway activation 
including but not limited to neuroblastoma, rhabdomyosarcoma, malignant 
peripheral nerve sheath tumors.
–
Recurrent or unresectable low grade gliomas (without BRAF V600E 
mutations)
–
Neurofibromatosis Type -1 associated plexiform neurofibromas (NF-1 with 
PN) that are unresectable and medically significant.
–
Recurrent or refractory leukemia harboring Ras pathway activation, including 
JMML

Part C is a limited dose escalation study of the combination of trametinib in combination 
with dabrafenib in children and adolescents with recurrent, refractory or unresectable 
BRAF V600 mutated tumors.  This part of the study, with a planned enrollment of up to 
18 subjects, will not open until the dose of dabrafenib in children is established in study 
BRF116013.  Part C will require an amendment to this study prior to enrollment to include 
updated safety data and dabrafenib dosing in children.  Part B and C may be open to 
accrual simultaneously.
Subjects may not participate in more than one part of the study.
Section 3.1 Discussion of Study Design, REVISED TEXT

Part A will be a pharmacokinetically driven limited dose escalation study in subjects with 
an expansion for safety, tolerability, and PK in three age ranges (1 month to <2years, 2 to 
≤12 years, and over 12 years of age).  The primary goal of Part A is to establish the 
toxicity profile, PK, and recommended Phase 2 dose (RP2D) of trametinib in each age 
cohort.  Approximately 18 subjects will be accrued to the dose escalation phase (subjects 
less than 2 years of age will not be included in the initial dose escalation 
(approximately 6-12 subjects) is complete and the age specific cohorts are opened)
and 18 subjects to the age expansion phase. 

Part B will be an expansion study to further evaluate the safety, tolerability, and 
preliminary clinical activity of trametinib in tumor-specific pediatric populations.  Disease 
cohorts are selected based on current data of Ras/MAPK activation in childhood solid 
tumors.  Forty subjects are planned for Part B, 10 subjects in each of 4 disease cohorts.


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–
B1:  Refractory or relapsed neuroblastoma solid tumors with Ras/MAPK 
pathway activation including but not limited to neuroblastoma, 
rhabdomyosarcoma, malignant peripheral nerve sheath tumors.
–
B2:  Recurrent or unresectable low grade gliomas with serine/threonine kinase 
B Raf (BRAF tandem duplication with fusion
–
B3:  Neurofibromatosis Type -1 associated plexiform neurofibromas (NF-1 
with PN) that are unresectable and medically significant.
Recurrent or refractory leukemia harboring Ras pathway activation, including 
JMML
–
B4:  BRAF V600 mutant tumors.

Part C is a limited dose escalation study of the combination of trametinib in combination 
with dabrafenib in children and adolescents with recurrent, refractory or unresectable 
BRAF V600 mutated tumors.  This part of the study, with a planned enrollment of up to 
18 subjects, will not open until the dose of dabrafenib in children is established in study 
BRF116013, the dose of trametinib monotherapy is established in Part A and all 
available PK and safety data is reviewed.  Part C will require an amendment to this 
study prior to enrollment to include updated safety data and dabrafenib dosing in children.  
Part B and C may be open to accrual simultaneously.
Subjects may not participate enroll in more than one part of the study.
Section 3.2 Part A: Trametinib Dose-Escalation Determination DELETED TEXT, 
2nd paragraph
During dose escalation, children will be closely monitored for drug-related toxicity. If MTD is 
determined dose limiting toxicity (DLT) is observed in 2 or more patients (or >33%) at a dose 
level, the RP2D will be defined by the MTD rather than by PK criteria.
Section 3.2.2 Trametinib Dose Escalation PREVIOUS TEXT, 3rd bullet, and last 
paragraph

If 2 or more of the initial 3-6 subjects enrolled at the starting dose experience DLT, 
accrual will be suspended and the MTD will have been exceeded.
Detailed PK sampling will be required on Day 15 for trametinib (see Section 7.4.1). In 
addition, PK trough blood samples (immediately prior to dosing and approximately 24 hr after 
prior dose) will be required on Day 15 and Day 22 in all subjects.  The Day 15 trametinib Cτ 
of all subjects in a dose level cohort will be compared to the target C(10 ng/mL) in adults 
who were treated with the recommended dose in adults.  If Dose Level 3 is reached without 
exceeding the MTD, additional subjects may be enrolled if necessary to determine C.  In the 
absence of an MTD, the PK target dose defined as the dose that meets the PK criteria for 
adequate exposure (Day 15 trametinib C≥10 ng/mL in at least 80% of subjects in a cohort of 
at least 6 subjects (i.e.; 5/6 subjects treated at that dose level). 
Section 3.2.2 Trametinib Dose Escalation REVISED TEXT, 3rd bullet, and last 
paragraph

If 2 or more of the initial 3-6 subjects enrolled at a dose level the starting dose experience 
DLT, accrual will be suspended and the MTD will have been exceeded.


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PK Criteria for Escalation:
Detailed PK sampling will be required on Day 15 for trametinib (see Section 7.4.1). Subjects 
who have a day 15 trametinib C<10 ng/mL will be considered to have failed to reach 
the PK target.  If more than 1 out of 3 to 6 patients at a dose level have failed to reach 
the PK target, and MTD criteria have not been met, dose escalation will continue.   In 
addition, PK trough blood samples (immediately prior to dosing and approximately 24 hr after 
prior dose) will be required on Day 15 and Day 22 in all subjects.  The Day 15 trametinib Cτ 
of all subjects in a dose level cohort will be compared to the target C(10 ng/mL) in adults 
who were treated with the recommended dose in adults.  If Dose Level 3 is reached without 
exceeding the MTD, additional subjects may be enrolled if necessary to determine C.  In the 
absence of an MTD, the RP2D will be the PK target dose defined as the dose that meets the 
PK criteria for adequate exposure (Day 15 trametinib C≥10 ng/mL in at least 80% of 
subjects in a cohort of at least 6 subjects (i.e.; 5/6 subjects) treated at that dose level 
(Apppendix 8).
Section 3.2.3 Dose Limiting Toxicity Definitions ADDED TEXT, paragraphs 2 
and 3
If a subject is withdrawn before completing at least 75% of doses (at least 21 doses 
during the first 28 days of study treatment), for any reason other than toxicity, the 
subject will be replaced with the next available subject if escalation or de-escalation 
rules have not been fulfilled.
An AE will be considered a DLT if it is considered by the investigator to be at least possibly 
related to study treatment and also meets any of the criteria listed in Section 3.2.3.1 or 
Section 3.2.3.2. DLTs will be reported to GSK using the procedures outlined for 
reporting of SAEs (Section 8.4.2).
Section 3.2.3.1 Non-Hematological Dose Limiting Toxicity DELETED and 
ADDEDTEXT
Grade 3 elevation in alanine aminotransferase (ALT) (see Section 3.11.1).

Dose limiting hypertension will be considered as the following:
–
Grade 4 hypertension
–
A blood pressure >25 mmHg above the 95th percentile for age, height, and 
gender (see Appendix 7) confirmed by repeated measurement (See Section 
13.3.3.1 and Section 13.3.3.2)
Section 3.2.3.2 Hematological Dose Limiting Toxicity DELETED and ADDED 
TEXT
Note: Participants enrolled on Part B with compromised bone marrow function and a 
neutrophil count < 1.5 x 109/L or platelet count < 100 x 109/L secondary to tumor infiltration 
of the bone marrow or prior therapy are not evaluable for hematologic toxicity, and the 
criteria for hematologic DLT will not be dose limiting toxicity in this population.

Grade 4 anemia 

Grade 3 or 4 hemolysis 


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Figure 1 and Figure 2 were updated to reflect changes in the protocol
Section 3.8.2 Rationale for Populations PREVIOUS TEXT, paragraph 1, last 
sentence
These include tumors positive for BRAF gene duplication (e.g., juvenile pilocytic 
astrocytoma, low grade gliomas); NF-1 related PN; and selected solid tumors with Ras/MEK 
pathway activation including but not limited to neuroblastoma, rhabdomyosarcoma, 
peripheral nerve sheath tumors.
Section 3.8.2 Rationale for Populations REVISEDTEXT, paragraph 1, last 
sentence
These include tumors positive for BRAF V600 mutation, BRAF gene duplication (e.g., 
juvenile pilocytic astrocytoma, low grade gliomas); NF-1 related PN; and selected solid 
tumors with Ras/MEK pathway activation including but not limited to neuroblastoma, 
rhabdomyosarcoma, peripheral nerve sheath tumors.
Section 3.8.4 Rationale for Endpoints, 2nd paragraph, DELETED TEXT
In the absence of dose limiting toxicity at the 0.025 mg/kg dose level (equivalent to 
therecommended dose in adults), if target Day 15 C in at least 80% of subjects is≥10 ng/mL, 
trametinib dose escalation will stop. However, in the absence of doselimiting toxicity, if Day 
15 C∀is less than 10 ng/mL in 20% or more of subjects, the dose will be escalated to 0.04 
mg/kg.
Section 3.10.1 Trametinib, PREVIOUS TEXT, 4th paragraph, 4th sentence
However, subject can take the missed dose immediately if the next scheduled dose is at least 
16 hours later.  
Section 3.10.1 Trametinib, REVISED TEXT, 4th paragraph, 4th sentence
However, subject can take the missed dose immediately if the next scheduled dose is at least 
12 hours later.  
Section 3.10.3 Meals and Dietary Restrictions ADDED TEXT, first bullet
∃
If it is not possible for a subject to tolerate the fasting conditions noted above, trametinib 
can be administered with a small non-fat meal (e.g., small amount of apple juice/sauce, a 
piece of dry toast). Children that are breastfeeding may continue to breast feed on 
demand.  If child is breast fed during collection of PK samples the time of 
breastfeeding should be recorded.
Section 3.12 Dose Delay and Modification for Events Considered Related to 
Trametinib ADDED TEXT
A maximum of one trametinib dose reductions is allowed.  If a second dose level reduction is 
required, treatment will be permanently discontinued.
Trametinib dose modification guidelines are outlined in Table 4 for clinically significant 
toxicities that are deemed related to trametinib (i.e. peripheral and periorbital edema) with 
exception for following events of special interest: 
rash (Section 3.13.1) 
diarrhea (Section 3.13.2), 




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Table 5 Management of Rash ADDED TEXT
CTCAE Grade
Adverse Event Management 
Action and Dose Modification
Grade 1
Initiate prophylactic and 
symptomatic treatment 
measuresa
Use moderate strength topical 
steroidb
Reassess after 2 weeks; 
Continue trametinib 
If rash does not recover to baseline within 2 weeks 
despite best supportive care, reduce trametinib by 
one dose level .
Grade 2
Initiate prophylactic and 
symptomatic treatment 
measuresa Use moderate 
strength topical steroidb  
Reassess after 2 weeks.
Reduce trametinib by one dose .
Reassess after 2 weeks:

If rash recovers to ≤Grade 1 within 2 
weeks, increase dose to previous dose 
level

If no recovery to ≤Grade 1 within 2 weeks, 
interrupt trametinib until recovery to ≤grade 
1, restart trametinib at reduced dose level
Grade 3
Use moderate strength topical 
steroidsb ( PLUS 
methylprednisolone dose pack.
Consult dermatologist   

Interrupt trametinib until rash recovers to 
Grade ≤1

Restartc with trametinib reduced by one 
dose leveld
If no recovery to grade ≤2 within 4 weeks, 
permanently discontinue trametinib.
Abbreviations:  CTCAE = Common Terminology Criteria for Adverse Events
a.
Rash prophylaxis is recommended for the first 6 weeks of study treatment
b.
Moderate-strength topical steroids  hydrocortisone 2.5% cream or fluticasone prioprionate 0.5% crean
c.
Approval of GSK medical monitor is required to re-start study treatment after >4 weeks of interruption
d.
Escalation of trametinib to previous dose level may be considered if no rash is evident 4 weeks after restarting 
study treatment
Section 3.13.3 Hypertension 
The algorithm in Figure 4 will be used to grade and manage trametinib related hypertension. 
Should initiation of anti-hypertensive therapy be required, single agent therapy (commonly 
including the calcium channel blockers amlodipine or nifedipine,) should be started and the 
blood pressure should be monitored at least twice weekly until BP is within the 95th 
percentile for age, height, and gender per Section 3.13.3.2
If patient is already on an anti-hypertensive medication at study enrollment, then their anti-
hypertensive therapy should be adjusted (by either adjusting the dose of their current anti-
hypertensive medication or by adding another anti-hypertensive agent) according to the 
algorithm in Section.3.13.3.1.
3.13.3.1 Baseline Blood Pressure


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
Baseline blood pressure (BP) is defined as the blood pressure obtained at the 
examination used for study enrollment. This baseline BP should be obtained as 
follows:
1) Obtain 3 serial blood pressures from the same extremity with the patient in the 
same position that are separated by at least 5 minutes. Avoid using the lower 
extremity if possible.
2) Average the systolic blood pressure from the 2nd and 3rd measurements.
3) Average the diastolic blood pressure from the 2nd and 3rd measurements.
4) The baseline BP is the average of the systolic and average of the diastolic 
measurements.
3.13.3.2 Management of Hypertension

The upper limit of normal (ULN) is defined as a BP equal to the 95th percentile 
for age, height, and gender. (Appendix 7)

The NCI CTCAE will be utilized to determine the grade of hypertension for 
reporting purposes.

Elevated BP measurements should be repeated on the same day to confirm the 
elevation. Patients with an elevated BP should have BP measurements performed 
at least twice weekly until BP is ≤ ULN.

The algorithm below will be used to manage trametinib related hypertension.

Hypertension should be managed with appropriate anti-hypertensive agent(s) as 
clinically indicated. It is strongly recommended that nephrology or cardiology be 
consulted in the evaluation and management of hypertension.


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Figure 4
Algorithm For Management of Trametinib-Related Hypertension
Arm 1 of algorithm:

If blood pressure (BP) ≤ 95%ile for age, height, and gender: continue trametinib at 
the same dose.
Arm 2 of algorithm:

If BP ≤ 10 mm Hg above the ULN: continue trametinib at the same dose and 
recheck the BP within 72 hours.
o
If the BP is ≤ ULN on recheck, continue trametinib at the same dose.
o
If the BP remains above the ULN on recheck, then start/adjust 
antihypertensive therapy and follow Arm 3 of the algorithm from the point 
that anti-hypertensive therapy is started/adjusted.
Arm 3 of algorithm:

If BP is 11 to 25 mm Hg above the ULN on ≥ 2 of 3 measurements or > 35 mmHg 
above baseline on ≥ 2 of 3 measurements, start/adjust anti-hypertensive therapy 
and continue trametinib at the same dose. Monitor BP at least twice weekly.
o
If the BP returns to ≤ ULN within 14 days, continue trametinib at the same 
dose and continue anti-hypertensive therapy.
o
If the BP remains elevated ≥25 mm Hg above the ULN or > 35 mm Hg above 
baseline for more than 14 days after the institution/adjustment of anti-
hypertensive therapy, hold trametinib, monitor BP at least every 3 days, and 


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follow Arm 4 of the algorithm from the point that trametinib is held. The anti-
hypertensive therapy should be continued until the BP is less than the ULN.

If the BP returns to ≤ ULN within 14 days, restart trametinib at a reduced dose.

If the BP remains > ULN for more than 14 days, patient must be removed from 
protocol therapy.
o
If the BP increases to > 25 mm Hg above the ULN despite anti-
hypertensive therapy, hold trametinib, but continue the anti-hypertensive 
agent(s). Monitor the BP as clinically indicated and follow Arm 4 of the 
algorithm from the point that trametinib is held.

If the BP is ULN within 14 days, trametinib may be restarted at a reduced dose 

If the BP is > ULN for > 14 days, the patient must be removed from protocol 
therapy (Section 6.3)
Arm 4 of algorithm:

If BP is > 25 mm Hg above the ULN hold trametinib, monitor BP, and 
administer/adjust anti-hypertensive therapy as clinically indicated.
o
If the BP returns to ≤ ULN within 14 days, trametinib may be restarted at a
reduced dose.
o
If the BP is > ULN for >14 days, the patient must be removed from 
protocol therapy (Section 6.3).
Arm 5 of algorithm:
If the participant develops Grade 4 hypertension, discontinue trametinib, monitor 
BP and administer anti-hypertensive therapy as clinically indicated. The patient is 
Off Protocol Therapy (Section 6.3).
Section 3.13.4 Visual Changes ADDED TEXT
Episodes of visual changes have been observed in subjects receiving trametinib, and ocular 
adverse events are known to be related to trametinib.  An ophthalmologist should 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)).  For events of visual changes (regardless of severity) for 
which an ophthalmic examination is conducted, a blood sample for PK analysis must be 
drawn as close as possible to the time of the event (Section 7.1 for PK sample volume).
Guidelines regarding management and dose reduction for visual changes considered to be 
related to study treatment are provided in Table 7.






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2.
Histologically confirmed solid tumors, which may include but are not limited to 
rhabdomyosarcoma and other soft tissue sarcomas, Ewing sarcoma family of 
tumors, osteosarcoma, neuroblastoma, Wilms’ tumor, hepatic tumors, germ cell 
tumors, and primary brain tumors.  In subjects with brain stem gliomas the 
requirement for histological confirmation can be waived if a biopsy was not 
performed.
3.
Measurable or evaluable tumors.  Subjects with neuroblastoma that is only detectable by 
MIBG scan are eligible. and considered to have measurable disease using the Curie scale.  
Subjects with neuroblastoma that is only detected by bone marrow aspirate/biopsy or 
elevated homovanillic acid / vanillylmandelic acid (HVA/VMA) are not eligible.
Section 5.2.1.3 Specific Eligibility Criteria, Part B ADDED and DELETED TEXT
1.
Tumor tissue (archived or fresh) is required and must be available to be shipped to GSK 
or site specific laboratory.
2.
Solid Tumor Cohort (B1) Specific Criteria:

Histologically confirmed neuroblastoma which have been associated with 
MAPK/RAS/MEK activation, which may include but are not limited to recurrent or 
refractory rhabdomyosarcoma, neuroblastoma, or unresectable, recurrent, or 
refractory malignant peripheral nerve sheath tumors (NF 1 associated or sporadic).  
Histological confirmation may be at diagnosis or recurrence.  Laboratory 
documentation of pathway activation is not required; however, archival tissue is 
requested at the time of enrollment.
5.
BRAF V600 mutant solid tumors Cohort (B4) Specific Criteria:

Male or female ≥12 months and <18 years of age at the time of signing the 
informed consent form;

BRAF V600 mutation-positive tumor as confirmed in a CLIA-approved 
laboratory or equivalent (the local BRAF testing may be subject to 
subsequent verification by centralized testing; centralized testing can confirm 
V600E and V600K mutations only)

Recurrent disease, refractory disease, or progressive disease after having 
received at least one standard therapy for their disease;
NOTE: Subjects with metastatic (and surgically unresectable) melanoma can 
be enrolled for first-line treatment; Melanoma subjects with CNS 
involvement may be enrolled.

Measurable or evaluable tumors.

Adequate hematologic function defined as:

Absolute neutrophil count (ANC) ≥1000/µL;

Hemoglobin ≥8.0 g/dL (may receive red blood cell transfusions)

Platelets ≥75,000/µL (transfusion independent, defined as not receiving 
platelet transfusions within a 7 day period prior to enrollment)
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3.
Subjects with NF-1 associated optic pathway tumors are excluded if they are actively 
receiving therapy for the optic pathway tumor or do not meet criteria for PN or malignant 
solid tumor (Subjects with NF-1 and isolated optic pathway tumors as only site of 
evaluable tumor are not eligible for enrollment).
5.
Subjects with NF-1 and active optic glioma are excluded.
10. Part B and Part C only:  Previous treatment with dabrafenib (cohort B4), 
trametinib or another MEK inhibitor (exception: prior treatment with sorafenib is 
permitted)
17. History or current evidence / risk of RVO or RPED:

History of RVO or RPED, or predisposing factors to RVO or RPED (e.g., 
uncontrolled glaucoma or ocular hypertension, uncontrolled systemic disease(s) such 
as hypertension, diabetes mellitus, or history of hyperviscosity or hypercoagulability 
syndromes).

Visible retinal pathology as assessed by ophthalmic exam performed within 1 month 
of enrollment that is considered a risk factor for RVO or RPED such as:

Evidence of new optic disc cupping

Evidence of new visual field defects

Intraocular pressure >21mm Hg
Section 6.6 Treatment after the End of the Study ADDED TEXT, last paragraph
Subjects who discontinued dabrafenib treatment will be followed every 3 months for  2 
years to monitor for the occurrence of SCC and monitored for up to 2 years for non-
cutaneous malignancy. 
Section 7.1, Time and Events Tables
Table 11, Screening through Day 28:
Archived tumor biopsy or bone marrow 
aspirate, Part B
Archived tissue at screening is required and must be available to be shipped 
to GSK; if not available fresh biopsy is acceptable. Central confirmation of
RAS mutation status does not have to be done within 14 days prior to 
dosing. 
Tumor tissue for V600 testing, Part B4 and 
Part C 
Local BRAF testing required for enrolment in the study; the local testing 
will be subject to subsequent confirmation by centralized testing.  Central 
confirmation can be from archival tissue or if no archival tissue is available, 
from fresh biopsy.  Central confirmation not required within 14 days prior 
to dosing.
Vital signs
Blood pressure (3 serial blood pressues; separated by at least 5 minutes 
see Section 3.13.3.1), body temperature, pulse rate, respirations
Tumor biopsy or bone marrow aspirate
Optional fresh biopsy or bone marrow aspirate




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Section 7.5.1.1 Part B, All Cohorts
REVISED TEXT (new text bold and underlined, deleted text in strikethrough):
Patients may be enrolled in the study on the basis on local test results, but archival tissue must 
be submitted during screening for subsequent confirmation of the Ras pathway activation or 
mutation status using a validated assay.  If archival specimen is not available, subjects will be 
required to undergo tumor biopsy prior to participation in the study.  If archived tissue is 
not available and a fresh tumor sample cannot be collected (i.e. subjects with brain 
tumors) the subject will not be eligible for participation in the study…..
Section 7.5.1.2 Part C, Subjects with Melanoma
REVISED TEXT (new text bold and underlined, deleted text in strikethrough):
Patients may be enrolled in the study on the basis of local test results, Archival tumor
tissue sample reflective of the current disease setting will be collected at Screening for central 
confirmation of the BRAF V600E mutation status. If an archival tumor tissue sample is not 
available, fresh tumor tissue should be collected (see SPM for further details) to determine the 
subject’s BRAF V600E mutation status. Submission of archival tumor tissue is optional for 
Parts A and B.If archived tumor tissue is not available and the collection of a fresh tumor 
tissue sample is not possible the subject will not be eligible to participate in the study.
Section 7.5.2 Tumor Tissue for Pharmacodynamic Testing
REVISED TEXT (new text bold and underlined, deleted text in strikethrough):
The collection of fresh tumor tissue is optional for PD testing but…
Section 8.4.2 Prompt Reporting of SAEs and Other Events to GSK
REVISED TEXT (new text bold and underlined, deleted text in strikethrough):
SAEs, DLTs, pregnancies….
All SAEs and DLTs
24 hr
SAE data collection tool
24 hr
Updated SAE data 
collection tool 
Changes to Appendices:
Appendix 2 Dosing Nomogram was updated to include dose in mg
Appendix 5 Response Criteria for CNS tumors was replaced with Response 
Assessment in Neuro-oncology (RANO) Criteria (Glioma Subjects)
Appendix 6 – Country Specific Amendment was deleted
Appendix 7 (added) Blood Pressure Levels for Children by Age and Height 
Percentile


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Appendix 8 (added) Dose Escalation Based on PK Criteria


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Amendment 2
Amendment 2
Where the Amendment Applies
Amendment 2 applies to all sites.
Summary of Amendment Changes with Rationale
This amendment was made in response to MHRA comments, as well as review from clinical 
sites. 
Section 1.6.3 Langerhans Cell Histiocytosis—new section
LCH is a rare proliferative disorder of unknown etiology that primarily affects children.  
It is distinguished by the clonal proliferation of pathologic histiocytes with the 
morphologic characteristics of Langerhans cells.  Langerhans cells are bone-marrow 
derived dendritic cells, characterized by the expression of CD1a, S100 and the 
production of Birbeck granules.  The pathogenesis of LCH is poorly understood.  
Clinical manifestations are related to the pattern of infiltration or organ involvement 
[Stockschlaeder, 2006; Arico, 1998].  The clinical presentation is heterogeneous, can 
involve single or multiple organs, and can be associated with varying, often 
unpredictable outcomes ranging from spontaneous regression to multiple episodes of 
reactivation, long term debilitating sequelae, rapid progression, and death. 
Patients with localized (single system) disease in ‘low risk’ organs typically have good 
prognosis and may require minimal treatment (for example, isolated bone lesion).  On 
the other hand, multisystem disease, especially disease involving key ‘high risk’ organs 
(hematopoietic, spleen, liver, lung), carries higher risk of poor outcomes and recurrent 
events (reactivation disease) after initial therapy. 
LCH occurs at an estimated rate of 2 to 10 per million children/adolescents under the 
age of 15 years [NCI, 2012; Stalemark, 2008], as compared to approximately 1 to 2 cases 
per million in adults.  Approximately 76% of cases occur in children less than 10 years 
old.  Risk of morbidity and mortality increases substantially when multifocal or multi-
organ disease is present [Satter, 2008].  
In a recent report, which is also the first to show activation of any oncogenic signalling 
pathway in LCH, BRAF V600E mutations were identified in nearly 60% of a cohort of 
archival lesion samples obtained from children and adults with LCH [Badalian-Very, 
2010].  The identification of BRAF V600E mutations in LCH has been confirmed in a 
recently published second report [Satoh, 2012].
Mutational analysis of BRAF V600 wild type LCH tumors has very recently revealed a 
second pathway activating alteration, MAP2K1 [Brown , 2014].  Of the roughly half of 
LCH specimens lacking the BRAF V600E mutation, half (about 25% overall) were 
found to have activation mutations of MAP2K1. This finding reinforces the important 
role of this pathway in the genesis of LCH and related diseases, and provides a rationale 
for additional investigation of inhibition of this pathway at more downstream positions, 
including that provided by inhibitors of MEK1/2.
Section 3.1 Discussion of study design PREVIOUS TEXT
Discussion of Study Design


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This is a 3-part (Part A, Part B, Part C), Phase I/IIa, multi-center, open label study in pediatric 
subjects with refractory or recurrent tumors likely to have pathway activation and thus more 
likely to benefit from therapy.  The overall goal of this trial is to efficiently establish safe, 
pharmacologically relevant dose of trametinib in infants, children and adolescents and 
determine preliminary activity of trametinib monotherapy in selected recurrent, refractory or 
unresectable childhood tumors.  In addition, Part C of the study is designed to establish the 
safety, tolerability and activity of trametinib in combination with dabrafenib in children and 
adolescents with recurrent, refractory or unresectable BRAFV600E mutated tumors.

Part A will be a pharmacokinetically driven limited dose escalation in subjects with 
an expansion for safety, tolerability, and PK in three age ranges (1 month to <2years, 2 
to ≤12 years, and over 12 years of age).  The primary goal of Part A is to establish the 
toxicity profile, PK, and recommended Phase 2 dose (RP2D) of trametinib in each age 
cohort.  Approximately 18 subjects will be accrued to the dose escalation phase 
(subjects less than 2 years of age will not be included in the initial dose escalation 
(approximately 6-12 subjects) is complete and the age specific cohorts are opened) and 
18 subjects to the age expansion phase
Section 3.1 Discussion of Design REVISED TEXT
This is a 3-part (Part A, Part B, Part C), Phase I/IIa, multi-center, open label study in pediatric 
subjects with refractory or recurrent tumors likely to have pathway activation and thus more 
likely to benefit from therapy.  The overall goal of this trial is to efficiently establish safe, 
pharmacologically relevant dose of trametinib in infants, children and adolescents and 
determine preliminary activity of trametinib monotherapy in selected recurrent, refractory or 
unresectable childhood tumors.  In addition, Part C of the study is designed to establish the 
safety, tolerability and activity of trametinib in combination with dabrafenib in children and 
adolescents with recurrent, refractory or unresectable BRAFV600E mutated tumors.

Part A will be a pharmacokinetically driven limited dose escalation in subjects with an 
expansion for safety, tolerability, and PK in three age ranges (1 month to <2years, 2 to 
≤12 years, and over 12 years of age).  The primary goal of Part A is to establish the 
toxicity profile, PK, and recommended Phase 2 dose (RP2D) of trametinib in each age 
cohort.  Approximately 18 subjects will be accrued to the dose escalation phase (subjects 
less than 2 years of age will not be included in the initial dose escalation (approximately 
6 12 subjects) is complete and the age specific cohorts are opened) and 18 subjects to the 
age expansion phase (subjects less than 2 years of age will not be included in the initial 
dose escalation until the age specific cohorts are opened).
Section 3.2.4  Part A: Age Group Expansion  PREVIOUS TEXT
Following the initial 3+3 dose escalation (Section 3.2.2), the dose will be confirmed and 
evaluated in the following specific age groups:

Infants and toddlers (age 1 month to <2 years).

Children (age 2 to ≤12 years).

Adolescents (age >12 years to <18 years).


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Section 3.2.4  Part A: Age Group Expansion  REVISED TEXT
Following the initial 3+3 dose escalation (Section 3.2.2), the dose will be confirmed and 
evaluated in the following specific age groups (age on day of consent):

Infants and toddlers (age 1 month to <2 years).

Children (age 2 to ≤12 years).

Adolescents (age >12 years to <18 years).
Note: For the purposes of this study, age 12 is considered to be the day of a subject’s 12th
birthday.  The day after the 12th birthday, a subject is considered to be greater than 12 
years.
SECTION 3.3   Part B:  Tumor-Specific Expansion PREVIOUS TEXT
Part B will evaluate the preliminary activity of trametinib monotherapy in 4 disease-specific 
cohorts of subjects.  Each cohort will enroll at least 10 response-evaluable subjects (evaluable 
for response is defined as a subject with a pre-dose and at least 1 post–dose disease 
assessment or clinical assessment of progression of disease). 
PK samples will be collected on Day 15 only. Archived or fresh tumor tissue to confirm Ras 
pathway activation is required from all subjects at screening.
Blood samples for clinical laboratory tests will be collected throughout the study, and safety, 
tolerability and clinical activity assessments will be conducted according to the Time and 
Events Tables (Section 7.1).
Trametinib will be continued until disease progression, until subjects are no longer obtaining 
clinical benefit from continued treatment, until they develop an unacceptable toxicity, or until 
they withdraw consent, begin a new anti-cancer therapy, or the Sponsor terminates the study.  
At the end of treatment, a final study visit will occur.  Additional details on subject 
completion are provided in Section 6.2.


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SECTION 3.3  Part B:  Tumor-Specific Expansion REVISED TEXT
Part B will evaluate the preliminary activity of trametinib monotherapy in 4 disease-specific 
cohorts of subjects.  Each cohort will enroll at least 10 response-evaluable subjects (evaluable 
for response is defined as a subject with a pre-dose and at least 1 post–dose disease 
assessment or clinical assessment of progression of disease). 
PK samples will be collected on Day 15 only. 
Archived or fresh tumor tissue to confirm BRAF V600 or Ras pathway activation is required 
from all subjects at screening, unless the patient is specifically exempt from the 
requirement for histologic confirmation (e.g. NF-1, some brainstem gliomas (refer to 
inclusion criteria)).  If tissue is unavailable, from non-exempt patients, then enrollment 
is not permitted.
Blood samples for clinical laboratory tests will be collected throughout the study, and safety, 
tolerability and clinical activity assessments will be conducted according to the Time and 
Events Tables (Section 7.1).
Trametinib will be continued until disease progression, until subjects are no longer obtaining 
clinical benefit from continued treatment, until they develop an unacceptable toxicity, or until 
they withdraw consent, begin a new anti-cancer therapy, or the Sponsor terminates the study.  
At the end of treatment, a final study visit will occur.  Additional details on subject 
completion are provided in Section 6.2.
SECTION 3.7 Study Schematics  PREVIOUS FIGURES
Figure 2
Trametinib Disease Specific Expansion
Figure 3
Trametinib in Combination with Dabrafenib


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SECTION 3.7 Study Schematics REVISED FIGURES
(added clarification note to each Figure for age requirements)
Figure 2
Trametinib Disease Specific Expansion
FIGURE 2 Note: A minimum of four subjects age younger than 6 years old is required in each of the four groups.
Figure 3
Trametinib in Combination with Dabrafenib
Figure 3 Notes: 
1. Allowable ages are between 12 months and less than 18 years inclusive. 
2. There is no specific age-expansion in Part C, however study goal is to enroll at least four subjects age younger 
than 12.
Section 3.11.3.1 LVEF stopping Criteria PREVIOUS TEXT
Decreases of the left-ventricular-ejection-fraction (LVEF) have been observed in subjects 
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 
Time and Events Table (Section 7.1). Dose modification guidance and stopping criteria for 
LVEF decrease are provided in Table 3.
ECHO should be performed at baseline and at follow up visit(s).  Electronic copies of all 
ECHO scans will be collected by GSK for review.  Instructions for submission of ECHO 
scans are provided in the Study Procedures Manual (SPM).










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SECTION 3.13.1.2 Reactive Management PREVIOUS TEXT
Table 5
Management of Rash
CTCAE Grade
Adverse Event Management 
Action and Dose Modification
Grade 1
Initiate prophylactic and 
symptomatic treatment 
measuresa
Use moderate strength topical 
steroidb
Reassess after 2 weeks; 
Continue trametinib 
If rash does not recover to baseline within 2 weeks 
despite best supportive care, reduce trametinib by 
one dose.
Grade 2
Initiate prophylactic and 
symptomatic treatment 
measuresa Use moderate 
strength topical steroidb  
Reassess after 2 weeks.
Reduce trametinib by one dose level.
Reassess after 2 weeks:

If rash recovers to ≤Grade 1 within 2 weeks, 
increase dose to previous dose level

If no recovery to ≤Grade 1 within 2 weeks, 
interrupt trametinib until recovery to ≤grade 1, 
restart trametinib at reduced dose level
Grade 3
Use moderate strength topical 
steroidsb ( PLUS 
methylprednisolone dose pack.
Consult dermatologist   

Interrupt trametinib until rash recovers to 
Grade ≤1

Restartc with trametinib reduced by one 
dose leveld
If no recovery to grade ≤2 within 4 weeks, 
permanently discontinue trametinib.
Abbreviations:  CTCAE = Common Terminology Criteria for Adverse Events
a.
Rash prophylaxis is recommended for the first 6 weeks of study treatment
b.
Moderate-strength topical steroids  hydrocortisone 2.5% cream or fluticasone prioprionate 0.5% cream
c.
Approval of GSK medical monitor is required to re-start study treatment after >4 weeks of interruption
d.
Escalation of trametinib to previous dose level may be considered if no rash is evident 4 weeks after restarting 
study treatment


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SECTION 3.13.1.2 Reactive Management REVISED TEXT (added reference to 
Appendix 2 Dose nomogram throughout)
Table 5
Management of Rash
CTCAE Grade
Adverse Event Management 
Action and Dose Modification
Grade 1
Initiate prophylactic and 
symptomatic treatment 
measuresa
Use moderate strength topical 
steroidb
Reassess after 2 weeks; 
Continue trametinib 
If rash does not recover to baseline within 2 weeks 
despite best supportive care, reduce trametinib by 
one dose level (Appendix 2).
Grade 2
Initiate prophylactic and 
symptomatic treatment 
measuresa Use moderate 
strength topical steroidb  
Reassess after 2 weeks.
Reduce trametinib by one dose level (Appendix 
2).
Reassess after 2 weeks:

If rash recovers to ≤Grade 1 within 2 weeks, 
increase dose to previous dose level

If no recovery to ≤Grade 1 within 2 weeks, 
interrupt trametinib until recovery to ≤grade 1, 
restart trametinib at reduced dose level
Grade 3
Use moderate strength topical
steroidsb ( PLUS 
methylprednisolone dose pack.
Consult dermatologist   

Interrupt trametinib until rash recovers to 
Grade ≤1

Restartc with trametinib reduced by one 
dose leveld (Appendix 2)
If no recovery to grade ≤2 within 4 weeks, 
permanently discontinue trametinib.
Abbreviations:  CTCAE = Common Terminology Criteria for Adverse Events
a.
Rash prophylaxis is recommended for the first 6 weeks of study treatment
b.
Moderate-strength topical steroids  hydrocortisone 2.5% cream or fluticasone prioprionate 0.5% cream
c.
Approval of GSK medical monitor is required to re-start study treatment after >4 weeks of interruption
d.
Escalation of trametinib to previous dose level may be considered if no rash is evident 4 weeks after restarting 
study treatment
SECTION 3.13.3 Hypertension PREVIOUS TEXT
The algorithm in Figure 4 will be used to grade and manage trametinib related hypertension. 
Should initiation of anti-hypertensive therapy be required, single agent therapy (commonly 
including the calcium channel blockers amlodipine or nifedipine,) should be started and the 
blood pressure should be monitored at least twice weekly until BP is within the 95th 
percentile for age, height, and gender per Section 3.11.3.2
If patient is already on an anti-hypertensive medication at study enrollment, then their anti-
hypertensive therapy should be adjusted (by either adjusting the dose of their current anti-


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hypertensive medication or by adding another anti-hypertensive agent) according to the 
algorithm in Section 3.13.3.1.
Baseline Blood Pressure

Baseline blood pressure (BP) is defined as the blood pressure obtained at the 
examination used for study enrollment. This baseline BP should be obtained as 
follows:
1) Obtain 3 serial blood pressures from the same extremity with the patient in the 
same position that are separated by at least 5 minutes. Avoid using the lower 
extremity if possible.
2) Average the systolic blood pressure from the 2nd and 3rd measurements.
3) Average the diastolic blood pressure from the 2nd and 3rd measurements.
4) The baseline BP is the average of the systolic and average of the diastolic 
measurements.
SECTION 3.13.3 Hypertension REVISED TEXT
(moved text to Section 7.3.4 Vital Signs to be more accessible to Investigators during safety 
evaluation as information is applicable there instead of stopping criteria section)
The algorithm in Figure 4 will be used to grade and manage trametinib related hypertension. 
Should initiation of anti-hypertensive therapy be required, single agent therapy (commonly 
including the calcium channel blockers amlodipine or nifedipine,) should be started and the 
blood pressure should be monitored at least twice weekly until BP is within the 95th 
percentile for age, height, and gender per Section 3.11.3.2
If patient is already on an anti-hypertensive medication at study enrollment, then their anti-
hypertensive therapy should be adjusted (by either adjusting the dose of their current anti-
hypertensive medication or by adding another anti-hypertensive agent) according to the 
algorithm in Section. 3.13.3.1.  See requirements for Baseline blood pressure 
measurements in Section 7.3.4.
Baseline Blood Pressure

Baseline blood pressure (BP) is defined as the blood pressure obtained at the 
examination used for study enrollment. This baseline BP should be obtained as 
follows:
1) Obtain 3 serial blood pressures from the same extremity with the patient in the 
same position that are separated by at least 5 minutes. Avoid using the lower 
extremity if possible.
2) Average the systolic blood pressure from the 2nd and 3rd measurements.
3) Average the diastolic blood pressure from the 2nd and 3rd measurements.
4) The baseline BP is the average of the systolic and average of the diastolic 
measurements.
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1. Written informed consent – a signed informed consent and/or assent (as age 
appropriate) for study participation including pharmacokinetics sampling will be 
obtained according to institutional guidelines.
2. Male or female between one month and < 18 years of age (inclusive) at the time of 
signing the informed consent form (Part C between 12 months and < 18 years of age, 
inclusive).
3. . Must have a disease that is relapsed/refractory to all potentially curative standard 
treatment regimens or have a disease for which there are no standard treatment 
regimens that are potentially curative.
4. Prior therapy: The subject’s cancer (not NF-1 with PN) must have relapsed after or 
failed to respond to frontline curative therapy or there must not be other potentially 
curative treatment options available.  Curative therapy may include surgery, radiation 
therapy, chemotherapy, or any combination of these modalities.  All subjects 
(including NF-1 with PN) must have recovered to grade ≤1 from the acute toxic 
effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to enrollment.

Myelosuppressive chemotherapy: The last dose of all myelosuppressive anticancer drugs 
must be at least 21 days prior to enrollment.  

Differentiating Agents/ Biologic response modifiers (small molecules, antibodies, viral 
therapies) (anti-cancer agent):  The last dose of all biologic agents for the treatment of the
subject’s cancer (such as retinoids) must be at least 7 days prior to study entry.  The last 
dose of monoclonal antibodies, immunotherapy, or viral therapy must be at least 30 days 
prior to enrollment.

Non-myelosuppressive anticancer agents: (antiangiogenic agents, tyrosine kinase 
inhibitors):  The last dose of non-investigational agent that is not cytotoxic must be at least 
2 weeks prior to enrollment.

Investigational agent: The last dose of all investigational agents must be at least 30 days 
prior to study entry.

Radiation therapy: The last dose of radiation (including therapeutic Iodine-131-meta-
iodobenzylguanidine [MIBG]) to more than 25% of marrow containing bones (pelvis, 
spine, skull) must be at least 28 days prior to enrollment.  The last dose of all other local 
palliative (limited port) radiation must be at least 14 days prior to enrollment.

Stem Cell Transplantation or Infusion.  Subjects must be at least 2 months post-
autologous transplant or stem cell infusion and must have recovered from toxicities.  
Subjects must be at least 6 months post- allogeneic transplant, must have recovered from 
toxicities, and must have no evidence of active graft-versus-host disease.  Subjects must 
also have been off of immunosuppressive treatment at least 30 days.

Number of prior treatment regimens: No limitation on the number of prior systemic or 
local treatment modalities that the subject may have received prior to study entry.

Colony stimulating factors: The last dose of colony stimulating factors, such as filgrastim, 
sargramostim, and epoetin, must be at least 48 hr prior to study entry, and the last dose of 


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long-acting colony stimulating factors, such as pegfilgrastim, must be at least 10 days 
prior to study entry.

Corticosteroids in subjects with solid tumors are permitted if the dose of corticosteroids is 
stable or decreasing for at least 7 days prior to enrollment.  .
5. Performance score of ≥50% according to the Karnofsky/Lansky performance status 
scale [Yates, 1980] (Appendix 1).
6. Females of child-bearing potential must be willing to practice acceptable methods of 
birth control (see Section 10.1).  Additionally, females of childbearing potential must 
have a negative serum pregnancy test within 14 days prior to enrollment, throughout 
treatment period and for 4 months after last dose of study drug.
7. Must have adequate organ function as defined by the following values:

Renal function:  24 hr creatinine clearance (revised Schwartz formula), or radioisotope 
glomerular filtration rate (GFR) ≥ 60 mL/min/1.73 m2; or a serum creatinine  ≤ ULN for 
age and gender as defined in the following table:
Age
Upper Limit of Normal Serum Creatinine
(Years)
(mg/dl)
Male
Female
Less than  6 months 
0.4
0.4
6 months to less than 1 year
0.5
0.5
1 year to less than 2 years
0.6
0.6
2 to less than 6 years
0.8
0.8
6 to less than 10 years
1
1
10 to less than 13 years
1.2
1.2
13 years to less than 16 years
1.5
1.4
Greater than 16 years
1.7
1.4
The threshold creatinine values in this table were derived from the Schwartz formula for 
estimating GFR [Schwartz, 1985] utilizing child length and stature data published by the Centers 
for Disease Control and Prevention (CDC).

Liver function defined as:

Bilirubin (sum of conjugated + unconjugated) ≤ 1.5 x ULN for age

ALT 2.5 x ULN; for the purposes of enrollment and toxicity monitoring the ULN 
for ALT will be 45 U/L.

Cardiac function defined as: 

Corrected QT (QTcB) interval <480 msec

LVEF ≥LLN by ECHO
8. Able to swallow and retain enterally (PO or nasogastric or gastric tube) administered 
medication and does not have any clinically significant gastrointestinal abnormalities 


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that may alter absorption such as malabsorption syndrome or major resection of the 
stomach or bowels.
9. Adequate Blood Pressure Control defined as:
a.
Blood pressure ≤ the 95th percentile for age, height, and gender) measured as 
described in Section7.3.4. 
10. French subjects: In France, a subject will be eligible for inclusion in this study only if 
either affiliated to or a beneficiary of a social security category
Section 5.2.1.1 General Eligibility Criteria (All Parts) REVISED TEXT
(Updated to clarify population for the trial and at the request of regulatory to shorten 
timeframe for pregnancy testing prior to enrollment from 14 to 7 days in applicable 
subjects)
1.
Written informed consent – a signed informed consent and/or assent (as age appropriate) 
for study participation including pharmacokinetics sampling will be obtained according 
to institutional guidelines.
2.
Male or female between one month and < 18 years of age (inclusive) at the time of 
signing the informed consent form (Part C between 12 months and < 18 years of age, 
inclusive).
3.
Must have a disease that is relapsed/refractory to all potentially curative standard 
treatment regimens or must have a current disease for which there is no known 
curative therapy, or therapy proven to prolong survival with an acceptable quality 
of life have a disease for which there are no standard treatment regimens that are 
potentially curative
4.
Prior therapy: The subject’s cancer disease (i.e. cancer, (not NF-1 with PN, or LCH) 
must have relapsed after or failed to respond to frontline curative therapy or there must 
not be other potentially curative treatment options available.  Curative therapy may 
include surgery, radiation therapy, chemotherapy, or any combination of these modalities.  
All subjects (including NF 1 with PN) must have recovered to grade ≤1 from the acute 
toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to 
enrollment.

Myelosuppressive chemotherapy: The last dose of all myelosuppressive anticancer drugs 
must be at least 21 days prior to enrollment.  

Differentiating Agents/ Biologic response modifiers (small molecules, antibodies, viral 
therapies) (anti-cancer agent):  The last dose of all biologic agents for the treatment of the 
subject’s cancer (such as retinoids) must be at least 7 days prior to study entry.  The last 
dose of monoclonal antibodies, immunotherapy, or viral therapy must be at least 30 days 
prior to enrollment.

Non-myelosuppressive anticancer agents: (antiangiogenic agents, tyrosine kinase 
inhibitors):  The last dose of non-investigational agent that is not cytotoxic must be at least 
2 weeks prior to enrollment.


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
Investigational agent: The last dose of all investigational agents must be at least 30 days 
prior to study entry.

Radiation therapy: The last dose of radiation (including therapeutic Iodine-131-meta-
iodobenzylguanidine [MIBG]) to more than 25% of marrow containing bones (pelvis, 
spine, skull) must be at least 28 days prior to enrollment.  The last dose of all other local 
palliative (limited port) radiation must be at least 14 days prior to enrollment.

Stem Cell Transplantation or Infusion.  Subjects must be at least 2 months post-
autologous transplant or stem cell infusion and must have recovered from toxicities.  
Subjects must be at least 6 months post- allogeneic transplant, must have recovered from 
toxicities, and must have no evidence of active graft-versus-host disease.  Subjects must 
also have been off of immunosuppressive treatment at least 30 days.

Number of prior treatment regimens: No limitation on the number of prior systemic or 
local treatment modalities that the subject may have received prior to study entry.

Colony stimulating factors: The last dose of colony stimulating factors, such as filgrastim, 
sargramostim, and epoetin, must be at least 48 hr prior to study entry, and the last dose of 
long-acting colony stimulating factors, such as pegfilgrastim, must be at least 10 days 
prior to study entry.

Corticosteroids in subjects with solid tumors are permitted if the dose of corticosteroids is 
stable or decreasing for at least 7 days prior to enrollment.  .
5. Performance score of ≥50% according to the Karnofsky/Lansky performance status scale 
[Yates, 1980] (Appendix 1).
6. Females of child-bearing potential must be willing to practice acceptable methods of birth 
control (see Section 10.1).  Additionally, females of childbearing potential must have a 
negative serum pregnancy test within 7 14 days prior to start of study drugs, throughout 
treatment period and for 4 months after last dose of study drug.
7. Must have adequate organ function as defined by the following values:

Renal function:  24 hr creatinine clearance (revised Schwartz formula), or radioisotope 
glomerular filtration rate (GFR) ≥ 60 mL/min/1.73 m2; or a serum creatinine  ≤ ULN for 
age and gender as defined in the following table:
Age
Upper Limit of Normal Serum Creatinine
(Years)
(mg/dl)
Male
Female
Less than  6 months 
0.4
0.4
6 months to less than 1 year
0.5
0.5
1 year to less than 2 years
0.6
0.6
2 to less than 6 years
0.8
0.8
6 to less than 10 years
1
1
10 to less than 13 years
1.2
1.2
13 years to less than 16 years
1.5
1.4


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Greater than 16 years
1.7
1.4
The threshold creatinine values in this table were derived from the Schwartz formula for 
estimating GFR [Schwartz, 1985] utilizing child length and stature data published by the Centers 
for Disease Control and Prevention (CDC).

Liver function defined as:

Bilirubin (sum of conjugated + unconjugated) ≤ 1.5 x ULN for age

ALT 2.5 x ULN; for the purposes of enrollment and toxicity monitoring the ULN 
for ALT will be 45 U/L.

Cardiac function defined as: 

Corrected QT (QTcB) interval <480 msec

LVEF ≥LLN by ECHO
8. 
Able to swallow and retain enterally (PO or nasogastric or gastric tube) administered 
medication and does not have any clinically significant gastrointestinal abnormalities that may 
alter absorption such as malabsorption syndrome or major resection of the stomach or bowels.
9.
Adequate Blood Pressure Control defined as:

Blood pressure ≤ the 95th percentile for age, height, and gender) measured as 
described in Section 7.3.4. 
10. French subjects: In France, a subject will be eligible for inclusion in this study only if 
either affiliated to or a beneficiary of a social security category
Section 5.2.1.2 Specific Eligibility Criteria, Part A     PREVIOUS TEXT
Subjects must meet General Eligibility Criteria. The specific eligibility criteria listed here 
will apply to subjects enrolling to Part A.
1. For the initial dose escalation to identify the maximum tolerable or PK target dose, age 
between 2 years and < 18 years (inclusive) at the time of signing the informed consent 
form. Children < 2 years of age will be enrolled once the age specific expansion cohorts 
are open.
2. Histologically confirmed solid tumors, which may include but are not limited to 
rhabdomyosarcoma and other soft tissue sarcomas, Ewing sarcoma family of tumors, 
osteosarcoma, neuroblastoma, Wilms’ tumor, hepatic tumors, germ cell tumors, and 
primary brain tumors.  In subjects with brain stem gliomas the requirement for histological 
confirmation can be waived if a biopsy was not performed.
3. Measurable or evaluable tumors.  Subjects with neuroblastoma that is only detectable by 
MIBG scan are eligible.  Subjects with neuroblastoma that is only detected by bone 
marrow aspirate/biopsy or elevated homovanillic acid / vanillylmandelic acid 
(HVA/VMA) are not eligible.
4. Adequate bone marrow function defined as:

Absolute neutrophil count (ANC) ≥1000/µL;

Hemoglobin ≥8.0 g/dL (may receive red blood cell transfusions)


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
Platelets ≥75,000/µL (transfusion independent, defined as not receiving platelet 
transfusions within a 7 day period prior to enrollment)
Section 5.2.1.2 Specific Eligibility Criteria, Part A REVISED TEXT (updated #2 criteria 
to make clear to investigators that subjects with NF-1 associated PNs and Subjects with LCH 
are eligible and to clarify tumor assessments)
Subjects must meet General Eligibility Criteria. In cases of conflict, the The specific 
eligibility criteria listed here will apply to subjects enrolling to Part A.
1. For the initial dose escalation to identify the maximum tolerable or PK target dose, age 
between 2 years and < 18 years (inclusive) at the time of signing the informed consent 
form. Children < 2 years of age will be enrolled once the age specific expansion 
cohorts are open.
2. Histologically confirmed solid tumors, which may include but are not limited to 
rhabdomyosarcoma and other soft tissue sarcomas, Ewing sarcoma family of tumors, 
osteosarcoma, neuroblastoma, Wilms’ tumor, hepatic tumors, germ cell tumors, and
primary brain tumors, NF-1 associated plexiform neurofibromas, and Langerhans 
Cell histocytosis (LCH).  In subjects with brain stem gliomas the requirement for 
histological confirmation can be waived if a biopsy was not performed.  For 
plexiform neurofibromas, histologic confirmation of tumor is not necessary in the 
presence of consistent clinical and radiological findings, but should be considered 
if malignant degeneration of a PN is clinically suspected. 
3. Measurable or evaluable tumors.  Subjects with neuroblastoma that is only detectable 
by MIBG scan are eligible.  Subjects with neuroblastoma that is only detected by bone 
marrow aspirate/biopsy or elevated homovanillic acid / vanillylmandelic acid 
(HVA/VMA) are not eligible. 
4. Adequate bone marrow function defined as:

Absolute neutrophil count (ANC) ≥1000/µL;

Hemoglobin ≥8.0 g/dL (may receive red blood cell transfusions)

Platelets ≥75,000/µL (transfusion independent, defined as not receiving platelet 
transfusions within a 7 day period prior to enrollment)
SECTION 5.2.2 Exclusion Criteria (All Parts) PREVIOUS TEXT
Deviations from exclusion criteria are not allowed because they can potentially jeopardize the 
scientific integrity of the study, regulatory acceptability or subject safety.  Therefore, 
adherence to the criteria as specified in the protocol is essential.
Subjects meeting any of the following criteria must not be enrolled in the study:
1.
Lactating or pregnant female.
2.
History of another malignancy including resected non-melanomatous skin cancer.
3.
Subjects with NF-1 associated optic pathway tumors are excluded if they are actively 
receiving therapy for the optic pathway tumor or do not meet criteria for PN or malignant 


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solid tumor (Subjects with NF-1 and isolated optic pathway tumors as only site of
evaluable tumor are not eligible for enrollment).
4.
Subjects with a history of NF-1 related cerebral vascular anomaly are excluded.
5.
Subjects with NF-1 and active optic glioma are excluded.
6.
Subjects with NF-1 and PN that cannot be evaluated by volumetric analysis.
7.
Any serious and/or unstable pre-existing medical, psychiatric disorder or other conditions 
that could interfere with subject’s safety, obtaining informed consent or compliance to the 
study procedures.
8.
Any prohibited medication(s), currently used or expected to be required, as described in 
Section 9.2.
9.
Any medications for treatment of left ventricular systolic dysfunction
10. Part B and Part C only:  Previous treatment with dabrafenib (cohort B4), trametinib or 
another MEK inhibitor (exception: prior treatment with sorafenib is permitted)
11. Administration of an investigational study treatment within 30 days preceding the first 
dose of study treatment(s) in this study.
12. Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs 
chemically related to study treatment or excipients that contraindicate their participation.
13. Current active liver or biliary disease (with the exception of Gilbert's syndrome or 
asymptomatic gallstones, or liver metastases).
14. History of hepatic sinusoid obstructive syndrome (venoocculsive disease) within the prior 
3 months.
15. History of sensitivity to heparin or heparin-induced thrombocytopenia.
16. History of interstitial lung disease or pneumonitis.
18. History or current evidence  RVO or RPED
19. For subjects with solid tumors that are not primary CNS tumors, subjects with 
symptomatic or untreated leptomeningeal or brain metastases or spinal cord compression 
are excluded.
NOTE: Subjects previously treated for these conditions that have had stable CNS disease 
(verified with consecutive imaging studies) for >3 months, are asymptomatic and are not 
currently taking corticosteroids, or are on stable dose or decreasing of corticosteroids for at 
least 7 days prior to enrolment are permitted.
20. A history of known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or 
Hepatitis C Virus (HCV) infection. Subjects with laboratory evidence of cleared HBV 
and HCV infection may be enrolled.
21. Unresolved toxicity of National Cancer Institute Common Terminology Criteria for 
Adverse Events, version 4.0 (NCI CTCAE v4.0) [NCI, 2009] Grade 2 or higher from 
previous anti-cancer therapy, except alopecia.


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22. Presence of active gastrointestinal disease or other condition that will interfere 
significantly with the absorption of drugs.  If clarification is needed as to whether a 
condition will significantly affect absorption of drugs, contact the GlaxoSmithKline 
(GSK) medical monitor for guidance to enrol the subject.
23. A history or evidence of cardiovascular disease

Part C only, Abnormal cardiac valve morphology (≥Grade 2) documented by 
echocardiogram.  Subjects with moderate valvular thickening should not be entered on 
study;
SECTION 5.2.2 Exclusion Criteria (All Parts) REVISED TEXT

(updated #3, 4,5,6,15,18,19,23; Changed to exclude only optic pathway tumors that 
are being actively treated This is because GSK now understands that the NF1 
academic community prefers to enroll such patients (NF-1 associated optic gliomas as 
only site of disease) into MEK inhibitor trials. Previously, our understanding was that 
such patients should not be treated on this study, and perhaps be treated in different 
investigational trials; Cardiovascular exclusion criteria were updated to be consistent 
with requirements in other trametinib and dabrafenib studies; Removal of RPED 
(retinal pigment epithelium detachment) as an exclusion criterion, based on current 
safety data that only requires history of RVO (retinal vein occlusion) as an exclusion; 
Removal of heparin-sensitivity as an exclusion as there are no known drug-drug 
interactions between heparin and trametinib or dabrafenib.  Heparin-induced 
thrombocytopenia remains as an exclusion.)
Deviations from exclusion criteria are not allowed because they can potentially jeopardize the 
scientific integrity of the study, regulatory acceptability or subject safety.  Therefore, 
adherence to the criteria as specified in the protocol is essential.
Subjects meeting any of the following criteria must not be enrolled in the study:
1.
Lactating or pregnant female.
2.
History of another malignancy including resected non-melanomatous skin cancer.
3.
Subjects with NF-1 associated optic pathway tumors are excluded if they are actively 
receiving therapy for the optic pathway tumor or do not meet criteria for PN or malignant 
solid tumor (Subjects with NF 1 and isolated optic pathway tumors as only site of 
evaluable tumor are not eligible for enrollment).
4.
Subjects with a history of NF-1 related cerebral vascular anomaly (such as Moyamoya)
are excluded.
5.
Subjects with NF-1 actively receiving therapy for the optic pathway tumor Subjects 
with NF 1 and active optic glioma are excluded.
6.
Subjects with NF-1 and only PN lesions that cannot be evaluated by volumetric analysis.
7.
Any serious and/or unstable pre-existing medical, psychiatric disorder or other conditions 
that could interfere with subject’s safety, obtaining informed consent or compliance to the 
study procedures.


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8.
Any prohibited medication(s), currently used or expected to be required, as described in 
Section 9.2.
9.
Any medications for treatment of left ventricular systolic dysfunction
10. Part B and Part C only:  Previous treatment with dabrafenib (cohort B4), trametinib or 
another MEK inhibitor (exception: prior treatment with sorafenib is permitted)
11. Administration of an investigational study treatment within 30 days preceding the first 
dose of study treatment(s) in this study.
12. Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs 
chemically related to study treatment or excipients that contraindicate their participation.
13. Current active liver or biliary disease (with the exception of Gilbert's syndrome or 
asymptomatic gallstones, or liver metastases).
14. History of hepatic sinusoid obstructive syndrome (venoocculsive disease) within the prior 
3 months.
15. History of sensitivity to heparin or heparin-induced thrombocytopenia.
16. History of interstitial lung disease or pneumonitis.
18. History or current evidence  RVO or RPED
19. For subjects with solid tumors that are not primary CNS tumors or NF-1 associated 
plexiform neurofibromas, subjects with symptomatic or untreated leptomeningeal or 
brain metastases or spinal cord compression are excluded.
NOTE: Subjects previously treated for these conditions that have had stable CNS disease 
(verified with consecutive imaging studies) for >3 months, are asymptomatic and are not 
currently taking corticosteroids, or are on stable dose or decreasing of corticosteroids for at 
least 7 days prior to enrolment are permitted.
20. A history of known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or 
Hepatitis C Virus (HCV) infection. Subjects with laboratory evidence of cleared HBV 
and HCV infection may be enrolled.
21. Unresolved toxicity of National Cancer Institute Common Terminology Criteria for 
Adverse Events, version 4.0 (NCI CTCAE v4.0) [NCI, 2009] Grade 2 or higher from 
previous anti-cancer therapy, except alopecia.
22. Presence of active gastrointestinal disease or other condition that will interfere 
significantly with the absorption of drugs.  If clarification is needed as to whether a 
condition will significantly affect absorption of drugs, contact the GlaxoSmithKline 
(GSK) medical monitor for guidance to enrol the subject.
23. A history or evidence of cardiovascular disease risk including any of the following:

A QT interval corrected for heart rate using the Bazett’s formula (QTcB) 480 
msec;


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
A history or evidence of current clinically significant uncontrolled arrhythmias; 
Clarification: Subjects with atrial fibrillation controlled for >30 days prior to 
dosing are eligible.

A history of acute coronary syndromes (including myocardial infarction or 
unstable angina), coronary angioplasty, or stenting within 6 months prior to 
randomization.

A history or evidence of current Class II congestive heart failure as defined by 
the New York Heart Association (NYHA) guidelines;

Patients with intra-cardiac defibrillators;

Abnormal cardiac valve morphology (≥grade 2) documented by echocardiogram 
(subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be 
entered on study).  Subjects with moderate valvular thickening should not be 
entered on study.  Subjects with prosthetic valves can be considered eligible 
provided they meet the criteria as stated above.

Treatment refractory hypertension defined as a blood pressure of systolic> 140 
mmHg and/or diastolic > 90 mm Hg (or above 95th age-specific percentile as listed 
in Appendix 8), which cannot be controlled by anti-hypertensive therapy;

Part C only, Abnormal cardiac valve morphology (≥Grade 2) documented by 
echocardiogram.  Subjects with moderate valvular thickening should not be entered on 
study;
Section 6.3 Permanent Discontinuation from Study Treatment Previous Text
Subjects will receive study treatment until disease progression, death or unacceptable toxicity, 
including meeting stopping criteria for liver chemistry defined in Section 3.11.1.  In addition, 
study treatment may be permanently discontinued for any of the following reasons:

serious deviation(s) from the protocol;

subject becomes pregnant;

request of the subject or proxy (withdrawal of consent by subject or proxy);

investigator’s discretion;

a dose delay due to administrative, scheduling or study treatment related toxicity of >28 
days;

intercurrent illness that prevents further administration of study treatment(s);

subject is lost to follow-up;

sponsor terminates the study.
The primary reason study treatment was permanently discontinued must be documented in the 
subject’s medical records and eCRF.
Subjects who require permanent discontinuation of one of the study treatments in a given 
treatment combination must permanently discontinue both treatments in that combination and 
the reason for discontinuation must be recorded.


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If the subject voluntarily discontinues from treatment due to toxicity, ‘AE’ will be recorded as 
the primary reason for permanently discontinuation on the eCRF.
Once a subject has permanently discontinued from study treatment, the subject will not be 
allowed to be retreated. All subjects who discontinue from study treatment will have safety 
assessments at the time of discontinuation and during post-study treatment follow-up as 
specified in Time and Events Table (see Section 7.1).  
Section 6.3 Permanent Discontinuation from Study Treatment REVISED TEXT
Subjects will receive study treatment until disease progression, death or unacceptable toxicity, 
including meeting stopping criteria for liver chemistry defined in Section 3.11.1.  In addition, 
study treatment may be permanently discontinued for any of the following reasons:

serious deviation(s) from the protocol;

subject becomes pregnant;

request of the subject or proxy (withdrawal of consent by subject or proxy);

investigator’s discretion;

a dose delay due to administrative, scheduling or study treatment related toxicity of >28 
days;

intercurrent illness that prevents further administration of study treatment(s);

subject is lost to follow-up;

sponsor terminates the study.
The primary reason study treatment was permanently discontinued must be documented in the 
subject’s medical records and eCRF.
Subjects who require permanent discontinuation of one of the study treatments in a given 
treatment combination must permanently discontinue both treatments in that combination and 
the reason for discontinuation must be recorded.
If the subject voluntarily discontinues from treatment due to toxicity, ‘AE’ will be recorded as 
the primary reason for permanently discontinuation on the eCRF.
Once a subject has permanently discontinued from study treatment, the subject will not be 
allowed to be retreated. All subjects who discontinue from study treatment will have safety 
assessments at the time of discontinuation and during post-study treatment follow-up as 
specified in Time and Events Table (see Section 7.1).  
Adverse Events must be followed for a minimum of 28days after the last dose. If it is not 
practical for the subject to return to the clinic, this data may be collected via telephone 
from the parent/caregiver/subject (as appropriate).
The discontinuation related safety assessments (same assessments as Final visit in the 
Time and Events Table 14) may be completed at any time from the last dose to 28 days 
after the last dose.  Ongoing toxicities should be followed to resolution if at all possible.  




















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Vital sign measurements will include systolic and diastolic blood pressure (see Section 
3.13.3.1) temperature, respiration rate and pulse rate.  Vital signs should be measured after 
resting for at least 5 minutes in a semi-supine position.  Vital signs will be measured more 
frequently if warranted by clinical condition of the subject.  On days where vital signs are 
measured multiple times, temperature does not need to be repeated unless clinically indicated.  
Refer to the SPM for details regarding measurement of vital signs.
SECTION 7.3.4 Vital Signs REVISED TEXT (moved text from Section 3.13.3.1 to this 
section)
Vital sign measurements will include systolic and diastolic blood pressure (See Section 
3.13.3.1), temperature, respiration rate and pulse rate.  Vital signs should be measured after 
resting for at least 5 minutes in a semi-supine position.  Vital signs will be measured more 
frequently if warranted by clinical condition of the subject.  On days where vital signs are 
measured multiple times, temperature does not need to be repeated unless clinically indicated.  
Refer to the SPM for details regarding measurement of vital signs.
Baseline blood pressure (BP) is defined as the blood pressure obtained at the 
examination used for study enrollment. This baseline BP should be obtained as follows:
1)
Obtain 3 serial blood pressures from the same extremity with the patient in the 
same position that are separated by at least 5 minutes. Avoid using the lower extremity if 
possible.
2)
Average the systolic blood pressure from the 2nd and 3rd measurements.
3)
Average the diastolic blood pressure from the 2nd and 3rd measurements.
4)
The baseline BP is the average of the systolic and average of the diastolic 
measurements.
SECTION 7.3.6 Echocardiogram PREVIOUS TEXT
The ECHOs will be performed to assess cardiac ejection fraction and cardiac valve 
morphology for the purpose of study eligibility and during the study as specified in the Time 
and Events Table (Section 7.1).  Additional ECHO assessments may be performed if 
clinically warranted.  The evaluation of the echocardiographer should include an evaluation 
for LVEF and both right and left-sided valvular lesions.
Copies of all ECHOs performed on subjects who experience grade 2 LVEF decrease, 
valvular regurgitation/stenosis or left ventricular systolic dysfunction that requires 
interruption, modification or discontinuation of study treatment may be required by GSK for 
review.
SECTION 7.3.6 Echocardiogram REVISED TEXT (updated to reflect all ECHOs will 
need to be provided to sponsor)
The ECHOs will be performed to assess cardiac ejection fraction and cardiac valve 
morphology for the purpose of study eligibility and during the study as specified in the Time 
and Events Table (Section 7.1).  Additional ECHO assessments may be performed if 
clinically warranted.  The evaluation of the echocardiographer should include an evaluation 
for LVEF and both right and left-sided valvular lesions.
Copies of all study ECHOs performed will be required to be provided to the sponsor. The 
ECHOs will not be reviewed in a real-time basis by the sponsor, but rather held for 


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review at a future time point.on subjects who experience grade 2 LVEF decrease, valvular 
regurgitation/stenosis or left ventricular systolic dysfunction that requires interruption, 
modification or discontinuation of study treatment may be required by GSK for review.


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SECTION 7.3.7 Laboratory Assessments
Table 16
List of Clinical Laboratory Tests
Hematology
Platelet Count
RBC Indices:
Automated WBC Differential:
Red blood cell (RBC) Count
MCV
Neutrophils
White blood cell (WBC) Count 
(absolute) 
MCH
Lymphocytes
Hemoglobin
MCHC
Monocytes
Hematocrit
Eosinophils
HbA1c
Basophils
Clinical Chemistry
Blood urea nitrogen 
(BUN)
Potassium
Aspartate aminotransferase 
(AST)
Total and direct bilirubin (Bilirubin 
fractionation recommended if 
total bilirubin is >2x the upper 
limit of normal)
Creatinine
Chloride
Alanine aminotransferase (ALT)
Total Protein
Glucose (recheck 
fasting if 
>160 mg/dL)
Total carbon 
dioxide (CO2)
Gamma glutamyl transferase 
(GGT)
Albumin
Sodium
Calcium
Alkaline phosphatase (ALP)
Magnesium
Phosphate
Routine Urinalysis
Specific gravity
pH, glucose, protein, blood and ketones by dipstick
Microscopic examination (if blood or protein is abnormal)
Urine Protein Creatinine – Part C only
Other screening tests
Urine or serum pregnancy test
HVA/VMA in random or 24 hr urine for subjects with neuroblastoma
In the event of abdominal pain or suspected pancreatitis, amylase and lipase laboratory samples should be 
collected.
RBC = Red Blood Cell; WBC = White Blood Cell; MCV = Mean Corpuscular Volume; MCH = Mean Corpuscular Hemoglobin:  
MCHC = Mean Corpuscular Hemoglobin Concentration; HVA/VMA = Homovanillic Acid / Vanillylmandelic Acid (ratio); CSF = 
Cerebrospinal fluid.


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SECTION 7.3.7 Laboratory Assessments REVISED TEXT  (changed to only allow 
Serum Pregnancy Test)
Table 16
List of Clinical Laboratory Tests
Hematology
Platelet Count
RBC Indices:
Automated WBC Differential:
Red blood cell (RBC) Count
MCV
Neutrophils
White blood cell (WBC) Count 
(absolute) 
MCH
Lymphocytes
Hemoglobin
MCHC
Monocytes
Hematocrit
Eosinophils
HbA1c
Basophils
Clinical Chemistry
Blood urea nitrogen 
(BUN)
Potassium
Aspartate aminotransferase 
(AST)
Total and direct bilirubin (Bilirubin 
fractionation recommended if 
total bilirubin is >2x the upper 
limit of normal)
Creatinine
Chloride
Alanine aminotransferase (ALT)
Total Protein
Glucose (recheck 
fasting if 
>160 mg/dL)
Total carbon 
dioxide (CO2)
Gamma glutamyl transferase 
(GGT)
Albumin
Sodium
Calcium
Alkaline phosphatase (ALP)
Magnesium
Phosphate
Routine Urinalysis
Specific gravity
pH, glucose, protein, blood and ketones by dipstick
Microscopic examination (if blood or protein is abnormal)
Urine Protein Creatinine – Part C only
Other screening tests
Urine or serum pregnancy test
HVA/VMA in random or 24 hr urine for subjects with neuroblastoma
In the event of abdominal pain or suspected pancreatitis, amylase and lipase laboratory samples should be 
collected.
RBC = Red Blood Cell; WBC = White Blood Cell; MCV = Mean Corpuscular Volume; MCH = Mean Corpuscular Hemoglobin:  
MCHC = Mean Corpuscular Hemoglobin Concentration; HVA/VMA = Homovanillic Acid / Vanillylmandelic Acid (ratio); CSF = 
Cerebrospinal fluid.
SECTION 7.3.8 Pregnancy Testing and Reporting PREVIOUS TEXT 
The need for a screening pregnancy test depends on whether a female subject is of 
childbearing potential or non-childbearing potential.
If a female subject is of childbearing potential, she must have a serum -Human Chorionic 
Gonadotropin (-HCG) pregnancy test performed within 7 days prior to the first dose of study 
treatment(s).  Subjects with a positive pregnancy test result must be excluded from the study.  
Subjects with a negative pregnancy test result must agree to use an effective contraception 
method as described below during the study until 30 days following the last dose of study 
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Any pregnancy that occurs during study participation must be reported using a clinical trial 
pregnancy form.  To ensure subject safety, each pregnancy must be reported to GSK within 2 
weeks of learning of its occurrence.  The pregnancy must be followed up to determine 
outcome (including premature termination) and status of mother and child.  Pregnancy 
complications and elective terminations for medical reasons must be reported as an AE or 
SAE.  Spontaneous abortions must be reported as an SAE.
Any SAE occurring in association with a pregnancy brought to the investigator’s attention 
after the subject has completed the study and considered by the investigator as possibly 
related to the study treatment(s), must be promptly reported to GSK.
In addition, the investigator must attempt to collect pregnancy information on any female 
partners of male study subjects who become pregnant while the subject is enrolled in the 
study.  Pregnancy information must be reported to GSK as described above.
SECTION 7.3.8 Pregnancy Testing and Reporting REVISED TEXT
(Lengthened requirement to 4 months for contraception use after last dose at request of 
regulatory authority)
The need for a screening pregnancy test depends on whether a female subject is of 
childbearing potential or non-childbearing potential.
If a female subject is of childbearing potential, she must have a serum -Human Chorionic 
Gonadotropin (-HCG) pregnancy test performed within 7 days prior to the first dose of study 
treatment(s).  Subjects with a positive pregnancy test result must be excluded from the study.  
Subjects with a negative pregnancy test result must agree to use an effective contraception 
method as described below during the study until 30 days4 months following the last dose of 
study treatment(s).
Any pregnancy that occurs during study participation must be reported using a clinical trial 
pregnancy form.  To ensure subject safety, each pregnancy must be reported to GSK within 2 
weeks of learning of its occurrence.  The pregnancy must be followed up to determine 
outcome (including premature termination) and status of mother and child.  Pregnancy 
complications and elective terminations for medical reasons must be reported as an AE or 
SAE.  Spontaneous abortions must be reported as an SAE.
Any SAE occurring in association with a pregnancy brought to the investigator’s attention 
after the subject has completed the study and considered by the investigator as possibly 
related to the study treatment(s), must be promptly reported to GSK.
In addition, the investigator must attempt to collect pregnancy information on any female 
partners of male study subjects who become pregnant while the subject is enrolled in the 
study.  Pregnancy information must be reported to GSK as described above.
SECTION 7.5 Translation Research PREVIOUS TEXT


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Table 17 List of Samples for Translational Research
Study Part
Sample type
Mandatory/Optional
Primary Purpose
Part A
Archival or fresh 
tumor tissue
Mandatory at screening.  If 
unavailable, the subject is 
not eligible to participate in 
the study.
For retrospective analysis for 
RAS mutation status
Part B
Archival or fresh 
tumor tissue
Mandatory at screening.  If 
unavailable, the subject is 
not eligible to participate in 
the study
For retrospective analysis for 
RAS mutation status
Part B4 and 
Part C
Archival or fresh 
tumor tissue
Mandatory at screening
Central confirmation of BRAF
V600 mutation status
All Parts
Fresh tissue at 
baseline
Optional (please note that 
the same baseline 
specimen may be used for 
 
pharmacodynamic testing)
All Parts
Fresh tissue at 
radiological 
progression
Optional
Resistance marker analysis
All Parts
Fresh tissue at 
baseline 
Optional (please note that 
the same baseline 
specimen may be used for 
 
pharmacodynamic testing)
Pharmacodynamic testing
Part A, 
Fresh tissue at 
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
Antiretroviral drugs (Note: Subjects with known human immunodeficiency virus (HIV) 
are ineligible for study participation);

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 inhibition, 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 (see list in Table 19) 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.  Approval of the GSK medical monitor is 
required in these situations.  The list may be modified based on emerging data.  Refer to the 
SPM for the most current list.
SECTION 9.2 Prohibited Medications REVISED TEXT (updated for clarity that there are 
no prohibited medications in Parts A & B)
9.2.1 Prohibited Medications Parts A & B
There are no prohibited medications while on treatment in Part A and Part B of this 
study.
9.2.2 Prohibited Medications; Part C (Dabrafenib)
The following medications or non-drug therapies are prohibited while on treatment in Part C 
of this study:

Other anti-cancer therapies;

Other investigational drugs;

Antiretroviral drugs (Note: Subjects with known human immunodeficiency virus (HIV) 
are ineligible for study participation);

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 inhibition, 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 
(see list in Table 19) 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.  
Approval of the GSK medical monitor is required in these situations.  The list may be 
modified based on emerging data.  Refer to the SPM for the most current list.
SECTION 9.3 PREVIOUS TEXT
Table 19 Medications to be used with Caution: Part C (Dabrafenib)
Section 9.3 REVISED TEXT 
Table 19 Table 20 Medications to be used with Caution: Part C (Dabrafenib)
SECTION 12.2.1 PREVIOUS TEXT
Table  20 Statistical Basis for Phase I Dose Escalation in a 3+3 Scheme


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Section 12.2.1 REVISED TEXT 
Table 20 Table  21 Statistical Basis for Phase I Dose Escalation in a 3+3 Scheme
SECTION 10.1.1 Female Subjects   PREVIOUS TEXT
A female of non-childbearing potential (i.e., physiologically incapable of becoming 
pregnant) is defined as any female who is premenarchal or has had a hysterectomy, bilateral 
oophorectomy (ovariectomy).
In questionable cases, consider obtaining follicle stimulating hormone (FSH) and estradiol
values (FSH must be >40 mIU/mL and estradiol <40pg/mL [<140 pmol/L] for non-
childbearing potential).
A female of childbearing potential is defined as any female who does not meet the criteria 
of non-childbearing potential as described in the previous paragraph.
Female subjects of childbearing potential must not become pregnant during the study and so 
must be sexually inactive by abstinence or use contraceptive methods with a failure rate of 
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Abstinence
Sexual inactivity by abstinence must be consistent with the preferred and usual lifestyle of the 
subject.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception.
Complete abstinence from sexual intercourse for 14 days prior to first dose of study treatment, 
through the dosing period, and for at least 28 days after the last dose of study treatment.
SECTION 10.1.1 Female Subjects REVISED TEXT (updated with same rationale as 
Section 7.3.8)
A female of non-childbearing potential (i.e., physiologically incapable of becoming 
pregnant) is defined as any female who is premenarchal or has had a hysterectomy, bilateral 
oophorectomy (ovariectomy).
In questionable cases, consider obtaining follicle stimulating hormone (FSH) and estradiol 
values (FSH must be >40 mIU/mL and estradiol <40pg/mL [<140 pmol/L] for non-
childbearing potential).
A female of childbearing potential is defined as any female who does not meet the criteria 
of non-childbearing potential as described in the previous paragraph.
Female subjects of childbearing potential must not become pregnant during the study and so 
must be sexually inactive by abstinence or use contraceptive methods with a failure rate of 
<1%.
Abstinence
Sexual inactivity by abstinence must be consistent with the preferred and usual lifestyle of the 
subject.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception.
Complete abstinence from sexual intercourse for 14 days prior to first dose of study treatment, 
through the dosing period, and for at least 28 days 4 months after the last dose of study 
treatment.
SECTION 12.2.1 PREVIOUS TEXT
Table  20 Statistical Basis for Phase I Dose Escalation in a 3+3 Scheme
Section 12.2.1 REVISED TEXT 
Table 20 Table  21 Statistical Basis for Phase I Dose Escalation in a 3+3 Scheme


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SECTION 12.2.2 PREVIOUS TEXT
Table 21 Exact Binomial Probabilities of Observing 0 and 1 (or more) Responses in 10 
Subjects
Section 12.2.2 REVISED TEXT 
Table 21 Table 22 Exact Binomial Probabilities of Observing 0 and 1 (or more) 
Responses in 10 Subjects
SECTION: APPENDIX 6: Response Criteria for PNs  PREVIOUS TEXT
Prior to starting treatment on this study all known measurable tumors should be imaged with 
MRI to obtain a baseline.  Tumor spread in subjects with NF-1 can be very extensive, and 
may not allow for all lesions to be followed using 3D-MRI.  The goal will therefore be to use 
3D-MRI only to follow the inoperable PN (a maximum of three lesions), which will be 
defined as index lesion(s).
Pre-study radiographic evaluation:
1. Identify and select the inoperable PN (a maximum of three lesions) for 3-D MRI 
evaluation based on prior imaging studies.  Should there be more than 3 inoperable 
PN, the three most clinically relevant PN will be followed by 3-D MRI analysis.
2. Perform 3-D MRI sequences on the selected index lesions as outlined in the MRI 
acquisition protocols below.
3. In addition, if possible, perform MRI of all additional measurable PN.
4. Send baseline MRI to address below for central review prior to enrolment.
On study radiographic evaluation:
Unless clinically indicated otherwise obtain MRI of the index lesions only as outlined in the 
MRI acquisition protocol below prior to cycles 4, 8, 12, and then after every 6 cycles as long 
as the subject remains on study.
MRI protocols:
Depending on the location of the index lesions the Spine, Head/Neck or Trunk/Extremities 
protocols outlined on the following pages will be used.
Participating institutions may modify the MRI sequences to optimize differentiation of tumor 
and surrounding tissue.  Modifications should be documented in the MRI protocols, and the 
same imaging protocol, and, if possible, the same MRI scanner should be used for all 
subsequent MRI studies.  Every attempt should be made to image the entire progressive PN.  
All MRI studies requested per protocol will be submitted to the NCI Pediatric Oncology 
Branch (POB) within 2 weeks of acquisition for volume analysis.  The studies have to be sent 
on Compact Disk in uncompressed Digital Imaging and Communications in Medicine 
(DICOM) format.  At the same time, a copy of the MRI protocol and the institutional 
radiology report will be sent to the NCI POB. 
For technical support, please contact:
, M.D. (phone 
, e-mail:  
Send MRI studies and protocols used to obtain studies and radiology reports to:


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Phone: 
, fax: 
, e-mail:  
All MRI data will be analyzed at the POB of the NCI.  The MRI data from each scan will be 
processed to assess the volume of the index PN(s).  Each subject’s volumetric measurement 
obtained from the initial MRI will serve as the baseline against which to assess incremental 
changes in volume that occur during the subsequent intervals.  The NCI POB will inform 
participating investigators about the results of the MRI study by written report.  MRI results 
will be transferred to GSK or GSK contracted third party imaging vendor.
MRI Protocol- Spine
STUDY ID NUMBER: _________
Note: Only the series outlined below are required for volumetric analysis of PNs and must be 
performed within protocol specifications as indicated below.  Additional series may be 
obtained as indicated per institutional PI.
1.
AXIAL FAST SPIN ECHO-INVERSION RECOVERY (FSEIR)
Axial FSEIR
Protocol
Specifications
Actual
Specifications
Reason For Change
Echo Train Length
5
TR
6000
TE
34
TI
150
Slice Thickness
5 mm
Skip
0
Matrix
256x256
FOV
22 cm
NEX
1
Frequency Direction
RL
Options
Tailored RF, FC, PC, 0.75 FOV


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2.
CORONAL FSEIR
Coronal FSEIR
Protocol
Specifications
Actual
Specifications
Reason For Change
Echo Train Length
5
TR
6000
TE
34
TI
150
Slice Thickness
5 mm
Skip
0
Matrix
256x256
FOV
22 cm
NEX
1
Frequency Direction
SI
Options
Tailored RF, FC, PC
Date:_________Signature (responsible MRI technician):______________________


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3.
Axial T2
Axial T2
Protocol
Specifications
Actual
Specifications
Reason For Change
Echo Train Length
16
TR
3000-6000
TE
100
Slice Thickness
5 mm
Skip
0
Matrix
320x256
FOV
18 cm
NEX
3
Options
Tailored RF, NPW
4.
Sagittal T2
Coronal FSEIR
Protocol
Specifications
Actual
Specifications
Reason For Change
Echo Train Length
16
TR
3000-6000
TE
100
Slice Thickness
5 mm
Skip
0
Matrix
320x256
FOV
24 cm
NEX
3
Options
Tailored RF, NPW
Date:_________Signature (responsible MRI technician):______________________
MRI Protocol- Head/Neck
STUDY ID NUMBER: _________
Note: Only the series outlined below are required for volumetric analysis of PNs and must be 
performed within protocol specifications as indicated below.  Additional series may be 
obtained as indicated per institutional PI.


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1.
AXIAL FSEIR
Axial FSEIR
Protocol
Specifications
Actual
Specifications
Reason For Change
Echo Train Length
5
TR
6000
TE
34
TI
150
Slice Thickness
54 mm
Skip
0
Matrix
256x256
FOV
22 cm
NEX
1
Frequency Direction
AP
Options
Tailored RF, FC, 0.75 FOV
2.
CORONAL FSEIR
Coronal FSEIR
Protocol
Specifications
Actual
Specifications
Reason For Change
Echo Train Length
5
TR
6000
TE
34
TI
150
Slice Thickness
5 mm
Skip
0 mm
Matrix
256x192
FOV
22 cm
NEX
1
Frequency Direction
SI
Options
Tailored RF, PC
Date:_________Signature (responsible MRI technician):________________________
MRI Protocol-Trunk/Extremities
STUDY ID NUMBER: _________
Note: Only the series outlined below are required for volumetric analysis of PNs and must be 
performed within protocol specifications as indicated below.  Additional series may be 
obtained as indicated per institutional PI.
1.
AXIAL PLANE-STIR
Axial Plane STIR
Protocol
Specifications
Actual
Specifications
Reason For Change


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Coil: Body
Sequence:  Fast Spin Echo (Turbo) FSEIR
Echo Train Length
5
TR
6000
TE
15
TI
150
Slice Thickness
10 mm
Skip
0
Matrix
512x160
FOV
40x30
No.  of Excitations/ 
Sequence
0.5
No.  of Acquisitions
1
Saturation
None
2.
CORONAL PLANE STIR
Coronal Plane STIR
Protocol
Specifications
Actual
Specifications
Reason For Change
Coil:  Body
Sequence:  Fast Spin Echo (Turbo) FSEIR
Echo Train Length
5
TR
3400
TE
15
TI
150
Slice Thickness
5 mm
Skip
0
Matrix
512x160
FOV
48x48
No.  of Excitations/ 
Sequence
1
No.  of Acquisitions
1
Saturation
None
Date:_________Signature (responsible MRI technician):________________________


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Response Criteria for NF-1 Associated PNs:
Response is assessed at the time that follow-up MRI scans are performed as outlined in 
Section7.1.  For the purpose of determining the level of response, measurements from the 
follow-up scans are compared to the tumor size in the pretreatment MRI scan using 3D data 
analysis.

Complete Response (CR): A complete resolution of the target plexiform neurofibroma for 
≥ 4 weeks

Partial Response (PR): A ≥20% reduction in the volume of the target plexiform 
neurofibroma lesion for ≥4 weeks. 

Stable Disease (SD): A <20% increase, and < 20% decrease in the volume of the target 
plexiform neurofibroma lesion for ≥4 weeks. 

Progressive Disease (PD): A ≥20% increase in the volume (by 3D-MRI) of the target 
plexiform neurofibroma compared to the pretreatment volume.

The appearance of new discrete subcutaneous neurofibromas does not qualify for 
disease progression. 
Worsening of existing symptoms or the appearance of new symptoms that persist for more 
than 7 days and that are felt to be definitely related to the plexiform neurofibroma should be 
evaluated by repeating the MRI.  Subjects should not be classified as having progressive 
disease solely on the basis of new or increased symptoms without discussing the case with the 
protocol Principal Investigator.
SECTION:  Appendix 6: Response Criteria for PNs  REVISED TEXT  (Updated to reflect 
procedural changes)
Prior to starting treatment on this study all known measurable tumors should be imaged with 
MRI to obtain a baseline.  Tumor spread in subjects with NF-1 can be very extensive, and 
may not allow for all lesions to be followed using 3D-MRI.  The goal will therefore be to use 
3D-MRI only to follow the inoperable PN (a maximum of three lesions), which will be 
defined as index lesion(s).
Pre-study radiographic evaluation:
1. Identify and select the inoperable PN (a maximum of three lesions) for 3-D MRI 
evaluation based on prior imaging studies.  Should there be more than 3 inoperable 
PN, the three most clinically relevant PN will be followed by 3-D MRI analysis.
2. Perform 3-D MRI sequences on the selected index lesions as outlined in the MRI 
acquisition protocols below.
3. In addition, if possible, perform MRI of all additional measurable PN.
4. Send baseline MRI to address below for central review prior to enrolment.
In Study Part B, central review of the MRI of the target PN is required prior to enrollment 
to ensure that the tumor is measurable and amenable to volumetric analysis.
On study radiographic evaluation:


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Unless clinically indicated otherwise obtain MRI of the index lesions only as outlined in the 
MRI acquisition protocol below prior to cycles 4, 8, 12, and then after every 6 cycles as long 
as the subject remains on study.
MRI protocols:
Depending on the location of the index lesions the Spine, Head/Neck or Trunk/Extremities 
protocols outlined on the following in the SPMpages will be used.
Participating institutions may modify the MRI sequences to optimize differentiation of tumor 
and surrounding tissue.  Modifications should be documented in the MRI protocols, and the 
same imaging protocol, and, if possible, the same MRI scanner should be used for all 
subsequent MRI studies.  Every attempt should be made to image the entire progressive PN.  
All MRI studies requested per protocol will be submitted to the NCI Pediatric Oncology 
Branch (POB) within 2 weeks of acquisition for volume analysis to the study central reader 
via the instructions provided in the SPM.  The studies have to be sent on Compact Disk in 
uncompressed Digital Imaging and Communications in Medicine (DICOM) format.  At the 
same time, a copy of the MRI protocol and the institutional radiology report will be sent to the 
NCI POB.  
For technical support, please contact:
 M.D. (phone 
, e mail:  
Send MRI studies and protocols used to obtain studies and radiology reports to:
, M.D.
Phone: 
, fax: 
, e mail:  
All MRI data will be analyzedat the POB of the NCI.  The MRI data from each scan will be 
processed to assess the volume of the index PN(s).  Each subject’s volumetric measurement 
obtained from the initial MRI will serve as the baseline against which to assess incremental 
changes in volume that occur during the subsequent intervals.  The NCI POB central reader
will inform participating investigators about the results of the MRI study by written report.  
MRI results will be transferred to GSK or GSK contracted third party imaging vendor.
MRI Protocol Spine
STUDY ID NUMBER: _________
Note: Only the series outlined below are required for volumetric analysis of PNs and must be 
performed within protocol specifications as indicated below.  Additional series may be 
obtained as indicated per institutional PI.


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Response Criteria for NF-1 Associated PNs [Dombi, 2013]:
Response is assessed at the time that follow-up MRI scans are performed as outlined in 
Section 7.1.  For the purpose of determining the level of response, measurements from the 
follow-up scans are compared to the tumor size in the pretreatment MRI scan using 3D data 
analysis.

Complete Response (CR): A complete resolution of the target plexiform neurofibroma for 
≥ 4 weeks

Partial Response (PR): A ≥20% reduction in the volume of the target plexiform 
neurofibroma lesion for ≥4 weeks. 

Stable Disease (SD): A <20% increase, and < 20% decrease in the volume of the target 
plexiform neurofibroma lesion for ≥4 weeks. 

Progressive Disease (PD): A ≥20% increase in the volume (by 3D-MRI) of the target 
plexiform neurofibroma compared to the pretreatment volume.

The appearance of new discrete subcutaneous neurofibromas does not qualify for 
disease progression. 
Worsening of existing symptoms or the appearance of new symptoms that persist for more 
than 7 days and that are felt to be definitely related to the plexiform neurofibroma should be 
evaluated by repeating the MRI.  Subjects should not be classified as having progressive 
disease solely on the basis of new or increased symptoms without discussing the case with the 
protocol Principal Investigator.
SECTION: APPENDIX 7 Definition of disease state, response criteria and response 
definition for LCH (NEW appendix, later Appendices renumbered)
Adapted from Histiocyte Society Evaluations and Treatment Guidelines, April 2009.


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Definition of Disease State
NON ACTIVE DISEASE 
(NAD) 
no evidence of 
disease 
resolution of all signs or symptoms 
ACTIVE DISEASE
regressive disease 
regression of signs or symptoms, no new 
lesions*
stable disease 
persistence of signs of symptoms, no new 
lesions 
progressive disease 
progression of signs or symptoms and/or 
appearance of new lesions**
*Plus partial or complete response by RECIST [Eisenhauer, 2009]; and/or pulmonary criteria if 
applicable
*/** Isolated pulmonary LCH: improvement in lung function is >10% increase in baseline FEV1 or 
DLCO at time of disease assessment.  Disease progression is >15% decline from baseline FEV1 or 
DLCO or FVC OR progression of symptoms (dyspnea, cough, constitutional symptoms) that cannot 
be explained by diagnoses other than pulmonary LCH (infection, heart disease, and/or other clinical 
issues excluded by careful clinical evaluation and testing)
** Isolated bone disease: progression is defined as appearance of new bone lesions or lesions in 
other organs
Response Criteria
BETTER
Complete Resolution
NAD
Regression
AD Better
INTERMEDIATE
Mixed
New lesions in one site, regression in another site
Stable
Unchanged
WORSE
Progression


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Response Definition for Efficacy
3 Month Assessment
6 Month Assessment 
(performance relative to 3 month assessment)
Response
NAD or AD Better
Mixed
Stable 
NAD or AD Better or Stable 
NAD or AD Better
NAD or AD Better
Failure
NAD or AD Better
NAD or AD Better
Mixed or Stable a
Progression
Mixed 
Progression
Mixed or Stable a or Progression
N/A
NAD = Non Active Disease
AD = Active Disease
Stable = Unchanged
Mixed = New lesions in one site, regression in another site
f.
Subjects who are assessed only as stable at the 3 and 6 month assessment are not considered a treatment 
response; however, they may be considered for continued treatment 
LCH Scoring System [Donadieu, 2004]
Variable
Modality
Score
Bone (a)
Pain
No Pain
1
0
Bone (b)
Compressing other organs (orbit or spine)
No compression
2
0
Fever (>38.5C)
Yes
No
1
0
Lung: iconography
Pneumothorax
Interstitial lesion on chest x-ray or lung CT
Normal chest x-ray or lung CT
2
1
0
Lung: function
Mechanical ventilation or PFT >50%
Supplemental oxygen or PFT between 50 and 80%
No dysfunction, no cyanosis, no supplemental oxygen
5
2
0
Skin: area
25%
5-25%
Below 5%
2
1
0
Soft tissue tumor 
(including CNS)
5 cm maximum diameter
2-5 cm maximum diameter
0-2 cm maximum diameter
2
1
0
Nodes (>2 cm)
Yes
No
1
0
Liver
Below umbilicus
Enlarged, above umbilicus
Not enlarged
2
1
0


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Variable
Modality
Score
Spleen
Below umbilicus
Enlarged, above umbilicus
Not enlarged
2
1
0
Liver (enzymes)
>10 ULN
3-10 ULN
<3 ULN
2
1
0
Liver (gamma GT)
>10 ULN
3-10 ULN
<3 ULN
2
1
0
Albumin
Perfusion required in past week
No perfusion but <30 g/L
>30 g/L
3
1
0
Platelet: requirements in 
past week
More than two transfusions
1 or 2 transfusions
Low platelet count, no transfusion
Normal count
4
3
2
0
Red cells: requirements 
in past week
More than 2 U
1 or 2 U
Hgb below 10 g/dL, no transfusion
No transfusion
4
3
1
0


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AMENDMENT 3
Amendment 3
Where the Amendment Applies
Amendment 3 applies to all sites.
Summary of Amendment Changes with Rationale
This amendment was generated to expand the description of Part C to include the dabrafenib 
recommended phase II dose levels and rationale along with the observed safety in pediatric 
patients on dabrafenib monotherapy.  Updated safety information from adult combination 
studies is included.  
Title Page
Authors PREVIOUS TEXT
Author (s):
 GSK Oncology Medicines 
Development
 GSK Oncology Medicines Development 
GSK Oncology Precision Medicine and Diagnostics
Authors REVISED TEXT
 Novartis Oncology Global Development
Novartis Oncology Global Development
Novartis Oncology Global Development
Novartis Oncology Global Development


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PROTOCOL SYNOPSIS
PREVIOUS TEXT
STUDY OBJECTIVES, 
ENDPOINTS AND 
HYPOTHESES
Primary Objective:

To determine the safe and tolerable trametinib dose(s) for 
chronic continuous daily dosing in pediatric subjects (infants, 
children, and adolescents) that achieves similar exposures 
(trough concentration [C]) to the recommended adult dose
Secondary Objectives:

To characterize the pharmacokinetics of trametinib

To characterize the safety and tolerability of trametinib

To assess any preliminary anti-tumor activity of trametinib

To determine the effect of covariates such as age and weight 
on the pharmacokinetics of trametinib using a population 
pharmacokinetics approach

To characterize the pharmacokinetics of trametinib and 
dabrafenib when administered in combination

To determine the acceptability and palatability of trametinib in 
pediatric subjects
 
 
 
 
Primary Endpoint(s):

Adverse Events (AEs); electrocardiograms (ECGs); 
echocardiograms (ECHOs); changes in laboratory values and 
vital signs.  Steady state Cof trametinib
Secondary Endpoint(s):

C(trough), AUC(0-t), AUC(0-), apparent clearance 
following oral dosing (CL/F), maximum observed 
concentration (Cmax), time of occurrence of Cmax (tmax) 
and half-life (t½) of trametinib, as appropriate


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
AEs; ECG; changes in laboratory values and vital signs

Tumor response as defined in Appendix 3 through Appendix 
7.

CL/F, volume of distribution (V/F), absorption rate (ka), and 
coefficients for significant covariates

C(trough), AUC(0-t), AUC(0-), apparent clearance 
following oral dosing (CL/F) Cmax, tmax and t½ of trametinib 
and dabrafenib when administered in combination
Hypothesis: 

Infants, children and adolescents will tolerate doses of 
trametinib alone or in combination with dabrafenib that 
achieve steady state trough concentrations associated with 
clinical benefit in adults.
STUDY DESIGN
This is a 3-part (Part A, Part B, Part C), Phase I/IIa, multi-center, 
open label, study in pediatric subjects with refractory or recurrent 
tumors.
Part A will be a pharmacokinetically driven limited dose escalation in 
subjects and will include an expansion for safety, tolerability, and 
pharmacokinetics (PK) in three age ranges (1 month to <2years, 2 to 
≤12 years, and over 12 years of age).  The primary goal of Part A is 
to establish the toxicity profile, PK, and recommended Phase 2 dose 
(RP2D) of trametinib in each age cohort.  Approximately 18 subjects 
will be accrued to the dose escalation phase and 18 subjects to the 
age expansion phase.
Part B will be a tumor cohort expansion part of the study to further 
evaluate the safety, tolerability, and preliminary clinical activity of 
trametinib in tumor-specific pediatric populations.  Disease cohorts 
are selected based on current data of proto-oncogene RAS (Ras)/ 
mitogen-activated protein kinase (MAPK) activation in childhood solid 
tumors.  Forty subjects are planned for Part B, 10 subjects in each of 
4 disease cohorts.

Refractory or relapsed neuroblastoma 

Recurrent or unresectable low grade gliomas with BRAF 
tandem duplication with fusion

Neurofibromatosis Type -1 associated plexiform 
neurofibromas that are unresectable and medically 
significant. 

BRAF V600 mutant tumors


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Part C is a limited dose escalation part of the study evaluating the 
combination of trametinib with dabrafenib in children and adolescents 
with recurrent, refractory or unresectable BRAF V600 mutated 
tumors.  This part of the study will enroll approximately 18 subjects 
and will not open to accrual until the dose of dabrafenib in children is 
established in study BRF116013, the dose of trametinib is established 
in Part A and review of the available safety and PK data of trametinib 
and dabrafenib monotherapy in children is completed.  Part C will 
require an amendment to this study prior to enrollment to include 
updated safety data and dabrafenib dosing in children.  Part B and C 
may be open to accrual simultaneously.
Subjects may not enroll in more than one part of the study. Subjects 
will receive study treatment until disease progression, death or 
unacceptable toxicity. 
All parts of the study will use trametinib tablet strengths (0.125, 0.5, 
and 2 mg tablets) for children who are able to reliably swallow tablets. 
In addition, an oral solution formulation (0.05 mg/mL) is available.  
Doses will be calculated using body weight and prescribed using a 
dosing nomogram. Rules for dose modifications in response to 
toxicity are provided in the protocol.
For Part C of the study dabrafenib capsules (10, 25, 50, 75 mg) or 
suspension (10 mg/ml) will be used.
INCLUSION/
EXCLUSION CRITERIA
General Inclusion Criteria for All Parts (for complete details and further 
eligibility criteria for specific parts please see full protocol):
1.
Written informed consent – a signed informed consent and/or 
assent (as age appropriate) for study participation including 
pharmacokinetics sampling will be obtained according to 
institutional guidelines;
2.
Male or female between one month and < 18 years of age 
(inclusive) at the time of signing the informed consent form
3.
Part C between 12 months and <18 years of age, inclusive;
4.
Part A subjects < 2 years of age will not be include in the initial 
dose escalation 
5.
Must have a disease that is relapsed/refractory to all potentially 
curative standard treatment regimens or must have a current 


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disease for which there is no known curative therapy, or therapy 
proven to prolong survival with an acceptable quality of life. 
6.
Prior therapy: The subject’s disease (i.e. cancer, NF-1 with 
Plexiform Neurofibromas, or Langerhans Cell Histiocytosis 
[LCH]) must have relapsed after or failed to respond to frontline 
curative therapy or there must not be other potentially curative 
treatment options available.  Curative therapy may include 
surgery, radiation therapy, chemotherapy, or any combination of 
these modalities.  Subjects must have recovered to grade ≤1 
from the acute toxic effects of all prior chemotherapy, 
immunotherapy, or radiotherapy prior to enrollment.
7.
Performance score of ≥50% according to the Karnofsky/Lansky 
performance status scale [Yates, 1980].
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 7 days prior to enrollment;
9.
Must have adequate organ function.
10. In France, subjects will be eligible for inclusion in this study only 
if either affiliated to or a beneficiary of a social security category.
General Exclusion Criteria for All Parts:
1.
Lactating or pregnant female.
2.
History of another malignancy including resected non-
melanomatous skin cancer.
3.
Subjects with Neurofibromatosis Type-1 (NF-1) associated 
optic pathway tumors are excluded if they are actively 
receiving therapy for the optic pathway tumor or do not meet 
criteria for Plexiform Neurofibroma or malignant solid tumor.
4.
Subjects with a history of NF-1 related cerebral vascular 
anomaly (such as Moyamoya).
5.
Subjects with NF-1 actively receiving therapy for the optic 
pathway tumor
6.
Subjects with NF-1 and only Plexiform Neurofibroma (PN) 
lesions that cannot be evaluated by volumetric analysis.


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7.
Any serious and/or unstable pre-existing medical, psychiatric 
disorder or other conditions that could interfere with subject’s 
safety, obtaining informed consent or compliance to the study 
procedures.
8.
Any prohibited medication(s) as described in Section 9.2.
9.
Any medications for treatment of left ventricular systolic 
dysfunction
10. Part B and Part C only: Previous treatment with dabrafenib 
(cohort B4) trametinib or another MEK inhibitor (exception: 
prior treatment with sorafenib is permitted)
11. Administration of an investigational study treatment within 30 
days preceding the first dose of study treatment(s) in this 
study.
12. Have a known hypersensitivity reaction or idiosyncrasy to 
drugs chemically related to study treatment or excipients that 
contraindicate their participation.
13. Current active liver or biliary disease (with the exception of 
Gilbert's syndrome or asymptomatic gallstones, or liver 
metastases).
14. History of hepatic sinusoid obstructive syndrome 
(Venoocculsive disease) within the prior 3 months.
15. History of heparin-induced thrombocytopenia.
16. History of interstitial lung disease or pneumonitis.
17. History of or current evidence of retinal vein occlusion (RVO) 
18. For subjects with solid tumors that are not primary central 
nervous system (CNS) tumors or NF-1 associated plexiform 
neurofibromas, subjects with symptomatic or untreated 
leptomeningeal or brain metastases or spinal cord 
compression are excluded.
19. A history of known Human Immunodeficiency Virus (HIV), 
Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection. 
20. Unresolved toxicity of National Cancer Institute Common 
Terminology Criteria for Adverse Events, version 4.0 (NCI 


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CTCAE v4.0) [NCI, 2009] Grade 2 or higher from previous 
anti-cancer therapy, except alopecia.
21. Presence of active gastrointestinal disease or other condition 
that will interfere significantly with the absorption of drugs.  If 
clarification is needed as to whether a condition will 
significantly affect absorption of drugs, contact the 
GlaxoSmithKline (GSK) medical monitor for guidance to enrol 
the subject.
22. A history or evidence of cardiovascular risk (as detailed in 
protocol Section 5.2.2)
REVISED TEXT
STUDY OBJECTIVES, 
ENDPOINTS AND 
HYPOTHESES
Primary Objective:

To determine the safe and tolerable trametinib dose(s) for 
chronic continuous daily dosing in pediatric subjects (infants, 
children, and adolescents) that achieves similar exposures 
(trough concentration [C]) to the recommended adult dose
Secondary Objectives:

To characterize the pharmacokinetics of trametinib

To characterize the safety and tolerability of trametinib

To assess any preliminary anti-tumor activity of trametinib

To determine the effect of covariates such as age and weight 
on the pharmacokinetics of trametinib using a population 
pharmacokinetics approach

To characterize the pharmacokinetics of trametinib and 
dabrafenib when administered in combination

To characterize the safety and tolerability of trametinib 
and dabrafenib when administered in combination

To determine the safe and tolerable dabrafenib dose(s) 
when administered in combination with the 
recommended trametinib dose for chronic continuous 
daily dosing in pediatric subjects (infants, children, and 
adolescents) that achieves similar exposures (trough 
concentration [C]) to the recommended adult dose

To determine the acceptability and palatability of trametinib in 
pediatric subjects


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Primary Endpoint(s):

Adverse Events (AEs); electrocardiograms (ECGs); 
echocardiograms (ECHOs); changes in laboratory values and 
vital signs.  Steady state Cof trametinib
Secondary Endpoint(s):

C(trough), AUC(0-t), AUC(0-), apparent clearance 
following oral dosing (CL/F), maximum observed 
concentration (Cmax), time of occurrence of Cmax (tmax) 
and half-life (t½) of trametinib, as appropriate

AEs; ECG; changes in laboratory values and vital signs

Tumor response as defined in Appendix 3 through Appendix 
7.

CL/F, volume of distribution (V/F), absorption rate (ka), and 
coefficients for significant covariates

C(trough), AUC(0-t), AUC(0-), apparent clearance 
following oral dosing (CL/F) Cmax, tmax and t½ of trametinib 
and dabrafenib when administered in combination
Hypothesis: 

Infants, children and adolescents will tolerate doses of 
trametinib alone or in combination with dabrafenib that 
achieve steady state trough concentrations associated with 
clinical benefit in adults.
STUDY DESIGN
This is a 3-part (Part A, Part B, Part C), Phase I/IIa, multi-center, 
open label, study in pediatric subjects with refractory or recurrent 
tumors.
Part A will be a pharmacokinetically driven limited dose escalation in 
subjects and will include an expansion for safety, tolerability, and 
pharmacokinetics (PK) in three age ranges (1 month to <2years, 2 to 
≤12 years, and over 12 years of age).  The primary goal of Part A is 
to establish the toxicity profile, PK, and recommended Phase 2 dose 


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(RP2D) of trametinib in each age cohort.  Approximately 18 subjects 
will be accrued to the dose escalation phase and 18 subjects to the 
age expansion phase.
Part B will be a tumor cohort expansion part of the study to further 
evaluate the safety, tolerability, and preliminary clinical activity of 
trametinib in tumor-specific pediatric populations.  Disease cohorts 
are selected based on current data of proto-oncogene RAS (Ras)/ 
mitogen-activated protein kinase (MAPK) activation in childhood solid 
tumors.  At least forty subjects are planned for Part B, 10 subjects in 
each of 4 disease cohorts.

Refractory or relapsed neuroblastoma 

Recurrent or unresectable low grade gliomas associated
with BRAF tandem duplication with fusion, or NF1 subjects 
with gliomas, not suitable for the NF1 with PN cohort

Neurofibromatosis Type -1 associated plexiform 
neurofibromas that are unresectable and medically 
significant. 

BRAF V600 mutant tumors
Part C is a limited dose escalation part of the study evaluating the 
combination of trametinib with dabrafenib in children and adolescents 
with recurrent, refractory or unresectable BRAF V600 mutated 
tumors.  This part of the study will enroll approximately 18 subjects 
(including up to 6 adolescent subjects with BRAF V600 mutant 
metastatic melanoma) and will not open to accrual until the dose of 
dabrafenib in children is established in study BRF116013, the dose of 
trametinib is established in Part A and review of the available safety 
and PK data of trametinib and dabrafenib monotherapy in children is 
completed.  Part C will require an amendment to this study prior to 
enrollment to include. Amendment 3 provides the updated safety 
data and dabrafenib dosing in children. Part B and C may be open to 
accrual simultaneously. Patients who have had prior dabrafenib 
therapy may enroll in part C if they have had prior benefit to 
dabrafenib monotherapy, as determined by the investigator.
Subjects may not enroll in more than one part of the study. Subjects 
will receive study treatment until disease progression, death or 
unacceptable toxicity. 
All parts of the study will use trametinib tablet strengths (0.125, 0.5, 
and 2 mg tablets) for children who are able to reliably swallow tablets.  


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In addition, an oral solution formulation (0.05 mg/mL) is available.  
Doses will be calculated using body weight and prescribed using a 
dosing nomogram. Rules for dose modifications in response to 
toxicity are provided in the protocol.
For Part C of the study dabrafenib capsules (10, 25, 50, 75 mg) or 
suspension (10 mg/ml) will be used.
INCLUSION/
EXCLUSION CRITERIA
General Inclusion Criteria for All Parts (for complete details and 
further eligibility criteria for specific parts please see full protocol):
11. Written informed consent – a signed informed consent and/or 
assent (as age appropriate) for study participation including 
pharmacokinetics sampling will be obtained according to 
institutional guidelines;
12. Male or female between one month and < 18 years of age 
(inclusive) at the time of signing the informed consent form
13. Part C between 12 months and <18 years of age, inclusive;
14.
Part A subjects < 2 years of age will not be includeincluded in 
the initial dose escalation 
15. Must have a disease that is relapsed/refractory to all potentially 
curative standard treatment regimens or must have a current 
disease for which there is no known curative therapy, or therapy 
proven to prolong survival with an acceptable quality of life. 
16. Prior therapy: The subject’s disease (i.e. cancer, NF-1 with 
Plexiform Neurofibromas, or Langerhans Cell Histiocytosis 
[LCH]) must have relapsed after or failed to respond to frontline 
curative therapy or there must not be other potentially curative 
treatment options available.  Curative therapy may include 
surgery, radiation therapy, chemotherapy, or any combination of 
these modalities.  Subjects must have recovered to grade ≤1 
from the acute toxic effects of all prior chemotherapy, 
immunotherapy, or radiotherapy prior to enrollment.
17. Performance score of ≥50% according to the Karnofsky/Lansky 
performance status scale [Yates, 1980].
18. 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 7 days prior to enrollment;


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19. Must have adequate multi organ function.
20. In France, subjects will be eligible for inclusion in this study only 
if either affiliated to or a beneficiary of a social security category.
General Exclusion Criteria for All Parts:
23. Lactating or pregnant female.
24. History of another malignancy including resected non-
melanomatous skin cancer.
25. Subjects with Neurofibromatosis Type-1 (NF-1) associated 
optic pathway tumors are excluded if they are actively 
receiving therapy for the optic pathway tumor or do not meet 
criteria for Plexiform Neurofibroma or malignant solid tumor.
26. Subjects with a history of NF-1 related cerebral vascular 
anomaly (such as Moyamoya).
27. Subjects with NF-1 actively receiving therapy for the optic 
pathway tumor
28. Subjects with NF-1 and only Plexiform Neurofibroma (PN) 
lesions that cannot be evaluated by volumetric analysis.
29. Any serious and/or unstable pre-existing medical, psychiatric 
disorder or other conditions that could interfere with subject’s 
safety, obtaining informed consent or compliance to the study 
procedures.
30. Any prohibited medication(s) as described in Section 9.2.
31. Any medications for treatment of left ventricular systolic 
dysfunction
32. Part B cohorts 1, 2 and Part C only3: Previous treatment 
with dabrafenib(cohort B4) trametinib or another MEK 
inhibitor (exception: prior treatment with sorafenib is 
permitted). Patients who have had prior dabrafenib 
therapy may enroll into cohort B4.  Patients who have 
had prior dabrafenib therapy and had benefit from that 
therapy  as determined by the investigator, are allowed in 
Part C)
33. Administration of an investigational study treatment within 30 
days preceding the first dose of study treatment(s) in this 
study.


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34. Have a known hypersensitivity reaction or idiosyncrasy to 
drugs chemically related to study treatment or excipients that 
contraindicate their participation.
35. Current active liver or biliary disease (with the exception of 
Gilbert's syndrome or asymptomatic gallstones, or liver 
metastases).
36. History of hepatic sinusoid obstructive syndrome 
(Venoocculsive disease) within the prior 3 months.
37. History of heparin-induced thrombocytopenia.
38. History of interstitial lung disease or pneumonitis.
39. History of or current evidence of retinal vein occlusion (RVO) 
40. For subjects with solid tumors that are not primary central 
nervous system (CNS) tumors or NF-1 associated plexiform 
neurofibromas, subjects with symptomatic or untreated 
leptomeningeal or brain metastases or spinal cord 
compression are excluded.
41. A history of known Human Immunodeficiency Virus (HIV), 
Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection. 
42. Unresolved toxicity of National Cancer Institute Common 
Terminology Criteria for Adverse Events, version 4.0 (NCI 
CTCAE v4.0) [NCI, 2009] Grade 2 or higher from previous 
anti-cancer therapy, except alopecia.
43. Presence of active gastrointestinal disease or other condition 
that will interfere significantly with the absorption of drugs.  If 
clarification is needed as to whether a condition will 
significantly affect absorption of drugs, contact the 
GlaxoSmithKline (GSK) medical monitor for guidance to enrol 
the subject.
44. A history or evidence of cardiovascular risk (as detailed in 
protocol Section 5.2.2)
Section 1.2.1
Pharmacokinetics of Trametinib in Humans
Additional new text added


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In the adult population PK model, trametinib CL/F was estimated as 5.07 L/hr and was 
dependent on gender and weight.  The typical CL/F of trametinib in male subjects was 
24% higher than that observed in female subjects. The effect of body weight at the 
minimum and maximum weight observed was within 16% of the typical CL/F value. 
Although smaller female subjects will tend to have higher exposure than heavier male 
subjects, no dosage adjustment is warranted in this population.
Section 1.2.2
Clinical Safety and Efficacy of Trametinib
PREVIOUS TEXT
Based on the adverse events (AEs) observed in the dose escalation phase of the early phase 
trials, the Maximum Tolerated Dose (MTD) of trametinib was 3 mg once daily, and the 
recommended Phase II dose of trametinib was 2 mg once daily.  Five monotherapy studies 
have administered trametinib 2 mg daily to 499 subjects.  Adverse events have been reported 
by 50% to 100% of subjects, with the most common being rash, diarrhea, fatigue, edema 
peripheral, nausea, dermatitis acneiform, vomiting, constipation, anemia, pruritus, alopecia, 
hypertension, decreased appetite, dyspnea and dry skin.  In these studies up to 32% of subjects 
reported serious AEs (SAEs), and up to 13% permanently discontinued study treatment due to 
AEs.
Rash, diarrhea, visual disorders, hepatic disorders, cardiac-related AEs, and pneumonitis are 
considered AEs of special interest because they are either known class effects (i.e., were 
observed with other MEK inhibitors) or potentially life-threatening.  Please refer to the 
GSK1120212 IB [GlaxoSmithKline Document Number HM2009/00151/03] for the most 
current safety information and additional details.
REVISED TEXT
Based on the adverse events (AEs) observed in the dose escalation phase of the early phase 
trials in adults, the Maximum Tolerated Dose (MTD) of trametinib was 3 mg once daily, and 
the recommended Phase II dose of trametinib was 2 mg once daily.  Five monotherapy studies 
have administered trametinib 2 mg daily to 499 subjects.  Adverse events have been reported 
by 50% to 100% of subjects, with the most common being rash, diarrhea, fatigue, edema 
peripheral, nausea, dermatitis acneiform, vomiting, constipation, anemia, pruritus, alopecia, 
hypertension, decreased appetite, dyspnea and dry skin.  In these studies up to 32% of subjects 
reported serious AEs (SAEs), and up to 13% permanently discontinued study treatment due to 
AEs.
Rash, diarrhea, visual disorders, hepatic disorders, cardiac-related AEs,hypertension, 
bleeding events, edema and pneumonitis are considered AEs of special interest for 
trametinib because they are either known class effects (i.e., were observed with other MEK 
inhibitors) or potentially life-threatening.  Please refer to the GSK1120212 IB 
[GlaxoSmithKline Document Number HM2009/00151/03] for the most current safety 
information and additional details.
1.2.4
Trametinib Pediatric Experience
PREVIOUS TEXT


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As of September 2013, no subject under the age of 18 has received trametinib monotherapy in 
a GSK sponsored clinical trial.
REVISED TEXT
As of September 2013, prior to the initiation of this trial, no subject under the age of 18 has 
received trametinib monotherapy in a GSK sponsored clinical trial.
1.3.1
Pharmacokinetics of Dabrafenib in Humans
New text added
In the adult population PK model for dabrafenib, body weight also impacted oral 
volume of distribution (Vc/F) and distributional clearance (Q/F).  The difference 
between female and male subjects (9%) and between subjects with low (50 kg) or high 
(140 kg) body weight relative to a typical body weight of 80 kg (<20%) was not 
considered clinically relevant.  
1.3.2
Clinical Safety and Efficacy of Dabrafenib
PREVIOUS TEXT
As of 25 June 2012, 586 subjects had received at least one dose of dabrafenib 150 mg BID.  
Integrated safety data from these subjects 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%) subjects experienced any serious 
adverse event (SAE), and 114 (19%) subjects had treatment-related SAEs.  The proportion of 
subjects who experienced AEs leading to discontinuation of study treatment was low (3%). 
[GlaxoSmithKline Document Number CM2010/00010/03]
In the pivotal Phase III study BRF113683 (BREAK-3), 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 subjects with BRAF V600E mutation positive 
melanoma and no brain metastases [Hauschild, 2012].  Dabrafenib provided a clear and 
meaningful benefit in subjects 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).  Subjects 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).
Dabrafenib (TAFINLAR™) was 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.
Combination of Trametinib and Dabrafenib
As of 2522 June 2012, 586 subjects had 2015, approximately 2,000 patients with various 
cancers have received at least one dose of dabrafenib 150 mg BID for up to 6 years and 
approximately 3,200 subjects have received trametinib in combination with dabrafenib 
for up to 5 years in GSK-sponsored ongoing or completed studies and compassionate 
care programs.  Cumulative postmarketing exposure to dabrafenib through 31 March 
2015 is estimated to be 3,546.16 patient-years.


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Integrated safety data from thesesubjects (N=586) receiving 150 mg BID showed that 97% 
had experienced AEs, the most common (≥20%) being hyperkeratosis (32%), headache
(30%), pyrexia (30%), arthralgia (29%), fatigue (26%), nausea (25%), alopecia (23%), skin 
papilloma (21%), and rash (20%).  A total of 174 (30%) subjects experienced any serious 
adverse event (SAE), and 114 (19%) subjects had treatment-related SAEs.  The proportion of 
subjects who experienced AEs leading to discontinuation of study treatment was low (3%). 
[GlaxoSmithKline Document Number CM2010/00010/03]
In the pivotal Phase III study BRF113683 (BREAK-3), 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 subjects with BRAF V600E mutation positive 
melanoma and no brain metastases [Hauschild, 2012].  Dabrafenib provided a clear and 
meaningful benefit in subjects 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).  Subjects 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).
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.
1.3.4
Dabrafenib Pediatric Experience
New section added 1.3.4.1
1.3.4.1
Background data from part 1 of study BRF116013
Twenty seven subjects were enrolled, with a median age of 9.0 years, ranging from 11 
months -17 years old; 56% were male.  Most subjects (89%) were caucasian. Most subjects 
(21 subjects, 78%) had measurable disease at baseline per the investigator, and all were 
previously treated for this tumor. Dose escalation was pharmacokinetically driven, to 
achieve exposures (measured as AUC 0-12) in pediatric patients that is similar to that seen 
in adults treated at recommended doses. Note that an MTD has not been determined in 
adults.
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 (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). The doses will be further defined based on modelling and simulation of 
all available data at the time of finalizing the protocol. 
An interim data cut from this ongoing study was made 7 March 2015, and resultant tables 
and listing prepared for the 27 patients enrolled into part 1. Twenty-one of these 27 
patients were continuing to receive dabrafenib at the time of the data cut off.  
Table 1
Patient Numbers Enrolled at Each Dose: Extent of exposure
Dose
Numbers enrolled




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patients, 3 had CRs, 2 had PRs and 4 of the eight patients were on study treatment for 9 
months or more. This is shown graphically in Figure 1 above.
These results compare very favorably to the historical data where paediatric patients with 
relapsed, refractory or progressive HGG are expected to have a less than 10% RR and a 
median survival of 5 months, using conventional therapy.
LGG
Fifteen pediatric patients with relapsed, refractory or progressive LGG with BRAFV600 
mutations were enrolled into the dose finding portion of BRF116013.  Of these 15 patients, 
5 had partial responses (33%), 7 had stable disease (47%), one had progressive disease 
and two were not yet evaluable for response.  
LCH
Two pediatric patients with previously treated severe LCH and BRAFV600 mutations 
were enrolled into BRF116013.  Both achieved complete responses as assessed by the 
investigator.
Other
Two patients with other solid tumors and BRAFV600 mutations were enrolled; neither 
had a response to dabrafenib therapy.
Safety Results
Adverse events
All subjects reported at least one AE.  The most common (>30%) AEs were pyrexia, 
fatigue, vomiting, headache, and nausea. There were nine subjects (33%) with AEs of 
maximal grade 3, and 2 subjects with maximal grade 4 (intracranial hemorrhage, 
hypotension). No grade 3 event occurred in >2 subjects. The most common body system 
impacted by AEs was skin (93% all grades, including 7% G2 and 7% G3 with multiple 
terms for rash most common), general disorders (81% all grades, including 33% G2, with 
pyrexia and fatigue most common), and metabolic (74% all grades, including 15% G2 and 
11% G3, various electrolyte abnormalities).
Serious Adverse Events 
Nine subjects (33%) reported 22 SAEs during this time period, all resolved.  Three 
subjects had related SAEs, one with rash, one with arthralgia, and one with pyrexia 
followed by DIC, hypotension, and increased INR.  All three remain on study as of July, 
2015.
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There was one subject with low grade glioma (
 years old at 4.5 mg/kg/d dose) who 
experienced a DLT of Grade 3 maculopapular rash with onset on day 1 of dosing.  After 
protocol specified dose interruption, the subject 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
Eleven of the 27 subjects had at least one dose interruption while on study, mostly for rash 
and/or pyrexia, and followed protocol guidelines.  Two subjects required dose reductions 
for toxicity, per protocol.
Discontinuations for toxicity
There were no subjects prematurely withdrawn from study for toxicity in part 1.  
However, through 7 March 2015, one subject in part 2 of the study was withdrawn for 
painful rash related to study drug, noted in the first week of study start, with recurrence 
upon re-challenge. The patient was aged 
 years, with a primary diagnosis of grade I 
Pilocytic Astrocytoma. An AE of grade 2 Erythema Nodosum resulted in study 
withdrawal. 
Deaths
There were no deaths on study treatment.
Laboratory data
Review of laboratory data reveals no apparent safety signals.  In most cases, it was possible 
to grade the laboratory data in this interim data analysis using local normal ranges. There 
were two events of G3 elevated hemoglobin and one event of G3 hypokalemia during viral 
upper respiratory tract infection. There was one patient with G2 hypokalemia and all 
other graded laboratory values were G1 or less.
Safety Conclusions
Based on preliminary data, the toxicity profile observed in these initial 27 paediatric 
subjects is generally similar to that observed in the adult subject experience.  Both 
populations experienced frequent rash, pyrexia, fatigue, arthralgia and headache (m2.7.4 
Section 2.1.1, common adverse events).  The frequency of rash and similar adverse events 
may be higher in this paediatric population than in adults.  There were two subjects (7%) 
with grade 3 Rash in the paediatric population while there is less than 1% rate in adults.  
Rash management guidelines suggested in the protocol were followed for subjects with 
rash as they remained on therapy.  In contrast, there were no cases of cutaneous SCC 
observed in these paediatric subjects and fewer paediatric subjects have discontinued 


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treatment due to toxicity (0 of 27 in part 1) than adult subjects.  The most common AEs 
were in the Skin body system.  There was one dose limiting toxicity, a G3 Rash, although 
higher doses were later shown to be tolerable in this age group.  There were no 
discontinuations due to toxicity.  Adequate exposures were obtained without reaching a 
maximally tolerated dose. 
Overall Conclusion 
Overall, these results suggest that dabrafenib monotherapy represents a potentially 
favorable benefit risk to pediatric patients < 18 years old with BRAFV600 mutant 
relapsed refractory or progressive gliomas including HGG.
1.4
Combination of Trametinib and Dabrafenib
PREVIOUS TEXT
Please refer to the most current version of the GSK1120212+GSK2118436 Investigator 
Brochure for the most current safety information and additional details [GlaxoSmithKline 
Document Number 2011N126811/01].
As of 31 May 2012, 365 subjects with BRAF V600 mutation positive melanoma had received 
various doses of trametinib and dabrafenib in combination therapy, with over 200 of these 
subjects receiving the recommended concomitant monotherapy doses of dabrafenib 150 mg 
twice daily and trametinib 2 mg once daily.
In terms of drug-drug interaction, following repeat dosing (Day 21), administration of 
dabrafenib 150 mg BID in combination with trametinib had little impact on dabrafenib Cmax 
and AUC(0-) with least squares (LS) mean ratios (90% confidence interval [CI]) of 
dabrafenib and trametinib in combination relative to dabrafenib alone of 1.16 (0.80, 1.68) and 
1.23 (0.89, 1.69), respectively.  Trametinib PK parameters were similar regardless of whether 
trametinib was administered with dabrafenib 75 mg BID or 150 mg BID.
The 55 subjects who received dabrafenib 150 mg BID and trametinib 2 mg once daily in 
Study BRF113220 (Part C 150/2 group) represent the population with the longest exposure 
(mean of approximately 11 months).  All subjects in this group had at least 1 AE and at least 1 
drug-related AE, with the most commonly reported AEs (≥40%) being pyrexia, chills, fatigue, 
nausea, and vomiting.  These AEs all occurred at frequencies that were higher than observed 
with either dabrafenib or trametinib monotherapy.  The safety profile of the combination 
therapy was primarily impacted by the emergence of a higher rate of pyrexia.  While fatigue 
and nausea occurred at a higher frequency relative to dabrafenib monotherapy, lower 
incidences of hyperkeratosis, alopecia, and skin papilloma were observed.  Relative to 
trametinib monotherapy, there was a higher incidence of fatigue, nausea, and vomiting 
observed but lower incidences of rash and diarrhea with combination therapy.
The incidence of SAEs, including drug-related SAEs, was up to 3-fold higher in the Part C 
150/2 group (SAE: 62%) compared with either trametinib monotherapy (22%) or dabrafenib 
monotherapy (30%).  The primary reason for this imbalance was due to the higher incidence 
of reported pyrexia.  The percentage of subjects with AEs leading to permanent 


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discontinuation of study treatment was similar between the Part C 150/2 group (9%) and 
trametinib monotherapy (10%), but higher than dabrafenib monotherapy (3%).
As reported in Flaherty, 2012b, progression free survival was significantly improved in 
subject receiving the combination of dabrafenib 150 mg twice daily plus trametinib 2 mg 
daily compared to dabrafenib monotherapy (9.4 months vs 5.8 months P <0.001).
REVISED TEXT
Please refer to the most current version of the GSK1120212+GSK2118436 Investigator 
Brochure for the most current safety information and additional details [GlaxoSmithKline 
Document Number 2011N126811/01].
As of 31 May 2012, 365 subjects with BRAF V600 mutation positive melanoma had received 
various doses of trametinib and dabrafenib in combination therapy, with over 200 of these 
subjects receiving the recommended concomitant monotherapy doses of dabrafenib 150 mg 
twice daily and trametinib 2 mg once daily.
In terms of drug drug interaction, following repeat dosing (Day 21), administration of Data 
summarizing the clinical safety profile for dabrafenib 150 mg BID in combination with 
trametinib had little impact on dabrafenib Cmax and AUC(0 ) with least squares (LS) mean 
ratios (90% confidence interval [CI]) of dabrafenib and trametinib in combination relative to 
dabrafenib alone of 1.16 (0.80, 1.68) and 1.23 (0.89, 1.69), respectively.  Trametinib PK 
parameters were similar regardless of whether trametinib was administered with dabrafenib 
75 mg BID 2 mg QD in adult patients with BRAF V600 mutation-positive unresectable or 
150 mg BID metastatic melanoma were pooled from two large randomized Phase III 
studies (N=559). The 55 subjects who received dabrafenib 150 mg BID and trametinib 2 mg 
once daily in Phase III data are supported by data from the Phase II Study BRF113220 
Part C (150/2 combination therapy group represent the population with the longest exposure 
(mean of approximately 11 months).  All subjects in this group had at least 1 AE and at least 1 
drug related AE, with the most commonly reported AEs (≥40%) being pyrexia, chills, fatigue, 
nausea, and vomiting.  These AEs all occurred at frequencies that were higher than observed 
with either dabrafenib or trametinib monotherapy. n=55) (m5.3.5.3 ISS Section 2.2), 
providing a total of over 600 subjects on randomized combination treatment. The safety 
profile of the combination therapy was primarily impacted by the emergence of a higher rate 
of pyrexia.  While fatigue and nausea occurred at a higher frequency relative to dabrafenib 
monotherapy, lower incidences of hyperkeratosis, alopecia, and skin papilloma were 
observed.  Relative to trametinib monotherapy, there was a higher incidence of fatigue, 
nausea, and vomiting observed but lower incidences of rash and diarrhea with combination 
therapy.
of dabrafenib and trametinib generally reflect AEs of the individual agents. The 
incidence of SAEs AE profile for combination therapy in both Phase III studies, including 
drug related SAEs, was up to 3 fold higher in the Part C 150/2 group (SAE: 62%) compared 
with either trametinib monotherapy (22%) or dabrafenib monotherapy (30%).  The primary 
reason for this imbalance was due to the higher incidence of reported pyrexia.  The percentage 
of subjects with SAEs and AEs leading to permanent discontinuation of study treatment was 
similar between the Part C 150/2 group (9%) and trametinib monotherapy (10%), but higher 
than dabrafenib monotherapy (3%). dose modifications, were similar, indicating that the 
pooled data is a reliable representation of the combination therapy safety profile. The 


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incidence of discontinuations and temporary dose modifications to manage AEs was 
higher for subjects on the combination therapy (discontinuations, 12%; dose reductions, 
31%; dose interruptions, 55%) compared to dabrafenib monotherapy (discontinuations, 
7%; dose reductions, 14%; dose interruptions, 37%) but similar to vemurafenib 
(discontinuations, 12%; dose reductions, 39%; dose interruptions, 56%). The intended 
dosing in subjects receiving combination therapy was not compromised.
As The most common SAE reported in, 2012b, progression free survival for combination 
therapy was significantly improved pyrexia, followed by ejection fraction decrease and 
chills. Discontinuations due to pyrexia and ejection fraction decrease each occurred in 
3% of subjects in subject receiving the combination of dabrafenib 150 mg twice daily plus 
trametinib 2 mg daily therapy group.
There were 8 fatal AEs reported for combination therapy; 6 of the 8 fatal SAEs were 
intracranial hemorrhages. The presence of various confounding factors in 5 of the 6 
subjects with intracranial hemorrhage makes the evaluation of causality difficult; 
contribution of the combination therapy cannot be ruled out.
The rate of permanent discontinuation due to AEs for combination therapy was 12%. 
Dose reductions due to AEs were required in approximately one-third of subjects 
receiving combination therapy (31%). Dose interruptions due to AEs were required in 
more than one-half of subjects receiving combination therapy (55%). The most 
frequently occurring AEs requiring dose modifications were those where management 
guidance was provided in the protocols. AEs of special interest were identified based on 
the clinical significance, frequency and the potential association with the mode of action 
of BRAF and MEK inhibitors.
Pyrexia occurred at increased frequency and severity for combination therapy 
subjects as compared to dabrafenib either monotherapy. Approximately 60% of the 
dose interruptions and 50% of the dose reductions in the combination therapy 
group were due to AEs of pyrexia. With appropriate management and dose 
modifications, most patients were able to continue on treatment.
Bleeding events occurred at a similar frequency on combination therapy 
compared to dabrafenib monotherapy, and at a higher frequency compared to 
vemurafenib monotherapy. The majority of bleeding events for all treatments 
were Grade 1, and resolved without dose modification. There were 6 fatal 
intracranial hemorrhages for combination treatment. Bleeding in other critical 
sites (e.g., gastrointestinal, pulmonary, genitourinary) have also occurred, none of 
which were fatal.
Ejection fraction decreased occurred in 7% of subjects for combination therapy 
and the majority of the LVEF decreases that met interruption criteria were 
asymptomatic and resolved. Most subjects who were re-challenged were able to 
continue on treatment without further dose modification. These findings suggest 
that by regular, longitudinal monitoring with appropriate dose modification, 
more severe sequelae may be prevented.
Hyperproliferative skin lesions, including keratoacanthoma and cuSCC, 
occurred at a reduced frequency and with a prolonged latency in subjects 
receiving this combination regimen as compared to BRAF inhibitors as 


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monotherapy; substantiating the non-clinical hypothesis that addition of 
trametinib abrogates an important safety concern resulting from the paradoxical 
activation of the MAP kinase pathway exerted by BRAF-inhibitors.
Other treatment-emergent malignancies (for example pancreatic  and colorectal) 
were reported at rates of 1% for combination treatment, which is not higher than 
what would be expected in the population, and comparable to that observed with 
monotherapy. 
Other adverse events of special interest such as renal insufficiency and 
pancreatitis for dabrafenib, and skin-related toxicities, ocular events, 
pneumonitis, and diarrhea for trametinib, appeared at a frequency and/or 
severity consistent with the known AE profiles of either dabrafenib or trametinib 
monotherapy.
The safety profile for dabrafenib + trametinib combination therapy in adult subjects 
with unresectable/metastatic melanoma has been established and is well-characterized 
with consistent results across two randomized Phase III studies, with 33% of subjects 
receiving >12 months vs 5.8  of combination treatment. There were no new or unexpected 
safety concerns compared to those observed in the Study BRF113220 Part C 
combination group. In addition, no new or unexpected safety concerns have been 
identified for subjects on combination treatment in studies with prolonged additional 
follow-up (an additional 17 months for MEK115306; an additional 20 months for 
BRF113220 Part C [m5.3.5.3 ISS Section 2.2]). The safety profile of the combination 
generally reflects the safety profiles of the individual agents.
The combination regimen of dabrafenib at the recommended dose of 150 mg BID and 
trametinib at the recommended dose of 2 mg QD has an acceptable safety profile in 
adult patients with unresectable or metastatic BRAF V600 mutation positive melanoma, 
with toxicities that are manageable with appropriate intervention. Administration of 
dabrafenib and trametinib in combination had no clinically relevant effect on the 
exposure of trametinib or of dabrafenib relative to administration of either compound 
alone.
There is no pediatric experience with the combination of dabrafenib and trametinib.  In 
adults, data from phase I/II and phase III studies of the combination of these two agents 
demonstrates that both agents can be delivered together at their full recommended 
monotherapy doses, and that generally the observed AE profile represents the profiles of 
each individual agent.  Some events were higher in the combination arms than in 
dabrafenib alone arms, including pyrexia, diarrhea, chills, vomiting and hypertension.  
Some events were lower in the combination arms than in the dabrafenib arms, including 
cuSCC alopecia, hyperkeratosis, PPES and skin papilloma. Bleeding events overall were 
similar in dabrafenib monotherapy and combination arms, although there were 6 fatal 
intracranial hemorrhage events out of 559 adult subjects treated in the combination 
therapy arms versus none in the 211 adult subjects on dabrafenib monotherapy.  These 
events of intracranial hemorrhage were generally confounded and were considered not 
related to treatment by the treating physicians but were more frequent in the combination 
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The combination therapy in the pediatric population may result in a higher frequency and 
severity of pyrexia as compared to dabrafenib monotherapy, including pyrexia requiring 
dose interruption and the use of antipyretics, as well as increased rates of chills, diarrhea, 
vomiting, and edema peripheral. The combination may result in a lower rate of 
hyperkeratosis, skin papilloma, alopecia, palmar plantar erythrodysesthesia syndrome, 
and palmoplantar keratoderma as compared to dabrafenib monotherapy.
The efficacy of the combination of dabrafenib plus trametinib in the treatment of adults 
with BRAFV600 mutant advanced melanoma has been shown to be superior to that of 
dabrafenib alone.  Similarly, the combination of dabrafenib and trametinib appears 
superior to that of dabrafenib alone in the treatment of adult subjects with BRAFV600 
mutant NSCLC.  Current clinical trial data on dabrafenib monotherapy in the treatment 
of pediatric subjects with BRAFV600 mutant solid tumors suggests clinically relevant 
efficacy that compares favorably with the current standard of care available for the 
various diseases that have been studied.  Nonetheless, there may be an opportunity for 
further improvement in efficacy with combination therapy, perhaps manifest as higher 
response rates, and/or responses of longer duration.
1.5
Rationale for BRAF and MEK inhibitors in Pediatric Cancers
PREVIOUS TEXT
Given the central role of MAPK signaling in cell proliferation, growth, and adhesion, and 
available evidence of enhanced MAPK activity in many human cancers, it is hypothesized 
that the MEK inhibitor trametinib may confer beneficial effects against the pediatric cancers 
including:
Relapsed or refractory neuroblastoma
Recurrent or unresectable low grade gliomas with BRAF tandem duplication with fusion
Neurofibromatosis (NF)-related PNs.
BRAF V600 mutant tumors 
The safety and activity of the combination of dabrafenib with trametinib in adults with BRAF 
V600 mutation positive melanoma has been demonstrated.  Once the doses of dabrafenib and 
trametinib monotherapy are determined in children and adolescents, a treatment arm to 
evaluate the safety of dabrafenib in combination with trametinib in children and adolescents 
will be opened.
REVISED TEXT
Given the central role of MAPK signaling in cell proliferation, growth, and adhesion, and 
available evidence of enhanced MAPK activity in many human cancers, it is hypothesized 
that the MEK inhibitor trametinib may confer beneficial effects against the pediatric cancers 
including:
Relapsed or refractory neuroblastoma
Recurrent or unresectable low grade gliomas with BRAF tandem duplication with fusion


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Neurofibromatosis (NF)-related PNs.
BRAF V600 mutant tumors 
Langerhans cell histiocytosis with MAP2K1 mutation
The safety and activity of the combination of dabrafenib with trametinib in adults with BRAF 
V600 mutation positive melanoma has been demonstrated.  Once the doses of dabrafenib and 
trametinib monotherapy are determined in children and adolescents, a treatment arm to 
evaluate the safety of dabrafenib in combination with trametinib in children and adolescents 
will be opened.
1.7.2
Predicted Toxicities for Combination of Trametinib and Dabrafenib
PREVIOUS TEXT
The assessment of the risk for the combination of trametinib and dabrafenib, and suggestions 
for management of risk, are based on clinical data from the concluded and ongoing 
combination studies in adults.  Additional information may be found in the IB for trametinib 
and dabrafenib [GlaxoSmithKline Document Number 2011N126811/01].
Pyrexia: Pyrexia was reported in clinical trials with dabrafenib monotherapy and in 
combination with trametinib. In dabrafenib monotherapy clinical studies, pyrexia was one of 
the most frequently occurring AEs in up to 27% of subjects across all dabrafenib studies. 
Most of the pyrexia events (64%) were considered to be related to study treatment. The 
incidence and severity of pyrexia are increased when dabrafenib is used in combination with 
trametinib. In patients who received the combination dose of dabrafenib 150 mg twice daily 
and trametinib 2 mg once daily and developed pyrexia, approximately half of the first 
occurrences of pyrexia happened within the first month of therapy. About half of the patients 
who experienced pyrexia had a single event. Pyrexia may be accompanied by severe rigors, 
dehydration and hypotension which in some cases can lead to acute renal insufficiency.
Guidelines for the management of pyrexia will be provided in the amendment to open Part C 
of the study.
Dermatological Effects
Cutaneous Squamous cell carcinoma (cuSCC): In vitro experiments have demonstrated a 
paradoxical activation of MAP-kinase signaling in keratinocytes and potentially other cells 
harboring a wild-type BRAF kinase but a mutated RAS kinase upon exposure to a BRAF 
inhibitor. This paradoxical MAP-kinase pathway activation is potentially associated with a 
higher risk for the development of squamous cell carcinoma induction.
Cases of cuSCC (which include those classified as keratoacanthoma or mixed 
keratoacanthoma subtype) have been reported in patients treated with dabrafenib in 
combination with trametinib. In patients who received the combination dose of dabrafenib in 
combination with trametinib, cutaneous SCC (including keratoacanthoma [KA]) occurred in a 
lower percentage of subjects and events occurred later than with dabrafenib monotherapy, 
with the median time to onset of 22 weeks. All patients on combination therapy who 
developed cuSCC continued on dabrafenib treatment without dose modification. Skin 
examination should be performed prior to initiation of dabrafenib and during treatment with 
dabrafenib, every 2 months throughout therapy. An additional examination should be 


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considered 2 months after discontinuation of dabrafenib. Cases of cuSCC should be managed 
by dermatological excision and dabrafenib treatment should be continued without any dose 
adjustment. Patients should be instructed to immediately inform their physician if new skin 
lesions develop.
New primary melanoma: New primary melanomas have been reported in patients treated 
with dabrafenib. These were identified within the first 5 months of therapy and did not require 
treatment modification other than excision. Monitoring for skin lesions should occur as 
described for cuSCC.
Rash: Skin-related toxicities, primarily rash (maculopapular type rash with dabrafenib and 
acneiform-type rash with trametinib) have been reported with both trametinib and dabrafenib 
monotherapies. The incidence of skin-related events reported with the combination regimen 
appears to be lower than what has been observed following trametinib monotherapy. Rash 
management guidelines are provided in Section 3.13.1.
Hemorrhage: Major hemorrhagic events can occur in patients receiving dabrafenib in 
combination with trametinib. Monitor for signs and symptoms of bleeding. 
Venous Thromboembolism: Deep vein thrombosis and pulmonary embolism can occur in 
patients receiving dabrafenib in combination with trametinib.
Interstitial lung disease (ILD)/Pneumonitis: 
Pneumonitis has been observed in subjects receiving trametinib.  To reduce the risk of 
pneumonitis, subjects will be monitored closely for symptoms, evaluated with imaging and 
functional tests if clinically indicated.
Pancreatitis – Pancreatitis has been observed in subjects receiving dabrafenib. Subjects will 
be monitored for abdominal pain or suspected pancreatitis, amylase and lipase laboratory 
samples should be collected for confirmation of the diagnosis. 
Hyperglycemia: Hyperglycemia requiring an increase in the dose of, or initiation of insulin or 
oral therapy can occur with dabrafenib. Serum glucose levels will be monitored as clinically 
appropriate during treatment with dabrafenib in subjects with pre-existing diabetes or 
hyperglycemia. 
Hepatic Events:
Hepatic adverse events have been reported in clinical trials with trametinib as monotherapy 
and in combination with dabrafenib. 
Ocular effects: Both trametinib and dabrafenib have been associated with ocular toxicities 
which appear to be class effects, including papilledema, RPED, and RVO, uveitis and iritis 
associated with trametinib and dabrafenib. Please refer to Section 1.7.1 and Section 3.13.3.
Decreased LVEF:  Left ventricular dysfunction was reported with trametinib as well as with 
other MEK inhibitors in clinical development. Please refer to Section 1.7.1 and Section 
3.11.3.1. 
Non-cutaneous secondary/recurrent malignancy: In vitro experiments have demonstrated 
paradoxical activation of MAP-kinase signaling in BRAF wild type cells with RAS mutations 
which are 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 


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been seen with BRAF inhibitors including dabrafenib, and with dabrafenib/trametinib 
combination therapy. Patients should be monitored as clinically appropriate.
Reproductive Effects: Dabrafenib may impair male and female fertility as adverse effects on 
male and female reproductive organs have been seen in animals given dabrafenib. In repeat 
dose studies, testicular degeneration/depletion was seen in rats and dogs (≥ 0.2 times the 
human clinical exposure based on AUC). Testicular changes in rat and dog were still present 
following a 4-week recovery period. Male subjects should be informed of the potential risk 
for impaired spermatogenesis, which may be irreversible.  In combined female fertility, early 
embryonic and embryofetal development studies in rats, numbers of ovarian corpora lutea 
were reduced in pregnant females at 300 mg/kg/day (approximately 3 times human clinical 
exposure based on AUC), but there were no effects on estrous cycle, mating or fertility 
indices. Developmental toxicity including embryo-lethality and ventricular septal defects were 
seen at 300 mg/kg/day, and delayed skeletal development and reduced fetal body weight at 
≥20 mg/kg/day (≥0.5 times human clinical exposure based on AUC).  There are no adequate 
and well-controlled studies of dabrafenib in pregnant women.
REVISED TEXT
The assessment of the risk for the combination of trametinib and dabrafenib, and suggestions 
for management of risk, are based on clinical data from the concluded and ongoing 
combination studies in adults.  Additional information may be found in the IB for trametinib 
and dabrafenib [GlaxoSmithKline Document Number 2011N126811/01].
Pyrexia: Pyrexia was reported in clinical trials with dabrafenib monotherapy and in 
combination with trametinib. In dabrafenib monotherapy clinical studies, pyrexia was one of 
the most frequently occurring AEs in up to 27% of subjects across all dabrafenib studies. 
Most of the pyrexia events (64%) were considered to be related to study treatment. The 
incidence and severity of pyrexia are increased when dabrafenib is used in combination with 
trametinib. In patients who received the combination dose of dabrafenib 150 mg twice daily 
and trametinib 2 mg once daily and developed pyrexia, approximately half of the first 
occurrences of pyrexia happened within the first month of therapy. About half one-third of 
the patients receiving combination therapy who experienced pyrexia had a single event 3 or 
more events. Pyrexia may be accompanied by severe rigors, dehydration and hypotension
which in some cases can lead to acute renal insufficiency.
Guidelines for the management of pyrexia will be provided in the amendment to open Part C 
of the study. Serious non-infectious febrile events have been observed.These events 
responded well to dose interruption and/or dose reduction and supportive care in 
clinical trials. Subjects should be evaluated for signs and symptoms of infection and 
work up considered as clinically indicated.  Dabrafenib must be held for fever of 38.5C 
or higher, and blood samples for an absolute neutrophil count (ANC) and serum 
creatinine must be drawn in the setting of fever.  Trametinib can be continued in 
subjects receiving combination therapy.  
Dermatological Effects
Cutaneous Squamous cell carcinoma (cuSCC): In vitro experiments have demonstrated a 
paradoxical activation of MAP-kinase signaling in keratinocytes and potentially other cells 
harboring a wild-type BRAF kinase but a mutated RAS kinase upon exposure to a BRAF 


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inhibitor. This paradoxical MAP-kinase pathway activation is potentially associated with a 
higher risk for the development of squamous cell carcinoma induction.
Cases of cuSCC (which include those classified as keratoacanthoma or mixed 
keratoacanthoma subtype) have been reported in patients treated with dabrafenib in 
combination with trametinib. In patients who received the combination dose of dabrafenib in 
combination with trametinib, cutaneous SCC (including keratoacanthoma [KA]) occurred in a 
lower percentage of subjects and events occurred later than with dabrafenib monotherapy, 
with the median time to onset of 22 weeks. All the first occurrence of 20 to 32 weeks as 
compared to approximately 8 weeks with dabrafenib monotherapy. Most patients on 
combination therapy who developed cuSCC continued on dabrafenib treatment without dose 
modification. Skin examination should be performed prior to initiation of dabrafenib and 
during treatment with dabrafenib, every 2 months throughout therapy. An additional 
examination should be considered 2 to 3 months after discontinuation of dabrafenib or until 
initiation of another anti-neoplastic therapy. Cases of cuSCC should be managed by 
dermatological excision and dabrafenib treatment should be continued without any dose 
adjustment. Patients should be instructed to immediately inform their physician if new skin 
lesions develop.
New primary melanoma: New primary melanomas have been reported in patients treated 
with dabrafenib. These were identified within the first 5 months of therapy and did not require 
treatment modification other than excision. Monitoring for skin lesions should occur as 
described for cuSCC.
Rash: Skin-related toxicities, primarily rash (maculopapular type rash with dabrafenib and 
acneiform-type rash with trametinib) have been reported with both trametinib and dabrafenib 
monotherapies. The incidence of skin-related events reported with the combination regimen 
appears to be lower than what has been observed following trametinib monotherapy. Rash 
management guidelines are provided in Section 3.13.1.
Hemorrhage: Major hemorrhagic events including fatal events can occur in patients 
receiving dabrafenib in combination with trametinib. Monitor for signs and symptoms of 
bleeding.
Venous Thromboembolism: Deep vein thrombosis and pulmonary embolism can occur in 
patients receiving dabrafenib in combination with trametinib.
Interstitial lung disease (ILD)/Pneumonitis: 
Pneumonitis has been observed in subjects receiving trametinib and trametinib in 
combination with dabrafenib.  To reduce the risk of pneumonitis, subjects will be monitored 
closely for symptoms, evaluated with imaging and functional tests if clinically indicated. No 
modification of dabrafenib is required when taken in combination with trametinib.
Pancreatitis – Pancreatitis has been observed in subjects receiving dabrafenib and 
dabrafenib in combination with trametinib. Subjects will be monitored for abdominal pain 
or suspected pancreatitis, amylase and lipase laboratory samples should be collected for 
confirmation of the diagnosis.
Hyperglycemia: Hyperglycemia requiring an increase in the dose of, or initiation of insulin or 
oral therapy can occur with dabrafenib. Serum glucose levels will be monitored as clinically 
appropriate during treatment with dabrafenib in subjects with pre-existing diabetes or 
hyperglycemia. 


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Hepatic Events:
Hepatic adverse events have been reported in clinical trials with trametinib as monotherapy 
and in combination with dabrafenib. 
Ocular effects: Both trametinib and dabrafenib have been associated with ocular toxicities 
which appear to be class effects, including papilledema, RPED, and RVO associated with 
trametinib, uveitis and iritis associated with trametinib and dabrafenib. Please refer to 
Section 1.7.1 and Section 3.13.3.
Decreased LVEF:  Left ventricular dysfunction was reported with trametinib as well as with 
other MEK inhibitors in clinical development. Please refer to Section 1.7.1 and Section 
3.11.3.1. 
Non-cutaneous secondary/recurrent malignancy: In vitro experiments have demonstrated 
paradoxical activation of MAP-kinase signaling in BRAF wild type cells with RAS mutations 
which are 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 including dabrafenib, and with dabrafenib/trametinib 
combination therapy. Patients should be monitored as clinically appropriate.
Reproductive Effects: Dabrafenib may impair male and female fertility as adverse effects on 
male and female reproductive organs have been seen in animals given dabrafenib. In repeat 
dose studies, testicular degeneration/depletion was seen in rats and dogs (≥ 0.2 times the 
human clinical exposure based on AUC). Testicular changes in rat and dog were still present 
following a 4-week recovery period. Male subjects should be informed of the potential risk 
for impaired spermatogenesis, which may be irreversible.  In combined female fertility, early 
embryonic and embryofetal development studies in rats, numbers of ovarian corpora lutea 
were reduced in pregnant females at 300 mg/kg/day (approximately 3 times human clinical 
exposure based on AUC), but there were no effects on estrous cycle, mating or fertility 
indices. Developmental toxicity including embryo-lethality and ventricular septal defects were 
seen at 300 mg/kg/day, and delayed skeletal development and reduced fetal body weight at 
≥20 mg/kg/day (≥0.5 times human clinical exposure based on AUC).  There are no adequate 
and well-controlled studies of dabrafenib in pregnant women.










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Protocol waivers or exemptions are not allowed.  Therefore, adherence to the study design 
requirements, including those specified in the Time and Events Table (Section 7.1), are 
essential.
Supplementary study conduct information not mandated to be present in this protocol is 
provided in the accompanying Study Procedures Manual (SPM).  The SPM provides site 
personnel with administrative and detailed technical information that does not impact subject 
safety.
REVISED TEXT
This is a 3-part (Part A, Part B, Part C), Phase I/IIa, multi-center, open label study in pediatric 
subjects with refractory or recurrent tumors likely to have pathway activation and thus more 
likely to benefit from therapy.  The overall goal of this trial is to efficiently establish safe, 
pharmacologically relevant dose of trametinib in infants, children and adolescents and 
determine preliminary activity of trametinib monotherapy in selected recurrent, refractory or 
unresectable childhood tumors.  In addition, Part C of the study is designed to establish the 
safety, tolerability and activity of trametinib in combination with dabrafenib in children and 
adolescents with recurrent, refractory or unresectable BRAFV600E mutated tumors.
Part A will be a pharmacokinetically driven limited dose escalation in subjects with an 
expansion for safety, tolerability, and PK in three age ranges (1 month to <2years, 2 to 
≤12 years, and over 12 years of age).  The primary goal of Part A is to establish the 
toxicity profile, PK, and recommended Phase 2 dose (RP2D) of trametinib in each age 
cohort.  Approximately 18 subjects will be accrued to the dose escalation phase and 18 
subjects to the age expansion phase (subjects less than 2 years of age will not be included 
in the initial dose escalation until the age specific cohorts are opened). 
Part B will be an expansion study to further evaluate the safety, tolerability, and preliminary 
clinical activity of trametinib in tumor-specific pediatric populations.  Disease cohorts are 
selected based on current data of Ras/MAPK activation in childhood solid tumors.  Forty 
subjects are planned for Part B, 10 subjects in each of 4 disease cohorts. Part B will use 
the dose determined in Part A. 
–
B1:  Refractory or relapsed neuroblastoma 
–
B2:  Recurrent or unresectable low grade gliomas with BRAF tandem 
duplication with fusion
–
B3:  Neurofibromatosis Type -1 associated plexiform neurofibromas (NF-1 
with PN) that are unresectable and medically significant.
–
B4:  BRAF V600 mutant tumors.
Part C is a limited dose escalation of the combination of trametinib in combination with 
dabrafenib in children and adolescents with recurrent, refractory or unresectable BRAF 
V600 mutated tumors.  This part of the study, with a planned enrollment of up to 18 
subjects with up to 6 adolescent subjects with BRAF V600 mutant metastatic 
melanoma, will not open until the dose of dabrafenib in children is established in study 
BRF116013, the dose of trametinib monotherapy is established in Part A and all available 
PK and safety data is reviewed. Part C will require an amendment prior to enrollment to 




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Blood samples for clinical laboratory tests will be collected throughout the study, and safety, 
tolerability and clinical activity assessments will be conducted according to the Time and 
Events Tables (Section 7.1).
Study treatment will be continued until disease progression, until subjects are no longer 
obtaining clinical benefit from continued treatment, until they develop an unacceptable 
toxicity, or until they withdraw consent, begin a new anti-cancer therapy, or the Sponsor 
terminates the study.  At the end of treatment, a final study visit will occur.  Additional details 
on subject completion are provided in Section 6.2.
REVISED TEXT
Part C will be a 3+3 study design to determine the safety, tolerability and preliminary 
activity of the RP2D of trametinib in combination with a limited dose escalation of dabrafenib 
(50% of pediatric RP2D and 100% RP2D).  Part C will enroll up to 18 subjects aged 1 to <18 
years with recurrent or refractory malignant solid tumors harboring a V600 mutation.
Part C of this study will not be open to enrolment until Amendment 3 provides information 
from the pediatric Phase 1 study of dabrafenib (BRF116013), which has established the 
recommended dabrafenib dose in children and provides relevant safety information for 
dabrafenib monotherapy in children and dabrafenib/trametinib combination therapy in 
adults. Once Part A of this study has been completed.  Starting dose for at least one of the 
combination and dose escalation schema three age specific cohorts, enrollment into Part C 
will commence. Enrollment for Part C will be provided in an amendment to close upon 
enrollment of 12 non melanoma pediatric patients and up to 6 BRAF V600 mutant 
melanoma patients or 36 months from the protocol. The amendment and supporting data 
will be submitted to relevant regulatory authorities prior to implementation. time Part C was 
opened for enrollment, whichever should come first. 
PK samples will be collected on Day1, Day 15, and Day 22.
Blood samples for clinical laboratory tests will be collected throughout the study, and safety, 
tolerability and clinical activity assessments will be conducted according to the Time and 
Events Tables (Section 7.1).
Study treatment will be continued until disease progression, until subjects are no longer 
obtaining clinical benefit from continued treatment, until they develop an unacceptable 
toxicity, or until they withdraw consent, begin a new anti-cancer therapy, or the Sponsor 
terminates the study.  At the end of treatment, a final study visit will occur.  Additional details 
on subject completion are provided in Section 6.2.
3.5
Criteria for Continuing in the Study
PREVIOUS TEXT
For subjects enrolled on Part A, Part B and Part C, the following criteria must be met to 
advance beyond the first 28 days:
Subjects have not met discontinuation of treatment criteria (Section 6.3)
No evidence of progressive disease (See Section 7.6) defined as no clinical evidence of 
progression for assessments that do not require imaging/disease assessment or no evidence 
of radiographic or histologic/morphologic progression if disease assessment included 
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Toxicity resolved to baseline or grade ≤ 2 with specific exception of:
Specific criteria for Ejection Fraction Results (Section 3.11.3).
For subjects in Part B who are not evaluable for hematological toxicity due to marginal 
bone marrow function from disease infiltration or prior therapy, the following 
hematologic criteria must be met:
–
Absolute neutrophil count > 500 cell/L,
–
Platelet count > 25,000/L (without transfusion in ≥ 7 days),
–
No life threatening consequences of anemia (no grade 4 anemia per NCI-CTCAE 
v4.03) [NCI, 2009].
REVISED TEXT
For subjects enrolled on Part A, Part B and Part C, the following criteria must be met to 
advance beyond the first 28 days:
Subjects have not met discontinuation of treatment criteria (Section 6.3)
No evidence of progressive disease (See Section 7.6) defined as no clinical evidence of 
progression for assessments that do not require imaging/disease assessment or no evidence 
of radiographic or histologic/morphologic progression if disease assessment included 
imaging (solid tumor) 
Patients will be permitted to continue study treatment beyond initial Investigator-
assessed disease progression, 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.  For this determination, the investigator should consider all 
relevant data, such as:
Absence of symptoms and signs of progressive disease 
No decline in performance status 
Absence of rapid progression of disease or of progressive tumor at critical 
anatomic sites (e.g., cord compression) that would require urgent medical 
intervention. 
Patient/guardian is willing to continue on the study
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 the appropriate Time and Events Tables (Section 7.1 
table.
After each tumor assessment, the investigator must confirm if the patient is still 
benefitting from study treatment, and document this in patient medical records. 
Toxicity resolved to baseline or grade ≤ 2 with specific exception of:


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Specific criteria for Ejection Fraction Results (Section 3.11.3).
For subjects in Part B who are not evaluable for hematological toxicity due to marginal 
bone marrow function from disease infiltration or prior therapy, the following 
hematologic criteria must be met:
–
Absolute neutrophil count > 500 cell/L,
–
Platelet count > 25,000/L (without transfusion in ≥ 7 days),
–
No life threatening consequences of anemia (no grade 4 anemia per NCI-CTCAE 
v4.03) [NCI, 2009].
3.6.2
Part B Intra-subject Dose Escalation
PREVIOUS TEXT
Not permitted.
REVISED TEXT
Not permitted.
Subjects may be allowed to re-escalate following dose reduction for AE upon resolution 
of AE. Please follow guidelines in Section 3.13 and Section 3.14. 
3.6.3
Part C Intra-subject Dose Escalation
PREVIOUS TEXT
Not permitted.
REVISED TEXT
Not permitted.
Subjects may be allowed to re-escalate following dose reduction for AE upon resolution 
of AE. Please follow guidelines in Section 3.13 and Section 3.14. 
3.8.3.2
Starting dose for Part C, Trametinib in Combination with Dabrafenib
PREVIOUS TEXT
In adults the recommended dose of trametinib in combination with dabrafenib is the full adult 
monotherapy dose of each: trametinib 2 mg PO daily and dabrafenib 150 mg PO twice daily.  
In the context of this clinical trial, the trametinib dose administered in Part C will be the 
trametinib monotherapy RP2D from Part A.  The monotherapy RP2D of dabrafenib in 
children will be established on a separate trial (BRF116013).  For the evaluation of 
combination therapy on this trial, the starting dose of dabrafenib will be 50% of the 
monotherapy dabrafenib dose from BRF116013.  If tolerated a single dose escalation to the 
dabrafenib RP2D will be evaluated.  Actual doses will be added to this protocol by a protocol 
amendment prior to enrolment to Part C.
REVISED TEXT
In adults the recommended dose of trametinib in combination with dabrafenib is the full adult 
monotherapy dose of each: trametinib 2 mg PO daily and dabrafenib 150 mg PO twice daily.  
In the context of this clinical trial, the trametinib dose administered in Part C will be the 
trametinib monotherapy RP2D from Part A.  The monotherapy RP2D of dabrafenib in 


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children will be was established on a separate trial (BRF116013).  The following RP2D 
doses were determined for dabrafenib:

< 12 years old subjects: 5.25 mg/kg/day dabrafenib administered orally, divided into 
two equal doses 

≥ 12 years old subjects: 4.5 mg/kg/day dabrafenib administered orally, divided into 
two equal doses
For the evaluation of combination therapy on this trial, the starting dose of dabrafenib (Dose 
Level 1) will be 50% of the monotherapy dabrafenib dose from BRF116013. RP2D, divided 
into two equal doses. If tolerated a single dose escalation to the full dabrafenib RP2D (Dose 
Level 2) will be evaluated. Actual doses will be added to this protocol by a protocol 
amendment prior to enrolment to Part C. If dose levels proposed are not well tolerated, 
intermediate dose levels of dabrafenib and/or trametinib may be evaluated if warranted. 
Table 4
Recommended dabrafenib dose levels
Dabrafenib
Trametinib
Dose Level
< 12 years
≥ 12 years
All ages
1 
(Starting dose)
2.63 mg/kg/d
2.25 mg/kg/d
RP2D
2
5.25 mg/kg/d
4.5 mg/kg/d
RP2D
3.8.4
Rationale for Endpoints
PREVIOUS TEXT
This study will be the first administration of trametinib to pediatric subjects.  Safety 
parameters will be carefully and systematically monitored.
Part A: The expectation is that a PK endpoint will help define a dose that will provide an 
efficacious exposure in pediatric subjects without the need to reach maximum toxicity levels. 
In the absence of DLT in this pediatric study, a PK target endpoint will be used as the primary 
endpoint for dose determination.  In adults, there is minimal intersubject variability in the 
steady state C(CV 19%, 95%CI=10.86-13.4), and responses were observed at exposures as 
low as C= 7 ng/mL in subjects with melanoma, while efficacy has been clearly identified at 
known plasma levels of study drug (≥10 ng/mL trough) which were well tolerated. However, 
safety will be carefully reviewed and DLT definitions are incorporated in the protocol should 
safety in pediatric subjects differ from those in adult subjects following treatment with 
trametinib.
Part B: The RP2D established in Part A and verified by age cohorts (1 month to <2 years, 2 
years to ≤12 years and >12 years) will be administered in Part B.  The primary objective in 
Part B will be objective response measured by specific disease appropriate measures.
Part C: Subjects will be monitored for DLT and toxicity. Safety, tolerability and preliminary 
activity are the primary endpoints of this part of the study.  In the absence of DLT, dose 
escalation will not exceed the trametinib monotherapy RP2D in combination with the 
dabrafenib monotherapy RP2D.


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REVISED TEXT
This study will be the first administration of trametinib to pediatric subjects.  Safety 
parameters will be carefully and systematically monitored.
Part A: The expectation is that a PK endpoint will help define a dose that will provide an 
efficacious exposure in pediatric subjects without the need to reach maximum toxicity levels. 
In the absence of DLT in this pediatric study, a PK target endpoint will be used as the primary 
endpoint for dose determination.  In adults, there is minimal intersubject variability in the 
steady state C(CV 19%, 95%CI=10.86-13.4), and responses were observed at exposures as 
low as C= 7 ng/mL in subjects with melanoma, while efficacy has been clearly identified at 
known plasma levels of study drug (≥10 ng/mL trough) which were well tolerated. However, 
safety will be carefully reviewed and DLT definitions are incorporated in the protocol should 
safety in pediatric subjects differ from those in adult subjects following treatment with 
trametinib.
Part B: The RP2D established in Part A and verified by age cohorts (1 month to <2 years, 2 
years to ≤12 years and >12 years) will be administered in Part B.  The primary objective in 
Part B will be objective response measured by specific disease appropriate measures.
Part C: Subjects will be monitored for DLT and toxicity using the same DLT criteria as 
Part A. Safety, tolerability and preliminary activity are the primary endpoints of this part of 
the study.  In the absence of DLT, dose escalation will not exceed the trametinib monotherapy 
RP2D in combination with the dabrafenib monotherapy RP2D.
3.10.1
Trametinib
PREVIOUS TEXT
Trametinib is administered orally once daily under fasting conditions, either 1 hr before or 
2 hr after a meal.  Subjects should be encouraged to take trametinib approximately 24 hours 
apart at the same time each day. Dose levels are provided in Section 3.2.1.
For trametinib tablets, it is recommended that subjects drink approximately 4 to 6 mL of 
water/kg body weight with each dose.
Trametinib pediatric oral solution formulation will be administered with a graduated syringe.  
It is recommended that subjects drink 4 to 6 mL of water/kg body weight following dosing.
A dosing nomogram (see Appendix 2) based on weight and dose level will be used to 
prescribe trametinib to minimize inter-subject dosing variability.  If a subject vomits after 
taking study medication, the subject should be instructed not to retake the dose and should 
take the next scheduled dose.  If a subject misses a dose, subject should not double the next 
regularly scheduled dose.  However, subject can take the missed dose immediately if the next 
scheduled dose is at least 12 hr later.  Subject should take the next dose at its usual time.
Refer to Section 3.12 and Section 3.13 for dose modifications for toxicity.
REVISED TEXT
Please note that study drug dispensed to subjects in the original container should not be 
repackaged without explicit permission from the Sponsor. Trametinib is administered 
orally once daily under fasting conditions, either 1 hr before or 2 hr after a meal.  Subjects 
should be encouraged to take trametinib approximately 24 hours apart at the same time each 
day. Dose levels are provided in Section 3.2.1.


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Ideally, patients will take the trametinib study drug in the morning up through the PK 
day.  After the PK day, the patient may change to evening dosing, if they prefer.  If the 
patient is on an evening dosing regimen as they enter the PK testing period, the evening 
dose prior to the PK day SHOULD BE taken by the patient.  In all cases, the timing of 
the dose prior to the PK sampling must be maintained and recorded accurately.
For trametinib tablets, it is recommended that subjects drink approximately 4 to 6 mL of 
water/kg body weight with each dose.
Trametinib pediatric oral solution formulation will be administered with a graduated syringe.  
It is recommended that subjects drink 4 to 6 mL of water/kg body weight following dosing.
A dosing nomogram (see Appendix 2) based on weight and dose level will be used to 
prescribe trametinib to minimize inter-subject dosing variability.  If a subject vomits after 
taking study medication, the subject should be instructed not to retake the dose and should 
take the next scheduled dose.  If a subject misses a dose, subject should not double the next 
regularly scheduled dose.  However, subject can take the missed dose immediately if the next 
scheduled dose is at least 12 hr later.  Subject should take the next dose at its usual time.
Refer to Section 3.12 and Section 3.13 for dose modifications for toxicity.
3.10.2
Dabrafenib
PREVIOUS TEXT
Dose levels, dose modifications for events of special interest, and a dosing nomogram will be 
added in a future amendment to open Part C once the RP2D of dabrafenib and trametinib 
monotherapy is established in children.
REVISED TEXT
Dose levels, dose modifications for events of special interest, and a dosing nomogram will be 
added in a future amendment to open Part C once the RP2D of dabrafenib and trametinib 
monotherapy is established in children. Please note that study drug dispensed to subjects in 
the original container and should not be repackaged without explicit permission from 
the Sponsor.
Capsules:  Dabrafenib capsules will be supplied by GSK (for subjects able to reliably 
and consistently swallow capsules).
Suspension: Dabrafenib will be supplied as a powder for oral suspension contained in 
single-use foil laminated stickpacks. The powder will be constituted with a specified 
volume of water at the time of use to form an oral suspension of 10 mg/mL dabrafenib. 
Administration will be performed using appropriate-sized oral syringes (1 mL, 5 mL, or 
20 mL) to enable adjustments in dosing volume for individualized doses. The constituted 
suspension is intended for immediate consumption and the unused portion of the 
suspension will be discarded. Supplies for constitution will be supplied by GSK. Detailed 
instructions for constitution and dosing will be provided in the SPM.
Dabrafenib (either formulation) will be administered orally, twice daily based on weight 
at the appropriate study dose level. A dosing nomogram (Appendix 2) based on weight 
and dose level will be used to prescribe dabrafenib to minimize inter-subject dosing 
variability. For capsule administration, only 50 mg and 75 mg dose strengths are 
available. Therefore, the dose recommendations by weight range are within 20% of the 






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ECHO should be performed at baseline and at follow up visit(s).  Electronic copies of all 
ECHO scans will be collected by GSK for review.  Instructions for submission of ECHO 
scans are provided in the Study Procedures Manual (SPM).




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Once LVEF recovers, including resolution of symptoms, restart of dabrafenib monotherapy only can be considered in 
consultation with GSK medical monitor. 










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REVISED TEXT
Rash is a frequent AE observed in subjects receiving trametinib and dabrafenib (see the 
Investigator’s Brochure for more information) A proactive approach is recommended. 
Encourage subjects to avoid unnecessary exposure to sunlight and encourage use of 
sunscreens and sunblock (see Section 3.13.1.1). If subjects develop rash, verify treatment 
intervention and consider recommended steps outlined under Section 3.13.1.2 and Table 57.
3.13.1.2
Reactive Management
PREVIOUS TEXT
It is strongly recommended that subjects who develop rash/skin toxicities receive evaluations 
for management of the specific side effect.
For pruritic lesions, the use of cool compresses and oral antihistamine agents may be helpful.
For fissuring, the use of Monsel’s solution, silver nitrate or zinc oxide cream is advised.
For desquamation, thick emollients and mild soap are recommended.
For paronychia, antiseptic bath and local potent corticosteroids in addition to oral antibiotics 
are recommended, and if no improvement is seen, a dermatology or surgery consultation 
is recommended.
For infected lesions, bacterial and fungal culturing followed by the appropriate culture-driven 
systemic or topical antibiotics is indicated.
Table 30
Management of Rash
CTCAE Grade
Adverse Event Management 
Action and Dose Modification
Grade 1
Initiate prophylactic and 
symptomatic treatment 
measuresa
Use moderate strength topical 
steroidb
Reassess after 2 weeks; 
Continue trametinib 
If rash does not recover to baseline within 2 weeks 
despite best supportive care, reduce trametinib by 
one dose level (Appendix 2).
Grade 2
Initiate prophylactic and 
symptomatic treatment 
measuresa Use moderate 
strength topical steroidb  
Reassess after 2 weeks.
Reduce trametinib by one dose level (Appendix 
2).
Reassess after 2 weeks:
If rash recovers to ≤Grade 1 within 2 weeks, 
increase dose to previous dose level
If no recovery to ≤Grade 1 within 2 weeks, interrupt 
trametinib until recovery to ≤grade 1, restart 
trametinib at reduced dose level
Grade 3
Use moderate strength topical 
steroidsb ( PLUS 
methylprednisolone dose pack.
Consult dermatologist   
Interrupt trametinib until rash recovers to Grade ≤1
Restartc with trametinib reduced by one dose 
leveld (Appendix 2)


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CTCAE Grade
Adverse Event Management 
Action and Dose Modification
If no recovery to grade ≤2 within 4 weeks, 
permanently discontinue trametinib.
Abbreviations:  CTCAE = Common Terminology Criteria for Adverse Events
a.
Rash prophylaxis is recommended for the first 6 weeks of study treatment
b.
Moderate-strength topical steroids  hydrocortisone 2.5% cream or fluticasone prioprionate 0.5% cream
c.
Approval of GSK medical monitor is required to re-start study treatment after >4 weeks of interruption
d.
Escalation of trametinib to previous dose level may be considered if no rash is evident 4 weeks after restarting 
study treatment
REVISED TEXT
It is strongly recommended that subjects who develop rash/skin toxicities receive evaluations 
for management of the specific side effect.
For pruritic lesions, the use of cool compresses and oral antihistamine agents may be helpful.
For fissuring, the use of Monsel’s solution, silver nitrate or zinc oxide cream is advised.
For desquamation, thick emollients and mild soap are recommended.
For paronychia, antiseptic bath and local potent corticosteroids in addition to oral antibiotics 
are recommended, and if no improvement is seen, a dermatology or surgery consultation 
is recommended.
For infected lesions, bacterial and fungal culturing followed by the appropriate culture-driven 
systemic or topical antibiotics is indicated.


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Table 5 7
Management of Rash
CTCAE Grade
Adverse Event Management 
Action and Dose Modification
Grade 1
Initiate prophylactic and 
symptomatic treatment 
measuresa
Use moderate strength topical 
steroidbsteroidsb
Reassess after 2 weeks; 
Continue trametinib study drug(s)
If rash does not recover to baseline within 2 weeks 
despite best supportive care, reduce trametinib
study drug (s) by one dose level (Appendix 2).
Grade 2
Initiate prophylactic and 
symptomatic treatment 
measuresa Use moderate 
strength topical steroidb  
Reassess after 2 weeks.
Reduce trametinib study drug (s) by one dose 
level (Appendix 2).
Reassess after 2 weeks:
If rash recovers to ≤Grade 1 within 2 weeks, 
increase dose to previous dose level
If no recovery to ≤Grade 1 within 2 weeks, interrupt 
trametinib study drug(s) until recovery to 
≤grade 1, restart trametinib study drug (s) at 
reduced dose level
Grade 3
Use moderate strength topical 
steroidsb ( PLUS consider a brief 
period of oral high dose steroid 
such as methylprednisolone dose 
pack.
Consult dermatologist   
Interrupt trametinib study drug(s) until rash 
recovers to Grade ≤1
Restartc with trametinib study drug(s) reduced by 
one dose leveld (Appendix 2)
If no recovery to grade ≤2 within 4 weeks, 
permanently discontinue trametinib study 
drug(s).
Abbreviations:  CTCAE = Common Terminology Criteria for Adverse Events
a.
Rash prophylaxis is recommended for the first 6 weeks of study treatment
b.
Moderate-strength topical steroids  hydrocortisone 2.5% cream or fluticasone prioprionate 0.5% cream
c.
Approval of GSK medical monitor is required to re-start study treatment after >4 weeks of interruption
d.
Escalation of trametinib study drug (s) to previous dose level may be considered if no rash is evident 4 weeks 
after restarting study treatment
3.13.3
Hypertension
PREVIOUS TEXT
The algorithm in Figure 4 will be used to grade and manage trametinib related hypertension. 
Should initiation of anti-hypertensive therapy be required, single agent therapy (commonly 
including the calcium channel blockers amlodipine or nifedipine,) should be started and the 
blood pressure should be monitored at least twice weekly until BP is within the 95th 
percentile for age, height, and gender per Section 3.11.3.2


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If patient is already on an anti-hypertensive medication at study enrollment, then their anti-
hypertensive therapy should be adjusted (by either adjusting the dose of their current anti-
hypertensive medication or by adding another anti-hypertensive agent) according to the 
algorithm in Section.3.13.3.1.  
See requirements for Baseline blood pressure measurements in Section 7.3.4.
REVISED TEXT
The algorithm in Figure will be used to grade and manage trametinib and dabrafenib related 
hypertension. Should initiation of anti-hypertensive therapy be required, single agent therapy 
(commonly including the calcium channel blockers amlodipine or nifedipine,) should be 
started and the blood pressure should be monitored at least twice weekly until BP is within the 
95th percentile for age, height, and gender per Section 3.11.3.2
If patient is already on an anti-hypertensive medication at study enrollment, then their anti-
hypertensive therapy should be adjusted (by either adjusting the dose of their current anti-
hypertensive medication or by adding another anti-hypertensive agent) according to the 
algorithm in Section 3.13.3.1.  
See requirements for Baseline blood pressure measurements in Section 7.3.4.
3.13.3.1
Management of Hypertension
PREVIOUS TEXT

The upper limit of normal (ULN) is defined as a BP equal to the 95th percentile 
for age, height, and gender. (Appendix 7)

The NCI CTCAE will be utilized to determine the grade of hypertension for 
reporting purposes.

Elevated BP measurements should be repeated on the same day to confirm the 
elevation. Patients with an elevated BP should have BP measurements performed 
at least twice weekly until BP is ≤ ULN.

The algorithm below will be used to manage trametinib related hypertension.

Hypertension should be managed with appropriate anti-hypertensive agent(s) as 
clinically indicated. It is strongly recommended that nephrology or cardiology be 
consulted in the evaluation and management of hypertension.


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Figure 4
Algorithm For Management of Trametinib-Related Hypertension
Arm 1 of algorithm:

If blood pressure (BP) ≤ 95%ile for age, height, and gender: continue trametinib at 
the same dose.
Arm 2 of algorithm:

If BP ≤ 10 mm Hg above the ULN: continue trametinib at the same dose and 
recheck the BP within 72 hours.
o
If the BP is ≤ ULN on recheck, continue trametinib at the same dose.
o
If the BP remains above the ULN on recheck, then start/adjust 
antihypertensive therapy and follow Arm 3 of the algorithm from the point 
that anti-hypertensive therapy is started/adjusted.
Arm 3 of algorithm:

If BP is 11 to 25 mm Hg above the ULN on ≥ 2 of 3 measurements or > 35 mmHg 
above baseline on ≥ 2 of 3 measurements, start/adjust anti-hypertensive therapy 
and continue trametinib at the same dose. Monitor BP at least twice weekly.
o
If the BP returns to ≤ ULN within 14 days, continue trametinib at 
the same dose and continue anti-hypertensive therapy.


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o
If the BP remains elevated ≥25 mm Hg above the ULN 
or > 35 mm Hg above baseline for more than 14 days after the 
institution/adjustment of anti-hypertensive therapy, hold 
trametinib, monitor BP at least every 3 days, and follow Arm 4 of 
the algorithm from the point that trametinib is held. The anti-
hypertensive therapy should be continued until the BP is less than 
the ULN.

If the BP returns to ≤ ULN within 14 days, restart trametinib at a reduced dose.

If the BP remains > ULN for more than 14 days, patient must be removed from 
protocol therapy.
o
If the BP increases to > 25 mm Hg above the ULN despite anti-
hypertensive therapy, hold trametinib, but continue the anti-hypertensive 
agent(s). Monitor the BP as clinically indicated and follow Arm 4 of the 
algorithm from the point that trametinib is held.

If the BP is ULN within 14 days, trametinib may be restarted at a reduced dose 

If the BP is > ULN for > 14 days, the patient must be removed from protocol 
therapy (Section 6.3)
Arm 4 of algorithm:

If BP is > 25 mm Hg above the ULN hold trametinib, monitor BP, and 
administer/adjust anti-hypertensive therapy as clinically indicated.
o
If the BP returns to ≤ ULN within 14 days, trametinib may be restarted at a
reduced dose.
o
If the BP is > ULN for >14 days, the patient must be removed from 
protocol therapy (Section 6.3).
Arm 5 of algorithm:
If the participant develops Grade 4 hypertension, discontinue trametinib, monitor 
BP and administer anti-hypertensive therapy as clinically indicated. The patient is 
Off Protocol Therapy (Section 6.3).
REVISED TEXT

The upper limit of normal (ULN) is defined as a BP equal to the 95th percentile 
for age, height, and gender. (Appendix 7)

The NCI CTCAE will be utilized to determine the grade of hypertension for 
reporting purposes.

Elevated BP measurements should be repeated on the same day to confirm the 
elevation. Patients with an elevated BP should have BP measurements performed 
at least twice weekly until BP is ≤ ULN.

The algorithm below will be used to manage trametinib study drug(s) related 
hypertension.


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
Hypertension should be managed with appropriate anti-hypertensive agent(s) as 
clinically indicated. It is strongly recommended that nephrology or cardiology be 
consulted in the evaluation and management of hypertension.
Figure 5
Algorithm For Management of Trametinib Study Drug(s)-Related 
Hypertension
Arm 1 of algorithm:

If blood pressure (BP) ≤ 95%ile for age, height, and gender: continue trametinib
study drug(s) at the same dose.
Arm 2 of algorithm:

If BP ≤ 10 mm Hg above the ULN: continue trametinib study drug(s) at the same 
dose and recheck the BP within 72 hours.
o
If the BP is ≤ ULN on recheck, continue trametinib study drug(s) at the 
same dose.
o
If the BP remains above the ULN on recheck, then start/adjust 
antihypertensive therapy and follow Arm 3 of the algorithm from the point 
that anti-hypertensive therapy is started/adjusted.
Arm 3 of algorithm:


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
If BP is 11 to 25 mm Hg above the ULN on ≥ 2 of 3 measurements or > 35 mmHg 
above baseline on ≥ 2 of 3 measurements, start/adjust anti-hypertensive therapy 
and continue trametinib study drug(s) at the same dose. Monitor BP at least twice 
weekly.
o
If the BP returns to ≤ ULN within 14 days, continue trametinib
study drug(s) at the same dose and continue anti-hypertensive 
therapy.
o
If the BP remains elevated ≥25 mm Hg above the ULN 
or > 35 mm Hg above baseline for more than 14 days after the 
institution/adjustment of anti-hypertensive therapy, hold trametinib,
study drug(s), monitor BP at least every 3 days, and follow Arm 4 
of the algorithm from the point that trametinib is held. The anti-
hypertensive therapy should be continued until the BP is less than 
the ULN.

If the BP returns to ≤ ULN within 14 days, restart trametinib sudy drug (s) at a 
reduced dose.

If the BP remains > ULN for more than 14 days, patient must be removed from 
protocol therapy.
o
If the BP increases to > 25 mm Hg above the ULN despite anti-
hypertensive therapy, hold trametinib, study drug(s), but continue the anti-
hypertensive agent(s). Monitor the BP as clinically indicated and follow 
Arm 4 of the algorithm from the point that trametinib study drug(s) is 
held.

If the BP is ULN within 14 days, trametinib study drug (s) may be restarted at a 
reduced dose 

If the BP is > ULN for > 14 days, the patient must be removed from protocol 
therapy (Section 6.3)
Arm 4 of algorithm:

If BP is > 25 mm Hg above the ULN hold trametinib, study drug (s), monitor 
BP, and administer/adjust anti-hypertensive therapy as clinically indicated.
o
If the BP returns to ≤ ULN within 14 days, trametinib study drug(s) may 
be restarted at a reduced dose.
o
If the BP is > ULN for >14 days, the patient must be removed from 
protocol therapy (Section 6.3).
Arm 5 of algorithm:


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If the participant develops Grade 4 hypertension, discontinue trametinib, study 
drug(s), monitor BP and administer anti-hypertensive therapy as clinically 
indicated. The patient is Off Protocol Therapy (Section 6.3).
Section 3.14 has been retitled.
PREVIOUS TEXT
3.14
Guidelines and Dose Modifications for Dabrafenib Events of 
Special Interest
Guidelines for dose modifications and interruptions for management of common toxicities 
associated with the combination of trametinib and dabrafenib will be provided along with 
dosing instructions for dabrafenib in the amendment to open Part C.
REVISED TEXT

3.14
Dose Delay and Modification for Events Considered Related 
to Dabrafenib
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. 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.  
These are general guidelines and investigators should use always use clinical judgment 
in determining dose adjustments for any individual patient.  Some toxicities may require 
hospitalization for stabilization, additional work-up, and consultation with a specialist 
before treatment can be restarted.  Specific adverse events and recommended 
management include:
PPES – Measures for PPES should include:
o
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
o
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.


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Pancreatitis – In the event of abdominal pain or suspected pancreatitis, amylase and 
lipase laboratory samples should be collected for confirmation of the diagnosis. 
Patients should be closely monitored when re-starting dabrafenib after an 
episode of pancreatitis.
Uveitis - 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.
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 subjects 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.
Investigators should always err on the side of caution in these settings if treatment-
related toxicity is a possibility.  
Please refer to Table 6 for general dose modification guidelines for trametinib and 
dabrafenib.
When an individual’s adverse reactions are under effective management, dose re-
escalation following the same dosing steps as de-escalation may be considered. The 
dabrafenib dose should not exceed 150 mg twice daily.
New Section added 3.15
3.15
Guidelines for Dose Modifications and Toxicity Management for 
Combination Therapy 
If treatment related toxicities occur when dabrafenib is used in combination with
trametinib then both treatments should be simultaneously dose reduced, interrupted or 
discontinued with the exception shown below:

Dose modification is necessary for only dabrafenib
o
Mild to moderate pyrexia (Section 3.15.1)
o
Uveitis

Dose modifications are necessary for only trametinib:

Retinal vein occlusions (RVO) and retinal pigment epithelial detachment (RPED) 
(Section 3.13.4)

Left ventricular ejection fraction (LVEF) reduction

Pneumonitis and interstitial lung disease (ILD)






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3.15.2
Renal insufficiency
Cases of renal insufficiency have occurred in adult subjects receiving dabrafenib.  Prior 
to start of study treatment, concomitant medications should be reviewed for the 
potential risk of inducing nephrotoxicity and concomitant medications should 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 in Table 13.
For the purposes of this guideline, increases from baseline should have at least the 
following absolute increase to qualify for the noted percent increase in this guideline. 
The normal serum creatinine values anticipated for young patients on this protocol are 
near the reporting limits of the laboratory analysis, and are thus subject to variability in 
reported results and high calculated percent changes.  The absolute increase values are 
intended to alleviate dosing changes due to spuriously high calculations for percentage 
change.
For a 25% increase – that must also be at least a 0.10mg/dL absolute increase
For a 50% increase – that must also be at least a 0.20 mg/dL absolute increase
For a 100% increase – that must also be at least a 0.40 mg/dL absolute increase


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Table 13
Renal Insufficiency Guidelines
For subjects with creatinine 
rise  ≥50% from baseline :
1 st  occurrence

If patient has fever: treat pyrexia as per Table 12 (please note 
NSAIDs can induce renal insufficiency, especially in patients with 
dehydration); consider IV hydration

Pediatric nephrology consult is recommended

Re-check within 24 hours

If creatinine rise is < 25% from baseline:

Continue dabrafenib and trametinib at current dose

Monitor creatinine weekly for 4 weeks to ensure levels 
remain within 25% of baseline 

If creatinine rise is ≥ 25% but < 50% from baseline:

Continue dabrafenib and trametinib at current dose

Monitor creatinine at least twice weekly, can decrease 
frequency if creatinine rise < 25% from baseline

Avoid nephrotoxic agents

If creatinine rise is ≥ 50% but < 100% from baseline:

Interrupt dabrafenib and trametinib

Monitor creatinine at least twice weekly

Avoid nephrotoxic agents

May restart dabrafenib at reduced dose and trametinib at 
reduced dose if creatinine rise returns to < 25% from baseline

If creatinine rise is ≥ 100% from baseline:
Permanently discontinue dabrafenib and trametinib
2nd occurrence
Permanently discontinue dabrafenib and continue trametinibdabrafenib
3.15.3
Malignancies
Cutaneous Squamous Cell Carcinomas (CuSCC)
Cases of cuSCC (which include those classified as keratoacanthoma or mixed 
keratoacanthoma subtype) have been observed in subjects treated with dabrafenib.  
Approximately 70% of events occurred within the first 12 weeks of treatment with a 
median time to onset of 8 weeks.  These should be surgically removed according to 
institutional practices.  Dose modification or interruption of study treatment is not 
required for cuSCC or KA, however cuSCC should be reports as an SAE. In addition, a 


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biopsy of the lesion should be taken, where possible, and a summary of the results 
submitted to the Sponsor. 
Patients should be instructed to immediately inform their physician if new lesions 
develop.  Skin examination should be performed prior to initiation of dabrafenib and 
during treatment with dabrafenib, every 2 months throughout therapy.  Monitoring of 
the skin should continue every 2 to 3 months for 6 months following discontinuation of 
dabrafenib or until initiation of another anti-neoplastic therapy.
New Primary Melanoma
New primary melanomas have been reported in patients treated with dabrafenib.  These 
were identified primarily within the first 5 months of therapy and did not require 
treatment modification other than excision.  Monitoring for skin lesions should occur as 
described for cuSCC.
Non-Cutaneous Malignancies
In vitro experiments have demonstrated paradoxical activation of MAP-kinase 
signalling 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.  Patients should be monitored as clinically 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.
New non-cutaneous malignancies should be reported as a SAE. A biopsy of the new 
malignancy should be taken, where possible, and submitted for further analyses with the 
results provided to GSK.  Testing of these biopsies may include analysis of genomic 
alterations, which include but not limited to DNA, RNA and protein analysis of these 
biopsy specimens, and would analyze the biological pathways known to be associated 
with, and relevant to, BRAF-mutant tumor activation.  For any new non-cutaneous 
maligancy every effort should be made to identify the RAS mutation status and submit 
the results to GSK.
Refer to Appendix 6 for French country specific dermatological follow up. 
3.15.4
Prolonged QTc
Guidelines for dose modification and stopping criteria due to QTC-prolongation are 
provided in Section 3.11.2. 
4.1.1
Trametinib
PREVIOUS TEXT
Table 31
Investigational Product
REVISED TEXT
Table 14
Investigational Product - Trametinib
4.1.2
Dabrafenib
PREVIOUS TEXT


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This information will be provided in the amendment to open Part C.
REVISED TEXT
Dabrafenib
This information will be provided in the amendment to open Part C.
Table 15
Investigational Product - Dabrafenib
Formulation description:
Dabrafenib capsules
Dabrafenib powder for oral 
suspension
Dosage form:
Capsule
Powder for oral suspension
Unit dose strengths:
50 mg and 75 mg
150 mg (in stickpack)
10 mg/mL (as oral 
suspension)
Route/ Frequency:
Oral / BID 
Oral / BID
Physical description:
50 mg: opaque capsules composed of a dark 
red body and cap, each printed with one thick 
black line and one thin black line
75 mg: opaque capsules composed of pink 
body and cap, each printed with one thick 
black line and one thin black line
Supplied to clinical sites as a 
powder for oral suspension 
contained in white foil 
laminated stickpacks.
Manufacturer/
source of procurement:
GSK
GSK
Method for individualizing 
dosage:
Unit dose capsules
Administered using oral 
syringes
4.2.2
Dabrafenib
PREVIOUS TEXT
This information will be provided in the amendment to open Part C.


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REVISED TEXT
This information will be provided in the amendment to open Part C.
Preparation
No special preparation of study treatment is required for dabrafenib HPMC capsules.
Dabrafenib powder for oral suspension requires constitution with water at the time of 
use. Instructions for preparation of the dabrafenib suspension are provided in the SPM. 
Supplies for constitution and dosing will be supplied by GSK.
Study treatment must be dispensed or administered according to procedures described 
herein. Only subjects enrolled in the study may receive study treatment. Only 
authorized site staff may prepare and supply [administration will be performed by 
caretakers] study treatment. 
Handling
Investigational product is not expected to pose significant occupational safety risk to site 
staff under normal conditions of use and administration. Take adequate precautions to 
avoid direct eye or skin contact and the generation of aerosols or mists. Notify the 
monitor of any unintentional occupational exposure. A Material Safety Data Sheet 
(MSDS)/equivalent document describing occupational hazards and recommended 
handling precautions either will be provided to the investigator, where this is required 
by local laws, or is available upon request from GSK.
However, precautions are to be taken to avoid direct skin contact, eye contact, and 
generating aerosols or mists. In the case of unintentional occupational exposure notify 
the monitor, medical monitor and/or study manager.
Storage
All study treatment must be stored in a secure area with access limited to the 
investigator and authorized site staff.
Dabrafenib capsules are to be stored at room temperature up to 30C. Maintenance of a 
temperature log (manual or automated) is required.
Dabrafenib powder for oral suspension is to be stored at up to 30C. Maintenance of a 
temperature log (manual or automated) is required.
5.1
Number of Subjects
PREVIOUS TEXT
Approximately 94 subjects will be enrolled in the study (approximately 36 subjects in Part A, 
40 subjects in Part B, and 18 subjects in Part C)  In Part A during the age expansion cohort, 
every attempt will be made to enroll 4-6 subjects in each age group.  In Part B a minimum of 
10 subjects will be enrolled in each group with at least 4 in each cohort under the age of 6.  In 
Part C, no specific age expansion is planned but every attempt will be made to enroll at least 4 
children under the age of 12.
REVISED TEXT
Approximately 94 subjects will be enrolled in the study (approximately 36 subjects in Part A,
at least 40 subjects in Part B, and 18 subjects in Part C)  In Part A during the age expansion 
cohort, every attempt will be made to enroll 4-6 subjects in each age group.  In Part B a 


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minimum of 10 subjects will be enrolled in each group with at least 4 in each cohort under the 
age of 6.  In Part C, no specific age expansion is planned but every attempt will be made to 
enroll at least 4 children under the age of 12.
5.2.1.1
General Eligibility Criteria (All Parts)
PREVIOUS TEXT
6.
Females of child-bearing potential must be willing to practice acceptable methods of 
birth control (see Section 10.1).  Additionally, females of childbearing potential must have a 
negative serum pregnancy test within 7 days prior to start of study drugs, throughout 
treatment period and for 4 months after last dose of study drug.
REVISED TEXT
6.
Females of child-bearing potential must be willing to practice acceptable methods of 
birth control (see Section 10.1).  Additionally, females of childbearing potential must have a 
negative serum pregnancy test within 7 days prior to start of study drugs, throughout 
treatment period and for 4 months after last dose of study drugs.
5.2.1.3
Specific Eligibility Criteria, Part B
PREVIOUS TEXT
3.
BRAF Fusion Cohort (B2) Specific Criteria:

Relapsed or refractory gliomas or other primary brain tumors with BRAF 
fusion/duplication documented in Clinical Laboratory Improvement Amendments 
(CLIA) certified laboratory at diagnosis or relapse.  

Adequate hematologic function defined as:

Absolute neutrophil count (ANC) ≥1000/µL;

Hemoglobin ≥8.0 g/dL (may receive red blood cell transfusions)

Platelets ≥75,000/µL (transfusion independent, defined as not receiving platelet 
transfusions within a 7 day period prior to enrollment)
REVISED TEXT
3.
BRAF Fusion Cohort (B2) Specific Criteria:

Relapsed or refractory gliomas or other primary brain tumors with BRAF 
fusion/duplication (documented in Clinical Laboratory Improvement Amendments 
(CLIA) certified laboratory at diagnosis) or relapse NF1 subjects with gliomas who 
are not suitable for the NF1 with PN cohort.  

Adequate hematologic function defined as:

Absolute neutrophil count (ANC) ≥1000/µL;

Hemoglobin ≥8.0 g/dL (may receive red blood cell transfusions)


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
Platelets ≥75,000/µL (transfusion independent, defined as not receiving platelet 
transfusions within a 7 day period prior to enrollment)
PREVIOUS TEXT
4.
NF-1 Plexiform Neurofibroma Cohort (B3) Specific Criteria

Subjects with NF-1 must have a PN(s) that are progressive OR are cause of 
significant morbidity, such as (but not limited to) head and neck lesions that could 
compromise the airway or great vessels, brachial or lumbar plexus lesions that could 
cause nerve compression and loss of function, lesions that could result in major 
deformity (e.g., orbital lesions) or are significantly disfiguring, lesions of the 
extremity that cause limb hypertrophy or loss of function, and painful lesions.  
Subjects with paraspinal PN will be eligible for this trial. Histologic confirmation of 
tumor is not necessary in the presence of consistent clinical and radiographic findings, 
but should be considered if malignant degeneration of a PN is clinically suspected.

A PN is defined as a neurofibroma that has grown along the length of a nerve and 
may involve multiple fascicles and branches.  A spinal PN involves two or more 
levels with connection between the levels or extending laterally along the nerve.

For subjects enrolled for tumor progression, progression is defined as: 

Presence of new PN on MRI or CT (documented by comparison with prior 
MRI or CT), OR

A measurable increase in PN size (≥ 20% increase in the volume, or a ≥ 13% 
increase in the product of the two longest perpendicular diameters, or a ≥ 6% 
increase in the longest diameter) documented by comparison of two scans 
(MRI or CT) in the time period of approximately one year or less prior to 
evaluation for this study.

For subjects enrolled for a “major deformity” or “significantly disfiguring” tumor, 
eligible tumors will be limited to tumors of the head & neck or those on other areas of 
the body that are unable to be concealed by standard garments.  

All subjects must have either the clinical diagnosis of NF-1 using the National 
Institutes of Health (NIH) Consensus Conference criteria or have a constitutional NF-
1 mutation documented in a CLIA/College of American Pathologist (CAP) certified 
lab.

Subjects must have measurable PN(s) amenable to volumetric MRI analysis. For the 
purpose of this study, the target lesion must be seen on at least 3 consecutive MRI 
slices and the field of view must contain the entire tumor of interest.  Tumors must be 
at least 3 mL in volume (most PNs 3 cm in longest diameter will meet this criteria).  
If the tumor is <3 cm in longest diameter, the subject may still be eligible.  Central 


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review of the MRI of the target PN is required prior to enrollment to ensure that the 
tumor is measurable and amenable to volumetric analysis.  After consenting, please 
follow instructions in Appendix 6 or the SPM for central review of MRI.  Central 
review will take 3-7 days (please plan accordingly).

Adequate hematologic function defined as:
Absolute neutrophil count (ANC) ≥1000/µL;
Hemoglobin ≥8.0 g/dL (may receive red blood cell transfusions)
Platelets ≥75,000/µL (transfusion independent, defined as not receiving platelet
transfusions within a 7 day period prior to enrollment)

Subjects with NF-1 will only be eligible if complete tumor resection is not feasible, or 
if a subject with a surgical option refuses surgery.

Since there is no standard effective chemotherapy for subjects with NF-1 and 
PN, subjects may be treated on this trial without having received prior medical 
therapy directed at their PN.

Must not have received myelosuppressive chemotherapy within prior 4 weeks.

Must be at least 2 weeks since undergoing major surgery and must be 
recovered from effects of surgery.

Subjects who have received previous investigational agents or biologic 
therapy, such as tipifarnib, pirfenidone, Peg-Intron, sorefenib, imatinib or 
vascular endothelial growth factor receptor (VEGFR) or MEK inhibitors are 
eligible for enrolment if general eligibility criteria are met.

Subjects who have received therapy for PN that included other MAPK/MEK 
/RAS inhibitors are eligible for this study.
REVISED TEXT
4.
NF-1 Plexiform Neurofibroma Cohort (B3) Specific Criteria

Subjects with NF-1 must have a PN(s) that are progressive OR are cause of significant 
morbidity, such as (but not limited to) head and neck lesions that could compromise 
the airway or great vessels, brachial or lumbar plexus lesions that could cause nerve 
compression and loss of function, lesions that could result in major deformity (e.g., 
orbital lesions) or are significantly disfiguring, lesions of the extremity that cause limb 
hypertrophy or loss of function, and painful lesions.  Subjects with paraspinal PN will 
be eligible for this trial. Histologic confirmation of tumor is not necessary in the 
presence of consistent clinical and radiographic findings, but should be considered if 
malignant degeneration of a PN is clinically suspected.


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
A PN is defined as a neurofibroma that has grown along the length of a nerve and may 
involve multiple fascicles and branches.  A spinal PN involves two or more levels with 
connection between the levels or extending laterally along the nerve.

For subjects enrolled for tumor progression, progression is defined as: 

Presence of new PN on MRI or CT (documented by comparison with prior 
MRI or CT), OR

A measurable increase in PN size (≥ 20% increase in the volume, or a ≥ 13% 
increase in the product of the two longest perpendicular diameters, or a ≥ 6% 
increase in the longest diameter) documented by comparison of two scans 
(MRI or CT) in the time period of approximately one year or less prior to 
evaluation for this study.

For subjects enrolled for a “major deformity” or “significantly disfiguring” tumor, 
eligible tumors will be limited to tumors of the head & neck or those on other areas of 
the body that are unable to be concealed by standard garments.  

All subjects must have either the clinical diagnosis of NF-1 using the National 
Institutes of Health (NIH) Consensus Conference criteria or have a constitutional NF-1 
mutation documented in a CLIA/College of American Pathologist (CAP) certified lab.

Subjects must have measurable PN(s) amenable to volumetric MRI analysis. For the 
purpose of this study, the target lesion must be seen on at least 3 consecutive MRI 
slices and the field of view must contain the entire tumor of interest.  Tumors must be 
at least 3 mL in volume (most PNs 3 cm in longest diameter will meet this criteria).  If 
the tumor is <3 cm in longest diameter, the subject may still be eligible.  Central 
review of the MRI of the target PN is required prior to enrollment to ensure that the 
tumor is measurable and amenable to volumetric analysis.  After consenting, please 
follow instructions in Appendix 6 or the SPM for central review of MRI.  Central 
review will take 3-7 days (please plan accordingly).

Adequate hematologic function defined as:

Absolute neutrophil count (ANC) ≥1000/µL;

Hemoglobin ≥8.0 g/dL (may receive red blood cell transfusions)

Platelets ≥75,000/µL (transfusion independent, defined as not receiving platelet 
transfusions within a 7 day period prior to enrollment)

Subjects with NF-1 and PN will only be eligible if complete tumor resection is not 
feasible, or if a subject with a surgical option refuses surgery.


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
Since there is no standard effective chemotherapy for subjects with NF-1 and 
PN, subjects may be treated on this trial without having received prior medical 
therapy directed at their PN.

Must not have received myelosuppressive chemotherapy within prior 4 weeks.

Must be at least 2 weeks since undergoing major surgery and must be 
recovered from effects of surgery.

Subjects who have received previous investigational agents or biologic 
therapy, such as tipifarnib, pirfenidone, Peg-Intron, sorefenib, imatinib or 
vascular endothelial growth factor receptor (VEGFR) or MEK inhibitors are 
eligible for enrolment if general eligibility criteria are met.

Subjects who have received therapy for PN that included other MAPK/MEK 
/RAS inhibitors are eligible for this study.
5.2.2
Exclusion Criteria (All Parts)
PREVIOUS TEXT
6.
Subjects with NF-1 and only PN lesions that cannot be evaluated by volumetric analysis.
10. Part B and Part C only:  Previous treatment with dabrafenib (cohort B4), trametinib or 
another MEK inhibitor (exception: prior treatment with sorafenib is permitted)
19. A history of known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or 
Hepatitis C Virus (HCV) infection. Subjects with laboratory evidence of cleared HBV 
and HCV infection may be enrolled.
REVISED TEXT
6.
Subjects with NF-1 and only PN lesions that cannot be evaluated by volumetric analysis
(only applicable to Part B). 
10. Part B and Part C only:  Previous treatment with dabrafenib (cohort B4), or any RAF 
inhibitor, trametinib or another MEK inhibitor, or an ERK inhibitor (exception: prior 
treatment with sorafenib is permitted). Patients who have received prior dabrafenib or 
another BRAF inhibitor may enrol into Part B4.  Patients who have had prior 
dabrafenib or BRAF inhibitor therapy may enroll in part C if they have had prior 
benefit to dabrafenib or BRAF inhibitor monotherapy, as determined by the 
investigator.


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19. A history of known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or 
Hepatitis C Virus (HCV) infection. Subjects with laboratory evidence of cleared HBV 
and HCV infection may be enrolled.




























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7.3.2
Ophthalmology Examination
PREVIOUS TEXT
An age-appropriate ophthalmologic examination should be performed by an ophthalmologist 
at screening and at the timepoints specified in the Time and Events Tables (Section 7.1).
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).
For subjects with clinical suspicion of RVO or RPED, fundus photography, fluorescein 
angiography, and/or optical coherence tomography are highly recommended.
REVISED TEXT
An age-appropriate ophthalmologic examination should be performed by an ophthalmologist 
at screening and at the timepoints specified in the Time and Events Tables (Section 7.1).
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).
For subjects with clinical suspicion of RVO or RPED, fundus photography, fluorescein 
angiography, and/or optical coherence tomography are highly recommended.


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7.3.7
Laboratory Assessments
PREVIOUS TEXT
Table 34
List of Clinical Laboratory Tests
Hematology
Platelet Count
RBC Indices:
Automated WBC Differential:
Red blood cell (RBC) Count
MCV
Neutrophils
White blood cell (WBC) Count 
(absolute) 
MCH
Lymphocytes
Hemoglobin
MCHC
Monocytes
Hematocrit
Eosinophils
HbA1c
Basophils
Clinical Chemistry
Blood urea nitrogen 
(BUN)
Potassium
Aspartate aminotransferase 
(AST)
Total and direct bilirubin (Bilirubin 
fractionation recommended if 
total bilirubin is >2x the upper 
limit of normal)
Creatinine
Chloride
Alanine aminotransferase (ALT)
Total Protein
Glucose (recheck 
fasting 
if >160 mg/dL)
Total carbon 
dioxide (CO2)
Gamma glutamyl transferase 
(GGT)
Albumin
Sodium
Calcium
Alkaline phosphatase (ALP)
Magnesium
Phosphate
Routine Urinalysis
Specific gravity
pH, glucose, protein, blood and ketones by dipstick
Microscopic examination (if blood or protein is abnormal)
Urine Protein Creatinine – Part C only
Other screening tests
Serum pregnancy test
HVA/VMA in random or 24 hr urine for subjects with neuroblastoma
In the event of abdominal pain or suspected pancreatitis, amylase and lipase laboratory samples should be 
collected.
RBC = Red Blood Cell; WBC = White Blood Cell; MCV = Mean Corpuscular Volume; MCH = Mean Corpuscular Hemoglobin:  
MCHC = Mean Corpuscular Hemoglobin Concentration; HVA/VMA = Homovanillic Acid / Vanillylmandelic Acid (ratio); CSF = 
Cerebrospinal fluid.


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REVISED TEXT
Table 21
List of Clinical Laboratory Tests
Hematology
Platelet Count
RBC Indices:
Automated WBC Differential:
Red blood cell (RBC) Count
MCV
Neutrophils
White blood cell (WBC) Count 
(absolute) 
MCH
Lymphocytes
Hemoglobin
MCHC
Monocytes
Hematocrit
Eosinophils
HbA1c
Basophils
Clinical Chemistry
Blood urea nitrogen 
(BUN)
Potassium
Aspartate aminotransferase 
(AST)
Total and direct bilirubin (Bilirubin 
fractionation recommended if 
total bilirubin is >2x the upper 
limit of normal)
Creatinine
Chloride
Alanine aminotransferase (ALT)
Total Protein
Glucose (recheck 
fasting 
if >160 mg/dL)
Total carbon 
dioxide (CO2)
Gamma glutamyl transferase 
(GGT)
Albumin
Sodium
Calcium
Alkaline phosphatase (ALP)
Magnesium
Phosphate
Routine Urinalysis
Specific gravity
pH, glucose, protein, blood and ketones by dipstick
Microscopic examination (if blood or protein is abnormal)
Urine Protein Creatinine Part C only
Other screening tests
Serum pregnancy test
HVA/VMA in random or 24 hr urine for subjects with neuroblastoma
In the event of abdominal pain or suspected pancreatitis, amylase and lipase laboratory samples should be 
collected.
RBC = Red Blood Cell; WBC = White Blood Cell; MCV = Mean Corpuscular Volume; MCH = Mean Corpuscular Hemoglobin:  
MCHC = Mean Corpuscular Hemoglobin Concentration; HVA/VMA = Homovanillic Acid / Vanillylmandelic Acid (ratio); CSF = 
Cerebrospinal fluid.






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Results in disability/incapacity, or
NOTE:  The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions.  This definition is not intended to include experiences of 
relatively minor medical significance such as uncomplicated headache, nausea, vomiting, 
diarrhea, influenza, and accidental trauma (e.g., sprained ankle) which may interfere or 
prevent everyday life functions but do not constitute a substantial disruption.
Is a congenital anomaly/birth defect.
Medical or scientific judgment should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
subject or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition.  These should also be considered serious.  
Examples of such events are invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions 
that do not result in hospitalization, or development of drug dependency or drug abuse.
Protocol-Specific SAEs:

All events of possible study treatment-induced liver injury with hyperbilirubinemia 
defined as alanine aminotransferase (ALT) 3 times ULN and bilirubin ≥2 times ULN 
(>35% direct) (or ALT ≥3 times ULN and international normalization ratio 
(INR) >1.5, if INR is measured) or termed ‘Hy’s Law’ events (INR measurement is 
not required and the threshold value stated will not apply to subjects receiving 
anticoagulants).
NOTE:  Bilirubin fractionation is performed if testing is available.  If testing is not 
available, record presence of detectable urinary bilirubin on dipstick indicating direct 
bilirubin elevations and suggesting liver injury.  If testing is unavailable and a subject 
meets the criterion of total bilirubin ≥2 times ULN, then the event is still reported as a 
SAE.  If INR is obtained, include values on the SAE form.  INR elevations >1.5
suggest severe liver injury.

Any new primary malignancy with a histology different from the primary tumor.

LVEF that meets stopping criteria.

RPED or RVO.

Pyrexia accompanied by ≥ Grade 3 hypotension or hypotension that is clinically 
significant in the judgement of the investigator, or dehydration requiring IV fluids for 
greater than 72 hours, or severe rigors/chills.
REVISED TEXT
An SAE is any untoward medical occurrence that, at any dose:
Results in death
Is life-threatening


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NOTE:  The term 'life-threatening' in the definition of 'serious' refers to an event in 
which the subject was at risk of death at the time of the event.  It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
Requires hospitalization or prolongation of existing hospitalization
NOTE:  In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or out-
subject setting.  Complications that occur during hospitalization are AEs.  If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious.  When in doubt as to whether “hospitalization” occurred or was necessary, the 
AE should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE.
Results in disability/incapacity, or
NOTE:  The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions.  This definition is not intended to include experiences of 
relatively minor medical significance such as uncomplicated headache, nausea, vomiting, 
diarrhea, influenza, and accidental trauma (e.g., sprained ankle) which may interfere or 
prevent everyday life functions but do not constitute a substantial disruption.
Is a congenital anomaly/birth defect.
Medical or scientific judgment should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
subject or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition.  These should also be considered serious.  
Examples of such events are invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions 
that do not result in hospitalization, or development of drug dependency or drug abuse.
Protocol-Specific SAEs:

All events of possible study treatment-induced liver injury with hyperbilirubinemia 
defined as alanine aminotransferase (ALT) 3 times ULN and bilirubin ≥2 times ULN 
(>35% direct) (or ALT ≥3 times ULN and international normalization ratio 
(INR) >1.5, if INR is measured) or termed ‘Hy’s Law’ events (INR measurement is 
not required and the threshold value stated will not apply to subjects receiving 
anticoagulants).
NOTE:  Bilirubin fractionation is performed if testing is available.  If testing is not 
available, record presence of detectable urinary bilirubin on dipstick indicating direct 
bilirubin elevations and suggesting liver injury.  If testing is unavailable and a subject 
meets the criterion of total bilirubin ≥2 times ULN, then the event is still reported as a 
SAE.  If INR is obtained, include values on the SAE form.  INR elevations >1.5 
suggest severe liver injury.


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
Any new primary malignancy with a histology different from the primary tumor.

LVEF that meets stopping criteria.

RPED or RVO.

Pyrexia accompanied by ≥ Grade 3 hypotension or hypotension that is clinically 
significant in the judgement of the investigator, or dehydration requiring IV fluids for 
greater than 72 hours, or severe rigors/chills.
8.2.1 
Sentinel Events
PREVIOUS TEXT
A Sentinel Event is a GSK-defined SAE that is not necessarily drug-related but has been 
associated historically with adverse reactions for other drugs and is therefore worthy of 
heightened pharmacovigilance.  The GSK Medical Monitor is accountable for reviewing all 
SAEs for possible Sentinel Events which is mandated at GSK.  The GSK medical monitor 
may request additional clinical information on an urgent basis if a possible Sentinel Event is 
identified on SAE review.  The current GSK-defined Sentinel Events are listed below:

Acquired Long QT Syndrome

Agranulocytosis/Severe Neutropenia 

Anaphylaxis & Anaphylactoid Reactions 

Hepatotoxicity

Acute Renal Failure

Seizure

Stevens Johnson syndrome/Toxic epidermal necrosis
REVISED TEXT
Section 8.2.1 has been removed completely.
8.3
Laboratory and Other Safety Assessment Abnormalities Reported as 
AEs and SAEs
PREVIOUS TEXT
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis), or other 
safety assessments (e.g., ECGs, radiological scans, vital signs measurements) including those 
that worsen from baseline, and events felt to be clinically significant in the medical and 
scientific judgment of the investigator are to be recorded as an AE or SAE, in accordance with 
the definitions provided.
In addition, an associated AE or SAE is to be recorded for any laboratory test result or other 
safety assessment that led to an intervention, including permanent discontinuation of study 
treatment, dose reduction, and/or dose interruption/delay.


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Any new primary cancer must be reported as a SAE.
However, any clinically significant safety assessments that are associated with the underlying 
disease, unless judged by the investigator to be more severe than expected for the subject's 
condition, are not to be reported as AEs or SAEs.
REVISED TEXT
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis), or other 
safety assessments (e.g., ECGs, radiological scans, vital signs measurements) including those 
that worsen from baseline, and events felt to be clinically significant in the medical and 
scientific judgment of the investigator are to be recorded as an AE or SAE, in accordance with 
the definitions provided.
In addition, an associated AE or SAE is to be recorded for any laboratory test result or other 
safety assessment that led to an intervention, including permanent discontinuation of study 
treatment, dose reduction, and/or dose interruption/delay.
Any new primary cancer must be reported as a SAE.
However, any clinically significant safety assessments that are associated with the underlying 
disease, unless judged by the investigator to be more severe than expected for the subject's 
condition, are not to be reported as AEs or SAEs.
12.2.2
Part B: Expansion Cohort
PREVIOUS TEXT
The sample size for Part B is s based on feasibility, practicality, and what would be sufficient 
for the characterization of the safety of trametinib and the plasma PK for the populations 
enrolled.  Each of the 4 expansion cohorts will enroll at least 10 evaluable subjects, 5 subjects 
in each cohort will be under the age of 6 years.  Therefore, an estimated 40 subjects will be 
enrolled into Part B.
If less than 1 response is observed after 10 subjects complete the study, the treatment could be 
considered to have insufficient clinical activity in that cohort.  The estimated sample size 
(n=10) for the Part 2 expansion cohorts was further evaluated using exact binominal 
distribution probabilities, and the details are provided in Table 22.  For example, if zero 
responses are observed among 10 subjects in a cohort [if the response rate (RR)=5%], the 
chance of declaring the cohort as having insufficient clinical activity after 10 subjects is 60%.  
If the true RR=15% for GSK1120212 in unresectable low grade gliomas subjects, the chance 
of declaring the cohort as having insufficient clinical activity after 10 subjects is 
approximately 20%.
REVISED TEXT
The sample size for Part B is s based on feasibility, practicality, and what would be sufficient 
for the characterization of the safety of trametinib and the plasma PK for the populations 
enrolled.  Each of the 4 expansion cohorts will enroll at least 10 evaluable subjects, 5 subjects 
in each cohort will be under the age of 6 years.  Therefore, an it is estimated that at least 40 
subjects will be enrolled into Part B.
If less than 1 response is observed after 10 subjects complete the study, the treatment could be 
considered to have insufficient clinical activity in that cohort.  The estimated sample size 


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(n=10) for the Part 2 expansion cohorts was further evaluated using exact binominal 
distribution probabilities, and the details are provided in Table 27.  For example, if zero 
responses are observed among 10 subjects in a cohort [if the response rate (RR)=5%], the 
chance of declaring the cohort as having insufficient clinical activity after 10 subjects is 60%.  
If the true RR=15% for GSK1120212 in unresectable low grade gliomas subjects, the chance 
of declaring the cohort as having insufficient clinical activity after 10 subjects is 
approximately 20%.
12.5.2.3
Clinical Laboratory Evaluations
PREVIOUS TEXT
Hematology and clinical chemistry data will be summarized using frequencies and 
proportions according to NCI-CTCAE v4.03 [NCI, 2009].  Laboratory test results outside the 
reference ranges that do not have associated NCI-CTCAE v4.03 criteria will be summarized 
using proportions.  Further details will be provided in the RAP.
REVISED TEXT
Hematology and, clinical chemistry and urinalysis data will be summarized using 
frequencies and proportions according to NCI-CTCAE v4.03 [NCI, 2009].  Laboratory test 
results outside the reference ranges that do not have associated NCI-CTCAE v4.03 criteria 
will be summarized using proportions.  Further details will be provided in the RAP.
15.2
Appendix 2:  Dosing Nomograms
PREVIOUS TEXT
DOSE LEVEL:
0.0125 mg/kg/dose 
SUBJECT WEIGHT: 
             ≤ 19.4 kg
FORMULATION:
TRAMETINIB 0.05 MG/ML 
ORAL SOLUTION
[The 0.05 mg/mL oral solution will be administered to all patients 
≤19.4 kg]
REVISED TEXT
Dosing nomogram - Trametinib
DOSE LEVEL:
0.0125 mg/kg/dose 
SUBJECT WEIGHT: 
≤ 19.4 kg
FORMULATION:
TRAMETINIB 0.05 MG/ML ORAL 
SOLUTION
[The[At this dose level, the 0.05 mg/mL oral solution will be 
administered to all patients ≤19.4 kg]
PREVIOUS TEXT
DOSE LEVEL:
0.025 mg/kg/dose 
SUBJECT WEIGHT: 
             < 10 kg
FORMULATION:
TRAMETINIB 0.05 MG/ML 
ORAL SOLUTION
[The 0.05 mg/mL oral solution will be administered to all patients ≤9.9 
kg]


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REVISED TEXT
DOSE LEVEL:
0.025 mg/kg/dose 
SUBJECT WEIGHT: 
< 10 kg
FORMULATION:
TRAMETINIB 0.05 MG/ML ORAL 
SOLUTION
[The[At this dose level, the 0.05 mg/mL oral solution will be 
administered to all patients ≤9.9 kg]


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PREVIOUS TEXT
DOSE LEVEL:
0.04 mg/kg/dose 
SUBJECT WEIGHT: 
             < 10 kg
FORMULATION:
TRAMETINIB 0.05 MG/ML 
ORAL SOLUTION
[The 0.05 mg/mL oral solution will be administered to all patients ≤9.9 
kg]
REVISED TEXT
DOSE LEVEL:
0.04 mg/kg/dose 
SUBJECT WEIGHT: 
< 10 kg
FORMULATION:
TRAMETINIB 0.05 MG/ML ORAL 
SOLUTION
[The[At this dose level, the 0.05 mg/mL oral solution will be 
administered to all patients ≤9.9 kg]
Additional New Text in Section 15.2
Dosing Nomogram - Dabrafenib
Dabrafenib Suspension Dosing Nomogram
Dose Level 1
< 12 year olds
≥ 12 year olds
Daily dose: 2.63 mg/kg dabrafenib suspension
Daily dose: 2.25 mg/kg dabrafenib suspension
Body 
weight 
(kg)
Unit 
dose 
(mg)
Dosing 
volume 
(mL)
Syringe 
size 
(mL)
No. of 
stickpacks
Body 
weight 
(kg)
Unit 
dose 
(mg)
Dosing 
volume 
(mL)
Syringe 
size 
(mL)
No. of 
stickpacks
10-11
14
1.4
5
1
10-11
12
1.2
5
1
12-13
16
1.6
5
1
12-13
14
1.4
5
1
14
18
1.8
5
1
14-15
16
1.6
5
1
15-16
20
2.0
5
1
16
18
1.8
5
1
17
22
2.2
5
1
17-18
20
2.0
5
1
18-19
24
2.4
5
1
19-20
22
2.2
5
1
20
26
2.6
5
1
21-22
24
2.4
5
1
21-22
28
2.8
5
1
23
26
2.6
5
1
23
30
3.0
5
1
24-25
28
2.8
5
1
24-25
32
3.2
5
1
26-27
30
3.0
5
1
26
34
3.4
5
1
28-29
32
3.2
5
1
27-28
36
3.6
5
1
30-31
34
3.4
5
1
29
38
3.8
5
1
32
36
3.6
5
1
30-31
40
4.0
5
1
33-34
38
3.8
5
1
32-47
50
5.0
5
1
35-36
40
4.0
5
1
48-71
75
7.5
20
1
37-38
42
4.2
5
1
72-94
100
10.0
20
1
39-55
50
5.0
5
1


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Protocol No CTMT212X2101
Dose Level 1
< 12 year olds
≥ 12 year olds
Daily dose: 2.63 mg/kg dabrafenib suspension
Daily dose: 2.25 mg/kg dabrafenib suspension
Body 
weight 
(kg)
Unit 
dose 
(mg)
Dosing 
volume 
(mL)
Syringe 
size 
(mL)
No. of 
stickpacks
Body 
weight 
(kg)
Unit 
dose 
(mg)
Dosing 
volume 
(mL)
Syringe 
size 
(mL)
No. of 
stickpacks
95-118
125
12.5
20
2
56-83
75
7.5
20
1
≥ 119
150
15.0
20
2
84-111
100
10
20
1
112-138
125
12.5
20
2
≥ 139
150
15.0
20
2
Dose Level 2
< 12 year olds
≥ 12 year olds
Daily dose: 5.25 mg/kg dabrafenib suspension
Daily dose: 4.5 mg/kg dabrafenib suspension
Body 
weight 
(kg)
Unit 
dose 
(mg)
Dosing 
volume 
(mL)
Syringe 
size 
(mL)
No. of 
stickpack
Body 
weight 
(kg)
Unit 
dose 
(mg)
Dosing 
volume 
(mL)
Syringe 
size 
(mL)
No. of 
stickpack
10
26
2.6
5
1
10
22
2.2
5
1
11
28
2.8
5
1
11
24
2.4
5
1
12
32
3.2
5
1
12
28
2.8
5
1
13
34
3.4
5
1
13
30
3.0
5
1
14
36
3.6
5
1
14
32
3.2
5
1
15
40
4.0
5
1
15
34
3.4
5
1
16-23
50
5.0
5
1
16
36
3.6
5
1
24-33
75
7.5
20
1
17
38
3.8
5
1
34-42
100
10.0
20
1
18
40
4.0
5
1
43-52
125
12.5
20
2
19-27
50
5.0
5
1
≥ 53
150
15.0
20
2
28-38
75
7.5
20
1
39-50
100
10.0
20
1
51-61
125
12.5
20
2
≥ 62
150
15.0
20
2






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Protocol No CTMT212X2101
procedures, invasive tests, or change in existing therapy), will be reported promptly to 
Novartis, as indicated in.
SAEs will be collected over the same time period as stated above for AEs.  In addition, any 
SAE assessed as related to study participation (e.g., protocol mandated procedures, invasive 
tests, or change in existing therapy), study treatment or GSK concomitant medication must be 
recorded from the time a subject consents to participate in the study up to and including any 
follow up contact.  All SAEs will be reported to GSK within 24 hr, as indicated in Section 
8.4.2. 
Reason for change:
Change in study sponsorship.
Section: Prompt Reporting of SAEs and Other Events to GSK: 
Text changed in Table 23:
Pregnancy
2 weeks
24 hours
Pregnancy Notification Form
2 Weeks
Pregnancy 
Follow-up Form
Reason for change:
Change in study sponsorship.
Section: Data Management: 
Text changed:
For this study subject data will be entered into GSK definedthe  eCRFs, transmitted 
electronically to GSKthe sponsor or designee and be combined with data provided from 
other sources in a validated data system.
Management of clinical data will be performed in accordance with applicable GSK standards 
and data cleaning procedures to ensure the integrity of the data, e.g., removing resolving
errors and inconsistencies in the data.  Adverse events and concomitant medications terms 
will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) and an 
internal validated medicationa custom drug dictionary, GSKDrug. The eCRFs (including 
queries and audit trails) will be retained by GSK, and copies will be sent to the investigator to 
maintain as the investigator copy. 
Reason for change:
Change in study sponsorship.
Section: Quality Control (Study Monitoring): 
In accordance with applicable regulations, Good Clinical Practice (GCP) and GSKNovartis 
personnel (or designated Clinical Research Organization [CRO]) will contact the site
procedures, the site will be contacted prior to the start of the study to review with the site staff 
the protocol, study requirements, and their responsibilities to satisfy regulatory, ethical, and 
GSKNovartis requirements.
Novartis (or designated CRO) personnel will monitor the studyMonitoring visits will be 
conducted in a manner to ensure that the:
Text changed:
Reason for change:
Change in study sponsorship.
Section: Study and Site Closure: 


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Upon completion or termination of the study, Novartis personnel (or designated CRO)the 
monitor will conduct site closure activities with the investigator or site staff (as appropriate), 
in accordance with applicable regulations, ICH GCP, and GSKNovartis Standard Operating 
Procedures.
Text changed:
Reason for change:
Change in study sponsorship.
Section: Records Retention: 
GSK will inform the investigator of the time period for retaining the site records in order to 
comply with all applicable regulatory requirements.  The minimum retention time will meet 
the strictest standard applicable to a particular site, as dictated by local laws/regulations, GSK 
standard operating procedures, and/or institutional requirements.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 the 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.
Text changed:
Reason for change:
Change in study sponsorship.
Section: Provision of Study Results to Investigators, Posting of Information on 
Publicly Available Clinical Trials Registers and Publication: 
The results summary will be posted to the GSK Clinical Study Register no later than 8 months 
after the final primary completion date, the date that the final subject was examined or 
received an intervention for the purposes of final collection of data for the primary outcome.  
In addition, a manuscript will be submitted to a peer reviewed journal for publication no later 
than 18 months after the last subject’s last visit (LSLV).  When manuscript publication in a 
peer reviewed journal is not feasible, a statement will be added to the register to explain the 
reason for not publishing.Novartis aims to post a results summary to the Novartis Clinical 
Trial Results website (novartisclinicaltrials.com) and other publicly available registers 
no later than twelve (12) months after the last subject’s last visit (LSLV). In addition, 
upon study completion and finalization of study report, Novaris aims to submit results of 
the study for publication. When publication is not feasible, please refer to the Novartis 
Clinical Trial Results website (www.novartisclinicaltrials.com) for a summary of the 
trial results.
Text changed:
Reason for change:
Change in study sponsorship.

SAP_001.pdf: 






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Table of contents
Table of contents .................................................................................................................4
List of abbreviations............................................................................................................6
1
Introduction .........................................................................................................................8
1.1
Study design.............................................................................................................8
1.2
Study objectives and endpoints .............................................................................10
2
Statistical methods.............................................................................................................12
2.1
Data analysis general information .........................................................................12
2.1.1
General definitions................................................................................13
2.2
Analysis sets ..........................................................................................................15
2.2.1
Subgroup of interest ..............................................................................17
2.3
Patient disposition, demographics and other baseline characteristics ...................18
2.3.1
Patient disposition.................................................................................19
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................19
2.4.1
Study treatment / compliance................................................................19
2.4.2
Prior, concomitant and post therapies...................................................22
2.5
Analysis of the primary objective..........................................................................23
2.5.1
Primary endpoint...................................................................................24
2.5.2
Statistical hypothesis, model, and method of analysis..........................24
2.5.3
Handling of missing values/censoring/discontinuations.......................24
2.6
Analysis of the key secondary objective ...............................................................24
2.7
Analysis of secondary efficacy objective(s)..........................................................24
2.7.1
Secondary endpoints .............................................................................25
2.7.2
Statistical hypothesis, model, and method of analysis..........................27
2.7.3
Handling of missing values/censoring/discontinuations.......................27
2.7.4
Supportive analyses...............................................................................28
2.8
Safety analyses.......................................................................................................28
2.8.1
Adverse events (AEs)............................................................................29
2.8.2
Deaths....................................................................................................31
2.8.3
Laboratory data .....................................................................................31
2.8.4
Other safety data ...................................................................................33
2.8.5
Vital signs..............................................................................................35
2.9
Pharmacokinetic endpoints....................................................................................37
39
2.11
Interim analysis......................................................................................................44
3
Sample size calculation .....................................................................................................44


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4
Change to protocol specified analyses ..............................................................................48
5
Appendix ...........................................................................................................................48
5.1
Imputation rules.....................................................................................................48
5.1.1
Study drug.............................................................................................48
5.1.2
AE, ConMeds and safety assessment date imputation..........................49
5.1.3
Other imputations..................................................................................50
5.1.4
Age calculation in Lab data...................................................................50
5.2
AEs coding/grading ...............................................................................................51
5.3
Laboratory parameters derivations ........................................................................52
5.4
Statistical models...................................................................................................53
5.4.1
Primary analysis....................................................................................53
5.4.2
Key secondary analysis.........................................................................53
53
6
Reference...........................................................................................................................54


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List of abbreviations
AE
Adverse Event
ADaM
Analysis Data Model
AESI
Adverse Events of Special Interest
ATC
Anatomical Therapeutic Chemical
AUC
Area Under the Curve
BOR
Best Overall Response
CI
Confidence Interval
COVID-19
Coronavirus Disease-2019
CR
Complete Response
CSR
Clinical Study Report
CTCAE
Common Terminology Criteria for Adverse Events
DBL
Database Lock
DI
Dose Intensity
DLT
Dose Limiting Toxicity
ECG
Electrocardiogram
ECHO
Echocardiogram
ECOG
Easter Cooperative Oncology Group
eCRF
Electronic Case Report Form
GSK
GlaxoSmithKline
IDMC
Independent Data Review Committee
ITT
Intent to Treat
LDH
Lactate Dehydrogenase
LLN
Lower Limit of Normal
LVEF
Left Ventricular Ejection Fraction
MAPK
Mitogen-activated protein kinase
MedDRA
Medical Dictionary for Medical Affairs
NCI
National Cancer Institutes
NF-1
Neurofibromatosis Type – 1
ORR
Overall Response Rate
OS
Overall Survival
PAS
Pharmacokinetic Analysis Set
PCI
Potential Clinical Importance
PD
Progressive Disease
PGx
Pharmacogenetics
PK
Pharmacokinetics
PN
Plexiform Neurofibromas
PR
Partial Response
PT
Preferred Term


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RANO
Response Assessment in Neuro-Oncology
RDI
Relative Dose Intensity
RECIST
Response Evaluation Criteria in Solid Tumors
RP2D
Recommended Phase 2 Dose
RR
Response Rate
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SD
Stable Disease
SOC
System Organ Class
SOP
Standard Operating Procedure
SRT
Safety Review Team
TBIL
Total Bilirubin
ULN
Upper Limit of Normal
WBC
White Blood Count


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1
Introduction
This statistical analysis plan (SAP) details all planned analyses required for a Clinical Study 
Report (CSR) of study CTMT212X2101(MEK116540). This is a phase I/II study to evaluate 
safety, pharmacokinetics, pharmacodynamics and clinical activity of the MEK inhibitor 
trametinib in children and adolescent patients with cancer or plexiform neurofibromas and 
trametinib in combination with dabrafenib in children and adolescents with cancers harboring 
V600 mutations using an open label, dose-escalation design. This SAP will be used for the final 
analysis.
The content of this SAP is based on protocol MEK116540 (CTMT212X2101) amendment 09. 
The SAP has been written in accordance with Novartis SOPs only. All decisions regarding 
final analysis, as defined in this SAP document, have been made prior to Database Lock
(DBL) of the study data. 
1.1
Study design
This is a 4-part (Part A, Part B, Part C and Part D), Phase I/IIa, multi-center, open label, study 
in pediatric subjects with refractory or recurrent tumors.
Part A will be a pharmacokinetically driven limited dose escalation (i.e., 0.0125, 0.025 and 
0.04 mg/kg/day) in subjects and will include an expansion for safety, tolerability, and 
pharmacokinetics (PK) in three age ranges (1 month to <2years, 2 to ≤12 years, and over 12 
years of age). The primary goal of Part A is to establish the toxicity profile, PK, and 
recommended Phase 2 dose (RP2D) of trametinib in each age cohort. Approximately 18 
subjects will be accrued to the dose escalation phase and 18 subjects to the age expansion 
phase. 
Part A extension will be an age-specific dose exploration in up to 12 subjects aged 1 
month to < 6 years old. Preliminary PK analysis of pediatric patients in this current study 
suggests that for patients < 6 years old, an intermediate dose (i.e., 0.032 mg/kg/day) may 
increase the proportion of these patients who achieves exposures similar to adults. The 
goal of this additional dose exploration is to establish the safety, tolerability, PK and 
further refine the RP2D of trametinib in this younger age cohort. 
Part B will be a tumor cohort expansion part of the study to further evaluate the safety, 
tolerability, and preliminary clinical activity of trametinib at the dose determined in Part A in 
tumor-specific pediatric populations. Disease cohorts are selected based on current data of 
proto-oncogene RAS (Ras)/ mitogen-activated protein kinase (MAPK) activation in childhood 
solid tumors. At least forty subjects are planned for Part B, 10 subjects in each of 4 disease 
cohorts.

B1: Refractory or relapsed neuroblastoma 

B2:Recurrent or unresectable low grade gliomas associated with BRAF tandem 
duplication with fusion, or NF-1 subjects with gliomas, not suitable for the NF-1 with 
PN cohort

B3:Neurofibromatosis Type -1 associated plexiform neurofibromas that are 
unresectable and medically significant.


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
B4:BRAF V600 mutant tumors
Part C will be a limited dose escalation part of the study evaluating the combination of 
trametinib with dabrafenib in children and adolescents with recurrent, refractory or 
unresectable BRAF V600 mutated tumors. This part of the study will establish recommended 
Phase 2 doses (RP2D) of dabrafenib and trametinib when given in combination in children 
and adolescents. This part of the study will enroll approximately 18 subjects (including up to 
6 adolescent subjects with BRAF V600 mutant metastatic melanoma) and will not open to 
accrual until the dose of dabrafenib in children is established in study BRF116013, the dose of 
trametinib is established in Part A and review of the available safety and PK data of 
trametinib and dabrafenib monotherapy in children is completed. Amendment 3 provides the 
updated safety data and dabrafenib dosing in children. Parts B and C may be open to accrual 
simultaneously. Patients who have had prior dabrafenib therapy may enroll in part C if they 
have had prior benefit to dabrafenib monotherapy, as determined by the investigator.
Part C extension will be an age-specific dose exploration in 6 subjects aged 
12 months to < 6 years old. If the trametinib dose of 0.032 mg/kg/day is 
tolerated in Part A extension, a combination of trametinib 0.032mg/kg/day and 
the full dabrafenib pediatric RP2D will be tested in this cohort. The goal of this 
additional dose exploration is to establish the safety, tolerability, PK and RP2D 
of the trametinib and dabrafenib combination in this younger age cohort
Part D will be a tumor cohort expansion part of the study to further evaluate the safety, 
tolerability, and preliminary clinical activity of the combination of trametinib and dabrafenib 
in tumor-specific pediatric populations listed below. 

D1: BRAF V600-mutant, relapsed or refractory low grade glioma (LGG)

D2: BRAF V600-mutant, relapsed or refractory Langerhans cell histiocytosis 
(LCH)
Disease cohorts are selected based on current data of proto-oncogene RAS (Ras)/ mitogen-
activated protein kinase (MAPK) activation in childhood solid tumors. Pediatric subjects 12 
months to < 18 years of age are to be enrolled. Approximately 20 subjects with LGG and 10 
subjects with LCH will be enrolled.
Subjects may not enroll in more than one part of the study. Subjects will receive study treatment 
until disease progression, death or unacceptable toxicity. 
All parts of the study will use trametinib tablet strengths (0.125, 0.5, and 2 mg) for children 
who are able to reliably swallow tablets. In addition, an oral solution formulation (0.05 mg/mL) 
of trametinib is available. Doses will be calculated using body weight and prescribed using a 
dosing nomogram. Rules for dose modifications in response to toxicity are provided in the 
protocol.
For Parts C and D of the study, dabrafenib capsules (50 and 75 mg) or suspension or dispersible 
(10 mg/ml) will be used.






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2
Statistical methods
2.1
Data analysis general information
Any interim and final analyses will be performed by a designated CRO (
). SAS 
version 9.3 or later will be used to perform all data analyses and to generate tables, figures, and 
listings.
Data included in the analysis
The final analysis will be produced after all patients are considered to have completed the study,
or if they discontinued the study treatment earlier, have completed post-treatment follow-up 
visit, or if they died while receiving treatment.
General analysis conventions
Pooling of center: Unless specified otherwise, data from all study centers will be pooled for 
the analysis. Due to expected small number of patients enrolled at centers, no center effect 
will be assessed.
Qualitative data: (e.g., gender, race, etc.) will be summarized by frequency counts and 
percentages by study parts and by dose for Part A and Part C dose exploration, by age (< 2 years, 
2 to < 6, 6 to <12, and 12 to 18 years) for Part A age expansion, by disease cohorts for Part B, 
and by tumor-specific cohorts for Part D, unless specified otherwise; a missing category will be 
included as applicable. Percentages will be calculated using the number of patients in the 
relevant population or subgroup as the denominator.
Quantitative data: (e.g., age, height, etc.) will be summarized by appropriate descriptive 
statistics (i.e. mean, standard deviation, median, minimum, and maximum) by study parts and 
by dose for Part A and Part C dose exploration, by age for Part A age expansion, by disease 
cohorts for Part B, and by tumor-specific cohorts for Part D, unless specified otherwise.


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Note for age the derivation will be as follows: round((date enrolled – birthdate +1 )/ 365.25) to 
the nearest 0.1 decimal place.
Note for Pharmacokinetic reporting, age categorizations will be as follows: < 2 years, 2 to < 6, 
6 to <12, and 12 to 18 years.
2.1.1
General definitions
Investigational drug and study treatment
Investigational drug, study drug and study treatment will refer to the trametinib for Part A and 
Part B of the study. For Part C and Part D, study treatment will refer to dabrafenib and trametinib 
combination whereas the study drug will refer to each component of study treatment.
Date of first administration of study treatment
For Part A and Part B with trametinib monotherapy, the date of first administration of study 
treatment is defined as the first date when a nonzero dose of trametinib is administered and 
recorded on the Study Treatment (EXPOSURE) eCRF. The date of first administration of study 
treatment will also be referred as start of study treatment.
For Part C and Part D with dabrafenib and trametinib combination therapy, the date of first 
administration of study treatment is derived as the first date when a nonzero dose of any 
component of the study treatment (i.e. dabrafenib and trametinib combination therapy) was 
administered as per the Study Treatment (EXPOSURE) eCRF. (Example: if 1st dose of 
trametinib is administered on 03-JAN-2016, and 1st dose of dabrafenib is administered on 01-
JAN-2016, then the date of first administration of study treatment is on 01-JAN-2016). For the 
sake of simplicity, the date of first administration of study treatment will also be referred as 
start of study treatment.
Date of last administration of study treatment
For Part A and Part B, the date of last administration of study treatment is defined as the last 
date when a nonzero dose of the study drug, trametinib, is administered and recorded on the 
Study Treatment (EXPOSURE) eCRF. The date of last administration of study drug will also 
be referred as end of study treatment.
For Part C and Part D, the date of last administration of study treatment is derived as the last 
date when a nonzero dose of any study drug was administered as per the Study Treatment 
(EXPOSURE) eCRF. (Example: if the last dose of trametinib is administered on 01-NOV-2016, 
and the last dose of dabrafenib is administered on 03-NOV-2016, then the date of last 
administration of study treatment is on 03-NOV-2016).
Study day
The study day describes the day of the event or assessment date, relative to the reference start 
date. The study day is defined by:

The date of the event (i.e. visit date, onset date of an event, assessment date etc.) –
reference start date+1 if the event is on or after the reference start date;


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
The date of the event (i.e. visit date, onset date of an event, assessment date etc.) –
reference start date if event precedes the reference start date.
The reference date for all assessments (safety, efficacy, pk, etc.) is the start of the study 
treatment.
The study day will be displayed in the data listings. If an event starts before the reference start 
date, the study day displayed on the listing will be negative.
Time unit
A year length is defined as 365.25 days. A month length is 30.4375 days (365.25/12). If duration 
is reported in months, duration in days will be divided by 30.4375. If duration is reported in 
years, duration in days will be divided by 365.25.
Baseline
For safety and efficacy evaluations, the last available assessment on or before the date of start 
of study treatment is defined as “baseline” assessment. In case time of assessment and time of 
treatment start is captured (e.g. pre-dose ECG), the last available assessment before the 
treatment start date/time is used for baseline.
In rare cases where multiple measurements meet the baseline definition, with no further flag or 
label that can identify the chronological order, then the following rule should be applied: If 
values are from central and local laboratories, the value from central assessment should be 
considered as baseline. If multiple values are from the same laboratory (local or central) or 
collected for ECGs, then an average of all the pre-dose values should be considered as baseline.
Baseline blood pressure measurements are performed in triplicate and is the average of the 
second and third measurements. 
For the laboratory evaluation of creatinine, the average (mean) of multiple assessments on or 
before study treatment start is defined as “baseline”.
If patients have no value as defined above, the baseline result will be missing.
Change from baseline
Change from baseline will be presented for safety data as described in Section 2.8.
Change from baseline is calculated as: For records occurring after baseline: (visit value) –
baseline value.
If either the baseline or visit value is missing, the change from baseline is set to missing as well.
On-treatment assessment/event and observation periods
For safety summaries, the overall observation periods will be divided into three mutually 
exclusive segments:
1. Pre-treatment period: from day of patient’s informed consent to the day before first 
administration of study treatment.


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2. On-treatment period: from date of first administration of study treatment to 30 days 
after date of last actual administration of any study treatment (including start and stop 
date)
3. Post-treatment period: starting at day 31 after last administration of study treatment.
Safety summaries (tables, figures) include only data from the on-treatment period with the 
exception of baseline data which will also be summarized where appropriate (e.g. change from 
baseline summaries). In addition, a separate summary for death including on treatment and post 
treatment deaths will be provided. In particular, summary tables for adverse events (AEs) will 
summarize only on-treatment events, with a start date during the on-treatment period 
(treatment-emergent AEs).
However, all safety data (including those from the post-treatment period) will be listed and 
those collected during the pre-treatment and post-treatment period will be flagged.
Windows for multiple assessments
In order to summarize (vital sign, performance status, etc.) data collected over time (including 
unscheduled visits), the assessments will be time slotted. The following general rule will be 
applied in creating the assessment windows: If more than one assessment is done within the 
same time window, the assessment performed closest to the target date will be used. If 2 
assessments within a time window are equidistant from the target date, then the worse of 2 
assessments (i.e farthest outside the normal range) will be used. If multiple assessment are on 
the same date then the worst case will be used. Data from all assessments (scheduled and 
unscheduled), including multiple assessments, will be listed.
For all analyses regarding abnormal assessments or analyses based on worst or best post-
baseline value (laboratory, ECGs, vital signs, Karnofsky/Lansky performance status, ECHO 
etc.), all post-baseline values will be included (scheduled, unscheduled, repeat). 
2.2
Analysis sets
All Treated Population
The All Treated Population is defined as all patients who received at least one dose of trametinib 
for Part A and Part B or at least one dose of any component of trametinib and dabrafenib 
combination for Part C and Part D. Baseline characteristics and anti-cancer activity will be 
evaluated based on this analysis population unless otherwise specified.
Safety Population
The safety population includes all patients who received at least one dose of trametinib for Part 
A and Part B or at least one dose of any component of trametinib and dabrafenib combination 
for Part C and Part D. All safety data will be analyzed using the Safety population. In this study, 
the All Treated population and Safety population are identical. 
DLT Evaluable Population
The DLT evaluable population is defined as those subjects participating in dose determining 
portion of the study (Part A and 3+3 design portion of Part A extension, Part C and Part C 


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extension) fulfilling the ‘All Treated’ population criteria and having received an adequate 
treatment in the first 28 days to enable an appropriate evaluation of study treatment related 
DLTs. Adequate exposure during the first 28 days will be defined as having received >75% of 
planned study treatment doses (at least 21 doses), exclusive of missed doses due to treatment-
related toxicity. Any patient in the ‘All Treated’ population who experiences a DLT, as defined 
in Section 3.2.3 of protocol, will also be included in the DLT evaluable population regardless 
of exposure. Subjects who are either withdrawn or dose reduced due to toxicity during the first 
28 days will be included in the DLT evaluable population. Patients enrolled for only PK 
characterization (Part A extension, Part C, or Part C extension) or for the melanoma cohort in 
Part C will not be observed for DLTs.
Pharmacokinetic Population
The Pharmacokinetic Population will consist of all patients from the All Treated Population for 
whom a PK sample is obtained and analyzed and is evaluable. For a concentration to be
evaluable, the following conditions are required:

Patient receives one of the planned treatments 

Patient provides at least one primary PK parameter
Validity of PK samples will be confirmed by checking sampling time window and occurrence 
of vomiting with respect to time of dose when PK profile is sampled. Only confirmed PK 
concentrations will be used in the analyses.
Additionally, a sample can be considered to be not evaluable as per scientific judgment of the 
clinical pharmacology expert. When a sample is considered not evaluable by the clinical 
pharmacology expert, the reason will be documented.
The pharmacokinetic population will be used in the analysis of PK data. Any blood samples 
missing blood collection date or time, or missing associated study drug dosing date or time will 
be excluded. 
Response Evaluable Population
The Response-evaluable Population is defined as those subjects fulfilling the All Treated 
Population criteria with a pre-dose and at least one post-dose disease efficacy assessment
(unless disease progression is observed before that time) or have discontinued for any reason. 
In addition, for patients evaluated by RANO criteria, their disease must be ‘measurable’ at 
baseline to be included in the Response-evaluable Population. This population will be used for 
sensitivity analysis on the efficacy endpoints. The sensitivity analysis will only be conducted 
in the final reporting effort.
Patient classifications:
Patients may be excluded from the analysis populations defined above based on the protocol 
deviations entered in the database and/or on specific patient classification rules defined in Table 
2-1.


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Table 2-1
Patient classification based on protocol deviations and non-PD 
criteria
Analysis set
Protocol deviations leading to 
exclusion
Non protocol deviation leading to 
exclusion
All 
treated 
population
No written inform consent
No dose of study medication
Safety population
No written inform consent
No dose of study medication
DLT 
evaluable 
population
No written inform consent
Did not receive adequate treatment 
(>75% of planned study doses) in 
the first 28 days of study
Response 
Evaluable 
population
No written inform consent
No baseline tumor assessment.
No 
post-baseline 
tumor 
assessments.
No measurable disease at baseline 
for patients adhering to the RANO 
criteria
PK Analysis Set
No written informed consent
Withdrawal of Informed Consent
Any data collected in the clinical database after a patient withdraws informed consent from all 
further participation in the trial, will not be included in the analysis data sets. The date on which 
a patient withdraws full consent is recorded in the eCRF.
Third party data e.g. PK, 
 etc., collected in the clinical database without having 
obtained consent for collection will not be included in the analysis data sets. These data will be 
excluded by the presence of the appropriate protocol deviation criterion.
2.2.1
Subgroup of interest
Safety subgroup analyses will use the same method as for the analysis in the overall analysis 
set. Key safety analyses including:

AEs, regardless of relationship to study drug, by primary system organ class and 
preferred term

Serious AEs, regardless of relationship to study drug, by primary system organ class 
and preferred term
will be repeated on safety set in the following subgroups:

Age group (< 2 years, 2 - < 6 years, 6 -< 12 years, 12 to 18years)
The objective for carrying out these subgroup analyses is to identify potential safety issues that 
may be limited to a subgroup of patients, or safety issues that are more commonly observed in 
a subgroup of patients.


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Summary tables will only be performed if at least 10% of patients or 10 patients are present in 
each subgroup. Some grouping of classes will be considered for age. For data that require a 
summary table by subgroup, a listing may be sufficient if less than 10% of patients or less than 
10 patients are present in each subgroup.
2.3
Patient disposition, demographics and other baseline 
characteristics
Unless otherwise stated, the All Treated population will be used for all baseline and 
demographic summaries and listings. All summaries and data listings in this section will be 
reported by dose level for Part A and Part C and by disease cohort for Part B and Part D. No 
inferential statistics will be provided
Basic demographic and background data
All demographic and baseline disease characteristic data will be summarized and listed by 
cohort and study treatment dose. Categorical data (e.g. gender, race, etc.) will be summarized 
by frequency counts and percentages; the number and percentage of patients with missing data 
will be provided. Continuous data (e.g. age, weight, height, etc.) will be summarized by 
descriptive statistics (N, mean, median, standard deviation, 25th and 75th percentiles, minimum 
and maximum). Body Surface Area (BSA) will be calculated using Gehan and George formula: 
BSA[m2] = 234.94 * (height[cm] ** 0.422) * (weight[kg] ** 0.515) /10000 unless otherwise 
specified. In addition, age will also be categorized and summarized by < 2 years, 2 - < 6 years, 
6 -< 12 years, 12 to 18 years. Race and racial combinations will be summarized and listed.
Diagnosis and extent of cancer
Summary statistics will be tabulated for diagnosis and extent of cancer. This analysis will 
include the following: primary site of cancer, details of tumor histology/cytology,
histological grade, stage at initial diagnosis, time since initial diagnosis, time since last 
recurrence, and time since last progression.
A summary of disease burden at baseline will be produced. Metastatic disease at screening 
will be listed and summarized.
Summary statistics with frequency and its percentage will be tabulated for central BRAF 
V600 mutation status in subjects taking mono and combined therapies and also in LCH 
subjects.
Medical history
Medical history and ongoing conditions, including current and past cancer-related conditions 
and symptoms entered on the eCRF will be summarized and listed by cohort and study treatment 
dosage. Separate summaries will be presented for ongoing and historical medical conditions.
The summaries will be presented by primary system organ class (SOC), preferred term (PT)
and by dose for part A and C, by cohort for Part B and Part D. Medical history and current 
medical conditions will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) terminology. The MedDRA version used for reporting will be specified in the CSR 
and as a footnote in the applicable tables/listings.


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Other
All data collected at baseline, including child bearing potential will be listed.
2.3.1
Patient disposition
A summary of patient status and reason for study withdrawal will be provided. This display will 
show the number and percentage of patients who withdrew from the study, including primary 
reasons for study withdrawal. Reasons for study withdrawal will be presented in the order they 
are displayed in the eCRF. A listing of reasons for study withdrawal will also be provided.
A summary of study treatment status will be provided. This display will show the number and 
percentage of patients who are ongoing or discontinued study treatment and a summary of the 
primary reasons for discontinuation of study treatment. Reasons for study treatment 
discontinuation will be presented in the order they are displayed in the eCRF. A listing of study 
treatment discontinuation will be generated. The listing will include last dose date and reasons 
for study treatment discontinuation. 
Protocol Deviations
The number (%) of patients in the All Treated population with any major protocol deviation 
will be tabulated by deviation category (as specified in the study protocol deviation plan). Major 
protocol deviations leading to exclusion from analysis sets will be tabulated separately. All 
protocol deviations will be listed. Similarly, a separate table and listing will be provided for 
protocol deviation related to COVID-19.
Analysis Populations
The number and percentages (based on the total number of patients in the All treated population)
of patients in each analysis population (defined in Section 2.2) will be summarized by study 
part and by Part A doses, Part B cohorts, Part C doses, and Part D cohorts.
2.4
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
The safety population will be used for all summaries and listings of study treatment. All 
summaries and data listings in this section will be reported by study parts and by dose level for 
Part A, and Part C, and by disease cohort for Part B and Part D.
2.4.1
Study treatment / compliance
Duration of exposure, actual cumulative dose, dose intensity (DI) and relative dose intensity 
(RDI) will be summarized for trametinib by dose cohorts for Part A and disease cohorts for Part 
B. For Part C and Part D they will be summarized separately for dabrafenib and trametinib by 
dose cohorts for Part C and by disease cohorts for Part D). Duration of exposure will be 
categorized into time intervals; frequency counts and percentages will be presented for the 
number (%) of patients in each interval. The number (%) of patients who have dose reductions


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or interruptions, and the reasons, will be summarized by trametinib monotherapy for Part A and 
Part B, and by dabrafenib and trametinib separately for Part C and Part D.
Patient level listings of all doses administered on treatment along with dose change reasons will 
be produced.
Duration of exposure to study treatment
Duration of exposure to study treatment is considered by taking into account the duration of 
exposure to trametinib for Part A and Part B and to any combination partner for Part C and 
Part D.
Duration of exposure to study treatment (days) = (last date of exposure to study treatment) –
(date of first administration of study treatment) +1.
The last date of exposure to study treatment is the last date of exposure to trametinib for Part A 
and Part B, and the latest of the last dates of exposure to any combination partner for Part C and 
Part D (see Table 2-2).
Summary of duration of exposure of study treatment will include categorical summaries based 
on <3 weeks, 3 weeks to 6 weeks, >6 weeks to 12 weeks, and >12 weeks intervals and using 
descriptive statistics (mean, standard deviation, etc.).
Table 2-2
Definition of last date of exposure of study drug
Scenario
Definition of last date of exposure 
of study drug 
Example
Daily 
administration 
of 
the study drug
Date of last administration of a non -
zero dose of the study drug.
Example: A patient had a 
permanent discontinuation of 
the study drug 06Jan2013 after 
being put on a temporary 
interruption since 01Jan2013. 
In this case the last date of 
exposure is 31Dec2012. 
Duration of exposure to combination partner
Duration of exposure to dabrafenib (days) = (last date of exposure to dabrafenib) – (date of
first administration of dabrafenib) + 1.
Duration of exposure to trametinib (days) = (last date of exposure to trametinib) – (date of
first administration of trametinib) + 1.
For Part C and Part D, combined duration of exposure to study drug (days) = (the latest date of 
exposure to study drug) – (date of the earliest administration of study drug) + 1.
Summary of duration of exposure of each combination partner will include categorical 
summaries based on <3 weeks, 3 weeks to 6 weeks, >6 weeks to 12 weeks, and >12 weeks
intervals and using descriptive statistics (mean, standard deviation, etc.).


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Cumulative dose
Cumulative dose of the study treatment is defined as the total dose given during the study 
treatment exposure and will be summarized for each of the study treatment components.
The planned cumulative dose for a study treatment component is the total planned dose as per 
the protocol up to the last date of investigational drug administration. The planned cumulative 
dose will not be summarized/listed. It will be used for relative dose intensity calculations.
The actual cumulative dose refers to the total actual dose administered, over the duration for 
which the patient is on the study treatment as documented in the Study Treatment (EXPOSURE) 
eCRF.
For patients that did not take any drug, the actual cumulative dose is by definition equal to zero
for that drug.
For continuous dosing, the actual cumulative dose is the sum of the non-zero doses recorded 
over the dosing period and the planned cumulative dose is the planned starting dose summed 
over the same dosing period.
Dose intensity and relative dose intensity
Dose intensity and relative dose intensity will be summarized by age categories (<12 years 
and >=12 years for Dabrafenib, and <6 years and >=6 years for Trametinib.
Dose intensity
(DI) for patients with non-zero duration of exposure is defined as follows:
DI (mg/kg/day) = Actual Cumulative dose( mg/kg) / Duration of exposure (day).
For patients who did not take any drug the DI is by definition equal to zero. Planned dose 
intensity (PDI) is defined as follows:
PDI (mg/kg/day) = Planned Cumulative dose(mg/kg)/ Duration of exposure (day)
Relative dose intensity
(RDI) is defined as follows: RDI = DI (mg/kg/day) / PDI (mg/kg/day).
In Parts A and Part B, DI and RDI will be summarized for trametinib monotherapy. Summary 
of RDI will include categorical summaries based on clinically meaningful intervals (<50%, 
50-<75%, 75-<90%, 90-<110%, >=110%).
In study Part C and Part D, where there is combination therapy, DI and RDI will be summarized 
separately for each study treatment components, using the duration of exposure of each of the 
components. Summary of RDI will include categorical summaries based on clinically 
meaningful intervals (<50%, 50-<75%, 75-<90%, 90-<110%, >=110%).
Dose reductions, interruptions, permanent discontinuations or escalations 
The number of patients who have dose reductions, escalations, permanent discontinuations or 
interruptions, and the reasons, will be summarized separately for each study part as well as 


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study treatment components for combination therapies Part C and Part D. They will also be 
listed.
For the purpose of summarizing interruptions and reasons, in case multiple entries for 
interruption that are entered on consecutive days with different reasons will be counted as 
separate interruptions. However, if the reason is the same in this block of entries, it will be 
counted as one interruption.
In addition, summaries of study treatment exposure and dose modifications (e.g., number of 
dose reductions, number of dose interruptions) will further characterize compliance. 
2.4.2
Prior, concomitant and post therapies
2.4.2.1
Prior anti-cancer therapy
Prior anti-cancer therapy and anti-neoplastic therapy’s medications will be coded using WHO
coding dictionary; anti-neoplastic surgery will be coded using MedDRA. A summary of the 
number of prior anti-cancer therapy regimens will be produced and listed. The number and 
percentage of patients who received any prior anti-neoplastic medications, prior anti-neoplastic 
radiotherapy or prior anti-neoplastic surgery will be summarized by study parts and disease 
cohorts. Prior anti-neoplastic medications will be summarized by therapy type (e.g. 
chemotherapy, hormonal therapy, etc.), setting (e.g. adjuvant, metastatic, etc.), and also by 
lowest ATC class, preferred term and study part. Separate listings will be produced for prior
anti-neoplastic medications, radiotherapy, and surgery. 
Details regarding MedDRA and most recent WHO coding dictionary will be included in the 
footnote in the tables/listings.
The above analyses will be performed using the All treated population.
Concomitant medications
Concomitant therapy is defined as all interventions (therapeutic treatments and procedures) 
other than the study treatment administered to a patient coinciding with the study treatment 
period. Concomitant therapy include medications (other than study drugs) starting on or after 
the start date of study treatment or medications starting prior to the start date of study treatment
and continuing after the start date of study treatment.
Concomitant medications will be coded using the World Health Organization (WHO) Drug 
Reference Listing (DRL) dictionary that employs the WHO Anatomical Therapeutic Chemical 
(ATC) classification system and summarized by lowest ATC class and preferred term using 
frequency counts and percentages. Surgical and medical procedures will be coded using 
MedDRA and summarized by SOC and preferred term, Outputs will be summarized, and listed
by dose for Part A, Part B, Part C, Part D, and by disease cohorts. The summary of concomitant 
medications will show the number and percentage of patients taking concomitant medications 
by Ingredient. Multi-ingredient products will be summarized by their separate ingredients rather 
than as a combination of ingredients. These summaries will include:
1. Medications starting on or after the start of study treatment but no later than 30 days 
after start of last dose of study treatment and


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2. Medications starting prior to start of study treatment and continuing after the start of 
study treatment.
In the summary of concomitant medications, each patient is counted once within each unique 
ingredient. For example, if a patient takes Amoxicillin on two separate occasions, the patient is 
counted only once under the ingredient “Amoxicillin”. All concomitant therapies will be listed
by dose level for Part A and Part C and by disease cohort for Part B and Part D. Any
concomitant therapies starting and ending prior to the start of study treatment or starting more
than 30 days after the last date of study treatment will be flagged in the listing. The safety
population will be used for all concomitant medication tables and listings.
Concomitant medications that have the potential to impact some specific analyses (e.g. PK, 
efficacy or safety analyses) will be identified prior to database lock. Separate summaries of 
these concomitant medications will be produced using the appropriate analysis set (e.g. All 
Treated Analysis Set) for those potentially affecting efficacy. According to the study protocol, 
certain treatment as listed in Protocol Section 9.2 (Prohibited Medications) should be avoided. 
However, some patients may take these substances during the treatment period so these 
concomitant medications will be selected via programming and tabulated and listed in the 
Clinical Study Report. Treatment with the prohibited substances mentioned above will be 
identified in the database as protocol deviations.
2.5
Analysis of the primary objective
Part A
The primary objective of Part A is to determine the safe and tolerable trametinib dose(s) for 
chronic dosing in pediatric patients (infants, children, and adolescents) that achieves similar 
exposures (Cτ) to the recommended adult dose.
Part A extension: Based on preliminary PK data from Parts A, B and C, there was a trend for 
lower trametinib exposure in patients < 6 years old. An intermediate dose that is between the 
RP2D established in Part A and the higher dose that exceeded MTD will be explored. Safety, 
tolerability and PK are the primary endpoints of this part of the study. 
Part B
Safety, tolerability and preliminary activity assessed by investigator are the primary endpoints 
of this part of the study.
Part C
The primary objective of Part C is safety, tolerability, and preliminary activity of the RP2D of 
trametinib in combination with a limited dose escalation of dabrafenib (50% of pediatric RP2D 
and 100% RP2D). 
Part C extension: If Part A extension indicates trametinib 0.032mg/kg/day is tolerated in 
patients < 6 years old, the same trametinib dose will be explored in Part C extension with full 
dabrafenib RP2D. Safety, tolerability and PK are the primary endpoints of this part of the study.


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Part D
Safety, tolerability and preliminary activity of dabrafenib and trametinib combination therapy 
assessed by investigator are the primary endpoints of this part of the study.
2.5.1
Primary endpoint
The primary endpoint for Part A (monotherapy), Part B (monotherapy), Part C (for trametinib 
and dabrafenib separately), and Part D (for trametinib and dabrafenib separately) is adverse 
events (AEs), ECG, ECHO, changes in laboratory values and vital signs. An additional primary 
endpoint specific to Part A is a steady state Cτ of trametinib.
2.5.2
Statistical hypothesis, model, and method of analysis
No formal statistical hypotheses are being tested for any part of this study. For Part A and Part 
C, analysis of the data obtained from each part will be focused on comparison between dose 
cohorts and only descriptive methods will be utilized. For Part B and Part D, the objective 
response rate and the corresponding exact 95% CI will be reported by each disease cohort.
2.5.3
Handling of missing values/censoring/discontinuations
As the duration of treatment for a given patient will depend on efficacy and tolerability, the 
duration of follow-up will vary between patients. Consequently there will be no imputation for 
missing data. 
Patients will be treated until disease progression, until the patient is no longer obtaining clinical 
benefit from continued treatment, unacceptable toxicity, the study is terminated, or the patient 
withdraws consent or begins a new therapy. Patients who withdraw from the study will be 
included in summaries up to the time of withdrawal, regardless of the duration of treatment.
Patients with the designation of treatment relationship for adverse events (AEs) and serious 
adverse events (SAEs) missing will have the worst case assumed to impute the relationship: if 
relationship to study treatment is missing it will be assumed to be “Yes”. There will be no other 
imputation for missing data other than what’s described in Section 5.3 for partial dates and for 
missing exposure end dates.
2.6
Analysis of the key secondary objective
There is no key secondary objective.
2.7
Analysis of secondary efficacy objective(s)
The secondary efficacy objectives are to:

To assess any preliminary anti-tumor activity of trametinib

To assess any preliminary anti-tumor activity of trametinib in combination with 
dabrafenib
All efficacy analyses will be based on the All Treated population as defined in Section 2.2
unless otherwise specified. All analyses will be 


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summarized by dose levels in Part A, by disease cohorts in Part B, by dose levels in Part C, by 
disease cohorts for Part D, and by five disease cohorts listed below.
(1) Glioma Fusion subjects in Trametinib monotherapy 
(2) BRAF V600 mutant glioma subjects in Trametinib monotherapy 
(3) BRAF V600 mutant glioma subjects in combination therapy 
(4) NF-1 with PN subjects in Trametinib monotherapy 
(5) LCH subjects in combination therapy
Inclusion of patients in the 5 disease cohorts will be based on the enrollment criteria where 
available and applicable, and will be based on the genetic analysis.
2.7.1
Secondary endpoints
Overall Response Rate(ORR) by Disease Type
Overall Response Rate (ORR) is defined as the proportion of patients with best overall 
response (BOR) with confirmation of CR or PR according to criteria for a specific disease 
type, among patients with disease assessment at baseline. ORR will be calculated based on the 
All Treated population using investigator assessment of tumor response data and will be based 
on confirmed responses.
BOR for each patient is determined from the sequence of overall responses according to the
following rules for RECIST 1.1,  RANO, and Dombi criteria.
1. CR = at least two confirmed CR at least 4 weeks apart before progression
2. PR = at least two confirmed PR or better response at least 4 weeks apart before 
progression and not qualifying for a CR.
3. SD = requires at least one SD assessment or better determined at or beyond 12 weeks 
from randomization before progression, and not qualifying for CR or PR. 
4. PD =  progression after start of study treatment and not qualifying for CR or PR or SD
5. UNK = all other cases (i.e., not qualifying for confirmed CR or PR and without SD at 
or beyond 12 weeks or progression).
Neuroblastoma 
Response evaluations for patients with neuroblastoma can include measurable disease (by 
CT/MRI alone) or Evaluable Disease (MIBG alone) and/or in combination with bone marrow, 
biochemical (urine HVA/VMA). 
Response criteria for neuroblastoma patients with measurable disease as a component of their 
disease burden at enrollment will have measurable disease assessed according to RECIST 
v1.1, as well as evaluable disease assessments, to determine overall response.


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Response criteria for neuroblastoma patients who have a positive MIBG scan at the start of 
therapy will be evaluable for MIBG response.
Response criteria from neuroblastoma patients who have bone marrow responses are 
determined by Haematoxylin and Eosin (H&E) staining of bilateral bone marrow biopsies and 
aspirates.
If patient receives any further anti-neoplastic therapy while on study, any subsequent 
assessments will be excluded from the ORR determination.
Refer to Appendix 4 in the Protocol for additional information.
Low Grade Glioma Patients
Anti-tumor activity for glioma patients will be assessed using Response Assessment in Neuro-
Oncology (RANO) criteria with solid tumors through MRI. All measurable and non-measurable
lesions should be assessed using the same techniques as at baseline.
Refer to Appendix 5 in the Protocol for additional information.
NF-1 Associated PNs
Response will be assessed using Dombi criteria at the time that follow-up MRI scans are 
performed as outlined in Section 7.1 of the Protocol. 
Refer to Appendix 6 in the Protocol for additional information.
LCH Patients
Response criteria is adapted from Histiocyte Society Evaluations and Treatment Guidelines, 
April 2009 and is used in combination with RECIST criteria v1.1.
In the case of LCH patients, the ORR is the number of patients deemed to have treatment 
response (CR+REG) relative to the total number of patients treated in that cohort as described 
in Appendix 3 of the Protocol
Refer to Appendix 7 of the Protocol for more information.
BOR for each patient is determined from the sequence of overall responses according to the
following rules for LCH subjects.
1. Complete resolution (CR)/Non-active disease (NAD) = at least two confirmed 
CR/NAD at least 4 weeks apart before progression
2. Regressive (REG) = at least two confirmed REG or better response at least 4 weeks 
apart before progression and not qualifying for a CR/NAD.
3. SD = requires at least one SD assessment or better determined at or beyond 12 weeks 
from randomization before progression, and not qualifying for CR/NAD or REG. 
4. PD =  progression after start of study treatment and not qualifying for CR/NAD or 
REG or SD


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5. UNK = all other cases (i.e., not qualifying for confirmed CR or REG and without SD 
at or beyond 12 weeks or progression).
All Other Solid Tumors
Tumor response will be assessed using RECIST version 1.1 for patients with solid tumors
except neuroblastomas, primary central nervous system tumors (gliomas), or PN(s).
Tumor assessments performed before the start of any further anti-cancer therapy (i.e. any 
additional secondary anti-cancer therapy or surgery) will be considered in the assessment of 
BOR. If a patient receives any further anti-neoplastic therapy while on study, any subsequent 
assessments will be excluded from the ORR determination.
Note that if a patient shows at least one Non-CR/Non-PD (NN) assessment determined at or 
beyond 12 weeks from randomization and not qualifying for CR, PR, SD, or PD, then BOR 
for the patient is NN.
ORR is defined as the proportion of patients with best overall response (BOR) with 
confirmation of CR or PR according to criteria for a specific disease type, among patients 
with disease assessment at baseline
BOR with confirmation and ORR will be summarized for all disease types by therapy
(monotherapy or combo-therapy) and by study part and dose based on the All treated population. 
Where appropriate, the lesion data will be listed for each patient.
A figure of percent change at maximum reduction from baseline in tumor measurement will 
also be provided, where appropriate. 
As sensitivity analyses, response data may also be summarized based on response-evaluable 
population. As supportive analyses, for LGG and NF-1 with PN patients, the response data 
assessed by independent review assessment will also be summarized based on the All treated 
population.
2.7.2
Statistical hypothesis, model, and method of analysis
The primary analysis of response data will be performed on the All treated population by 
investigator assessment. Point estimate and exact confidence intervals (CIs) of ORR will be 
provided by disease type and by trametinib monotherapy and dabrafenib plus trametinib 
combination therapy, as well as by study part and dose.
2.7.3
Handling of missing values/censoring/discontinuations
Dates associated with response
For each disease assessment after baseline, determine a date associated with the response. For 
complete response (CR) and partial response (PR), assign to the latest date within the disease 
assessments. For stable disease (SD), Non-CR/Non-PD or Not Evaluable, assign to the 
earliest date within the disease assessments. For progressive disease (PD), assign to the 
earliest assessment date associated with the progression.
Unknown or Missing Tumor Assessments


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Patients with unknown or missing best overall response (BOR) will be counted as non-
responders. 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 All Treated Analysis Set and will be counted as 
‘failures’.
2.7.4
Supportive analyses
ORR by independent review assessment
The analyses of ORR will be repeated by independent review for LGG cohorts. For LGG 
patients, this incorporates the radiographic data which includes the lesion measurements from 
target lesions, non-target lesions, new lesion, corticosteroid status, and clinical status per old 
RANO (2010) and new RANO (2017). Please refer to the Protocol Appendix 5.
Waterfall plot will be presented for the analysis. Waterfall graphs will be used to depict the anti-
tumor activity. These plots will display the best percentage change from baseline in the sum of 
diameters of all target lesions for each patient. Only patients with measurable disease at baseline 
will be included in the waterfall graphs. Patients without any valid assessments will be 
completely excluded from the graphs.
The total number of patients displayed in the graph will be shown. Footnote will explain the 
reason for excluding some patients (due to absence of any valid assessment).
Concordance analysis of ORR
Concordance analysis of ORR for LGG cohorts will be performed for assessment of the best 
overall responses by investigator and independent reviewer per old RANO (2010) and new 
RANO (2017). Concordance rate of ORR is calculated as Percent Agreement for responders 
and non-responders.
2.8
Safety analyses
Unless otherwise specified, all the DLT safety analyses will be based on the safety population
as defined in Section 2.2 and summaries will include all events or assessments collected during 
the study. For all other safety analyses (i.e. AE, ECG, Labs, Vitals, etc.) they will be 
summarized by dose levels in Part A, by disease cohorts in Part B, by dose levels in Part C, by 
disease cohorts for Part D, and by five disease cohorts listed below.
(1) Glioma Fusion subjects in Trametinib monotherapy 
(2) BRAF V600 mutant subjects in Trametinib monotherapy 
(3) BRAF V600 mutant subjects in combination therapy 
(4) NF-1 with PN subjects in Trametinib monotherapy 
(5) LCH subjects in combination therapy 


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2.8.1
Adverse events (AEs)
AEs will be graded according to the CTCAE, Version 4.0. Adverse events will be coded to the 
preferred term (PT) level using the Medical Dictionary for Regulatory Affairs (MedDRA 
dictionary). The latest available MedDRA version at the time of the analyses will be used. The 
MedDRA version used for reporting will be specified in the CSR and as a footnote in the 
applicable tables/listings.
AE summaries will include all AEs occurring during on treatment period. All AEs collected in 
the AE eCRF page will be listed along with information collected on those AEs (e.g. AE 
relationship to study drug, AE outcome, etc.) AEs with start date outside of on-treatment period 
will be flagged in the listings.
AEs will be summarized by number and percentage of patients having at least one AE, having 
at least one AE in each primary system organ class (SOC) and for each preferred term (PT)
using MedDRA coding. A patient with multiple occurrences of an AE will be counted only 
once in the respective AE category. A patient with multiple CTCAE grades for the same 
preferred term will be summarized under the maximum CTCAE grade recorded for the event.
AE with missing CTCAE grade will be included in the ‘All grades’ column of the summary 
tables.
In AE summaries, the primary system organ class will be presented alphabetically and the 
preferred terms will be sorted within primary SOC in descending frequency. The sort order for 
the preferred term will be based on their frequency.
The following adverse event summaries will be produced by dose for Part A and Part C dose 
exploration, by disease cohorts for Part B, by tumor-specific cohorts for Part D, by age group
(< 2 years, 2 to < 6, 6 to 12, and 12 to 18 years) for monotherapy (Part A and Part B combined) 
and combination therapy (Part C and Part D combined) ; 

overview of adverse events 

Overview of deaths and SAEs,

AEs by SOC, PT and severity (post-text)

AEs by SOC and severity (in-text)

AEs by PT and severity (in-text)

AEs suspected to be related by SOC, PT and severity (post-text),

AEs suspected to be related by PT and severity (in-text),

SAEs by SOC, PT and severity (post-text)

SAEs by PT and severity (in-text)

AEs leading to study treatment discontinuation by SOC, PT and severity (post-text)

AEs leading to study drug discontinuation by PT and severity (in-text), 

AEs leading to dose reductions, leading to dose interruptions, and leading to fatal 
outcome (post-text). 


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
AESIs (in-text)
A summary of serious and non-serious adverse events with number of occurrences will be 
produced as per EudraCT requirements. 
For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables for on-
treatment adverse event which are not SAE’s with an incidence greater than and equal to 5% 
and on on-treatment SAE's and SAE’s suspected to be related to study treatment will be 
provided by system organ class and preferred term on the safety set population.
If for a same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT:

a single occurrence will be counted if there is  ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE

more than one occurrence will be counted if there is > 1 day gap between the end date 
of the preceding AE and the start date of the consecutive AE
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non SAE has to be checked in a block e.g., among AE's in a ≤ 1 day gap block, if at 
least one SAE is occurring, then one occurrence is calculated for that SAE.
The number of deaths resulting from SAEs suspected to be related to study treatment and SAEs 
irrespective of study treatment relationship will be provided by SOC and PT.
Dose Limiting Toxicity
An AE will be considered a DLT if it is considered by the investigator to be at least possibly 
related to study treatment, meets any of the criteria listed in Section 3.2.3.1 or Section 3.2.3.2 
of protocol and occurred during the first 28 days of treatment in the dose determining portion 
of the study (Part A and 3+3 design portions of Part A extension, Part C and Part C 
extension).
DLTs will be listed and summarized for age and the dose determining portion of Part A and 
Part C. Only the first cycle (28 days) of treatment will be considered when summarizing data 
regarding the dose limiting toxicities. The table will display the number of DLT’s at each dose 
level. AE summary of DLTs will also be presented.
Note that isolated clinical laboratory value(s) considered not clinically significant by the 
investigators are not AEs and therefore, would not be DLTs.
2.8.1.1
Adverse events of special interest / grouping of AEs
Data analysis of AESIs
An adverse event of special interest (AESI) is a grouping of adverse events that are of scientific 
and medical concern specific to compound, dabrafenib and trametinib. These groupings are 
defined using MedDRA terms, SMQs (standardized MedDRA queries), HGLTs (high level 
group terms), HLT (high level terms) and PTs (preferred terms). Customized SMQs (Novartis 


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MedDRA queries, NMQ) may also be used. A NMQ is a customized group of search terms 
which defines a medical concept for which there is no official SMQ available or the available 
SMQ does not completely fit the need. It may include a combination of single terms and/or an 
existing SMQ, narrow or broad. For each specified AESI, number and percentage of patients 
with at least one event of the AESI occurring during on treatment period will be summarized.
The events considered as AESI’s will be based off of the latest CRS.
Summaries of these AESIs will be provided by trametinib and dabrafenib, by dose and study 
part, (specifying grade, SAE, relationship, leading to treatment discontinuation, leading to dose 
adjustment/interruption, hospitalization, death etc.). If sufficient number of events occurred, 
analysis of time to first occurrence will be applied.
A listing of all grouping levels down to the MedDRA preferred terms used to define each AESI 
will be generated.
2.8.2
Deaths
In the event that a patient has withdrawn consent, no data after the withdrawal of consent date 
from this patient including death is supposed to appear in the database, which should be part of 
the data cleaning process. 
Separate summaries for on-treatment and all deaths will be produced by study part, system 
organ class and preferred term. 
All deaths will be listed, post treatment deaths will be flagged. A separate listing of deaths prior 
to starting treatment will be provided for all screened subjects.
2.8.3
Laboratory data
On analyzing laboratory, data from all sources (central and local laboratories) will be combined. 
The summaries will include all assessments available for the lab parameter collected no later 
than 30 days after the last study treatment administration date (see Section 2.1.1).
The following summaries will be produced for hematology and biochemistry laboratory data 
(by laboratory parameter and study part):

Worst post-baseline CTCAE grade (regardless of baseline status). Each patient will be 
counted only for the worst grade observed post-baseline.

Shift tables using CTCAE grades to compare baseline to the worst post-baseline value

For laboratory tests where CTCAE grades are not defined, shift tables using the 
low/normal/high classification to compare baseline to the worst post-baseline value.

Trends of lab parameter values over time (baseline and selected on-treatment time points) 
should be displayed via boxplots based on time windows and corresponding tables 
displaying the statistics used for the box plots by the selected time points.
The following listings will be produced for laboratory data:


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
Listings of all laboratory data, with CTC grades and classification relative to the 
laboratory normal range. Lab data collected during the post-treatment period will be 
flagged.

Listing of all CTC grade 3 or 4 laboratory toxicities
For laboratory tests (e.g.potassium, sodium, calcium, glucose, magnesium, hemoglobin and 
lymphocytes) that are graded for both low and high values, summaries will be done separately 
and labeled by direction, e.g. sodium will be summarized as hyponatremia and hypernatremia.
Unless otherwise specified, the denominator in percentage calculation at each scheduled visit 
will be based on the number of patients with non-missing value at each particular visit.
Liver function parameters
Liver function parameters of interest are total bilirubin (TBL), ALT, AST and alkaline 
phosphatase (ALP). The number (%) of patients with worst post-baseline values as per Novartis 
Liver Toxicity guidelines will be summarized:
The following summaries will be produced:

AST or ALT > 3 x Baseline

ALT or AST > 3xULN 

ALT or AST > 5xULN

ALT or AST > 8xULN

ALT or AST > 10xULN

ALT or AST > 20xULN

TBL> 2 x Baseline 

TBL > 2xULN

TBL > 3xULN

ALT or AST > 3xULN & TBL > 2xULN

ALT or AST > 3xULN & TBL > 2xULN & ALP < 2xULN

[AST or ALT > 3 x Baseline] & [TBL> 2 x Baseline AND TBL > 2.0 x ULN]

[AST or ALT > 8.0 x ULN] & [TBL> 2 x Baseline AND TBL > 2.0 x ULN]

Lower ([AST or ALT > 3 x Baseline] OR [AST or ALT > 8.0 x ULN]) & [TBL> 2 
x Baseline AND TBL > 2.0 x ULN]
A clinically significant liver safety signal corresponding to Hy’s Law events are defined as a 
patient with abnormal ALT or AST baseline value and combined elevations post baseline 
(based on the peak values at any post-baseline time for a patient). [AST or ALT > 3 x
Baseline] OR [AST or ALT > 8.0 x ULN], whichever is lower and combined with [TBL> 2 x 
Baseline AND TBL > 2.0 x ULN]


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2.8.4
Other safety data
2.8.4.1
ECG and cardiac imaging data
ECG Data handling
In case the study requires ECG replicates at any assessment, the average of the ECG parameters 
at that assessment should be used in the analyses.
ECG Data analysis
The number and percentage of patients with notable ECG values at scheduled assessments will 
be presented by Parts A, B, C, and D.

QTcB
-
New value of > 450 and ≤ 480 ms
-
New value of > 480 and ≤ 500 ms
-
New value of > 500 ms
-
Increase from Baseline of > 30 ms to ≤60ms
-
Increase from Baseline of > 60 ms

PR
-
Increase from baseline >25% and to a value > 200 ms
-
New value of > 200 ms

QRS
-
Increase from baseline >25% and to a value > 120 ms 
-
New values of QRS > 120 ms
The normal range for HR is displayed in Table 2-7 Recommendation for normal heart rate per 
age group and gender. The number and percentage of patients with notable values will be 
presented.
Table 2-7
Recommendation for normal heart rate per age group and gender
Age group
0-1
month
1-3
months
3-6
months
6-12
months
1-3
years
3-5
years
5-8
years
8-12
years
12-18
years
HR (bpm)
Boys
(125, 190)
(125, 185)
(110, 165)
(105, 165)
(95, 155)
(75, 125)
(60, 115)
(55, 100)
(50, 100)
HR (bpm)
Girls
(135, 215)
(125, 200)
(120, 190)
(105, 185)
(95, 180)
(80, 125)
(70, 115)
(60, 110)
(50, 100)
Data shown as upper limit of normal, lower limit of normal for HR= heart rate. Ref.: adapted from 
Rijnbeek et al. 2001.
The summaries will include all ECG assessments performed no later than 30 days after the last 
date of study drug. A listing of all ECG assessments will be provided and notable values will 


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be flagged. In the listing, the assessments collected outside of on-treatment period will be 
flagged.
The denominator to calculate percentages for each category is the number of patients with both 
a baseline and a post-baseline evaluation. A newly occurring post-baseline ECG notable value 
is defined as a post-baseline value that meets the criterion post-baseline but did not meet the 
criterion at baseline.
For each of the ECG parameter, descriptive statistics at baseline, at each post-baseline time 
point and changes from baseline at each post-baseline time point will be summarized.
Descriptive statistics at worst post-baseline and changes from baseline to worst post-baseline 
will also be summarized separately. For each of the QTcB and QT intervals, shift tables based 
on notable parameter categories (<450, 450-<481, 481-<501, 501 ms) at baseline and the worst 
post-baseline value observed.
Patients with notable ECG interval values and newly occurring qualitative ECG abnormalities 
will be listed and the corresponding notable values and abnormality findings will be included 
in the listings.
2.8.4.2
ECHO Data handling
ECHO data will be analyzed based on local reported results. The summaries will include all 
ECHO assessments performed no later than 30 days after the last date of study drug. All ECHO 
assessments will be listed, and those collected later than 30 days after study drug 
discontinuation will be flagged in the listing.
The same modality (ECHO or MUGA) for determining cardiac scan data (e.g., left ventricular 
ejection fraction (LVEF)) should be used to follow a patient throughout the study. The absolute 
change from baseline values will not be calculated for any patients where the post-baseline 
value was determined by a cardiac scan modality that is different than the one used to determine 
baseline value. 
ECHO Data analysis
Absolute change from baseline in LVEF will be summarized at each scheduled assessment time 
and by worst case post-baseline. Only the post-baseline assessments that used the same method 
(ECHO or MUGA) as the baseline assessments will be used to derive the change from baseline. 
The absolute change from baseline will be categorized as follows:

Any increase

No change

Any decrease:
-
0 - <10% decrease
-
10 - <20% decrease
-
≥20% decrease

≥10% decrease and ≥Lower Limit Normal (LLN)

≥10% decrease and < LLN


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
≥20% decrease and ≥LLN

≥20% decrease and < LLN
A listing of all LVEF assessments will be provided including patient level details of absolute 
change from baseline. Assessments collected outside of on-treatment period will be flagged.
2.8.5
Vital signs
The following parameters will be collected: height (cm), weight (kg), body temperature (°C),
heart rate (beats per minute), respiration rate (breathes/min), systolic and diastolic blood 
pressure (mmHg).
Data handling
Vital signs collected on treatment will be summarized by scheduled visit. Values measured 
outside of on treatment period will be flagged in the listings.
The baseline blood pressure is the average of the systolic and average of the diastolic 
measurements.
Data analysis
For analysis of vital signs the clinically notable vital sign criteria are provided in Table 2-9.
Table 2-9
Clinically notable changes in vital signs
Vital sign 
(unit)
Clinically notable criteria
above normal value 
below normal value
Weight (kg)
increase > 10% from Baseline
decrease > 10% from Baseline
Systolic blood 
pressure (mmHg)
>=180 with increase from 
baseline of >=20
<=90 with decrease from baseline 
of >=20
Diastolic blood 
pressure (mmHg)
>=105 with increase from 
baseline of >=15
<=50 with decrease from baseline 
of >=15
Body temperature
>= 38.5
≤ 35.0
The number and percentage of patients with notable vital sign values (high/low) will be 
presented as described in Section 2.8. Shift tables for vital sign values will also be presented.
Descriptive statistics (mean, median, standard deviation, minimum and maximum) will be 
tabulated for baseline, at each post-baseline time point and changes from baseline at each post-


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baseline time point for each vital sign measure. For each parameter, only patients with a value 
at both baseline and post baseline (on treatment) will be included.
A listing of all vital sign assessments will be produced by cohorts and notable values will be 
flagged. In the listing, the assessments collected outside of on-treatment period will be flagged.
2.8.5.1
Karnofsky and Lansky Performance Status
Data handling
The Karnofsky and Lansky PS scale (see Appendix 1) will be used to assess physical health of 
patients, ranging from 10 (least active) to 100 (most active).
Data analysis
Frequency counts and percentages of patients in each score category of 100, 90, 80, 70, and < 
70 will be provided by cohorts and age groups at baseline and at each scheduled post-baseline 
visit. A patient will be reported only in the age group set at baseline. A summary of change 
from baseline by scheduled visits as well as the worst case post-baseline and the best case 
post-baseline changes during the study will be performed.
A supporting listing will also be provided.
2.8.5.2
Palatability
Palatability assessments (bitterness, sweetness, texture and overall taste) will be listed for each 
patient receiving oral liquid formulation (i.e. trametinib solution or dabrafenib suspension) and 
summarized by assessment time. The number and percentages of patients for each category of 
palatability assessments will be summarized.
2.8.5.3
Physical Examination
Dermatologic skin assessments, radiograph of wrist and tibial growth plate, and 
ophthalmologic examination will be listed for each patient at each time point.
In addition, tanner staging will be listed for each patient at each time point.
2.8.5.4
Cardiovascular Events
Cardiovascular events will be listed for all patients in which an event occurred.
2.8.5.5
Pregnancies
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy for medical reasons will be recorded as an AE or SAE as 
described in the protocol. If patients become pregnant while on the study, the information will 
be included in the narratives and no separate table or listing will be produced.


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2.9
Pharmacokinetic endpoints
Pharmacokinetic analyses will be conducted based on the PK population unless otherwise 
specified.
PK parameters
PK parameters for trametinib, dabrafenib and dabrafenib metabolites will be calculated based 
on non-compartmental methods using Phoenix WinNonlin version 5.2 or higher (Pharsight, 
Mountain View, CA). All calculations of non-compartmental parameters will be based on actual 
blood sampling times. PK parameters listed in Table 2-10 will be estimated and reported as data 
permit.
Population PK parameters may include the following and are dependent upon the final 
population PK model for both trametinib and/or dabrafenib: apparent clearance following oral 
dosing (CL/F), central volume of distribution (Vc/F), absorption rate constants (ka) and 
MTIME (time when absorption rate changes).
Final PK parameters will be summarized and will be compared to historical adult data.
Table 2-10
PK parameters 
AUClast
The AUC from time zero to the last measurable plasma concentration 
sampling time (tlast) (ng*hr*mL-1)
AUCtau
The AUC calculated to the end of a dosing interval (tau) at steady-state (after 
repeated dose). The plasma concentration at 12 or 24 hours after dosing will 
be set equal to the predose plasma concentration for the calculation of 
AUCtau
Cmax
The maximum (peak) observed plasma concentration following a single 
dose administration (ng/mL)
Tmax
The time to reach maximum (peak) plasma concentration following a single 
dose administration (hr)
CL/F
The total apparent body clearance of drug from plasma (L*hr-1)
Ctrough
The observed plasma concentration just prior to the beginning of, or at the 
end, of a dosing interval
Cavg
The average steady-state plasma concentration will be calculated as the ratio 
of AUCtau (where tau = 24 h for trametinib and 12 h for dabrafenib), as data 
permit


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For Part A and Part A extension, PK parameters will be summarized by day and dose level. 
Additionally, PK parameters will be summarized by age categories (<2 years, 2-<6 years, 6-
<12 years,12 to 18 years) for each dose cohort.
For Part B, PK parameters will be summarized by day, dose and disease cohort. Additionally,
PK parameters will be summarized by age categories (<2 years, 2-<6 years, 6-<12 years, 12 to 
18 years)for each disease cohort.
For Part C and C extension, PK parameters for trametinib, dabrafenib and dabrafenib
metabolites 
will 
be 
summarized 
by 
day 
and 
combination 
regimen(e.g. 
TMT 
0.0025mg/kg+DRB 2.25 mg/kg). Additionally, PK parameters will be summarized by age 
categories (<2 years, 2-<6 years, 6-<12 years, 12 to 18 years) for each combination regimen.
For Part D, PK parameters will be summarized by day, dose and disease cohort. Additionally,
PK parameters will be summarized by age categories (<2 years, 2-<6 years, 6-<12 years, 12 to 
18 years) for each disease cohort.
Descriptive statistics for trametinib, dabrafenib and dabrafenib metabolites (n, arithmetic mean,
CV% mean, standard deviation (SD), median, geometric mean, CV% geo-mean, minimum and 
maximum) will be presented for all PK parameters, except Tmax, where only n, median, 
minimum and maximum will be presented. 
All individual PK parameters will be listed by study part and treatment.
PK concentrations
Descriptive statistics (n, m (number of non-zero concentrations), mean, CV% mean, SD, 
median, geometric mean, CV% geo-mean, minimum and maximum) will be presented for 
trametinib, dabrafenib and dabrafenib metabolite concentration at each scheduled time point by 
study part, day, and treatment dose .
Individual concentration-time profiles for trametinib, dabrafenib and dabrafenib metabolites 
with median will be displayed graphically by study part, day and treatment for All treated 
population on semi-log view. In addition, the median/geometric mean concentration-time 
profiles for trametinib, dabrafenib and dabrafenib metabolites will be displayed graphically by 
study part, day and treatment for PK population on linear and semi-log view.
All individual plasma trametinib, dabrafenib and dabrafenib metabolite concentrations will be 
listed by timepoint and summarized by study part, planned sampling time, treatment day and 
treatment.
Handling of PK data below LLOQ or missing
All concentration values below the lower limit of quantitation (LLOQ) are set to zero by the 
Bioanalyst, and will be displayed in the listings as zero and flagged. LLOQ values 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%. The number of non-zero concentrations will 
also be reported in the summary statistics.
Missing values for any PK data will not be imputed and will be treated as missing.


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Population Pharmacokinetic Analysis
All trametinib and dabrafenib concentration-time data may be combined and included in
a population PK analysis that will examine the influence of demographics (especially age
and weight) on the PK of study treatment. Trametinib and dabrafenib PK parameters
estimated in the population PK analysis will include: apparent oral clearance (CL/F), central 
volume of distribution (Vc/F) and absorption rate constants (ka) (trametinib only). Data may 
be pooled with PK data from adult studies. These analyses will be documented in a separate
analysis plan, and the results will be reported in a separate population PK report outside of the 
CSR.


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4
Change to protocol specified analyses
No changes from the protocol specified analyses were made.
5
Appendix
5.1
Imputation rules
In general, imputed partial dates will not be used to derive study day, duration (e.g. duration of 
adverse events), or elapsed time variables.
Imputed dates will not be displayed in listings. However, where necessary, display macros 
may impute dates as temporary variables for the purpose of sorting data in listings only. In 
addition partial dates may be imputed for ‘slotting’ data to study time periods (see [Section
9.3 in Protocol]) or for specific analysis purposes as outlined below. 
5.1.1
Study drug
The following rule should be used for the imputation of the dose end date for a given study 
treatment component:
Scenario 1: If the dose end date is completely missing and there is no Study Treatment 
Discontinuation page and no death date, the patient is considered as on-going:
The patient should be treated as on-going and the cut-off date should be used as the last 
dosing date. 
Scenario 2: If the dose end date is completely or partially missing and the Study Treatment 
Discontinuation page is available:
Case 1: The dose end date is completely missing, and the Study Treatment Discontinuation 
date is complete, then this latter date should be used.
Case 2: Only Year (yyyy) of the dose end date is available and yyyy < the year of Study 
Treatment Discontinuation date:
Use Dec31yyyy
Case 3: Only Year (yyyy) of the dose end date is available and yyyy = the year of Study 
Treatment Discontinuation date:
Use Study Treatment Discontinuation date
Case 4: Both Year (yyyy) and Month (mm) are available for dose end date, and yyyy = the 
year of Study Treatment Discontinuation date and mm < the month of  Study Treatment 
Discontinuation date: 
Use last day of the Month (mm)


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All other cases should be considered as a data issue and the statistician should contact the data 
manager of the study.
After imputation, compare the imputed date with start date of treatment, if the imputed date is 
< start date of treatment:
Use the treatment start date
Patients with missing start dates are to be considered missing for all study treatment 
component related calculations and no imputation will be made. If start date is missing then 
end-date should not be imputed.
5.1.2
AE, ConMeds and safety assessment date imputation
Table 5-1
Imputation of start dates (AE, CM) and assessments (LB, EG, VS)
Missing 
Element
Rule
day, month, 
and year

No imputation will be done for completely missing dates
day, month

If available year = year of study treatment start date then 
o
If stop date contains a full date and stop date is earlier than 
study treatment start date then set start date = 01JanYYYY
o
Else set start date = study treatment start date. 

If available year > year of study treatment start date then 01JanYYYY
o
If available year < year of study treatment start date then 01JulYYYY
day

If available month and year = month and year of study treatment start 
date then 
o
If stop date contains a full date and stop date is earlier than 
study treatment start date then set start date= 01MONYYYY. 
o
Else set start date = study treatment start date.

If available month and year > month and year of study treatment start 
date then 01MONYYYY  

If available month and year < month year of study treatment start date 
then 15MONYYYY  
Table 5-2
Imputation of end dates (AE, CM) 
Missing 
Element
Rule
(*=last treatment date plus 30 days ( not death date, cut-off date, 
withdrawal of consent date))
day, month, 
and year

Completely missing end dates (incl. ongoing events) will be imputed 
by the end date of the on-treatment period* 


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Missing 
Element
Rule
(*=last treatment date plus 30 days ( not death date, cut-off date, 
withdrawal of consent date))
day, month

If partial end date contains year only, set end date = earliest of 
31DecYYYY or end date of the on-treatment period * 
day

If partial end date contains month and year, set end date = earliest of 
last day of the month or end date of the on-treatment period*
Any AEs and ConMeds with partial/missing dates will be displayed as such in the data listings.
Any AEs and ConMeds which are continuing as per data cut-off will be shown as ‘ongoing’ 
rather than the end date provided. 
5.1.3
Other imputations
Incomplete date of initial diagnosis of cancer and date of most recent 
recurrence 
Missing day is defaulted to the 15th of the month and missing month and day is defaulted to 01-
Jan. 
Incomplete assessment dates for tumor assessment
All investigation dates (e.g. MRI scan, CT scan) must be completed with day, month and year. 
If one or more assessment dates are incomplete but other investigation dates are available, 
this/these incomplete date(s) are not considered for calculation of the assessment date and 
assessment date is calculated as the latest of all investigation dates (e.g. MRI scan, CT scan) if 
the overall response at that assessment is CR/PR/SD/UNK. Otherwise – if overall response is 
progression – the assessment date is calculated as the earliest date of all investigation dates at 
that evaluation number. If all measurement dates have no day recorded, the 1st of the month is 
used. If the month is not completed, for any of the investigations, the respective assessment will 
be considered to be at the date which is exactly between previous and following assessment. If 
a previous and following assessment is not available, this assessment will not be used for any 
calculation.
Applying the cut-off to tumor assessment
For tumor related assessments, if an evaluation has some assessments done prior to cut-off date 
and others after the cut-off date , then the evaluation is considered post-cut-off date and will be 
excluded from analysis.
5.1.4
Age calculation in Lab data
Following algorithm will be applied to derive the age at each visit in the Lab dataset and will 
be used in mapping the Lab normal reference ranges per age. 
Step 1


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For screening visit:
Use the age that the site provided in raw data (Age in Days, Age in Months, Age in Years)
Age in month will be age in days/30.4375.
Age in month will floor to integer, for example, if the calculated age in month is 14.3 then the 
age will be considered as 14 months and will be used when mapping with local reference 
ranges.
For other visits:
If Age is provided in Days, Age at each visit calculated as [Date of sample Collection(LBDT) 
- ICF date + Age in Days]
If Age is provided in Months, Age at each visit is calculated as [Date of sample 
Collection(LBDT) - ICF date + Age in Months + 15 days]
If Age is provided in Years, , Age at each visit is calculated as [Date of sample 
Collection(LBDT) - ICF date + Age in Years + 6 months].
If age is missing in demo then age in each visit is calculated as [Date of sample 
Collection(LBDT) - ICF date.
Age in month will be age in days/30.4375.
Step 2
If reference ranges are not mapped and still missing from Step 1, apply the following rules. If 
Age is provided in Days, Age at each visit = [Date of sample Collection(LBDT) - ICF date + Age in 
Days] 
If Age is provided in months, Age is [Date of sample Collection(LBDT) - ICF date + Age in Months -
15 days] <=Age at each visit < [Date of sample Collection(LBDT) - ICF date + Age in Months + 15 
days]
If Age is provided in years, Age is [Date of sample Collection(LBDT) - ICF date + Age in Months –
6months] <= Age at each visit < [Date of sample Collection(LBDT) - ICF date + Age in Months + 
6months]
For both cases above, when there are more than one age ranges, select the ranges in order of (1) lower 
range (2) upper range. For example, if the age ranges are 13-60 and 61-119, then choose 13-60.
5.2
AEs coding/grading
Adverse events (AEs) will be graded according to the CTCAE, Version 4.0. Adverse events 
will be coded to the preferred term (PT) level using the Medical Dictionary for Regulatory 
Affairs (MedDRA dictionary).
The CTCAE represents a comprehensive grading system for reporting the acute and late 
effects of cancer treatments. CTCAE grading is by definition a 5-point scale generally 
corresponding to mild, moderate, severe, life threatening, and death. This grading system 
inherently places a value on the importance of an event, although there is not necessarily 
proportionality among grades (a grade 2 is not necessarily twice as bad as a grade 1). The 
CTCAE grade of 5 (death) is not used; rather, ‘fatal’ is collected as AE outcome and death 
information is also collected on a separate (e)CRF page.


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5.3
Laboratory parameters derivations
Grade categorization of lab values will be assigned programmatically as per NCI Common
Terminology Criteria for Adverse Events(CTCAE) version 4.0. The calculation of CTCAE 
grades will be based on the observed laboratory values only, clinical assessments will not be 
taken into account. 
For laboratory tests where grades are not defined by CTCAE v4.0, results will be graded by the 
low/normal/high classifications based on laboratory normal ranges.
A severity grade of 0 will be assigned for all non-missing lab values not graded as 1 or higher. 
Grade 5 will not be used. For laboratory tests that are graded for both low and high values, 
summaries will be done separately and labelled by direction, e.g., sodium will be summarized 
as hyponatremia and hypernatremia.
Imputation Rules
CTC grading for blood differentials is based on absolute values. However, this data may not be 
reported as absolute counts but rather as percentage of WBC. 
If laboratory values are provided as ‘<X’ (i.e. below limit of detection) or ‘>X’, prior to 
conversion of laboratory values to SI unit, these numeric values are set to X.
The following rules will be applied to derive the WBC differential counts when only 
percentages are available for a xxx differential
xxx count = (WBC count) * (xxx %value / 100)
Further derivation of laboratory parameters might be required for CTCAE grading. For instance, 
corrected calcium can be derived using the reported total calcium value and albumin at the same 
assessment using the following formula:
Corrected Calcium (mg/dL) = Calcium (mg/dL) – 0.8 [Albumin (g/dL)-4]
In order to apply the above formula, albumin values in g/L will be converted to g/dL by
multiplying by 0.1, calcium values in mmol/L will be converted to mg/dL by dividing by 0.2495. 
For calculation of laboratory CTC grades 0 and 1, the normal range for derived corrected 
calcium is set to the same limits (in mg/dL) as for calcium.
CTC grades for the derived absolute WBC differential counts (neutrophils, lymphocytes) and 
corrected calcium will be assigned as described above for grading.
Lab normal reference ranges
Local laboratory reference ranges will be collected throughout the study and will be provided 
by derived age at each visit using the age calculation algorithm provided in Appendix 5.14.


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5.4
Statistical models
5.4.1
Primary analysis
For Part A, Part B, Part C, and Part D there are no formal statistical hypothesis are to be tested.
As stated in protocol, the primary focus of the study is to characterize the safety and tolerability 
of trametinib and to determine the safe and tolerable dose.
5.4.2
Key secondary analysis
There is no key secondary objective.