An Open-Label, Single-arm Study to Evaluate the Safety and Efficacy of Dabrafenib in Combination With Trametinib in Chinese Patients With BRAF V600E Mutation-Positive Metastatic Non-Small Cell Lung Cancer
Phase: PHASE2
Conditions: Carcinoma, Non-Small-Cell Lung
Sponsor: Novartis Pharmaceuticals



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Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................6
List of figures ......................................................................................................................7
List of abbreviations............................................................................................................8
Glossary of terms...............................................................................................................10
Amendment 4 (13-Mar-2023) ...........................................................................................12
Amendment 3 (15-Oct-2021) ............................................................................................15
Amendment 2 (08-Jun-2020) ............................................................................................18
Amendment 1 ....................................................................................................................20
Protocol summary..............................................................................................................23
1
Introduction .......................................................................................................................26
1.1
Background............................................................................................................26
1.2
Purpose ..................................................................................................................28
2
Objectives and endpoints...................................................................................................28
3
Study design ......................................................................................................................29
4
Rationale............................................................................................................................30
4.1
Rationale for study design .....................................................................................30
4.2
Rationale for dose/regimen and duration of treatment ..........................................30
4.3
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs ......................................................................................................................30
4.4
Purpose and timing of interim analyses/design adaptations..................................31
4.5
Risks and benefits..................................................................................................31
4.6
Rationale for Public Health Emergency mitigation procedures ............................31
5
Population..........................................................................................................................32
5.1
Inclusion criteria ....................................................................................................32
5.2
Exclusion criteria...................................................................................................33
6
Treatment...........................................................................................................................36
6.1
Study treatment......................................................................................................36
6.1.1
Investigational and control drugs..........................................................36
6.1.2
Additional study treatments ..................................................................36
6.1.3
Treatment arms/group ...........................................................................36
6.1.4
Treatment duration................................................................................36
6.2
Other treatment(s)..................................................................................................37
6.2.1
Concomitant therapy.............................................................................37
6.2.2
Prohibited medication ...........................................................................39
6.3
Participant numbering, treatment assignment, randomization ..............................39

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6.3.1
Participant numbering...........................................................................39
6.3.2
Treatment assignment, randomization ..................................................40
6.4
Treatment blinding.................................................................................................40
6.5
Dose escalation and dose modification..................................................................40
6.5.1
Dose modifications................................................................................40
6.5.2
Dose Modification Guidelines - Adverse Events of Special Interest....42
6.6
Additional treatment guidance...............................................................................59
6.6.1
Treatment compliance...........................................................................59
6.6.2
Treatment of overdose...........................................................................59
6.7
Preparation and dispensation.................................................................................59
6.7.1
Handling of study treatment and additional treatment..........................60
6.7.2
Instruction for prescribing and taking study treatment .........................60
7
Informed consent procedures ............................................................................................61
8
Visit schedule and assessments .........................................................................................62
8.1
Screening ...............................................................................................................68
8.1.1
Eligibility screening ..............................................................................69
8.1.2
Information to be collected on screening failures.................................69
8.2
Participant demographics/other baseline characteristics .......................................69
8.3
Efficacy..................................................................................................................70
8.3.1
Efficacy assessments.............................................................................70
8.3.2
Transmission of radiological data to central independent review.........72
8.4
Safety.....................................................................................................................73
8.4.1
Laboratory evaluations..........................................................................74
8.4.2
Cardiac assessments..............................................................................75
8.4.3
Pregnancy and assessments of fertility .................................................76
8.4.4
Hepatitis marker....................................................................................77
8.4.5
Ophthalmic examination.......................................................................78
8.5
Additional assessments..........................................................................................78
8.5.1
Clinical Outcome Assessments (COAs) ...............................................78
8.5.2
Pharmacokinetics ..................................................................................79
8.5.3
Biomarkers............................................................................................80
9
Study discontinuation and completion ..............................................................................81
9.1
Discontinuation......................................................................................................81
9.1.1
Discontinuation of study treatment .......................................................81
9.1.2
Survival follow-up ................................................................................82
9.1.3
Withdrawal of informed consent/Opposition to use data/biological 
samples..................................................................................................82

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9.1.4
Lost to follow-up...................................................................................83
9.1.5
Early study termination by the sponsor.................................................83
9.2
Study completion and post-study treatment ..........................................................83
10 Safety monitoring and reporting........................................................................................84
10.1
Definition of adverse events and reporting requirements......................................84
10.1.1
Adverse events ......................................................................................84
10.1.2
Serious adverse events ..........................................................................86
10.1.3
SAE reporting........................................................................................87
10.1.4
Pregnancy reporting ..............................................................................88
10.1.5
Reporting of study treatment errors including misuse/abuse................88
10.2
Additional Safety Monitoring................................................................................89
11 Data Collection and Database management......................................................................89
11.1
Data collection.......................................................................................................89
11.2
Database management and quality control............................................................89
11.3
Site monitoring ......................................................................................................90
12 Data analysis and statistical methods ................................................................................91
12.1
Analysis sets ..........................................................................................................91
12.2
Participant demographics and other baseline characteristics.................................91
12.3
Treatments .............................................................................................................91
12.4
Analysis of the primary endpoint(s) ......................................................................92
12.4.1
Definition of primary endpoint(s).........................................................92
12.4.2
Statistical model, hypothesis, and method of analysis..........................92
12.4.3
Handling of missing values/censoring/discontinuations.......................92
12.4.4
Sensitivity analyses ...............................................................................92
12.5
Analysis of secondary endpoints ...........................................................................92
12.5.1
Efficacy endpoint(s)..............................................................................92
12.5.2
Safety endpoints....................................................................................93
12.5.3
Pharmacokinetics ..................................................................................95
12.5.4
Patient reported outcomes.....................................................................95
95
12.7
Interim analyses.....................................................................................................95
95
95
96
13 Ethical considerations and administrative procedures ......................................................96
13.1
Regulatory and ethical compliance........................................................................96
13 2
Responsibilities of the investigator and IRB/IEC
..............................96

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13.3
Publication of study protocol and results...............................................................96
13.4
Quality Control and Quality Assurance.................................................................97
14 Protocol adherence ............................................................................................................97
14.1
Protocol amendments.............................................................................................97
15 References .........................................................................................................................99
16 Appendices ......................................................................................................................102
16.1
Appendix 1: Response Criteria; Response Evaluation Criteria in Solid 
Tumors (RECIST) ...............................................................................................102
16.1.1
Introduction.........................................................................................102
16.1.2
Efficacy assessments...........................................................................103
16.1.3
Efficacy definitions .............................................................................112
16.1.4
Data handling and programming rules................................................122
16.1.5
References (available upon request) ...................................................125

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List of tables
Table 2-1
Objectives and related endpoints ..........................................................28
Table 6-1
Investigational drug...............................................................................36
Table 6-2
Dose Modification Guidelines - General ..............................................40
Table 6-3
Dose Modification steps for dabrafenib and trametinib........................41
Table 6-4
Reference of AEs and toxicity management guidelines .......................42
Table 6-5
Mandatory dose modification and recommended clinical 
management guidelines for suspected treatment-related pyrexia .........43
Table 6-6
Guidelines for Supportive Care of Rash ...............................................44
Table 6-7
Mandatory dose modifications and recommended clinical 
management guidelines for rash............................................................44
Table 6-8
Mandatory dose modifications and recommended clinical 
management guidelines for hand foot skin reaction (palmar-plantar 
erythrodysesthesia)................................................................................46
Table 6-9
Management and Dose Modification Guidelines for Diarrhea.............47
Table 6-10
Management and Dose Modification Guidelines for Pneumonitis.......48
Table 6-11
Mandatory dose modifications and recommended clinical 
management guidelines for renal insufficiency ....................................49
Table 6-12
Mandatory dose modification and recommended clinical 
management for hypertension suspected to be related to dabrafenib 
and/or trametinib treatment...................................................................52
Table 6-13
Mandatory dose modification and recommended clinical 
management for changes in LVEF........................................................53
Table 6-14
Mandatory dose modification and recommended clinical 
management for visual changes and/or ophthalmic examination 
findings..................................................................................................54
Table 6-15
Mandatory dose modification and recommended clinical 
management for retinal pigment epithelial detachments (RPED) 
suspected to be related to trametinib treatment.....................................55
Table 6-16
Mandatory dose modifications and recommended clinical 
management guidelines for abnormal liver enzyme test.......................57
Table 6-17
Dose treatment and schedule.................................................................61
Table 8-1
Assessment Schedule ............................................................................63
Table 8-2
Imaging Assessment Collection Plan....................................................72
Table 8-3
Physical Examination, Vital Signs, Height and Weight 
& Specifications....................................................................................73
Table 8-4
ECOG performance status scale............................................................74
Table 8-5
Clinical laboratory parameters collection plan .....................................74
Table 8-6
ECG collection plan..............................................................................75

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Table 8-7
Sample log table for the evaluation of pharmacokinetics 
of trametinib , dabrafenib, and related metabolites...............................79
Table 8-8
Biomarker sample collection plan.........................................................80
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse .........................................................................................89
96
Table 16-1
Response criteria for target lesions .....................................................108
Table 16-2
Response criteria for non-target lesions..............................................110
Table 16-3
Overall lesion response at each assessment ........................................111
Table 16-4
Overall lesion response at each assessment: patients with non-
target disease only...............................................................................119
Table 16-5
Options for event dates used in PFS, TTP, duration of response........120
List of figures
Figure 3-1
Study Design .........................................................................................30

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List of abbreviations
AE
adverse event
AESI
adverse event of special interest
ALK
anaplastic lymphoma kinase
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
b.i.d.
twice a day
BMI
Body Mass Index
BUN
blood urea nitrogen
CDS
Core Data Sheet (for marketed drugs)
CFR
Code of Federal Regulation
CRF
Case Report/Record Form (paper or electronic)
CRO
Contract Research Organization
CRP
C-reactive protein
CSCO
Chinese Society of Clinical Oncology
CTC
Common Toxicity Criteria
CTRD
Clinical Trial Results Database
CV
coefficient of variation
DoR
Duration of response
EC
Ethics committee
ECG
Electrocardiogram
EDC
Electronic Data Capture
EGFR
epithelial growth factor receptor
FDA
Food and Drug Administration
FPFV
First patient first visit
GCP
Good Clinical Practice
GGT
Gamma-glutamyl transferase
h
hour
HIV
human immunodeficiency virus
HLH
hemophagocytic lymphohistiocytosis 
i.v.
intravenous
IB
Investigator’s Brochure
ICF
Informed consent form
ICH
International Council for Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IRB
Institutional Review Board
IRT
Interactive Response Technology
LDH
lactate dehydrogenase
LFT
Liver function test
LLN
lower limit of normal
LLQ
lower limit of quantification
LPLV
Last patient last visit
MedDRA
Medical dictionary for regulatory activities

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mg
milligram(s)
mL
milliliter(s)
MOH
Ministry of Health
NMPA
National Medical Products Administration
NSCLC
Non-small cell lung cancer
o.d.
once a day
ORR
Overall response rate
OS
Overall survival
p.o.
oral
PD
pharmacodynamic(s)
PFS
Progression-free survival
PK
pharmacokinetic(s)
PTA
Post-trial access
REB
Research Ethics Board
RECIST
response evaluation criteria in solid tumors
SAE
serious adverse event
SCAR
Serious cutaneous adverse reaction
SD
standard deviation
SOM
Site Operations Manual
SUSAR
Suspected Unexpected Serious Adverse Reactions
ULN
upper limit of normal
WHO
World Health Organization

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Glossary of terms
Assessment
A procedure used to generate data required by the study
Biologic Samples
A biological specimen including, for example, blood (plasma, serum), saliva, 
tissue, urine, stool, etc. taken from a study participant
Clinical Outcome
Assessment (COA)
A measure that describes or reflects how a participant feels, functions, or survives
Coded Data
Personal Data which has been de-identified by the investigative center team
by replacing personal identifiers with a code.
Cohort
A specific group of participants fulfilling certain criteria
Control drug
A study drug used as a comparator to reduce assessment bias, preserve blinding 
of investigational drug, assess internal study validity, and/or evaluate comparative 
effects of the investigational drug.
Dosage
Dose of the study treatment given to the participant in a time unit (e.g. 100 mg 
once a day, 75 mg twice a day)
Discontinuation from
study
Point/time when the participant permanently stops receiving the study
treatment and further protocol required assessments or follow-up, for any reason. 
No specific request is made to stop the use of their samples or data.
Discontinuation from 
study treatment
Point/time when the participant permanently stops receiving the study
treatment for any reason (prior to the planned completion of study
intervention administration, if any). Participant agrees to the other
protocol required assessments including follow-up. No specific request is
made to stop the use of their samples or data.
Electronic Data Capture 
(EDC)
Electronic data capture (EDC) is the electronic acquisition of clinical study data 
using data collection systems, such as Web-based applications, interactive voice 
response systems and clinical laboratory interfaces. EDC includes the use of 
Electronic Case Report Forms (eCRFs) which are used to capture data 
transcribed from source data/documents used at the point of care.
Enrollment
Point/time of participant entry into the study at which informed consent must be 
obtained (i.e. prior to starting any of the procedures described in the protocol)
Enrollment number
A unique identifier assigned to each enrolled participant
Epoch
Interval of time in the planned conduct of a study. An epoch is associated with a 
purpose (e.g. screening, randomization, treatment, follow-up), which applies 
across all arms of a study.
Healthy volunteer
A person with no known significant health problems who volunteers to be a study 
participant 
Investigational drug
The study drug whose properties are being tested in the study
Investigational treatment
All investigational drug(s) whose properties are being tested in the study as well 
as their associated treatment controls. This includes any placebos, any active 
controls, as well as approved drugs used outside of their indication/approved 
dosage or tested in a fixed combination. Investigational treatment generally does 
not include other treatments administered as concomitant background therapy 
required or allowed by the protocol when used within approved indication/dosage.
Medication number
A unique identifier on the label of each study drug package in studies that 
dispense study drug using an IRT system.
Medication pack number
A unique identifier on the label of each drug package in studies that dispense 
study treatment using an IRT system
Non-investigational 
medicinal Product (NIMP)
Products which are not the object of investigation (e.g. any background therapy 
administered to each of the clinical trial participants, regardless of randomization 
group, rescue medication, active drug run-ins etc.)

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Part
A single component of a study which contains different objectives or populations 
within that single study. Common parts within a study are: a single dose part and 
a multiple dose part, or a part in patients with established disease and in those 
with newly-diagnosed disease.
Patient
An individual with the condition of interest
Patient-Reported
Outcome (PRO)
A measurement based on a report that comes directly from the participant about 
the status of a participant's health condition without amendment or interpretation 
of the participant’s report by a clinician or anyone else.
Period
A minor subdivision of the study timeline; divides phases into smaller functional 
segments such as screening, baseline, titration, washout, etc.
Premature participant 
withdrawal
Point/time when the participant exits from the study prior to the planned
completion of all study drug administration and assessments; at this time all study 
drug administration is discontinued and no further assessments are planned.
Screen Failure
A participant who is screened but is not treated or enrolled
Stage
A major subdivision of the study timeline; begins and ends with major study 
milestones such as enrollment, randomization, completion of treatment, etc.
Study completion
Point/time at which the participant came in for a final evaluation visit or when 
study drug was discontinued whichever is later.
Study drug 
discontinuation
Point/time when participant permanently stops taking study drug for any reason; 
may or may not also be the point/time of premature participant withdrawal.
Study drug/treatment
Any drug (or combination of drugs) administered to the participant as part of the 
required study procedures; includes investigational drug, active drug run-ins or 
background therapy.
Study treatment
Any drug administered to the study participants as part of the required study 
procedures; includes investigational drug (s), control(s) or non-investigational 
medicinal product(s)
Study treatment 
discontinuation
When the participant permanently stops taking study treatment prior to the 
defined study treatment completion date
Participant
An individual who has consented to participate in this study. The term Participant 
may be used to describe either a healthy volunteer or a patient.
Participant number
A number assigned to each participant who enrolls in the study. When combined 
with the center number, a unique identifier is created for each participant in the 
study. This number is the definitive, unique identifier for the participant and should 
be used to identify the participant throughout the study for all data collected, 
sample labels, etc.
Treatment number
A unique identifier assigned in non-randomized studies to each dosed participant, 
corresponding to a specific treatment arm 
Variable
Information used in the data analysis; derived directly or indirectly from data
collected using specified assessments at specified timepoints.
Withdrawal of study 
consent (WoC) / 
Opposition to use of data 
/biological samples
Withdrawal of consent from the study occurs when the participant explicitly 
requests to stop use of their data and biological samples (opposition to use data 
and biological samples) AND no longer wishes to receive study treatment, AND 
does not agree to further protocol required assessments. This request should be 
in writing (depending on local regulations) and recorded in the source 
documentation.
Opposition to use data/biological samples occurs in the countries where collection 
and processing of personal data is justified by a different legal reason than 
consent.

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Amendment 4 (13-Mar-2023)
Amendment rationale 
As of the release date of this amendment, 34 participants have been enrolled and treated in this 
study. China NMPA provided NDA conditional approval on 22-Mar-2022 Tafinlar (Dabrafenib 
Mesylate Capsules) in combination with Mekinist (Trametinib Tablets) for the treatment of 
patients with metastatic non-small cell lung cancer (NSCLC) with BRAF V600 mutation.
The main purpose for this amendment is to add updated safety information, hemophagocytic 
lymphohistiocytosis (HLH) observed with dabrafenib and trametinib combination therapy, 
obtained from post marketing experience. 
This amendment also introduces the following changes:

Align the dose modification section of the protocol for hemophagocytic 
lymphohistiocytosis (HLH) with the dabrafenib Investigator’s Brochure (IB) edition 15 
and trametinib IB edition 15.

Clarify description of the requirements for central BRAF V600 E mutation testing

Update the rescreening procedure for screen failure subjects.

Clarify the study completion and post-study treatment requirements

Clarify the safety endpoint description for Adverse Events.

Clarify the use of platinum-based treatment as mandatory for pre-treated subjects

Wording changes to align with new Novartis protocol template v5.0 language:

Add new section on reference to treatment of overdose

Add sentence to clarify that data and samples collected from participants prior to 
screen failures may still be analyzed

Clarify the documentation of efficacy assessment in Central Imaging

Update the wording for women of child-bearing potential

Add text that eCOA assessments will not be reviewed by the Investigator/ study 
personnel.

Update the Pregnancy reporting language

Clarify the reporting of study treatment errors including misuse/abuse

Removal of text relating to the withdrawal of consent in certain countries where 
consent is not required for the use of personal and coded data
In addition, editorial revisions, corrections are made throughout the protocol to improve 
consistency.

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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.
Updated List of abbreviations
Updated Glossary of terms
Protocol summary: Updated to align with the amended protocol
Section 5.1 Inclusion Criteria

Clarified the inclusion criteria wording regarding BRAF central lab testing. Inclusion 
criteria 3: the term “fresh tumor tissue sample” changed to “new tumor tissue sample” (to 
align with Section 8.5.3)

Clarified the text of the Inclusion Criteria 4 for the use of platinum-based treatment as 
mandatory for pre-treated subjects (to align with Table 3-1)
Section 6.5.2.10 Guideline dose modification and management for hemophagocytic 
lymphohistiocytosis (HLH)

Added the guideline dose modification and management for hemophagocytic 
lymphohistiocytosis (HLH)
Section 6.6.2 Treatment of overdose

Added new section on reference to treatment of overdose
Section 8.1 Screening

Updated the rescreening procedure for screen failure subjects to enable the rescreening of 
all the subjects regardless of the initial screen failure reason (i.e CT /MRI results have 
expired (>28 days prior to enrollment) due to unexpected administrative issues or 
unexpected drug supply issue

Clarification that a new sample is not needed if participant already provided the tumor 
tissue samples for central testing of BRAF V600E mutation.
Section 8.1.2 Information to be collected on screening failures

Added sentence to clarify that data and samples collected from participants prior to screen 
failures may still be analyzed
Section 8.3.1 Efficacy assessments

Clarified the documentation of efficacy assessment in Central Imaging
Section 8.4.3 Pregnancy and assessments of fertility

Updated the wording for women of child-bearing potential
Section 8.5.1 Clinical Outcome Assessments (COAs)

Added text that eCOA assessments will not be reviewed by the Investigator/ study 
personnel.
Section 8.5.3 Biomarkers

Updated description of the requirements for central BRAF V600 E mutation testing

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Section 9.1.3 Withdrawal of informed consent/Opposition to use data/biological samples

Removed text related to the withdrawal of consent in certain countries where consent is 
not required for the use of personal and coded data
Section 9.2 Study completion and post-study treatment

Clarified the study completion date from ‘approximately’ 17 months to 17 months and 
separated from post-study treatment requirements
Section 10.1.4 Pregnancy Reporting

Updated the Pregnancy reporting language
Section 10.1.5 Reporting of study treatment errors including misuse/abuse

Clarified the reporting of study treatment errors including misuse/abuse
Section 12.5.2 Safety Endpoints

Clarified the safety endpoint description for Adverse Events.
Section 15 References

Updated list of references
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation.
The changes herein do not affect the Informed Consent. The Informed Consent for this study 
was already updated to reflect the hemophagocytic lymphohistiocytosis (HLH) safety measure 
after the IB updates in 2022.

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Amendment 3 (15-Oct-2021)
Amendment rationale 
As of the release date of this protocol amendment, 20 participants have been enrolled and treated 
in this study. A primary analysis has been conducted with a cut-off date of 11-Mar-2021. 
The main purpose for this amendment is to increase the sample size from 20 to 40 participants 
to further investigate the efficacy and safety of dabrafenib and trametinib in Chinese patients 
with BRAF V600E mutation-positive metastatic non-small cell lung cancer (NSCLC). As per 
China National Medical Products Administration (NMPA) guidance, the sample size was 
increased. 
This amendment also introduces the following changes :

Align the dose modification section of the protocol for pyrexia with the dabrafenib 
Investigator’s Brochure (IB) edition 13 and trametinib IB edition 13.

Removed the carboxy-dabrafenib metabolite from the pharmacokinetic (PK) analysis. 
Based on exposure, relative potency, and PK properties, the activity of carboxy-dabrafenib 
is not likely to be clinically relevant. Analysis of carboxy-dabrafenib will be discontinued 
and PK of this metabolite for the additional patients will not be performed.

Include a section related to Public Health Emergency mitigation procedures.

Update the permitted concomitant therapy section of the protocol with a clarification on 
the use of vaccines. 

Include pandemic disruption proofing language under protocol sections 6.7, 7, 8, 8.3.1, 
8.4, 8.4.1, 8.4.3, and 8.5.1. 

Update the withdrawal of informed consent language to align with the new Novartis 
protocol template version 4.0.

Update the end of study definition.

Replace “subjects” with term “participants” throughout the protocol. 
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions.
List of abbreviations: updated the ORR definition, and added CRP/IB/ICF/MOH/PTA 
abbreviations 
Glossary of terms: updated withdrawal of study consent definition
Protocol summary: updated to align with the amended protocol
Section 1.2 Purpose

Updated the additional number of patients to be enrolled 

Updated the additional number of previously treated, and treatment naive patients to be 
enrolled
Section 2 Table 2-1 Objectives and related endpoints 

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
Updated the ORR defined form

Clarified dabrafenib metabolites
Section 3 Study design

Updated the total number of patients to be enrolled 
Section 4.1 Rationale for study design

Updated the additional number of patients to be enrolled as well as the enrolment period 

Removed the follow-up period for Study BRF113928
Section 4 Rationale

Added new sub-section 4.6 Rationale for Public Health Emergency mitigation procedures
Section 6.2.1 Concomitant therapy 

Removed “Inactivated vaccines” as a clarification is provided under section 6.2.1.1 
Permitted concomitant therapy requiring caution and/or action
Section 6.2.1.1 Permitted concomitant therapy requiring caution and/or action 

Clarified the use of vaccines 
Section 6.5.2.1 Pyrexia 

Updated dose modification guidelines for cases of pyrexia 
Section 6.5.2.1 Table 6-5 Mandatory dose modification and recommended clinical management 
guidelines for suspected treatment-related pyrexia 

Updated requirement for suspected treatment-related cases of pyrexia
Section 6.7 Preparation and dispensation 

Added disruption proofing language 
Section 7 Informed consent procedures 

Added disruption proofing language 
Section 8 Visit schedule and assessments 

Added disruption proofing language 
Section 8.3.1 Table 8-2 Imaging Assessment collection Plan 

Added disruption proofing language 
Section 8.4 Safety 

Added disruption proofing language 
Section 8.4.1 Laboratory evaluations 

Added disruption proofing language 
Section 8.4.3 Pregnancy and assessments of fertility 

Added disruption proofing language 
Section 8.5.1 Clinical Outcome Assessments (COAs) 

Added disruption proofing language 

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Amendment 2 (08-Jun-2020)
Amendment rationale 
As of the release date of this protocol amendment, no patients have been screened or treated in 
this study.
The main purpose for this amendment is to reduce the amount of tumor material required for 
central BRAF V600E testing, following Human Genetic Resource Administration of China 
(HGRAC) recommendation and data obtained during the assay testing by the central laboratory. 
In order to complete the BRAF V600E testing at the central lab, the number of formalin-fixed 
paraffin-embedded (FFPE) tumor slides is reduced from minimum 10, to minimum 3 to 
maximum 5 slides, and tumor blocks are no longer needed.
This amendment also introduces the following changes:

Update to exclusion criteria #1 in order to exclude patients with leptomeningeal 
metastases (LM) under the same conditions as patients with brain metastases: patients 
with non-small cell lung cancer (NSCLC) experience LM in 3-9% of cases. Because 
overall survival (OS) and performance status of those patients with LM are very poor, they 
are mostly excluded from clinical trials. In order to avoid confounding efficacy results, 
exclusion criteria #1 has been updated.

An ophthalmic evaluation is added at Week 3, in accordance with the median time to 
onset of MEK inhibitor associated retinopathy. Retinopathy is a known adverse event seen 
with MEK inhibitor therapy, including trametinib.
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.
Protocol summary: updated to align with the amended protocol
Section 3 Study design

Clarification regarding central BRAF V600E testing
Section 5.1 Inclusion criteria

Clarification regarding central BRAF V600E testing
Section 5.2 Exclusion criteria

Added leptomeningeal metastases to exclusion criteria #1
Section 6.5.2.10 Mandatory dose modification and management guideline for visual changes

Added information regarding MEK inhibitor associated retinopathy
Section 7 Informed consent procedures

Updated common adverse effects
Section 8 Visit schedule and assessments

Clarification about assessments to record in the subject’s source documentation
Table 8-1 Assessment schedule

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
Clarification about assessments to record in the subject’s source documentation

Harmonized presentation of assessments to perform at week 15 and every 3 weeks 
thereafter

Clarification of period and visit names for post treatment follow-up phase

Added ophthalmic assessment at Week 3
Section 8.1 Screening

Updated the requirements for assigned subject number in case of subject re-screening

Updated number of tumor slides to minimum 3 to maximum 5

Clarification regarding central BRAF V600E testing

Removed tumor block for BRAF V600E testing

Removed sentence regarding centrally confirmed BRAF V600E
Section 8.3.1. Efficacy assessments

Updated to Novartis guideline version 3.2 based on RECIST 1.1

Added information regarding cytology and histology report form shared with imaging 
CRO
Table 8-2 Imaging Assessment Collection Plan

Clarified assessments may be performed if clinically indicated
Section 8.5.3 Biomarkers and Table 8-8 Biomarker sample collection plan

Clarification regarding central BRAF V600E testing

Removed tumor block for BRAF V600E testing

Updated number of tumor slides to minimum 3 to maximum 5
Section 10.1.1 Adverse Events

Updated list of AESI for trametinib
Section 15 References

Added two references
Section 16 Appendices

Updated Appendix 1 to reflect Novartis guideline version 3.2 based on RECIST 1.1
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.

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Section 4.1 Rationale for study design

Updated to ORR by central independent review
Section 5.1 Inclusion criteria

Updated inclusion criteria #4 for pre-treated subjects
Section 5.2 Exclusion criteria

Updated exclusion criteria #4 for previous chemotherapy
Section 6.1.4 Treatment duration

Updated to disease progression determined by investigator
Table 6-7 Mandatory dose modifications and recommended clinical management guidelines for 
rash

Added requirement for suspected cases of serious skin reactions section
Section 6.5.2.3 Mandatory dose modifications and recommended clinical management of 
serious skin reactions

Added dose modification guidelines and clinical management for cases of SCARs
Table 8-1 Assessment schedule

Clarified tumor follow-up phase and efficacy follow-up schedule

Added survival follow-up period

Added requirements for patient reported outcome at week 15 and every 3 weeks thereafter
Section 8.1 Screening

Clarified BRAF V600E mutation testing requirements at screening
Section 8.3.1 Efficacy assessments

Updated to tumor assessment by investigator and by central independent review

Updated to reflect the use of a central independent review

Updated requirement for whole body scan at baseline
Table 8-2 Imaging assessment collection plan

Updated requirement for whole body scan
Section 8.3.2 Transmission of efficacy data to central independent review

New section added to describe the process for sharing images with the imaging CRO and 
timepoints for central independent review
Table 8-5 Clinical laboratory parameters collection plan

Removed Bands from the laboratory parameters
Section 9.1.1 Discontinuation of study treatment

Added timeframe for preventing to repeat assessments at EOT

Updated to disease progression determined by investigator

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Section 9.1.2 Survival follow-up

New section added to describe the survival follow-up visit and timelines
Section 10.1.1 Adverse events

Updated CTCAE to version 4.03
Section 12.4.1 Definition of primary endpoint(s)

Updated to ORR by central independent review
Section 12.5.1 Efficacy endpoints

Added definition of ORR
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval and Health 
Authority notification according to local regulations prior to implementation.
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 

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
Participants who have received prior therapy with checkpoint inhibitor therapy 
(i.e. anti-PD-1/PD-L1) as the last treatment regimen must have had a 
confirmed disease progression while on or after this therapy prior to 
enrollment. 

Participants with EGFR or ALK mutation who have previously received 
therapy with EGFR or ALK inhibitor(s) respectively are eligible.
Key Exclusion 
criteria
Key exclusion criteria are listed below, please refer to the protocol for the full list of 
exclusion criteria:

Participants with brain or leptomeningeal metastases are excluded if these 
metastases are: 

Symptomatic OR

Treated (surgery, radiation therapy) but not clinically and radiographically 
stable 3 weeks after local therapy (as assessed by contrast enhanced 
magnetic resonance imaging [MRI] or computed tomography [CT]), OR

Asymptomatic and untreated but >1 cm in the longest dimension

Previous treatment with a BRAF inhibitor or a MEK inhibitor.

All prior anti-cancer treatment-related toxicities (except alopecia and laboratory 
values as listed on Table 8-5) must be Grade 2 or less according to the Common 
Terminology Criteria for Adverse Events version 4 (CTCAE version 4.03; NCI, 2009) 
at the time of enrollment.

Prior systemic anti-cancer treatment (chemotherapy, radiotherapy, biologic therapy, 
vaccine therapy, or investigational treatment) within the last 2 weeks, and prior 
treatment with immune checkpoint inhibitor within 4 weeks preceding the first dose of 
the combination.
Study treatment
Dabrafenib (DRB436), and trametinib (TMT212)
Efficacy 
assessments
Radiological tumor response will be assessed by investigator assessment and in 
addition independently assessed by central review using RECIST version 1.1.
The following assessments are required at screening/baseline:

Chest, abdomen, and pelvis CT or MRI

Brain CT or MRI

Whole body bone scan

Localized bone CT, MRI, or x-ray, for any lesions identified on the whole body bone 
scan that are not visible on the chest, abdomen, and pelvis CT or MRI

Color photography including a metric ruler to measure the size of the lesion for any 
skin lesions present

CT or MRI of other metastatic sites (e.g. neck), if clinically indicated
Post-baseline imaging assessments will be performed every 6 weeks until week 36, and 
then every 12 weeks until disease progression per RECIST version 1.1 (as assessed by 
the investigator), death, lost to follow-up or withdrawal of consent.
Pharmacokinetic 
assessments 
Pharmacokinetics of dabrafenib, dabrafenib metabolites (hydroxy-dabrafenib, and 
desmethyl-dabrafenib), and trametinib.
Key safety 
assessments

Adverse events

Physical examination

Weight and vital signs

Dermatological examination, skin biopsy, photography

Eastern Cooperative Oncology Group (ECOG) performance status

Laboratory assessments including hematology, chemistry, urinalysis, coagulation, 
hepatitis markers, and pregnancy test

12-lead ECG

Echocardiogram

Ophthalmic examination

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Other 
assessments 

Patient reported outcomes (PROs) assessments by the European Organization for 
Research and Treatment of Cancer core quality of life (EORTC QLQ-C30 and 
EORTC QLQ-LC13) and EuroQoL (EQ-5D-5L) questionnaires.

Biomarkers: archival or new tumor biopsy sample for BRAF V600E mutation testing.
Data analysis
The primary endpoint of the study is overall response rate (ORR), defined as the 
proportion of participants with best overall response (BOR) of complete response (CR) 
or partial response (PR), as per central independent review and according to RECIST 
1.1. The ORR will be summarized along with its exact 95% confidence intervals.
Key words
Metastatic Non-Small Cell Lung Cancer (NSCLC), Chinese patients, dabrafenib 
(DRB436), trametinib (TMT212), BRAF V600

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1
Introduction
1.1
Background
Lung cancer is one of the most frequently diagnosed cancer globally, with an estimated 1.8 
million new cases worldwide in 2012 and represents the leading cause of cancer-related deaths 
globally, with approximately 1.6 million deaths in 2012 (Ferlay et al 2015). Lung cancer is also 
the most prevalent cancer in China, with about 733,000 new cases per year and the leading 
cause of cancer-related death (Chen et al 2015). The prognosis for patients with metastatic 
disease remain extremely poor, with 5 years survival rates reported as less than 5% 
(Lu et al 2019).
Non-small cell lung cancer (NSCLC) accounts for approximately 85% of lung cancer diagnoses 
and approximately 70% of patients present with advanced disease (Molina et al 2008, 
Siegel et al 2015). Driver oncogene mutation have been identified in a subset of patients with 
NSCLC (Hirsch et al 2017). The more common targetable mutation are epidermal growth 
factor receptor (EGFR)-activated mutation or anaplastic lymphoma kinase (ALK) gene fusion. 
EGFR mutations occur in 10–20% of patients not of east Asian descent with NSCLC and in 
about 40% of Asian patients, while ALK-driven tumors represent 2–7% of NSCLCs and are 
more frequent in the Asian population (Hirsch et al 2017). With the completion of genomic 
analysis in lung cancer by The Cancer Genome Atlas (TCGA) Research Network, more and 
more sensitizing molecular alterations have been identified in genes such as KRAS, ROS1, 
RET,BRAF, HER2, MET exon 14, and PIK3CA that could potentially be targeted in NSCLC 
(The Cancer Genome Atlas Research Network 2014).
BRAF, one of the serine/threonine protein kinase, belongs to the RAF kinase family in the RAS-
RAF-MEK-ERK signaling pathway (Caparica et al 2016, Sánchez-Torres et al 2013). When 
activated by mutations, BRAF activates MEK and this leads to the activation of the ERK 
signaling pathway to promote cell growth, proliferation, and survival (Pao and Girard 2011). 
The most common mutation in BRAF is the valine (V) to glutamate acid (E) substitution at 
residue 600 (BRAF V600E), which results in a mutant BRAF protein that no longer requires 
dimerization for its activity and is constitutively active and transforming in vitro 
(Dankort et al 2007, Davies et al 2002, Ji et al 2007,Yang et al 2010). Somatic mutations in 
BRAF are found in several kinds of cancers, including melanoma, ovarian carcinomas, 
colorectal cancers, papillary thyroid cancers, and lung cancers. BRAF mutations are observed 
in 1–3% of NSCLC (Cardarella et al 2013, Marchetti et al 2011, Pratilas et al 2008).
Surgery is the treatment of choice for participants with NSCLC stages I through IIA, while 
participants with stage IIIB and IV NSCLC without targetable oncogenic drivers are usually 
treated with chemotherapy. The median overall survival of patients treated with platinum-based 
doublet chemotherapy is only 8-10 months, with approximately 50-70% of patients having 
disease stabilization or tumor shrinkage in response to first line chemotherapy 
(Scagliotti et al 2002, Scagliotti et al 2008, Schiller et al 2002). For NSCLC patients with 
known genetic alterations, such as EGFR, ALK, BRAF, or ROS-1 target therapies have been 
approved and completely transformed the treatment landscape and life expectancy for lung 
cancer (Barlesi et al 2016, National Health Commission of the People’s Republic of China 
2019). More recently immune checkpoint inhibitors have been introduced for the treatment of 
locally advanced and metastatic NSCLC patients without a targetable mutation monoclonal 

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antibodies targeting PD-1 and PD-L1 (nivolumab, durvalumab, pembrolizumab, and 
atezolizumab) have each demonstrated significant activity as monotherapy and superiority over 
single agent chemotherapy in pretreated NSCLC either PD-L1 selected or unselected and have 
been recently approved by the Health Authorities in this setting (Antonia et al 2017, 
Barlesi et al 2016, Langer et al 2016).
In China, the current standard of care for advanced NSCLC without targetable oncogenic 
drivers remain systemic chemotherapy with platinum-based regimens despite the recent 
approval of pembrolizumab as single agent or in combination with platinum-based doublet 
chemotherapy in first-line NSCLC. Second line choices for systemic therapy include docetaxel, 
pemetrexed, and EGFR-TKIs. Recently, PD-1 inhibitor became available in China as a new 
second-line choice for patients with metastatic NSCLC with intolerance to or progression after 
previous platinum-based chemotherapy (National Health Commission of the People’s Republic 
of China 2019). According to the Chinese Society of Clinical Oncology (CSCO), EGFR and 
ALK tyrosine kinase inhibitors could be used as first line systemic therapy in patients with 
EGFR and ALK sensitizing mutation and gene fusion that are documented before the 
application of first line therapy (National Health Commission of the People’s Republic of China 
2019).
Currently in China no target therapy is available for patients with BRAF mutation. The 
prevalence of BRAF V600 mutation in Chinese population with NSCLC is approximatively 
1.7% - 1.8% which is similar to the rate seen globally (Ding et al 2017, Gao et al 2018). Data 
on Chinese patients with BRAFV600-mutant NSCLC are inadequate as the majority of the 
studies have been conducted in Caucasian and enrolled patients mainly from Europe and 
America (Ding et al 2017). In a recent study the clinicopathologic features and outcomes of 
Chinese patients with NSCLC and BRAF mutations have been analyzed. Compared to patients 
with non-V600E mutations, patients with V600E-mutated tumors had a shorter progression-
free survival (PFS) to first-line chemotherapy, and BRAF mutation was more likely to be 
associated with adenocarcinoma and never smokers. Those finding further highlight the urgent 
need for novel and effective drugs inhibiting the BRAF pathway for Chinese patients with 
BRAF mutated NSCLC (Ding et al 2017).
Dabrafenib is a potent and selective inhibitor of BRAF kinase activity. Dabrafenib has 
demonstrated inhibition of a downstream pharmacodynamic biomarker (phosphorylated ERK 
[pERK]) in tumor cell lines, demonstrated anti-proliferative activity against multiple BRAF 
mutant tumor cell lines. Trametinib is a reversible, highly selective, allosteric inhibitor of 
MEK1 and MEK2. Trametinib is non-competitive towards adenosine triphosphate (ATP) and 
inhibits both MEK activation and kinase activity. 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 BRAF-inhibitors is often associated with reactivation 
of the MAPK pathway, which might render BRAF-inhibitor resistant melanoma cells 
susceptible to the combination of BRAF and MEK inhibition (Alcalá and Flaherty 2012). 
Moreover, combining a MEK and BRAF inhibitor may attenuate BRAF inhibitor-mediated 
hyperproliferative skin toxicities (Hatzivassiliou et al 2010).
Combination of dabrafenib and trametinib have been approved in United States (US), the 
European Union (EU), Japan and many other countries as treatments in patients with BRAF 

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mutated metastatic and adjuvant melanoma and non-small cell lung cancer (NSCLC). This 
combination is also approved for BRAF V600E mutated anaplastic thyroid carcinoma (ATC) in 
United States (US).
1.2
Purpose
The purpose of this single arm, open label, multicenter phase II study is to evaluate the efficacy 
and safety of dabrafenib in combination with trametinib in Chinese patients with BRAF V600E 
mutation-positive metastatic NSCLC.
As of today, no targeted therapy for advanced NSCLC with BRAF V600E mutation has been 
approved in China. The current standard therapy for BRAF V600E mutant advanced NSCLC 
remains chemotherapy, which is considered not effective (National Health Commission of the 
People’s Republic of China 2019).
In a global phase II study (DRB436E2201) of 57 patients with previously treated, advanced 
NSCLC with BRAF V600E mutation (cohort B), the combination of dabrafenib plus trametinib 
was associated with an ORR of 63% in 52 evaluable patients, and the disease control rate was 
79%. The median PFS was 9.7 months. In another cohort (cohort C) of the same phase II study, 
36 previously untreated patients with BRAF V600E mutation positive advanced NSCLC were 
treated with dabrafenib plus trametinib. The ORR was 64% and included two patients with a 
complete response and 21 with a partial response. The median PFS was 10.9 months as assessed 
by investigators. The side effect profile in both cohorts was consistent with that observed in 
unresectable or metastatic melanoma (Planchard et al 2016, Planchard et al 2017). Based on the 
results of this study, dabrafenib in combination with trametinib was approved for the treatment 
of patients with BRAF V600E mutant advanced NSCLC in the US, EU, Japan and other 
countries.
This study was originally conducted in 20 BRAF V600E mutated NSCLC patients 
(approximately 10 previously treated and 10 treatment naive patients) with the aim to provide 
evidence of efficacy of dabrafenib and trametinib treatment in Chinese patients. Following 
primary analysis cut-off on 11-Mar-2021, approximately 20 additional patients will be enrolled 
(approximately 10 previously treated and 10 treatment naive patients) to further investigate the 
efficacy and safety of dabrafenib and trametinib in Chinese patients with BRAF V600E 
mutation-positive metastatic NSCLC. 
2
Objectives and endpoints
Table 2-1
Objectives and related endpoints
Objective(s)
Endpoint(s)
Primary objective(s)
Endpoint(s) for primary objective(s)

To assess the overall response rate (ORR) 
by central independent review 

ORR, defined as the percentage of participants with a 
confirmed complete response (CR) or partial response 
(PR) by central independent review as per RECIST 1.1 
criteria
Secondary objective(s)
Endpoint(s) for secondary objective(s)

To assess overall response rate (ORR), 
progression-free survival (PFS), duration of 
response (DoR) by investigator assessment

ORR, defined as the percentage of participants with a 
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Objective(s)
Endpoint(s)

To evaluate overall survival (OS)
(PR) by investigator assessment as per RECIST 1.1 
criteria

PFS, defined as the interval between first dose and the 
earliest date of disease progression or death due to 
any cause.

DoR, defined for the subset of participants with 
confirmed CR or PR, as the time from first documented 
evidence of CR or PR until time of first documented 
disease progression or death due to any cause.

OS, defined as the time from first dose until death due 
to any cause.

To characterize the safety and tolerability of 
dabrafenib in combination with trametinib in 
Chinese patients with BRAF V600E 
mutation-positive stage IV NSCLC

Measurements used to evaluate safety will include 
AEs, physical and dermatological examinations, 
ophthalmic examination, vital signs, 12-lead ECGs, 
ECHO, and clinical laboratory tests.

To characterize PK of dabrafenib, 
dabrafenib metabolites (hydroxy-
dabrafenib, and desmethyl-dabrafenib), and 
trametinib

Trough concentrations of dabrafenib, dabrafenib 
metabolites (hydroxy-dabrafenib, and desmethyl-
dabrafenib), and trametinib at Visits of week 3, 6, and 
12.

To characterize quality of life as measured 
by the EORTC-QLQ C30, LC13 and the 
EQ-5D-5L

Change from baseline in EORTC QLQ-C30/LC13, and 
EQ-5D-5L
3
Study design
This is a single arm, open label, multicenter phase II study evaluating the efficacy and safety of 
dabrafenib in combination with trametinib in Chinese participants with BRAF V600E mutation-
positive AJCC v8 stage IV NSCLC.
Participants with stage IV BRAF V600E mutant NSCLC confirmed by local qualified assay 
(NMPA and/or MOH-approved) will be enrolled in this study. Central testing for BRAF V600E 
will be performed. This study will enroll participants:
1. who have not received any prior systemic anti-cancer therapy for metastatic disease (i.e. 
dabrafenib/trametinib will be the 1st line treatment for metastatic disease)
2. who have relapsed or progressed on at least one prior platinum-based chemotherapy prior 
to enrollment but cannot have received more than 3 prior systemic therapies for metastatic 
disease (i.e. dabrafenib/trametinib will be no less than second line treatment for metastatic 
disease).
All participants must not have been previously exposed to a BRAF or MEK inhibitor. 
Participants will receive the recommended dose of both drugs (dabrafenib 150 mg twice daily 
and trametinib 2 mg once daily).
The primary endpoint for the study is ORR as determined by central independent review using 
Response Evaluation Criteria in Solid Tumors (RECIST 1.1).
Approximately 40 Chinese patients over 18 years old will be enrolled in this study and will 
receive dabrafenib (150 mg BID) and trametinib (2 mg once daily) combination therapy until 

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disease progression by RECIST 1.1 as determined by investigator, unacceptable toxicity, start 
of a new antineoplastic therapy, pregnancy, withdrawal of consent, lost to follow-up, 
physician’s decision, death, or if study is terminated by the sponsor. Doses of study treatment 
may be modified and/or interrupted for management of toxicities associated with study 
treatment (Section 6.5).
Treatment beyond disease progression per RECIST as determined by investigator is allowed if 
protocol specific criteria are met (see Section 6.1.4.1). The tumor assessments will be 
performed every 6 weeks until Week 36, and every 12 weeks thereafter (See Table 8-2) until 
disease progression, death, lost of follow-up, or withdrawal of consent. Survival and new anti-
cancer therapy follow-up will continue until study completion.
Figure 3-1
Study Design
*For previously treated patients: up to three systemic treatments for metastatic disease with at least 
one prior approved platinum-based regimen will be allowed.
4
Rationale
4.1
Rationale for study design
The study is an open-label, single arm design with ORR by central independent review as the 
primary endpoint. The general study design has been discussed and agreed with China National 
Medical Products Administration (NMPA) and is using a similar design used in the global 
pivotal phase II study (BRF113928). The initial enrollment period was planned to last 
approximately 12 months (for the first 20 patients); the enrollment period for the 20 additional 
patients is also planned to last approximately 12 months. 
4.2
Rationale for dose/regimen and duration of treatment
Rationale for dabrafenib and trametinib combination dose
The starting dose in this study will be dabrafenib 150 mg twice daily (BID) and trametinib 2 
mg once-daily (QD) will be used in the study. These are the approved combination doses in EU 
and US for patients with advanced NSCLC with BRAF V600E mutation, based on results from 
Studies BRF113928, MEK115306, MEK116513, and MEK115532. No significant ethnic 
difference is found in Asian patients with respect to PK, safety and efficacy for both dabrafenib 
and trametinib.
4.3
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs
Not applicable.

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4.4
Purpose and timing of interim analyses/design adaptations
Not applicable.
4.5
Risks and benefits
The efficacy of dabrafenib and trametinib combination therapy for BRAF V600E mutation 
positive non-small cell lung cancer has been demonstrated in study BRF113928, based on the 
positive risk/benefit profile, and is an accepted treatment option globally for the population 
studied (Anguera and Majem 2018).The safety profile of dabrafenib in combination with 
trametinib is well characterized, and in study BRF113928 the observations were mostly 
consistent with the previously described safety profile in the melanoma Phase III studies 
(Hauschild et al 2012, Long et al 2015, Long et al 2014, Robert et al 2015). Adverse events 
primarily driven by the underlying lung cancer, such as cough, dyspnea, pleural effusion were 
more frequently reported in this study than those seen in the melanoma studies. Neutropenia 
was also more frequently reported in the Combination Second-Line Plus population (any grade: 
21%, grade 3/4: 11%) than melanoma studies. Neutropenia was less frequent with less severity 
in Combination First-Line population (any grade: 11%, grade 3/4: 8%). Overall, in study 
BRF113928 the safety profile was similar between the First-Line and Second-Line Plus 
Population except for neutropenia, as discussed above. The most frequently reported AEs of 
any grade with dabrafenib in combination with trametinib were: pyrexia, nausea, diarrhea, 
edema peripheral, dry skin, fatigue, and vomiting (Clinical Study Report Study No. 
CDRB436E2201). In this study we do not expect a different risk/safety profile compared to the 
one observed in the global study due to absence in ethnic sensitivity for BRAF and MEK 
inhibitors.
The study incorporates routine safety monitoring and regularly scheduled safety assessments to 
identify and report any potential safety issues. All participants must have safety evaluations for 
30 days after the last dose of study drug. Comprehensive dose modification, stopping rules and 
toxicity management plan for drug related adverse events are provided in the protocol in 
Section 6.5. The risk to these stage IV NSCLC patients in this trial may be minimized by 
compliance with the eligibility criteria and study procedures, as well as close clinical 
monitoring.
Women of child bearing potential and sexually active males must be informed that taking the 
study treatment may involve unknown risks to the fetus if pregnancy were to occur during the 
study and must agree that in order to participate in the study they must adhere to the 
contraception requirements outlined in the exclusion criteria. If there is any question that the 
participant will not reliably comply, they should not be entered or continue in the study.
The Investigator’s Brochure fully characterizes both efficacy and safety aspects of dabrafenib 
and/or trametinib treatment to enable its appropriate use to maximize benefit while minimizing 
risks to patients.
4.6
Rationale for Public Health Emergency mitigation procedures
During a Public Health emergency as declared by Local or Regional authorities (i.e., pandemic, 
epidemic or natural disaster), mitigation procedures to ensure participant safety and trial 
integrity are listed in relevant sections. Notification of the Public health emergency should be 

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discussed with Novartis prior to implementation of mitigation procedures and 
permitted/approved by Local or Regional Health Authorities and Ethics Committees as 
appropriate.
5
Population
Deviation from any eligibility criterion below excludes a patient from enrollment into the study. 
Patients who discontinue the study will not be replaced. Participants eligible in this study must 
meet all inclusion and none of the exclusion criteria:
5.1
Inclusion criteria
Participants eligible for inclusion in this study must meet all of the following criteria:
1. Signed informed consent must be obtained prior to performing any screening procedure.
2. Male or female ≥ 18 years of age at time of informed consent.
3. Histologically or cytologically confirmed diagnosis of Stage IV NSCLC (according to 
AJCC 8th edition) that is BRAF V600E mutation-positive by local test result from a 
qualified assay (NMPA and/or MOH-approved).

An archival or new tumor tissue sample should be available at the time of enrollment 
for central testing of BRAF V600E status (see Section 8.5.3 for details).
4. Previously treated or untreated for metastatic NSCLC (prior systemic treatment in the 
adjuvant setting is allowed) 

Participants previously treated should have received no more than 3 prior systemic 
therapies for metastatic disease, with at least one prior platinum based chemotherapy, 
and should have documented disease progression on a prior treatment regimen (i.e. 
RECIST 1.1)

Participants who have received prior therapy with checkpoint inhibitor therapy (i.e. 
anti-PD-1/PD-L1) as the last treatment regimen must have had confirmed disease 
progression (i.e. RECIST 1.1) while on or after this therapy prior to enrollment.

Participants with EGFR or ALK mutation who have previously received therapy with 
EGFR or ALK inhibitor(s) respectively are eligible.
5. Measurable disease per RECIST 1.1.
6. Anticipated life expectancy of at least 3 months.
7. ECOG performance status ≤ 2.
8. Adequate bone marrow and organ function as defined by the following laboratory values 
without continuous supportive treatment (such as blood transfusion, coagulation factors 
and/or platelet infusion, or red/white blood cell growth factor administration) as assessed 
by local laboratory for eligibility:
Hematological

Hemoglobin ≥ 9 g/dL

Absolute neutrophil count ≥ 1.5 × 109/L

Platelets ≥ 100 × 109/L

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Coagulation

PT/INR and PTT ≤ 1.5 x ULN. Participants receiving anticoagulation treatment may 
be allowed to participate with INR established within the therapeutic range prior to 
enrollment.
Renal

Serum creatinine < 1.5 mg/dL
Hepatic

Total bilirubin ≤ 1.5 × ULN (upper limit of normal) except for participants with 
Gilbert’s syndrome who 
may only be included if the total bilirubin is ≤ 3.0 × ULN or direct bilirubin ≤ 1.5 × 
ULN

AST and ALT ≤ 2.5 × ULN, except for participants with liver metastasis, who may 
only be included if AST/ALT ≤ 5.0 × ULN

Albumin ≥ 2.5 g/dL
9. Left ventricular ejection fraction (LVEF) ≥ lower limit of institutional normal (LLN) as 
assessed by ECHO or MUGA scan
10. Able to swallow and retain oral medication and must not have any clinically significant 
gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome
or major resection of the stomach or bowels.
5.2
Exclusion criteria
Participants meeting any of the following criteria are not eligible for inclusion in this study.
1. Participants with brain or leptomeningeal metastases are excluded if these metastases are:

Symptomatic OR

Treated (surgery, radiation therapy) but not clinically and radiographically stable 3 
weeks after local therapy (as assessed by contrast enhanced magnetic resonance 
imaging [MRI] or computed tomography [CT]), OR

Asymptomatic and untreated but >1 cm in the longest dimension
2. Previous treatment with a BRAF inhibitor or a MEK inhibitor.
3. All prior anti-cancer treatment-related toxicities (except alopecia and laboratory values as 
listed on Table 8-5) must be Grade 2 or less according to the Common Terminology 
Criteria for Adverse Events version 4 (CTCAE version 4.03; NCI, 2009) at the time of 
enrollment.
4. Prior anti-cancer treatment (chemotherapy, radiotherapy, biologic therapy, vaccine 
therapy, or investigational treatment) within the last 2 weeks, and prior treatment with 
immune checkpoint inhibitors within 4 weeks preceding the first dose of the study 
treatment.
5. Current use of a prohibited medication as described in Section 6.2.2.
6. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs 
chemically related to the study treatments, their excipients, and/or dimethyl sulfoxide 
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7. Participants with known history for testing positive for Human Immunodeficiency Virus 
(HIV)
8. History of another malignancy <3 years prior to starting study treatment or any 
malignancy with confirmed activating RAS-mutation. Note: Prospective RAS testing is 
not required. However, if the results of previous RAS testing are known, they must be 
used in assessing eligibility.
Exceptions: participants with any of the following malignancies within 3 years (does not 
include malignancies with confirmed activating RAS-mutation) are eligible: (a) a history 
of completely resected skin cancer, (b) successfully treated in situ carcinoma, (c) chronic 
lymphocytic lymphoma (CLL) in stable remission, or (d) indolent prostate cancer 
(definition: clinical stage T1 or T2a, Gleason score ≤ 6, and prostate specific antigen 
[PSA] <10 ng/mL) requiring no or only anti-hormonal therapy with histologically 
confirmed tumor lesions that can be clearly differentiated from lung cancer target and non-
target lesions are eligible
9. Cardiac or cardiac repolarization abnormality, including any of the following:

History or current diagnosis of cardiac disease indicating a significant risk of safety 
for participants participating in the study such as uncontrolled or significant cardiac 
disease, including any of the following: 

Recent (within last 6 months) myocardial infarction

Unstable angina (within last 6 months),

Uncontrolled congestive heart failure

Clinically significant (symptomatic) cardiac arrhythmias (e.g., sustained 
ventricular tachycardia, and clinically significant second or third-degree 
atrioventricular block without a pacemaker)
10. A history or current evidence/risk of retinal vein occlusion (RVO) or serous retinopathy 
including:

Presence of predisposing factors to RVO or serous retinopathy (e.g., uncontrolled 
glaucoma or ocular hypertension, uncontrolled hypertension, uncontrolled diabetes 
mellitus, or a history of hyperviscosity or hypercoagulability syndromes); or

Visible retinal pathology as assessed by ophthalmic examination that is considered a 
risk factor for RVO or central serous retinopathy such as: 

Evidence of new optic disc cupping;

Evidence of new visual field defects on automated perimetry;

Intraocular pressure >21 mmHg as measured by tonometry.
11. History or current interstitial lung disease or non-infectious pneumonitis.
12. Any serious or unstable pre-existing medical conditions (aside from malignancy 
exceptions specified above), psychiatric disorders, or other conditions that, in the opinion 
of the investigator, could interfere with the participant’s safety, obtaining informed 
consent, or compliance with study procedures.
13. Pregnant or nursing (lactating) women. Female patients who are lactating must 
discontinue nursing prior to the first dose of study treatment and must refrain from nursing 
throughout the treatment period and for 4 months following the last dose of study 
treatment.

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14. Women of childbearing potential, women physiologically capable of becoming pregnant, 
must use highly effective methods of contraception like:

Total abstinence (when this is in line with the preferred and usual lifestyle of the 
participant) Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of contraception.

Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy, or 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.

Male sterilization (at least 6 months prior to screening). The vasectomized male 
partner should be the sole partner for that participant.

Placement of a non-hormonal intrauterine device (IUD) or intrauterine system (IUS) 
with documented failure rate of less than 1% per year.
Above measures for effective contraception must be applied for the following period of 
time: during dosing and for 16 weeks after stopping treatment with dabrafenib in 
combination with trametinib.
Note(s):

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

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

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.
15. Sexually active males (including those that have had a vasectomy) must use a condom 
during intercourse and should not father a child during this period. The amount of time a 
patient must use a condom after last treatment is as follows:

16 weeks post treatment discontinuation of dabrafenib in combination with trametinib
16. Participants with active Hepatitis B infection (HbsAg positive) will be excluded.
Note: Participants with antecedent of Hepatitis B (anti-HBc positive, HbsAg and HBV-
DNA negative) are eligible.
17. Participants with positive test for hepatitis C ribonucleic acid (HCV RNA)
Note: Participants in whom HCV infection resolved spontaneously (positive HCV 
antibodies without detectable HCV-RNA) or those that achieved a sustained virological 
response after antiviral treatment and show absence of detectable HCV RNA ≥ 6 months 
(with the use of IFN-free regimes) or ≥ 12 months (with the use of IFN-based regimes) 
after cessation of antiviral treatment are eligible

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18. Concurrent participation in other clinical trials using experimental therapies.
6
Treatment
6.1
Study treatment
Study treatment includes the investigational drugs dabrafenib (DRB436) using 50 mg and 75
mg capsules and trametinib (TMT212) using 2 mg and 0.5 mg tablets. Study treatment will be 
provided as global clinical open-labeled supply or commercially sourced supply. Global 
supplies will be packed and labeled under the responsibility of Novartis Global Clinical Supply 
(GCS).
6.1.1
Investigational and control drugs
Table 6-1
Investigational drug
Investigational 
Drug
(Name and 
Strength)
Pharmaceutical 
Dosage Form
Route of 
Administration
Supply Type
Sponsor (global 
or local)
DRB436 75 mg
Capsule
Oral use
Open label 
participant packs; 
bottle
Sponsor (global or 
local)
DRB436 50 mg
Capsule
Oral use
Open label 
participant packs; 
bottle
Sponsor (global or 
local)
TMT212 2 mg
Tablet
Oral use
Open label 
participant packs; 
bottles
Sponsor (global or 
local)
TMT212 0.5 mg
Tablet
Oral use
Open label 
participant packs; 
bottles
Sponsor (global or 
local)
Dispense a 3 week supply of the study treatment with instructions. Allow for +/- 7 day visit 
window. Record dose reductions, dose interruptions/delays, and/or dose escalations in CRF.
6.1.2
Additional study treatments
No other treatment beyond investigational drug and control drug are included in this trial.
6.1.3
Treatment arms/group
This is a single arm study. Participants meeting all eligibility criteria as defined in Section 5
will receive dabrafenib 150 mg BID in combination with trametinib 2 mg once daily, starting 
from Day 1.
6.1.4
Treatment duration
Study treatment will be administered until the participant experiences one of the following: 
disease progression by RECIST 1.1 as determined by investigator assessment (and not meeting 
the criteria in Section 6.1.4.1), unacceptable toxicity, pregnancy, treatment discontinuation at 

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the discretion of the investigator or the participant, start of a new anti-neoplastic therapy, 
withdrawal of consent, lost to follow-up, death, or study termination by the sponsor.
6.1.4.1
Treatment beyond disease progression
Participants will be permitted to continue study treatment beyond disease progression per 
RECIST 1.1 as assessed by investigator review provided they meet all the following criteria:
1. Informed consent for treatment beyond disease progression is provided by the participant
2. The participant experienced a confirmed tumor response according to RECIST 1.1 while 
receiving study treatment or disease under study has remained no worse than stable for a 
period of at least 3 months while receiving study treatment.
3. Absence of signs and symptoms of clinical disease progression despite disease progression 
based on RECIST 1.1 criteria.
4. No treatment-related AEs of CTCAE grade 4 or serious AEs (SAEs) have occurred during 
the last 4 weeks of study treatment
5. Participant remains with stable performance status.
6. Continuation of treatment beyond progression should not delay critical interventions to 
treat/prevent severe complications of disease progression (e.g, CNS metastases), or 
prevent participants from receiving adequate care.
Participants who meet the above criteria are permitted to continue study treatment and continue 
all study procedures as outlined in Table 8-1. The reasons for the participant continuing 
treatment beyond progression will be documented in the eCRF.
In case of clinical deterioration or suspicion of disease progression, a follow-up imaging 
assessment should be performed promptly rather than waiting for the next scheduled assessment. 
Participants with evidence of further disease progression on an imaging assessment or who are 
no longer deriving clinical benefit will be permanently discontinued.
6.2
Other treatment(s)
6.2.1
Concomitant therapy
The investigator must instruct the participant to notify the study site of any new medication(s) 
he/she takes after start of study participation.
Prior antineoplastic therapies including medications, radiotherapy, and surgery are to be 
recorded on the separate prior antineoplastic therapy Case Report Forms during screening.
All medications, procedures, and significant non-drug therapies (including physical therapy, 
herbal/natural medications and blood transfusions) administered after the participant was 
enrolled into the study must be recorded on the appropriate Case Report Forms. Medication
entries must be specific to trade name, dose and units, frequency and route of administration, 
start and discontinuation dates, and reason for therapy. For medications administered one time, 
the frequency column may reflect “once.”
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt, the investigator should contact the Novartis medical monitor before

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allowing a new medication to be started. If the participant is already enrolled, contact 
Novartis to determine if the participant should continue participation in the study.
In general, concomitant medications and therapies deemed necessary for the supportive care 
(e.g., such as anti-emetics, anti-diarrhea) and safety of the participant are allowed except those 
prohibited in Section 6.2.2. Participants are permitted to use the following medications during 
study treatment:

Limited-field palliative radiotherapy to non-target lesion(s) may be allowed after 
documented discussion with Novartis study physician as concomitant therapy such as 
local therapies administered during the study treatment. Any radiotherapy must be listed 
on the appropriate eCRF. In case of palliative radiotherapy, the participant should 
interrupt dabrafenib and trametinib for fractionated radiotherapy and stereotactic 
radiosurgery before and after radiotherapy as outlined below (Anker et al 2016). 

Interrupt dabrafenib and trametinib ≥ 3 days before and after fractionated radiation

Interrupt dabrafenib and trametinib ≥ 1 day before and after stereotactic radiosurgery 
(SRS)

Antivirus medications to manage HBV or HCV infection and/or prevent reactivation (e.g., 
tenofovir); supportive care.

Medications to prevent or treat nausea or vomiting.

Anti-diarrheal medications (e.g., loperamide) for participants who develop diarrhea.

Pain medication to allow the participant to be as comfortable as possible.

Bone targeted therapies (e.g., bisphosphonates, denosumab) to treat bone metastases or to 
prevent skeletal related events.

Nutritional support or appetite stimulants (e.g., megestrol).

Oxygen therapy and blood products or transfusions.

The participant must be told to notify the investigational site about any new medications 
he/she takes after the start of the study drug
All medications (other than study drug) and significant non-drug therapies (including physical 
therapy, herbal/natural medications and blood transfusions) administered after the participant 
signed consent and through 30 days after the last dose of study treatment must be listed on the 
Concomitant Medications or the Procedures and Surgical and Medical Procedures eCRF.
Any anti-neoplastic therapy (including surgery, radiotherapy, medications) administered in the 
Follow-up Period after discontinuation of study treatment must be listed on Antineoplastic 
Medication Since Discontinuation eCRF pages including best response to therapy, if available.
6.2.1.1
Permitted concomitant therapy requiring caution and/or action
Dabrafenib 
Effect of other drugs on dabrafenib
Based on in vitro studies, dabrafenib was shown to be primarily metabolized by CYP2C8 and 
CYP3A4. Medicinal products that are strong inhibitors or inducers of CYP2C8 or CYP3A4 are 
likely to increase or decrease, respectively, dabrafenib concentrations. Alternative agents 
should be considered during administration with dabrafenib when possible. Use caution if 

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strong inhibitors (e.g ketoconazole, nefazodone, clarithromycin, ritonavir, gemfibrozil) or 
inducers (e.g rifampin, phenytoin, carbamazepine, phenobarbital, St John's wort) of CYP2C8 
or CYP3A4 are co-administered with dabrafenib.
Effect of dabrafenib on other drugs
Dabrafenib induces CYP3A4 and CYP2C9 mediated metabolism and may induce other 
enzymes including CYP2B6, CYP2C8, CYP2C19 and UDP glucoronosyltransferases (UGT). 
Dabrafenib may also induce transporters (e.g P-glycoprotein [P-gp]).Co-administration of 
dabrafenib and medicinal products which are affected by the induction of CYP3A4 or CYP2C9 
such as hormonal contraceptives, warfarin or dexamethasone may result in decreased 
concentrations and loss of efficacy. If co-administration of these medications is necessary, 
monitor participants for loss of efficacy or consider substitutions of these medicinal products.
Use caution if co-administration of CYP2C or CYP3A4 substrates with narrow therapeutic 
index is required. Refer to the Tafinlar label for further information.
Trametinib
Based on in vitro and in vivo data, trametinib is unlikely to significantly affect the 
pharmacokinetics of other medicinal products via interactions with CYP enzymes or 
transporters.
Dabrafenib and trametinib
Based on the mechanism of action of dabrafenib and trametinib, vaccines are not expected to 
have an interaction with these drugs, therefore are not prohibited. However, investigators 
should use their best clinical judgment on the use of live vaccines considering the potential 
immunocompromised state of cancer patients. 
6.2.2
Prohibited medication
The following medications or non-drug therapies are also prohibited while on treatment in this 
study:

Other anti-cancer therapies

Other investigational drugs
Although not contraindicated/prohibited, certain medications drugs should be used with caution 
due to potential drug-drug interactions (see Section 6.2.1.1).
6.3
Participant numbering, treatment assignment, randomization
6.3.1
Participant numbering
Each participant is identified in the study by a Subject Number (Subject No.), that is assigned 
when the participant is first enrolled for screening and is retained as the primary identifier for 
the participant throughout his/her entire participation in the trial. The Subject No. consists of 
the Center Number (Center No.) (as assigned by Novartis to the investigative site) with a 
sequential participant number suffixed to it, so that each participant is numbered uniquely across 
the entire database. Upon signing the informed consent form, the participant is assigned to the 
next sequential Subject No. available.

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6.3.2
Treatment assignment, randomization
Not applicable. 
6.4
Treatment blinding
Treatment will be open to participants, investigator staff, persons performing the assessments, 
and the CTT.
6.5
Dose escalation and dose modification
6.5.1
Dose modifications
General guidelines regarding management and dose reduction for adverse events that are 
considered by the investigator to be related to study treatment and for which specific guidelines 
do not apply are provided in Table 6-2. 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.
The following section(s) address the specific instructions for mandatory dose modifications and 
recommended management for AEs considered suspected to be related to study treatment. For 
participants who do not tolerate the protocol-specified dosing schedule, dose interruptions or 
modifications are mandated in order to allow participants to continue study treatment.
If treatment related toxicities occur when dabrafenib and trametinib are used in combination, 
then both treatments should be simultaneously dose reduced, interrupted or discontinued with 
the exceptions shown below:
Exception where dose modification is necessary for only dabrafenib:

Uveitis (Table 6-14)
Exception where dose modifications are necessary for only trametinib:

Retinal vein occlusions (RVO) (Table 6-14) and retinal pigment epithelial detachment 
(RPED) (Table 6-15)

Left ventricular ejection fraction (LVEF) reduction (Table 6-13)

Pneumonitis and ILD (Table 6-10)
Table 6-2
Dose Modification Guidelines - General
Grade
Recommended adverse event 
management guidelines
Mandatory dose modification 
requirements
Grade 1 or Grade 2 tolerable

Monitor closely

Provide supportive care 
according to institutional 
standards

Continue dabrafenib and 
trametinib at the same dose 
level.
Grade 2 (intolerable) or
Grade 3

Monitor closely.

Provide supportive care 
according to institutional 
standards

Interrupt dabrafenib and 
trametinib

When toxicity resolves to ≤ 
Grade 1 or baseline, restart 
dabrafenib and trametinib 

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Grade
Recommended adverse event 
management guidelines
Mandatory dose modification 
requirements
reduced by one dose level per 
Table 6-3.

If the Grade 2 (intolerable) or 
Grade 3 toxicity recurs, 
interrupt dabrafenib and 
trametinib.

If following an interruption of 
dabrafenib and trametinib, the 
AE doesn’t recover to ≤ Grade 
1 or baseline within 3 weeks, 
dabrafenib and trametinib 
must be discontinued

Re-escalation of the 
participant’s dose is 
recommended if criteria in 
Section 6.5.1.2 are met.
Grade 4

Monitor closely.

Provide supportive care 
according to institutional 
standards

Interrupt study treatment until 
=< Grade 1 and restart at next 
lower dose level or 
permanently discontinue study 
treatment

If the Grade 4 toxicity recurs, 
permanently discontinue study 
treatment
6.5.1.1
Dose Reduction
Deviations to mandatory dose interruptions and/or reductions are not allowed. A maximum of 
two trametinib dose level reductions and three dose level reduction for dabrafenib are allowed. 
Steps for dose modifications for trametinib and dabrafenib are listed in Table 6-3.
Table 6-3
Dose Modification steps for dabrafenib and trametinib
Dabrafenib
Trametinib
Starting dosea
150 mg BID
2 mg once daily
1st level dose reduction
100 mg BID
1.5 mg once daily
2nd level dose reduction
75 mg BID
1 mg once daily
3rd level dose reduction
50 mg BID
Not allowed
a Dose modification should be based on the worst toxicity demonstrated at the last dose
A dose reduction below 50 mg BID for dabrafenib or below 1 mg QD for trametinib is not 
allowed. If a dose reduction below 50 mg BID for dabrafenib is required, dabrafenib will be 
permanently discontinued but these participants will be allowed to continue trametinib. If a dose 
reduction below 1.0 mg QD for trametinib is required, then trametinib will be permanently 
discontinued, but these participants will be allowed to continue dabrafenib.
6.5.1.2
Dose Re-escalation
If a participant’s dose of dabrafenib and trametinib has been reduced per the dose modification 
instructions, re-escalation of the participant’s dose is recommended provided the following 
criteria are met:

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
A period of 4 weeks of treatment has passed since restarting dosing at the lower dose level 
and there is no recurrence of the AE

The participant is deriving clinical benefit
6.5.1.3
Dose Delay
For dabrafenib and/or trametinib related adverse events: if following an interruption of 
dabrafenib and trametinib, an AE doesn’t recover to ≤ Grade 1 or baseline within 4 weeks, 
dabrafenib and trametinib must be discontinued.
Approval from the Medical Lead is required to restart study treatment after 4 weeks.
Table 6-4 provides a list of AEs of special interest and relevant sections where detailed dose 
modification and management requirements for relevant AEs can be found. All AEs are to be 
graded according to NCI-CTCAE v4.03, unless otherwise specified. Investigators should refer 
to the current dabrafenib and trametinib local prescribing information and/or Investigator’s 
Brochure for additional information regarding the background of each drug and the 
management of other AEs or potential safety-related issues not specifically mentioned in this 
protocol.
Table 6-4
Reference of AEs and toxicity management guidelines
Adverse Events
dabrafenib
trametinib
Guideline
General
X
X
X
Pyrexia
X
X
X
Rash
X
X
X
Serious skin reactions
X
X
X
Hand foot skin reactions
X
X
X
Diarrhea
X
X
X
Pneumonitis / ILD
X
X
Renal function alterations
X
X
X
Hypertension
X
X
X
LVEF decrease
X
X
X
Visual changes
X (Uveitis)
X (RVO)
X
RPED
X
X
Hyperglycemia
X
X
Hemorrhage
X
X
X
Thromboembolic events
X
X
New malignancies
X
X
X
Abnormal liver enzyme 
tests
X
X
X
6.5.2
Dose Modification Guidelines - Adverse Events of Special Interest
6.5.2.1
Pyrexia
Pyrexia is a common AE in patients receiving dabrafenib and/or trametinib, and the incidence 
and severity of pyrexia is increased with combination therapy. Pyrexia may be accompanied by 
severe rigors, dehydration and hypotension, which in some cases can lead to acute renal 

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insufficiency. Pyrexia often occurs within the first month of treatment, and participants may 
experience more than one event.
Before starting study drug treatment, participants should be comprehensively educated and 
receive guidance regarding pyrexia and be instructed on the importance of immediately 
reporting pyrexia or pyrexia symptoms (chills, rigors, night sweats or flu-like symptoms).
Guidelines for dose modification and management for pyrexia considered to be related to 
dabrafenib and/or trametinib are provided in Table 6-5.
Table 6-5
Mandatory dose modification and recommended clinical management 
guidelines for suspected treatment-related pyrexia
Occurrence 
Recommended management 
Mandatory dose modification
First occurrence 

Clinical evaluation for infection and 
hypersensitivitya

Laboratory work-upa

Prompt administration of anti-pyretic 
treatment b

Oral corticosteroids should be 
considered in those instances in which 
anti-pyretics are insufficient,

i.e.prednisone 10 mg/d for at least 5 
days or as clinically indicatedc

Optimize oral corticosteroid dose as 
clinically indicated for pyrexia that 
cannot be managed with dose 
interruptionsc

Oral hydration should be encouraged in 
participants without evidence of 
dehydration. Intravenous hydration is 
recommended in participants 
experiencing pyrexia complicated by 
dehydration/hypotension.
Dabrafenib and trametinib must be 
interrupted promptly at the very first 
observation of pyrexia (temperature ≥ 
38°C (100.4°F)).
Dabrafenib and trametinib should be 
restarted if patient is symptom free for at 
least 24 hours either (1) at the same dose 
level, or (2) reduced by one dose level per 
Table 6-3, if pyrexia is recurrent and/or 
was accompanied by other severe 
symptoms including dehydration, 
hypotension or renal failure.
For re-escalation, refer to 
Section 6.5.1.2.
Subsequent 
occurrences
Same as above 
In case of recurrence, dabrafenib and 
trametinib can be interrupted at the first 
symptom of pyrexia (presence of pyrexia 
symptoms chills, rigors, night sweats or 
flu-like symptoms) without documented 
temperature ≥ 38°C (100.4°F).
a. Laboratory work-up may include full-blood-count, electrolytes, creatinine, blood urea nitrogen (BUN), C-
reactive protein (CRP), liver-function tests, blood culture, and urine culture. In participants experiencing pyrexia 
higher than 40°C (104°F), and/or pyrexia associated with rigors, severe chills, dehydration or hypotension, 
renal function should be monitored frequently. The frequency of monitoring must be adapted based on the 
individual clinical presentation.
b. Anti-pyretic treatment should be started immediately at the onset of pyrexia or pyrexia symptoms. Anti-
pyretic treatment may include acetaminophen, ibuprofen, metamizole, or suitable anti-pyretic medication 
according to institutional standards. 
c. Corticosteroids are recommended for recurrent pyrexia that cannot be managed with dose interruptions and
anti-pyretic treatments and for pyrexia associated with complications as per local institutional guidelines where 
available, or investigator’s discretion.

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6.5.2.2
Rash
Rash is a frequent AE observed in participants receiving trametinib, dabrafenib, or the 
combination of both therapies. Recommended guidelines for rash management are provided 
below tables (Table 6-6, Table 6-7).
Table 6-6
Guidelines for Supportive Care of Rash
Type of Care
Action
Prevention/Prophylaxis:
Start from Day 1

Avoid unnecessary exposure to sunlight

Apply broad-spectrum sunscreen (containing titanium dioxide or zinc oxide) 
with a skin protection factor (SPF) ≥15 at least twice daily.

Use thick, alcohol-free emollient cream (e.g., glycerine and cetomacrogol 
cream) on dry areas of the body at least twice daily.
Prevention/Prohylaxis:
Start from Day 29 and 
implement for a total of 6 
weeks

Topical steroids and antibiotics should be applied at least twice daily starting 
on Day 29 of study treatment and to body areas such as face, chest, and 
upper back.

Use mild-strength topical steroid (hydrocortisone 1% cream and topical 
antibiotic (e.g., clindamycin) or oral antibiotics (e.g., doxycycline 100 mg BID, 
minocycline 100 mg BID)
Symptomatic Care

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
Guidelines for management and dose reduction for rash considered to be related to study 
treatment are provided in Table 6-7.
Table 6-7
Mandatory dose modifications and recommended clinical 
management guidelines for rash
Rash Events (NCI-CTCAE v4.03)
Grade
Recommended adverse event 
management guidelines
Mandatory dose modification 
requirements
Grade 1: Rash covering < 10% 
body surface area

Initiate prophylactic and 
symptomatic treatment 
measures.

Consider use of topical 
corticosteroids or urea 
containing creams in 
combination with oral 
antipruritics or moderate 
strength topical steroid 
(hydrocortisone 2.5% cream 
or fluticasone propionate 0.5% 
cream)

Reassess after 2 weeks

Continue dabrafenib and 
trametinib at the same dose.
Grade 2: 10-30% of body surface 
area

If tolerable, as per Grade 1

If intolerable, initiate systemic 
steroids (0.5 to 1 mg/kg/day 
prednisone or equivalents)

If tolerable, continue 
dabrafenib and trametinib at 
the same dose.

If intolerable:

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Rash Events (NCI-CTCAE v4.03)
Grade
Recommended adverse event 
management guidelines
Mandatory dose modification 
requirements

If symptoms persist or recur 
consider skin biopsy.
1st and subsequent occurrences

Interrupt dabrafenib and 
trametinib until ≤ Grade 1, and 
then restart dabrafenib and 
trametinib at next lower dose 
level.
Grade 3: More than 30% of body 
surface area

Obtain a skin biopsy and 
dermatology consult.

Initiate therapy with high dose 
steroids (1 to 2 mg/kg/d 
prednisone or equivalents)
1st 2nd, and 3rd occurrences

Interrupt dabrafenib and 
trametinib until ≤ Grade 1, and 
then restart dabrafenib and 
trametinib at next lower dose 
level.
4th occurrence
Permanently discontinue 
dabrafenib and trametinib.
Grade 4: Life-threatening

Same as Grade 3

Permanently discontinue 
dabrafenib and trametinib.
NOTE: suspected cases of SCAR require permanent discontinuation of study treatment (see Section 6.5.2.3)
6.5.2.3
Mandatory dose modifications and recommended clinical 
management of serious skin 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.
6.5.2.4
Mandatory dose modifications and recommended clinical 
management guidelines for hand-foot reaction (palmar-plantar 
erythrodysesthesia)
In general, management of hand-foot skin reactions include:

Prevention/prophylaxis: promote sunscreen use and avoidance of unnecessary sun 
exposure, use alcohol-free emollient creams, topical steroids and antibiotics as needed.

Pruritic lesions: cool compresses and oral antihistamines

Fissuring lesions: Monsel’s solution, silver nitrate or zinc oxide cream

Desquamation: thick emollients and mild soap

Paronychia: antiseptic bath, local potent corticosteroids, antibiotics, surgery as needed

Infected lesions: topical or systemic antibiotics

Measures for PPES should include: 

Lifestyle modification: avoidance of hot water, traumatic activity, constrictive 
footwear, or excessive friction on the skin and the use of thick cotton socks and 
gloves, and shoes with padded insoles

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
Symptomatic treatments: apply moisturizing creams frequently, topical keratolytics 
(e.g., urea 20-40% cream, salicylic acid 6%, tazarotene 0.1% cream, fluorouracil 5% 
cream), clobetasol propionate 0.05% ointment for erythematous areas, topical 
lidocaine 2%, and / or systemic pain medication such as nonsteroidal anti-
inflammatory drugs, codeine, and pregabalin for pain.
Guidelines for dose modification for hand foot skin reaction considered to be related to study 
treatment by the investigator are provided in Table 6-8.
Table 6-8
Mandatory dose modifications and recommended clinical 
management guidelines for hand foot skin reaction (palmar-plantar 
erythrodysesthesia)
Hand foot skin reaction (NCI-CTCAE v4.03)
Grade
Recommended adverse event 
management guidelines
Mandatory dose modification 
requirements
Grade 1: Minimal skin changes or 
dermatitis (e.g., erythema, edema, 
or hyperkeratosis) without pain

Recommend topical therapy 
for symptomatic relief.

Continue dabrafenib and 
trametinib at the same dose.
Grade 2: Skin changes (e.g., 
peeling, blisters, bleeding, edema, 
or hyperkeratosis) with pain; 
limiting instrumental ADL

Recommend topical therapy 
for symptomatic relief

Continue treatment and if no 
improvement within 7 days, 
see below.

No improvement within 7 days
or 2nd or 3rd occurrence:

Interrupt dabrafenib and 
trametinib until toxicity 
resolves to ≤ Grade 1 or 
baseline.

Reduce dabrafenib and 
trametinib at the next lower 
dose.
4th occurrence:

Discontinue dabrafenib and 
trametinib.
Grade 3: Severe skin changes 
(e.g., peeling, blisters, bleeding, 
edema, or hyperkeratosis) with 
pain; limiting self-care ADL

Recommend topical therapy 
for symptomatic relief
1stoccurrence:

Interrupt dabrafenib and 
trametinib until toxicity 
resolves to ≤ Grade 1 or 
baseline.

Once recovered, restart 
dabrafenib and trametinib at 
the next lower dose level.
2nd occurrence:

Interrupt dabrafenib and 
trametinib until toxicity 
recovers to ≤ Grade 1 or 
baseline.

Once recovered, restart 
dabrafenib and trametinib at 
the next lower dose level.
3rd occurrence:

Discontinue dabrafenib and 
trametinib.

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6.5.2.5
Guidelines for Diarrhea
Episodes of diarrhea have occurred in participants receiving dabrafenib, trametinib, or both 
therapies in combination. 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, etc., should be clinically excluded. Guidelines regarding 
management and dose reduction for diarrhea considered to be related to study treatment by the 
investigator are provided in Table 6-9.
Table 6-9
Management and Dose Modification Guidelines for Diarrhea
Diarrhea (NCI-CTCAE v4.03)
CTCAE Grade
Adverse Event Management
Mandatory dose modification 
requirements
Grade 1 diarrhea (increase of <4 
stools per day over baseline; mild 
increase in ostomy output 
compared to baseline)
OR
Grade 2 diarrhea (increase of 4 - 6 
stools per day over baseline; 
moderate
increase in ostomy output
compared to baseline)

Diet: stop all lactose 
containing products; eat small 
meals, BRAT-diet (banana, 
rice, apples, toast)

Hydration: 8-10 large glasses 
of clear liquids per day (e.g., 
Gatorade or broth)

Loperamidea: initially 4 mg, 
followed by 2 mg every four 
hours or after every unformed 
stool; maximum 16 mg/day. 
Continue until diarrhea free for 
12 hours

Diarrhea > 24h: loperamide 
2 mg every two hours; 
maximum 16 mg/day. 
Consider adding oral 
antibiotics

Diarrhea > 48h: loperamide 
2 mg every two hours; 
maximum 16 mg/day. Add 
budesonide or other second-
line therapies (otreotide, or 
tincture of opium) and oral 
antibiotics

Continue dabrafenib and 
trametinib

If diarrhea is grade 2 for > 
48h, interrupt dabrafenib and 
trametinib until diarrhea 
resolves to grade ≤1

Restart dabrafenib and 
trametinib at the same dose 
level
Grade 3 diarrhea (increase of ≥7 
stools per day over baseline; 
incontinence;
hospitalization indicated;
severe increase in ostomy
output compared to baseline; 
limiting self-care ADL)

Clinical evaluation mandatory

Loperamidec: initially 4 mg, 
followed by 2 mg every four 
hours or after every unformed 
stool; maximum 16 mg/day. 
Continue until diarrhea free for 
12 hours

Oral antibiotics and second-
line therapies if clinically 
indicated

Hydration: intravenous fluids if 
clinically indicated

Antibiotics (oral or 
intravenous) if clinically 
indicated

Interrupt dabrafenib and 
trametinib until diarrhea 
resolves to grade ≤1

Restart with dabrafenib and 
trametinib reduced by one 
dose levelb

If 3 dose reductions of study 
treatment are clinically 
indicated, permanently 
discontinue dabrafenib and 
trametinib

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Diarrhea (NCI-CTCAE v4.03)
CTCAE Grade
Adverse Event Management
Mandatory dose modification 
requirements

Intervention should be 
continued until the participant 
is diarrhea free for ≥ 24 hours

Intervention may require 
hospitalization for participants 
at risk of life-threatening 
complications
Grade 4: (Life-threatening
consequences; urgent
intervention indicated)

Same as Grade 3

Permanently discontinue, 
dabrafenib and trametinib.
Abbreviation: CTCAE = Common Terminology Criteria for Adverse Events
a.
Loperamide should be made available prior to start of study treatment so loperamide administration can 
begin at the first signs of diarrhea
b.
Escalation of study treatment 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.
6.5.2.6
Guidelines for Pneumonitis
Pneumonitis has been observed in participants receiving trametinib. To reduce the risk of 
pneumonitis, participants will be monitored closely for symptoms, evaluated with imaging and 
functional tests. Dose modification and supportive care guidelines for pneumonitis are 
described in Table 6-10.
Table 6-10
Management and Dose Modification Guidelines for Pneumonitis
Pneumonitis (NCI-CTCAE v4.03)
Grade
Adverse Event Management
Mandatory dose modification 
requirements
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 dabrafenib and 
trametinib at current dose
Grade 2

CT scan (high-resolution with 
lung windows)

Clinical evaluation and 
laboratory work-up for infection

Consult pulmonologist

Bronchoscopy with biopsy 
and/or BAL recommended

Symptomatic therapy including 
corticosteroids if clinically 
indicated

Interrupt trametinib until toxicity 
recovers to ≤ Grade 1 or 
baseline. Dabrafenib may 
continue 

Once recovered, restart 
trametinib at the next lower 
dose level.

Escalation to previous dose 
level after 4 weeks possible 
and consultation with 
Medical Lead

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Pneumonitis (NCI-CTCAE v4.03)
Grade
Adverse Event Management
Mandatory dose modification 
requirements

If no recovery to grade ≤1 
within 4 weeks, permanently 
discontinue trametinib. 
Dabrafenib may continue
Grade 3

CT scan (high-resolution with 
lung windows)

Clinical evaluation and 
laboratory work-up for infection

Consult pulmonologist

Bronchoscopy with biopsy 
and/or BAL if possible

Symptomatic therapy including 
corticosteroids as clinically 
indicated

Oxygen indicated

Interrupt trametinib until toxicity 
recovers to ≤ Grade 1 or 
baseline. Dabrafenib may 
continue 

Once recovered, restart 
trametinib at the next lower 
dose level after consultation 
with medical lead.

Escalation to previous dose 
level after 4 weeks and 
consultation with Medical 
Lead is possible

If no recovery to grade ≤1 
within 4 weeks, permanently 
discontinue trametinib. 
Dabrafenib may continue
Grade 4

Life-threatening respiratory 
compromise; urgent 
intervention indicated (e.g. 
tracheotomy or intubation)

Permanently discontinue 
trametinib. Dabrafenib may 
continue
Abbreviations: BAL= bronchoalveolar lavage; CT = computed tomography; CTCAE = Common Terminology 
Criteria for Adverse Events
6.5.2.7
Guidelines for Renal Insufficiency
Cases of renal insufficiency have occurred in participants 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. Management and dose 
modifications guidelines are provided in Section 6.2. Close monitoring of serum creatinine, 
treatment associated pyrexia (see Table 6-5), and treatment interruption for increased serum 
creatinine > 2 mg/dL (or > 0.5 mg/dL above baseline). Nephrology consultation should also be 
obtained in absence of obvious cause for persistent creatinine elevation (e.g volume depletion).
Table 6-11
Mandatory dose modifications and recommended clinical 
management guidelines for renal insufficiency
Acute kidney injury (NCI-CTCAE v4.03)
Grade
Recommended adverse event 
management guidelines
Mandatory dose modification 
requirements
Grade 1 (Creatinine level increase 
of >0.3 mg/dL; creatinine 1.5 - 2.0 
x above baseline)

If the increase in creatinine is 
confirmed: 
a.
Assess fluid status and 
consider fluid bolus
b.
Monitor serum creatinine 
at least every 2 days until 
back to baseline

If the increase in creatinine is 
confirmed: 
a.
Interrupt dabrafenib and 
trametinib

If creatinine returns to baseline: 

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Acute kidney injury (NCI-CTCAE v4.03)
Grade
Recommended adverse event 
management guidelines
Mandatory dose modification 
requirements
c.
If creatinine returns to 
baseline: 
a.resume routine 
creatinine monitoring 
per protocol

Promote hydration and 
cessation of nephrotoxic drugs
a.Continue dabrafenib and 
trametinib at the same 
dose.
Grade 2: (Creatinine 2 - 3 x 
above baseline)

Closely monitor creatinine

Consult with specialist and 
consider renal biopsy

Promote hydration and 
cessation of nephrotoxic drugs.
1st occurrence:

Interrupt dabrafenib and 
trametinib until ≤ Grade 1 or 
baseline and then reinstate 
dabrafenib and trametinib at 
the same dose.
2nd occurrence:

Interrupt dabrafenib and 
trametinib until ≤ Grade 1 or 
baseline. Once recovered, 
reduce dabrafenib and 
trametinib to the next dose 
level. Re-escalation of the 
participant’s dose is 
recommended if criteria in 
Section 6.5.1.2 are met.
3rd occurrence:

Interrupt dabrafenib and 
trametinib until ≤ Grade 1 or 
baseline. Once recovered, 
reduce dabrafenib and 
trametinib to the next dose 
level. Re-escalation of the 
participant’s dose is 
recommended if criteria in 
Section 6.5.1.2 are met.
4th occurrence

Permanently discontinue 
dabrafenib and trametinib.
Grade 3 (Creatinine > 3.0 x 
baseline or >4.0 mg/dL; 
hospitalization indicated)

Hospitalization is indicated with 
frequent creatinine monitoring

Consult with nephrologist.

Promote hydration and 
cessation of nephrotoxic drugs.
1st occurrence:

Interrupt dabrafenib and 
trametinib until ≤ Grade 1 or 
baseline and then reduce 
dabrafenib and trametinib to 
the next lower dose. Re-
escalation of the participant’s 
dose is recommended if criteria 
in Section 6.5.1.2 are met.
2nd occurrence:

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Acute kidney injury (NCI-CTCAE v4.03)
Grade
Recommended adverse event 
management guidelines
Mandatory dose modification 
requirements

Interrupt dabrafenib and 
trametinib until ≤ Grade 1 or 
baseline and then reduce 
dabrafenib and trametinib to 
the next lower dose. Re-
escalation of the participant’s 
dose is recommended if criteria 
in Section 6.5.1.2 are met.
3rd occurrence:

Interrupt dabrafenib and 
trametinib until ≤ Grade 1 or 
baseline and then reduce 
dabrafenib and trametinib to 
the next lower dose, if available 
as dose level -2. If already at 
dose level-2 at time of 
occurrence, permanently 
discontinue dabrafenib and 
trametinib. Re-escalation of the 
participant’s dose is 
recommended if criteria in 
Section 6.5.1.2 are met.
4th occurrence:
Permanently discontinue 
dabrafenib and trametinib
Grade 4: Life-threatening 
consequences; dialysis 
indicated

Consult with specialist and 
recommend renal biopsy.

Promote hydration and 
cessation of nephrotoxic drugs.

Permanently discontinue 
dabrafenib and trametinib.
6.5.2.8
Mandatory dose modification and management guideline for 
hypertension suspected to be related to dabrafenib and/or trametinib 
treatment
Increases in blood pressure have been observed in participants receiving trametinib. For 
adequate monitoring and management of hypertension, all blood pressure assessments should 
be performed under the following optimal conditions:

the participant has been seated with back support, ensuring that legs are uncrossed and flat 
on the floor

the participant is relaxed comfortably for at least 5 minutes

restrictive clothing has been removed from the cuff area and the right cuff size has been 
selected

the participant’s arm is supported so that the middle of the cuff is at heart level

the participant remains quiet during the measurement.
In participants with an initial blood pressure reading within the hypertensive range, a second 
reading should be taken at least 1 minute later, with the 2 readings averaged to obtain a final 
blood pressure measurement. The averaged value should be recorded in the eCRF.

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Persistent hypertension is defined as an increase of systolic blood pressure (SBP) > 140 mm Hg 
and/or diastolic blood pressure (DBP) > 90 mm Hg in three consecutive visits with blood 
pressure assessments from two readings collected as described above. Visits to monitor 
increased blood pressure can be scheduled independently from the per- protocol visits outlined 
in the Visit Evaluation Schedule (Table 8-1). Ideally, subsequent blood pressure assessments 
should be performed within one week.
Asymptomatic hypertension is defined as an increase of SBP >140 mm Hg and/or DBP >90 
mmHg in the absence of headache, light-headedness, vertigo, tinnitus, episodes of fainting or 
other symptoms indicative of hypertension.
For participants experiencing an increase in systolic and/or diastolic blood pressure that is 
persistent and may be associated with the study treatment, recommendations for dose 
modifications and management of hypertension are described below in Table 6-12.
Table 6-12
Mandatory dose modification and recommended clinical management 
for hypertension suspected to be related to dabrafenib and/or 
trametinib treatment
Severity
Recommended adverse event 
management guidelines
Mandatory dose modification 
requirements
(Scenario A)

Asymptomatic and 
persistent a SBP of >140 
and <160 mmHg, or DBP 
>90 and <100 mmHg, or

Clinically significant increase 
in DBP of 20 mmHg (but still 
below 100 mmHg).

Adjust current or initiate new 
antihypertensive medication.

Titrate antihypertensive 
medication(s) during the next 2 
weeks as indicated to achieve 
well-controlled b BP

If BP is not well controlled within 
2 weeks, recommended to refer 
to a specialist and go to scenario 
(B).

Continue dabrafenib and 
trametinib at the same dose.
(Scenario B)

Asymptomatic SBP ≥160 
mmHg, or DBP ≥100 mmHg, 
or
Failure to achieve well-controlled 
BP within 2 weeks in Scenario A

Adjust current or initiate new 
antihypertensive medication(s).

Titrate antihypertensive 
medication(s) during the next 2 
weeks as indicated to achieve 
well-controlled BP.

Interrupt dabrafenib and 
trametinib if clinically 
indicated.

Once BP is well controlled, 
restart dabrafenib and 
trametinib at next lower level

Symptomatic c hypertension 
or

Persistent SBP ≥160 mmHg, 
or DBP ≥100 mmHg, despite 
antihypertensive medication 
and dose reduction of study 
treatment.

Adjust current or initiate new 
antihypertensive medication(s)

Titrate antihypertensive 
medication during the next 2 
weeks as indicated to achieve 
well-controlled BP.

Referral to a specialist for further 
evaluation and follow-up is 
recommended

Interrupt dabrafenib and 
trametinib.

Once BP is well controlled, 
restart dabrafenib and 
trametinib at next lower level.

Refractory hypertension 
unresponsive to above 
interventions or hypertensive 
crisis.

Continue follow-up per protocol.

Permanently discontinue 
dabrafenib and trametinib.
a.
Hypertension detected in two separate readings during up to three consecutive visits.
b.
Well-controlled blood pressure defined as SBP ≤140 mm Hg and DBP ≤90 mm Hg in two separate 
readings during up to three consecutive visits.
c.
Symptomatic hypertension defined as hypertension aggravated by symptoms (e.g., headache, light-
headedness, vertigo, tinnitus, episodes of fainting) that resolve after the blood pressure is controlled within 
the normal range.

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6.5.2.9
Mandatory dose modification and management guideline for changes 
in LVEF suspected to be related to dabrafenib and/or trametinib 
treatment
Decreases of left-ventricular-ejection-fraction (LVEF) have been observed in participants 
receiving trametinib monotherapy and in combination with dabrafenib. Therefore, ECHOs must 
be performed to assess cardiac ejection fraction in regular intervals as outlined in the Visit 
Evaluation Schedule (Table 8-1). Dose modification guidance and stopping criteria for LVEF 
decrease are provided in Table 6-13.
Table 6-13
Mandatory dose modification and recommended clinical management 
for changes in LVEF
Clinical symptoms & LVEF drop 
(%) or CTCAE grade
Recommended adverse event 
management guidelines
Mandatory dose modification 
requirements
Asymptomatic, absolute 
decrease of >10% in LVEF 
compared to baseline and ejection 
fraction below the institution’s LLN

Report as SAE.

Closely monitoring LVEF via 
ECHO, repeat ECHO within 2 
weeks*.

If the LVEF recovers within 4 
weeks (defined as LVEF ≥LLN 
and absolute decrease ≤10% 
compared to baseline)

Repeat ECHO 2, 4, 8 and 12 
weeks after re-start; continue 
in intervals of 12 weeks 
thereafter.

If repeat LVEF does not 
recover within 4 weeks.

Consult with cardiologist

Repeat ECHO after 2, 4, 8, 
12, and 16 weeks or until 
resolution

Interrupt trametinib. 
Dabrafenib may continue

If the LVEF recovers, restart 
trametinib reduced next lower 
level and continue dabrafenib 
at the same dose level.

More than two occurrence, 
permanently discontinue 
trametinib.

Permanently discontinue
trametinib if repeat LVEF does 
not recover within 4 weeks.
Symptomatic or

Resting LVEF 39-20% or 
>20% absolute reduction from 
baseline (CTCAE grade 3)

Resting LVEF <20% (CTCAE 
grade 4)

Report as SAE.

Consult with cardiologist.

Intervention indicated.

Repeat ECHO after 2, 4, 8, 
12, and 16 weeks or until 
resolution.

Permanently discontinue 
trametinib.

Interrupt dabrafenib

Restart dabrafenib if LVEF 
recovers including resolution 
of symptoms.
* If ECHO does not show LVEF recovery after 2 weeks, repeat ECHO 2 weeks later.
6.5.2.10 Guideline dose modification and management for hemophagocytic 
lymphohistiocytosis (HLH)
In post marketing experience, hemophagocytic lymphohistiocytosis (HLH) has been observed 
with dabrafenib and trametinib combination therapy. Since post-marketing adverse drug 
reactions are reported from a population of uncertain size, the exact frequency of HLH in 
patients receiving dabrafenib and trametinib is unknown. HLH is a rare, life-threatening 
condition caused by an overactive, abnormal response of the immune system (Kikuchi et al 
2022), HLH is associated with a constellation of multiple clinical and laboratory features that 
may include fever, hepatosplenomegaly, hypertriglyceridemia, hypofibrinogenemia, high 
serum ferritin, multilineage cytopenias and hemophagocytosis. If HLH is suspected, treatment 

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should be interrupted. If HLH is confirmed, treatment should be permanently discontinued 
and appropriate management of HLH per institutional standards should be initiated. 
6.5.2.11 Mandatory dose modification and management guideline for visual 
changes
Episodes of visual changes have been observed in participants receiving trametinib, dabrafenib 
or the combination of dabrafenib/trametinib. An ophthalmologist should be consulted if 
changes in vision develop. However, if the visual changes are clearly unrelated to study 
treatment (e.g., allergic conjunctivitis), then monitor closely as it may be reasonable to defer 
ophthalmic examination.
Treatment with dabrafenib has been associated with the development of uveitis, including iritis. 
Monitor participants for visual signs and symptoms (such as, change in vision, photophobia and 
eye pain) during therapy. Permanently discontinue dabrafenib for persistent ≥ Grade 2 uveitis 
(including iritis and iridocyclitis) of > 6 weeks duration. No dose modification of trametinib is 
required when taken in combination with dabrafenib.
In participants treated with trametinib, special attention should be given to retinal findings (e.g., 
RPED) or retinovascular abnormalities (i.e., branch or central RVO). Retinopathy is a known 
adverse drug reactionseen with MEK inhibitor therapy, including trametinib. MEK inhibitor 
associated serous retinopathy typically manifests bilaterally within days of treatment initiation 
with a median time to onset of one month (Cruz-Merino et al 2017, Francis et al 2017).
Treatment emergent cases of RVO and RPED should be reported as SAEs.
Guidelines for dose modification and management for visual changes and/or ophthalmic 
examination findings considered to be related to dabrafenib and/or trametinib are provided in 
Table 6-14 and Table 6-15.
Table 6-14
Mandatory dose modification and recommended clinical management 
for visual changes and/or ophthalmic examination findings
Visual changes (Eye disorders – Other, CTCAE Version 4.03)
Grade
Recommended adverse event 
management guidelines
Mandatory dose modification requirements
Grade 1 a
Consult ophthalmologist within 7 
days of onset

If dilated fundus examination cannot be 
performed within 7 days of onset, interrupt 
trametinib until RPED and RVO can be 
excluded by retina specialist/ophthalmologist. 
Continue dabrafenib.

If RPED and RVO excluded, continue (or 
restart) trametinib at the same dose level.

If RPED suspected or diagnosed: see RPED 
dose modification in Table 6-15; report as SAE 
if diagnosed.

If RVO diagnosed: Permanently discontinue 
trametinib and report as SAE.
Grade 2 and
Grade 3
Consult ophthalmologist immediately

Interrupt trametinib. Dabrafenib may be 
continued at the same dose b.If RPED and RVO 
excluded, restart trametinib at the same dose 
level.

If RPED diagnosed, see RPED dose 
modification in Table 6-15; report as SAE.

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Visual changes (Eye disorders – Other, CTCAE Version 4.03)
Grade
Recommended adverse event 
management guidelines
Mandatory dose modification requirements

If RVO diagnosed: Permanently discontinue 
trametinib and report as SAE.
Grade 4
Consult ophthalmologist immediately

Interrupt trametinib. Dabrafenib may be 
continued at the same dose b.If RPED and RVO 
excluded, should consider restarting trametinib 
at same or reduced dose after discussion with 
study medical monitor.

If RVO or RPED diagnosed, permanently 
discontinue trametinib and report as SAE.
a. If visual changes are clearly unrelated to study treatment (e.g., allergic conjunctivitis), monitor closely but 
ophthalmic examination is not required.
b. Permanently discontinue dabrafenib for ≥ Grade 2 uveitis (including iritis and iridocyclitis) of > 6 weeks 
duration.
Table 6-15
Mandatory dose modification and recommended clinical management 
for retinal pigment epithelial detachments (RPED) suspected to be 
related to trametinib treatment
Retinal pigment epithelial detachments (RPED)
Grade
Recommended adverse event 
management guidelines
Mandatory dose modification 
requirements

Grade 1 (Asymptomatic; 
clinical or diagnostic 
observations only)

If RPED worsens follow 
instructions below.

Continue dabrafenib and 
trametinib with retinal 
evaluation monthly until 
resolution.

Grade 2-3 RPED 
(Symptomatic with mild to 
moderate decrease in visual 
acuity).

Retinal evaluation monthly.

Interrupt trametinib and 
continue dabrafenib.

If improved to ≤ Grade 1, 
restart trametinib at next lower 
level

If not improved to ≤ Grade 1 
within 3 weeks, permanently 
discontinue trametinib
6.5.2.12 Monitoring guideline for hyperglycemia suspected to be related to 
dabrafenib treatment
Hyperglycemia requiring an increase in the dose of, or initiation of insulin or oral therapy can 
occur with dabrafenib. Monitor serum glucose levels as clinically appropriate during treatment 
with dabrafenib in participants with pre-existing diabetes or hyperglycemia.
Advise participants to report symptoms of severe hyperglycemia such as excessive thirst or any 
increase in the volume or frequency of urination.
6.5.2.13 Mandatory dose modification and management guideline for 
hemorrhage
Hemorrhage, including major hemorrhage defined as symptomatic bleeding in a critical area or 
organ, can occur when dabrafenib is administered with trametinib. Permanently discontinue 
dabrafenib and trametinib for all Grade 4 hemorrhagic events and for any persistent Grade 3 

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hemorrhagic events. Withhold dabrafenib and trametinib for Grade 3 hemorrhagic events; if 
improved, resume at the next lower dose level.
6.5.2.14 Mandatory dose modification and management guideline 
thromboembolic events
Advise patients to immediately seek medical care if they develop symptoms of deep vein 
thrombosis (DVT) or pulmonary embolism (PE), such as shortness of breath, chest pain, or arm 
or leg swelling. If any signs or symptoms of venous thromboembolism are present, the 
participant will undergo specific laboratory and medical imaging studies to confirm it. The 
medical imaging study or studies selected will depend on the anatomic site or organ of
involvement (e.g., Doppler ultrasound, venography, ventilation perfusion lung scan, 
angiography, MRI). If the diagnosis is confirmed, appropriate medical care according to 
standard local clinical practice should be initiated immediately.
Permanently discontinue trametinib for life threatening PE. Withhold trametinib for 
uncomplicated venous thromboembolism for up to 3 weeks; if improved, trametinib may be 
resumed at a lower dose level.
6.5.2.15 Mandatory dose modification and management guideline for new 
malignancies suspected to be related to dabrafenib and/or trametinib 
treatment
New cutaneous malignancies:
Cutaneous squamous cell carcinoma (CuSCC), keratoacanthomas (KA) and new primary 
melanomas 
have 
been 
observed 
in 
participants 
treated 
with 
dabrafenib 
and 
dabrafenib/trametinib combination therapy. These treatment-related lesions should be 
surgically removed according to institutional practices. Dose modification or interruption of 
study treatment is not required for CuSCC, KA, or new primary melanoma, however CuSCC 
and new primary melanoma should be reported as a SAE. In addition, a biopsy of the lesion 
should be taken, where possible, and submitted for further analyses and a summary of the results 
submitted to Novartis.
Participants should be instructed to immediately inform their physician if new lesions develop. 
Skin examination should be performed prior to initiation of study treatment and throughout 
therapy as detailed in the Visit Evaluation Schedule. Monitoring should continue every month 
for 6 months following discontinuation of dabrafenib or until initiation of another anti-
neoplastic therapy.
New non-cutaneous malignancies:
In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling in 
BRAF wild type cells with RAS mutations when exposed to BRAF inhibitors, which may lead 
to increased risk of non-cutaneous malignancies in participants treated with dabrafenib. Cases 
of RAS-driven malignancies have been seen with BRAF inhibitors, including dabrafenib. 
Participants should be monitored as clinically appropriate. Consider the benefits and risks 
before continuing treatment with dabrafenib in participants with a non-cutaneous malignancy 
harboring a RAS mutation. No dose modification of trametinib is required when taken in 
combination with dabrafenib.

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Following discontinuation of dabrafenib, monitoring for non-cutaneous secondary/recurrent 
malignancies should continue for up to 6 months or until initiation of another anti-neoplastic 
therapy.
New cutaneous and non-cutaneous malignancies that are reported to the Investigator should be 
reported as a SAE. A biopsy of the new malignancy should be taken, where possible, and 
submitted for further analyses including RAS mutation status. Testing of these biopsies may 
include analysis of genomic alterations, which include but not limited to DNA, RNA and protein 
analysis of these biopsy specimens, and would analyze the biological pathways known to be 
associated with, and relevant to, BRAF-mutant tumor activation.
6.5.2.16 Mandatory dose modifications and recommended clinical 
management guidelines for abnormal liver enzyme
Guidelines for dose modification and management of abnormal liver enzyme functions 
considered to be related to study treatment by the investigator are provided in Table 6-16.
In addition to the instructions below, participants with normal baseline transaminases and 
bilirubin who experience sudden elevations even within Grade 1, should be monitored more 
closely.
Table 6-16
Mandatory dose modifications and recommended clinical 
management guidelines for abnormal liver enzyme test
Abnormal liver enzyme tests/hepatitis
Grade
Recommended adverse event 
management guidelines
Mandatory dose modification 
requirements
Grade 2: AST or ALT >3× ULN to 
≤ 5× ULN and/or bilirubin > 1.5× 
ULN to ≤ 3× ULN

Monitor hepatic laboratory 
tests more frequently(every 2-
3 days) until returned to 
baseline values

Interrupt, dabrafenib and 
trametinib until ≤ Grade 1, and 
then reinstate, dabrafenib and 
trametinib at the same dose 
level.
Grade 3 or 4: AST or ALT > 5× 
ULN and/or bilirubin > 3× ULN

Monitor hepatic laboratory 
tests more frequently (every 2-
3 days) until return to baseline 
values.

Consider appropriate 
consultation* with hepatologist 
and liver biopsy to establish 
etiology of hepatic injury, if 
necessary.
1st and 2nd occurrences

Interrupt dabrafenib and 
trametinib until recovery to ≤ 
Grade 1 or baseline

Reduce dabrafenib and 
trametinib to the next lower 
dose level per Table 6-3. Re-
escalation of the participant’s 
dose is recommended if 
criteria in Section 6.5.1.2 are 
met.
3rd occurrence

Permanently discontinue 
dabrafenib and trametinib
Rule out viral hepatitis and other potential causes of liver injury
**For participants with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT increase 
by ≥ 50% relative to baseline and last for at least 1 week then the participant should be discontinued

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Follow up on potential drug-induced liver injury (DILI) cases
Participants with transaminase increase combined with an elevation of total bilirubin (TBIL) 
may be indicative of potential DILI. These events should be considered as clinically important 
and managed accordingly.
The threshold for potential DILI may depend on the participant’s baseline AST/ALT and TBIL 
value; participants meeting any of the following criteria will require further follow-up as 
outlined below:

For participants with normal ALT and AST and TBIL value at baseline: AST or ALT > 
3.0 x ULN combined with TBIL > 2.0 x ULN

For participants with elevated AST or ALT or TBIL value at baseline: [AST or ALT > 2 x 
baseline AND > 3.0 x ULN] OR [AST or ALT > 8.0 x ULN], combined with [TBIL > 2 x 
baseline AND > 2.0 x ULN]
Medical review needs to ensure that liver test elevations are not caused by cholestasis, defined 
as ALP elevation > 2.0 x ULN with R value < 2 in participants without bone metastasis, or 
elevation of ALP liver fraction in participants with bone metastasis.
Note: (The R value is calculated by dividing the ALT by the ALP, using multiples of the ULN 
for both values. It denotes whether the relative pattern of ALT and/or ALP elevation is due to 
cholestatic (R ≤ 2), hepatocellular (R ≥ 5), or mixed (R >2 and < 5) liver injury).
In the absence of cholestasis, these participants should be immediately discontinued from study 
drug treatment, and repeat LFT testing as soon as possible, preferably within 48 hours from the 
awareness of the abnormal results. The evaluation should include laboratory tests, detailed 
history, physical assessment and the possibility of liver metastasis or new liver lesions, 
obstructions/compressions, etc.
1. Laboratory tests should include ALT, AST, albumin, creatine kinase, total bilirubin, direct 
and indirect bilirubin, GGT, prothrombin time (PT)/INR and alkaline phosphatase.
2. A detailed history, including relevant information, such as review of ethanol, concomitant 
medications, herbal remedies, supplement consumption, history of any pre-existing liver 
conditions or risk factors, should be collected.
3. Further testing for acute hepatitis A, B, C or E infection and liver imaging (e.g., biliary 
tract) may be warranted.
4. Additional testing for other hepatotropic viral infection (e.g., CMV, EBV, Adenovirus, 
HSV, HHV6, HIV), autoimmune hepatitis or liver biopsy may be considered as clinically 
indicated or after consultation with specialist/hepatologist.
All cases confirmed on repeat testing meeting the laboratory criteria defined above, with no 
other alternative cause for LFT abnormalities identified should be considered as “medically 
significant”, thus, met the definition of SAE (Section 10) and reported as SAE using the term 
“potential drug-induced liver injury”. All events should be followed up with the outcome clearly 
documented.

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6.6
Additional treatment guidance
6.6.1
Treatment compliance
The investigator must promote compliance by instructing the participant to take the study 
treatment exactly as prescribed and by stating that compliance is necessary for the participant’s 
safety and the validity of the study. The participant must also be instructed to contact the 
investigator if he/she is unable for any reason to take the study treatment as prescribed. 
Compliance will be assessed by the investigator and/or study personnel at each visit using pill 
counts (if applicable) and information provided by the participant. This information should be 
captured in the source document at each visit. All study treatment dispensed and returned must 
be recorded in the Drug Accountability Log.
Pharmacokinetic parameters (measures of treatment exposure) will be determined in all 
participants treated with dabrafenib, metabolites of dabrafenib and trametinib, as detailed in 
pharmacokinetics section.
6.6.2
Treatment of overdose
Investigators should refer to the current dabrafenib and trametinib local prescribing information 
and/or Investigator’s Brochure for additional information regarding overdose.
6.7
Preparation and dispensation
Each study site will be supplied with study drug in packaging as described under the 
investigational drug section.
A unique medication number is printed on the study treatment label.
As per the treatment assigned to the participant, investigator staff will select the study treatment 
to dispense to the participant. The study treatment has a 2-part label (base plus tear-off label), 
immediately before dispensing the package to the participant, site personnel will detach the 
outer part of the label from the package and affix it to the participant’s source document.
As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities (i.e. pandemic, epidemic or natural disaster), that limits or prevents on-site study 
visits, delivery of study treatment directly to a participant's home may be permitted (if allowed 
by Local or Regional Health Authorities and Ethics Committees as appropriate) in the event the 
Investigator has decided that an on-site visit by the participant is no longer appropriate or 
possible, and that it is in the interest of the participant's health to administer the study treatment 
even without performing an on-site visit. The dispatch of study treatment from the site to the 
participant’s home remains under the accountability of the Investigator. In this case, regular 
phone calls or virtual contacts will occur between the site and the participant for instructional 
purposes, safety monitoring, investigation of any adverse events, ensuring participants continue 
to benefit from treatment, and discussion of the participant's health status until the participants 
can resume visits at the study site.

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6.7.1
Handling of study treatment and additional treatment
6.7.1.1
Handling of study treatment
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly and kept in a secured location to which only the investigator and designated 
site personnel have access. Upon receipt, all study treatment must be stored according to the 
instructions specified on the labels and in the Investigator’s Brochure. Clinical supplies are to 
be dispensed only in accordance with the protocol. Technical complaints are to be reported to 
the respective Novartis CO Quality Assurance.
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the study treatment but no information about 
the participant except for the medication number.
The investigator must maintain an accurate record of the shipment and dispensing of study 
treatment in a drug accountability log. Monitoring of drug accountability will be performed by 
monitors during site visits or remotely and at the completion of the trial. Participants will be 
asked to return all unused study treatment and packaging at the end of the study or at the time 
of discontinuation of study treatment.
At the conclusion of the study, and as appropriate during the course of the study, the investigator 
will return all unused study treatment, packaging, drug labels, and a copy of the completed drug 
accountability log to the Novartis monitor or to the Novartis address provided in the investigator
folder at each site.
6.7.2
Instruction for prescribing and taking study treatment
Dabrafenib and trametinib should be taken as follows:

Dabrafenib will be administered orally twice daily (BID) during the treatment period.

Trametinib will be administered orally once daily (QD) during the treatment period.

Participants should be instructed to take the dabrafenib and trametinib concurrently in the 
morning, at approximately the same time every day. The second (evening) dose of 
dabrafenib (150 mg) should be administered approximately 12 (± 4) hours apart from the 
first dose (morning) of dabrafenib.

Dabrafenib and trametinib should be taken with approximately 120-240 mL of water 
under fasting conditions, at least 1 hour before or 2 hours after a meal.

Participants should be instructed to swallow whole capsules of dabrafenib and not chew or 
open them.

If a participant vomits after taking study drug, the participant should be instructed not to 
retake the dose and wait for the next scheduled dose. The occurrence and frequency of any 
vomiting during treatment must be noted in the AE section of the eCRF.

If a participant misses a scheduled dose not due to interruption for any AE, he/she should 
be instructed not to double the next regularly scheduled dose. However, participant may 
take the missed dose immediately if the next scheduled dose is at least 6 hours later for 
dabrafenib and 12 hours later for trametinib. Participant may then take the next dose at the 
scheduled time.

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
Global clinical open-label supply kits of study treatment assigned by the IRT will be 
recorded in the IRT system.
Table 6-17
Dose treatment and schedule
Study treatment
Pharmaceutical 
form and route of 
administration
Strength
Frequency and/or 
Regimen
Dose
Dabrafenib
Capsules for oral 
use
50 mg, 75 mg
BID
150 mg BID (300 
mg/day)
Trametinib
Tablets for oral use
0.5 mg, 2 mg
QD
2 mg/day
7
Informed consent procedures
Eligible participants may only be included in the study after providing (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent.
If applicable, in cases where the participant's representative(s) gives consent (if allowed 
according to local requirements), the participant must be informed about the study to the extent 
possible given his/her understanding. If the participant is capable of doing so, he/she must 
indicate agreement by personally signing and dating the written informed consent document.
Informed consent must be obtained before conducting any study-specific procedures (e.g. all of 
the procedures described in the protocol). The process of obtaining informed consent must be 
documented in the participant source documents.
Novartis will provide to investigators in a separate document a proposed informed consent form 
that complies with the ICHE6 GCP guidelines and regulatory requirements and is considered 
appropriate for this study. Any changes to the proposed consent form suggested by the 
investigator must be agreed by Novartis before submission to the IRB/IEC.
Information about common adverse drug reactions already known about the investigational 
drug can be found in the Investigator's Brochure (IB) and/or Core Data Sheet (CDS). This 
information will be included in the participant informed consent and should be discussed with 
the participant during the study as needed. Any new information regarding the safety profile of 
the investigational drug that is identified between IB updates will be communicated as 
appropriate, for example, via an investigator notification or an aggregate safety finding. New 
information might require an update to the informed consent and then must be discussed with 
the participant.
Women of child bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order 
to participate in the study they must adhere to the contraception requirements.
Male participants must be informed that if a female partner becomes pregnant while he is 
enrolled in the study, contact with the female partner will be attempted to request her consent 
to collect pregnancy outcome information.
A copy of the approved version of all consent forms must be provided to Novartis after IRB/IEC 
approval.

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As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities i.e. pandemic, epidemic or natural disaster, that may challenge the ability to obtain 
a standard written informed consent due to limits that prevent an on-site visit, Investigator may 
conduct the informed consent discussion remotely (e.g. telephone, videoconference) if 
allowable by a local Health Authority.
Guidance issued by local regulatory bodies on this aspect prevail and must be implemented and 
appropriately documented (e.g., the presence of an impartial witness, sign/dating separate 
informed consent forms (ICFs) by trial participant and person obtaining informed consent, etc.).
8
Visit schedule and assessments
Assessment schedule (Table 8-1) lists all of the assessments when they are performed. All 
assessment (marked as "X") should be recorded in the clinical database or received 
electronically from a vendor. All data obtained from these assessments must be supported in 
the participant’s source documentation. Other assessments (marked as “S”) will be recorded in 
the participant’s source documentation only.
Participants should be seen for all visits/assessments as outlined in the assessment schedule 
(Table 8-1) or as close to the designated day/time as possible. Missed or rescheduled visits 
should not lead to automatic discontinuation. Participants who prematurely discontinue the 
study for any reason should be scheduled for a visit as soon as possible, at which time all of the 
assessments listed for the final visit will be performed. At this final visit, all dispensed 
investigational product should be reconciled, and the adverse event and concomitant 
medications recorded on the CRF.
As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities i.e., pandemic, epidemic or natural disaster that limits or prevents on-site study visits, 
alternative methods of providing continuing care may be implemented by the investigator as 
the situation dictates. If allowable by a local Health Authority and depending on operational 
capabilities, phone calls, virtual contacts (e.g., tele consult) or visits by site staff/ home nursing 
staff to the participant´s home, can replace on-site study visits, for the duration of the disruption 
until it is safe for the participant to visit the site again.

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Table 8-1
Assessment Schedule
Period
Screening
Treatment Phase
Post-
treatment 
Follow-up 
Phase
Survival 
Follow-up
Study 
Completion
Visit Name
Screening
Day 
1
Wee
k 3
Week 6
Week 
9
Week 12
Week 15 and 
every 3 weeks 
thereafter
End of 
Treatment (to 
be completed 
within 7 days 
of permanent 
discontinuatio
n of study 
treatment)
Post 
treatment 
follow-up
End of 
Study (EoS)
Days
-28 to -1
Day 
1
21
±7
42
±7
63
±7
84
±7
105
±7
EoT
FU visit
Survival
EoS
Informed consent
X
Enrollment
X
Inclusion / 
Exclusion criteria
X
Demography
X
BRAF V600E 
mutation testing
X
Tumor sample 
collection for 
central BRAF 
V600E testing. 
Note: if local 
BRAF V600E 
mutation result is 
not available, 
sample should 
be sent for 
central testing by 
Day -20
X

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Period
Screening
Treatment Phase
Post-
treatment 
Follow-up 
Phase
Survival 
Follow-up
Study 
Completion
Visit Name
Screening
Day 
1
Wee
k 3
Week 6
Week 
9
Week 12
Week 15 and 
every 3 weeks 
thereafter
End of 
Treatment (to 
be completed 
within 7 days 
of permanent 
discontinuatio
n of study 
treatment)
Post 
treatment 
follow-up
End of 
Study (EoS)
Days
-28 to -1
Day 
1
21
±7
42
±7
63
±7
84
±7
105
±7
EoT
FU visit
Survival
EoS
Serum 
pregnancy test 
and menstrual 
history
S
S
Medical 
history/current 
medical 
conditions
X
IRT Registration
S
S
S
S 
S
S
S 
S 
Diagnosis and 
extent of cancer
X
Prior 
Antineoplastic 
Therapy 
(Medication, 
Radiation, 
Surgery)
X
Hepatitis screen
X
Family history
S
Smoking history
X
Alcohol 
Consumption
X

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Period
Screening
Treatment Phase
Post-
treatment 
Follow-up 
Phase
Survival 
Follow-up
Study 
Completion
Visit Name
Screening
Day 
1
Wee
k 3
Week 6
Week 
9
Week 12
Week 15 and 
every 3 weeks 
thereafter
End of 
Treatment (to 
be completed 
within 7 days 
of permanent 
discontinuatio
n of study 
treatment)
Post 
treatment 
follow-up
End of 
Study (EoS)
Days
-28 to -1
Day 
1
21
±7
42
±7
63
±7
84
±7
105
±7
EoT
FU visit
Survival
EoS
Physical 
Examination
S
S
S
S
S
S
S
S
Vital Signs
X
X
X
X
X
X
X
X
Body Weight
X
X
X
X
X
X
X
Dermatological 
Assessment
S
S
S
S
S
S
S
X 
Ophthalmic 
Examination
X
X
X
Week 12 
and 
every 12 
weeks 
thereafter
X
Electrocardiogra
m (ECG)
X
X
X
Week 15 and 
every 9 weeks 
thereafter
X
Echocardiogram
X
X
Week 15 and 
every 9 weeks 
thereafter
X
Concomitant 
medications
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X

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Period
Screening
Treatment Phase
Post-
treatment 
Follow-up 
Phase
Survival 
Follow-up
Study 
Completion
Visit Name
Screening
Day 
1
Wee
k 3
Week 6
Week 
9
Week 12
Week 15 and 
every 3 weeks 
thereafter
End of 
Treatment (to 
be completed 
within 7 days 
of permanent 
discontinuatio
n of study 
treatment)
Post 
treatment 
follow-up
End of 
Study (EoS)
Days
-28 to -1
Day 
1
21
±7
42
±7
63
±7
84
±7
105
±7
EoT
FU visit
Survival
EoS
ECOG 
Performance 
Status
X
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
X
Clinical 
Chemistry
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
X
Coagulation 
Panel
X
PK blood 
collection
X
X
X
Pregnancy 
(Urine)
S
S
S
S
S
S
Tumor 
Assessment 
(Imaging)
X
X
Every 6 
weeks 
until 
Week 36, 
and then 
every 12 
weeks
Every 6 
weeks until 
Week 36, and 
then every 12 
weeks

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Period
Screening
Treatment Phase
Post-
treatment 
Follow-up 
Phase
Survival 
Follow-up
Study 
Completion
Visit Name
Screening
Day 
1
Wee
k 3
Week 6
Week 
9
Week 12
Week 15 and 
every 3 weeks 
thereafter
End of 
Treatment (to 
be completed 
within 7 days 
of permanent 
discontinuatio
n of study 
treatment)
Post 
treatment 
follow-up
End of 
Study (EoS)
Days
-28 to -1
Day 
1
21
±7
42
±7
63
±7
84
±7
105
±7
EoT
FU visit
Survival
EoS
Fluid/Tissue 
collection results 
(if available)
As 
clinically 
indicated 
As 
clinically 
indicated 
As 
clinically 
indicated 
As clinically 
indicated 
Patient reported 
outcomes
X
X
X
X
X
X
X
Study drug 
administration
X
X
X
X
X
X
Study treatment 
discontinuation
X
Survival Follow 
Up
X
Antineoplastic 
therapies since 
discontinuation of 
study treatment
X
X
X

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8.1
Screening
Participants must sign an informed consent form (ICF) prior to any study specific screening 
evaluations, within 28 days prior to the first dose of study treatment. The screening phase begins 
once written informed consent is provided and ends after 28 days or when participant receives 
the first dose of study treatment. Following completion of screening procedures and verifying 
participant eligibility based on assessments, the participant will be enrolled via the Interactive 
Response Technology (IRT) system. Laboratory results from the local laboratory will be used 
to determine participant’s eligibility to the study. Refer to Table 8-1 for additional details.
For laboratory evaluations used to determine eligibility, a repeated evaluation within the 
screening window is permitted for screening results out of the defined range. If the repeated 
laboratory result meets the criteria, that result may be used to determine eligibility. If the 
repeated laboratory result does not meet the criteria, the patient will be considered a screening 
failure. Participants who do not meet the criteria for participation in this study (screen failure) 
may be rescreened once. Each case must be discussed and agreed with Novartis on a case-by-
case basis.
All required screening assessments must be repeated if they do not meet the allowed time 
window for screening, when the subject will be rescreened for participation in the study.
If the participant already provided the archival tumor tissue samples for central testing of BRAF 
V600E mutation status it is not required to submit a new sample
Procedure for re-screening is as follows:

Site must register the patient as a screen failure in IRT

Subject number will be different from the initial screening
Adverse events that begin or worsen after informed consent should be recorded in the Adverse 
Events CRF. Conditions that were already present at the time of informed consent should be 
recorded in Medical History CRF. CRA is to review and confirm patient‘s eligibility for re-
screening with the site. Patients may be re-screened only once and must be enrolled within 28 
days after the recorded rescreening date. All evaluations including original assessments and 
repeated assessments must be collected on the eCRF.
Participants will be enrolled based on a positive BRAF V600E mutation test performed using 
an NMPA/MOH-approved assay as part of study inclusion criteria (Section 5.1). 

Patients with local BRAF V600E mutation performed by an NMPA/MOH-approved assay 
at screening will be enrolled based on local testing results. Local BRAF V600E mutation 
result should be locally documented and verified by a Novartis monitor and testing 
method should be recorded in the eCRF. For these patients it is required to provide an 
archival tumor tissue sample (minimum 3 to maximum 5 tumor slides) at screening but 
central testing of BRAF V600E mutation status is not required prior to enrollment. These 
patients will not be excluded if centralized testing is later found to be discordant or 
uninformative (e.g. inadequate sample).

Patients who do not have locally documented BRAF V600E results available, or have 
BRAF V600E results based on NMPA/MOH unapproved assays at screening will be 
enrolled based on central BRAF testing results. For these patients, a tumor sample 

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(minimum 3 to maximum 5 tumor slides, see Section 8.5.3) for prospective central testing 
must be submitted during screening, performed prior to enrollment. A positive BRAF
V600E mutation result must be obtained prior to enrollment.
8.1.1
Eligibility screening
Following registering in the IRT for screening, participant eligibility will be checked once all 
screening procedures are completed. The eligibility check will be embedded in the IRT system. 
Please refer and comply with detailed guidelines in the IRT manual.
8.1.2
Information to be collected on screening failures
Participants who sign an informed consent form and subsequently found to be ineligible will be 
considered a screen failure. The reason for screen failure should be entered on the applicable 
Case Report Form. The demographic information, informed consent, and Inclusion/Exclusion 
pages must also be completed for screen failure participants. No other data will be entered into 
the clinical database for participants who are screen failures, unless the participant experienced 
a serious adverse event during the screening phase (see SAE section for reporting details).
Participants who sign an informed consent and are considered eligible but fail to be started on 
treatment for any reason will be considered an early terminator. The reason for early termination 
should be captured on the appropriate disposition Case Report Form. Data and samples 
collected from participants prior to screen failures may still be analyzed (i.e. specifically, 
mutation test for BRAF from either Central or Local Lab collected from participants prior to 
screen failure.)
8.2
Participant demographics/other baseline characteristics
The data to be collected on participant characteristics at screening includes:

Demography (age, gender, childbearing potential, race and ethnicity, or as allowed by 
local regulations)

Past and current medical conditions including cardiovascular medical history and risk 
factors

Diagnosis and extent of cancer using AJCC edition 8

Alcohol history

Smoking history

HIV history

Prior antineoplastic therapies (medications, radiation, surgeries)

Prior and current concomitant medications, surgical and medical procedures and 
significant non-drug therapies. Note: All other medications taken within 28 days or 5 half-
lives, whichever is shorter before the first dose of study treatment is administered must be 
recorded on the Prior and current concomitant medication eCRF page and updated on an 
ongoing basis if there is new change to the medication.
Assessments to be performed at screening/baseline include:

Physical examination (e.g. performance status (ECOG), height, weight, vital signs, 
ophthalmic and skin examination)

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
Cardiovascular assessments (e.g., ECG, ECHO or MUGA)

Laboratory assessments (e.g., hematology, chemistry, thyroid function, coagulation, 
urinalysis, serum pregnancy test)

Tumor assessment (RECIST 1.1, color digital photography including metric ruler for skin 
lesions, etc.)
8.3
Efficacy
8.3.1
Efficacy assessments
Tumor response will be assessed locally and by independent central review according to the 
Novartis guideline version 3.2 (Section 16) based on RECIST 1.1 (Eisenhauer et al 2009). The 
imaging assessment collection plan is presented in Table 8-2. Details of the central review 
process will be described in the independent review charter.
Imaging data will be centrally collected and checked for quality by an imaging Contract 
Research Organization (CRO) designated by Novartis. The central independent review’s 
assessment will be used for the primary endpoint analysis and local investigator’s assessment 
will be used for treatment decision making.
Information regarding prior interventions (e.g., radiotherapy), pre-existing radiographic 
findings that mimic metastatic disease at baseline/screening and prior interventions should be 
transmitted to the imaging CRO via the Baseline Clinical Form along with the baseline images. 
Sites must ensure the data entered on the form is consistent with the data entered in the clinical 
database.
Information regarding cytology/histology results should be transmitted to the imaging CRO via 
the cytology and histology report form for all visits, when applicable, for review by the 
independent radiologist. Sites must ensure the data entered on the form is consistent with the 
data entered in the clinical database.
Baseline imaging assessments
Imaging assessments will be performed at screening/baseline within 28 days of start of 
treatment (Day -28 to Day -1 prior to Day 1).
Any imaging assessments already completed during the regular work-up of the participant 
within 28 days prior to start of treatment, including before signing the main study ICF, can be 
considered as the baseline images for this study. Any imaging assessments obtained after 
enrollment cannot be considered baseline images. The following assessments are required at 
screening/baseline:

Chest, abdomen, and pelvis CT or MRI

Brain CT or MRI

Whole body bone scan

Localized bone CT, MRI, or x-ray, for any lesions identified on the whole body bone scan 
that are not visible on the chest, abdomen, and pelvis CT or MRI

Color photography including a metric ruler to measure the size of the lesion for any skin 
lesions present

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
CT or MRI of other metastatic sites (e.g. neck), if clinically indicated
If a participant is known to have a contraindication to CT intravenous (IV) contrast media or 
develops a contraindication during the trial, a non-contrast CT of the chest (MRI is not 
recommended due to respiratory artifacts; however, if CT is not feasible per local regulations, 
MRI can be performed instead) plus a contrast-enhanced MRI (if possible) of the abdomen and 
pelvis should be performed.
A brain MRI or CT should be completed for all participants to identify brain metastases. 
Contrast enhanced brain MRI is preferred, however, if MRI contrast is contraindicated, then 
MRI without contrast or CT with/without contrast is acceptable.
A whole body bone scan should be performed per institutional standard of care [e.g. Tc-99 bone 
scan, whole body bone MRI, Fluorodeoxyglucose positron emission tomography (FDG-PET), 
or sodium fluoride (NaF) PET]. Localized CT, MRI, or X-rays should be acquired for all 
skeletal lesions identified on the screening whole body bone scan, which are not visible on the 
chest, abdomen, and pelvis CT/MRI.
If clinically indicated, CT or MRI of other areas (e.g. neck) of disease as appropriate should be 
performed.
If skin lesions are present at screening, color photography should be acquired using a digital 
camera in clear focus, including a scale/ruler, in such a way that the size of the lesion(s) can be 
determined from the photograph.
Any potentially measurable lesion that has been previously treated with radiotherapy should be 
considered as a non-measurable lesion. However, if a lesion previously treated with 
radiotherapy has clearly progressed since the radiotherapy, it can be considered as a measurable 
lesion.
Chest x-rays and ultrasound should not be used to measure tumor lesions.
Post-baseline imaging assessments
Imaging assessments as described in Table 8-2 should be performed using the same imaging 
modality used at baseline, irrespective of study treatment interruption or actual dosing (see 
Table 8-1). Imaging assessments for response evaluation will be performed every 6 weeks (+/-
7 days) for the first 36 weeks, and every 12 weeks (+/- 7 days) thereafter until disease 
progression , death, lost to follow-up or withdrawal of consent. Imaging assessments should be 
scheduled using the enrollment date as the reference date (not the date of the previous tumor 
assessment), and should be respected regardless of whether treatment with study treatment is 
temporarily withheld or unscheduled assessments performed.
Additional imaging assessments may be performed at any time during the study at the 
investigator’s discretion to support the efficacy evaluations for a participant, as necessary. 
Clinical suspicion of disease progression at any time requires a physical examination and 
imaging assessments to be performed promptly rather than waiting for the next scheduled 
imaging assessment.
Each lesion that is measured at baseline must be measured by the same method (either same 
imaging method or by photography, including a metric ruler) and when possible, the same local 

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radiologist/physician throughout the study so that the comparison is consistent. If an off-
schedule imaging assessment is performed because progression is suspected, subsequent 
imaging assessments should be performed in accordance with the original imaging schedule.
Combined PET/CT may be used only if the CT is of similar diagnostic quality as a CT 
performed without PET, including the utilization of IV contrast media. At the discretion of the 
Investigators, FDG-PET scans may be performed to document progressive disease per RECIST 
1.1 (Appendix 1).
Table 8-2
Imaging Assessment Collection Plan
Procedure
Screening/Baseline
During Treatment/Follow-up
Chest, abdomen and pelvis CT or 
MRI (with intravenous contrast 
enhancement)
Mandated
Mandated, every 6 weeks (+/- 7 
days) until Week 36, and every 12 
weeks (+/- 7 days) thereafter
Brain CT or MRI
Mandated
If lesions were documented at 
baseline, follow same schedule as 
CT/MRI of chest, abdomen, and 
pelvis, or if clinically indicated
Whole body bone scan
Mandated
If clinically indicated
Localized bone CT, MRI, or x-ray
For any lesions identified on the 
whole body bone scan that are not 
visible on the chest, abdomen and 
pelvis CT or MRI
If lesions were documented at 
baseline, follow same schedule as 
CT/MRI of chest, abdomen, and 
pelvis, or if clinically indicated
Color photography (with 
scale/ruler)
For any skin lesions present
If lesions were documented at 
baseline, follow same schedule as 
CT/MRI of chest, abdomen, and 
pelvis, or if clinically indicated
CT or MRI of other metastatic sites 
(e.g. neck)
If clinically indicated
If lesions were documented at 
baseline, follow same schedule as 
CT/MRI of chest, abdomen, and 
pelvis, or if clinically indicated
During a Public Health emergency as declared by Local or Regional authorities i.e., pandemic, epidemic, or 
natural disaster, that limits or prevents on-site study visits, the collection of images may be modified by 
Novartis and will be communicated to the investigator
8.3.2
Transmission of radiological data to central independent review
All radiological assessments will be read locally and should be submitted promptly after 
acquisition to the imaging vendor designated by Novartis. Rapid image transmission to the 
central imaging vendor will be accomplished by transferring the images acquired by the 
investigator electronically in a secured website (e.g.: via the internet).
All imaging timepoints will be read on an ongoing basis as detailed in the imaging manual to 
be provided by the designated imaging vendor and independent review charter. In all instances, 
the process at the imaging vendor will ensure that the central reviewers remain blinded to the 
results of the local assessment. Results of these readings will not be communicated to the sites.
In case patients continue treatment beyond disease progression as outlined in Section 6.1.4.1, 
images should still be sent to the imaging vendor.

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8.4
Safety
Safety assessments are specified below with the assessment schedule detailing when each 
assessment is to be performed.
For details on AE collection and reporting, refer to AE section.
As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities i.e., pandemic, epidemic or natural disaster, that limits or prevents on-site study visits, 
regular phone or virtual calls can occur for safety monitoring and discussion of the participant´s 
health status until it is safe for the participant to visit the site again.
Table 8-3
Physical Examination, Vital Signs, Height and Weight & Specifications
Assessment
Specification
Physical examination
A complete physical examination will be performed at screening and later as 
clinically indicated and will include the examination of general appearance, skin, 
neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, 
lymph nodes, extremities, vascular, and neurological. If indicated based on 
medical history and/or symptoms, rectal, external genitalia, breast, and pelvic 
exams will be performed.
A short physical exam will include the examination of general appearance and vital 
signs (blood pressure [SBP and DBP] and pulse). A short physical exam will be 
performed at all visits starting from visit 3 as per schedule in Table 8-1 except 
where a complete physical examination is required. 
Information for all physical examinations must be included in the source 
documentation at the study site. Clinically relevant findings that are present prior to 
signing informed consent must be recorded on the appropriate CRF that captures 
medical history. Significant findings made after signing informed consent which 
meet the definition of an Adverse Event must be recorded as an adverse event.
Vital signs
Vital signs include blood pressure (supine position preferred when ECG is 
collected), pulse measurement, and body temperature. Vital signs will be 
measured at screening and at subsequent time points as specified in Table 8-1
Height and weight
Height in centimeters (cm) will be measured at screening. Body weight (to the 
nearest 0.1 kilogram (kg) in indoor clothing, but without shoes) will be measured at 
screening and at subsequent time points as specified in Table 8-1.
Dermatological 
Examination/Skin 
Biopsy/Photography
A full body dermatological examination will be performed by a dermatologist (or 
suitably qualified medical personnel) to identify abnormal skin lesions. All findings 
will be photographed and identified during screening. Dermatological examinations 
should include examination of skin and assessment of any skin changes. 
Dermatological examinations will be obtained at each time point as noted in the 
Assessment Schedule (Table 8-1). Wherever possible, the same individual should 
perform these examinations. Biopsy in or around skin lesions that change during 
the study may be obtained if clinically indicated. Skin photography and de-
identified pathology reports of new lesions or lesions that change during the study 
must be obtained and forwarded to Novartis or designee.

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ECOG Performance status:
Performance status will be assessed as described in the Table 8-1. More frequent examinations 
may be performed at the investigator’s discretion, if medically indicated. ECOG Performance 
status scale will be used as described in Table 8-4:
Table 8-4
ECOG performance status scale
Score
Performance Status
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 housework, 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
5
Dead
8.4.1
Laboratory evaluations
Local laboratory will be used for analysis of scheduled hematology, biochemistry, and other 
blood specimens collected as part of safety monitoring (as detailed in Table 8-5). The frequency 
of the assessments is indicated in the Table 8-1.
For assessment of participants’ eligibility to the study, laboratory results from local laboratory 
will be used.
The results of the local laboratory will be recorded in the eCRF.
The CRA will obtain the local laboratory reference ranges and a copy of the laboratory 
certification for all laboratory results that are entered into the eCRF.
As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities i.e., pandemic, epidemic or natural disaster, that limits or prevents on-site study visits, 
if participants cannot visit the site for protocol specified safety lab assessments, an alternative 
lab collection site may be used.
Table 8-5
Clinical laboratory parameters collection plan
Test Category
Test Name
Hematology
Hemoglobin, Platelets, White blood cells, Differential (Basophils, Eosinophils, 
Lymphocytes, Monocytes, Neutrophils, Other (absolute value preferred , %s are 
acceptable)
Chemistry
Albumin, Alkaline phosphatase, ALT , AST, Calcium, Magnesium, Phosphorus, 
Chloride, Sodium, Potassium, Creatinine, Creatine kinase, Direct Bilirubin, Total 
Bilirubin, Total Cholesterol, Triglycerides, Blood Urea Nitrogen (BUN) or Urea, Uric 
Acid, Amylase, Lipase, Glucose (fasting)
Urinalysis
Microscopic Panel: Red Blood Cells, White Blood Cells, Casts, Crystals, Bacteria, 
Epithelial cells
Coagulation
International normalized ratio [INR]), Activated partial thromboplastin time (APTT)
Hepatitis markers
HBV-DNA, HbsAg, HbsAb, HbcAb, HCV RNA-PCR (at baseline and as clinically 
indicated)

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Test Category
Test Name
Pregnancy Test
A serum pregnancy test must be performed at screening (at the local laboratory) ≤ 14 
days before first dose of study treatment, and at EOT. Subsequent tests may be urine 
tests (refer to 'Pregnancy and assessments of fertility' section).
8.4.2
Cardiac assessments
8.4.2.1
Electrocardiogram (ECG)
A standard 12 lead ECG (single or triplicate) will be performed according to the relevant Visit 
Evaluation Schedule (Table 8-1). Electrocardiograms (ECGs) must be recorded after 10 
minutes rest in the supine position to ensure a stable baseline/according to the ECG investigator 
manual. The preferred sequence of cardiovascular data collection during study visits is ECG 
collection first, followed by vital signs, and blood sampling. Additional, unscheduled, ECGs 
may be performed at the discretion of the investigator at any time during the study as clinically 
indicated. Unscheduled ECGs with clinically significant findings should be collected in 
triplicate. The Fridericia QT correction formula (QTcF) should be used for clinical decisions.
Triplicate ECGs should be recorded approximately 2 minutes apart. The mean QTcF value 
should be calculated from each of the triplicate ECGs assessments. All ECGs need to be 
collected and copies kept in the medical record for central review, if requested by the sponsor.
Twelve (12)-lead ECGs will be obtained using an ECG machine that automatically calculates 
heart rate and measures PR, QRS, QT, and QTcF intervals. ECG data will be read and 
interpreted locally.
Any identifier details must be redacted e.g. participant initials, date of birth.
Clinically significant abnormalities must be recorded on the CRF as either medical 
history/current medical conditions or adverse events as appropriate. 
Table 8-6
ECG collection plan
Week (or Cycle)
Day
Time
ECG Type
Number of ECG
Screening
-28 to -1
Anytime
12 Lead
3
3
1
Anytime
12 Lead
3
6
1
Anytime
12 Lead
3
Week 15 and every 
9 weeks thereafter 
and at EoT
1
Anytime
12 Lead
3
Unscheduled (as clinically indicated)
Anytime
12 Lead
1 (3 if clinically 
significant)
Interpretation of the tracing must be made by a qualified physician and documented on the 
appropriate CRF. Each ECG tracing should be labeled with the study number, participant 
initials (where regulations permit), subject number, date, and kept in the source documents at 
the study site. 
Clinically significant abnormalities present when the participant signed informed consent 
should be reported on the Medical History eCRF page. Clinically significant findings must be 
discussed with Novartis prior to enrolling the participant in the study. New or worsened 

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clinically significant findings occurring after informed consent must be recorded on the Adverse 
Events eCRF page. 
8.4.2.2
Echocardiogram (ECHO)
Decreases of the LVEF have been observed in participants receiving trametinib. Therefore, 
ECHO or MUGA (ECHO is preferred) must be performed to assess cardiac ejection fraction in 
regular intervals according to the relevant schedule (Table 8-1).
The same procedure (ECHO or MUGA) should be performed at baseline and at follow-up 
visit(s). Dose modification guidance and stopping criteria for LVEF decrease are provided 
in Table 6-13.
8.4.3
Pregnancy and assessments of fertility
Male participants
A condom is required for all sexually active male participants to prevent them from fathering a 
child AND to prevent delivery of study treatment via seminal fluid to their partner.
Male patients (including those that have had a vasectomy) taking the dabrafenib and trametinib 
combination therapy must use a condom during intercourse, and for 16 weeks after stopping 
treatment, and should not father a child during these periods.
In addition, male participants should not donate sperm for the time period specified above.
Women of child-bearing potential
All pre-menopausal women who are not surgically sterile will have pregnancy testing. 
Additional pregnancy testing might be performed if requested by local requirements.
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 with dabrafenib and trametinib combination therapy. Highly effective 
contraception methods include:
a. Total abstinence (when this is in line with the preferred and usual lifestyle of the participant). 
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 participant.
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.

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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
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.
As per Section 4.6, changes in safety assessments can be added as one of the risk mitigation 
procedure during public health emergency declared by local or regional authorities. If 
participants cannot visit the site to have serum pregnancy tests during a Public Health 
emergency as declared by Local or Regional authorities i.e., pandemic, epidemic or natural 
disaster, that limits or prevents on-site study visits, urine pregnancy test kits may be used. 
Relevant participants can perform the urine pregnancy test at home and report the result to the 
site. It is important that participants are instructed to perform the urine pregnancy test first and 
only if the test result is negative proceed with the administration of the study treatment. A 
communication process should be established with the participant so that the Site is informed 
and can verify the pregnancy test results (e.g., following country specific measures).
8.4.4
Hepatitis marker
Hepatitis panels listed in Table 8-5 will be performed at screening and as clinically indicated 
while on study treatment.
HBV-DNA serology (including HBV-DNA, HBsAg, HBsAb, HBcAb) and HCV RNA-PCR 
test will be performed at baseline/screening (≤ 28 days prior to start of study treatment) and as 
clinically indicated (hepatitis markers should be evaluated for precautionary safety monitoring 
of viral re-activation while on study treatment).
During the screening period, participants must be screened for HBV and HCV (current or past 
history of infection). Careful medical history must be taken for all participants to look for risk 
factors (family history of HBV and HCV, intravenous drug abuse, unprotected sex, dialysis, 
blood transfusions, etc.), and any past or present HBV symptoms (e.g., jaundice, dark urine, 
light colored stools, right upper quadrant pain).
After start of the study treatment and until 150-day safety follow-up, testing for HBV and HCV 
should be performed if clinically indicated (for example: rule out viral causality in case of DILI).

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8.4.5
Ophthalmic examination
Episodes of visual changes have been observed in participants receiving trametinib, dabrafenib, 
and combination therapy.
A standard ophthalmic examination by an ophthalmologist will be performed as per schedule 
in Table 8-1. 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 (dilation only required if clinically indicated). Optical 
coherence tomography is mandated if retinal abnormalities are suspected. Other types of 
ancillary testing including color fundus photography and fluorescein angiography are also 
recommended if clinically indicated.
8.5
Additional assessments
8.5.1
Clinical Outcome Assessments (COAs)
Patient Reported Outcomes
The impact of treating BRAF+ NSCLC with dabrafenib in combination with trametinib on 
health-related quality-of-life (QoL), physical functioning, lung cancer symptoms, treatment-
related side effects, global health status, and utilities will be assessed with the the European 
Organization for Research and Treatment of Cancer core quality of life questionnaire (EORTC-
QLQ-C30), it’s lung cancer specific module (QLQ-LC13), and the EuroQoL 5-level instrument 
(EQ-5D-5L, tablet version) (Aaronson et al 1993, Bergman et al 1994, Rabin and de Charro 
2001):
PRO data will be recorded by participants onto an electronic tablet device maintained at the 
study site. Investigators or study personnel should provide technical assistance but should not 
encourage the participants to change responses reported in questionnaires. All ePRO 
assessments should be administered in the participant’s local language according to the 
assessment schedule in Table 8-1, prior to any assessments (including imaging assessments), 
treatments, or receipt of results from any test to avoid biasing the participant’s perspective.
The ePROs will be completed prior to any other assessments on Cycle 1 Day 1 prior to 
enrollment, then at every visit (with and without dosing) while the patient is on treatment until 
treatment discontinuation and/or at the End of Treatment visit (EOT). 
Participants should be given sufficient space and time to complete all study questionnaires. The 
responses stored electronically on the database will be considered the source file. If missing 
responses are noted, the tablet will alert participants of any missing responses. Attempts should 
be made to collect questionnaires for all participants. If participants refuse to complete 
questionnaires, this should be documented in the source documents. A participant’s refusal to 
complete study questionnaire(s) are not protocol deviations. Please refer to the study ePRO 
manual for detailed instructions for completion and handling of the ePROs.
The participant should be made aware that completed questionnaires are not reviewed by the 
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As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities i.e. pandemic, epidemic or natural disaster, that limits or prevents on-site study visits, 
COA data may be collected remotely.
8.5.2
Pharmacokinetics
8.5.2.1
Pharmacokinetic blood collection and handling
Blood samples (2 mL) for pharmacokinetic analysis of dabrafenib and metabolites (hydroxy-
dabrafenib, and desmethyl-dabrafenib) and trametinib will be collected during the study visits 
in Week 3, Week 6, and Week 12 shown in Table 8-1 and Table 8-7. For each visit, participants 
will be instructed to withhold their morning dose prior to the study visit, and a pharmacokinetic 
sample will be obtained prior to study treatment administration (between 8-14 hours after the 
evening dose of the previous day). The exact clock time of dosing, as well as actual sample 
collection date and time will be entered on the PK blood collection summary page of the 
CRF. Sampling problems will be noted in the relevant field of the CRF.
For events of visual changes regardless of severity, a blood sample for PK analysis must be 
drawn as close as possible to the time of the event.
Details of pharmacokinetic blood sample collection (including volume to be collected, timing 
of samples, recording of pharmacokinetic sample information), processing, storage and 
shipping procedures are provided in the Laboratory Manual.
Table 8-7
Sample log table for the evaluation of pharmacokinetics 
of trametinib , dabrafenib, and related metabolites
Weeks
Scheduled 
Time
Dose 
Reference
ID for 
trametinib
Dose 
Reference
ID for 
dabrafenib
PK Sample 
Number
Volume (mL)
3
0 h (pre-dose)a
101/1001b
201/2001c
1
2
6
0 h (pre-dose)a
102/1002b
202/2002c
2
2
12
0 h (pre-dose)a
103/1003b
203/2003c
3
2
NA
Unscheduledd
NA
NA
1001+d
2
aSamples will be collected prior to the morning dose of trametinib and dabrafenib (between 8-14 hours after the 
evening dose of the previous day).
bThe first Dose Reference ID for trametinib is for current dose, while the second PK collection number is for last 
dose the participant received prior to the collection of the PK sample
cThe first Dose Reference ID for dabrafenib is for current dose, while the second PK collection number is for 
last dose the participant received prior to the collection of the PK sample
dFor events of visual changes regardless of severity, a blood sample for PK analysis must be drawn as close 
as possible to the time of the event, sequentially numbered 1001, 1002, etc.
8.5.2.2
Analytical method
Plasma analysis will be performed under the control of PK Sciences, the details of which will 
be included in the Lab Manual. Concentrations of dabrafenib, hydroxy-dabrafenib, desmethyl-
dabrafenib and trametinib will be quantified in one validated assay. Raw data will be stored in 
the Good Laboratory Practice (GLP) Archives.

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Once the plasma has been analyzed for dabrafenib and its metabolites and trametinib, any 
remaining plasma may be analyzed for other compound-related metabolites and the results 
reported.
8.5.3
Biomarkers
Central BRAF V600E mutation testing
For this study, biomarker analysis is limited to central BRAF V600E mutation testing in tumor 
tissue samples. If available, it is mandatory to provide an archival specimen obtained at or since 
the time of diagnosis for central BRAF V600E mutation testing. A sample from the most recent 
biopsy is preferred. Tumor tissue samples will be provided as a minimum of 3 to a maximum 
of 5 formalin-fixed paraffin-embedded (FFPE) tumor slides. Every effort should be made to 
submit freshly cut tissue sectioned onto tumor slides. Slide cut date is required on sample 
requisition form. CNS and bone are excluded organs for new biopsy.
If a suitable archival tumor tissue sample is not available, minimum 3 to maximum 5 slides 
from a newly acquired biopsy sample can be accepted, if a new biopsy is medically feasible. 
Table 8-8
Biomarker sample collection plan
Sample Type
Volume
Visit
Time point
Archival or new tumor 
biopsy sample for central 
BRAF V600E mutation 
testing 
Minimum 3 to maximum 
5 tumor slides freshly cut 
from FFPE archival tumor 
sample or from new 
tumor biopsy sample. 
Fine needle aspirates are 
not acceptable.
Screening
At C1D1 with local BRAF
V600E result or by 
screening Day -20, if 
local BRAF V600E result 
not available.
Tumor biopsy samples will be tested to centrally confirm the BRAF V600E status at the 
Novartis-designated laboratory. Provision of a minimum of 3 to a maximum of 5 freshly cut 
tumor slides is indicated in order to allow for sufficient material for central BRAF V600E 
mutation testing, as described below:

If local documentation of BRAF V600E mutation status by local test result from a 
qualified assay (NMPA and/or MOH-approved) is available, BRAF V600E mutation 
results will be subjected to retrospective central testing by a Novartis designated 
laboratory with a MOH/NMPA approved assay.

In cases where an acceptable local result for BRAF V600E mutation is not available, a 
tumor sample for central prospective testing must be submitted during screening, prior to 
enrollment. To allow sufficient time for testing, the tumor sample should be sent to a 
Novartis designated central laboratory for testing by screening Day -20.

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9
Study discontinuation and completion
9.1
Discontinuation
9.1.1
Discontinuation of study treatment
Discontinuation of study treatment for a participant occurs when study treatment is stopped 
earlier than the protocol planned duration and can be initiated by either the participant or the 
investigator.
The investigator must discontinue study treatment for a given participant if, he/she believes that 
continuation would negatively impact the participant's well-being.
Study treatment must be discontinued under the following circumstances:

Disease progression

Adverse events, abnormal laboratory values, or abnormal test result that indicate a safety 
risk to the participant as described in Section 6.5.2.

Participant/guardian decision

Pregnancy

Use of prohibited treatment as per recommendations in Section 6.2.2

Any situation in which study participation might result in a safety risk to the participant
If a participant discontinues study treatment at a scheduled visit, the assessments performed at 
that visit can be used to fulfil the treatment discontinuation visit requirements. Laboratory 
assessments and other required assessments do not need to be repeated at the discontinuation 
visit if they were performed within 14 and 30 days, respectively, of the discontinuation visit. If 
the last efficacy assessment was >6 weeks prior to study withdrawal and disease progression 
had not been documented, efficacy assessment should be obtained.
Participants who discontinue study treatment or who decide they do not wish to participate in 
the study further should NOT be considered withdrawn from the study UNLESS they withdraw 
their consent (see Section 9.1.2). Where possible, they should return for the assessments 
indicated in the Assessment Schedule. If they fail to return for these assessments for unknown 
reasons, every effort (e.g. telephone, e-mail, letter) should be made to contact the 
participant/pre-designated contact as specified in Section 9.1.3. This contact should preferably 
be done according to the study visit schedule.
If the participant cannot or is unwilling to attend any visit(s), the site staff should maintain 
regular telephone contact with the participant, or with a person pre-designated by the participant. 
This telephone contact should preferably be done according to the study visit schedule.
The investigator must also contact the IRT to register the participant’s discontinuation from 
study treatment.
For participants who discontinue treatment for reasons other than documented disease 
progression as determined by investigator, death, lost to follow-up, or withdrawal of consent, 
tumor assessments must continue to be performed every 6 weeks until Week 36 and then every 
12 weeks until documented disease progression as determined by investigator, death, lost to 
follow-up, or withdrawal of consent.

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In some circumstances participants may be allowed to continue to receive study treatment 
beyond disease progression as per RECIST criteria as determined by investigator. These 
participants will continue assessments as outlined in the assessments section, and will complete 
the EOT visit only after permanent discontinuation of study treatment. After study treatment 
discontinuation, at a minimum, in abbreviated visits, the following data should be collected at 
clinic visits or via telephone/email contact (per assessment schedule in Table 8-1)

new / concomitant treatments including any radiotherapy, surgical procedure or new 
anticancer therapy

adverse events/Serious Adverse Events

survival status
Monthly safety follow up should continue for up to 6 months or until initiation of another anti-
neoplastic therapy for monitoring for patients with cutaneous and non-cutaneous malignancies.
9.1.2
Survival follow-up
All patients who discontinued from tumor assessments will subsequently be followed for 
survival information every 3 months until death, lost to follow-up or withdrawal of consent for 
survival. The investigator or his/her designee will collect this survival information and any new 
anti-neoplastic therapies for all patients until the final survival analysis.
Follow-up can be done via a phone contact. Antineoplastic therapies will be captured on the 
relevant eCRF page following the last dose of the study treatment.
9.1.3
Withdrawal of informed consent/Opposition to use data/biological 
samples
Withdrawal of consent/opposition to use data/biological samples occurs when a participant:

Explicitly requests to stop use of their biological samples and/or data (opposition to use 
participant’s data and biological samples)
and

No longer wishes to receive study treatment
and

Does not want any further visits or assessments (including further study-related contacts)
This request should be in writing (depending on local regulations) and recorded in the source 
documentation.
In this situation, the investigator should make a reasonable effort (e.g., telephone, e-mail, letter) 
to understand the primary reason for the participant’s decision to withdraw their 
consent/opposition to use data/biological samples and record this information.
In the event that a participant withdraws consent and/or opposes the use of data/biological 
samples, study treatment must be discontinued, and no further assessments conducted, and the 
data that would have been collected at subsequent visits will be considered missing. Further 
attempts to contact the participant are not allowed unless safety findings require communicating 
or follow-up. If the participant agrees, a final evaluation at the time of the participant’s 

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withdrawal of consent/opposition to use data/biological samples should be made as detailed in
the assessment table (refer to Section 8).
Novartis will continue to retain and use all research results (data) that have already been 
collected for the study evaluation, including processing of biological samples that has already 
started at time of consent withdrawal/opposition. No new Personal Data (including biological 
samples) will be collected following withdrawal of consent/opposition.
9.1.4
Lost to follow-up
For participants whose status is unclear because they fail to appear for study visits without 
stating an intention to discontinue or withdraw, the investigator must show "due diligence" by 
documenting in the source documents steps taken to contact the participant, e.g. dates of 
telephone calls, registered letters, etc. A participant should not be considered as lost to follow-
up until due diligence has been completed or until the end of the study.
9.1.5
Early study termination by the sponsor
The study can be terminated by Novartis at any time for any reason. This may include reasons 
related to the benefit/ risk assessment of participating in the study, practical reasons (including 
slow enrollment), or for regulatory or medical reasons. In taking the decision to terminate, 
Novartis will always consider the participant welfare and safety. Should early termination be 
necessary, participants must be seen as soon as possible (provide instruction for contacting the 
participant, when the participant should stop taking drug, when the participant should come for 
a final visit) and treated as a prematurely withdrawn participant. The investigator may be 
informed of additional procedures to be followed in order to ensure that adequate consideration 
is given to the protection of the participant’s interests. The investigator or sponsor depending 
on the local regulation will be responsible for informing IRBs/IECs of the early termination of 
the trial.
9.2
Study completion and post-study treatment
Study completion is defined as when the last participant finishes their Study Completion visit 
and any repeat assessments associated with this visit have been documented and followed-up 
appropriately by the Investigator or, in the event of an early study termination decision, the date 
of that decision.
All treated participants should have a safety follow-up call conducted 30 days after last 
administration of study treatment. The information collected is kept as source documentation. 
All SAEs reported during this time period must be reported as described in Section 10.1.3. 
Documentation of attempts to contact the participant should be recorded in the source 
documentation.
Following discontinuation of study treatment, all participants are to be followed as specified in 
Section 9.1. The End of Study eCRF should only be completed when a participant is no longer 
being followed.
The primary analysis was conducted when the first 20 enrolled participants have had at least 
two post-baseline tumor assessments or have discontinued study earlier for any reason prior to 
the second post-baseline disease assessment. The primary analysis data will be summarized in 

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the primary clinical study report (CSR). Following the cut-off date for the analysis reported in 
the primary CSR, the study will remain open. Ongoing participants will continue to receive 
study treatment and be followed as per the schedule of assessments, as long as participants 
derive benefit from dabrafenib in combination with trametinib.
The study will end 17 months after the LPFV or when all participants have died or 
discontinued from the study, whatever occurs first. 
At the end of the study, every effort will be made to continue provision of study treatment 
outside this study in alignment with local regulations through an alternative setting (e.g. 
another clinical study, Post Trial Access (PTA)) to participants who in the opinion of the 
Investigator are still deriving clinical benefit. The final analysis will occur at the end of the 
study. All available data from all participants up to this cut-off date will be analyzed and 
summarized in a final CSR.
10
Safety monitoring and reporting
10.1
Definition of adverse events and reporting requirements
10.1.1
Adverse events
An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a participant 
or clinical investigation participant after providing written informed consent for participation 
in the study. Therefore, an AE may or may not be temporally or causally associated with the 
use of a medicinal (investigational) product.
The investigator has the responsibility for managing the safety of individual participant and 
identifying adverse events.
Novartis qualified medical personnel will be readily available to advise on trial related medical 
questions or problems.
The occurrence of adverse events must be sought by non-directive questioning of the participant 
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the participant during or between visits or through physical examination findings, laboratory 
test findings, or other assessments.
Adverse events will be assessed and graded according to the Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.03.
Adverse events must be recorded under the signs, symptoms, or diagnosis associated with them, 
accompanied by the following information (as far as possible) (if the event is serious refer to 
Section 10.1.2):
1. The severity grade OR the Common Toxicity Criteria (CTC) AE grade (version 4.03).
1. its relationship to the study treatment. If the event is due to lack of efficacy or progression 
of underlying illness (i.e. progression of the study indication) the assessment of causality 
will usually be ‘Not suspected.’ The rationale for this guidance is that the symptoms of a 
lack of efficacy or progression of underlying illness are not caused by the trial drug, they 
happen in spite of its administration and/or both lack of efficacy and progression of 

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underlying disease can only be evaluated meaningfully by an analysis of cohorts, not on a 
single participant
2. its duration (start and end dates) or if the event is ongoing, an outcome of not 
recovered/not resolved must be reported
3. whether it constitutes a SAE (see Section 10.1.2 for definition of SAE) and which 
seriousness criteria have been met
4. action taken regarding with study treatment
All adverse events must be treated appropriately. Treatment may include one or more of the 
following:

Dose not changed

Dose Reduced/increased

Drug interrupted/withdrawn
1. its outcome (i.e. recovery status or whether it was fatal)
If the event worsens the event should be reported a second time in the CRF noting the start date 
when the event worsens in toxicity. For grade 3 and 4 adverse events only, if improvement to a 
lower grade is determined a new entry for this event should be reported in the CRF noting the 
start date when the event improved from having been Grade 3 or Grade 4.
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the participant.
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms.
Adverse event monitoring should be continued for at least 30 days (or end of study visit) 
following the last dose of study treatment.
Progression of malignancy (including fatal outcomes), if documented by use of appropriate 
method (for example, as per RECIST criteria for solid tumors), should not be reported as a 
serious adverse event.
Adverse events separate from the progression of malignancy (i.e. deep vein thrombosis at the 
time of progression or hemoptysis concurrent with finding of disease progression) will be 
reported as per usual guidelines used for such events with proper attribution regarding 
relatedness to the drug.
Information about adverse drug reactions for the investigational drug can be found in the 
Investigator's Brochure (IB).
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria:

they induce clinical signs or symptoms

they are considered clinically significant

they require therapy
Adverse events of special interest (AESI) are defined as events (serious or non-serious) which 
are ones of scientific and medical concern specific to the sponsor’s product or program, for 
which ongoing monitoring and rapid communication by the investigator to the sponsor may be 

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appropriate. Such events may require further investigation in order to characterize and 
understand them.
Adverse events of special interest are defined on the basis of an ongoing review of the safety 
data. AESI are discussed in detail in the Investigator Brochure, and a list of Medical Dictionary 
for Regulatory Activities (MedDRA) preferred terms to flag as AESI’s will be included in the 
SAP.
AESI for dabrafenib include:

Hypersensitivity

Complicated pyrexia and/or Grade 3 and Grade 4

New primary/secondary malignancy

pre-renal and intrinsic renal failure

Uveitis

Hyperglycemia

Pancreatitis
AESI for trametinib include:

Skin related toxicities

Ocular events

Cardiac related events

Hepatic disorders

Pneumonitis/interstitial lung disease

Bleeding events

Hypertension

Hypersensitivity

Venous thromboembolism
AESI for dabrafenib in combination with trametinib include:

Neutropenia
10.1.2
Serious adverse events
An SAE is defined as any adverse event [appearance of (or worsening of any pre-existing)] 
undesirable sign(s), symptom(s), or medical conditions(s) which meets any one of the following 
criteria:

fatal

life-threatening
Life-threatening in the context of a SAE refers to a reaction in which the participant was at risk 
of death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to the ICH-E2D Guidelines).

results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect

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
requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 

routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition

elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent

social reasons and respite care in the absence of any deterioration in the participant’s 
general condition

treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission

is medically significant, e.g. defined as an event that jeopardizes the participant or may 
require medical or surgical intervention to prevent one of the outcomes listed above
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the participant or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered as “medically significant.” Examples of such events are 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 dependency or abuse (please refer to the ICH-
E2D Guidelines).
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met and the malignant neoplasm is not a disease progression of the 
study indication.
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
All reports of intentional misuse and abuse of the product are also considered serious adverse 
event irrespective if a clinical event has occurred.
10.1.3
SAE reporting
To ensure participant safety, every SAE, regardless of causality, occurring after the participant 
has provided informed consent and until 30 days following the last administration of study 
treatment must be reported to Novartis safety immediately, without undue delay, under no 
circumstances later than within 24 hours of learning of its occurrence. Detailed instructions 
regarding the submission process and requirements are to be found in the investigator folder 
provided to each site.
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
immediately, without undue delay, under no circumstances later than within 24 hours of the 
investigator receiving the follow-up information. An SAE occurring at a different time interval 
or otherwise considered completely unrelated to a previously reported one must be reported 
separately as a new event.

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If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the study treatment, a CMO & PS Department 
associate may urgently require further information from the investigator for health authority 
reporting. Novartis may need to issue an Investigator Notification (IN) to inform all 
investigators involved in any study with the same study treatment that this SAE has been 
reported.
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with EU Guidance 
2011/C 172/01 or as per national regulatory requirements in participating countries.
Any SAEs experienced after the 30 day period following the last administration of study 
treatment (or longer, depending on the elimination half-life of the specific compound) should 
only be reported to Novartis Safety if the investigator suspects a causal relationship to study 
treatment.
10.1.4
Pregnancy reporting
If a trial participant becomes pregnant, the study treatment should be stopped, and the pregnancy 
consent form should be presented to the trial participant. The participant must be given adequate 
time to read, review and sign the pregnancy consent form. This consent form is necessary to 
allow the Investigator to collect and report information regarding the pregnancy. To ensure 
participant safety, each pregnancy occurring after signing the informed consent must be 
reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications.
Pregnancy should be recorded and reported by the investigator to the Novartis Chief Medical 
Office and Patient Safety (CMO&PS). Pregnancy follow-up should be recorded on the same 
form and should include an assessment of the possible relationship to the study treatment any 
pregnancy outcome. Any SAE experienced during pregnancy must be reported.
If a female partner of a male trial participant who took study treatment in this study becomes 
pregnant, pregnancy outcomes should be collected. Consent to report information regarding 
these pregnancy outcomes should be obtained from the mother.
After consent is provided, the pregnancy reporting will occur up to one year after the estimated 
date of delivery.
10.1.5
Reporting of study treatment errors including misuse/abuse
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, participant or 
consumer (EMA definition).
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol.
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, 
which is accompanied by harmful physical or psychological effects.

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Study treatment errors and uses outside of what is foreseen in the protocol will be recorded on 
the appropriate Case Report Form (CRF) irrespective of whether or not associated with an 
AE/SAE. Study treatment errors and uses outside of what is foreseen in the protocol, misuse or 
abuse will be collected and reported in the safety database irrespective of it being associated 
with an AE/SAE within 24 hours of Investigator’s awareness. For more information on AE and 
SAE definition and reporting requirements, please see the respective sections.
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse
Treatment error type
Document in Dosing 
CRF (Yes/No)
Document in AE eCRF
Complete SAE form
Unintentional study 
treatment error
Yes
Only if associated with an 
AE
Only if associated with an 
SAE
Misuse/Abuse
Yes
Yes
Yes, even if not 
associated with a SAE
For more information on AE and SAE definition and reporting requirements, please see the 
respective sections.
10.2
Additional Safety Monitoring
Not applicable.
11
Data Collection and Database management
11.1
Data collection
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (eCRF). The eCRFs have been built using fully validated secure web-
enabled software that conforms to 21 CFR Part 11 requirements, Investigator site staff will not 
be given access to the EDC system until they have been trained. Automatic validation programs 
check for data discrepancies in the eCRFs, allow modification and/or verification of the entered 
data by the investigator staff.
The investigator/designee is responsible for assuring that the data (recorded on CRFs) (entered 
into eCRF) is complete, accurate, and that entry and updates are performed in a timely manner. 
The Investigator must certify that the data entered are complete and accurate.
After final database lock, the investigator will receive copies of the participant data for 
archiving at the investigational site.
All data should be recorded, handled, and stored in a way that allows its accurate reporting, 
interpretation, and verification.
11.2
Database management and quality control
Novartis personnel will review the data entered by investigational staff for completeness and 
accuracy. Electronic data queries stating the nature of the problem and requesting clarification 
will be created for discrepancies and missing values and sent to the investigational site via the 

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EDC system. Designated investigator site staff are required to respond promptly to queries and 
to make any necessary changes to the data.
Concomitant treatments and prior medications entered into the database will be coded using the 
World Health Organization (WHO) Drug Reference List, which employs the Anatomical 
Therapeutic Chemical classification system. Medical history/current medical conditions and 
adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology.
Data about all study treatment (s) dispensed to the participant and all dosage changes will be 
tracked using an Interactive Response Technology (IRT). The system will be supplied by a 
vendor, who will also manage the database. The data will be sent electronically to Novartis at 
specific timelines.
Each occurrence of a code break via IRT will be reported to the clinical team and monitor. The 
code break functionality will remain available until study shut down or upon request of Novartis.
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked. Any changes to the database after that time can only 
be made after written agreement by Novartis development management.
11.3
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and data capture requirements (i.e. eSource DDE or 
eCRFs) with the investigators and their staff. During the study, Novartis employs several 
methods of ensuring protocol and GCP compliance and the quality/integrity of the sites’ data. 
The field monitor will visit the site to check the completeness of participant records, the 
accuracy of data capture / data entry, the adherence to the protocol and to Good Clinical Practice, 
the progress of enrollment, and to ensure that study treatment is being stored, dispensed, and 
accounted for according to specifications. Key study personnel must be available to assist the 
field monitor during these visits. Continuous remote monitoring of each site’s data may be 
performed by a centralized Novartis. Additionally, a central analytics organization may analyze 
data & identify risks & trends for site operational parameters, and provide reports to Novartis 
clinical teams to assist with trial oversight.
The investigator must maintain source documents for each participant in the study, consisting 
of case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
participant’s file. The investigator must also keep the original informed consent form signed by 
the participant (a signed copy is given to the participant).
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the CRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
participants will be disclosed.

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12
Data analysis and statistical methods
It is planned that the data from all centers participating in the trial will be pooled for analysis. 
Novartis and/or a designated CRO will perform all analyses.
The primary efficacy and safety analysis will be conducted when the first 20 enrolled 
participants have had at least two post-baseline tumor assessments or have discontinued study 
earlier for any reason prior to the second post-baseline tumor assessment. Any additional data 
collected past this time, as allowed by the protocol, will be further summarized in a final study 
report once these participants completed the study. Any data analysis carried out independently 
by the investigator should be submitted to Novartis before publication or presentation.
12.1
Analysis sets
The Full Analysis Set (FAS) comprises all participants that received any study treatment.
Efficacy and safety analysis will be based on this analysis set.
The Pharmacokinetic Analysis Set (PAS) will consist of those participants in the FAS for whom 
a pharmacokinetic sample is obtained and analyzed.
12.2
Participant demographics and other baseline characteristics
Demographic and other baseline data including disease characteristics will be listed and 
summarized descriptively for FAS.
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented.
Relevant medical histories and current medical conditions at baseline will be summarized by 
system organ class and preferred term for FAS.
12.3
Treatments
The FAS will be used for the analyses below. Categorical data will be summarized as 
frequencies and percentages. For continuous data, mean, standard deviation, median, 25th and 
75th percentiles, minimum, and maximum will be presented.
The duration of exposure in months to Dabrafenib and Trametinib respectively, as well as the 
dose intensity (computed as the ratio of actual cumulative dose received and actual duration of 
exposure) and the relative dose intensity (computed as the ratio of dose intensity and planned 
dose intensity) will be summarized by means of descriptive statistics using the safety set.
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed and summarized according to the Anatomical Therapeutic 
Chemical (ATC) classification system.
The number of participants with dose adjustments (reductions, interruption, or permanent 
discontinuation) and the reasons will be summarized and all dosing data will be listed.

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12.4
Analysis of the primary endpoint(s)
The primary objective is to assess the ORR of dabrafenib in combination with trametinib in
Chinese patients with BRAF V600E mutation-positive metastatic NSCLC by central 
independent assessment.
12.4.1
Definition of primary endpoint(s)
The primary endpoint of the study is overall response rate (ORR), defined as the proportion of 
participants with best overall response (BOR) of complete response (CR) or partial response 
(PR) as per central independent review assessment and according to RECIST 1.1 (see 
Section 16 for details).
12.4.2
Statistical model, hypothesis, and method of analysis
The ORR will be summarized along with its exact 95% confidence intervals.
12.4.3
Handling of missing values/censoring/discontinuations
Participants in the study who are of unknown clinical response will be treated as non-responders.
Other missing data are simply noted as missing on appropriate tables/listings.
12.4.4
Sensitivity analyses
Not applicable.
12.5
Analysis of secondary endpoints
The secondary objectives in this study are:

To assess overall response rate (ORR), progression-free survival (PFS), duration of 
response (DoR) and overall survival (OS) by investigator assessment

To characterize the safety and tolerability of dabrafenib in combination with trametinib

To characterize PK of dabrafenib, dabrafenib metabolites (hydroxy-dabrafenib, and 
desmethyl-dabrafenib), and trametinib

To characterize quality of life as measured by the EORTC-QLQ C30, LC13 and the EQ-
5D-5L
12.5.1
Efficacy endpoint(s)
ORR is defined as the percentage of participants with a confirmed complete response (CR) or 
partial response (PR) by investigator assessment as per RECIST 1.1 criteria. ORR will be 
analyzed in the FAS population. ORR will be summarized along with its exact 95% confidence 
intervals.
PFS is defined as the time from the date of first dose to the date of the first documented 
progression or death due to any cause. PFS will be assessed via local review according to 
RECIST 1.1 (see Section 16 for further details). PFS will be censored if no PFS event is 
observed before the first to occur between: (i) the analysis cut-off date, and (ii) the date when a 
new anti-neoplastic therapy is started. The censoring date will be the date of the last adequate 
tumor assessment prior to cut-off/start of new anti-neoplastic therapy.

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PFS will be analyzed in the FAS population. The PFS distribution will be estimated using the 
Kaplan-Meier method, and the Kaplan-Meier curves, medians and 95% confidence intervals of 
the medians will be presented, if appropriate.
Duration of response (DOR) only applies to participants whose best overall response is 
complete response (CR) or partial response (PR) according to RECIST 1.1 based on tumor 
response data per local review. The start date is the date of first documented response of CR or 
PR (i.e. the start date of response, not the date when response was confirmed), and the end date 
is defined as the date of the first documented progression or death due to any cause. Participants 
continuing without progression or death will be censored at the date of their last adequate tumor 
assessment. DOR will be listed and summarized for all participants in the FAS with confirmed 
BOR of CR or PR.
OS is defined as the time from date of first dose to date of death due to any cause. If a participant 
is not known to have died, then OS will be censored at the latest date the participant was known 
to be alive (on or before the cut-off date).
OS will be analyzed in the FAS population. The OS distribution will be estimated using the 
Kaplan-Meier method, and the Kaplan-Meier curves, medians and 95% confidence intervals of 
the medians will be presented, if appropriate.
12.5.2
Safety endpoints
For all safety analyses, the FAS will be used.
Safety summaries (tables, figures) include only data from the on-treatment period with the 
exception of baseline data which will also be summarized where appropriate (e.g. change from 
baseline summaries). In addition, a separate summary for death including on treatment and post 
treatment deaths will be provided. In particular, summary tables for adverse events (AEs) will 
summarize only on-treatment events, with a start date during the on-treatment period 
(treatment-emergent AEs).
The on-treatment period lasts from the date of first administration of study treatment to 30 days 
after the date of the last actual administration of any study treatment.
The overall observation period will be divided into three mutually exclusive segments:
1. Pre-treatment period: from day of participant's informed consent to the day before first 
dose of study treatment
2. On-treatment period: from day of first dose of study treatment to 30 days after last dose of 
study treatment
3. Post-treatment period: starting at 31 day after last dose of study treatment.
Adverse events
The number (and percentage) of participants with treatment emergent adverse events (events 
started after the first dose of study treatment or events present prior to start of treatment but 
increased in severity based on preferred term) will be summarized in the following ways:

by primary system organ class and preferred term.

by primary system organ class, preferred term and severity (based on CTCAE v 4.03)

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Separate summaries will be provided for study treatment related adverse events, death, serious 
adverse events, adverse events of special interest (AESI), other significant adverse events 
leading to dose adjustment and discontinuation.
The list of AESI's will also include relevant events for dabrafenib and trametinib which will be 
defined in the SAP.
A participant with multiple adverse events within a primary system organ class is only counted 
once towards the total of the primary system organ class.
Vital signs
All vital signs data will be listed by participant, and visit/time and if ranges are available, 
abnormalities (and relevant orthostatic changes) will be flagged. Summary statistics will be 
provided by treatment and visit/time.
12-lead ECG
1. PR, QRS, QT, QTcF, and RR intervals will be obtained from 12-lead ECGs for each 
participant during the study. ECG data will be read and interpreted (centrally/locally).
2. Categorical Analysis of QT/QTc interval data based on the number of participants meeting 
or exceeding predefined limits in terms of absolute QT/QTc intervals or changes from 
baseline will be presented. In addition, a listing of these participants will be produced (by 
treatment group).
All ECG data will be listed by participant and visit/time, abnormalities will be flagged. 
Summary statistics will be provided by treatment and visit/time.
Clinical laboratory evaluations
All laboratory data will be listed by participant, and visit/time and if normal ranges are available 
abnormalities will be flagged. Summary statistics will be provided by visit/time. Shift tables 
using the low/normal/high/ (low and high) classification will be used to compare baseline to the 
worst on-treatment value.
Grading of laboratory values will be assigned programmatically as per NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03. The calculation of CTCAE 
grades will be based on the observed laboratory values only, clinical assessments will not be 
taken into account.
CTCAE Grade 0 will be assigned for all non-missing values not graded as 1 or higher. Grade 5 
will not be used.
For laboratory tests where grades are not defined by CTCAE v4.03, results will be categorized 
as low/normal/high based on laboratory normal ranges.
The following summaries will be generated separately for hematology, and biochemistry tests:

Listing of all laboratory data with values flagged to show the corresponding CTCAE 
v4.03 grades if applicable and the classifications relative to the laboratory normal ranges
For laboratory tests where grades are defined by CTCAE v4.03:

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results website and all required Health Authority websites (e.g. Clinicaltrials.gov, EudraCT 
etc.).
For details on the Novartis publication policy including authorship criteria, please refer to the 
Novartis publication policy training materials that were provided to you at the trial investigator 
meetings.
13.4
Quality Control and Quality Assurance
Novartis maintains a robust Quality Management System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written Standard 
Operating Procedures as well as applicable global/local GCP regulations and ICH Guidelines.
Audits of investigator sites, vendors, and Novartis systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of the 
clinical trial. The clinical audit process uses a knowledge/risk based approach.
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes.
14
Protocol adherence
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of participants should be 
administered as deemed necessary on a case by case basis. Under no circumstances including 
incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the investigator shall immediately disclose it to 
Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants.
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by 
Novartis and approved by the IRB/IEC and Health Authorities, where required, it cannot be 
implemented.
14.1
Protocol amendments
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation.
Only amendments that are required for participant safety may be implemented immediately 
provided the health authorities are subsequently notified by protocol amendment and the 
reviewing IRB/IEC is notified.

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Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any participant included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis should 
be notified of this action and the IRB/IEC at the study site should be informed according to 
local regulations.

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15
References
References are available upon request
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Combined BRAF Inhibitor and Radiation Treatment: Consensus Guidelines from the Eastern 
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Antonia et al (2017) Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung 
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Planchard D, Besse B, Groen HJM, et al (2016) Dabrafenib plus trametinib in patients with 
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5518-27.

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The efficacy assessments described in Section 16.1.2 and the definition of best response in 
Section 16.1.3.1 are based on the RECIST 1.1 criteria but also give more detailed instructions 
and rules for determination of best response. Section 16.1.3.2 is summarizing the “time to event” 
variables and rules which are mainly derived from internal discussions and regulatory 
consultations, as the RECIST criteria do not define these variables in detail. Section 16.1.4 of 
this guideline describes data handling and programming rules. This section is to be referred to 
in the SAP (Statistical Analysis Plan) to provide further details needed for programming.
16.1.2
Efficacy assessments
Tumor evaluations are made based on RECIST criteria (Therasse, et al 2000), New Guidelines 
to Evaluate the Response to Treatment in Solid Tumors, Journal of National Cancer Institute, 
Vol. 92; 205-16 and revised RECIST guidelines (version 1.1) (Eisenhauer, et al 2009) European
Journal of Cancer; 45:228-247.
16.1.2.1 Definitions
16.1.2.1.1
Disease measurability
In order to evaluate tumors throughout a study, definitions of measurability are required in order 
to classify lesions appropriately at baseline. In defining measurability, a distinction also needs 
to be made between nodal lesions (pathological lymph nodes) and non-nodal lesions.

Measurable disease - the presence of at least one measurable nodal or non-nodal lesion. 
If the measurable disease is restricted to a solitary lesion, its neoplastic nature should be 
confirmed by cytology/histology.
For patients without measurable disease see Section 16.1.3.2.8
Measurable lesions (both nodal and non-nodal)

Measurable non-nodal - As a rule of thumb, the minimum size of a measurable non-nodal 
target lesion at baseline should be no less than double the slice thickness or 10mm 
whichever is greater - e.g. the minimum non-nodal lesion size for CT/MRI with 5mm cuts 
will be 10 mm, for 8 mm contiguous cuts the minimum size will be 16 mm.

Lytic bone lesions or mixed lytic-blastic lesions with identifiable soft tissue components, 
that can be evaluated by CT/MRI, can be considered as measurable lesions, if the soft 
tissue component meets the definition of measurability.

Measurable nodal lesions (i.e. lymph nodes) - Lymph nodes 15 mm in short axis can be 
considered for selection as target lesions. Lymph nodes measuring 10 mm and <15 mm 
are considered non-measurable. Lymph nodes smaller than 10 mm in short axis at 
baseline, regardless of the slice thickness, are normal and not considered indicative of 
disease.

Cystic lesions: 

Lesions that meet the criteria for radiographically defined simple cysts (i.e., spherical 
structure with a thin, non-irregular, non-nodular and non-enhancing wall, no 
septations, and low CT density [water-like] content) should not be considered as 
malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts.

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
‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. 
However, if noncystic lesions are present in the same patient, these are preferred for 
selection as target lesions.

Non-measurable lesions - all other lesions are considered non-measurable, including small 
lesions (e.g. longest diameter <10 mm with CT/MRI or pathological lymph nodes with 
10 to < 15 mm short axis), as well as truly non-measurable lesions e.g., blastic bone 
lesions, leptomeningeal disease, ascites, pleural/pericardial effusion, inflammatory breast 
disease, lymphangitis cutis/pulmonis, abdominal masses/abdominal organomegaly 
identified by physical exam that is not measurable by reproducible imaging techniques.
16.1.2.1.2
Eligibility based on measurable disease
If no measurable lesions are identified at baseline, the patient may be allowed to enter the study 
in some situations (e.g. in Phase III studies where PFS is the primary endpoint). However, it is 
recommended that patients be excluded from trials where the main focus is on the Overall 
Response Rate (ORR). Guidance on how patients with just non-measurable disease at baseline 
will be evaluated for response and also handled in the statistical analyses is given in 
Section 16.1.3.2.8.
16.1.2.2 Methods of tumor measurement - general guidelines
In this document, the term “contrast” refers to intravenous (i.v.) contrast.
The following considerations are to be made when evaluating the tumor:

All measurements should be taken and recorded in metric notation (mm), using a ruler or 
calipers. All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment.

Imaging-based evaluation is preferred to evaluation by clinical examination when both 
methods have been used to assess the antitumor effect of a treatment.

For optimal evaluation of patients, the same methods of assessment and technique should 
be used to characterize each identified and reported lesion at baseline and during follow-
up. Contrast-enhanced CT of chest, abdomen and pelvis should preferably be performed 
using a 5 mm slice thickness with a contiguous reconstruction algorithm. CT/MRI scan 
slice thickness should not exceed 8 mm cuts using a contiguous reconstruction algorithm. 
If, at baseline, a patient is known to have a medical contraindication to CT contrast or 
develops a contraindication during the trial, the following change in imaging modality will 
be accepted for follow up: a non-contrast CT of chest (MRI not recommended due to 
respiratory artifacts) plus contrast-enhanced MRI of abdomen and pelvis.

A change in methodology can be defined as either a change in contrast use (e.g. keeping 
the same technique, like CT, but switching from with to without contrast use or vice-versa, 
regardless of the justification for the change) or a major change in technique (e.g. from CT 
to MRI, or vice-versa), or a change in any other imaging modality. A change from 
conventional to spiral CT or vice versa will not constitute a major “change in method” for 
the purposes of response assessment. A change in methodology will result by default in a 
UNK overall lesion response assessment as per Novartis calculated response. However, 

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another response assessment than the Novartis calculated UNK response may be accepted 
from the investigator or the central blinded reviewer if a definitive response assessment 
can be justified, based on the available information.

FDG-PET: can complement CT scans in assessing progression (particularly possible for 
‘new’ disease). New lesions on the basis of FDG-PET imaging can be identified according 
to the following algorithm:

Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion.

No FDG-PET at baseline with a positive FDG-PET at follow-up:

If new disease is indicated by a positive PET scan but is not confirmed by CT (or some 
other conventional technique such as MRI) at the same assessment, then follow-up 
assessments by CT will be needed to determine if there is truly progression occurring at 
that site. In all cases PD will be the date of confirmation of new disease by CT (or some 
other conventional technique such as MRI) rather than the date of the positive PET scan. 
If there is a positive PET scan without any confirmed progression at that site by CT, then a 
PD cannot be assigned.

If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on 
CT that is not progressing on the basis of the anatomic images, this is not PD.

Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they 
are clearly defined and surrounded by aerated lung. However, CT is preferable.

Physical exams: Evaluation of lesions by physical examination is accepted when 
lesions are superficial, with at least 10mm size, and can be assessed using calipers. 

Ultrasound: When the primary endpoint of the study is objective response evaluation, 
ultrasound (US) should not be used to measure tumor lesions, unless pre-specified by 
the protocol. It is, however, a possible alternative to clinical measurements of 
superficial palpable lymph nodes, subcutaneous lesions and thyroid nodules. US 
might also be useful to confirm the complete disappearance of superficial lesions 
usually assessed by clinical examination. 

Endoscopy and laparoscopy: The utilization of endoscopy and laparoscopy for 
objective tumor evaluation has not yet been fully and widely validated. Their uses in 
this specific context require sophisticated equipment and a high level of expertise that 
may only be available in some centers. Therefore, the utilization of such techniques 
for objective tumor response should be restricted to validation purposes in specialized 
centers. However, such techniques can be useful in confirming complete pathological 
response when biopsies are obtained.

Tumor markers: Tumor markers alone cannot be used to assess response. However, 
some disease specific and more validated tumor markers (e.g. CA-125 for ovarian 
cancer, PSA for prostate cancer, alpha-FP, LDH and Beta-hCG for testicular cancer) 
can be integrated as non-target disease. If markers are initially above the upper 
normal limit they must normalize for a patient to be considered in complete clinical 
response when all lesions have disappeared.

Cytology and histology: Cytology and histology can be used to differentiate between PR 
and CR in rare cases (i.e., after treatment to differentiate between residual benign lesions 
and residual malignant lesions in tumor types such as germ cell tumors). Cytologic 

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confirmation of neoplastic nature of any effusion that appears or worsens during treatment 
is required when the measurable tumor has met the criteria for response or stable disease. 
Under such circumstances, the cytologic examination of the fluid collected will permit 
differentiation between response and stable disease (an effusion may be a side effect of the 
treatment) or progressive disease (if the neoplastic origin of the fluid is confirmed).

Clinical examination: Clinical lesions will only be considered measurable when they are 
superficial (i.e., skin nodules and palpable lymph nodes). For the case of skin lesions, 
documentation by color photography, including a ruler to estimate the size of the lesion, is 
recommended.
16.1.2.3 Baseline documentation of target and non-target lesions
For the evaluation of lesions at baseline and throughout the study, the lesions are classified at 
baseline as either target or non-target lesions:

Target lesions: All measurable lesions (nodal and non-nodal) up to a maximum of five 
lesions in total (and a maximum of two lesions per organ), representative of all involved 
organs should be identified as target lesions and recorded and measured at baseline. Target 
lesions should be selected on the basis of their size (lesions with the longest diameter) and 
their suitability for accurate repeated measurements (either by imaging techniques or 
clinically). Each target lesion must be uniquely and sequentially numbered on the CRF 
(even if it resides in the same organ).
Minimum target lesion size at baseline

Non-nodal target: Non-nodal target lesions identified by methods for which slice 
thickness is not applicable (e.g. clinical examination, photography) should be at least 10 
mm in longest diameter. See Section 16.1.2.1.1.

Nodal target: See Section 16.1.2.1.1.
A sum of diameters (long axis for non-nodal lesions, short axis for nodal) for all target lesions 
will be calculated and reported as the baseline sum of diameters (SOD). The baseline sum of 
diameters will be used as reference by which to characterize the objective tumor response. Each 
target lesion identified at baseline must be followed at each subsequent evaluation and 
documented on eCRF.

Non-target lesions: All other lesions are considered non-target lesions, i.e. lesions not 
fulfilling the criteria for target lesions at baseline. Presence or absence or worsening of 
non-target lesions should be assessed throughout the study; measurements of these lesions 
are not required. Multiple non-target lesions involved in the same organ can be assessed as 
a group and recorded as a single item (i.e. multiple liver metastases). Each non-target 
lesion identified at baseline must be followed at each subsequent evaluation and 
documented on eCRF.
16.1.2.4 Follow-up evaluation of target and non-target lesions
To assess tumor response, the sum of diameters for all target lesions will be calculated (at 
baseline and throughout the study). At each assessment response is evaluated first separately 
for the target (Table 16-1) and non-target lesions (Table 16-2) identified at baseline. These 

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evaluations are then used to calculate the overall lesion response considering both the target and 
non-target lesions together (Table 16-3) as well as the presence or absence of new lesions.
16.1.2.4.1
Follow-up and recording of lesions
At each visit and for each lesion the actual date of the scan or procedure which was used for the 
evaluation of each specific lesion should be recorded. This applies to target and non-target 
lesions as well as new lesions that are detected. At the assessment visit all of the separate lesion 
evaluation data are examined by the investigator in order to derive the overall visit response. 
Therefore all such data applicable to a particular visit should be associated with the same 
assessment number.
Non-nodal lesions
Following treatment, lesions may have longest diameter measurements smaller than the image 
reconstruction interval. Lesions smaller than twice the reconstruction interval are participant to 
substantial “partial volume” effects (i.e., size may be underestimated because of the distance of 
the cut from the longest diameter; such lesions may appear to have responded or progressed on 
subsequent examinations, when, in fact, they remain the same size).
If the lesion has completely disappeared, the lesion size should be reported as 0 mm.
Measurements of non-nodal target lesions that become 5 mm or less in longest diameter are 
likely to be non-reproducible. Therefore, it is recommended to report a default value of 5 mm, 
instead of the actual measurement. This default value is derived from the 5 mm CT slice 
thickness (but should not be changed with varying CT slice thickness). Actual measurement 
should be given for all lesions larger than 5 mm in longest diameter irrespective of slice 
thickness/reconstruction interval.
In other cases where the lesion cannot be reliably measured for reasons other than its size (e.g., 
borders of the lesion are confounded by neighboring anatomical structures), no measurement 
should be entered and the lesion cannot be evaluated.
Nodal lesions
A nodal lesion less than 10 mm in size by short axis is considered normal. Lymph nodes are not 
expected to disappear completely, so a “non-zero size” will always persist.
Measurements of nodal target lesions that become 5 mm or less in short axis are likely to be 
non-reproducible. Therefore, it is recommended to report a default value of 5 mm, instead of 
the actual measurement. This default value is derived from the 5 mm CT slice thickness (but 
should not be changed with varying CT slice thickness).Actual measurement should be given 
for all lesions larger than 5 mm in short axis irrespective of slice thickness/reconstruction 
interval.
However, once a target nodal lesion shrinks to less than 10 mm in its short axis, it will be 
considered normal for response purpose determination. The lymph node measurements will 
continue to be recorded to allow the values to be included in the sum of diameters for target 
lesions, which may be required subsequently for response determination.

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16.1.2.4.2
Determination of target lesion response
Table 16-1
Response criteria for target lesions
Response Criteria
Evaluation of target lesions
Complete Response (CR):
Disappearance of all non-nodal target lesions. In addition, any pathological lymph 
nodes assigned as target lesions must have a reduction in short axis to < 10 mm 1
Partial Response (PR):
At least a 30% decrease in the sum of diameter of all target lesions, taking as 
reference the baseline sum of diameters.
Progressive Disease (PD):
At least a 20% increase in the sum of diameter of all measured target lesions, 
taking as reference the smallest sum of diameter of all target lesions recorded at or 
after baseline. In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm 2.
Stable Disease (SD):
Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which 
would qualify for PD.
Unknown (UNK)
Progression has not been documented and one or more target lesions have not 
been assessed or have been assessed using a different method than baseline.3
1.
SOD for CR may not be zero when nodal lesions are part of target lesions
2.
Following an initial CR, a PD cannot be assigned if all non-nodal target lesions are still not present and all 
nodal lesions are <10 mm in size. In this case, the target lesion response is CR
3.
In exceptional circumstances an UNK response due to change in method could be over-ruled by the 
investigator or central reviewer using expert judgment based on the available information (see Notes on target 
lesion response and methodology change in Section 16.1.2.2).
Notes on target lesion response
Reappearance of lesions: If the lesion appears at the same anatomical location where a target 
lesion had previously disappeared, it is advised that the time point of lesion disappearance (i.e., 
the “0 mm” recording) be re-evaluated to make sure that the lesion was not actually present 
and/or not visualized for technical reasons in this previous assessment. If it is not possible to 
change the 0 value, then the investigator/radiologist has to decide between the following 
possibilities:
The lesion is a new lesion, in which case the overall tumor assessment will be considered 
as progressive disease
The lesion is clearly a reappearance of a previously disappeared lesion, in which case the 
size of the lesion has to be entered in the CRF and the tumor assessment will remain based 
on the sum of tumor measurements as presented in Table 16-1 above (i.e., a PD will be 
determined if there is at least 20% increase in the sum of diameters of all measured target 
lesions, taking as reference the smallest sum of diameters of all target lesions recorded at or 
after baseline with at least 5 mm increase in the absolute sum of the diameters). Proper 
documentation should be available to support this decision. This applies to patients who 
have not achieved target response of CR. For patients who have achieved CR, please refer 
to last bullet in this section.
For those patients who have only one target lesion at baseline, the reappearance of the 
target lesion which disappeared previously, even if still small, is considered a PD.
Missing measurements: In cases where measurements are missing for one or more target 
lesions it is sometimes still possible to assign PD based on the measurements of the 
remaining lesions. For example, if the sum of diameters for 5 target lesions at baseline is 
100 mm at baseline and the sum of diameters for 3 of those lesions at a post-baseline visit 

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is 140 mm (with data for 2 other lesions missing) then a PD should be assigned. However,
in other cases where a PD cannot definitely be attributed, the target lesion response would 
be UNK.
Nodal lesion decrease to normal size: When nodal disease is included in the sum of target 
lesions and the nodes decrease to “normal” size they should still have a measurement 
recorded on scans. This measurement should be reported even when the nodes are normal 
in order not to overstate progression should it be based on increase in the size of nodes.
Lesions split: In some circumstances, disease that is measurable as a target lesion at 
baseline and appears to be one mass can split to become two or more smaller sub-lesions. 
When this occurs, the diameters (long axis - non-nodal lesion, short axis - nodal lesions) of 
the two split lesions should be added together and the sum recorded in the diameter field on 
the case report form under the original lesion number. This value will be included in the 
sum of diameters when deriving target lesion response. The individual split lesions will not 
be considered as new lesions, and will not automatically trigger a PD designation.
Lesions coalesced: Conversely, it is also possible that two or more lesions which were 
distinctly separate at baseline become confluent at subsequent visits. When this occurs a 
plane between the original lesions may be maintained that would aid in obtaining diameter 
measurements of each individual lesion. If the lesions have truly coalesced such that they 
are no longer separable, the maximal diameters (long axis - non-nodal lesion, short axis -
nodal lesions) of the “merged lesion” should be used when calculating the sum of 
diameters for target lesions. On the case report form, the diameter of the “merged lesion” 
should be recorded for the size of one of the original lesions while a size of “0”mm should 
be entered for the remaining lesion numbers which have coalesced.

The measurements for nodal lesions, even if less than 10 mm in size, will contribute to 
the calculation of target lesion response in the usual way with slight modifications.

Since lesions less than 10 mm are considered normal, a CR for target lesion response 
should be assigned when all nodal target lesions shrink to less than 10 mm and all non-
nodal target lesions have disappeared.

Once a CR target lesion response has been assigned a CR will continue to be appropriate 
(in the absence of missing data) until progression of target lesions.

Following a CR, a PD can subsequently only be assigned for target lesion response if 
either a non-nodal target lesion “reappears” or if any single nodal lesion is at least 10 mm 
and there is at least 20% increase in sum of the diameters of all nodal target lesions 
relative to nadir with at least 5 mm increase in the absolute sum of the diameters. 

A change in method for the evaluation of one or more lesions will usually lead to an UNK 
target lesion response unless there is progression indicated by the remaining lesions which 
have been evaluated by the same method. In exceptional circumstances an investigator or 
central reviewer might over-rule this assignment to put a non-UNK response using expert 
judgment based on the available information. E.g. a change to a more sensitive method 
might indicate some tumor shrinkage of target lesions and definitely rule out progression 
in which case the investigator might assign an SD target lesion response; however, this 
should be done with caution and conservatively as the response categories have well 
defined criteria.

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16.1.2.4.3
Determination of non-target lesion response
Table 16-2
Response criteria for non-target lesions
Response Criteria
Evaluation of non-target lesions
Complete Response (CR):
Disappearance of all non-target lesions. In addition, all lymph nodes assigned a 
non-target lesions must be non-pathological in size (< 10 mm short axis)
Progressive Disease (PD):
Unequivocal progression of existing non-target lesions.1
Non-CR/Non-PD:
Neither CR nor PD
Unknown (UNK)
Progression has not been documented and one or more non-target lesions have 
not been assessed or have been assessed using a different method than baseline2.
1.
The assignment of PD solely based on change in non-target lesions in light of target lesion response of CR, 
PR or SD should be exceptional. In such circumstances, the opinion of the investigator or central reviewer 
does prevail..
2.
It is recommended that the investigator and/or central reviewer should use expert judgment to assign a Non-
UNK response wherever possible (see notes section for more details)
Notes on non-target lesion response

The investigator and/or central reviewer can use expert judgment to assign a non-UNK 
response wherever possible, even where lesions have not been fully assessed or a different 
method has been used. In many of these situations it may still be possible to identify 
equivocal progression (PD) or definitively rule this out (non-CR/Non-PD) based on the 
available information. In the specific case where a more sensitive method has been used 
indicating the absence of any non-target lesions, a CR response can also be assigned.

The response for non-target lesions is CR only if all non-target non-nodal lesions which 
were evaluated at baseline are now all absent and with all non-target nodal lesions 
returned to normal size (i.e. < 10 mm). If any of the non-target lesions are still present, or 
there are any abnormal nodal lesions (i.e. 10 mm) the response can only be ‘Non-
CR/Non-PD’ unless there is unequivocal progression of the non-target lesions (in which 
case response is PD) or it is not possible to determine whether there is unequivocal 
progression (in which case response is UNK).

Unequivocal progression: To achieve “unequivocal progression” on the basis of non-target 
disease there must be an overall level of substantial worsening in non-target disease such 
that, even in presence of CR, PR or SD in target disease, the overall tumor burden has 
increased sufficiently to merit discontinuation of therapy. A modest “increase” in the size 
of one or more non-target lesions is usually not sufficient to qualify for unequivocal 
progression status. The designation of overall progression solely on the basis of change in 
non-target disease in the face of CR, PR or SD of target disease is therefore expected to be 
rare. In order for a PD to be assigned on the basis of non-target lesions, the increase in the 
extent of the disease must be substantial even in cases where there is no measurable 
disease at baseline. If there is unequivocal progression of non-target lesion(s), then at least 
one of the non-target lesions must be assigned a status of “Worsened”. Where possible, 
similar rules to those described in Section 16.1.2.4.2 for assigning PD following a CR for 
the non-target lesion response in the presence of non-target lesions nodal lesions should be 
applied.

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16.1.2.4.4
New lesions
The appearance of a new lesion is always associated with Progressive Disease (PD) and has to 
be recorded as a new lesion in the New Lesion CRF page.

If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm 
there is definitely a new lesion, then progression should be declared using the date of the 
first observation of the lesion

If new disease is observed in a region which was not scanned at baseline or where the 
particular baseline scan is not available for some reason, then this should be considered as 
a PD. The one exception to this is when there are no baseline scans at all available for a 
patient in which case the response should be UNK, as for any of this patient's assessment 
(see Section 16.1.2.5).

A lymph node is considered as a “new lesion” and, therefore, indicative of progressive 
disease if the short axis increases in size to 10 mm for the first time in the study plus 5 
mm absolute increase.
FDG-PET: can complement CT scans in assessing progression (particularly possible for 
‘new’ disease). See Section 16.1.2.2.
16.1.2.5 Evaluation of overall lesion response
The evaluation of overall lesion response at each assessment is a composite of the target lesion 
response, non-target lesion response and presence of new lesions as shown below in 
Table 16-3.
Table 16-3
Overall lesion response at each assessment
Target lesions
Non-target lesions
New Lesions
Overall
lesion response
CR
CR
No
CR1
CR
Non-CR/Non-PD3
No
PR
CR, PR, SD
UNK
No
UNK
PR
Non-PD and not UNK
No
PR1
SD
Non-PD and not UNK
No
SD1, 2
UNK
Non-PD or UNK
No
UNK1
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
1.
This overall lesion response also applies when there are no non-target lesions identified at baseline.
2.
Once confirmed PR was achieved, all these assessments are considered PR.
3.
As defined in Section 16.1.2.4.
If there are no baseline scans available at all, then the overall lesion response at each assessment 
should be considered Unknown (UNK).
In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends on this determination, it is recommended 
that the residual lesion be investigated (fine needle aspirate/biopsy) to confirm the CR.

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16.1.3
Efficacy definitions
The following definitions primarily relate to patients who have measurable disease at baseline. 
Section 16.1.3.2.8 outlines the special considerations that need to be given to patients with no 
measurable disease at baseline in order to apply the same concepts.
16.1.3.1 Best overall response
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for PD the smallest measurements recorded 
since the treatment started). In general, the patient's best response assignment will depend on 
the achievement of both measurement and confirmation criteria.
The best overall response will usually be determined from response assessments undertaken 
while on treatment. However, if any assessments occur after treatment withdrawal the protocol 
should specifically describe if these will be included in the determination of best overall 
response and/or whether these additional assessments will be required for sensitivity or 
supportive analyses. As a default, any assessments taken more than 30 days after the last dose 
of study treatment will not be included in the best overall response derivation. If any alternative 
cancer therapy is taken while on study any subsequent assessments would ordinarily be 
excluded from the best overall response determination. If response assessments taken after 
withdrawal from study treatment and/or alternative therapy are to be included in the main 
endpoint determination, then this should be described and justified in the protocol.
Where a study requires confirmation of response (PR or CR), changes in tumor measurements 
must be confirmed by repeat assessments that should be performed not less than 4 weeks after 
the criteria for response are first met.
Longer intervals may also be appropriate. However, this must be clearly stated in the protocol. 
The main goal of confirmation of objective response is to avoid overestimating the response 
rate observed. In cases where confirmation of response is not feasible, it should be made clear 
when reporting the outcome of such studies that the responses are not confirmed.

For non-randomized trials where response is the primary endpoint, confirmation is needed.

For trials intended to support accelerated approval, confirmation is needed

For all other trials, confirmation of response may be considered optional.
The best overall response for each patient is determined from the sequence of overall (lesion) 
responses according to the following rules:

CR = at least two determinations of CR at least 4 weeks apart before progression where 
confirmation required or one determination of CR prior to progression where confirmation 
not required

PR = at least two determinations of PR or better at least 4 weeks apart before progression 
(and not qualifying for a CR) where confirmation required or one determination of PR 
prior to progression where confirmation not required

SD = at least one SD assessment (or better) > 6 weeks after randomization/start of 
treatment (and not qualifying for CR or PR).

PD = progression 12 weeks after randomization/ start of treatment (and not qualifying 
for CR, PR or SD).

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
UNK = all other cases (i.e. not qualifying for confirmed CR or PR and without SD after 
more than 6 weeks or early progression within the first 12 weeks)
The time durations specified in the SD/PD/UNK definitions above are defaults based on a 6 
week tumor assessment frequency. However these may be modified for specific indications 
which are more or less aggressive. In addition, it is envisaged that the time duration may also 
take into account assessment windows. E.g. if the assessment occurs every 6 weeks with a time 
window of +/- 7 days, a BOR of SD would require a SD or better response longer than 5 weeks 
after randomization/start of treatment.
Overall lesion responses of CR must stay the same until progression sets in, with the exception 
of a UNK status. A patient who had a CR cannot subsequently have a lower status other than a 
PD, e.g. PR or SD, as this would imply a progression based on one or more lesions reappearing, 
in which case the status would become a PD.
Once an overall lesion response of PR is observed (which may have to be a confirmed PR 
depending on the study) this assignment must stay the same or improve over time until 
progression sets in, with the exception of an UNK status. However, in studies where 
confirmation of response is required, if a patient has a single PR (30% reduction of tumor 
burden compared to baseline) at one assessment, followed by a <30% reduction from baseline 
at the next assessment (but not 20% increase from previous smallest sum), the objective status 
at that assessment should be SD. Once a confirmed PR was seen, the overall lesion response 
should be considered PR (or UNK) until progression is documented or the lesions totally 
disappear in which case a CR assignment is applicable. In studies where confirmation of 
response is not required after a single PR the overall lesion response should still be considered 
PR (or UNK) until progression is documented or the lesion totally disappears in which case a 
CR assignment is applicable.
Example: In a case where confirmation of response is required the sum of lesion diameters is 
200 mm at baseline and then 140 mm - 150 mm - 140 mm - 160 mm - 160 mm at the subsequent 
visits. Assuming that non-target lesions did not progress, the overall lesion response would be 
PR - SD - PR - PR - PR. The second assessment with 140 mm confirms the PR for this patient. 
All subsequent assessments are considered PR even if tumor measurements decrease only by 
20% compared to baseline (200 mm to 160 mm) at the following assessments.
If the patient progressed but continues study treatment, further assessments are not considered 
for the determination of best overall response.
Note: these cases may be described as a separate finding in the CSR but not included in the 
overall response or disease control rates.
The best overall response for a patient is always calculated, based on the sequence of overall 
lesion responses. However, the overall lesion response at a given assessment may be provided 
from different sources:

Investigator overall lesion response

Central Blinded Review overall lesion response

Novartis calculated overall lesion response (based on measurements from either 
Investigator or Central Review)

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The primary analysis of the best overall response will be based on the sequence of central 
blinded review/calculated (central) overall lesion responses.
Based on the patients’ best overall response during the study, the following rates are then 
calculated:
Overall response rate (ORR) is the proportion of patients with a best overall response of CR 
or PR. This is also referred to as ‘Objective response rate’ in some protocols or publications.
Disease control rate (DCR) is the proportion of patients with a best overall response of CR or 
PR or SD. The objective of this endpoint is to summarize patients with signs of “activity” 
defined as either shrinkage of tumor (regardless of duration) or slowing down of tumor growth. 
Clinical benefit rate (CBR) is the proportion of patients with a best overall response of CR or 
PR , or an overall lesion response of SD or Non-CR/Non-PD which lasts for a minimum time 
duration (with a default of at least 24 weeks in breast cancer studies). This endpoint measures 
signs of activity taking into account duration of disease stabilization.
Another approach is to summarize the progression rate at a certain time point after baseline. In 
this case, the following definition is used:
Early progression rate (EPR) is the proportion of patients with progressive disease within 
8 weeks of the start of treatment.
The protocol should define populations for which these will be calculated. The timepoint for 
EPR is study specific. EPR is used for the multinomial designs of Dent and Zee (2001) and 
counts all patients who at the specified assessment (in this example the assessment would be at 
8 weeks ± window) do not have an overall lesion response of SD, PR or CR. Patients with an 
unknown (UNK) assessment at that time point and no PD before, will not be counted as early 
progressors in the analysis but may be included in the denominator of the EPR rate, depending 
on the analysis population used. Similarly when examining overall response and disease control, 
patients with a best overall response assessment of unknown (UNK) will not be regarded as 
“responders” but may be included in the denominator for ORR and DCR calculation depending 
on the analysis population (e.g. populations based on an ITT approach).
16.1.3.2 Time to event variables
16.1.3.2.1
Progression-free survival
Usually in all Oncology studies, patients are followed for tumor progression after 
discontinuation of study treatment for reasons other than progression or death. If this is not used, 
e.g. in Phase I or II studies, this should be clearly stated in the protocol. Note that randomized 
trials (preferably blinded) are recommended where PFS is to be the primary endpoint.
Progression-free survival (PFS) is the time from date of randomization/start of treatment to 
the date of event defined as the first documented progression or death due to any cause. If a 
patient has not had an event, progression-free survival is censored at the date of last adequate 
tumor assessment.
PFS rate at x weeks is an additional measure used to quantify PFS endpoint. It is recommended 
that a Kaplan Meier estimate is used to assess this endpoint. 

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16.1.3.2.2
Overall survival
All patients should be followed until death or until patient has had adequate follow-up time as 
specified in the protocol whichever comes first. The follow-up data should contain the date the 
patient was last seen alive / last known date patient alive, the date of death and the reason of 
death (“Study indication” or “Other”).
Overall survival (OS) is defined as the time from date of randomization/start of treatment to 
date of death due to any cause. If a patient is not known to have died, survival will be censored 
at the date of last known date patient alive.
16.1.3.2.3
Time to progression
Some studies might consider only death related to underlying cancer as an event which indicates 
progression. In this case the variable “Time to progression” might be used. TTP is defined as 
PFS except for death unrelated to underlying cancer.
Time to progression (TTP) is the time from date of randomization/start of treatment to the 
date of event defined as the first documented progression or death due to underlying cancer. If 
a patient has not had an event, time to progression is censored at the date of last adequate tumor 
assessment.
16.1.3.2.4
PFS2
A recent EMA guidance (EMA 2012) recommends a substitute end point intermediate to PFS 
and OS called PFS2, a surrogate for OS when OS cannot be measured reliably, which assesses 
the impact of the experimental therapy on next-line treatment. The main purpose of this 
endpoint is to assess long term maintenance strategies, particularly of resensitizing agents and 
where it is necessary to examine the overall “field of influence”.
PFS2, which could be termed PFS deferred, PFS delayed, tandem PFS, or PFS version 2.0, is 
the time from date of randomization/start of treatment to the date of event defined as the first 
documented progression on next-line treatment or death from any cause. The censoring rules 
for this endpoint will incorporate the same principles as those considered for PFS in this 
document, and in addition may involve other considerations which will need to be detailed in 
the protocol.
Please note that data collection for the PFS2 is limited to the date of progression and not specific 
read of the tumor assessments.
It is strongly recommended that the teams consult regulatory agencies for scientific advice given 
the limited experience with the use of this endpoint in regulatory setting in light of 
methodological issues w.r.t. censoring foreseen.
16.1.3.2.5
Time to treatment failure
This endpoint is often appropriate in studies of advanced disease where early discontinuation is 
typically related to intolerance of the study drug. In some protocols, time to treatment failure 
may be considered as a sensitivity analysis for time to progression. The list of discontinuation 
reasons to be considered or not as treatment failure may be adapted according to the specificities 
of the study or the disease.

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Time to treatment failure (TTF) is the time from date of randomization/start of treatment to 
the earliest of date of progression, date of death due to any cause, or date of discontinuation due 
to reasons other than ‘Protocol violation’ or ‘Administrative problems’. The time to treatment 
failure for patients who did not experience treatment failure will be censored at last adequate 
tumor assessment.
16.1.3.2.6
Duration of response
The analysis of the following variables should be performed with much caution when restricted 
to responders since treatment bias could have been introduced. There have been reports where 
a treatment with a significantly higher response rate had a significantly shorter duration of 
response but where this probably primarily reflected selection bias which is explained as 
follows: It is postulated that there are two groups of patients: a good risk group and a poor risk 
group. Good risk patients tend to get into response readily (and relatively quickly) and tend to 
remain in response after they have a response. Poor risk patients tend to be difficult to achieve 
a response, may have a longer time to respond, and tend to relapse quickly when they do respond. 
Potent agents induce a response in both good risk and poor risk patients. Less potent agents 
induce a response mainly in good risk patients only. This is described in more detail by Morgan 
(1988)
It is recommended that an analysis of all patients (both responders and non-responders) be 
performed whether or not a “responders only” descriptive analysis is presented. An analysis of 
responders should only be performed to provide descriptive statistics and even then interpreted 
with caution by evaluating the results in the context of the observed response rates. If an 
inferential comparison between treatments is required this should only be performed on all 
patients (i.e. not restricting to “responders” only) using appropriate statistical methods such as 
the techniques described in Ellis et al (2008). It should also be stated in the protocol if duration 
of response is to be calculated in addition for unconfirmed response.
For summary statistics on “responders” only the following definitions are appropriate. (Specific 
definitions for an all-patient analysis of these endpoints are not appropriate since the status of 
patients throughout the study is usually taken into account in the analysis).
Duration of overall response (CR or PR): For patients with a CR or PR (which may have to 
be confirmed the start date is the date of first documented response (CR or PR) and the end date 
and censoring is defined the same as that for time to progression.
The following two durations might be calculated in addition for a large Phase III study in which 
a reasonable number of responders is seen.
Duration of overall complete response (CR): For patients with a CR (which may have to be 
confirmed) the start date is the date of first documented CR and the end date and censoring is 
defined the same as that for time to progression.
Duration of stable disease (CR/PR/SD): For patients with a CR or PR (which may have to be 
confirmed) or SD the start and end date as well as censoring is defined the same as that for time 
to progression.

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16.1.3.2.7
Time to response
Time to overall response (CR or PR) is the time between date of randomization/start of 
treatment until first documented response (CR or PR). The response may need to be confirmed 
depending on the type of study and its importance. Where the response needs to be confirmed 
then time to response is the time to the first CR or PR observed.
Although an analysis on the full population is preferred a descriptive analysis may be performed 
on the “responders” subset only, in which case the results should be interpreted with caution 
and in the context of the overall response rates, since the same kind of selection bias may be 
introduced as described for duration of response in Section 16.1.3.2.5. It is recommended that 
an analysis of all patients (both responders and non-responders) be performed whether or not a 
“responders only” descriptive analysis is presented. Where an inferential statistical comparison 
is required, then all patients should definitely be included in the analysis to ensure the statistical 
test is valid. For analysis including all patients, patients who did not achieve a response (which 
may have to be a confirmed response) will be censored using one of the following options.

at maximum follow-up (i.e. FPFV to LPLV used for the analysis) for patients who had a 
PFS event (i.e. progressed or died due to any cause). In this case the PFS event is the 
worst possible outcome as it means the patient cannot subsequently respond. Since the 
statistical analysis usually makes use of the ranking of times to response it is sufficient to 
assign the worst possible censoring time which could be observed in the study which is 
equal to the maximum follow-up time (i.e. time from FPFV to LPLV)

at last adequate tumor assessment date otherwise. In this case patients have not yet 
progressed so they theoretically still have a chance of responding
Time to overall complete response (CR) is the time between dates of randomization/start of 
treatment until first documented CR. Similar analysis considerations including (if appropriate) 
censoring rules apply for this endpoint described for the time to overall response endpoint.
16.1.3.2.8
Definition of start and end dates for time to event variables
Assessment date
For each assessment (i.e. evaluation number), the assessment date is calculated as the latest of 
all measurement dates (e.g. X-ray, CT-scan) if the overall lesion response at that assessment is 
CR/PR/SD/UNK. Otherwise - if overall lesion response is progression - the assessment date is 
calculated as the earliest date of all measurement dates at that evaluation number.
In the calculation of the assessment date for time to event variables, any unscheduled 
assessment should be treated similarly to other evaluations.
Start dates
For all “time to event” variables, other than duration of response, the randomization/ date of 
treatment start will be used as the start date.
For the calculation of duration of response the following start date should be used:

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
Date of first documented response is the assessment date of the first overall lesion 
response of CR (for duration of overall complete response) or CR / PR (for duration of 
overall response) respectively, when this status is later confirmed.
End dates
The end dates which are used to calculate ‘time to event’ variables are defined as follows:

Date of death (during treatment as recorded on the treatment completion page or during 
follow-up as recorded on the study evaluation completion page or the survival follow-up 
page).

Date of progression is the first assessment date at which the overall lesion response was 
recorded as progressive disease.

Date of last adequate tumor assessment is the date the last tumor assessment with overall 
lesion response of CR, PR or SD which was made before an event or a censoring reason 
occurred. In this case the last tumor evaluation date at that assessment is used. If no post-
baseline assessments are available (before an event or a censoring reason occurred) the 
date of randomization/start of treatment is used.

Date of next scheduled assessment is the date of the last adequate tumor assessment plus 
the protocol specified time interval for assessments. This date may be used if back-dating 
is considered when the event occurred beyond the acceptable time window for the next 
tumor assessment as per protocol (see Section 16.1.3.2.8).
Example (if protocol defined schedule of assessments is 3 months): tumor assessments at 
baseline - 3 months - 6 months - missing - missing - PD. Date of next scheduled assessment 
would then correspond to 9 months.

Date of discontinuation is the date of the end of treatment visit.

Date of last contact is defined as the last date the patient was known to be alive. This 
corresponds to the latest date for either the visit date, lab sample date or tumor assessment 
date. If available, the last known date patient alive from the survival follow-up page is 
used. If no survival follow-up is available, the date of discontinuation is used as last 
contact date.

Date of secondary anti-cancer therapy is defined as the start date of any additional 
(secondary) antineoplastic therapy or surgery.
16.1.3.2.9
Handling of patients with non-measurable disease only at baseline
It is possible that patients with only non-measurable disease present at baseline are entered into 
the study, either because of a protocol violation or by design (e.g. in Phase III studies with PFS 
as the primary endpoint). In such cases the handling of the response data requires special 
consideration with respect to inclusion in any analysis of endpoints based on the overall 
response evaluations.
It is recommended that any patients with only non-measurable disease at baseline should be 
included in the main (ITT) analysis of each of these endpoints.
Although the text of the definitions described in the previous sections primarily relates to 
patients with measurable disease at baseline, patients without measurable disease should also 

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be incorporated in an appropriate manner. The overall response for patients with non-
measurable disease is derived slightly differently according to Table 16-4.
Table 16-4
Overall lesion response at each assessment: patients with non-target 
disease only
Non-target lesions
New Lesions
Overall lesion response
CR
No
CR
Non-CR/Non-PD1
No
Non-CR/non-PD
UNK
No
UNK
PD
Yes or No
PD
Any
Yes
PD
1 As defined in Section 16.1.2.4.
In general, the non-CR/non-PD response for these patients is considered equivalent to an SD 
response in endpoint determination. In summary tables for best overall response patients with 
only non-measurable disease may be highlighted in an appropriate fashion e.g. in particular by 
displaying the specific numbers with the non-CR/non-PD category.
In considering how to incorporate data from these patients into the analysis the importance to 
each endpoint of being able to identify a PR and/or to determine the occurrence and timing of 
progression needs to be taken into account.
For ORR it is recommended that the main (ITT) analysis includes data from patients with only 
non-measurable disease at baseline, handling patients with a best response of CR as “responders” 
with respect to ORR and all other patients as “non-responders”. 
For PFS, it is again recommended that the main ITT analyses on these endpoints include all 
patients with only non-measurable disease at baseline, with possible sensitivity analyses which 
exclude these particular patients. Endpoints such as PFS which are reliant on the determination 
and/or timing of progression can incorporate data from patients with only non-measurable 
disease.
16.1.3.2.10
Sensitivity analyses
This section outlines the possible event and censoring dates for progression, as well as addresses 
the issues of missing tumor assessments during the study. For instance, if one or more 
assessment visits are missed prior to the progression event, to what date should the progression 
event be assigned? And should progression event be ignored if it occurred after a long period 
of a patient being lost to follow-up? It is important that the protocol and RAP specify the 
primary analysis in detail with respect to the definition of event and censoring dates and also 
include a description of one or more sensitivity analyses to be performed.
Based on definitions outlined in Section 16.1.3.2.7, and using the draft FDA guideline on 
endpoints (Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics, April 
2005) as a reference, the following analyses can be considered:

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Table 16-5
Options for event dates used in PFS, TTP, duration of response
Situation
Options for end-date (progression or 
censoring)1
(1) = default unless specified differently in the 
protocol or RAP
Outcome
A
No baseline assessment
(1) Date of randomization/start of treatment3
Censored
B
Progression at or before next scheduled 
assessment
(1) Date of progression
(2) Date of next scheduled assessment2
Progressed
Progressed
C1
Progression or death after exactly one
missing assessment
(1) Date of progression (or death)
(2) Date of next scheduled assessment2
Progressed
Progressed
C2
Progression or death after two or more
missing assessments
(1) Date of last adequate assessment2
(2) Date of next scheduled assessment2
(3) Date of progression (or death)
Censored
Progressed
Progressed
D
No progression
(1) Date of last adequate assessment
Censored
E
Treatment discontinuation due to ‘Disease 
progression’ without documented 
progression, i.e. clinical progression 
based on investigator claim
(1) Ignore clinical progression and follow 
situations above 
(2) Date of discontinuation (visit date at which 
clinical progression was determined)
As per above 
situations
Progressed
F
New anticancer therapy given
(1) Ignore the new anticancer therapy and follow
situations above (ITT approach) 
(2) Date of last adequate assessment prior to new 
anticancer therapy
(3) Date of secondary anti-cancer therapy
(4) Date of secondary anti-cancer therapy
As per above 
situations
Censored
Censored
Event
G
Deaths due to reason other than 
deterioration of ‘Study indication’
(1) Date of last adequate assessment
Censored 
(only TTP and 
duration of 
response)
1.
=Definitions can be found in Section 16.1.3.2.7.
2.
=After the last adequate tumor assessment. “Date of next scheduled assessment” is defined in Section 
16.1.3.2.7.
3.
=The rare exception to this is if the patient dies no later than the time of the second scheduled assessment 
as defined in the protocol in which case this is a PFS event at the date of death.
The primary analysis and the sensitivity analyses must be specified in the protocol. Clearly 
define if and why options (1) are not used for situations C, E and (if applicable) F.
Situations C (C1 and C2): Progression or death after one or more missing assessments: The 
primary analysis is usually using options (1) for situations C1 and C2, i.e.

(C1) taking the actual progression or death date, in the case of only one missing 
assessment.

(C2) censoring at the date of the last adequate assessment, in the case of two or more 
consecutive missing assessments.
In the case of two or missing assessments (situation C2), option (3) may be considered jointly 
with option (1) in situation C1 as sensitivity analysis. A variant of this sensitivity analysis 
consists of backdating the date of event to the next scheduled assessment as proposed with 
option (2) in situations C1 and C2.

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Situation E: Treatment discontinuation due to ‘Disease progression’ without documented 
progression: By default, option (1) is used for situation E as patients without documented PD 
should be followed for progression after discontinuation of treatment. However, option (2) may 
be used as sensitivity analysis. If progression is claimed based on clinical deterioration instead 
of tumor assessment by e.g. CT-scan, option (2) may be used for indications with high early 
progression rate or difficulties to assess the tumor due to clinical deterioration.
Situation F: New cancer therapy given: the handling of this situation must be specified in 
detail in the protocol. However, option (1) (ITT) is the recommended approach; events 
documented after the initiation of new cancer therapy will be considered for the primary 
analysis i.e. progressions and deaths documented after the initiation of new cancer therapy 
would be included as events. This will require continued follow-up for progression after the 
start of the new cancer therapy. In such cases, it is recommended that an additional sensitivity 
analysis be performed by censoring at last adequate assessment prior to initiation of new cancer 
therapy.
Option (2), i.e. censoring at last adequate assessment may be used as a sensitivity analysis. If a 
high censoring rate due to start of new cancer therapy is expected, a window of approximately 
8 weeks performed after the start of new cancer therapy can be used to calculate the date of the 
event or censoring. This should be clearly specified in the analysis plan. 
In some specific settings, local treatments (e.g. radiation/surgery) may not be considered as 
cancer therapies for assessment of event/censoring in PFS/TTP/DoR analysis. For example, 
palliative radiotherapy given in the trial for analgesic purposes or for lytic lesions at risk of 
fracture will not be considered as cancer therapy for the assessment of BOR and PFS analyses. 
The protocol should clearly state the local treatments which are not considered as antineoplastic 
therapies in the PFS/TTP/DoR analysis.
The protocol should state that tumor assessments will be performed every x weeks until 
radiological progression irrespective of initiation of new antineoplastic therapy. It is strongly 
recommended that a tumor assessment is performed before the patient is switched to a new 
cancer therapy.
Additional suggestions for sensitivity analyses
Other suggestions for additional sensitivity analyses may include analyses to check for potential 
bias in follow-up schedules for tumor assessments, e.g. by assigning the dates for censoring and 
events only at scheduled visit dates. The latter could be handled by replacing in Table 16-5 the 
“Date of last adequate assessment” by the “Date of previous scheduled assessment (from 
baseline)”, with the following definition:

Date of previous scheduled assessment (from baseline) is the date when a tumor 
assessment would have taken place, if the protocol assessment scheme was strictly 
followed from baseline, immediately before or on the date of the last adequate tumor 
assessment.
In addition, analyses could be repeated using the Investigators’ assessments of response rather 
than the calculated response. The need for these types of sensitivity analyses will depend on the 
individual requirements for the specific study and disease area and have to be specified in the 
protocol or RAP documentation.

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16.1.4
Data handling and programming rules
The following section should be used as guidance for development of the protocol, data 
handling procedures or programming requirements (e.g. on incomplete dates).
16.1.4.1 Study/project specific decisions
For each study (or project) various issues need to be addressed and specified in the protocol or 
RAP documentation. Any deviations from protocol must be discussed and defined at the latest 
in the RAP documentation.
The proposed primary analysis and potential sensitivity analyses should be discussed and 
agreed with the health authorities and documented in the protocol (or at the latest in the RAP 
documentation before database lock).
16.1.4.2 End of treatment phase completion
Patients may voluntarily withdraw from the study treatment or may be taken off the study 
treatment at the discretion of the investigator at any time. For patients who are lost to follow-
up, the investigator or designee should show "due diligence" by documenting in the source 
documents steps taken to contact the patient, e.g., dates of telephone calls, registered letters, etc.
The end of treatment visit and its associated assessments should occur within 7 days of the last 
study treatment. 
Patients may discontinue study treatment for any of the following reasons:

Adverse event(s)

Lost to follow-up

Physician decision

Pregnancy

Protocol deviation

Technical problems

Participant/guardian decision

Progressive disease

Study terminated by the sponsor

Non-compliant with study treatment

No longer requires treatment

Treatment duration completed as per protocol (optional, to be used if only a fixed number 
of cycles is given)
Death is a reason which “must” lead to discontinuation of patient from trial. 
16.1.4.3 End of post-treatment follow-up (study phase completion)
End of post-treatment follow-up visit will be completed after discontinuation of study treatment 
and post-treatment evaluations but prior to collecting survival follow-up.
Patients may provide study phase completion information for one of the following reasons:

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
Adverse event

Lost to follow-up

Physician decision

Pregnancy

Protocol deviation

Technical problems

Participant/guardian decision

Death

Progressive disease

Study terminated by the sponsor
16.1.4.4 Medical validation of programmed overall lesion response
In order to be as objective as possible the RECIST programmed calculated response assessment 
is very strict regarding measurement methods (i.e. any assessment with more or less sensitive 
method than the one used to assess the lesion at baseline is considered UNK) and not available 
evaluations (i.e. if any target or non-target lesion was not evaluated the whole overall lesion 
response is UNK unless remaining lesions qualified for PD). This contrasts with the slightly 
more flexible guidance given to local investigators (and to the central reviewers) to use expert 
judgment in determining response in these type of situations, and therefore as a consequence 
discrepancies between the different sources of response assessment often arise. To ensure the 
quality of response assessments from the local site and/or the central reviewer, the responses 
may be re-evaluated by clinicians (based on local investigator data recorded in eCRF or based 
on central reviewer data entered in the database) at Novartis or external experts. In addition, 
data review reports will be available to identify assessments for which the investigators’ or 
central reader’s opinion does not match the programmed calculated response based on RECIST 
criteria. This may be queried for clarification. However, the investigator or central reader’s 
response assessment will never be overruled.
If Novartis elect to invalidate an overall lesion response as evaluated by the investigator or 
central reader upon internal or external review of the data, the calculated overall lesion response 
at that specific assessment is to be kept in a dataset. This must be clearly documented in the 
RAP documentation and agreed before database lock. This dataset should be created and stored 
as part of the ‘raw’ data.
Any discontinuation due to ‘Disease progression’ without documentation of progression by 
RECIST criteria should be carefully reviewed. Only patients with documented deterioration of 
symptoms indicative of progression of disease should have this reason for discontinuation of 
treatment or study evaluation.
16.1.4.5 Programming rules
The following should be used for programming of efficacy results:
16.1.4.5.1
Calculation of ‘time to event’ variables
Time to event = end date - start date + 1 (in days)

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When no post-baseline tumor assessments are available, the date of randomization/start of 
treatment will be used as end date (duration = 1 day) when time is to be censored at last tumor 
assessment, i.e. time to event variables can never be negative.
16.1.4.5.2
Incomplete assessment dates
All investigation dates (e.g. X-ray, CT scan) must be completed with day, month and year.
If one or more investigation dates are incomplete but other investigation dates are available, 
this/these incomplete date(s) are not considered for calculation of the assessment date (and 
assessment date is calculated as outlined in Section 16.1.3.2.7). If all measurement dates have 
no day recorded, the 1st of the month is used.
If the month is not completed, for any of the investigations, the respective assessment will be 
considered to be at the date which is exactly between previous and following assessment. If a 
previous and following assessment is not available, this assessment will not be used for any 
calculation.
16.1.4.5.3
Incomplete dates for last known date patient alive or death
All dates must be completed with day, month and year. If the day is missing, the 15th of the 
month will be used for incomplete death dates or dates of last contact.
16.1.4.5.4
Non-target lesion response
If no non-target lesions are identified at baseline (and therefore not followed throughout the 
study), the non-target lesion response at each assessment will be considered ‘not applicable 
(NA)’.
16.1.4.5.5
Study/project specific programming
The standard analysis programs need to be adapted for each study/project.
16.1.4.5.6
Censoring reason
In order to summarize the various reasons for censoring, the following categories will be 
calculated for each time to event variable based on the treatment completion page, the study 
evaluation completion page and the survival page.
For survival the following censoring reasons are possible:

Alive

Lost to follow-up
For PFS and TTP (and therefore duration of responses) the following censoring reasons are 
possible:

Ongoing without event

Lost to follow-up

Withdrew consent

Adequate assessment no longer available*

Event documented after two or more missing tumor assessments (optional, see Table 16-5)

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
Death due to reason other than underlying cancer (only used for TTP and duration of 
response)

Initiation of new anti-cancer therapy
* Adequate assessment is defined in Section 16.1.3.2.7. This reason is applicable when adequate 
evaluations are missing for a specified period prior to data cut-off (or prior to any other 
censoring reason) corresponding to the unavailability of two or more planned tumor 
assessments prior to the cut-off date. The following clarifications concerning this reason should 
also be noted:

This may be when there has been a definite decision to stop evaluation (e.g. 
reason=“Sponsor decision” on study evaluation completion page), when patients are not 
followed for progression after treatment completion or when only UNK assessments are 
available just prior to data cut-off).

The reason "Adequate assessment no longer available" also prevails in situations when 
another censoring reason (e.g. withdrawal of consent, loss to follow-up or alternative anti-
cancer therapy) has occurred more than the specified period following the last adequate 
assessment.

This reason will also be used to censor in case of no baseline assessment.
16.1.5
References (available upon request)
Dent S, Zee (2001) application of a new multinomial phase II stopping rule using response 
and early progression, J Clin Oncol; 19: 785-791
Eisenhauer E, et al (2009) New response evaluation criteria in solid tumors: revised RECIST 
guideline (version 1.1). European Journal of Cancer, Vol.45: 228-47
Ellis S, et al (2008) Analysis of duration of response in oncology trials. Contemp Clin Trials 
2008; 29: 456-465
EMA Guidance: 2012 Guideline on the evaluation of anticancer medicinal products in man
FDA Guidelines: 2005 Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics, April 2005
FDA Guidelines: 2007 Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics, May 2007
Morgan TM (1988) Analysis of duration of response: a problem of oncology trials. Cont Clin 
Trials; 9: 11-18
Therasse P, Arbuck S, Eisenhauer E, et al (2000) New Guidelines to Evaluate the Response to 
Treatment in Solid Tumors, Journal of National Cancer Institute, Vol. 92; 205-16