Clinical trial NCT02034110
Conditions: Cancer
Keywords: solid tumors anaplastic thyroid cancer (ATC) biliary tract cancer (BTC) gastrointestinal stromal tumor (GIST) low grade (WHO G1/G2) glioma (LGG) high grade (WHO G3/G4) glioma (HGG) non-seminomatous germ cell tumors (NSGCT)/non-germinomatous germ cell tumors (NGGCT) adenocarcinoma of the small intestine (ASI) hairy cell leukemia (HCL) multiple myeloma (MM) efficacy safety BRAF V600E mutation Trametinib Dabrafenib
Sponsor: Novartis Pharmaceuticals
Start date: 2014-03-12; Completion date: 2021-12-10
Enrollment: 206 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This was a Phase II, open-label, non-randomized, multi-center study of oral dabrafenib in combination with oral trametinib in subjects with rare cancers harboring the BRAF V600E mutation including anaplastic thyroid cancer (ATC), biliary tract cancer (BTC), gastrointestinal stromal tumor (GIST), low grade (WHO G1/G2) glioma (LGG), high grade (WHO G3/G4) glioma (HGG), non-seminomatous germ cell tumors (NSGCT) / non-germinomatous germ cell tumors (NGGCT), adenocarcinoma of the small intestine (ASI), hairy cell leukemia (HCL) and multiple myeloma (MM).

Detailed description:
This study was designed to determine the overall response rate (ORR) of oral Dabrafenib in combination with oral Trametinib in subjects with rare BRAF V600E mutated cancers. Subjects needed to have a fresh or frozen tumor tissue sample provided to confirm the BRAF V600E mutation status. Only subjects with histologically confirmed advanced disease and no available standard treatment options were eligible for enrollment. Subjects underwent screening assessments within 14 days (up to 35 days for ophthalmology exam, echocardiogram or disease assessments) prior to the start of treatment to determine their eligibility for enrollment in the study. All subjects enrolled received oral dabrafenib 150 mg bid in combination with oral trametinib 2 mg once daily. Subjects continued treatment until an unacceptable toxicity, disease progression, withdrawal of consent or death. Once a subject discontinued treatment, a post-treatment follow-up visit was conducted within 28 days (+ 7 days) after the last dose of study treatment(s). Extended follow-up visits were conducted every 4 weeks (+/- 7 days) for the first 6 months and then every 3 months (+/- 14 days) thereafter. A subject was considered to have discontinued the study if the subject was lost to follow-up or withdrew consent or another reason existed that prevented additional data from being collected on the subject. A subject was considered to have completed the study at the time of death.

For each histology, up to 25 patients were planned to be enrolled in each of the 9 primary analysis cohorts. A cohort could be closed or stopped early (prior to capping at 25 patients) for futility or efficacy. An uncapped expansion cohort was planned when a particular cohort was stopped early for efficacy. All planned histology cohorts enrolled at least one subject, with the exception of the germ cell tumor cohort. Enrolment in the study was closed in July 2018.

Arms: arm 1: Subjects received Dabrafenib 150 mg twice daily orally plus Trametinib 2 mg once daily orally on a continuous basis. Dabrafenib was administered under fasted conditions, either 1 hour (hr) before or 2 hours (hrs) after a meal with approximately 200 mL of water with an interval of 12 hours. Trametinib was administered under fasted conditions, either 1 hr before or 2 hrs after a meal with approximately 200 mL of water. Subjects took their dose of Trametinib concurrently with the morning dose of Dabrafenib. A treatment cycle was 28 days in duration. Subjects continued treatment until an unacceptable toxicity, disease progression, or death occurs.
Interventions: intervention 1: Dabrafenib intervention 2: Trametinib
Intervention descriptions: intervention 1: A 150 mg twice daily capsule administered orally on a continuous basis. intervention 2: A 2 mg once daily tablet administered orally on a continuous basis.

Protocol documents:
Prot_000.pdf: 


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Table of contents
Table of contents.......................................................................................................2
AMENDMENT 11 (04-Jun-2020)............................................................................7
LIST OF ABBREVIATIONS.................................................................................35
1
INTRODUCTION ..................................................................................................40
1.1
Background.................................................................................................40
1.2
Dabrafenib(GSK2118436)..........................................................................40
1.3
Trametinib(GSK1120212)..........................................................................41
1.4
Risk Assessment for Dabrafenib + Trametinib Combination Therapy .......41
1.4.1
Benefit Assessment ....................................................................45
1.4.2
Overall Benefit: Risk Conclusion...............................................46
1.5
Histology-SpecificBackground...................................................................46
1.5.1
Cohort 1: Anaplastic Thyroid Cancer (ATC).............................46
1.5.2
Cohort 2: Biliary Tract Cancer (BTC)........................................47
1.5.3
Cohort 3: Gastrointestinal Stromal Tumors (GIST)...................48
1.5.4
Cohort 4: WHO Grade 1 and 2 Glioma......................................49
1.5.5
Cohort 5: WHO Grade 3 and 4 Glioma......................................50
1.5.6
Cohort 6: Non-Seminomatous/Non-Germinomatous Germ Cell
Tumors (NSGCT/NGGCT)........................................................51
1.5.7
Cohort 7: Adenocarcinoma of the Small Intestine (ASI)
including Periampullary and Ampullary....................................52
1.5.8
Cohort 8: Hairy Cell Leukemia (HCL).......................................53
1.5.9
Cohort 9: Multiple Myeloma (MM)...........................................54
2
RATIONALE..........................................................................................................55
2.1
Rationale for the Combination of Dabrafenib and Trametinib...................55
2.2
StudyRationale ...........................................................................................56
2.3
Dose Rationale ............................................................................................57
2.4
Design Rational ...........................................................................................58
3
OBJECTIVES AND ENDPOINTS ........................................................................58
4
STUDY DESIGN ...................................................................................................59
4.1
Discussion of Design...................................................................................61
4.1.1
BRAF Mutation Test and Companion Diagnostic .....................61
5
SUBJECT SELECTION.........................................................................................62
5.1
Primary analysis cohort ...............................................................................62
5.2
Expansion cohorts .......................................................................................62
5.3
Number of Subjects.....................................................................................62
5.4
Eligibility ....................................................................................................62
5.4.1
Inclusion Criteria........................................................................63
5.4.2
Exclusion Criteria.......................................................................67


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6
STUDY TREATMENTS........................................................................................70
6.1
TreatmentAssignment.................................................................................70
6.2
Blinding.......................................................................................................70
6.3
InvestigationalProducts ..............................................................................70
6.3.1
Dabrafenib (GSK2118436) Capsule...........................................70
6.3.2
Trametinib (GSK1120212) Tablet .............................................71
6.4
Handling/Accountabilityof Investigational Products ..................................72
6.5
TreatmentCompliance ................................................................................72
6.6
Treatment of Overdose................................................................................73
6.6.1
Dabrafenib..................................................................................73
6.6.2
Trametinib ..................................................................................73
6.7
Continuation of Treatment...........................................................................73
7
STUDY ASSESSMENTS AND PROCEDURES..................................................74
7.1
Time and Event Table .................................................................................75
7.2
Demographic/MedicalHistoryAssessments ...............................................84
7.3
Critical Baseline Assessments .....................................................................84
7.3.1
Baseline Confirmation of BRAF-Mutation Status .....................84
7.3.2
Baseline Documentation of Target and Non-Target Lesions for
Solid Tumor Histologies.............................................................85
7.4
Safety ..........................................................................................................85
7.4.1
Physical Examinations................................................................85
7.4.2
Dermatological Examinations ....................................................85
7.4.3
Ophthalmic Examinations ..........................................................86
7.4.4
Vital Signs ..................................................................................86
7.4.5
Performance Status.....................................................................86
7.4.6
Electrocardiogram ......................................................................87
7.4.7
Echocardiogram..........................................................................87
7.4.8
Clinical Laboratory Assessments ...............................................87
7.4.9
Monitoring for Non-Cutaneous Secondary/Recurrent 
Malignancy.................................................................................89
7.4.10
Pregnancy Testing and Reporting...............................................90
7.5
Disease Assessment.....................................................................................91
7.5.1
Disease Assessment for Solid Tumor Histologies......................91
7.5.2
Disease Assessment for Histologies of Hematologic
Malignancies...............................................................................93
8
DOSE MODIFICATIONS AND STOPPING CRITERIA.....................................95
8.1
Dose Modification.......................................................................................95
8.1.1
Cardiovascular Events................................................................97
8.1.2
Pancreatitis ...............................................................................100


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8.1.3
Hepatobiliary Events ................................................................100
8.2
Dose Modification and Management Guidelines for Events of Special
Interest.......................................................................................................104
8.2.1
Dermatological Events .............................................................104
8.2.2
Malignancies.............................................................................107
8.2.3
Pyrexia......................................................................................108
8.2.4
Pneumonitis..............................................................................109
8.2.5
Diarrhea....................................................................................110
8.2.6
Renal Insufficiency...................................................................111
8.2.7
Visual Changes.........................................................................112
9
LIFESTYLE AND/OR DIETARY RESTRICTIONS..........................................114
9.1
ContraceptionRequirements .....................................................................114
9.1.1
Female Subjects........................................................................114
9.1.2
Male Subjects ...........................................................................115
9.2
Lactation....................................................................................................115
9.3
Caffeine and Alcohol.................................................................................115
9.4
Activity......................................................................................................115
10 CONCOMITANT MEDICATIONS AND NON-DRUG THERAPIES .............115
10.1
Permitted Medications and Non-Drug Therapies ......................................116
10.2
Prohibited Medications and Non-Drug Therapies .....................................116
10.3
Medications to be used with Caution.........................................................117
11 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS.............................119
11.1
Definition of Adverse Event......................................................................119
11.2
Definition of Serious Adverse Event.........................................................120
11.3
Laboratory and Other Safety Assessment Abnormalities Reported as AEs
and SAEs...................................................................................................121
11.4
CardiovascularEvents...............................................................................121
11.5
Death Events .............................................................................................122
11.6
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying
as SAEs .....................................................................................................122
11.7
Time Period and Frequency of Detecting AEs and SAEs..........................122
11.8
Method of Detecting AEs and SAEs .........................................................122
11.9
Recording of AEs and SAEs......................................................................123
11.10 Evaluating AEs and SAEs .........................................................................123
11.10.1
Assessment of Intensity............................................................123
11.10.2
Assessment of Causality...........................................................124
11.11 Follow-Up of AEs and SAEs.....................................................................124
11.12 Prompt Reporting of SAEs to Sponsor......................................................124
11.13 Regulatory Reporting Requirements for SAEs..........................................125


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12 PHARMACOKINETICS......................................................................................125
12.1
PharmacokineticEndpoints.......................................................................125
12.2
PharmacokineticAssessments...................................................................125
12.2.1
Blood Sample Collection..........................................................125
12.2.2
Pharmacokinetic Sample Analysis ...........................................126
13
PHARMACODYNAMIC BIOMARKERS........................126
13.1
Tumor Tissue for BRAFV600E Mutation Pre-Screening..........................126
126
127
127
128
128
128
128
128
16 COMPLETION OR WITHDRAWAL OF SUBJECTS .......................................129
16.1
Screen Failures ..........................................................................................129
16.2
Criteria for Permanent Discontinuation of Study Treatments....................129
16.3
Follow-Up Assessments after Discontinuation of Study Treatment or Study
Withdrawal................................................................................................130
16.4
Subject Completion...................................................................................130
16.5
StudyCompletion......................................................................................130
16.6
Subject Withdrawal Procedures.................................................................131
17 DATA MANAGEMENT......................................................................................131
132
18 DATA ANALYSIS AND STATISTICAL CONSIDERATIONS.......................132
18.1
Hypotheses and Treatment Comparisons...................................................132
18.2
Sample Size Considerations ......................................................................133
18.2.1
Sample Size Assumptions ........................................................133
18.2.2
Sample Size Sensitivity............................................................133
18.2.3
Sample Size Re-estimation.......................................................134
18.3
Data Analysis Considerations....................................................................134
18.3.1
Analysis Populations ................................................................134
18.3.2
Interim Analysis........................................................................134
18.3.3
Final Analyses ..........................................................................135
18.4
Simulations and Design Operating Characteristics....................................138
18.4.1
Simulation Description.............................................................138
18.4.2
Operating Characteristics .........................................................140
18.4.3
Example Trials..........................................................................148


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19 STUDY CONDUCT CONSIDERATIONS..........................................................148
19.1
Posting of Information on Publicly Available Clinical Trial Registers.....148
19.2
Regulatory and Ethical Considerations, Including the Informed Consent
Process ......................................................................................................148
19.3
Data Monitoring Committee......................................................................149
19.4
Quality Control (Study Monitoring)..........................................................149
19.5
QualityAssurance .....................................................................................150
19.6
Study and Site Closure ..............................................................................150
19.7
Records Retention .....................................................................................150
19.8
Provision of Study Results to Investigators, Posting of Information on
Publicly Available Clinical Trials Registers and Publication....................151
20 REFERENCES .....................................................................................................152
21 APPENDICES ......................................................................................................160
21.1
Appendix 1: ECOG Performance Status....................................................160
21.2
Appendix 2: NYHA Functional Classification System..............................160
21.3
Appendix 3: Cockcroft-Gault Formula for Creatinine Clearance .............161
161
166
21.6
Appendix 6: Details of Bayesian Hierarchical Model ...............................167
21.7
Appendix 7: Supporting Simulation Results..............................................169
21.8
Appendix 8: Hypothetical Example Trial Results .....................................170
21.9
Appendix 9: Country-Specific Requirements...........................................183
21.10 Appendix 10: RECIST, version 1.1..........................................................185
21.11 Appendix 11: Response Criteria for NSGCT/NGGCT with Elevated Tumor
Markers (AFP and -HCG) at Baseline.....................................................190
21.12 Appendix 12: Response Criteria for HCL .................................................191
21.13 Appendix 13: RANO Response Criteria: Response Assessment Criteria for
WHO Grade 1 or 2 Glioma........................................................................194
21.14 Appendix 14: RANO Response Criteria: Updated Response Assessment
Criteria for WHO Grade 3 and 4 Glioma ..................................................197
21.15 Appendix 15: Consensus Recommendations for the Uniform Reporting of
Clinical Trials............................................................................................200
21.16 Appendix 16: Imaging Guidelines for WHO Grade I or II Glioma...........203
21.17 Appendix 17: Volumes of Collected Blood Samples ................................205
21.18 Appendix 18: Liver Safety Drug Restart or Rechallenge Guidelines.......206
21.19 Appendix 19: Protocol Amendment Changes...........................................210


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Amendment 11 (04-Jun-2020)
Amendment Rationale
As of the end of enrollment on 29-Jun-2018, the study had enrolled a total of 206 subjects.  
As of 06-Apr-2020, 55 subjects continued on study treatment (36 Hairy Cell Leukemia, 10 
WHO Grade III or IV Glioma, 6 WHO Grade I or II Glioma, 2 Anaplastic Thyroid Cancer, 
1 Biliary Tract Cancer) and 23 were in follow up (7 Hairy Cell Leukemia (HCL), 5 Anaplastic 
Thyroid Cancer (ATC), 5 Biliary Tract Cancer (BTC), 3 WHO Grade I or II Glioma, 2 
Multiple Myeloma (MM), 1 WHO Grade III or IV Glioma).
The main purposes of this amendment are to extend the study by one additional year and to 
change the primary analysis population of the final efficacy analysis from the BRAF V600E 
population to the ITT population.
The study is being extended to obtain more mature estimates for duration of response, 
progression free survival and overall survival. The new study completion and the timing of 
the final analysis will now be the date that represents a minimum follow up of approximately 
3 years for all subjects enrolled.
The primary analysis population for the final efficacy analysis is changed from the BRAF 
V600E (centrally confirmed) population to the ITT population.  It is considered that including 
all enrolled subjects gives a better reflection of outcomes in the patient population likely to 
be treated in a real-world setting. This also provides consistency with previous interim study 
reports.  Of the 206 subjects in the ITT population, 20 were excluded from the BRAF V600E 
population (mutation status not centrally confirmed 5 HCL, 3 WHO Grade III or IV Glioma, 
5 WHO Grade I or II Glioma, 4 BTC, 3 ATC).
To reduce burden on patients, collections for blood and tissue samples for 
 
pharmacodynamic biomarker research as well as PK sampling at follow up are being 
discontinued as the majority of the planned biomarker analyses have been completed and the 
PK profile of the regimen is now well characterized.  (NOTE: PK samples collected in 
response to liver and ocular toxicity per Section 8 “Dose Modifications and Stopping Criteria” 
continue to be required).
Disease assessment intervals after the first 48 weeks of study treatment for subjects in the 
HCL cohort are being extended from “at least every 8 weeks” to “at least every 12 weeks”.  
This change is based on the indolent nature of the disease coupled with Interim Analysis #15 
data which observed durable responses in HCL subjects treated with dabrafenib and 
trametinib without compromise to patient safety or data integrity.  Safety assessment intervals 
are not affected by this change and continue to be required every 4 weeks.  (Efficacy 
assessments for other cohorts remain unchanged.)
Changes to the Protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions.

Section 4.1.1 BRAF Mutation Test and Companion Diagnostic

Removal of sentence “The primary analysis to determine the efficacy of dabrafenib 
+ trametinib therapy for the rare cancers will be based on the BRAF V600E mutation 
status determined by central reference laboratory testing” to align with change made 
to the primary analysis population.


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
Section 7.1 Time and Event Table (Table 4)

Assessments of “Blood sample for CBC”, “Peripheral Blood Sample Staining for 
Hairy Cell count” and “Flow cytometry: peripheral blood sample” under the heading 
of “Disease Assessment: HCL Cohort ONLY” changed from being indicated “Every 
8 weeks (+/-3 days)” to “Every 12 weeks (+/-3 days)”.  Footnote 31 was also changed 
accordingly.

Footnotes 45, 48, 49, 50, 52, and 53 updated to indicate that corresponding sampling 
is no longer requested as of Protocol Amendment 11.

Section 7.4.6 Electrocardiogram

Instructions updated regarding discontinuing transmission of ECGs to a central 
storage facility.  Copies of ECGs are now to be stored in the study file for retrospective 
collection by the sponsor if necessary. 

Section 7.5.2.1 Laboratory and Disease Assessments: HCL

Language under “Post-Baseline Assessments”
updated to align with the 
aforementioned change in interval between response assessments.

The following sections were updated with a note indicating that samples are no longer 
collected as of Protocol Amendment 11.

Section 12.2.1 Blood Sample Collection

Section 13.2.1 Peripheral Blood Sample Collection and Analysis

Section 16.5 Study Completion

Updated language to align with study extension of one additional year

Language updated to clarify that safety will be followed as part of the rollover study
in the event a subject is transitioned.

Section 16.6 Subject Withdrawal Procedures

Clarified that “withdrawal from study” in this context refers to “withdrawal from 
study treatment”.

Section 18.3.1 Analysis Populations

Updated to reflect the aforementioned change in the primary analysis population.

Section 18.3.3 Final Analyses

Updated language to align with study extension of one additional year

Formatting and typographical errors corrected throughout the document


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IRB/IEC/REB Approval
A copy of this amended protocol will be sent to the Institutional Review Boards 
(IRB)/Independent Ethics Committees (IECs), Research Ethics Boards (REBs) and Health 
Authorities.
The changes described in this amended protocol require IRB/IEC/REB approval prior to its 
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 
amended protocol.
Amendment 10 (09-Jan-2020)
Amendment Rationale
As of the end of enrollment on 29-Jun-2018 the study had enrolled a total of 206 subjects.  
As of 18-Nov-2019, 62 subjects continued on treatment and 34 were in follow up.
The primary purpose of amendment 10 is to align the dose modification section of the 
protocol related to severe cutaneous adverse reactions (SCAR), as updated in the dabrafenib 
and trametinib investigator’s brochures edition 11.
In addition, baseline results of IDH Mutation Status and MGMT Methylation Status will now 
be collected as part of disease characteristics for subjects in the WHO Grade 1/2 Glioma or 
WHO Grade 3/4 Glioma cohorts only.  Assessment of IDH1 and IDH2 mutations is in 
accordance with the 2016 WHO classification of Central Nervous System Tumors (Louis et 
al 2016) which was established after study start. Further, MGMT methylation status is a 
predictive marker for the activity of alkylating agents (i.e. temozolomide), which are
considered standard of care for the studied population.  The collection of these additional data 
points are important for the interpretation of the study results.  Data are collected only where 
available as part of medical records; retrospective testing is not requested or required.
References to the use of oral (hormonal) contraceptives being “permitted” or “used with 
caution” were removed from the relevant sections in alignment with changes made at protocol 
amendment #9 to update female contraception requirements.  These sections were 
inadvertently not updated at the previous amendment.
Changes to the Protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions.

List of Abbreviations section updated to include acronyms of DRESS, IDH, and SCAR 
used within the document.

Section 1.4 Risk Assessment for Dabrafenib + Trametinib Combination Therapy was 
updated to include added SCAR risk.


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
Section 7.1 Time and Event (Table 4)

Footnote #3 “Disease Characteristics” updated to include the collection of baseline 
IDH Mutation Analysis status and MGMT Methylation Analysis status if available.

Footnote #58 “Extended Follow-Up” part “e” was corrected to indicate that subjects 
may have CT and/or MRI scans of the chest and abdomen for up to 6 months to 
monitor for secondary or recurrent malignancy.  Previously, listed as every 6 months

Section 8.2.1.3 SCARs (Severe Cutaneous Adverse Reactions)

Section added in the dose modification section to include the following language
Cases of severe cutaneous adverse reactions (SCARs), including Stevens-Johnson 
syndrome, and drug reaction with eosinophilia and systemic symptoms (DRESS), 
which can be life-threatening or fatal, have been reported during treatment with 
dabrafenib in combination with trametinib. Before initiating treatment, patients 
should be advised of the signs and symptoms and monitored closely for skin reactions. 
If signs and symptoms suggestive of SCARs appear, dabrafenib and trametinib should 
be permanently discontinued.

Section 10.1 Permitted Medications and Non-Drug Therapies

Listing of “oral (hormonal) contraceptives:” and associated information removed as 
no longer permitted as of protocol amendment #9

Section 10.2 Prohibited Medication and Non-Drug Therapies

“Oral hormonal contraceptives” added to the list in this section per updates made to 
female contraception requirements at protocol amendment #9

Section 10.3 Medications to be Used with Caution

The reference to “hormonal contraceptives” in this section has been removed as no 
longer permitted as of protocol amendment #9  

Section 18.3 Data Analysis Considerations

Correction made to indicate that the reporting standard to be used to list and 
summarize data is the GSK Integrated Data Standard Library (IDSL).  Previously this 
was listed incorrectly as a Novartis reporting standard

Section 18.3.3.2 Efficacy Analysis

Updated to reflect that ORR estimates along with 95% exact confidence interval (CI) 
will be provided, rather than on a confidence interval based on normal approximation
as previously stated

Section 20 References

Added citation [Louis, DN 2016] 

Formatting and typographical errors corrected throughout the document


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IRB/IEC/REB Approval
A copy of this amended protocol will be sent to the Institutional Review Boards 
(IRB)/Independent Ethics Committees (IECs), Research Ethics Boards (REBs) and Health 
Authorities.
The changes described in this amended protocol require IRB/IEC/REB approval prior to its 
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 
amended protocol.
AMENDMENT 09 (12-Feb-2019)
Amendment Rationale
As of the end of enrollment on 29-Jun-2018 the study had enrolled a total of 206 subjects.  
As of 04-Feb-2019, 85 patients were ongoing.
The primary purpose of amendment 9 is to revise female contraception requirements as 
follows,
1. Double barrier contraception methods are no longer allowed in the study as they are not 
classified as highly effective methods per the Clinical Trial Facilitation Group (CTFG) 
and Novartis internal guidelines.
2. For subjects taking trametinib, contraception using oral contraceptives are not allowed 
while the drug interaction study between trametinib and oral contraceptives is still 
ongoing and Novartis would like to take a conservative approach and restrict oral 
contraceptives until the results are available from the interaction study.
Throughout the document where contraception requirements after discontinuation of study 
treatments are discussed, language is clarified as follows,
“Women of childbearing potential should use effective methods of contraception during 
therapy and for 16 weeks following discontinuation of trametinib when taken in combination 
with dabrafenib, or for 2 weeks following discontinuation of dabrafenib monotherapy.”
The Study Completion (Section 16.5) and Data Analysis and Statistical Considerations 
(Section 18) sections have been amended as they relate to study completion and data analysis.
A new end of study definition is implemented.
Justification
At the time of Interim Analysis #14, 54 of 178 subjects had died, representing a death rate of 
approximately 30%.  As a result, a new end of study definition is implemented with this 
protocol amendment to accommodate the better than expected outcome in this study.  A 
minimum follow-up period of approximately 2 years for all patients is sufficient for collection 
and maturity of data for the analysis of the secondary endpoints, and will be the new end of 
study definition.
Details of the specific changes made in each section of the protocol are described below in 
the Changes to the Protocol section below.


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Changes to the Protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions.

Section 9.1.1. Contraception Requirements for Female Subjects.  

Updated per change to contraception requirements (see above).

Section 16.5. Study Completion.  

Updated definition for study completion.  Study will be considered complete at a 
date that would represent a minimum follow up of approximately 2 years for all 
subjects enrolled.” 

Updated language clarifying the possible options for alternative supply of study 
treatment for those subjects which continue to derive clinical benefit at study 
completion. 

Section 18.3.1. Analysis Populations.

Clarified the analysis population for supportive final efficacy analysis

Section 18.3.3. Final Analyses.  

Updated date of final analyses as the date representing a minimum follow up of 
approximately 2 years for all subjects enrolled.

Section 18.3.3.2 Efficacy Analysis

Removed reference to pooled ORR calculations across histologies.

Changes to Medical Lead Contact, Clinical Trial Head Contact and Signatory.

Formatting and Typographical errors corrected throughout the document.
IRB/IEC/REB Approval
A copy of this amended protocol will be sent to the Institutional Review Boards 
(IRB)/Independent Ethics Committees (IECs), Research Ethics Boards (REBs) and Health 
Authorities.
The changes described in this amended protocol require IRB/IEC/REB approval prior to its 
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 
amended protocol. 
AMENDMENT 08 (14-Dec-2017)
Amendment Rationale
As of 20-Nov-2017:

One hundred fifty five patients have been enrolled in 35 sites located in 13 countries 
(Austria, Belgium, Canada, Denmark, France, Germany, Italy, Korea, Netherlands, 
Norway, Spain, Sweden and the United States).  


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
Eighty patients have discontinued the study treatments (60 due to disease progression, 
12 due to adverse events, 7 due to patient or investigator decision and 1 due to a 
protocol deviation).  

Forty-seven patient deaths have been reported of which three occurred during study 
treatment with the reason noted as sepsis for all the deaths.
The primary purpose of amendment 8 is to implement a change in the duration of 
contraception measures for male participants.  The duration of male contraception measures 
are increased from 12 to 16 weeks in the period following stopping of the study treatments.  
This change was prompted by re-evaluation of the existing pre-clinical data and the 
application of Novartis contraception guidance.  Furthermore, amendment 8 implements a 
change in the IND number under which the study is conducted, to comply with a request from 
the Food and Drug Administration (FDA) to administratively split Study  CDRB436X2201 
from IND#113557 and to file this study under a new IND (137160) and, other minor changes 
or clarifications to the study procedures.
Details of the specific changes made in each section of the protocol are described below in 
the Changes to the Protocol section below.
Changes to the Protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions.

Sponsor Information Page.  Updated the US IND # to 137160 (Previously 113557).

List of Abbreviations.  Added alloSCT (allogenic stem cell transplantation) and 
autoSCT (autologous stem cell transplantation) and removed ASCT (allogenic stem cell 
transplantation) to avoid ambiguity.

Section 7.1 Time and Event Table.  Added the following changes:

Table headings.  Added “All Cohorts” or “Cohorts” to the applicable Assessment 
Headings for clarity,

Pregnancy19 Under “Every 12 weeks (+/-3 days)” heading, added “X21 serum or 
urine” to align with footnote 21 instructing every 12 week testing requirement after 
week 48,

TSH, Free T4. Added (ATC only) to clarify these tests are only required for 
patients enrolled to the ATC cohort,

Blood sample for CBC.  Under “every 4 weeks (+/-3 days)” and “every 8 weeks 
(+/-3 days)” headings, added 31 and X31 respectively to clarify and align with 
footnote 31,

Peripheral Blood Sample Staining for Hairy Cell Count.  Under “every 4 weeks (+/-
3 days)” and “every 8 weeks (+/-3 days)” headings, added footnote 31 and X31
respectively, to clarify and align with the text noted in footnote 31,

Flow Cytometry: peripheral blood sample33. Under “every 4 weeks (+/-3 days)” 
heading, added 31 to clarify and align with the text noted in footnote 31,

Footnote 31.  Modified the instruction for HCL patients who are tolerating study 
drug treatment beyond week 48.  These patients may reduce the frequency of 
response assessment evaluation from every 4 weeks (+/-3 days) to every 8 weeks 
(+/-3 days) if appropriate in the judgement of the treating investigator.

Footnote 58. Modified the instruction for extended follow-up as follows:


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58EXTENDED FOLLOW-UP: The following evaluations will be performed for all patients 
in all cohorts
a. Dermatologic exam.  Exams will be performed every 4 weeks (+/-7 days) for the first 6 
months.  The skin will be carefully examined and pictures and biopsy will be taken of 
any new or changed skin lesions.
b. If study treatments are permanently discontinued prior to the subject having confirmed 
disease progression, the subject will continue to have disease assessments every 12 
weeks (+/-14 days) until disease progression or initiation of new anti-cancer treatment, 
or death, whichever comes first.
c. Subjects will be followed every 12 weeks (+/-14 days) for survival until the subject dies 
or withdraws consent or is lost to follow up, or up to a time period as defined in Section 
16.3.  Survival follow up may be performed via clinic visit, a telephone contact, an
email or by mail.  The initiation of any new anti-cancer treatment(s) and date of last 
contact should also be documented.
d. Subjects will have a head and neck exam performed every 12 weeks for the first 6
months to monitor for secondary or recurrent malignancy.
e. Subjects may have CT and/or MRI scans of the chest and abdomen every 6 months to 
monitor for secondary or recurrent malignancy.

Footnote List.  Corrected previous mis-numbering error that caused inaccurate 
references for footnotes 39  through 58.

Section 7.4.8. Table 6. Added Footnote 6 to clarify that although HbA1c testing is 
included in “Clinical Chemistry” section it is performed at an interval of every 12 
weeks (+/-3 days).

Section 7.5.2.1. Laboratory and Disease Assessments: HCL.  Updated post-baseline 
assessments statement to align with change indicated in footnote 31 of Time and Event 
Table.

Section 9.1.2. Added a new section to include the contraception requirements for male 
subjects.
1. “Male subjects (including those that have had a vasectomy) must use a condom 
during intercourse while taking dabrafenib and/or trametinib treatment.  Once 
dabrafenib and trametinib are both permanently discontinued, the patient must use a 
condom for 16 weeks after the last dose of the study treatments.  The patient should 
not father a child during the study treatment period or during the specified time 
frames after discontinuation of study treatment.”

Section 10.3. Medications to be used with Caution.  Removed statement regarding 
Dabrafenib solubility at higher pH. Consequently, proton pump inhibitors removed 
from Table 28 of Medications to be used with Caution.

Section 11.7. Reinstated a sentence outlining the time period for detecting adverse 
events and serious adverse events inadvertently removed at amendment 7.

Section 12.1. Pharmacokinetic Endpoints.  Change of Novartis department name 
responsible for PK analysis “Institutes for BioMedical Research (NIBR) PK Sciences 
(PKS)”

Section 12.2.2. Pharmacokinetic Sample Analysis.  Change of Novartis department 
name performing plasma analysis “PKS Bioanalytics”

Section 13.2.1. Peripheral Blood Sample Collection and Analysis.  Corrected the 
number of samples and amount of peripheral blood to be collected.


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
Section 21.13. Appendix 13: RANO Response Criteria: Response Assessment Criteria 
for WHO Grade 1 or 2 Glioma.  Clarified the second bullet point under “Disease 
Progression (PD)”,
(Bolded text below added to statement as previously written)
“A 25% increase in the sum of the products of perpendicular diameters of the T2 or 
FLAIR enhancing or non-enhancing lesion on stable or increasing doses of 
corticosteroids compared with baseline scan or best response after initiation of therapy, 
not attributable to radiation effect or to comorbid events.”
IRB/IEC/REB Approval
A copy of this amended protocol will be sent to the Institutional Review Boards 
(IRB)/Independent Ethics Committees (IECs), Research Ethics Boards (REBs) and Health 
Authorities.
The changes described in this amended protocol require IRB/IEC/REB approval prior to its 
implementation.
The changes herein affect the Informed Consent.  Sites required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
amended protocol.
AMENDMENT 07 
Amendment Rationale
Subsequent to the acquisition of GlaxoSmithKline (GSK) compounds GSK1120212 and 
GSK2118436, the purpose of this protocol Amendment 07 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 07-Feb-2017:
-
121 patients have received study treatment in 11 countries (Austria, Belgium, 
Canada, Denmark, France, Germany, Italy, Korea, Netherlands, Norway and US); 
-
63 patients have completed or discontinued study treatment.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities (HAs).
The changes herein affect the Informed Consent and all sites are required to update and 
submit for approval, a revised Informed Consent that takes into account the change of study 
sponsorship described in the protocol amendment.
Upon approval of this amendment, patients who have already been enrolled in the study will 
sign a new informed consent form indicating Novartis is the new study sponsor and continue 
the appropriate visit schedule.


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REVISION CHRONOLOGY
GlaxoSmithKline
Document Number
Date
Version
2012N145247_00
2013-JUL-09
Original
2012N145247_01
2013-JUL-25
Amendment No. 1

List of Authors was updated to add 
, 
 and 
 and to 
remove 
 due to changes in study assignments within GSK.

Previous primary Medical Monitor (
) was replaced by
 (formerly
secondary Medical Monitor) and
named secondary Medical Monitor.

EudraCT Number was added.

List of Abbreviations updated to insert any abbreviations omitted in original protocol

Section 7.3.8, Clinical Laboratory Assessments, Table 4, removed cardiac enzyme:
troponin from list of assessments to be completed.

Section 7.4.1, Physical Examination, revised to indicate that other medical personnel (i.e.,
physician assistant or nurse practitioner) may be able to perform the physical examinations

Section 8: Time and Event tables were revised to correct for inconsistencies with 
individual cohort text pertaining to samples to be obtained for BRAF mutation status, 
disease assessment, PD and biomarker assessments.

Section 8: Time and Events tables were revised the frequency of select assessment for the 
first 52 weeks of treatment to 48 weeks of treatment to align with the timing of other 
assessments

Section 8.1.2, Section 8.2.2, Section 8.3.2, Section 8.4.2, Section 8.5.2, Section 8.6.2, 
Section 8.7.2, Inclusion Criteria: clarified mandatory tumor sample required at Screening

Section 8.8.2 and Section 8.9.2, Inclusion Criteria: clarified mandatory BM aspirate
sample required at Screening

Section 8.6.2, Section 8.7.2, Section 8.8.2, and Section 8.9.2, Exclusion Criteria: added
text to confirm that no histology-specific exclusion criteria were included

Section 8.4.3 and Section 8.5.3, Disease Assessments: corrected reference to CT scan; 
changed to MRI as CT is not permitted in these cohorts

Section 8.6.4, Laboratory Assessments: corrected reference in cohort number

Section 9.2.3.4, Restarting Study Treatment was revised to remove reference to restart of 
study treatment.

Section 14.1.2: removed statement that PD sample collection was mandatory for ATC,
HCL and MM cohorts as it was inconsistent with Time and Events tables.
2012N145247 02
2013-DEC-18
Amendment No. 2

Section 3, Objectives and End points, revised Table 3 primary endpoint to reflect use of 
Modified RANO and RANO is assessing tumor response in gliomas.


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
Section 4, Study Design: revised sentence regarding eligibility of subjects to be 
consistent with new general inclusion criteria #5; revised to correctly identify timing of
screening assessments and exceptions for consistency with Time and Events Tables.

Section 5.2.1, General Inclusion Criteria #5: revised to delete the reference to a CLIA 
approved laboratory as this certification is not applicable to countries other than the US.

Section 5.2.1, General Inclusion Criteria #7 (renumbered to #8): revised to describe
contraception consistently with other sections of protocol; added “highly” to effective
contraception.

Section 5.2.1, General Inclusion Criteria (new) #5: new criteria added to clarify
inclusion of subjects with specified histology and no available treatment options per 
local or regional standard of care.

Section 7.3, Safety: inserted new text to provide estimation of blood volume collected
during the study and to reference Appendix 17.

Section 7.3.1, Physical Examination: replaced term ‘neurological’ to ‘CNS’ to better
describe assessment to be made.

Section 7.3.6, Electrocardiogram, second paragraph, revised to remove reference to 
QTcF as stopping criteria for QTc prolongation is limited to use of Bazett formula for
correction.

Section 7.3.7, Echocardiogram, revised to remove the use of MUGA scans to assess 
cardiac ejection fraction.

Section 7.3.9, Monitoring of Non-Cutaneous Secondary/Recurrent Malignancy, added 
as a new section to reflect monitoring required per the special warnings and precautions
required for use of dabrafenib.

Section 8.3.2, Eligibility Criteria: GIST, added new inclusion criteria (#4) requiring
progression with imatinib and sunitinib treatment; subsequent criteria were renumbered.

Section 8.4.2, Eligibility Criteria: WHO Grade 1 or 2 Glioma: added new criteria for 
subjects with WHO Grade 2 glioma: only subjects for whom chemotherapy are not an
option may be eligible for study participation

Section 8.8.2, Eligibility Criteria: HCL, Inclusion Criteria #2, revised inclusion criteria

#2 to provide examples of a purine analog and to clarify definition of refractory disease.

Section 8.9.2, Eligibility Criteria: MM, Inclusion Criteria #2, revised to clarify prior
treatment received by subjects with MM.

Section 9.2.1, Cardiovascular Events, revised to indicate that cardiovascular events may
occur with not only trametinib but also dabrafenib or both in combination.

Section 9.2.1.1, QTc Prolongation, revised to be in line with the special warnings and
precautions required for use of dabrafenib.

Section 9.2.1.2, Left Ventricular Ejection Fraction Stopping Criteria, revised to remove
use of MUGA scan and to request procedure to be performed by same operator
throughout the study; removed requirement of reporting symptomatic events as SAE, 
and to provide that in case of asymptomatic absolute decrease of >10% in LVEF 


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compared to baseline and ejection fraction below the institutional LLN, study treatment 
(trametinib and dabrafenib) must be temporary or definitely discontinued.

Section 9.2.1.3.2, Management of Hypertension, clarified dose added new text directing
subjects with persistent increase in systolic and/or diastolic BP that may be treatment-
related to be managed by recommendations in Table 21 and revised to indicate that
continuing treatment by dabrafenib in case of asymptomatic or symptomatic
hypertension
is not justified. In this situation, study treatment (trametinib and 
dabrafenib) must be temporary or definitely discontinued.

Section 9.3.1.2, Cutaneous SCC, revised to remove reference to keratoacanthomas and 
added requirement of dermatological examinations monthly for 6 months after 
treatment discontinuation.

Section 9.3.5, Renal Insufficiency, revised to include guidelines for management and
dose reduction for renal insufficiency when considered treatment related (Table 26 
added). (Tables from this point forwarded were renumbered accordingly.)

Section 10.1.1, Female Subjects, revised in order to describe contraception consistently 
with other sections of protocol; added “highly” to effective contraception

Section 11.3, Medications to be Used with Caution, revised to add updated reference
for drugs known to induce QTc prolongation.

Section 14.1, Tumor Tissue for BRAF V600E Mutation Pre-Screening, revised to delete
the reference to a CLIA approved laboratory as this certification is not applicable to 
countries other than the US.

Section 20.1, Data Monitoring Committee, new section added to address the formation 
of a data monitoring committee for review of data during interim analysis and to indicate
that independent hematologist and oncologist will serve on data monitoring committee.

Appendix 9, Country Specific Requirements, deleted text pertaining to French-specific
QTc stopping criteria as the criteria was incorporated into Section 9.2.1.1.

Appendix 17, Volumes of Collected Blood Samples, added new table to provide the 
volume of blood collected at various time points during study.
2012N145247 03
2014-JUL-21
Amendment No. 3

Amendment No.: 03 was prepared to revise the trametinib and dabrafenib sections in order 
to remove information that was outdated and to reduce information that is found in product 
IBs.

Revised information pertaining to BRAF mutation test and companion diagnostic.

Reformatted the inclusion/exclusion criteria to eliminate repeated language found when 
previously presented in separate cohort sections.

Revised inclusion/exclusion cohort where appropriate based on additional input from
investigators or subject experts or to clarify criteria; revised text pertaining to treatment of
overdose for both dabrafenib and trametinib to align with new standard protocol language.

Condensed 9 separate Time and Events table into one table to eliminate duplication of 
information for ease of user; added language pertaining to retrospective confirmation of 
histology type for ATC cohort.


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
Revised vision changes and ophthalmic exam language in appropriate sections with 
revised standard asset language.

Reformatted document to eliminate individual cohort sections and reduce duplication of
text describing study assessments such as laboratory and disease assessment, etc.

Revised disease assessment sections to clarify type of assessment, timing and evaluation 
criteria.

Stopping criteria and management and dose modification for special events were revised
to reflect changes in standard asset language.

Liver chemistry stopping criteria were revised to reflect recent changes in standard 
protocol language to be used.

Concomitant medication and non-drug therapies section was revised to clarify use of 
anticoagulants, palliative radiation and use of dabrafenib during radiotherapy.

Addressed change in information collected for screen failures.

New reference citations added, references no longer cited in text were removed.

List of abbreviations updated to reflect revisions in overall text.

Other general administrative changes were made to correct typographical errors, etc.
2012N145247 04
2014-OCT-24
Amendment No. 4
The changes made with Amendment No. 4 are to revise the protocol in response to the
recent decision for the substantial amendment of a Voluntary Harmonization Procedure
(VHP-SA) submission of Amendment 03 of the protocol.  Specific changes made with
Amendment No. 04 include the following:

Section 1.3: revised to update regulatory approval status of trametinib monotherapy and 
trametinib in combination with dabrafenib

Section 4.0: revised to correct inconsistency between text in protocol section and text 
change noted in summary of amendment changes in Appendix 20 for Amendment 03.

Section 5.2.1.1.4 and Section 5.2.1.1.5: revised Inclusion Criteria #5 and #4, respectively,
to clarify that the criterion applies to subjects who are already receiving corticosteroid 
therapy.

Section 5.2.2: revised to Criterion #1 to clarify that the status of delayed toxicity applies 
to all types of therapy and not solely chemotherapy.

Section 8.1.1.2, Table 12: reverted text in Table 20 to the Amendment 02 version as it was 
previously approved by the VHP.

Section 8.1.3.1, Section 8.1.3.1.1, Section 8.1.3.1.2, Section 8.1.3.1.3: the liver chemistry
stopping criteria sections were revised to correct omission of a portion of the criteria and 
to reformat the text originally found in Appendix 18 in Amendment 03 to assure that all 
guidelines were located together in Section 8.1.3.

Section 8.2: revised to delete table that was incorrectly placed under this section heading; 
should have been included in previous section of protocol


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
Section 8.2.3: revised based on recent revision of the asset standard language for 
pneumonitis

Section 8.2.6, Table 21: revised text in Table 21 to align with the Summary of Product 
Characteristics (SmPC) language as requested by the VHP

Section 13.1: revised to correct inconsistency between text in protocol section and text 
change noted in summary of amendment changes in Appendix 20 for Amendment 03.

Other changes were made due to reassignment of GSK personnel (i.e., list of authors,
secondary medical monitor and sponsor signatory for protocol).
2012N145247 05
2015-APR-28
Amendment No. 5
Amendment No. 05 was prepared to revise information pertaining to BRAF mutation test
and companion diagnostic

Revised inclusion/exclusion cohort where appropriate based on additional input from
investigators or subject experts or to clarify criteria.

Revised language in appropriate sections with revised standard asset language.

Clarified who can perform physical exams.

Clarified number of blood pressure readings to be taken and averaged value to be reported.

Revised disease assessment sections to clarify type of assessment, timing and evaluation 
criteria.

Revised LVEF stopping criteria to indicate when to report as SAE.

Removed BRAT diet from diarrhea management guidelines.

Removed oral contraceptives from the prohibited medications list and provided supporting
information regarding interaction with dabrafenib; specified oral formulation for selected
prohibited medications and medications to be used with caution.

Concomitant medication
and non-drug therapies section was revised to clarify use of 
NSAIDs.

Clarified which samples to be submitted for confirmation of BRAF mutation status.

Definition of SAEs revised for protocol specific SAEs based on updated list of AE of 
special interest.

Added new section for malignancies to include section on cutaneous squamous cell
carcinoma, new primary melanoma and non-cutaneous malignancies based on updated 
asset language for dabrafenib and trametinib.

Clarified use of NSAIDs in subjects with MM for pyrexia and action to be taken with
dabrafenib with pneumonitis.

Revised disease assessments for solid tumors to clarify imaging modality to be used for
specific cohorts.

Statistical section revised to reflect change in study sample size and trial simulation
output.


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
Revised the Time and Event Table to correct footnoting, clarify timing of assessments in
particular PD biomarkers (tumor sample, BM aspirate and blood samples) for all cohorts.

Revised Bayesian hierarchical model specification to correct typographical error.

Updated reference citations, list of abbreviations updated to reflect revisions in overall
text, and other general administrative changes were made to correct typographical errors.
2012N145247 06
2016-JAN-05
Amendment No. 6
Amendment 6 implements additional updates to the protocol Sections noted below:

Section Sponsor/Medical Monitor Information Page: Updates the contact details for
Medical Monitor and Sponsor Contact information.

List of Abbreviations: Adds “SPEP – Serum Protein Electrophoresis” and “UPEP -
Urine Proteine Electrophoreis” to the list.

Section 1.2 Dabrafenib (GSK2118436): Updates the last paragraph as follows: Refer to
the dabrafenib monotherapy and dabrafenib+trametinib combination
therapy and
updates the new IB v.07 document number.

Section 1.3 Trametinib (GSK1120212): 
o
Updates the second paragraph as follows: “….Trametinib in combination with 
dabrafenib has been approved in the US, EU, Chile, and Australia for the treatment 
of patients with unresectable or metastatic melanoma with BRAF V600E or V600K 
mutation.
o
Updates the third paragraph as follows: Refer to the dabrafenib monotherapy and 
dabrafenib IB for a complete summary….. and updates the new IB document 
number.

Section 1.4 Risk Assessment for Dabrafenib + Trametinib Combination Therapy:
o
Adds a new paragraph about the safety profile for dabrafenib + trametinib 
combination therapy.
o
Updates the guidance and timepoints for dermatolgical exams for cuSCC as follows: 
A brief dermatological exam should be performed every 4 weeks (±7 days) for the 
first 6 months after discontinuation of study treatments to monitor for new cutaneous 
malignancies.
o
Updates information for Pyrexia as follows: … About one-third of the subjects who 
experienced pyrexia had 3 or more events.
o
Adds the following guidance: trametinib should be continued at the same dose.
o
Adds information for decrease left ventricular ejection fraction as follows: Left 
ventricular dysfunction has been reported with trametinib as well as with other MEKi 
in clinical development. In the 2 Phase III studies decreased ejection fraction 
occurred in 7% of subjects receiving combination therapy and the majority of 
the LVEF decreases that met interruption criteria were asymptomatic and
resolved.
Most subjects who were re-challenged were able to continue on 
treatment without further dose modification. Subjects enrolled in studies with 
dabrafenib in combination with trametinib undergo regular cardiac assessments with


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echocardiograms (ECHOs). Guidelines for clinical management of treatment-related 
LVEF decreases have been provided in Section 8.1.1.2.
o
Adds new information for hemorrhage as follows: Hemorrhage: Hemorrhagic
events, including major hemorrhagic events defined as symptomatic bleeding in 
a critical area or organ, and fatal intracranial hemorrhages, have occurred in 
patients taking dabrafenib in combination with trametinib. The majority of 
bleeding events were mild. Three of 209 subjects (1%) receiving trametinib in 
combination with dabrafenib in a phase III trial had fatal intracranial
hemorrhagic events. The management of hemorrhagic events may require 
treatment interruption, dose reduction, or treatment discontinuation.
o
Updates new information for Hyperglycemia
as follows: Hyperglycemia:
Hyperglycemia requiring an increase in the dose of, or initiation of, insulin or oral 
therapy can occur with dabrafenib or dabrafenib in combination with trametinib.
o
Updates information for Pancreatitis as follows: Pancreatitis: Subjects receiving 
dabrafenib or dabrafenib in combination with trametinib have reported AEs of 
acute pancreatitis or pancreatitis. In some cases, serious adverse events (SAEs) of
Grade 4 pancreatitis were reported as treatment-related by the investigator. The time 
to onset of pancreatitis ranged from study Day 21 to 292 (median 138 days) with 
dabrafenib monotherapy, and from Study Day 24 to 312 (median 50 days) with 
combination therapy.  Discontinuation of study treatment due to pancreatitis was 
not deemed necessary in any of the cases by the investigators.
o
Updates information for Fertility as follows: Trametinib may impair fertility in 
humans.
o
Updates information for Pregnancy as follows: Women of childbearing potential 
should use effective methods of contraception during therapy and for 4 months 
following discontinuation of trametinib when taken in combination with dabrafenib, 
or for 4 weeks following discontinuation of dabrafenib.

Section 1.5.6 Cohort 6: Non-Seminomatous/Non-Germinomatous Germ Cell Tumors 
(NSGCT/NGGCT): Updates the second paragraph as follows: Chest pain and difficulty 
breathing are early signs of NSGCT. Other symptoms include: cough, fever, headache, 
and change in bowel habits, fatigue, difficulty walking and visual problems (difficulty
seeing or moving eyes).

Section 2.1 Rational: Updates information about overall survival data for combination 
therapy in advanced melanoma.

Section 2.3 Dose Rationale:
o
Updates 
the 
trametinib 
PK 
[GlaxoSmithKline 
Document 
Number 
to
CM2010/00010/05 and modifies the last sentence“The combination was relatively 
well tolerated in study BRF113220, study MEK115306 and study MEK116513, 
with toxicities manageable with appropriate intervention.
o
Modifies the second paragraph as follows: As determined in Phase III studies, the 
safety profile of the combination of dabrafenib and trametinib generally reflects the 
well established safety profiles of the individual approved agents, with toxicities that 
are manageable with appropriate intervention.


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
Section 4 Study Design:
o
Updates the first paragraph as follows: “…For each cohort, up to 25 evaluable 
subjects will be enrolled in the primary analysis cohort as defined in Section 5.1. 
If a given cohort is stopped early for efficacy, a histology specific expansion 
cohort may be opened to allow for additional patient enrollment (see Section 
5.2)”
o
Updates the fourth paragraph regarding disease assessments as follows: “Subjects 
will undergo disease assessment of response after receiving at least 8 weeks of 
treatment”

Section 5.1 Primary analysis cohort: Adds new section as follows: The “primary
analysis cohort” will be comprised of those patients enrolled within a histology-specific 
group prior to capping at 25 patients per cohort or prior to early stopping for efficacy 
or futility. The primary analysis cohort will form the basis of the Bayesian modelling.

Section 5.2 Expansion cohort: Adds a new section as follows: If a cohort closes early 
at an interim analysis because it meets the rules for early stopping for efficacy, an 
expansion cohort may be opened to allow additional patient enrollment for that 
particular histology. The patients in the expansion cohort will provide supportive 
efficacy data and will NOT contribute to the Bayesian modeling. The expansion 
cohort (s) will enroll subjects for the duration of trial enrollment.  The same
general and histology specific eligibility criteria and T&E tables
and 
biomarker/histology confirmation analyses will apply to patients in the expansion 
cohort.

Section 5.1 became 5.3 Number of Subjects: Updates first paragraph as follows: For 
the primary analysis cohort, enrollment will not exceed 25 subjects per histology
cohort to ensure adequate subjects in the BRAF V600E confirmed population.  After 25 
subjects have been enrolled, the histology cohort will be closed to further enrollment.
See Section 18.2 for sample size assumptions.

5.4 Eligibility: Updates reference to updated for the IB of dabrafenib + trametinib
combination

Section 5.4.1 Inclusion Criteria Table 3 Adequate Baseline Organ Function: Updates 
legend 2 as follows: PTT and PT/INR >1.5 times ULN will be acceptable in case of 
subjects receiving therapeutic anticoagulants such as warfarin as long as INR is 
monitored during the study according to clinical practice.

5.4.2 Exclusion Criteria: Modifies the time window for radiotherapy for the Glioma 
Grade 1-4 cohort only: Subjects may be ≥2 weeks from radiotherapy if a new lesion 
relative to the pre-radiation MRI develops outside the primary radiation field.

5.4.2.1.3 WHO Grade 1, 2, 3 or 4 Glioma: Adds additional clarification to the Note 
concerning the WHO Grade 1,2,3 or 4 Glioma as follows: NOTE: Extended period of 
time (>3 months) needed to prevent subjects with pseudo-progression from radiotherapy 
being enrolled in the study. Subjects may be ≥2 weeks from radiotherapy if a new
lesion relative to the pre-radiation MRI develops outside the primary radiation 
field. Treatment-related AEs must have resolved prior to enrollment.


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
Section 7.1 T&E Table: Clarifies the assessment timelines and corrects discrepancies 
between the T&E Table and footnotes as follows:
o
Updates footnote and legend numbering as deemed necessary.
o
Updates footnote 4: Subjects may be enrolled based on local determination of BRAF 
V600E mutation status.  A subject may be tested for the BRAF V600E mutation 
greater than 28 days prior to enrollment NOTE: For subjects with HCL or MM:  A 
fresh BM aspirate sample and a peripheral blood sample are required for 
confirmation testing by a sponsor designated central reference laboratory. If a BM 
aspirate cannot be obtained due to a dry tap, please contact the Medical Monitor. In 
the event of a dry tap, fresh or archived tumor tissues such as lymph node or 
plasmacytoma biopsies may be acceptable pending medical monitor approval.
o
Updates footnote 6: All screening assessments must be completed within 14 days 
prior to first dose except informed consent. Disease Assessment (if MRI is used) can 
occur within 35 days prior to the first dose. Note: Procedures conducted as part of 
the subject’s routine clinical management(e.g., blood counts, imaging study) and 
obtained prior to signing of informed consent may be utilized for screening or 
baseline purposes provided these procedures meet the protocol requirements.
o
Deletes footnote 7: Screening ECGs, ECHO, laboratory assessments and tumor 
marker tests must be performed within 3 days prior to the first dose of study
treatments.
o
Foot Note 12, 14 and 17: Clarifies the time window for screening assessment for the 
dermatological exam, ophthalmic exam and ECHO by adding “(or within 35 days 
prior to the first dose)”.
o
Implements “Tissue Sample for Histology Confirmation” for independent pathology
confirmation of ATC and WHO Grade 1-4 Glioma cohort only and corresponding 
footnote 28 (A tissue specimen for possible retrospective histology confirmation 
should be obtained and submitted to a GSK designated central reference laboratory. 
Please refer to the SPM for the requirements of the tissue specimen that is required 
for the histology confirmation.
o
Updates foot note 29: AFP, B-HCG and LDH are the disease assessment markers 
for the NSGCT/NGGCT cohort. LDH result obtained from clinical chemistry panel 
can be used as a tumor marker result. Regardless of baseline values of AFP, β-HCG 
and LDH, a blood sample will be drawn every 4 weeks for first 48 weeks of study
treatment, then every 8 to 12 weeks thereafter, and at the time of disease progression.
Synchronize the collection of the blood sample with the imaging schedule.
o
Updates foot note 31 for HCL cohort only as follows: All required disease 
assessments necessary for a post-baseline response
determination should be 
performed every 4 weeks +/- 3 days. A response is to be determined every 4 weeks 
based on the response criteria (please consult Appendix 12) using data collected from 
the scheduled disease assessments.
o
Clarifies foot note 32 for the HCL cohort only as follows: BM biopsy and aspiration 
with H/E stain and IHC will be performed when blood counts are consistent 
with CR or PR for 4 weeks. If a patient has a CR or PR, and then blood counts
become consistent with a CR or PR for 4 weeks, a repeat BM aspirate and biopsy 


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is required to assess a response of CR or PR. Following best response, a bone 
marrow biopsy and aspirate must be performed every 6 months for two time
intervals, then after a year for two time intervals, then every two years.
o
Clarifies Disease assessments post baseline (BM biopsy and aspirate with H/E stain 
and IHC and BM aspirate with flow cytometry) for HCL cohort only within 
corresponding section in T&E table as follows: When counts are consistent with CR 
or PR for 4 weeks; if evidence of response, then after every 6 months twice, then 
after a yearly twice and then every 2 years
o
Clarifies foot note 33 for the HCL cohort only as follows: Recommend that flow 
cytometry panel consists of CD19, CD20, CD22, SmIg, CD11c, CD25, CD103 and 
CD123. Flow cytometry of the bone marrow aspirate sample will be performed
when blood counts are consistent with CR or PR for 4 weeks (please consult
Appendix 12). If a patient has a PR, and then blood counts become consistent 
with a CR for 4 weeks, a repeat flow cytometry of the BM aspirate is required
to assess a response of CR. Following best response, a flow cytometry of the bone 
marrow aspirate must be performed every 6 months for two time intervals, then 
after a year for two time intervals, then every two years.
o
Adds foot note 34 for HCL cohort as follows: BM biopsy (with H/E stain and IHC), 
BM aspirate (with flow cytometry) and peripheral blood sample (with flow 
cytometry) will be assessed within 28 days prior to enrollment.
o
Clarifies foot note 35 regarding the timelines for tumor assessment (chest CT scan, 
abdominal CT scan with contrast and MRI (if needed) at baseline for the HCL cohort 
only as follows: A chest CT scan and an abdominal CT scan with contrast will be 
performed within 28 days prior to enrollment. If an abdominal CT scan with 
contrast cannot be performed, then a MRI may be performed within 35 days prior 
to enrollment. If lymph nodes or spleen are enlarged at baseline, then the abnormal 
organ needs to be followed on post-baseline assessments using the same modality of 
imaging.
o
Clarifies Disease assessments post baseline (Chest CT scan and Abdominal CT scan 
w/o contrast) for HCL cohort only within corresponding section in T&E table as 
follows: When counts are consistent with CR or PR for 4 weeks; then 6 months later
o
Clarifies foot note 36 regarding timelines of skeletal survey at screening for MM 
cohort only as follows: A skeletal survey should be performed within 28 days 
prior to enrollment. If myeloma associated bony lesions are present at baseline, 
skeletal surveys should be performed every 16 weeks or more frequently in order to 
assess response or upon clinical suspicion of progressive disease. Skeletal surveys
typically consist of lateral radiographs of the skull, AP and lateral views of the spine, 
and AP views of the humeri, ribs, pelvis, and femurs.
o
Modifies foot note 37 for MM cohort only as follows: Each patient should be 
clinically examined for soft tissue plasmacytomas / extramedullary disease at 
baseline and at each visit for response assessment. If extramedullary disease is 
present at baseline, then Chest/Abdominal/Pelvis CT scan with contrast should be 
performed to confirm and to determine size and location of the soft tissue 
plasmacytoma. If no disease is identified at baseline, then subsequent scans are only
required if clinicallyindicated.  Alternative imaging modality (i.e., MRI) may be used 




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
Section 7.4.8 Clinical Laboratory Assessments Table 6: Adds lab tests information as 
follows: Amylase and lipase [monitor via local laboratory when clinically indicated to 
evaluate certain AEs (i.e., abdominal pain, pancreatitis, etc.)

Section 7.4.8.1 Modifies the header to read as follows: Additional Histology Specific 
Assessments and Histology Confirmation:
o
Adds a new paragraph for histology confirmation for the ATC cohort and Glioma 
G1-G4 cohort only as follows: A tissue specimen from the biopsy of a primary
or metastatic site that served as the basis for the
o
Original diagnosis must be submitted to a GSK designated central reference 
laboratory as soon as possible after enrollment for possible retrospective 
confirmation of histologic type. Refer to the SPM for details regarding sample 
submission.

Section 7.49 Monitoring for Non-Cutaneous Secondary/Recurrent Malignancy:
Modifies the second paragraph as follows: Abnormal findings should be managed
according to standard clinical practice.

Section 7.5.1 Disease Assessments Methods for Glioma Grade 1-4 cohorts: Updates
both Tables to indicate that MRI with contrast is the only method of tumor assessment 
allowed at baseline and post-baseline for this particular cohort.

Section 7.5.2.1 Laboratory and Disease Assessments HCL:
o
Clarifies timelines as follows: “The following baseline disease assessments will be 
performed at the time points indicated in the Time and Event Table (Section 7.1)”
o
Clarifies that a BM aspirate is required at baseline.
o
Clarifies the timelines for post-baseline assessments as follows: A response is to be 
determined every 4 weeks based on the HCL response criteria (please consult 
Appendix 12) using data collected from the scheduled disease assessments.
o
Clarifies that a BM aspirate is required at post-baseline.
o
Modifies the the 4th bullet point (post-baseline) to read as follows “Flow cytometry
on BM aspirate sample will be performed as indicated in the Time and Event Table 
(Section 7.1)”
o
Clarifies assessments of lymph nodes and spleen as follows: If lymph nodes and/or 
spleen were enlarged at baseline, they must be followed by post-baseline assessments 
using a consistent imaging modality as indicated in the Time and Event Table 
(Section 7.1)

Section 7.5.2.2 Laboratory and Disease Assessment: MM:
o
Clarifies timelines of baseline assessments as follows: The following baseline disease
assessments will be performed at the time points indicated in the Time and Event 
Table (Section 7.1):
o
Simplifies list of baseline assessments as follows: Extramedullary disease.
o
Simplifies list of baseline assessments as follows: UPEP


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o
Modifies post-baseline assessment for MM cohort only as follows: Laboratory tests 
(SPEP, UPEP, CRP, β-2 microglobulin, serum FLC assay, levels of IgG, IgA, and 
IgM will be performed as indicated in the Time and Event Table (Section 7.1).
o
Modifies post-baseline assessment for MM cohort only as follows: Extramedullary
disease assessment:   If no disease is identified at baseline, then subsequent 
assessments are only required if clinically indicated.

Section 8.1 Dose Modification:
o
Revises the dose modification guidelines for trametinib as follows: If a dose 
reduction of trametinib is required, but the toxicity resolves and no additional 
toxicities are seen after one treatment cycle (4 weeks), the dose of trametinib may
be re-escalated but should not exceed 2 mg once daily.
o
Clarifies: If a dose reduction of dabrafenib is required, but the toxicity resolves 
and no additional toxicities are seen after one treatment cycle (4 weeks), the dose
of dabrafenib may be re-escalated but should not exceed 150 mg BID daily.

Section 8.1.1.3.2 Management of Hypertension Table 14: Clarifies foot note 3 as
follows: Escalation to previous dose level can be considered if BP remains well-
controlled for 4 weeks after restarting. Approval from the Medical Monitor is required.

Section 8.1.2 Pancreatitis: Clarifies the first paragraph as follows: “Subjects should be 
closely monitored when re-starting study treatment after an episode of pancreatitis.”

Section 8.2.1.2 Palmar-plantar Erythrodysesthesia: Adds a new Section as follows:
Palmar-plantar erythrodysesthesia (PPE) syndrome: Measures for PPE syndrome 
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) and symptomatic treatments.
Apply 
moisturizing creams frequently, topical keratolytics (e.g., urea 20 to 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.

Section 8.2.2.1 Cutaneous squamous cell carcinoma (cuSCC):
o
Updates the document reference number for the new  Investigator’s Brochure (v07) .
o
Deletes the following text: Approximately 70 % of events occurred within the first 
12 weeks of treatment with a median time to onset of 8 weeks. These should be 
surgically removed according to institutional practices. Dose modification or 
interruption of study treatment is not required for cuSCC or KA, however cuSCC 
should be reported as an SAE. Tumor tissue should also be submitted for further 
analyses as described in the SPM.
o
Adds the following paragraph: “In a Phase III study, 10% of patients receiving 
dabrafenib monotherapy developed cuSCC, with a median time to onset of the first 
occurrence of approximately 8 weeks.
In patients who received dabrafenib in 
combination with trametinib, 3% of patients developed cuSCC with median time to 
onset of the first occurrence of 32 weeks”




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Immunosuppressants may
result in decreased concentrations and loss of 
effectiveness.
∀
11.2 Definition of Serious Adverse Event:
o
Updates h) Protocol-specific SAEs first bullet point as follows: cuSCC (Section 
8.2.2.1), new primary melanomas (Section 8.2.2.2) and non- cutaneous malignancies 
(Section 8.2.2.3) with the exception of basal cell carcinoma (BCC). BCC should be 
reported as an AE or SAE based on the discretion of the investigator.
∀
Section 18.1 Hypotheses and Treatment Comparisons:
o
Revises the third paragraph to read as follows: “The study is powered to detect a high 
clinicallymeaningful response rate and is based on the hierarchical model assessment 
of whether there is sufficiently high probability that j exceeds Cj. The posterior 
probability that the ORR for a given histology is greater than Cj will be computed 
according to the following comparison:”
∀
18.2.1 Sample Size Assumptions:
o
Updates the first paragraph as follows: Each cohort of BRAF V600E mutation-
positive tumor type of a given histology will enroll a maximum of 25 subjects in the
primary analysis cohort as defined in Section 5.1. If all histologies enroll the 
maximum of 25 subjects, this will result in no more than 225 subjects in the primary 
analysis cohort.
o
Updates the second paragraph to include expansion cohort as follows: Enrollment 
into specific histology cohorts may be halted early based on results from interim 
analyses incorporating emerging response data. Response data from a minimum of 5 
subjects will be required in a histologic cohort before it may discontinue enrollment 
for futility and response data from a minimum of 10 subjects will be required before
discontinuing a histologic cohort for efficacy. If a cohort closes early for efficacy 
at an interim analysis, a histology specific expansion cohort (see Section 5.2) may 
be opened to allow additional enrolment. At the final analysis and after the study
has been closed, a minimum of 2 subjects will be required in a histologic cohort in 
order to meet statistical success at the final analysis.  See Section 18.3.2 for more 
details.
∀
Section 18.3.1 Analysis Population: Updates this particular section as follows: 
As the design for the study calls for repeated interim analyses to evaluate the 
accumulating efficacy data, it is necessary to shift the focus of the analysis 
population for efficacy depending upon the time at which the data are being 
analyzed.  Table 30 presents the population of interest based on the timing of the 
analysis for both efficacy and safety; accompanying definitions are provided 
beneath the table.
Table 30
Definition of Population for specific analysis
Analysis Period
Analysis Intent
Interim Analyses
Final Analysis
Efficacy
Primary
ITT/Evaluable
BRAF V600E


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Supportive
BRAF
V600/Evaluable
ITT Histology-
specific cohortsa
Safety
Primary
ATS
ATS
a Subset of the BRAF V600E population that include histologically similar 
subjects for cohorts that were stopped for promising efficacy; includes those from 
the primary analysis cohort and those from the expansion cohort, as defined in 
Section 5.1 and Section 5.2.
The BRAF V600E Population is defined as all enrolled subjects regardless of whether 
or not treatment was administered, who obtain positive verification of the BRAF 
V600E mutation from a certified central reference laboratory.
The Intent-to-Treat (ITT) population is defined as all enrolled subjects regardless of 
whether or not treatment was administered.
The All-Treated Subjects (ATS) population is defined as all subjects who receive at 
least one dose of dabrafenib (GSK2118436) or trametinib (GSK1120212).
The Intent-to-Treat (ITT)/Evaluable population is defined as all ITT subjects in 
the primary analysis cohort who are also evaluable according to the evaluability
defined in the interim analysis RAP.
The BRAF V600E/Evaluable Population is defined as all BRAF V600E subjects 
in the primary analysis cohort who are also evaluable according to the evaluability 
defined in the interim analysis RAP.

18.3.3 Final Analysis: Updates first paragraph as follows: The final primary analysis 
for ORR will occur once all subjects in the primary analysis cohorts have either 
discontinue treatment or have received treatment for at least 6 months, whichever comes 
first.

Section 18.3.3.1 Safety Analysis: Updates as follows: Safety data will be presented in 
tabular and/or graphical format and summarized descriptively according to GSK’s
IDSL standards. The ATS population will be used for the analysis of safety data. In 
general, safety data will be summarized by histology and across all cohorts.
Complete details of the safety analyses will be provided in the RAP.

Section 18.3.3.1.3 Other Safety Measures:
o
Deletes the word “MUGA” as planned on amendment 5. It reads as follows: The 
results of scheduled assessments of vital signs, 12-lead ECG, ECHO and ECOG 
performance status will be summarized.

Section 18.3.3.2 Efficacy Analyses:
o
Deletes the following paragraph: The BRAF V600E Population will be used for all 
final efficacy analyses and used as the supportive population for interim analyses for 


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ORR. The ITT Population will be used for interim analyses for ORR and used as the 
supportive population for efficacy analyses.
o
Updates the second paragraph as follows: “ORR will be analyzed using an integrated 
analysis with the hierarchical model as well as analyzed independently for each 
histology”
o
Updates the Response Subcategories in Table 31 to include Marker-Negative CR, 
Marker-Positive CR, Marker-Negative PR and Marker-Positive PR as response 
categories for the NSGCT/NGGCT cohort
o
Adds a reference to the RAP in regards to further details on response confirmation 
criteria for each histological cohort.
o
Modifies the following sentence: “Bayesian inference based on summary statistics 
from the posterior distributions of each ORR will be reported”
o
Clarifies the definition for Duration of Response as: Duration of response for the 
subset of subjects who have a confirmed response (See Table 31) is defined as the 
time from first documented evidence of response until the first documented sign of 
disease progression or death.

18.4.1 Simulation Description: Updates section to clarify that the expansion cohort will 
not be taken into consideration in the simulation description.

Section 20 References: Updates the reference to the new version of Dabrafenib
(GSK2118436) 
Monotherapy 
and 
Dabrafenib+Trametinib 
(GSK1120212)
Combination Therapy Investigator’s Brochure (v7).

Section 21.19 Appendix 19 Protocol Amendment Changes: Updates inconsistency with 
T&E Table: Laboratory tests (24-hr urine collection; SPEP, UPEP [perform if protein 
is present in 24-hr urine], CRP, β-2 microglobulin, serum free FLC
assay, 
immunoglobulin levels [IgG, IgA, and IgM]) will be performed as indicated in the Time 
and Event Table.
2012N145247 07
2016-Jul-19
Amendment No. 7
1. Delete or replace references to GSK or its staff with that of Novartis/Novartis and its 
authorized agents.
2. Make administrative changes to align with Novartis processes and procedures.




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INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol number BRF117019
I confirm agreement to conduct the study in compliance with the protocol, as amended by 
this protocol amendment.
I acknowledge that I am responsible for overall study conduct. I agree to personally conduct 
or supervise the described study.
I agree to ensure that all associates, colleagues and employees assisting in the conduct of the 
study are informed about their obligations. Mechanisms are in place to ensure that site staff 
receives the appropriate information throughout the study.
Investigator Name:
Investigator Address:
Investigator Phone Number:
Investigator Signature
Date


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LIST OF ABBREVIATIONS
AA
Anaplastic astrocytoma
ABMT
Autologus bone marrow transplant
ACS
American Cancer Society
ADL
Activities of daily living
AFP
Alpha fetoprotein
AE(s)
Adverse Event(s)
alloSCT
Allogenic stem cell transplantation
ALT
Alanine aminotransferase
ANC
Absolute neutrophil count
AO
Anaplastic oligodendroglioma
APXA
Anaplastic pleomorphic xanthroastrocytoma
ASI
Adenocarcinoma of small intestine
AST
Aspartate aminotransferase
ATC
Anaplastic thyroid cancer
ATP
Adenosine triphosphate
ATS
All-Treated Subjects
autoSCT
Autologous stem cell transplantation
BAL
Bronchioalveolar lavage
BBB
Blood brain barrier
BEP
Bleomycin, etoposide and cisplatin
-HCG
Beta-Human Chorionic Gonadotropin
BID
Twice daily or two times a day
BLQ
Below the lower limit of quantification
BM
Bone marrow
BP
Blood pressure
BRAFi
BRAF inhibitor
BTC
Biliary tract cancer
BUN
Blood urea nitrogen
C
Degrees centigrade
CBC
Complete blood count
cfDNA
Circulating free DNA
CI
Confidence interval
cm
Centimeter
Cmax
Maximum observed concentration
CNS
Central nervous system
CONSORT
Consolidated Standards of Reporting Trials
CR
Complete response
CRO
Clinical Research Organization
CRP
C-reactive protein
CT
Computed tomography
CTCAE
Common Toxicity Criteria for Adverse Events
cuSCC
Cutaneous squamous cell carcinoma
CYP
Cytochrome
DBP
Diastolic blood pressure
DILI
Drug-induced liver injury


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dL
Deciliter
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic acid
DPM
Dirichlet Process Mixtures
DRESS
Drug Reaction with Eosinophilia and systemic symptoms
DSC
Dynamic susceptibility contrast
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
ECHO
Echocardiogram
EDTA
Ethylenediamine tetraacetic acid
eCRF
Electronic case report form
EGFR
Epidermal growth factor receptor
EU
Europe
F
Degrees Fahrenheit
FDA
Food and Drug Administration
FDG-PET
[18F] fluorodeoxyglucose-positron emission tomography
FET
Fluoroethyltryrosine
FFPE
Formalin-fixed paraffin-embedded
FISH
Fluorescence in situ hybridization
FLAIR
Fluid attenuation inversion recovery
FLC
Free light chain
FSH
Follicle Stimulating Hormone
g
Gram
GBM
Glioblastoma
GCP
Good Clinical Practice
GCPH
Global Clinical Program Head
GCT
Germ cell tumor
GGT
Gamma glutamyl transferase
GI
Gastrointestinal
GIST
Gastrointestinal stromal tumor
GSK
GlaxoSmithKline
HA
Health Authority
HbA1C
Hemoglobin A1C
HBsAg
Hepatitis B surface antigen
HCC
Hepatocellular carcinoma
HCL
Hairy cell leukemia
HDCT
High dose chemotherapy
H/E
Hematoxylin and eosin stain
HMG-CoA
3-hydroxy-3-methylglutaryl-coenzyme A
HPMC
Hydroxypropyl methylcellulose
hr/hrs
Hour(s)
HR
Hazard ratio
HRT
Hormone replacement therapy
IB
Investigator brochure
IBW
Ideal body weight


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ICF
Informed consent form
ICH
International Conference on Harmonization
IDH
Isocitrate Dehydrogenase
IEC
Independent Ethics Committee
IGCCCG
International Germ Cell Cancer Consensus Group
Ig
Immunoglobulin
IHC
Immunohistochemistry
IMiD
Immunomodulatory drugs
IMWG
International Myeloma Working Group
INR
International normalized ratio
IP
Investigational product
IRB
Institutional Review Board
ITT
Intent-to-treat
IV
Intravenous
IVRS
Interactive voice response system
kg
Kilogram
L
Liter
LBBB
Left bundle branch block
LDH
Lactate dehydrogenase
LDT
Laboratory developed test
LFT
Liver function test
LLN
Lower limit of normal
LVEF
Left ventricular ejection fraction
LSLV
Last subject, last visit
m2
Meter squared
MAO
Mixed anaplastic oligoastrocytoma
MAPK
Mitogen-activated protein kinase
MCH
Mean corpuscular hemoglobin
MCHC
Mean corpuscular hemoglobin concentration
MCV
Mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
MEK
Mitogen-activated extracellular signal-regulated kinase kinase
MEKi
MEK inhibitor
MET
Methionine
mg
Milligram
MGMT
06-methylguanine-DNA-methyl transferase
mL
Milliliter
MM
Multiple myeloma
mm
Millimeter
mm3
Cubic millimeter
mmHg
Millimeters of mercury
MR
Minimal/minor response
MRD
Minimal residual disease
MRI
Magnetic resonance imaging
MSDS
Material Safety Data Sheet
msec
Milliseconds
MUGA
Multigated acquisition scan
NA
Not applicable


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NCCN
National Comprehensive Cancer Network
NCDB
National Cancer Data Base
NE
Not evaluable
ng
Nanogram
NGGCT
Non-geminomatous germ cell tumor
NHL
Non-Hodgkin’s lymphoma
NSAID(s)
Non-steroidal anti-inflammatory drug(s)
NSCLC
Non-small cell lung cancer
NSGCT
Non-seminomatous germ cell tumor
NYHA
New York Heart Association
ORR
Overall response rate
OS
Overall survival
PBSCT
Peripheral blood stem cell transplant
PCR
Polymerase chain reaction
PCV
Procarbazine, lomustine and vincristine
PD
Pharmacodynamic or progressive disease
PDGFRA
Platelet-derived grow factor receptor alpha
pERK
Phosphorylated extracellular signal related kinase
PET
Positron emission tomography
PFS
Progression-free survival
PK
Pharmacokinetics
PPE
Palmar-plantar erythrodysesthesia
PR
Partial response or partial remission
PS
Performance status
PT
Prothrombin time
PTC
Papillary thyroid cancer
PTT
Partial thromboplastin time
PXA
Pleomorphic xanthoastrocytoma
QTc
Corrected QT interval
QTcB
Bazett-corrected QT interval
RANO
Response Assessment for Neuro-Oncology
RAP
Reporting and Analysis Plan
RBC
Red blood cell
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
Ribonucleic acid
RPED
Retinal pigment epithelial detachment
RR
Response rate
RTK
Receptor tyrosine kinase
RVO
Retinal vein occlusion
SAE
Serious adverse event(s)
SBP
Systolic blood pressure
sCR
Stringent complete response
SCAR
Severe Cutaneous Adverse Reaction
SD
Stable disease or standard deviation
SEER
Surveillance, Epidemiology and End Results
SmPC
Summary of Product Characteristics
SPEP
Serum Protein Electrophoresis


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SPF
Skin protection factor
SPM
Study Procedures Manual
SUV
Standard uptake value
T/B
Tumor background ratio
TKI
Tyrosine kinase inhibitor
TMZ
Temozolomide
TSH
Thyroid stimulating hormone
ULN
Upper limit of normal
UGT
Uridine 5’-diphosphoglucuronosyltransferase
UPEP
Urine Protein Electrophoresis
US
United States
VEGF
Vascular endothelial growth factor
VGPR
Very good partial response
VHP
Voluntary harmonization procedure
VHP-SA
Substantial amendment of a Voluntary Harmonization Procedure
vs
Versus
WBC
White blood cells
WHO
World Health Organization


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1
INTRODUCTION
1.1
Background
The RAS/RAF/MEK/ERK pathway, also known as the mitogen-activated protein kinase
(MAPK) pathway, is a critical signal transduction cascade implicated in normal growth and 
the uncontrolled proliferation of many human cancers. Under normal physiological
conditions, signal transduction through the MAPK pathway is tightly regulated through
multiple negative feedback mechanisms [Niault, 2010]. However, this pathway can be
constitutively activated by alterations in specific proteins, including BRAF, which 
phosphorylates mitogen-activated extracellular signal-regulated kinase kinase (MEK) on
two regulatory serine residues. BRAF mutations have been identified at a high frequency in 
specific cancers [Davies, 2002].  Approximately 90% of all identified BRAF mutations that 
occur in human cancers are T1799A transversions (exon 15), which result in a V600E amino 
acid substitution [Wellbrock, 2004]. In melanoma, the BRAF V600E mutation has been 
identified in about 50% of subjects as a key driver mutation of tumorigenesis, and BRAF 
inhibitors (BRAFi), such as vemurafenib and dabrafenib, have demonstrated substantial 
efficacy in this setting [Chapman, 2011a].
While the introduction of BRAFi represent a significant advance in the treatment of BRAF 
V600 mutation-positive metastatic melanoma [Chapman, 2011a], limitations of this novel 
therapy have already been identified. As has been the pattern with other highly selective 
small molecule kinase inhibitors (e.g., imatinib, erlotinib and gefitinib) the rapid onset of 
drug resistance restricts the efficacy.  Understanding the specific mechanisms of resistance 
to BRAFi is critical for the development of more effective strategies to inhibit the MAPK-
pathway in order to delay or prevent the onset of resistance in BRAF-mutant melanoma.
Experimental data generated with a BRAFi and MEK inhibitor (MEKi) combination therapy 
in BRAF-mutant melanoma cell lines in vitro and xenografts in vivo support this concept by
demonstrating activity of the combination therapy in models of acquired RAF resistance.  
More importantly, superior anti-tumor activity of the BRAFi and MEKi combination as 
compared to each agent as monotherapy was also observed in BRAF-sensitive models. These 
data clearly indicate that a concomitant and more potent inhibition of the MAPK-pathway at 
the critical level of the BRAF- and MEK-kinases leads to a more pronounced tumor 
inhibition, thus significantly delaying the onset of resistance. In addition, pre-clinical safety 
data obtained with this combination therapy in a rat-model indicate that the potential for 
proliferative skin lesions and secondary cutaneous malignancies is reduced in comparison to 
treatment with a BRAFi alone [Su, 2012].
1.2
Dabrafenib (DRB436/GSK2118436)
Dabrafenib (GSK2118436) is an orally bioavailable, potent and selective RAF kinase
inhibitor of human wild-type B-RAF and C-RAF enzymes as well as the mutant forms of the 
BRAF enzyme, BRAF V600E, BRAF V600K and BRAF V600D. The mode of action of 
dabrafenib is consistent with adenosine triphosphate (ATP)-competitive
inhibition.  
Dabrafenib has demonstrated suppression of a downstream pharmacodynamic
(PD) 
biomarker phosphorylated extracellular signal-related kinase (pERK) in tumor cell lines, 
demonstrated anti-proliferative activity against multiple BRAF-mutant tumor cell lines, and 
achieved biomarker suppression and tumor regression in BRAF mutant xenograft 
models.BRAF mutations have been identified at a high frequency in specific cancers, 
including approximately 40 to 60% of melanomas.  The frequency of this activating mutation 


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and the pathway addiction to which it leads makes mutated BRAF an extremely attractive 
target. Dabrafenib has been approved in the United States (US), European Union (EU), and 
multiple other countries for the treatment of BRAF-mutant unresectable or metastatic
melanoma. In addition, dabrafenib is also being studied in a Phase II trial in BRAF- mutant 
non-small cell lung cancer (NSCLC).
Refer to the dabrafenib monotherapy and dabrafenib+trametinib combination therapy
Investigator’s Brochure (IB) for a complete summary of currently available preclinical, safety, 
pharmacokinetic (PK), and clinical data.
1.3
Trametinib (TMT212/GSK1120212)
Trametinib (GSK1120212) is a reversible, highly selective, allosteric inhibitor of MEK1 and 
MEK2 and kinase activity [Gilmartin, 2011].  Trametinib has been approved for the treatment 
of BRAF-mutant unresectable or metastatic melanoma in several countries, including the US, 
EU, Kazakhstan and Australia. Trametinib has been studied in Phase II trials in pancreatic 
cancer and RAS-mutant NSCLC as well as RAS-mutant acute myeloid leukemia.
Trametinib is non-competitive towards ATP and inhibits both MEK activation and kinase 
activity. Because BRAF and MEK are in the same pathway, and because MEK is a substrate 
of activated BRAF, inhibiting both proteins simultaneously rather than individually could 
provide more effective pathway inhibition. In addition emerging data indicate that acquired 
resistance to BRAFi is often associated with reactivation of the MAPK pathway, which might 
render BRAFi-resistant melanoma cells susceptible to the combination of BRAF and MEK 
inhibition [Alcala, 2012]. Data generated in cell line, mouse xenograft, and rat safety models 
with the combination of BRAFi and MEKi suggest enhanced effects on efficacy and less 
potential for proliferative skin lesions as compared to treatment with a BRAFi alone. 
Trametinib in combination with dabrafenib has been approved in the US, EU, Chile, and 
Australia for the treatment of patients with unresectable or metastatic melanoma with BRAF 
V600E or V600K mutation.
Refer to the dabrafenib monotherapy and dabrafenib+trametinib IB for a complete summary 
of the currently available chemistry, nonclinical, and clinical data to support the use of the 
combination in subjects with BRAF V600 mutation-positive solid tumors [GlaxoSmithKline 
Document Number CM2010/00010/05]. A separate IB is also available summarizing the 
preclinical, safety, PK, and clinical data for trametinib monotherapy [GlaxoSmithKline 
Document Number HM2009/00151/05].
1.4
Risk Assessment for Dabrafenib + Trametinib Combination
Therapy
The assessment of the risk of dabrafenib + trametinib combination therapy, and suggestions 
for management of risk, is based on non-clinical data and clinical data from the ongoing and 
completed dabrafenib and trametinib monotherapy and combination studies in adults.  In the 
event that any adverse events (AEs) are reported or observed, supportive treatment will be 
provided according to standard medical practice. Subjects will be withdrawn from the study
if a clinically significant toxicity is reported or observed.
The safety profile for dabrafenib + trametinib combination therapy has been established and 
is well-characterized in subjects with unresectable/metastatic melanoma, with consistent 
results across two randomized Phase III studies. The safety profile of the combination of 


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dabrafenib and trametinib generally reflect AEs of the individual agents; some notable 
exceptions are described below.
Cutaneous squamous cell carcinoma (cuSCC): In vitro experiments have demonstrated a 
paradoxical activation of MAPK signalling in kerationcytes and potentially other cells
harboring a wild-type BRAF kinase but a mutated RAS kinase upon exposure to a BRAFi.  
This paradoxical MAPK pathway activation is potentially associated with a higher risk for 
the development of cuSCC induction. Cases of cuSCC (which include those classified as 
keratoacanthoma or mixed keratoacanthoma subtypes) have been reported in subjects treated 
with dabrafenib + trametinib.
Skin examination should be performed prior to initiation of dabrafenib or dabrafenib +
trametinib treatment and while receiving therapy. Dermatologic examinations should be
performed following discontinuation of dabrafenib monotherapy or in combination with
trametinib, or until initiation of another anti-neoplastic therapy (see Section 7.1, Time and 
Events Table for schedule of assessments).
Cases of cuSCC should be managed by
dermatological excision; dabrafenib and trametinib treatment should be continued without 
any dose adjustment. A brief dermatological exam should be performed every 4 weeks (±7
days) for the first 6 months after discontinuation of study treatments to monitor for new 
cutaneous malignancies.
Subjects should be instructed to immediately inform their physician if new skin lesions
develop.
New primary melanoma: New primary melanomas have been reported in subjects with pre-
existing unresected or metastatic melanoma treated with dabrafenib monotherapy or in 
combination with trametinib.  These were identified within the first 5 months of treatment 
with dabrafenib and did not require treatment modification other than excision. Monitoring 
for skin lesions should occur as described for cuSCC.
Non-cutaneous secondary/recurrent malignancy: In vitro experiments have demonstrated 
paradoxical activation of MAP-kinase signaling in BRAF wild-type cells with RAS 
mutations which are exposed to BRAFi, which may lead to increased risk of non-cutaneous 
malignancies in subjects treated with dabrafenib.  Cases of RAS-driven malignancies have 
been seen with BRAFi including dabrafenib monotherapy or in combination with trametinib. 
Subjects should be monitored as clinically appropriate. Following discontinuation of 
dabrafenib monotherapy or in combination with trametinib, monitoring for non-cutaneous 
secondary/recurrent malignancies should continue for up to 6 months or until initiation of 
another anti-neoplastic therapy.
Rash: Skin-related toxicities, primarily rash (maculo-papular type rash with dabrafenib and 
acneiform-type rash with trametinib) have been reported with trametinib and dabrafenib 
monotherapies.  The incidence of trametinib-related rash across all previous trametinib 
monotherapy studies was 57%, with 7% of subjects experiencing Grade 3 rash events.
The incidence and severity of the majority of skin-related toxicities, especially those most
often seen with either trametinib or dabrafenib monotherapy, appear to be reduced when both 
compounds are combined.  Rash management guidelines are incorporated into all dabrafenib 
+ trametinib combination studies (see Section 8.2.1.1).
Severe Cutaneous Adverse Reactions: Cases of severe cutaneous adverse reactions (SCARs), 
including Stevens-Johnson syndrome, and drug reaction with eosinophilia and systemic 
symptoms (DRESS), which can be life-threatening or fatal, have been reported during 


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treatment with dabrafenib in combination with trametinib.  Guidelines for clinical 
management of treatment-related SCARs are provided in Section 8.2.1.3.
Ocular effects: Both dabrafenib and trametinib as monotherapies and in combination have 
been associated with ocular toxicities.  An ophthalmologist should be consulted if changes in 
vision develop. However, if the visual changes are clearly unrelated to study treatment (e.g., 
allergic conjunctivitis), then monitor closely as it may be reasonable to defer ophthalmic 
examination.
Treatment with dabrafenib has been associated with the development of uveitis, including 
iritis.
Monitor subjects for visual signs and symptoms (such as, change in vision,
photophobia and eye pain) during treatment.  Special attention should be given to retinal
findings (e.g., retinal pigment epithelial detachment (RPED)) or retinovascular abnormalities 
(i.e., branch or central retinal vein occlusions (RVO)).
For events of visual changes 
(regardless of severity) for which an ophthalmic examination is conducted, a blood sample 
for PK analysis must be drawn as close as possible to the time of the event. Subjects with a 
history of RVO should not receive trametinib.
Guidelines for clinical management of treatment-related ocular events including stopping
and dose modification criteria are detailed in Section 8.2.7. An ophthalmic evaluation is
required for subjects at Screening, Week 4 and as clinically indicated with additional exams 
required for subjects developing visual disturbances at any time while on trametinib therapy.
Pyrexia: Pyrexia has been reported in clinical trials with dabrafenib monotherapy and in
combination with trametinib. In dabrafenib monotherapy studies, pyrexia was one of the most 
frequently occurring AEs in up to 27% of subjects across all dabrafenib studies. Most of the 
pyrexia events (64%) were considered treatment-related.  The incidence and severity of
pyrexia are increased when dabrafenib is used in combination with trametinib. In subjects 
who received the combination dose of dabrafenib 150 mg twice daily (BID) and trametinib 2 
mg once daily and developed pyrexia, approximately half of the first occurrences of pyrexia 
happened within the first months of therapy.
About one-third of
the subjects who 
experienced pyrexia had 3 or more events.
Pyrexia may be accompanied by severe 
chills/rigors, dehydration and hypotension which in some cases can lead to acute renal 
insufficiency.
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 
101.3ºF but trametinib should be continued at the same dose. In the event of a fever, the 
subject should be instructed to take anti-pyretics (i.e., ibuprofen or acetaminophen/
paracetamol) as appropriate to control fever.
The use of oral corticosteroids should be 
considered in those instances in which anti-pyretics are insufficient. Monitor serum 
creatinine and other evidence of renal function during and following severe events of pyrexia.
(See Section 8.2.3 for additional details.)
Decreased left ventricular ejection fraction (LVEF):  Left ventricular dysfunction has been 
reported with trametinib as well as with other MEKi in clinical development. In the 2 Phase 
III studies decreased ejection fraction occurred in 7% of subjects receiving combination 
therapy and the majority of the LVEF decreases that met interruption criteria were 
asymptomatic and resolved.  Most subjects who were re-challenged were able to continue on 
treatment without further dose modification. Subjects enrolled in studies with dabrafenib in 
combination with trametinib undergo regular cardiac assessments with echocardiograms 


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(ECHOs). Guidelines for clinical management of treatment-related LVEF decreases have 
been provided in Section 8.1.1.2.
Hemorrhage: Hemorrhagic events, including major hemorrhagic events defined
as 
symptomatic bleeding in a critical area or organ, and fatal intracranial hemorrhages, have 
occurred in patients taking dabrafenib in combination with trametinib. The majority of 
bleeding events were mild. Three of 209 subjects (1%) receiving trametinib in combination 
with dabrafenib in a phase III trial had fatal intracranial hemorrhagic events. The management 
of hemorrhagic events may require treatment interruption, dose reduction, or treatment 
discontinuation.
Acute renal failure: Acute renal failure/renal failure has been reported in subjects receiving 
dabrafenib (monotherapy or in combination with trametinib), and a case of granulomatous 
interstitial nephritis has also been reported in a clinical study. 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.  (see Section 8.2.3 for additional details on pyrexia.) Prior to the start 
of study treatment, concomitant medications should be reviewed for the potential risk of 
inducing nephrotoxicity.  Concomitant medications should be modified if clinically possible. 
Management guidelines for renal failure, including management of pyrexia to minimize the 
risk of renal failure is included in Section 8.2.6.
Hyperglycemia:  Hyperglycemia requiring an increase in the dose of, or initiation of, insulin 
or oral therapy can occur with dabrafenib or dabrafenib in combination with trametinib.  
Monitor serum glucose levels as clinically appropriate during treatment with dabrafenib in 
subjects with pre-existing diabetes or hyperglycemia.  Advise subjects to report symptoms of 
severe hyperglycemia such as excessive thirst or any increase in the volume or frequency of 
urination.
Pancreatitis: Subjects receiving dabrafenib or dabrafenib in combination with trametinib 
have reported AEs of acute pancreatitis or pancreatitis.  In some cases, serious adverse events 
(SAEs) of Grade 4 pancreatitis were reported as treatment-related by the investigator. The 
time to onset of pancreatitis ranged from study Day 21 to 292 (median 138 days) with 
dabrafenib monotherapy, and from Study Day 24 to 312 (median 50 days) with combination 
therapy.  Discontinuation of study treatment due to pancreatitis was not deemed necessary in 
any of the cases by the investigators. For AEs of abdominal pain or suspected pancreatitis, 
amylase and lipase laboratory samples should be monitored locally.  Subjects should be 
closely monitored when re-starting dabrafenib after an episode of pancreatitis.
Hypersensitivity:
Hypersensitivity with dabrafenib has been reported by 1 subject who
experienced blister formation (bullous rash) within hours (hrs) of exposure to dabrafenib and 
upon re-challenge, requiring discontinuation of dabrafenib.  The subject recovered after 
interruption/discontinuation of dabrafenib. Hypersensitivity to trametinib has been reported 
by 1 subject 7 days after starting trametinib who experienced fever, asthenia, visual 
disturbance, and symptoms suggestive of a hypersensitivity reaction described by the 
investigator as “vascularity.” This subject also developed liver function test (LFT) elevations, 
lower limb nodules that by biopsy showed “dermo-hypodermatitis with plasmocyte and 
lymphocyte infiltrate.”  The subject recovered after discontinuation of trametinib.
Renal impairment: No dosage adjustment of dabrafenib or trametinib is required in subjects 
with mild or moderate renal impairment.
Mild or moderate renal impairment had no 
significant effect on the population PK of dabrafenib or trametinib. There are no clinical data 


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with dabrafenib or trametinib in subjects with severe renal impairment and the potential need 
for starting dose adjustment cannot be determined.  Dabrafenib and trametinib should be used 
with caution in subjects with severe renal impairment.
Hepatic impairment:
No dose adjustment is required for subjects with mild hepatic
impairment.
Based on the population PK analysis, mild hepatic impairment had no
significant effect on dabrafenib or trametinib oral clearance and thus exposure was not
significantly different in subjects with mild hepatic impairment compared to subjects with 
normal hepatic function.  There are no clinical data in subjects with moderate or severe 
hepatic impairment; therefore, the potential need for starting dose adjustment cannot be 
determined.  Dabrafenib and trametinib should be used with caution in subjects with 
moderate or severe hepatic impairment.
Use during Pregnancy and Lactation
Fertility: There is no information on the effect of dabrafenib or trametinib on human fertility.  
Animal studies with dabrafenib monotherapy or in combination with trametinib have shown 
reproductive toxicity which may impair fertility in humans. In dogs, rats and mice given 
dabrafenib and in dogs given dabrafenib in combination with trametinib, male reproductive 
effects, including testicular degeneration/depletion with secondary epididymal oligospermia, 
have occurred without clear evidence of reversibility. Male subjects should be informed of 
the potential risk for impaired spermatogenesis, which may be irreversible. Trametinib may
impair fertility in humans.
Pregnancy: No adequate and well-controlled studies of dabrafenib or trametinib in pregnant 
women have been conducted. Animal studies with trametinib and dabrafenib have shown 
embryo fetal developmental toxicities, including teratogenic effects. Dabrafenib or trametinib 
should not be administered to pregnant women or nursing mothers.  Women of childbearing 
potential should use effective methods of contraception during therapy and for 16 weeks
following discontinuation of trametinib when taken in combination with dabrafenib, or for 2
weeks following discontinuation of dabrafenib monotherapy. Dabrafenib may decrease the 
efficacy of oral hormonal contraceptives; therefore, an alternative method of contraception 
must be used. (see Section 9.1.1. for acceptable methods of contraception.)  If dabrafenib or 
trametinib is used during pregnancy, or if the subject becomes pregnant while taking
dabrafenib or trametinib, the subject should be informed of the potential hazard to the fetus.
Lactation: It is not known whether dabrafenib or trametinib is excreted in human milk.
Because many medicinal products are excreted in human milk, a risk to the nursing infant
cannot be excluded.
A decision should be made whether to discontinue nursing or to 
discontinue dabrafenib and/or trametinib, taking into account the importance of study
treatment to the mother.
1.4.1
Benefit Assessment
This is not the initial clinical experience with dabrafenib in combination with trametinib, 
therefore, the risk benefit ratio has been established and should be favorable if the anticipated
level of efficacy is demonstrated.
Other considerations for subjects who participate in this study may include:

Contribution to the ongoing process of developing a new treatment

Medical evaluations/assessments associated with study procedures (e.g., physical
examinations, electrocardiograms [ECGs], clinical laboratory tests, etc.)


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1.4.2
Overall Benefit: Risk Conclusion
Taking into account the measures to be taken to minimize the risk to subjects participating in 
this study, the potential risks identified in association with dabrafenib + trametinib 
combination therapy are justified by the anticipated benefits that may be afforded to subjects.
1.5
Histology-SpecificBackground
1.5.1
Cohort 1: Anaplastic Thyroid Cancer (ATC)
The American Cancer Society (ACS) estimates approximately 56,460 new cases of thyroid 
cancer in the US alone for 2012 [ACS, 2012].  Only 0.5% to 1.7% of all thyroid cancers are 
diagnosed as ATC [Papay, 2009; Pitt, 2010].
While differentiated thyroid cancers are 
typically curable, ATC is one of the most aggressive and fatal forms of thyroid cancer 
[Caronia, 2011].
Patients with ATC have the worst survival; a 1-year survival rate of 
approximately 10% [Goutsouliak, 2005].  Anaplastic thyroid carcinoma (ATC) is more 
commonly seen in females than males and is typically diagnosed in the elderly (median age: 
70 years) [Papay, 2009; Pitt, 2010].
Patients with ATC typically present with a rapidly growing neck mass and commonly with 
complaints of sore throat, hoarseness, coughing, dysphagia, dyspnea, and neck pain. Airway
and esophageal compromise is a major concern; therefore, obtaining local control of the 
disease in the neck is critical and essential to the quality of life of the patient in order to 
prevent asphyxiation and maintain oral nutrition with the hope of improving overall survival 
[Haigh, 2001; Papay, 2009; Pitt, 2010].  Methods utilized to improve local control in ATC 
include surgery and/or radiation therapy (e.g., radioactive iodine). The median survival from 
these methods is <6 months.
Surgery is limited as ATC tumors are rarely resectable at time of diagnosis due to ill- defined 
borders and/or attachment to surrounding vital structures in the neck [Haigh, 2001].  If the 
disease is confined to a local area, a total thyroidectomy is warranted to reduce symptoms 
due to the tumor mass; a tracheostomy is frequently required [GlaxoSmithKline Document 
Number HM2009/00151/05; Goldman, 1980]. There is some evidence suggesting that 
surgery followed by post-operative radiation therapy and chemotherapy results in improved 
outcome than radiotherapy alone [Haigh, 2001].
Patients who are not candidates for surgery or whose tumor cannot be surgically excised may
receive external beam radiation therapy.  However, treating ATC with high dose radiation is 
limited by the presence of the spinal cord and lungs due to their close proximity to the tumor 
target.  Combining radiation therapy with chemotherapy has been shown to prolong survival 
in patients who have also completed surgical resection [Posner, 2000].
Single-agent doxorubicin is typically considered the “standard” chemotherapy agent for
treating ATC in advanced disease with a reported response rate of approximately 22%
[Nagaiah, 2011]. It appears that the combination of doxorubicin plus cisplatin is more active 
than doxorubicin alone and has been reported to result in a greater number of responses (3
complete responses [CRs] and 3 partial responses [PRs]) being reported [Shimaoka, 1985].
Ain et al reported a 53% response rate (using a non-conventional definition of response rate) 
with one CR and nine PRs reported in 19 evaluable subjects treated with a 96-hr continuous 
infusion of paclitaxel [Ain, 2000].
However, the response rate did not translate to 
prolongation of median survival which was only 25 weeks.  Chemotherapy combined with 
radiation therapy in patients following complete resection has been evaluated and may


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provide prolonged survival [Haigh, 2001; DeCrevoisier, 2004].  None of the approaches to 
date provide sustainable duration of response.
Molecular signaling mechanisms such as activation of the RTK-RAS-RAF-MAPK pathway, 
p53 mutation, epidermal growth factor receptor (EGFR) expression and vascular epithelial 
growth factor (VEGF) secretion, are thought to be significant factors in the progression of 
ATC [Kojic, 2011].
Mutations of the RAS oncogene and p53, a well-known tumor-
suppressor gene, are frequently seen in molecular studies of ATC [Papay, 2009; Pitt, 2010].  
Recently alternations in the BRAF oncogene have been seen and may be involved in the 
progression of BRAF-mutated papillary thyroid cancer (PTC) to ATC.  Specifically, BRAF 
V600E mutation has been found in both PTC and papillary- derived ATC in which it initiates 
follicular cell transformation [Caronia, 2011; Kojic, 2011].  The average frequency of BRAF 
mutations in ATC is 24% and tends to have more aggressive phenotypes that often become 
resistant to traditional therapies. BRAF mutations may lead to changes in the sodium-iodide 
symporter limiting adjunct radioactive iodine treatment by decreasing iodine uptake [Kojic, 
2011].
Pre-clinical studies in human ATC cell lines have shown the importance of therapeutic agents 
that selectively target BRAF kinase, significantly inhibiting tumor growth [Caronia, 2011; 
Kojic, 2011].  Vemurafenib, a BRAFi, has shown decreased cell
proliferation and 
aggressiveness and markedly inhibit tumor growth in animal models using human ATC cell 
lines [Nucera, 2011].  Rosove et al reported a significant response to vemurafenib in a patient 
with BRAF-mutated ATC with radiological assessment confirming nearly complete clearing 
of metastatic disease after 38 days [Rosove 2013]. Trametinib in combination with 
dabrafenib is more active than dabrafenib and trametinib alone in BRAF V600E thyroid 
cancer lines.  The combination was synergistic and/or enhanced cell growth inhibition in 
three out of four, and induced apoptosis in 2 out of 4 BRAF V600E ATC lines.  Synergy was 
also observed in one BRAF V600E papillary and one undifferentiated thyroid carcinoma line. 
Such findings suggest that the combination of dabrafenib (BRAFi) with trametinib (MEKi) 
could be more effective than either MEKi or BRAFi alone for thyroid cancer therapy.
1.5.2
Cohort 2: Biliary Tract Cancer (BTC)
Biliary tract cancers (BTC) include a spectrum of invasive adenocarcinomas encompassing 
both cholangiocarcinoma, which refers to cancers arising in the intrahepatic, peri-hilar, or 
distal biliary tree, and gall bladder carcinoma.  Gallbladder carcinoma is an uncommon 
cancer in developed Western countries, afflicts approximately 12,000 people in the US 
annually, 
with 
a 
recently
appreciated 
increasing
incidence 
of 
intrahepatic 
cholangiocarcinoma [Hezel, 2010]. Cholangiocarcinoma is an adenocarcinoma of the bile 
duct with a poor prognosis given the invasiveness of the disease and its resistance to 
conventional chemotherapy.
About 5 to 10% of all primary
liver cancers are 
cholangiocarcinoma. Only 10% of patients present with early-stage disease and are 
considered candidates for surgical resection, which offers the only chance for cure. The 
prognosis is poor for the majority of patients with locally advanced or metastatic BTC, with 
a median survival of <1 year. No standard post-operative treatment has been established.
Gemcitabine with or without cisplatin is being studied for treatment in the adjuvant setting 
for gallbladder carcinoma, intra-hepatic and extra- hepatic bile duct.  Results of a study by
Valle et al concluded that gemcitabine plus cisplatin provided a significant survival advantage 
over gemcitabine alone. The median overall survival (OS) is 11.7 months with gemcitabine 
plus cisplatin vs. 8.1 months with gemcitabine monotherapy [Valle, 2010].


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Tannapfel et al conducted the first study of mutational status of BRAF in liver tumors where 
the frequency of mutations of BRAF and KRAS oncogenes in hepatocellular carcinoma 
(HCC) and cholangiocarcinoma was evaluated [Tannapfel, 2003]. No BRAF mutations were 
detected in HCC; however, specific BRAF mutations were noted in approximately 21% of 
the cholangiocarcinoma cases. Saetta et al reported in the second year that the BRAF 
mutations were observed in 7 of 21 (33%) gallbladder carcinomas examined [Saetta, 2004].  
In the Tannapfel et al study, mutations of KRAS (45% of cases) together with BRAF 
mutations (22%), the RAS/RAF/MEK/ERK/MAPK pathway had a high frequency of 
alteration in cholangiocarcinoma.  The results of such studies support the significance of the 
role disruption of the MAPK cascade may have in the development of gallbladder cancer.  
The alterations in the RAS/RAF/MEK/ERK/MAPK pathway may also play a significant role 
in new treatment strategies for BTC and support the use of BRAFi and/or MEKi.
1.5.3
Cohort 3: Gastrointestinal Stromal Tumors (GIST)
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors in the 
gastrointestinal (GI) tract, mainly within the stomach and small intestine. Most GIST cells 
are positive for c-kit.  Malignant GIST cells are expected to harbor a mutation of c-kit that 
results in the activation of c-kit leading to cell division and tumor growth. Tyrosine receptor 
inhibitors (TKIs) such as imatinib selectively inhibit c-kit and therefore, are indicated for the 
treatment of GIST.  Tyrosine kinase inhibitors (TKIs), imatinib and sunitinib, are currently 
the standard of care in treating metastatic or unresectable GIST. Imatinib is approved for 
first-line therapy of metastatic GIST with disease control achieved in approximately 85% of 
treated patients; median progression- free survival (PFS) is 20 to 24 months [Italiano, 2011].  
Sunitinib is the onlyapproved drug for imatinib-resistant GIST.  Clinical benefit was reported 
in approximately 50% of the patients treated, with a PFS of 7 to 10 months [Demetri, 2006].  
Mutational status of KIT and platelet-derived growth factor receptor alpha (PDGFRA) and 
albumin levels have been significantly associated with PFS [Italiano, 2011]. Low levels of 
albumin may be indicative of the nutritional status but also the presence of a systemic 
inflammatory response.
Following treatment with imatinib and/or sunitinib, patients with advanced GIST often
develop drug-resistant tumors which drive the need for alternative treatment.
Imatinib-
resistance is observed in 10 to 15% of patients following initial treatment with secondary 
resistance observed in almost all patients who initially have a clinical response from imatinib 
[Italiano, 2011].  Data has suggested that the resistance to imatinib in GISTs may be due to 
the activation of the MAPK pathway and may explain why some patients with GIST who are 
treated with imatinib fail to respond to treatment despite having KIT- sensitive mutations 
[Miranda, 2012].  While most of the GISTs carry mutations in KIT (80%) or the PDGFRA 
gene (8%), 3 to 13% of adult GIST cases have a wild-type genotype [Hostein, 2010; Agaram, 
2008; Caram, 2011].  The MAPK pathway (RAS/RAF/MEK/ERK) is one that is activated 
by KIT and PDGFRA. The BRAF protein when activated transmits signaling through the
MAPK pathway as well but only further downstream without the stimulation of KIT or 
PDGFRA.  BRAF mutations have been detected in a limited number of patients with 
imatinib-naïve or –resistant GISTs, occurring preferentially in small intestinal and gastric
high risk GISTs that lack the KIT and PDGFRA mutations [Agaram, 2008; Hostein, 2010].  
Drugs that inhibit KIT and PDGFRA would be ineffective in treating GISTs with BRAF 
mutations.  Patients with wild-type GIST have poor responses to TKIs and poor overall 
survival [Heinrich, 2008].  Therefore, these patients could benefit from having select BRAF 
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1.5.4
Cohort 4: WHO Grade 1 and 2 Glioma
According to the ACS, there were an estimated 22,910 new cases of malignant brain and 
other central nervous system (CNS) tumors in 2012, leading to over 13,700 deaths in the US 
alone [ACS, 2012].  Worldwide the number of new cases of brain and other CNS tumors 
diagnosed in 2008 was approximately 238,000 with an estimated 175,000 deaths [Ferlay, 
2011].  Gliomas account for 32% of all the primary brain tumors and are historically
classified by the World Health Organization (WHO) as either Grade 1 2, 3 or 4.
The most common pediatric brain tumor, pilocytic astrocytoma, occurs in 20% of brain
tumors in patients under 20 years of age and is classified as a WHO Grade 1 glioma [Sadighi, 
2013]. While the 10-year OS rate is high at 96%, recurrent and progressive disease occurs 
in 20% of patients [Sadighi, 2013].  In these patients, total resection remains the treatment of 
choice. For inoperable tumors, radiotherapy or chemotherapy is the first line treatment 
[Sadighi, 2013]. Recent findings have indicated that certain types of low grade and pediatric 
brain tumors, such as pilocytic astrocytoma, may have a higher rate of BRAF alterations 
[Schindler, 2011].
BRAF V600E mutations are also found in WHO Grade 1 gliomas 
including 18% of WHO Grade 1 gangliogliomas and 9% of pilocytic astrocytoma (especially
extra-cerebellar pilocytic astrocytoma) [Dias-Santagata,
2011; Schindler, 2011].  Such 
aberrations are known to activate the MAPK pathway which provides the platform by which 
novel molecular targeted therapy can develop. Agents such as MEKi can serve as novel 
treatment options for patients with progressive pilocytic astrocytomas.
Currently there are Phase II studies with MEKi such as selumetinib underway. Preliminary
results have indicated a favorable pharmacologic profile.  However, drug- resistance when 
administered as a single agent has been seen in some tumor models [Sadighi, 2013].  One 
explanation for this resistance may be due to the activation of an alternative pathway such as 
MEK-1 mutations.  Therefore, it may be more effective to offer a combination therapy than 
single agent to decrease the potential for resistance.
WHO Grade 2 tumors such as diffuse astrocytoma, oligodendroglioma and oligoastrocytoma 
are usually non-enhancing (>90%) and typically affect patients in their third and fourth 
decade of life. Although WHO Grade 2 tumors have a less aggressive course than WHO 
Grade 3 or 4 gliomas that are considered to be high grade, the outcome of these tumors is 
ultimately fatal in most patients.
BRAF V600E mutations have been identified in 
approximately 60% of WHO Grade 2 pleomorphic xanthoastrocytoma (PXA), (a similar 
mutation rate as seen in melanoma).
For adult WHO Grade 2 gliomas, treatment guidelines have been established.  Surgical 
resection represents the first treatment option.  For patients with unfavorable prognostic
factors such as older age, incomplete or no resection and existing neurological symptoms,
adjuvant radiotherapy is indicated. Chemotherapy is an option for patients with recurrence 
after surgery and radiation therapy and is also an option as initial treatment for patients with 
large residual tumors after surgery or unresectable tumors, especially when 1p/19q loss is 
present.  Treatment with procarbazine, lomustine and vincristine (PCV) or temozolomide 
(TMZ) yield similar response rate and duration of response with a toxicity profile favoring 
TMZ.  The prognosis of patients who have recurrent or progressive disease following 
radiotherapy and chemotherapy is usually poor.
The Response Assessment for Neuro-Oncology (RANO) Working Group proposed a
response criteria for non-enhancing low grade tumors to be adapted in clinical trials when
response rate or PFS is used as the primary endpoint. In addition to CR and PR categories in 


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WHO Grade 3 or 4 glioma Modified RANO response criteria, minor response (MR) is 
proposed as an additional response category of the WHO Grade 1 or 2 Modified RANO 
response criteria.  In contrast to WHO Grade 3 or 4 glioma, MR is assumed to be particular 
important for WHO Grade 1 or 2 gliomas for it is often the best achievable response category
[van den Bent, 2011].
Several preclinical studies have been performed to evaluate the brain penetration of 
dabrafenib.  A single dose brain study in mice and a positron emission tomography (PET)
study in pigs were performed that showed no brain penetration.  There is additional data after 
repeat dosing in mice that may suggest that the metabolite, M8, could possibly penetrate an 
intact blood-brain barrier (BBB).  In the clinic, activity has been reported in subjects with 
brain metastases but the penetration is thought to be related to non-intact BBB or limited 
contribution with M8.
With trametinib, following a single oral dose of [14C] GSK1120212 (trametinib) at 8 mg/m2, 
tissue distribution of radioactivity was widespread and consistent with the high permeability
and moderate to high distribution of trametinib, detectable levels of drug- related material 
were observed in brain tissue 2 hrs post-dose but declined rapidly to below the lower limit of 
quantification (BLQ) by 24 hrs post-dose.
In vivo anti-tumor activity of trametinib has been assessed in mice with doses as low as 1 
mg/kg reaching blood concentrations that caused sustained reductions of pERK, an 
accumulation of p27, and a decrease of Ki67 in tumor xenografts; brain exposure levels were 
~10% of those in blood, and no significant pERK inhibition was measured in brain tissue.
1.5.5
Cohort 5: WHO Grade 3 and 4 Glioma
Gliomas classified by the WHO as either Grade 3 or 4 are often referred to as high-grade.
The incidence of adult high grade gliomas is 2 to 4 per 100,000 patients [Perry, 2004]. WHO 
Grade 3 or 4 gliomas are locally invasive and associated with a poor prognosis and include 
Grade 3 anaplastic astrocytoma (AA), anaplastic oligodendroglioma (AO), anaplastic mixed 
anaplastic oligoastrocytoma (MAO), anaplastic pleomorphic xanthroastrocytomas (APXA) 
and Grade 4 glioblastoma (GBM) and accounts for approximately 60 to 75% of all gliomas 
[Hadziahmetovic, 2011].  Metastasis outside of the CNS has been reported but is extremely
infrequent until multiple local relapses have occurred.
Biologic markers, such as O6-
methylguanine-deoxyribonucleic acid (DNA)-methyltransferase (MGMT) and mutation 
status, may be useful predictors of outcome in patients with WHO Grade 3 or 4 gliomas.
WHO Grade 3 anaplastic gangiogliomas and WHO Grade 4 GBM have also been reported to 
have BRAF V600E mutations [Dias-Santagata, 2011; Schindler, 2011].  pERK was detected 
in all tumors independent of the BRAF mutation status [Dias-Santagata, 2011].
Historically, the gold standard for treating WHO Grade 3 or 4 gliomas has been surgery
followed by radiotherapy resulting in an estimated 5-year OS of 2 to 3 % [Hadziahmetovic, 
2011].  Demonstrating efficacy with the addition of chemotherapy to the treatment standard 
has been more difficult. The treatment of WHO Grade 3 or 4 gliomas with carmustine or a 
combination regimen of PCV has recently shifted to the addition of concurrent or adjuvant 
TMZ with radiation.  Until recently the treatment of all WHO Grade 3 or 4 gliomas has been 
much the same; however, ongoing clinical trials are segmenting the Grade 4 gliomas so the 
treatment modalities can focus on AA, AO and anaplastic MOA tumors [Hadziahmetovic, 
2011].  The European Organization for Research and Treatment of Cancer (EORTC) 
conducted a randomized trial in AA, AO and anaplastic MOA tumors in adjuvant 


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radiotherapy with or without PCV chemotherapy.  The addition of PCV improved the PFS 
(1.9 vs. 1.1 years) but not OS (3.4 vs. 2.6 years) [Hadziahmetovic, 2011].  Seeking a more 
favorable regimen, studies with TMZ have reported objective response rates of 58% with 32% 
CRs, rate of progression of only 10% with TMZ administered prior to radiation.
Considerable interest in determining the frequency and distribution of BRAF V600E 
mutations in central and peripheral nervous system tumors has been generated recently to
help identify the tumor entities that may potentially benefit from BRAF V600E targeted 
therapy. In study BRF113929, which was to evaluate the safety and efficacy of dabrafenib 
in subjects with BRAF V600E/K mutation-positive melanoma metastatic to the brain, 
response rates of 31% and 39% were observed in 74 subjects without prior brain treatment 
and 53 subjects with treatment.  This suggests that the study treatment can have activity in 
brain tumors.
1.5.6
Cohort 6: Non-Seminomatous/Non-Germinomatous Germ Cell
Tumors (NSGCT/NGGCT)
The worldwide incidence of germ cell tumors (GCT) has more than doubled in the past 40
years.  Germ cell tumors (GCTs) are relatively uncommon and account for only 2% of all 
human malignancies.  Non-seminomatous germ cell tumors (NSGCT) are malignant
extragonadal germ cell tumors that generally form in the pineal gland of the brain, the
mediastinum or the abdomen from cells meant to form sperm in the testicles or eggs in the 
ovaries and account for 48% of all GCTs.  These tumors are managed in the same way as 
testicular GCTs. In the US, approximately 8,590 new cases of testicular cancer will be 
diagnosed in 2012 [Siegel, 2012].  Testicular cancer is the most common solid tumor in males 
between the ages of 15 and 35 years with 95% of the testicular cancers being testicular GCTs 
(evenly reported as seminoma and non-seminoma) [Le Gal, 2005; Mannuel, 2011].
Non-seminomatous GCTs (NSGCTs) tend to be more clinically aggressive and grow quicker 
than the seminoma-type of GCT.  If untreated, NSGCTs can spread to the lungs, liver, lymph 
nodes, or bones. Common risk factors include being male, under the age of 20 and having 
Klinefelter syndrome [Nichols, 1987].  Chest pain and difficulty breathing are early signs of 
NSGCT. Other symptoms include: cough, fever, headache, and change in bowel habits, 
fatigue, difficulty walking and visual problems (difficulty seeing or moving eyes).  Testicular 
GCTs present with a painless, solid testicular mass and often discomfort or swelling; 
persistent conditions warrant further evaluation.
Serum tumor markers alpha-fetoprotein (AFP), lactate dehydrogenase (LDH) and beta-
human chorionic gonadotropin (β-HCG) are used in determining the diagnosis and prognosis 
as well as assessing treatment in GCTs.
These tumor markers are especially useful in 
monitoring NSGCT at all stages. Tumor markers AFP and β-HCG are more specific than 
LDH; AFP may be seen at any stage of disease.  An elevation in AFP generally indicates the 
presence of an undetected focus of non-seminoma [Nazeer, 1998; Weissbach, 1997]. An 
elevated β-HCG should be interpreted with caution if the use of marijuana is suspected or 
the development of hypogonadism as benign elevation in  β-HCG may result.
In 1997, the International Germ Cell Cancer Consensus Group (IGCCCG) developed a
classification system based upon prognostic factors such as extent of disease and serum tumor 
markers. Post-orchiectomy markers are used to determine the IGCCCG risk classification 
[IGCCCG, 1997].  This classification categorizes patients into risk groups designated as good, 
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Following diagnosis, NSGCT patients with persistent elevation of serum tumor markers are
typically treated with a cisplatin-based chemotherapy regimen consisting of 4 cycles of 
bleomycin, etoposide and cisplatin (BEP) considered the standard first-line therapy
[Williams, 1987; Hinton, 2003]. Although the tumor volume tends to be very large, initial 
debulking surgery is rarely considered useful.  Long-term disease-free survival may be 
achieved following post-chemotherapy surgery to resect residual disease following initial 
chemotherapy treatment [Schneider, 2004]. Patients with NSGCT who relapse following 
first-line chemotherapy generally have poor responses to salvage chemotherapy or bone 
marrow (BM) transplantation and are therefore candidates for new therapies [Saxman, 1994; 
Beyer, 1996]. Gemcitabine containing palliative chemotherapy provides 30 to 40% ORR 
with median survival only between 5 to 9 months [Bokemeyer, 2008; Einhorn, 2007].
The median OS is 6 to 9 months following treatment with best supportive care
[Kollmannsberger, 2004; Einhorn, 2007].  The cure rate for intermediate risk (Stage IIIB)
NSGCT is approximately 70% following 4 cycles of BEP [DeWit, 1998; Frohlich, 1998]. In 
the poor risk (Stage IIIC) patients, between 20 and 30% of all patients with metastatic
NSGCT remain not cured following cisplatin-based chemotherapy.
Less than 50% of
patients experience a durable CR to BEP, leaving them with limited treatment options other 
than investigational therapy [Jones, 2003].
Of the patients with NSGCT who develop refractory disease, the BRAF V600E mutation is 
detected in 2 to 3% [Mayer, 2010; Honecker, 2009].  The BRAF V600E mutation is not 
detected in seminomatous GCT.
The tumors with the positive mutation tend to be
extragonadal, especially with an origin in the mediastinum.  Furthermore, the BRAF V600E 
mutation has only been reported in adult NSGCT patients, excluding pediatric or adolescent 
patients [Masque-Soler, 2012].  As seen in melanoma, those patients with NSGCT and the 
BRAF positive-mutation show a trend to longer PFS.
1.5.7
Cohort 7: Adenocarcinoma of the Small Intestine (ASI) including
Periampullary and Ampullary
Adenocarcinoma of the small intestine (ASI) is a rare cancer; less than 2.3% of GI cancers 
arise in the small intestine. According to the ACS, 6230 new cases and 1110 deaths due to 
small intestine cancers were estimated in 2009 in the US. Adenocarcinoma of the small 
intestine (ASI) has historically been the most commonly diagnosed histologic subtype of 
small bowel tumors, but has recently been surpassed by carcinoid tumors according to the 
National Cancer Data Base (NCDB). There are approximately 2000 to 3000 new patients 
per year in the US [Bilimoria, 2009; Jemal, 2009]. Adenocarcinoma of the small intestine 
(ASI) typically includes those arising from the ampulla of Vater and the periampullary region; 
however, these were not included in the NCDB in the category of small bowel tumors.
Tumors of amulla of Vater include tumors arising in the ampulla (intra-ampullary type), 
tumors arising in the periampullary region of the duodenum (periampullary type), or tumors 
involving both the intra- ampullary and periampullary region of the duodenum (mixed 
periampullary and intra- ampullary type).  The rare nature of ASI has led to a poor 
understanding of disease pathogenesis, delay in diagnosis, and a paucity of information 
regarding treatment. Thirty-two percent of patients with ASI present with advanced disease 
[Overman, 2012]. The treatment of choice for ASI is curative surgical resection. However, 
no standard protocol has been defined for use when the disease is unresectable or relapsed.
The majority of chemotherapy experience has been with 5-fluororuacil, alone or in
combination with some of the newer chemotherapeutic agents such as irinotecan, platinum 


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compounds and gemcitabine. Response rates with chemotherapy agents have ranged from 
6% and 41%.  The median OS was between 9 to 18.6 months [Speranzaa, 2010]. Mutations 
of BRAF V600E were detected in 4 out of 37 subjects with ASI by Warth et al [Warth, 2011] 
and in one periampullary adenocarcinoma by Schonleben et al [Schonleben, 2009].
1.5.8
Cohort 8: Hairy Cell Leukemia (HCL)
Hairy cell leukemia (HCL) is a rare B-cell lymphoproliferative disease accounting for 2 to 
3% of all leukemias in adults in Western world [Riccioni, 2007]. The incidence in the US 
was 0.33 per 100,000 in 2011 [Morton, 2006]. Virtually all patients with HCL carry the 
BRAF V600E mutation, the HCL variant, which typically presents with leukocytosis instead 
of leukopenia, and absence of CD25, TRAP or Annexin A1, is uniformly wild-type for BRAF 
[Xi, 2012; Tiacci, 2011; Matutes, 2003]. Sequencing the gene in 47 HCL patients disclosed 
BRAF V600E mutations in nearly all patients.  pERK was also found in BM biopsies from 
these patients indicating that the BRAF mutation was activating. Incubation of primary hairy
cells with a BRAFi led to reversal of ERK and MEK phosphorylation [Tiacci, 2011].  
Recently, Dietrich et al reported that a refractory HCL patient had been successfully treated 
with a BRAFi validating that BRAF mutation is an appropriate therapeutic target in HCL
[Dietrich, 2012].
Patients are categorized as having untreated HCL or progressive HCL for the purpose of 
determining treatment.
Treatment is based on symptomatic cytopenias, massive
splenomegaly or the presence of other complications.  Ten percent of all patients will not
require any treatment [Saven, 2001].  Untreated HCL is characterized by splenomegaly,
leukopenia and/or pancytopenia, and BM infiltration by an atypical cell with prominent
cytoplasmic projections (i.e., hairy cells). Bone marrow (BM) biopsy is required for
diagnosis and to determine the degree of hairy cell infiltration. Asymptomatic disease is
often not treated if blood counts remain in an acceptable range [Grever, 2011]. Replacement 
of the BM by hairy cells with pancytopenia refractory to treatment characterizes progressive 
HCL.  The treatment of choice for patients with advanced HCL is cladribine (2-
chlorodeoxyadenosine, 2-Cda) or pentostatin (2-deoxycoformycin); both with comparable 
response rates [Gidron, 2006; Grever, 2011]. The survival rate with systemic therapy is 
estimated to be >85% at 5 years following the initiation of systemic therapy [Estey, 1992;
Frassoldati, 1994].
Consolidation or maintenance therapy with additional purine analog in preventing relapse or 
disease progression following purine analog treatment has not been formally evaluated, but 
the clinical impression is that repeated courses of purine analog have increasing cumulative 
toxicity with decreasing benefit, and should not be added unless patients require retreatment 
due to cytopenias.
Moreover, cytopenias due to disease requiring retreatment must be 
differentiated from cytopenias due to toxicity, and it is very rare for retreatment within 6 
months after prior purine analog therapy to be advisable. Most patients have relapsed disease
by 16 years [Else, 2009].  There is no plateau on the disease-free survival curves to suggest 
that purine analogs can cure HCL [Goodman, 2003; Else, 2009].  At a median of 16 years 
after treatment, the Scripps population of 358 subjects contained 19 who were still being 
followed in continuous complete remission, nine of whom were still without evidence of 
minimal residual disease (MRD) [Sigal, 2010].  Thus, it is not clear if purine analogs have 
curative potential, but clearly they fail in most patients who live long enough. Multiple 
immune defects present in HCL appear to have a role in the development of second cancers.
Skin cancers were found to be the most numerous before the availability of nucleoside 


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analogs for the treatment of HCL [Dasanu, 2010].  Treatment with either nucleoside analogs 
can result in profound CD4 suppression that may last up to 4 years [Seymour, 1994; Seymour, 
1997], and this may increase the risk of secondary malignancies [Goodman, 2003; Hisada
2007]. A study of HCL survivors from the Surveillance Epidemiology and End Results 
(SEER) database confirmed the increased risk of second cancers, especially for Hodgkin 
lymphoma and non-Hodgkin’s lymphoma (NHL), among those treated with cladribine but 
not with pentostatin [Morton, 2006; Hisada, 2007; Dasanu, 2010]. For those patients who 
experience severe thrombocytopenia, splenectomy may be considered, particularly if all 
other options have failed.
However, while splenectomy derives a palliative, usually
temporary benefit in blood counts, few patients have sustained remissions [Golomb, 1983], 
and disease may continue to worsen in the blood, lymph nodes, BM and visceral sites.
Virtually all patients progress and the median OS in large retrospective studies were less than 
6 years [Jansen, 1981; Chrobak, 1993; Haberman, 2006; Haberman, 2011]. Interferon-alpha 
is largely a drug of historical significance [Haberman, 2006; Haberman, 2011]. In fact, the 
response rate was 0% in subjects not responding to pentostatin who crossed over to interferon 
[Grever, 1995].
Patients who relapse after the first course of cladribine or pentostatin treatment often respond, 
but with less chance of CR, to repeated treatment with purine analog, with no benefit if a 
different purine analog is used [Saven, 1998; Else, 2009]. Rituximab, although not approved 
for HCL by the US Food and Drug Administatrion (FDA), remains a common treatment but 
most patients, particularly those with prior purine analog treatment and significant disease 
burden, do not respond and need alternative treatment. In a study of 24 subjects with prior 
therapy with purine analogs and need for retreatment due to cytopenias, the overall response 
rate (ORR) of rituximab was only 26% with only 13% CRs [Nieva, 2003].  Rituximab with 
cladribine or pentostatin may be an alternative, but the increased efficacy of this combination 
must be weighed against its toxicity, and it is not considered standard at this time [Else, 2007; 
Else, 2009; Ravandi, 2006]. In clinical practice, pentostatin is usually not considered for 
patients already resistant to cladribine, and vice versa. Thus, there is an unmet medical need 
for a non-chemotherapy option in HCL resistant to purine analogs.
1.5.9
Cohort 9: Multiple Myeloma (MM)
Multiple myeloma (MM) is a systemic malignancy of plasma cells in the BM that secretes 
all or part of a monoclonal antibody. It is the second most common hematologic malignancy, 
accounting for 10% of all hematologic cancers and 2% of annual cancer- related deaths 
[Anderson, 2011].  The incidence of multiple myeloma in the US in 2008 was 5.579 per 
100,000 [Ferlay, 2011]  According to the ACS, it was expected that almost 21,700 new cases 
of MM and 10,700 MM related deaths would occur during 2012 [ACS, 2012].
Chapman et al and Walker et al genotyped MM patients and detected the BRAF V600E
mutation in 2.4% and 4%, respectively [Chapman, 2011b; Walker, 2012]. The finding of
BRAF mutations in patients with MM has important clinical implications because such 
patients may benefit from treatment with a BRAFi. These results also support the observation 
that inhibitors acting downstream of BRAF (i.e., MEK) may have activity in MM [Kim, 
2010].
Multiple myeloma (MM) is further classified on the basis of the patient’s characteristics.
Patients who are younger than 65 years of age and without other severe co-morbidities are 
considered eligible for allogenic stem cell transplantation (alloSCT). Patients older than 65 
years or with serious co-morbidities are usually not considered SCT candidates and a gentler 


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approach is needed.  Although MM is not curable, it is treatable.  The median survival with 
chemotherapy is 24 to 30 months with a 10-year survival rate of 3%.  With newer therapies 
of immunomodulatory drugs (IMiD: thalidomide, lenalidomide), proteosome inhibitor 
(bortezomib) and stem cell transplantation, the median OS has been prolonged 7 to 8 years 
[Kumar, 2008; Anderson, 2011].
In the bortezomib registration study of over 600 subjects, the response rate to bortezomib and 
dexamethasone for subjects with MM relapsing after at least one systemic therapy not 
containing bortezomib was 38% [Richardson, 2005]. The PFS for the bortezomib arm in this 
study was 6.2 months (median follow-up of 8.3 months). A subset analysis showed that the 
ORR and survival was higher for the less heavily pre-treated subjects. Amongst the IMids, 
both thalidomide and lenalidomide have been extensively investigated in the 
induction/consolidation/maintenance settings and both agents have been approved by the US 
FDA.
Despite these agents and along with other agents such as carfilzomib and pomalidomide, MM 
continues to remain incurable.  In particular, patients resistant to novel agents represent a 
challenging group. Kumar et al. conducted an analysis in subjects who relapsed or were 
refractory to one of the IMiDs as well as bortezomib that determined the median event-free 
survival to be 5 months and the median OS was 8 months [Kumar, 2010]. Therefore, these 
patients require novel strategies.
2
RATIONALE
2.1
Rationale for the Combination of Dabrafenib and Trametinib
Pre-clinical studies have demonstrated that the combination of dabrafenib and trametinib is
synergistic and/or enhances cell growth inhibition in majority of the BRAF V600E mutant 
melanoma, colon, thyroid, and lung cancer cells.  The combination delayed dabrafenib 
resistance and reduced hyperproliferation skin adverse effect in pre-clinical models.  The 
scientific rationale suggesting MEK-mediated re-activation of the MAPK pathway as a 
prominent mechanism of resistance to BRAFi single-agent therapy supports the combination 
study of trametinib with BRAFi in cancer [Alcala, 2012; Greger, 2012]. Because BRAF 
V600E mutated tumors have been shown to develop resistance to BRAF inhibitors, the 
combination of a BRAFi and MEKi provides a rational approach for dual vertical inhibition 
within the MAPK pathway to address such drug resistance [Johannessen, 2010].  Both have 
demonstrated substantial clinical activity with ORR between 28 to 53% and PFS ranging 
between 4.8 to 5.1 months. Further, the combination of both dabrafenib and trametinib 
indicated increased efficacy over both monotherapies with ORR of 63% and an increase of 
PFS to approximately 10 to 11 months for the 150 mg BID dabrafenib and 2 mg once daily 
trametinib dose cohort [Flaherty, 2012; Hauschild, 2012; Weber, 2012]. Furthermore, the 
combination of dabrafenib and rametinib has demonstrated overall survival of a median of
more than 25 months in advanced melanoma. This robust survival data for the combination 
is further supported by other efficacy measures such as progression free survival of >11 
months , overall response rates  of about 64-69% (13-16% of patients achieving a complete
response) with duration of response of 12.9-13.8 months and a disease control rate of 94% 
across two randomized Phase-III studies. (Long GV ,2015; Robert C, 2015).
Substantial safety and efficacy data across these clinical development programs in metastatic 
melanoma demonstrated the scientific validity of dual inhibition targeting the MAPK 


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pathway through dabrafenib and trametinib in human cancer.  The combination therapy of 
dabrafenib + trametinib may offer greater benefit to BRAF V600E mutated cancers than 
either agent alone.
2.2
Study Rationale
Mutations of BRAF V600E have been identified at a high frequency in melanoma, PTC, 
colorectal and ovarian cancers. Such mutations have also been reported in some rare cancers 
such as ATC, HCL, GIST, NSGCT/NGGCT, BTC, MM, ASI (including periampullary and 
ampullary), WHO Grade 1 and 2 gliomas and WHO Grade 3 and 4 (high-grade) gliomas.  
These rare cancers have an incidence rate in the US ranging between 0.07 to 6.3 per 100,000 
and have a frequency of BRAF V600E mutations ranging between 3% in WHO Grade 3 and 
4 glioma to 90% in HCL (refer to Table 1) [Caronia, 2011; Tiacci, 2011; Hostein, 2010; 
Mayer, 2010; Honecker, 2009; Borger, 2012; Chapman, 2011a; Chapman, 2011b; 
Schonleben, 2009; Warth, 2011; Schindler, 2011]. These BRAF-mutated rare cancers have 
no effective treatment available either in the first-line setting for ATC, ASI and BRAF 
V600E-mutated GIST or in the refractory disease setting for NSGCT/NGGCT, BTC, WHO 
Grade 1 or 2 glioma, WHO Grade 3 or 4 glioma, HCL and MM.  Therefore, there is a high 
unmet medical need for these rare cancer indications.
Table 1 Overall Incidence Rate and BRAF V600E Mutation Rate of Rare Cancers
Tumor Type
Overall Incidence Rate per
100,000 in US (2011)
BRAF V600E Mutation
Rate (%)
Anaplastic Thyroid Cancer (ATC)
0.10
24%
Biliary Tract Cancer (BTC)
0.6
7 to 30%
Gastrointestinal Stromal Tumor (GIST)
0.7 to 1.1
2 to 5%
Germ Cell Tumor (GCT)
(approximately 50% non-seminomatous)
6.31 (White males)
1.38 (Black males)
3%
World Health Organization (WHO) Grade 1 or 2 
glioma
6.5
Approximately 7%
WHO Grade 3 or 4 glioma
2 to 4
Approximately 3%
(glioblastoma [GBM])
Hairy Cell Leukemia (HCL)
0.33
90 to 100%
Multiple Myeloma (MM)
5.579
4%
Adenocarcinoma of the Small Intestine (ASI)
0.073
Approximately 10%
References: Caronia, 2011; Tiacci, 2011; Hostein, 2010; Mayer, 2010; Honecker, 2009; Borger,
2012;Chapman, 2011b; Schonleben, 2009; Warth, 2011; Schindler, 2011
It is expected that in some of these BRAF-mutated rare cancers substantial clinical activity
of BRAF and MEK inhibition will be observed similar to that in metastatic melanoma 
(breakthrough efficacy).  For most rare cancers, conventional drug development programs 
are not feasible due to the low incidence of disease and the limited commercial opportunities.
These challenges may reduce the incentive to explore the potential benefit of new targeted 
therapies for rare cancers. An alternative and likely more feasible approach may be based on 
the detection of BRAF V600E mutations in these rare cancers as a common denominator for 
investigation of a BRAF + MEK inhibitor in such well-defined subject populations.  Enriched 
Bayesian statistical designs and a high target effect size may enable meaningful clinical 
investigation of targeted therapies in these small patient groups.
A somewhat similar approach was taken with imatinib, where several label indications were 
granted by US FDA based on an open-label, Phase II clinical trial of imatinib in subjects with 
multiple rare tumor types associated with imatinib sensitive tyrosine kinases along with 


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published reports. The results of this one Phase II study in 186 subjects provided the basis 
for approvals in myelodysplastic/ myeloproliferative
diseases, aggressive systemic 
mastocytosis,
hypereosinophilic 
syndrome/chronic
eosinophilic 
leukemia, 
and 
dermatofibrosarcoma protuberans.  There were three responders out of seven subjects with 
myelodysplastic/ myeloproliferative diseases, one in five subjects with aggressive systemic 
mastocytosis, four out of 14 in the hypereosinophilic syndrome/chronic eosinophilic 
leukemia cohort and 10 out of 12 in the dermatofibrosarcoma protuberans cohort of that 
particular study [Heinrich, 2008]. It repeatedly appeared in the US FDA review of the 
submission for the extension of indication for Gleevec (2006) that “the (US) FDA medical 
reviewers recommended approval based on ‘long duration of responses’ and the rarity of 
disease and the occurrence of associated gene arrangement makes randomized trials 
impractical”.
While it is anticipated that several rare cancers with V600E mutations will have clinically
substantial response rates of 50% or more to BRAF plus MEK inhibition, in some settings 
resistance mechanisms may prevent such high response rates.  For example, the BRAFi 
vemurafenib and dabrafenib have shown response rates of greater than 50% in BRAF-mutant 
metastatic melanoma, but show substantially lower response rates in BRAF-mutant 
metastatic colorectal cancer based on resistance mechanisms through receptor tyrosine 
kinases (RTKs) [Prahallad, 2012].  This reaffirms that pathways of resistance may vary
between histologic disease entities and underscores – in the absence of a full understanding 
of such mechanisms of resistance for all histologies – that individual assessment of histologic 
types remains a relevant component of the investigation together with adequate PD markers 
to understand them.
Therefore, a Phase II study is proposed to investigate BRAF-mutant rare cancers in individual 
cohorts defined by histology with the objective to demonstrate breakthrough clinical effects 
from combination therapy with dabrafenib + trametinib. To address the inevitable small 
sample sizes per histologic cohort, the study will utilize a Bayesian hierarchical statistical 
design, which increases the power of the overall investigation by borrowing information 
across histology cohorts based on the emerging rate of response in these cohorts.  
Pharmacodynamic markers will be evaluated to ensure we gain insights into the biology of 
each cancer type and also understand potential mechanisms of resistance.
2.3
Dose Rationale
Administration of dabrafenib + trametinib in the ongoing study BRF113220 indicates that 
dabrafenib does not have a clinically relevant effect on trametinib PK [GlaxoSmithKline
Document Number CM2010/00010/05].  Cross-study comparisons indicate that exposure to 
dabrafenib may be greater after repeat-dose administration of dabrafenib in combination with 
trametinib relative to administration of dabrafenib alone at 150 mg BID. The combination 
was relatively well tolerated in study BRF113220,
study MEK115306 and study 
MEK116513, with toxicities manageable with appropriate intervention.
In this study, dabrafenib will be administered at the dose of 150 mg BID continuously that 
demonstrated significant benefit in PFS in a Phase III trial [Hauschild, 2012]. Trametinib 
administered at a dose of 2 mg once daily has demonstrated significant benefit in PFS (hazard 
ratio [HR] = 0.45), a confirmed response rate (22% vs. 8%), and OS (HR = 0.54) relative to 
chemotherapy [Flaherty, 2012]. As determined in Phase III studies, the safety profile of 
the combination of dabrafenib and trametinib generally reflects the well established 


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safety profiles of the individual approved agents, with toxicities that are manageable 
with appropriate intervention.
2.4
Design Rational
Due to the common pathway activation with the BRAF V600E mutation, multiple histologies 
may demonstrate substantial response to BRAF plus MEK inhibition. However, pathways of 
resistance may vary between histologic diseases resulting in different responses to the 
targeted combination therapy.
This single-arm, multi-histology study incorporates analyses based on a hierarchical model 
that allows for the possibility that the response profile for the population of histologies may
be homogenous or heterogeneous.  There may be ‘clusters’, or subsets of histologies, some 
in which the combination therapy is effective, and others not.  The design borrows 
information in a limited sense from histologies that demonstrate similar response rates based 
on the accumulated trial data. If response rates are sufficiently different across particular 
histologies, the design recognizes this and borrowing is minimal.  The analysis is entirely
data driven.  The number of clusters used to characterize the distribution of histologies is 
solely based on the observed responses. At each interim analysis as well as the final analysis, 
the entire model including clustering specification is fit based on the available data.
Prospectively, the entire design including model specification and decision criteria is
developed by evaluating its performance from simulated trials.  Hence, the false-positive rate 
can be controlled and power assessed.  The advantages of a hierarchical model, both due to 
borrowing, are 1) increased precision of estimates of ORR, and 2) more accurate estimates 
of ORR.
Borrowing via a hierarchical model analysis is a type of shrinkage estimation; it provides a 
formal mechanism by which extreme observations are shrunk toward the mean. Shrinkage 
estimators have long been supported by literature. In particular, Berry et al. [Berry, 2013] 
highlighted that in the 1950s, Charles Stein [Stein, 1956; James, 1961], under normality, 
demonstrated that when there are three or more groups, estimating the groups separately 
(without borrowing) is inadmissible in the sense that the mean squared error is improved 
uniformly by borrowing.
For all these reasons, borrowing information generally increases the power to detect a
clinically meaningful ORR compared to a traditional analysis while controlling the type I
error rate.  Independent analyses do not consider the possibility that some of the histologic 
cohorts may respond similarly to the targeted combination therapy. And due to the rarity of 
the biomarker subtypes of the diseases being considered, a traditional approach will likely
have difficulty accruing a sufficient number of subjects to have adequate power to detect even 
a very large treatment effect in several of the histologic cohorts.
3
OBJECTIVES AND ENDPOINTS
The study objectives and corresponding endpoints are presented in Table 2.
Table 2
Study Objectives and Endpoints
OBJECTIVES
ENDPOINTS
Primary
● To determine the ORR of dabrafenib and trametinib 
anti-cancer combination therapy in subjects with 
● Tumor response as defined by: RECIST, v1.1 for 
solid tumor histologies, Modified RANO and RANO 




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histologically or cytologically confirmed advanced disease with no available treatment 
options as determined by locally or regionally available standards of care and by the treating 
physician’s discretion will be eligible for enrollment. Subjects may be enrolled based on local 
BRAF V600E mutation results and mutation status will be confirmed by a central reference 
laboratory.
Subjects will undergo screening assessments prior to the start of treatment to determine their 
eligibility for study enrollment.  Baseline disease assessment must be completed prior to the 
first dose of study treatment.  For female subjects, a pregnancy test must be performed within 
7 days prior to first dose of study treatment.  No study procedures, including submission of 
tumor tissue, will be performed unless written informed consent has been obtained.  
Screening evaluations will include demography, medical history, review of prior treatment, 
physical, dermatologic and ophthalmic examinations, vital signs, 12-lead ECG, ECHO, 
clinical laboratory assessments including urinalysis and histologic-specific assessments.  
Screening assessments may be repeated at the discretion of the investigator.
Subjects will have radiologic tests to identify target lesions and to assess disease status per 
protocol-defined response assessment criteria.  Subjects will be evaluated following the first 
dose of study treatment according to the assessment schedule (see Time and Events Table, 
Section 7.1). Assessments may be performed more frequently if medically necessary.  A 
treatment cycle is 28 days.  Subjects will be assessed for AEs, study treatment compliance, 
and use of concomitant medications.
Subjects will receive dabrafenib 150 mg BID orally plus trametinib 2 mg once daily orally 
on a continuous dosing schedule.  Subjects will undergo disease assessment of response after 
receiving at least 8 weeks of treatment. Dose adjustments will be made as needed based on 
toxicity.  Subjects will continue treatment until an unacceptable toxicity, disease progression, 
or death occurs.  Subjects who continue on treatment will undergo disease assessment 
according to the applicable response assessment criteria for the specific histology (i.e., for 
solid tumors, radiologic assessment every 8 weeks following initial response assessment).  
Subjects who experience disease progression will discontinue study treatments and be 
withdrawn from the study, unless the investigator, with approval of the Medical Lead, 
indicates that the subject may receive clinical benefit from continued study treatment.  Once 
a subject discontinues treatment and/or is withdrawn from the study, a post-treatment follow-
up visit will be conducted within 28 days (+7 days) after the last dose of study treatment(s) 
with extended follow-up visits conducted every 4 weeks (±7 days) for the first 6 months and 
then every 3 months (±14 days) thereafter.
A hierarchical model that borrows information across cohorts will be utilized to strengthen 
the overall evidence within each cohort.  Using the hierarchical model, continuous monitoring 
for both futility and efficacy will be undertaken throughout the study. Reviews will take place 
in approximately 12-week intervals depending on the enrollment rate.  Enrollment for each 
cohort may be stopped early for futility or efficacy should various criteria occur based on 
accrued data.  Response data from a minimum of five subjects will be required in a histologic
cohort before it may discontinue enrollment for futility, and response data from a minimum 
of 10 subjects are required before discontinuing a histologic cohort for efficacy.  In addition, 
at the final analysis and after the study has been closed, response data from a minimum of 2 
subjects will be required in a histologic cohort in order to meet statistical success at the final 
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Decisions are based on whether the posterior probability that the ORR exceeds its 
corresponding historical control is sufficiently low or high compared to fixed statistical 
thresholds. Historical controls vary across histologic cohorts, but are all very low due to a 
lack of effective treatment options (Section 18.3.2.1).  If this posterior probability is 
sufficiently low within a given histology (≤0.30), then enrollment may be halted early for 
futility.  Conversely, if this posterior probability is sufficiently high within a given histology 
(≥0.95), then enrollment may be halted early for success. At the final analysis and after the 
study has been closed, if the posterior probability is sufficiently high (≥0.92), then the 
combination will be declared efficacious for that histology.  Separate from model estimates, 
the observed ORR will also be reported for each histology. Further details regarding the 
statistical study design and analysis along with simulated example trials to illustrate the study 
may run is provided in Section 18.4.
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 (Section 7.1) is essential and required for study conduct. 
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 site 
personnel with administrative and detailed technical information that does not impact subject 
safety.
4.1
Discussion of Design
The design of this Phase II study allows for the simultaneous evaluation of clinical activity 
and early signals of efficacy in each of the histologies under study. In addition, the safety of 
dabrafenib in combination with trametinib will be evaluated to support the use of the 
combination treatment in subjects with selected rare tumor types. Study treatment will begin 
on Study Day 1 and will continue until protocol-defined treatment withdrawal criteria are met 
(Section 16).  While on study treatment, subjects will be closely monitored for safety.  
Procedures to minimize or monitor potential risks, dose modification guidance, and 
supportive care recommendations are provided in Section 8.1.
In the event one of the combination agents is discontinued, subjects may still receive the 
remaining agent (either dabrafenib or trametinib) as monotherapy provided the investigator 
concludes that continued therapy will be in the best interest of the subject and will result in 
potential clinical benefit. Once subjects are permanently withdrawn from all study treatments, 
a post-treatment follow-up assessment should be completed within approximately 28 days 
from the last dose of study treatment.
4.1.1
BRAF Mutation Test and Companion Diagnostic
Subjects will be enrolled in the study based on local BRAF V600 mutation test results.

For subjects with solid tumors to be eligible for the study, archived tumor tissue
sample(s) and/or fresh tumor tissue sample(s) must be available to allow for central 
confirmation of BRAF V600E mutation status.

For subjects with HCL or MM, a fresh BM aspirate sample and a peripheral blood
sample must be available to allow for central confirmation of BRAF V600E mutation 
status.  See Section 7.3.1 for additional details.
A sponsor designated central reference laboratory will be employed for the central 
confirmation of BRAF V600 mutation status. For solid tumors or hematological malignancies 


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where application of the sponsor designated test is not feasible, an alternative approach of 
BRAF V600E mutation testing by immunohistochemistry (IHC) or Sanger sequencing may 
be employed.
5
SUBJECT SELECTION
5.1
Primary analysis cohort
The “primary analysis cohort” will be comprised of those patients enrolled within a histology-
specific group prior to capping at 25 patients per cohort or prior to early stopping for efficacy 
or futility. The primary analysis cohort will form the basis of the Bayesian modelling.
5.2
Expansion cohorts
If a cohort closes early at an interim analysis because it meets the rules for early stopping for 
efficacy, an expansion cohort may be opened to allow additional patient enrollment for that 
particular histology. The patients in the expansion cohort will provide supportive efficacy 
data and will NOT contribute to the Bayesian modeling. The expansion cohort(s) will enroll 
subjects for the duration of trial enrollment. The same general and histology specific 
eligibility criteria and T&E tables and biomarker/histology confirmation analyses will apply 
to patients in the expansion cohort.
5.3
Number of Subjects
Subjects with BRAF V600E positive-mutations will be enrolled in separate cohorts based on 
histologic type.  Once 16 weeks of response data is available from a minimum of 5 subjects 
in a particular cohort, interim analyses will occur every 12 weeks to assess whether 
enrollment in the particular cohort will be continued or closed. For the primary analysis 
cohort, enrollment will not exceed 25 subjects per histology cohort to ensure adequate 
subjects in the BRAF V600E confirmed population.  After 25 subjects have been enrolled, 
the histology cohort will be closed to further enrollment for patients contributing to the 
Bayesian modeling. Histology specific expansion cohorts may be opened to allow additional 
patient enrollment.  See Section 18.2 for sample size assumptions.
The study is expected to enroll subjects over an approximate 3 to 4 year time period. This 
flexibility is intended to accommodate recruitment rates in these rare histologic cohorts.
Projected 3-year recruitment rates are described in Section 18.4.1.2, and are used for 
simulated trials to assess design operating characteristics.
5.4
Eligibility
Specific information regarding warnings, precautions, contraindications, AEs, and other 
pertinent information on the study treatment(s) that may impact subject eligibility is provided 
in the IB for dabrafenib + trametinib combination [GlaxoSmithKline Document Number 
CM2010/00010/05].
Deviations from inclusion/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 eligibility criteria as specified in the protocol is essential.


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5.4.1
Inclusion Criteria
Subjects must meet all of the following inclusion criteria in order to be considered eligible 
for this study:
1. Signed, written informed consent
2. Sex: male or female
3. Age: 18 years of age at the time of providing informed consent
4. Eastern Cooperative Oncology Group (ECOG) performance status: 0, 1 or 2 (Appendix 
1).
5. Must have advanced disease and no standard treatment options as determined by 
locally/regionally available standards of care and treating physician’s discretion.
6. Must have a BRAF V600E mutation-positive tumor as confirmed by an approved local 
laboratory or a sponsor designated central reference laboratory.
7. NOTE: All subjects must provide an archived or fresh tumor sample (for solid tumors) 
or a fresh BM aspirate and peripheral blood sample (for HCL and MM) for 
confirmation testing of the BRAF V600E mutation by a sponsor designated central 
reference laboratory using a sponsor designated assay. See Section 7.3.1 for additional 
details.
8. ATC, BTC, GIST, NSGCT/NGGCT, and ASI ONLY: Must have at least one
measurable lesion per RECIST 1.1 outside of a prior radiation field or within the field 
with evidence of progression.
9. Able to swallow and retain orally administered medication.
10. Female Subjects of Childbearing Potential:  Subjects must have a negative serum
pregnancy test within 7 days prior to the first dose of study treatment and agrees to use 
highly effective contraception, as defined in Section 9.1, from 7 days prior to 
enrollment, throughout the treatment period and for 16 weeks following discontinuation 
of trametinib when taken in combination with dabrafenib, or for 2 weeks following 
discontinuation of dabrafenib monotherapy.
11. Has adequate baseline organ function as outlined in Table 3
Table 3
Adequate Baseline Organ Function
SYSTEM
Adequate Baseline 
Organ Function
TEST
Histology
LABORATORY VALUES1
Hematologic
ANC3
ATC, BTC, GIST, WHO
Grade 1-4 Glioma, NSGCT/NGGCT, ASI
1.2 109/L
MM
1 109/L
Hemoglobin3
ATC, BTC, GIST, WHO
Grade 1-4 Glioma, NSGCT/NGGCT, ASI
9 g/dL
Platelets3
ATC, BTC, GIST, NSGCT/NGGCT, ASI
75 109/L
MM
50 109/L
WHO Grade 1-4 Glioma
100 109/L
PT, PTT, INR2
ATC, BTC, GIST, WHO
Grade 1-4 Glioma, NSGCT/NGGCT, ASI, 
HCL, MM
1.5 times ULN
Hepatic
Albumin
ATC, BTC, GIST, WHO
Grade 1-4 Glioma, NSGCT/NGGCT, ASI, 
HCL, MM
2.5 g/dL
ATC
1.5 times ULN


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SYSTEM
Adequate Baseline 
Organ Function
TEST
Histology
LABORATORY VALUES1
Total Bilirubin4
BTC
3 times ULN if stable for 14 days 
prior to enrollment
GIST, WHO Grade 1-4 Glioma,
NSGCT/NGGCT, MM
2 times ULN
HCL
<3 times ULN
ASI
2 times ULN OR 3 times ULN if 
stable for 14 days prior to enrollment 
for ampullary and periampullary 
carcinoma
ALT and AST5
ATC, GIST, NSGCT/NGGCT
2 times ULN without liver
metastases 2.5 times ULN if 
documented liver metastases
BTC, ASI, MM
3 times ULN without liver
metastases 5 times ULN if
documented liver metastases
HCL
<5 times ULN
WHO Grade 1, 2, 3 or 4 Glioma
3 times ULN
Renal
Creatinine
ATC, BTC, GIST, WHO
Grade 1-4 Glioma, NSGCT/NGGCT, ASI, 
HCL, MM
1.5 mg/dL
OR
Calculated Creatinine
Clearance6 or 24-hr Urine 
Creatinine Clearance
ATC, BTC, GIST, WHO
Grade 1-4 Glioma, NSGCT/NGGCT, ASI, 
HCL, MM
50 mL/min
Cardiac
LVEF
ATC, BTC, GIST, WHO
Grade 1-4 Glioma, NSGCT/NGGCT, ASI, 
HCL, MM
LLN7 by ECHO
Abbreviations: ALT, alanine aminotransferase; ANC, absolute neutrophil count; ASI, adenocarcinoma of small intestine AST, aspartate
aminotransferase; CBC, complete blood count; ECHO, echocardiogram; HCL, hairy cell leukemia; hr, hour; INR, international
normalization n ratio; LLN, lower limit of normal; LVEF, left ventricular ejection fraction; PT, prothrombin time; PTT, partial thromboplastin
time; ULN, upper limit of normal
1. Laboratory values are obtained within 14 days prior to first dose of study treatment.
2. PTT and PT/INR >1.5 times ULN will be acceptable in case of subjects receiving therapeutic anticoagulants such as warfarin as long
as INR is monitored during the study according to clinical practice.
3. HCL: No minimum CBC criteria if the cytopenias are due to disease under study.
4. HCL: Subjects will be allowed to enroll with indirect hyperbilirubinemia; however, this condition must be confirmed due to hemolysis,
hypersplenism or direct bilirubin ratio <35%, and requires approval from the Medical Lead.
5. HCL: Subjects will be allowed to enroll with elevated ALT/AST values up to 5 times ULN; however this condition must be confirmed
due to hemolysis and/or hypersplenism and not associated with hepatic dysfunction and required approval from the Medical Lead.
6. Calculated by the Cockcroft-Gault formula (see Appendix 3).
7. If LLN is not defined for a given institution, then ejection fraction must be ≥ 50%.
NOTE: Subjects with AST, ALT or total bilirubin values outside the range(s) in Table 3 due to Gilbert's syndrome
or asymptomatic gallstones are not excluded. Laboratory results obtained during Screening should be used to determine eligibility
criteria. In situations where laboratory results are outside the permitted range, the investigator may opt to retest the subject and the
subsequent within-range screening result may be used to confirm eligibility
12. French subjects: In France, a subject will be eligible for inclusion in this study only if 
either affiliated to or a beneficiary of a social security category.


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5.4.1.1
Histology Specific Inclusion Criteria
5.4.1.1.1 ATC
1. Histologically or cytologically confirmed, unresectable, metastatic ATC including ATC 
originating from within well-differentiated thyroid cancers or an ATC as part of a
thyroid carcinoma of another histologic type.
NOTE: Squamoid differentiated subtype is not permitted. Diagnosis noted to be
“consistent with ATC” with presence of thyroid mass is acceptable.
2. Has undergone evaluation via indirect or direct laryngoscopy to ensure patency of
trachea/airway prior to enrollment if bulky thyroid/neck masses are present and/or
airway obstruction is suspected.
3. Has undergone prior external beam radiotherapy and/or surgery to the primary tumor.
NOTE: Subjects with small primary tumor that has been totally removed by surgical 
excision whereby no radiotherapy was indicated (only metastatic lesions are 
manifested) or subjects with metastatic disease who do not require radiation or surgery
to the neck mass will be eligible for participation in the study.
5.4.1.1.2 BTC
1. Histologically or cytologically confirmed, unresectable, metastatic or locally advanced 
or recurrent adenocarcinoma of the biliary tract or gallbladder
2. Must have progressed on or demonstrated intolerance (despite standard measures of 
supportive care and dose reduction) to treatment with a gemcitabine-based
chemotherapy regimen.
5.4.1.1.3 GIST
1. Histologically confirmed diagnosis of c-Kit and PDGFRA wild-type GIST.
2. Must have metastatic or locally advanced, unresectable, or recurrent post-surgical
disease.
3. Must have progressed on or demonstrated intolerance (despite standard measures of 
supportive care and dose reduction) to treatment with a TKI (i.e., imatinib, sunitinib).
5.4.1.1.4 WHO Grade 1 or 2 Glioma
1. Histologically confirmed recurrent or progressive WHO Grade 1 or 2 glioma
2. For WHO Grade 1 glioma ONLY: To be considered eligible for study treatment,
subject must:
a. Present with adequate level of favorable risk/benefit ratio including, but not limited 
to, the exhibited initial symptoms, AND
b. Be evaluated by a panel of neuro-oncologists and the Medical Lead prior to 
enrollment.
3. For WHO Grade 2 glioma ONLY:  To be considered eligible for study treatment, 
subject must not be eligible for treatment with chemotherapy.
4. Must have measurable non-enhancing disease based on two-dimensional magnetic
resonance imaging (MRI) with contrast assessments as per RANO response criteria 
(Appendix 13).
NOTE: Enhancing disease is acceptable for pilocytic astrocytomas.
5. For WHO Grade 1 or 2 glioma subjects receiving corticosteroid treatment: Must be 
receiving a stable or decreasing dose of corticosteroid treatment for 7 days prior to first 


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dose of study treatment.
NOTE: Steroids dose is limited to up to 8 mg/day of dexamethasone or equivalent dose 
of steroid.
NOTE: Subjects are not required to be on corticosteroids to be eligible.
5.4.1.1.5 WHO Grade 3 or 4 Glioma
1. Histologically confirmed recurrent or progressive WHO Grade 3 or 4 glioma.
2. Had prior treatment with radiotherapy and first-line chemotherapy or concurrent
chemoradiation therapy.
NOTE: Subjects who have a WHO Grade 3 or 4 glioma for which chemotherapy
and/or radiotherapy is not considered standard of care may remain eligible for the study.
Consult the Medical Lead to discuss and determine if subject is eligible for enrollment.
3. Must have measurable disease at least 1 cm x 1 cm as per RANO response criteria
(Appendix 14).
4. For WHO Grade 3 or 4 glioma subjects receiving corticosteroid treatment:
Must be receiving a stable or decreasing dose of corticosteroid treatment for 7 days
prior to first dose of study treatments.
NOTE: Steroids dose is limited to up to 8 mg/day of dexamethasone or equivalent dose 
of steroid.
NOTE: Subjects are not required to be on corticosteroids to be eligible.
5.4.1.1.6 NSGCT/NGGCT
1. Histologically confirmed NSGCT/NGGCT.
2. Must have either:

Refractory disease defined as disease progression during or relapsed after salvage 
high-dose chemotherapy (HDCT), or disease progression during cisplatin-based 
salvage chemotherapy.
OR

Relapsed disease and ineligible for cisplatin-based salvage chemotherapy or
HDCT.
5.4.1.1.7 ASI
1. Histologically confirmed, metastatic or locally advanced ASI, adenocarcinoma of the 
ampulla, or adenocarcinoma of the peri-ampulla.
2. Must have progressed on or demonstrated intolerance (despite standard measures of 
supportive care and dose reduction) to one line of chemotherapy.
5.4.1.1.8 HCL
1. Histologically confirmed diagnosis of HCL according to morphological and
immunophenotypic criteria of WHO classification [WHO, 2008] of lymphoid
neoplasms.
2. Must have either:

Refractory disease defined as no response or disease progression in 1 year
following first-line treatment with a purine analog (i.e., pentostatin, cladribine or 
fludarabine)
OR


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
Relapsed disease defined as having relapsed following treatment with at least two 
prior treatments
3. Must have the presence of leukemic cells in the peripheral blood or BM aspirate or BM 
biopsy AND one or more of the following:

Bulky/symptomatic splenomegaly

Hemoglobin <10 g/dL

Platelets <100 109/L

Absolute neutrophil count (ANC) <1 109/L
4. For subjects with an opportunistic infection: the infection must be adequately managed 
and the subject must be clinically stable. The investigator may discuss this issue with 
the Medical Lead.
5.4.1.1.9 MM
1. Histologically confirmed secretory MM.
2. Has received at least 2 prior lines of therapy, such as prior treatment with a proteasome 
inhibitor and IMiD, and is now refractory or has demonstrated intolerance (despite
standard measures of supportive care and dose reduction) to the most recent therapy
received
3. Must have measurable disease of MM as defined by at least ONE of the following:

Serum M-protein 1 g/dL (10 g/L)

Urine M-protein 200 mg/24 hr

Serum free light chain (FLC) assay: involved FLC level 5 mg/dL (50 mg/L) and 
an abnormal serum FLC ratio (<0.26 or >1.65), or

Biopsy proven plasmacytoma (measured within 28 days of Screening)
4. For subjects with an opportunistic infection: the infection must be adequately 
managed and the subject must be clinically stable. The investigator may discuss this 
issue with the Medical Lead.
5.4.2
Exclusion Criteria
ANY subject who meets any of the following criteria is excluded from enrollment in this
study:
1. Prior treatment with:

BRAF and/or MEK inhibitor(s)

Chemotherapy, immunotherapy, biologic therapy or chemoradiation with delayed
toxicity within 21 days (or within 42 days if prior therapy contains nitrosourea or 
mitomycin C) prior to enrollment

Chemotherapy or biologic therapy without evidence of delayed toxicity within 14 
days prior to enrollment

Investigational product(s) (IP) within 30 days or 5 half-lives, whichever is longer, 
prior to enrollment

Subjects enrolled in France: Subject has participated in any study using an 
IP(s) within 30 days prior to enrollment in this study.
2. History of malignancy with confirmed activating RAS mutation at any time.
NOTE:  Prospective RAS testing is not required. However, if the results of previous 
RAS testing are known, then those results must be used in assessing eligibility.


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3. Prior radiotherapy less than 14 days prior to enrollment, except for WHO Grade 1-4 
glioma and ATC. Treatment-related AEs must have resolved prior to enrollment.
For WHO Grades 1, 2, 3, or 4 Glioma ONLY:  Radiotherapy is not permitted within 
3 months prior to enrollment (extended period of time of > 3 months needed to prevent 
subjects with pseudo-progression from radiotherapy from being enrolled in the study).  
Subjects may be ≥ 2 weeks from radiotherapy if a new lesion relative to the pre-
radiation MRI develops outside the primary radiation field. Treatment-related AEs must 
have resolved prior to enrollment.
For ATC Only: Radiotherapy is not permitted within 7 days prior to enrollment.
Treatment-related AE(s) must have resolved prior to enrollment.
4. Prior major surgery less than 14 days prior to enrollment.  Any surgery-related AE(s) 
must have resolved prior to enrollment.
5. Prior solid organ transplantation or allogenic stem cell transplantation (alloSCT)
NOTE: Previous autologous BM transplant (autoSCT) or autologous peripheral blood 
stem cell transplant (PBSCT) is permitted.
6. History of another malignancy
NOTE: Subjects with another malignancy are eligible if: 
a. disease-free for 3 years, or 
b. have a history of completely resected non-melanoma skin cancer, and/or 
c. have an indolent second malignancy(ies).
Consult a Medical Lead if unsure whether second malignancies meet requirements 
specified above.
7. Presence of:

Brain metastases (except for subjects in the WHO Grade 1 or 2 Glioma or WHO 
Grade 3 or 4 Glioma histology cohorts) that are symptomatic or untreated or not 
stable for 3 months (must be documented by imaging) or requiring 
corticosteroids. Subjects on a stable dose of corticosteroids > 14 days and have not
required treatment with enzyme-inducing anticonvulsants for >30 days prior to 
enrollment can be enrolled with approval of the Medical Lead.

Symptomatic or untreated leptomeningeal or spinal cord compression
NOTE:  Subjects who have been previously treated for these conditions and have 
stable CNS disease (documented by consecutive imaging studies) for >60 days, are
asymptomatic and currently not taking corticosteroids, or have been on a stable 
dose of corticosteroids for at least 30 days prior to enrollment, are permitted.

Interstitial lung disease or pneumonitis

Any unresolved Grade 2 (per Common Terminology Criteria for Adverse Events 
[CTCAE] version 4.0) toxicity from previous anti-cancer therapy at the time of 
enrollment, except alopecia or Grade 2 anemia
NOTE:  Subjects with MM who have ≤Grade 2 peripheral neuropathy (per 
CTCAE v4.0) are permitted.

Any serious and/or unstable pre-existing medical disorder, psychiatric disorder, or 
other conditions that could interfere with subject’s safety, obtaining informed 
consent or compliance to the study procedures
8. History of RVO


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9. Clinically significant GI abnormalities that may alter absorption such as malabsorption 
syndrome or major resection of the stomach or bowels.  For example, subjects should 
have no more than 50% of the large intestine removed and no sign of malabsorption 
(i.e., diarrhea).
NOTE: If clarification is needed as to whether a condition will significantly affect the 
absorption of study treatments, contact the Medical Lead.
10. History or evidence of cardiovascular risk including any of the following:

Acute coronary syndromes (including myocardial infarction and unstable angina), 
coronary angioplasty, or stenting within 6 months prior to enrollment

Clinically significant uncontrolled arrhythmias
NOTE:  Subjects with controlled atrial fibrillation for >30 days prior to enrollment 
are eligible.

Class II or higher congestive heart failure as defined by the New York Heart 
Association (NYHA) criteria (Appendix 2)

Left ventricular ejection fraction (LVEF) below the institutional LLN
NOTE: If a LLN does not exist at an institution, then use LVEF <50%.

Abnormal cardiac valve morphology (≥Grade 2) documented by ECHO
NOTE:  Subjects with Grade 1 abnormalities (i.e., mild regurgitation/stenosis) may
be entered on study. Subjects with moderate valvular thickening should NOT be 
enrolled.

Corrected QT (QTc) interval for heart rate using Bazett-corrected QT interval 
(QTcB) 480 msec

Intracardiac defibrillator

Treatment-refractory hypertension defined as a blood pressure (BP) >140/90 
mmHg which may not be controlled by anti-hypertensive medication(s) and/or 
lifestyle modifications

Subjects enrolled in Germany: Subjects with a left bundle branch block (LBBB)
are NOT eligible for inclusion in this study.
11. Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test 
result within 3 months prior to first dose of study treatment.
NOTE: Subjects with positive Hepatitis C antibody due to prior exposure can be
enrolled, only if a confirmatory negative Hepatitis C RNA polymerase chain reaction 
(PCR) test is obtained.
12. Current use of prohibited medication(s) or requirement for prohibited medications 
during study (see Section 10.2).
NOTE: Use of anticoagulants such as warfarin is permitted; however, international 
normalization ratio (INR) must be monitored according to local institutional practice.
13. Clinically significant known immediate or delayed hypersensitivity reaction or
idiosyncrasy to drugs chemically related to study treatment, or excipients, or to
dimethyl sulfoxide (structural component of dabrafenib).
14. Female subjects: Pregnant, lactating or actively breastfeeding


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5.4.2.1
Histology Specific Exclusion Criteria
5.4.2.1.1 ATC
1. Presence of thyroid lymphomas, sarcomas, or metastatic disease from other sites of 
origin to the thyroid.
2. Has potentially curable ATC by surgical excision alone or subjects who have not 
received treatment that might be considered standard of care.
5.4.2.1.2 BTC
1. Has biliary duct obstruction, unless a treatable, clinically relevant obstruction has been 
relieved by internal endoscopic drainage/stenting, palliative by-pass surgery or 
percutaneous drainage prior to enrollment.
5.4.2.1.3 WHO Grade 1, 2, 3 or 4 Glioma
1. Prior treatment with enzyme-inducing anticonvulsants within 14 days prior to
enrollment.
2. Radiotherapy treatment within 3 months prior to enrollment.
NOTE: Extended period of time (>3 months) needed to prevent subjects with pseudo-
progression from radiotherapy being enrolled in the study. Subjects may be 2 weeks 
from radiotherapy if a new lesion relative to the pre-radiation MRI develops 
outside the primary radiation field. Treatment-related AEs must have resolved 
prior to enrollment.
6
STUDY TREATMENTS
The term ‘study treatment’ is used throughout the protocol to describe any combination of IP
received by the subject as per the protocol design. Study treatment may therefore refer to the 
individual study treatments or the combination of those study treatments.
6.1
Treatment Assignment
Subjects will be identified by a unique subject number that will remain consistent for the 
duration of the study.  Subjects will be categorized by histology group based on tumor type 
and mutation status in a non-randomized manner.
Upon completion of all the required screening assessments, including signed informed
consent; eligible subjects will be registered into the designated interactive voice response 
system (IVRS) by the investigator or authorized site staff.
6.2
Blinding
This is an open-labeled study.
6.3
Investigational Products
6.3.1
Dabrafenib (DRB436/GSK2118436) Capsule
Dabrafenib capsules will be provided to sites by the sponsor. The contents of the label will 
be in accordance with all applicable regulatory requirements.
Product name :
Investigational Product
Dabrafenib (DRB436/GSK2118436) 50 mg
Dabrafenib (DRB436/GSK2118436) 75 mg


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Formulation
description:
Each capsule contains DRB436/GSK2118436B (mesylate salt) equivalent to 50 mg 
or 75 mg of DRB436/GSK2118436A and inactive ingredients including: 
microcrystalline cellulose, magnesium stearate, and colloidal silicon dioxide.
50 mg capsule shell composition: hypromellose or HPMC (E464), red iron oxide
(E172), and titanium dioxide (E171)
75 mg capsule shell composition: hypromellose or HPMC (E464), red iron oxide
(E172) and titanium dioxide (E171)
Black bars printed on capsules: black ink containing black iron oxide (E172),
shellac, propylene glycol, and ammonium hydroxide.
Dosage form :
Capsule
Unit dose strength(s):
50 mg
75 mg
Physical Description:
50 mg: Swedish orange, size 2
capsules with identifying markings of 4 
black bars
75 mg: Pink, size 1 capsules with
identifying markings of 4 black bars
Route/Schedule/
Duration:
Oral/ BID/Continuous
Abbreviations: BID, twice daily; HPMC, hydroxypropyl methyl cellulose
6.3.1.1
Administration and Storage of Dabrafenib Capsules
Administration: Dabrafenib capsules must be dispensed only to subjects enrolled in the
study and in accordance with the protocol. Dabrafenib should be administered under fasted 
conditions, either 1 hr before or 2 hrs after a meal with approximately 200 mL of water.  
Subjects should be encouraged to take their doses at 12 hr intervals and at similar times every
day.
Missed Dose: If a subject misses a dose of dabrafenib, the subject may take the dose
immediately if the next dose is scheduled for at least 6 hrs later. If the next scheduled dose 
is due in less than 6 hrs, the subject should skip the dose and resume dosing at the next 
scheduled dose.
Storage:
Dabrafenib must be stored in a secure area under the appropriate physical
conditions for the product. Access to and administration of the dabrafenib will be limited to 
the investigator and authorized site staff.
Dabrafenib is to be stored and dispensed in an opaque bottle. The recommended storage 
conditions for dabrafenib are stated on the product label.  Maintenance of a temperature log 
(manual or automated) at the site is required.
6.3.2
Trametinib (TMT212/GSK1120212) Tablet
Trametinib tablets will be provided to sites by the sponsor.  The contents of the label will be 
in accordance with all applicable regulatory requirements.
Product name :
Investigational Product
Trametinib (TMT212/GSK1120212) 0.5 mg
Trametinib (TMT/GSK1120212) 2 mg
Formulation description:
Each immediate-release oral tablet contains TMT212/GSK1120212B 
equivalent to 0.5 mg or 2 mg of TMT212/GSK1120212 (non-solvated parent) 
blended with inert ingredients (mannitol, sodium lauryl sulfate, colloidal silicon 
dioxide, microcrystalline cellulose, hypromellose, croscarmellose sodium, and
magnesium stearate [non-animal]) and compressed into tablets.
The 0.5 mg tablets are aqueous film-coated with Opadry White (OY-S-28876;
hypromellose, titanium dioxide and polyethylene gycol) or Opadry yellow
(03B120006; containing hypromellose, titanium dioxide, polyethylene glycol,
and iron oxide yellow).
The 2 mg tablets are aqueous film-coated with Opadry Pink (YS-1-14763-A;
containing hypromellose, titanium dioxide, polyethylene glycol, polysorbate
80, and iron oxide red).


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Dosage form :
Tablet
Unit dose strength(s):
0.5 mg
2 mg
Physical Description:
White or yellow, modified oval,
biconvex, film-coated tablets
Pink, round, biconvex film-coated
tablets
Route/Schedule/Duration:
Oral/once-daily/Continuous
6.3.2.1
Administration and Storage of Trametinib Tablets
Administration: Trametinib must be dispensed only to subjects enrolled in the study and in 
accordance with the protocol.  Trametinib should be administered under fasted conditions, 
either 1 hr before or 2 hrs after a meal with approximately 200 mL of water. Subjects should 
be instructed to take their dose of trametinib concurrently with the morning dose of 
dabrafenib.
Vomiting: If a subject vomits after taking study treatment, the subject should be instructed 
not to retake the dose but should be instructed to take the next scheduled dose.
Missed Dose:
If a subject misses a dose of trametinib, the subject may take the dose
immediately if the next dose is scheduled for at least 12 hrs later. If the next scheduled dose 
is due in less than 12 hrs, the subject should skip the dose and resume dosing at the next 
scheduled dose.
Storage:
Trametinib must be stored in a secure area under the appropriate physical
conditions for the product.  Trametinib is to be stored at the temperature specified on the label.  
Maintenance of a temperature log (manual or automated) is required. Access to and 
administration of trametinib will be limited to the investigator and authorized site staff.  Refer 
to the SPM for further detailed instructions on IP storage.
6.4
Handling/Accountability of Investigational Products
Handling: Adequate precautions must be taken to avoid direct contact with the IP. The
occupational hazards and recommended handling procedures are provided in the Material 
Safety Data Sheet (MSDS).  A description of the occupational hazards and recommended
handling precautions for each IP (MSDS) will be provided to the site staff and/or subjects if 
required by local laws or will otherwise be available from the sponsor upon request.  In the 
case of unintentional occupational exposure, notify the study monitor, the Medical Lead, 
and/or study manager.
Accountability: In accordance with local regulatory requirements, the investigator,
designated site staff, or head of the medical institution (where applicable) must document the 
amount of each IP dispensed and/or administered to study subjects, the amount returned by
study subjects, and the amount received from and returned to the sponsor, when applicable.  
Accountability records for each IP must be maintained throughout the course of the study.
Refer to the SPM for further detailed instructions on IP accountability.
6.5
Treatment Compliance
Subjects will be asked to maintain a dosing diary to record their daily administration of study
treatments.  At each visit, the subject should return the dosing diary; an evaluation of subject 
compliance with study treatments taken will be performed.  The investigator will make every
effort to bring non-compliant subjects into compliance. A record of the number of trametinib 
tablets and dabrafenib capsules dispensed to and taken by each subject must be maintained
and reconciled with study treatment and compliance records.  Compliance with dosing will 


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be assessed through querying the subject during site visits and documented in the source 
documents and electronic case report form (eCRF) including treatment start and stop dates, 
dates for treatment delays and/or dose reductions.
6.6
Treatment of Overdose
6.6.1
Dabrafenib
In the event of a dabrafenib overdose (defined as administration of >300 mg as a single dose 
or 600 mg daily, the highest dose administered to date), the investigator should contact the 
Medical Lead immediately and closely monitor the subject for AEs/SAEs and laboratory
abnormalities.  The sponsor does not recommend specific treatment.  The investigator will 
use clinical judgment to treat any overdose. Hemodialysis is not expected to enhance the 
elimination of dabrafenib as it is highly bound to plasma proteins.
A plasma sample for PK analysis may be requested by the Medical Lead on a case-by- case 
basis. This plasma sample should be collected as soon as possible; record date and time of 
the PK sample and last dose of study treatment.
Information regarding the quantity of the excess dose as well as the duration of the
overdosing should be documented in the eCRF.
6.6.2
Trametinib
In the event of a trametinib overdose, defined as administration of more than 3.0 mg once
daily (the maximum tolerated dose defined in the study MEK111054), the investigator should 
contact the Medical Lead immediately and closely monitor the subject for AEs/SAEs and 
laboratory abnormalities.  The sponsor does not recommend specific treatment.
The 
investigator will use clinical judgment to treat any overdose. Hemodialysis is not expected to 
enhance the elimination of trametinib as it is highly bound to plasma proteins.
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Medical Lead based on the clinical evaluation of the subject.
A plasma sample for PK analysis may be requested by the Medical Lead on a case-by- case 
basis.  This plasma sample should be collected as soon as possible, but within 10 days from 
the date of the last dose of on-study dosing.
Information regarding the quantity of the excess dose as well as the duration of the
overdosing should be documented in the eCRF.
6.7
Continuation of Treatment
In the absence of an unacceptable toxicity, disease progression or withdrawal of consent by
subject, treatment may continue.  However, if at the time of investigator-reported disease 
progression, the investigator determines that the subject is still clinically benefitting from 
study treatment(s) and the subject is willing to continue study treatment(s); consultation with 
the Medical Lead is required. If further progressive disease is noted at the next response 
assessment, the subject must discontinue study treatment(s).
If the study treatment(s) is continued beyond the initial disease progression, study procedures, 
including response assessments, will be continued according to the Time and Events Table 
(Section 7.1)


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7
STUDY ASSESSMENTS AND PROCEDURES
Study assessments and procedures, including the timing of the assessments, are summarized 
in the Time and Events Table (Section 7.1).
A signed, written informed consent form (ICF) must be obtained from the subject or a legal 
representative prior to any study-specific procedures or assessments.
Procedures conducted as part of the subject’s routine clinical management (e.g., blood count, 
imaging study) and obtained prior to signing of informed consent may be utilized for 
screening or baseline purposes provided the procedure meets the protocol-defined criteria 
and has been performed in the timeframe of the study.
Investigators may be requested to perform additional safety tests during the course of the
study based on newly available data to ensure appropriate safety monitoring. Appropriate 
local regulatory and ethical approvals should be obtained before any additional testing is 
performed.


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7.1
Time and Event Table
Table 4
Time and Event Table for All Cohorts
Screening
Treatment5
Follow-up Visit55
Extended
Follow-
up58
Day 1 7
Day 15
(1 day)
Every
4 weeks
(3 days)
Every
8 weeks
(3 days)
Every
12
weeks
(3
days)
Every
16 weeks
(3 days)
Treatment or Study
Withdrawal
Every
3 months
(14
days)
except
when
noted
Clinical Assessments: ALL Cohorts
Informed Consent1
X
Demographics
X
Medical History2
X
X8
DiseaseCharacteristics3
X
BRAF V600E Mutation Testing
(Mandatory)4
X
ECOG Performance Status
X6
X8
X
X
Safety Assessments: ALL Cohorts
Physical Exam(including
weight)
X
(Complete)6,9
X
(Brief)10
X
(Brief)10
X
(Complete)9
Height
X6,11
Dermatologic Exam
X (Full)12
X (Brief)13
X (Brief)13
X (Brief)13
Ophthalmic Exam14
X
Week 4
Only
Vital Signs15
X6
X8
X
X
12-lead ECG16
X6
X8
X
X56
ECHO17
X
Week 4
Only
X
X57


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Screening
Treatment5
Follow-up Visit55
Extended
Follow-
up58
Day 1 7
Day 15
(1 day)
Every
4 weeks
(3 days)
Every
8 weeks
(3 days)
Every
12
weeks
(3
days)
Every
16 weeks
(3 days)
Treatment or Study
Withdrawal
Every
3 months
(14
days)
except
when
noted
Adverse Events
Continuous
Safety Assessments: ALL Cohorts continued
ConcomitantMedications
X6
X8
X
X
X
Laboratory Assessments: ALL Cohorts
Chemistry and Hematology
X6
X8
X
X56
Pregnancy test19
X20
(serum)
X21
(serum or
urine)
X21
(serum or
urine)
X21,56
(serum or urine)
HbA1c
X6
X
Coagulation:
PT, PTT, INR
X6
Urinalysis
X6
X8
X
X56
Monitoring for Non-Cutaneous Secondary/Recurrent Malignancy22: ALL Cohorts 
Head and neck exam23
X6
X
X24
Chest and Abdominal CT scan
or MRI
X6
As clinically indicated
X24
Disease Assessment: ATC, ASI, BTC, GIST, NSGCT/NGGCT, and WHO Grade 1-4 Glioma Cohorts ONLY
Disease Assessment:
Imaging25
X26
X27
X27
X27
X27
TSH, Free T4 (ATC Only)
X6
X
X
Histology Confirmation: ATC and WHO Grade 1-4 Glioma Cohorts ONLY
Tissue Sample for Histology
Confirmation28
X
Disease Assessment: NSGCT/NGGCT Cohort ONLY
AFP, -HCG
X6
X29
Every 8 to 12 weeks29
At Disease Progression29


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Screening
Treatment5
Follow-up Visit55
Extended
Follow-
up58
Day 1 7
Day 15
(1 day)
Every
4 weeks
(3 days)
Every
8 weeks
(3 days)
Every 12
weeks
(3
days)
Every
16 weeks
(3 days)
Treatment or Study
Withdrawal
Every
3 months
(14
days)
except
when
noted
Disease Assessment: BTC and ASI Cohorts ONLY
CEA, CA19-9
X6
X30
Every 8 to 12 weeks30
At Disease Progression30
Disease Assessment: HCL Cohort ONLY31
Blood sample for CBC
X6
X31
X31
Peripheral Blood Sample
Staining for Hairy Cell count
X
X31
X31
BM biopsy and aspirate with
H/E stain and IHC
X34
When counts are consistent with CR or PR for 4 weeks; if evidence of
response, then after every 6 months twice, then after a year twice and
then every 2 years32
At time of relapse
Flow cytometry:
BM aspirate sample
X34
When counts are consistent with CR or PR for 4 weeks; if evidence of
response, then after every 6 months twice, then after a year twice, and
then every 2 years33
At time of relapse
Flow cytometry: peripheral
blood sample33
X34
X31
X31
Chest CT scan and Abdominal
CT scan w/contrast
X35
When counts are consistent with CR or PR for 4 weeks; then 6 months
later
At time of relapse
Disease Assessments: MM Cohort ONLY
Skeletal surveys36
X
X
X
ExtramedullaryDisease
Assessment37
X
X
X
BM aspirate
X38
At Week 8 and at time of achieving CR or
best response39
At Disease Progression
BM biopsy
X38
At Week 8 and at time of achieving CR or
best response39
At Disease Progression
SPEP40
X
X
X
X
UPEP41,42
X
X
X
X


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Screening
Treatment5
Follow-up Visit55
Extended
Follow-
up58
Day 1 7
Day 15
(1 day)
Every
4 weeks
(3 days)
Every
8 weeks
(3 days)
Every
12 
weeks
(3
days)
Every
16 weeks
(3 days)
Treatment or Study
Withdrawal
Every
3 months
(14
days) 
except 
when
noted
CRP,2microglobulin;IgG,
IgA and IgM43
X
X
X
X
Serum FLC assay43
X
X
X
X
Pharmacokinetic Assessments for Subjects Receiving Dabrafenib Capsules and/or Trametinib Tablets: ALL Cohorts
PK: blood sample(s)
Week 4
Only44
Week 8
Only45
Week 12
Only45
X45


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Screening
Treatment5
Follow-up Visit55
Extended
Follow-
up58
Day 1 7
Day 15
(1 day)
Every
4 weeks
(3 days)
Every
8 weeks
(3 days)
Every
12 
weeks
(3
days)
Every
16 weeks
(3 days)
Treatment or Study
Withdrawal
Every
3 months
(14
days) 
except 
when
noted
Study Treatments: ALL Cohorts
Dispensation of study
treatments
X54
X
Dabrafenib Dosing
Continuous Twice Daily Dosing
Trametinib Dosing
Continuous Once Daily Dosing
Compliance Assessment
X
X
Abbreviations: AFP, alpha- fetoprotein; ANC, absolute neutrophil count; AP, anteroposterior; ASI, adenocarcinoma of small intestine; -HCG, beta-human chorionic gonadotropin; BM, bone 
marrow ; CBC, complete blood count; CR, complete response; CRP, C-reactive protein; CT, computed tomography; ECG, electrocardiogram; ECHO, echocardiogram; ECOG, Eastern 
Cooperative Oncology Group; 
; FFPE, formalin-fixed, paraffin- embedded; FISH, 
fluorescence in situ hybridization; FLC, free light chain; H/E, Hematoxylin and eosin; hr(s), hour(s); ICF, informed consent form; IHC, immunohistochemistry; INR, international normalization 
ratio; PD, pharmacodynamic; 
; PK, pharmacokinetics; PT, prothrombin time; PTT, partial thromboplastin time; SPEP, serum protein electrophoresis; TSH, thyroid 
stimulating hormone; UPEP, urine protein electrophoresis
1. ICF: Informed consent should be obtained prior to performing any study-related procedure(s).
2. MEDICAL HISTORY: Medical History will include past and current medical conditions, including cardiovascular medical history and risk factors
3. DISEASE CHARACTERISTICS: Disease characteristics will include date of initial diagnosis, primary tumor type, histology, stage, etc.  NOTE: For WHO grade 1-4 cohorts only: IDH 
1/2 mutation status and MGMT methylation status will be collected, where available.
4. MUTATION TESTING:  Subjects may be enrolled based on local determination of BRAF V600E mutation status. A subject may be tested for the BRAF V600E mutation greater than 28 
days prior to enrollment. (Any past results of local BRAF V600E mutation testing may be used to determine eligibility regardless of when the results were obtained.) To enroll a subject,
the result of mutation testing from a sponsor designated central reference laboratory is not required; however, if the subject does not have a local result available, the sponsor 
designated central reference laboratory mutation test result will be required to determine eligibility for enrollment. NOTE:  For subjects with a solid tumor: An archived or fresh tumor 
tissue sample must be available to send to a sponsor designated central reference laboratory for confirmation testing. NOTE: For subjects with HCL or MM:  A fresh BM aspirate 
sample and a peripheral blood sample are required for confirmation testing by a sponsor designated central reference laboratory. If a BM aspirate cannot be obtained due to a dry tap, 
please contact the Medical Lead. In the event of a dry tap, fresh or archived tumor tissues such as lymph node or plasmacytoma biopsies may be acceptable pending
medical lead approval. An archived tissue sample (such as FFPE tissue sample from a BM biopsy)  BM core samples and BM clot samples cannot be used. The same BM aspirate 
sample may be used for BRAF mutation testing, the baseline assessment




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26. DISEASE ASSESSMENTS (Solid Tumor Cohorts only): Baseline disease assessments must be performed within 28 days prior to enrollment (or within 35 days if MRI is used for
disease assessment).
27. DISEASE ASSESSMENTS (Solid Tumor Cohorts only): Disease assessments are every 8 weeks during the first 48 weeks of study treatment, then every 12 weeks thereafter unless
otherwise noted, and at the Follow-up Visit. Confirmatory scan(s) are to be performed ≥28 days after documented CR or PR. If subject discontinues treatment for reasons other than
disease progression, disease assessments should continue every 12 weeks until disease progression, initiation of new anti-cancer treatment, subject withdrawal of consent, or death.
28. HISTOLOGY CONFIRMATION: (ATC and WHO grade 1-4 cohorts only) A tissue specimen for possible retrospective histology confirmation should be obtained and submitted to a
Novartis designated central reference laboratory. Please refer to the SPM for the requirements of the tissue specimen that is required for the histology confirmation.
29. NSGCT/NGGCT ONLY: AFP, B-HCG and LDH are the disease assessment markers for the NSGCT/NGGCT cohort. LDH result obtained from clinical chemistry panel can be used
as a tumor marker result. Regardless of baseline values of AFP, -HCG and LDH, a blood sample will be drawn every 4 weeks for first 48 weeks of study treatment, then every 8 to 12
weeks thereafter, and at the time of disease progression. Synchronize the collection of the blood sample with the imaging schedule.
30. BTC/ASI ONLY: A blood sample will be drawn to assess CEA and CA 19-9 every 4 weeks for first 48 weeks of study treatment, then every 8 to 12 weeks thereafter, and at the time of
disease progression. Synchronize the collection of the blood sample with the imaging schedule.
31. HCL ONLY: All required disease assessments necessary for a post-baseline response determination should be performed every 4 weeks (+/- 3 days) for the first 48 weeks 
of study treatment.  Beyond 48 weeks, patients tolerating study drug in the judgement of the treating investigator may transition to a response assessment evaluation 
interval of at least every 12 weeks (+/- 3 days) (Changed from “at least every 8 weeks (+/- 3 days)” indicated in Protocol Amendments 8 through 11).  Patients that are not 
tolerating study drug in the judgement of the treating investigator must continue (or return to) response assessment evaluation every 4 weeks (+/- 3 days).  Assessments 
must be collected in agreement with those required in the response criteria (please consult Appendix 12).
32. HCL ONLY: BM biopsy and aspiration with H/E stain and IHC will be performed when blood counts are consistent with CR or PR for 4 weeks (please consult Appendix 12). If
a patient has a PR, and then blood counts become consistent with a CR for 4 weeks, a repeat BM aspirate and biopsy is required to assess a response of CR. Following
best response, a bone marrow biopsy and aspirate must be performed every 6 months for two time intervals, then after a year for two time intervals, then every two years.
33. HCL ONLY: Recommend that flow cytometry panel consists of CD19, CD20, CD22, SmIg, CD11c, CD25, CD103 and CD123. Flow cytometry of the bone marrow aspirate sample
will be performed when blood counts are consistent with CR or PR for 4 weeks (please consult Appendix 12). If a patient has a PR, and then blood counts become consistent
with a CR for 4 weeks, a repeat flow cytometry of the BM aspirate is required to assess a response of CR. Following best response, a flow cytometry of the bone marrow
aspirate must be performed every 6 months for two time intervals, then after a year for two time intervals, then every two years.
34. HCL ONLY: BM biopsy and aspirate (with H/E stain and IHC), BM aspirate (with flow cytometry) and peripheral blood sample (with flow cytometry) will be assessed within 28
days prior to enrollment.
35. HCL ONLY: A chest CT scan and an abdominal CT scan with contrast will be performed within 28 days prior to enrollment. If an abdominal CT scan with contrast cannot be
performed, then a MRI may be performed within 35 days prior to enrollment. If lymph nodes or spleen are enlarged at baseline, then the abnormal organ needs to be followed on
post-baseline assessments using the same modality of imaging.
36. MM ONLY: A skeletal survey should be performed within 28 days prior to enrollment. If myeloma associated bony lesions are present at baseline, skeletal surveys should be performed
every 16 weeks or more frequently in order to assess response or upon clinical suspicion of progressive disease. Skeletal surveys typically consist of lateral radiographs of the skull, AP
and lateral views of the spine, and AP views of the humeri, ribs, pelvis, and femurs.
37. MM ONLY: Each patient should be clinically examined for soft tissue plasmacytomas/extramedullary disease at baseline and at each visit for response assessment. If extramedullary
disease is present at baseline, then Chest/Abdominal/Pelvis CT scan with contrast should be performed to confirm and to determine size and location of the soft tissue plasmacytoma.  If
no disease is identified at baseline, then subsequent scans are only required if clinically indicated. Alternative imaging modality (i.e., MRI) may be used if it is better to assess the lesion
and approved by a Medical Lead. The same imaging modality should be used for all subsequent assessments.
38. MM ONLY: BM aspirate and BM biopsy samples will be assessed by IHC, flow cytometry, FISH and cytogenetics within 90 days prior enrollment.






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7.2
Demographic/Medical History Assessments
The following demographic parameters will be captured: date of birth, gender, race and 
ethnicity.  Medical/medication historywill also be assessed as related to the eligibility criteria.
7.3
Critical Baseline Assessments
7.3.1
Baseline Confirmation of BRAF-Mutation Status
In order to be eligible for the study, subjects must also have archived tumor sample material 
available or be willing to undergo a biopsy in order to meet eligibility for the study.
If multiple results are available, eligibility should be based on the most recent test result. If 
the subsequent central laboratory testing is negative and, in the opinion of the investigator, 
the subject is deriving benefit, the subject may continue in the study.
For Solid Tumor Histologies:
For solid tumor histologies, archived tumor tissue sample or fresh tumor tissue sample 
obtained by biopsy must be submitted to the sponsor designated central reference laboratory
for central confirmatory testing of the BRAF V600E mutation.
If sufficient archived tumor tissue is not available for central confirmation of BRAF mutation 
status and the subject cannot undergo a repeat biopsy to obtain an additional tumor tissue 
sample(s), the subject is NOT eligible for the study.
Table 5
BRAF V600E Mutation Testing Scenarios for Solid Tumors
Scenario
Decision
Local BRAF V600E
Mutation Test
Performed? Result?
Archived
Tumor
Tissue 
Sample?
Tumor Sample 
to be Obtained
Eligible for Enrollment?
BRAF V600E
Mutation Test
to be
Performed?
1
Yes. Positive
Not 
available
Fresh tumor
tissue obtained 
by biopsy
Yes, only after submission
of fresh tumor tissue
sample for central testing
Yes, Central
2
Yes. Positive
Available
Archived tumor 
tissue
Yes, only after submission
of archived tumor tissue
sample for central testing
Yes, Central
3
No. No result.
Not 
available
Fresh tumor
tissue obtained 
by biopsy
Yes, only If central test
result on fresh tumor
tissue is positive for a
BRAF V600E mutation
Yes, Central
4
No. No result.
Available
Archived tumor 
tissue
Yes, only if central test
result on archived tumor
tissue is positive for a
BRAF V600E mutation.
Yes, Central
5
Yes. Negative
Subject is not eligible for participation.
For Hematologic Histologies:
For the HCL and MM cohorts, a fresh BM aspirate sample and a corresponding peripheral 
blood sample are required.
NOTE: For subjects in the HCL and MM cohorts, an archived tissue sample (such as 
formalin-fixed paraffin-embedded [FFPE] tissue sample from a BM
biopsy), BM core 


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samples and BM clot samples are NOT acceptable for BRAF V600E testing. If a BM aspirate 
cannot be obtained due to a dry tap, please contact the Medical Lead.
Details on sample collection, processing, storage and shipping procedures are provided in the 
lab manual.
7.3.2
Baseline Documentation of Target and Non-Target Lesions for Solid 
Tumor Histologies
All baseline lesion assessments must be performed within 28 days of enrollment except
where indicated differently in the T&E table (Section 7.1). Guidance on baseline
documentation of target and non-target lesions will be provided in the SPM.
7.4
Safety
Safety assessments and procedures, including the timing of the assessments, are summarized 
in the Time and Events Table (Section 7.1). Additional time points for safety tests (such as 
vital signs, physical examinations, and laboratory safety tests) may be added during the 
course of the study based on newly available data to ensure appropriate safety monitoring.
7.4.1
Physical Examinations
Complete Physical Examination: A complete physical examination will be performed by
a qualified physician, physician assistant or nurse practitioner under the supervision of a 
qualified physician, or another designee as permitted by local practices or laws. At minimum, 
the examination should include assessments of the head and neck, eyes, ears, nose, throat, 
skin, thyroid, CNS, lungs, cardiovascular system, abdomen (liver and spleen), lymph nodes, 
extremities and genitalia.  Height (measured only at Screening) and weight will be measured 
and recorded. Complete physical examinations will be performed at Screening and at the 
post-treatment follow-up visit.
Complete physical examinations will also include thorough rectal and genitourinary (pelvic) 
examinations to assess secondary malignancies.

Rectal Examinations: Including digital rectal examination and visual inspection of
the anus and perianal area.

Pelvic Examinations (for female subjects only): Including visualization of cervix. At 
Screening, pelvic examinations may be completed up to 24 weeks prior to date of first 
dose; thus, a subject’s most recent gynecological examination may be used to satisfy the 
screening requirements.  (Pap smear and/or colposcopy are not required unless 
clinically indicated.)

Brief Physical Examination: A brief physical examination will include assessments of
the lymph nodes, skin, lungs, cardiovascular system and abdomen (including liver and 
spleen assessment). Weight will be measured and recorded. Brief physical 
examination will be performed on Day 1 and every 4 weeks while on study treatment.
7.4.2
Dermatological Examinations
Dermatological examinations will be performed by an investigator or the subject may be
referred to a dermatologist, at the discretion of the investigator. A complete or full body
dermatological examination will be performed at the time points indicated in the Time and 
Event Table (Section 7.1) to identify any abnormal skin lesions. All abnormal findings (i.e.,




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7.4.6
Electrocardiogram
Electrocardiograms (12-Lead ECGs) will be obtained using an ECG machine that 
automatically calculates heart rate and measures PR, QRS, QT, and QTc intervals. At each 
assessment, a 12-lead ECG will be performed by qualified site personnel after the subject has 
rested at least 5 minutes in a semi-recumbent or supine position.
Those QTc values >480 msec as calculated by the machine must be confirmed manually 
using Bazett’s formula given below:
QTcB = QT x (1/√RR)
If there are any clinically significant abnormalities including, but not limited to, a QTcB >500 
msec, confirm with two additional ECGs taken at least 5 minutes apart.
As of Protocol Amendment 11, transmission of ECGs to a central storage facility is 
discontinued.  For all new ECGs obtained, two copies of the ECG tracings should be obtained 
at the time of the ECG; the first copy will be kept in the subject’s medical chart and the 
second copy will be kept in the study file for retrospective collection by the sponsor if 
necessary.
Refer to Section 8.1.1.1 for QTc withdrawal criteria and additional QTc readings that may
be necessary.
7.4.7
Echocardiogram
Echocardiograms (ECHOs) will be performed to assess cardiac ejection fraction and cardiac 
valve abnormalities. ECHOs will be performed at the time points indicated in the Time and 
Event Table (Section 7.1). The evaluation by the echocardiographer should include an 
evaluation for LVEF and both right and left-sided valvular lesions.
The procedure (ECHO) to document the subject’s baseline LVEF status must be used 
consistently throughout the study.  If possible, it is also preferred that interpretation of LVEF 
status be performed consistently by the same reviewer throughout the study. Copies of all 
ECHOs performed on ALL subjects will be required by the sponsor for review.  Instructions 
for submission of ECHOs are provided in the SPM.
7.4.8
Clinical Laboratory Assessments
General laboratory assessments and histology-specific laboratory assessments will be 
required during the study and should be performed by a local laboratory.  Laboratory tests 
may be done 7 days prior to the scheduled visit in order to have results available for review 
by investigator prior to the scheduled visit date.
Urine tests for protein/creatinine may be done up to 3 days prior to the scheduled visit date. 
If a 24-hr urine collection for protein has been completed within 5 days prior to scheduled 
visit date, a urine sample for protein/creatinine is not necessary.
If additional non-protocol specified laboratory assessments are performed at the institution’s 
local laboratory and result in a change in subject management or are considered clinical 
significant by the investigator (i.e., AE, SAE or dose modification) the results must be 
recorded in the subject’s eCRF.
All laboratory tests with values that are significantly abnormal during study participation or 
within 28 days after the last dose of study treatment(s) should be repeated until the values 


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return to within normal range or baseline. All subjects who have a Grade 3 or 4 laboratory 
abnormality at time of study withdrawal must be followed until resolution to Grade 2 or less, 
unless it is unlikely to improve due to underlying disease.  If such values do not return to 
within normal range within a period judged reasonable by the investigator, the etiology 
should be identified and the Medical Lead notified.
Laboratory requisition forms must be completed and samples must be clearly labeled with 
the subject number, protocol number, site/center number, and visit date. Refer to the lab 
manual for appropriate processing and handling of samples to avoid duplicate and/or 
additional blood draws.
Refer to Appendix 17 for an estimation of the volume of blood samples collected during the 
study.
Table 6
Clinical Laboratory Assessments
Hematology
RBC Count
RBC Indices (at Screening and if hemoglobin
decreases 2 g/dL compared to baseline):
Automated WBC
Differential:
Platelets
MCV
MCH
MCHC
Reticulocyte Count
Lymphocytes
Monocytes
Eosinophils
Basophils
WBC Count
(absolute)
Hemoglobin
Hematocrit
Absolute neutrophil
count (ANC)
Clinical Chemistry
BUN
Potassium
Total Protein
Total and direct bilirubin1
Creatinine3
Chloride2
Phosphorus
AST
Glucose
Uric Acid2
Magnesium
ALT
Sodium
Calcium
LDH
Alkaline Phosphatase
Albumin
HbA1c6
GGT
Coagulation
PT
PTT
INR
Urinalysis4
Color
Specific gravity
Ketones
Urobilinogen
Appearance
Glucose
Blood
pH
Protein5
Leukocyte esterase
Other Tests
Amylase and lipase [monitor via local laboratory when clinically indicated to evaluate certain AEs
(i.e., abdominal pain, pancreatitis, etc.)
Serum or urine -hCG6
For subjects with a history of chronic HBV and/or HCV, the following tests will be performed at
Screening:
● Viral hepatitis serology;
● Hepatitis B surface antigen and Hepatitis B core antibody (IgM); and/or
● Hepatitis C RNA


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Abbreviations: ALT, alanine aminotransferase; ANC, absolute neutrophil count; AST, aspartate
aminotransferase; - hCG, Beta-human chorionic gonadotropin; BUN, blood urea nitrogen; GGT,
gamma glutamyl transferase; INR, international normalization ratio; HbA1C, hemoglobin A1C; HBV,
hepatitis B virus; HCV, hepatitis C virus; LDH, lactate dehydrogenase; MCV, mean corpuscular
volume; MCH, mean corpuscular hemoglobin; MCHC, mean corpuscular hemoglobulin
concentration; PT, prothrombin time; PTT, partial thromboplastin time; RBC, red blood cells; TSH,
thyroid stimulating hormone; ULN, upper limit of normal; WBC, white blood cells
1. Direct bilirubin is required only if the total bilirubin is elevated (2 times the ULN)
2. Chemistry evaluation of chloride or uric acid is not required where there are logistical constraints.
3. If serum creatinine is >2.0 mg/dL, calculate creatinine clearance using standard Cockcroft-Gault
method (Appendix 3).
4. If urine protein result is not available, urine albumin result may be used.
5. For female subjects of childbearing potential only, unless subject has had a hysterectomy,
undergone a tubal ligation within 1 year prior to Screening or has been post-menopausal for at least
1 year prior to Screening.
HbA1c testing to be performed every 12 weeks (+/-3 days) 
7.4.8.1
Additional Histology Specific Assessments and Histology 
Confirmation
For ATC Cohort ONLY: Thyroid stimulating hormone (TSH) and Free T4: Serum TSH 
suppression (lowering TSH below the LLN) through the use of thyroid hormone replacement 
(e.g., levothyroxine) should be considered prior to the first dose of study treatment and 
throughout the study.  However, the decision to suppress TSH is optional and dependent 
upon the investigator weighing the risk and benefits for each individual subject.  If the 
investigator is unsure about suppressing the TSH, it is recommended that an endocrinologist 
be consulted. Free T4 will also be evaluated.
For NSGCT/NGGCT Cohort ONLY: -HCG and AFP: These laboratory assessments
will be completed as indicated in the Time and Event Table (Section 7.1).
For BTC and ASI Cohorts ONLY: CEA and CA19-9: These laboratory assessments will 
be completed as indicated in the Time and Event Table (Section 7.1).
Histology Confirmation for ATC and WHO Grade 1-4 Glioma Cohorts ONLY:
A tissue specimen from the biopsy of a primary or metastatic site must be submitted to 
a Novartis designated central reference laboratory as soon as possible after enrollment 
for possible retrospective confirmation of histologic type. Refer to the SPM and the Lab 
Manual for details regarding sample submission.
7.4.9
Monitoring for Non-Cutaneous Secondary/Recurrent Malignancy
Prior to initiation of treatment subjects should undergo a head and neck examination with 
minimally visual inspection of oral mucosa and lymph node palpitation, as well as 
chest/abdomen CT scan. Subjects should be monitored as clinically indicated during 
treatment and for up to 6 months after treatment discontinuation or until a new anti- cancer 
therapy is initiated. Anal examinations and pelvic examinations (for women) are required 
before and at the end of treatment or when considered clinically indicated. Complete blood 
cell counts should be performed as clinically indicated. Abnormal findings should be 
managed according to standard clinical practice.
Any new non-cutaneous secondary/recurrent malignancy should be reported as an SAE and 
treated according to standard clinical practice.


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7.4.10
Pregnancy Testing and Reporting
7.4.10.1 Pregnancy Testing
The need for a screening pregnancy test depends on whether a female subject is of 
childbearing or non-childbearing potential.
A female of non-childbearing potential (i.e., physiologically incapable of becoming
pregnant) is defined as any female who has had a hysterectomy, bilateral oophorectomy
(ovariectomy) or bilateral tubal ligation, or is post-menopausal defined as 1 year without
menses with an appropriate clinical profile, e.g., age appropriate, >45 years in the absence 
of hormone replacement therapy (HRT). In questionable cases, the subject must have a 
follicle stimulating hormone (FSH) value >40 mIU/mL and an estradiol value <40 pg/mL 
(<140 pmol/L).
A female of child-bearing potential is defined as any female who does not meet the criteria 
of non-childbearing potential as described in the previous paragraph.
If a female subject is of childbearing potential, she must have a serum -HCG pregnancy test 
performed within 7 days prior to the first dose of study treatment.  Subjects with a positive 
pregnancy test result must be excluded from the study.  Subjects with a negative pregnancy
test result must agree to use a highly effective contraception method (see Section 9.1) during 
the study and for 16 weeks following discontinuation of trametinib when taken in combination 
with dabrafenib, or for 2 weeks following discontinuation of dabrafenib monotherapy.
7.4.10.2 Pregnancy Reporting
Any pregnancy that occurs during study participation must be reported using a clinical trial 
pregnancy form. To ensure subject safety, each pregnancy must be reported to the sponsor 
within 24 hours of learning of its occurrence.  The pregnancy must be followed up to 
determine outcome (including premature termination) and status of mother and child.  
Pregnancy complications and elective terminations for medical reasons must be reported as 
an AE or SAE. Spontaneous abortions must be reported as an SAE.  Any SAE occurring in 
association with a pregnancy brought to the investigator’s attention after the subject has 
completed the study and considered by the investigator as possibly related to the study 
treatment, must be promptly reported to the sponsor.
7.4.10.3 Time period for collecting pregnancy information
All pregnancies in female subjects and/or female partners of male subject will be collected 
after the start of dosing until the follow-up visit.
7.4.10.4 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 the sponsor 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 the sponsor.  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.


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7.5
Disease Assessment
If CT scan with contrast is contraindicated (except for chest CT scan), a MRI may be used 
as an alternative method of baseline disease assessment. If a chest CT scan with contrast is 
contraindicated, a chest CT scan without contrast should be performed.
The method used to document baseline status should be used consistently throughout study 
to facilitate comparison of scan results. Assessments must be performed on a calendar 
schedule and should not be affected by dose interruptions or delays. Refer to the Time and 
Events Table (Section 7.1) for the schedule of disease assessments.
7.5.1
Disease Assessment for Solid Tumor Histologies
Disease assessment for solid tumor types (ATC, BTC, GIST, NSGCT/NGGCT, WHO Grade 
1 and 2 gliomas, WHO Grade 3 and 4 gliomas and ASI) will be conducted as noted below.  
For subjects whose disease may be followed by well-characterized tumor markers, disease 
assessment should also include results of tumor marker measurements.
Disease assessments will be completed as indicated in the Time and Events Table (Section 
7.1).
Please refer to the IAG for additional details on imaging assessments for this study.
Baseline Assessments: The following baseline disease assessments are required for all 
subjects within 28 days prior to enrollment (or within 35 days if MRI is used for disease 
assessment:
Histology
Area(s) of
Assessment
Imaging to be
Performed
Alternative Imaging Methods if
Contraindications are Present
ATC1
Brain
MRI with
contrast
1st alternative: MRI without contrast
2nd alternative: CT scan with contrast
Neck
CT scan with
contrast
1st alternative: a MRI with contrast 2nd
alternative: CT scan without contrast (if
1st alternative is contraindicated)
Chest/Abdomen
(including liver and
adrenal glands)
CT scan2
  N/A
BTC/ASI
Chest/Abdomen/Pelvis
CT scan with
contrast
CT scan without contrast of the
Chest and MRI with contrast of
Abdomen/Pelvis
NSGCT/NGGCT
Chest/Abdomen/Pelvis
CT scan with
contrast
CT scan without contrast of the
Chest and MRI with contrast of
Abdomen/Pelvis
GIST
Chest/Abdomen/Pelvis
CT scan with
contrast
CT scan without contrast of the
Chest and MRI with contrast of
Abdomen/Pelvis
ATC1 BTC GIST
NSGCT/NGGCT ASI
WHO Grade 1-4
Glioma
Regions with known or
suspected metastatic
lesions
CT scan, MRI,
or bone scan
as appropriate
  N/A
WHO Grade 1- 4
Glioma
Brain
MRI with
contrast3
N/A
NSGCT/NGGCT4
Brain (for pituitary
GCT)
MRI with
contrast
1st alternative: MRI without contrast
2nd alternative: CT scan with contrast
Abbreviations: ASI, adenocarcinoma of small intestine; ATC, anaplastic thyroid carcinoma; BTC, biliary tract carcinoma;
CNS, central nervous system; CR, complete response; CT, computed tomography; GCT, germ cell tumor; GIST,


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gastrointestinal stromal tumor; MRI, magnetic resonance imaging; NGGCT, non-geminomatous germ cell tumor;
NSGCT, non-seminomatous germ cell tumor; PET, positron emission tomography; SPM, Study Procedures Manual;
WHO, World Health Organization
1.
For ATC subjects without CNS and neck disease at baseline, subsequent brain and neck imaging
should only be performed as clinically indicated.
2.
Optional: Whole body PET/CT scan
3.
MRI of the brain with contrast is mandated in this cohort; CT scan is not permitted. Please refer to
imaging details in the SPM.
4.
For NSGCT/NGGCT subjects without CNS disease at baseline, subsequent MRI of the brain with
contrast should only be performed as clinically indicated (e.g., symptoms suggestive of CNS
progression). For subjects with CNS disease at baseline, a MRI of the brain with contrast is required
every 4 to 8 weeks or as clinically indicated. In addition, in order to confirm a CR in a subject with brain
disease at baseline, a MRI of the brain with contrast must be performed 1 week prior to the first set of
images showing CR to 4 weeks after the next protocol specified assessment.
Post-Baseline Assessments: All post-baseline assessments require imaging of disease sites 
identified by baseline scans.  The same imaging modality used at baseline should be utilized 
for all post-baseline assessments. If subject discontinues treatment prior to Week 48 for 
reasons other than disease progression, disease assessments (imaging) should continue every 
12 weeks until a new treatment is initiated.
Histology
Area(s) of
Assessment
Imaging to be
Performed
Alternative Imaging Methods if
Contraindications are Present
ATC
Chest/Abdomen
(including liver and
adrenal glands)
CT scan1
  N/A
BTC, ASI
Chest/Abdomen/Pelvis
CT scan with
contrast
CT scan without contrast of the Chest and 
MRI with contrast of Abdomen/Pelvis
WHO Grade 1-4
Glioma
Brain
MRI with
contrast2
N/A
NSGCT/NGGCT,
GIST
Chest/Abdomen/Pelvis
CT scan with
contrast
CT scan without contrast of the Chest and 
MRI with contrast of Abdomen/Pelvis
Abbreviations: ASI, adenocarcinoma of small intestine; ATC, anaplastic thyroid carcinoma; BTC, biliary tract carcinoma;
CT, computed tomography; GIST, gastrointestinal stromal tumor; MRI, magnetic resonance imaging; NGGCT, non-
geminomatous germ cell tumor; NSGCT, non-seminomatous germ cell tumor; SPM, Study Procedures Manual; WHO,
World Health Organization
1.
Optional: Whole body PET/CT scan
2.
MRI with contrast is mandated in this cohort; CT scan is not permitted. Please refer to imaging details in
SPM.
7.5.1.1
Response Criteria for Solid Tumor Histologies
For solid tumor types (ATC, BTC, GIST, NSGCT/NGGCT, WHO Grade 1 and 2 gliomas, 
WHO Grade 3 and 4 gliomas and ASI), response evaluations will be determined according 
to the response assessment criteria listed in Table 7.
Table 7
Response Criteria for Solid Tumor Histologies
Histology
Response Criteria
Response Subcategories defined
as ‘Response4
ATC, BTC, GIST, ASI,
NSGCT/NGGCT
RECIST v 1.11
CR, PR
WHO Grade 1 and 2
Glioma
RANO Response Criteria: Response
Assessment Criteria for
WHO Grade 1 and 2 Glioma2
CR, PR and MR


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WHO Grade 3 and 4
Glioma
RANO Response Criteria: Updated
Response Assessment Criteria for 
WHO Grade 3 and 4 Glioma3
CR, PR
Abbreviations: ATC, anaplastic thyroid carcinoma; BTC, biliary tract cancer; CR, complete response;
GIST, gastrointestinal stromal tumor; MR, minor response; NGGCT, non-geminomatous germ cell
tumor; NSGCT, non- seminomatous germ cell tumor; PR, partial response; RANO, Response
Assessment in Neuro-Oncology; RECIST, Response Evaluation Criteria in Solid Tumors; SPM,
Study Procedures Manual; WHO, World Health Organization
1.
Refer to Appendix 10 for details response criteria.
2.
Refer to Appendix 13 for details response criteria
3.
Refer to Appendix 14 for details response criteria
4.
Serum tumor markers normalization will not be considered as part of response criteria.
7.5.2
Disease Assessment for Histologies of Hematologic Malignancies
For hematologic malignancies (HCL and MM), disease assessment will be conducted as 
noted below. For subjects whose disease may be followed by well-characterized tumor 
markers, disease assessment should also include results of tumor marker measurements. 
Disease assessments will be completed as indicated in the Time and Events Table (Section 
7.1).
7.5.2.1
Laboratory and Disease Assessments: HCL
Baseline Assessments: The following baseline disease assessments will be performed at the 
time points indicated in the Time and Event Table (Section 7.1):

Complete blood count

Routine stain of peripheral blood sample

BM aspirate and biopsy sample with H/E stain and IHC

Flow cytometry on BM aspirate sample and peripheral blood sample

Chest CT scan and abdominal CT scan with contrast
NOTE: MRI of the abdomen may be performed if abdominal CT cannot be performed. The 
method used to document baseline status is used consistently throughout the study to 
facilitate comparison of results.
If lymph nodes and spleen were enlarged at baseline, they must be followed by post- baseline 
assessments using a consistent imaging modality.
Post-Baseline Assessments: A response is to be determined every 4 weeks (+/-3 days) for 
the first 48 weeks of study treatment.  Beyond 48 weeks, patients tolerating study drug in the 
judgement of the treating investigator may transition to a response assessment evaluation 
interval of at least every 12 weeks (+/-3 days) (Changed from “at least every 8 weeks (+/- 3 
days)” indicated in Protocol Amendments 8 through 11).  Patients that are not tolerating study 
drug in the judgement of the treating investigator must continue (or return to) response 
assessment evaluation every 4 weeks (+/-3 days).  Assessments must be collected in 
agreement with those required in the response criteria (please consult Appendix 12).

Complete blood count

Routine stain of peripheral blood sample

BM aspirate and biopsy sample with H/E stain and IHC

Flow cytometry on BM aspirate sample will be performed as indicated in the Time and 
Event Table (Section 7.1).


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
Flow cytometry on peripheral blood sample will be performed as indicated in the Time 
and Event Table (Section 7.1)

If lymph nodes and/or spleen were enlarged at baseline, they must be followed by post-
baseline assessments using a consistent imaging modality as indicated in the Time and 
Event Table (Section 7.1).
7.5.2.2
Laboratory and Disease Assessment: MM
Baseline Assessments: The following baseline disease assessments will be performed at the 
time points indicated in the Time and Event Table (Section 7.1):

Skeletal surveys

Extramedullary disease assessment BM aspirate and biopsy samples:  Samples will be 
assessed by IHC, flow cytometry, fluorescence in situ hybridization (FISH) and 
cytogenetics.

UPEP

SPEP

CRP, -2 microglobulin, serum FLC assay, levels of immunoglobulin (Ig)G, IgA, and 
IgM
Post-baseline Assessments: All post-baseline assessments require imaging of disease sites 
identified by baseline scans.  The same imaging modality used at baseline should be utilized 
for all post-baseline assessments.

BM aspirate and biopsy samples will be performed and assessed as indicated in the 
Time and Event Table (Section 7.1)

Laboratory tests (SPEP, UPEP , CRP, -2 microglobulin, serum FLC assay, levels of 
IgG, IgA, and IgM will be performed as indicated in the Time and Event Table (Section 
7.1).

Skeletal surveys:  Post-baseline assessments only need to be performed if disease is 
noted on the baseline assessment. If no disease is identified at baseline, then subsequent 
skeletal surveys are only required if clinically indicated.

Extramedullary disease assessment:  Post-baseline assessments only need to be
performed if disease is noted on the baseline assessment.  If no disease is identified at 
baseline, then subsequent assessments are only required if clinically indicated.
7.5.2.3
Response Criteria for Hematologic Histologies
For hematologic malignancies (HCL and MM), response evaluations will be determined
according to the response assessment criteria listed in Table 8.
Table 8
Response Criteria for Hematologic Histologies
Histology
Response Criteria
Response Subcategories
defined as ‘Response'
HCL
Adapted from NCCN guidelines, Consensus
Resolution Criteria and previous studies definition1
CR±MRD, PR


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MM
IMWG Uniform Response Criteria for MM2
sCR, CR, PR, VGPR
Abbreviations: CR, complete response; HCL, hairy cell leukemia; IMWG, International Myeloma
Working Group; MM, multiple myeloma; MRD, minimal residual disease; NCCN, National
Comprehensive Cancer Network; PR, partial response; sCR, stringent complete response; SPM,
Study Procedures Manual; VGPR, very good partial response
1.
Refer to Appendix 12 for details on response criteria.
2.
Refer to Appendix 15 for details on response criteria.
8
DOSE MODIFICATIONS AND STOPPING CRITERIA
8.1
Dose Modification
General guidelines regarding management and dose reduction for AEs that are considered by
the investigator to be related to study treatment and for which specific guidelines do not apply
are provided in Table 11. A maximum of two trametinib dose level reductions are allowed.  
If a third dose level reduction is required, study treatment should be permanently 
discontinued.
If a dose reduction of trametinib is required, but the toxicity resolves and no additional
toxicities are seen after one treatment cycle (4 weeks), the dose of trametinib may be re-
escalated but should not exceed 2 mg once daily.
If a dose reduction of dabrafenib is required, but the toxicity resolves and no additional 
toxicities are seen after one treatment cycle (4 weeks), the dose of dabrafenib may be re-
escalated but should not exceed 150 mg BID daily.
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 subject.
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.
Dose delay: Treatment with dabrafenib and trametinib may be delayed for up to 21 days to 
allow resolution of toxicity, or based on investigator discretion (e.g., scheduling issues).  If 
the investigator and the Medical Lead conclude that continued treatment will benefit a subject 
who has experienced a treatment delay >21 days, then the subject may continue treatment 
with the approval of the Medical Lead. If a dose delay continues for 60 or more days, then 
both study treatments (dabrafenib and trametinib) will be permanently discontinued.
Subjects should complete the Follow-Up Visit and then proceed to the extended follow-up 
phase as indicated in the Time and Events Table (Section 7.1).
Dose reduction: A dose reduction below 75 mg BID for dabrafenib or below 1 mg once
daily for trametinib is not allowed.  If a dose reduction below 75 mg BID for dabrafenib is 
required, dabrafenib will be permanently discontinued, but the subjects will be allowed to 
continue treatment with trametinib.  If a dose reduction below 1 mg once daily for trametinib 
is required, then trametinib will be permanently discontinued, but these subjects will be 
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If both study treatments are reduced below the minimum dose levels (75 mg BID for 
dabrafenib and 1 mg once daily for trametinib), then both study treatments will be 
permanently discontinued. Subjects should complete the Follow-Up Visit and then proceed 
to the extended follow-up phase as indicated in the Time and Events Table (Section 7.1).
For Grade 2 or 3 laboratory abnormalities that are considered unrelated to the study treatment 
or those that are reversible in <48 hrs (except for liver enzymes) such as electrolyte 
abnormalities may continue without dose reductions.
Dose Escalation: Following a dose reduction, subjects may be re-escalated to a higher dose 
level with the approval of the Medical Lead.  If the AE has resolved to Grade 1 or baseline 
at the reduced dose level, and no additional toxicities are seen after 4 weeks of study
treatment at the reduced dose, the dose may be increased to the previous dose level.
Table 9 describes the dose /schedule to be used for any necessary dose modifications (based 
on the initial dose level of 150 mg BID) for dabrafenib.
Table 9
Dabrafenib Dose Levels
Dose Level
Dose/Schedule
0
150 mg BID
-1 (first dose reduction)
100 mg BID
-2 (second dose reduction)
75 mg BID
Table 10 describes the dose /schedule to be used for any necessary dose modifications (based 
on the initial dose level of 2 mg once daily) for trametinib.
Table 10
Trametinib Dose Levels
Dose Level
Dose/Schedule
0
2 mg once daily
-1 (first dose reduction)
1.5 mg once daily
-2 (second dose reduction)
1 mg once daily
Table 11
Dose Modification Guidelines – General
CTCAE Grade
Action and Dose Modification1,2
Grade 1 or Grade 2 (Tolerable)
Any occurrence

Continue treatment with dabrafenib and trametinib at same dose 
level (no dose modification)
 Grade 2 (Intolerable) or Grade 3
1st, 2nd or 3rd occurrence

Interrupt dabrafenib and trametinib until toxicity resolves to ≤
Grade 1 then restart at next lower dose level
4th or greater occurrence

Discontinue treatment with dabrafenib and trametinib
 Grade 4


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1st occurrence

Interrupt dabrafenib and trametinib until toxicity resolves to ≤
Grade 1 or baseline then restart at next lower dose level or 
discontinue at the discretion of the investigator
2nd occurrence

Interrupt dabrafenib and trametinib until toxicity resolves to ≤
Grade 1 or baseline then restart at 2 dose levels lower than the 
starting dose or discontinue at the discretion of the investigator 
and after discussion with the Medical Lead.
3rd occurrence

Discontinue treatment with dabrafenib and trametinib
1.
Treatment should be discontinued if more than 2 dose reductions are required
2.
Approval from the Medical Lead is required to restart study treatment after ≥21 days
8.1.1
Cardiovascular Events
Cardiovascular AEs have been seen in subjects receiving trametinib, dabrafenib or both in
combination.  Guidelines for prolonged QTc interval, LVEF decreases, and hypertension are 
provided in Section 8.1.1.1, Section 8.1.1.2 and Section 8.1.1.3, respectively.
8.1.1.1
QTc Prolongation
Guidelines for dose modification and stopping criteria due to the QTc prolongation are 
provided in Table 12.
Table 12
Withholding and Stopping Criteria for QTc Prolongation
QTc Prolongation1
Action and Dose Modification

QTcB ≥501 msec
Interrupt treatment with trametinib and dabrafenib until QTc 
prolongation resolves to Grade 1 or baseline
Test serum potassium, calcium, phosphorus and magnesium. If 
abnormal, correct per routine clinical practice to within normal 
limits.
Review concomitant medication usage for agents that prolong 
QTc.
If event resolves, restart trametinib and dabrafenib at current dose 
level2
If event does not resolve, permanently discontinue study 
treatments. Consider evaluation with cardiologist.
If event recurs, permanently discontinue trametinib and dabrafenib. 
Consider evaluation with cardiologist.
Abbreviations: ECG, electrocardiogram; msec, milliseconds; QTc, corrected QT interval; QTcB, QT interval on ECG
corrected using the Bazett’s formula
1.
Based on average QTc value of triplicate ECGs. For example, if an ECG demonstrates a prolonged QT interval,
obtain 2 or more ECGs over a brief period, and then use the averaged QTc values of the 3 ECGs to determine
if trametinib and dabrafenib should be interrupted or discontinued.
2.
If the QTc prolongation resolves to Grade 1 or baseline, the subject may resume treatment with trametinib and
dabrafenib if the investigator and Medical Lead agree that the subject will benefit from further treatment.
8.1.1.2
Left Ventricular Ejection Fraction (LVEF) Stopping Criteria
Decreases of the LVEF have been observed in subjects receiving trametinib monotherapy
and in combination with dabrafenib.  Therefore, ECHOs must be performed to assess cardiac 
ejection fraction at regular intervals as outlined in the Time and Events Table (Section 7.1).


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Echo assessment should be performed by the same operator throughout the study where
possible.  Copies of all ECHOs will be collected by the sponsor for review.  Instructions for 
submission of ECHOs are provided in the SPM. Dose modification guidance and stopping 
criteria for LVEF decrease are provided in Table 13.
Table 13
Dose Modification Guidelines and Stopping Criteria for LVEF
Decreases
Presentation
LVEF decrease (%)
or CTCAE Grade
Action and Dose Modification
Asymptomatic
Absolute decrease of
>10% in LVEF
compared to baseline
and ejection fraction
below the institutional
LLN
● Interrupt study treatment and repeat ECHO within 2 weeks1
● Report as an AE If the LVEF recovers within 4 weeks (defined as
LVEF ≥LLN and absolute decrease ≤10% compared to baseline)
● Consult with the Medical Lead and request approval for restart
● Restart treatment with trametinib reduced dose by one dose
level
● Restart dabrafenib at previous dose level
● Repeat ECHO 2 , 4 , 8 and 12 weeks after re-start; continue in
intervals of 12 weeks thereafter
● If LVEF does not recover within 4 weeks
● Consult with cardiologist
● Permanently discontinue study treatment
● Repeat ECHO after 2, 4, 8, 12, and 16 weeks or until
resolution
● Consult with the Medical Lead
Symptomatic2
Grade 3:
● Permanently discontinue study treatment
resting LVEF 39 to
20%
or >20% absolute
● Report as a SAE
reduction from
baseline
● Consult with cardiologist
Grade 4:
resting LVEF <20%
● Repeat ECHO after 2, 4, 8, 12, and 16 weeks or until resolution2,
Abbreviations: AE, adverse event; CTCAE, Common Toxicity Criteria for Adverse Events; ECHO,
echocardiogram; LLN, lower limit of normal; LVEF, left ventricular ejection fraction; SAE, serious
adverse event
1. If ECHO does not show LVEF recovery after 2 weeks, repeat ECHO 2 weeks later.
2. Symptoms may include: dyspnea, orthopnea, and other signs and symptoms of pulmonary
congestion and edema.
8.1.1.3
Hypertension
Increases in BP have been observed in subjects receiving trametinib. Recommendations for 
blood pressure monitoring and management are provided in Section 8.1.1.3.1 and Section
8.1.1.3.2, respectively.
8.1.1.3.1 Monitoring of Hypertension
All BP assessments should be performed under optimal conditions:

the subject is seated in a semi-supine position with back support, ensuring that legs are 
uncrossed and flat on the floor

the subject sits relaxed comfortably for at least 5 minutes

restrictive clothing is removed from the cuff area and the right cuff size is selected

the subject’s arm is supported so that the middle of the cuff is at the heart level

the subject remains quiet during the measurement


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Three readings of BP and pulse rate should be taken. The first reading should be rejected and 
the second and third readings averaged to give the measurement to be recorded in the eCRF.
Persistent hypertension is defined as an increase of systolic blood pressure (SBP) >140 
mmHg and/or diastolic blood pressure (DBP) >90 mmHg in 3 consecutive visits with BP 
assessments from the readings collected as described above. Visits to monitor increased BP 
should be scheduled independently from the per-protocol visits outlined in the Time and 
Events Table (Section 7.1). Ideally, subsequent BP assessments should be performed within 
7 days.
Asymptomatic hypertension is defined as an increase of SBP >140 mmHg and/or DBP >90 
mmHg in the absence of headache, lightheadedness, vertigo, tinnitus, episodes of fainting or 
other symptoms indicative of hypertension.
8.1.1.3.2 Management of Hypertension
For subjects experiencing an increase in systolic and/or diastolic BP that is persistent and
may be associated with the study treatment, recommendations for the clinical management 
of hypertension are described in Table 14.
Table 14
Management and Dose Modification Guidelines for Hypertension
Hypertension
Action and Dose Modification
(A). Asymptomatic and persistent1
SBP of ≥140 mmHg and <160
mmHg, or DBP
≥90 mmHg and <100 mmHg, or a 
clinically significant increase in
DBP of 20 mmHg (but still
<100 mmHg).
● Continue study treatments at the current dose
● Adjust current or initiate new antihypertensive medication(s)
● Titrate antihypertensive medication(s) during the next 2 weeks as
indicated to achieve well-controlled2 BP
● If BP is not well controlled within 2 weeks, consider referral to a
specialist and go to scenario (B).
(B). Asymptomatic SBP
≥160 mmHg, or
DBP ≥100 mmHg, or failure to
achieve well-controlled BP within
2 weeks in scenario (A).
● Interrupt study treatments if clinically indicated
● Adjust current or initiate new antihypertensive medication(s)
● Titrate antihypertensive medication(s) during the next 2 weeks as
indicated to achieve well-controlled BP
● Once BP is well controlled2, restart study treatments reduced by one
dose level3
(C). Symptomatic4 hypertension
or persistent SBP ≥160 mmHg, or 
DBP ≥100 mmHg, despite
antihypertensive medication(s)
and dose reduction of study
treatment
● Interrupt study treatments
● Adjust current or initiate new antihypertensive medication(s)
● Titrate antihypertensive medication(s) during the next 2 weeks as
indicated to achieve well-controlled BP
● Referral to a specialist for further evaluation and follow-up is
recommended
● Once BP is well controlled2, restart study treatments reduced by one
dose level3
Hypertension
Action and Dose Modification
(D). Refractory hypertension
unresponsive to above
interventions or hypertensive crisis
● Permanently discontinue study treatments
● Continue follow-up per protocol.
Abbreviations: BP, blood pressure; DBP, diastolic blood pressure; mmHg, millimeters of mercury; SBP, systolic blood
pressure
1.
Hypertension detected in 2 separate readings during up to 3 consecutive visits
2.
Well-controlled BP defined as SBP 140 mmHg and DBP 90 mmHg in 2 separate readings during up to 3
consecutive visits
3.
Escalation to previous dose level can be considered if BP remains well-controlled for 4 weeks after
restarting. Approval from the Medical Lead is required.


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4.
Symptomatic hypertension defined as hypertension aggravated by symptoms (e.g. headache,
lightheadedness, vertigo, tinnitus, episodes of fainting) that resolve after the BP is controlled within the
normal range.
8.1.2
Pancreatitis
In the event of abdominal pain or suspected pancreatitis, amylase and lipase laboratory
samples should be collected for confirmation of the diagnosis.  Subjects should be closely
monitored when re-starting study treatment after an episode of pancreatitis.
8.1.3
Hepatobiliary Events
8.1.3.1
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to assure
subject safety and evaluate liver event etiology in alignment with the FDA premarketing
clinical liver safety guidance
fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid 
ances/UCM174090.pdf
8.1.3.1.1 Liver Chemistry Stopping and Increased Monitoring Algorithm for
Subjects WITH entry criteria ALT ≤2.5xULN


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Table 15
Liver Chemistry Stopping Criteria – Liver Stopping Event for
Subjects WITH Entry Criteria ALT≤2.5xULN
ALT-absolute
ALT 5xULN
ALT Increase
ALT 3xULN persists for 4 weeks
Bilirubin1, 2
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin)
INR2
ALT 3xULN and INR>1.5, if INR measured
Cannot Monitor
ALT 3xULN and cannot be monitored weekly for 4 weeks
Symptomatic3
ALT  3xULN associated with symptoms (new or worsening) believed to be related
to liver injury or hypersensitivity
Abbreviations: ALT, alanine aminotransferase; INR, international normalization ratio; ULN, upper limit of normal
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not
immediately available, discontinue study treatment for that subject if ALT 3xULN and bilirubin 2xULN.
Additionally,if serumbilirubin fractionationtesting is unavailable, recordpresenceof detectableurinary bilirubin
on dipstick, indicating direct bilirubin elevations and suggesting liver injury.
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR
measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated
will not apply to subjects receiving anticoagulants
3.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or
eosinophilia)
8.1.3.1.2 Liver Chemistry Stopping and Increased Monitoring Algorithm
including Subjects WITH Documented Liver Metastases/Tumor
Infiltration at Baseline AND entry criteria ALT>2.5xULN but ≤5xULN


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Table 16
Liver Chemistry Stopping Criteria
– Liver Stopping Event: 
Subjects with Documented Liver Metastases/Tumor Infiltration at 
Baseline AND Entry Criteria ALT >2.5xULN but ≤5xULN
ALT-absolute
Both ALT ≥5xULN and ≥2x baseline value
ALT Increase
Both ALT ≥3xULN and ≥1.5x baseline value that persists for 4 weeks
Bilirubin1, 2
ALT ≥3xULN and bilirubin 2xULN (>35% direct bilirubin)
INR2
ALT ≥3xULN and INR>1.5, if INR measured
Cannot Monitor
Both ALT ≥3xULN and ≥1.5x baseline value that cannot be monitored for 4 weeks
Symptomatic3
Both ALT ≥3xULN and ≥1.5x baseline value associated with symptoms (new or
worsening) believed to be related to liver injury or hypersensitivity
Abbreviations: ALT, alanine aminotransferase; INR, international normalization ratio; ULN, upper limit of normal
1. Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not immediately
available, discontinue study treatment for that subject if ALT %3xULN and bilirubin %2xULN. Additionally, if serum bilirubin
fractionation testing is unavailable, record presence of detectable urinary bilirubin on dipstick, indicating direct bilirubin
elevations and suggesting liver injury.
2. All events of ALT %3xULN and bilirubin %2xULN (>35% direct bilirubin) or ALT %3xULN and INR>1.5, if INR measured
which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding studies of hepatic
impairment or cirrhosis); INR measurement is not required and the threshold value stated will not apply to subjects
receiving anticoagulants
3. New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper quadrant
pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or eosinophilia)
8.1.3.1.3 Liver Safety Required Actions and Follow-Up
Table 17
Required Actions and Follow-Up Assessments Following ANY
Liver Stopping Event
Actions
Follow-Up Assessments
∀
Immediately discontinue study treatments
∀
Report the event to the sponsor within 
24 hrs
∀
Complete the liver event eCRF and
complete an SAE data collection tool if 
the event also meets the criteria for an 
SAE2
∀
Perform liver event follow-up assessments
∀
Monitor the subject until liver 
chemistries resolve, stabilize, or return 
to within baseline (see MONITORING
below)
∀
Do not restart/rechallenge subject 
with study treatment unless allowed per
protocol and the sponsor Medical
Governance approval is granted (refer
to Appendix 18)
∀
Viral hepatitis serology1
∀
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 antibody3.
∀
Blood sample for PK analysis, obtained 24-
72 hrs after last dose4
∀
Serum creatine phosphokinase 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 liver injury, or 
hypersensitivity, on the AE eCRF
∀
Record use of concomitant medications 
on the concomitant medications report 


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
If restart/rechallenge not allowed per
protocol or not granted, permanently
discontinue study treatments and may
continue subject in the study for any
protocol specified follow-up 
assessments
MONITORING:
For bilirubin or INR criteria:

Repeat liver chemistries (include ALT,
AST, alkaline phosphatase, bilirubin) 
and perform liver event follow-up 
assessments within 24 hrs

Monitor subjects twice weekly until 
liver chemistries resolve, stabilize or 
return to within baseline

A specialist or hepatology consultation 
is recommended
For All other criteria:
Repeat liver chemistries(include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow-up assessments within 24-
72 hrs

Monitor subjects weekly until liver
chemistries resolve, stabilize or return to
within baseline
form including acetaminophen, herbal 
remedies, other OTC medications

Record alcohol use on the liver event alcohol 
intake eCRF
For bilirubin or INR criteria:

Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney microsomal 
antibodies, 
and
quantitative
total 
immunoglobulin G (IgG or gamma globulins).

Serum acetaminophen adduct HPLC assay
(quantifies potential acetaminophen 
contribution to liver injury in subjects with 
definite or likely acetaminophen use in the 
preceding week
[James, 2009]).

Liver imaging (ultrasound, MRI or CT) and /or 
liver biopsy to evaluate liver disease;
complete Liver Imaging and/or Liver Biopsy 
eCRF.
Abbreviations: AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CT, computed
tomography; DNA, deoxyribonucleic acid; eCRF, electronic case report form; HPLC, high performance liquid
chromatography; hrs, hours; IgG, Immunoglobulin G; IgM, Immunoglobulin M; INR, international normalization ratio; MRI,
magnetic resonance imaging; OTC, over-the-counter; PCR, polymerase chain reaction; PK, pharmacokinetic; RNA,
ribonucleic acid; SAE, serious adverse event; SRM, study reference manual; ULN, upper limit of normal
1.
Includes: 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.
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR
measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated will
not apply to subjects receiving anticoagulants
3.
If hepatitis delta antibody assay cannot be performed, it can be replaced with a PCR of hepatitis D RNA virus (where
needed) [Le Gal, 2005].
4.
PK sample may not be required for subjects known to be receiving placebo or non-sponsor comparator treatments.)
Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment 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 SRM.


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Table 18
Liver Chemistry Increased Monitoring Criteria with Continued
Therapy
Criteria
Actions
Subject with entry criteria ALT≤2.5xULN
ALT 3xULN but <5xULN and bilirubin
<2xULN, without symptoms believed to be 
related to liver injury or hypersensitivity and
who can be monitored weekly for
4 weeks
Subject with documented liver
metastases/tumor infiltration at baseline 
AND entry criteria ALT>2.5xULN but 
≤5xULN
ALT ≥3xULN and 1.5x baseline value but
ALT <5xULN and 2x baseline value and
bilirubin <2xULN, without symptoms
believed to be related to liver injury, or
hypersensitivity and who can be monitored 
weekly for 4 weeks

Notify the Medical Lead within 24 hrs of learning of 
the abnormality to discuss subject safety.

Subject can continue study treatments

Subject must return weekly for repeat liver 
chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilise or return to 
within baseline

If at any time subject meets the liver chemistry 
stopping criteria, proceed as described above
For subjects with entry criteria ALT≤2.5xULN

If, after 4 weeks of monitoring, ALT <3xULN and 
bilirubin
<2xULN, monitor subjects twice monthly until liver
chemistries normalize or return to within baseline.
For subjects with documented liver metastases/tumor
infiltration at baseline AND entry criteria ALT>2.5xULN but
≤5xULN
If, after 4 weeks of monitoring, ALT <3xULN and <1.5x
baseline value, and bilirubin <2xULN, monitor subjects twice 
monthly until liver chemistries normalize or return to within 
baseline
Refer to Appendix 18 for liver safety drug restart or rechallenge guidelines.
8.2
Dose Modification and Management Guidelines for Events of
Special Interest
The severity of AEs will be graded utilizing the CTCAE v4.0 [NCI, 2009]. Brief guidelines 
for dose modifications and interruptions for management of common toxicities associated 
with the study treatments are provided in this section.
8.2.1
Dermatological Events
8.2.1.1
Rash
Rash is frequently observed in subjects receiving trametinib, dabrafenib, or the combination 
of both therapies.  Guidelines for management are based on experience with other MEK 
inhibitors and epidermal growth factor receptor inhibitors [Balagula, 2011; LaCouture, 2011].
The institutional standards for the management of skin-related AEs can differ from these
guidelines. In this case, best clinical judgment should be applied and a consultation with the 
Medical Monitor may be required.
Table 19
Guidelines for Supportive Care of Rash


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Type of Care
Action
Prevention/Prophylaxis1

Avoid unnecessary exposure to sunlight

Apply broad-spectrum sunscreen (containing titanium dioxide or zinc 
oxide) with a skin protection factor (SPF) ≥15 at least BID.

Use thick, alcohol-free emollient cream (e.g., glycerine and 
cetomacrogol cream) on dry areas of the body at least BID.

Topical steroids and antibiotics should be applied at least BID 
starting on Day 1 of study treatment, to body areas such as face, 
chest, and upper back.

Use mild-strength topical steroid (hydrocortisone 1% 
cream)
or

topical antibiotic (e.g., clindamycin) or oral antibiotics 
(e.g., doxycycline 100 mg BID, minocycline 100 mg 
BID)
Symptomatic Care2

Pruritic lesions: cool compresses and oral antihistamine therapies

Fissuring lesions: Monsel’s solution, silver nitrate, or zinc oxide cream

Desquamation: thick emollients and mild soap

Paronychia: antiseptic bath, local potent corticosteroids in addition 
to oral antibiotics; if no improvement, consult dermatologist or 
surgeon

Infected lesions: appropriate bacterial/fungal culture-driven 
systemic or topical antibiotics
Abbreviations: BID, twice daily; SPF, sun protection factor
1.
Rash prophylaxis is recommended for the first 6 weeks of study treatment
2.
Subjects who develop rash/skin toxicities should be seen by a qualified physician and should receive
evaluation for symptomatic/supportive care management
Guidelines for management and dose reduction for rash considered to be related to study
treatment are provided in Table 20.
Table 20 
Management and Dose Modification Guidelines for Rash
CTCAE Grade
Adverse Event Management
Action and Dose Modification
Grade 1



Initiate prophylactic and
symptomatic treatment measures1
Use moderate strength topical
steroid2
Reassess after 2 weeks

Continue study treatment

If rash does not recover to
baseline within 2 weeks 
despite best supportive 
care, reduce trametinib by 
one dose level3
Grade 2



Initiate prophylactic and
symptomatic treatment measures
Use moderate strength topical
steroid2
Reassess after 2 weeks

Reduce study treatment by 
one dose level

If rash recovers to
≤Grade 1 within 2 weeks, 
increase dose to previous 
dose level


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CTCAE Grade
Adverse Event Management
Action and Dose Modification

If no recovery to ≤Grade 
1 within 2 weeks, 
interrupt study treatment 
until recovery to
≤Grade 1

Restart study 
treatment at reduced
dose level3
Grade ≥3


Use moderate strength topical
steroids2 PLUS oral methyl-
prednisolone dose pack
Consult dermatologist

Interrupt study treatment until 
rash recovers to Grade ≤1

Restart3 with study 
treatment reduced by 
one dose level4

If no recovery to Grade ≤2
within 4 weeks, permanently 
discontinue study treatment.
Abbreviations: CTCAE, Common Terminology Criteria for Adverse Events
1.
Rash prophylaxis is recommended for the first 6 weeks of study treatment
2.
Moderate-strength topical steroids: hydrocortisone 2.5% cream or fluticasone propionate 0.5% cream
3.
Approval of the Medical Lead is required to restart study treatment after >4 weeks of interruption.
4.
Escalation of study treatment to previous dose level may be considered if no rash is evident 4 weeks after restarting
study treatment
8.2.1.2
Palmar-plantar Erythrodysesthesia
Palmar-plantar erythrodysesthesia (PPE) syndrome: Measures for PPE syndrome 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) and symptomatic treatments. Apply moisturizing creams 
frequently, topical keratolytics (e.g., urea 20 to 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.
8.2.1.3
SCARs (Severe Cutaneous Adverse Reactions)
Cases of severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome, 
and drug reaction with eosinophilia and systemic symptoms (DRESS), which can be life-
threatening or fatal, have been reported during treatment with dabrafenib in combination with 
trametinib.  Before initiating treatment, patients should be advised of the signs and symptoms 
and monitored closely for skin reactions.  If signs and symptoms suggestive of SCARs appear, 
dabrafenib and trametinib should be permanently discontinued.




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8.2.3
Pyrexia
Pyrexia, defined as a body temperature 38.5○C (101.3○F), has been observed in subjects
receiving dabrafenib monotherapy, and is increased in incidence and severity in subjects
receiving dabrafenib in combination with trametinib.  In a minority of cases, pyrexia was
accompanied by symptoms such as severe chills/rigors, dehydration, hypotension, dizziness 
or weakness and required hospitalization.
Subjects should be instructed on the importance of immediately reporting febrile episodes.  
In the event of a fever, the subject should be instructed to take anti-pyretics (i.e., 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 and after pyrexia associated with rigors, severe chills, dehydration, 
hypotension, serum creatinine and other evidence of renal function should be monitored 
carefully.
Guidelines regarding management and dose reduction for pyrexia considered to be related to 
dabrafenib are provided in Table 21.
Table 21
Management and Dose Modification Guidelines for Pyrexia
Occurrence
Action and Dose Modification
Any2
1.
Clinical evaluation for infection and hypersensitivity3
2.
Laboratory work-up3
3.
Hydration as required4
First Event2:
1.
Administer anti-pyretic treatment if clinically indicated and initiate prophylactic
treatment if associated with rigors, renal failure, dehydration or hypotension5
2.
Interrupt treatment with dabrafenib; continue treatment with trametinib.
3.
Once pyrexia resolves to baseline, restart treatment with dabrafenib at the 
same dose level; continue treatment with trametinib at current dose level.
4.
If fever is associated with dehydration, hypotension, or renal insufficiency,
reduce dabrafenib by one dose level; continue treatment with trametinib at 
current dose level7.
Second Event
1.
Follows same guidelines as for First Event (see above), and
2.
Within 3 days of onset

Optimize anti-pyretic therapy

Consider oral corticosteroids (i.e., prednisone 10 mg) for at least 5 days 
or as clinically indicated6
Subsequent
Events:
1.
Interrupt treatment with dabrafenib; continue treatment with trametinib.
2.
Once pyrexia resolves to baseline, restart treatment with dabrafenib at dose
reduced by one dose level; continue treatment with trametinib at current dose
level.6
3.
Within 3 days of onset:
Optimize oral corticosteroid dose as clinically indicated for recalcitrant
pyrexia.7
If corticosteroids have been tapered and pyrexia recurs, restart steroids.
If corticosteroids cannot be tapered, consult Medical Lead.
Abbreviations: BUN, blood urea nitrogen; CRP, C-reactive protein
1.
Pyrexia is defined as a body temperature equal to or above 38.5○C (101.3○F)
2.
For subjects experiencing pyrexia complicated by rigors, severe chills, etc., a clinical evaluation and laboratory work-
up is mandatory for each event; non-steroidal anti-pyretic treatments should be started immediately at the first
occurrence and prophylactic non-steroidal anti-pyretic treatment is recommended when restarting after an
interruption.


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3.
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, liver function tests, blood culture, and urine
culture.
4.
Oral hydration should be encouraged in subjects without evidence of dehydration. Intravenous (IV) hydration is
recommended in subjects experiencing pyrexia complicated by dehydration/hypotension.
5.
Non-steroidal anti-pyretic treatment may include acetaminophen (paracetamol), ibuprofen, or other suitable anti-
pyretic medication according to institutional standards. Prophylactic non-steroidal anti-pyretic treatment may be
discontinued after 3 days in the absence of pyrexia
NOTE: For subjects with MM, alternative anti-pyretic treatment (i.e., acetaminophen [paracetamol] or other suitable
anti-pyretic medication should be taken as NSAIDs are prohibited (see Section 10.2)
6.
Dabrafenib should be reduced by one dose level at discretion of the investigator if pyrexia is accompanied by severe
recurring rigors 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.
7.
In subjects experiencing pyrexia complicated by rigors, severe chills, etc., which cannot be controlled with non-
steroidal anti-pyretic medication, oral corticosteroids should be started at the second event and doses should be
gradually increased for subsequent events.
8.2.4
Pneumonitis
Pneumonitis has been observed in subjects receiving trametinib monotherapy and trametinib 
in combination with dabrafenib.  To reduce the risk of pneumonitis, subjects will be 
monitored closely for symptoms and evaluated with imaging and functional tests. Dose 
modification and supportive care guidelines for pneumonitis are described in Table 22.
Table 22
Guidelines 
for 
Management 
and 
Dose 
Modification 
for 
Pneumonitis
CTCAE Grade
Adverse Event Management
Action and Dose Modification
Grade 1
CT scan (high-resolution with 
lung windows) recommended
Clinical evaluation and 
laboratory work-up for 
infection
Monitoring of oxygenation via 
pulse- oximetry recommended
Consultation of 
pulmonologist
recommended
Continue trametinib at current dose
Grade 2
CT scan (high-resolution with 
lung windows)
Clinical evaluation and 
laboratory work-up for 
infection
Interrupt trametinib until 
recovery to Grade ≤1
Restart with trametinib reduced 
by one dose level
  Grade 3




Consult pulmonologist
Pulmonary function tests –
if < normal, repeat every 8 weeks
until ≥normal
Bronchoscopy with biopsy and/or BAL
recommended
Symptomatic therapy including
corticosteroids if clinically indicated
Consider use of corticosteroids 
prior to and during restart
Escalation to previous dose level 
is possible after 4 weeks and 
consultation with the Medical Lead
If no recovery to Grade ≤1
within 4 weeks, permanently 
discontinue trametinib


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CTCAE Grade
Adverse Event Management
Action and Dose Modification
Grade 3 cont...






CT scan (high-resolution with lung
windows)
Clinical evaluation and laboratory work-
up for infection
Consult pulmonologist
Pulmonary function tests-if < normal,
repeat every 8 weeks until ≥normal
Bronchoscopy with biopsy and/or BAL
if possible
Symptomatic therapy including
corticosteroids as clinically indicated
Interrupt trametinib until 
recovery to Grade ≤1
After consultation with the 
Medical Lead, trametinib may 
be restarted reduced by one 
dose level
Consider use of corticosteroids 
prior to and during restart
If no recovery to Grade ≤1
within 4 weeks, permanently 
discontinue trametinib
Grade 4
Same as Grade 3
Permanently discontinue trametinib
Abbreviations: BAL, bronchioalveolar lavage; CT, computed tomography
8.2.5
Diarrhea
Episodes of diarrhea have occurred in subjects receiving dabrafenib in combination with 
trametinib and /or trametinib monotherapy. Other frequent causes for diarrhea, including 
concomitant medications (e.g., stool softeners, laxatives, antacids, etc.), infections by C. 
difficile or other pathogens, partial bowel obstruction, should be clinically excluded. 
Guidelines regarding management and dose reduction for diarrhea considered to be related 
to dabrafenib and/or trametinib by the investigator are provided in Table 23.
Table 23
Management and Dose Modification Guidelines for Diarrhea
Grade
Management
Action and Dose
Modification
Uncomplicated
Diarrhea1
Grade 1 or 2

Diet: stop all lactose-containing products, eat small
meal portions; recommend bland diet to avoid fatty 
and greasy foods, raw fruits and vegetables, 
alcohol, dairy products, and citrus fruits

Hydration: 8 to10 large glasses of clear liquids per 
day (e.g., Gatorade or broth)

Loperamide3: initially 4 mg, followed by 2 mg 
every 4 hrs or after every unformed stool; 
maximum
16 mg/day. Continue until diarrhea free for 12 hrs

Diarrhea > 24h: loperamide 2 mg every 2 hrs;
maximum 16 mg/day. Consider adding oral 
antibiotics

Diarrhea > 48h: loperamide 2 mg every 2 hrs;
maximum 16 mg/day. Add budesonide or other
second-line therapies (otreotide, or tincture of 
opium) and oral antibiotics

Continue 
treatment
with
trametinib
and
dabrafenib

If diarrhea is Grade 
2 for >48 hrs, 
interrupt treatment 
with trametinib and
dabrafenib until
diarrhea resolves to
≤Grade 1

Restart treatment 
with trametinib and 
dabrafenib at the
same dose levels
Uncomplicated
Diarrhea1
Grade 3 or 4

Clinical evaluation mandatory

Loperamide3: initially 4 mg, followed by 2 mg 
every 4 hrs or after every unformed stool; 
maximum

Interrupt treatment
with trametinib
and dabrafenib 


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Grade
Management
Action and Dose
Modification
Any
Complicated
Diarrhea2
16 mg/day. Continue until diarrhea-free for 12 hrs

Oral antibiotics and second-line therapies if 
clinically indicated

Hydration: IV fluids if clinically indicated

Antibiotics (oral or IV) if clinically indicated

Intervention should be continued until the 
subject is diarrhea-free for ≥24 hrs

Intervention may require hospitalization for 
subjects at risk of life-threatening complications
until diarrhea 
resolves to
≤Grade 1

Restart treatment 
with trametinib and
dabrafenib each
reduced by one 
dose level4

If 3 dose 
reductions of 
trametinib and
dabrafenib are
clinically
indicated,
permanently
discontinue treatment
with trametinib and
dabrafenib.
Abbreviation: hrs, hours; IV, intravenous; PS, performance status
1.
Uncomplicated diarrhea defined by absence of symptoms: cramping, nausea/vomiting ≥Grade 2, decreased
PS, pyrexia, sepsis, neutropenia ≥Grade 3, frank bleeding, and/or dehydration requiring IV fluid substitution.
2.
Complicated diarrhea defined by presence of symptoms: cramping, nausea/vomiting ≥Grade 2, decreased
PS, pyrexia, sepsis, neutropenia ≥Grade 3, frank bleeding, and/or dehydration requiring IV fluid substitution.
3.
Loperamide should be made available prior to start of study treatment so loperamide administration can begin
at the first signs of diarrhea.
4.
Escalation of trametinib and dabrafenib to previous dose level is allowed after consultation with the Medical
Lead and in the absence of another episode of complicated or severe diarrhea in the 4 weeks subsequent to
dose reduction.
8.2.6
Renal Insufficiency
Cases of renal insufficiency have occurred in subjects receiving dabrafenib and the 
combination of dabrafenib and trametinib.  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 24.
Table 24
Management and Dose Modification Guidelines for Renal
Insufficiency
Serum Creatinine Level
Adverse Event Management
Action and Dose
Modification
Serum creatinine increase
>0.2 mg/dL (18 umol/L) but 
0.5 mg/dL
Recheck serum creatinine within 1 week
Serum creatinine increase >1 week:
contact the Medical Lead.  If elevation
Continue study
treatment at the 
same dose level


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(44 umol/L) above baseline
persists beyond 4 weeks, recommend
evaluation (consider renal biopsy) for
etiology; consider nephrology
consultation.
If pyrexia is present, treat pyrexia as 
per guidelines1
Serum creatinine increase
>0.5 mg/dL (44 umol/L)
above baseline or serum
creatinine >2 mg/dL
(>177 umol/L)
Monitor serum creatinine ≥2 times 
per week
Hospitalization may be necessary if
serum creatinine cannot be 
monitored frequently
If pyrexia is present, treat pyrexia per
guidelines1
Consult nephrologist if clinically indicated
Perform renal biopsy if clinically 
indicated, for example:
Renal insufficiency persists despite
volume repletion
Subject has new rash or signs of
hypersensitivity (such as
elevated eosinophil count)
Interrupt study
treatment until 
serum
creatinine 
recovers to
baseline
Restart with 
study
treatment2
Abbreviations: NSAIDS, non-steroidal anti-inflammatory drugs
1.
NSAIDs can induce renal insufficiency, especially in subjects with dehydration; encourage oral fluids or
consider intravenous fluids as clinically indicated. See guidelines for pyrexia in Section 8.2.3.
2.
Investigator may restart at either the same or a reduced dose level. Escalation of study treatment to
previous dose level is allowed if another episode of renal insufficiency does not occur after 4 weeks of
dose reduction. Consultation with the Medical Lead is required before restarting study treatment if there is
evidence of thromboticmicroangiopathy.
8.2.7
Visual Changes
Episodes of visual changes have been observed in subjects receiving trametinib, dabrafenib 
and combination therapy.  An ophthalmologist should be consulted if changes in vision 
develop. However, if the visual changes are clearly unrelated to study treatment (e.g., allergic 
conjunctivitis), then monitor closely as it may be reasonable to defer ophthalmic examination.  
Treatment with dabrafenib has been associated with the development of uveitis, including 
iritis. Monitor subjects for visual signs and symptoms (such as, change in vision, photophobia 
and eye pain) during therapy.
Special attention should be given to retinal findings (e.g., RPED) or retinovascular 
abnormalities (i.e., branch or central RVO). For events of visual changes (regardless of 
severity) for which an ophthalmic examination is conducted, a blood sample for PK analysis 
must be drawn as close as possible to the time of the event.
Guidelines regarding management and dose reduction for visual changes considered to be 
related to trametinib treatment are provided in Table 25. 
For events of uveitis and related toxicities (e.g. iritis, iridocyclitis), no dose modifications 
are required as long as effective local therapies can control ocular inflammation. If
uveitis does not respond to local ocular therapy, withhold dabrafenib until resolution


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of ocular inflammation and then restart dabrafenib reduced by one dose level. No dose 
modification of trametinib is required when taken in combination with dabrafenib.
Table 25
Management and Dose Modification Guidelines for Visual
Changes and/or Ophthalmic Examination Findings
CTCAE Grade1
Adverse Event Management
Action and Dose Modification
Grade 12

Consult ophthalmologist within
7 days of onset

If dilated fundus examination cannot be performed
within 7 days of onset, interrupt treatment with
trametinib until RPED and RVO can be excluded
by retina specialist/ophthalmologist. Dabrafenib
may be continued.

If RPED and RVO excluded, continue (or restart)
treatment with trametinib at same dose level

If RPED suspected or diagnosed: see table below;
report as SAE if diagnosed.

If RVO diagnosed: Permanently discontinue
trametinib and report as SAE.
Grade 2 and
Grade 3

Consultophthalmologist
immediately

Interrupt treatment with trametinib. If
subject is receiving
trametinib/dabrafenibcombination
therapy dabrafenib may be
continued

If RPED and RVO excluded, restart trametinib at
same dose level

If RPED diagnosed, see RPED dose modification
table (Table 26); report as SAE.

If RVO diagnosed, permanently discontinue
trametinib and report as SAE
Grade 4

Consultophthalmologist
immediately

Interrupt treatment with trametinib. If
subject is receiving trametinib/
dabrafenib combination therapy
dabrafenib may be continued

If RPED and RVO excluded, may consider
restarting trametinib at same or reduced dose
after discussion with Medical Lead

If RVO or RPED diagnosed, permanently
discontinue trametinib and report as SAE.
Abbreviations: CTCAE, Common Terminology Criteria for Adverse Events; RPED, retinal pigment epithelial
detachment; RVO, retinal vein occlusion; SAE, serious adverse event
1.
Refers to CTCAE Version 4.0 ‘Eye disorders – Other, specify’
2.
If visual changes are clearly unrelated to study treatment (e.g., allergic conjunctivitis), monitor closely
but ophthalmic examination is not required.
Table 26
Recommended Dose Modifications for Trametinib for RPED
CTCAE Grade1
Action and Dose Modification
Grade 1 RPED
(Asymptomatic; clinical or diagnostic observations
only)

Continue treatment with dabrafenib +
trametinib with retinal evaluation monthly 
until resolution. If RPED worsens follow 
instructions below and withhold trametinib 
for up to 3 weeks
Grade 2 or 3 RPED
(Symptomatic with mild to moderate decrease in
visual acuity; limiting instrumental ADL)

Interrupt trametinib for up to 3 weeks; 
continue treatment with dabrafenib

Retinal evaluation monthly

If improved to ≤Grade 1 within 3 weeks, 
restart trametinib at lower dose (reduced by 
0.5 mg) or discontinue in subjects taking 
trametinib 1 mg once daily


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CTCAE Grade1
Action and Dose Modification

Grade 2-3 RPED that does not improve
to at least Grade 1 within 3 weeks, 
permanently discontinue trametinib.
Abbreviations: ADL, activities of daily living; CTCAE, Common Terminology Criteria for Adverse Events; RPED, retinal
pigment epithelial detachment
1. Refers to retinopathy in CTCAE v4.0
9
LIFESTYLE AND/OR DIETARY RESTRICTIONS
9.1
ContraceptionRequirements
9.1.1
Female Subjects
Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, must use highly effective methods of contraception during dosing and 
for 16 weeks after stopping treatment.
Highly effective contraception methods include:
a. Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject).  Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception.
b. Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy, or tubal ligation at least six weeks before taking 
study treatment.  In case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow up hormone 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.
Notes:
a. 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.
b. Hormonal based methods (e.g. oral contraceptives) are not considered as highly 
effective methods of contraception due to potential drug-drug interactions with 
dabrafenib and/or trametinib (see Section 10.2).
c. 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.
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
treatment(s), preferably as close to the first dose as possible. Subjects must have used highly 


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effective contraception since the pregnancy test and agree to use adequate contraception 
during the study and for 16 weeks following discontinuation of trametinib when taken in 
combination with dabrafenib, or for 2 weeks following discontinuation of dabrafenib
monotherapy.
These allowed methods of contraception are only effective when used consistently, correctly 
and in accordance with the product label.  The investigator is responsible for ensuring 
subjects understand how to properly use these methods of contraception.
If a subject becomes pregnant during the treatment period of the study, the study treatments 
should be stopped immediately.
9.1.2
Male Subjects
Male subjects (including those that have had a vasectomy) must use a condom during 
intercourse while taking dabrafenib and/or trametinib treatment.  Once dabrafenib and 
trametinib are both permanently discontinued, the patient must use a condom for 16 weeks 
after the last dose of the study treatments.  The patient should not father a child during the 
study treatment period or during the specified time frames after discontinuation of study 
treatment.
9.2
Lactation
Female subjects who are lactating must discontinue nursing prior to the first dose of study 
treatments and must refrain from nursing throughout the treatment period and for 4 months 
following the last dose of study treatments.
9.3
Caffeine and Alcohol
On PK sampling days, subjects will abstain from ingesting caffeine- or xanthine- containing 
products (e.g., coffee, tea, cola drinks, energy drinks) and alcohol for 24 hours prior to the 
start of collection of the samples and until collection of the last sample.
9.4
Activity
Subjects will abstain from strenuous exercise (e.g., competitive sports) for 48 hrs prior to 
each blood collection for clinical laboratory tests.  Subjects may participate in light 
recreational activities during the study.
10
CONCOMITANT 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.
If emerging data results in a change to the list of permitted/prohibited medications, formal 
documentation will be provided to the investigative site by the sponsor.  Any such changes 


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will be communicated to the investigative sites in the form of a letter. Sites may also refer to 
any updates to the SPM regarding changes to the list of permitted/prohibited medications.
Questions regarding concomitant medications should be directed to the Medical Lead for 
clarification.
10.1
Permitted Medications and Non-Drug Therapies
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 INR monitoring is recommended when dabrafenib is used 
concomitantly with warfarin.
Radiation: While subjects are on study treatment, palliative radiation therapy is permitted
for non-target lesions that are either new or present at baseline. Radiation skin injuryhas been 
reported with concurrent use of dabrafenib and radiation. It is recommended that dabrafenib 
be held for 7 days before and 2 days after radiotherapy in subjects receiving dabrafenib 
monotherapy or in combination with trametinib. These recommendations can be modified 
based on the physician’s assessment of the risk of radiation skin injury.
10.2
Prohibited Medications and Non-Drug Therapies
The use of illicit drugs and the following medications within 28 days or 5 half-lives,
whichever is shorter, prior to start of treatment will not be allowed:

Antiretroviral drugs

Herbal remedies (e.g., St. John’s wort)

Oral hormonal contraceptives

Drugs that are strong inhibitors or inducers of CYP2C8 or CYP3A4 (Table 27)
The following medications or non-drug therapies (excluding topical formulations) 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)

For MM cohort only: non-steroidal anti-inflammatory drugs (NSAIDS)
NOTE:
Use of NSAIDS by subjects with MM is prohibited as it will worsen renal 
insufficiency.

Drugs that are strong inhibitors or inducers of CYP2C8 or CYP3A4 (Table 27)
NOTE:  Dabrafenib is metabolized primarily by CYP2C8 and CYP3A4.  Co- administration 
of dabrafenib with ketoconazole, a CYP3A4 inhibitor, or gemfibrozil, a CYP2C8 inhibitor, 
increased the area under the concentration-time curve (AUC) of dabrafenib by 71% and 47%, 
respectively. Drugs that are strong inhibitors or inducers of CYP2C8 or CYP3A4 are likely
to increase or decrease, respectively, dabrafenib concentrations.  Strong inhibitors or 
inducers should only be used under special circumstances (e.g., as a single use for a 
procedure) while study treatment is interrupted as they may alter dabrafenib concentrations; 


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consider therapeutic substitutions for these medications.  Approval from the Medical Lead 
is required in these situations.
Table 27
Prohibited Medications
PROHIBITED1 – strong inducers of CYP3A4 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, oxcarbazepine phenobarbital, phenytoin, s-mephenytoin
Miscellaneous
Bosentan, St-John’s wort
PROHIBITED1 – Strong inhibitors of CYP3A4, 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
Antiretroviral
Ritonavir, saquinavir, atazanavir
Miscellaneous
Conivaptan
1.
Topical formulations of prohibited medication(s) are permitted.
10.3
Medications to be used with Caution
The following medications should be used with caution as their concentrations maybe altered 
by dabrafenib or they may alter dabrafenib concentrations:

Drugs that are moderate inhibitors or inducers of CYP3A and CYP2C8 as they may 
alter concentrations of dabrafenib.

Dabrafenib has been shown to induce CYP3A4 and CYP2C9 in vivo using midazolam 
(CYP3A4 substrate) and S-warfarin (CYP2C9 substrate). Dabrafenib is an in vitro 
inducer of CYP2B6 and may affect other enzymes such as CYP2C8, CYP2C19, UDP-
glucuronyl transferases, and transporters.  Co-administration of dabrafenib and 
medicinal products which are affected by the induction of these enzymes such as 
warfarin, dexamethasone, antiretroviral agents, or immunosuppressants may result in 
decreased concentrations and loss of effectiveness. Where possible consider 
substitutions of these medicinal products if therapeutic effects cannot be monitored.

Onset of induction is likely to occur after 3 days of repeat dosing with dabrafenib.
Transient inhibition of CYP3A4 may be observed during the first few days of
treatment.  Upon discontinuation of dabrafenib, concentrations of these sensitive 
substrates may increase and subjects should be monitored for toxicity and dosage of
these agents may need to be adjusted.

Where possible consider substitutions of these medicinal products if therapeutic effects 
cannot be monitored. 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 28 and in the 
SPM.

Therapeutic level dosing of warfarin can be used with approval by the Medical Lead
and close monitoring of PT/INR by the site. Exposure decreased by 37% due to


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enzyme induction when on treatment, thus warfarin dosing may need to be adjusted 
based upon PT/INR.  Consequently, when discontinuing dabrafenib, warfarin exposure 
may be increased and thus close monitoring via PT/INR and warfarin dose adjustments 
must be made as clinically appropriate. Prophylactic low dose warfarin may be given 
to maintain central catheter patency.

Drugs known to induce QT prolongation interval should be used with caution.  Refer to 
the following link for a list of drugs known to have a risk of QT prolongation:
crediblemeds.org/everyone/composite-list-all-qtdrugs/
Table 28
Medications to be used with Caution
USE WITH CAUTION: Moderate inhibitors of CYP3A4, or CYP2C8 since concentrations of
dabrafenib may be increased
Class/Therapeutic Area
Moderate CYP3A4 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
USE WITH CAUTION: Moderate inhibitors of CYP3A4, or CYP2C8 since concentrations of
dabrafenib may be increased
Antihypertensives
Amlodipine, diltiazem, felodipine, nifedipine, nilvadipine, nisoldipine,
verapamil
Antimigraine Agents
Diergotamine, eletriptan, ergotamine
Corticosteroids
Dexamethasone, methylprednisolone, oral budesonide
Erectile Dysfunction Agents
Sildenafil, tadalafil, vardenafil
HMG-CoA Reductase
Inhibitors
Atorvastatin, lovastatin, simvastatin, rosuvastatin, pravastatin
Hypnotics and Sedatives
Alprazolam, brotizolam, diazepam, estazolam, midazolam, triazolam,
zolpidem, zopiclone
Immunosuppressants
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Miscellaneous
Aprepitant, cisapride, darifenacin, disopyramide, leflunomide, methohexital,
quinine, ranitidine, solifenacin, sulfasalazine, tramadol,
tolvaptan, 
chloroquine, zopiclone
Selective Aldosterone Blockers
Eplerenone
Abbreviations: CYP = cytochrome P450; HMG-CoA = 3-hydroxy-3-methylglutaryl-coenzyme A.
11
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS
The investigator or site staff will be responsible for detecting, documenting and reporting
events that meet the definition of an AE or SAE as outlined in Section 11.1 and Section 11.2, 
respectively.
11.1
Definition of Adverse Event
Any untoward medical occurrence in a subject or clinical investigation subject, temporally
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product.
Note: An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with 
the use of a medicinal product.  For marketed medicinal products, this also includes failure 
to produce expected benefits, abuse, or misuse. Examples of events meeting the definition of 
an AE include:

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or grade of the condition

New conditions detected or diagnosed after study treatment administration even though 
it may have been present prior to the start of the study

Signs, symptoms, or the clinical sequelae of a suspected interaction

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study
treatment or a concomitant medication (overdose per se will not be reported as an 
AE/SAE 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 is not to be 
reported as an AE or SAE. However, any signs and symptoms and/or clinical sequelae 
resulting from “lack of efficacy” will be reported as an AE or SAE, if they fulfill the 
definition of an AE or SAE.
Events that do not meet the definition of an AE include:

Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition that 
leads to the procedure is an AE.

Situations where an untoward medical occurrence did not occur (social and/or
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.

The disease/disorder under study, or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the subject’s 
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11.2
Definition of Serious Adverse Event
A SAE is any untoward medical occurrence that, at any dose:
a. Results in death
NOTE: Death due to disease under study is to be recorded in the Death eCRF and
does not need to be reported as an SAE.
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 outpatient 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 treatment-induced liver injury with hyperbilirubinemia defined
as:

ALT 5 times ULN and bilirubin 3 times ULN (>35% direct) or ALT 5 times
ULN and INR >1.5, if INR is measured, with no existing liver disease
OR

ALT ≥8 times ULN and bilirubin ≥5 times ULN (>35% direct) or INR >1.5, if
INR is measured, with pre-existing liver disease
NOTE: INR measurement is not required and the threshold value stated will not apply
to subjects receiving anticoagulants.


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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 criterion of total bilirubin 3 times ULN, if no existing liver
disease or 3 times ULN if pre-existing liver disease; the event is still reported as 
an SAE.  If INR is obtained, include values on the SAE form.  Elevations in 
INR >1.5 suggest severe liver injury.
h. Protocol-specific SAEs:

cuSCC (Section 8.2.2.1), new primary melanomas (Section 8.2.2.2) and non-
cutaneous malignancies (Section 8.2.2.3) with the exception of basal cell
carcinoma (BCC). BCC should be reported as an AE or SAE based on the
discretion of the investigator.

LVEF that meets the dose interruption criteria (Section 8.1.1.2): absolute LVEF
decreases of >10% from baseline (not relative decrease) and below the LLN

Liver chemistry events of ALT 3xULN and bilirubin 2xULN (>35% direct
bilirubin) or ALT 3xULN and INR>1.5, if INR measured which may indicate
severe liver injury (possible ‘Hy’s Law’) (Section 8.1.3.1)

RPED also referred to as central serous retinopathy (CSR) or RVO (Section 8.2.7)

Pyrexia accompanied by hypotension or dehydration requiring IV fluids or renal
insufficiency or severe rigors/chills in the absence of an obvious infectious cause 
(Section 8.2.3).
11.3
Laboratory and Other Safety Assessment Abnormalities
Reported as AEs and SAEs
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis), or other 
safety assessments (e.g., ECGs, radiological scans, vital signs measurements) including those 
that worsen from baseline, and events felt to be clinically significant in the medical and 
scientific judgment of the investigator are to be recorded as an AE or SAE, in accordance 
with the definitions provided.
In addition, an associated AE or SAE is to be recorded for any laboratory test result or other 
safety assessment that led to an intervention, including permanent discontinuation of study
treatment(s), dose reduction, and/or dose interruption/delay.
However, any clinically significant safety assessments that are associated with the
underlying disease, unless judged by the investigator to be more severe than expected for the 
subject's condition, are not to be reported as AEs or SAEs.
11.4
Cardiovascular Events
Investigators will be required to fill out event specific data collection tools for the following 
AEs and SAEs:

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension


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
Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thrombosis

Deep Venous Thrombosis

Revascularization
This information should be recorded within 1 week of when the AE/SAE(s) is first reported.
11.5
Death Events
In addition, all deaths, whether or not they are considered SAEs, will require a specific death 
data collection tool to be completed.  The death data collection tool includes questions 
regarding cardiovascular (including sudden cardiac death) and non- cardiovascular death.
This information should be recorded within 1 week of when the death is first reported.
11.6
Disease-Related Events and/or Disease-Related Outcomes Not
Qualifying as SAEs
An event which is part of the natural course of the disease under study (i.e., disease
progression or hospitalization due to disease progression) does not need to be reported as an 
SAE. Death due to disease under study is to be recorded on the Death eCRF form.  However, 
if the underlying disease (i.e., progression) is greater than that which would normally be 
expected for the subject, or if the investigator considers that there was a causal relationship 
between treatment with study treatment(s) or protocol design/procedures and the disease 
progression, then this must be reported as an SAE.
11.7
Time Period and Frequency of Detecting AEs and SAEs
The investigator or site staff is responsible for detecting, documenting and reporting events 
that meet the definition of an AE or SAE.
Adverse events (AEs) will be collected from the time the first dose of study treatment(s) is 
administered until 30 days following discontinuation of study treatment(s) regardless of 
initiation of a new cancer therapy or transfer to hospice.
Serious adverse events (SAEs) will be collected over the same time period as stated above 
for AEs.  In addition, any SAE assessed as related to study participation (e.g., protocol-
mandated procedures, invasive tests, or change in existing therapy), study treatment or 
concomitant medication(s) must be recorded from the time a subject consents to participate 
in the study up to and including any follow-up contact.
After discontinuation of study treatment(s), the investigator will monitor all AEs/SAEs that 
are ongoing until resolution or stabilization of the event or until the subject is lost to follow-
up. At any time after 30 days the investigator may report any AE that they believe possibly
related to study treatment(s).
11.8
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?”


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
“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?”
11.9
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 the sponsor in lieu of completion of the AE/SAE data collection tool.
However, there may be instances when copies of medical records for certain cases are
requested by the sponsor.  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 of 
to the sponsor.
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.
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.
11.10
Evaluating AEs and SAEs
11.10.1
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.

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.


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11.10.2
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 is
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 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.
11.11
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 the sponsor 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 the sponsor 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 the sponsor within the designated 
reporting time frames.
11.12
Prompt Reporting of SAEs to Sponsor
Once the investigator determines that an event meets the protocol definition of an SAE, the 
SAE will be reported to the sponsor within 24 hours.  Any follow-up information on a
previously reported SAE will also be reported to the sponsor 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 the sponsor 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 11.10.2, Assessment of
Causality.
The primary mechanism for reporting SAEs to the sponsor will be the electronic data 
collection tool. If the electronic system is unavailable for greater than 24 hrs, the site will 
use the paper SAE data collection tool and fax it to the 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


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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 sponsor protocol contact by telephone.
The sponsor contacts for SAE receipt can be found at the beginning of this protocol on the 
Sponsor/Medical Lead Contact Information page.
11.13
Regulatory Reporting Requirements for SAEs
Prompt notification of SAEs by the investigator to the sponsor is essential so that legal 
obligations and ethical responsibilities towards the safety of subjects are met.
The sponsor (currently 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.
The sponsor will comply with country specific regulatory requirements
relating to safety reporting to the regulatory authority, IRB/IEC and investigators.
Investigator safety reports are prepared for suspected unexpected serious adverse reactions 
according to local regulatory requirements and Novartis policy and are forwarded to 
investigators as necessary.
An investigator who receives an investigator safety report
describing a SAE(s) or other specific safety information (e.g., summary or listing of SAEs) 
from the sponsor will file it with the IB and will notify the IRB/IEC, if appropriate according 
to local requirements.
12
PHARMACOKINETICS
12.1
PharmacokineticEndpoints
Pharmacokinetic (PK) analysis will be the responsibility of the Novartis Institutes for 
BioMedical Research (NIBR) PK Sciences (PKS) department. Mixed-effects PK models
developed previously for dabrafenib and trametinib may be fit to the dabrafenib and 
trametinib concentration-time data using NONMEM.  Post-hoc estimates of population PK 
parameters (CL/F, V/F, Ka, and predicted exposure) may be determined for trametinib and 
dabrafenib.
12.2
PharmacokineticAssessments
12.2.1
Blood Sample Collection
NOTE: Sample collection for this purpose is no longer requested as of Protocol 
Amendment 11
Blood samples for PK analysis of dabrafenib and its metabolites (hydroxy- and desmethyl-
dabrafenib) and trametinib will be collected at the time points indicated in the Time and 
Events Table (Section 7.1).  The actual date and time of each blood sample collection and 
the date and time of each dose administration of study treatments prior to the PK sample will 
be recorded.
Details of PK blood sample collection (including volume to be collected, timing of sample 
and recording of PK sample information), processing, storage and shipping procedures are 
provided in the lab manual.


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12.2.2
Pharmacokinetic Sample Analysis
Plasma analysis will be performed under the management of PKS Bioanalyticals, Novartis.
Concentrations of dabrafenib and its metabolites (hydroxy- and carboxy- dabrafenib) and 
trametinib will be determined in plasma samples using the currently approved analytical 
methodology.  Raw data will be stored in the GLP Archives, Novartis.
13
PHARMACODYNAMIC BIOMARKERS
13.1
Tumor Tissue for BRAFV600E Mutation Pre-Screening
Only those subjects whose samples test positive for the BRAF V600E mutation will be 
eligible for this study.  Subjects may be enrolled and started on study treatment if the local
BRAF result is positive for the BRAF V600E mutation.  If a local test result is not available, 
a tumor sample reflective of the current disease will be collected at pre- screening to test for
BRAF V600E mutation status.
Confirmatory Testing: All local test results for BRAF V600E mutation will be subject to
central confirmation using a sponsor designated central reference lab.
1. For the solid tumor histology cohorts, an archived or fresh tumor tissue sample must 
be submitted to the central reference laboratory.
2. For the HCL and MM cohorts, a fresh BM aspirate and a corresponding peripheral 
blood sample are required to be submitted to the central reference laboratory.
NOTE: An archived tissue sample (such as a FFPE tissue sample from a BM biopsy), 
BM core samples, and BM clot samples are NOT acceptable for BRAF V600E 
testing. If a BM aspirate cannot be obtained due to a dry tap, please contact the 
Medical Lead.
Details on sample collection, processing, storage and shipping procedures are provided in the 
lab manual.








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
Subject is lost to follow-up

Study is closed or terminated by the Sponsor
The primary reason study treatment(s) were permanently discontinued must be documented 
in the subject’s medical record and the eCRF.  If the subject voluntarily discontinues from 
treatment due to toxicity, ‘AE/SAE’ will be recorded as the primary reason for permanently
discontinuation in the eCRF.
16.3
Follow-Up Assessments after Discontinuation of Study
Treatment or Study Withdrawal
If study treatment is permanently discontinued without disease progression:

the subject will complete the Post-Treatment Follow-Up Visit (see Time and Events 
Table) within 28 days (+7 days) after last dose of study treatment and prior to starting a 
new anti-cancer treatment or treatment with an investigational agent.

the subject will continue to have disease assessments performed every 12 weeks until 
disease progression, initiation of a new anti-cancer treatment, or death, whichever 
comes first.
If study treatment is permanently discontinued with disease progression and/or subject is 
withdrawn from the study:

The subject must make every effort to complete the Post-Treatment Follow-Up Visit 
(see Time and Events Table [Section 7.1]) within 28 days (+7 days) after last dose of 
study treatment and prior to starting any other anti-cancer treatment or treatment with 
an investigational agent.
All subjects permanently discontinuing study treatment will have a dermatologic exam
performed monthly (7 days) for the first 6 months following discontinuation of study
treatment. Subjects will be followed concurrently for survival and subsequent anti-cancer
treatment every 3 months (14 days) until they die, withdraw consent, are lost to follow, or 
up to a time period that is dependent on the criteria defined in Section 16.4. When subjects 
are no longer required to be followed for survival, they will be notified accordingly.
If subjects are unable to attend clinic visits during survival follow-up, contact may be made 
via another form of communication (e.g., phone, mail, etc.).
16.4
Subject Completion
A subject is considered to have discontinued the study if the subject is lost to follow-up or 
withdraws consent or another reason exists that prevents additional data from being collected 
on the subject.
A subject is considered to have completed the study if they die while receiving study 
treatment(s) or during the extended follow-up period.  The cause of death should be
documented in the eCRF.
Data collection will continue until a subject has completed or discontinued the study.
16.5
Study Completion
The study will be considered complete at a date that would represent a minimum follow up 
of approximately 3 years for all subjects enrolled.


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Subjects who continue to benefit from study treatment at the time of study completion or 
closure may transition to an alternative supply of MEK and/or BRAF inhibitor through 
commercial supply or post trial access mechanism such as a rollover study, if available, at the 
time of study completion. In the event subjects are transitioned to a rollover study, only
safety will be followed in that study.
16.6
Subject Withdrawal Procedures
If subject is withdrawn from study treatment due to an AE or SAE, subject should be followed
until:

AE or SAE stabilizes or resolves

AE or SAE is otherwise explained

Subject is lost to follow-up
If subject is withdrawn from  study treatment with an ongoing Grade 3 or 4 laboratory 
abnormality:

Subject should be followed until laboratory abnormality improves to Grade 2 or less, 
unless condition is unlikely to improve due to underlying disease, or resolves
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 (three 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.
17
DATA MANAGEMENT
For this study, subject data will be entered into the sponsor-defined eCRFs, transmitted
electronically to the sponsor 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 Novartis 
standards and data cleaning procedures to ensure the integrity of the data, e.g., removing
errors and inconsistencies in the data.  Adverse events (AEs) and concomitant medications 
terms will be coded using Medical Dictionary for Regulatory Activities (MedDRA) and a 
custom drug dictionary. An appropriate medical dictionary that covers all approved drugs in 
studies where Japan is participating will be referenced. Electronic CRFs (eCRFs), including 
queries and audit trails, will be retained by the sponsor and copies will be sent to the 
investigator to maintain as the investigator copy.




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WHO Grade 1 or 2 Glioma
10%
50%
WHO Grade 3 or 4 Glioma (high-grade)
10%
50%
MM
15%
60%
NSGCT/NGGCT
25%
75%
Small Intestine Adenocarcinoma
10%
50%
Abbreviations: ATC, anaplastic thyroid cancer; BTC, biliary tract cancer; C, control; GIST,
gastrointestinal stromal tumor; HCL, hairy cell leukemia; MM, multiple myeloma; NGGCT, non-
geminomatous germ cell tumor; NSGCT, non- seminomatous germ cell tumor; WHO, World Health
Organization
Full details regarding the hierarchical modeling framework are in Appendix 6.
18.2
Sample Size Considerations
18.2.1
Sample Size Assumptions
Each cohort of BRAF V600E mutation-positive tumor type of a given histology will enroll a 
maximum of 25 subjects in the primary analysis cohort as defined in Section 5.1. If all 
histologies enroll the maximum of 25 subjects, this will result in no more than 225 subjects 
in the primary analysis cohort.
Enrollment into specific histology cohorts may be halted early based on results from interim 
analyses incorporating emerging response data.  Response data from a minimum of 5 subjects 
will be required in a histologic cohort before it may discontinue enrollment for futility and 
response data from a minimum of 10 subjects will be required before discontinuing a 
histologic cohort for efficacy. If a cohort closes early for efficacy at an interim analysis, 
a histology specific expansion cohort (see Section 5.2) may be opened to allow additional 
enrollment. At the final analysis and after the study has been closed, a minimum of 2 subjects 
will be required in a histologic cohort in order to meet statistical success at the final analysis.
See Section 18.3.2 for more details.
Simulation studies were conducted to evaluate the performance of the design under various 
assumptions for the distribution of true ORRs across the histologic cohorts and accounting 
for the anticipated small sample sizes (refer to Section 18.4.1.2). Operating characteristics 
including power, type I error, estimation of the ORR, and the probability of halting 
enrollment at interim analyses were assessed.
When the treatment effects are similar across all histologies, the design maintains power 84% 
to 98% and type I error rate ≤0.04.  Estimation efficiencies due to borrowing result in very
good operating characteristics in these situations, even in histologies with very low sample 
sizes.
In mixed scenarios where some histologies show large treatment effects and others do not, 
the type I error can range from 0.03 to 0.14 while the power ranges from 55%- 96%. This 
variation is hugely dependent upon the expected sample sizes of the individual histologies 
as well as the overall distribution of treatment effects across the histologies.
Full presentation and discussion of the simulation parameters and corresponding simulation 
results are in Section 18.4.
18.2.2
Sample Size Sensitivity
Sample size sensitivities are included in Section 18.4.2.


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18.2.3
Sample Size Re-estimation
No sample size re-estimation will be performed.
18.3
Data Analysis Considerations
Data will be listed and summarized according to GSK Integrated Data Standard Library
(IDSL) reporting standard where applicable.
Complete details will be provided in the 
Reporting and Analysis Plan (RAP).
18.3.1
Analysis Populations
As the design for the study calls for repeated interim analyses to evaluate the accumulating 
efficacy data, it is necessary to shift the focus of the analysis population for efficacy 
depending upon the time at which the data are being analyzed. This is achieved using 
evaluability criteria to ensure that only patients with sufficient data to determine their best 
response status are included in the interim efficacy analyses. Table 30 presents the population 
of interest based on the timing of the analysis for both efficacy and safety; accompanying 
definitions are provided beneath the table.
Table 30
Definition of Population for Specific Analysis
Analysis Period
Analysis Intent
Interim Analyses
Final Analysis
Efficacy
Primary
ITT/Evaluable
ITT
Supportive
BRAF V600/Evaluable
BRAF V600E
Safety
Primary
ATS
ATS
The BRAF V600E Population is defined as all enrolled subjects regardless of whether or not 
treatment was administered, who obtain positive verification of the BRAF V600E mutation 
from a certified central reference laboratory.
The Intent-to-Treat (ITT) population is defined as all enrolled subjects regardless of whether 
or not treatment was administered.
The All-Treated Subjects (ATS) population is defined as all subjects who receive at least one 
dose of dabrafenib (DRB436/GSK2118436) or trametinib (TMT212/GSK1120212).
The Intent-to-Treat (ITT)/Evaluable population is defined as all ITT subjects in the
primary analysis cohort who are also evaluable according to the evaluability defined in 
the interim analysis RAP.
The BRAF V600E /Evaluable Population is defined as all BRAF V600E subjects in the 
primary analysis cohort who are also evaluable according to the evaluability defined in
the interim analysis RAP.
18.3.2
Interim Analysis
Interim data will be evaluated to monitor efficacy and safety. Enrollment may be stopped
early for futility or efficacy, should various criteria occur based on accrued data.  The
decision criteria for futility and efficacy are described below.


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18.3.2.1 Early Stopping for Futility/Harm
For each histology, the therapeutic effect of the combination therapy will be declared
insufficient and enrollment terminated if a minimum of 5 subjects have response data
available and the posterior probability that the ORR is greater than its corresponding 
historical control (Cj) is sufficiently low (<30%) based on the hierarchical model. That is,
P (j > Cj | current data) < 30%, for the j-th histology.
18.3.2.2 Early Stopping for Efficacy
For each histology, the combination therapy will be declared efficacious and enrollment
terminated if a minimum of 10 subjects have response data available and the posterior 
probability that the ORR exceeds its corresponding historical control (Cj) is sufficiently high 
(>95%) based on the hierarchical model.  That is,
P (j > Cj | current data) > 95%, for the j-th histology.
18.3.3
Final Analyses
The final primary analysis for ORR will occur once all subjects in the primary analysis cohort 
have either discontinued treatment or have received treatment for at least 8 months, 
whichever comes first. Secondary efficacy endpoints will likely not be mature at this time, 
but will still be reported. Subsequent analyses for secondary endpoints will occur at a date 
that would represent a minimum follow up of approximately 3 years for all subjects enrolled.
These latter analyses will provide mature estimates/incidence for duration of response, PFS, 
OS, and safety.
18.3.3.1 Safety Analyses
Safety data will be presented in tabular and/or graphical format and summarized descriptively 
according to GSK’ IDSL standards.
The ATS population will be used for the analysis of safety data. In general, safety data will 
be summarized by histology and across all cohorts
Complete details of the safety analyses will be provided in the RAP.
18.3.3.1.1
Adverse Events
Adverse events (AEs) will be coded using the standard MedDRA and grouped by system 
organ class.  Adverse events (AEs) will be graded by the investigator according to the
CTCAE, version 4.0.
Events will be summarized based on frequency and proportion of total subjects, by system 
organ class and preferred term. Separate summaries will be given for all AEs, treatment-
related AEs, AEs by toxicity grade, SAEs and AEs leading to discontinuation of study
treatment and dose modification.
Adverse events (AEs) of special interest will be identified and additional summaries provided.
The incidence of deaths and the primary cause of death will be summarized.


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18.3.3.1.2
Clinical Laboratory Evaluations
Hematology and clinical chemistry data will be summarized by each scheduled assessment 
according to CTCAE, version 4.0, grade.
The proportion of values lying outside the 
reference range will also be presented for laboratory tests that are not graded because there 
are no associated CTCAE grading criteria. 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 (i.e., no visit windows will be applied). Unscheduled data will be included 
in “overall” and “any post-screening” summaries which will capture a worst case across all 
scheduled and unscheduled visits post first dose of study treatment.
18.3.3.1.3
Other Safety Measures
The results of scheduled assessments of vital signs, 12-lead ECG, ECHO and ECOG
performance status will be summarized.  Summaries will include data from scheduled 
assessments only. All data will be reported according to the nominal visit date for which it 
was recorded; no visit windows will be applied.  All data will be listed.
18.3.3.2 Efficacy Analyses
ORR will be analyzed using an integrated analysis with the hierarchical model as well as
analyzed independently for each histology.
At the final analysis a histology will be declared active if the posterior probability that the
ORR exceeds its corresponding historical control (10%) is sufficiently high (>92%)
based on the hierarchical model.  That is,
P (j > Cj % | current data) > 92%, for the j-th histology.
The observed ORR and the estimated ORR based on the hierarchical model will be reported 
for each histology. Confirmed ORR will be calculated as the proportion of subjects that have 
a confirmed response relative to the total number of subjects enrolled.  Standard response 
assessments vary by histology; the following subcategories for each histology will be 
considered a ‘response’ to therapy when computing confirmed ORR.
Table 31
Response Subcategories Defined as ‘Response’ by Histology
Histology
Response Criteria
Response Subcategories
defined as ‘Response’
ATC, BTC, GIST, Small
Intestine Adenocarcinoma
RECIST 1.1
CR, PR
NSGCT/NGGCT
RECIST 1.1.
Tumor Markers: -HCG and AFP
Marker-Negative CR, Marker-
Positive CR, Marker-Negative PR,
Marker-Positive PR
MM
IMWG Uniform Response Criteria for MM
sCR, CR, PR, VGPR
HCL
Adapted from NCCN guidelines, Consensus
Resolution Criteria and previous studies definition
CR±MRD, PR
WHO Grade 1 and 2
Gliomas
Response Assessment Criteria for WHO Grade 1
or 2 Gliomas: RANO Working Group
CR, PR, MR
WHO Grade 3 and 4
Gliomas
Updated Response Assessment Criteria for WHO
Grade 3 or 4 Gliomas: RANO Working Group
CR, PR
Abbreviations: AFP, alpha-fetoprotein; ATC, anaplastic thyroid cancer; -hCG, beta-human chorionic
gonadotropin; BTC, biliary tract cancer; CR, complete response; GIST, gastrointestinal stromal tumor; HCL,
hairy cell leukemia; IMWG, International Myeloma Working Group; MM, multiple myeloma; MR, minor response;






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should not have a significant impact on operating characteristics of the design.  Simulations 
assumed interim analyses occurred every 12 weeks, with the first interim analysis occurring 
once 10 subjects have been enrolled.
The time from subject entry until the response 
assessment was performed is assumed to be 8 weeks. The maximum length of time for each 
study is 156 weeks 6 weeks (roughly 3 years).
Although actual enrollment may vary, predicted enrollment during a 3-year time period is
incorporated into the simulations.  Because enrollment varies by histology, a numbering
scheme (1 through 9) is used in simulations and corresponding results to index the nine
histologies.
Histology indexing, projected enrollments and the historical control and
clinically meaningful response rates used in simulations are shown in Table 32.
Table 32
Projected Enrollment and Indexing by Histology
Histology
Histology
Index
Projected enrollment in a 3-year
time period
Historical Control/
Clinically
Meaningful RRs
Case 1
Case 2
Case 3
Case 4
ATC
3
10
20
25
25
15% / 60%
BTC
2
10
16
16
10
10% / 50%
GIST
7
5
5
5
2
10% / 50%
HCL
1
15
17
20
20
10% / 50%
WHO Grade 1 or 2 Glioma
6
5
8
8
5
10% / 50%
WHO Grade 3 or 4 Glioma
(high-grade)
5
5
16
16
8
10% / 50%
MM
8
5
17
20
20
15% / 60%
NSGCT/NGGCT
9
5
5
5
2
25% / 75%
ASI
4
8
5
5
2
10% / 50%
Abbreviations: ASI, adenocarcinoma of small intestine; ATC, anaplastic thyroid cancer; BTC, biliary tract cancer; GIST,
gastrointestinal stromal tumor; HCL, hairy cell leukemia; MM, multiple myeloma; NGGCT, non-geminomatous germ cell
tumor; NSGCT, non-seminomatous germ cell tumor; RR, response rate; WHO, World Health Organization
18.4.1.3 Overall Response Rate Scenarios
Due to the ‘borrowing’ nature of the model, the design is evaluated across a variety of
scenarios for the distribution of true ORRs across the histologic cohorts. These are shown 
in Table 33.
The “Alternative ” scenario assumes all histologies are responsive at the defined clinically
meaningful RR levels.  The “Null” case assumes all histologies are non- responsive at the 
historical control RRs.  The “All Moderate” scenario assumes all histologies show moderate 
RR levels inbetween the historical control and clinically meaningful RR levels. The “Mixed 
(0.1-0.5)” assumes a range of response rates across the nine histologies. The other three 
scenarios consider various situations where histologies are either responsive (at the clinically
meaningful RR level) or not (at the historical control RR level).


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Table 33
Simulation Scenarios: Various Assumptions for the True ORR for
each Histology
Scenario
Histology
1
2
3
4
5
6
7
8
9
Alternative
50%
50%
60%
50%
50%
50%
50%
60%
75%
Null
10%
10%
15%
10%
10%
10%
10%
15%
25%
All Moderate
30%
30%
40%
30%
30%
30%
30%
40%
50%
Mixed
50%
10%
30%
40%
10%
20%
30%
45%
75%
5 Greats: Mixed
50%
10%
60%
10%
50%
10%
10%
60%
75%
5 Greats: Low
10%
10%
15%
10%
50%
50%
50%
60%
75%
2 Greats
10%
50%
15%
10%
50%
10%
10%
15%
25%
Abbreviations: ORR = overall response rate
NOTE: Color indicates responsiveness of the true ORR for each histology. Red indicates non-responsive and is equal to
the assumed historical control rate, green indicates responsive and is equal to the clinically meaningful ORR, and blue
indicates moderate responsiveness and is in-between the historical control rate and clinically meaningful ORR.
18.4.1.4 Output from Simulated Trials
For each scenario specified in Table 33, overall descriptive measures are reported for each 
histology and sample sizes specified in Case 1 and include:

Proportion of studies that declare the histology efficacious at the final analysis

Proportion of studies that halt enrollment to each histology early for futility

Proportion of studies that halt enrollment to each histology early for efficacy

For each possible combination of sample size and observed number of responses, the 
proportion and number of times the model declares such data efficacious at the final 
analysis (by scenario, combining across histologic cohorts)
In-depth information is also provided for a small number of simulated example trials. These 
illustrate the flow and outcome of possible trials based on the pre-specified statistical 
decision rules.
18.4.2
Operating Characteristics
18.4.2.1 Power and Type I Error Rate
Power and type I error rate are examined across scenarios for the distribution of assumed
true ORRs for each histology. The power is the probability of declaring efficacy within a
histology when the true underlying ORR is greater than its corresponding historical control.  
Type 1 error rate is the probability of declaring efficacy within a histology when the true 
underlying response rate is equal to the historical control. Figure 1 illustrates the proportion 
of trials that declare each histology efficacious at the final analysis across simulation 
scenarios. Supporting tables for the simulation results are provided in Appendix 7.
The power and type I error rate are dependent upon the sample sizes and response rates across 
the distribution of histologies. When the treatment effects are the same across all histologies 
(either all responsive or all non-responsive), estimation efficiencies, due to borrowing, result 
in very good operating characteristics, even in histologies with very low sample sizes.  Under 
sample size Case 1, the type I error rate is controlled to 0.04 across all histologies (All Null 
scenario). The design maintains power 93% to 98% for the higher enrolling cohorts, and 84% 


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to 90% for the smallest enrolling 5 cohorts (All Great scenario).  Also, the design exhibits 
reasonable power to detect a moderate level of activity (All moderate scenarios).
When the treatment effects vary across histologies, the amount of appropriate borrowing also 
varies, impacting the operating characteristics. The ‘2 Greats: Mixed’ investigates design 
performance where most histologies are not responsive.  In this situation, the type I error rate 
is controlled to 0.06 and the power is 82% for the higher enrolling cohort and 55% for the 
low enrolling cohort. The ‘5 Greats: Mixed’, ‘5 Greats: Low’ and ‘Mixed’ scenarios 
investigate the design performance in situations where roughly half the histologies are 
responsive. The type I error rate ranges from 0.09 to 0.14 while the power ranges from 93% 
to 96% for the higher enrolling cohorts and ranges from 67% to 84% for the lower enrolling 
cohorts. Generally, improvement in the overall distribution of treatment effects tends to 
coincide with slight increases in type I error rate and moderate increases in power.
Figure 1
Proportion of Studies that Declare each Histology Efficacious at 
the Final Analysis under Sample Size Case 1
18.4.2.2 Probability that the Model Declares Success Across Different 
Sample Sizes and Numbers of Observed Responses
No pre-determined number of responses or response rate will necessarily dictate model
success or model failure.  In addition to a particular histology response data, their
corresponding
historical control response rate and the overall distribution of treatment
effects across the histologies impacts the model decision in that particular histology. To
further understand the likelihood of model success, for each possible combination of sample 
size (≤15) and number of observed responses, the proportion of times the model declares 
such data efficacious at the final analysis is assessed by scenario but combining across 
histologic cohorts with the same historical control response rate. Hence, the likelihood of 
declaring success is explored for histologies with historical control response rates of 0.10 
(histologies 1, 2, 4, 5, 6, and 7), 0.15 (histologies 3 and 8), and 0.25 (histology 9). Actual 
histologies, their simulation indexing number, and the appropriate historical control response 
rates are in Table 29 in Section 18.4.1.3.


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Figure 1 illustrate the proportion of trials that declare success across all possible
combinations of sample sizes and number of observed responses and for each historical
control response rate. Figure 2 illustrates a subset of this data, more clearly describing the 
probability of declaring success when 1, 2, 3, or 4 responses are observed.
Supporting tables for these simulation results are provided in Appendix 7.  Some variability
is expected in these estimates due to low sample sizes in some of these observed data 
combinations.
Should statistical success be met while only a moderate response rate observed, it will be 
critical that the entirety of the data, including secondary efficacy endpoints, support a
meaningful high level of activity to demonstrate evidence of a very large treatment effect. 
Based on the decision criteria, data from at least two subjects must be available to declare 
success. Hence, if data is only available for 1 subject, the success criteria will not be met, 
regardless of that 1 subject’s response status. When the observed ORR is 10%, success is 
never declared for any histology across all seven scenarios.  Hence, if zero responses are 
observed, a histology will never meet the success criteria. And, at least two responses are 
needed if response data is available for more than 10 subjects within a particular histology.
When one response is observed within a histology, there is positive probability of meeting 
success only in mixed situations when the sample size is small (roughly 5). When 2, 3 or 4 
responses are observed, there is increasing probability of meeting success, but this is largely 
dependent upon the overall distribution of treatment effects as well as the final sample size.  
Also, the probability of declaring success for a particular dataset is higher for histologies 
with lower historical control response rates. Five responses are almost always sufficient to 
meet statistical success regardless of the sample size, scenario, and historical control response 
rate.  Further details for all situations can be visually explored in Figure 3.
18.4.2.3 Probability that the Model Declares Success Across Different 
Sample Sizes
To evaluate the model performance for various sample sizes, simulations are also performed 
under the following four scenarios for sample sizes specified in Case 2, 3, and 4 with the 
maximum sample size for a given histology can be as high as 25.
Table 34
Simulation 
Scenarios 
for 
Enrollment 
Sensitivity:
Various
Assumptions for the True ORR for Each Histology
Scenario
Histology
1
2
3
4
5
6
7
8
9
Mixed1
20%
30%
60%
30%
40%
40%
10%
15%
75%
5 Greats: Mixed1
10%
50%
60%
50%
10%
50%
10%
15%
75%
4 Greats: Low
10%
10%
15%
50%
10%
50%
50%
15%
75%
2 Greats: Mixed1
10%
10%
60%
10%
10%
10%
50%
15%
25%
When the sample size for some histology increases from 15 to 25, the largest type I error
increases from 0.14 to 0.18. Under sample size Case 2, the type I error rate is ranges from
0.04-0.17; the design maintains power 94% to 98% for the higher enrolling cohorts (>10 
subjects enrolled per cohort), and 61% to 87% for the smallest enrolling three cohorts (5 
subjects enrolled per cohort).  Under sample size Case 3, the type I error rate is ranged from
0.04 to 0.18; the power is ranged from 92% to 98% for high enrolling cohorts (>10 subjects 
enrolled per cohort) and ranged from 62% to 86% for low enrolling cohorts (5-8 subjects 


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enrolled per cohort).  Under sample size case 4, the type I error ranges from 0.02 to 0.16; the 
power ranges from 93% to 96% for high enrolling cohorts (>10 subjects enrolled per cohort), 
59% to 71% for low enrolling cohorts (5-8 subjects enrolled per cohort) and 26% to 44% for 
ultra low enrolling cohorts (2 subjects enrolled per cohort). Figure 4 illustrates the proportion 
of trials that declare success across all possible combinations of sample sizes and number of 
observed responses and for each historical control response rate. Supporting tables for the 
simulation results are provided in Appendix 7.
Also, the design exhibits reasonable power to detect a moderate level of activity.  The type I 
error rate maintains well under different sample size scenarios and reasonable power are 
achieved for cohorts which enroll no less than 5 subjects per cohort. The powers for cohorts 
that have super low enrollment (n=2 or less) can be lower than 50%.  Overall the design 
performance is robust to overenrolling up to 25 subjects for a given histology.


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Figure 2
For Each Combination of Sample Size and Observed Number of Responses, the Probability of Model 
Success at the Final Analysis (by scenario, combined across histologies with the same historical 
control RR)


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Figure 3
For All Sample Sizes and When the Number of Observed Responses is 1, 2, 3, or 4, the Probability of 
Model Success at the Final Analysis (by scenario, combinated across histologies with the same 
historical control RR)


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Figure 4
Proportion of Studies that Declare Each Histology Efficacious at the Final Analysis under Sample Size Case 2, 
3 and 4


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Stopping Early Figure 5 and Figure 6 illustrate the proportion of trials that halt enrollment 
early for futility and efficacy across simulation scenarios.
Supporting tables for the 
simulation results are provided in Appendix 7.
Since the study requires at least five subjects in a particular histology prior to stopping early 
for futility and 10 subjects in a histology prior to stopping early for efficacy, the ability for 
histologies to stop early is largely dependent upon the projected maximum sample size per 
histology.  The overall distribution of treatment effects across histologies also impacts the 
likelihood of halting enrollment early.
When the expected 3-year enrollment is greater than 5, non-responsive histologies stop early 
for futility between 32% and 66% of the time.  When the expected 3-year enrollment is five 
subjects, non-responsive histologies stop early for futility between 8% and 35% of the time.
When the expected 3-year enrollment is at least 10, responsive histologies stop early for 
futility between 41% and 90% of the time.  When the expected 3-year enrollment is less than 
10, the probability of stopping early for success is very low. Across simulation scenarios, 
non-responsive histologies generally do not stop early for efficacy while responsive 
histologies generally do not stop early for futility.
Figure 5
Proportion of Trials that Halt Enrollment Early for Futility for Each
Histology


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Figure 6
Proportion of Trials that Halt Enrollment Early for Success for each
Histology
18.4.3
Example Trials
Select interim and final analysis results are presented for six simulated trials in Appendix 8.
The simulated trials were chosen to represent a variety of potential data outcomes that may
be observed.  These illustrate the flow and outcome of possible trials based on the pre-
specified statistical decision rules.
Because the overall distribution of treatment effects across the histologies impacts the model 
decision, no pre-determined number of responses or response rate will necessarily dictate 
model success or model failure at interim or final analyses. The above simulation results 
describe the likelihood of different model outcomes based on different scenarios for the
assumed distribution of treatment effects. The example trials provide additional insight into 
how the model will perform and the level of evidence required to meet statistical success for 
possible trial outcomes.
19
STUDY CONDUCT CONSIDERATIONS
19.1
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.
19.2
Regulatory and Ethical Considerations, Including the Informed
Consent Process
Prior to initiation of a study site, the sponsor will obtain favorable opinion/approval from the 
appropriate regulatory agency to conduct the study in accordance with International Council


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on Harmonization (ICH) Good Clinical Practice (GCP) and applicable country-specific 
regulatory requirements.
The study will be conducted in accordance with all applicable regulatory requirements.
The study will be conducted in accordance with ICH GCP, all applicable subject privacy 
requirements, and the ethical principles that are outlined in the Declaration of Helsinki 2008, 
including, but not limited to:

IRB /IEC review and favorable opinion/approval of study protocol and any subsequent 
amendments

Subject informed consent

Investigator reporting requirements
The sponsor will provide full details of the above procedures, either verbally, in writing, or 
both.
Written informed consent must be obtained from each 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 
 
, unless otherwise indicated.  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.
19.3
Data Monitoring Committee
A Data Monitoring Committee (DMC) will be utilized in this study and will be comprised of 
individuals who are not members of the clinical study team. At least one independent 
hematologist and one independent oncologist (external to the sponsor) will serve on the 
committee.  The objective of the DMC will be to ensure objective medical and/or statistical 
review of safety and/or efficacy issues in order to protect the ethical and safety interests of 
subjects and to protect the scientific validity of the study. The schedule of any planned 
interim analyses and the analysis plan for DMC review will be described in the committee’s 
charter.
19.4
Quality Control (Study Monitoring)
In accordance with applicable regulations, 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 the sponsor’s requirements.  When 
reviewing data collection procedures, the discussion will include identification, agreement 
and documentation of data items for which the eCRF will serve as the source document.
The investigator and the head of the medical institution (where applicable) agrees to allow 
the monitor direct access to all relevant documents and to allocate their time and the time to 
their staff to monitor to discuss findings and any issues.


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Monitoring visits will be conducted in a manner 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, ICH GCP, and all applicable regulatory requirements.
19.5
Quality Assurance
To ensure compliance with GCP and all applicable regulatory requirements, the sponsor 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
19.6
Study and Site Closure
The end of the study is defined as the date of the last subject, last visit.
Upon completion or termination of the study, Novartis personnel (or designated CRO) will 
conduct site closure activities with the investigator or site staff (as appropriate), in accordance 
with applicable regulations, ICH GCP, and Novartis Standard Operating Procedures.
The sponsor reserves the right to temporarily suspend or terminate the study at any time for 
reasons including (but not limited to) safety issues, ethical issues, or severe noncompliance.  
If the sponsor determines that such action is required, the sponsor will discuss the reasons for 
taking such action with the investigator or head of the medical institution (where applicable).
When feasible, the sponsor will provide advance notice to the investigator or head of the 
medical institution of the impending action.
If a study is suspended or terminated for safety reasons, the sponsor will promptly inform all 
investigators, heads of the medical institutions (where applicable),and/or institutions 
conducting the study.  The sponsor will also promptly inform the relevant regulatory
authorities of the suspension/termination along with the reasons for such action.  Where 
required by applicable regulations, the investigator or head of the medical institution must 
inform the IRB/IEC promptly and provide the reason(s) for the suspension/termination.
Study sites and/or the study may be closed by the sponsor if the site/study fails to recruit
within a pre-defined timeframe, as defined within the SPM.
19.7
Records Retention
Following closure of the study, the investigator or head of the medical institution (where
applicable) must maintain all site study records (except for those required by local regulations 
to be maintained elsewhere) in a safe and secure location. The records must be easily 
accessible when needed (e.g., for a sponsor audit or regulatory inspection) and must be 
available for review in conjunction with assessment of the facility, supporting systems, and 
relevant site staff.


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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.
The investigator must notify the sponsor 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.
19.8
Provision of Study Results to Investigators, Posting of
Information on Publicly Available Clinical Trials Registers and
Publication
Where required by applicable regulatory requirements, an investigator signatory will be
identified for the approval of the clinical study report.  The investigator will be provided
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a sponsor site or other mutually- agreeable 
location.
The sponsor will also provide the investigator with the full summary of the study results. The 
investigator is encouraged to share the summaryresults with the study subjects, as appropriate.
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 
(novartisclinicaltrials.com) for a summary of the trial results.






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Siegel R, Naishadham D, Jemal A. Cancer Statistics, 2012. Cancer Journal for Clinicians. 
2012;10-29. Doi:10.3322/caac.20138)
Sigal DS, Sharpe R, Burian C, Saven A. Very long term eradication of minimal residual
disease in patients with hairy cell leukemia after a single course of cladribine. Blood.
2010;115:1893-1896.
Speranzaa G, Doroshow JH, Kummar S. Adenocarcinoma of the small bowel: changes in 
the landscape? Current Opin in Oncology. 2010;22:387-393.
Stein C. Inadmissibility of the Usual Estimator for the Mean of a Multivariate Normal
Distribution.  Proc Third Berkeley Symp on Math Statist and Prob.1956;1:197–206.
Su F, Viros A, Milagre C, et al. RAS-mutaions in cutaneous squamous-cell carcinomas in
patients treated with BRAF inhibitors. N Engl J Med; 2012;366:207-215.
Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW.  
WHO Classification of Tumours of Haemotopoietic and Lymphoid Tissues. 4th ed.
Geneva, Switzerland: IARC; 2008.
Tannapfel A, Sommerer F, Benicke M, et al. Mutations of the BRAF gene in 
cholangiocarcinoma but not in hepatocellular carcinoma. Gut. 2003;52:706-712.
The Criteria Committee of the New York Heart Association (NYHA). Nomenclature and
Criteria for Diagnosis of Diseases of the Heart and Great Vessels. 9th Ed. Boston, Mass: 
Little, Brown & Co.; 1994:253-256.
Tiacci E, Trifonov V, Schiavoni G, et al. BRAF Mutations in Hairy Cell Leukemia. N Engl 
J Med. 2011;364:2305-2315.
Trials and mechanisms of resistance. Clin Cancer Res. 2012;18:33-39.
Valle J, Wasan H, Palmer DH, et al. Cisplatin plus Gemcitabine versus Gemcitabine for 
Biliary Tract Cancer. N Engl J Med. 2010;362:1273-1281.
van den Bent MJ, Wefel JS, Schiff D, et al. Response assessment in neuro-oncology (a
report of the RANO group): assessment of outcome in trials of diffuse low grade gliomas. 
The Lancet. 2011;12:583-593.
Walker BA, Wardell CP, Melchor L, et al. Intraclonal heterogeneity and distinct molecular 
mechanisms characterize the development of t(4;14) and t(11:14) myeloma. Blood. 
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adenocarcinoma: the interactions of CIN, MSI, and CIMP. Modern Pathology.
2011;24(4):564–570.
Weber JS, Flaherty KT, Infante JR, et al. Updated safety and efficacy results from a Phase 
I/II study of the oral BRAF inhibitor dabrafenib (GSK2118436) combined with the oral 
MEK 1/2 inhibitor trametinib (GSK1120212) in patients with BRAF-naive metastatic 
melanoma. J Clin Oncol. 2012;30:(suppl;abstr8510).
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Williams SD, Birch R, Einhorn LH, et al. Treatment of disseminated germ-cell tumors with 
cisplatin, bleomycin, and either vinblastine or etoposide. N Engl J Med.
1987;316(23):1435-1440.
Xi L, Arons E, Navarro W, et al. Both variant and IGHV4-34-expressing hairy cell
leukemia lack the BRAF V600E mutation. Blood. 2012;119:3330-3332
21
APPENDICES
21.1
Appendix 1: ECOG Performance Status
Assessment of Eastern Cooperative Oncology Group (ECOG) performance status to evaluate 
daily living abilities is required at Screening as well as routinely throughout the treatment 
and at treatment discontinuation.
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature, e.g., light house work, office work
2
Ambulatory and capable of all self care but unable to carry out any work activities; 
up and about more than 50% of waking hours
3
Capable of only limited self care, confined to bed or chair more than 50% of waking 
hours
4
Completely disabled; cannot carry on any self care; totally confined to bed or chair
Reference:
Oken MM, Creech RH, et al. Toxicity and response criteria of the Eastern Cooperative 
Oncology Group. American J of Clinical Oncology. 1982;5:649-655.
21.2
Appendix 2: NYHA Functional Classification System
The New York Heart Association (NYHA) Functional Classification: Class I, II, III or 
IV Heart Failure provides a simple way of classifying the extent of heart failure. It places 
subjects in one of 4 categories based on the level of limitation experienced during physical
activity.
Class
Symptoms
Class I 
(Mild)
No limitation of physical activity. Ordinary physical activity does not cause undue
fatigue, palpitation or dyspnea (shortness of breath).
Class II 
(Mild)
Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity 
results in fatigue, palpitation or dyspnea.
Class III 
(Moderate)
Marked limitation of physical activity. Comfortable at rest, but less than ordinary
physical activity results in fatigue, palpitation or dyspnea.
Class IV 
(Severe)
Unable to carry out any physical activity without discomfort. Symptoms of cardiac
insufficiency at rest. If any physical activity is undertaken, discomfort is increased.
Reference:
The Criteria Committee of the New York Heart Association (NYHA).  Nomenclature and 
Criteria for Diagnosis of Diseases of the Heart and Great Vessels. 9th Ed. Boston, Mass: 
Little, Brown & Co.; 1994:253-256.


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21.3
Appendix 3: Cockcroft-Gault Formula for Creatinine Clearance
Creatinine Clearance (mL min
⁄
) = Q x (140 −age[yr]) x ideal body wt[kg]#
72 x serum creatinine [mg/dL]
Q = 0.85 for females
Q = 1.0 for males
OR
Creatinine Clearance (mL min
⁄
) = K x (140 −age[yr]) x ideal body wt[kg]#
serum creatinine [μmol/L]
K = 1.0 for females
K = 1.23 for males
1.
Use ideal body weight (IBW) if body weight >30% of IBW. Otherwise, use body weight.
2.
Creatinine clearance has a maximum value of 125 mL/min. Clearance values >125 mL/min by this
calculation must use 125 mL/min in the Calvert formula to determine carboplatin dosing.
Calculation of IBW using the Devine Formula [Devine, 1974]:
Males = 50.0 kg + (2.3 kg x each inch over 5 ft) or 50.0 kg + (0.906 kg x each cm over 152.4 
cm)
Females = 45.5 kg + (2.3 kg x each inch over 5 ft) or 45.5 kg + (0.906 kg x each cm over 152.4 
cm)
Example:

Male 

Actual Body Weight = 90.0 kg, 

Height = 68 inches 
IBW = 50.0 + (2.3) (68 - 60) = 68.4 kg
This subject’s actual body weight is >30% over IBW. Therefore, in this case, the subject’s 
IBW of 68.4 kg should be used in calculating estimated creatinine clearance.
Reference:
Devine BJ. Case Number 25 Gentamicin Therapy: Clinical Pharmacy Case Studies. Drug 
Intelligence and Clinical Pharmacy. 1974;8:650-655.


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21.6
Appendix 6: Details of Bayesian Hierarchical Model
Yi is the response indicator for the ith subject, and j = P(Yi =1 | ji = j) is the true response
rate for histology j. In the logic scale, θj is the mean log odds treatment effect of response:
+, = -./ 0
1,
1 −1,
2 −-./ 0
3,
1 −3,
2
Basic Hierarchical Model
A basic hierarchical model structure is described here and is incorporated within the clustered 
hierarchical model framework used in this study.
Borrowing occurs to the extent indicated by the data using a hierarchical normal model on 
the treatment effects:
+, ~ 5(μ, 7).
Were only this basic hierarchical model used for analysis, the prior distributions would be:
μ ~ 5(0,3) 9:; 7 ~ <=(0.5,0.125)
where IG(,) is the inverse gamma distribution defined by:
ƒ(A|C, D) =
EFℯHI/J
KFLM Г (O) ,
This distribution is non-informative in the sense that its parameters are analogous to having
a single observation. The variance component is a key parameter that plays a role in the 
degree of borrowing among histologies.  Small values of τ result in a greater degree of 
borrowing while large values of correspond to less borrowing. The distribution of is based 
on the variability of the observations, and the observed between- histology variation is an 
important component of the model’s performance. The effects of any particular prior 
distribution for can be assessed via simulations in evaluating a design’s operating 
characteristics, type I error rate and statistical power.


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Clustered Hierarchical Model
A clustered hierarchical model considers the possibility that “clusters” exist among the
collection of histologies. A therapy may be effective for some histologies but not for others. 
Histologies within the same cluster have greater influence on each other than they do on 
histologies in other clusters. On the other hand, histologies in different clusters are 
conditionally independent given any particular configuration of clusters. There is borrowing 
at the cluster level and borrowing across histologies within a particular cluster.
Borrowing across clusters depends only on similarities between clusters and not of individual 
histologies.
The number of clusters is unknown in advance but information will be gleaned from the data 
using Dirichlet Process Mixtures (DPM). The full prior is constructed in 2 stages. In the first 
stage, the histologies are assigned to particular clusters, with the number of clusters 
unspecified. Conditional on this particular clustering, the hierarchical model is fit within each 
cluster. A difference from the basic hierarchical model is in the parameter . Each cluster has 
its own . And the prior distribution on is now different:
7 ~ <=(3, 0.5).
Without the clustering, an informative prior on that places high probability on small values 
of could yield conclusions similar to simple pooling across histologies. This is not desirable. 
Instead it is preferred to preserve the integrity of individual histologies to the extent that they
give dissimilar results. With the clustering, a prior such as the one selected above meets this 
desideratum. When is small, as evinced by the data, histologies will only be placed in the 
same cluster if the data for those histologies are sufficiently similar to other histologies in the 
cluster. When is large, the histologies will be assigned to separate clusters and response 
rates estimated separately. This clustering approach provides further protection against 
borrowing between dissimilar histologies while enhancing the borrowing between similar 
histologies.
The prior distribution in a DPM is governed by the parameter . When is small, the prior 
favors large clusters. As tends to zero, the prior tends to place all its mass on a single cluster 
containing all the histologies. As increases, the prior places more mass on clustering with 
a large number of clusters. As becomes large, the prior places all of its mass on having a 
separate cluster for each histology (thus, no borrowing across histologies). A value of = 0 
corresponds to the usual hierarchical model with no clustering, while a very large treats 
all the histologies separately. Common values of might be between 0.5 and 5. We have 
selected = 2 for the final model. This value has been used for the final algorithm and the 
operating characteristics including type I error and power.
The key aspect of the clustering portion of the prior involves which histologies are clustered 
together. This is accomplished by creating a sequence of bins (in theory there are infinitely
many bins, but the number of bins actually used cannot exceed the number of histologies). 
Thus imagine a sequence of bins C1,C2,C3,… with associated probabilities pC1,pC2,pC3 and 
so forth. In the prior, each histology is placed in a bin according to the pCk probabilities. Thus, 
if one pCk is near 1, then all histologies will be likely to randomly fall in the same bin. If all 
the pCk values are small, it will be likely that all the histologies will randomly fall in separate 
bins. Histologies that fall within the same bin are defined as being in the same cluster. More 
details may be found in Escobar 1995 or Neal 2000.


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The pCk probabilities are determined through a stick breaking process [Sethuraman, 1994]. 
Let pC1~Beta(1,α). This leaves 1-pC1 probability to be allocated to the remaining bins. Let pC2
be a Beta(1,α) proportion of that remaining mass, so pC2~Beta(1,α)*[1-pC1]. There is now 1-
pC1-pC2 mass unallocated. Let pC3 be a Beta(1,α) proportion of the remaining mass, so 
pC3~Beta(1,α)*[1-pC1-pC2] and so on for pC4, pC5, and so forth. This process generates an 
infinite sequence of pCk values, but generally the first few contain most of the probability. In 
terms of the posterior distribution, only the bins which contain the histologies are of interest, 
and thus only 9 of the infinite bins will actually be used.
The role of α can be seen from this construction. If α is very small, then the Beta(1,α) 
proportions will tend to be close to 1. Thus, the first pC1 is quite likely to be near 1, and thus 
all the histologies will tend to lie in the first bin. If α is very large, all the Beta(1,α) values 
will tend to be small, and thus each pCk will tend to be small. This creates a situation where 
each histology is likely to be in a separate bin. Our proposed value of α=2 avoids these forced 
extremes and allows the data to drive the posterior distribution.
After the histologies have been assigned to bins in the prior, histologies within the same bin 
will tend to have more similar data than histologies in separate bins. Thus, in the posterior 
distribution, histologies with similar data are viewed as more likely to be from the same bin 
(and hence the same cluster). Histologies with very different data, in contrast, will have high 
posterior probability of being in separate bins/clusters, and thus will be estimated separately.
The posterior distribution also can be thought of in 2 stages, the first being a posterior 
distribution on the clustering, and then conditional on the clustering the posterior distribution 
from the hierarchical model. Conditional on the clustering, borrowing happens within 
clusters, but not across clusters. In situations where the clustering is uncertain (always in 
practice), one will see a proportional amount of borrowing between histologies, proportional 
on the posterior probability the histologies are within the same cluster. The aim of the 
clustering is to identify situations where the drug generally works for some histologies and 
generally does not work for others, so that these two disparate effects are not averaged 
together through the borrowing.
Reference:
Sethuraman J.  A Constructive Definition of Dirichlet Priors.  Statistica Sinica. 1994;4:639-
650.
21.7
Appendix 7: Supporting Simulation Results
Operating Characteristics for the Clustered Hierarchical Design for Different Sample 
Sizes: Power, Type I Error Rate
Histology
Scenario
1
2
3
4
5
6
7
8
9
Proportion of Trials that Declare each Histology Efficacious
(Measure of Power or Type I Error Rate)
Sample size Case 2
17
16
20
5
16
8
5
17
5
Mixed1
0.17
0.74
0.98
0.87
0.9
0.81
0.17
0.48
0.53
5 Greats: Mixed1
0.1
0.94
0.96
0.82
0.11
0.85
0.12
0.1
0.75
4 Greats: Low
0.09
0.08
0.08
0.77
0.08
0.82
0.68
0.07
0.65
2 Greats: Mixed1
0.08
0.06
0.94
0.08
0.08
0.06
0.61
0.07
0.04






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Example 2: Observed ORR at each Interim Analysis and the Final Analysis
Example 3: Mixed Scenario, Most Histologies Declared Successful
In this example, the nine histologies demonstrate varying levels of responsiveness.  Most
histologies meet the criteria for statistical success at the final analysis.
Six histologies have ORRs ranging from 30% to 67%. All of these histologies declare 
success. Due to moderate ORRs in some of these histologies, it will be particularly critical 
that the entirety of the data, including secondary efficacy endpoints, support clinically
relevant results to demonstrate evidence of meaningful high levels of activity.
The ORR for the remaining three histologies is 0, 14% and 29%, none of which is
sufficient to meet the pre-specified success criteria. Two histologies halted enrollment
early for success and one for futility.




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Example 3: Observed ORR at each Interim Analysis and the Final Analysis
Example 4: Mixed Scenario, Most Histologies not Declared Successful
In this example, seven of the histologies demonstrate a range of ORRs from 0 to 31%. The 
remaining two histologies (histologies 7 and 9) have ORRs of 71% and 80% respectively.
Three of the histologies (histologies 1, 7, and 9) which demonstrated the highest ORRs of 
31%, 71%, and 80%, respectively, meet statistical success.  To demonstrate evidence of 
meaningful high levels of activity in these three histologies, it will be critical that in 
addition to statistical success, the totality of the data support clinically relevant results.
The remaining size histologies with ORRs of 29% do not meet the pre-specified success 
criteria.  Histology 1 stopped early for success while two histologies (2 and 3) stopped
early for futility.








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Example 5: Observed ORR at each Interim Analysis and the Final Analysis
Example 6: Mixed Scenario, Most of the Low-enrolling Histologies 
Declare Success while the Higher-enrolling Histologies Do Not
In this example, most of the lower enrolling cohorts (three to six subjects each) have 
relatively high ORRs while the higher enrollment cohorts demonstrate low ORRs.
Four low-enrolling histologies (histology 6, 7, 8 and 9) have ORRs of 50%, 50%, 67%, and 
75% respectively, and statistical success is declared in each. To demonstrate evidence of 
meaningful high levels of activity in these three histologies, it will be critical that in 
addition to statistical success, the totality of the data support clinically relevant results.
The four histologies (histologies 1, 2, 3, and 4) expected to enroll higher numbers of 
patients demonstrate much lower ORRs, ranging from 0-12% and none declare success.
Though the actual sample sizes aren’t very large (five to eight subjects), three of these 
histologies stopped early due to futility and larger sample sizes would likely have been
possible had they not halted enrollment early.  The remaining histology (histology 5) has an 
ORR of 33% (1/3) which also does not declare success.




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Example 6: Observed ORR at each Interim Analysis and the Final 
Analysis


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21.9
Appendix 9: Country-Specific Requirements
AUSTRIA:
In compliance with the Austrian Drug Law Amendment Act of 2004, the following
regulatory requirements will be applied to all study centers in Austria:
Pregnancy: §30. The clinical testing of drugs may only be carried out or continued in
women of childbearing potential, with the exception of cases as stated in §44, if non-
pregnancy is confirmed prior to and at adequate intervals during the clinical trial.
Clinical Trials in Emergency Situations:
§43a. (1) If a clinical trial, by its very nature, can only be conducted in emergency
situations in which the consent of the legal representative cannot be obtained within a
reasonable length of time, then a clinical trial may be conducted on a person who is not in 
a position to give his or her consent if:
1.
there is no informative basis that the subject has objected to or would object to the
clinical trial,
2.
such research is implicitly required for the validation of data that were obtained from 
clinical trials on persons able to give their informed consent or by means of other
research methods and which can only be conducted in emergency situations,
3.
the drug to be tested is intended to identify, heal, mitigate or prevent diseases in an
emergency situation,
4.
the application of the drug to be tested is indicated according to the latest findings in 
medical science in order to identify, heal or to mitigate a disease in emergency patients 
or to protect them from further diseases and the benefit of being included in the clinical 
trial outweighs the risk for the trial participant,
5.
the conduct of the trial and the protocol have been approved by an ethics committee
that has knowledge of the area of the disease in question and of the emergency situation 
concerned and the patient population involved or that has been advised on the clinical 
and ethical questions in the area of the disease in question and on the emergency
situation concerned and the patient population involved, specifically for the conduct 
of clinical trials in emergency situations on persons who are unable to give their 
consent personally, and




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21.10
Appendix 10: RECIST, version 1.1
MEASURABILITY OF TUMOR LESIONS AT BASELINE
Measurable lesion:
A non-nodal lesion that can be accurately measured in at least one dimension (longest
dimension) of:

10 mm with magnetic resonance imaging (MRI) or computed tomography (CT) when 
the scan slice thickness is no greater than 5 mm.  If the slice thickness is greater than 5 
mm, the minimum size of a measurable lesion must be at least double the slice thickness 
(e.g., if the slice thickness is 10 mm, a measurable lesion must be 20 mm)

10 mm calliper/ruler measurement by clinical examination or medical photography

20 mm by chest x-ray
Additionally, lymph nodes can be considered pathologically enlarged and measurable if:

15 mm in the short axis when assessed by CT or MRI (slice thickness recommended 
to be no more than 5 mm). At baseline and follow-up, only the short axis will be 
measured
Non-measurable lesion:
All other lesions including lesions too small to be considered measurable (longest diameter 
<10 mm or pathological lymph nodes with ≥10 mm and <15 mm short axis) as well as truly
non-measurable lesions, which include: leptomeningeal disease, ascites, pleural or 
pericardial effusions, inflammatory breast disease, lymphangitic involvement of the skin or 
lung, abdominal masses/abdominal organomegaly identified by physical exam that is not 
measurable by reproducible imaging techniques.
Measurable disease: The presence of at least one measurable lesion.  Palpable lesions that 
are not measurable by radiologic or photographic evaluations may not be utilized as the 
only measurable lesion.
Non-Measurable only disease: The presence of only non-measurable lesions.
Specifications by methods of measurements:


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
The same diagnostic method, including use of contrast when applicable, must be used 
throughout the study to evaluate a lesion.

All measurements should be taken and recorded in millimeters (mm), using a ruler or 
calipers.

Ultrasound is not a suitable modality of disease assessment.
If new lesions are 
identified by ultrasound, confirmation by CT or MRI is required.

Fluorodeoxyglucose-positron emission tomography (FDG-PET) is generally not
suitable for ongoing assessments of disease. However, FDG-PET can be useful in
confirming new sites of disease where a positive FDG-PET scans correlates with the
new site of disease present on CT/MRI or when a baseline FDG-PET was previously
negative for the site of the new lesion. FDG-PET may also be used in lieu of a standard 
bone scan providing coverage allows interrogation of all likely sites of bone disease 
and FDG-PET is performed at all assessments.

If FDG-PET/CT is performed then the CT component can only be used for standard
response assessments if performed to diagnostic quality, which includes the required
anatomical coverage and prescribed use of contrast.  The method of assessment should 
be noted as CT on the case report form.
Clinical Examination: Clinically detected lesions will only be considered measurable 
when they are superficial (e.g., skin nodules).  In the case of skin lesions, documentation by
color photography, including a ruler/calipers to measure the size of the lesion, is required.
CT and MRI: Contrast enhanced CT with 5 mm contiguous slices is recommended.
Minimum size of a measurable baseline lesion should be twice the slice thickness, with a
minimum lesion size of 10 mm when the slice thickness is 5 mm. MRI is acceptable, but 
when used, the technical specification of the scanning sequences should be optimised for 
the evaluation of the type and site of disease and lesions must be measured in the same
anatomic plane by use of the same imaging examinations. Whenever possible the same
scanner should be used.
X-ray: Should not be used for target lesion measurements owing to poor lesion definition. 
Lesions on chest X-ray may be considered measurable if they are clearly defined and 
surrounded by aerated lung; however, chest CT is preferred over chest X-ray.
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.


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
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 (SD): Neither sufficient shrinkage to qualify for PR nor sufficient
increase to qualify for PD.

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): Target lesions not present at baseline.

Not Evaluable (NE): Unable to classify using 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 SD, 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 SD, the diameter of the reappearing lesion should be added to the remaining 


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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): Non-target lesions not present at baseline.

Not Evaluable (NE): Unable to classify using 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 SD or PR in 
target disease, the overall tumor burden has increased sufficiently to merit
discontinuation of therapy.

In the presence of non-measurable only disease consideration should be given to
whether or not the increase in overall disease burden is comparable in magnitude to the 
increase that would be required to declare PD for measurable disease.

Sites of non-target lesions, which are not assessed at a particular time point based on
the assessment schedule, should be excluded from the response determination (e.g. non-
target response does not have to be "NE").
Frequency of tumor re-evaluation
Target and non-target lesions will be re-evaluated every 8 weeks.
Confirmation of Response

To be assigned a status of PR or CR, a confirmatory disease assessment should be 
performed no less than 4 weeks (28 days) after the criteria for response are first met.


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OVERALL RESPONSE CRITERIA
The table 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.
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
SD
Non-PD or NA or NE
No
SD
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
Abbreviations: CR = complete response; NA = not applicable; NE = not evaluable; PD = progressive disease; PR =
partial response; SD = stable disease
NOTE:

Subjects with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of PD 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.
Reference:
Eisenhauer EA, Therasse P, Bogaerts, J, et al. New response evaluation criteria in solid 
tumors: revised RECIST guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-247.


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Appendix 11: Response Criteria for NSGCT/NGGCT with Elevated
Tumor Markers (AFP and -HCG) at Baseline
Serum tumor markers alpha-fetoprotein (AFP) and beta-human chorionic gonadotropin (-
HCG) will be measured as indicated in the Time and Events Table

Marker-Negative Complete Response (CR-) is defined as meeting the Response
Evaluation Criteria in Solid Tumors (RECIST), v1.1 criteria for CR plus normalization 
of previously elevated tumor markers for a minimum of 4 weeks.

Marker-Positive Complete Response (CR+) is defined as meeting the RECIST, v1.1 
criteria for CR plus a tumor marker decrease for at least 4 weeks, but without complete 
normalization of previously elevated tumor markers.

Marker-Negative Partial Remission (PR-) is defined as meeting the RECIST,
v1.1 criteria for partial response (PR) plus normalization of previously elevated 
tumor markers for a minimum of 4 weeks.

Marker-Positive Partial Remission (PR+) is defined as meeting the RECIST, v1.1 
criteria for PR plus a tumor marker decrease for at least 4 weeks, but without complete 
normalization of previously elevated tumor markers.

Progressive Disease (PD) is defined as a significant elevation (≥50%) in tumor
markers after 4 weeks of therapy; treatment will be stopped despite of radiological
response.
References:
Bokemeyer C, Oechsle K, Honecker F, et al. Combination chemotherapy with gemcitabine, 
oxaliplatin, and paclitaxel in patients with cisplatin-refractory or multiple relapsed germ-cell 
tumors: a study of the German Testicular Cancer Study Group. Annals of Oncology. 
2008;19:448-453.
Einhorn LH, Brames MJ, Juliar B, Williams SD. Phase II Study of Paclitaxel plus
Gemcitabine Salvage Chemotherapy for Germ Cell Tumors after Progression Following
High-Dose Chemotherapy with Tandem Transplant. J Clin Oncol. 2007;25(5):513-516.
Kollmannsberger C, Beyer J, Liersch R, et al. Combination chemotherapy with gemcitabine 
plus oxaliplatin in patients with intensively pretreated or refractory germ cell cancer: A Study
of the German Testicular Cancer Study Group. J Clin Oncol.
2004;22:108-114.


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Appendix 12: Response Criteria for HCL
Response status for hairy cell leukemia (HCL) will be assessed according to the following 
criteria adapted from the NCCN guideline - Consensus Resolution, and previous HCL
studies.
Complete response (CR) with or without Minimal Residual Disease (±MRD):

No evidence of leukemic cells by routine and H/E stains of the peripheral blood and 
bone marrow (BM).

MRD: CR with HCL evident in blood by flow cytometry (FACS) or in BM biopsy by
immunohistochemistry (IHC)

No hepatomegaly, splenomegaly, or abnormal (< 2cm minimum length)
lymphadenopathy by appropriate radiographic techniques.

NOTE: Enlarged liver or spleen associated with a negative nuclear medicine study
will not prevent consideration of CR for those subjects meeting all other criteria.

Normal complete blood count (CBC) as exhibited by: absolute neutrophil count (ANC) 
≥1.5 x 109/L, platelets ≥100 × 109/L, and hemoglobin ≥11 g/dL without transfusions 
or growth factors for at least 4 weeks.
After this 4-week period, BM biopsy and computed tomography (CT) scan must be
performed to confirm CR. The BM biopsy and aspirate need not be performed at the
beginning of this 4-week interval.
Complete response (CR): defined as the complete disappearance of all evidence of
disease and requires all of the following:

Normal CBC as exhibited by: ANC ≥1.5×109/L, platelets ≥100×109/L and hemoglobin 
≥11 g/dL

Absence of hairy cells (by morphological examination) in the peripheral blood and in 
the BM

Regression to normal of disease-related organomegaly


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Confirmation of CR: At the confirmatory ≥6 month visit, a BM biopsy, hematology,
immunoglobulins and flow cytometry will be reassessed.
Duration of CR: The duration of complete remission is calculated from the time of 
achievement of all criteria of CR to the time of relapse from CR.
Partial response (PR): requires all of the following for a period of at least 4 weeks:

Normal peripheral blood counts (as in CR)
o
ANC ≥1.5×109/L or 50% improvement over baseline without growth factors for 
at least 4 weeks, AND
o
Platelets ≥100 × 109/L or 50% improvement over baseline, AND
o
Hemoglobin ≥11 g/dL or 50% improvement over baseline without transfusions or 
growth factors for at least 4 weeks.
NOTE: For subjects who are transfusion-dependent at baseline, a hemoglobin 
of ≥9 g/dL without transfusions or growth factors for at least 4 weeks.

circulating hairy cells ≤5% of lymphocytes

≥50% reduction of BM infiltration by hairy cells

≥50% reduction of palpable disease-related organomegaly.
Subject must have the following (if abnormal prior to treatment):

≥50% decrease or normalization (<5000/mm3) in peripheral blood lymphocyte count 
from the pre-treatment baseline value

≥50% reduction in lymphadenopathy, based on sum of products of perpendicular 
diameters, or resolution to size consistent with CR

≥50% reduction in abnormal hepatosplenomegaly by imaging, or resolution to size 
consistent with CR
Minor response (MR): requires all of the following:

≥50% reduction of circulating hairy cells


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
Improvement of one or more of the peripheral blood counts (ANC, platelets or
hemoglobin).
Relapse: defined as the reappearance of leukemia/lymphoma in a subject who previously
achieved a CR or documentation of PD in a subject who previously achieved a PR
Stable Disease (SD): defined as not meeting the criteria for CR, PR, MR or PD
Disease progression (PD): defined as the occurrence of at least one of the following
compared to pre-treatment:

≥50% increase in the sum of the products of the greatest perpendicular dimensions of 
at least two lymph nodes on two consecutive examinations at least 2 weeks apart (at 
least one node must be ≥2 cm in minimum length) or appearance of new palpable 
lymph nodes

≥50% increase in the absolute number of circulating lymphocytes, on two consecutive 
examinations showing abnormal lymphocytosis at least 2 weeks apart

≥25% decrease in hemoglobin (must be <10g/dL), platelets (must be <100,000/uL), or 
ANC (must be <1500/uL) unless these are judged to be effects of treatment.
References:
Catovsky D, Golomb HM, Golde DW. Consensus Resolution: Proposed Criteria for 
Evaluation of Response to Treatment in Hairy Cell Leukemia. Leukemia. 1987;4(1):405-
406.
Kreitman RJ, Fitzgerald DJ, Pastan I. Approach to the patient after relapse of hairy cell
leukemia. Leuk Lymphoma. 2009a;50(suppl 1):32-37.
Kreitman RJ, Tallman MS, Robak T, et al. Phase I trial of anti-CD22 recombinant
immunotoxin moxetumomab pasudotox (CAT-8015 or HA22) in patients with hairy cell
leukemia. J Clin Oncol. 2012;30:1822-1828.
Kreitman, R.J., Stetler-Stevenson, M., Margulies, I., et al. Phase II trial of recombinant
immunotoxin RFB4(dsFv)-PE38 (BL22) in patients with hairy cell leukaemia. J Clin
Oncol. 2009b;27:2983–2990.
Nieva J, Bethel K, Saven A. Phase 2 study of rituximab in the treatment of cladribine-
failed patients with hairy cell leukemia. Blood 2003;102:810-813.
Saven A, Burian C, Koziol JA, Piro LD. Long-term follow-up of patients with hairy cell
leukemia after cladribine treatment. Blood. 1998;92(6):1918-1926.


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Appendix 13: RANO Response Criteria: Response Assessment
Criteria for WHO Grade 1 or 2 Glioma
Measureable disease is defined as bidimensionally contrast non-enhancing or enhancing
lesions with clearly defined margins by magnetic resonance imaging (MRI) scan, with two 
perpendicular diameters of at least 10 mm, visible on 2 or more axial slices that are 
preferably, at most, 5 mm apart with 0 mm skip.
Non-measurable disease is defined as either unidimensionally measurable lesions, masses 
with margins not clearly defined, or lesions with maximal perpendicular diameters less than 
10 mm.
All measurable and non-measurable lesions must be assessed using the same techniques as at 
baseline.
Complete response (CR): Requires all the following criteria compared with the baseline
scan:

Complete disappearance of the lesion on T2 or FLAIR (fluid attenuated inversion 
recovery) imaging (if enhancement had been present, it must have
resolved 
completely);

no new lesions, no new T2 or FLAIR abnormalities apart from those consistent with 
radiation effects, and no new or increased enhancement;

subject must be off corticosteroids or only on physiological replacement doses, and

subject should be stable or improved clinically
Partial response (PR): Requires all of the following criteria compared with the baseline
scan:

greater than or equal to 50% decrease in the product of perpendicular diameters of the 
lesion on T2 or FLAIR imaging sustained for at least 4 weeks compared with baseline;

no new lesions, no new T2 or FLAIR abnormalities apart from those consistent with 
radiation effects, and no new or increased enhancement;

subject 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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Minor response (MR): Requires the following criteria compared with the baseline scan:

a decrease of the area of enhancing or non-enhancing lesion on T2 or FLAIR MR 
imaging between 25% and 50% compared with baseline

no new lesions, no new T2 or FLAIR abnormalities apart from those consistent with 
radiation effect, and no new or increased enhancement; and

subject 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): Stable disease (SD) is present if the changes do not qualify for CR, PR, 
MR or progression and requires:

stable area of enhancing or non-enhancing abnormalities on T2 or FLAIR imaging

no new lesions, no new T2 or FLAIR abnormalities apart from those consistent with 
radiation effect, and no new or increased enhancement

subject 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
Disease progression (PD): Disease progression (PD) is defined by any of the following:

development of new lesions or increase of enhancement (radiological evidence of 
malignant transformation)

a 25% increase in the sum of the products of perpendicular diameters of the T2 or 
FLAIR enhancing or non-enhancing lesion on stable
or increasing doses of 
corticosteroids compared with baseline scan or best response after initiation of therapy, 
not attributable to radiation effect or to comorbid events

definite clinical deterioration not attributable to other causes apart from the tumour, 
or decrease in corticosteroid dose;

or failure to return for evaluation because of death or deteriorating condition, unless 
caused by documented non-related disorders
References:


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van den Bent MJ, Wefel JS, Schiff D, et al. Response assessment in neuro-oncology (a 
report of the RANO group): assessment of outcome in trials of diffuse low grade gliomas. 
The Lancet. 2011;12:583-593.


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Appendix 14: RANO Response Criteria: Updated Response
Assessment Criteria for WHO Grade 3 and 4 Glioma
Measureable disease is defined as bidimensionally contrast-enhancing or enhancing lesions 
with clearly defined margins by magnetic resonance imaging (MRI) scan, with two 
perpendicular diameters of at least 10 mm, visible on 2 or more axial slices that are 
preferably, at most, 5 mm apart with 0 mm skip.
Non-measurable disease is defined as either unidimensionally measurable lesions, masses 
with margins not clearly defined, or lesions with maximal perpendicular diameters less than 
10 mm.
All measurable and non-measurable lesions must be assessed using the same techniques as at 
baseline.
Complete response (CR): Requires all of the following:

complete disappearance of all enhancing measurable and non-measurable disease 
sustained for at least 4 weeks

no new lesions

stable or improved non-enhancing (T2/FLAIR [fluid attenuated inversion recovery]) 
lesions

subjects must be off corticosteroids (or on physiologic replacement doses only)

stable or improved clinically.
Note: Subjects with non-measurable disease only cannot have a CR; the best response
possible is stable disease (SD).
Partial response (PR): Requires all of the following:

50% decrease compared with baseline, in the sum of products of perpendicular 
diameters of all measurable enhancing lesions sustained for at least 4 weeks

no progression of non-measurable disease; no new lesions

stable or improved non-enhancing (T2/FLAIR) lesions on same or lower dose of
corticosteroids compared with baseline scan


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
corticosteroid dose at the time of the scan evaluation should be no greater than the 
dose at time of baseline scan

stable or improved clinically.
Note: Subjects with non-measurable disease only cannot have a PR; the best response
possible is SD.
Stable disease (SD): Requires all of the following:

does not qualify for CR, PR, or progression

stable non-enhancing (T2/FLAIR) lesions on same or lower dose of corticosteroids 
compared with baseline scan.
In the event that the corticosteroid dose was increased for new symptoms and signs without 
confirmation of disease progression (PD) on neuro-imaging, and subsequent follow-up 
imaging shows that this increase in corticosteroids was required because of PD, the last scan 
considered to show SD will be the scan obtained when the corticosteroid dose was equivalent 
to the baseline dose.
NOTE: Stable doses of corticosteroids include subjects not on corticosteroids.
Disease progression (PD): Disease progression (PD) is defined by any of the following:

25% increase in sum of the products of perpendicular diameters of enhancing 
lesions compared with the smallest tumor measurement obtained either at baseline 
(if no decrease) or best response, on stable or increasing doses of corticosteroids

significant increase in T2/FLAIR non-enhancing lesion on stable or increasing
doses of corticosteroids compared with baseline scan or best response after initiation 
of therapy not caused by co-morbid events (e.g., radiation therapy, demyelination, 
ischemic injury, infection, seizures, post-operative changes, or other treatment 
effects)

any new lesion; clear clinical deterioration not attributable to other causes apart from 
the tumor (e.g., seizures, medication adverse effects, complications of therapy, 
cerebrovascular events, infection) or changes in corticosteroid dose

failure to return for evaluation as a result of death or deteriorating condition


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
clear progression of non-measurable disease.
Summary of RANO Response Criteria
Criterion
CR
PR
SD
PD
T1 gadolinium-
enhancing disease
None
50%decrease
<50% decrease but
<25%increase
25%increase1
T2/FLAIR
Stable or decrease
Stable or decreasing
Stable or decrease
Increase
New Lesion
None
None
None
Present
Corticosteroids
None
Stable or decreasing dose
Stable or Decreasing
dose
NA2
Clinical Status
Stable or increase
Stable or increase
Stable or increase
Decrease
Requirement for
Response
All
All
All
Any
Abbreviations: CR = complete response; FLAIR = fluid-attenuated inversion recovery; NA = not applicable; PD =
progressive disease; PR = partial response; RANO = Response Assessment in Neuro-Oncology: SD = stable disease
Progression occurs when this criterion is present.
Increase in corticosteroids alone will not be taken into account in determining progression in the absence of persistent
clinical deterioration.
References:
Wen PY. Updated Response Assessment Criteria for High-Grade Gliomas: Response
Assessment in Neuro-Oncology Working Group. J Clin Oncol. 2010;28(11):1963-1972.


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Appendix 15: Consensus Recommendations for the Uniform
Reporting of Clinical Trials
Report of the International Myeloma Workshop Consensus Panel
International Myeloma Workshop Consensus (IMWC) Response Criteria: 
Stringent Complete Response (sCR):
Complete response (CR) as defined below plus:

normal free light chain (FLC) ratio and

absence of clonal cells in bone marrow (BM) by immunohistochemistry (IHC) or 2 to 
4 color flow cytometry
Complete Response (CR):

Negative serum and urine immunofixation, and

Disappearance of any soft tissue plasmacytomas, and

≤5% plasma cells in BM
Very Good Partial Response (VGPR):

Serum and urine M-component detectable by
immunofixation but not on
electrophoresis
OR

90% or greater reduction in serum M-component plus urine M-component <100 mg 
per 24 hrs
Partial Response (PR):

≥50% reduction of serum M-protein and reduction in 24-hr urinary M-protein by ≥90% 
or to <200 mg per 24 hrs
AND


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
If the serum and urine M-protein are not measurable, a ≥50% decrease in the difference 
between involved and uninvolved FLC levels is required in place of the M-protein 
criteria. If serum and urine M-protein are not measurable, and serum FLC assay is also 
not measurable, ≥50% reduction in BM plasma cells is required in place of M-protein, 
provided baseline BM plasma cell percentage was ≥30%, and in the size of the soft 
tissue plasmacytomas is also required.
Minimal Response (MR):

≥25% but ≤49% reduction of serum M-protein and reduction in 24-hr urinary M-
protein by 50% to 89%
AND

If present at baseline, 25% to 49% reduction in the size of soft tissue plasmacytomas 
is also required.

No increase in size or number of lytic bone lesions (development of compression
fracture does not exclude response).
Stable Disease (SD):

Not meeting criteria for CR, VGPR, PR, MR or PD
Progressive Disease (PD):
Requires an increase of ≥25% from lowest response value in any one or more of the
following:
•
serum M-component (absolute increase must be ≥0.5 g/dL), or
•
urine M-component (absolute increase must be ≥200 mg/24 hr), or
•
the difference between involved and uninvolved FLC levels (absolute increase 
must be >10 mg/dL): only for subjects without measurable serum and urine M-
protein levels, or
•
bone marrow plasma cell percentage (the absolute % must be ≥10%) – only for 
subjects without measurable serum and urine M-protein levels and without 
measurable disease by FLC level


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•
definite development of new bone lesions or soft tissue plasmacytomas or definite 
increase in the size of existing bone lesions or soft tissue plasmacytomas
•
development of hypercalcemia (corrected calcium >11.5 mg/dL or 2.65 mmol/L) 
that can be attributed solely to the plasma cell proliferative disorder
a. All response categories (CR, sCR, VGPR, PR, MR and PD) require 2 consecutive assessments 
made at any time before the institution of any new therapy; CR, sCR, VGPR, PR, MR, and 
SD categories also require no known evidence of progressive or new bone lesions if 
radiographic studies were performed. VGPR and CR categories require serum and urine 
studies regardless of whether disease at baseline was measurable on serum, urine, both, or 
neither. Radiographic studies are not required to satisfy these response requirements. Bone 
marrow assessments need not be confirmed. For PD, serum M- component increases of more 
than or equal to 1 g/dL are sufficient to define relapse if starting M-component is ≥5 g/dL.
b. Clarifications to IMWG criteria for coding CR and VGPR in subjects in whom the only
measurable disease is by serum FLC levels: CR in such subjects indicates a normal FLC ratio 
of 0.26 to 1.65 in addition to CR criteria listed above. VGPR in such subjects requires a >90% 
decrease in the difference between involved and uninvolved FLC levels.
c. Clarifications to IMWG criteria for coding PD: Bone marrow criteria for PD are to be used 
only in subjects without measurable disease by M protein and by FLC levels; “25% increase” 
refers to M protein, FLC, and BM results, and does not refer to bone lesions, soft tissue 
plasmacytomas, or hypercalcemia and the “lowest response value” does not need to be a 
confirmed value.
References:
Durie BGM, Harousseau J-L, Miguel JS, et. al. International uniform response criteria for
multiple myeloma. Leukemia. 2006:20:1467-73.
Rajkumar SV, Harousseau JL, Durie B, et al. Consensus recommendations for the uniform 
reporting of clinical trials: Report of the International Myeloma Workshop Consensus Panel 
1. Blood. 2011;117:4691-4695.


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Appendix 16: Imaging Guidelines for WHO Grade I or II Glioma
Basic MRI protocol:

Axial FLAIR (canthomeatal alignment): 3 to 5 mm sections, 1 mm interslice gaps, 
slice registration preserved as much as possible between sequential studies

Axial T2: 5 mm sections, 1 mm interslice gap

Coronal T1: 5 mm sections, 1 mm interslice gap

Post-gadolinium chelate (contrast agent per local clinical practice): cornoal T1, axial 
T1
Alternatively pre-gadolinium and post-gadolinium volumetric T1 may replace axial and
coronal T1-weighted sequences.
Supplementary imaging methods:

Two-dimensional or 3-dimensional spectroscopic imaging (MR spectroscopy)

Perfusion imaging (DSC-MRI)

Diffusion-weighted imaging (-B=0, B=1000)
PET imaging:
For 11C-MET and 18F-FET PET:

Subject must fast for 4 hrs prior to imaging

Images must be obtained in a supine position

10 min transmission scan must be done prior to tracer application

C-MET or F-FET administered intravenously as a bolus injection of 740 MBq (20 
mCi; MET) or 370 MBq (10 mCi; FET)


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
Accumulation of tracer will be recorded over 60 min in 47 transaxial slices of entire 
brain

Spatial resolution of C-MET PET and F-FET PET: 6 mm or better in all dimensions

SUV, T/B ratios and uptake kinetics: calculated in tumor and corresponding mirror 
regions
Abbreviations: DSC, dynamic susceptibility contrast; FET, 18F-fluoroethyltyrosine; FLAIR, 
fluid attenuation inversion recovery; MET, 11C-methionine; PET, positron emission 
tomography; SUV, standard uptake value; T/B, tumor background ratio
References:
van den Bent MJ, Wefel JS, Schiff D, et al. Response assessment in neuro- oncology (a 
report of the RANO group): assessment of outcome in trials of diffuse low grade gliomas. 
The Lancet. 2011;12:583-593.


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Appendix 17: Volumes of Collected Blood Samples
Assuming a subject remains on treatment for a period of 6 months, the total blood volume 
collected is estimated to be 306 mL (excluding any unpredictable events that would require 
additional blood samples to be obtained 
).
Reason for
Blood Sample
Screening
Day 1
Day 15
Week 4
Week 8
Week 12
Week 16
Trmt
Disc
PK Analysis
N/A
N/A
N/A
4mL
2mL
2mL
N/A
2mL
BRAF V600E
(HCL and MM
cohorts only)
3mL
N/A
N/A
N/A
N/A
N/A
N/A
N/A
PD and
Biomarker
Analyses
21mL
N/A
18mL
N/A
N/A
N/A
N/A
18mL
Clinical 
Laboratory
Assessments
17mL
17mL
N/A
17mL
17mL
17mL
17mL
17mL
TOTAL
Volume
38mL
23mL
18mL
21mL
19mL
19mL
17mL
37mL
Abbreviations: HCL = Hairy Cell Leukemia; MM = Multiple Myeloma; PD = pharmacodynamics;
; PK = pharmacokinetics; Trmt Disc = treatment discontinuation


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Appendix 18: Liver Safety Drug Restart or Rechallenge
Guidelines
If subject meets liver chemistry stopping criteria do not restart/rechallenge subject with
study treatment unless:

Novartis Medical Governance approval is granted (as described below),

Independent Ethics Committee (IEC) and/or institutional review board (IRB) 
approval is obtained, if required, and

Separate consent for treatment restart/rechallenge is signed by the subject
If Novartis Medical Governance approval to restart/rechallenge subject with study
treatment
is not granted, then subject must permanently discontinue study treatment and may
continue in the study for protocol-specified follow-up assessments.
1. Rechallenge Following Liver Stopping Events that are Possibly Related 
to Study Treatment
Following drug-induced liver injury (DILI), drug rechallenge is associated with a 13%
mortality across all drugs in prospective studies [Andrade, 2009] Clinical outcomes vary
by drug, with nearly 50% fatality with halothane readministered within 1 month of initial 
injury. However, some drugs seldom result in recurrent liver injury or fatality.
Risk factors for a fatal drug rechallenge outcome include:

hypersensitivity1 with initial liver injury (e.g. fever, rash, eosinophilia)

jaundice or bilirubin >2xULN with initial liver injury (direct bilirubin
>35% of total)

subject currently exhibits severe liver injury defined by: ALT 3xULN,
bilirubin 2xULN (direct bilirubin >35% of total), or INR1.5

serious adverse event or fatality has earlier been observed with drug 
rechallenges [Papay, 2009; Hunt, 2010]


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
evidence of drug-related preclinical liability (e.g. reactive metabolites;
mitochondrial impairment) [Hunt, 2010]
Rechallenge refers to resuming study treatment following DILI.  Because of the risks 
associated with rechallenge after DILI this should only be considered for a subject for
whom there is compelling evidence of benefit from a critical or life-saving medicine, there 
is no alternative approved medicine available, and a benefit:risk assessment of rechallenge 
is considered to be favorable.
Approval by the sponsor for rechallenge with study treatment can be considered where:

Investigator requests consideration of rechallenge with study treatment for a subject 
who is receiving compelling benefit with study treatment that exceeds risk, and no
effective alternative therapy is available.

EC or IRB approval for rechallenge with study treatment must be obtained, as required.

If the rechallenge is approved by Novartis Medical Governance in writing, the subject 
must be provided with a clear description of the possible benefits and risks of study 
treatment administration, including the possibility of recurrent, more severe liver injury
or death.

The subject must also provide signed informed consent specifically for the rechallenge 
with study treatment.  Documentation of informed consent must be recorded in the study
chart.

Study treatment must be administered at the dose specified by the sponsor.

Subjects approved by Novartis Medical Governance for rechallenge with study
treatment must return to the clinic twice a week for liver chemistry tests until stable
liver chemistries have been demonstrated and then standard laboratory monitoring may
resume as per protocol.

If after study treatment rechallenge, subject meets protocol-defined liver chemistry
stopping criteria, study treatment should be permanently discontinued.

Medical Lead, and the IEC or IRB as required, must be informed of the subject’s
outcome following study treatment rechallenge.

The sponsor to be notified of any AEs, as per Section 11.
2. Restart Following Transient Resolving Liver Stopping Events NOT 
Related to Study Treatment


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Restart refers to resuming study treatment following liver stopping events in which there is 
a clear underlying cause (other than DILI) of the liver event (e.g. biliary obstruction,
pancreatic events, hypotension, acute viral hepatitis). Furthermore, there should be no
evidence of alcoholic hepatitis or hypersensitivity, and the study treatment should not be
associated with HLA markers of liver injury.
Approval by the sponsor for study treatment restart can be considered where:

Investigator requests consideration for study treatment restart if liver chemistries have 
a clear underlying cause (e.g., biliary obstruction, hypotension and liver chemistries 
have improved to normal or are within 1.5x baseline and ALT <3xULN).

Restart risk factors (e.g. fever, rash, eosinophilia, or hypersensitivity, alcoholic hepatitis, 
possible study treatment-induced liver injury or study treatment has an HLA genetic 
marker associated with liver injury (e.g. lapatinib, abacavir, amoxicillin/clavulanate) 
are reviewed and excluded.

IEC or IRB approval of study treatment restart must be obtained, as required.

If restart of study treatment is approved by Novartis Medical Governance in writing, 
the subject must be provided with a clear description of the possible benefits and risks 
of study treatment 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.  Documentation of informed consent must be recorded in the study 
chart.

Study treatment must be administered at the dose specified by the sponsor.

Subjects approved by Novartis Medical Governance 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 after study treatment re-start, subject meets protocol-defined liver chemistry stopping 
criteria, follow usual stopping criteria instructions.

Medical Lead, and the IEC or IRB as required, must be informed of the subject’s
outcome following study treatment restart.

The sponsor to be notified of any AEs, as per Section 11.


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References:
Andrade RJ, Robles M, Lucena MI. Rechallenge in drug-induced liver injury: the
attractive hazard. Expert Opin Drug Saf. 2009;8:709-714.
Hunt, CM.  Mitochondrial and immunoallergic injury increase risk of positive drug
rechallenge after drug-induced liver injury: A systematic review.  Hepatol. 2010;52:2216-
2222.
Papay JI, Clines D, Rafi R, et al.  Drug-induced liver injury following positive drug
rechallenge. Regul Tox Pharm. 2009;54:84-90


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21.19
Appendix 19: Protocol Amendment Changes
AMENDMENT 06
Where the Amendment Applies
Amendment 06 applies to all sites that are or will be participating in this study.
Summary of Amendment Changes
The changes made with Amendment No. 6 were to update contact details for Medical 
Monitor, to implement reference to new Investigator’s Brochure (v7), to update list of 
abbreviation, to update risk assessment for dabrafenib + trametinib combination therapy, to 
change in time window for radiotherapy in Glioma Grade 1-4 cohort only, to clarify
assessment timelines and correct discrepancies between T&E Table and text, to
implementing “Tissue Sample for Histology Confirmation” for ATC and WHO Grade 1- 4 
Glioma cohort only, to clarify Disease Assessments Methods for Glioma Grade 1-4
cohorts, to correct timelines for re-escalation of toxicity induced dose reduction, to clarify
instructions for prohibited medications and non-drug therapies, to add additional analysis 
populations that are planned for the interim analyses, to add an expansion cohort to allow 
enrollment of patients if a given cohort{ is stopped early for efficacy, to add the language 
to refer to the RAP for the response confirmation criteria for each histological cohort, to 
update Table 31 to include Marker-Negative CR, Marker-Positive CR, Marker-Negative PR 
and Marker-Positive PR as response categories for NSGCT/NGGCT cohort, to clarify the 
definition for Duration of Response to include all response categories as defined in Table 
31 for NSGCT/NGGCT, WHO Grades 1 and 2Gliomas, MM and HCL cohorts, and to 
make other administrative or formatting revisions that did not affect the conduct of the 
study.
List of Specific Changes
Section Sponsor/Medical Monitor Information 
Page: REVISED TEXT
Role
Name
Day Time
Phone
Number
After-hours
Phone/Cell/
Pager
Number
Fax Number
Novartis Address
NovartisPharmaceuticals
Corporation One Health Plaza East
MD, PhD
Hanover, NJ 07936-1080
USA
NovartisPharmaceuticals




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The safety profile for dabrafenib + trametinib combination therapy has been 
established and is well-characterized in subjects with unresectable/metastatic
melanoma, with consistent results across two randomized Phase III study. The safety 
profile of the combination of dabrafenib and trametinib generally reflect AEs of the 
individual agents; some notable exceptions are described below.
Cutaneous Squamous cell carcinoma (cuSCC):  In vitro experiments have demonstrated a
paradoxical activation of MAPK signalling in kerationcytes and potentially other cells
harboring a wild-type BRAF kinase but a mutated RAS kinase upon exposure to a BRAFi.  
This paradoxical MAPK pathway activation is potentially associated with a higher risk for 
the development of cuSCC induction. Cases of cuSCC (which include those classified as 
keratoacanthoma or mixed keratoacanthoma subtypes) have been reported in subjects 
treated with dabrafenib + trametinib.
Skin examination should be performed prior to initiation of dabrafenib or dabrafenib +
trametinib treatment and while receiving therapy. Dermatologic examinations should be
performed following discontinuation of dabrafenib monotherapy or in combination with
trametinib, or until initiation of another anti-neoplastic therapy (see Section 7.1, Time and 
Events Table for schedule of assessments). Cases of cuSCC should be managed by
dermatological excision; dabrafenib and trametinib treatment should be continued
without any dose adjustment. A brief dermatological exam should be performed every 4 
weeks (±7 days) for the first 6 months after discontinuation of study treatments to
monitor for new cutaneous malignancies.
Pyrexia has been reported in clinical trials with dabrafenib monotherapy and in
combination with trametinib.  In dabrafenib monotherapy studies, pyrexia was one of the
most frequently occurring AEs in up to 27% of subjects across all dabrafenib studies.
Most of the pyrexia events (64%) were considered treatment-related.  The incidence and
severity of pyrexia are increased when dabrafenib is used in combination with trametinib.
In subjects who received the combination dose of dabrafenib 150 mg twice daily (BID) and 
trametinib 2 mg once daily and developed pyrexia, approximately half of the first
occurrences of pyrexia happened within the first months of therapy.  About one-third of
the subjects who experienced pyrexia had 3 or more events. Pyrexia may be accompanied 
by severe chills/rigors, dehydration and hypotension which in some cases can lead to acute 
renal insufficiency.
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°F but trametinib should be continued at the same dose. In the event of 
a fever, the subject should be instructed to take anti-pyretics (i.e., ibuprofen or
acetaminophen/paracetamol) as appropriate to control fever.  The use of oral corticosteroids 
should be considered in those instances in which anti-pyretics are insufficient. Monitor 
serum creatinine and other evidence of renal function during and following severe events of 
pyrexia.  (See Section 8.2.3 for additional details.)


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Decreased left ventricular ejection fraction (LVEF): Left ventricular dysfunction has
been reported with trametinib as well as with other MEKi in clinical development. In the
2 Phase III studies decreased ejection fraction occurred in 7% of subjects receiving 
combination therapy and the majority of the LVEF decreases that met interruption 
criteria were asymptomatic and resolved.  Most subjects who were re-challenged
were able to continue on treatment without further dose modification. Subjects 
enrolled in studies with dabrafenib in combination with trametinib undergo regular 
cardiac assessments with echocardiograms (ECHOs).  Guidelines for clinical
management of treatment-related LVEF decreases have been provided in Section 8.1.1.2.
Hemorrhage: Hemorrhagic events, including major hemorrhagic events defined as
symptomatic bleeding in a critical area or organ, and fatal intracranial hemorrhages, 
have occurred in patients taking dabrafenib in combination with trametinib. The
majority of bleeding events were mild. Three of 209 subjects (1%) receiving 
trametinib in combination with dabrafenib in a phase III trial had fatal intracranial 
hemorrhagic events. The management of hemorrhagic events may require treatment 
interruption, dose reduction, or treatment discontinuation….
Hyperglycemia: Hyperglycemia requiring an increase in the dose of, or initiation of,
insulin or oral therapy can occur with dabrafenib or dabrafenib in combination with
trametinib.  Monitor serum glucose levels as clinically appropriate during treatment with
dabrafenib in subjects with pre-existing diabetes or hyperglycemia. Advise subjects to
report symptoms of severe hyperglycemia such as excessive thirst or any increase in the
volume or frequency of urination.
Pancreatitis:  Subjects receiving dabrafenib or dabrafenib in combination with 
trametinib have reported AEs of acute pancreatitis or pancreatitis. In some cases,
serious adverse events (SAEs) of Grade 4 pancreatitis were reported as treatment-related
by the investigator. The time to onset of pancreatitis ranged from study Day 21 to 292 
(median 138 days) with dabrafenib monotherapy, and from Study Day 24 to 312
(median 50 days) with combination therapy. Discontinuation of study treatment due to
pancreatitis was not deemed necessary in any of the cases by the investigators. For AEs
of abdominal pain or suspected pancreatitis, amylase and lipase laboratory samples
should be monitored locally.  Subjects should be closely monitored when re-starting
dabrafenib after an episode of pancreatitis.
Use during Pregnancy and Lactation
Fertility:  There is no information on the effect of dabrafenib or trametinib on human
fertility.  Animal studies with dabrafenib monotherapy or in combination with trametinib 
have shown reproductive toxicity which may impair fertility in humans. In dogs, rats and 
mice given dabrafenib and in dogs given dabrafenib in combination with trametinib, male
reproductive effects, including testicular degeneration/depletion with secondary epididymal 
oligospermia, have occurred without clear evidence of reversibility. Male subjects should 
be informed of the potential risk for impaired spermatogenesis, which may be irreversible. 
Trametinib may impair fertility in humans.


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Pregnancy:  No adequate and well-controlled studies of dabrafenib or trametinib in
pregnant women have been conducted. Animal studies with trametinib and dabrafenib
have shown embryofetal developmental toxicities, including teratogenic effects.
Dabrafenib or trametinib should not be administered to pregnant women or nursing 
mothers. Women of childbearing potential should use effective methods of contraception
during therapy and for 4 months following discontinuation of trametinib when taken in
combination with dabrafenib, or for 4 weeks following discontinuation of dabrafenib.
Dabrafenib may decrease the efficacy of hormonal contraceptives; therefore, an alternative 
method of contraception such as barrier methods should be used. If dabrafenib or trametinib 
is used during pregnancy, or if the subject becomes pregnant while taking dabrafenib or 
trametinib, the subject should be informed of the potential hazard to the fetus.
Section 1.5.6 Cohort 6: Non-Seminomatous/Non-Germinomatous Germ Cell Tumors 
(NSGCT/NGGCT): 2nd paragraph
REVISED TEXT
Non-seminomatous GCTs (NSGCTs) tend to be more clinically aggressive and grow
quicker than the seminoma-type of GCT.  If untreated, NSGCTs can spread to the lungs,
liver, lymph nodes, or bones. Common risk factors include being male, under the age of 20 
and having Klinefelter syndrome [Nichols, 1987].  Chest pain and difficulty breathing are 
early signs of NSGCT. Other symptoms include: cough, fever, headache, and change in 
bowel habits, fatigue, difficulty walking and visual problems (difficulty seeing or moving 
eyes). Testicular GCTs present with a painless, solid testicular mass and often discomfort 
or swelling; persistent conditions warrant further evaluation.
Section 2.1 Rationale for the Combination of Dabrafenib and Trametinib: 
REVISED TEXT
Pre-clinical studies have demonstrated that the combination of dabrafenib and trametinib is
synergistic and/or enhances cell growth inhibition in majority of the BRAF V600E mutant 
melanoma, colon, thyroid, and lung cancer cells.  The combination delayed dabrafenib 
resistance and reduced hyperproliferation skin adverse effect in pre-clinical models.  The 
scientific rationale suggesting MEK-mediated re-activation of the MAPK pathway as a 
prominent mechanism of resistance to BRAFi single-agent therapy supports the 
combination study of trametinib with BRAFi in cancer [Alcala, 2012; Greger, 2012]. 
Because BRAF V600E mutated tumors have been shown to develop resistance to BRAF
inhibitors, the combination of a BRAFi and MEKi provides a rational approach for dual 
vertical inhibition within the MAPK pathway to address such drug resistance [Johannessen, 
2010]. Both have demonstrated substantial clinical activity with ORR between 28 to 53% 
and PFS ranging between 4.8 to 5.1 months. Further, the combination of both dabrafenib 
and trametinib indicated increased efficacy over both monotherapies with ORR of 63% and 
an increase of PFS to approximately 10 to 11 months for the 150 mg BID dabrafenib and 2 
mg once daily trametinib dose cohort [Flaherty, 2012; Hauschild, 2012; Weber, 2012].
Furthermore, the combination of dabrafenib and rametinib has demonstrated overall 
survival of a median of  more than 25 months in advanced melanoma. This robust 


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survival data for the combination is further supported by other efficacy measures 
such as progression free survival of >11 months, overall response rates of about 64-
69% (13-16% of patients achieving a complete response) with duration of response of 
12.9-13.8 months and a disease control rate of 94% across two randomized Phase-III 
studies ( Long GV ,2015; Robert C et al, 2015).
Section 2.3 Dose Rational: 
REVISED TEXT
Administration of dabrafenib + trametinib in the ongoing study BRF113220 indicates that
dabrafenib does not have a clinically relevant effect on trametinib PK [GlaxoSmithKline
Document Number CM2010/0010/05 ].  Cross-study comparisons indicate that exposure 
to dabrafenib may be greater after repeat-dose administration of dabrafenib in combination 
with trametinib relative to administration of dabrafenib alone at 150 mg BID. The 
combination was relatively well tolerated in study BRF113220 and study MEK115306, 
with toxicities manageable with appropriate intervention.
In this study, dabrafenib will be administered at the dose of 150 mg BID continuously that 
demonstrated significant benefit in PFS in a Phase III trial [Hauschild, 2012].
Trametinib administered at a dose of 2 mg once daily has demonstrated significant benefit 
in PFS (hazard ratio [HR] = 0.45), a confirmed response rate (22% vs. 8%), and OS (HR =
0.54) relative to chemotherapy [Flaherty, 2012]. As determined in Phase III studies, the 
safety profile of the combination of dabrafenib and trametinib generally reflects the 
well established safety profiles of the individual approved agents, with toxicities that 
are manageable with appropriate intervention.
Section 4 Study Design: 4th paragraph
REVISED TEXT
This is a Phase II, open-label, non-randomized, multi-center study of oral dabrafenib in
combination with oral trametinib in subjects with rare cancers with the BRAF V600E 
mutation. The following histologies will be included in this study: ATC, BTC, GIST,
WHO Grade 1 or 2 glioma, WHO Grade 3 or 4 (high-grade) glioma, NSGCT/NGGCT, 
ASI, HCL and MM (Cohorts 1 to 9, respectively). This study is designed to determine the
ORR of dabrafenib in combination with trametinib in subjects with rare BRAF V600E 
mutated cancers.  Further supporting secondary objectives include the evaluation of 
duration of response, PFS, OS, and safety of the combination treatment. For each cohort,
up to 25 evaluable subjects will be enrolled in the primary analysis cohort as defined in 
Section 5.2. If a given cohort is stopped early for efficacy, a histology specific
expansion cohort may be opened to allow for additional patient enrollment (see
Section 5.3). Only subjects with histologically or cytologically confirmed advanced disease 
with no available treatment options as determined by locally or regionally available 
standards of care and by the treating physician’s discretion will be eligible for enrollment. 
Subjects may be enrolled based on local BRAF V600E mutation results and mutation status 
will be confirmed by a central reference laboratory. …


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…Subjects will receive dabrafenib 150 mg BID orally plus trametinib 2 mg once daily
orally on a continuous dosing schedule.  Subjects will undergo disease assessment of 
response after receiving at least 8 weeks of treatment. …
Section 5.2 Primary analysis cohorts 
New Section
5.1.
Primary analysis cohorts
The “primary analysis cohort” will be comprised of those patients enrolled within a 
histology-specific group prior to capping at 25 patients per cohort or prior to early
stopping for efficacy or futility. The primary analysis cohort will form the basis of 
the Bayesian modelling.
Section 5.2 Expansion cohorts 
New Section
5.2.
Expansion cohorts
If a cohort closes early at an interim analysis because it meets the rules for early
stopping for efficacy, an expansion cohort may be opened to allow additional patient 
enrollment for that particular histology. The patients in the expansion cohort will 
provide supportive efficacy data and will NOT contribute to the Bayesian modeling. 
The expansion cohort(s) will enroll subjects for the duration of trial enrollment.
The same general and histology specific eligibility criteria and T&E tables and 
biomarker/histology confirmation analyses will apply to patients in the expansion 
cohort.
Section 5.3 Number of Subjects: 1st paragraph
REVISED TEXT
Section 5.1 became 5.3
Subjects with BRAF V600E positive-mutations will be enrolled in separate cohorts based
on histologic type.  Once 16 weeks of response data is available from a minimum of 5 
subjects in a particular cohort, interim analyses will occur every 12 weeks to assess whether 
enrollment in the particular cohort will be continued or closed. For the primary analysis 
cohort, enrollment will not exceed 25 subjects per histology cohort to ensure adequate 
subjects in the BRAF V600E confirmed population.  After 25 subjects have been enrolled, 
the histology cohort will be closed to further enrollment. See Section 18.2 for sample size 
assumptions.
Section 5.4 Eligibility: 1st paragraph


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REVISED TEXT
Specific information regarding warnings, precautions, contraindications, AEs, and other 
pertinent information on the study treatment(s) that may impact subject eligibility is
provided in the IB for dabrafenib + trametinib combination [GlaxoSmithKline Document 
Number CM2010/00010/05].
Section 5.4.1 Inclusion Criteria: 5th Table 3
REVISED TEXT
SYSTEM
TEST
Histology
LABORATORY VALUES1
Hematologic
ANC3
ATC, BTC, GIST, WHO
Grade 1-4 Glioma,
NSGCT/NGGCT, ASI
1.2 109/L
MM
1 109/L
Hemoglobin3
ATC, BTC, GIST, WHO
Grade 1-4 Glioma,
NSGCT/NGGCT, ASI
9 g/dL
Platelets3
ATC, BTC, GIST,
NSGCT/NGGCT, ASI
75 109/L
MM
50 109/L
WHO Grade 1-4 Glioma
100 109/L
PT, PTT, INR2, 3
ATC, BTC, GIST, WHO
Grade 1-4 Glioma,
NSGCT/NGGCT, ASI, HCL,
MM
1.5 times ULN
Hepatic
Albumin
ATC, BTC, GIST, WHO
Grade 1-4 Glioma,
NSGCT/NGGCT, ASI, HCL,
MM
2.5 g/dL
Total Bilirubin4
ATC
1.5 times ULN
BTC
3 times ULN if stable for
14 days prior to enrollment
GIST, WHO Grade 1-4 Glioma,
NSGCT/NGGCT, MM
2 times ULN
HCL
<3 times ULN
ASI
2 times ULN OR 3 times
ULN if stable for 14 days
prior to enrollment for
ampullary and periampullary
carcinoma
SYSTEM
TEST
Histology
LABORATORY VALUES1
ALT and AST5
ATC, GIST, NSGCT/NGGCT
2 times ULN without liver
metastases 2.5 times ULN
if documented liver
metastases
BTC, ASI, MM
3 times ULN without liver
metastases 5 times ULN if
documented liver
metastases


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HCL
<5 times ULN
WHO Grade 1, 2, 3 or 4 Glioma
3 times ULN
Renal
Creatinine
ATC, BTC, GIST, WHO
Grade 1-4 Glioma,
NSGCT/NGGCT, ASI, HCL,
MM
1.5 mg/dL
OR
Calculated Creatinine
Clearance6 or 24-hr
Urine Creatinine
Clearance
ATC, BTC, GIST, WHO
Grade 1-4 Glioma,
NSGCT/NGGCT, ASI, HCL,
MM
50 mL/min
Cardiac
LVEF
ATC, BTC, GIST, WHO
Grade 1-4 Glioma,
NSGCT/NGGCT, ASI, HCL,
MM
LLN7 by ECHO
Abbreviations: ALT, alanine aminotransferase; ANC, absolute neutrophil count; ASI, adenocarcinoma of small
intestine AST, aspartate aminotransferase; CBC, complete blood count; ECHO, echocardiogram; HCL, hairy cell
leukemia; hr, hour; INR, international normalization n ratio; LLN, lower limit of normal; LVEF, left ventricular
ejection fraction; PT, prothrombin time; PTT, partial thromboplastin time; ULN, upper limit of normal
1.
Laboratory values are obtained within 14 days prior to first dose of study treatment.
2.
PTT and PT/INR >1.5 times ULN will be acceptable in case of subjects receiving therapeutic
anticoagulants such as warfarin as long as INR is monitored during the study according to clinical
practice.
3.
HCL: No minimum CBC criteria if the cytopenias are due to disease under study.
4.
HCL: Subjects will be allowed to enroll with indirect hyperbilirubinemia; however, this condition must
be confirmed due to hemolysis, hypersplenism or direct bilirubin ratio <35%, and requires approval
from the Medical Monitor.
5.
HCL: Subjects will be allowed to enrol with elevated ALT/AST values up to 5 times ULN; however
this condition must be confirmed due to hemolysis and/or hypersplenism and not associated with
hepatic dysfunction and required approval from the Medical Monitor.
6.
Calculated by the Cockcroft-Gault formula (see Appendix 3).
7.
If LLN is not defined for a given institution, then ejection fraction must be ≥50%.
NOTE: Subjects with AST, ALT or total bilirubin values outside the range(s) in Table 3 due to Gilbert's syndrome or
asymptomatic gallstones are not excluded. Laboratory results obtained during Screening should be used to
determine eligibility criteria. In situations where laboratory results are outside the permitted range, the investigator
may opt to retest the subject and the subsequent within-range screening result may be used to confirm eligibility.
Section 5.4.2 Exclusion Criteria: 3rd bulletpoint
REVISED TEXT
Prior radiotherapy less than 14 days prior to enrollment, except for WHO Grade 1-4 glioma 
and ATC. Treatment-related AEs must have resolved prior to enrollment.
For WHO Grades 1, 2, 3, or 4 Glioma ONLY: Radiotherapy is not permitted within 3 
months prior to enrollment (extended period of time of >3 months needed to prevent 
subjects with pseudo-progression from radiotherapy from being enrolled in the study).
Subjects may be 2 weeks from radiotherapy if a new lesion relative to the pre-
radiation MRI develops outside the primary radiation field. Treatment-related AEs must
have resolved prior to enrollment.


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For ATC Only: Radiotherapy is not permitted within 7 days prior to enrollment.
Treatment-related AE(s) must have resolved prior to enrollment.
Section 5.4.2.1.3 WHO Grade 1, 2, 3 or 4 Glioma: Note 
REVISED TEXT
1.
Prior treatment with enzyme-inducing anticonvulsants within 14 days prior to enrollment.
2.
Radiotherapy treatment within 3 months prior to enrollment.
NOTE:  Extended period of time (>3 months) needed to prevent subjects with pseudo-
progression from radiotherapy being enrolled in the study. Subjects may be ≥2 weeks from
radiotherapy if a new lesion relative to the pre-radiation MRI develops outside the 
primary radiation field. Treatment-related AEs must have resolved prior to
enrollment.










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Screening
Treatment5
Follow-up Visit55
Extended
Follow-
up58
Day 1 5,7
Day 15
(1 day)
Every
4 weeks
(3 days)
Every
8 weeks
(3 days)
Every
12 weeks
(3 days)
Every
16 weeks
(3 days)
Treatment or Study
Withdrawal
Every
3 months
(14 days)
except
when
noted
Dispensation of study
treatments
X54
X
Dabrafenib Dosing
Continuous Twice Daily Dosing
Trametinib Dosing
Continuous Once Daily Dosing
ComplianceAssessment
X
X
Abbreviations: AFP, alpha- fetoprotein; ANC, absolute neutrophil count; AP, anteroposterior; ASI, adenocarcinoma of small intestine; -HCG, beta-human chorionic gonadotropin;
BM, bone marrow ; CBC, complete blood count; CR, complete response; CRP, C-reactive protein; CT, computed tomography; ECG, electrocardiogram; ECHO, echocardiogram;
ECOG, Eastern Cooperative Oncology Group;
; FFPE, formalin-fixed,
paraffin- embedded; FISH, fluorescence in situ hybridization; FLC, free light chain; H/E, Hematoxylin and eosin; hr(s), hour(s); ICF, informed consent form; IHC,
immunohistochemistry; INR, international normalization ratio; PD, pharmacodynamic;
; PK, pharmacokinetics; PT, prothrombin time; PTT, partial
thromboplastin time; SPEP, serum protein electrophoresis; TSH, thyroid stimulating hormone; UPEP, urine protein electrophoresis
1.
ICF: Informed consent should be obtained prior to performing any study-related procedure(s).
2.
MEDICAL HISTORY: Medical History will include past and current medical conditions, including cardiovascular medical history and risk factors
3.
DISEASE CHARACTERISTICS: Disease characteristics will include date of initial diagnosis, primary tumor type, histology, stage, etc.
4.
MUTATION TESTING: Subjects may be enrolled based on local determination of BRAF V600E mutation status. A subject may be tested for the BRAF V600E mutation greater
than 28 days prior to enrollment. (Any past results of local BRAF V600E mutation testing may be used to determine eligibility regardless of when the results were obtained.) To
enroll a subject, the result of mutation testing from a sponsor designated central reference laboratory is not required; however, if the subject does not have a local result
available, the sponsor designated central reference laboratory mutation test result will be required to determine eligibility for enrollment. NOTE: For subjects with a solid tumor:
An archived or fresh tumor tissue sample must be available to send to a sponsor designated central reference laboratory for confirmation testing. NOTE: For subjects with HCL
or MM: A  fresh BM aspirate sample and a peripheral blood sample are required for confirmation testing by a sponsor designated central reference laboratory. If a BM aspirate
cannot be obtained due to a dry tap, please contact the Medical Monitor. In the event of a dry tap, fresh or archived tumor tissues such as lymph node or plasmacytoma
biopsies  may be acceptable pending medical monitor approval. An archived tissue sample (such as FFPE tissue sample from a BM biopsy), BM core samples and BM clot
samples cannot be used. The same BM aspirate sample may be used for BRAFmutation testing, the baseline assessment
5.
Dose interruptions should not alter the assessment schedule.




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26. DISEASE ASSESSMENTS (Solid Tumor Cohorts only): Baseline disease assessments must be performed within 28 days prior to enrollment (or within 35 days if MRI is used for
diseaseassessment).
27. DISEASE ASSESSMENTS (Solid Tumor Cohorts only): Disease assessments are every 8 weeks during the first 48 weeks of study treatment, then every 12 weeks thereafter
unless otherwise noted, and at the Follow-up Visit. Confirmatory scan(s) are to be performed ≥28 days after documented CR or PR. If subject discontinues treatment for reasons
other than disease progression, disease assessments should continue every 12 weeks until disease progression, initiation of new anti-cancer treatment, subject withdrawal of
consent, or death.
28. HISTOLOGY CONFIRMATION: (ATC and WHO grade 1-4 cohorts only) A tissue specimen for possible retrospective histology confirmation should be obtained and
submitted to a Novartis designated central reference laboratory. Please refer to the SPM for the requirements of the tissue specimen that is required for the histology
confirmation.
29. NSGCT/NGGCT ONLY: AFP, B-HCG and LDH are the disease assessment markers for the NSGCT/NGGCT cohort. LDH result obtained from clinical chemistry panel can  
be used as a tumor marker result. Regardless of baseline values of AFP, -HCG and LDH, a blood sample will be drawn every 4 weeks for first 48 weeks of study treatment, then
every 8 to 12 weeks thereafter, and at the time of disease progression. Synchronize the collection of the blood sample with the imaging schedule.
30. BTC/ASI ONLY: A blood sample will be drawn to assess CEA and CA 19-9 every 4 weeks for first 48 weeks of study treatment, then every 8 to 12 weeks thereafter, and at the
time of disease progression. Synchronize the collection of the blood sample with the imaging schedule.
31. HCL ONLY: All required disease assessments necessary for a post-baseline response determination should be performed every 4 weeks +/- 3 days. A response is to
be determined every 4 weeks based on the response criteria (please consult Appendix 12) using data collected from the scheduled disease assessments.
32. HCL ONLY: BM biopsy and aspiration with H/E stain and IHC will be performed when blood counts are consistent with CR or PR for 4 weeks (please consult Appendix
12). If a patient has a CR, and then blood counts become consistent with a CR for 4 weeks, a repeat BM aspirate and biopsy is required to assess a response of CR.
Following best response, a bone marrow biopsy and aspirate must be performed every 6 months for two time intervals, then after a year for two time intervals, then
every two years.
33. HCL ONLY: Recommend that flow cytometry panel consists of CD19, CD20, CD22, SmIg, CD11c, CD25, CD103 and CD123. Flow cytometry of the bone marrow aspirate
sample will be performed when blood counts are consistent with CR or PR for 4 weeks (please consult Appendix 12). If a patient has a CR, and then blood counts
become consistent with a CR for 4 weeks, a repeat flow cytometry of the BM aspirate is required to assess a response of CR. Following best response, a flow
cytometry of the bone marrow aspirate must be performed every 6 months for two time intervals, then after a year for two time intervals, then every two years.
34. HCL ONLY: BM biopsy (with H/E stain and IHC), BM aspirate (with flow cytometry) and peripheral blood sample (with flow cytometry) will be assessed within 28 days
prior to enrollment.
35. HCL ONLY: A chest CT scan and an abdominal CT scan with contrast will be performed within 28 days prior to enrollment. If an abdominal CT scan with contrast cannot be
performed, then a MRI may be performed within 35 days prior to enrollment. If lymph nodes or spleen are enlarged at baseline, then the abnormal organ needs to be followed
on post-baseline assessments using the same modality of imaging.
36. MM ONLY: A skeletal survey should be performed within 28 days prior to enrollment. If myeloma associated bony lesions are present at baseline, skeletal surveys should be
performed every 16 weeks or more frequently in order to assess response or upon clinical suspicion of progressive disease. Skeletal surveys typically consist of lateral
radiographs of the skull, AP and lateral views of the spine, and AP views of the humeri, ribs, pelvis, and femurs.
37. MM ONLY: Each patient should be clinically examined for soft tissue plasmacytomas/extramedullary disease at each visit for response assessment. If extramedullary
disease is present at baseline, then Chest/Abdominal/Pelvis CT scan with contrast should be performed to confirm and to determine size and location of the soft tissue
plasmacytoma. If no disease is identified at baseline, then subsequent scans are only required if clinically indicated. Alternative imaging modality (i.e., MRI) may be used if it is
better to assess the lesion and approved by a Medical Monitor. The same imaging modality should be used for all subsequent assessments.
38. MM ONLY: BM aspirate and BM biopsy samples will be assessed by IHC, flow cytometry, FISH and cytogenetics within 90 days prior enrollment.




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55. FOLLOW-UP VISIT: The Follow-up Visit should take place within 28 days (+7 days) of the last dose of study treatments. If the subject is unable to return to clinic due to
hospitalization, site staff is encouraged to call subject for assessment of AEs.
56. FOLLOW-UP VISIT: All safety and laboratory assessments should be performed unless the assessments were performed within 4 weeks prior to the Follow-up Visit.
57. FOLLOW-UP VISIT: If the last cardiac assessment was >12 weeks prior to the Follow-up Visit, an ECHO should be performed.
58. EXTENDED FOLLOW-UP: Subjects should be contacted every 4 weeks (7 days) for the first 6 months and then every 3 months (14 days) until death, withdrawal of consent,
or subject is lost to follow-up. Contact may include a clinic visit, a telephone contact, an e-mail or by mail. The initiation of any new anti-cancer treatment(s) and date of last
contact should also be documented.


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Section 7.3.2 Baseline Documentation of Target and Non-Target Lesions for Solid 
Tumor Histologies
REVISED TEXT
All baseline lesion assessments must be performed within 28 days of enrollment except
where indicated differently in the T&E table (Section 7.1). Guidance on baseline 
documentation of target and non-target lesions will be provided in the SPM.
Section 7.4.2 Dermatological Examinations; 1st paragraph
REVISED TEXT
Dermatological examinations will be performed by an investigator or the subject may be
referred to a dermatologist, at the discretion of the investigator. A complete or full body 
dermatological examination will be performed at the time points indicated in the
Time and Event Table (Section 7.1) to identify any abnormal skin lesions. All
abnormal findings (i.e., suspicious for proliferative skin lesions) will be identified and 
photographed during the Screening examination. Brief dermatological examinations
should be performed every 4weeks or more frequently if clinically indicated while on 
study treatment and every 4 weeks (7 days) for the first 6 months following treatment
discontinuation.  Wherever possible, the same individual should perform all of the 
examinations.  Follow-up skin examinations by a referral dermatologist should be
conducted if clinically indicated.
Section 7.4.3 Ophthalmic Examinations; 1st paragraph
REVISED TEXT
Subjects are required to have a standard ophthalmology exam performed by an
ophthalmologist at the time points indicated in the Time and Event Table (Section 
7.1).  The exam will include best corrected visual acuity, tonometry, slit lamp
biomicroscopic examination, visual field examination, and dilated indirect fundoscopy
with special attention to retinal abnormalities. Optical coherence tomography is strongly
recommended at scheduled visits, and if retinal abnormalities are suspected. Other types
of ancillary testing including color fundus photography and fluorescein angiography are
also recommended if clinically indicated. Refer to Section 8.2.7 for additional details on 
management of visual changes.
Section 7.4.3 Echocardiogram; 1st paragraph
REVISED TEXT
Echocardiograms (ECHOs) will be performed to assess cardiac ejection fraction and
cardiac valve abnormalities. ECHOs will be performed at the time points indicated in
the Time and Event Table (Section 7.1). The evaluation by the echocardiographer
should include an evaluation for LVEF and both right and left-sided valvular lesions.
The procedure (ECHO) to document the subject’s baseline LVEF status must be used


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consistently throughout the study.  If possible, it is also preferred that interpretation of LVEF 
status be performed consistently by the same reviewer throughout the study.
Section 7.4.8 Clinical Laboratory Assessments; Table 3 
REVISED TEXT
Hematology
RBC Count
RBC Indices (at Screening and if hemoglobin decreases
2 g/dL compared to baseline):
Automated WBC
Differential:
Platelets

MCV

MCH

MCHC

Reticulocyte Count

Lymphocytes

Monocytes

Eosinophils

Basophils
WBC Count (absolute)
Hemoglobin
Hematocrit
Absolute neutrophil
count (ANC)
Clinical Chemistry
BUN
Potassium
Total Protein
Total and direct bilirubin1
Creatinine3
Chloride2
Phosphorus
AST
Glucose
Uric Acid2
Magnesium
ALT
Sodium
Calcium
LDH
Alkaline Phosphatase
Albumin
HbA1c
GGT
Coagulation
PT
PTT
INR
Urinalysis4
Color
Specific gravity
Ketones
Urobilinogen
Appearance
Glucose
Blood
pH
Protein5
Leukocyte esterase
Other Tests
Amylase and lipase [monitor via local laboratory when clinically indicated to evaluate certain AEs (i.e.,
abdominal pain, pancreatitis, etc.)
Serum or urine -hCG6
For subjects with a history of chronic HBV and/or HCV, the following tests will be performed at Screening:

Viral hepatitis serology;

Hepatitis B surface antigen and Hepatitis B core antibody (IgM); and/or

Hepatitis C RNA
Abbreviations: ALT, alanine aminotransferase; ANC, absolute neutrophil count; AST, aspartate aminotransferase; -
hCG, Beta-human chorionic gonadotropin; BUN, blood urea nitrogen; GGT, gamma glutamyl transferase; INR,
international normalization ratio; HbA1C, hemoglobin A1C; HBV, hepatitis B virus; HCV, hepatitis C virus; LDH, lactate
dehydrogenase; MCV, mean corpuscular volume; MCH, mean corpuscular hemoglobin; MCHC, mean corpuscular
hemoglobulin concentration; PT, prothrombin time; PTT, partial thromboplastin time; RBC, red blood cells; TSH, thyroid
stimulating hormone; ULN, upper limit of normal; WBC, white blood cells
1.
Direct bilirubin is required only if the total bilirubin is elevated (2 times the ULN)
2.
Chemistry evaluation of chloride or uric acid is not required where there are logistical constraints.
3.
If serum creatinine is >2.0 mg/dL, calculate creatinine clearance using standard Cockcroft-Gault method
(Appendix 3).
4.
If urine protein result is not available, urine albumin result may be used.


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5.
For female subjects of childbearing potential only, unless subject has had a hysterectomy, undergone a tubal
ligation within 1 year prior to Screening or has been post-menopausal for at least 1 year prior to Screening.
Section 7.4.8.1 Additional Histology Specific Assessments and Histology Confirmation; 
Headline
REVISED Header
Additional Histology Specific Assessments and Histology Confirmation
Section 7.4.8.1 Additional Histology Specific Assessments and Histology Confirmation; 
new paragraph (4th)
REVISED TEXT
Histology Confirmation for ATC and WHO Grade 1-4 Glioma Cohorts ONLY:
A tissue specimen from the biopsy of a primary or metastatic site must be
submitted to a GSK designated central reference laboratory as soon as possible
after enrollment for possible retrospective confirmation of histologic type. Refer
to the SPM and the Lab Manual for details regarding sample submission.
Section 7.4.9 Monitoring for Non-Cutaneous Secondary/Recurrent Malignancy; 2nd
paragraph
REVISED TEXT
Abnormal findings should be managed according to standard clinical practice.
Section 7.5.1 Disease Assessments for Solid Tumor Histologies; Tables 
REVISED TEXT
Histology
Area(s) of
Assessment
Imaging to be
Performed
Alternative Imaging Methods if
Contraindications are Present
ATC1
Brain
MRI with
contrast
1st alternative: MRI without contrast
2nd alternative: CT scan with contrast
Neck
CT scan with
contrast
1st alternative: a MRI with contrast 2nd
alternative: CT scan without contrast
(if 1st alternative is contraindicated)
Chest/Abdomen
(including liver and
adrenal glands)
CT scan2


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BTC/ASI
Chest/Abdomen/Pelvis
CT scan with
contrast
CT scan without contrast of the
Chest and MRI with contrast of
Abdomen/Pelvis
Histology
Area(s) of
Assessment
Imaging to be
Performed
Alternative Imaging Methods if
Contraindications are Present
NSGCT/NGGCT
Chest/Abdomen/Pelvis
CT scan with
contrast
CT scan without contrast of the
Chest and MRI with contrast of
Abdomen/Pelvis
GIST
Chest/Abdomen/Pelvis
CT scan with
contrast
CT scan without contrast of the
Chest and MRI with contrast of
Abdomen/Pelvis
ATC1
BTC
GIST
NSGCT/NGGCT
ASI
WHO Grade 1-4
Glioma
Regions with known or
suspected metastatic
lesions
CT scan, MRI,
or bone scan
as appropriate
WHO Grade 1- 4
Glioma
Brain
MRI with
contrast3
N/A
NSGCT/NGGCT4
Brain (for pituitary
GCT)
MRI with
contrast
1st alternative: MRI without contrast
2nd alternative: CT scan with contrast
Abbreviations: ASI, adenocarcinoma of small intestine; ATC, anaplastic thyroid carcinoma; BTC, biliary tract
carcinoma; CNS, central nervous system; CR, complete response; CT, computed tomography; GCT, germ cell tumor;
GIST, gastrointestinal stromal tumor; MRI, magnetic resonance imaging; NGGCT, non-geminomatous germ cell tumor;
NSGCT, non-seminomatous germ cell tumor; PET, positron emission tomography; SPM, Study Procedures Manual;
WHO, World Health Organization
1.
For ATC subjects without CNS and neck disease at baseline, subsequent brain and neck imaging should
only be performed as clinically indicated.
2.
Optional: Whole body PET/CT scan
3.
MRI of the brain with contrast is mandated in this cohort; CT scan is not permitted. Please refer to imaging
details in the SPM.
4.
For NSGCT/NGGCT subjects without CNS disease at baseline, subsequent MRI of the brain with contrast
should only be performed as clinically indicated (e.g., symptoms suggestive of CNS progression). For
subjects with CNS disease at baseline, a MRI of the brain with contrast is required every 4 to 8 weeks or as
clinically indicated. In addition, in order to confirm a CR in a subject with brain disease at baseline, a MRI of
the brain with contrast must be performed 1 week prior to the first set of images showing CR to 4 weeks after
the next protocol specified assessment.
Post-Baseline Assessments: All post-baseline assessments require imaging of disease sites 
identified by baseline scans.  The same imaging modality used at baseline should be utilized 
for all post-baseline assessments. If subject discontinues treatment prior to
Week 48 for reasons other than disease progression, disease assessments (imaging) should 
continue every 12 weeks until a new treatment is initiated.
Histology
Area(s) of
Assessment
Imaging to be
Performed
Alternative Imaging Methods if
Contraindications are Present


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ATC
Chest/Abdomen
(including liver and
adrenal glands)
CT scan1
BTC, ASI
Chest/Abdomen/Pelvis
CT scan with
contrast
CT scan without contrast of the Chest
and MRI with contrast of
Abdomen/Pelvis
WHO Grade 1-4
Glioma
Brain
MRI with
contrast2
N/A
NSGCT/NGGCT,
GIST
Chest/Abdomen/Pelvis
CT scan with
contrast
CT scan without contrast of the Chest
and MRI with contrast of
Abdomen/Pelvis
Abbreviations: ASI, adenocarcinoma of small intestine; ATC, anaplastic thyroid carcinoma; BTC, biliary tract
carcinoma; CT, computed tomography; GIST, gastrointestinal stromal tumor; MRI, magnetic resonance imaging;
NGGCT, non-geminomatous germ cell tumor; NSGCT, non-seminomatous germ cell tumor; SPM, Study Procedures
Manual; WHO, World Health Organization
1.
Optional: Whole body PET/CT scan
2.
MRI with contrast is mandated in this cohort; CT scan is not permitted. Please refer to imaging details in
SPM.
Section 7.5.2.1 Laboratory and Disease Assessments: HCL
REVISED TEXT
Baseline Assessments:  The following baseline disease assessments are will
be performed at the time points indicated in the Time and Event Table (Section 7.1):

Complete blood count

Routine stain of peripheral blood sample

BM aspirate and biopsy sample with H/E stain and IHC

Flow cytometry on BM aspirate sample and peripheral blood sample

Chest CT scan and abdominal CT scan with contrast
NOTE: MRI of the abdomen may be performed if abdominal CT cannot be performed.
The method used to document baseline status is used consistently throughout the study to 
facilitate comparison of results.
If lymph nodes and spleen were enlarged at baseline, they must be followed by post- baseline 
assessments using a consistent imaging modality.
Post-Baseline Assessments: A response is to be determined every 4 weeks based on the 
HCL response criteria (please consult Appendix 12) using data collected from the 
scheduled disease assessments.

Complete blood count


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
Routine stain of peripheral blood sample

BM aspirate and biopsy sample with H/E stain and IHC

Flow cytometry on BM aspirate sample will be performed as indicated in the Time and 
Event Table (Section 7.1).

Flow cytometry on peripheral blood sample will be performed as indicated in the Time 
and Event Table (Section 7.1)

If lymph nodes and/or spleen were enlarged at baseline, they must be followed by post-
baseline assessments using a consistent imaging modality as indicated in the Time and 
Event Table (Section 7.1).
Section 7.5.2.2 Laboratory and Disease Assessments: MM 
REVISED TEXT
Baseline Assessments:  The following baseline disease assessments will be performed at 
the time points indicated in the Time and Event Table (Section 7.1):

Skeletal surveys

Extramedullary disease assessment

NOTE: An alternative imaging modality (i.e., MRI) maybe used to assess extramedullary
disease if the investigator considers the other modality to be better in assessing the lesion 
and if approval is received from a Medical Monitor. The same type of imaging should be 
used for all subsequent assessments.

BM aspirate and biopsy samples: Samples will be assessed by IHC, flow cytometry,
fluorescence in situ hybridization (FISH) and cytogenetics.

UPEP: to be performed using a 24-hr urine collection

SPEP

CRP, -2 microglobulin, serum FLC assay, levels of immunoglobulin (Ig)G, IgA, and 
IgM
Post-baseline Assessments:  All post-baseline assessments require imaging of disease sites 
identified by baseline scans.  The same imaging modality used at baseline should be utilized 
for all post-baseline assessments.

BM aspirate and biopsy samples will be performed and assessed as indicated in the Time 
and Event Table (Section 7.1)

Laboratory tests (SPEP, UPEP, CRP, -2 microglobulin, serum FLC assay, levels of 
IgG,
IgA, and IgM will be performed as indicated in the Time and Event Table (Section 7.1).

Skeletal surveys:  Post-baseline assessments only need to be performed if disease is
noted on the baseline assessment. If no disease is identified at baseline, then subsequent 
skeletal surveys are only required if clinically indicated.


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
Extramedullary disease assessment:  Post-baseline assessments only need to be
performed if disease is noted on the baseline assessment. If no disease is identified at 
baseline, then subsequent assessments are only required if clinically indicated.
Section 8.1 Dose Modification; 2nd and 3rd paragraph
REVISED TEXT
If a dose reduction of trametinib is required, but the toxicity resolves and no additional
toxicities are seen after one treatment cycles (4 weeks), the dose of trametinib may be re-
escalated but should not exceed 2 mg once daily.
If a dose reduction of dabrafenib is required, but the toxicity resolves and no additional 
toxicities are seen after one treatment cycle (4 weeks), the dose of dabrafenib may be re-
escalated but should not exceed 150 mg BID daily.
Section 8.1.1.3.2 Management of Hypertension; Table 14 
REVISED TEXT
Hypertension
Action and Dose Modification
(A). Asymptomatic and
persistent1 SBP of 140 mmHg
and <160 mmHg, or DBP
90 mmHg and <100 mmHg, or
a clinically significant increase in
DBP of 20 mmHg (but still
<100 mmHg).

Continue study treatments at the current dose

Adjust current or initiate new antihypertensive medication(s)

Titrate antihypertensive medication(s) during the next 2
weeks as indicated to achieve well-controlled2 BP

If BP is not well controlled within 2 weeks, consider 
referral to a specialist and go to scenario (B).
(B). Asymptomatic SBP
160 mmHg, or
DBP 100 mmHg, or failure to
achieve well-controlled BP within
2 weeks in scenario (A).

Interrupt study treatments if clinically indicated

Adjust current or initiate new antihypertensive medication(s)

Titrate antihypertensive medication(s) during the next 2
weeks as indicated to achieve well-controlled BP

Once BP is well controlled2, restart study treatments 
reduced by one dose level3
(C). Symptomatic4 hypertension
or persistent SBP 160 mmHg,
or DBP 100 mmHg, despite
antihypertensive medication(s)
and dose reduction of study

Interrupt study treatments

Adjust current or initiate new antihypertensive medication(s)

Titrate antihypertensive medication(s) during the next 2
weeks as indicated to achieve well-controlled BP

Referral to a specialist for further evaluation and follow-up is
Hypertension
Action and Dose Modification


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treatment
recommended

Once BP is well controlled2, restart study treatments 
reduced by one dose level3
(D). Refractory hypertension
unresponsive to above
interventions or hypertensive
crisis

Permanently discontinue study treatments

Continue follow-up per protocol.
Abbreviations: BP, blood pressure; DBP, diastolic blood pressure; mmHg, millimeters of mercury; SBP, systolic blood
pressure
1.
Hypertension detected in 2 separate readings during up to 3 consecutive visits
2.
Well-controlled BP defined as SBP 140 mmHg and DBP 90 mmHg in 2 separate readings during up to
3 consecutive visits
3.
Escalation to previous dose level can be considered if BP remains well-controlled for 4 weeks after
restarting. Approval from the Medical Monitor is required.
4.
Symptomatic hypertension defined as hypertension aggravated by symptoms (e.g. headache,
lightheadedness, vertigo, tinnitus, episodes of fainting) that resolve after the BP is controlled within the
normal range.
Section 8.1.2 Pancreatitis; 1st paragraph
REVISED TEXT
In the event of abdominal pain or suspected pancreatitis, amylase and lipase laboratory
samples should be collected for confirmation of the diagnosis. Subjects should be closely 
monitored when re-starting study treatment after an episode of pancreatitis.
Section 8.2.1.2 Palmar-plantar Erythrodysesthesia
NEW TEXT
Palmar-plantar erythrodysesthesia (PPE) syndrome: Measures for PPE syndrome
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) and symptomatic treatments.
Apply moisturizing creams frequently, topical keratolytics (e.g., urea 20 to 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.
Section 8.2.2.1 Cutaneous squamous cell carcinoma (cuSCC); 1st paragraph
REVISED TEXT




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restart dabrafenib reduced by one dose level. No dose modification of trametinib is 
required when taken in combination with dabrafenib.
Section 10.2 Prohibited Medications and Non-Drug Therapies 
REVISED TEXT
The use of illicit drugs and the following medications within 28 days or 5 half-lives,
whichever is shorter, prior to start of treatment will not be allowed:
Antiretroviral drugs
Herbal remedies (e.g., St. John’s wort)
Drugs that are strong inhibitors or inducers of CYP2C8 or
CYP3A4 (Table 27):
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 (excluding topical formulations) 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)

For MM cohort only: non-steroidal anti-inflammatory drugs (NSAIDS)
NOTE: Use of NSAIDS by subjects with MM is prohibited as it will worsen renal 
insufficiency.

Drugs that are strong inhibitors or inducers of CYP2C8 or CYP3A4 (Table 27):
NOTE:  Dabrafenib is metabolized primarily by CYP2C8 and CYP3A4.  Co- administration 
of dabrafenib with ketoconazole, a CYP3A4 inhibitor, or gemfibrozil, a CYP2C8 inhibitor, 
increased the area under the concentration-time curve (AUC) of dabrafenib by 71% and 47%, 
respectively.  Drugs that are strong inhibitors or inducers of CYP2C8 or CYP3A4 are likely
to increase or decrease, respectively, dabrafenib concentrations.  Strong inhibitors or 
inducers should only be used under special circumstances (e.g., as a single use for a 
procedure) while study treatment is interrupted as they may alter dabrafenib concentrations; 
consider therapeutic substitutions for these medications.  Approval from the Medical Monitor 
is required in these situations.
Section 10.3 Medications to be used with Caution; 2nd bullet point
REVISED TEXT


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•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 may affect other enzymes such as CYP2C8, CYP2C19, UDP- glucuronyl 
transferases, and transporters.  Co-administration of dabrafenib and medicinal products which 
are affected by the induction of these enzymes such as hormonal contraceptives, warfarin, 
dexamethasone, antiretroviral agents, or immunosuppressants may result in decreased 
concentrations and loss of effectiveness.  Where possible consider substitutions of these 
medicinal products if therapeutic effects cannot be monitored.
Section 11.2 Definition of Serious Adverse Event; point h. Protocol-specific SAEs: first 
bullet point
REVISED TEXT
h. Protocol- specific SAEs:
• cuSCC (Section 8.2.2.1), new primary melanomas (Section 8.2.2.2) and non-
cutaneous malignancies (Section 8.2.2.3) with the exception of basal cell carcinoma
(BCC). BCC should be reported as an AE or SAE based on the discretion of the 
investigator.
Section 18.1 Hypotheses and Treatment Comparisons; 3rd paragraph 
REVISED TEXT
j is the true response rate for histology j, where j = 1,…, 9 and indexes the nine histologies.
Cj is the historical control response rate for the jth histology.  The historical controls vary
by histology and are provided in Table 29. The study is powered to detect a high 
clinically meaningful response rate and is based on the hierarchical model assessment 
of whether there is sufficiently high probability that j exceeds Cj. The posterior 
probability that the ORR for a given histology is greater than Cj will be computed 
according to the following comparison:
Section 18.2.1 Sample Size Assumption
REVISED TEXT
Each cohort of BRAF V600E mutation-positive tumor type of a given histology will
enroll a maximum of 25 subjects in the primary analysis cohort as defined in Section
5.1. If all histologies enroll the maximum of 25 subjects, this will result in no more than
225 subjects in the primary analysis cohort.
Enrollment into specific histology cohorts may be halted early based on results from interim 
analyses incorporating emerging response data.  Response data from a minimum of 5 subjects 
will be required in a histologic cohort before it may discontinue enrollment for futility and 


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response data from a minimum of 10 subjects will be required before discontinuing a 
histologic cohort for efficacy. If a cohort closes early for efficacy at an interim analysis, a 
histology specific expansion cohort (see Section 5.2) may be opened to allow additional 
enrollment. At the final analysis and after the study has been closed, a minimum of 2 
subjects will be required in a histologic cohort in order to meet statistical success at the final 
analysis. See Section 18.3.2 for more details.
Section 18.3.1 Analysis Population 
REVISED TEXT
As the design for the study calls for repeated interim analyses to evaluate the 
accumulating efficacy data, it is necessary to shift the focus of the analysis
population for efficacy depending upon the time at which the data are being 
analyzed. Table 30 presents the population of interest based on the timing of the
analysis for both efficacy and safety; accompanying definitions are provided 
beneath the table.
Table 30
Definition of Population for specific analysis
Analysis Period
Analysis Intent
Interim Analyses
Final Analysis
Efficacy
Primary
ITT/Evaluable
BRAF V600E
Supportive
BRAF
V600/Evaluable
ITT Histology-
specific cohortsa
Safety
Primary
ATS
ATS
a Subset of the BRAF V600E population that include histologically similar subjects 
for cohorts that were stopped for promising efficacy; includes those from the 
primary analysis cohort and those from the expansion cohort, as defined in Section 
5.1and Section 5.2.
The BRAF V600E Population is defined as all enrolled subjects regardless of whether or 
not treatment was administered, who obtain positive verification of the BRAF V600E 
mutation from a certified central reference laboratory.
The Intent-to-Treat (ITT) population is defined as all enrolled subjects regardless of
whether or not treatment was administered. 
The All-Treated Subjects (ATS) population is defined as all subjects who receive at least
one dose of dabrafenib (GSK2118436) or trametinib (GSK1120212).


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The Intent-to-Treat (ITT)/Evaluable population is defined as all ITT subjects in the
primary analysis cohort who are also evaluable according to the evaluability defined in 
the interim analysis RAP.
The BRAF V600E /Evaluable Population is defined as all BRAF V600E subjects in 
the primary analysis cohort who are also evaluable according to the evaluability
defined in the interim analysis RAP.
Section 18.3.3 Final Analysis REVISED 
TEXT
The final primary analysis for ORR will occur once all subjects in the primary analysis 
cohorts have either discontinue treatment or have received treatment for at least 6 months, 
whichever comes first. Secondary efficacy endpoints will likely not be mature at this time, 
but will still be reported. Subsequent analyses for secondary endpoints will occur as follows:

Duration of response, PFS and OS when 70% of subjects have reached a PFS event 
(progressed or died)

OS when 70% of subjects have died

Safety will be updated once the last subject has discontinued and been off all study
treatment for 30 days.
These latter analyses will provide mature estimates/incidence for duration of response, PFS, 
OS, and safety.
Section 18.3.3.1 Safety Analysis 
REVISED TEXT
Safety data will be presented in tabular and/or graphical format and summarized descriptively 
according to GSK’s IDSL standards.
The ATS population will be used for the analysis of safety data. In general, safety data will be 
summarized by histology and across all cohorts.
Complete details of the safety analyses will be provided in the RAP.
Section 18.3.3.1.3 Other Safety Measures 
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The results of scheduled assessments of vital signs, 12-lead ECG, ECHO and ECOG 
performance status will be summarized. Summaries will include data from scheduled 
assessments only.  All data will be reported according to the nominal visit date for which it 
was recorded; no visit windows will be applied.  All data will be listed.
Section 18.3.3.2 Efficacy Analysis 
REVISED TEXT
ORR will be analyzed using an integrated analysis with the hierarchical model as well as 
analyzed independently for each histology.
Section 18.3.3.2 Efficacy Analysis; Table 31 Response Subcategories Define as 
‘Response’ by Histology
REVISED TEXT
Histology
Response Criteria
ResponseSubcategories
defined as ‘Response’
ATC, BTC, GIST, Small
IntestineAdenocarcinoma
RECIST 1.1
CR, PR
NSGCT/NGGCT
RECIST 1.1.
Tumor Markers: -HCG and AFP
Marker-NegativeCR,
Marker-PositiveCR,
Marker-NegativePR,
Marker-PositivePR
MM
IMWG Uniform Response Criteria for MM
sCR, CR, PR, VGPR
HCL
Adapted from NCCN guidelines, Consensus
Resolution Criteria and previous studies definition
CR±MRD, PR
WHO Grade 1 and 2 Gliomas
Response Assessment Criteria for WHO Grade 1 or
2 Gliomas: RANO Working Group
CR, PR, MR
WHO Grade 3 and 4 Gliomas
Updated Response Assessment Criteria for WHO
Grade 3 or 4 Gliomas: RANO Working Group
CR, PR
Abbreviations: AFP, alpha-fetoprotein; ATC, anaplastic thyroid cancer; -hCG, beta-human chorionic
gonadotropin; BTC, biliary tract cancer; CR, complete response; GIST, gastrointestinal stromal tumor; HCL,
hairy cell leukemia; IMWG, International Myeloma Working Group; MM, multiple myeloma; MR, minor
response; NCCN, National Comprehensive Cancer Network; NGGCT, non-geminomatous germ cell tumor;
NSGCT, non-seminomatous germ cell tumor; PR, partial response; RANO, Response Assessment for Neuro-
Oncology; RECIST, Response Evaluation Criteria in Solid Tumors; sCR, stringent complete response; VGPR,
very good partial response; WHO, World Health Organization
Further details on response confirmation criteria for each histological cohort will be 
provided in the RAP.
Bayesian inference based on summary statistics from the posterior distributions of each ORR 
will be reported. The posterior mean and posterior 2.5% and 97.5% percentiles of the ORR 
will be calculated for each histology. In addition, the posterior probability that the ORR 
exceeds its corresponding historical control will be reported for each histology.


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Duration of response is defined for the subset of subjects who have a confirmed response (as 
defined in Table 31), as the time from first documented evidence of response until the first 
documented sign of disease progression or death. Duration of response will be summarized 
descriptively for each histology, if data warrant, using Kaplan-Meier medians and quartiles.  
Details on rules for censoring will be provided in the RAP.
Section 18.4.1 Simulation Description
REVISED TEXT
Extensive simulations have been conducted to develop and understand the performance of 
the adaptive design; the hierarchical model including clustering mechanism, interim
monitoring, and decision criteria. Subject enrollments into the expansion cohorts as
defined in Section 5.2 are not taken into consideration in the simulations presented 
in this section.
Section 20 References
REVISED TEXT
GlaxoSmithKline Document Number CM2010/00010/05. Dabrafenib Investigator’s 
Brochure. Version 07. Report dated 09-Oct-2015.
Long GV et al. Dabrafenib and trametinib versus dabrafenib and placebo for Val600
BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised
controlled trial. Lancet. 2015; 386(9992): 444-51
Robert C et al. Improved overall survival in melanoma with combined dabrafenib 
and trametinib. N Engl J Med. 2015; 372(1): 30 – 9
AMENDMENT 07
This amendment applies to all study sites. Bolded text indicates revised text and strike 
through indicates deleted text.
Amendment Summary of Main Changes:
Section(s)
Change
Rationale
Sponsor signatory
Change of sponsor signatory Change in study sponsor from GSK to Novartis
Multiple
Delete or replace references 
to GlaxoSmithKline or its 
To align with the change of sponsorship from 
GSK to Novartis.


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Section(s)
Change
Rationale
staff with that of Novartis and 
its authorized agents
Multiples
Change “medical monitor” to 
“Medical Lead”
To align with Novartis processes
Multiple
Make administrative changes To align with the change of sponsorship from 
GSK to Novartis.
Amendment Details:
Section: Title Page: 
Text changed:
The title page replaced as per Novartis requirements. 
Reason for change:
Change in study sponsorship and to bring into line with Novartis processes.
Section: Sponsor Information Page
Text changed:
The GSK contact information has been replaced with Novartis details.
The term medical monitor has been replaced by Medical Lead and the email for Medical Lead 
provided.
Reason for change:
Change in study sponsorship and to bring into line with Novartis processes.
LIST OF ABBREVIATIONS
Text changed:
CRO Clinical Research Organization
GCPHGlobal Clinical Program Head
HA
Health Authority
Reason for change: 
Change in study sponsorship and to bring into line with Novartis processes.
Section: 7.4.10.2.
Pregnancy Reporting


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Text changed:
To ensure subject safety, each pregnancy must be reported to the sponsor within 24 hours of 
learning of its occurrence.
Reason for change: 
Change in study sponsorship and to bring into line with Novartis processes.
Section: 7.4.10.4.
Action to be taken if pregnancy occurs in a female partner of 
a male study subject
Text changed:
The investigator will record pregnancy information on the appropriate form and submit it to 
the sponsor within 24 hours of learning of the partner’s pregnancy.
Reason for change: 
Change in study sponsorship and to bring into line with Novartis processes.
Section: 
11.7.
Time Period and Frequency of Detecting AEs and SAEs
Text changed:
Reason for change: 
Change in study sponsorship and to bring into line with Novartis processes.
Section: 11.13.
Regulatory Reporting Requirements for SAEs
Text changed:
An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from the sponsor will file it 
with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
Reason for change: 
Change in study sponsorship and to bring into line with Novartis processes.
Section: 17.
DATA MANAGEMENT
Text changed:
Adverse events (AEs) and concomitant medications terms will be coded using Medical 
Dictionary for Regulatory Activities (MedDRA) and a custom drug dictionary .


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Reason for change: 
Change in study sponsorship and to bring into line with Novartis processes.
Section: 19.4. Quality Control (Study Monitoring)
Text changed:
In accordance with applicable regulations, 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 the sponsor’s requirements.
Reason for change:
Change in study sponsorship and to bring into line with Novartis processes.
Section: 19.6. Study and Site Closure
Text changed:
Upon completion or termination of the study, Novartis personnel (or designated CRO)
will conduct site closure activities with the investigator or site staff (as appropriate), in 
accordance with applicable regulations, ICH GCP, and Novartis Standard Operating 
Procedures.
Reason for change:
Change in study sponsorship and to bring into line with Novartis processes.
Section: 19.7. Records Retention
Text changed:
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.
Reason for change:
Change in study sponsorship and to bring into line with Novartis processes.
Section: 
19.8.
Provision of Study Results to Investigators, Posting of 
Information on Publicly Available Clinical Trials Registers and Publication
Text changed:


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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 .

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)


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Table of contents
Table of contents .................................................................................................................3
List of abbreviations............................................................................................................5
1
Introduction .........................................................................................................................6
1.1
Study design.............................................................................................................6
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 ..........................................................................................................10
2.2.1
Subgroup of interest ..............................................................................11
2.3
Patient disposition, demographics and other baseline characteristics ...................11
2.3.1
Patient disposition.................................................................................11
2.3.2
Demographics and baseline data...........................................................11
2.3.3
Study treatment / compliance................................................................11
2.3.4
Prior, concomitant and post therapies...................................................12
2.3.5
Protocol Deviations...............................................................................13
2.4
Analysis of the primary objective..........................................................................13
2.4.1
Primary endpoint...................................................................................13
2.4.2
Statistical hypothesis, model, and method of analysis..........................18
2.4.3
Handling of missing values/censoring/discontinuations.......................19
2.4.4
Supportive analyses...............................................................................19
2.5
Analysis of the key secondary objective ...............................................................19
2.6
Analysis of secondary efficacy objective(s)..........................................................19
2.6.1
Duration of response .............................................................................19
2.6.2
Progression-free survival ......................................................................21
2.6.3
Overall survival.....................................................................................22
2.7
Safety analyses.......................................................................................................22
2.7.1
Adverse events (AEs)............................................................................22
2.7.2
Deaths....................................................................................................24
2.7.3
Laboratory data .....................................................................................24
2.7.4
Other safety data ...................................................................................25
2.8
Pharmacokinetic endpoints....................................................................................25
26
2.10
Biomarkers.............................................................................................................26
2.11
Other Exploratory analyses....................................................................................26
2.12
Interim analysis......................................................................................................27


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3
Change to protocol specified analyses ..............................................................................27
4
Appendix ...........................................................................................................................27
4.1
Clinical review of anti-cancer therapies for censoring criteria..............................27
4.2
Extended Loss to Follow-up or Extended Time without an Adequate 
Assessment ............................................................................................................27
4.3
Date Associated with Response.............................................................................28
4.4
Imputation rules.....................................................................................................28
4.4.1
Demography (ADSL)............................................................................28
4.4.2
Initial diagnosis of primary tumor type under study.............................29
4.4.3
Adverse events (ADAE) .......................................................................29
4.4.4
Surgery and radiotherapy......................................................................30
4.4.5
Concomitant medication and blood and blood supportive care 
products.................................................................................................30
4.4.6
Time to event (Duration of response and Progression-free survival) 
and best confirmed overall response.....................................................31
4.4.7
Imputation of missing exposure end dates............................................32
4.5
Multiple Assessments............................................................................................33
4.6
Laboratory parameters derivations ........................................................................33
4.7
ECG parameters.....................................................................................................33
4.8
Cardiac Scan Modalities (ECHO) .........................................................................34
4.9
Left ventricular ejection fraction ...........................................................................34
4.10
Vital signs..............................................................................................................34
4.11
Statistical models...................................................................................................35
5
Reference...........................................................................................................................35


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List of abbreviations
AE
ASI
ATC
BTC
Adverse Event
Adenocarcinoma of the small intestine
Anaplastic Thyroid Cancer
Biliary Tract Cancer
CRF
CSR
DMS
ECG
eCRF
eCRS
GIST
HCL
Case Report Form
Clinical Study Report
Document Management System
Electrocardiogram
electronic Case Report Form
electronic Case Retrieval Sheet
Gastrointestinal stromal tumor
Hairy Cell Leukemia
HGG
High Grade Glioma
IA
Interim Analyses
LGG
Low Grade Glioma
MedDRA
MM
MRD
NGGCT
NSGCT
Medical Dictionary for Regulatory Activities
Multiple Myeloma
Minimal Residual Disease
Non-geminomatous germ cell tumor
Non-seminomatous germ cell tumor
PK
Pharmacokinetics
PRO
Patient-reported Outcomes
RAP
Reporting & Analysis Process
SAP
SAS
Statistical Analysis Plan
Statistical Analysis System
TFLs
Tables, Figures, Listings
WHO
World Health Organization


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1
Introduction
This statistical analysis plan (SAP) details all planned analyses to support the final clinical study 
report (CSR) and publication of final study results from BRF117019/CDRB436X2201.  This is 
a phase II study to evaluate the clinical efficacy and safety of the combination therapy of 
dabrafenib (DRB436) and trametinib (TMT212) using a single-arm multi-histology study 
design in several rare cancer types. 
In this SAP, references will be made to the following documents: 
•
Protocol amendment 11 dated 04 Jun 2020
•
Annotated electronic Case Report Form (eCRF) BRF117019/CDRB436X2201 SV16.0
•
Charter for the Independent Data Monitoring Committee (IDMC) version 2.0 dated 23 
Jun 2016
1.1
Study design
This is a Phase II, open-label, non-randomized, multi-center study of oral dabrafenib in 
combination with oral trametinib in subjects with rare cancers with the BRAF V600E mutation.  
The following histologies will be included in this study: ATC, BTC, GIST, WHO Grade 1 or 2 
glioma, WHO Grade 3 or 4 glioma, NSGCT/NGGCT, ASI, HCL and MM (Cohorts 1 to 9, 
respectively). 
For each cohort, up to 25 evaluable subjects will be enrolled in the primary analysis cohort. If 
a given cohort is stopped early for efficacy, a histology specific expansion cohort may be 
opened to allow for additional patient enrollment.  
The primary analysis cohort is comprised of those patients enrolled within a histology-specific 
group prior to capping at 25 patients per cohort or prior to early stopping for efficacy or futility. 
The primary analysis cohort will form the basis of the Bayesian modelling of ORR. 
If a cohort closes early at an interim analysis because it meets the rules for early stopping for 
efficacy, an expansion cohort may be opened to allow additional patient enrollment for that 
particular histology. The patients in the expansion cohort will provide supportive efficacy data 
and will NOT contribute to the Bayesian modeling of ORR. The expansion cohort(s) will enroll 
subjects for the duration of trial enrollment. 
Only subjects with histologically or cytologically confirmed advanced disease with no available 
treatment options as determined by locally or regionally available standards of care and by the 
treating physician’s discretion will be eligible for enrollment.  Subjects may be enrolled based 
on local testing of the BRAF V600E mutation and mutation status will be confirmed by a central 
reference laboratory.  
Subjects will receive dabrafenib 150 mg BID orally plus trametinib 2 mg once daily orally on 
a continuous dosing schedule.  An adaptive design with multiple interim evaluations will 
determine if one or more histologic cohorts should discontinue enrolment early due to either 
success or futility.  Evaluations are based on a hierarchical statistical model that borrows 
information in a limited way from histologies that demonstrate similar response rates based on 
the accumulated trial data.  A complete description of the study design and rationale is included 
in the Protocol.




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Data from all participating centers will be pooled prior to analysis. Subject accrual is spread 
thinly across centers and summaries of data by center would be unlikely to be informative and 
therefore will not be provided.
All data up to death or study withdrawal will be included in each analysis.  Unscheduled visits 
will not be included in summaries, except to derive minimum/maximum post-baseline or on-
treatment values. Unscheduled visits will be presented in subject listings.
Planned times relative to study drug dosing will be used in all tables and summary figures.
Unless otherwise stated, continuous variables will be summarized with n, mean, median, 
standard deviation, minimum and maximum, and categorical variables will be summarized with 
frequency counts and percentages. 
2.1.1
General definitions
Study treatment
Study treatment in this study refers to either dabrafenib or trametinib.
Reference dates
There are two reference dates:

The date of screening is the reference date for determination of age, since age is an 
eligibility requirement. 

The study treatment start date is the reference date for efficacy and safety.
Study day
If the date of interest occurs on or after the reference date then the study day will be calculated 
as (date of interest - reference date) + 1. If the date of interest occurs before the reference date
then the study day will be calculated as (date of interest – reference date). There is no study day 
0.
Duration and elapsed time
Durations (e.g., the duration of an adverse event, duration of exposure, etc.) are calculated as
the stop date minus the start date plus one.
For elapsed time (e.g., the time since initial diagnosis):

If the event date is on or after the reference date, then the elapsed time is the event date 
minus the reference date + 1

If the event date is before the reference date then the elapsed time is the event date minus 
the reference date
When reporting time to event (TTE) durations such as PFS in months, divide the number of 
days by 30.4375; to report in weeks divide the number of days by 7; to report in years divide 
the number of days by 365.25.


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Baseline
Baseline will be defined as the most recent, non-missing value prior to or on the first study 
treatment dose date. For laboratory data, baseline will be defined as the most recent, non-
missing value from a central laboratory prior to or on the first study treatment dose date. If there 
are no central labs collected for a subject and lab test prior to or on the first dose of study 
treatment, the most recent, non-missing value from a local laboratory prior to or on the first 
dose of study treatment will be defined as the baseline value.
Change from baseline
Change from baseline will be presented for safety data.  Change from baseline is calculated as:
For records occurring after baseline: (visit value) - baseline value.
Percent change from baseline is calculated as:
For records occurring after baseline: ((change from baseline) / Baseline value) *100.
If either the baseline or visit value is missing, the change from baseline and/or percent change 
from baseline is set to missing as well.
Time in relation to treatment
Adverse events, serious adverse events, death, laboratory data, vitals, ECG and ECHO, will be 
assigned to the study time periods defined below. Partial dates will be imputed into full dates, 
if applicable, for slotting data to the appropriate categories below (see Section 4.4). Flag 
variables (time in relation to study treatment) indicating the study time periods will be added to 
these datasets.
Pre-therapy is defined as the time prior to the subject’s first dose of study treatment. 
On-therapy is defined as the time from first dose of study treatment until 30 days after the last 
dose date of study treatment. 
Post-therapy is defined as any time beyond the on-therapy period.
Some datasets include the first dose day as On-therapy and some exclude the first dose date as 
On-Therapy. The first dose day (Day 1) is considered pre-therapy for ECOG, ECG, vital signs, 
liver events, lab tests, and cardiac scan. The first dose day (Day 1) is considered to be On-
therapy for adverse events and concomitant medications.
Study time period for concomitant medications and blood and blood 
supportive care products
Concomitant Medication and Blood and Blood Supportive Care Product start and end dates will 
be assigned to study time periods in relation to first dose of study treatment as defined below. 
The start date reference time flag variables and end date reference time flag variables will be 
added to the concomitant medications and blood and blood supportive products datasets, 
respectively.
Start relative to treatment: Assign to 'BEFORE' if start date is prior to study treatment start 
date or if subject has not taken any study treatment or (start date is missing and end date is 
before study treatment start date). Else assign to 'DURING' if the start date falls on or between 
the first and last dose dates of study treatment or if subject is ongoing (not all study treatment 


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discontinuation records completed) or start date is missing. Else assign to 'AFTER' if start date 
is after the on-therapy period.
End relative to treatment: Assign to 'BEFORE' if end date is prior to study treatment start 
date or if subject has not taken any study treatment. Else assign to 'DURING' if end date falls 
on or between the first and last dose dates of study treatmentor if subject is ongoing (not all 
study treatment discontinuation records completed) or (end date is missing and start relative to 
treatment not 'AFTER'). Else assign to 'AFTER' if start date is after the on-therapy period or 
(end date is missing and start relative to treatment='AFTER').
Only on-therapy blood and blood supportive care products that start after the start of study 
treatment are included in the Blood Products and Blood Supportive Care Product summaries. 
Therefore, for summary tables, include blood and blood supportive care product records where 
start relative to treatment in ('DURING') and end relative to treatment in ('DURING','AFTER'). 
All data will be reported in listings. 
Concomitant medication start relative to treatment and end relative to treatment flags are used 
to select data to include in the Concomitant Medication summaries as follows:

Summary of Concomitant Medications: This summary will contain medications including 
those with start date prior to study treatment start date and continue (missing end date or 
end date after study treatment start date) on therapy. Note that any medications with start 
date and end date prior to study treatment start date will be excluded. In addition, any 
medication that was started during post-therapy will be excluded. Include concomitant 
medication records where start relative to treatment in ('BEFORE','DURING') and end 
relative to treatment in ('DURING','AFTER').

Summary of Concomitant Medications with On-Therapy Onset: This summary will 
contain medications with start date after study treatment start date. In addition, any 
medication that was started during post-therapy (see above for definition of post-therapy) 
will be excluded. Include concomitant medication records where start relative to treatment 
in ('DURING') and end relative to treatment in ('DURING','AFTER').
Other derivations or data handling procedures related to this analysis plan are given in section 
4.
2.2
Analysis sets
As specified in the protocol, for the final analysis the Intent-to-Treat population will be used 
for primary analysis of efficacy endpoints. The BRAF V600E population will be used for 
supportive analysis of efficacy.  The All Treated Subjects population will be used for Safety 
analysis. These analysis populations are defined below:
The Intent-to-Treat (ITT) population is defined as all enrolled subjects regardless of whether or 
not treatment was administered.
The BRAF V600E population is defined as all enrolled subjects regardless of whether or not 
treatment was administered, who obtain positive verification of the BRAF V600E mutation 
from a certified central reference laboratory.
The All Treated Subjects population is defined as all subjects who receive at least one dose of 
dabrafenib or trametinib.


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A summary of the number of subjects in each of the analysis populations will be provided. A 
listing of subjects included in each analysis population will also be provided.
2.2.1
Subgroup of interest
Efficacy data (investigator and independent reviewer-assessed ORR, DoR, PFS and OS) will 
be presented for the following subgroups within the WHO Grade 3 or 4 Glioma cohort:

By grade (3 or 4)

By age group (18-39 or 40+)
2.3
Patient disposition, demographics and other baseline 
characteristics
2.3.1
Patient disposition
A summary of subject status and reason for study withdrawal will be provided for the ITT 
population. This display will show the number and percentage of subjects who withdrew from 
the study, including primary reason for study withdrawal. Reasons for study withdrawal will be 
presented in the order they are displayed in the eCRF. A listing of the subject disposition/end 
of study record for all subjects who discontinued the study prematurely will be produced.
2.3.2
Demographics and baseline data
The demographic characteristics including age, sex, race, ethnicity, child-bearing potential, 
baseline height and weight will be summarized and listed for each histologic cohort.  The 
count (n), mean, standard deviation, median, minimum value, and maximum value will be 
computed for age, height, and weight. The count and percentage will be computed for sex, 
race, ethnicity, child-bearing potential, and age categories (<18, 18-64, 65-74, and 75-84, 
and >=85 years).
Disease history and characteristics at initial diagnosis and screening will be listed. Separate 
summaries of disease characteristics at initial diagnosis and screening will be provided for each 
histologic cohort.
Medical conditions will be graded according to the CTCAE, Version 4.0 and coded to preferred 
term using the MedDRA dictionary.  Medical conditions present at screening will be 
summarized and listed.
2.3.3
Study treatment / compliance
A summary of study treatment status will be provided for the ATS population. This display will 
show the number and percentage of subjects who are ongoing or discontinued study and the 
primary reason(s) for discontinuation of study treatment. Reasons for study treatment 
discontinuation will be presented in the order they are displayed in the eCRF. Separate tables 
will be produced for dabrafenib and trametinib.  Separate listings for study treatment 
discontinuation will also be generated for dabrafenib and trametinib.
Summary of exposure to study treatment will be provided. The summary will include subject 
daily dose, population level daily dose, cumulative dose, duration on treatment for dabrafenib, 
duration on treatment for trametinib, and duration on combination treatment. The subject 
average daily dose is defined as the subject’s cumulative dose divided by the duration on study 


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treatment.  For the analysis of population level daily dose, a dose on each day for each subject 
will be treated as an observation and the summary will be based on the dose on each individual 
day for all subjects.  Duration on treatment for dabrafenib or trametinib is defined as months 
from the first dose to the last non-zero dose, regardless of dose interruption before the last non-
zero dose. In addition to mean, median, min and max, duration on dabrafenib, duration on 
trametinib and duration on combination treatment will also be summarized in the following 
categories: <3 months, 3-6 months, >6-9 months, >9-12 months, >12-24 months, >24-36 
months, and >36 months.
Dose reductions will be summarised by number of reductions and reasons for reductions for 
dabrafenib and trametinib separately. 
Dose interruptions will be summarised by number of interruptions and reasons for the 
interruptions for dabrafenib and trametinib separately.
A summary of overall compliance based on the exposure data will be produced separately for 
dabrafenib and trametinib for the ATS population. Percentage overall compliance will be 
summarized using the mean, standard deviation, minimum, median, and maximum. In addition, 
percentage overall compliance will be categorized and summarized by <80%, 80%-105%, 
and >105%. 
The calculation of overall compliance is based on the entire interval of dosing for dabrafenib 
and trametinib. The formula for daily dose medication is compliance (%) = [total cumulative 
actual dose / (duration of study treatment x prescribed dose)] x 100 where duration of study 
treatment is last dose-first dose +1. For dabrafenib, the prescribed dose is 300mg per day, and 
for trametinib, the prescribed daily dose is 2mg per day.
Listings of overall compliance will be produced separately for dabrafenib and trametinib.
2.3.4
Prior, concomitant and post therapies
Concomitant medications will be coded using WHO Drug coding dictionary, summarized, and 
listed. The summary of concomitant medications will show the number and percentage of 
subjects taking concomitant medications by Ingredient. Multi-ingredient products will be 
summarized by their separate ingredients rather than as a combination of ingredients. 
Anatomical Therapeutic Chemical (ATC) classification Level 1 (Body System) information 
will be included in the data listing only. In order to be considered a concomitant medication, 
the concomitant medication must have been taken at some point during the on-therapy window.
Prior anti-cancer therapy will be coded using WHO Drug coding dictionary, then summarized
by type of therapy and listed.  Separate tables will be produced displaying prior medications by 
ingredient (counting multiple ingredients taken as part of a combined treatment on separate 
rows) and displaying combination regimens as single rows e.g. cisplatin + gemcitabine. 
Combined regimens will be defined based on common start dates of each ingredient, which are 
entered separately on the eCRF. A summary of the number of prior anti-cancer therapy 
regimens will also be produced.
Prior anti-cancer radiotherapy and prior cancer and non-cancer surgical procedures will be listed.
The number and percentage of subjects that received chemotherapy, immunotherapy, hormonal 
therapy, biologic therapy, radioactive therapy, small molecule targeted therapy, radiotherapy 
and cancer-specific surgery as post study treatment anti-cancer therapy will be summarized.  


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Summary statistics for the time from study treatment discontinuation to the first post study 
treatment anti-cancer therapy (in weeks) will also be included in this summary table.
Follow-up anti-cancer therapy will be coded using WHO Drug coding dictionary, then 
summarized by ingredient. A listing of the type of follow-up anti-cancer therapy received 
(chemotherapy, immunotherapy, hormonal therapy, biologic therapy, radioactive therapy, small 
molecule targeted therapy) and details of the anti-cancer therapy for each subject will be 
provided. 
Anti-cancer radiotherapy and both cancer- and non-cancer related surgical procedures will be 
listed separately.
2.3.5
Protocol Deviations
Protocol deviations identified during the study are reviewed by the study team.  During this 
review, deviations are classified as important or not important based on their impact on data 
reliability and/or patient safety, wellbeing or rights.
Important protocol deviations including inclusion/exclusion criteria deviations will be 
summarized. A separate summary of inclusion/exclusion criteria deviations will also be 
provided. All important protocol deviations will be listed. Following the COVID-19 pandemic, 
separate tables will be created to display the protocol deviations related to COVID-19 and those 
not related to COVID-19.  Deviations related to COVID-19 will be classified as important to 
ensure transparent presentation of the impact of the pandemic in the clinical study report. Where 
applicable, the relationship of a protocol deviation to COVID-19 will be displayed in the listing.
Deviations will not result in subject exclusion from any population. However, for protocol 
deviations that are deemed by clinical team as having a significant impact on the interpretation 
of the efficacy results (e.g. subject with incorrect histologic type enrolled), sensitivity analysis 
for efficacy may be conducted by excluding subjects with such deviations.
2.4
Analysis of the primary objective
The analyses of the primary endpoint will take place once all patients have either died or been 
transitioned off the study. The primary analysis population for efficacy analyses is ITT. The 
BRAF V600E population will be used for supportive analyses of efficacy. Summaries of 
primary endpoint results may be provided for the primary analysis cohort, the expansion cohort 
and primary and expansion cohorts combined.
2.4.1
Primary endpoint
The primary efficacy assessment will be the evaluation of overall response rate (ORR) 
calculated as a proportion of the subjects who have a confirmed response relative to the total 
number of subjects in the analysis population.  Clinical response to dabrafenib in combination 
with trametinib will be assessed according to the appropriately established response criteria for 
each histologic cohort. Table 2-1 outlines the response criteria and subcategories for overall 
response for each histologic cohort. Following feedback on the WHO Grade 1 and 2 Glioma 
cohort from the FDA, additional summaries of best response and duration of response will be 
produced excluding Minor Response (MR) from the subcategories defined as Response for this 
cohort.


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Table 2-1
Response Criteria and Definition of Response by Histology
Histology
Response Criteria
Response Subcategories 
defined as Overall 
Response
ATC, BTC, GIST, ASI
RECIST 1.1
CR, PR
NSGCT/NGGCT
RECIST 1.1; Serum tumor 
markers normalization or not 
will be considered as part of 
response criteria 
(serum tumor markers: AFP, 
-HCG)
Marker-Negative CR (CR-), 
Marker-Positive CR (CR+), 
Marker-Negative Partial 
Remission (PR-), Marker-
Positive Partial Remission
(PR+)
WHO Grade 1 and 2 Glioma
Response Assessment 
Criteria for WHO Grade 1 or 
2 Glioma: RANO Working 
Group 
CR, PR, MR
WHO Grade 3 and 4 Glioma
Updated Response 
Assessment Criteria for 
WHO Grade 3 or 4 Glioma: 
RANO Working Group 
CR, PR
MM
IMWG Uniform Response 
Criteria for MM
sCR, CR, PR, VGPR
HCL
Adapted from NCCN 
guidelines, Consensus 
Resolution Criteria and 
previous studies definition
CR without MRD (CR-MRD), 
CR with MRD (CR+MRD), 
PR
Abbreviations: AFP, alpha-fetoprotein; ASI, adenocarcinoma of the small intestine; ATC, 
anaplastic thyroid cancer; -hCG, beta-human chorionic gonadotropin; BTC, biliary tract 
cancer; CR, complete response; GIST, gastrointestinal stromal tumor; HCL, hairy cell 
leukemia; IMWG, International Myeloma Working Group; MM, multiple myeloma; MR, 
minor response; MRD, minimal residual disease; NCCN, National Comprehensive Cancer 
Network; NGGCT, non-geminomatous germ cell tumor; NSGCT, non-seminomatous germ 
cell tumor; PR, partial response; RANO, Response Assessment for Neuro-Oncology; 
RECIST, Response Evaluation Criteria in Solid Tumors; sCR, stringent complete response; 
VGPR, very good partial response; WHO, World Health Organization
The best confirmed overall response is the best confirmed response recorded from the start of 
treatment until disease progression or start of new anti-cancer therapy, whichever earlier, and 
will be determined programmatically based on investigator assessment at each time point.
If there are two assessments separated by not evaluable (NE) assessment(s) the best response 
shall be assessed applying the algorithm below, collapsing data by ignoring NE assessments.
Subjects with best response of Not Evaluable (NE), unknown or missing will be considered 
non-responders; i.e. they will be included in the denominator when calculating the percentage.
The first assessment may occur before the first planned assessment.  Confirmation of response 
may be based on planned and/or unscheduled assessments. 
Table 2-2, Table 2-3, and Table 2-4 below outline the programming algorithm used to define 
confirmed response for each of the histologic cohorts.


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Table 2-2
Confirmed Response Criteria for Solid Tumors following RECIST 1.1 
(ATC, BTC, GIST, ASI, NSGCT/NGGCT) or RANO (WHO Grade 1&2 
Glioma, WHO Grade 3&4 Glioma)
Confirmed 
Response Category
Criteria for Definition of Confirmed Response
CR, PR, MR, CR-, 
CR+, PR- and PR+.  
(MR only applicable 
for WHO Grade 
1&2 glioma)
(CR-, CR+, PR-, and 
PR+ only applicable 
to NSGCT/NGGCT)
•
Two consecutive assessments are required. A confirmatory disease 
assessment should be performed no less than 4 weeks (28 days) from the 
time of initial CR, PR, MR, CR-, CR+, PR- or PR+. If a response of any 
type is assessed and the consecutive assessment is a response of lower 
magnitude then the confirmed response corresponds with the latter 
assessment which is the response of lower magnitude.  For example, a CR 
followed by PR results in a confirmed PR response.
•
If there is 1 assessment within this category, the timing of this assessment is 
less than 6 weeks after the first dosing and all other assessments are either 
NE, missing or not done then the confirmed response is NE.
•
Confirmed responses in this category cannot be assigned for assessments 
after a patient has an overall response assessment of PD.
•
For NSGCT/NGGCT, ordering of response magnitude from high to low is 
CR-, CR+, PR-, PR+.  For WHO Grade 1&2 glioma, ordering of response 
magnitude from high to low is CR, PR, MR.  For all other solid tumors, the 
ordering of response magnitude from high to low is CR, PR.
SD
•
SD does not need to be confirmed by a second assessment if the disease 
assessment meets the SD criteria after first dose of study drug at a minimum 
interval of 6 weeks (42 days). No further minimum window adjustment for 
assessment will be permitted.  If the minimum time for SD is not met, the 
best response will depend on the subsequent assessments or will be NE. For 
example, if an assessment of SD is followed by PD and SD does not meet 
the minimum time requirement for SD, the best response will be PD. When 
the only assessment (other than NE) after initiation of treatment is SD and 
the minimum time of 6 weeks from first dose of study drug is not met, the 
best confirmed response is NE.
•
If an assessment in the following categories (CR, PR, MR, CR-, CR+, PR-
and PR+) is followed by SD or PD, and the timing of the initial assessment 
is greater than or equal to 6 weeks after the first dosing, then the confirmed 
response is SD.
•
If there is 1 assessment in the following categories (CR, PR, MR, CR-, 
CR+, PR- and PR+) and the timing of the assessment is greater than or 
equal to 6 weeks after the first dosing, and consecutive assessments are 
either missing, not done or NE then the confirmed response is SD.
•
Confirmed responses in this category cannot be assigned for assessments 
after a patient has an overall response assessment of PD.
PD
•
PD does not need to be confirmed by a second assessment of PD to confirm 
PD as the best response.  When the only assessment (other than NE) at any 
point after initiation of treatment is PD the confirmed response is PD.
NE
•
When a confirmation (of any above category except SD and PD) cannot be 
made due to lack of assessments the confirmed response is NE.


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•
If there is 1 assessment in the following categories (CR, PR, MR, CR-, 
CR+, PR- and PR+) and the timing of the assessment is less than 6 weeks 
after the first dosing,  and consecutive assessments are either missing, not 
done or NE then the confirmed response is NE.
•
If all assessments were NE or missing then the confirmed response is NE.
•
If only non-measurable disease exists at baseline and the response is given 
as Non-CR/Non-PD then the confirmed response is NE.
Table 2-3
Confirmed Response Criteria for MM
Confirmed Response 
Category
Criteria for Definition of Confirmed Response
sCR, CR, VGPR, PR, 
Minimal Response 
(MnR), SD

Two consecutive assessments are required.  At least one day of 
separation between two consecutive assessments is required to confirm 
response.

If a response of any type is assessed and the consecutive assessment is a 
response of lower magnitude then the confirmed response corresponds 
with the latter assessment which is the response of lower magnitude. 
For example, a PR followed by MnR results in a confirmed MnR 
response, or a PR followed by SD results in a confirmed SD.  Two 
consecutive assessments of SD will constitute a confirmed SD.

If there is 1 assessment and consecutive assessments are either missing 
or not done then the confirmed response is NE.

The ordering of response magnitude from high to low is sCR, CR, 
VGPR, PR, MnR SD.

Confirmed responses in this category cannot be assigned for 
assessments after a patient has an overall response assessment of PD.
PD

PD does not need to be confirmed by a second assessment of PD to 
confirm PD as the best response.  When the only assessment (other than 
NE) at any point after initiation of treatment is PD the confirmed 
response is PD.
NE

When a confirmation (of sCR, CR, VGPR, PR, MnR or SD) cannot be 
made due to lack of assessments the confirmed response is NE.  For 
example, if there is 1 assessment in the following categories (sCR, CR, 
VGPR, PR, MnR, SD) and consecutive assessments are either missing, 
not done or NE then the confirmed response is NE.

If all assessments were NE or missing then the confirmed response is 
NE.


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Table 2-4
Confirmed Response Criteria for HCL
Confirmed Response 
Category
Criteria for Definition of Confirmed Response
CR-MRD, CR+MRD, 
PR, MR

Two consecutive assessments are required.  A confirmatory disease 
assessment should be performed no less than 4 weeks (28 days) from the 
time of initial CR - MRD, CR + MRD, PR or MR.

If a response of any type (CR-MRD, CR+MRD, PR, MR) is assessed and 
the consecutive assessment is a response of lower magnitude then the 
confirmed response corresponds with the latter assessment which is the 
response of lower magnitude.  For example, a PR followed by MR 
results in a confirmed MR response.

The ordering of response magnitude from high to low is CR- MRD, CR+ 
MRD, PR, MR.

Confirmed responses in this category cannot be assigned for assessments 
after a patient has an overall response assessment of PD.
SD

SD does not need to be confirmed by a second assessment if the disease 
assessment meets the criteria after first dose of study drug at a minimum 
interval of 4 weeks (28 days). If the minimum time for SD is not met, the 
best response will depend on the subsequent assessments or will be NE. 
For example, if an assessment of SD is followed by PD and SD does not 
meet the minimum time requirement, the best response will be PD. When 
the only assessment (other than NE) after initiation of treatment is SD 
and the minimum time for SD is not met, the best confirmed response is 
NE.

If an assessment in the following categories (CR-MRD, CR+MRD, PR, 
MR) is followed by SD or PD, and the timing of the initial assessment is 
greater than or equal to 4 weeks after the first dosing, then the confirmed 
response is SD.

If there is 1 assessment in the following categories (CR-MRD, 
CR+MRD, PR, MR) and the timing of the assessment is greater than or 
equal to 4 weeks after the first dosing,  and consecutive assessments are 
either missing, not done or NE then the confirmed response is SD.

Confirmed responses in this category cannot be assigned for assessments 
after a patient has an overall response assessment of PD.
PD

PD does not need to be confirmed by a second assessment of PD to 
confirm PD as the best response.  When the only assessment (other than 
NE) at any point after initiation of treatment is PD the confirmed 
response is PD.
NE

When a confirmation (of CR-MRD, CR+MRD, PR or MR) cannot be 
made due to lack of assessments the confirmed response is NE.

If there is 1 assessment in the following categories (CR-MRD, 
CR+MRD, PR, MR) and the timing of the assessment is less than 4 
weeks after the first dosing,  and consecutive assessments are either 
missing, not done or NE then the confirmed response is NE.


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Confirmed Response 
Category
Criteria for Definition of Confirmed Response

If all assessments were NE or missing then the confirmed response is 
NE.
2.4.2
Statistical hypothesis, model, and method of analysis
Confirmed ORR will be calculated as the proportion of subjects that have a confirmed response 
relative to the total number of subjects in the corresponding analysis population.
Confirmed ORR will be analyzed using an integrated analysis across the histologic cohorts with 
the hierarchical model.  Model-based interim decision rules have been used through the study 
to identify whether one or more histologic cohorts halt enrolment early for futility/harm or 
benefit based on efficacy data.
Model-based decision rules for the final analysis are provided in the protocol. At the final 
analysis, a minimum of 2 subjects will be required in a histologic cohort in order to meet 
statistical success. A histologic cohort will be declared active if the posterior probability that the 
ORR exceeds its corresponding historical control is sufficiently high (>92%) based on the 
hierarchical model. That is, 
P (j > Cj % | current data) > 92%, for the j-th histology.
This decision rule has been determined based on extensive simulations of the study design as 
described in the protocol.
A summary of the Bayesian hierarchical model-based analysis will be provided.  For each 
histology the following measures will be reported: the total number of subjects, the protocol-
specified historical control response rate, the estimated response rate and 95% credible interval 
(based on the posterior mean and 2.5% and 97.5% percentiles), and the posterior probability 
that the ORR exceeds its corresponding historical control response rate.
Descriptive summaries of best confirmed response along with the corresponding 95% exact 
confidence intervals will be provided for each response criteria for the varying histologic 
cohorts in order to characterize the observed response data and support the model-based 
analyses for ORR. Best response and ORR will be presented for the primary cohort, expansion 
cohort and primary and expansion combined for each histology for which an expansion cohort 
was opened.
The model-based analysis of ORR and supporting summaries of best confirmed response will 
be re-produced based on the BRAF V600E Population.
All supporting individual response and lesion data will be listed. For histologic cohorts using 
RECIST 1.1 (ATC, BTC, GIST, ASI), a listing of all investigator-assessed lesion assessments 
will be provided. For glioma cohorts (WHO Grade 1 or 2 and WHO Grade 3 or 4), listings of 
measureable, non-measureable, and new lesions will be provided.  For HCL, separate listings 
of lymph nodes including palpable lymph nodes will be provided. For MM, supportive 
laboratory results including serum and urine monoclonal protein, serum free light chain (FLC) 
and FLC ratio will be listed.


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2.4.3
Handling of missing values/censoring/discontinuations
Response assessments occurring after disease progression or the start of new anti-cancer 
therapy will not be included in the determination of best response. Response assessments 
occurring after end of study treatment but before disease progression or the start of new anti-
cancer therapy will be included. There will be no imputation of missing values.
2.4.4
Supportive analyses
Descriptive summaries of best response based on independent radiology review will be 
provided for the ATC, BTC, ASI, WHO Grade 1 or 2 Glioma and WHO Grade 3 or 4 Glioma 
cohorts as sensitivity analyses. Specifically, the best response based on independent reviewer 
assessment will be determined programmatically and summarized in the same way as the best 
response based on investigator assessment. 
An assessment of the concordance between the investigator-assessed response and independent 
reviewer-assessed response will be performed for each of the cohorts listed above. Kappa 
coefficient will be reported along with the corresponding 95% confidence interval.  
The concordance rate is calculated as percent agreement (the proportion of best response that 
agree between investigator assessment and independent reviewer assessment):
	 
	 = #  
	ℎ  + #  
	ℎ  −
		
 #  	 

If ORR from either investigator assessment or independent reviewer assessment for a subject is 
missing, then the subject will be excluded from the calculation of the concordance rate. 
An overall listing of subject response data based on independent radiology review will be 
provided alongside the investigator assessed responses for the ITT population in the ATC, BTC, 
ASI, GIST, WHO Grade 1 or 2 Glioma and WHO Grade 3 or 4 Glioma cohorts.  This listing 
will display both independent reviewer-assessed and investigator assessed response evaluations, 
the best confirmed responses, and BRAF V600E central confirmation status.
2.5
Analysis of the key secondary objective
There is no key secondary objective for this study.
2.6
Analysis of secondary efficacy objective(s)
The secondary efficacy endpoints include duration of response (DoR), progression free survival 
(PFS) and overall survival (OS).  The secondary efficacy endpoints will be analyzed for ATC, 
BTC, ASI, WHO Grade 1 or 2 Glioma, WHO Grade 3 or 4 Glioma, MM and HCL cohorts. The 
analyses of the secondary endpoints will take place once all patients have either died or been 
transitioned off the study. The main population for efficacy analyses is ITT. The BRAF V600E 
population will be used for supportive analyses of efficacy.
2.6.1
Duration of response
For the subset of subjects who show a confirmed response as defined for each cohort in Error! 
Reference source not found. 2.4.1, duration of response (DoR) is defined as the time (in weeks) 
from the first documented evidence of response (the first response prior to confirmation) until 
the time of documented disease progression or death due to any cause.


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For the cohorts assessed using RECIST 1.1 and RANO criteria, the analysis of DoR will be 
based on radiological response from investigator assessment. The date of disease progression 
is defined as the date of radiological disease progression based on the appropriate disease 
response criteria.  Clinical progression, defined as investigator assessed clinical progression in 
the absence of radiological confirmation, is not considered a progression event in this analysis.  
Specifically, in the event of clinical progression leading to discontinuation of study treatment 
and radiological assessment, if radiological assessments do not indicate radiological 
progression, then the subject will be censored at the time of last radiological assessment. If a 
subject has not progressed, not died, and not started new anti-cancer therapy, DoR will be 
censored at the date of the last adequate assessment.
For the HCL cohort, the overall investigator-assessed response will be used to determine timing 
of response and/or progression.  Relapsed disease will be considered as progression for the 
analysis.
Details of censoring after extended time without adequate assessment are given in section 4.2. 
For subjects who receive subsequent anti-cancer therapy, the following rule will apply:

If anti-cancer therapy is started without documented progression or is started prior to 
progression, then DoR will be censored at the date of the last adequate disease assessment 
that is no later than the date of initiation of anti-cancer therapy (i.e. if disease assessment 
occurs on the same day as the start of new anti-cancer therapy then the assessment will be 
used, as it will be assumed that the assessment occurs prior to the administration of new 
anti-cancer therapy).
DoR based on the investigator response will be summarized for ATC, BTC, ASI, WHO Grade 
1 or 2 Glioma, WHO Grade 3 or 4 Glioma and HCL cohorts. If data warrant, Kaplan-Meier 
method will be used to summarize DoR descriptively and graphically. The median DoR and the 
first and third quartiles will be presented, along with corresponding 95% confidence intervals. 
Brookmeyer-Crowley method will be used for the confidence interval calculation. DoR will
also be summarized at 6 months, 12 months and 24 months. 
Listing of DoR based on investigator assessment will also be provided.
In addition, swim lane plots will be generated for response data based on investigator 
assessment. These plots will present the best confirmed response category, duration of treatment, 
time of the first response, duration of response, time of the first disease progression based on 
radiological assessment and study treatment status at the time of data cut-off for the analysis.  
As a sensitivity analysis, DoR based on independent radiology review will be summarized and 
listed for the ATC, BTC, WHO Grade 1 or 2 Glioma, and WHO Grade 3 or 4 Glioma cohorts, 
including the estimated median, first and third quartiles, 6 and 12 month Kaplan-Meier 
estimates. The derivation of DoR based on independent radiology review is similar to that based 
on the investigator assessment. 
For the HCL cohort only, and for the subset of subjects who have a confirmed complete 
response (with or without MRD), the complete response duration will be calculated as the time 
from first CR until the earliest of the first subsequent non-CR adequate assessment or death due 
to any cause. Censoring rules will be applied the same as with Duration of Response. Kaplan-
Meier estimates will be used to estimate the median and quartiles of the complete response 
duration as well as the complete response duration at 180 days. The number and proportion of 


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the ITT population with complete response duration of at least 180 days will be calculated along 
with the corresponding Clopper-Pearson exact confidence interval. The time to first confirmed 
complete response and time to first confirmed overall response will both be summarized with 
the minimum, maximum, 1st and 3rd quartiles and median displayed in weeks. Only confirmed 
responders will be included in each of the summaries.
Summaries of reasons for censoring DoR by both investigator assessment and independent 
radiology review will be produced with additional information about censoring due to COVID-
19 related protocol deviations.  The number and percentage of subjects with each censoring 
reason (1. PD or death after >=2 consecutive missed visits, 2. New anti-cancer treatment started 
prior to documented PD, 3. No baseline (or adequate post-baseline) assessments, 4. No 
progression or death, separated into follow-up ended and follow-up ongoing) will be displayed 
along with relevant COVID-19 related censoring reasons (study withdrawal due to COVID-19 
and missing visits due to COVID-19) derived from protocol deviations data.  Further details of 
these outputs are given in the programming notes to the TFL shells.
2.6.2
Progression-free survival
Progression-free survival (PFS) is defined as the interval (in weeks) between the first dose of 
study treatment and earlier date of disease progression or death due to any cause.  
For the cohorts assessed using RECIST 1.1 and RANO criteria, the primary analysis of PFS 
will be based on radiological response from investigator assessment.  The date of disease 
progression is defined as the date of radiological progression based on imaging data.  Subjects 
who do not meet the RECIST 1.1 or RANO criteria for progression and are still alive will be 
censored.  Clinical progression, defined as investigator assessed clinical progression in the 
absence of radiological confirmation, is not considered a progression event in this analysis.  
Specifically, in the event of clinical progression leading to discontinuation of study treatment 
and radiological assessment, if radiological assessments do not indicate radiological 
progression, then the subject will be censored at the time of last radiological assessment. If a 
subject has not progressed, not died, and not started new anti-cancer therapy, PFS will be 
censored at the date of the last adequate assessment. For the HCL cohort, the overall 
investigator-assessed response will be used to determine timing of progression.  
Details of censoring after extended time without adequate assessment are given in section 4.2. 
For subjects who receive subsequent anti-cancer therapy, the following rule will apply:

If anti-cancer therapy is started without documented progression or is started prior to 
progression, then PFS will be censored at the date of the last adequate disease assessment 
that is no later than the date of initiation of anti-cancer therapy (i.e. if disease assessment 
occurs on the same day as the start of new anti-cancer therapy then the assessment will be 
used, as it will be assumed that the assessment occurs prior to the administration of new 
anti-cancer therapy).  

If a subject does not have an adequate post-baseline assessment that is no later than the 
date of initiation of anti-cancer therapy, PFS will be censored at the date of the first dose. 
If any adequate post-baseline assessment exists after the date of initiation of anti-cancer 
therapy, the reason for censoring will be recorded as “new anti-cancer treatment started 
prior to disease progression”.  Otherwise if no adequate post-baseline assessments exist, 


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the reason for censoring will be recorded as “no baseline (or post-baseline adequate) 
tumor assessments”.
PFS based on the investigator assessment will be summarized descriptively and graphically 
using Kaplan-Meier methods. The Kaplan-Meier estimate for the median progression-free 
survival time and the first and third quartiles will be determined along with approximate 95% 
confidence intervals.  Brookmeyer-Crowley method will be used for the confidence interval 
calculation. Kaplan-Meier estimate of PFS at 6 months, 12 months and 24 months will be 
summarized. 
Listing of progression free survival based on investigator assessment will also be provided. 
As a sensitivity analysis, PFS based on independent reviewer assessment will be summarized 
and listed (except for the MM and HCL cohorts which have no independent review) similarly 
as that of PFS based on investigator assessment.
Summaries of reasons for censoring PFS by both investigator assessment and independent 
radiology review will be produced with additional information about censoring due to COVID-
19 related protocol deviations.  The number and percentage of subjects with each censoring 
reason (1. PD or death after >=2 consecutive missed visits, 2. New anti-cancer treatment started 
prior to documented PD, 3. No baseline (or adequate post-baseline) assessments, 4. No 
progression or death, separated into follow-up ended and follow-up ongoing) will be displayed
along with relevant COVID-19 related censoring reasons (study withdrawal due to COVID-19 
and missing visits due to COVID-19) derived from protocol deviations data.  Further details of 
these outputs are given in the programming notes to the TFL shells.
2.6.3
Overall survival
Overall survival (OS) is defined as the time (in weeks) from first dose until death due to any 
cause. The length of this interval is estimated as the date of death minus date of first dose plus 
1 day.  Subjects who have not died will be censored at the date of last contact (as recorded in 
the eCRF). The last date of contact will be defined as the maximum date of any visit date, 
survival follow-up date, or date of study withdrawal.  Only patient contacts recorded in the 
eCRF can be used for the calculation of last date of contact.
Overall survival will be summarized descriptively and graphically using Kaplan-Meier method.  
The Kaplan-Meier estimate for the median overall survival time and the first and third quartiles 
will be presented, along with approximate 95% confidence intervals. Brookmeyer-Crowley 
method will be used for the confidence interval calculation. Overall survival at 6 months, 12 
months and 24 months will be summarized using the Kaplan-Meier method.  
Listing of overall survival data will also be provided. 
2.7
Safety analyses
All safety analyses will be based on the All-Treated subjects (ATS) population.
2.7.1
Adverse events (AEs)
Adverse events (AEs) will be graded according to the CTCAE, Version 4.0. Adverse events 
will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). For the final 
analysis, version 24.1 of MedDRA will be used.


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All AEs will be summarized based on frequency and proportion of total subjects experiencing 
the event, grouped by system organ class and preferred term (PT).
A summary of number and percentage of subjects with any adverse events by maximum grade 
will be produced for each histologic cohort. In this summary AEs will be sorted by PT in 
descending order of total incidence. The summary will use the following algorithms for 
counting the subject:
Preferred term row: Subjects experiencing the same AE preferred term several times with 
different grades will only be counted once with the maximum grade.
Any event row: Each subject with at least one adverse event will be counted only once at the 
maximum grade no matter how many events they have.
For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables of on-therapy 
adverse events which are not serious adverse events with an incidence of at least 5% and on-
therapy serious adverse events and SAEs suspected to be related to study treatment will be 
provided by system organ class and preferred term for the all treated subjects population.
If for the 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 AEs 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.
All SAEs and fatal SAEs will be tabulated based on the number and percentage of subjects who 
experienced the event. The summary tables will be displayed in descending order of total 
incidence by PT only.
Separate listings with subject-level details will be generated for fatal SAEs and non-fatal SAEs. 
These listings will include PT, verbatim text, onset date, data of resolution, outcome, event 
duration, time since first and last dose, maximum grades, seriousness, action taken with study 
treatment and relatedness to study treatment.
The following categories of AEs will be summarized in descending order of total incidence by 
PT only:

AEs Leading to Permanent Discontinuation of Any Study Treatment 

AEs Leading to Dose Interruptions

AEs Leadings to Dose Reductions.
2.7.1.1
Adverse events of special interest / grouping of AEs
A comprehensive list of MedDRA terms based on the program-level electronic case retrieval 
sheet (eCRS) will be used to identify each type of events. Changes to the MedDRA dictionary 


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may occur between the start of the study and the time of reporting and/or emerging data from 
on-going studies may highlight additional adverse events of special interest, therefore the list 
of terms to be used for each event of interest and the specific events of interest will be based on 
the safety management team (SMT) agreements in place at the time of reporting. 
Adverse events of special interest include:

Skin related toxicities

Ocular events

Cardiac related events

Hepatic disorders

Pneumonitis/Interstitial lung disease

Bleeding events

Hypertension

Hypersensitivity

New primary or secondary malignancy

Venous thromboembolism

Pyrexia

Uveitis

Pre-renal and Intrinsic Renal Failure

Pancreatitis

Hyperglycemia

Neutropenia
The summary of number and percentage of subjects with each type of adverse event of special 
interest by maximum grade will be produced for each histologic cohort and all cohorts
combined. AEs will be sorted by PT in descending order of total incidence.
2.7.2
Deaths
All deaths will be summarized based on the number and percentage of subjects, by time of death 
(on-therapy and post-therapy) and the primary cause of death. On-therapy and post-therapy are 
defined in section 2.1.1. A supportive listing will be generated to provide subject-specific details 
for subject who died.
2.7.3
Laboratory data
The full list of laboratory tests is given in the study protocol section 7.4.8.
Laboratory grades will be reported using the Common Terminology Criteria for Adverse Events 
(CTCAE v4.0).
Summaries of worst case grade increase from baseline grade will be provided for all the lab 
tests that are gradable by CTCAE v4.0. These summaries will display the number and 
percentage of subjects with a maximum on-therapy grade increasing from their baseline grade. 
Any increase in grade from baseline will be summarized along with any increase to a maximum 
grade of 3 and any increase to a maximum grade of 4. Missing baseline grade will be assumed 
as grade 0. In addition, the summary will include grade increase from baseline by scheduled 


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visits. For laboratory tests that are graded for both low and high values, summaries will be done 
separately and labeled by direction, e.g., sodium will be summarized as hyponatremia and 
hypernatremia.
For lab tests that are not gradable by CTCAE v4.0, summaries of worst case changes from 
baseline with respect to normal range will be generated. Decreases to low, changes to normal 
or no changes from baseline, and increases to high will be summarized at each scheduled visit 
as well as for the worst case on-therapy. If a subject has a decrease to low and an increase to 
high during the same time interval, then the subject is counted in both the “Decrease to Low” 
categories and the “Increase to High” categories. Detailed derivation of baseline assessment is 
specified in Section 2.1.1.
Unless otherwise specified, the denominator in percentage calculation at each scheduled visit 
will be based on the number of subjects with non-missing value at each particular visit.
An eDISH plot showing the peak on-therapy total bilirubin versus peak on-therapy ALT will 
be plotted by histological cohort combining primary analysis and expansion cohorts. Upon data 
review during the conduct of the study, an additional eDISH plot might be considered showing 
peak on-therapy total bilirubin versus peak on-therapy AST if there are potential cases based 
on AST rather than ALT. Subject plots showing the time course of ALT, AST, ALP and total 
bilirubin will also be produced. The number and percentage of subjects with ALT, AST and 
bilirubin above relevant thresholds (e.g. 3 x ULN) at any time on-therapy will be displayed.  
Criteria relating to the combined elevations of ALT or AST and bilirubin are based on the peak 
values at any time on-therapy and do not have to be concurrent.
2.7.4
Other safety data
2.7.4.1
ECG and cardiac imaging data
The results of scheduled assessments of ECG will be summarized. A summary of ECG findings 
will classify each result into “Normal”, “Abnormal, not clinically significant” or “Abnormal, 
clinically significant” as entered on the eCRF. Bazett’s and Fridericia’s corrections of QT 
values will be summarized using the categories in section 4.7 for both an increase in grade from 
baseline and the amount of increase. The summaries will display results by visit and for the 
worst case (largest increase) post-baseline.
2.7.4.2
Vital signs
Systolic and diastolic blood pressure, heart rate, temperature in degrees Celsius will be 
summarized by histologic cohort and visit. The worst case post baseline will display the largest 
value after baseline in the study. Changes from baseline in systolic and diastolic blood pressure, 
heart rate and temperature in degrees Celsius will be summarized including the categories in 
section 4.10.
2.8
Pharmacokinetic endpoints
Summary statistics of concentration-time data for trametinib, dabrafenib and metabolites of 
dabrafenib (Hydroxy-dabrafenib and Desmethyl-dabrafenib) will be provided, both for the full 
PK population and separately for subjects from Japanese and non-Japanese race categories.  
Concentration-time data for trametinib, dabrafenib and its metabolites will be listed.




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2.12
Interim analysis
Interim analyses have been carried out to monitor efficacy and safety at regular intervals 
through the study enrollment and for health authority submission and publication after the end 
of enrollment. Details of interim analyses are given in section 18.3.2 of the protocol and the 
interim reporting and analysis plans. 
3
Change to protocol specified analyses
No changes were made to analyses specified in the protocol.
4
Appendix
4.1
Clinical review of anti-cancer therapies for censoring criteria
Due to the inconsistent recording of anti-cancer therapies (including surgeries) in the eCRF, a 
manual review of all relevant therapies will be carried out to ensure that the correct records are 
used to censor the best confirmed overall response, progression-free survival and duration of 
response.  Specifically, spreadsheets of unique on-therapy or follow-up anti-cancer therapies, 
radiotherapies, and cancer-related surgeries will be sent to a clinical reviewer to identify the 
interventional treatments for the disease under study and distinguish them from diagnostic 
procedures, such as biopsies, and surgeries for adverse events not connected with the disease 
under study, such as squamous cell carcinoma.
4.2
Extended Loss to Follow-up or Extended Time without an 
Adequate Assessment
Since missing scheduled disease assessments prior to progression or death increases the 
uncertainty about when the event actually occurs, PFS and DoR will be censored for subjects 
who have progression or die after missing two or more scheduled disease assessments. 
Specifically, if there are two or more scheduled assessments which are missing followed by 
progression or death, PFS and DoR will be censored at the last adequate assessment prior to 
progression or death.
For the purpose of this calculation, the last adequate assessment is defined as the last assessment 
prior to progression or death with response other than NE or missing.
For solid tumor cohorts (ATC, BTC, GIST, NSGCT/NGGCT, ASI, WHO Grade 1 or 2 Glioma 
and Grade 3 or 4 Glioma) and MM cohort, when the scheduled disease assessment is every 8 
weeks (for the first 48 weeks of study treatment), a window of 119 days (16 weeks + 7 day 
window) will be used to determine whether there was an extended time without adequate 
assessment. When the scheduled disease assessment is every 12 weeks (after the first 48 weeks 
of study treatment), a window of 175 days (24 weeks + 7 day window) will be used to determine 
whether there was an extended time without adequate assessment. Specifically, extended lost-
to-follow-up period is defined using different time windows as described in Table 4-1.
Table 4-1
Extended lost-to-follow-up period at different study times
Last adequate assessment 
Extended lost-to-follow-up period
<= end of week 44 
16 + 1 weeks (119 days)


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Last adequate assessment 
Extended lost-to-follow-up period
(<=308 days)
>= beginning of week 45  –  <= end of week 54
(>308 days,  <=378 days)
20 + 1 weeks (147 days)
>= beginning of week 55  
(>378 days)
24 + 1 weeks (175 days)
For the HCL cohort, the scheduled disease assessment is every 4 weeks for the first 48 weeks 
of study treatment, then at least every 8 weeks for patients tolerating the study drug in the 
judgement of the treating investigator. Following protocol amendment 11, the interval between 
assessments beyond the first 48 weeks is increased to at least every 12 weeks. To provide 
reasonable allowance for missed assessments within the new schedule, the same rules will be 
used for HCL as for the solid tumor cohorts and MM to determine whether there was an 
extended time without adequate assessment.
4.3
Date Associated with Response
For MM and HCL, investigator assessment of disease is entered in the eCRF on the VISIT form.  
The date of the VISIT is captured but the date of the response assessment is not captured 
separately.  The date associated with response will be the visit date for the VISIT on which the 
investigator assessed disease. A disease assessment may occur at an unscheduled visit.  The 
date of the unscheduled visit would be assigned to any response assessed on that date.   
For all solid tumor histologies, for each disease assessment after baseline, determine a date 
associated with the response. For complete response (CR), partial response (PR), and when 
applicable minor response (MR), assign to the latest date within the disease assessments. For 
stable disease (SD), Non-CR/Non-PD or Not Evaluable, assign to the earliest date within the 
disease assessments. For progressive disease (PD), assign to the earliest assessment date 
associated with the progression.
4.4
Imputation rules
Partial dates may be imputed for ‘slotting’ data to study time periods or for specific analysis 
purposes as outlined below.
4.4.1
Demography (ADSL)
Dataset
Date
Missing 
Element
Rule
ADSL
Birth date 
(BRTHDT)
day, 
month, 
and year
No Imputation for completely missing dates
day and 
month
Imputed to June 30


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4.4.2
Initial diagnosis of primary tumor type under study
Dataset
Date
Missing 
Element
Rule
Disease  
Characteristics 
(ADDC)
Initial 
Diagnosis
Date
day, 
month, 
and year
No imputation for completely missing date
day, 
month
Impute the missing month and day as January 1
day
Impute the missing day as 1st of the month.
4.4.3
Adverse events (ADAE)
Imputations in the adverse events dataset are used for slotting events to the appropriate study 
time periods and for sorting in data listings.
Dataset
Date
Missing 
Element
Rule
Adverse 
Events 
(ADAE)
Start 
Date
day, 
month, 
and year
No Imputation for completely missing dates
day, 
month

If study treatment start date is missing (i.e. subject did not 
start study treatment), then set start date = January 1.

Else if study treatment start date is not missing: 
o
If year of start date = year of study treatment start 
date then 

If stop date contains a full date and stop 
date is earlier than study treatment start 
date then set start date = January 1. 

Else set start date = study treatment 
start date. 
o
Else set start date = January 1.
day

If study treatment start date is missing (i.e. subject did not 
start study treatment), then set start date = 1st of month. 

Else if study treatment start date is not missing: 
o
If month and year of start date = month and year of 
study treatment start date then 

If stop date contains a full date and stop 
date is earlier than study treatment start 
date then set start date= 1st of month. 

Else set start date = study treatment 
start date.
o
Else set start date = 1st of month.
End 
Date
No imputation for partial end dates will be performed


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4.4.4
Surgery and radiotherapy
The following imputation will be used for surgical procedures and start dates of radiotherapy.  
End dates of radiotherapy will not be imputed.
Dataset
Missing 
Element
Rule
Surgical 
Procedures and 
Radiotherapy 
(ADPR)
day, month, 
and year

No Imputation for completely missing dates
day, month

If partial date contains a year only set to January 1st.
day

If partial date contains a month and year set to the 1st
of the month
4.4.5
Concomitant medication and blood and blood supportive care 
products
Impute start and end dates for use in derivation of the reference variables, concomitant 
medication start and end relative to treatment and blood and blood supportive care start and end 
relative to treatment, but do not permanently store the imputed start and end dates in the analysis 
datasets. The reference variables will be used to differentiate before, during and after for the 
concomitant medication or blood or blood supportive care start and end dates. 
Dataset
Date
Missing 
Element
Rule
Concomitant 
Medication
Blood 
and 
Blood 
Supportive 
Care Products 
Start 
Date
day, 
month, 
and year

No Imputation for completely missing dates
day, 
month

If study treatment start date is missing (i.e. subject 
did not start study treatment), then set start date = 
January 1. 

Else if study treatment start date is not missing: 
o
If year of start date = year of study treatment 
start date then 

If stop date contains a full date and 
stop date is earlier than study 
treatment start date then set start date 
= January 1. 


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Dataset
Date
Missing 
Element
Rule

Else set start date = study treatment 
start date. 
o
Else set start date = January 1.
day

If study treatment start date is missing (i.e. subject 
did not start study treatment), then set start date = 
1st of month. 

Else if study treatment start date is not missing: 
o
If month and year of start date = month and 
year of study treatment start date then 

If stop date contains a full date and 
stop date is earlier than study 
treatment start date then set start 
date= 1st of month. 

Else set start date = study treatment 
start date.
o
Else set start date = 1st of month.
End 
Date
day, 
month, 
and year

No Imputation for completely missing dates
day, 
month

If partial end date contains year only, set end date = 
earliest of December 31 or date of last contact. 
day

If partial end date contains month and year, set end 
date = earliest of last day of the month or date of last 
contact.
4.4.6
Time to event (Duration of response and Progression-free survival) 
and best confirmed overall response
On-therapy or follow-up anti-cancer therapy, including radiotherapy and cancer-related surgery 
start dates, may be imputed to determine date of first new anti-cancer therapy, in order to define 
event and censoring dates for progression-free survival and duration of response and inclusion 
of correct records in derivation of best confirmed overall response. 
Dates will only be imputed when a month and year are available but the day is missing. In this 
case, only the date of first new anti-cancer therapy (not all anti-cancer therapy and radiotherapy 
start dates) will be stored on appropriate efficacy datasets.
The date of first new anti-cancer therapy is derived as the earliest date of new anti-cancer 
therapy (e.g. chemotherapy), radiotherapy, or cancer related surgical procedure and will include 
imputed dates.  If the date is an imputed date, then the flag variable is assigned the value of 'D' 
to indicate that the day portion of the date is imputed (following ADaM convention).


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As multiple dates are used to derive the new anti-cancer therapy date ensure that the flag is only 
set to ‘D’ if the derived date is imputed.  For example, if the date of new radiotherapy is imputed 
but the date of new systemic anti-cancer therapy is prior to date of new radiotherapy and the 
new systemic anti-cancer therapy date is not a partial date then the flag should be set to missing 
as the date used for first new anti-cancer therapy is not an imputed date. The following rules 
will be used to impute the date when partial start dates are present.
Dataset
Date
Missing 
Element
Rule
Anti-Cancer 
Therapy 
Where 
applicable: 
Radiotherapy 
Surgical 
Procedures
Start 
Date
day, month, 
and year

No Imputation for completely missing dates
day, month

No imputation for missing day and month 
(note the eCRF should only allow for missing 
day)
day

If partial date falls in the same month as the 
last dose of study treatment, then assign to 
earlier of (date of last dose of study 
treatment+1, last day of month). 

If partial date falls in the same month as the 
subject’s first occurrence of PD, then assign to 
earlier of (date of PD+1, last day of month). 

If both rules above apply, then assign to latest 
of the 2 dates 

Otherwise, impute missing day to the first of 
the month.
End 
Date

No imputation for partial end dates will be 
performed
4.4.7
Imputation of missing exposure end dates
Exposure end dates should be completed for the final study analysis.  For any subjects with 
missing exposure end dates at the final analysis, the missing date will be imputed to the earliest
of date of withdrawal from the study or death date.  If none of these dates are available then the 
date of last patient last visit will be used. The imputed exposure end date will be stored in the 
exposure analysis dataset and an exposure end date imputation flag variable will be derived 
indicating which exposure end date records are imputed. Imputed exposure end dates will also 


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be stored on the study treatment end date variable (ADSL.TRTEDT). This variable will hold 
the last date of exposure across both study treatments.
4.5
Multiple Assessments
All data will be reported according to the nominal visit date for which it was reported (that is, 
no visit windows will be applied during dataset creation). Unscheduled data will only be 
included in the display sections that report worst-case on-therapy.
If multiple assessments are reported on the same date for the same scheduled planned time, then 
the mean of multiple measurements reported for the same date will be analyzed, with the 
exception of laboratory data reported from both central and local laboratories. If laboratory data 
is reported from both central and local laboratories with the same date, then the central 
laboratory data will be analyzed to provide consistency with measurements from other subjects.
4.6
Laboratory parameters derivations
Reference ranges for all laboratory parameters collected throughout the study are provided by 
the laboratory. A laboratory value that is outside the reference range is considered either high 
abnormal (value above the upper limit of the reference range) or low abnormal (value below 
the lower limit of the reference range). Note: a high abnormal or low abnormal laboratory value 
is not necessarily of clinical concern. The laboratory reference ranges will be provided on the 
listings of laboratory data. Clinical laboratory test results outside of the reference range will be 
flagged in the listings.
To identify laboratory values of potential clinical importance, National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI-CTCAE v4.0) will be used to assign 
grades to the relevant laboratory parameters.
4.7
ECG parameters
To identify QTc (Bazett’s and Fridericia’s) values of potential clinical importance, NCI-
CTCAE v4.0 will be used to assign grades (see adverse event ‘Electrocardiogram QT corrected 
interval prolonged’). 
ECG Parameter
Potential Clinical Importance (PCI) Range
Unit
Absolute QTcB  or 
QTcF interval
450 to <481 (Grade 1)
481 to <501 (Grade 2)
501 (Grade 3)
Msec
Increase from baseline 
Increase of 31 to 60
Increase of >60
Msec
The following criteria will be used to flag other ECG values that are values of potential clinical 
importance: 


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ECG Parameter
Potential Clinical Importance (PCI) Range
Unit
PR interval
<110 (L) and >220 (H)
Msec
QRS interval
<75 (L) and >110 (H)
Msec
4.8
Cardiac Scan Modalities (ECHO)
An ECHO modality will be used for determining cardiac scan data (e.g., left ventricular ejection 
fraction (LVEF)) for all subjects throughout the study. The absolute change from baseline value 
will not be calculated for any time point in which the post-baseline value was determined by a 
cardiac scan modality other than ECHO.
4.9
Left ventricular ejection fraction
The following criteria will be used to flag LVEF values that are values of potential clinical 
importance: 
To identify LVEF values of potential clinical importance, NCI-CTCAE v4.0 will be used to 
assign categories that align with the grades for ‘Ejection fraction decreased’.
LVEF Parameter
Unit
Potential Clinical Importance (PCI) Range
Absolute change from 
baseline LVEF
%

No change or any increase

Any decrease
o
>0-<10 decrease
o
10-19 decrease
o
20 decrease
o
10 decrease and LLN
o
10 decrease and below LLN
o
20 decrease and LLN
o
20 decrease and below LLN
Relative 
change 
from 
baseline LVEF
%

20 decrease and LLN

20 decrease and below LLN
4.10
Vital signs 
To identify heart rate values of potential clinical importance, NCI-CTCAE v4.0 will be used to 
assign categories that align with the grades for ‘Sinus bradycardia’, ‘Sinus tachycardia’, 
‘Supraventricular tachycardia’, and ‘Ventricular tachycardia’.
The following criteria will be used to flag heart rate values that are values of potential clinical 
importance:


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SAP
CDRB436X2201 / BRF117019
Vital Sign Parameter
Potential Clinical Importance (PCI) Range
Unit
Decrease from baseline 
Heart Rate
Decrease to <60
bpm
Increase from baseline 
Heart Rate
Increase to >100
bpm
To identify blood pressure values of potential clinical importance, NCI-CTCAE v4.0 will be 
used to assign categories that align with the grades for ‘Hypertension’.
Vital Sign Parameter
Potential Clinical Importance (PCI) Range
Unit
Increase from baseline
Systolic Blood Pressure
120 to <140 (Grade 1)
140 to <160 (Grade 2)
160 (Grade 3)
mmHg
Increase from baseline 
Diastolic Blood Pressure
80 to <90 (Grade 1)
90 to <100 (Grade 2)
100 (Grade 3)
mmHg
To identify temperature values of potential clinical importance, NCI-CTCAE v4.0 will be used 
to assign categories that align with the grades for ‘Hypothermia’ and ‘Fever’.
Vital Sign Parameter
Potential Clinical Importance (PCI) Range
Unit
Increase from baseline 
temperature
Increase to 38
Degrees 
C
Decrease from baseline 
Diastolic Blood Pressure
Decrease to 35
Degrees 
C
4.11
Statistical models
For the evaluation of ORR, extensive simulation studies were conducted and described in the 
Protocol to evaluate the performance of the design that incorporates multiple interim analyses, 
and develop the Bayesian statistical model. No Type I error rate adjustments for multiplicity in 
primary or secondary analyses will be conducted. 
5
Reference