Conditions: Neoplasms, Brain
Keywords: Children and Adolescents BRAF dabrafenib dose escalation BRF116013 V600-mutation positive BRF
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 85
Healthy volunteers: no

Brief summary:
This was a 2-part, Phase I/IIa, multi-center, open label, study in pediatric and adolescent patients with advanced BRAF V600 mutation-positive solid tumors. Part 1 was a dose escalation study in patients with any BRAF V600 mutation-positive solid tumor using a modified Rolling 6 Design (RSD). Part 2 was an expansion study to further evaluate the safety, tolerability, and clinical activity of dabrafenib in 4 tumor-specific pediatric populations. Patients participated in only either part 1 or part 2 of the study.

Detailed description:
Part 1 was a dose escalation study in subjects with any BRAF V600 mutation-positive solid tumor, designed to optimize efficiency of enrollment, minimize the number of subjects being treated at potentially sub-efficacious dose levels, and incorporating the evolving pharmacokinetic, safety and efficacy data from the adult development program. Dose escalation part of the study was to determine the maximum tolerated dose (MTD) and recommend the dose for phase 2 studies (RP2D). An MTD has not been identified for dabrafenib in the adult population. This does not preclude the identification of an MTD in the pediatric population. Modified RSD was employed to determine the MTD. Part 1 used dual criteria of dose limiting toxicity (DLT) and observed dabrafenib exposures to make decisions to advance to the next dose level. Target exposure criteria based on adults treated at the approved adult dose of 300 mg (150 mg given BID) were observed in this study before meeting criteria for stopping dose escalation due to observations of DLTs, and served as the criteria for determining the RP2D for dabrafenib in pediatric subjects. Thus, MTD has not been established in pediatric population, similar to the previous dose finding efforts in adult subjects.

Part 2 was a tumor specific expansion study to further evaluate the safety/tolerability profile and to discover possible clinical efficacy of dabrafenib in 4 tumor-specific pediatric populations known to have BRAFV600 activation: high grade glioma (HGG), low grade glioma (LGG), Langerhans cell histiocytosis (LCH), miscellaneous tumors including melanoma and papillary thyroid carcinoma (Other). The exposures for subjects dosed on the basis of weight were also evaluated by age categories.

Arms:
arm 1: Three subjects will receive a single dose of 3 mg/kg dabrafenib on Day 1 and repeat dose will begin from Day 2, evenly divided in two daily doses. Once all 3 subjects have been fully evaluated for the first 28 days (including Day 15 PK) and no DLTs are observed, a next subject will be enrolled at the next higher dose levels (i.e., dose escalation to 3.75 mg/kg \[+1\] and may be further to 4.5 mg/kg \[+2\] and so on). If all 3 subjects have not been fully evaluated for the first 28 days or 1 DLT occurred, the fourth subject will be enrolled at the same dose level. If 2 or more DLTs are observed, the next subject will be enrolled at the next lower dose level (i.e., de-escalated to 2.25 mg/kg \[-1\] and may be further to 1.5 mg/kg \[-2\]). Similarly, the process is repeated for the fifth and sixth subjects in a cohort. All subjects will receive treatment till end of study. arm 2: Subjects with low-grade gliomas with BRAF V600 mutations will receive the single selected final dose (based on MTD and the age of the subjects) from Part 1 on Day 1. Repeat dosing will begin from Day 2, twice daily till end of study. arm 3: Subjects with high-grade gliomas with BRAF V600 mutations will receive the single selected final dose (based on MTD and the age of the subjects) from Part 1 on Day 1. Repeat dosing will begin from Day 2, twice daily till end of study. arm 4: Subjects with LCH with BRAF V600 mutations will receive the single selected final dose (based on MTD and the age of the subjects) from Part 1 on Day 1. Repeat dosing will begin from Day 2, twice daily till end of study. arm 5: Subjects with other tumors with BRAF V600 mutations will receive the single selected final dose (based on MTD and the age of the subjects) from Part 1 on Day 1. Repeat dosing will begin from Day 2, twice daily till end of study.

Interventions: intervention 1: Dabrafenib
Intervention descriptions: intervention 1: Dabrafenib is available as 50 mg or 75 mg capsules and as oral suspension (10 mg/mL for subjects unable to swallow capsules). Dabrafenib (either formulation) will be administered orally as a single dose on Day 1 and twice daily from Day 2, based on weight at the appropriate study dose level.

Protocol document:
Prot_000.pdf: 
Clinical Development 
Dabrafenib (DRB436)
Protocol BRF116013 / NCT01677741
Phase I/IIa, 2-part, Multi-Center, Single-Arm, Open-Label 
Study to Determine the Safety, Tolerability and 
Pharmacokinetics of Oral Dabrafenib in Children and 
Adolescent Subjects with Advanced BRAF V600-Mutation 
Positive Solid Tumors 
Document type 
Amended Protocol Version (Clean) 
EUDRACT number 
2012-001499-12 
Version number 
11 
Development phase 
I/IIa 
Document status 
Final 
Release date 
21-Aug-2020
Novartis internal 
reference number 
CDRB436A2102 
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 


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Amendment 11 (21-Aug-2020) 
Amendment Rationale 
As of 17-Jul-2020, 85 patients have received study treatment in 8 countries; Part 1 dose 
escalation has enrolled 27 patients and is closed to enrollment. Part 2 has enrolled 58 pediatric 
patients, and is closed to enrollment. These 58 patients include: 28 patients with High Grade 
Glioma (HGG), 17 patients with Low Grade Glioma (LGG), 11 patients with Langerhans Cell 
Histiocytosis (LCH) and 2 patients with other (miscellaneous) solid tumors. 52 patients in Part 
1 or Part 2 have completed or discontinued study treatment. 
The purpose of this amendment is to change the target patient enrollment number for the 
miscellaneous tumor cohort.  The clinical trial has achieved its major aims of identifying 
suitable doses to reach target exposure across various ages, demonstrated acceptable toxicity, 
and importantly, identified several disease cohorts where dabrafenib demonstrated sufficient 
antitumor activity to merit further clinical investigation.  These aims have been previously 
aligned with EU and US regulatory agencies.   
Note that the trial has enrolled only four patients with miscellaneous tumor types (those that are 
BRAFV600 mutant but are not HGG, LGG, or LCH); two in the dose finding portion, two in 
the dedicated miscellaneous cohort, over the more than 5 years of  enrollment. The 
miscellaneous cohort is not required for regulatory obligations, and is not required to meet the 
aims of the clinical trial.  Hence, the proposed enrollment target for the miscellaneous cohort is 
modified from ‘at least 10 patients’ to ‘up to ten patients.’   
The protocol is also being amended 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.   
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: 
• List of Abbreviations Table: updated to include PIP and RANO. 
• Removal of named contact details and integrated signature pages in alignment with 
current Novartis template and standards. 
• Section 3.1.2: Amended to match the clinical measures in the current approved PIP. 


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• Appendix 15.2: 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.  
 
 


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Amendment 10 (04-Apr-2019) 
Amendment Rationale 
As of 06-Feb-2019, 85 patients have received study treatment in 8 countries; Part 1 dose 
escalation has enrolled 27 patients and is closed to enrollment. Based on the data from these 27 
subjects, no maximum tolerated dose was established in this pediatric population and the 
recommended Phase 2 doses (RP2Ds) for dabrafenib monotherapy were determined based on 
exposure target as 5.25 mg/kg/day for patients < 12 years old and 4.5 mg/kg/day for patients ≥ 
12 years old, divided into two equal daily doses, and not to exceed adult dose. 
Part 2 has enrolled 58 pediatric patients, and is closed to enrollment. These 58 patients include: 
28 patients with High Grade Glioma (HGG), 17 patients with Low Grade Glioma (LGG), 11 
patients with Langerhans Cell Histiocytosis (LCH) and 2 patients with other solid tumors. 52 
patients in Part 1 or Part 2 have completed or discontinued study treatment. 
The purpose of this amendment is to add additional interim analyses of data to support health 
authority 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 5.3.2: Updated to include additional interim analyses to support health authority 
requests. 
• Section 7.1.1: 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 8.2: Table 12 updated to remove oxcarbazepine from list of prohibited 
medications during study treatment. Based on the 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 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. 
Amendment 9 (17-Sep-2018) 
Amendment rationale  
84 subjects have received study treatment in 7 countries; Part 1 dose escalation has enrolled 27 
subjects and is closed to enrollment. Based on the data from these 27 subjects, no maximum 
tolerated dose was established in this pediatric population and the recommended Phase 2 doses 
(RP2Ds) for dabrafenib monotherapy were determined based on exposure target as 5.25 


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mg/kg/day for subjects < 12 years old and 4.5 mg/kg/day for subjects ≥ 12 years old, divided 
into two equal daily doses, and not to exceed adult dose. 
Part 2 has enrolled 57 pediatric patients (27 patients with High Grade Glioma (HGG), 17 
patients with Low Grade Glioma (LGG), 11 patients with Langerhans Cell Histiocytosis (LCH) 
and 2 patients with other solid tumors). Currently only the HGG and other solid tumor cohorts 
are open for enrollment in Part 2. 47 subjects in Part 1 or 2 have completed or discontinued 
study treatment. 
The purpose of this amendment is:  
i) Addition of a new pediatric formulation dosage form of dabrafenib 10mg as dispersible 
tablets. 
ii) Update the withdrawal of consent language to align with the new Global Data Protection 
Requirements. 
Changes to 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: 
• Sponsor Signatory Page: update to current team member 
• Section 1.1.4: Addition of PK data of Dabrafenib dispersible tablet formulation 
• Section 3.2, 3.6, 10.3, 10.4: Addition of Dabrafenib dispersible tablet language 
• Section 9.3: Withdrawal of consent wording added to align with new Global Data 
Protection Requirements. 
• Section 4.2, 7.1: Updated program standard language regarding contraceptive methods 
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. 
Amendment 8 (19-May-2017) 
Amendment rationale  
As of 04-May-2017 
78 subjects have received study treatment in 7 countries; Part 1 dose escalation has enrolled 27 
subjects and is closed to enrollment. Based on the data from these 27 subjects, no maximum 
tolerated dose was established in this pediatric population and the recommended Phase 2 doses 
(RP2Ds) for dabrafenib monotherapy were determined based on exposure target as 5.25 


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mg/kg/day for subjects < 12 years old and 4.5 mg/kg/day for subjects ≥ 12 years old, divided 
into two equal daily doses, and not to exceed adult dose. 
Part 2 has enrolled 51 subjects (21 pediatric High Grade Glioma (HGG), 17 pediatric Low 
Grade Glioma (LGG), 11 Langerhans Cell Histiocytosis (LCH) and 2 other solid tumor 
subjects). Currently only the HGG and other solid tumor cohorts are open for enrollment in Part 
2. 40 subjects in Part 1 or 2 have completed or discontinued study treatment. 
An interim analysis was performed in 2016 after all subjects with LGG had enrolled in Part 2 
and completed at least 6 months of treatment or had discontinued treatment earlier. The interim 
analysis showed preliminary efficacy in overall response rate for subjects with HGG and LGG 
sufficient for further investigation. 
The main objective of this protocol amendment 8 is  
• To allow the enrollment of additional subjects in the HGG cohort of Part 2 of the study. 
This cohort was originally planned to include approximately 10 subjects and has enrolled 
21 subjects in Part 2 to date. In view of the promising efficacy in this otherwise very poor 
prognosis disease, enrollment will remain open until another pediatric HGG study is open 
for enrollment of this population across all age groups in the same countries (expected by 
the end of 2018 and no later than mid 2019). Enrollment into the LGG and LCH cohorts 
have not been extended as subjects may be able to enroll into another pediatric study 
(MEK116540).    
Additional changes were made as follow: 
• The safety monitoring and management sections were revised to distinguish the 
procedures that are recommended or mandatory and updated to align with the program 
standard language. The management of renal insufficiency section was clarified to account 
for the young age population studied and their normal range.  
• The monitoring process of dermatologic lesions was modified to allow local assessment 
during non-clinic visits or dermatologic assessment only visits to accommodate subjects 
who have to travel from afar. 
• Collection of imaging scans from the most recent prior chemotherapy for subjects with 
LGG was added to explore the comparison of retrospective data with data collected while 
on treatment. Tumor shrinkage at a six month time-point of treatment has been utilized as 
a surrogate for treatment effect in LGG, where durable stability or shrinkage is considered 
clinical benefit.  Performing a similar comparison in subjects with HGG would be more 
difficult due to the aggressive nature of the disease and the need to review the entire prior 
clinical course.   
• The table of time and events schedule was modified to align the assessments to decrease 
the frequency of visits after one year of treatment.  
• The data analysis and statistical consideration was updated to align the analysis 
populations with the statistical analysis plan. 
• Two interim analyses were added to explain a past unplanned interim analysis and a future 
interim analysis for decision making of development options. 
• Independent review of HGG tumor histology was clarified in the protocol.  It has been 
shown that LGG can be misdiagnosed for HGG, so the independent review will ensure 


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consistent application of the WHO glioma classification scale to allow for more reliable 
comparison to historical studies. As a sensitivity analysis, the efficacy data will be 
analyzed including only subjects with centrally confirmed HGG. 
• Due to the possible harm to the fetus from dabrafenib exposure, male contraception 
requirement was added. 
• The permitted and prohibited concomitant medication section was modified to permit 
immunization and to remove the need to be cautious with medicinal products that increase 
gastric pH due to the low drug-drug interaction risk.  Co-administration of dabrafenib with 
the pH elevating agent rabeprazole (proton pump inhibitor) did not result in clinically 
meaningful changes to dabrafenib PK (study CDRB436A2103).  
• Editorial changes and text corrections were made for clarification, where required, and to 
align with Novartis terminology procedures and format. 
Changes to 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 2: Clarified anti-tumor activity objectives between investigator assessed and 
independent assessed response 
• Section 3.1, Section 3.1.2, Section 4.1, Section 5.2.1.2, Section 5.2.2: Amended to 
increase the sample size 
• Section 3.3: Clarified DLT evaluable population definition 
• Section 3.7.4.1, Section 3.7.4.2, Section 3.7.4.4: These sections and tables were updated to 
provide clarity on the recommended or mandatory safety monitoring and management 
procedures. The adverse event management guidelines remain largely the same as 
protocol amendment 7. 
• Section 3.7.4.2: Added clarification on management of renal insufficiency in this young 
studied population 
• Section 3.7.4.3, Section 3.8, Section 6.3: Added and modified dermatologic monitoring 
and assessment. 
• Section 3.7.5: Added dose modification guidance for uveitis 
• Section 3.8: Updated table to provide clarity on assessments and to decrease frequency of 
assessments after 48 weeks of treatment 
• Section 3.8, Section 6.1: Added collection of imaging scans from the most recent prior 
chemotherapy for subjects with LGG 
• Section 5.3: Clarified analysis population definition and aligned with Novartis 
terminologies. 
• Section 5.3.2: Added 2 interim analyses (one past unplanned interim analysis and a future 
interim analysis) 
• Section 5.3.3.1, Section 5.3.3.1.3, Section 5.3.3.1.4, Section 5.3.3.3: Clarified analysis 
plan 
• Section 6.2.1: Clarified BRAF mutation testing procedure 
• Section 6.2.3: Clearly described the independent review of HGG tumor histology 


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• Section 6.3: Removed ANC testing requirement.  Percentage is acceptable. Clarified 
laboratory testing requirement needed for LCH scoring. 
• Section 7.1.2: Added male contraception requirement 
• Section 8.1: Added immunization to the permitted medication and non-drug therapies 
section. 
• Section 8.3: removed a risk from ‘Medications to be Used with Caution’ as studies have 
shown it is not considered a risk.  
• Section 11.1, Section 11.7: Clarified adverse event definition and SAE reporting 
requirement 
• Section 13.7: Amended timing of study result posting 
• Section 14: Added one reference 
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. 
Amendment 7  
Amendment rationale  
Subsequent to the acquisition of GlaxoSmithKline (GSK) compound GSK2118436 by Novartis, 
the purpose of this protocol Amendment 7 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 19-Aug-2016: 
• 68 patients have received study treatment in 6 countries;  
• 28 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. 


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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. 
Amendments 1 to 6 
Amendment rationale and summary of changes for previous amendments 1 to 6 are provided 
below in the Revision Chronology section and also in Appendix 07 as tracked changes. 
 
Revision Chronology: 
2012N131371_00 
2012-JUL-24 
Original 
2012N131371_01 
2012-OCT-19 
Amendment No. 01 corrected Inclusion Criteria #6 to ensure 
consistency with the contraception requirements as outlined in 
Section 7.1.1; the requirement for male contraception was deleted 
since the risk of embryofetal developmental toxicity as a 
consequence of exposure to female pregnant partners is very low.  
In addition, the dose escalation procedure table provided in 
Appendix 1 was changed to ensure that escalation of dose when 6 
subjects are enrolled occurs only if there are ≤1 subject with a DLT 
and no subject data pending, and to fix the reference and formatting. 
2012N131371_02 
2012-DEC-13 
Amendment No. 02 is a country-specific amendment for France 
which prohibits children younger than 6 years and children older 
than 6 years with a risk of choking when swallowing capsules from 
inclusion in the study in France (pending availability of an oral 
suspension formulation); changes the QTc stopping criteria to 500 
msec for French subjects (as compared to 530 msec); adds cardiac 
monitoring by echocardiogram (ECHO) at Week 4; and highlights 
that ECHOs are to be performed by the same operator throughout 
the study, where possible. 
2012N131371_03 
2013-MAR-28 
Amendment No.: 03: To take into account potential renal effects, 
Amendment 03 changed the lower age limit of inclusion criterion #2 
from subjects 1 month old to ≥12 months old, adjusted criteria for 
adequate renal function in inclusion criterion #7, added guidelines 
for renal insufficiency and additional laboratory testing.  Information 
on the new suspension formulation was incorporated. The section 
on dose modification was re-organized for consistency. The Time 
and Events Table was adjusted to include assessments on Day 22, 
Week 4 was clarified to be Day 29, and increased chemistry and 
urinalysis evaluations were added. The timing and volume of PK 
samples for subjects <25 kg and ≥10 kg was corrected 
2012N131371_04 
2013-JUN-19 
Amendment No. 04 expanded eligibility to subjects with refractory 
disease, and allows for BID dosing on Day 1. Clarifications made to 
glioma scan requirements and BRAF mutation testing timing. 
Pyrexia management guidelines updated and Prohibited and 
Cautionary medication section updated.   


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2012N131371_05 
2013-JUL-25 
Amendment No.: 05 was made to allow an administrative change 
(i.e. additional abbreviation added); 
to clarify the dose escalation rules to allow selection of the 
appropriate dose by age group in the absence of MTD;  
to include 2 additional dose levels:  
To clarify that at least 5 subjects less than 6 years old will be 
enrolled to be consistent with the binding elements of the PIP 
to permit intra-subject dose escalation during Part 1; intra-subject 
dose escalation determined on case by case basis after evaluation 
of PK and safety;  subjects who are allowed to dose escalate will be 
required to have   additional PK samples collected 15 days after 
starting the higher dose level; 
to include the recommendation for an additional dermatological 
examination 2 months after discontinuation of dabrafenib; 
to clarify the general dose modification guidelines; 
to incorporate instructions for due diligence in contacting subjects 
who may be lost to follow up; 
to clarify the DLT evaluable population and PK population; 
to update the T&E table to specify that ECHOs will be collected for 
all subjects; 
to correct Appendix 1.  
2012N131371_06 
2013-AUG-20 
Re-Publishing to include a component of the binding elements; to 
include some details that were missed in the previous version.  
2012N131371_07 
2014-JUL-30 
Amendment No.: 06  
Title changed to specify children and adolescents instead of specific 
years.  Lower age range increased to ≥12 months from >1 month.   
Study rationale updated to specify refractory disease.   
Clarification of the dose escalation rules for selection of the 
appropriate dose by age group in the absence of MTD.   
Correction of units for exposure criterion.   
Update of dose modification guidelines in accordance with the most 
recent information available for dabrafenib.   
Addition of LCH assessments to the time and events schedule, and 
addition of the LCH scoring system.   
Addition of follow-up skin assessments to the time and events 
schedule and safety assessments, including French country specific 
guidelines.   
Clarification of timing for final study visit in the time and events 
schedule.   
.  Removal of the restriction on 
foods that may inhibit cytochrome (CYP) 3A4 activity.   
Clarification that children that are breastfeeding may continue to 
breast feed on demand, but that if child is breast fed during 
collection of PK samples the time of breastfeeding should be 
recorded.   
Overdose section updated in accordance with the most recent 
information available for dabrafenib. 
SAE definition of protocol-specific SAEs updated for clarity and 
modified based on additional understanding of the compound. 
2012N131371_08 
2016-Sep-15 
Amendment No.: 07  
References to GSK or its staff were deleted and replaced with those 
of Novartis/Novartis and its authorized agents. 
Administrative changes to align with Novartis processes and 
procedures were made 


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Sponsor Information Page 
 
Clinical Study Identifier: 
BRF116013 
Sponsor Contact Addresses 
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 contact information and further details. 
If you have any questions regarding the protocol, please contact your local Novartis office or 
its authorized agents. 
• Regulatory Agency Identifying Number(s): 
• IND No.: 117,898 
• EudraCT Number: 2012-001499-12  
        
 
 


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Table of contents 
Amendment 11 (21-Aug-2020) ........................................................................................... 2 
Amendment 10 (04-Apr-2019) ............................................................................................ 4 
Amendment 9 (17-Sep-2018) .............................................................................................. 4 
Amendment 8 (19-May-2017) ............................................................................................. 5 
Amendment 7 ...................................................................................................................... 8 
Amendments 1 to 6 .............................................................................................................. 9 
Sponsor Information Page ................................................................................................. 11 
Table of contents ............................................................................................................... 12 
List of tables ...................................................................................................................... 17 
List of figures .................................................................................................................... 17 
1 
INTRODUCTION ............................................................................................................. 21 
1.1 
Background ............................................................................................................ 21 
1.1.1 
Summary of Safety Data (All Studies) and Available Clinical 
Activity Data (BRF112680 and BRF113710)....................................... 21 
1.1.2 
Pharmacokinetics .................................................................................. 25 
1.1.3 
Pharmacodynamics ............................................................................... 26 
1.1.4 
Relative Bioavailability of Dabrafenib Administered as HPMC 
versus Suspension and dispersible tablet .............................................. 26 
1.1.5 
Dabrafenib in Pediatric Cancers ............................................................ 27 
1.2 
Rationale ................................................................................................................ 29 
1.2.1 
Study Rationale ..................................................................................... 29 
1.2.2 
Dose Rationale ...................................................................................... 30 
1.3 
Summary of Risk Management ............................................................................. 31 
2 
OBJECTIVES AND ENDPOINTS ................................................................................... 34 
3 
INVESTIGATIONAL PLAN ........................................................................................... 34 
3.1 
Study Design/Schematic ........................................................................................ 34 
3.1.1 
Part 1 – Dose Escalation ....................................................................... 36 
3.1.2 
Part 2:  Tumor-Specific Expansion ....................................................... 37 
3.1.3 
Study End .............................................................................................. 38 
3.1.4 
Follow-Up ............................................................................................. 38 
3.2 
Discussion of Study Design ................................................................................... 38 
3.3 
Dose Limiting Toxicity Definitions ....................................................................... 39 
3.4 
Maximum Tolerated Dose (MTD) ......................................................................... 40 
3.5 
Treatment Assignment ........................................................................................... 40 


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3.6 
Investigational Product and Other Study Treatment Dosage/Administration ....... 40 
3.7 
Dose Adjustment/Stopping Criteria ....................................................................... 42 
3.7.1 
Dabrafenib Intra-Subject Dose Escalation ............................................ 43 
3.7.2 
Dabrafenib Dose Modifications/Interruption for Toxicity .................... 43 
3.7.3 
General supportive guidelines ............................................................... 43 
3.7.4 
Dose Modification Guidelines - Adverse Events of Special Interest .... 44 
3.7.5 
Management Guidelines for Additional AEs ........................................ 48 
3.7.6 
Left Ventricular Ejection Fraction Stopping Criteria ............................ 48 
3.7.7 
Valvular Toxicity Stopping Criteria ...................................................... 49 
3.7.8 
Liver Chemistry Stopping Criteria ........................................................ 50 
3.8 
Time and Events Schedule ..................................................................................... 52 
4 
STUDY POPULATION .................................................................................................... 61 
4.1 
Number of Subjects ............................................................................................... 61 
4.2 
Eligibility Criteria .................................................................................................. 61 
4.2.1 
Inclusion Criteria ................................................................................... 61 
4.2.2 
Exclusion Criteria .................................................................................. 62 
4.3 
Screen and Baseline Failures ................................................................................. 63 
4.4 
Withdrawal from Study and Missing Visits .......................................................... 64 
5 
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS .................................... 64 
5.1 
Hypotheses and Treatment Comparisons .............................................................. 64 
5.2 
Sample Size Considerations .................................................................................. 64 
5.2.1 
Sample Size Assumptions ..................................................................... 64 
5.2.2 
Sample Size Re-estimation ................................................................... 65 
5.3 
Data Analysis Considerations ................................................................................ 66 
5.3.1 
Analysis Populations ............................................................................. 66 
5.3.2 
Interim Analysis .................................................................................... 66 
5.3.3 
Final Analyses ....................................................................................... 67 
6 
STUDY ASSESSMENTS AND PROCEDURES ............................................................ 69 
6.1 
Demographic/Medical History Assessments ......................................................... 69 
6.2 
Critical Baseline Assessments ............................................................................... 70 
6.2.1 
Confirmation of BRAF Mutation Positive Status ................................. 70 
6.2.2 
Baseline Documentation of Target and Non-target Lesions ................. 70 
6.2.3 
Independent review of HGG tumor histology ....................................... 70 
6.3 
Safety and Tolerability .......................................................................................... 70 
6.4 
Pregnancy .............................................................................................................. 73 
6.4.1 
Time period for collecting pregnancy information ............................... 73 


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6.4.2 
Action to be taken if pregnancy occurs ................................................. 73 
6.4.3 
Action to be taken if pregnancy occurs in a female partner of a 
male study subject ................................................................................. 73 
6.5 
Pharmacokinetics ................................................................................................... 73 
6.5.1 
Blood Sample Collection ...................................................................... 73 
6.5.2 
Sample Analysis .................................................................................... 74 
6.6 
Anti-tumor Assessment ......................................................................................... 74 
6.6.1 
Assessment of Subject Completion ....................................................... 75 
 
 75 
7 
LIFESTYLE AND/OR DIETARY RESTRICTIONS ...................................................... 75 
7.1 
Contraception Requirements ................................................................................. 75 
7.1.1 
Female Subjects .................................................................................... 75 
7.1.2 
Male Subjects ........................................................................................ 76 
7.2 
Meals and Dietary Restrictions .............................................................................. 76 
7.3 
Caffeine, Alcohol, and Tobacco ............................................................................ 77 
7.4 
Activity .................................................................................................................. 77 
8 
CONCOMITANT MEDICATIONS AND NON-DRUG THERAPIES .......................... 77 
8.1 
Permitted Medications and Non-Drug Therapies .................................................. 77 
8.2 
Prohibited Medications and Non-Drug Therapies ................................................. 78 
8.3 
Medications to be Used with Caution .................................................................... 78 
9 
COMPLETION OR EARLY WITHDRAWAL OF SUBJECTS ..................................... 80 
9.1 
Subject Completion ............................................................................................... 80 
9.2 
Subject Withdrawal Criteria .................................................................................. 80 
9.3 
Subject Withdrawal Procedures ............................................................................. 80 
9.3.1 
Subject Withdrawal from Study ............................................................ 80 
9.3.2 
Subject Withdrawal from Study Treatment .......................................... 80 
9.3.3 
Withdrawal of Consent ......................................................................... 81 
9.4 
Treatment after the End of the Study ..................................................................... 82 
10 STUDY TREATMENT ..................................................................................................... 82 
10.1 
Blinding ................................................................................................................. 82 
10.2 
Packaging and Labeling ......................................................................................... 82 
10.3 
Preparation/Handling/Storage/Accountability ....................................................... 82 
10.4 
Assessment of Compliance .................................................................................... 83 
10.5 
Treatment of Study Treatment Overdose .............................................................. 84 
11 ADVERSE EVENTS (AE) AND SERIOUS ADVERSE EVENTS (SAE) ..................... 84 
11.1 
Definition of Adverse Events ................................................................................ 85 


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11.2 
Definition of Serious Adverse Events ................................................................... 86 
11.3 
Method of Detecting AEs and SAEs ..................................................................... 87 
11.4 
Recording of AEs and SAEs .................................................................................. 87 
11.5 
Evaluating AEs and SAEs ..................................................................................... 87 
11.5.1 
Assessment of Intensity......................................................................... 87 
11.5.2 
Assessment of Causality ....................................................................... 88 
11.6 
Follow-up of AEs and SAEs .................................................................................. 88 
11.7 
Prompt Reporting of SAEs to Novartis ................................................................. 88 
11.8 
Regulatory Reporting Requirements for SAEs ...................................................... 89 
12 LIVER CHEMISTRY FOLLOW-UP PROCEDURES .................................................... 89 
12.1 
Liver Chemistry Monitoring Criteria ..................................................................... 90 
12.2 
Restarting Investigational Product ......................................................................... 91 
13 STUDY CONDUCT CONSIDERATIONS ...................................................................... 92 
13.1 
Posting of Information on Publicly Available Clinical Trial Registers ................. 92 
13.2 
Regulatory and Ethical Considerations, Including the Informed Consent 
Process ................................................................................................................... 92 
13.2.1 
Urgent Safety Measures ........................................................................ 92 
13.3 
Quality Control (Study Monitoring) ...................................................................... 93 
13.4 
Quality Assurance .................................................................................................. 93 
13.5 
Study and Site Closure........................................................................................... 93 
13.6 
Records Retention .................................................................................................. 94 
13.7 
Provision of Study Results to Investigators, Posting of Information on 
Publically Available Clinical Trials Registers and Publication ............................. 94 
13.8 
Data Management .................................................................................................. 94 
14 REFERENCES .................................................................................................................. 96 
15 APPENDICES ................................................................................................................. 100 
15.1 
Appendix 1: Modified Rolling Six Design Dose Escalation Procedures ............ 100 
15.2 
Appendix 2: Response Criteria ............................................................................ 101 
15.3 
Appendix 3: Performance Status Criteria / Scoring System ................................ 112 
15.4 
Appendix 4: Liver Safety Algorithms ................................................................. 113 
15.5 
Appendix 5: Country Specific Amendment 2 for France .................................... 114 
15.6 
Appendix 6 French Country Guidelines for additional dermatological 
monitoring while on therapy and after IP discontinuation .................................. 129 
15.7 
Appendix 7: Protocol Amendment Changes ....................................................... 130 
Amendment 07 ..................................................................................................... 130 
Amendment 06 ..................................................................................................... 141 
Amendment 05 ..................................................................................................... 172 


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Amendment 04 ..................................................................................................... 179 
Amendment 03 ..................................................................................................... 182 
Amendment 02 ..................................................................................................... 196 
Amendment 01 ..................................................................................................... 197 


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List of tables 
Table 1-1 
Investigator–Assessed Response for V600 Mutation-Positive CRC 
from Part 1 and Part 2 of Study BRF112680 ........................................ 22 
Table 1-2 
Investigator-Assessed Response for V600 Mutation Positive 
Papillary Thyroid Cancer from Part 1 and Part 2 in Study 
BRF112680 ........................................................................................... 22 
Table 3-1 
 Dabrafenib Dose Levels a ..................................................................... 36 
Table 3-2 
 Investigational Product ......................................................................... 41 
Table 3-3 
 Dose Modification Guidelines - General ............................................. 44 
Table 3-4 
Mandatory Dose Modification and Recommended Clinical 
Management for Pyrexia ....................................................................... 45 
Table 3-5 
Mandatory Dose Modification and Required Clinical Management 
Guidelines for Renal function alterations ............................................. 46 
Table 3-6 
Withholding and Stopping Criteria for QTc-Prolongation ................... 47 
Table 3-7 
Part 1 and Part 2 Treatment Phase:  Screening through Day 21 (See 
also PK sampling table for PK sampling schedule on Day 1 and 
Day 15) .................................................................................................. 52 
Table 3-8 
PK Sampling Table for Day 1 and Day 15 (Part 1 and Part 2) ............. 55 
Table 3-9 
Part 1 and Part 2 Treatment Phase:  Week 4 (Day 29) through End 
of Study ................................................................................................. 57 
Table 5-1 
Exact Binomial Probabilities of Observing 0 and 1 (or more) 
Responses in 10 Subjects ...................................................................... 65 
Table 5-2 
Exact Binomial 95% Confidence Intervals around Potential 
Observed Objective Responses Rates for 10 and 35 Subjects .............. 65 
Table 8-1 
 Prohibited Medications ........................................................................ 78 
Table 8-2 
Medications to be used with Caution .................................................... 79 
Table 15-1 
Evaluation of Overall Response for Subjects with Measurable 
Disease at Baseline .............................................................................. 102 
 
List of figures 
Figure 3-1 
Study Design ......................................................................................... 35 
 


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ABBREVIATIONS 
ACCIS 
Automated Childhood Cancer Information System 
AE 
Adverse Event 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
AST 
Aspartate aminotransferase 
ATP 
Adenosine triphosphate 
AUC 
Area under concentration-time curve 
AUC(0-∞) 
Area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time 
AUC(0-t) 
Area under the concentration-time curve from time zero (pre-dose) to last time of quantifiable 
concentration within a subject across all treatments 
AUC(0-τ) 
Area under the concentration-time curve over the dosing interval 
β-HCG 
Beta-Human Chorionic Gonadotropin 
BID 
Twice daily 
BUN 
Blood urea nitrogen 
CI 
Confidence Interval 
CLIA 
Clinical Laboratory Improvement Amendments 
CL/F 
Apparent clearance following oral dosing 
Cmax 
Maximum observed concentration  
CNS 
Central nervous system 
Cτ 
Pre-dose (trough) concentration at the end of the dosing interval 
CPK 
Creatine phosphokinase 
CR 
Complete response 
CRC 
Colorectal cancer 
CRF 
Case Report Form 
CRP 
C-Reactive protein 
CRO 
Contract Research Organization 
CT 
Computed tomography 
cuSCC 
Cutaneous squamous cell carcinomas 
DLT 
Dose limiting toxicity 
DNA 
Deoxyribonucleic acid 
DTIC 
Dacarbazine 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
eCRF 
Electronic Case Report Form 
ED50 
One-half the maximal effect 
eGFR 
Calculated Glomerular Filtration Rate 
ERK 
Extra-cellular signal related kinase 
EU 
Europe 
FDA 
Food and Drug Administration 
FDG-PET 
Fludeoxyglucose positron emission tomography 
FTIH 
First time in humans 
G6PD 
Glucose-6-phosphate dehydrogenase 
GCP 
Good Clinical Practice 
GCPH 
Global Clinical Program Head 
GGT 
Gamma glutamyltransferase 
GI 
Gastrointestinal 


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GSK 
GlaxoSmithKline 
hCG 
Human chorionic gonadotropin 
HFSR 
Hand foot skin reactions 
HGG 
High grade gliomas 
HIV 
Human Immunodeficiency Virus 
HPMC 
Hydroxylpropyl methylcellulose 
IB 
Investigator’s Brochure 
IEC 
Independent Ethics Committee 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
ka 
Absorption rate 
KA 
Keratoacanthomas 
Kg 
Kilogram 
L 
Liter 
LCH 
Langerhans cell histiocytosis 
LGG 
Low-grade gliomas 
LLN 
Lower limit of normal 
LVEF 
Left ventricular ejection fraction 
µg 
Microgram 
MCH 
Mean corpuscular hemoglobin 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligrams 
mL 
Milliliter 
MRI 
Magnetic resonance imaging 
MSDS 
Material Safety Data Sheet 
msec 
Milliseconds 
NCI 
National Cancer Institute 
NSCLC 
Non-small cell lung cancer 
PD 
Progression of disease 
pERK 
Phosphorylated ERK 
PIP 
Pediatric Investigation Plan 
PK 
Pharmacokinetic 
PP 
Polypropylene 
PPES 
Palmar Plantar erythrodysaethesia Syndrome 
PR 
Partial response 
PTC 
Papillary Thyroid Carcinoma 
QTc 
QT duration corrected for heart rate 
QTcB 
QT duration corrected for heart rate by Bazett’s formula 
RANO 
Response Assessment in Neuro-Oncology 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RBC 
Red blood cells 
RR 
Response rate 
RSD 
Rolling six design 
SAE 
Serious adverse event(s) 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis Software 


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SCC 
Squamous cell carcinoma 
SD 
Standard deviation 
SEER 
Surveillance Epidemiology and End Results 
SNIFS 
Serious non-infectious febrile syndrome 
SPM 
Study Procedures Manual 
t½ 
Terminal phase half-life 
TID 
Three times a day 
tmax 
Time of occurrence of Cmax 
ULN 
Upper limit of normal 
UK 
United Kingdom 
UPC 
Urine Protein:Creatinine Ratio 
US 
United States 
V/F 
Volume of distribution 
WBC 
White blood cells 


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1 
INTRODUCTION 
1.1 
Background 
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 biomarker 
(phosphorylated extracellular signal-related kinase [pERK]) in tumor cell lines, demonstrated 
anti-proliferative activity against multiple BRAF mutation-positive tumor cell lines, achieved 
proximal biomarker suppression and tumor regression in BRAF mutant xenograft models, and 
has demonstrated significant anti-tumor efficacy in BRAF V600-mutation positive tumors, 
including melanoma, papillary thyroid cancer, and non-small cell lung cancer. Dabrafenib is 
currently approved in many jurisdictions for adult subjects with BRAF V600 mutation-positive 
advanced or metastatic melanoma, and is being studied in subjects with other BRAF V600 
mutation-positive tumor types. 
As of May, 2012, there were 4 completed Phase I studies including the First-Time-in-Human 
(FTIH) study (BRF112680), a food effect/particle size evaluation study (BRF113468) with 2 
different capsule shells (gelatin and hydroxylpropylmethyl cellulose [HPMC]), a human mass 
balance study (BRF113463), and a microdose absolute bioavailability study (BRF113479), and 
1 ongoing clinical pharmacology study, a repeat dose, drug-drug interaction study 
(BRF113771).  There were ongoing Phase II studies (BRF113710 in subjects with metastatic 
melanoma, BRF113928 in subjects with non-small cell lung cancer [NSCLC] and BRF113929 
in subjects with metastatic melanoma to the brain), and one ongoing Phase III study 
(BRF113683) in advanced or metastatic melanoma.  Three pediatric subjects were given 
dabrafenib on a compassionate use basis.  There is an ongoing Phase I/II combination study 
with trametinib (GSK1120212), a MEK inhibitor (BRF113220).  A separate rollover protocol 
is available for subjects still benefitting from treatment at the end of the Phase I, II or III studies. 
Complete safety, clinical activity and pharmacokinetic (PK) data for clinical and non-clinical 
studies conducted with dabrafenib are provided in the Investigator Brochure (IB).  A summary 
of safety, clinical activity and PK data are also provided below. Please refer to the current 
Investigator’s Brochure for the most up to date safety and efficacy data.   
1.1.1 
Summary of Safety Data (All Studies) and Available Clinical Activity 
Data (BRF112680 and BRF113710) 
1.1.1.1 
BRF112680 (FTIH) 
As of 20 February, 2012, a total of 184 subjects received at least one dose of dabrafenib.  As of 
19 March 2012 all subjects were discontinued from the study.  One hundred and eighty-two 
(99%) subjects experienced an adverse event (AE) of any grade. The most common (>20% of 
all subjects) AEs of any grade across all dosing cohorts in Part 1 and Part 2 were fatigue (42%), 
pyrexia (37%), headache (35%), nausea (34%), hyperkeratosis (33%), diarrhoea (27%), 
arthralgia (25%), pain in extremity (25%), decreased appetite (24%), alopecia (23%) and rash 
(23%).  Serious adverse events (SAEs) were reported in 39% of subjects.  SAEs occurring in 
3% or more subjects were squamous cell carcinoma (SCC) (12%), pyrexia (7%), and urinary 
tract infection (3%).  Sixty four subjects are reported to have had study drug interrupted due to 


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the occurrence of AEs.  Pyrexia was the most common AE leading to a dose interruption.  
Fifteen subjects reported a dose reduction due to the occurrence of 23 AEs.  There were no 
instances of discontinuation of study treatment due to AEs and no fatal AEs reported in the 
study among subjects who received at least one dose of dabrafenib. 
PK, pharmacodynamic and clinical activity results supported 1) the conclusion that the 
recommended clinical dose of dabrafenib in adult subjects is 150 mg twice daily (BID) and 2) 
the conclusion that dabrafenib has demonstrated significant efficacy in subjects with BRAF 
V600E or V600K mutant-positive advanced melanoma. 
An investigator-assessed best unconfirmed response rate of 67% was observed in subjects with 
BRAF V600E/K mutation-positive melanoma receiving the recommended dose of 150 mg BID 
(n=45). 
In addition, data from a small number of adult subjects with BRAF V600 mutation-positive 
solid tumors other than melanoma, who were enrolled in an expansion cohort in the FTIH study, 
suggested that dabrafenib may have beneficial effects in these subjects as well [BRF112680].  
There were 7 subjects enrolled with colorectal cancer (CRC), 10 subjects with thyroid cancer, 
1 subject with NSCLC and 1 subject with ovarian cancer.  A summary of investigator-assessed 
unconfirmed response for CRC and thyroid cancer are summarized in Table 1 and Table 2, 
respectively.  The NSCLC subject was enrolled in Part 2 (150 mg BID) and reported an 
unconfirmed partial response (PR) at 6 weeks followed by disease progression at 12 weeks.  
The ovarian cancer subject was enrolled in Part 1 (100 mg BID) and reported stable disease 
before progressing at approximately 36 weeks. 
 
Table 1-1 
Investigator–Assessed Response for V600 Mutation-Positive CRC 
from Part 1 and Part 2 of Study BRF112680 
 
Part 1 (N=1) 
Part 2 (N=6) 
Total (N=7) 
Best Response, n (%) 
Complete Response (CR) 
0 
0 
0 
Partial Response (PR) 
0 
1 (17%) 
1 (14%) 
Stable Disease 
0 
5 (83%) 
5 (71%) 
Progressive Disease (PD) 
0 
0 
0 
Unknown 
1 (100%) 
0 
1 (14%) 
Response Rate, n (%) 
CR+PR 
0 
1 (17%) 
1 (14%) 
95% Confidence Interval 
 
(0.4%, 64.1%) 
(0.4%, 57.9%) 
 
Table 1-2 
Investigator-Assessed Response for V600 Mutation Positive Papillary 
Thyroid Cancer from Part 1 and Part 2 in Study BRF112680 
 
Part 1 (N=2) 
Part 2 (N=8) 
Total (N=10) 
Best Response, n (%) 
Complete Response (CR) 
0 
0 
0 
Partial Response (PR) 
1 (50%) 
1 (13%) 
2 (20%) 
Stable Disease 
0 
6 (75%) 
6 (60%) 


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Progressive Disease (PD) 
1 (50%) 
0 
1 (10%) 
Unknown 
0 
1 (13%) 
1 (10%) 
Response Rate, n (%) 
CR+PR 
1 (50%) 
1 (13%) 
2 (20%) 
95% Confidence Interval 
(1.3%, 98.7%) 
(0.3%, 52.7%) 
(2.5%, 55.6%) 
1.1.1.2 
BRF113710 (Phase II in Metastatic Melanoma) 
As of 20 February 2012, 92 subjects were enrolled in BRF113710 and 87 (95%) of subjects 
experienced at least one AE of any grade.  The majority of all AEs were Grade 1 or 2.  The 
most commonly reported AEs (>20% of subjects) were arthralgia (33%), hyperkeratosis (28%), 
pyrexia (27%), fatigue (23%), headache (23%) and nausea (21%).  SAEs were reported in 29 
(32%) subjects.  SAEs occurring in 3% or more subjects were cutaneous SCC (9%), basal cell 
carcinoma (4%), anemia (3%), pyrexia (3%) and vomiting (3%).  Twenty-nine subjects (32%) 
had study drug interrupted and 16 (17%) subjects required dose reduction due to the occurrence 
of AEs.  One adverse event (pancytopenia, unrelated to dabrafenib) resulted in permanent 
discontinuation of study drug.  No fatal Grade 5 SAEs were reported in the study. 
The primary objective of this study was achieved with an overall investigator-assessed 
confirmed response rate in the BRAF V600E Population of 59% (95% CI:  48.2-70.3%), 
including a 7% complete response rate.  Additionally, 16% of subjects in the BRAF V600E 
Population experienced stable disease for a minimum of 12 weeks.  Two subjects (13%) in the 
BRAF V600K Population had a confirmed response (95% CI: 0-28.7%).  Seven subjects (44%) 
in the BRAF V600K Population had SD for a minimum of 12 weeks and 5 subjects (31%) had 
PD as a best response. 
1.1.1.3 
BRF113683 (Phase III in Advanced or Metastatic Melanoma) 
As of 19 December 2011, 187 (75%) subjects randomized to dabrafenib and 59 (25%) subjects 
randomized to dacarbazine (DTIC) and received at least one dose of study treatment.  The 
majority of subjects in both treatment arms (99% in the dabrafenib arm and 92% in the DTIC 
arm) experienced at least 1 AE.  Grade 3 AEs were reported at a similar frequency in both arms 
(dabrafenib: 29%; DTIC: 27%) and Grade 4 AEs were more frequently experienced by 14% of 
subjects in the DTIC arm compared to the 4% of subjects in the dabrafenib arm.  The most 
common (≥20% of subjects) AEs of any grade reported in the dabrafenib arm were 
hyperkeratosis (37%), headache (32%), pyrexia (28%), arthralgia (27%), skin papilloma (24%), 
alopecia (22%) and palmar-plantar erythrodysaethesia (PPE) syndrome (20%).  Each of these 
events was reported in a greater proportion of subjects in the dabrafenib arm than in the DTIC 
arm.  AEs typically expected with cytotoxic chemotherapy including gastrointestinal (GI) 
symptoms (nausea, vomiting, abdominal pain) and cytopenias (including neutropenia, anemia 
and thrombocytopenia) were more common in the DTIC arm than in the dabrafenib arm.  
Fatigue and asthenia were common (≥15%) in both arms of the study.   
A similar proportion of subjects experienced SAEs in both treatment groups (dabrafenib: 43 
[23%] subjects; DTIC 13 [22%] subjects).  SAEs reported in more than 1% of the dabrafenib 
arm were cutaneous SCC (5%); reported under the preferred terms of squamous cell carcinoma 
[4%] and squamous cell carcinoma of the skin [2%]), pyrexia (4%) and malignant melanoma 
(2%). 


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The same proportion of subjects (27%) experienced AEs resulting in dose interruptions/delays 
in the 2 treatment arms.  The AEs resulting in dose delays/interruptions in ≥ 2% of subjects in 
the dabrafenib arm were pyrexia (11%), PPE syndrome (3%), chills (3%), alanine 
aminotransferase increased (2%), hyperkeratosis (2%) and in the DTIC arm the events were the 
known events for this compound.  During the randomized phase, AEs resulting in 
discontinuation of study treatment occurred in 3% of subjects in both treatment groups.  In the 
dabrafenib arm the following AEs caused a discontinuation: hepatic pain, constipation, mitral 
and tricuspid valve disease, muscular weakness and myocardial infarction. 
A similar proportion of subjects experienced AEs resulting in dose reductions (dabrafenib: 
18%; DTIC: 17%).  The AEs resulting in dose reductions in ≥2% of the subjects in the 
dabrafenib arm were pyrexia (9%), PPE syndrome (3%), chills (3%), fatigue (2%), and 
headache (2%). 
Twenty-one (11%) subjects in the dabrafenib arm and 9 (15%) subjects in the DTIC arm have 
died.  All but 1 death (elective euthanasia, dabrafenib arm) was attributed to the disease under 
study. 
Preliminary efficacy data from this study have now been published (Hauschild, 2012). 
1.1.1.4 
BRF113929 (Phase II, Metastatic Melanoma to the Brain) 
As of 28 November 2011, 172 subjects were enrolled into BRF113929 with 89 subjects in 
Cohort A (subjects with no prior local therapy for brain metastasis) and 83 subjects in Cohort 
B (subjects who received prior local therapy for brain metastasis).  Most subjects (92%) 
experienced at least one AE.  Most AEs experienced by subjects in the study were of Grade 1 
or 2 in intensity.  The most common AEs (experienced by ≥20% subjects) in both cohorts were 
headache (28%), hyperkeratosis (26%), nausea (26%), pyrexia (26%), fatigue (25%) and 
vomiting (20%). 
A total of 51 (30%) subjects experienced SAEs.  Grade 3 or 4 AEs occurred in 68 (40%) 
subjects.  Headache, PPE syndrome, SCC, hypokalemia and hyponatremia were the most 
frequent Grade 3 AEs (3% each), while neutropenia at 2% was the most frequent Grade 4 AE.  
Fifty-five (32%) subjects had an AE leading to dose interruption.  Pyrexia was the most 
common AE leading to dose interruptions in the study (10%).  Other AEs that led to dose 
interruptions in at least 2 subjects in the study were vomiting, chills, hypotension, decreased 
appetite, and fatigue. 
Twenty-four (14%) subjects experienced AEs leading to dose reductions in the study; pyrexia 
(4%) and hypophosphatemia (2%) were the 2 most common AEs leading to dose reductions. 
Few subjects (2%) discontinued study treatment due to AEs.  Two subjects in Cohort A and 1 
in Cohort B died as a result of cerebral hemorrhage unrelated to study treatment; according to 
the investigator, the primary cause of death for all 3 cases was disease under study. 
Preliminary efficacy data from this study have now been published (Hauschild, 2012). 




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dabrafenib 3 metabolites have been characterized in multiple studies and compared to 
dabrafenib.  Based on the pre-clinical activity and systemic exposure of the metabolites relative 
to dabrafenib, hydroxy- and desmethyl-dabrafenib are thought to be likely to contribute to 
clinical activity while the carboxy-metabolite is predicted to be inactive. 
1.1.3 
Pharmacodynamics 
Analyses of the relationship between dabrafenib exposure and efficacy endpoints were 
conducted with combined data from the FTIH (BRF112680), the Phase II (BRF113710), and 
Phase III (BRF113683) studies.  Different measures of exposure were evaluated including 
average dose, predicted average concentration of dabrafenib (Cavg), and predose 
concentrations of hydroxy-, carboxy- and desmethyl-dabrafenib to assess contribution of 
metabolite(s) to the activity of dabrafenib.  Predose concentrations of dabrafenib (observed or 
predicted) were also evaluated.  Predicted concentrations were based on the population PK 
model. 
Objective response rate at first assessment (dabrafenib doses of 35 mg BID to 300 mg BID) or 
confirmed response (dabrafenib doses of 50 mg BID to 300 mg BID) from different studies 
were evaluated in the analysis. The probability (P) that the response was CR/PR, stable disease 
or PD was modeled using an ordered categorical logistic regression model. Across studies, 
higher exposure was associated with greater response rate, until the response rate reached a 
maximum value at dabrafenib Cavg of approximately 300 ng/mL.  Response rate data were 
related to dabrafenib Cavg using an Emax model with estimated EC50 (95% CI) values of 68.9 
(14.9, 159) and 77.4 (21.4, 176) ng/mL, for first assessment and confirmed response, 
respectively. 
A model of tumor growth kinetics was developed based on the sum of longest diameter over 
time to demonstrate the effect of dabrafenib on tumor growth.  A total of 392 subjects who 
received dabrafenib and 58 subjects who received dacarbazine (DTIC) were included in the 
analysis.  The tumor size model was able to characterize baseline tumor size (BSL), tumor 
growth dynamics with exponential growth (KL), dabrafenib drug effect on tumor growth (KD) 
and drug resistance/disease progression (λ).  Consistent with the analysis of objective response, 
dabrafenib Cavg was a significant predictor of changes in tumor size.  Drug effect was 
significant on the parameter describing disease progression/resistance (λ) using a linear model, 
with subjects with higher dabrafenib Cavg having longer duration of response (lower value of 
λ) than those with lower exposures. 
Administration of dabrafenib 150 mg BID (gelatin) resulted in inhibition (>80%) of tumor 
phosphorylated extracellular signal-related kinase (pERK), a downstream biomarker of the 
RAS/RAF/MEK/ERK pathway that has been shown to be associated with clinical response in 
BRAF mutant tumor models (Bollag, 2010). 
1.1.4 
Relative Bioavailability of Dabrafenib Administered as HPMC versus 
Suspension and dispersible tablet 
Dabrafenib was administered as a suspension to 4 subjects with BRAF mutation positive tumors 
in a Phase I study (Study BRF113463) to characterize the absorption, distribution, metabolism, 
and excretion of dabrafenib.  Administration of dabrafenib as a suspension resulted in faster 


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absorption (tmax 1 hr), higher Cmax, but similar overall exposure relative to administration of 
HPMC capsules.  Based on cross-study comparisons, the bioavailability of dabrafenib as the 
suspension is approximately 85% relative to administration as HPMC capsules. 
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. 
1.1.5 
Dabrafenib in Pediatric Cancers 
When present, the BRAF V600 mutation appears to result in constitutive activation of the 
BRAF enzyme in cancer cells regardless of tumor context, and as such, BRAF V600 mutations 
may be relevant drivers of cancer in other settings, including childhood cancers.  Reports citing 
the frequencies of BRAF mutations in childhood cancers are currently limited in the scientific 
literature, however, to date, BRAF V600E mutations have been positively identified in 50% of 
pediatric patients with malignant melanoma (Daniotti, 2009), 57% of patients with Langerhans 
cell histiocytosis (LCH) (Badalian-Very, 2010), and >10% of patients with certain types of 
gliomas (both low- and high-grade tumors) (Dougherty, 2010; MacConaill, 2009; Schiffman, 
2010).  As more childhood tumors are analyzed for the presence of relevant DNA mutations, 
other tumor types with BRAF mutations are likely to be identified.  Given that non-melanoma 
BRAF V600 mutant tumors have been shown to be responsive to treatment with dabrafenib, 
strong rationale exists for exploring the activity of dabrafenib in BRAF V600 mutant pediatric 
tumors.  A brief overview of pediatric tumors with known BRAF V600 activating mutations is 
provided below. 
1.1.5.1 
Malignant Melanoma 
Cutaneous melanoma is the most aggressive form of all skin cancers.  In Europe, 67,400 
incident melanoma cases occur each year, which accounts for approximately 2.7% of all cancers 
(Ferlay, 2010).  The overwhelming majority of these cases occur in adult patients. 
Malignant melanoma is extremely rare in children <12 years of age, but does occur among 
adolescents aged 12-18 years, with approximately 271 new melanoma cases were expected to 
occur during 2010 in the European Union (EU), with the most cases in United Kingdom (UK) 
(n=62), Germany (n=54) and France (n=47) (WEUKBRE5092, 2010) based on an estimation 
made using the incidence rates from the Automated Childhood Cancer Information System 
(ACCIS) (deVries, 2006) applied to age-specific 2010 mid-year population projections (United 
Nations, 2010) using an incidence rates across Europe range from 0.04-0.14 per 100,000 for 
children (0-14 years) and 0.63-1.87 per 100,000 for adolescents (15-19 years) (deVries, 2006).  
In the United States (US), the numbers of incident cases were 206 for Stage I, 22 for Stage II, 
35 for Stage III and 5 for Stage IV, based on the Surveillance Epidemiology and End Results 
(SEER) stage distribution for 0-19 year olds (SEER, 2010). 
Histopathologically, adult and pediatric melanomas appear to be similar.  According to the 
scientific literature, approximately 50% of cases of pediatric melanoma may involve BRAF 
V600E mutations, which is a proportion similar to that observed in adults (Daniotti, 2009). 


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1.1.5.2 
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 (National Cancer Institute (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). 
1.1.5.3 
Low-Grade and High-Grade Gliomas 
As compared to adults, where primary brain tumors represent only 1-2% of new cases of cancer 
in adult, central nervous system (CNS) tumors comprise approximately 25% of all pediatric 
cancers, and are second only to leukemia in terms of incidence.  Among children in the US, the 
overall incidence rate for 2004-2006 for malignant primary brain and CNS tumors was 3.2 cases 
per 100,000 person-years for children 0-19 years of age (CBTRUS, 2010).  Approximately 50% 
of all CNS tumors are astrocytomas, most of which are low-grade (Qaddoumi, 2009; 
Dougherty, 2010).  Specific low-grade tumor types include ganglioglioma, diffuse astrocytoma, 
pleomorphic xanthoastrocytoma, pilomyxoid astrocytoma, and pilocytic astrocytoma. Glioma 
accounts for 71% of malignant CNS tumors among those aged 0-14 years and accounts for 74% 
among those aged 15-19 years (CBTRUS, 2010), resulting in an incidence of approximately 
2.3 cases per 100,000 person-years. The annual incidence of low-grade gliomas (LGGs) in 
general is approximately 1 case per 100,000 children.  Of all the low-grade tumor types, 
pilocytic astrocytomas are the most frequently occurring, accounting for approximately 20% of 
all pediatric brain tumors (Dougherty, 2010).  The incidence of pilocytic astrocytoma in 
children is over 10 times that in adults (0.5 per million in adults versus 8.3 per million in 
children).  Conversely, high-grade gliomas (HGGs) are less common in children than adults, 


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comprising <10% of all pediatric CNS tumors.  Similar rates have been reported for UK and 
Great Britain (Cancer Research UK, 2010).  Examples of HGGs are glioblastoma multiforme 
and anaplastic astrocytoma.  
BRAF V600E point mutations have been reported to occur in several low- and high-grade tumor 
types in pediatric patients, including 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).  While there is 
only limited evidence, it appears that the frequency of BRAF activating mutations may be more 
common in pediatric astrocytomas than in adult tumors (Knobbe, 2004).  This is consistent with 
observations that while grade 3 to 4 pediatric astrocytomas share histopathologic similarities 
with their corresponding adult counterparts, the pattern of genetic alterations seen in adult 
astrocytomas is distinct from that seen in pediatric astrocytomas (Schiffman, 2010). 
1.1.5.4 
Papillary Thyroid Carcinoma (PTC) 
Thyroid nodules are rare in childhood and adolescence, with a general prevalence of less than 
2%; however, they are more frequently malignant than in adults (approximately 20% of cases) 
(Corrias, 2010).  Thyroid carcinomas have an average incidence of approximately 5 per million 
in patients under the age of 20 years (NCI, 2012).  Incidence typically increases with age in this 
time-frame, such that the majority of cases are observed in adolescents 15 to 19 years old 
(approximately 15 per million) (NCI, 2012).  PTC currently comprises approximately 70% of 
all diagnoses (NCI, 2012). 
Pediatric PTC usually presents at an advanced stage, but still has excellent prognosis, with a 5-
year survival rate of >99% (NCI, 2012).  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).  Conditions known to increase 
risk of childhood PTC are elevated plasma thyroid stimulating hormone (TSH) concentration, 
Hashimoto’s disease, exposure to radiation, and mutations in RET-oncogene. 
BRAF V600E mutations are common in adult PTC, reported at a rate of approximately 50% 
(Nikiforova, 2009; Melck, 2010).  In pediatric PTC, the proportion of BRAF V600E-positive 
tumors appears to be slightly lower.  In recent publications, BRAF V600E mutations were 
identified in approximately 20% of cases in patients aged <20 years (Rosenbaum, 2005; 
Kumagai, 2004).  
1.2 
Rationale 
1.2.1 
Study Rationale 
The proposed study is a Phase I/IIa, open-label study to determine the safety, tolerability, and 
pharmacokinetics of oral dabrafenib in pediatric and adolescent subjects aged ≥12 months to 
less than 18 years of age with advanced BRAF V600 mutation positive advanced solid tumors.  
As noted above, dabrafenib has demonstrated promising efficacy in adults with BRAF V600 
mutation-positive advanced or metastatic melanoma as well as other tumors types with BRAF 
V600 mutations.  For patients with refractory, recurrent gliomas, LCH, melanoma, or PTC, the 
use of second- and third-line cytotoxic chemotherapies, even in dose-intensive regimens, has 


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yet to yield significant impact on progression-free survival or overall survival.  Recent data 
identifying BRAF V600 activating mutations in pediatric melanoma, gliomas, LCH, and PTC 
coupled with the recent development of specific BRAF inhibitors may allow for the 
development of a new therapeutic opportunity for children, and is the primary rationale for this 
study. 
In addition, BRAF inhibitors such as dabrafenib have a substantially different safety profile 
than cytotoxic chemotherapeutics and radiation therapy, both of which are employed in standard 
of care regimens for advanced pediatric solid tumors.  Moreover, radiation and cytotoxic 
therapies can have significant long-term effects on the health and development (both physical 
and cognitive) of children.  The Childhood Cancer Survivors Study, a large cohort study 
conducted in the United States, found that greater than 40% of survivors of pediatric cancers 
are burdened with long-term adverse health effects (Hudson, 2002). Specifically, the individual 
components of current therapy for solid tumors lead to both short and long term morbidities.  
Surgical resection can lead to loss of function or disfigurement, or in the case of CNS tumors, 
long term neurologic and cognitive sequelae.  Cytotoxic chemotherapeutics, especially when 
administered in dose- or time-intensive manners, can lead to neutropenia and increased risk of 
infection, sepsis, and death, cardiac dysfunction (doxorubicin), infertility (cyclophosphamide), 
renal injury and hearing loss (cisplatin).  In addition, many of these cytotoxic agents, in 
particular, DNA alkylating agents and epipodophyllotoxins, have long been known to 
predispose patients to treatment-associated leukemias (Hawkins, 1992).  Radiotherapy can also 
have profound effects on skeletal growth and, for patients with CNS tumors, on endocrine 
function, cognition, vasculopathy and risk of second tumors.  New targeted therapeutics such 
as dabrafenib may offer a way of reducing the need for cytotoxics, or may offer a means by 
which to reduce dose or exposure, thereby reducing the likelihood of treatment-associated 
morbidity and mortality. 
Given the similarity between adult and pediatric melanoma, data from this study will be used 
to support a bridging approach to demonstrate that the PK, and (where available) 
pharmacodynamic and efficacy data in adolescent subjects are similar to that of adults, using a 
modelling and simulation approach. 
In summary, it is thought that dabrafenib has the potential to provide therapeutic benefit to those 
pediatric patients with advanced solid tumors with BRAF V600 activating mutations.  Due to 
the scarcity of BRAF mutation positive tumors in children, and the anticipated favourable safety 
profile of dabrafenib in children (based on adult data), enrolment of different pediatric age 
groups will not be staggered.   
1.2.2 
Dose Rationale 
A maximum tolerated dose (MTD) was not established in adults for dabrafenib in Study 
BRF112680.  However, relationships between the total daily dabrafenib dose and markers of 
clinical benefit (reduction in FDG-PET uptake and tumor shrinkage) were determined and the 
PK, safety, pharmacodynamic and efficacy data were used to identify a recommended Phase II 
dose of 150mg BID.  As such, in this pediatric study, dabrafenib dose escalation will proceed 
to the target geometric mean steady-state plasma exposure observed in adults given the 
efficacious Phase III dose of dabrafenib 150 mg BID as HPMC capsules.  It is not anticipated 


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that a true MTD will be identified given the low incidence of dose-limiting toxicities (DLTs) 
seen in the adult clinical development of dabrafenib. 
The rationale for this pharmacokinetically-based dose-escalation approach is based on the 
likelihood that therapeutic benefit in children will be achieved by targeting the adult dabrafenib 
exposure, principally steady-state AUC(0-τ) following 150 mg BID dabrafenib as HPMC 
capsules.  The geometric mean (95% CI) dabrafenib AUC(0-τ) after administration of 150 mg 
BID as the HPMC capsule in the Phase III study (BRF113683) was 4341 (3749, 5485) 
ng*h/mL.  These Phase III data were consistent with the preliminary results from the 
monotherapy arm of study BRF113220 where geometric mean dabrafenib AUC(0-τ) after 
administration of 150 mg BID as the HPMC capsule was 4648 ng*h/mL.  Therefore, the median 
population target AUC(0-τ) for pediatric subjects will be approximately 4500 ng*h/mL, with 
the goal of identifying, where possible, a dose for each age grouping (12-18, 6-12, 2-6, and less 
than 2 years of age) that results in a median dabrafenib AUC(0-τ) that is within the 95% CI for 
the geometric mean exposure measured in adults in the Phase III study (3749, 5485 ng*h/mL). 
The dabrafenib dose selection will be weight-based according to regulatory guidances 
(European Medicines Agency, 2006; U.S. Food and Drug Administration, 2000).  The 
recommended adult dose of dabrafenib is 150 mg BID.  This dose corresponds to a 3.75 mg/kg 
total daily dose in an 80 kg adult.  The starting dose in Part 1 will be 3 mg/kg total daily dose, 
approximately 80% of the adult dose adjusted for body weight.  Dose escalation in Part 1 will 
occur in a stepwise manner until the median AUC(0-τ) is greater than approximately 4000 
ng*h/mL and does not exceed approximately 5500 ng*h/mL.  Dose escalation in Part 1 also 
will be influenced by the real-time analysis of the safety and other available data obtained 
during the study. 
Based on clinical pharmacology considerations in the pediatric population, the selection of 
suitable dabrafenib doses for ages 2 to <18 years is not expected to be significantly complicated 
by developmental factors.  However, given the rapidly changing absorption, distribution, 
metabolism, and excretion processes in children <2 years old, it is difficult to predict the impact 
of the physiology of infants on dabrafenib exposure.  As noted above, since a MTD of 
dabrafenib was not established in adult subjects with cancer, it is expected that dose-limiting 
toxicities also will be rare in children.  Therefore, a starting dose of 80% of the weight-based 
dose in adults will provide an adequate safety margin for infants.  The total daily dose 
administered in this study will not exceed 300 mg (150 mg BID). 
1.3 
Summary of Risk Management 
The assessment of the risk of dabrafenib, and suggestions for management of risk, is based on 
non-clinical data and clinical data from an integrated safety population of 578 adult subjects 
with melanoma receiving 150 mg dabrafenib BID. 
Dermatological effects:  Epidermal hyperplasia (acanthosis) and hyperkeratosis of the skin was 
seen in dogs and in rats. In clinical studies hyperkeratosis (29%), skin lesions including actinic 
keratosis (7%) and seborrhoeic keratosis (7%), palmar-plantar erythrodysesthesia (PPE) 
syndrome (13%), rash (18%) and cutaneous squamous cell carcinomas (cuSCC) including 
keratoacanthomas (KA) (9%) have been observed.  Most events were Grade 1 with the 
exception of cutaneous squamous cell carcinomas, which were predominantly Grade 3. 


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Dermatological changes are being monitored in subjects through interim medical history, 
assessment of adverse events and physical examination including examination of the skin. 
Guidelines on management of hand foot skin reactions (HFSR)/ PPE syndrome and skin rashes 
have been provided, with stopping criteria for persistent National Cancer Institute Common 
Terminology Criteria for Adverse Events, version 4.0 (NCI CTCAEv4.0 or higher) NCI-
CTCAE Grade 2 or Grade 3 HFSR toxicity.  Treatment of SCC, KA and keratotic lesions should 
occur based upon institutional practice.  Dose interruptions or modifications are usually not 
required for SCC/KA. 
Ophthalmology effects:  Eye effects including blurred vision (2%), uveitis/iritis (<1%), eye 
pain (<1%), visual impairment (<1%) and reduced visual acuity (<1%) have been observed in 
clinical studies to date, with all events Grade 1 or 2.  An ophthalmologic consult is required for 
subjects developing symptoms associated with uveitis including blurry vision, eye pain or 
erythema. 
Pyrexia:  In clinical studies, pyrexia was one of the most frequently occurring AEs (27%), most 
of which (64%) were considered to be related to study treatment.  Events were primarily Grade 
1 (55%) or Grade 2 (39%) in severity.  The majority of events occurred early during study 
treatment, with a median time to onset of 1st occurrence of 3 weeks, and most cases (74% of 
first occurrences) were of short duration (≤5 days).  The majority of subjects with pyrexia were 
managed without dose interruption or dose reduction. Across dabrafenib studies, all SAEs of 
pyrexia, influenza-like illness, cytokine release syndrome, and systemic inflammatory response 
syndrome underwent clinical review for the identification of serious non-infectious febrile 
events, with complications of severe rigors, hypotension, dehydration, or renal failure in the 
absence of another identifiable etiology (i.e., infection).  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.  Subjects with fever should have a 
medical evaluation including measurement of blood pressure.  Cases of fever with severe rigors 
or fever with hypotension should be reported as SAEs (regardless of whether or not 
hospitalization was required). 
Acute Renal Failure:  Acute renal failure/renal failure has been rarely reported (<1%) in 
subjects receiving dabrafenib, and a case of granulomatous interstitial nephritis has also been 
reported in a clinical trial.  In some cases complicated pyrexia may be associated with renal 
insufficiency/renal failure, possibly secondary to dehydration or hypotension.  Renal function 
should be monitored carefully, especially in subjects with pyrexia.  Dabrafenib should be 
interrupted in subjects with significantly elevated serum creatinine (creatinine rise >0.5 mg/dL 
[44 µmol/L] above baseline or creatinine >2.0 mg/dL [177 µmol/L]).   
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 


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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. 
Pancreatitis: Pancreatitis (<1%) and/or increased lipase/amylase (2%) have been reported at a 
low frequency with dabrafenib, typically occurring within 14 days of starting therapy. For AEs 
of abdominal pain or suspected pancreatitis, amylase and lipase laboratory samples must be 
monitored locally. 
Hypersensitivity:  There has been a report of hypersensitivity (blisters), occurring on the same 
day as the first dose of study drug as well as upon rechallenge.  Grade 1 AEs of blisters on limbs 
(4 subjects) and drug hypersensitivity (rash, 1 subject) have been reported in previous studies 
with dabrafenib. However, the precise etiology of these events is unclear. 
Embryofetal Development and Reproductive Effects:  In embryofetal development studies 
in rats, developmental toxicities including reduced fetal body weight, embryo-lethality, cardiac 
ventricular septal defect malformations, delayed skeletal development and variation in thymic 
shape have been observed. Dabrafenib must not be administrated to pregnant women or nursing 
mothers.  Female subjects of childbearing potential are required to use effective methods of 
contraception from the time of a negative serum pregnancy test within 14 days prior to the first 
dose of study medication, until 4 weeks after the last dose of study medication. In dogs and in 
rats, testicular degeneration/depletion has been observed in repeat dose studies (up to 13 weeks 
duration) with no clear evidence of recovery following off-treatment periods of up to 4 weeks 
duration.  Spermatid retention was observed in mice in a 14 day study. Male subjects enrolled 
or in follow-up in clinical trials are informed of the potential risk for impaired spermatogenesis, 
which may be irreversible. 
Cardiovascular effects: Data from preclinical studies with dabrafenib suggest the potential for 
cardiovascular effects, including cardiac valve effects in the 28 day dog study, coronary 
vascular effects in the 7 day dog study, hepatic vascular effects in a 10 day rat study, increased 
incidence of minimal cardiomyopathy in male rats and mild increases in heart rate in single 
dose studies in dogs and rats. In a 13-week oral toxicity study in dogs right atrial wall thickening 
characterized microscopically by fibrovascular proliferation (transmural granulation tissue) was 
observed. In the ongoing monotherapy clinical studies, 3 (<1%) non-serious valvular 
abnormalities meeting stopping criteria have been identified to date; two of these subjects had 
baseline valvular abnormalities Additionally,  a blinded independent review of available 
echocardiogram results from subjects participating in the phase 2 BREAK-2 study was 
performed to further examine the effect of dabrafenib on valvular function. No persistent 
findings suggestive of a drug effect were observed.  Because valvular abnormalities were 
observed in a minority of subjects in the integrated dabrafenib population, and the results of the 
central analysis in BREAK-2 were not suggestive of a drug effect, valvular toxicity is no longer 
considered an AE of special interest for dabrafenib.  Subjects with clinically significant baseline 
cardiac abnormalities are excluded from the study.  Safety evaluations include physical 
examination, 12-lead electrocardiogram (ECG) and echocardiogram (ECHO) monitoring as 
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Respiratory Effects:  Lobar bronchoalveolar inflammation has been observed in dogs, with 
shallow and/or labored breathing noted during the treatment phase in 2 dogs given dabrafenib 
for 13 weeks. Respiratory changes are being monitored through medical history and physical 
examination.  There have been no corresponding clinical findings identified in clinical trials to 
date. 
2 
OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary 
● To determine the safe and tolerable dabrafenib 
dose(s) for chronic dosing in pediatric subjects 
(infants, children, and adolescents) that achieves 
similar exposures to the dabrafenib adult dose, in 
subjects with BRAF V600 mutation positive 
tumors 
● Adverse Events (AEs); ECG; ECHO; changes in 
laboratory values and vital signs in Part 1 and Part 2. 
● Cmax, area under the concentration-time curve from 
time zero (pre-dose) to last time of quantifiable 
concentration [AUC(0-τ] and AUC(0-inf) of dabrafenib 
Secondary 
● To characterize the pharmacokinetics of 
dabrafenib, and its metabolites 
● Cτ (trough), AUC(0-t), AUC(0-τ), apparent clearance 
following oral dosing (CL/F) (dabrafenib only), Cmax, 
tmax and t½ of dabrafenib and its metabolites, as 
appropriate 
● To characterize the longer term safety and 
tolerability of dabrafenib  
● AEs; ECG; changes in laboratory values and vital 
signs 
● To assess any preliminary anti-tumor activity of 
dabrafenib  
● Tumor response as defined in Appendix 2 by 
investigator assessment 
● To determine the effect of age and weight on 
the pharmacokinetics of dabrafenib using a 
population pharmacokinetics approach 
● CL/F, volume of distribution (V/F), absorption rate 
(ka), and coefficients for significant covariates 
Exploratory 
● To determine the palatability of dabrafenib in 
pediatric subjects 
● Palatability questionnaire data 
3 
INVESTIGATIONAL PLAN 
3.1 
Study Design/Schematic 
This is a 2-part, Phase I/IIa, multi-center, open label, study in pediatric subjects with advanced 
BRAF V600 mutation-positive solid tumors (Figure 3-1).  Subjects will participate in only 1 
part.  Part 1 will be a dose escalation study in subjects with any BRAF V600 mutation-positive 
solid tumor using a modified Rolling 6 Design (RSD).  Part 2 will be an expansion study to 
further evaluate the safety / tolerability profile and clinical activity of dabrafenib in 4 tumor-


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specific pediatric populations.  Approximately 6 to 18 subjects are estimated for Part 1, and 
approximately 65 subjects are planned for Part 2 (at least 10 evaluable subjects in each of 
4 cohorts; evaluable for the purpose of clinical activity analysis is defined as a subject with a 
pre-dose and at least 1 post-dose disease assessment). The HGG cohort will continue 
recruitment until enrollment on another pediatric HGG study is available (expected by the end 
of 2018 and no later than mid 2019). 
 
Figure 3-1 
Study Design 
Part 1 
Dose Escalation 
Identify the recommended Part 2 dose(s) and regimen (based on safety, tolerability and PK data) of 
dabrafenib in pediatric subjects with a BRAF V600 mutation-positive solid tumor  
↓ 
Part 2 
Tumor-Specific Expansion 
Evaluate the safety, tolerability, PK and clinical activity of dabrafenib in pediatric subjects with a 
BRAF V600 mutation-positive solid tumors: 
Cohort A:  low-grade gliomas with BRAF V600 mutations  
Cohort B:  high-grade gliomas with BRAF V600 mutations 
Cohort C:  LCH with BRAF V600 mutations 
Cohort D:  other tumors that have BRAF V600 mutations (e.g., PTC, melanoma) 
The screening visit will be completed within 21 days prior to administration of the first dose of 
study medication.  No study specific procedure will start before the signature of the informed 
consent form (and assent, according to institutional guidelines).  Screening assessments may be 
carried out over more than one day provided that all required assessments are completed within 
21 days prior to the first dose of study drug.  Screening assessments may be repeated once at 
the discretion of the investigator. 
Safety and PK assessments will be performed at regular intervals as outlined in the Time and 
Events Tables (Table 3-7 and Table 3-9).  Overall response will be assessed at regular intervals 
as outlined in the Time and Events Tables according to the appropriate guidelines as determined 
by the disease(s) under study (see Appendix 2).  Additional details for the conduct of Part 1 and 
Part 2 are provided in Section 3.1.1 and Section 3.1.2, respectively. 
Guidelines for dabrafenib dose modifications are outlined in Section 3.7.  Dabrafenib treatment 
may be delayed for up to 7 days to allow for resolution of toxicity.  For treatment delays >7 
days due to toxicity, subjects should be withdrawn from dabrafenib permanently (unless the 
investigator determines that clinical benefit from continued administration of dabrafenib 
outweighs any risks associated with continued use). 
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns.  Therefore, adherence to the study design requirements, including those specified in 
the Time and Events Table, are essential and required for study conduct. 


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Supplementary study conduct information not mandated to be present in this protocol is 
provided in the accompanying Study Procedures Manual (SPM).  The SPM will provide the site 
personnel with administrative and detailed technical information that does not impact subject 
safety. 
3.1.1 
Part 1 – Dose Escalation 
Part 1 is a repeat dose, dose escalation study.  The RSD (Skolnik, 2008) builds on the classic 
3+3 design, but allows for continued recruitment of subjects while the data from the first 3 
subjects in each cohort is collected (up to 6 subjects per cohort).  For dose escalation decisions, 
all available data are used to inform the decision.  The starting dose will be 3 mg/kg with dose 
levels for subsequent dose levels (+1 and +2 Dose Levels) as outlined in Table 3-1. 
 
Table 3-1 
 
Dabrafenib Dose Levels a 
Dose Level 
Total Daily Dose (mg/kg) c 
-2 Dose Level 
1.5 mg/kg 
-1 Dose Level 
2.25 mg/kg 
Starting Dose Level b 
3 mg/kg 
+1 Dose Level 
3.75 mg/kg 
+2 Dose Level 
4.5 mg/kg 
+3 Dose Level  
5.25 mg/kg 
+4 Dose Level  
6.0 mg/kg 
a. 
Intermediate and additional dose levels may be explored based on emerging PK and safety data. 
b. 
Starting dose level.  The first cohort of subjects will receive approximately 80% of the adult mg/kg dose (doses will be 
rounded based on the smallest 10mg capsule increments for subjects receiving capsules).  The adult dose is 3.75 
mg/kg given as 2 divided doses. 
c. 
The total daily dose will be split evenly into a morning and evening dose (BID dosing).  The total daily dose will not 
exceed 300 mg (150 mg BID). 
The actual weight-adjusted dose to be administered for a given dose level may be adjusted based 
on safety, tolerability and preliminary PK data at previous dose levels; these dose adjustments 
may involve either an increase or a decrease in the planned dose for a given dose level.  Dosing 
frequency may also be adjusted based on emerging PK and/or safety data.  Cohorts may be 
added in order to evaluate additional dose levels.  The study procedures for these additional 
subject(s) or cohort(s) will be the same as those described for other study subjects. 
Up to 6 subjects can be enrolled concurrently at one dose level dependent upon the number of 
subjects enrolled at the current dose level, the number of subjects who have experienced a dose 
limiting toxicity (DLT, see Section 3.3) at the current dose level, and the number of subjects 
enrolled but with data pending at the current dose level.  Dose escalation schematic is in 
Appendix 1. 
For example, if 3 subjects are enrolled at a dose level and all 3 subjects have been fully evaluated 
for the first 28 days (including Day 15 PK) and no DLTs were observed, a fourth subject can 
be enrolled at the next higher dose level (i.e., dose escalation).  If all 3 subjects have NOT been 
fully evaluated for the first 28 days or 1 DLT occurred, the fourth subject will be enrolled at the 
same dose level.  If 2 or more DLTs are observed, the fourth subject will be enrolled at the next 


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lower dose level (i.e., de-escalated).  Similarly, the process is repeated for the fifth and sixth 
subjects in a cohort. 
Beyond the sixth subject in an ongoing cohort, additional subjects wanting to be enrolled before 
the next cohort is open for enrollment, can be enrolled at the previous lower dose level. 
On Day 1, serial blood samples for PK analysis will be collected in subjects ≥10 kg in weight 
after the first dose of dabrafenib.  A second dose may be administered on Day 1 if the timing is 
in compliance with Section 3.6.  Twice a day dosing will begin on Day 2.  PK samples in 
subjects ≥10 kg in weight will also be collected on Day 15.  For subjects <10 kg in weight, 
blood samples for PK analysis will be collected after repeated administration on Day 15 only. 
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 3.8). 
Treatment with dabrafenib will be continued until disease progression, until the subject is no 
longer obtaining clinical benefit from continued treatment, they develop an unacceptable 
toxicity, the study is terminated, or the subject withdraws consent or begins a new therapy.  At 
the end of treatment, a final study visit will occur.  Additional details on subject completion are 
provided in Section 9.1. 
3.1.1.1 
Dose Escalation 
Dose escalation decisions will take into account all available safety and PK data (from the 
current and all previous cohorts, if available) and will be documented. 
If a subject is withdrawn before the first 28 days in Part 1 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 at the time the next available subject enrolls in the study. 
The dose in Part 1 will be escalated until the maximum tolerated dose (MTD) is reached (based 
on toxicity, Section 3.4) OR in the absence of reaching the MTD, the dose in which the median 
AUC(0-τ) is between approximately 4000 ng*h/mL and approximately 5500 ng*h/mL. The 
proportion of subjects who achieve an AUC(0-12) ≥ 4000 ng*h/mL also will be considered 
when selecting the dose for Part 2. In the absence of meeting criteria for MTD, if less than 80% 
of subjects in an age group (≤2 yrs, >2 and ≤12 yrs, >12 yrs) achieve an AUC(0-12) ≥ 
approximately 4000 ng*h/mL OR if fewer than two subjects in a specific age group have been 
evaluated at a given dose level, the study sponsor and study team will review all available safety 
and PK data and determine if further Part 1 evaluation of a specific age group is required before 
these subjects may enroll in Part 2. Intermediate doses may be explored. 
3.1.2 
Part 2:  Tumor-Specific Expansion 
Part 2 will have four disease-specific cohorts of subjects with tumors known to have BRAF 
V600 activation (cohort 1: pediatric low-grade gliomas, cohort 2: pediatric high-grade gliomas 
cohort 3: Langerhans cell histiocytosis, and, cohort 4: miscellaneous tumors such as melanoma 
and PTC).  At least 40 patients will be recruited into Part 2, with at least 10 patients each for 
cohort 1, 2 and 3, and up to 10 patients in cohort 4. The HGG cohort will continue recruitment 
until enrollment on another pediatric HGG study is available (expected by the end of 2018 and 


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no later than mid 2019). The study will attempt to enroll at least 5 children in each cohort who 
are <6 years of age. 
On Day 1, serial blood samples for PK analysis will be collected in subjects ≥10 kg in weight 
after the first dose of dabrafenib.  A second dose may be administered on Day 1 if the timing is 
in compliance with Section 3.6.  Twice a day dosing will begin on Day 2.  PK samples in 
subjects ≥10 kg in weight will also be collected on Day 15.  For subjects <10 kg in weight, 
blood samples for PK analysis will be collected after repeated administration on Day 15 only. 
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 3.8). 
Treatment with dabrafenib will be continued until disease progression, until the subject is no 
longer obtaining clinical benefit from continued treatment, they develop an unacceptable 
toxicity, the study is terminated, or the subject withdraws consent or begins a new therapy. At 
the end of treatment, a final study visit will occur.  Additional details on subject completion are 
provided in Section 9.1. 
3.1.3 
Study End 
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 protocol is 
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. 
3.1.4 
Follow-Up 
Follow-up care will be offered to subjects from Part 1 and Part 2.  Details are provided in Section 
9.4. 
3.2 
Discussion of Study Design 
Dabrafenib is not being developed for BRAF V600 wild-type (non-mutation positive) tumors 
for several reasons: 1) dabrafenib has 10-fold less affinity for wild-type BRAF protein; 2) data 
from the FTIH study showed no evidence of anti-tumor activity in BRAF V600 wild-type 
subjects and no evidence of anti-tumor activity in BRAF non-V600 mutation positive subjects 
(e.g., K601 mutations) and 3) there is pre-clinical data to indicate that inhibition of wild-type 
RAF with BRAF inhibitors could lead to paradoxically enhanced signalling in cells with wild-
type BRAF via transactivation of dimerized RAF (Poulikakos, 2010).  This enhanced signalling 
could manifest as cell proliferation in BRAF wild-type tumors. 
Identification of BRAF V600 mutant pediatric tumors will be enabled by molecular genotyping 
assays which are available at many major academic pediatric oncology centres.  In addition, a 
central genotyping assay has already been developed by GlaxoSmithKline (GSK), with an 
external partner, for use in the adult dabrafenib program.  Because this central assay is DNA-
based, it can be employed for any tissue, including those from pediatric tumors.  Sites may 
enroll subjects based on genotyping performed at a local (non-central) laboratory using a 
standardized assay performed in a Clinical Laboratory Improvement Amendments (CLIA)-


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approved (or equivalent) laboratory.  Sites without access to local laboratory testing may enroll 
subjects based on genotyping performed at a central laboratory.  For enrolled subjects with 
available archived tissue, BRAF V600 genotyping will also be performed at a central 
laboratory. 
With regard to the dose escalation design, employing a modified RSD (as opposed to the 
commonly used 3+3 design) allows for more continuous accrual of subjects into the study and 
avoids delays in accruing and treating subjects with BRAF V600-mutant tumors as they are 
identified.  In the 3+3 design, accrual is stopped until 3 subjects have been evaluated for a 
specified evaluation period (typically 28 days or more).  With the modified RSD, suspension of 
subject accrual occurs less frequently and therefore the enrolment period is shortened.  The 
ability to detect and respond to safety signals is the same in the modified RSD as in the 3+3 
design (Skolnik, 2008). 
Exposure-response relationships between plasma dabrafenib concentrations and clinical 
efficacy have been established in adult subjects with melanoma.  Given that the available 
published data indicates that the histopathology, molecular pathology of melanoma is similar 
between adolescent patients and adult patients, and that the molecular biology of mutant BRAF 
activity is identical between adult patients and patients in the pediatric population, it should be 
possible to extrapolate adult response data to adolescent patients, if the pharmacologic 
exposures achieved in adolescent patients are similar.  Also, no maximally tolerated dose has 
been identified in adult subjects with melanoma.  Therefore, in addition to monitoring for DLTs, 
systemic exposure to dabrafenib will be used to determine the optimal dose in the pediatric 
population.  
In the absence of compelling pre-clinical and clinical data to indicate a similar likelihood of 
response in pediatric BRAF V600 mutation-positive non-melanoma tumors to that seen in adult 
BRAF V600 mutation-positive melanoma, the introduction of new agents such as dabrafenib 
into pediatric oncology treatment regimens typically occurs in later lines of therapy.  In keeping 
with this standard, this study will be conducted in subjects who have experienced recurrent, 
refractory, or progressive disease after receiving at least 1 standard therapy.  One exception will 
be for subjects with metastatic melanoma (i.e., subjects with metastatic and surgically 
unresectable disease can be enrolled as first-line therapy) since there is sufficient clinical data 
from Phase III adult studies with dabrafenib to allow this treatment option. 
The study will use the currently available dabrafenib capsule strengths (50 mg and 75 mg) from 
the adult program for children who are able to reliably swallow capsules.  In addition, two lower 
strength capsules (10 mg and 25 mg),a powder for oral suspension formulation, and dispersible 
tablet formulation are available for pediatric subjects who may have difficulty swallowing 
larger capsules. In France, children younger than 6 years and children 6 years and older 
with a risk of choking when swallowing capsules are required to use the oral suspension 
formulation or dispersible tablet formulation. 
3.3 
Dose Limiting Toxicity Definitions 
The DLT evaluable population is defined as those subjects in Part 1 fulfilling the ‘All Subjects’ 
population criteria and having received an adequate treatment in the first 28 days to enable an 
appropriate evaluation of study drug related DLTs.  Adequate exposure during the first 28 days 


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will be defined as having received >75% of planned study drug doses, exclusive of missed doses 
due to treatment-related toxicity.  For those subjects who are either withdrawn or dose reduced 
due to toxicity during the first 28 days will be included in the DLT evaluable population. 
An AE will be considered a DLT if it occurs within the first 28 days of treatment with 
dabrafenib, and if it is considered by the investigator to be related to treatment with dabrafenib, 
and if meets at least one of the following additional criteria:  
• Grade 4 hematologic AE (specifically neutropenia, anemia, thrombocytopenia and 
lymphopenia); 
• Grade 3 or 4 non-hematologic AE.  Grade 3 nausea, vomiting, and diarrhea will only be 
considered dose limiting if uncontrolled with standard supportive measures.  Cutaneous 
SCC is not considered a DLT; 
• Treatment delay of greater than 7 consecutive days due to unresolved AE 
• Ejection fraction less than the lower limit of normal (LLN) with an absolute decrease 
of >10% from baseline with confirming assessment within 7 days; 
• A Grade 2 or greater non-hematological AE that in the judgment of the investigator and 
Novartis Medical Lead is dose limiting; 
• AEs requiring a dose reduction. 
3.4 
Maximum Tolerated Dose (MTD) 
An MTD has not been identified for dabrafenib in the adult population.  This does not preclude 
the identification of an MTD in the pediatric population.  As such, in the current study 
employing a modified RSD, if dose de-escalation occurs (due to the occurrence of DLTs) 
resulting in 6 subjects being entered at the next lower dose level, and there are ≤1 DLT in that 
next lower dose level (see Appendix 1), then the MTD will have been defined (Skolnik, 2008).  
3.5 
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 in accordance with the randomization schedule generated prior to the start of the study, 
using validated software. 
3.6 
Investigational Product and Other Study Treatment 
Dosage/Administration 
In France, children younger than 6 years and children 6 years and older with a risk of 
choking when swallowing capsules will be required to use the powder suspension 
formulation or the dispersible tablets. 
Capsules:  Dabrafenib capsules will be supplied by Novartis (for subjects able to reliably and 
consistently swallow capsules). 


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Powder for oral suspension: Dabrafenib will be supplied by Novartis 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 Novartis or its authorized agent. 
Detailed instructions for constitution and dosing will be provided in the SPM. 
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 dispersion. 
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 (supplied in the SPM) based on 
weight and dose level will be used to prescribe dabrafenib to minimize inter-subject dosing 
variability. 
Investigational product details are provided in Table 3-2. 
 
Table 3-2 
 
Investigational Product 
Formulation 
description: 
HPMC Dabrafenib capsules 
Dabrafenib powder 
for oral suspension 
Dabrafenib  
Dispersible Tablets for 
oral suspension 
Dosage form: 
Capsule 
Powder for oral 
suspension 
Dispersible Tablet 
Unit dose 
strengths: 
10 mg, 25 mg, 50 mg and 75 
mg 
150 mg (in 
stickpack) 
10 mg/mL (as oral 
suspension) 
10mg 
Route/ 
Frequency: 
Oral / BID  
Oral / BID 
Oral / BID 


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Physical 
description: 
10 mg: opaque capsules 
composed of a white body and 
cap 
25 mg: opaque capsules 
composed of a pink body and 
cap 
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 silver 
laminated foil 
stickpacks. 
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 
Novartis 
Method for 
individualizing 
dosage: 
Unit dose capsules 
Administered using 
oral syringes (1, 5, 
and 20 mL sizes) 
Administered using 
dosing cup / PP oral 
liquid dispenser 
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. 
Dabrafenib should be administered under fasting conditions, either approximately 1 hour before 
or approximately 2 hours after a meal. 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, dabrafenib can be administered with a small non-fat meal 
(e.g., small amount of apple juice/sauce, a piece of dry toast). Subjects and their parents should 
be advised to avoid administering dabrafenib with milk or high-fat, high-calorie foods. 
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. 
The total daily dose will not exceed 300 mg (150 mg BID). 
3.7 
Dose Adjustment/Stopping Criteria 
All dose adjustments will be made by a Novartis Medical Lead in collaboration with the 
investigator. 


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3.7.1 
Dabrafenib Intra-Subject Dose Escalation 
In certain circumstances in Part 1 of this study, a subject’s dose level may be increased up to 
the highest dose level that is open to enrollment. Only subjects who have completed their DLT 
assessment period (28 days), who have tolerated treatment, but have measured AUC(0-12) less 
than target level, may be eligible for escalation. Decisions to increase a subject’s current dose 
will be based on all available data, including safety data and PK data for that subject, and must 
be agreed by the investigator and the Novartis Medical Lead. Predicted exposure AUC(0-12) at 
the escalated dose may not exceed 6000 ng*h/mL. Documentation of the dose escalation 
agreement and predicted exposure must be kept in the study files for the subject.  
Dose escalation is only allowed in subjects who are willing to consent to additional PK sampling 
at the escalated dose level. Additional PK samples will be collected on Day 15 following 
administration of the escalated dose. 
Intra-subject dose escalation will not occur in Part 2. 
Subjects will be summarized based on the treatment level to which they were originally 
assigned.  
3.7.2 
Dabrafenib Dose Modifications/Interruption for Toxicity 
The severity of adverse events will be graded utilizing the National Cancer Institute (NCI) 
CTCAE, version 4.0.  The following sections include: 
• Supportive guidelines for managing common toxicities 
• General dose modification guidelines for toxicities related to study treatments   
• Specific management guidelines for pyrexia, cardiovascular adverse events, and cutaneous 
squamous cell carcinoma/keratoacanthoma 
Investigators should also refer to the dabrafenib Investigator’s Brochure for the most current 
product safety information.  
3.7.3 
General supportive guidelines 
3.7.3.1 
Dose Modification for General Toxicities 
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 3-3.  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. 
Investigators should always err on the side of caution in these settings if treatment-related 
toxicity is a possibility.  Note that guidelines for management of hepatobiliary adverse events 


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are provided separately in Section 3.7.8. Additionally, please refer to the SPM for additional 
dose modification guidance.  
Table 3-3 
 
Dose Modification Guidelines - General 
CTCAE Grade 
Action and Dose Modificationa,b 
Grade 1  or Grade 2 
(tolerable) 
Continue study treatments at same dose level (no dose modification) and 
monitor as clinically indicated 
Grade 2 (Intolerable)  or Grade 3 
1st, 2nd, or 3rd occurrence 
Interrupt study treatments until toxicity resolves to ≤ grade 1 then restart at next 
lower dose level 
4th or greater occurrence  
Discontinue treatment.  
Grade 4 
1st occurrence 
Interrupt study treatments until toxicity resolves to ≤ grade 1 or baseline then 
restart at next lower dose level or discontinue at discretion of investigator 
All other occurrences 
Discontinue treatments 
a. 
Treatments should be discontinued if more than 3 dose reductions are required. 
b. 
Approval from the Novartis Medical Lead is required to restart study treatments after ≥21 days interruption 
When an individual’s adverse reactions are under effective management, dose re-escalation 
following the same dosing steps as de-escalation may be considered. 
3.7.4 
Dose Modification Guidelines - Adverse Events of Special Interest 
3.7.4.1 
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. 
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.  
In subjects experiencing pyrexia associated with rigors, severe chills, dehydration or 
hypotension, serum creatinine and other evidence of renal function (e.g. creatinine clearance, 
BUN) should be monitored carefully during and following severe events of pyrexia. Pyrexia 
accompanied by hypotension, dehydration requiring intravenous fluids, renal insufficiency 
and/or severe (≥ Grade 3) rigors/chills in the absence of an obvious infectious cause should be 
reported as a SAE.  
Guidelines regarding management and dose reduction for pyrexia considered to be related to 
dabrafenib are provided in Table 3-4. 


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Table 3-4 
Mandatory Dose Modification and Recommended Clinical 
Management for Pyrexia  
Occurrence a,b 
Recommended adverse event management 
guidelines 
Mandatory dose modification 
requirements 
Any 
● Clinical evaluation for infection and 
hypersensitivityc 
● Laboratory (local lab) work-upc 
● Hydration as requiredd 
 
1st Eventb: 
● Administer anti-pyretic treatment as clinically 
indicated and initiate prophylactic treatment if 
associated with rigors, renal failure, 
dehydration, or hypotensione 
● Interrupt dabrafenib 
● Once pyrexia resolves to 
baseline, restart dabrafenib at 
the same dose level 
● If fever was associated with 
dehydration, hypotension, or 
renal insufficiency, reduce 
dabrafenib to the next lower 
dose level. g 
2nd Event e 
● Same as for 1st event, and 
● Within 3 days of onset of pyrexia 
 
● Optimize anti-pyretic therapy 
 
● Consider oral corticosteroids for at least 
5 days or as clinically indicatedf  
● Same as 1st 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 
● Once pyrexia resolves to 
baseline, restart dabrafenib 
reduced by one dose levelg  
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. 
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 after 3 episodes of pyrexia complicated by rigors, severe chills 
etc., which cannot be managed by best supportive care, including increasing doses of oral steroids.  Re-
escalation of dabrafenib is allowed if no episode of pyrexia is observed in the 4 weeks subsequent to dose 
reduction 
3.7.4.2 
Renal insufficiency 
Cases of renal insufficiency have occurred in adult subjects receiving dabrafenib.  Prior to start 
of study treatment, concomitant medications must be reviewed for the potential risk of inducing 
nephrotoxicity and concomitant medications may be modified if clinically possible.  






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● Consider evaluation with cardiologist 
(recommended). 
● If event recurs, permanently discontinue study 
treatments.  
Abbreviations:  ECG = electrocardiogram; msec = milliseconds; QTcB = QT duration corrected for heart rate by 
Bazett’s formula. 
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  
3.7.5 
Management Guidelines for Additional AEs 
• Palmar Plantar Erythrodysesthesia (PPES) – Measures for PPES should include: 
• Lifestyle modification:  avoidance of hot water, traumatic activity, constrictive 
footwear, or excessive friction on the skin and the use of thick cotton socks and 
gloves, and shoes with padded insoles 
• Symptomatic treatments:  apply moisturizing creams frequently, topical keratolytics 
(e.g. urea 20-40 % cream, salicylic acid 6%, tazarotene 0.1% cream, fluorouracil 5% 
cream), clobetasol propionate 0.05% ointment for erythematous areas, topical 
lidocaine 2%, and / or systemic pain medication such as nonsteroidal anti-
inflammatory drugs, codeine, and pregabalin for pain. 
• Dose modification may also be required. 
• 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 iridocylitis) of > 6 week duration.  
• 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. 
3.7.6 
Left Ventricular Ejection Fraction Stopping Criteria 
ECHO must be performed at baseline and at follow-up visit(s) per the schedule in the Time and 
Events Table.  Subjects who have an asymptomatic, absolute decrease of >10% in LVEF 
compared to baseline and the ejection fraction is below the institution’s LLN should 
temporarily discontinue dabrafenib and have a repeat evaluation of LVEF within 1 week.  
ECHO should be repeated every 1-2 weeks for 4 weeks or until LVEF recovery to above 
institutional lower limit of normal and within 10% of baseline. 
• If the LVEF recovers (defined as ≥ LLN and absolute decrease ≤10% compared to 
baseline) at any time during the next 4 weeks, after consultation and approval of the 
Medical Lead, the subject may be restarted on dabrafenib at a reduced dose(s).  For such 
subjects, monitoring of LVEF will then be performed 2 and 4 weeks after rechallenge, and 
every 4 weeks thereafter for 12 weeks and then per protocol. 


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• If repeat LVEF does not recover within 4 weeks, then the subject should permanently 
discontinue dabrafenib. Ejection fraction should continue to be monitored every 4 weeks 
for 16 weeks or until resolution. 
Subjects with a Grade 3 or 4 (symptomatic) left ventricular systolic dysfunction must 
discontinue dabrafenib.  Ejection fraction should continue to be monitored every 4 weeks for 
16 weeks or until resolution.  If recovery occurs (LVEF to above institutional LLN and 
symptom resolution) within 4 weeks, the subject may restart dabrafenib at a reduced dose in 
consultation with the Medical Lead (if in the opinion of the investigator, the subject was 
receiving or likely to receive clinical benefit with continued treatment). 
All events of LVEF meeting the stopping criteria should be reported as SAEs (refer to 
Section 11.7). 
Copies of all ECHO(s) will be required for possible central review.  Copies of all cardiology 
consultations performed on subjects who experience a >10% decrease in LVEF from baseline 
and whose cardiac ejection fraction is below the institution’s LLN will also be required for 
possible central review.  Details for central collection of ECHOs will be provided in the SPM. 
3.7.7 
Valvular Toxicity Stopping Criteria 
Subjects who have an asymptomatic, moderate regurgitation or stenosis by ECHO (Grade 2 
mitral/tricuspid/aortic valvular toxicity per CTC AE v4.0) should temporarily discontinue 
Dabrafenib and have a repeat evaluation by ECHO within 1 week. ECHO should be repeated 
every 1-2 weeks for 4 weeks or until valve recovery to baseline. 
• If the valve recovers to baseline any time during the next 4 weeks, after consultation and 
approval of the Medical Lead, the subject may be restarted on Dabrafenib at a reduced 
dose(s).  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 12 weeks and then per 
protocol. 
• If repeat ECHO does not reveal valve recovery to baseline within 4 weeks, then the 
subject should permanently discontinue Dabrafenib.  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 dabrafenib.  
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 Dabrafenib at a reduced dose after consultation and approval 
of the Medical Lead. 
Copies of all ECHO(s) will be required for possible central review.  Details for central collection 
of ECHOs will be provided in the SPM.  Copies of all cardiology consultations performed on 
subjects who experience a valvular toxicity will also be required by Novartis for review. 


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3.7.8 
Liver Chemistry Stopping Criteria 
Liver chemistry stopping and follow up criteria have been designed to assure subject safety 
and evaluate liver event etiology in alignment with the FDA Guidance for Industry – Drug-
Induced Liver Injury: Premarketing Clinical Evaluation (July 2009, www.fda.gov). 
Liver chemistry stopping criteria 1-5 are defined as: 
1. Alanine aminotransferase (ALT) ≥3 times the upper limit of normal (xULN) and bilirubin 
≥ 2xULN (>35% direct bilirubin) (or ALT≥3xULN and International Normalized Ratio 
(INR) >1.5, if INR measured) 
NOTE: If serum bilirubin fractionation is not immediately available, study drug should be 
discontinued if ALT ≥ 3xULN and bilirubin ≥ 2xULN.  Serum bilirubin fractionation 
should be performed if testing is available. If testing is unavailable, record presence of 
detectable urinary bilirubin on dipstick, indicating direct bilirubin elevations and 
suggesting liver injury. 
2. ALT ≥8xULN 
3. ALT ≥5xULN but <8 xULN persists for ≥2 weeks 
4. ALT ≥3xULN if associated with the appearance or worsening of symptoms of hepatitis or 
hypersensitivity such as fatigue, nausea, vomiting, right upper quadrant pain or tenderness, 
fever, rash or eosinophilia. 
5. ALT ≥5xULN but <8 xULN and cannot be monitored weekly for >2 weeks. 
When any of the liver chemistry stopping criteria 1 – 5 is met, do the following: 
• Immediately discontinue subject from study treatment.  
• Report the event to Novartis within 24 hours of learning its occurrence. 
• Complete the liver event electronic case report form (eCRF) and SAE data collection tool 
if the event also meets the criteria for an SAE.  
• All events of ALT ≥ 3xULN and bilirubin ≥ 2xULN (>35% direct bilirubin) (or 
ALT≥3xULN and INR>1.5, if INR measured; INR measurement is not required and the 
threshold value stated will not apply to subjects receiving anticoagulants), termed ‘Hy’s 
Law’, must be reported as an SAE (excluding studies of hepatic impairment or 
cirrhosis).  
• NOTE: if serum bilirubin fractionation is not immediately available, study drug should be 
discontinued if ALT ≥ 3xULN and bilirubin ≥ 2xULN. Serum bilirubin fractionation 
should be performed if testing is available. If testing is unavailable, record presence of 
detectable urinary bilirubin on dipstick, indicating direct bilirubin elevations and 
suggesting liver injury 
• Complete the liver imaging and/or liver biopsy eCRFs if these tests are performed. 
• Perform liver event follow up assessments (Section 12), and monitor the subject until liver 
chemistries resolve, stabilize, or return to baseline values as described below.  
• Withdraw the subject from the study after completion of the liver chemistry monitoring 
(unless further safety follow up is required or Novartis Medical Governance approval of 
drug restart is granted, as described in Section 12).  


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• For studies where survival or progression is an endpoint, follow-up for overall 
survival or progression is required following discontinuation from study treatment  
• Do not restart investigational product unless written approval is granted by Novartis 
Medical Governance (details for restarting investigational product are described in Section 
12), whereupon the subject continues in the study after completion of the liver chemistry 
monitoring described in Section 12).  
• Subjects meeting criterion 5 should be monitored as frequently as possible. 
In addition, for subjects meeting criterion 1:  
• Make every reasonable attempt to have subjects return to clinic within 24 hours for repeat 
liver chemistries, liver event follow up assessments (refer to Section 12), and close 
monitoring. 
• A specialist or hepatology consultation is recommended. 
• Monitor subjects twice weekly until liver chemistries [ALT, aspartate aminotransferase 
(AST), alkaline phosphatase, bilirubin] resolve, stabilize or return to within baseline 
values. 
In addition, for subjects meeting any of the criteria 2 - 5: 
• Make every reasonable attempt to have subjects return to clinic within 24-72 hours for 
repeat liver chemistries and liver event follow up assessments (refer to Section 12). 
• Monitor subjects weekly until liver chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) resolve, stabilize or return to within baseline values;  
• Subjects meeting criterion 5 should be monitored as frequently as possible. 










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PK (1 mL samples) 
 
 
 
 
 
 
X 
 
X 
 
 
PK (2 mL samples) 
 
 
 
X 
 
 
 
 
 
 
 
Plasma concentrations of dabrafenib and all metabolites (hydroxy-dabrafenib, desmethyl-dabrafenib, and carboxy-dabrafenib) will be measured in the 2 mL blood samples. Plasma 
concentrations of dabrafenib, hydroxy-dabrafenib and desmethyl-dabrafenib will be measured in 1 mL blood samples. Carboxy-dabrafenib will not be measured in the 1 mL blood 
sample. 
a Subjects who are approved for intra-subject dose escalation must provide PK samples on day 15 at the higher dose level.  










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4 
STUDY POPULATION 
4.1 
Number of Subjects 
Approximately 6 to 18 subjects will be enrolled in Part 1. In Part 2, each expansion cohort will 
attempt to enroll at least 10 evaluable subjects; evaluable for the purpose of clinical activity 
analysis is defined as a subject with a pre-dose and at least 1 post-dose disease assessment. The 
HGG cohort will continue recruitment until enrollment on another pediatric HGG study is 
available (expected by the end of 2018 and no later than mid 2019). It is estimated that 
approximately 35 subjects with HGG will be enrolled into Part 2.   
Additional subjects/cohorts may be enrolled to allow for evaluation of additional dose levels.  
If subjects prematurely discontinue the study, additional subjects may be enrolled as 
replacement subjects at the discretion of the Sponsor. 
4.2 
Eligibility Criteria 
4.2.1 
Inclusion Criteria 
Specific information regarding warnings, precautions, contraindications, adverse events, and 
other pertinent information on the Novartis investigational product or other study treatment that 
may impact subject eligibility is provided in the IB. 
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. 
A subject will be eligible for inclusion in this study only if all of the following criteria apply: 
1. Written informed consent – a signed informed consent and/or assent (as age appropriate) 
will be obtained according to institutional guidelines; 
2. Male or female ≥12 months and <18 years of age at the time of signing the informed 
consent form; 
3. 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. 
4. At least one evaluable lesion; 
5. 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); 
6. Performance score of ≥50% according to the Karnofsky/Lansky performance status scale 
(Yates, 1908) (Appendix 3); 
7. NOTE:  Subjects with a performance status of <50% can be enrolled if the subject’s 
confinement to bed and inability to carry out activities is due solely to cancer-related pain, 
as assessed by the investigator. 


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8. Females of child-bearing potential must be willing to practice acceptable methods of birth 
control (see Section 7.1).  Additionally, females of childbearing potential must have a 
negative serum pregnancy test within 7 days prior to the first dose of study medication. 
Sexually active males (including those that have had a vasectomy), who do not agree to 
abstinence, must be willing to use a condom during intercourse while taking the study 
drug, and for 4 weeks after stopping treatment and should not father a child in this period. 
9. Must have adequate organ function as defined by the following values: 
• 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 
10. Adequate renal and metabolic function defined as: 
• Calculated eGFR (Schwartz formula, http://www.medcalc.com/pedigfr.html), or 
radioisotope GFR ≥90 mL/min/1.73 m2; or 
• A serum creatinine within the institutional reference range upper limit of normal (for 
age/gender, if available); 
11. Adequate liver function defined as: 
• Bilirubin (sum of conjugated + unconjugated) ≤ 1.5 x upper limit of normal (ULN) 
for age 
• AST and ALT ≤2.5 x ULN; AST/ALT may be <5 x ULN at baseline if disease under 
treatment involves the liver (requires radiographic confirmation of liver involvement) 
12. Adequate cardiac function defined as:  
• LVEF of either ≥50% by ECHO or greater than institutional LLN by ECHO (while 
not receiving medications for cardiac function) 
• Corrected QT (QTcB) interval <450 msecs. 
4.2.2 
Exclusion Criteria 
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. 
A subject will not be eligible for inclusion in this study if any of the following criteria apply: 
1. Part 2 ONLY:  Previous treatment with dabrafenib, another RAF inhibitor, or a MEK 
inhibitor (exception:  prior treatment with sorafenib is permitted); 
2. Malignancy OTHER than the BRAF mutant malignancy under study 
3. Had chemotherapy or radiotherapy within 3 weeks (or 6 weeks for nitrosoureas or 
mitomycin C) prior to administration of the first dose of study treatment; 
4. The subject has received an investigational product within the following time period prior 
to the first dosing day in the current study: 28 days or 5 half-lives or twice the duration of 
the biological effect of the investigational product (whichever is warranted by the data); 
5. History of another malignancy; 


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Exception:  (a) Subjects who have been successfully treated and are disease-free for 3 
years, (b) a history of completely resected non-melanoma skin cancer, (c) successfully 
treated in situ carcinoma, or (d) CLL in stable remission, are eligible 
6. Current use of a prohibited medication (Section 8.2) or herbal preparation or requires any 
of these medications during the study;  
7. Unresolved toxicity greater than NCI CTCAE v4.0 (NCI, 2009) Grade 2 or higher from 
previous anti-cancer therapy, including major surgery, except those that in the opinion of 
the investigator are not clinically relevant given the known safety/toxicity profile of 
dabrafenib (e.g., alopecia and/or peripheral neuropathy related to platinum or vinca 
alkaloid based chemotherapy); 
8. Has leukaemia; 
9. History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to dabrafenib and its excipients; 
10. Autologous or allogeneic stem cell transplant within 3 months prior to enrolment [NOTE:  
subjects with evidence of active graft versus host disease are excluded]; 
11. History of myocardial infarction, severe or unstable angina, peripheral vascular disease or 
familial QTc prolongation; 
12. Abnormal cardiac valve morphology (≥ grade 2) documented by echocardiogram (NOTE:  
subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be entered on 
study); 
13. Moderate valvular thickening; 
14. Known, uncontrolled cardiac arrhythmias (except sinus arrhythmia) within the past 24 
weeks; 
15. Uncontrolled medical conditions (e.g., diabetes mellitus, hypertension, liver disease or 
uncontrolled infection), psychological, familial, sociological, or geographical conditions 
that do not permit compliance with the protocol; or unwillingness or inability to follow the 
procedures required in the protocol; 
16. Presence of active GI disease or other condition (e.g., small bowel or large bowel 
resection) that will interfere significantly with the absorption of drugs.  If clarification is 
needed as to whether a condition will significantly affect absorption of drugs, contact the 
Novartis Medical Lead; 
17. Hepatitis B Virus, or Hepatitis C Virus infection (subjects with laboratory evidence of 
Hepatitis B Virus clearance may be enrolled); 
18. Pregnant females as determined by positive human chorionic gonadotropin (hCG) test at 
screening or prior to dosing; 
19. Lactating females who are actively breast feeding. 
4.3 
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. 


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4.4 
Withdrawal from Study and Missing Visits 
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 appropriately be 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. 
5 
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS 
5.1 
Hypotheses and Treatment Comparisons 
With respect to the primary objectives and endpoints, the primary focus will be on determining 
the MTD (or recommended dose based on available safety, PK, and response data), the safety 
profile, and PK/PD relationship of dabrafenib in paediatric subjects with advanced BRAF 
V600-mutation positive solid tumors.  Most analyses will be descriptive 
. 
5.2 
Sample Size Considerations 
5.2.1 
Sample Size Assumptions 
5.2.1.1 
Part 1 Dose Escalation 
A minimum of 3 subjects will be evaluated at each dose level for determination of an 
appropriate pediatric dose using the modified RSD.  It is estimated that approximately 6 to 18 
subjects will be enrolled into Part 1. 
5.2.1.2 
Part 2 Cohort Expansion 
The sample size for Part 2 is based on feasibility, practicality, and what would be sufficient for 
the characterization of the safety of dabrafenib and the plasma pharmacokinetics for the 
populations enrolled.  Each of the 4 expansion cohorts will attempt to enroll at least 10 evaluable 
subjects; the HGG cohort will continue recruitment until enrollment on another pediatric HGG 
study is available (expected by the end of 2018 and no later than mid 2019).  It is estimated that 
approximately 35 subjects with HGG will enroll into Part 2. 
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) 


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for the Part 2 expansion cohorts was further evaluated using exact binominal distribution 
probabilities, and the details are provided in Table 5-1.  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 dabrafenib in high grade glioma subjects, the chance declaring the cohort as having 
insufficient clinical activity after 10 subjects is approximately 20%. 
 
Table 5-1 
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 
5.2.2 
Sample Size Re-estimation 
The HGG cohort in Part 2 will continue recruitment after 10 subjects are enrolled until 
enrollment on another study is available (expected by the end of 2018 and no later than mid 
2019).  The exact number of subjects recruited to the HGG cohort will depend on both the 
recruitment rate of subjects with HGG and the time it takes to begin recruitment to the new 
study. It is estimated that around 35 subjects with HGG will be recruited prior to the full opening 
of the new study based on the current plans, although the actual figure could be higher or lower 
than this. As promising efficacy has already been demonstrated with the initial subjects enrolled 
in this cohort, the additional increase in enrollment is to ensure that subjects can have access to 
a beneficial treatment, while also providing important additional refinement of the response rate 
estimate. For illustration, the improvement of precision in response rate estimate is shown in 
the Table below with the 95% exact binomial confidence intervals (CIs) at N=35 compared to 
the 95% CIs at N=10. 
 
Table 5-2 
Exact Binomial 95% Confidence Intervals around Potential Observed 
Objective Responses Rates for 10 and 35 Subjects 
Observed # of Responses 
(Response Rate) (N=10) 
Exact 95% Confidence 
Interval (%) (N=10) 
Observed # of 
Responses (Response 
Rate) (N=35) 
Exact 95% Confidence 
Interval (%) (N=35) 
1 (10%) 
0.3, 44.5 
4 (11%) 
3.2, 26.7 
2 (20%) 
2.5, 55.6 
7 (20%) 
8.4, 36.9 
3 (30%) 
6.7, 65.2 
11 (31%) 
16.9, 49.3 
4 (40%) 
12.2, 73.8 
14 (40%) 
23.9, 57.9 
5 (50%) 
18.7, 81.3 
18 (51%) 
34.0, 68.6 
6 (60%) 
26.2, 87.8 
21 (60%) 
42.1, 76.1 


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Observed # of Responses 
(Response Rate) (N=10) 
Exact 95% Confidence 
Interval (%) (N=10) 
Observed # of 
Responses (Response 
Rate) (N=35) 
Exact 95% Confidence 
Interval (%) (N=35) 
7 (70%) 
34.8, 93.3 
25 (71%) 
53.7, 85.4 
5.3 
Data Analysis Considerations 
All data will be summarized or listed.  Subjects will be summarized based on the treatment level 
to which they were originally assigned. Additionally, selected analyses and summaries will be 
provided by age group as appropriate. 
Complete details will be provided in the Statistical and Analysis Plan (SAP). 
5.3.1 
Analysis Populations 
Populations will be considered for the analysis as follows: 
The ‘All Treated’ population is defined as all subjects who receive at least 1 dose of study 
treatment.  An incorrect treatment schedule or drug administration or an early termination of 
treatment will not result in exclusion of subjects from this population.   
The ‘Safety’ population consists of all subjects who receive at least 1 dose of study treatment. 
All safety data will be analyzed using the Safety population. 
The ‘DLT Evaluable’ population is defined as those subjects in Part 1 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 drug 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 3.3, will also be included in the DLT evaluable 
population regardless of exposure. 
The ‘PK Population’ is defined as those subjects fulfilling the All Treated population criteria 
who contribute PK samples. 
5.3.2 
Interim Analysis 
Safety and PK data will be examined while the study is being conducted for dose escalation 
decisions. 
At the time of Amendment 7, an unplanned interim analysis was performed after all subjects 
with LGG had enrolled in Part 2 and completed at least 6 months of treatment or had 
discontinued treatment earlier. The interim analysis included analysis of all Part 1 subjects and 
other disease cohorts from Part 2 were analyzed as appropriate. This interim analysis was used 
for decision making of future development options and for publications. No statistical 
hypothesis testing was planned or conducted. 
An interim analysis is planned after all subjects with LCH have enrolled in Part 2 and have 
completed at least 1 year of treatment or have discontinued treatment earlier. The results will 
be used for decision making of future development options and may be used for publications. 
At this time, no statistical hypothesis testing is planned, and no decision regarding the conduct 


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of this study will be made. The data for all Part 1 and Part 2 subjects may also be analyzed at 
this interim. In addition, safety and tolerability will be monitored closely on a continued basis.  
Additional interim analyses may be performed to support any health authority requests as and 
when needed.  No efficacy or futility conclusions will be drawn based on these interim analyses. 
5.3.3 
Final Analyses 
5.3.3.1 
Safety and Tolerability Analyses 
All relevant safety data will be summarized or listed based on the Safety population. 
All safety data will be reported according to the initial treatment regimen the subject received 
(initial dose of dabrafenib). Additionally, selected analyses and summaries will be provided by 
age group as appropriate.  AEs will be summarized by maximum toxicity grade for each initial 
dose level of dabrafenib. The toxicity grade for laboratory data will be calculated using NCI 
CTCAEv4.0 or higher (NCI, 2009).  The lab data will then be summarized according to the 
subjects’ baseline grade and maximum grade for each cycle of therapy (done for each initial 
dose level of dabrafenib). 
DLTs will be summarized. 
5.3.3.1.1 Extent of Exposure 
Extent of exposure of dabrafenib will depend on tolerability of the subjects to the doses 
administered and the course of their disease. The number of subjects exposed to dabrafenib will 
be summarized for each dose level administered. 
5.3.3.1.2 Adverse Events 
AEs will be coded and grouped by body system.  AEs will be summarized by frequency and 
proportion of total subjects, event type and body system.  Separate summaries will be given for 
all AEs, drug-related AEs, SAEs, and AEs leading to withdrawal from the study. 
Adverse events (AEs) and toxicities will be graded according to the NCI-CTCAE, Version 4.0.  
Summaries of the number of toxicity grades for both laboratory and non-laboratory data will be 
presented.  If the AE is listed in the NCI-CTCAE, Version 4.0, the maximum grade will be 
summarized.  Otherwise, the maximum intensity will be summarized. 
5.3.3.1.3 Clinical Laboratory Evaluations 
Hematology and clinical chemistry data will be summarized at each scheduled assessment 
according to NCI CTCAE grade (version 4.0). For laboratory tests where grades are not defined 
by CTCAE v4.0, results will be categorized as low/normal/high based on laboratory normal 
ranges. Summaries will include data from scheduled assessments only, and all data will be 
reported according to the nominal visit date for which it was recorded; no visit windows will 
be applied. Unscheduled data will be included in “post-baseline” summaries which will capture 
a worst case across all scheduled and unscheduled visits after the first dose of study medication. 
Further details will be provided in the SAP. 


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5.3.3.1.4 Other Safety Measures 
Performance status (Karnofsky/Lansky) assessments will be summarized by the originally 
assigned dose level.  Vital signs, ECG, and ECHOs will be summarized at all measured time 
points.  A descriptive summary including change from baseline pre-dose will also be presented. 
Further details will be provided in the SAP. 
5.3.3.2 
Pharmacokinetic Analyses 
PK parameters for dabrafenib and its metabolites for subjects in whom the full blood sampling 
scheme was used will be calculated with standard non-compartmental methods.  The PK 
parameters calculated with non-compartmental methods include; AUC(0-∞) (single dose only), 
AUC(0-t), Cmax, Tmax, Cτ, CL/F (dabrafenib only), and AUC (0-τ) (where τ = 12 hours).  For 
subjects in whom the sparse blood sample collection scheme is used, AUC(0-τ) and the average 
steady-state concentration will be estimated with a population PK model.  Final PK parameters 
will be summarized and will be compared to historical adult data.  
All 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 pharmacokinetics 
of dabrafenib and its metabolites.  PK parameters estimated in the population PK analysis will 
include: apparent clearance following oral dosing (CL/F), volume of distribution (V/F), and 
absorption rate (ka).  Data may be pooled with PK data from adult studies. 
5.3.3.3 
Efficacy Analyses 
Anti-tumor activities will be calculated based on clinical evidence and the investigator-
determined response assessment algorithms as described in Appendix 2.  Where appropriate, 
the lesion data will be listed for each subject.  For subjects with solid tumors, the percent change 
from baseline and nadir will be calculated for each subject and listed, along with their calculated 
response [complete response (CR), partial response (PR), stable disease and progression of 
disease (PD)] according to response criteria in Appendix 2. Response data will be summarized 
by disease cohort and by dose using the All Treated population. If the data warrant, the response 
data may also be summarized by the dose level of dabrafenib. For the LGG, HGG, and other 
solid tumors disease cohorts, response will also be assessed by an independent reviewer, and 
this data will be used to provide supportive analyses. 
Additionally, all efficacy analyses will also be performed on the subset of central laboratory 
confirmed BRAF mutant subjects, excluding subjects who were centrally confirmed to be 
BRAF Wild-Type. In the event that central confirmation of mutation status is not obtained, the 
local laboratory testing result for BRAF mutation status will be utilized.  
Response Rate (RR) with 95% exact confidence intervals will be calculated as the proportion 
of subjects with best overall response of confirmed CR or PR, as defined in Appendix 2, relative 
to the total number of subjects treated in each expansion cohort. In the case of LCH subjects, 
the RR is the number of subjects assessed to have treatment response relative to the total number 
of subjects treated in that cohort.  See Appendix 2 for further information.  
In addition to the frequentist analysis approach mentioned above, RR will be compared to the 
target RR using Bayesian posterior probabilities.  A posterior estimate of RR will be calculated 
for each expansion cohort along with associated 95% credible intervals as calculated on 




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Medical/medication/alcohol history will be assessed as related to the eligibility criteria listed in 
Section 4.2. 
Additional retrospective data will be collected, if available, on subjects 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. 
6.2 
Critical Baseline Assessments 
6.2.1 
Confirmation of BRAF Mutation Positive Status 
Subjects with BRAF V600 mutation- positive tumors as determined by local testing conducted 
in a CLIA-approved facility (or equivalent) may be enrolled on the study. Archived tumor tissue 
sample will be collected at screening for retrospective confirmation of the BRAF mutation 
status.  If an archived tumor tissue sample is not available, fresh tumor tissue should be collected 
for the assessment and confirmation of BRAF V600 mutation status in a CLIA approved facility 
(see SPM for further details on sample collection).  
6.2.2 
Baseline Documentation of Target and Non-target Lesions 
All baseline lesion assessments must be performed within 21 days of the first dose of study 
medication (or within 35 days for MRIs).  Guidance on baseline documentation of target and 
non-target lesions will be provided (by tumor type) in the SPM or Imaging Manual. 
6.2.3 
Independent review of HGG tumor histology 
A central review of tumor histology and grade will be performed by an independent pathologist 
for all subjects with HGG diagnosis.  
Slides and/or blocks collected during the study will be used for the central review. 
6.3 
Safety and Tolerability 
Planned time points for all safety assessments are listed in the Time and Events Table (Section 
3.8). 
Physical and Dermatological Examinations 
• A complete physical examination will include assessments of the head, eyes, ears, nose, 
throat, skin, thyroid, neurological, lungs, cardiovascular, abdomen (liver and spleen), 
lymph nodes and extremities 
• Height and weight will also be measured and recorded. 
• A brief physical examination will include height and weight, assessments of the skin, 
lungs, cardiovascular system, and abdomen (liver and spleen) [and neurological exam as 
clinically indicated]. 




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QTcB intervals.  Refer to Section 3.7.4.4 for QTcB withdrawal criteria and additional 
QTcB readings that may be necessary. 
Echocardiography (ECHO) 
• ECHOs will be performed to assess cardiac ejection fraction.  The echocardiographer's 
evaluation should include an evaluation of left ventricular ejection fraction.  Post-dose 
ECHOs should be compared to baseline to note if there are any changes. 
• Copies of all ECHOs and cardiology consultations performed on subjects who experience 
a >10% absolute decrease in LVEF from baseline and whose cardiac ejection fraction is 
less than institution’s LLN will be required by Novartis for review. 
Clinical Laboratory Assessments 
Hematology, clinical chemistry and additional parameters to be tested are listed below: 
Hematology 
 
Platelet Count: 
Red blood cell (RBC) Indices ( at screening 
and if hemoglobin decrease ≥2 g/dL 
compared to baseline): 
Automated White Blood Cell 
(WBC) Differential: 
RBC Count 
MCV 
Neutrophils 
WBC Count (absolute)  
MCH 
Lymphocytes 
Hemoglobin 
MCHC 
Monocytes 
 
Reticulocyte Count 
 
Eosinophils 
 
 
Basophils 
Clinical Chemistry 
BUN 
Potassium 
AST 
Total and direct bilirubin a 
Creatinine 
Chloride 
ALT 
Uric Acid 
Glucose 
Total CO2 
Alkaline phosphatase 
Albumin 
Sodium 
Calcium 
 
Total Protein 
Magnesium 
Phosphate 
 
 
Other tests 
Pregnancy tests 
Amylase and lipase [monitor via local laboratory where appropriate to evaluate certain AEs (i.e., 
abdominal pain, pancreatitis, etc.)] 
Creatine phosphokinase (CPK) at screening and pre-dose Day 1 only 
Liver gamma GT for subject with LCH to complete the LCH scoring system (see Appendix 2) 
a. Direct bilirubin is required only if the total bilirubin is elevated (> or = 2 times the ULN) 
Palatability 
For subjects ≥12 years of age who receive the suspension, the subject will complete a form 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, 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 


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evaluate the suspension with the child based on verbal and non-verbal feedback.  Additional 
details (and an example questionnaire) are provided in the SPM. 
6.4 
Pregnancy 
6.4.1 
Time period for collecting pregnancy information 
All pregnancies in female subjects and/or female partners of male subjects will be collected 
after the start of dosing and until 5 terminal half-lives post-last dose. 
6.4.2 
Action to be taken if pregnancy occurs 
The investigator will collect pregnancy information on any female subject, who becomes 
pregnant while participating in this study.  The investigator will record pregnancy information 
on the appropriate form and submit it to Novartis within 24 hours of learning of a subject's 
pregnancy.  The subject will also be followed to determine the outcome of the pregnancy.  
Information on the status of the mother and child will be forwarded to Novartis.  Generally, 
follow-up will be no longer than 6 to 8 weeks following the estimated delivery date.  Any 
premature termination of the pregnancy will be reported. 
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. 
A spontaneous abortion is always considered to be an SAE and will be reported as such.  
Furthermore, any SAE occurring as a result of a post-study pregnancy and is considered 
reasonably related to the study treatment by the investigator, will be reported to Novartis as 
described in Section 11.7. While the investigator is not obligated to actively seek this 
information in former study participants, he or she may learn of an SAE through spontaneous 
reporting. 
Any female subject who becomes pregnant while participating will be withdrawn from the 
study. 
6.4.3 
Action to be taken if pregnancy occurs in a female partner of a male 
study subject 
The investigator will attempt to collect pregnancy information on any female partner of a male 
study subject who becomes pregnant while participating in this study.  The investigator will 
record pregnancy information on the appropriate form and submit it to Novartis within 24 hours 
of learning of the partner’s pregnancy.  The partner will also be followed to determine the 
outcome of the pregnancy.  Information on the status of the mother and child will be forwarded 
to Novartis.  Generally, follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date.  Any premature termination of the pregnancy will be reported. 
6.5 
Pharmacokinetics 
6.5.1 
Blood Sample Collection 
Blood samples for PK analysis of dabrafenib and its metabolites, hydroxy-dabrafenib, carboxy-
dabrafenib, and desmethyl-dabrafenib, will be collected at the time points indicated in Section 


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3.8, Time and Events Table.  The actual date and time of each blood sample collection will be 
recorded.  The timing of PK samples may be altered to ensure thorough PK monitoring (but the 
total number of samples and total blood volume collected will not change).  Plasma 
concentrations of dabrafenib and its metabolites (hydroxy-dabrafenib, carboxy-dabrafenib, and 
desmethyl-dabrafenib) will be determined from the 2 mL blood samples collected.  Plasma 
concentrations of dabrafenib and certain metabolites (hydroxy-dabrafenib and desmethyl-
dabrafenib) will be determined from the 1 mL blood samples collected. Carboxy-dabrafenib 
will not be determined from the 1 mL blood sample. 
Details of PK blood sample collection (including volume to be collected), processing, storage 
and shipping procedures are provided in the Study Procedures Manual (SPM). 
6.5.2 
Sample Analysis 
Until 31 Dec 2015 plasma analysis was performed under the management of Bioanalytical 
Science and Toxicokinetics, Drug Metabolism and Pharmacokinetics, Platform Technology and 
Sciences, GSK and raw data is stored in the GlaxoSmithKline Archives until transfer to 
Novartis archive. Since 1 Jan 2016 plasma analysis is performed under the management of 
Novartis DMPK and raw data are stored in the archives of the analytical site until transfer to 
Novartis archive. 
Concentrations of dabrafenib and its metabolites (hydroxy-dabrafenib, desmethyl-dabrafenib, 
and carboxy-dabrafenib) will be determined in plasma samples using validated analytical 
methods. Once the plasma has been analyzed for dabrafenib and its metabolites, any remaining 
plasma may be analyzed qualitatively for other circulating metabolites or quantitatively to 
perform long term stability evaluation or cross validation and the results reported under a 
separate DMPK protocol. 
6.6 
Anti-tumor Assessment 
Disease progression and response evaluations will be determined according to the appropriate 
guidelines (Appendix 2). 
See the Time and Events Table (Section 3.8) for the schedule of assessments.  Assessments 
must be performed on a calendar schedule and should not be affected by dose 
interruptions/delays.  For post baseline assessments, a window is permitted to allow for flexible 
scheduling (see Time and Events Table, Section 3.8). 
Confirmation of CR and partial response (PR) are required per protocol.  Complete response/PR 
confirmation assessments may take place at Week 16 (but not earlier than week 12) if initial 
response was seen at the Week 8 assessments.  Initial responses (CR/PR) that occur at Week 16 
(or after) should be confirmed not less than 4 and not more than 8 weeks after the initial 
response.  If a confirmation assessment is performed prior to the next protocol schedule 
assessment, the next protocol scheduled evaluation is still required (e.g. evaluations must occur 
at each protocol scheduled time point regardless of unscheduled assessments).  If the criteria 
for a CR or PR are not confirmed, then stable disease can be considered the best response if it 
has been demonstrated for a minimum of 12 weeks. 




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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 level assessment. 
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. 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. 
All menstruating female subjects (as required per local requirements and/or regulations) must 
have a negative serum pregnancy test within 7 days prior to the first dose of study medication, 
preferably as close to the first dose as possible, If serum pregnancy test is performed within 7 
days of first dose of study drug, it does not need to be repeated on Day 1 (pre-dose). All female 
subjects who begin to menstruate during the study must have a negative serum pregnancy test 
(as required per local requirements and/or regulations) during the study and for 4 weeks 
following the last dose of study drug. 
NOTES:   
• Oral contraceptives are not considered as highly effective methods of contraception due to 
potential drug-drug interactions with dabrafenib. 
• 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] 
• 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. 
7.1.2 
Male Subjects 
Male subjects (including those that have had a vasectomy)  taking dabrafenib in the study must 
use a condom during intercourse while taking the drug and not to father a child during the study 
and for the period of 4 weeks following stopping of study treatment. 
7.2 
Meals and Dietary Restrictions 
Subjects no longer need to abstain from ingestion of any food or drink containing grapefruit 
and grapefruit juice, Seville oranges (orange marmalade) or pommelos within 7 days prior to 
the first dose of dabrafenib until the end of the study. 
Dabrafenib should be administered under fasting conditions, either approximately 1 hour before 
or approximately 2 hours after a meal. If it is not possible for a subject to tolerate the fasting 
conditions noted above, dabrafenib can be administered with a small non-fat meal (e.g., small 


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amount of apple juice/sauce, a piece of dry toast). Subjects and their parents should be advised 
to avoid administering dabrafenib with milk or high-fat, high-calorie foods. 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. 
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. 
7.3 
Caffeine, Alcohol, and Tobacco 
• On PK sampling days, subjects will abstain from ingesting caffeine- or xanthine-
containing products (e.g. coffee, tea, cola drinks, energy drinks) for 24 hours prior to the 
start of collection of the samples and until collection of the last sample. 
• On PK sampling days, subjects will abstain from alcohol for 24 hours prior to the start of 
collection of the samples and until collection of the last sample. 
• Subjects who use tobacco products will be instructed that use of nicotine-containing 
products (including nicotine patches) will not be permitted while they are in the Clinical 
Unit. 
7.4 
Activity 
Subjects will abstain from strenuous exercise (e.g., competitive sports) for 48 hours prior to 
each blood collection for clinical laboratory tests.  Subjects may participate in light recreational 
activities during studies. 
8 
CONCOMITANT MEDICATIONS AND NON-DRUG 
THERAPIES 
8.1 
Permitted Medications and Non-Drug Therapies 
The investigator must be informed as soon as possible about any medication taken from the 
time of screening until 30 days after the last dose of study treatment.  Any concomitant 
medication(s), including dietary supplements, taken during the study will be recorded in the 
eCRF.  The minimum requirement is that drug name, dose, and the dates of administration are 
to be recorded.  Additionally, a complete list of all prior surgical procedures will be recorded 
in the eCRF.   
Subjects should receive full supportive care during the study, including transfusions of blood 
and blood products, and treatment with antibiotics, anti-emetics, anti-diarrheals, and analgesics, 
and other care as deemed appropriate, and in accordance with their institutional guidelines.  Use 
of anticoagulants such as warfarin is permitted, however, caution should be exercised and 
additional International Normalized Ratio (INR) monitoring is recommended when dabrafenib 
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Immunization is permitted while on dabrafenib if subject has been on treatment and is deemed 
stable. 
8.2 
Prohibited Medications and Non-Drug Therapies 
The use of certain medications and illicit drugs within 28 days or 5 half-lives, whichever is 
shorter, prior to randomization and for the duration of the study will not be allowed.  
The following medications or non-drug therapies are also prohibited while on treatment in this 
study: 
• Other anti-cancer therapies; 
• Other investigational drugs; 
• Antiretroviral drugs; 
• Herbal remedies (e.g., St. John’s wort); 
• Dabrafenib is metabolized primarily by Cytochrome P450 (CYP) 2C8 and CYP3A4.  Co-
administration of dabrafenib with ketoconazole, a CYP3A4 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 8-1) 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 of the Novartis 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 8-1 
 
Prohibited Medications 
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  
8.3 
Medications to be Used with Caution 
The following medications should be used with caution 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 
8-2 and in the SPM. 
• Therapeutic level dosing of warfarin can be used with approval by the Novartis Medical 
Lead and close monitoring of 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.  
Table 8-2 
Medications to be used with Caution 
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 
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 


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Erectile Dysfunction Agents 
Sildenafil, tadalafil, vardenafil 
HMG-CoA Reductase 
Inhibitors 
Atorvastatin, lovastatin, simvastatin, rosuvastatin, pravastatin 
Hypnotics and Sedatives 
Alprazolam, brotizolam, diazepam, estazolam, midazolam, triazolam, 
zolpidem, zopiclone 
Immunosuppressants 
Everolimus, sirolimus, tacrolimus 
Miscellaneous 
Aprepitant, cisapride, darifenacin, digoxin, disopyramide, leflunomide, 
methohexital, oral contraceptives, quinine, ranitidine, solifenacin, 
sulfasalazine, tramadol, tolvaptan, chloroquine, zopiclone 
Selective Aldosterone 
Blockers 
Eplerenone 
Abbreviations: CYP = cytochrome P450; HMG-CoA = 3-hydroxy-3-methylglutaryl-coenzyme A. 
Questions regarding concomitant medications should be directed to the Novartis Medical Lead 
for clarification. 
9 
COMPLETION OR EARLY WITHDRAWAL OF SUBJECTS 
9.1 
Subject Completion 
A subject will be considered to have completed the study if the subject dies, otherwise 
progresses during the study treatment (or is not clinically benefiting from continued treatment), 
is withdrawn due to an unacceptable toxicity, withdraws consent or begins a new therapy.  A 
final study visit within 28 days after last dose of study drug should be completed. 
9.2 
Subject Withdrawal Criteria 
Refer to Section 3.7 for dose adjustment/stopping criteria. 
A subject may withdraw from study treatment at any time at his/her own request, at the request 
of his/her parents, or may be withdrawn at any time at the discretion of the investigator for 
safety, behavioral or administrative reasons. 
9.3 
Subject Withdrawal Procedures 
9.3.1 
Subject Withdrawal from Study 
A subject will be considered to have withdrawn from the study if the subject has not died or 
progressed and is lost to follow-up, has withdrawn consent, or at the investigator’s discretion is 
no longer being followed. 
9.3.2 
Subject Withdrawal from Study Treatment 
Subjects will receive study treatment until disease progression, death or unacceptable AE 
(including meeting stopping criteria for liver chemistry defined in Section 3.7.8 or for 
hematologic and other non-hematologic toxicity as described in Section 3.7.2).  Treatment 
beyond disease progression may be considered if the investigator determines that the subject is 
still clinically benefiting from study treatment and the subject or their parent (guardian) is 
willing to continue study drug, following consultation with the study Medical Lead. In this case, 
the study treatment as well as the study procedures may be continued until study treatment 


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discontinuation.  These subjects will be considered as having progressive disease (as of the date 
of the scan showing progression). 
Study medication may also be permanently discontinued for any of the following reasons: 
• deviation(s) from the protocol that result in a significant risk to the patient’s safety; 
• request of the subject or parent/guardian’s request 
• investigator’s discretion 
• subject is lost to follow-up 
• study is closed or terminated. 
The primary reason study treatment was permanently discontinued must be documented in the 
subject’s medical records and electronic Case Report Form (eCRF).  
If the subject voluntarily discontinues from treatment due to toxicity, ‘adverse event’ should be 
recorded as the primary reason for permanent 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 a Final Visit (as defined in Table 
10) which should be completed at the time of discontinuation (within 28 days after last dose of 
study drug). Subjects will be offered post study treatment follow-up as specified in Section 9.4. 
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. 
9.3.3 
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. 
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.  


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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. 
9.4 
Treatment after the End of the Study 
After study participation in the current study and for subjects still benefitting from treatment 
with dabrafenib, subjects will be given the option to transition to the rollover study, where 
subjects continue receiving dabrafenib alone as specified in rollover study, provided subjects 
are still benefiting from dabrafenib. 
Subjects who are no longer receiving 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 2 to 3 months according 
to the instructions in Section 6.3.  
The investigator is responsible for ensuring that consideration has been given to the post-study 
care of the subject’s medical condition, whether or not Novartis is providing specific post-study 
treatment. 
10 
STUDY TREATMENT 
Study treatment dosage and administration details are listed in Section 3.6. 
10.1 
Blinding 
This will be an open label study.  
10.2 
Packaging and Labeling 
The contents of the label will be in accordance with all applicable regulatory requirements. 
10.3 
Preparation/Handling/Storage/Accountability 
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 Novartis. 


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Dabrafenib dispersible tablets will be dispersed in a defined 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.  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. 
Dabrafenib dispersible tablets are to be stored at up to 25°C.  Maintenance of a temperature log 
(manual or automated) is required. 
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance.  The 
investigator or the head of the medical institution (where applicable), or designated site staff 
(e.g., storage manager, where applicable) must maintain study treatment accountability records 
throughout the course of the study.  The responsible person(s) will document the amount of 
study treatment received from and returned to Novartis and the amount supplied and/or 
administered to and returned by subjects.  The required accountability units for this study will 
be number of capsules, number of dispersible tablets, or weight of suspension.  Discrepancies 
are to be reconciled or resolved.  Procedures for final disposition of unused study treatment are 
listed in the SPM. 
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. 
10.4 
Assessment of Compliance 
When 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. 


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When dosing occurs outside the clinic, parents/subjects will be provided a supply of study drug 
(powder stickpacks, dispersible tablets, or capsules).  On each return visit to the clinic, the 
parent/subject will return all unused study drug in its dispensed container, and the study site 
staff will note the number of capsules, number of tablets, or number of stickpacks returned in 
the source documents. 
10.5 
Treatment of Study Treatment Overdose 
In the event of a dabrafenib overdose, defined as administration of more than the highest dose 
tested in pediatric clinical studies without reaching a manageable specific toxicity, the 
investigator should contact a Novartis Medical Lead immediately and closely monitor the 
subject for AEs/SAEs and laboratory abnormalities. 
Further management should be as clinically indicated or as recommended by the national 
poisons centre, where available.  Haemodialysis is not expected to enhance the elimination of 
dabrafenib as it is highly bound to plasma proteins. 
Decisions regarding dose interruptions or modifications should be made by the investigator in 
consultation with a Novartis Medical Lead based on the clinical evaluation of the subject. 
A plasma sample for PK analysis may be requested by a Novartis Medical Lead on a case-by-
case basis.  This plasma sample should be collected as soon as possible. 
Information regarding the quantity of the excess dose as well as the duration of the overdosing 
should be documented in the eCRF. 
11 
ADVERSE EVENTS (AE) AND SERIOUS ADVERSE EVENTS 
(SAE) 
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 start of Study Treatment and until the end of the follow-up 
period.  
SAEs will be collected over the same time period as stated above for AEs.  However, any SAEs 
assessed as related to study participation (e.g. study treatment, protocol-mandated procedures, 
invasive tests, or change in existing therapy) or related to a Novartis product will 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 recorded and reported to Novartis within 24 hours, as indicated in 
Section 11.6. 
Investigators are not obligated to actively seek AEs or SAEs in former study participants. 
However, if the investigator learns of any SAE, including a death, at any time after a subject 
has been discharged from the study, and he/she considers the event reasonably related to the 
study treatment or study participation, the investigator would promptly notify Novartis. 


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11.1 
Definition of Adverse Events 
An AE is any untoward medical occurrence in a patient 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. 
Events meeting the definition of an AE include: 
• 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 felt to be clinically significant in the 
medical and scientific judgement of the investigator. 
• Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity 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 unless 
this is an intentional overdose taken with possible suicidal/self-harming intent.  This 
should be reported regardless of sequelae.). 
• "Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE.  However, the signs and symptoms and/or clinical sequelae 
resulting from lack of efficacy will be reported if they fulfil the definition of an AE or 
SAE. 
Events that do not meet the definition of an AE include: 
• Any clinically significant abnormal laboratory findings or other abnormal 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. 
• 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. 
• 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. 


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11.2 
Definition of Serious Adverse Events 
If an event is not an AE per Section 11.1, then it cannot be an SAE even if serious conditions 
are met (e.g., hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease, etc.). 
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-patient 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 
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. All events of possible drug-induced liver injury with hyperbilirubinaemia defined as ALT 
≥ 3xULN and bilirubin ≥ 2xULN (>35% direct) (or ALT ≥ 3xULN and INR>1.5, if INR 
measured) 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 unavailable, 
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 


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criterion of total bilirubin ≥ 2xULN, then the event is still reported as an SAE. If INR is 
obtained, include values on the SAE form. INR elevations >1.5 suggest severe liver injury 
h. Protocol-specific SAEs: LVEF meeting stopping criteria; any new primary cancers and 
treatment emergent malignancies (including squamous cell carcinoma and new primary 
melanoma); basal cell carcinoma (BCC) is required to be reported as a protocol-specific 
SAE for all non-melanoma indications. 
11.3 
Method of Detecting AEs and SAEs 
Care will 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 “How does your child seem to feel?” 
• “Have you had any (other) medical problems since your last visit/contact?” or “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 “Has your child needed to take any medicines, other than those 
provided in this study, since his/her last visit/contact?” 
11.4 
Recording of AEs and SAEs 
When an AE/SAE occurs, it is the responsibility of the investigator to review all documentation 
(e.g., hospital progress notes, laboratory, and diagnostics reports) relative to the event.  The 
investigator will then record all relevant information regarding an AE/SAE in the appropriate 
data collection tool.  
It is not acceptable for the investigator to send photocopies of the subject’s medical records to 
Novartis in lieu of completion of the Novartis, AE/SAE data collection tool.  However, there 
may be instances when copies of medical records for certain cases are requested by Novartis.  
In this instance, all subject identifiers, with the exception of the subject number, will be blinded 
on the copies of the medical records prior to submission to Novartis. 
The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information.  In such cases, the diagnosis will be documented as the 
AE/SAE and not the individual signs/symptoms. 
11.5 
Evaluating AEs and SAEs 
11.5.1 
Assessment of Intensity 
The investigator will make an assessment of intensity for each AE and SAE reported during the 
study and will assign it to one of the following categories: 
Mild:  An event that is easily tolerated by the subject, causing minimal discomfort and not 
interfering with everyday activities. 
Moderate:  An event that is sufficiently discomforting to interfere with normal everyday 
activities. 


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Severe:  An event that prevents normal everyday activities. 
An AE that is assessed as severe will not be confused with an SAE.  Severity is a category 
utilized for rating the intensity of an event; and both AEs and SAEs can be assessed as severe.  
An event is defined as ‘serious’ when it meets at least one of the pre-defined outcomes as 
described in the definition of an SAE. 
11.5.2 
Assessment of Causality 
The investigator is obligated to assess the relationship between study treatment and the 
occurrence of each AE/SAE.  A "reasonable possibility" is meant to convey that there are 
facts/evidence or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out.  The investigator will use clinical judgment to determine the relationship.  
Alternative causes, such as natural history of the underlying diseases, concomitant therapy, 
other risk factors, and the temporal relationship of the event to the study treatment will be 
considered and investigated.  The investigator will also consult the Investigator Brochure (IB) 
and/or Product Information, for marketed products, in the determination of his/her assessment. 
For each AE/SAE the investigator must document in the medical notes that he/she has reviewed 
the AE/SAE and has provided an assessment of causality. 
11.6 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each subject 
at subsequent visits/contacts.  All AEs and SAEs will be followed until resolution, until the 
condition stabilizes, until the event is otherwise explained, or until the subject is lost to follow-
up. 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as may be indicated or as requested by Novartis to elucidate 
as fully as possible the nature and/or causality of the AE or SAE.   The investigator is obligated 
to assist.  This may include additional laboratory tests or investigations, histopathological 
examinations or consultation with other health care professionals.  If a subject dies during 
participation in the study or during a recognized follow-up period, the investigator will provide 
Novartis with a copy of any post-mortem findings, including histopathology.  
New or updated information will be recorded in the originally completed data collection tool.  
The investigator will submit any updated SAE data to Novartis within the designated reporting 
time frames. 
11.7 
Prompt Reporting of SAEs to Novartis 
Once the investigator determines that an event meets the protocol definition of an SAE, the 
SAE will be reported to Novartis within 24 hours.  Any follow-up information on a previously 
reported SAE will also be reported to Novartis within 24 hours. 
If the investigator does not have all information regarding an SAE, he/she will not wait to 
receive additional information before notifying Novartis of the event and completing the 
appropriate data collection tool.  The investigator will always provide an assessment of causality 
at the time of the initial report as described in Section 11.5.2, Assessment of Causality. 


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The primary mechanism for reporting SAEs to Novartis will be the electronic data collection 
tool.  If the electronic system is unavailable for greater than 24 hours, the site will use the paper 
SAE data collection tool and fax it to a Novartis Medical Lead.  Then the site will enter the 
SAE data into the electronic system as soon as it becomes available. 
After the study is completed at a given site, the electronic data collection tool (e.g., InForm 
system) will be taken off-line to prevent the entry of new data or changes to existing data.  If a 
site receives a report of a new SAE from a study participant or receives updated data on a 
previously reported SAE after the electronic data collection tool has been taken off-line, the site 
can report this information on a paper SAE form or to their Novartis protocol contact by 
telephone. 
Novartis contacts for SAE receipt can be found at the beginning of this protocol on the 
Sponsor/Medical Lead Contact Information page. 
11.8 
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 regulatory 
authorities, IRBs/IECs 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 an 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. 
12 
LIVER CHEMISTRY FOLLOW-UP PROCEDURES 
Refer to the diagram in Appendix 4 for a visual presentation of the procedures listed below. 
The procedures listed below are to be followed if a subject meets the liver chemistry stopping 
criteria defined in Section 3.7.8: 
• 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, obtain heterophile 
antibody or monospot testing)   
• Hepatitis E IgM antibody. 


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• Blood sample for PK analysis, obtained within 96 hours of last dose.  Record the date/time 
of the PK blood sample draw and the date/time of the last dose of investigational product 
prior to 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/time of the last dose cannot be 
approximated OR a PK sample cannot be collected in the time period indicated above, do 
not obtain a PK sample.  Instructions for sample handling and shipping are in the SPM.  
• Serum CPK and lactate dehydrogenase. 
• Fractionate bilirubin, if total bilirubin ≥2xULN. 
• Obtain complete blood count with differential to assess eosinophilia. 
• Record the appearance or worsening of clinical symptoms of hepatitis or hypersensitivity, 
such as fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever rash or 
eosinophilia as relevant on the AE report form. 
• Record use of concomitant medications, acetaminophen, herbal remedies, other over the 
counter medications, or putative hepatotoxins, on the concomitant medications report 
form. 
• Record alcohol use on the liver event alcohol intake case report form. 
The following assessments are required for subjects with ALT ≥3xULN and bilirubin ≥2xULN 
(>35% direct) but 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, magnetic resonance, or computerized tomography) to evaluate 
liver disease. 
• Serum acetaminophen adduct assay (quantifies potential acetaminophen contribution to 
liver injury, detectable by HPLC assay more than 1 week following acetaminophen use).  
• Only in those with underlying chronic hepatitis B at study entry (identified by positive 
hepatitis B surface antigen): quantitative hepatitis B DNA and hepatitis delta antibody. 
NOTE: if hepatitis delta antibody assay cannot be performed, it can be replaced with a 
PCR of hepatitis D RNA virus (where needed) – as outlined in: 
ncbi.nlm.nih.gov/pmc/articles/PMC1153793/. 
12.1 
Liver Chemistry Monitoring Criteria 
For subjects with ALT ≥5xULN and <8xULN which exhibit a decrease to ALT ≥3xULN, but 
<5xULN and bilirubin <2xULN without hepatitis symptoms or rash, and who can be monitored 
weekly for 4 weeks, do the following: 
• Notify the Novartis Medical Lead within 24 hours of learning of the abnormality to 
discuss subject safety 
• Continue investigational product  
• Return weekly for repeat liver chemistries (ALT, AST, alkaline phosphatase, bilirubin) 
until they resolve, stabilize or return to within baseline  
• If at any time these subjects meet any of the liver chemistry stopping criteria 1 - 5 in 
Section 3.7.8, then proceed as described above 


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• If, after 4 weeks of monitoring, ALT <3xULN and bilirubin <2xULN, then monitor 
subjects twice monthly until liver chemistries normalize or return to within baseline 
values.  
Refer to Appendix 4 for algorithm of liver chemistry stopping and follow up criteria. 
12.2 
Restarting Investigational Product 
Drug Restart/Rechallenge Following Liver Events that are Possibly Related to Study 
Treatment 
Approval by Novartis for drug restart can be considered where: 
• The subject is receiving compelling benefit, benefit of drug restart exceeds risk, and no 
effective alternative therapy is available.  Ethics Committee or Institutional Review Board 
approval of drug restart/rechallenge must be obtained, as required. 
• If the restart/rechallenge is approved by Novartis in writing, the subject must be provided 
with a clear description of the possible benefits and risks of drug administration, including 
the possibility of recurrent, more severe liver injury or death. 
• The subject must also provide signed informed consent specifically for the study treatment 
restart/rechallenge.  Documentation of informed consent must be recorded in the study 
chart. 
• Study drug must be administered at the dose specified by Novartis. 
Subjects approved by Novartis for restart/rechallenge of study treatment must return to the 
clinic twice a week for liver chemistry tests until stable, liver chemistries have been 
demonstrated and then laboratory monitoring may resume as per protocol.  
Drug Restart Following Transient Resolving Liver Events Not Related to Study 
Treatment 
Approval by Novartis for drug restart can be considered where: 
• Liver chemistries have a clear underlying cause (e.g., biliary obstruction, hypotension and 
liver chemistries have improved to normal or are within 1.5 x baseline and ALT 
<3xULN).  Ethics Committee or Institutional Review Board approval of drug 
restart/rechallenge must be obtained, as required. 
• If restart of drug is approved by Novartis in writing, the subject must be provided with a 
clear description of the possible benefits and risks of drug administration, including the 
possibility of recurrent, more severe liver injury or death.  
• The subject must also provide signed informed consent specifically for the restart.  
Documentation of informed consent must be recorded in the study chart. 
• Study drug must be administered at the dose specified by Novartis. 
Subjects approved by Novartis for restarting study treatment must return to the clinic once a 
week for liver chemistry tests until stable, liver chemistries have been demonstrated and then 
laboratory monitoring may resume as per protocol. If protocol defined stopping criteria for liver 
chemistry elevations are met, study drug must be stopped. 


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13 
STUDY CONDUCT CONSIDERATIONS 
13.1 
Posting of Information on Publicly Available Clinical Trial 
Registers 
Study information from this protocol will be posted on publicly available clinical trial registers 
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 applicable country-specific regulatory 
requirements including those required under a US IND. 
The study will be conducted in accordance with all applicable regulatory requirements. 
The study will also be conducted in accordance with Good Clinical Practice (GCP), all 
applicable subject privacy requirements, and, the guiding principles of the 2008 Declaration of 
Helsinki.  This includes, but is not limited to, the following: 
• IRB/IEC review and approval to conduct the study and of any subsequent relevant 
amended documents 
• Written informed consent/assent (and any amendments) to be obtained for each subject 
before participation in the study 
• Investigator reporting requirements (e.g. reporting of AEs/SAEs/protocol deviations to 
IRB/IEC) 
Written informed consent must be obtained from parent(s), LAR or subject prior to participation 
in the study. 
In approving the clinical protocol the IEC/IRB and, where required, the applicable regulatory 
agency are also approving the optional assessments. Where permitted by regulatory authorities, 
approval of the optional assessments can occur after approval is obtained for the rest of the 
study.  If so, then the written approval will clearly indicate approval of the optional assessments 
is being deferred and the study, except for the optional assessments, can be initiated.  When the 
optional assessments are not approved, then the approval for the rest of the study will clearly 
indicate this and therefore, the optional assessments will not be conducted. 
13.2.1 
Urgent Safety Measures 
If an event occurs that is related to the conduct of the study or the development of the study 
treatment, and this new event is likely to affect the safety 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 IEC/IRB is notified. 


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13.3 
Quality Control (Study Monitoring) 
In accordance with applicable regulations including GCP, and Novartis procedures, 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 also include identification, agreement and 
documentation of data items for which the eCRF will serve as the source document. 
Novartis (or designated CRO) personnel will monitor the study to ensure that the:  
• 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, GCP, and all applicable regulatory requirements. 
The investigator and the head of the medical institution (where applicable) agrees to allow the 
monitor direct access to all relevant documents 
13.4 
Quality Assurance 
To ensure compliance with GCP and all applicable regulatory requirements, Novartis may 
conduct a quality assurance assessment and/or audit of the site records, and the regulatory 
agencies may conduct a regulatory inspection at any time during or after completion of the 
study. In the event of an assessment, audit or inspection, the investigator (and institution) must 
agree to grant the advisor(s), auditor(s) and inspector(s) direct access to all relevant documents 
and to allocate their time and the time of their staff to discuss the conduct of the study, any 
findings/relevant issues and to implement any corrective and/or preventative actions to address 
any findings/issues identified. 
13.5 
Study and Site Closure 
Upon completion or premature discontinuation of the study, the monitor will conduct site 
closure activities with the investigator or site staff, as appropriate, in accordance with applicable 
regulations including GCP, and Novartis Standard Operating Procedures. 
In addition, Novartis reserves the right to temporarily suspend or prematurely discontinue this 
study at any time for reasons including, but not limited to, safety or ethical issues or severe non-
compliance.  For multicenter studies, this can occur at one or more or at all sites.  If Novartis 
determines such action is needed, Novartis will discuss this with the investigator or the head of 
the medical institution (where applicable), including the reasons for taking such action.  When 
feasible, Novartis will provide advance notification to the investigator or the head of the medical 
institution, where applicable, of the impending action prior to it taking effect. 
If the study is suspended or prematurely discontinued for safety reasons, Novartis will promptly 
inform investigators or the head of the medical institution (where applicable) and the regulatory 
authorities of the suspension or premature discontinuation of the study and the reason(s) for the 
action.  If required by applicable regulations, the investigator or the head of the medical 
institution (where applicable) must inform the IRB/IEC promptly and provide the reason for the 
suspension or premature discontinuation. 


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13.6 
Records Retention 
Following closure of the study, the investigator or the head of the medical institution (where 
applicable) must maintain all site study records, except for those required by local regulations 
to be maintained by someone else, in a safe and secure location.  The records must be maintained 
to allow easy and timely retrieval, when needed (e.g., for a Novartis audit or regulatory 
inspection), and, whenever feasible, to allow any subsequent review of data in conjunction with 
assessment of the facility, supporting systems, and staff.   
Where permitted by local laws/regulations or institutional policy, some or all of these records 
can be maintained in a format other than hard copy (e.g., microfiche, scanned, electronic); 
however, caution needs to be exercised before such action is taken.  The investigator must 
assure that all reproductions are legible and are a true and accurate copy of the original, and 
meet accessibility and retrieval standards, including re-generating a hard copy, if required.  
Furthermore, the investigator must ensure there is an acceptable back-up of these reproductions 
and that an acceptable quality control process exists for making these 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 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 at an off-site facility or transfer of ownership of the records in the 
event the investigator leaves the site. 
13.7 
Provision of Study Results to Investigators, Posting of 
Information on Publically 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.  Investigators 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 investigators with the full summary of the study results.  Investigators 
are encouraged to share the summary results with the study subjects, as appropriate. 
Novartis aims to post a results summary to the Novartis Clinical Trial Results website 
(novartisclinicaltrials.com) and other publicly available registers no later than six (6) months 
after the last subject’s last visit (LSLV). In addition, upon study completion and finalization of 
study report, Novartis 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. 
13.8 
Data Management 
Data Management will identify and implement the most effective data acquisition and 
management strategy for each clinical trial protocol and deliver datasets that support the 
protocol objectives. 


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For this study subject data will be entered into Novartis defined electronic case report forms 
(eCRFs), transmitted electronically to the sponsor (or designee) and be combined with data 
provided from other sources in a validated data system. 
Clinical data management will be performed in accordance with applicable standards and data 
cleaning procedures with the objective of resolving errors and inconsistencies in the data which 
would otherwise impact on the analysis and reporting objectives, or the credibility of the 
Clinical Study Report. All AEs and concomitant medications terms will be coded using 
MedDRA (Medical Dictionary for Regulatory Activities) and a custom dictionary. Laboratory 
data (i.e., hematology and clinical chemistry) will be stored in a database maintained by the 
central laboratory and transferred to Novartis at agreed times. 
eCRFs (including queries and audit trails) will be retained by Novartis, and copies will be sent 
to the investigator to maintain as the investigator copy. 






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MacConaill LE, Campbell CD, Kehoe SM, Bass AJ, et al. Profiling Critical Cancer Gene 
Mutations in Clinical Tumor Samples. PLoSONE. 2009;4(11):e7887. 
Melck AL, Yip L, Carty SE. The utility of BRAF testing in the management of papillary 
thyroid cancer. The Oncologist. 2010;15:1285–1293. 
NCI. Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. DHHS, NCI, 
NIH, Bethesda, MD; 2009.  
National Cancer Institute (NCI).  9 January 2012.  Langerhans Cell Histiocytosis Treatment 
PDQ http://www.cancer.gov/cancertopics/pdq/treatment/lchistio/HealthProfessional/ 
National Cancer Institute (NCI).  11 May 2012.  Melanoma Treatment PDQ 
http://www.cancer.gov/cancertopics/pdq/treatment/melanoma/HealthProfessional 
National Cancer Institute (NCI).  9 May 2012.  Thyroid Cancer Treatment PDQ 
http://www.cancer.gov/cancertopics/pdq/treatment/thyroid/HealthProfessional 
Nikiforova MN, Nikiforov YE. Molecular diagnostics and predictors in thyroid cancer. 
Thyroid. 2009;19(12):1351-1361. 
Pfister S, Janzarik WG, Remke M, Ernst A, et al. BRAF gene duplication constitutes a 
mechanism of MAPK pathway activation in low-grade astrocytomas. J Clin Invest. 
2008;118:1739–1749. 
Poulikakos PI, Zhang C, Bollag G, Shokat KM and Rosen N. RAF inhibitors transactivate 
RAF dimers and ERK signalling in cells with wild-type BRAF. Nature 2010; 464:427-430. 
Prados MD, Edwards MS, Rabbitt J, Lamborn K, et al. Treatment of paediatric low-grade 
gliomas with a nitrosourea-based multiagent chemotherapy regimen. J Neurooncol. 
1997;32(3):235–241. 
Qaddoumi I, Sultan I, Broniscer A. Paediatric low-grade gliomas and the need for new options 
for therapy. Cancer Biol Ther. 2009;8:1-7. 
Rosenbaum E, Hosler G, Zahurak M, Cohen Y, et al. Mutational activation of BRAF is not a 
major event in sporadic childhood papillary thyroid carcinoma. Modern Pathol. 2005;18:898-
902. 
Satoh T, Smith A, Sarde A, et al.  B-RAF mutant alleles associated with Langerhans cell 
histiocytosis.  PLoS ONE.  2012;7:4. 
Satter EK, High WA. Langerhans cell histiocytosis: a review of the current recommendations 
of the histiocyte society. Paediatr Dermatol. 2008;25(3):291-295. 
Schiffman JD, Hodgson JG, VandenBerg SR, Flaherty P, et al. Oncogenic BRAF mutation 
with CDKN2A inactivation is characteristic of a subset of paediatric malignant astrocytomas. 
Cancer Res. 2010;70(2):512–519. 
Sievert AJ, Lang SS, Boucher KL, Madsen PJ, Slaunwhite E, Choudhari N, Kellet M, Storm 
PB, Resnick AC. Paradoxical activation and RAF inhibitor resistance of BRAF protein kinase 
fusions characterizing pediatric astrocytomas. Proc Natl Acad Sci USA  2013; 110:5957–
5962. 
Skolnik J, Barret J, Jayaraman B, et al.  Shortening the Timeline of Pediatric Phase I Trials:  
The Rolling Six Design. J Clin Onc. 2008; 26:190-196. 


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Stalemark H, Laurencikas E, Karis J, Gavhed D, et al. Incidence of Langerhans cell 
histiocytosis in children: a population-based study. Paediatr Blood Cancer. 2008;51:76-81. 
Stockschlaeder M, Sucker C. Adult Langerhans cell histiocytosis. Eur J Haematol. 
2006;76(5):363-368. 
Sugiyama I, Murayama N, Kuroki A, Kota J, Iwano S, Yamazaki H, Hirota T, et al. 
Evaluation of cytochrome P450 inductions by anti-epileptic drug oxcarbazepine, 10-
hydroxyoxcarbazepine, and carbamazepine using human hepatocytes and HepaRG cells. 
Xenobiotica. 2016 Sep;46(9):765-74 
Surveillance, Epidemiology, and End Results (SEER) Program. 2010.  www.seer.cancer.gov 
Trileptal SPC; 
http://www.medicines.org.uk/EMC/searchresults.aspx?term=trileptal&searchtype=QuickSear
ch 
U.S. Food and Drug Administration.  2000; Guidance for industry. E11 Clinical investigation 
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/UCM129477.pdf 
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Wen PY, Macdonald DR, Reardon DA, et al. Updated response assessment criteria for high-
grade gliomas: Response assessment in neuro-oncology working group. J Clin Oncol. 2010; 
28:1963-1972. 
Wen PY, Chang S, Van den Bent, MJ, et al. Response Assessment in Neuro-Oncology 
Clinical Trials.  J Clin Oncol. 2017; 35(21):2439-2449. 
Yates JW, Chalmer B, McKegney FP. Evaluation of patients with advanced cancer using the 
Karnofsky Performance Status. Cancer. 1908;45:2220-2224.  
Zhao L, Lee, J, et al.  The superiority of the time-to-event continual reassessment method to 
the rolling six design in pediatric oncology Phase I trials.  Clinical Trials.  2011;8:361-369. 


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15 
APPENDICES 
15.1 
Appendix 1: Modified Rolling Six Design Dose Escalation 
Procedures 
Dose Escalation Procedure 
Number of Subjects 
Enrolled 
Number of Subjects 
with a DLT 
Number of Subjects 
with Data Pending 
Decision 
1 
-- 
-- 
Same dose level 
2 
2 
-- 
De-escalate 
 
Other 
-- 
Same dose level 
3 
≥2 
-- 
De-escalate 
 
0 
0 
Escalate 
 
Other 
-- 
Same dose level 
4 
≥2 
-- 
De-escalate 
 
0 
0 
Escalate 
 
Other 
-- 
Same dose level 
5 
≥2 
-- 
De-escalate 
 
0 
0 
Escalate 
 
Other 
-- 
Same dose level 
6 
≥2 
-- 
De-escalate 
  
≤1 
0 
Escalatea 
  
0 
1 
Escalatea 
  
Other 
-- 
Suspend 
a. 
Modified from the Zhao, 2011 publication 


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15.2 
Appendix 2: Response Criteria 
Response criteria for subjects with solid tumors and measurable disease 
Anti-tumor activity will be assessed based on clinical evidence and the Response Evaluation 
Criteria in Solid Tumors (RECIST) Version 1.1 criteria for solid tumors (Eisenhauer, 2009). 
Evaluation of Target Lesions 
Definitions for assessment of response for target lesion(s) are as follows: 
• Complete Response (CR):  Disappearance of all target lesions.  Any pathological lymph 
nodes must be <10 mm in the short axis. 
• Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target 
lesions, taking as a reference, the baseline sum of the diameters (e.g. percent change from 
baseline). 
• Stable Disease:  Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for progressive disease. 
• Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target 
lesions, taking as a reference, the smallest sum of diameters recorded since the treatment 
started (e.g. percent change from nadir, where nadir is defined as the smallest sum of 
diameters recorded since treatment start). In addition, the sum must have an absolute 
increase from nadir of 5 mm. 
• Not Applicable (NA):  No target lesions at baseline. 
• Not Evaluable (NE):  Cannot be classified by one of the five preceding definitions. 
Note: 
• If lymph nodes are documented as target lesions the short axis is added into the sum of the 
diameters (e.g. sum of diameters is the sum of the longest diameters for non-nodal lesions 
and the short axis for nodal lesions).  When lymph nodes decrease to non-pathological size 
(short axis <10 mm) they should still have a measurement reported in order not to 
overstate progression. 
• If at a given assessment time point all target lesions identified at baseline are not assessed, 
sum of the diameters cannot be calculated for purposes of assessing CR, PR or stable 
disease or for use as the nadir for future assessments.  However, the sum of the diameters 
of the assessed lesions and the percent change from nadir should be calculated to ensure 
that progression has not been documented.  If an assessment of PD cannot be made, the 
response assessment should be NE. 
• All lesions (nodal and non-nodal) should have their measurements recorded even when 
very small (e.g. 2 mm).  If lesions are present but too small to measure, 5 mm should be 
recorded and should contribute to the sum of the diameters, unless it is likely that the 
lesion has disappeared in which case 0 mm should be reported. 
• If a lesion disappears and reappears at a subsequent time point it should continue to be 
measured.  The response at the time when the lesion reappears will depend upon the status 
of the other lesions.  For example, if the disease had reached a CR status then PD would 
be documented at the time of reappearance.  However, if the response status was PR or 


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stable disease the diameter of the reappearing lesion should be added to the remaining 
diameters and response determined based on percent change from baseline and percent 
change from nadir. 
Evaluation of Non-target Lesions 
Definitions for assessment of response for non-target lesions are as follows: 
• Complete Response (CR):  The disappearance of all non-target lesions. All lymph nodes 
identified as a site of disease at baseline must be non-pathological (e.g. <10 mm short 
axis). 
• Non-CR/Non-PD:  The persistence of 1 or more non-target lesion(s) or lymph nodes 
identified as a site of disease at baseline ≥10 mm short axis. 
• Progressive Disease (PD): Unequivocal progression of existing non-target lesions.  
• Not Applicable (NA):  No non-target lesions at baseline. 
• Not Evaluable (NE):  Cannot be classified by one of the four preceding definitions. 
Note: 
• In the presence of measurable disease, progression on the basis of solely non-target 
disease requires substantial worsening such that even in the presence of stable disease or 
PR in target disease, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy. 
• Sites of non-target lesions, which are not assessed at a particular timepoint based on the 
assessment schedule, should be excluded from the response determination (e.g. non-target 
response does not have to be "Not Evaluable").  
New Lesions 
New malignancies denoting disease progression must be unequivocal.  Lesions identified in 
follow-up in an anatomical location not scanned at baseline are considered new lesions. 
Any equivocal new lesions should continue to be followed.  Treatment can continue at the 
discretion of the investigator until the next scheduled assessment.  If at the next assessment the 
new lesion is considered to be unequivocal, progression should be documented.   
Evaluation of Overall Response 
Table 15-1 presents the overall response at an individual time point for all possible 
combinations of tumor responses in target and non-target lesions with or without the appearance 
of new lesions for subjects with measurable disease at baseline. 
Table 15-1 
Evaluation of Overall Response for Subjects with Measurable Disease 
at Baseline 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR or NA 
No 
CR 
CR 
Non-CR/Non-PD or NE 
No 
PR 
PR 
Non-PD or NA or NE 
No 
PR 
Stable disease 
Non-PD or NA or NE 
No 
SD 


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NE 
Non-PD or NA or NE 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR=complete response, PR = partial response, PD=progressive disease, NA= not applicable, and NE=not 
evaluable 
 
Note: 
• Subjects with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be classified as 
having "symptomatic deterioration." Objective response status is determined by 
evaluations of disease burden. Every effort should be made to document the objective 
progression even after discontinuation of treatment.   
• In some circumstances, it may be difficult to distinguish residual disease from normal 
tissue. When the evaluation of CR depends on this determination, it is recommended that 
the residual lesion be investigated (fine needle aspirate/biopsy) to confirm the CR. 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence and will be determined programmatically by Novartis based on 
the investigators assessment of response at each time point.  
• To be assigned a status of stable disease, follow-up disease assessment must have met the 
SD criteria at least once after first dose of study medication at a minimum interval of 
12 weeks. 
• If the minimum time for stable disease is not met, best response will depend on the 
subsequent assessments.  For example if an assessment of PD follows the assessment of 
stable disease and stable disease does not meet the minimum time requirement the best 
response will be PD.  Alternative subjects lost to follow-up after a stable disease 
assessment not meeting the minimum time criteria will be considered not evaluable. 
Confirmation Criteria: 
• To be assigned a status of PR or CR, a confirmatory disease assessment should be 
performed at Week 16 if initial response was seen at the Week 8 scan.  Initial responses 
(CR/PR) that occur Week 16 or after should be confirmed not less than 4 and not more 
than 8 weeks after the criteria for response are first met. 
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 V11, 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 (Wen, 2010).  These criteria are noted in 
section 15.2.   


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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) 
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 


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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. 
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 v11. This review is in addition to the previously performed review using 
RANO (Wen, 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 


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between slices), visible on two or more axial slices that are preferably, at most, 5 mm apart with 
0mm 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. 
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. 


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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 
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** 


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Criterion  
Complete 
Response  
Partial Response  
Stable 
Disease  
Progressive 
Disease  
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. 
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. 


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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. 
 
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 
 


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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  
(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 
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 
2 
1 


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Variable 
Modality 
Score 
0-2 cm maximum diameter 
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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15.3 
Appendix 3: Performance Status Criteria / Scoring System 
Karnofsky (age >=16 years of age) and Lansky (age <16 years) Performance 
Scores (Yates, 1908) 
 
 


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15.4 
Appendix 4: Liver Safety Algorithms 
 
 


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15.5 
Appendix 5: Country Specific Amendment 2 for France 
TITLE PAGE 
Division: Worldwide Development 
Retention Category: GRS019 
Information Type: Protocol Amendment 
 
Title: 
Phase I/IIa, 2-Part, Multi-Center, Single-Arm, Open-Label Study 
to Determine the Safety, Tolerability and Pharmacokinetics of 
Oral Dabrafenib in Pediatric Subjects Aged 1 Month to <18 years 
with Advanced BRAF V600-Mutation Positive Solid Tumors 
Compound Number: 
GSK2118436  
Effective Date: 
13-DEC-2012 
 
Protocol Amendment Number:  02 
Subject:  Dabrafenib, pediatrics, V600-mutation positive, BRAF, dose escalation 
Authors:   


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Revision Chronology: 
 
 
2012N131371_00 
2012-JUL-24 
Original 
2012N131371_01 
2012-OCT-19 
Amendment No. 01 corrected Inclusion 
Criteria #6 to ensure consistency with 
the contraception requirements as 
outlined in Section 7.1.1; the 
requirement for male contraception was 
deleted since the risk of embryofetal 
developmental toxicity as a consequence 
of exposure to female pregnant partners 
is very low.  In addition, the dose 
escalation procedure table provided in 
Appendix 1 was changed to ensure that 
escalation of dose when 6 subjects are 
enrolled occurs only if there are ≤1 
subject with a DLT and no subject data 
pending, and to fix the reference and 
formatting. 
2012N131371_02 
2012-DEC-13 
Amendment No. 02 is a country-specific 
amendment for France which prohibits 
children younger than 6 years and 
children older than 6 years with a risk of 
choking when swallowing capsules from 
inclusion in the study in France (pending 
availability of an oral suspension 
formulation); changes the QTc stopping 
criteria to 500 msec for French subjects 
(as compared to 530 msec); adds cardiac 
monitoring by echocardiogram (ECHO) 
at Week 4; and highlights that ECHOs 
are to be performed by the same operator 
throughout the study, where possible. 
 
Copyright 2012 the GlaxoSmithKline group of companies.  All rights reserved.  Unauthorised 
copying or use of this information is prohibited. 
 


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Sponsor Signatory: 
 
 
 
 MD 
 
Date 
 
 


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Sponsor Information Page 
Medical Monitor and Sponsor Contact Information: 
Role 
Name 
Day Time 
Phone 
Number 
After-hours 
Phone/Cell/ 
Pager 
Number 
Fax 
Number 
GSK Address 
Primary 
Medical 
Monitor 
M.D. 
Mobile: 
 
 
 
GlaxoSmithKline 
1250 South Collegeville Road 
PO Box 5089 
Collegeville, PA  19426-0989 
Email:  
 
Secondary 
Medical 
Monitor 
M.D. 
Mobile:
  
 
 
GlaxoSmithKline 
1250 South Collegeville Road 
PO Box 5089 
Collegeville, PA  19426-0989 
Email:  
 
Sponsor Legal Registered Address: 
GlaxoSmithKline Research & Development Limited 
980 Great West Road 
Brentford 
Middlesex, TW8 9GS 
UK 
In some countries, the clinical trial sponsor may be the local GlaxoSmithKline affiliate 
company (or designee). If applicable, the details of the alternative Sponsor and contact person 
in the territory will be provided to the relevant regulatory authority as part of the clinical trial 
application. 
Regulatory Agency Identifying Numbers:   
IND No.: 
105,032 
EudraCT Number: 
2012-001499-12 
 
 


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Investigator PROTOCOL Agreement Page 
I confirm agreement to conduct the study in compliance with the protocol, as amended by this 
protocol amendment. 
 
Investigator Name: 
 
Investigator Address: 
 
 
Investigator Phone Number: 
 
 
 
Investigator Signature 
Date 
 


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LIST OF ABBREVIATIONS 
ANSM 
Agence Nationale de Securite du Medicament et des Produits de Sante 
ECHO 
echocardiogram 
ECG 
electrocardiogram 
msec 
millisecond 
 
Trademark Information 
Trademarks of the GlaxoSmithKline group 
of companies 
 
Trademarks not owned by the 
GlaxoSmithKline group of companies 
NONE 
 
None 
 


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Amendment 02 
Where the Amendment Applies 
Amendment 02 is a country specific amendment for France.  Bolded text indicates new 
language, and strikethrough text indicates deleted language.   
Summary of Amendment Changes with Rationale 
Amendment No. 02 is a country-specific amendment for France.  Amendment 02 prohibits 
children younger than 6 years and children older than 6 years with a risk of choking when 
swallowing capsules from inclusion in the study in France (pending availability of an oral 
suspension formulation).  In addition, Amendment 02 changes the QTc stopping criteria to 
500 msec for French subjects (as compared to 530 msec) and adds cardiac monitoring by 
echocardiogram (ECHO) at Week 4 as requested by the French Agency [the Agence 
Nationale de Securite du Medicament et des Produits de Sante (ANSM)].  It is noted in the 
Study Procedures Manual, and highlighted in this country-specific amendment, that ECHOs 
are to be performed by the same operator throughout the study, where possible. 
List of Specific Changes 
Change #1, Section 3.2, Discussion of Study Design:  in response to ANSM review of the 
protocol. 
Previous Text (last paragraph in Section) 
The study will use the currently available dabrafenib capsule strengths (50 mg and 75 mg) 
from the adult program for children who are able to reliably swallow capsules.  In addition, 
two lower strength capsules (10 mg and 25 mg) and an oral suspension formulation are 
available for pediatric subjects who may have difficulty swallowing larger capsules.  The 
suspension will only be available at those sites that are capable of and meet the applicable 
regulatory requirements to prepare the suspension. 
Revised Text: 
The study will use the currently available dabrafenib capsule strengths (50 mg and 75 mg) 
from the adult program for children who are able to reliably swallow capsules.  In addition, 
two lower strength capsules (10 mg and 25 mg) and an oral suspension formulation are 
available for pediatric subjects who may have difficulty swallowing larger capsules.  The 
suspension will only be available at those sites that are capable of and meet the applicable 
regulatory requirements to prepare the suspension.  In France, children younger than 6 
years and children older than 6 years with a risk of choking when swallowing capsules 
cannot be included in the study, pending availability of an oral suspension formulation. 
 


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Change #2, Section 3.6, Investigational Product and Other Study Treatment 
Dosage/Administration; rationale for change:  in response to ANSM review of the protocol. 
Previous Text 
Capsules:  Dabrafenib capsules will be supplied by GSK (for subjects able to reliably and 
consistently swallow capsules). 
Suspension:  Bottles of bulk GSK2118436B drug substance with bottles of individual 
excipients (4 components) will be supplied by GSK for on-site extemporaneous compounding 
of a suspension formulation (for subjects unable to swallow capsules).  Only sites meeting 
local, applicable regulations regarding extemporaneous compounding will be permitted to 
enroll subjects requiring suspension administration.  Detailed preparation instructions are 
supplied in the SPM.  The suspension will be administered with an oral dosing syringe 
supplied by GSK (oral syringes, 1 mL, 5 mL, and 20 mL for single use).   
Revised Text (added to beginning of section): 
In France:  Children younger than 6 years and children older than 6 years with a risk of 
choking when swallowing capsules cannot be included in the study, pending availability 
of an oral suspension formulation. 
Capsules:  Dabrafenib capsules will be supplied by GSK (for subjects able to reliably and 
consistently swallow capsules). 
Suspension:  Bottles of bulk GSK2118436B drug substance with bottles of individual 
excipients (4 components) will be supplied by GSK for on-site extemporaneous compounding 
of a suspension formulation (for subjects unable to swallow capsules).  Only sites meeting 
local, applicable regulations regarding extemporaneous compounding will be permitted to 
enroll subjects requiring suspension administration.  Detailed preparation instructions are 
supplied in the SPM.  The suspension will be administered with an oral dosing syringe 
supplied by GSK (oral syringes, 1 mL, 5 mL, and 20 mL for single use).   
 
Change #3, Section 3.7.8, QTc Stopping Criteria; rationale for change:  in response to 
ANSM review of the protocol. 
Previous Text: 
A subject that meets the criteria below will be withdrawn from the study.  The QT correction 
formula used to determine discontinuation should be the same one used throughout the study 
[QT duration corrected for heart rate by Bazett’s formula (QTcB)]. 
• 
QTcB >500 msec or uncorrected QT >600 msec 
• 
If subject has underlying bundle branch block then the QTcB withdrawal criteria 
depends on the baseline value: 
Baseline QTcB value (with  
underlying bundle branch block) 
QTcB withdrawal 
criteria 
<450 ms 
>500 ms 
450-480 ms 
≥530 ms 
 
















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15.6 
Appendix 6 French Country Guidelines for additional 
dermatological monitoring while on therapy and after IP 
discontinuation 
This Section applies to subject 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 non-cutaneous secondary/recurrent malignancy should be reported 
as a protocol-specific SAE and treated according to standard clinical practice.  




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1.1.1.1 
BRF112680 (FTIH) 
Previous text: 
In addition, data from a small number of adult subjects with BRAF V600 mutation-positive 
solid tumors other than melanoma, who were enrolled in an expansion cohort in the FTIH study, 
suggested that dabrafenib may have beneficial effects in these subjects as well 
[GlaxoSmithKline Document Number RM2009/00673/00].  There were 7 subjects enrolled 
with colorectal cancer (CRC), 10 subjects with thyroid cancer, 1 subject with NSCLC and 1 
subject with ovarian cancer.  A summary of investigator-assessed unconfirmed response for 
CRC and thyroid cancer are summarized in Table 1 and Table 2, respectively.   The NSCLC 
subject was enrolled in Part 2 (150 mg BID) and reported an unconfirmed partial response (PR) 
at 6 weeks followed by disease progression at 12 weeks.  The ovarian cancer subject was 
enrolled in Part 1 (100 mg BID) and reported stable disease before progressing at approximately 
36 weeks. 
Revised text: 
In addition, data from a small number of adult subjects with BRAF V600 mutation-positive 
solid tumors other than melanoma, who were enrolled in an expansion cohort in the FTIH study, 
suggested that dabrafenib may have beneficial effects in these subjects as well 
[BRF112680GlaxoSmithKline Document Number RM2009/00673/00].  There were 7 subjects 
enrolled with colorectal cancer (CRC), 10 subjects with thyroid cancer, 1 subject with NSCLC 
and 1 subject with ovarian cancer.  A summary of investigator-assessed unconfirmed response 
for CRC and thyroid cancer are summarized in Table 1 and Table 2, respectively.   The NSCLC 
subject was enrolled in Part 2 (150 mg BID) and reported an unconfirmed partial response (PR) 
at 6 weeks followed by disease progression at 12 weeks.  The ovarian cancer subject was 
enrolled in Part 1 (100 mg BID) and reported stable disease before progressing at approximately 
36 weeks. 
5 
Hypotheses and Treatment Comparisons 
Previous text: 
With respect to the primary objectives and endpoints, the primary focus will be on determining 
the MTD (or recommended dose based on available safety, PK, and response data), the safety 
profile, and PK/PD relationship of dabfabranib in paediatric subjects with advanced BRAF 
V600-mutation positive solid tumors.  Most analyses will be descriptive or exploratory. 
Revised text: 
With respect to the primary objectives and endpoints, the primary focus will be on determining 
the MTD (or recommended dose based on available safety, PK, and response data), the safety 
profile, and PK/PD relationship of dabfabranib dabrafenib paediatric subjects with advanced 
BRAF V600-mutation positive solid tumors.  Most analyses will be descriptive or exploratory. 
5.2.1.2 
Part 2 Cohort Expansion 
Previous text: 


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The sample size for Part 2 is s based on feasibility, practicality, and what would be sufficient 
for the characterization of the safety of dabfabranib and the plasma pharmacokinetics for the 
populations enrolled.  Each of the 4 expansion cohorts will attempt to enrol at least 10 evaluable 
subjects.  Therefore, an estimated 40 subjects will be enrolled into Part 2.    
Revised text: 
The sample size for Part 2 is s based on feasibility, practicality, and what would be sufficient 
for the characterization of the safety of dabfabranib dabrafenib and the plasma 
pharmacokinetics for the populations enrolled.  Each of the 4 expansion cohorts will attempt to 
enrol at least 10 evaluable subjects.  Therefore, an estimated 40 subjects will be enrolled into 
Part 2. 
Section 6.2.1. 
Confirmation of BRAF Mutation Positive Status 
Previous text: 
Subjects with V600 mutation- positive tumors as determined by local testing conducted in a 
CLIA-approved facility (or equivalent) may be enrolled on the study. Archived tumor tissue 
sample will be collected at screening for retrospective confirmation of the BRAF mutation 
status using the bioMerieux (bMx) BRAF mutation assay (THxID assay) being developed by 
GSK in collaboration with bMx.  If an archived tumor tissue sample is not available, fresh tumor 
tissue should be collected for the assessment and confirmation of BRAF V600 mutation status 
in a CLIA approved facility (see SPM for further details on sample collection).  
Revised text: 
Subjects with V600 mutation- positive tumors as determined by local testing conducted in a 
CLIA-approved facility (or equivalent) may be enrolled on the study. Archived tumor tissue 
sample will be collected at screening for retrospective confirmation of the BRAF mutation 
status using the bioMerieux (bMx) BRAF mutation assay (THxID assay) being developed by 
GSK in collaboration with bMx.  If an archived tumor tissue sample is not available, fresh tumor 
tissue should be collected for the assessment and confirmation of BRAF V600 mutation status 
in a CLIA approved facility (see SPM for further details on sample collection).  
Section 6.4.2. 
Action to be taken if Pregnancy occurs 
Previous text: 
The investigator will collect pregnancy information on any female subject, who becomes 
pregnant while participating in this study.  The investigator will record pregnancy information 
on the appropriate form and submit it to GSK within 2 weeks of learning of a subject's 
pregnancy.  The subject will also be followed to determine the outcome of the pregnancy.  
Information on the status of the mother and child will be forwarded to GSK.  Generally, follow-
up will be no longer than 6 to 8 weeks following the estimated delivery date.  Any premature 
termination of the pregnancy will be reported. 
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. 


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A spontaneous abortion is always considered to be an SAE and will be reported as such.  
Furthermore, any SAE occurring as a result of a post-study pregnancy and is considered 
reasonably related to the study treatment by the investigator, will be reported to GSK as 
described in Section 11.7. While the investigator is not obligated to actively seek this 
information in former study participants, he or she may learn of an SAE through spontaneous 
reporting. 
Any female subject who becomes pregnant while participating will be withdrawn from the 
study. 
Revised text: 
The investigator will collect pregnancy information on any female subject, who becomes 
pregnant while participating in this study.  The investigator will record pregnancy information 
on the appropriate form and submit it to NovartisGSK within 24 hours 2 weeks of learning of 
a subject's pregnancy.  The subject will also be followed to determine the outcome of the 
pregnancy.  Information on the status of the mother and child will be forwarded to 
NovartisGSK.  Generally, follow-up will be no longer than 6 to 8 weeks following the 
estimated delivery date.  Any premature termination of the pregnancy will be reported. 
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. 
A spontaneous abortion is always considered to be an SAE and will be reported as such.  
Furthermore, any SAE occurring as a result of a post-study pregnancy and is considered 
reasonably related to the study treatment by the investigator, will be reported to NovartisGSK 
as described in Section 11.7. While the investigator is not obligated to actively seek this 
information in former study participants, he or she may learn of an SAE through spontaneous 
reporting. 
Any female subject who becomes pregnant while participating will be withdrawn from the 
study. 
Section 6.4.2. 
Action to be taken if Pregnancy occurs in a female partnet of 
a male study subject 
Previous text: 
The investigator will attempt to collect pregnancy information on any female partner of a male 
study subject who becomes pregnant while participating in this study.  The investigator will 
record pregnancy information on the appropriate form and submit it to GSK within 2 weeks of 
learning of the partner’s pregnancy.  The partner will also be followed to determine the outcome 
of the pregnancy.  Information on the status of the mother and child will be forwarded to GSK.  
Generally, follow-up will be no longer than 6 to 8 weeks following the estimated delivery date.  
Any premature termination of the pregnancy will be reported. 
Revised Text: 
The investigator will attempt to collect pregnancy information on any female partner of a male 
study subject who becomes pregnant while participating in this study.  The investigator will 
record pregnancy information on the appropriate form and submit it to Novartis within 24 


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hours GSK within 2 weeks of learning of the partner’s pregnancy.  The partner will also be 
followed to determine the outcome of the pregnancy.  Information on the status of the mother 
and child will be forwarded to GSKNovartis.  Generally, follow-up will be no longer than 6 to 
8 weeks following the estimated delivery date.  Any premature termination of the pregnancy 
will be reported. 
Section 6.5.2. 
Sample Analysis 
Previous text: 
Plasma analysis will be performed under the management of Bioanalytical Science and 
Toxicokinetics, Drug Metabolism and Pharmacokinetics, Platform Technology and Sciences, 
GSK.  Concentrations of dabrafenib and its metabolites (GSK2285403, GSK2298683 and 
GSK2167542) will be determined in plasma samples using the currently approved analytical 
methodology.  Raw data will be stored in the Archives, GlaxoSmithKline.  Once the plasma has 
been analyzed for dabrafenib and its metabolites (GSK2285403, GSK2298683 and 
GSK2167542) any remaining plasma may be analyzed qualitatively for other circulating 
metabolites and the results reported under a separate DMPK protocol.   
Revised Text: 
Plasma analysis will be performed under the management of Bioanalytical Science and 
Toxicokinetics, Drug Metabolism and Pharmacokinetics, Platform Technology and Sciences, 
GSK.  Concentrations of dabrafenib and its metabolites (GSK2285403, GSK2298683 and 
GSK2167542) will be determined in plasma samples using the currently approved analytical 
methodology.  Raw data will be stored in the Archives, GlaxoSmithKline.  Once the plasma has 
been analyzed for dabrafenib and its metabolites (GSK2285403, GSK2298683 and 
GSK2167542) any remaining plasma may be analyzed qualitatively for other circulating 
metabolites and the results reported under a separate DMPK protocol.   
Until 31 Dec 2015 plasma analysis was performed under the management of Bioanalytical 
Science and Toxicokinetics, Drug Metabolism and Pharmacokinetics, Platform Technology and 
Sciences, GSK and raw data is stored in the GlaxoSmithKline Archives, until transfer to 
Novartis archive. Since 1 Jan 2016 plasma analysis is performed under the management of 
Novartis DMPK, and raw data are stored in the archives of the analytical site until transfer to 
Novartis archive. 
Concentrations of dabrafenib and its metabolites (GSK2285403, GSK2298683 and 
GSK2167542) will be determined in plasma  samples using validated analytical methods. Once 
the plasma has been analyzed for dabrafenib and its metabolites (GSK2285403, GSK2298683 
and GSK2167542) any remaining plasma may be analyzed qualitatively for other circulating 
metabolites or quantitatively to perform long term stability evaluation or cross validation and 
the results reported under a separate DMPK protocol. 
Section 13.2. 
Regulatory and Ethical Considerations, Including the 
Informed Consent Process 
Previous text: 


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GSK will obtain favorable opinion/approval to conduct the study from the appropriate 
regulatory agency in accordance with any applicable country-specific regulatory requirements 
prior to a site initiating the study in that country. 
The study will be conducted in accordance with all applicable regulatory requirements. 
The study will also be conducted in accordance with ICH Good Clinical Practice (GCP), all 
applicable subject privacy requirements, and, the guiding principles of the 2008 Declaration of 
Helsinki.  This includes, but is not limited to, the following: 
• IRB/IEC review and favorable opinion/approval to conduct the study and of any 
subsequent relevant amended documents 
• Written informed consent/assent (and any amendments) to be obtained for each subject 
before participation in the study 
• Investigator reporting requirements (e.g. reporting of AEs/SAEs/protocol deviations to 
IRB/IEC) 
Written informed consent must be obtained from parent(s), LAR or subject prior to participation 
in the study. 
In approving the clinical protocol the IEC/IRB and, where required, the applicable regulatory 
agency are also approving the optional assessments. Where permitted by regulatory authorities, 
approval of the optional assessments can occur after approval is obtained for the rest of the 
study.  If so, then the written approval will clearly indicate approval of the optional assessments 
is being deferred and the study, except for the optional assessments, can be initiated.  When the 
optional assessments are not approved, then the approval for the rest of the study will clearly 
indicate this and therefore, the optional assessments will not be conducted. 
Revised Text: 
Prior to initiation of a study site, Novartis GSK will obtain favorable opinion/approval to 
conduct the study from the appropriate regulatory agency to conduct the study in accordance 
with any applicable country-specific regulatory requirements prior to a site initiating the study 
in that country including those required under a US IND. 
The study will be conducted in accordance with all applicable regulatory requirements. 
The study will also be conducted in accordance with ICH Good Clinical Practice (GCP), all 
applicable subject privacy requirements, and, the guiding principles of the 2008 Declaration of 
Helsinki.  This includes, but is not limited to, the following: 
• IRB/IEC review and favorable opinion/approval to conduct the study and of any 
subsequent relevant amended documents 
• Written informed consent/assent (and any amendments) to be obtained for each subject 
before participation in the study 
• Investigator reporting requirements (e.g. reporting of AEs/SAEs/protocol deviations to 
IRB/IEC) 
Written informed consent must be obtained from parent(s), LAR or subject prior to participation 
in the study. 


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In approving the clinical protocol the IEC/IRB and, where required, the applicable regulatory 
agency are also approving the optional assessments. Where permitted by regulatory authorities, 
approval of the optional assessments can occur after approval is obtained for the rest of the 
study.  If so, then the written approval will clearly indicate approval of the optional assessments 
is being deferred and the study, except for the optional assessments, can be initiated.  When the 
optional assessments are not approved, then the approval for the rest of the study will clearly 
indicate this and therefore, the optional assessments will not be conducted. 
Section 13.3. 
Quality Control (Study Monitoring) 
Previous text: 
In accordance with applicable regulations including GCP, and GSK procedures, GSK monitors 
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 GSK requirements.  
When reviewing data collection procedures, the discussion will also include identification, 
agreement and documentation of data items for which the eCRF will serve as the source 
document. 
GSK will monitor the study and site activity to verify that the: 
• 
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, GCP, and all applicable regulatory requirements. 
The investigator and the head of the medical institution (where applicable) agrees to allow the 
monitor direct access to all relevant documents 
Revised Text: 
In accordance with applicable regulations including GCP, and NovartisGSK procedures, 
Novartis personnel (or designated Clinical Research Organization [CRO]) GSK monitors 
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 NovartisGSK 
requirements.  When reviewing data collection procedures, the discussion will also include 
identification, agreement and documentation of data items for which the eCRF will serve as the 
source document. 
Novartis (or designated CRO) personnel will monitor the study to ensure that the: GSK 
will monitor the study and site activity to verify that the: 
• 
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, GCP, and all applicable regulatory requirements. 
The investigator and the head of the medical institution (where applicable) agrees to allow the 
monitor direct access to all relevant documents 


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Section 13.6. 
Records Retention 
Previous text: 
Following closure of the study, the investigator or the head of the medical institution (where 
applicable) must maintain all site study records, except for those required by local regulations 
to be maintained by someone else, in a safe and secure location.  The records must be maintained 
to allow easy and timely retrieval, when needed (e.g., audit or inspection), and, whenever 
feasible, to allow any subsequent review of data in conjunction with assessment of the facility, 
supporting systems, and staff.  Where permitted by local laws/regulations or institutional policy, 
some or all of these records can be maintained in a format other than hard copy (e.g., microfiche, 
scanned, electronic); however, caution needs to be exercised before such action is taken.  The 
investigator must assure that all reproductions are legible and are a true and accurate copy of 
the original, and meet accessibility and retrieval standards, including re-generating a hard copy, 
if required.  Furthermore, the investigator must ensure there is an acceptable back-up of these 
reproductions and that an acceptable quality control process exists for making these 
reproductions. 
GSK will inform the investigator of the time period for retaining these records to comply with 
all applicable regulatory requirements.  The minimum retention time will meet the strictest 
standard applicable to that site for the study, as dictated by any institutional requirements or 
local laws or regulations, or GSK standards/procedures; otherwise, the retention period will 
default to 15 years. 
The investigator must notify GSK of any changes in the archival arrangements, including, but 
not limited to, archival at an off-site facility or transfer of ownership of the records in the event 
the investigator leaves the site. 
Revised Text: 
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 GSK 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 
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. 


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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. 
The investigator must notify Novartis GSK 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. 
Section 13.7. 
Provision of Study Results to Investigators, Posting to the 
Clincal Trials Register and Publication 
Previous text: 
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report.  Investigators 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 GSK site or other mutually-agreeable location. 
GSK will also provide investigators with the full summary of the study results.  Investigators 
are encouraged to share the summary results with the study subjects, as appropriate. 
GSK aims to post a results summary to the GSK Clinical Study Register and other publicly 
available registers no later than 6 months after the last subject’s last visit [this applies to each 
data analysis phase for studies with multiple phases, e.g., primary analysis, follow up analysis 
etc].  In addition, the aim is to submit a manuscript to a peer-reviewed journal for publication 
within 18 months of LSLV.  GSK also aims to publish the full study protocol on the GSK 
Clinical Study Register at the time the results of the study are published as a manuscript in the 
scientific literature.   
When manuscript publication in a peer-reviewed journal is not feasible, further study 
information will be posted to the GSK Clinical Study Register to supplement the results 
summary. 
 
Revised Text: 
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 GSK Novartis site or other mutually-agreeable 
location. 
Novartis GSK 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. 
GSK aims to post a results summary to the GSK Clinical Study Register and other publicly 
available registers no later than 6 months after the last subject’s last visit [this applies to each 
data analysis phase for studies with multiple phases, e.g., primary analysis, follow up analysis 
etc].  In addition, the aim is to submit a manuscript to a peer reviewed journal for publication 
within 18 months of LSLV.  GSK also aims to publish the full study protocol on the GSK 


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Clinical Study Register at the time the results of the study are published as a manuscript in the 
scientific literature.   
When manuscript publication in a peer-reviewed journal is not feasible, further study 
information will be posted to the GSK Clinical Study Register to supplement the results 
summary. Novartis aims to post a results summary to the Novartis Clinical Trial Results 
website (www.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, Novartis 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. 
 
Section 13.8. 
Data Management 
Previous text: 
For this study subject data will be entered into GSK defined electronic case report forms 
(eCRFs), transmitted electronically to GSK or designee and 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 errors and 
inconsistencies in the data.  Adverse events and concomitant medications terms will be coded 
using MedDRA (Medical Dictionary for Regulatory Activities) and an internal validated 
medication dictionary, GSKDrug.    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.  Subject 
initials will not be collected or transmitted to GSK according to GSK policy. 
Revised Text: 
Data Management will identify and implement the most effective data acquisition and 
management strategy for each clinical trial protocol and deliver datasets that support the 
protocol objectives. 
For this study subject data will be entered into NovartisGSK defined electronic case report 
forms (eCRFs), transmitted electronically to the sponsor (or designee) GSK or designee and 
be combined with data provided from other sources in a validated data system. 
Management of clinical data Clinical data management will be performed in accordance with 
applicable GSK standards and data cleaning procedures with the objective of resolving errors 
and inconsistencies in the data which would otherwise impact on the analysis and 
reporting objectives, or the credibility of the Clinical Study Report. to ensure the integrity 
of the data, e.g., removing errors and inconsistencies in the data.  Adverse events All AEs and 
concomitant medications terms will be coded using MedDRA (Medical Dictionary for 
Regulatory Activities) and a custom dictionary.and an internal validated medication 
dictionary, GSKDrug. Laboratory data (i.e., hematology and clinical chemistry) will be 
stored in a database maintained by the central laboratory and transferred to Novartis at 
agreed times.  


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eCRFs (including queries and audit trails) will be retained by Novartis GSK, and copies will 
be sent to the investigator to maintain as the investigator copy.  Subject initials will not be 
collected or transmitted to GSK according to GSK policy. 


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Amendment 06 
WHERE THE AMENDMENT APPLIES 
Amendment 06 applies to all sites conducting the study. 
SUMMARY OF AMENDMENT CHANGES WITH RATIONALE 
Title changed to specify children and adolescents instead of specific years (corrected to align 
with previous protocol changes).   
Administrative change (i.e. addition of information for an abbreviation and an additional 3 
abbreviations added).   
Background updated to reflect approval for dabrafenib in many jurisdictions.   
Study rationale updated to increase lower age to ≥12 months from >1 month (corrected to align 
with previous protocol changes) and to specify refractory disease.   
Summary of risk management updated to remove paragraph on glucose-6-phosphate 
dehydrogenase.   
Clarification of the dose escalation rules for selection of the appropriate dose by age group in 
the absence of MTD.   
Correction of units for exposure criterion.   
Update of dose modification guidelines for clarity and in accordance with the most recent 
information available for dabrafenib.  Rash guidelines have not been proven to be effective. 
Addition of new section on management guidelines for additional AEs, added according to the 
02 May 2014 Asset language changes.   
Addition of LCH assessments to the time and events schedule, and addition of the LCH scoring 
system, to establish baseline disease burden.   
Addition of follow-up skin assessments to the time and events schedule and safety assessments, 
including French country specific guidelines, to provide additional safety oversight of the 
patient.   
Clarification of timing for final study visit in the time and events schedule.  Inclusion criterion 
10 updated to replace references to liver metastases with liver involvement.   
Exclusion criterion 7 updated to include major surgery as previous anti-cancer therapy.   
Exclusion criterion 17 updated to remove history of known HIV, as risk to patients is minimal 
and they will not be excluded; reference to HIV patients’ ineligibility removed from prohibited 
medications and non-drug therapies section.  
 Exclusion criterion 18 (subjects with known G6PD deficiency) removed as further information 
indicates that this is no longer a risk.   
Dermatological examinations clarified for safety monitoring.  The time for stable disease to be 
considered best response reduced to 12 weeks from 16 weeks.   
   


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Removal of the restriction on foods that may inhibit cytochrome (CYP) 3A4 activity, as further 
information indicates that this is no longer a risk, and inclusion of all dietary information for 
clarity.   
Clarification that children that are breastfeeding may continue to breast feed on demand, but 
that if child is breast fed during collection of PK samples the time of breastfeeding should be 
recorded.   
Addition in section on treatment after the end of the study of reference to Section 6.3 for follow 
up instructions for subjects who discontinue.   
Overdose section updated to provide additional guidance in accordance with the most recent 
information available for dabrafenib.   
SAE definition of protocol-specific SAEs updated for clarity and modified based on additional 
understanding of the compound.   
New appendix added in Section 15.6 (Appendix 6 French Country Guidelines for additional 
dermatological monitoring while on therapy and after IP discontinuation). 
LIST OF SPECIFIC CHANGES 
Title 
Previous text: 
Phase I/IIa, 2-Part, Multi-Center, Single-Arm, Open-Label Study to Determine the Safety, 
Tolerability and Pharmacokinetics of Oral Dabrafenib in Pediatric Subjects Aged 1 Month to 
<18 Years with Advance BRAF V600-Mutation Positive Solid Tumors. 
Revised text: 
Phase I/IIa, 2-Part, Multi-Center, Single-Arm, Open-Label Study to Determine the Safety, 
Tolerability and Pharmacokinetics of Oral Dabrafenib in Children and Adolescent Subjects with 
Advanced BRAF V600-Mutation Positive Solid Tumors. 
 


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Abbreviations corrected and added 
eGFR 
Calculated Glomerular Filtration Rate 
PPE 
Palmar Plantar erythrodysaethesia Syndrome 
QTc 
QT duration corrected for heart rate 
UPC 
Urine Protein:Creatinine Ratio 
 
Section 1.1. 
Background 
Previous text: 
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 biomarker 
(phosphorylated extracellular signal-related kinase [pERK]) in tumor cell lines, demonstrated 
anti-proliferative activity against multiple BRAF mutation-positive tumor cell lines, achieved 
proximal biomarker suppression and tumor regression in BRAF mutant xenograft models, and 
has demonstrated significant anti-tumor efficacy in BRAF V600-mutation positive tumors, 
including melanoma, papillary thyroid cancer, and non-small cell lung cancer.  Dabrafenib is 
currently being developed in adult subjects with BRAF V600 mutation-positive advanced or 
metastatic melanoma, and is being studied in subjects with other BRAF V600 mutation-
positive tumor types.   
Revised text: 
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 biomarker 
(phosphorylated extracellular signal-related kinase [pERK]) in tumor cell lines, demonstrated 
anti-proliferative activity against multiple BRAF mutation-positive tumor cell lines, achieved 
proximal biomarker suppression and tumor regression in BRAF mutant xenograft models, and 
has demonstrated significant anti-tumor efficacy in BRAF V600-mutation positive tumors, 
including melanoma, papillary thyroid cancer, and non-small cell lung cancer.  Dabrafenib is 
currently approved in many jurisdictions for adult subjects with BRAF V600 mutation-
positive advanced or metastatic melanoma, and is being studied in subjects with other BRAF 
V600 mutation-positive tumor types. 
 
Section 1.2. 
Study Rationale 
Previous text: 
The proposed study is a Phase I/IIa, open-label study to determine the safety, tolerability, and 
pharmacokinetics of oral dabrafenib in pediatric subjects aged 1 month to less than 18 years 
of age with advanced BRAF V600 mutation positive advanced solid tumors.  As noted above, 
dabrafanib has demonstrated promising efficacy in adults with BRAF V600 mutation-positive 
advanced or metastatic melanoma as well as other tumors types with BRAF V600 mutations.  
For patients with recurrent gliomas, LCH, melanoma, or PTC, the 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.  Recent data identifying BRAF V600 
activating mutations in pediatric melanoma, gliomas, LCH, and PTC coupled with the recent 


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development of specific BRAF inhibitors may allow for the development of a new therapeutic 
opportunity for children, and is the primary rationale for this study.   
Revised text: 
The proposed study is a Phase I/IIa, open-label study to determine the safety, tolerability, and 
pharmacokinetics of oral dabrafenib in pediatric and adolescent subjects aged ≥12 months to 
less than 18 years of age with advanced BRAF V600 mutation positive advanced solid 
tumors.  As noted above, dabrafanib has demonstrated promising efficacy in adults with 
BRAF V600 mutation-positive advanced or metastatic melanoma as well as other tumors 
types with BRAF V600 mutations.  For patients with refractory, recurrent gliomas, LCH, 
melanoma, or PTC, the 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.  Recent data identifying BRAF V600 activating mutations in pediatric melanoma, 
gliomas, LCH, and PTC coupled with the recent development of specific BRAF inhibitors 
may allow for the development of a new therapeutic opportunity for children, and is the 
primary rationale for this study. 
 
Section 1.3. 
Summary of Risk management 
The following paragraph has been deleted: 
Glucose-6-phosphate dehydrogenase:  Subjects with a history of known glucose-6-
phosphate dehydrogenase (G6PD) deficiency are excluded from clinical trials as they may 
develop nonimmune hemolytic anemia in response to dabrafenib which contains a 
sulfonamide, a potential risk factor for subjects with this deficiency.  No cases of hemolytic 
anemia have been reported to date in dabrafenib clinical trials. 
 
Section 3.1.1.1. 
Dose Escalation 
Previous text: 
The dose in Part 1 will be escalated until the maximum tolerated dose (MTD) is reached 
(based on toxicity, Section 3.4) OR in the absence of reaching the MTD, the dose in which 
the median AUC(0-τ) is between approximately 4000 ng*h/mL and approximately 5500 
ng*h/mL. The proportion of subjects who achieve an AUC(0-12) ≥ 4000 ng*h/mL also will 
be considered when selecting the dose for Part 2. In the absence of meeting criteria for MTD, 
if <80% of subjects in an age group (≤2 yrs, >2 and ≤12 yrs, >12 yrs) fail to achieve an 
AUC(0-12) ≥ approximately 4000 ng*h/mL OR if fewer than two subjects in a specific age 
group have been evaluated at a given dose level, the study sponsor and study team will review 
all available safety and PK data and determine if further Part 1 evaluation of a specific age 
group is required before these subjects may enroll in Part 2. Intermediate doses may be 
explored. 
Revised text: 
The dose in Part 1 will be escalated until the maximum tolerated dose (MTD) is reached 
(based on toxicity, Section 3.4) OR in the absence of reaching the MTD, the dose in which 
the median AUC(0-τ) is between approximately 4000 ng*h/mL and approximately 
5500 ng*h/mL. The proportion of subjects who achieve an AUC(0-12) ≥ 4000 ng*h/mL also 
will be considered when selecting the dose for Part 2. In the absence of meeting criteria for 


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MTD, if less than 80% of subjects in an age group (≤2 yrs, >2 and ≤12 yrs, >12 yrs) achieve 
an AUC(0-12) ≥ approximately 4000 ng*h/mL OR if fewer than two subjects in a specific age 
group have been evaluated at a given dose level, the study sponsor and study team will review 
all available safety and PK data and determine if further Part 1 evaluation of a specific age 
group is required before these subjects may enroll in Part 2. Intermediate doses may be 
explored. 
 
Section 3.7.1.  
Dabrafenib Intra-Subject Dose Escalation 
Previous text: 
In certain circumstances in Part 1 of this study, a subject’s dose level may be increased up to 
the highest dose level that is open to enrollment. Only subjects who have completed their 
DLT assessment period (28 days), who have tolerated treatment, but have measured AUC(0-
12) less than target level, may be eligible for escalation. Decisions to increase a subject’s 
current dose will be based on all available data, including safety data and PK data for that 
subject, and must be agreed by the investigator and the GSK medical monitor. Predicted 
exposure AUC(0-12) at the escalated dose may not exceed 6000 µg*h/mL. Documentation of 
the dose escalation agreement and predicted exposure must be kept in the study files for the 
subject. 
Revised text: 
In certain circumstances in Part 1 of this study, a subject’s dose level may be increased up to 
the highest dose level that is open to enrollment. Only subjects who have completed their 
DLT assessment period (28 days), who have tolerated treatment, but have measured AUC(0-
12) less than target level, may be eligible for escalation. Decisions to increase a subject’s 
current dose will be based on all available data, including safety data and PK data for that 
subject, and must be agreed by the investigator and the GSK medical monitor. Predicted 
exposure AUC(0-12) at the escalated dose may not exceed 6000ng*h/mL. Documentation of 
the dose escalation agreement and predicted exposure must be kept in the study files for the 
subject.  
 


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Section 3.7.3.  
General supportive guidelines 
The following subsection has been deleted: 
3.7.3.1. 
Skin Toxicity (Rash, Palmar-Plantar Erythrodysesthaesia syndrome) 
Rash and Palmar-Plantar Erythrodysesthaesia Syndrome (PPES) are frequently observed in 
subjects receiving dabrafenib therapy. Guidelines for management are based on experience 
with other MEK inhibitors and EGFR inhibitors [Balagula, 2010; Lacouture, 2012] and 
include: 
• 
Prevention/prophylaxis: promote sunscreen use and avoidance of unnecessary sun 
exposure, use alcohol-free emollient creams, topical steroids and antibiotics as 
needed. 
• 
Pruritic lesions:  cool compresses and oral antihistamines 
• 
Fissuring lesions:  Monsel’s solution, silver nitrate or zinc oxide cream 
• 
Desquamation: thick emollients and mild soap 
• 
Paronychia:  antiseptic bath, local potent corticosteroids, antibiotics, surgery as 
needed 
• 
Infected lesions:  topical or systemic antibiotics 
Additional measures for PPES should include: 
• 
Lifestyle modification:  avoidance of hot water, traumatic activity, constrictive 
footwear, or excessive friction on the skin and the use of thick cotton socks and 
gloves, and shoes with padded insoles 
• 
Symptomatic treatments:  apply moisturizing creams frequently, topical keratolytics 
(e.g. urea 20-40 % cream, salicylic acid 6%, tazarotene 0.1% cream, fluorouracil 5% 
cream), clobetasol propionate 0.05% ointment for erythematous areas, topical 
lidocaine 2%, and / or systemic pain medication such as nonsteroidal anti-
inflammatory drugs, codeine, and pregabalin for pain. 
Dose modification may also be required (refer toTable 5 - General Dose Modification 
Guidelines).  
 
Section 3.7.4. Dose Modification for General Toxicities to Section 3.7.9. 
Liver 
Chemistry Stopping Criteria 
Previous text: 
3.7.4. Dose Modification for General Toxicities 
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 5.  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.   
Investigators should always err on the side of caution in these settings if treatment-related 
toxicity is a possibility.   




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For subjects with creatinine increase of ≥50% from baseline or eGFR (a) decrease of >25% from 
baseline: 
1st occurrence 
• 
Interrupt dabrafenib 
• 
If subject has fever: treat pyrexia as per Table 7 (please note NSAIDs can 
induce renal insufficiency, especially in subjects with dehydration); 
consider IV hydration 
• 
Pediatric nephrology consult is recommended 
• 
Re-check within 24 hours 
• 
If <50% increase in creatinine or ≤25% decrease in eGFR from 
baseline then may restart dabrafenib 
• 
If ≥50% increase in creatinine from baseline or eGFR decrease 
of >25% from baseline 
- Recommend monitor creatinine at least twice weekly 
- May restart dabrafenib if creatinine/eGFR returns to baseline with 
approval of medical monitor. 
- If creatinine<50% increase from baseline or eGFR returns to 
≤25% decrease from baseline may restart dabrafenib at a reduced 
dose with approval of the medical monitor 
2nd occurrence 
• 
Follow above recommendations.   
• 
If restart of dabrafenib is approved by medical monitor 
o Upon restart reduce dabrafenib by one dose level  
3rd occurrence 
 
Permanently discontinue dabrafenib 
 
For subjects with creatinine increase of ≥100% from baseline or eGFR (a) decrease of >50% from 
baseline 
 
• 
Interrupt dabrafenib 
• 
If subject has fever: treat pyrexia as per Table 7 (please note NSAIDs 
can induce renal insufficiency, especially in subjects with dehydration); 
consider IV hydration 
• 
Pediatric nephrology consultation recommended 
• 
Re-check within 24 hours 
o If creatinine increase of ≥100% or eGFR decrease of >50% is 
confirmed, permanently discontinue dabrafenib 
o If creatinine increase ≥50% or eGFR decrease >25% from baseline 
and ≤50% from baseline, continue to hold dabrafenib and follow 
guidelines above 
o If creatinine increase <50% or eGFR is ≤25% decrease from 
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NOTE: If serum bilirubin fractionation is not immediately available, study drug 
should be discontinued if ALT ≥ 3xULN and bilirubin ≥ 2xULN.  Serum bilirubin 
fractionation should be performed if testing is available. If testing is unavailable, 
record presence of detectable urinary bilirubin on dipstick, indicating direct bilirubin 
elevations and suggesting liver injury. 
2. ALT ≥8xULN 
3. ALT ≥5xULN but <8 xULN persists for ≥2 weeks 
4. ALT ≥3xULN if associated with the appearance or worsening of symptoms of 
hepatitis or hypersensitivity such as fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash or eosinophilia. 
5. ALT ≥5xULN but <8 xULN and cannot be monitored weekly for >2 weeks. 
When any of the liver chemistry stopping criteria 1 – 5 is met, do the following: 
• 
Immediately discontinue subject from study treatment.  
• 
Report the event to GSK within 24 hours of learning its occurrence. 
• 
Complete the liver event electronic case report form (eCRF) and SAE data collection 
tool if the event also meets the criteria for an SAE.  
• 
All events of ALT ≥ 3xULN and bilirubin ≥ 2xULN (>35% direct bilirubin) (or 
ALT≥3xULN and INR>1.5, if INR measured; INR measurement is not required and 
the threshold value stated will not apply to subjects receiving anticoagulants), termed 
‘Hy’s Law’, must be reported as an SAE (excluding studies of hepatic 
impairment or cirrhosis).  
• 
NOTE: if serum bilirubin fractionation is not immediately available, study drug 
should be discontinued if ALT ≥ 3xULN and bilirubin ≥ 2xULN. Serum bilirubin 
fractionation should be performed if testing is available. If testing is unavailable, 
record presence of detectable urinary bilirubin on dipstick, indicating direct 
bilirubin elevations and suggesting liver injury 
• 
Complete the liver imaging and/or liver biopsy eCRFs if these tests are performed. 
• 
Perform liver event follow up assessments (Section 12), and monitor the subject until 
liver chemistries resolve, stabilize, or return to baseline values as described below.  
• 
Withdraw the subject from the study after completion of the liver chemistry 
monitoring (unless further safety follow up is required or GSK Medical Governance 
approval of drug restart is granted, as described in Section 12.2).  
• 
For studies where survival or progression is an endpoint, follow-up for overall 
survival or progression is required following discontinuation from study 
treatment  
• 
Do not restart investigational product unless written approval is granted by GSK 
Medical Governance (details for restarting investigational product are described in 
Section 12.2), whereupon the subject continues in the study after completion of the 
liver chemistry monitoring described in Section 12.2).  


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• 
Subjects meeting criterion 5 should be monitored as frequently as possible. 
In addition, for subjects meeting criterion 1:  
• 
Make every reasonable attempt to have subjects return to clinic within 24 hours for 
repeat liver chemistries, liver event follow up assessments (refer to Section 12), and 
close monitoring. 
• 
A specialist or hepatology consultation is recommended. 
• 
Monitor subjects twice weekly until liver chemistries [ALT, aspartate 
aminotransferase (AST), alkaline phosphatase, bilirubin] resolve, stabilize or return 
to within baseline values. 
In addition, for subjects meeting any of the criteria 2 - 5: 
• 
Make every reasonable attempt to have subjects return to clinic within 24-72 hours 
for repeat liver chemistries and liver event follow up assessments (refer to 
Section 12). 
• 
Monitor subjects weekly until liver chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) resolve, stabilize or return to within baseline values;  
• 
Subjects meeting criterion 5 should be monitored as frequently as possible. 
3.7.7. QTc Stopping Criteria 
A subject that meets the criteria below will be withdrawn from the study.  The QT correction 
formula used to determine discontinuation should be the same one used throughout the study 
[QT duration corrected for heart rate by Bazett’s formula (QTcB)]. 
• 
QTcB >500 msec or uncorrected QT >600 msec 
• 
If subject has underlying bundle branch block then the QTcB withdrawal criteria 
depends on the baseline value: 
Baseline QTcB value (with  
underlying bundle branch block) 
QTcB withdrawal 
criteria 
<450 ms 
>500 ms 
450-480 ms 
≥530 ms 
 
Withdrawal decisions are to be based on an average QTcB value of triplicate ECGs.  If an 
ECG demonstrates a prolonged QT interval, obtain 2 more ECGs over a brief period (e.g., 5 
minutes between each ECG), and then use the averaged QTcB values of the 3 ECGs to 
determine whether the subject should be discontinued from the study. 
Subjects recruited in France, please refer to Appendix 5 for French specific QTc stopping 
criteria Appendix 6. 


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3.7.8. Left Ventricular Ejection Fraction Stopping Criteria 
ECHO must be performed at baseline and at follow-up visit(s) per the schedule in the Time 
and Events Table.  Subjects who have an asymptomatic, absolute decrease of >10% in LVEF 
compared to baseline and the ejection fraction is below the institution’s LLN should 
temporarily discontinue dabrafenib and have a repeat evaluation of LVEF within 1 week.  
ECHO should be repeated every 1-2 weeks for 4 weeks or until LVEF recovery to above 
institutional lower limit of normal and within 10% of baseline. 
• 
If the LVEF recovers (defined as ≥ LLN and absolute decrease ≤10% compared to 
baseline) at any time during the next 4 weeks, after consultation and approval of 
the Medical Monitor, the subject may be restarted on dabrafenib at a reduced 
dose(s).  For such subjects, monitoring of LVEF will then be performed 2 and 4 
weeks after rechallenge, and every 4 weeks thereafter for 12 weeks and then per 
protocol. 
• 
If repeat LVEF does not recover within 4 weeks, then the subject should permanently 
discontinue dabrafenib. Ejection fraction should continue to be monitored every 4 
weeks for 16 weeks or until resolution. 
Subjects with a Grade 3 or 4 (symptomatic) left ventricular systolic dysfunction must 
discontinue dabrafenib.  Ejection fraction should continue to be monitored every 4 weeks for 
16 weeks or until resolution.  If recovery occurs (LVEF to above institutional LLN and 
symptom resolution) within 4 weeks, the subject may restart dabrafenib at a reduced dose in 
consultation with the Medical Monitor (if in the opinion of the investigator, the subject was 
receiving or likely to receive clinical benefit with continued treatment). 
All events of LVEF meeting the stopping criteria should be reported as SAEs (refer to Section 
11.7). 
Copies of all ECHO(s) will be required for possible central review.  Copies of all cardiology 
consultations performed on subjects who experience a >10% decrease in LVEF from baseline 
and whose cardiac ejection fraction is below the institution’s LLN will also be required for 
possible central review.  Details for central collection of ECHOs will be provided in the SPM. 
3.7.9. Valvular Toxicity Stopping Criteria 
Subjects who have an asymptomatic, moderate regurgitation or stenosis by ECHO (Grade 2 
mitral/tricuspid/aortic valvular toxicity per CTC AE v4.0) should temporarily discontinue 
Dabrafanib and have a repeat evaluation by ECHO within 1 week. ECHO should be repeated 
every 1-2 weeks for 4 weeks or until valve recovery to baseline. 
• 
If the valve recovers to baseline any time during the next 4 weeks, after 
consultation and approval of the Medical Monitor, the subject may be restarted on 
Dabrafanib at a reduced dose(s).  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 12 weeks and then per protocol. 
• 
If repeat ECHO does not reveal valve recovery to baseline within 4 weeks, then the 
subject should permanently discontinue Dabrafanib.  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 dabrafanib.  






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• 
Optimize oral corticosteroid dose as clinically indicated for 
recalcitrant pyrexiaf  
• 
If corticosteroids have been tapered and pyrexia recurs, 
restart steroids  
• 
If corticosteroids cannot be tapered or escalating doses are 
required, consult medical monitor 
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. 
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 after 3 episodes of pyrexia complicated by rigors, severe chills etc, 
which cannot be managed by best supportive care, including increasing doses of oral steroids.  Re-escalation of 
dabrafenib is allowed if no episode of pyrexia is observed in the 4 weeks subsequent to dose reduction. 
 
3.7.5.2. 
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 7. 
TABLE 7 
RENAL INSUFFICIENCY GUIDELINES 
For subjects with creatinine rise  ≥50% from baseline : 
1 st  occurrence 
• 
If subject has fever: treat pyrexia as per Table 6 (please note NSAIDs can 
induce renal insufficiency, especially in subjects with dehydration); 
consider IV hydration 
• 
Pediatric nephrology consult is recommended 
• 
Re-check within 24 hours 
• 
If creatinine rise is < 25% from baseline: 
• 
Continue dabrafenib at current dose 
• 
Monitor creatinine weekly for 4 weeks to ensure levels 
remain within 25% of baseline  








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• 
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. 
3.7.7. Left Ventricular Ejection Fraction Stopping Criteria 
ECHO must be performed at baseline and at follow-up visit(s) per the schedule in the Time 
and Events Table.  Subjects who have an asymptomatic, absolute decrease of >10% in LVEF 
compared to baseline and the ejection fraction is below the institution’s LLN should 
temporarily discontinue dabrafenib and have a repeat evaluation of LVEF within 1 week.  
ECHO should be repeated every 1-2 weeks for 4 weeks or until LVEF recovery to above 
institutional lower limit of normal and within 10% of baseline. 
• 
If the LVEF recovers (defined as ≥ LLN and absolute decrease ≤10% compared to 
baseline) at any time during the next 4 weeks, after consultation and approval of 
the Medical Monitor, the subject may be restarted on dabrafenib at a reduced 
dose(s).  For such subjects, monitoring of LVEF will then be performed 2 and 4 
weeks after rechallenge, and every 4 weeks thereafter for 12 weeks and then per 
protocol. 
• 
If repeat LVEF does not recover within 4 weeks, then the subject should permanently 
discontinue dabrafenib. Ejection fraction should continue to be monitored every 4 
weeks for 16 weeks or until resolution. 
Subjects with a Grade 3 or 4 (symptomatic) left ventricular systolic dysfunction must 
discontinue dabrafenib.  Ejection fraction should continue to be monitored every 4 weeks for 
16 weeks or until resolution.  If recovery occurs (LVEF to above institutional LLN and 
symptom resolution) within 4 weeks, the subject may restart dabrafenib at a reduced dose in 
consultation with the Medical Monitor (if in the opinion of the investigator, the subject was 
receiving or likely to receive clinical benefit with continued treatment). 
All events of LVEF meeting the stopping criteria should be reported as SAEs (refer to 
Section 11.7). 
Copies of all ECHO(s) will be required for possible central review.  Copies of all cardiology 
consultations performed on subjects who experience a >10% decrease in LVEF from baseline 
and whose cardiac ejection fraction is below the institution’s LLN will also be required for 
possible central review.  Details for central collection of ECHOs will be provided in the SPM. 
3.7.8. Valvular Toxicity Stopping Criteria 
Subjects who have an asymptomatic, moderate regurgitation or stenosis by ECHO (Grade 2 
mitral/tricuspid/aortic valvular toxicity per CTC AE v4.0) should temporarily discontinue 
Dabrafanib and have a repeat evaluation by ECHO within 1 week. ECHO should be repeated 
every 1-2 weeks for 4 weeks or until valve recovery to baseline. 
• 
If the valve recovers to baseline any time during the next 4 weeks, after 
consultation and approval of the Medical Monitor, the subject may be restarted on 
Dabrafanib at a reduced dose(s).  For such subjects, monitoring of the valve via 


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ECHO will then be performed 2 and 4 weeks after rechallenge, and every 4 weeks 
thereafter for 12 weeks and then per protocol. 
• 
If repeat ECHO does not reveal valve recovery to baseline within 4 weeks, then the 
subject should permanently discontinue Dabrafanib.  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 dabrafanib.  
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 Dabrafanib at a reduced dose after consultation and 
approval of the Medical Monitor. 
Copies of all ECHO(s) will be required for possible central review.  Details for central 
collection of ECHOs will be provided in the SPM.  Copies of all cardiology consultations 
performed on subjects who experience a valvular toxicity will also be required by GSK for 
review. 
3.7.9. Liver Chemistry Stopping Criteria 
Liver chemistry stopping and follow up criteria have been designed to assure subject safety 
and evaluate liver event etiology in alignment with the FDA Guidance for Industry – Drug-
Induced Liver Injury: Premarketing Clinical Evaluation (July 2009, www.fda.gov). 
Liver chemistry stopping criteria 1-5 are defined as: 
1. Alanine aminotransferase (ALT) ≥3 times the upper limit of normal (xULN) and 
bilirubin ≥ 2xULN (>35% direct bilirubin) (or ALT≥3xULN and International 
Normalized Ratio (INR) >1.5, if INR measured) 
NOTE: If serum bilirubin fractionation is not immediately available, study drug should 
be discontinued if ALT ≥ 3xULN and bilirubin ≥ 2xULN.  Serum bilirubin fractionation 
should be performed if testing is available. If testing is unavailable, record presence of 
detectable urinary bilirubin on dipstick, indicating direct bilirubin elevations and 
suggesting liver injury. 
2. ALT ≥8xULN 
3. ALT ≥5xULN but <8 xULN persists for ≥2 weeks 
4. ALT ≥3xULN if associated with the appearance or worsening of symptoms of 
hepatitis or hypersensitivity such as fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash or eosinophilia. 
5. ALT ≥5xULN but <8 xULN and cannot be monitored weekly for >2 weeks. 
When any of the liver chemistry stopping criteria 1 – 5 is met, do the following: 
• 
Immediately discontinue subject from study treatment.  
• 
Report the event to GSK within 24 hours of learning its occurrence. 
• 
Complete the liver event electronic case report form (eCRF) and SAE data collection 
tool if the event also meets the criteria for an SAE.  


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• 
All events of ALT ≥ 3xULN and bilirubin ≥ 2xULN (>35% direct bilirubin) (or 
ALT≥3xULN and INR>1.5, if INR measured; INR measurement is not required and 
the threshold value stated will not apply to subjects receiving anticoagulants), termed 
‘Hy’s Law’, must be reported as an SAE (excluding studies of hepatic 
impairment or cirrhosis).  
• 
NOTE: if serum bilirubin fractionation is not immediately available, study drug 
should be discontinued if ALT ≥ 3xULN and bilirubin ≥ 2xULN. Serum bilirubin 
fractionation should be performed if testing is available. If testing is unavailable, 
record presence of detectable urinary bilirubin on dipstick, indicating direct 
bilirubin elevations and suggesting liver injury 
• 
Complete the liver imaging and/or liver biopsy eCRFs if these tests are performed. 
• 
Perform liver event follow up assessments (Section 12), and monitor the subject until 
liver chemistries resolve, stabilize, or return to baseline values as described below.  
• 
Withdraw the subject from the study after completion of the liver chemistry 
monitoring (unless further safety follow up is required or GSK Medical Governance 
approval of drug restart is granted, as described in Section 12.2).  
• 
For studies where survival or progression is an endpoint, follow-up for overall 
survival or progression is required following discontinuation from study treatment  
• 
Do not restart investigational product unless written approval is granted by GSK 
Medical Governance (details for restarting investigational product are described in 
Section 12.2), whereupon the subject continues in the study after completion of the 
liver chemistry monitoring described in Section 12.2).  
• 
Subjects meeting criterion 5 should be monitored as frequently as possible. 
In addition, for subjects meeting criterion 1:  
• 
Make every reasonable attempt to have subjects return to clinic within 24 hours for 
repeat liver chemistries, liver event follow up assessments (refer to Section 12), and 
close monitoring. 
• 
A specialist or hepatology consultation is recommended. 
• 
Monitor subjects twice weekly until liver chemistries [ALT, aspartate 
aminotransferase (AST), alkaline phosphatase, bilirubin] resolve, stabilize or return 
to within baseline values. 
In addition, for subjects meeting any of the criteria 2 - 5: 
• 
Make every reasonable attempt to have subjects return to clinic within 24-72 hours 
for repeat liver chemistries and liver event follow up assessments (refer to 
Section 12). 
• 
Monitor subjects weekly until liver chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) resolve, stabilize or return to within baseline values;  
Subjects meeting criterion 5 should be monitored as frequently as possible. 




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Section 4.2.1. Inclusion Criteria 
Previous text: 
10. 
Adequate liver function defined as: 
• 
Bilirubin (sum of conjugated + unconjugated) ≤ 1.5 x upper limit of normal (ULN) 
for age 
• 
AST and ALT ≤2.5 x ULN; AST/ALT may be <5 x ULN at baseline if liver 
metastases are present (requires radiographic confirmation of liver metastases) 
Revised text: 
10. 
Adequate liver function defined as: 
• 
Bilirubin (sum of conjugated + unconjugated) ≤ 1.5 x upper limit of normal (ULN) 
for age 
• 
AST and ALT ≤2.5 x ULN; AST/ALT may be <5 x ULN at baseline if disease 
under treatment involves the liver (requires radiographic confirmation of liver 
involvement) 
 
Section 4.2.2. Exclusion Criteria 
Previous text: 
7. 
Unresolved toxicity greater than NCI CTCAE v4.0 [NCI, 2009] Grade 2 or higher 
from previous anti-cancer therapy except those that in the opinion of the investigator are not 
clinically relevant given the known safety/toxicity profile of dabrafenib (e.g., alopecia and/or 
peripheral neuropathy related to platinum or vinca alkaloid based chemotherapy); 
Revised text: 
7. 
Unresolved toxicity greater than NCI CTCAE v4.0 [NCI, 2009] Grade 2 or higher 
from previous anti-cancer therapy, including major surgery, except those that in the opinion 
of the investigator are not clinically relevant given the known safety/toxicity profile of 
dabrafenib (e.g., alopecia and/or peripheral neuropathy related to platinum or vinca alkaloid 
based chemotherapy); 
Previous text: 
17. 
A history of known Human Immunodeficiency Virus (HIV), Hepatitis B Virus, or 
Hepatitis C Virus infection (subjects with laboratory evidence of Hepatitis B Virus clearance 
may be enrolled); 
18. 
Subjects with known G6PD deficiency; 
Revised text: 
17. 
Hepatitis B Virus, or Hepatitis C Virus infection (subjects with laboratory evidence of 
Hepatitis B Virus clearance may be enrolled); 
18. 
Note: this criterion was deleted in Protocol Amendment 6; 
 
Section 6.3 
Safety and Tolerability 
New bullet point added under the subheading “Dermatological Examination/Skin 
Biopsy/Photography”: 
Revised text: 


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• Dermatological examinations should be performed every 2 months during treatment, and 
every 2-3 months 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. 
New subheading added: 
Revised text: 
Non-cutaneous secondary/recurrent malignancy 
• During treatment subjects should be monitored as clinically appropriate. 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 non-cutaneous secondary/recurrent malignancy should be 
reported as a protocol-specific SAE and treated according to standard clinical practice. 
• See Appendix 6 for French country specific guidelines. 
 
Section 6.6. 
 
Anti-tumor Assessment 
Previous text: 
Confirmation of CR and partial response (PR) are required per protocol.  Complete 
response/PR confirmation assessments may take place at Week 16 (but not earlier than week 
12) if initial response was seen at the Week 8 assessments.  Initial responses (CR/PR) that 
occur at Week 16 (or after) should be confirmed not less than 4 and not more than 8 weeks 
after the initial response.  If a confirmation assessment is performed prior to the next protocol 
schedule assessment, the next protocol scheduled evaluation is still required (e.g. evaluations 
must occur at each protocol scheduled time point regardless of unscheduled assessments).  If 
the criteria for a CR or PR are not confirmed, then stable disease can be considered the best 
response if it has been demonstrated for a minimum of 16 weeks. 
Revised text: 
Confirmation of CR and partial response (PR) are required per protocol.  Complete 
response/PR confirmation assessments may take place at Week 16 (but not earlier than week 
12) if initial response was seen at the Week 8 assessments.  Initial responses (CR/PR) that 
occur at Week 16 (or after) should be confirmed not less than 4 and not more than 8 weeks 
after the initial response.  If a confirmation assessment is performed prior to the next protocol 
schedule assessment, the next protocol scheduled evaluation is still required (e.g. evaluations 
must occur at each protocol scheduled time point regardless of unscheduled assessments).  If 
the criteria for a CR or PR are not confirmed, then stable disease can be considered the best 
response if it has been demonstrated for a minimum of 12 weeks. 
 
 




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Section 7.2 
Meals and Dietary Restrictions 
Previous text: 
7.2. 
Meals and Dietary Restrictions 
Subjects shall abstain from ingestion of any food or drink containing grapefruit and grapefruit 
juice, Seville oranges (orange marmalade) or pommelos within 7 days prior to the first dose of 
dabrafenib until the end of the study, as these have been shown to inhibit cytochrome (CYP) 
3A4 activity. 
Revised text: 
7.2. 
Meals and Dietary Restrictions 
Subjects no longer need to abstain from ingestion of any food or drink containing grapefruit 
and grapefruit juice, Seville oranges (orange marmalade) or pommelos within 7 days prior to 
the first dose of dabrafenib until the end of the study.  
Dabrafenib should be administered under fasting conditions, either approximately 1 
hour before or approximately 2 hours after a meal. If it is not possible for a subject to 
tolerate the fasting conditions noted above, dabrafenib can be administered with a small 
non-fat meal (e.g., small amount of apple juice/sauce, a piece of dry toast). Subjects and 
their parents should be advised to avoid administering dabrafenib with milk or high-fat, 
high-calorie foods. 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. 
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. 
 
Section 8.2. 
Prohibited Medications and Non-Drug Therapies 
Previous text: 
The following medications or non-drug therapies are also prohibited while on treatment in this 
study: 
• 
Other anti-cancer therapies; 
• 
Other investigational drugs; 
• 
Antiretroviral drugs (Note: Subjects with known HIV are ineligible for study 
participation); 
Revised text: 
The following medications or non-drug therapies are also prohibited while on treatment in this 
study: 
• 
Other anti-cancer therapies; 
• 
Other investigational drugs; 
• 
Antiretroviral drugs; 
 


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Section 9.4. 
Treatment after the End of the Study 
Previous text: 
After study participation in the current study and for subjects still benefitting from treatment 
with dabrafenib, subjects will be given the option to transition to the rollover study 
(BRF114144), where subjects continue receiving GSK2118436 alone as specified in rollover 
study BRF114144, provided subjects are still benefiting from GSK2118436. 
Subjects who are no longer receiving dabrafenib will be offered Follow-Up from GSK 
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. 
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the subject’s medical condition, whether or not GSK is providing specific post-
study treatment. 
Revised text: 
After study participation in the current study and for subjects still benefitting from treatment 
with dabrafenib, subjects will be given the option to transition to the rollover study 
(BRF114144), where subjects continue receiving GSK2118436 alone as specified in rollover 
study BRF114144, provided subjects are still benefiting from GSK2118436. 
Subjects who are no longer receiving dabrafenib will be offered Follow-Up from GSK 
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 2 to 3 months 
according to the instructions in Section 6.3.  
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the subject’s medical condition, whether or not GSK is providing specific post-
study treatment. 
 


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Section 10.5. Treatment of Study Treatment Overdose 
Previous text: 
In the event of a dabrafenib overdose, defined as administration of more than the highest dose 
tested in pediatric clinical studies without reaching a manageable specific toxicity, the 
investigator should contact a GSK Medical Monitor immediately and closely monitor the 
subject for AEs/SAEs and laboratory abnormalities.   
Decisions regarding dose interruptions or modifications should be made by the investigator in 
consultation with a GSK Medical Monitor based on the clinical evaluation of the subject. 
A plasma sample for PK analysis may be requested by a GSK Medical Monitor on a case-by-
case basis.  This plasma sample should be collected as soon as possible. 
Information regarding the quantity of the excess dose as well as the duration of the overdosing 
should be documented in the eCRF. 
Revised text: 
In the event of a dabrafenib overdose, defined as administration of more than the highest dose 
tested in pediatric clinical studies without reaching a manageable specific toxicity, the 
investigator should contact a GSK Medical Monitor immediately and closely monitor the 
subject for AEs/SAEs and laboratory abnormalities. 
Further management should be as clinically indicated or as recommended by the 
national poisons centre, where available.  Haemodialysis is not expected to enhance the 
elimination of dabrafenib as it is highly bound to plasma proteins. 
Decisions regarding dose interruptions or modifications should be made by the investigator in 
consultation with a GSK Medical Monitor based on the clinical evaluation of the subject. 
A plasma sample for PK analysis may be requested by a GSK Medical Monitor on a case-by-
case basis.  This plasma sample should be collected as soon as possible. 
Information regarding the quantity of the excess dose as well as the duration of the overdosing 
should be documented in the eCRF. 
 
Section 11.2. Definition of Serious Adverse Events 
Previous text: 
h. 
Protocol-specific SAEs: SCC, LVEF meeting stopping criteria; treatment emergent 
malignancies [basal cell carcinoma (BCC) is not required to be reported as a protocol-specific 
SAE and it should be reported as an AE or SAE based on the discretion of the investigator.); 
and pyrexia accompanied by hypotension, dehydration requiring IV fluids, renal insufficency 
and/or severe (≥Grade 3) rigors/chills in the absence of an obvious infectious cause. 
Revised text: 
h. 
Protocol-specific SAEs: LVEF meeting stopping criteria; any new primary cancers 
and treatment emergent malignancies (including squamous cell carcinoma and new 
primary melanoma); basal cell carcinoma (BCC) is required to be reported as a protocol-
specific SAE for all non-melanoma indications. 
 
Section 15.2. Appendix 2: Response Criteria 
New table added: 


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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 
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 


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Variable 
Modality 
Score 
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 
 
 
Section 15.6 
New appendix added: 
15.6. Appendix 6 French Country Guidelines for additional dermatological monitoring 
while on therapy and after IP discontinuation 
This Section applies to subject 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 non-cutaneous 
secondary/recurrent malignancy should be reported as a protocol-specific SAE and treated 
according to standard clinical practice. 
 




N o v arti s  
C o nfi d e nti al  
P a g e 1 7 3  
A m e n d e d Pr ot o c ol V er si o n 1 1 ( Cl e a n)  
 
Pr ot o c ol N o. B R F 1 1 6 0 1 3  
 
 
t he me dia n A U C( 0-τ) is bet wee n a p pr o xi matel y 4 0 0 0 n g * h/ m L a n d a p pr o xi matel y 
5 5 0 0 n g * h/ m L, w hic he ver occ urs first. 
Re vise d Te xt:  
T he d ose i n Part 1 will be escal ate d u ntil t he ma xi m u m t olerate d d ose ( M T D) is reac he d 
( base d o n t o xicit y, Secti o n 3. 4) O R  i n t he a bse nce of reac hi n g t he M T D, t h e d ose i n w hic h 
t he me dia n A UC( 0 -τ) is bet wee n a p pr o xi matel y 4 0 0 0 n g * h/ m L a n d a p pr o xi matel y 
5 5 0 0 n g * h/ m L.  T he pr o p orti o n of s u bjects w h o ac hie ve a n A U C( 0- 1 2) ≥ 4 0 0 0 n g * h/ m L als o 
will be c o nsi dere d w h e n selecti n g t he d ose f or Part 2. I n t he a bse nce of meeti n g criteria f or 
M T D, if < 8 0 % of s u bjects i n a n a ge gr o u p ( ≤2 yrs, > 2 a n d ≤1 2 yrs, > 1 2 yrs) fail t o ac hie ve a n 
A U C( 0 -1 2) ≥ a p pr o xi matel y 4 0 0 0 n g * h/ m L O R if fe wer t ha n t w o s u bjects i n a s pecific a ge 
gr o u p ha ve bee n e v al uate d at a gi ve n d ose le v el, t he st u d y s p o ns or a n d st u d y tea m will re vie w 
all a vaila ble saf et y a n d P K data a n d d eter mi ne if f urt her Part 1 e v al uati o n of a s pecifi c a ge 
gr o u p is re q uire d b ef or e t hese s u bjects ma y e nr oll i n Part 2. I nter me diate d oses ma y be 
e x pl ore d. 
S e cti o n 3. 1. 2. P art 2 T u m or -S p e cifi c E x p a n si o n  
Pre vi o us T e xt 
T he st u d y will ai m  t o e nr ol at least 5 c hil dre n i n eac h c o h ort w h o are < 6 years of a g e. 
Re vise d Te xt  
 T he st u d y will e nr ol at least 5 c hil dre n i n eac h c o h ort w h o are < 6 years of a ge. 
 
S e cti o n 3. 7. 1  D a br af e ni b I ntr a -S u bj e ct D o s e E s c al ati o n  
Pre vi o us Te xt 
I n cert ai n circ u msta nces, a s u bject’s d ose le v el ma y be i ncrease d u p t o t he hi g hest d ose le vel 
t hat has pre vi o usl y bee n c o nfir me d b y t he i n vesti gat or a n d G S K Me dical M o nit or as n ot 
e xcee di n g t he M T D.   
I n Part 1, i ntra-s u bject d ose escal ati o ns will n ot be all o we d u ntil Part 2 is o pe n f or e nr ol me nt 
a n d a rec o m me n de d Part 2 d ose has bee n s electe d.  F or a n y s u bject w h o e nr olle d d uri n g Part 1 
a n d re mai ns o n st u d y w h e n Part 2 is o pe ne d, eac h s u bject ma y be c o nsi dere d f or d ose 
escalati o n o n a case b y case basis.I ntra -s u bject d ose escal ati o n will n ot occ ur i n Part 2. 
I ntr a-s u bject d ose escalati o n will n ot occ ur i n Part 2 
Re vise d Te xt  
I n cert ai n circ u msta nces i n Part 1 of t his st u d y, a s u bject’s d ose le vel ma y b e i ncrease d u p t o 
t he hi g hest d ose le vel t hat is o pe n t o e nr oll me nt.  O nl y s u bjects w h o ha ve c o m plete d t heir 
D L T assess me nt peri o d ( 2 8 da ys), w h o ha v e t olerate d treat me nt, b ut ha v e meas ure d A U C ( 0-
1 2) less t ha n tar get le v el, ma y be eli gi ble f or escal ati o n .  Decisi o ns t o i ncrease as u bject’s 
c urre nt d ose will be base d o n all a vaila ble data, i n cl u di n g safet y data a n d P K data f or t h at 
s u bject, a n d m ust be a gr ee d b y t he i n vesti gat or a n d t he G S K me dical m o nit or.  Pre dicte d 
e x p os ure A U C ( 0- 1 2) at t he escal ate d d o se ma y n ot e xcee d 6 0 0 0 g * h/ m L.  D oc u me ntati o n 






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Table 9 PK Sampling Table for Day 1 and Day 15 (Part 1 and Part 2) 
Footnote added: 1Subjects who are approved for intra-subject dose escalation must provide PK 
samples on day 15 at the higher dose level. 
Section 4.4 Withdrawal from Study and Missing Visits 
New section added: 
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 appropriately be 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. 
Section 5.3 Data Analysis Considerations 
Additional wording: Subjects will be summarized based on the treatment level to which they 
were originally assigned. Additionally, selected analyses and summaries will be provided by 
age group as appropriate. 
Section 5.3.1 Analysis Populations 
Previous Text: 
The ‘DLT Evaluable’ population is defined as those subjects 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 drug doses, exclusive of missed doses 
due to treatment-related toxicity.  For those subjects who are either withdrawn or dose reduced 
due to toxicity during the first 28 days will be included in the DLT evaluable population. 
The ‘PK Population’ is defined as those subjects who contribute PK samples. 
Revised Text  
The ‘DLT Evaluable’ population is defined as those subjects 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 drug doses, exclusive of missed doses 
due to treatment-related toxicity.  Any subject in the ‘All Treated’ population who experiences 


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a DLT, as defined in section 3.3, will also be included in the DLT evaluable population 
regardless of exposure. 
The ‘PK Population’ is defined as those subjects fulfilling the All Treated population criteria 
who  who contribute PK samples. 
Section 5.3.3.1 Safety and Tolerability Analyses 
Additional text: Additionally, selected analyses and summaries will be provided by age group 
as appropriate. 
Section 15.1 Appendix 1: Modified Rolling Six Design Dose Escalation 
Procedures 
Previous table 
Number of Subjects 
Enrolled 
Number of Subjects 
with a DLT 
Number of Subjects 
with Data Pending 
Decision 
1 
-- 
-- 
Same dose level 
2 
2 
-- 
De-escalate 
 
Other 
-- 
Same dose level 
3 
≥2 
-- 
De-escalate 
 
0 
0 
Escalate 
 
Other 
-- 
Same dose level 
4 
≥2 
-- 
De-escalate 
 
0 
0 
Escalate 
 
Other 
-- 
Same dose level 
5 
≥2 
-- 
De-escalate 
 
0 
0 
Escalate 
 
Other 
-- 
Same dose level 
6 
≥2 
-- 
De-escalate 
 
≤1 
1 
Suspend1 
 
≤1 
0 
Escalate1 
 
0 
-- 
Escalate 
 
Other 
-- 
Suspend 
1. 
Modified from the Zhao, 2011 publication 
Revised Table 
Dose Escalation Procedure 
Number of Subjects 
Enrolled 
Number of Subjects 
with a DLT 
Number of Subjects 
with Data Pending 
Decision 
1 
-- 
-- 
Same dose level 
2 
2 
-- 
De-escalate 
 
Other 
-- 
Same dose level 
3 
≥2 
-- 
De-escalate 
 
0 
0 
Escalate 
 
Other 
-- 
Same dose level 
4 
≥2 
-- 
De-escalate 


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Number of Subjects 
Enrolled 
Number of Subjects 
with a DLT 
Number of Subjects 
with Data Pending 
Decision 
 
0 
0 
Escalate 
 
Other 
-- 
Same dose level 
5 
≥2 
-- 
De-escalate 
 
0 
0 
Escalate 
 
Other 
-- 
Same dose level 
6 
≥2 
-- 
De-escalate 
  
≤1 
0 
Escalatea 
  
0 
1 
Escalatea 
  
Other 
-- 
Suspend 
b. 
Modified from the Zhao, 2011 publication 
 
 


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Amendment 04 
WHERE THE AMENDMENT APPLIES 
Amendment 04 applies to all sites conducting the study.   
Section 3.1.1.1 Dose Escalation 
Previous text 
SUMMARY OF AMENDMENT CHANGES WITH RATIONALE 
Amendment 04 expanded eligibility to include subjects with refractory disease. An allowance 
for BID dosing on Day 1 was added. Clarifications were made to glioma scan requirements and 
BRAF mutation testing timing. Pyrexia management guidelines and the section on prohibited 
and cautionary medications were updated. 
LIST OF SPECIFIC CHANGES 
Sponsor Information Page (page 4) 
The 
 monitor was changed from 
, MD to 
, MD, 
PhD. 
Section 3.1.1, Part 1 – Dose Escalation 
The following changes were made to the 3rd from last paragraph: 
On Day 1, a single first dose will be administered, followed by the collection of serial blood 
samples for PK analysis will be collected in subjects ≥10 kg in weight after the first dose of 
dabrafenib.  A second dose may be administered on Day 1 if the timing is in compliance 
with Section 3.6.   
Section 3.1.2, Part 2 – Tumor-Specific Expansion 
The following changes were made to the 2nd paragraph: 
On Day 1, a single first dose will be administered, followed by the collection of serial blood 
samples for PK analysis will be collected in subjects ≥10 kg in weight after the first dose of 
dabrafenib.  A second dose may be administered on Day 1 if the timing is in compliance 
with Section 3.6.   
Section 3.7.5.1, Pyrexia 
Updated recommendations for any occurrence and aligned footnotes: 
• Consider clinical evaluation for infection and hypersensitivity if clinically warranted 
• Laboratory (local lab) work-up: CBC with differential, chemistry with creatinine, UA with microscopic 
• Hydration as requiredd 
• Blood sample for cytokine analysise 
 
Section 3.8, Time and Events Schedule 
Added the following clarification to comment on tumor tissue for V600 testing: 


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Local testing for inclusion in the study; can be from archival tissue or if no archival tissue is 
available, from fresh biopsy; the local BRAF test result will be subject to retrospective 
central confirmation. BRAF testing may be completed prior to the 21 day screening 
period. Availability of tissue suitable for central testing must be documented prior to first 
dose. 
Added the following clarification to comment on brain MRI: 
If an MRI of the brain was obtained within 35 days of the first dose, this can be used as screening 
MRI.  CT with contrast allowed only if brain MRI is contraindicated). Glioma patients are not 
required to have CT of chest, abdomen and pelvis unless clinically indicated. 
Added the following clarification to comment on study medication: 
Dispense a 2 to 4 week supply of the study medication with instructions.  Record dose 
reductions, dose interruptions/delays, and/or dose escalations. Two doses may be 
administered the first day if the time between doses is in compliance with protocol section 
3.6. 
Section 4.2.1, Inclusion Criteria 
Added refractory disease to inclusion criterion #3: 
Recurrent disease, refractory disease, or progressive disease after having received at least one 
standard therapy for their disease 
Section 8.1, Permitted Medications and Non-drug Therapies 
Added to end of section: 
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. 
Section 8.2, Prohibited Medications and Non-drug Therapies 
Inserted new data to last bullet: 
GSK2118436 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... 
Inserted anti-retroviral agents Ritonavir, Saquinavir, Atazanavir to Table 12. 
Section 8.3, Medications to be Used with Caution 
Clarifications to second bullet: 
Dabrafenib has been shown to induce CYP3A4 and CYP2C9 in vivo using midazolam 
(CYP3A4 substrate) and S-warfarin (CYP2C9 substrate).  GSK2118436 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... 


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New information to third bullet: 
Therapeutic level dosing of warfarin can be used with approval by the GSK Medical Monitor 
and close monitoring of 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 
New fourth bullet: 
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 pharmacokinetics. 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. 
Updated Table 13: 
CYP3A4, CYP2B6, CYP2C8, CYP2C9, CYP2C19 or Transporter Substrates that May be 
Affected by Induction 
Rosuvastatin, pravastatin added to HMG-CoA reductase inhibitors 
Digoxin to miscellaneous inhibitors 
New section of table on pH altering agents: dexlansoprazole. esomeprazole, famotidine, 
ilaprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole, ranitidine 


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Amendment 03 
WHERE THE AMENDMENT APPLIES 
Amendment 03 applies to all sites conducting the study.   
SUMMARY OF AMENDMENT CHANGES WITH RATIONALE 
To take into account potential renal effects, Amendment 03 changed the lower age limit of 
inclusion criterion #2 from subjects 1 month old to ≥12 months old, adjusted criteria for 
adequate renal function in inclusion criterion #7, added guidelines for renal insufficiency and 
additional laboratory testing.  Information on the new suspension formulation was incorporated. 
The section on dose modification was re-organized for consistency. The Time and Events Table 
was adjusted to include assessments on Day 21, Week 4 was clarified to be Day 29, and 
increased chemistry and urinalysis evaluations were added. The timing and volume of PK 
samples for subjects <25 kg and ≥10 kg was corrected. 
LIST OF SPECIFIC CHANGES 
Sponsor Information Page (page 4): 
The 
 medical monitor was changed from 
, MD to
, MD. 
The IND No. was changed from 105, 032 to 117,898. 
Section 1.2.2, Dose Rationale 
Units corrected from µg*h/mL to ng*h/mL. 
Section 1.3, Summary of Risk Management 
Added the following paragraph to the section on acute renal failure: 
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. 
Section 3.1.1, Part 1 – Dose Escalation 
Revised text: 
Beyond the sixth subject in an ongoing cohort, additional subjects wanting to be enrolled before 
the next cohort is open for enrollment, can be enrolled at the previous lower dose level (this is 


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to ensure that any subject eligible for enrolment is given a place in the study but is not de
escalation). 
Section 3.1.1.1, Dose Escalation 
Units corrected from µg*h/mL to ng*h/mL. 
Section 3.1.1.2, Selection of Final Dose(s) for Part 2 
Previous text: 
After the selection of the dose to be administered in Part 2, consideration may be given based 
on the age of subjects (subjects younger than 2 years of age, subjects ≥2 years, subject older 
than 6 years of age, and subjects ≥6 years of age) enrolled in Part 1.  That is, if the dose level 
for Part 2 is identified based on data from fewer than 2 subjects in an age group, Part 1 can 
remain open in an attempt to enrol subjects in a different age group to confirm the previously 
selected Part 2 dose (i.e., Part 1 and Part 2 may enrol concurrently if a sufficient number of 
subjects in a given age group have not been evaluated in Part 1).  This will allow for selection 
of a different Part 2 dose for subjects in that particular age group, if necessary. 
Revised text: 
Data from all enrolled subjects will be considered at the time of Part 2 dose selection. 
However, if there are insufficient data in a specific age category at the time of Part 2 dose 
selection, additional patients in that age category may continue to be enrolled into Part 1. 
Age categories are ≥1 year but ≤5 years of age and ≥6 years but <18 years of age. 
Tolerability and PK data should be available from at least two subjects at the Part 2 dose 
in each age category before Part 1 of the protocol is considered fully enrolled for that age 
category.  Once sufficient data are available for subjects from a given age category, all 
subsequent subjects in that age group should be enrolled into Part 2 of the protocol.  With 
this approach, it is possible that the Part 2 dose will not be identical across age groups. 
Section 3.1.2, Part 2: Tumor-Specific Expansion 
Previous text: 
Treatment with dabrafenib will be continued until disease progression or until subjects are no 
longer obtaining clinical benefit from continued treatment, until they develop an unacceptable 
toxicity, or until they withdraw consent or begins a new therapy.   
Revised text: 
Treatment with dabrafenib will be continued until disease progression, until the subject is no 
longer obtaining clinical benefit from continued treatment, they develop an unacceptable 
toxicity, the study is terminated, or the subject withdraws consent or begins a new therapy. 
Section 3.2, Discussion of Study Design 
Previous text: 
In France, children younger than 6 years and children older than 6 years with a risk of choking 
when swallowing capsules cannot be included in the study, pending availability of an oral 
suspension formulation. The suspension will only be available at those sites that are capable of 
and meet the applicable regulatory requirements to prepare the suspension. 


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Revised text: 
In France, children younger than 6 years and children 6 years and older with a risk of 
choking when swallowing capsules are required to use the oral suspension formulation. 
Section 3.3, Dose Limiting Toxicity Definitions 
Deleted the following sentence: 
Isolated clinical laboratory value(s) considered NOT CLINICALLY SIGNIFICANT by 
the investigators are not AEs (and therefore, would not be DLTs). 
Section 3.4, Maximum Tolereated Dose (MTD) 
Deleted the following paragraph: 
If the identified MTD is identified due to a specific toxicity that can be managed with 
supportive care, an additional cohort of subjects may be enrolled at the dose level that 
exceeded MTD with institution of supportive care measures, and if tolerable, dose escalation 
may resume.  A summary of the available safety data and a description of the plans for 
supportive measures with further enrolment at that dose level will be provided to Institutional 
Review Boards (IRBs)/Institutional Ethics Committee (IEC) prior to dosing, if required. 
Section 3.6, Investigational Product and Other Study Treatment Dosage/Administration  
Previous text: 
In France, children younger than 6 years and children older than 6 years with a risk of 
choking when swallowing capsules cannot be included in the study, pending availability 
of an oral suspension formulation. 
Revised text: 
In France, children younger than 6 years and children 6 years and older with a risk of 
choking when swallowing capsules will be required to use the suspension formulation. 
Previous text: 
Suspension: Bottles of bulk GSK2118436B drug substance with bottles of individual 
excipients (4 components) will be supplied by GSK for on-site extemporaneous compounding 
of a suspension formulation (for subjects unable to swallow capsules). Only sites meeting 
local, applicable regulations regarding extemporaneous compounding will be permitted to 
enroll subjects requiring suspension administration.  Detailed preparation instructions are 
supplied in the SPM. The suspension will be administered with an oral dosing syringe 
supplied by GSK (oral syringes, 1 mL, 5 mL, and 20 mL for single use. 
Revised text: 
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. 


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Previous text: 
TABLE 15 
INVESTIGATIONAL PRODUCT 
 
Dabrafenib capsules 
Dabrafenib powder for oral 
suspension 
Formulation description: 
HPMC 
Powder for reconstitution, for 
multi-dose use 
Dosage form: 
Capsule 
Powder for oral suspension 
Unit dose strengths: 
10 mg, 25 mg, 50 mg and 75 mg 
10 mg/mL (as oral 
suspension) 
Route/ Frequency: 
Oral / BID  
Oral / BID 
Physical description: 
10 mg: opaque capsules composed of a white 
body and cap 
25 mg: opaque capsules composed of a pink 
body and cap 
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 
white to slightly colored solid. 
Oral suspension is 
extemporaneously prepared 
by reconstituting the drug 
substance with an aqueous 
vehicle. 
Manufacturer/ 
source of procurement: 
GSK 
GSK 
Method for individualizing 
dosage: 
Unit dose capsules 
Administered using oral 
syringes 
 
Dabrafenib capsules will be taken with approximately 3-5 mL/kg of water, twice a 
day.  Subjects should be encouraged to take their doses at approximate 12 hour intervals and at 
similar times every day 
Revised text: 




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If the AE does not resolve to at least Grade 1 in ≤7 days, withdrawal from the study is 
recommended.  However, if the investigator and a GSK Medical Monitor agree that the 
subject has benefited from treatment and further treatment will continue to benefit the subject 
in a manner that outweighs the risk posed by the AE, then treatment can continue with at least 
a 25% dose reduction for next cycle of treatment.  If well tolerated at the reduced dose and 
both the investigator and a GSK medical monitor agree with favorable benefit risk for this 
subject, the previous dose level can be resumed in subsequent cycles. Any dose modification 
or interruption will be recorded. 
Section 3.7.4. Dose Modification for General Toxicities  
Previous text: 
• 
Renal insufficiency – close monitoring of serum creatinine, treatment of associated 
pyrexia (see Table 7  Management and dose modification guidelines for pyrexia), 
and treatment interruption for increased serum creatinine >2 mg/dl (or >0.5 mg/dl 
above baseline).  Nephrology consultation should also be obtained if no obvious 
cause for persistent creatinine elevation (e.g. volume depletion).   
Revised text: 
• 
Renal insufficiency – Please refer to Table 6.  
TABLE 18 
GUIDELINES FOR RENAL INSUFFICIENCY 
For subjects with creatinine increase of ≥50% from baseline or eGFR (a) decrease of >25% from 
baseline: 
1st occurrence 
• 
Interrupt dabrafenib 
• 
If subject has fever: treat pyrexia as per Table 7 (please note NSAIDs 
can induce renal insufficiency, especially in subjects with dehydration); 
consider IV hydration 
• 
Pediatric nephrology consult is recommended 
• 
Re-check within 24 hours 
• 
If <50% increase in creatinine or ≤25% decrease in eGFR from 
baseline then may restart dabrafenib 
• 
If ≥50% increase in creatinine from baseline or eGFR decrease 
of >25% from baseline 
- Recommend monitor creatinine at least twice weekly 
- May restart dabrafenib if creatinine/eGFR returns to baseline 
with approval of medical monitor. 
- If creatinine<50% increase from baseline or eGFR returns to 
≤25% decrease from baseline may restart dabrafenib at a 
reduced dose with approval of the medical monitor 
2nd occurrence 
• 
Follow above recommendations.   
• 
If restart of dabrafenib is approved by medical monitor 


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For subjects with creatinine increase of ≥50% from baseline or eGFR (a) decrease of >25% from 
baseline: 
o Upon restart reduce dabrafenib by one dose level  
3rd occurrence 
 
Permanently discontinue dabrafenib 
For subjects with creatinine increase of ≥100% from baseline or eGFR (a) decrease of >50% from 
baseline 
 
• 
Interrupt dabrafenib 
• 
If subject has fever: treat pyrexia as per Table 7 (please note NSAIDs 
can induce renal insufficiency, especially in subjects with dehydration); 
consider IV hydration 
• 
Pediatric nephrology consultation recommended 
• 
Re-check within 24 hours 
• 
If creatinine increase of ≥100% or eGFR decrease of >50% is 
confirmed, permanently discontinue dabrafenib 
• 
If creatinine increase ≥50% or eGFR decrease >25% from baseline and 
≤50% from baseline, continue to hold dabrafenib and follow guidelines 
above 
• 
If creatinine increase <50% or eGFR is ≤25% decrease from baseline 
may restart dabrafenib 
(a). eGFR calculated according to Schwartz formula (http://www.medcalc.com/pedigfr.html) 
 
Section 3.7.4. Dose Modification for General Toxicities  
Revised text added after Table 5 
If the AE does not resolve to at least Grade 1 in ≤7 days, withdrawal from the study is 
recommended.  However, if the investigator and a GSK Medical Monitor agree that the 
subject has benefited from treatment and further treatment will continue to benefit the 
subject in a manner that outweighs the risk posed by the AE, then treatment can 
continue with at least a 25% dose reduction for next cycle of treatment.  If well tolerated 
at the reduced dose and both the investigator and a GSK medical monitor agree with 
favorable benefit risk for this subject, the previous dose level can be resumed in 
subsequent cycles. Any dose modification or interruption will be recorded. 
 












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Section 4.2.1, Inclusion Criteria,  
Previous text: 
2. Male or female between one month and <18 years of age (inclusive) at the time of signing 
the informed consent form; 
Revised text: 
2. Male or female ≥12 months and <18 years of age at the time of signing the informed 
consent form 
Section 4.2.1, Inclusion Criteria,  
Previous text: 
7. Adequate renal and metabolic function defined as: 
• 
Calculated creatinine clearance (Cockcroft-Gault), calculated GFR (revised Schwartz 
formula), or radioisotope GFR ≥ 60 mL/min/1.73 m2; or 
Revised text: 
7. Adequate renal and metabolic function defined as: 
• 
Calculated eGFR (Schwartz formula, http://www.medcalc.com/pedigfr.html), or 
radioisotope GFR ≥90 mL/min/1.73 m2; or 
Section 4.2.2, Exclusion Criteria,  
Revised text: 
5. 
History of another malignancy; 
Exception:  (a) Subjects who have been successfully treated and are disease-free for 3 years, 
(b) a history of completely resected non-melanoma skin cancer, (c) successfully treated in situ 
carcinoma, or (d) CLL in stable remission, or (e) indolent prostate cancer (definition: clinical 
stage T1 or T2a, Gleason score ≤6, and PSA < 10 ng/mL) requiring no or only anti hormonal 
therapy with histologically confirmed tumour lesions that can be clearly differentiated from 
lung cancer target and non target lesions are eligible 
Section 9.1, Subject Completion,  
Revised text: 
A final study visit within 28 days after last dose of study drug should be completed. 
Section 9.3.2, Subject Withdrawal from Study Treatment,  
Revised text: 
All subjects who discontinue from study treatment will have a Final Visit (as defined in 
Table 10) which should be completed at the time of discontinuation (within 28 days after 
last dose of study drug). Subjects will be offered post study treatment follow-up as specified 
in Section 9.4 
Section 10.3, Preparation/Handling/Storage/Accountability,  
Previous text: 
A description of the methods and materials required for preparation of the suspension 
formulation of dabrafenib are provided in the SPM. 
Revised text: 
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. 


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Text deleted: 
Dabrafenib suspension is to be stored at 2 8°C, protected from light.  Maintenance of a 
temperature log (manual or automated) is required (after preparation). 
Section 10.4, Assessment of Compliance,  
Text deleted: 
Study site personnel will examine each subject’s mouth to ensure that the study treatment was 
ingested 
Section 11.4, Recording fo AEs and SAEs,  
Text deleted: 
Subject completed health outcomes questionnaires and the collection of AE data are 
independent components of the study.  Responses to each question in the health outcomes 
questionnaire will be treated in accordance with standard scoring and statistical procedures 
detailed by the scale’s developer.  The use of a single question from a multidimensional health 
survey to designate a cause effect relationship to an AE is inappropriate. 
Appendix 2, Response Criteria 
LCH Scoring System [Donadieu, 2004] table deleted. 


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Amendment 02 
Amendment 02 was a country specific amendment for France.  Please see Appendix 5.  


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Amendment 01 
WHERE THE AMENDMENT APPLIES 
Amendment 01 applies to all sites conducting the study.   
SUMMARY OF AMENDMENT CHANGES WITH RATIONALE 
Amendment No. 01 corrected Inclusion Criteria #6 to ensure consistency with the contraception 
requirements as outlined in Section 7.1.1.  In addition, the dose escalation procedure table 
provided in Appendix 1 was changed to ensure that escalation of dose when 6 subjects are 
enrolled occurs only if there are ≤1 subject with a DLT and no subject data pending, and to fix 
the reference and formatting.   
LIST OF SPECIFIC CHANGES 
Section 4.2.1, Inclusion Criteria (#6) 
Rationale for change:  The requirement for male contraception was deleted since the risk of 
embryofetal developmental toxicity as a consequence of exposure to female pregnant partners 
is very low.  
Previous Text 
6. Females of child-bearing potential and males with reproductive potential must be willing to 
practice acceptable methods of birth control (see Section 7.1).  Additionally, females of 
childbearing potential must have a negative serum pregnancy test within 7 days prior to the 
first dose of study medication; 
Revised Text 
6. Females of child-bearing potential and males with reproductive potential must be willing to 
practice acceptable methods of birth control (see Section 7.1).  Additionally, females of 
childbearing potential must have a negative serum pregnancy test within 7 days prior to the 
first dose of study medication; 
Appendix 1 
Rationale for change:  Changed to ensure that escalation of dose when 6 subjects are enrolled 
occurs only if there are ≤1 subject with a DLT and no subject data pending. 
Previous Text 
Appendix 1: Rolling Six Design Dose Escalation Procedures 
DOSE ESCALATION PROCEDURE [SKOLNIK, 2008] 


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Number of Subjects 
Enrolled 
Number of Subjects with 
a DLT 
Number of Subjects 
with Data Pending 
Decision 
1 
-- 
-- 
Same dose level 
2 
2 
-- 
De-escalate1 
 
Other 
-- 
Same dose level 
3 
≥2 
-- 
De-escalate1 
 
0 
0 
Escalate 
 
Other 
-- 
Same dose level 
4 
≥2 
-- 
De-escalate1 
 
0 
0 
Escalate 
 
Other 
-- 
Same dose level 
5 
≥2 
-- 
De-escalate1 
 
0 
0 
Escalate 
 
Other 
-- 
Same dose level 
6 
≥2 
-- 
De-escalate1 
 
≤1 
1 
Escalate 
 
0 
-- 
Escalate 
 
Other 
-- 
Suspend 
 
Revised Text 
Appendix 1: Modified Rolling Six Design Dose Escalation Procedures 
DOSE ESCALATION PROCEDURE [SKOLNIK, 2008]  
Number of Subjects 
Enrolled 
Number of Subjects with 
a DLT 
Number of Subjects 
with Data Pending 
Decision 
1 
-- 
-- 
Same dose level 
2 
2 
-- 
De-escalate1 
 
Other 
-- 
Same dose level 
3 
≥2 
-- 
De-escalate1 
 
0 
0 
Escalate 
 
Other 
-- 
Same dose level 
4 
≥2 
-- 
De-escalate1 
 
0 
0 
Escalate 
 
Other 
-- 
Same dose level 
5 
≥2 
-- 
De-escalate1 
 
0 
0 
Escalate 
 
Other 
-- 
Same dose level 
6 
≥2 
-- 
De-escalate1 
 
≤1 
1 
Escalate Suspend1 
 
≤1 
0 
Escalate1 
 
0 
-- 
Escalate 
 
Other 
-- 
Suspend 
1.  Modified from the Zhao, 2011 publication 
 

SAP_001.pdf: 


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Document History – Changes compared to previous final version of SAP 
 
Date 
Time 
point 
Reason for 
update 
Outcome for update 
Section and title 
impacted 
(Current) 
21-
Sep-
2017 
Prior 
to 
DB 
lock 
Creation of 
first 
version 
N/A – First version 
NA 
09-
Mar-
2020 
Prior 
to 
DB 
lock 
As per 
client 
comment 
[2] Added the references 
Section 2.11 
updated 




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Table of contents 
Table of contents ................................................................................................................. 4 
List of abbreviations ............................................................................................................ 6 
1 
Introduction ......................................................................................................................... 7 
1.1 
Study design............................................................................................................. 7 
1.2 
Study objectives and endpoints ............................................................................... 7 
2 
Statistical methods ............................................................................................................... 7 
2.1 
Data analysis general information ........................................................................... 7 
2.1.1 
General definitions .................................................................................. 8 
2.2 
Analysis sets ............................................................................................................ 8 
2.2.1 
All Treated Population ............................................................................ 8 
2.2.2 
Safety  Population ................................................................................... 8 
2.2.3 
Dose Limiting Toxicity Evaluable Population ........................................ 8 
2.2.4 
Pharmacokinetic Population.................................................................... 8 
2.2.5 
Response-evaluable Population .............................................................. 9 
2.2.6 
Subgroup of interest ................................................................................ 9 
2.3 
Patient disposition, demographics and other baseline characteristics ..................... 9 
2.3.1 
Patient disposition ................................................................................... 9 
2.3.2 
Protocol deviation ................................................................................... 9 
2.4 
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance) ............................................................................................................ 10 
2.5 
Analysis of the primary objective .......................................................................... 10 
2.5.1 
Primary endpoint ................................................................................... 10 
2.5.2 
Statistical hypothesis, model, and method of analysis .......................... 10 
2.5.3 
Handling of missing values/censoring/discontinuations ....................... 10 
2.6 
Analysis of the key secondary objective ............................................................... 10 
2.6.1 
Secondary endpoint ............................................................................... 10 
2.6.2 
Handling of missing values/censoring/discontinuations ....................... 11 
 
 11 
 
 11 
2.8 
Safety analyses ....................................................................................................... 11 
2.8.1 
Adverse events (AEs) ............................................................................ 11 
2.8.2 
Seriouse Adverse events ....................................................................... 12 
2.8.3 
Deaths .................................................................................................... 12 
2.8.4 
Laboratory data ..................................................................................... 12 
2.8.5 
Other safety data ................................................................................... 12 
2.9 
Pharmacokinetic endpoints .................................................................................... 12 


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 12 
 
 12 
 
 12 
 
 13 
 
 14 
 
 16 
2.12 
Interim analysis ...................................................................................................... 16 
3 
Sample size calculation ..................................................................................................... 16 
4 
Change to protocol specified analyses .............................................................................. 16 
5 
Appendix ........................................................................................................................... 16 
5.1 
Laboratory parameters derivations ........................................................................ 16 
 
 16 
6 
Reference ........................................................................................................................... 18 


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List of abbreviations 
AE 
Adverse Event 
ATC 
Anatomical Therapeutic Chemical 
COVID-19 
Coronavirus Disease-2019 
CRF 
Case Report Form 
DLT 
Dose Limiting Toxicity 
DRL 
Drug Reference Listing 
ECG 
Electrocardiogram 
HGG 
High grade gliomas 
HR 
Heart Rate 
LCH 
Langerhans cell histiocytosis 
LGG 
Low-grade gliomas 
LLOQ 
Lower limit of quantification 
MedDRA 
Medical Dictionary for Regulatory Activities 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
QTcB 
QT duration corrected for heart rate by Bazett’s formula 
RANO 
Response Assessment in Neuro-oncology 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class 
WHO 
World Health Organization 
 
 


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1 
Introduction 
This statistical analysis plan (SAP) details the planned analysis for the final CSR of the study. 
This is a 2-part, phase I/IIa study to evaluate the safety, tolerability and pharmacokinetics of 
oral dabrafenib in pediatric patients with advanced BRAF V600-mutation positive solid tumors.   
The contents are based on the previous SAP Interim I, the GSK CSR SAP and the study protocol 
11.0 and this SAP will only describe the changes/additions from the previous analyses 
conducted/planned. All outputs detailed in the previous SAP are required for this final analysis. 
The TFL shell document will list all of the outputs in the previous SAP for this final analysis as 
well as providing shells for the new or modified outputs. 
For a more detailed statistical analysis plan for the study please refer to the first version of the 
SAP – CDRB436A2102_SAP_CSR_1_final (GSK template)_amendment 01.docx stored in 
CREDI under the location DRB436A2102/Administrative files (study level)/RAP and RAMP 
Meeting. Hereafter this document will be referred as GSK SAP. 
The previous interim analysis SAP is also stored in the above mentioned location. 
1.1 
Study design 
For information on the study design, see the GSK SAP. 
1.2 
Study objectives and endpoints 
For information on the study objectives and endpoints, see the GSK SAP. 
2 
Statistical methods 
For information on the statistical hypotheses, see the GSK SAP. 
2.1 
Data analysis general information 
Prior anti-cancer therapy and anti-neoplastic therapy’s medications will be coded using World 
Health Organization (WHO) Drug Reference Listing (DRL) dictionary; anti-neoplastic surgery 
will be coded using Medical Dictionary for Regulatory Affairs (MedDRA). Concomitant 
medications will be coded using the WHO 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. 
Refer to the study GSK SAP for more information. 
For final CSR analysis, in addition to the analysis performed by study parts, to understand 
disease specific reporting, pooled analysis will also be performed by combining all the patient 
data from part 1 and part 2 of the study based on disease specific cohorts. This pooled analysis 
will be carried out for four disease cohorts; i.e. LGG BRAF V600 Mutant, HGG BRAF V600 
Mutant, LCH BRAF V600 Mutant and other tumor. 
The disease specific cohorts from Part 1 will be identified based on their tumor type data 
collected in the Regimen form of eCRF. 


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For example, if tumor type is High Grade Glioma then disease cohort will be “HGG, BRAF 
V600 Mutant” and if tumor type is Low Grade Glioma then disease cohort will be “LGG, BRAF 
V600 Mutant”. Similary, if tumor type is Langerhans Cell Histiocytosis (LCH) then disease 
cohort will be “LCH, BRAF V600 Mutant” and if tumor type is Other/Solid tumor then disease 
cohort will be “Other”. 
For part 2 expansion,  the disease cohort will be similar to the enrollment cohort. 
2.1.1 
General definitions  
For more information, see the GSK SAP. 
2.2 
Analysis sets 
2.2.1 
All Treated Population 
The All Treated population is defined as all  patients who receive at least one dose of study 
treatment. An incorrect treatment schedule or drug administration or an early termination of 
treatment will not result in exclusion of patients from this population. 
2.2.2 
Safety  Population 
The Safety population consists of all patients who received at least one dose of study 
treatment. All safety data will be analysed using the Safety population. 
In this study, the All Treated population and Safety population are identical. 
2.2.3 
Dose Limiting Toxicity Evaluable Population 
The Dose Limiting Toxicity (DLT) Evaluable population is defined as those Part 1 patients 
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 
drug doses, exclusive of missed doses due to treatment-related toxicity. Patients who are 
either withdrawn or dose reduced due to toxicity during the first 28 days will be included in 
the DLT evaluable population. Any patient from Part 1 in the ‘All Treated’ population who 
experiences a DLT, as defined in section 3.3 of the protocol, will also be included in the DLT 
evaluable population regardless of exposure. 
2.2.4 
Pharmacokinetic Population 
The Pharmacokinetic (PK) population is defined as those patients fulfilling the All Treated 
population criteria and for whom pharmacokinetic sample(s) are obtained and analysed. This 
population will be used for the primary, secondary PK endpoints,
 
analyses. 
Patients may be removed from the estimation of certain PK parameters on an individual basis 
depending on the number of available blood samples. Specific time points might be removed 
from the analysis set if technical issues with the sample are reported (e.g. sampling issues, 
missing information) or if LLOQ sample is observed in between measurable concentrations. 
These patients and concentration data points will be identified at the time of analysis. 


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2.2.5 
Response-evaluable Population 
The Response-evaluable population is defined as those patients fulfilling the All Treated 
population criteria with a pre-dose and at least 1 post–dose disease efficacy assessment. 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. 
 
2.2.6 
Subgroup of interest 
There are no formal plans for examining subgroups. 
2.3 
Patient disposition, demographics and other baseline 
characteristics 
Age (years, months or days) will be collected in CRF based on the derivation in the table 
below.   There will be 2 age variables calculated in ADS, age in years, and derived age: age in 
years, months and days. 
AGE in years =round ( (AGEY*365.25+AGEM*30.4375+AGED)/365.25, 0.1  ) 
where AGEY for age in years; AGEM for age in months; AGED for age in days. 
 
If Age in years > 0, then AAGE = floor(Age in years); 
Else if Age in months > 0, then AAGE = floor(Age in months); 
Else if Age in days > 0, then AAGE = floor(Age in days). 
 
Listing will include the birth year and age as collected. 
For details, refer to section 10.3 of GSK SAP. 
In addition to the analysis mentioned in section 10.3 of GSK SAP , the similar summary of 
subject demographics, baseline characterstics, disease history, prior anti-cancer treatments and 
change from baseline in Karnofsky and Lansky performance status will be carried out by pooled 
disease cohort (as defined in section 2.1). 
2.3.1 
Patient disposition 
For details, refer to study GSK SAP. 
Additionally, the similar anlysis will be carried out for subject disposition by pooled disease 
cohort (as defined in section 2.1). 
2.3.2 
Protocol deviation 
The number and percentage 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).  


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Similarly, a separate table and listing will be provided for protocol deviations related to 
COVID-19. 
2.4 
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance) 
Refer to GSK SAP for more information. 
For pooled disease cohort,  similar summary of treatment exposure will be carried out for overall 
duration of exposure and also for dose reductions/interruptions. 
Dose intensity and relative dose intensity will be summarized by age categories (<12 years 
and >=12 years 
2.5 
Analysis of the primary objective 
2.5.1 
Primary endpoint 
Refer to study GSK SAP. 
2.5.2 
Statistical hypothesis, model, and method of analysis 
There are no formal tests of hypotheses planned for this trial. With respect to the primary 
objectives and endpoints, the primary focus will be on determining the maximum tolerated dose 
(or recommended dose based on available safety, PK, and response data), the safety profile, and 
PK/PD relationship of dabrafenib in pediatric patients with advanced BRAF V600-mutation 
positive solid tumors. Most analyses will be descriptive or exploratory. 
2.5.3 
Handling of missing values/censoring/discontinuations 
Refer to study GSK SAP. 
Supportive analyses Refer to study GSK SAP. 
2.6 
Analysis of the key secondary objective 
2.6.1 
Secondary endpoint 
The All Treated population will be used for all efficacy analyses. 
Overall response rates along with 95% confidence intervals will be separately calculated for 
all the disease cohorts including the LGG, HGG, LCH and Other disease cohorts.  
Efficacy assessments are based on RANO criteria for LGG and HGG patients. In addtion, for 
LGG patients, the updated RANO criteria will be used for independent review. For LCH 
patients, the response assessment criteria are described in Appendix 2 of the protocol. For 
patients with other solid tumor, efficacy assessments are based on RECIST 1.1. 
Refer to study GSK SAP for additional details. 


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2.6.2 
Handling of missing values/censoring/discontinuations 
Refer to study GSK SAP. 
2.8 
Safety analyses 
The Safety population will be used for all safety analyses. 
Refer to study GSK SAP for additional details. 
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 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 as a footnote in the applicable tables/listings. 
For more details, refer to study GSK SAP.  
Similar summary of overview of AEs for pooled disease cohorts will be generated. Moreover, 
summary of AEs regardless of relationship by preferred term and maximum grade and summary 
of AEs suspected to be related to study drug by preferred term will also be carried out by pooled 
disease cohort.  
In addition, For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables 
on on-treatment adverse events which are not serious adverse events with an incidence greater 
than 5% and on on-treatment serious adverse events and SAE 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. 


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2.8.2 
Seriouse Adverse events  
For SAEs, in a similar way as of AEs, summary by preferred term regardless of relationship to 
study drug and also summary for suspected study drug related SAEs by preferred term will be 
carried out by pooled disease cohorts.  
Refer to study GSK SAP for additional details.  
2.8.3 
Deaths 
Refer to study GSK SAP for additional details.  
2.8.4 
Laboratory data 
Refer to study GSK SAP for additional details. 
Summary of shift from baseline, based on CTC grade will be carried out for Hematology and 
Biochemistry laboratory parameters by pooled disease cohorts instead of treatment. 
2.8.5 
Other safety data 
Refer to study GSK SAP for additional details. 
2.8.5.1 
ECG and cardiac imaging data 
The corrected QT duration for heart rate (QTcB) will be manually calculated using Bazett’s 
formula if the data is not available.  See Appendix 5.1.  
2.8.5.2 
Vital signs 
Refer to study GSK SAP. 
2.9 
Pharmacokinetic endpoints   
Refer to study GSK SAP.  


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2.12 
Interim analysis 
A number of previous interim analyses have been performed for Health Authority interactions, 
or when a specified minimum follow up was reached in certain cohorts. These interim analyses 
are documented in separate CSRs. 
No efficacy or futility conclusions were made based on these interim analyses. 
3 
Sample size calculation 
Refer to study GSK SAP; Section 5. 
4 
Change to protocol specified analyses 
No change from protocol specified analysis except 
 
 reporting of protocol deviations related to COVID-19.  
5 
Appendix 
5.1 
Laboratory parameters derivations 
Bazett's formula is as follows: 
 
where QTcB is the QT interval corrected for heart rate, QT is the measured QT interval and RR 
is the interval from the onset of one QRS complex to the onset of the next QRS complex (all 
measurements in seconds). RR is often derived from the heart rate (HR) as 60/HR. QT interval 
is collected in milliseconds on the CRF and will be displayed in milliseconds in the outputs.  


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6 
Reference 
Refer to the study GSK SAP.