Clinical trial NCT01750918
Conditions: Cancer
Keywords: MEK inhibitor anti-EGFR antibody colorectal cancer BRAF inhibitor
Sponsor: Novartis Pharmaceuticals
Start date: 2012-12-19; Completion date: 2020-06-18
Enrollment: 166 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This was a four part, phase I/II study aimed to evaluate the safety, tolerability and efficacy of combination of an anti-EGFR antibody panitumumab (P) either with a BRAF inhibitor (dabrafenib (D); GSK2118436) alone or with the combination of a BRAF inhibitor and a MEK inhibitor (trametinib (T); GSK1120212) in patients with BRAF-mutant V600E advanced or mCRC. The goal was to: 1) Determine RP2R/MTD for doublet (D+P) and triplet (D+T+P) combinations in Part 1; 2) Assess clinical activity for these combinations in Part 2; 3) Determine RP2R/MTD for double (T+P) combination in Part 4A, and assess clinical activity of this combination in two patient populations in Part 4B (patients with BRAF-V600E mutation-positive advanced or metastatic CRC and patients with advanced or metastatic CRC with secondary resistance to anti-EGFR therapy).

Detailed description:
Part 1: Dose escalation This was a dose escalation part intended to evaluate safety, tolerability, PK, PD, clinical activity and determine RP2R/MTD for the doublet (D+P) and the triplet (D+T+P) combinations in patients with BRAF-mutation V600E positive advanced or metastatic CRC. A 3+3 dose escalation procedure was followed. Dosing for dabrafenib and trametinib was continuous daily dosing while panitumumab was dosed once every two weeks (Q2W). Patients were evaluated for dose-limiting toxicities (DLTs) during the first 28 days of treatment.

Part 2A:

This was a cohort expansion part to assess the safety and preliminary clinical activity of the optimal safe and tolerable dose combinations (D+P)/(D+T+P) defined in Part 1.

Part 2B:

In this part, additional patients were enrolled into the triplet (D+T+P) combination at two dose levels in to further explore safety, tolerability and clinical activity. Up to 10 patients each with no prior treatment (First Line Population), and up to 20 patients each with at least one prior treatment (Second to Fourth Line Population) were planned to be enrolled in dose Cohorts 3A and 4.

Part 3: Randomized Phase 2 Study The randomized phase 2 portion (Phase 3) of the study was not pursued as the observed responses in any of the cohorts did not meet the predefined criteria at the time of the preliminary analysis (data cut-off date: 06-May-2016).

Part 4 This part was designed to identify the RP2R/MTD and initial clinical activity for the doublet (T+P) combination in patients BRAF-mutation V600E positive advanced or metastatic CRC, and advanced or metastatic CRC with secondary resistance to prior anti-EGFR therapy.

Part 4A: Dose Escalation This was a dose escalation part intended to determine RP2R/MTD for the doublet (T+P) combination in patients with BRAF-mutation V600E positive advanced or metastatic CRC. Approximately 18 patients (\~6 each cohort) were planned to be enrolled in Part 4A. A 3+3 dose escalation procedure was followed. Dosing for trametinib was continuous daily dosing while panitumumab was dosed once every two weeks (Q2W). Patients were evaluated for DLTs during the first 28 days of treatment.

Part 4B: Cohort Expansion This was a cohort expansion part intended to evaluate safety and efficacy of the doublet (T+P) combination. Up to 20 patients in each of two expansion cohorts were planned to be enrolled at the starting dose cohort or MTD from Part 4A.

Arms: arm 1: In Part 1 subjects will be assigned to escalation cohort of the doublet of dabrafenib and panitumumab based on the monotherapy doses of dabrafenib (150 milligrams \[mg\] twice daily) and panitumumab (6 milligrams per kilogram \[mg/kg\] every-2-week \[Q2W\]). Dose escalation will follow a 3+3 dose escalation procedure. If the initial combination dose of dabrafenib and panitumumab in Cohort 1 (starting dose) is not tolerable, lower dose combination(s) may be evaluated. arm 2: In Part 1 after the dabrafenib/panitumumab combination dose is defined, subsequent cohorts will evaluate the addition of trametinib based on a panitumumab dose that is one dose level lower than the dabrafenib/panitumumab dose defined in Cohort 1. Trametinib starting at 1.5 mg once daily will be added to the combination of dabrafenib and panitumumab. Dose escalation will follow a 3+3 dose escalation procedure until the full monotherapy doses of all agents are evaluated or the maximum tolerated dose is determined. arm 3: In Part 2, subjects will be assigned to expansion cohorts at a selected dose of dabrafenib in combination with panitumumab arm 4: In Part 2, subjects will be assigned to expansion cohorts at selected dose of trametinib plus dabrafenib in combination with panitumumab. arm 5: Subject will be administered starting dose of Trametinib 2 mg once daily and Panitumumab 6mg/kg Q2W. If the initial combination dose of trametinib and panitumumab in Cohort 1 (starting dose) is not tolerable, the lower dose combination defined in de-escalation cohorts (Cohort -1A, -1B and/or -1C) may be evaluated. Cohort -1A: Trametinib 1.5 mg once daily and Panitumumab 6 mg/kg Q2W; Cohort -1B: Trametinib 2 mg once daily and Panitumumab 4.8 mg/kg Q2W; Cohort-1C: Trametinib 1.5 mg once daily and Panitumumab 4.8 mg/kg Q2W arm 6: In Part 4B cohort expansion, subjects will be assigned to expansion cohorts at a selected dose of trametinib in combination with panitumumab. Enrollment in expansion cohorts will be initiated once dose escalation for the trametinib /panitumumab combination has been completed. Subjects with advanced/metastatic CRC with either a BRAF-mutation (Cohort 1E) or who developed secondary resistance to prior anti-EGFR therapy (Cohort 2E). arm 7: Subjects will be randomized to receive dabrafenib plus panitumumab. Dose levels for dabrafenib, and panitumumab in Part 3 will be chosen based on emerging PK, PD, and tolerability data from Part 1 and Part 2. arm 8: Subjects will be randomized to receive study treatment as dabrafenib plus trametinib plus panitumumab. Dose levels for dabrafenib, trametinib and panitumumab in Part 3 will be chosen based on emerging PK, PD, and tolerability data from Part 1 and Part 2. arm 9: Subjects will be randomized to receive chemotherapy comparator. The chemotherapy comparator will consist of a standard chemotherapy regimen with or without the addition of a biological agent, based on local practice preferences. The available chemotherapy regimens includes 5-fluorouracil-based chemotherapy
Interventions: intervention 1: Dabrafenib intervention 2: Trametinib intervention 3: Panitumumab intervention 4: 5-fluorouracil
Intervention descriptions: intervention 1: Each capsule contains 50 mg or 75 mg of GSK2118436; 50 mg strength capsules are Swedish orange (dark red) opaque hypromellose size 2 capsules and 75 mg strength capsules are pink opaque hypromellose size 1 capsules. The initial dosing regimen will be twice daily (BID) continuous oral daily dosing. intervention 2: Each tablet contains 0.5mg or 2.0 mg GSK1120212; 0.5 mg is yellow modified oval biconvex film-coated tablets of size 4.8 mm X 8.9 mm and 2 mg as pink round biconvex film coated tablets;7.5 mm in diameter. The initial dosing regimen will be once daily continuous oral daily dosing. intervention 3: Panitumumab is a sterile, colorless, translucent-to-white amorphous, proteinaceous powder available as 100 mg panitumumab in 5 mL (20 mg/mL) single-use vial; 200 mg panitumumab in 10 mL (20 mg/mL) single-use vial; 400 mg panitumumab in 20 mL (20 mg/mL) single-use vial; to be administered as an intravenous infusion over 60 minutes, every 14 days. Doses higher than 1000 mg should be administered over 90 minutes. intervention 4: 5-fluorouracil-based chemotherapy

Protocol documents:
Prot_000.pdf: 
Clinical Development
GSK1120212 and GSK2118436
Protocol MEK116833 / NCT01750918    
An Open-Label, Four-Part, Phase I/II Study to Investigate 
the Safety, Pharmacokinetics, Pharmacodynamics, and 
Clinical Activity of the MEK Inhibitor GSK1120212, BRAF 
Inhibitor GSK2118436 and the anti-EGFR Antibody 
Panitumumab in Combination in Subjects with BRAF-
mutation V600E Positive Colorectal Cancer and in 
Subjects with CRC With Secondary Resistance to Prior 
Anti-EGFR Therapy    
Authors
Document type
Amended Protocol Version (Clean)
EUDRACT number
2012-004802-81
Version number
05
Development phase
II
Document status
Final
Release date
08-FEB-2017
Novartis internal 
reference number
DRB436C2201
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis


Novartis
Confidential
Page 2
Clinical Study Protocol Version 05
Protocol No. MEK116833
Amendment 05 
Amendment rationale 
Subsequent to the acquisition of GlaxoSmithKline (GSK) compound GSK1120212 and 
GSK2118436, the purpose of this protocol Amendment 05 is to:
-
Delete or replace references to GlaxoSmithKline or its staff with that of Novartis 
and its authorized agents to align with the change of sponsorship;
-
Make administrative changes to align with Novartis processes and procedures;
As of 08 February 2017:
166 patients have received study treatment in 8 countries.
161 patients have completed or discontinued study treatment.
The changes described in this amended protocol require Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) approval prior to implementation. 
A copy of this amended protocol will be sent to the IRBs/IECs and Health Authorities 
(HAs).
The changes herein affect the Informed Consent and all sites are required to update and 
submit for approval, a revised Informed Consent that takes into account the change of 
study sponsorship described in the protocol amendment.
Upon approval of this amendment, patients who have already been enrolled in the study 
will sign a new informed consent form indicating Novartis is the new study sponsor and 
continue the appropriate visit schedule.


Novartis
Confidential
Page 3
Clinical Study Protocol Version 05
Protocol No. MEK116833
Revision Chronology
GlaxoSmithKline
Document Number
Date
Version
2012N139131_00
2012-OCT-10
Original
2012N139131_01
2013-JUN-07
Amendment No. 1
Restriction of enrollment to V600E mutation positive CRC; formerly allowed V600E or 
V600K mutations
Move of pharmacodynamics from 
 Secondary Objective 
Simplification of Part 1 study schematic 
Revision to Cardiac DLT Definition 
Clarification that intra-subject dose escalation is allowed in triplet cohorts only 
Addition of guideline for cuSCC 
Text revised to allow use of MUGA to evaluate LVEF if ECHO is not available
Updated visual changes stopping criteria 
Clarification of time and events tables
Allow use of therapeutic warfarin (previously exclusionary)
Addition of text on Bayesian design for Part 2
Addition of section on follow-up (PFS, OS) for subjects who discontinue study treatment
Updates to prohibited medications
Revision of study completion criteria
Addition of Sentinel Events and Cardiovascular Events 
Updates to blood volume requirements in Appendix 2
For subjects enrolled at sites in France---Revised criteria for assessment of valvular 
toxicity, and withholding and stopping criteria for QTc prolongation per request by 
ANSM
2012N139131_02
2013-OCT-28
Amendment No. 2
Revised medical monitor contact information
Updated abbreviations table
Changed central serous retinopathy (CSR) to retinal pigment epithelium detachment 
(RPED) throughout
Revised headers in Table 1, and text in Section 3.4.2 for clarity
Clarified opening of Part 2 cohorts in Section 3.4.2
Revised text in Section 3.7.3 to allow subjects in Part 1 and Part 2 to crossover from 


Novartis
Confidential
Page 4
Clinical Study Protocol Version 05
Protocol No. MEK116833
doublet to triplet dosing
Updated QTc withholding and stopping criteria in Section 3.7.9
For all Time and Events tables (Section 3.8.1, Section 3.8.2 and Section 3.8.3), added 
cross-reference to table in inclusion/exclusion criteria defining adequate organ function at 
baseline; added footnote regarding dermatological toxicity monitoring for subjects 
enrolled in France
For Part 1 and Part 2 Time and Events tables (Section 3.8.1 and Section 3.8.2), clarified 
collection of tumor biopsy in subjects with a response to study treatment
For Part 3 Time and Events table (Section 3.8.3), added optional tumor biopsy at 
progression
Section 4.2.1.1, Section 4.2.1.2, Section 7.1.1 and Section 7.1.2, updated text on timing 
of use of contraception prior to start of dosing and after last dose of study treatments
Section 5.2.3, defined crossover population
Section 5.3.8.7.1, clarified text regarding crossover population and efficacy analysis
Added Section 6.7.2 Fresh Tumor Tissue at Progression 
For subjects enrolled at sites in France---Revised criteria for monitoring of 
dermatological toxicity per request by ANSM
2012N139131_03
2014-MAY-01
Amendment No. 3
Revision of medical monitor information
Addition of text throughout protocol describing Part 4 (study and dose rationale; 
objectives and endpoints; eligibility criteria; investigational plan; Part 4 study design and 
schematic; time and events table)
Revision of eligibility criteria to allow enrolment of subjects who have been previously 
treated with anti-EGFR, and to reflect updated asset-specific guidances on toxicities.
Revision of general guidelines for clinically significant toxicities. 
2012N139131_04
2015-MAR-26
Amendment No. 4
Addition of text and schema for Part 2B, dose cohort expansion to enroll additional 
subjects to the triplet regimen at two different doses of panitumumab including updated 
Bayesian probabilities to accommodate increase sample size for triplet.
Collection of OS overall survival data for subjects in all parts has been included to the 
Time and Events Tables as well as to Section 6.3.1.
Revision of dose modification guidelines.
Clarification of intrasubject crossover from doublet to triplet including the addition of a 
Time and Events Table for crossover. 


Novartis
Confidential
Page 5
Clinical Study Protocol Version 05
Protocol No. MEK116833
Minor changes to the timing of assessment in the Time and Events Tables for Part 2 and 
Part 4.
Revision of medical monitor information.
2012N139131_05
2015-APR-13
Amendment No. 4
Republished
Compound number was updated from the GSK reference to the combination of 
trametinib and dabrafenib to the GSK compound numbers for trametinib and dabrafenib, 
GSK112012 + GSK2118436.
NA
2017-FEB-08
Amendment No. 5
Delete or replace references to GSK or its staff with that of Novartis/Novartis and its 
authorized agents.
Make administrative changes to align with Novartis processes and procedures.


Novartis
Confidential
Page 6
Clinical Study Protocol Version 05
Protocol No. MEK116833
SPONSOR SIGNATORY
 Novartis Pharma AG
Date


Novartis
Confidential
Page 7
Clinical Study Protocol Version 05
Protocol No. MEK116833
SPONSOR INFORMATION PAGE
Novartis Pharmaceuticals Corporation
Clinical Leader and Sponsor Contact Information:
Role
Name
Day Time 
Phone 
Number
After-hours 
Phone/Cell/
Pager 
Number
Novartis Contact Information
MD, PhD
NA
Novartis
Novartis
Novartis Pharma AG
Postfach
CH-4002 Basel
Switzerland
In some countries, the clinical trial sponsor may be the local Novartis and its authorized 
agents. If applicable, the details of the alternative Sponsor and contact person in the 
territory will be provided to the relevant regulatory authority as part of the clinical trial 
application.
If you have any questions regarding the protocol, please contact your local Novartis 
office.
Regulatory Agency Identifying Number(s):   IND# 113557, EUDRACT# 2012-004802-
81, NCT# 01750918


Novartis
Confidential
Page 8
Clinical Study Protocol Version 05
Protocol No. MEK116833
INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol number:  MEK116833
I confirm agreement to conduct the study in compliance with the protocol, as amended by 
this protocol amendment.
I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described study.
I agree to ensure that all associates, colleagues and employees assisting in the conduct of 
the study are informed about their obligations. Mechanisms are in place to ensure that site 
staff receives the appropriate information throughout the study. 
Investigator Name:
Investigator Address:
Investigator Phone Number:
Investigator Signature
Date


Novartis
Confidential
Page 9
Clinical Study Protocol Version 05
Protocol No. MEK116833
TABLE OF CONTENTS
PAGE
LIST OF ABBREVIATIONS...........................................................................................14
1.
INTRODUCTION....................................................................................................18
1.1.
Background ................................................................................................18
1.1.1.
Colorectal Cancer: Unmet Medical Need .....................................18
1.1.2.
Dabrafenib (GSK2118436) ..........................................................20
1.1.3.
Trametinib (GSK1120212)...........................................................21
1.1.4.
Panitumumab, Vectibix ................................................................21
1.2.
Preliminary Clinical Data for Dabrafenib (GSK2118436) and 
Trametinib (GSK1120212)..........................................................................22
1.3.
Rationale ....................................................................................................23
1.3.1.
Study Rationale for Parts 1, 2, 3, 4 ..............................................23
1.3.2.
Study Rationale for Part 4............................................................23
1.3.2.1.
Preliminary data from ongoing MEK116833 
study ..........................................................................24
1.3.3.
Dose Rationale ............................................................................25
1.3.3.1.
Potential for Drug-Drug Interactions ...........................25
1.3.3.2.
Potential for Overlapping Toxicities ............................26
1.3.3.3.
Part 1 .........................................................................26
1.3.3.4.
Part 2 .........................................................................27
1.3.3.5.
Part 3 .........................................................................28
1.3.3.6.
Part 4 .........................................................................29
1.4.
Summary of Risk Management...................................................................30
1.4.1.
GSK2118436: Dabrafenib............................................................30
1.4.2.
GSK1120212: Trametinib ............................................................31
1.4.3.
Panitumumab ..............................................................................32
2.
OBJECTIVES AND ENDPOINTS...........................................................................34
2.1.
Part 1: Phase 1 Dose Escalation ................................................................34
2.2.
Part 2: Cohort Expansions ..........................................................................35
2.3.
Part 3: Randomized Phase 2 ......................................................................36
2.4.
Part 4A: Dose Escalation............................................................................37
2.5.
Part 4B: Cohort Expansion .........................................................................39
3.
INVESTIGATIONAL PLAN.....................................................................................40
3.1.
Part 1 Dose Escalation Study Design/Schematic........................................40
3.2.
Part 2A: Cohort Expansions Study Design/Schematic ................................40
3.3.
Part 2B:  Cohort Expansion ........................................................................41
3.4.
Part 3: Randomized Phase 2 Study Design//Schematic..............................41
3.5.
Part 4A Dose Escalation.............................................................................42
3.6.
Part 4B Cohort Expansion ..........................................................................42
3.7.
Discussion of Design ..................................................................................42
3.7.1.
Prescreening for KRAS and BRAF Mutation Status.....................43
3.7.2.
Part 1...........................................................................................43
3.7.2.1.
Dose-Limiting Toxicity Definitions...............................45
3.7.2.2.
Maximum Tolerated Dose and Recommended 
Phase 2 Dose.............................................................46
3.7.3.
Part 2...........................................................................................46


Novartis
Confidential
Page 10
Clinical Study Protocol Version 05
Protocol No. MEK116833
3.7.3.1.
Part 2A:  Cohort Expansion ........................................47
3.7.3.2.
Part 2B:  Cohort Expansion ........................................47
3.7.4.
Part 3...........................................................................................48
3.7.5.
Part 4A Dose Escalation..............................................................49
3.7.5.1.
Dose-Limiting Toxicity Definitions...............................50
3.7.6.
Part 4B Cohort Expansion ...........................................................50
3.8.
Treatment Assignment................................................................................51
3.9.
Investigational Products and Other Study Treatment 
Dosage/Administration................................................................................52
3.10.
Dose Adjustment/Stopping Criteria .............................................................53
3.10.1.
Continuation on Study..................................................................53
3.10.2.
Dose Adjustment .........................................................................54
3.10.3.
Intra-subject Doublet to Triplet Crossover and Dose 
Escalation: Part 1, 2 or 4..............................................................55
3.10.4.
General Guidelines for Clinically Significant Toxicities .................56
3.10.4.1.
Guidelines for Treatment of Pyrexia ...........................58
3.10.4.2.
Management of Dermatological Adverse 
Events Skin Toxicity ...................................................60
3.10.4.2.1.
Rash Prophylaxis and Supportive 
Care .......................................................60
3.10.4.2.2.
Acneiform Rash......................................62
3.10.4.2.3.
Non-Acneiform Rash ..............................64
3.10.4.2.4.
Hand-Foot-Skin Reaction (HFSR)...........64
3.10.4.3.
Guidelines for cuSCC.................................................66
3.10.5.
Guidelines for Diarrhea................................................................66
3.10.6.
Guidelines for Renal Insufficiency................................................67
3.10.7.
Guidelines for Cardiovascular Adverse Events ............................68
3.10.7.1.
Left Ventricular Ejection Fraction (LVEF)....................69
3.10.8.
Monitoring and Management of Hypertension..............................70
3.10.8.1.
Monitoring of Hypertension.........................................70
3.10.8.2.
Management of Hypertension.....................................71
3.10.9.
Guidelines for Prolonged QTc......................................................73
3.10.10. Liver Chemistry Stopping Criteria ................................................73
3.10.11. Guidelines for Visual Changes or Specified Ophthalmic 
Examination Findings...................................................................75
3.10.12. Supportive Care...........................................................................77
3.10.12.1. Supportive Measures for Respiratory 
Symptoms ..................................................................77
3.10.12.2. Supportive Measures for Abdominal Pain or 
Suspected Pancreatitis...............................................77
3.10.13. Pneumonitis/ Interstitial Lung Disease Management 
Guidelines....................................................................................77
3.11.
Time and Events Tables .............................................................................79
3.11.1.
Part 1 Dose Escalation ................................................................79
3.11.2.
Part 2 Expansion Cohorts............................................................84
3.11.3.
Part 3 Randomized Phase 2 ........................................................89
3.11.4.
Part 4 Dose Escalation and Cohort Expansion ............................92
3.11.5.
Intra-subject Doublet to Triplet Crossover....................................97
4.
STUDY POPULATION.........................................................................................100
4.1.
Number of Subjects ..................................................................................100
4.2.
Eligibility Criteria .......................................................................................100


Novartis
Confidential
Page 11
Clinical Study Protocol Version 05
Protocol No. MEK116833
4.2.1.
Part 1, 2 and 4 Inclusion and Exclusion Criteria.........................100
4.2.1.1.
Part 1, 2 and 4 Inclusion Criteria...............................100
4.2.1.2.
Part 1, Part 2, and Part 4 Exclusion Criteria .............103
4.2.2.
Part 3 Inclusion and Exclusion Criteria.......................................106
4.2.2.1.
Part 3 Inclusion Criteria ............................................106
4.2.2.2.
Part 3 Exclusion Criteria ...........................................108
5.
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS.................................111
5.1.
Hypotheses and Treatment Comparisons.................................................111
5.1.1.
Part 1 and Part 4 Dose Escalation .............................................111
5.1.2.
Part 2 and Part 4 Cohort Expansion...........................................111
5.1.3.
Part 3.........................................................................................113
5.2.
Sample Size Considerations.....................................................................114
5.2.1.
Sample Size Assumptions .........................................................114
5.2.1.1.
Part 1 and Part 4 Dose Escalation............................114
5.2.1.2.
Part 2 and Part 4 Cohort Expansions .......................114
5.2.1.3.
Part 3 .......................................................................117
5.2.2.
Sample Size Sensitivity..............................................................118
5.2.3.
Analysis Populations..................................................................118
5.2.4.
Analysis Data Sets.....................................................................119
119
5.2.5.
Sample Size Re-estimation........................................................119
5.3.
Data Analysis Considerations ...................................................................119
5.3.1.
Withdrawal.................................................................................119
5.3.2.
Missing Data..............................................................................119
5.3.3.
Protocol Violations.....................................................................119
5.3.4.
Derived and Transformed Data..................................................119
5.3.5.
Assessment Windows................................................................120
5.3.6.
Other Issues ..............................................................................120
5.3.7.
Interim Analysis .........................................................................120
5.3.7.1.
Part 1 and Part 4 Dose Escalation............................120
5.3.7.2.
Part 2 and Part 4 Cohort Expansion .........................121
5.3.7.3.
Part 3 .......................................................................121
5.3.8.
Final Analyses ...........................................................................122
5.3.8.1.
Safety Analyses........................................................122
5.3.8.2.
Extent of Exposure ...................................................122
5.3.8.3.
Adverse Events ........................................................122
5.3.8.4.
Clinical Laboratory Evaluations ................................123
5.3.8.5.
Other Safety Measures.............................................123
5.3.8.6.
Pharmacokinetic Analyses........................................123
5.3.8.7.
Efficacy Analyses .....................................................124
5.3.8.7.1.
Part 1, Part 2 and Part 4.......................124
5.3.8.7.2.
Part 3....................................................125
6.
STUDY ASSESSMENTS AND PROCEDURES ...................................................126
6.1.
Demographic/Medical History Assessments .............................................126
6.2.
Safety .......................................................................................................126
6.3.
Disease Assessments...............................................................................130
6.3.1.
Follow-up Assessments for Subjects Permanently 
Discontinued from Study Treatment...........................................131
6.4.
Blood Requirements .................................................................................131
6.5.
Pregnancy ................................................................................................131


Novartis
Confidential
Page 12
Clinical Study Protocol Version 05
Protocol No. MEK116833
6.5.1.
Time period for collecting pregnancy information.......................131
6.5.2.
Action to be taken if pregnancy occurs ......................................132
6.5.3.
Action to be taken if pregnancy occurs in a female partner 
of a male study subject ..............................................................132
6.6.
Pharmacokinetics .....................................................................................132
6.6.1.
Blood Sample Collection............................................................132
6.6.2.
Sample Analysis ........................................................................133
6.7.
133
6.7.1.
Fresh Pre-and Post-dose Tumor Tissues...................................133
6.7.2.
Fresh Tumor Tissue at Progression...........................................133
134
134
134
134
6.7.4.
Archival tumor tissue .................................................................134
134
135
7.
LIFESTYLE AND/OR DIETARY RESTRICTIONS................................................135
7.1.
Contraception Requirements ....................................................................135
7.1.1.
Female Subjects........................................................................135
7.1.2.
Male Subjects............................................................................136
7.2.
Meals and Dietary Restrictions .................................................................137
8.
CONCOMITANT MEDICATIONS AND NON-DRUG THERAPIES .......................137
8.1.
Permitted Medications ..............................................................................137
8.2.
Prohibited Medications..............................................................................138
8.3.
Cautionary Medications ............................................................................139
8.4.
Non-Drug Therapies .................................................................................141
9.
COMPLETION OR EARLY WITHDRAWAL OF SUBJECTS ................................142
9.1.
Screen and Baseline Failures ...................................................................142
9.2.
Subject Completion Criteria ......................................................................142
9.3.
Permanent Discontinuation from Study Treatment....................................142
9.4.
Subject Withdrawal Procedures................................................................143
9.4.1.
Subject Withdrawal from Study..................................................143
9.4.2.
Subject Withdrawal from Study Treatment.................................143
9.5.
Treatment After the End of the Study........................................................144
10. STUDY TREATMENT ..........................................................................................144
10.1.
Blinding.....................................................................................................144
10.2.
Packaging and Labeling............................................................................144
10.3.
Preparation/Handling/Storage/Accountability............................................144
10.3.1.
Preparation................................................................................144
10.3.2.
Handling and Storage of Study Treatments ...............................145
10.3.3.
Accountability ............................................................................146
10.4.
Assessment of Compliance ......................................................................146
10.5.
Treatment of Study Treatment Overdose..................................................147
11. ADVERSE EVENTS (AE) AND SERIOUS ADVERSE EVENTS (SAE) ................147
Definition of Adverse Events ................................................................................148
11.1.
Definition of Serious Adverse Events........................................................149


Novartis
Confidential
Page 13
Clinical Study Protocol Version 05
Protocol No. MEK116833
11.2.1.
Sentinel Events..........................................................................150
11.2.
Laboratory and Other Safety Assessment Abnormalities Reported 
as AEs and SAEs .....................................................................................151
11.3.1.
Cardiovascular Events...............................................................151
11.3.
Method of Detecting AEs and SAEs..........................................................152
11.4.1.
Assessment of Causality............................................................152
11.4.
Follow-up of AEs and SAEs......................................................................152
11.5.
Prompt Reporting of SAEs to Novartis......................................................153
11.6.
Regulatory Reporting Requirements for SAEs ..........................................155
12. LIVER CHEMISTRY FOLLOW-UP PROCEDURES.............................................155
12.1.
Liver Chemistry Testing Procedures .........................................................155
12.2.
Liver Chemistry Monitoring Criteria...........................................................156
12.3.
Drug Restart/Rechallenge Following Liver Events that are Possibly 
Related to Study Drug(s) ..........................................................................156
12.4.
Drug Restart Following Transient, Resolving Liver Events Not 
Related to Study Drug(s) ..........................................................................157
13. STUDY CONDUCT CONSIDERATIONS .............................................................158
13.1.
Posting of Information on Publicly Available Clinical Trial Registers..........158
13.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ......................................................................................158
13.2.1.
Urgent Safety Measures ............................................................158
13.3.
Quality Control (Study Monitoring) ............................................................159
13.4.
Quality Assurance.....................................................................................159
13.5.
Study and Site Closure .............................................................................159
13.6.
Records Retention....................................................................................160
13.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication ...............160
13.8.
Data Management ....................................................................................161
13.9.
Independent Data Monitoring Committee (IDMC) .....................................161
14. REFERENCES.....................................................................................................162
APPENDICES.............................................................................................................167
Appendix 1: Liver Safety Algorithms.....................................................................167
Appendix 2: Blood Requirements .........................................................................169
Appendix 3: Liver Safety Drug Restart Guidelines................................................171
Appendix 4: RECIST 1.1 Criteria..........................................................................174
Appendix 5: Withholding and Stopping Criteria for QTc Prolongation for 
Subjects Enrolled in France ......................................................................179
Appendix 6: Bazett’s Correction ...........................................................................180
181
Appendix 8: Protocol Amendment Changes .........................................................184


Novartis
Confidential
Page 14
Clinical Study Protocol Version 05
Protocol No. MEK116833
LIST OF ABBREVIATIONS
µg
Microgram
µL
Microliter
ADL
Activities of daily living
AE
Adverse Event
ALT
Alanine aminotransferase (SGPT)
AML
Acute myeloid leukemia
ANC
Absolute neutrophil count
AST
Aspartate aminotransferase (SGOT)
ATP
Adenosine triphosphate
AUC
Area under concentration-time curve
AUC(0-)
Area under the concentration-time curve from time zero (pre-dose) 
extrapolated to infinite time
AUC(0-)
Area under the concentration-time curve over the dosing interval
AUC(0-8)
Area under the concentration-time curve from zero (pre-dose) 8 hours
AUC(0-t)
Area under the concentration-time curve from time zero (pre-dose) to 
last time of quantifiable concentration within a subject across all 
treatments
BAL
Bronchoalveolar lavage
BBB
Bundle-branch block
BID
twice daily
BLRM
Bayesian logistic regression model
BORR
Best overall response rate
BP
Blood pressure
BPM
Beat Per Minute
BQL
Below quantifiable limits
BRAT
Bananas, rice, apples, toast (diet)
BST
Bioanalytical Science & Toxicokinetic
BUN
Blood urea nitrogen
CBC
Complete blood count
CI
Confidence Interval
CL
Systemic clearance of parent drug
CL/F
Apparent clearance following oral dosing
Cmax
Maximum observed concentration 
Cmin
Minimum observed concentration
CO2
Carbon dioxide
CPK
Creatinine phosphokinase
CPK/M&S PK
Clinical Pharmacokinetics/ Modeling & Simulation Pharmacokinetic
CPMS
Clinical Pharmacology Modeling & Simulation
CR
Complete response
CRC
Colorectal cancer
CRP
C-reactive protein
Ct
Last observed quantifiable concentration


Novartis
Confidential
Page 15
Clinical Study Protocol Version 05
Protocol No. MEK116833
CT
Computed tomography
CuSCC
Cutaneous squamous cell carcinoma
Cτ
Pre-dose (trough) concentration at the end of the dosing interval
DBP
Diastolic blood pressure
DLT
Dose-limiting toxicity
DMPK
Drug Metabolism and Pharmacokinetics
ECG
Electrocardiogram
ECHO
Echocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EGFR
Epidermal growth factor receptor
FDA
Food and Drug Administration
FSH
Follicle Stimulating Hormone
FTIH
First time in humans
GCP
Good Clinical Practice
GCPH
Global Clinical Program Head
GCSP
Global Clinical Safety and Pharmacovigilance
GGT
Gamma glutamyltransferase
GI
Gastrointestinal 
GLP
Good Laboratory Practice
GSK
GlaxoSmithKline
h/hr
Hour(s)
HA
Health Authorities
HBsAg
Hepatitis B surface antigen
hCG
Human chorionic gonadotropin
HFSR
Hand-foot skin reaction
HR
Heart rate
HRT
Hormone replacement therapy
IB
Investigator’s Brochure
IC50
Half maximal inhibitory concentration
ICH
International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use
IDMC
Independent Data Monitoring Committee
IDSL
Integrated Data Standards Library
IEC
Independent Ethics Committee
IgM
Immunoglobulin M
ILD
Interstitial lung disease
IND
Investigational New Drug
INR
International normalized ratio
IP
Investigational Product
IRB
Institutional Review Board
ITT
Intent to treat
IU
International Unit
IUD
Intrauterine device
IUS
Intrauterine system


Novartis
Confidential
Page 16
Clinical Study Protocol Version 05
Protocol No. MEK116833
IV
Intravenous
Ka
Absorption rate constant
KA
Keratoacanthoma
Kg
Kilogram
L
Liter
LDH
Lactate dehydrogenase
LFTs
Liver function tests
LLN
Lower limit of normal
LMWH
Low molecular weight heparin
LSLV
Last subject last visit
LVEF
Left ventricular ejection fraction
MCH
Mean corpuscular hemoglobin
MCHC
Mean corpuscular hemoglobin concentration
MCV
Mean corpuscular volume
mCRC
Metastatic colorectal cancer
MedDRA
Medical Dictionary for Regulatory Activities
Mg
Milligrams
mL
Milliliter
MRI
Magnetic resonance imaging
MRT
Mean residence time
MSDS
Material Safety Data Sheet
msec
Milliseconds
MTD
Maximum tolerated dose
MUGA
Multigated acquisition scan
NCI-CTCAE
National Cancer Institute Common Terminology Criteria for Adverse 
Events 
NED
No evidence of disease
NSAIDs
Nonsteroidal anti-inflammatory drugs
NYHA
New York Heart Association
ORR
Overall response rate
OS
Overall survival
PD
Progressive Disease
pEGFR
phosphorylated epidermal growth factor receptor
PFS
Progression-free survival
PGx
Pharmacogenetics
PK
Pharmacokinetic
PR
Partial response
PSRI
Periodic Safety Reports for Investigators
PT
Prothrombin time
PTT
Partial thromboplastin time
Q
Every
QC
Quality control
QTcB
QT duration corrected for heart rate by Bazett’s formula
QTcF
QT duration corrected for heart rate by Fridericia’s formula
RAP
Reporting and Analysis Plan
RBC
Red blood cells


Novartis
Confidential
Page 17
Clinical Study Protocol Version 05
Protocol No. MEK116833
RECIST
Response Evaluation Criteria In Solid Tumors
REML
Restricted maximum likelihood
RNA
Ribonucleic acid
RP2R
Recommended Phase 2 Regimen
RPED
Retinal pigment epithelium detachment
RR
Response rate
RTK
Receptor tyrosine kinase
RVO
Retinal vein occlusion
SAE
Serious adverse event(s)
SMT
Safety Monitoring Team
SAS
Statistical Analysis Software
SAS Proc Mixed
SAS procedure MIXED
SBP
Systolic blood pressure
SCC
Squamous cell carcinoma
SD
Standard deviation
SD
Stable disease
SGOT
Serum glutamic-oxaloacetic transaminase
SGPT
Serum glutamic pyruvic transaminase
SOC
Standard of care
SOP
Standard Operating Procedure
SPM
Study Procedures Manual
SUSAR
Suspected, Unexpected, Serious Adverse drug Reaction
T
Infusion duration
t
Time of last observed quantifiable concentration
t½
Terminal phase half-life
tmax
Time of occurrence of Cmax
ULN
Upper limit of normal
US
United States
V/F
oral volume of distribution
WBC
White blood cells
τ
Dosing interval


Novartis
Confidential
Page 18
Clinical Study Protocol Version 05
Protocol No. MEK116833
1.
INTRODUCTION
1.1.
Background
1.1.1.
Colorectal Cancer: Unmet Medical Need
Colorectal cancer (CRC) is the fourth most common visceral malignancy and the second 
most frequent cause of cancer death. Although the incidence of CRC has increased 
significantly over the past 3 decades, the mortality rate has decreased.  This is due, in part, 
to improved screening techniques but also to improved therapies.  While there has been 
improvement, the unmet need remains very high, particularly for subjects with BRAF-
mutation V600E positive CRC, which has substantially worse outcomes than both the 
KRAS-mutant and the KRAS/BRAF-wild type populations.  
One improvement in CRC therapy has been the inclusion of anti-epidermal growth factor 
receptor (EGFR) therapy.  Cetuximab, the first anti-EGFR therapy approved for the 
treatment of CRC, was demonstrated to have a benefit on progression free survival (PFS) 
and overall survival (OS) as a single agent in subjects with CRC that was resistant to 
standard chemotherapy [Jonker, 2007].  Subsequently it was demonstrated that cetuximab 
also demonstrated improvement in PFS when combined with standard chemotherapy 
(leucovorin calcium, fluorouracil, irinotecan hydrochloride; FOLFIRI) in previously 
untreated CRC subjects [Van Cutsem, 2009].  However, subsequent analyses of these 
studies, and a randomized Phase 2 evaluation of cetuximab with FOLFOX (leucovorin 
calcium, fluorouracil, oxaliplatin) demonstrated that the improvement in PFS was limited 
to cancers that harboured the wild-type version of the proto-oncogene KRAS [Karapetis, 
2008; Bokemeyer, 2009; Van Cutsem, 2009].  Furthermore, a benefit in overall survival 
could also be demonstrated in wild-type KRAS subjects.  More recently, the fully 
humanized anti-EGFR antibody panitumumab (Vectibix) was demonstrated to have very 
similar efficacy in the first line and second line settings with less frequent dosing (once 
every two weeks) and a lower rate of infusion reactions [VECTIBIX, 2014; Douillard, 
2010; Peeters, 2010].  Again, the therapeutic benefit was limited to the KRAS wild-type 
population.  Subsequent analyses of studies that have investigated anti-EGFR therapy 
(cetuximab and panitumumab) in CRC have confirmed that the clinical benefit of these 
therapies is limited to subjects with wild-type KRAS/NRAS [DeRoock, 2010, 
Schwartzberg, 2014; Douillard, 2013]. 
The RAS/RAF/MEK/ERK pathway is a critical proliferation pathway in many human 
cancers.  Under normal circumstances, this pathway is activated by the stimulation of 
upstream signalling pathways, particularly receptor tyrosine kinases (RTKs).  It is 
through the aberrant stimulation of this pathway that the KRAS mutation confers 
resistance to anti-EGFR therapy [Lievre, 2010].
The RAS/RAF/MEK/ERK pathway can also be constitutively activated by alterations in 
the BRAF oncogene.  BRAF, which activates MEK through its phosphorylation on two 
regulatory serine residues, is frequently mutated in a number of cancers, including 
melanoma, CRC, and thyroid cancer.  The most common point mutations of BRAF result 
in a change at valine 600, usually V600E.   In melanomas that harbour mutant BRAF, 


Novartis
Confidential
Page 19
Clinical Study Protocol Version 05
Protocol No. MEK116833
small molecule inhibitors of BRAF, or the downstream kinase MEK, result in substantial 
therapeutic benefit [Chapman, 2011; Flaherty, 2012; Hauschild, 2012]. 
Although the BRAF mutation rate varies substantially across studies, approximately 8-
12% of metastatic colorectal cancer cases harbors a BRAF mutation [Maughan, 2011; 
Souglakos, 2009; Bokemeyer, 2012; Tveit, 2012; Richman, 2009; Tran, 2011; Yokota, 
2011; Tie, 2011].  Approximately 90% of all identified BRAF mutations that occur in 
human cancer are a T1799A transversion mutation in exon 15, which results in a V600E 
amino acid substitution [Wan, 2004].  This mutation appears to mimic regulatory 
phosphorylation and increases BRAF activity approximately 10-fold as compared to 
wild-type [Davies, 2002].  Accumulating data demonstrate that the presence of a BRAF-
mutation is a poor prognostic factor in CRC, with BRAF-mutation positive CRC 
demonstrating a more aggressive natural history than either KRAS mutant or 
KRAS/BRAF wild-type CRC.  Although the data are derived from a series of 
retrospective analyses of the BRAF-mutant population that typically have relatively small 
sample sizes, the efficacy of current therapies can be summarized in the first line and 
post-first line settings.  In the first line setting, current chemotherapy-based regimens (
bevacizumab or anti-EGFR therapy) tend to have a response rate in the range of 15 to 
25%, median PFS of ~4 to 7 months and median OS of ~9 to 14 months in subjects with 
BRAF-mutant CRC[Maughan, 2011; Souglakos, 2009; Bokemeyer, 2012; Tveit, 2012; 
Richman, 2009; Tran, 2011; Yokota, 2011; Tie, 2011].  Beyond the first line setting, 
currently available therapies appear to provide very little benefit, with very few responses, 
median PFS of 1.5 to 3 months and median OS of 4 to 7 months [Loupakis, 2009; Di 
Nicolantonio, 2008; Laurent-Puig, 2009].
The utility of anti-EGFR therapy in the BRAF-mutation positive CRC patient population 
is an unsettled question.  The literature includes a number of conflicting reports, some 
suggesting benefit [Bokemeyer, 2012] and others suggesting the absence of benefit [Di 
Nicolantonio, 2008; Loupakis, 2009; Maughan, 2011].  Since the BRAF mutation 
activates the same primary pathway as the KRAS mutation, the conferral of resistance to 
anti-EGFR therapy would not be surprising; however the available clinical data do not 
yet provide a clear answer.  What does appear clear is that, given the poor prognosis and 
limited activity of currently available agents in all lines of treatment, BRAF-mutant CRC 
is a substantial unmet medical need.  
As mentioned above, recently developed inhibitors of the BRAF and MEK kinases have 
demonstrated substantial clinical benefit in the treatment of subjects with BRAF-mutant 
melanoma [Chapman, 2011; Flaherty, 2012; Hauschild, 2012].  This benefit has come in 
the form of profound tumor shrinkage (confirmed response rates of >50%), prolonged 
progression free survival and improvements in overall survival.  Preliminary studies 
evaluating the activity of these same targeted inhibitors of BRAF and MEK have not 
demonstrated similar efficacy in BRAF-mutant CRC as they have demonstrated in 
BRAF-mutant melanoma, with overall response rates in BRAF-mutant CRC of <10% 
[Falchook, 2012; Kopetz, 2010].
Recently published preclinical studies provide a potential molecular explanation for the 
discrepant activity of BRAF inhibitors in BRAF-mutant melanoma vs. BRAF-mutant 
CRC.  Similar to the clinical experience to date, CRC cell lines are relatively insensitive 


Novartis
Confidential
Page 20
Clinical Study Protocol Version 05
Protocol No. MEK116833
to BRAF inhibitors, both in vitro and in vivo.  However, whereas BRAF-mutant 
melanoma cell lines generally lack expression of EGFR, BRAF-mutant CRC cell lines 
express high levels of activated EGFR protein (pEGFR).  The addition of an anti-EGFR 
therapy (including anti-EGFR biological agents [cetuximab] and small molecule 
inhibitors of EGFR [e.g., erlotinib and gefitinib]) sensitized the CRC cell lines to the 
BRAF inhibitor, resulting in synergistic activity of the combination in in vitro and in vivo 
models [Prahallad, 2012; Corcoran, 2012].  Based on these data, the differential 
expression of EGFR in BRAF-mutant CRC, and not in BRAF-mutant melanoma, may 
explain the insensitivity of BRAF-mutant CRC and provides a strong rationale to 
evaluate the combination of anti-EGFR antibodies with a BRAF inhibitor and with the 
combination of a BRAF inhibitor and a MEK inhibitor.
The current study is designed to test the hypothesis that the combination of an anti-EGFR 
antibody with either a BRAF inhibitor (dabrafenib; GSK2118436) alone or with the 
combination of a BRAF inhibitor and a MEK inhibitor (trametinib; GSK1120212) will 
result in clinically meaningful anti-tumor activity that represents an improvement over 
the chemotherapy comparator (a regimen of FOLFOX, FOLFIRI or irinotecan with or 
without panitumumab or bevacizumab) for BRAF-mutant CRC.  This will include the 
evaluation of the safety and tolerability of the two combinations, a preliminary 
assessment of clinical activity and then a randomized evaluation relative to the 
chemotherapy comparator therapy.  In addition, the study will test the hypothesis that the 
combination of panitumumab and trametinib can overcome secondary resistance to an 
anti-EGFR therapy in patients that initially derived benefit from the anti-EGFR therapy 
(further rationale in Section 1.3.2).
1.1.2.
Dabrafenib (GSK2118436)
Dabrafenib is a 4-(3-aminosulfonylphenyl)-5-(pyrimidin-3-yl) thiazole, is a potent and 
selective inhibitor of BRAF kinase activity with a mode of action consistent with 
adenosine triphospate (ATP)-competitive inhibition, and is currently in Phase 3 
development in BRAF V600E-mutation positive metastatic melanoma.  
Excluding Raf enzymes, dabrafenib demonstrated high selectivity with the half maximal 
inhibitory concentration (IC50) values <100nM against only 7 other kinases from ~300 
protein and lipid kinases tested.  Dabrafenib inhibits phosphorylation of MEK and ERK 
in vitro, inhibits cell proliferation, and achieved tumor regression in xenograft cancer 
models that encode BRAFV600E.  The investigator should refer to the GSK2118436 
Investigator’s Brochure [GlaxoSmithKline Document Number 2012N136095_00] for 
detailed information regarding ongoing clinical studies, pharmacokinetics in the target 
disease populations, as well as observed safety and efficacy findings.
Clinical data in subjects with metastatic BRAF-mutation positive melanoma have 
demonstrated clear benefit of dabrafenib over chemotherapy.  In a randomized Phase 3 
study, dabrafenib demonstrated significant benefit in PFS (hazard ratio=0.35) and 
confirmed response rate (50% vs. 6%) relative to chemotherapy [Hauschild, 2012].  In 
addition, although the OS data were still immature, there was a trend toward improved 
OS (HR=0.61, not statistically significant).


Novartis
Confidential
Page 21
Clinical Study Protocol Version 05
Protocol No. MEK116833
A complete safety summary for all ongoing studies is provided in the dabrafenib IB 
[GlaxoSmithKline Document Number 2012N136095_00].  Please also reference Section 
1.4.1 for additional information on the safety profile and the Summary of Risk Mitigation.
1.1.3.
Trametinib (GSK1120212)
Trametinib is a pyrido-pyrimidine derivative that is a potent and highly selective 
allosteric non-competitive inhibitor of MEK1/MEK2 activation and kinase activity 
[Gilmartin, 2011].  A Phase 3 study of trametinib in BRAF V600E-mutation positive 
metastatic melanoma (as monotherapy and in combination with dabrafenib) has been 
completed; trametinib is in Phase 2 development in pancreatic cancer and RAS-mutation 
positive acute myeloid leukemia (AML).
Trametinib has potent anti-proliferative activity against multiple cell lines, but has 
minimal effect on normal, non-proliferating cells.  Trametinib is a potent, reversible, 
highly selective, allosteric inhibitor of MEK1/MEK2 activation and kinase activity. The 
specificity of trametinib to MEK1 and MEK2 was confirmed against a large panel of 
kinases and no significant inhibitory activity was measured. The investigator should 
refer to the GSK1120212 IB and Supplement [GlaxoSmithKline Document Number 
HM2009/00151/03, GlaxoSmithKline Document Number 2013N164649_00] for detailed 
information regarding ongoing clinical studies, pharmacokinetics in the target disease 
populations, as well as observed safety and efficacy findings.
Clinical data in subjects with BRAF-mutation positive metastatic melanoma have 
demonstrated clear benefit of trametinib over chemotherapy.  In a randomized Phase 3 
study, trametinib demonstrated significant benefit in PFS (hazard ratio =0.45), confirmed 
response rate (22% vs. 8%), and OS (hazard ratio =0.54) relative to chemotherapy 
[Flaherty, 2012].
A complete safety summary for all ongoing studies is provided in the trametinib IB and 
Supplement [GlaxoSmithKline Document Number HM2009/00151/03, GlaxoSmithKline 
Document Number 2013N164649_00].  Please also reference Section 1.4.2 for additional 
information on the safety profile and the Summary of Risk Mitigation.
1.1.4.
Panitumumab, Vectibix
Panitumumab is a high-affinity (kd 5 x 10-11 M), human immunoglobulin G2 (IgG2) 
monoclonal antibody directed against human EGFR [Davis, 1999; Yang, 1999].  
Panitumumab blocks EGFR binding of epidermal growth factor (EGF), transforming 
growth factor-alpha (TGF), amphiregulin, betacellulin, epiregulin, and heparin-binding 
EGF.  Panitumumab [VECTIBIX, 2014] is currently licensed in the United States by the 
Food and Drug administration (FDA) for the treatment of patients with wild-type KRAS
mCRC as determined by an FDA-approved test for this use as first-line therapy in 
combination with FOLFOX and as monotherapy following disease progression after prior 
treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-containing regimens.  Use 
of panitumumab is not indicated for the treatment of patients with KRAS–mutant mCRC 
or for whom KRAS mutation status is unknown.  Further, panitumumab is approved in 
Canada and other regions for use in the treatment of chemotherapy-refractory mCRC that 
expresses EGFR and wild-type form of the KRAS gene.  In Japan, panitumumab is 


Novartis
Confidential
Page 22
Clinical Study Protocol Version 05
Protocol No. MEK116833
approved for treatment of patient with unresectable, advanced or recurrent CRC with 
wild-type KRAS.  However in the European Union and Australia, panitumumab is 
indicated for the treatment of adult patients with wild-type RAS mCRC in first- and 
second-lines as well as monotherapy.  Refer to the current regionally-approved labelling 
for further details.
Panitumumab is administered as an intravenous infusion.  The most common adverse 
events of panitumumab are skin rash, hypomagnesemia, paronychia, fatigue, abdominal 
pain, nausea and diarrhea.  Please also reference Section 1.4.3 for additional information 
on the safety profile and the Summary of Risk Mitigation.
1.2.
Preliminary Clinical Data for Dabrafenib (GSK2118436) and 
Trametinib (GSK1120212)
The safety, pharmacokinetic (PK) and pharmacodynamic (PD) profiles and activity of 
dabrafenib and trametinib administered either as monotherapy or in combination with 
other anti-cancer agents are currently being evaluated in multiple clinical trials involving 
subjects with a variety of cancers.  The investigator should refer to the GSK2118436 IB 
[GlaxoSmithKline Document Number 2012N136095_00], the GSK1120212 IB and 
Supplement [GlaxoSmithKline Document Number HM2009/00151/03, GlaxoSmithKline 
Document Number 2013N164649_00] and the GSK1120212 + GSK2118436 Clinical IB 
and Supplements [GlaxoSmithKline Document Number, 2011N126811_00, 
GlaxoSmithKline Document Number 2012N152310_00, GlaxoSmithKline Document 
Number 2012N152310_01] for detailed information regarding ongoing clinical studies, 
pharmacokinetics in the target disease populations, as well as observed safety and 
efficacy findings.
Dabrafenib and trametinib have been studied in combination, primarily in subjects with 
advanced BRAF-V600E or V600K mutation-positive melanoma and BRAF mutation 
V600E -positive CRC.  The combination, in which both agents are dosed at the current 
maximum monotherapy doses (150mg BID for dabrafenib and 2mg once daily for 
trametinib), has proven to be well tolerated.  
Emerging data from BRF113220, a Phase I/II study to establish the recommended dose 
for the combination of dabrafenib and trametinib, suggest that the safety profile of the 
combination is consistent with the profiles observed for single-agent therapies, except 
that a higher incidence of pyrexia and chills, and a lower incidence of squamous cell 
carcinoma and hyperkeratosis were observed for the combination compared to dabrafenib 
monotherapy. In addition, the incidence of skin-related toxicities appeared to be lower for 
the combination therapy as compared to trametinib monotherapy.  A complete safety 
summary for all ongoing studies with the combination of dabrafenib and trametinib is 
provided in the dabrafenib/trametinib combination IB and Supplements 
[GlaxoSmithKline Document Number 2011N126811_00, GlaxoSmithKline Document 
Number 2012N152310_00, GlaxoSmithKline Document Number 2012N152310_01].  
Please also reference Section 1.4 for additional information on the safety profile and the 
Summary of Risk Mitigation.


Novartis
Confidential
Page 23
Clinical Study Protocol Version 05
Protocol No. MEK116833
The clinical efficacy of this combination also appears to be superior to either agent when 
dosed as monotherapy.  A single arm Phase 2 study demonstrated a PFS of 10.8 months 
in subjects with metastatic BRAF-V600 mutation positive melanoma, which would be a 
significant improvement over results obtained with monotherapy inhibition of either 
BRAF or MEK [Weber, 2012].
1.3.
Rationale
1.3.1.
Study Rationale for Parts 1, 2, 3, 4
BRAF-mutation V600E positive CRC is more aggressive than KRAS-mutation positive-
or KRAS/BRAF- wild-type colorectal cancer, with a lower overall response rate (ORR), 
reduced progression-free (PFS) and overall survival (OS) [Di Nicolantonio, 2008; 
Laurent-Puig, 2009; Maughan, 2011; Souglakos, 2009; Bokemeyer, 2012; Tveit, 2012; 
Richman, 2009; Tran, 2011; Yokota, 2011; Tie, 2011].  Efforts to target BRAF-mutant 
CRC with BRAF inhibitors and MEK inhibitors as monotherapies have not been 
successful to date [Falchook, 2012; Kopetz, 2010].  Recently published nonclinical data 
suggest a role for receptor tyrosine kinase activation (particularly EGFR) in the resistance 
mechanism and have demonstrated synergistic activity of the combination of a BRAF 
inhibitor and an EGFR inhibitor in in vitro and in vivo models of BRAF-mutant CRC 
[Prahallad, 2012; Corcoran, 2012].  Therefore, the combination of potent inhibition of the 
BRAF pathway (with dabrafenib alone or dabrafenib/trametinib) with an anti-EGFR 
agent to prevent EGFR-mediated resistance is a rational and promising approach to treat 
BRAF-mutant CRC.
Thus, this study is designed to identify the recommended Phase 2 dose/regimen (RP2R)
for the dabrafenib/panitumumab doublet and the dabrafenib/trametinib/panitumumab 
triplet in Part 1 and for the trametinib/panitumumab doublet in Part 4A. In part 2 and 4B 
the study will identify an initial signal of clinical activity for these combinations. In Part 
3, a randomized comparison of the experimental arms to a chemotherapy comparator arm 
(a regimen of FOLFOX or FOLFIRI with or without panitumumab or bevacizumab) will 
be performed.  
Extrapolating from the experience in BRAF V600E/V600K -mutation positive melanoma, 
it is expected that the triple combination is likely to provide the greatest benefit to 
subjects, in which case the inclusion of the double combination serves as a control to 
assess the important “contribution of components” question.  However, another possible 
outcome is that the double combination is superior (e.g., due to poor tolerability of the 
triple combination), an outcome that this study design will also adequately evaluate. 
1.3.2.
Study Rationale for Part 4
Part 4 of the study is designed to identify the RP2R for trametinib dosed orally in 
combination with IV infusions of panitumumab in dose escalation and to identify an 
initial signal of clinical activity in two patient populations, subjects with BRAF-V600E 
mutation-positive CRC (described above) and subjects with CRC that developed 
secondary resistance to anti-EGFR therapy after initially deriving benefit.   


Novartis
Confidential
Page 24
Clinical Study Protocol Version 05
Protocol No. MEK116833
It is also important to understand whether dabrafenib is contributing to the clinical 
activity that has been seen with the triplet.  Therefore, patients with BRAF-mutant CRC 
will be included in the dose escalation of the trametinib/panitumumab doublet (Part 4A) 
and an expansion cohort (Part 4B) further evaluating safety and efficacy of the 
trametinib/panitumumab doublet.
Anti-EGFR therapies, either in combination with chemotherapy or as monotherapy, are 
approved therapy for KRAS wild-type (wt) colorectal cancer.  Although a significant 
proportion of patients with KRAS wt CRC derive benefit from anti-EGFR therapy, they 
inevitably become resistant to this therapy.  In a large proportion of cases, the mechanism 
of resistance to anti-EGFR therapy involves the reactivation of the RAS/MEK/ERK 
pathway, often through acquisition of mutations to RAS genes (KRAS or NRAS) 
converging on activation of the RAS/MEK/ERK pathway [Misale, 2012; Misale, 2014].  
This is similar to the example of BRAF mutant melanoma in which a frequent 
mechanism of resistance involves the reactivation of this pathway [Flaherty, 2012].
Vertical pathway inhibition can be an effective therapeutic strategy in tumors that are 
highly dependent on a single signaling pathway [Flaherty, 2012]. The addition of a MEK 
inhibitor, trametinib, to the BRAF inhibitor dabrafenib results in a significant 
improvement in both the depth and durability of responses in preclinical models of or in 
patients with BRAF mutant melanoma [TAFINLAR prescribing information January 
2014].  Using a similar rationale, the combination of an anti-EGFR agent and a MEK 
inhibitor demonstrated efficacy in preclinical models of CRC that had developed 
resistance to anti-EGFR therapy [Misale, 2014].
Based on above data, the combination of the anti-EGFR agent panitumumab with the 
MEK inhibitor trametinib is of great interest to study in patients who were eligible for 
and derived benefit from anti-EGFR therapy and have subsequently developed secondary 
resistance to anti-EGFR therapy. 
1.3.2.1.
Preliminary data from ongoing MEK116833 study
Preliminary clinical data from Parts 1 and 2A of this ongoing study suggest that the 
triplet combination of dabrafenib/trametinib/panitumumab is more efficacious than the 
dabrafenib/panitumumab doublet in the BRAF-mutant patient population (see Table 1).  


Novartis
Confidential
Page 25
Clinical Study Protocol Version 05
Protocol No. MEK116833
Table 1
Summary of investigator-assessed best confirmed response, Part 1 
and Part 2A
Best confirmed 
response, n (%)
Doublet 
Cohorta, 
n=20
Triplet Cohorts
Cohort 2b,
n=3
Cohort 3Ac
n=4
Cohort 3Bd
n=4
Cohort 4e
N=24
Not evaluable
0
0
0
0
1 (4%)
PD
2 (10%)
0
0
2 (50%)
3 (13%)
SD
16 (80%)
1 (33%)
2 (50%)
2 (50%)
16 (67%)
PR
1 (5%)
2 (67%)
1 (25%)
0
4 (17%)
CR
1 (5%)
0
1 (25%)
0
0
PR+CR, n (%)
(95% CI)
2 (10%)
(1.2%, 31.7%)
2 (66%) 
(9.4%, 99.2%)
2 (50%) 
(6.8%, 93.2%)
0 (0%) 
(0%, 60.2%)
4 (16.7%) 
(4.7%, 37.4%)
From 20 October 2014 data cut-off
a.
Doublet cohort combines patients enrolled in Part 1 Cohort 1 and Part 2 doublet expansion cohort; all dosed with 
Dabrafenib 150mg BID + Panitumumab 6mg/kg/Q2W
b.
Dabrafenib 150mg BID + Panitumumab 4.8mg/kg/Q2W + Trametinib 1.5mg QD
c.
Dabrafenib 150mg BID + Panitumumab 4.8mg/kg/Q2W + Trametinib 2mg QD
d.
Dabrafenib 150mg BID + Panitumumab 6mg/kg/Q2W + Trametinib 1.5mg QD
e.
Dabrafenib 150mg BID + Panitumumab 6mg/kg/Q2W + Trametinib 2mg QD
1.3.3.
Dose Rationale
Parts 1, 2 and 3 of this study will evaluate the safety, tolerability and efficacy of the 
doublet dabrafenib/panitumumab and triplet trametinib/dabrafenib/panitumumab 
combinations in subjects with BRAF- V600E mutation positive CRC.  Part 1 includes a 
3+3 dose escalation that will identify tolerable combination doses for the two 
combinations.  The safety and tolerability of these combination doses will be confirmed 
in expansion cohorts in Part 2, followed by a randomized evaluation of the efficacy and 
safety of the combinations in Part 3.
Part 4 of the study includes a 3+3 dose escalation that will identify tolerable combination 
doses for trametinib dosed orally in combination with IV infusions of panitumumab.  The 
safety and tolerability of the RP2R will be confirmed in the expansion cohorts.
1.3.3.1.
Potential for Drug-Drug Interactions
Dabrafenib is metabolized via CYP2C8- and CYP3A4-mediated oxidation and is a 
moderate inducer of CYP3A4 and potentially CYP2B6, and CYP2C enzymes. 
Trametinib is metabolized by non-CYP-mediated deacetylation.  Panitumumab, a 
recombinant human immunoglobulin, is cleared through non-CYP pathways.  
Administration of dabrafenib plus trametinib in the ongoing study BRF113220 indicates 
that dabrafenib does not have a clinically relevant effect on trametinib pharmacokinetics 
(see the GSK1120212 + GSK2118436 Clinical IB and Supplements [GlaxoSmithKline 
Document Number, 2011N126811_00, GlaxoSmithKline Document Number 
2012N152310_00, GlaxoSmithKline Document Number 2012N152310_01] for 
additional information).  Cross-study comparisons indicates that exposure to dabrafenib 
may be greater after repeat dose administration of dabrafenib in combination with 
trametinib relative to administration of dabrafenib alone, at 150mg BID.  The 
combination was relatively well tolerated.  Therefore, no clinically relevant 


Novartis
Confidential
Page 26
Clinical Study Protocol Version 05
Protocol No. MEK116833
pharmacokinetic drug-drug interactions between dabrafenib, trametinib, and 
panitumumab are expected.
1.3.3.2.
Potential for Overlapping Toxicities
Fatigue, diarrhea, and nausea are common adverse reactions observed after 
administration of dabrafenib, trametinib, or panitumumab.  In addition, dermatologic 
toxicities are common after administration of trametinib or panitumumab. Severe 
(National Cancer Institute Common Terminology Criteria for Adverse Events NCI-
CTCAE Grade 3 or higher) dermatologic toxicities have been reported in 16% of all 
subjects (and ~25% of subjects with KRAS wild-type CRC) with metastatic carcinoma of 
the colon or rectum after administration of panitumumab alone.  In addition, there is an 
apparent small risk for pneumonitis/interstitial lung disease (ILD) with both trametinib 
and panitumumab, respectively.
1.3.3.3.
Part 1
The maximum tolerated dose (MTD)/Recommended Phase 2 Regimen (RP2R) of 
dabrafenib plus panitumumab was defined first in Part 1.  The starting dose of dabrafenib 
was the recommended monotherapy dose of 150mg twice daily (BID).  Panitumumab 
was administered at the recommended dose of 6mg/kg, administered as an intravenous 
infusion over 60 minutes, every 14 days.  Additional details regarding dose escalation are 
provided in Section 3.7.2.  These doses are clinically active with manageable toxicity 
with prolonged dosing and the potential for overlapping toxicities appears relatively low.  
However, if unexpected toxicities were to have been observed in Cohort 1, subjects 
would have been enrolled in Cohort -1, in which the dose of one or both agents 
(depending on the toxicities observed) would be reduced. 
Upon definition of a tolerable dose of dabrafenib plus panitumumab, trametinib was
added to the combination in Cohort 2 (see Section 3.1).  Dabrafenib was administered in 
the triple combination at the dose that was tolerated in combination with panitumumab in 
Cohort 1.  Due to overlapping dermatologic toxicities, the starting doses of panitumumab 
and trametinib were reduced.  The starting dose of trametinib was 1.5mg once daily, 
which is below the current recommended monotherapy dose of 2mg once daily, but is a 
dose that has demonstrated both pharmacodynamic and clinical activity in subjects with 
melanoma.  The starting dose for panitumumab was one dose level below the dose that 
was tolerated in combination with dabrafenib in Cohort 1, administered as an intravenous 
infusion over 60 minutes, every 14 days.  It should be noted that a recent clinical study of 
the combination of the MEK inhibitor selumetinib and the chimeric anti-EGFR agent 
cetuximab was able to achieve the full monotherapy dose for both agents in combination, 
although there was an increased rate of skin toxicity and an episode of Grade 4 
hypomagnesemia [Deming, 2012].  Also of note, panitumumab has demonstrated 
pharmacodynamic and clinical activity at doses as low as 1 to 2.5 mg/kg weekly 
[Rowinsky, 2004; Weiner, 2008].  
Dose escalation is permitted, details are provided in Section 3.7.2, and dose adjustment/ 
stopping criteria are described in Section 3.10.  Doses in combination will not exceed the 
monotherapy top dose for any single agent.


Novartis
Confidential
Page 27
Clinical Study Protocol Version 05
Protocol No. MEK116833
1.3.3.4.
Part 2
For each combination (dabrafenib/panitumumab and 
dabrafenib/trametinib/panitumumab), the optimal safe and tolerable dose combinations 
defined in Part 1 were brought forward into Part 2A.  This was the maximal dose from 
Part 1 for each combination, although a lower dose combination could have been selected 
if significant delayed or prolonged toxicities required frequent dose modifications.  In 
Part 2A, expansion cohorts of 20 and 35 subjects with BRAF-V600E mutation positive 
CRC (including the subjects enrolled at this dose in Part 1) were enrolled to confirm 
safety and tolerability, and to generate signals of activity of the doublet and triplet 
regimens, respectively (See Table 1 for clinical data from Parts 1 and 2A).  
Preliminary data from Part 2A suggested that compliance of dabrafenib, trametinib and 
panitumumab was similar between dose cohorts in Weeks 1 to Week4.  However, during 
Weeks 5 to 8, the compliance of dabrafenib, trametinib and panitumumab decreased to 
70-80% of the expected dose amounts in Cohort 3B and Cohort 4 compared to Cohort 2 
and Cohort 3A. Adverse events leading to dose modifications were greater in the Cohort 
3B and Cohort 4 compared to Cohort 2 and Cohort 3A as shown in Table 2.


Novartis
Confidential
Page 28
Clinical Study Protocol Version 05
Protocol No. MEK116833
Table 2
AEs Leading to Dose Modification (Triplet Cohorts)
Preferred Term
Cohort 2
N=3
Cohort 3A
N=4
Cohort 3B
N=4
Cohort 4
N=24
Total Triplet
N=35
AEs Leading to Investigational Product Discontinuation of any Study Treatment 
Any event 
0
1 (25%)
0
0
1 (3%)
Subdural haematoma 
0
1 (25%)
0
0
1 (3%)
AEs Leading to Dose Reduction of any Study Treatment 
Any event 
2 (67%)
1 (25%)
2 (50%)
9 (38%)
14 (40%)
Dermatitis acneiform 
0
1 (25%)
2 (50%)
2 (8%)
5 (14%)
Rash 
0
1 (25%)
0
1 (4%)
2 (6%)
AEs Leading to Dose Interruption/Delay of any Study Treatment 
Any event 
2 (67%)
3 (75%)
4 (100%)
20 (83%)
29 (83%)
Dermatitis acneiform 
0
1 (25%)
2 (50%)
2 (8%)
5 (14%)
Vomiting 
1 (33%)
0
3 (75%)
1 (4%)
5 (14%)
Dehydration 
0
1 (25%)
1 (25%)
2 (8%)
4 (11%)
Dry skin 
0
0
1 (25%)
3 (13%)
4 (11%)
Fatigue 
0
0
0
4 (17%)
4 (11%)
Nausea 
0
0
3 (75%)
1 (4%)
4 (11%)
ALT increased 
0
0
0
3 (13%)
3 (9%)
AST increased 
0
0
0
3 (13%)
3 (9%)
Diarrhoea 
0
0
2 (50%)
1 (4%)
3 (9%)
Rash 
0
1 (25%)
0
2 (8%)
3 (9%)
Based on data from 20 Oct 2014 cut-off
The dose of panitumumab in Cohort 3B and Cohort 4 was 6mg/kg every two weeks. In 
Part 2B, an additional 60 subjects will be enrolled into 1 of 2 dose cohorts. Subjects will 
be enrolled at the Cohort 3A dose (Dabrafenib 150mg BID + Panitumumab 
4.8mg/kg/Q2W + Trametinib 2mg QD) and Cohort 4 dose (Dabrafenib 150mg BID 
+Panitumumab 6mg/kg Q2W + Trametinib 2mg QD) to further explore safety, 
tolerability and clinical activity at the two dose levels. In addition, subjects will be 
enrolled by lines of therapy in order to provide a more homogeneous patient population. 
1.3.3.5.
Part 3
In Part 3, the randomized Phase 2 portion of the study, subjects with second line BRAF-
mutation V600E positive CRC (previously failed or were intolerant to first line 
fluoropyrimidine-containing chemotherapy) will be randomized to 1 of 3 cohorts:  
1) dabrafenib plus panitumumab, 
2) dabrafenib plus trametinib plus panitumumab, or 


Novartis
Confidential
Page 29
Clinical Study Protocol Version 05
Protocol No. MEK116833
3) chemotherapy comparator (a regimen of FOLFOX or FOLFIRI with or without 
panitumumab or bevacizumab).    
Dose levels for dabrafenib, trametinib, and panitumumab in Part 3 will be chosen based 
on emerging PK, PD, and tolerability data from Part 1 and Part 2.  The chemotherapy 
comparator will consist of a standard chemotherapy regimen with or without the addition 
of a biological agent, based on local practice preferences.  The available chemotherapy 
regimens include either a fluoropyrimidine-containing regimen including either 
irinotecan or oxaliplatin OR irinotecan alone.  In addition to the chemotherapy regimen, a 
biological agent, limited to panitumumab or bevacizumab, may be included.   Selection 
of the chemotherapy comparator may be revised based on emerging data from Part 1 and 
Part 2.  Available data from Parts 1 and 2 of this study will be provided to ethics review 
boards, along with any necessary changes to the protocol, prior to starting Part 3.  The 
addition of additional arms to assess the contribution of the trametinib, dabrafenib or 
panitumumab monotherapies or trametinib/dabrafenib combination was considered but 
available clinical data are considered sufficient to demonstrate the limited activity of 
these therapeutic options in this clinical setting.  In the event that the benefit/risk ratio for 
either of the two experimental combinations is not sufficiently positive (either due to 
excessive toxicity or clearly inferior efficacy), one of the arms may be excluded from 
Part 3 of the study.
1.3.3.6.
Part 4
Data from Parts 1 and 2A of this ongoing study have demonstrated that both the 
dabrafenib/panitumumab doublet and the dabrafenib/trametinib/panitumumab triplet are 
tolerated by patients (see Table 3). The triplet combination studies in Cohorts 3A and 3B, 
in which dabrafenib is dosed at the full marketed dose (150mg po BID) and either 
trametinib or panitumumab is also dosed at the full marketed dose (2mg po QD or 6 
mg/kg IV Q2W, respectively), with the other agent dosed at one dose level lower (1.5mg 
po QD or 4.8mg/kg IV Q2W, respectively) have been well tolerated to date, with no 
DLTs being identified.  The highest triplet combination (all three agents at full dose) also 
has been evaluated in Cohort 4 of the dose escalation with no DLTs and an additional 20 
patients has been enrolled in the expansion cohort at the full dose of all three agents.  
Based on the tolerability of the triplet at full dose in Part 1, the starting dose 
trametinib/panitumumab combinations that is being studied in the initial dose escalation 
cohort of Part 4 will be  full dose of both agents. If these doses are not well tolerated, 
there will be an option to dose reduce (see Section 3.5). The optimal safe and tolerable 
dose combinations defined in dose escalation will be brought forward into expansion 
cohorts.  This will likely be the maximal dose for each combination in dose escalation, 
although a lower dose combination may be selected if significant delayed or prolonged 
toxicities require frequent dose modifications.  Expansion cohorts of approximately 20 
subjects with BRAF V600E mCRC or advanced CRC/mCRC who progressed on 
previous anti-EGFR will be enrolled to confirm safety and tolerability, and to generate 
signals of activity.  


Novartis
Confidential
Page 30
Clinical Study Protocol Version 05
Protocol No. MEK116833
Table 3
DLTs, Related AEs ≥Gr 3, and Related SAEs in Part 1 and Part 2 
(preliminary data)
Doublet 
Cohorta, 
n=20
Triplet Cohorts
Cohort 2b,
n=3
Cohort 3Ac
n=4
Cohort 3Bd
n=4
Cohort 4e
N=24
DLTs
None
None
None
None
None
Related SAEs
6
1
None
1
6
Related AEs 
≥Grade 3
3
2
2
2
11
From 20 October 2014 data cut-off
a. Doublet cohort combines patients enrolled in Part 1 Cohort 1 and Part 2 doublet expansion cohort; all dosed with 
dabrafenib 150mg BID + panitumumab 6mg/kg/Q2W.
b. Part 1 Cohort 2 dose dabrafenib 150mg BID + panitumumab 4.8mg/kg/Q2W + trametinib 1.5mg QD 
c. Part 1 Cohort 3A dose dabrafenib 150mg BID + panitumumab 4.8mg/kg/Q2W + trametinib 2mg QD
d. Part 1 Cohort 3B dose dabrafenib 150mg BID + panitumumab 6mg/kg/Q2W + trametinib 1.5mg QD
e. Dabrafenib 150mg BID + Panitumumab 6mg/kg/Q2W + Trametinib 2mg QD
1.4.
Summary of Risk Management
Risk of administration of dabrafenib and trametinib has been assessed in clinical trials 
and in nonclinical toxicology studies.  Based on the available risk assessments, 
enrollment criteria (Section 4.2) and dose adjustment guidelines (Section 3.10.2) will be 
followed to minimize risk of known toxicities.  Procedures to minimize or monitor 
potential risks are listed below.
1.4.1.
GSK2118436: Dabrafenib
The assessment of the risk of dabrafenib is based on clinical data from the concluded and 
ongoing dabrafenib studies, as well as preclinical toxicity data from 28-day studies.  As a 
single agent, dabrafenib has been well tolerated across a range of doses.  At the 
recommended dose of 150mg BID, the most common adverse events have been fatigue, 
pyrexia, headache, nausea, hyperkeratosis, skin papilloma, diarrhea, arthralgia, pain in 
extremity, decreased appetite, alopecia, rash and palmar-plantar erythrodysaethesia (PPE) 
syndrome.  The most frequent serious AEs (SAEs) include squamous cell carcinoma 
(SCC) and pyrexia.The potential adverse events (AEs) will be managed as follows in this 
study:
Gastrointestinal (GI) effects:  Interim medical history, continuous assessment of AEs, 
physical examination, and clinical laboratory assessments will be used to identify and 
assess toxicity in the GI tract.  Supportive therapy will be provided according to standard 
medical practice; guidelines for management of diarrhea are provided in Section 3.10.5.  
Participation will be discontinued for intolerable toxicity.
Skin effects:  Primary skin findings in dabrafenib-treated subjects include benign 
keratotic lesions, skin papillomas, hand foot skin reactions (HFSR), skin rashes and 
squamous cell carcinoma (SCC) including keratoacanthomas.  Interim medical history, 
continuous assessment of AEs, and dermatological examination will be used to identify 
and assess skin effects.  Guidelines for management of skin effects are provided in 
Section 3.10.4.2.


Novartis
Confidential
Page 31
Clinical Study Protocol Version 05
Protocol No. MEK116833
Renal effects:  Acute renal failure has been reported in subjects receiving dabrafenib, and 
granulomatous interstitial nephritis has been reported in a clinical trial.  In some cases 
complicated pyrexia may be associated with renal insufficiency/renal failure, possibly 
secondary to dehydration or hypotension.  Guidelines for management of renal 
insufficiency are provided in Section 3.10.6.
Pyrexia:  In clinical trials pyrexia, which may be associated with hypotension, rigors, 
dehydration, weakness, and/or renal failure, has been identified in subjects.  Although 
this AE is considered to be related to dabrafenib, the frequency and severity of pyrexia is 
greater in patients receiving the combination of dabrafenib and trametinib, as compared 
to patients receiving dabrafenib alone.  Subjects should be evaluated for signs and 
symptoms of infection.  Guidelines for management of pyrexia are provided in 
Section 3.10.4.1.
Pancreatitis: There have been reports of pancreatitis and/or increased lipase/amylase with 
dabrafenib, typically occurring within 14 days of starting therapy. For adverse events of 
abdominal pain or suspected pancreatitis, amylase and lipase laboratory samples should 
be monitored locally.
Ophthalmology effects: Eye effects including blurred vision (2%), uveitis/iritis (<1%), 
eye pain (<1%), visual impairment (<1%) and reduced visual acuity (<1%) have been 
observed in clinical studies to date, with all events Grade 1 or 2.  An ophthalmologic 
consult is required for subjects developing symptoms associated with uveitis including 
blurry vision, eye pain or erythema.
Hypersensitivity: There has been a report of hypersensitivity (blisters), occurring on the 
same day as the first dose of study drug as well as upon rechallenge. Grade 1 AEs of 
blisters on limbs (4 subjects) and drug hypersensitivity (rash, 1 subject) have been 
reported in previous studies with dabrafenib. However, the precise etiology of these 
events is unclear.
1.4.2.
GSK1120212: Trametinib
As a single agent, trametinib has been well tolerated across a range of doses.  At the 
recommended dose of 2mg once daily, the most common AEs were rash, diarrhea, 
fatigue, edema peripheral, nausea, dermatitis acneiform, vomiting, constipation, anemia, 
pruritus, alopecia, hypertension, decreased appetite, dyspnea and dry skin. AEs of Special 
interest for trametinib include left ventricular dysfunction, ocular toxicities (e.g., retinal 
pigment epithelium detachment (RPED) and retinal vein occlusion (RVO), diarrhea, rash 
and transaminitis.
The potential AEs (based on pre-clinical and clinical studies and data from other 
compounds in the same class) include:
Ocular toxicity:  Ocular toxicities in a fraction of subjects (including central serous 
retinopathy and retinal vein occlusion) are known class effects of MEK inhibitors and 
have been seen with trametinib.  To reduce the risk of ocular toxicity, subjects diagnosed 
with glaucoma within 1 month prior to study Day 1 or with history of retinal vein 
occlusion (RVO), RPED, predisposing factors for RVO or RPED or predisposing retinal 


Novartis
Confidential
Page 32
Clinical Study Protocol Version 05
Protocol No. MEK116833
pathology as determined by ophthalmologic exams are excluded.  Visual disturbance has 
been monitorable and reversible in the ongoing study of the dabrafenib/trametinib 
combination (GSK study BRF113220).  Ophthalmologic exams will be performed at 
baseline and as clinically warranted, by an ophthalmologist.
Cardiac function: A reduction in cardiac function in a fraction of subjects (specifically, 
left ventricular ejection fraction) is a known class effect of MEK inhibitors and have been 
seen with trametinib.  Subjects with pre-existing heart failure will be excluded from this 
study.  Cardiac function will be assessed prior to enrollment, and will be monitored on 
study. In addition, withholding criteria for left ventricular ejection fraction decreases will 
be implemented.
Gastrointestinal toxicity: To reduce the risk of excessive gastrointestinal (GI) toxicity 
(primarily diarrhea), subjects will be monitored closely and supportive care guidelines 
implemented. In addition, due to the potential for overlapping toxicity with panitumumab, 
the starting dose for each of these agents will be below its recommended monotherapy 
dose.  It should be noted that, while trametinib and dabrafenib can both cause GI toxicity, 
the combination of the two agents did not result in an increase in toxicities relative the 
rate or severity defined for each agent when administered as monotherapy.
Cutaneous toxicity Skin rash is expected to be a common event in this study.  To reduce 
the risk of excessive cutaneous toxicity, subjects will be monitored closely and 
supportive care guidelines implemented. In addition, due to the potential for overlapping 
toxicity with panitumumab, the starting dose for trametinib and panitumumab when they 
are combined will be below the recommended monotherapy dose for each agent.  It 
should be noted that, while trametinib and dabrafenib can both cause rash, the 
combination of the two agents did not result in an increase in toxicities relative the rate or 
severity defined for each agent when administered as monotherapy.
Pneumonitis/Interstitial lung disease:  Pneumonitis has been observed in subjects 
receiving trametinib. To reduce the risk of pneumonitis, subjects will be monitored 
closely for symptoms, evaluated with imaging and functional tests.  Subjects with a 
history of interstitial lung disease or pneumonitis are excluded per criteria in Section 
4.2.1.2 and Section 4.2.2.2.  Dose modification and supportive care guidelines for 
pneumonitis are provided in Section 3.10.13.  
1.4.3.
Panitumumab
Please refer to the FDA approved label and/or EU SmPC for panitumumab for updated 
detailed information.  The following text is summarized from the approved FDA label 
[VECTIBIX (panitumumab) Injection for Intravenous Use, Revised March 2014].
The most common adverse events of panitumumab are skin rash with variable 
presentations (frequently acneiform), hypomagnesemia, paronychia, fatigue, abdominal 
pain, nausea, and diarrhea, including diarrhea resulting in dehydration.  The most serious 
adverse events of panitumumab are pulmonary fibrosis, pulmonary embolism, severe 
dermatologic toxicity complicated by infectious sequelae and septic death, infusion 
reactions, abdominal pain, hypomagnesemia, nausea, vomiting, and constipation.  


Novartis
Confidential
Page 33
Clinical Study Protocol Version 05
Protocol No. MEK116833
Adverse reactions requiring discontinuation of panitumumab were infusion reactions, 
severe skin toxicity, paronychia, and pulmonary fibrosis.
Cutaneous toxicity:  Cutaneous toxicities were reported in approximately 90% of subjects 
receiving the 6mg/kg every (Q) 2 weeks, and were severe (Grade 3 or higher) in 12 to 
16% of subjects receiving panitumumab as monotherapy.  The incidence of paronychia 
was 25% and was severe in 2% of subjects.  Nail disorders occurred in 9% of subjects.  
The median time to the development of dermatologic, nail, or ocular toxicity was 14 days 
after the first dose of panitumumab; the median time to most severe skin/ocular toxicity 
was 15 days after the first dose of panitumumab; and the median time to resolution after 
the last dose of panitumumab was 84 days. To reduce the risk of excessive cutaneous 
toxicity, subjects will be monitored closely and supportive care guidelines implemented.
Infusion reactions:  Severe infusion reactions occurred in approximately 1% of subjects.  
Infusional toxicity was defined as any event within 24 hours of an infusion during the 
clinical study described as allergic reaction or anaphylactoid reaction, or any event 
occurring on the first day of dosing described as allergic reaction, anaphylactoid reaction, 
fever, chills, or dyspnea.  Vital signs and temperature were measured within 30 minutes 
prior to initiation and upon completion of the panitumumab infusion.  The use of 
premedication was not standardized in the clinical trials.  Thus, the utility of 
premedication in preventing the first or subsequent episodes of infusional toxicity is 
unknown.  Across several clinical trials of panitumumab monotherapy, 3% experienced 
infusion reactions of which approximately 1% were severe (Grade 3 or Grade 4).
Ocular toxicities:  Ocular toxicities occurred in 15% of subjects and included, but were 
not limited to, conjunctivitis, ocular hyperemia, increased lacrimation, and eye/eyelid 
irritation. Stomatitis and oral mucositis were reported. One patient experienced a Grade 3 
event of mucosal inflammation.  Ophthalmologic exams will be performed at baseline 
and as clinically warranted, by an ophthalmologist.
Pulmonary fibrosis:  Pulmonary fibrosis occurred in less than 1% (2/1467) of subjects 
enrolled in clinical studies of panitumumab.  Following an initial fatality in a patient with 
underlying idiopathic pulmonary fibrosis, subjects with a history of interstitial 
pneumonitis, pulmonary fibrosis, evidence of interstitial pneumonitis, or pulmonary 
fibrosis were excluded from clinical studies.  Therefore, the estimated risk in a general 
population that may include such subjects is uncertain. Subjects with pre-existing 
pneumonitis, interstitial lung disease or pulmonary fibrosis will be excluded from this 
study (Section 4.2.1.2 and Section 4.2.2.2).  Subjects developing interstitial lung disease, 
pneumonitis, or lung infiltrates should permanently discontinue panitumumab therapy.
Electrolyte depletion:  Clinically significant hypomagnesemia and hypocalcemia have 
occurred in patients receiving panitumumab and may be worsened with the addition of 
trametinib.  Subjects’ electrolytes will be periodically monitored during and after the 
completion of panitumumab therapy.   Appropriate therapy (e.g., oral or intravenous 
electrolyte repletion) will be administered to correct abnormalities in electrolytes that 
occur prior to or while on panitumumab.


Novartis
Confidential
Page 34
Clinical Study Protocol Version 05
Protocol No. MEK116833
2.
OBJECTIVES AND ENDPOINTS
2.1.
Part 1: Phase 1 Dose Escalation
Objectives
Endpoints
Primary 
To determine the safety, tolerability 
and range of tolerated combination 
doses in subjects with BRAF-V600E 
mutation-positive CRC in two dosing 
groups:

dabrafenib dosed orally in 
combination with 
panitumumab

trametinib dosed orally in 
combination with dabrafenib 
and panitumumab
Adverse events and changes in 
laboratory values, vital signs and 
dose interruptions, modifications and 
discontinuations
Secondary
To describe the pharmacokinetics of 
dabrafenib, trametinib and 
panitumumab after combination 
therapy
To determine preliminary clinical 
activity of dabrafenib dosed orally in 
combination with panitumumab 
To determine clinical activity of 
trametinib dosed orally in 
combination with dabrafenib and 
panitumumab
To evaluate the pharmacodynamic 
response in colorectal tumors 
following combination treatment
Maximum observed concentration 
(Cmax), time of occurrence of Cmax 
(tmax), and area under the 
concentration-time curve from zero 
(pre-dose) 8 hours (AUC(0-8)), pre-
dose (trough) concentration at the 
end of the dosing interval (C) of 
trametinib and dabrafenib.  Predose 
(C) and Cmax concentrations of 
panitumumab.
Response rate (complete response 
[CR] + partial response [PR]) 
Progression free survival
Duration of response
Response rate (CR +PR)
Progression free survival
Duration of response
Change in levels of proteins/RNA 
implicated in MAPK/PI3K/EGFR 
pathways in pre- and post-dose 
tumor tissue. 


Novartis
Confidential
Page 35
Clinical Study Protocol Version 05
Protocol No. MEK116833
Objectives
Endpoints
2.2.
Part 2: Cohort Expansions
Objectives
Endpoints
Primary 
To confirm the safety and tolerability 
of combination doses in subjects with 
BRAF-V600E mutation-positive CRC 
in two dosing groups:

dabrafenib dosed orally in 
combination with 
panitumumab

trametinib dosed orally in 
combination with dabrafenib 
and panitumumab
To determine clinical activity in 
subjects with BRAF-V600E mutation-
positive CRC in two dosing groups:

dabrafenib dosed orally in 
combination with 
panitumumab

trametinib dosed orally in 
combination with dabrafenib 
and panitumumab
Adverse events and changes in 
laboratory values, vital signs and 
dose interruptions, modifications and 
discontinuations
Response rate (CR +PR)
Secondary
To characterize the population PK 
parameters of dabrafenib and 
trametinib dosed orally in 
combination with anti-EGFR antibody 
(panitumumab) 
To characterize the durability of 
response with dabrafenib dosed 
orally in combination with 
panitumumab 
Population PK parameters,  oral 
clearance (CL/F),  oral volume of 
distribution (V/F), and absorption rate 
constant (Ka) 
Duration of response
Progression-free survival 
Overall survival


Novartis
Confidential
Page 36
Clinical Study Protocol Version 05
Protocol No. MEK116833
Objectives
Endpoints
To characterize the durability of 
response with trametinib dosed orally 
in combination with dabrafenib and 
panitumumab 
To evaluate the pharmacodynamic 
response in colorectal tumors 
following combination treatment
Duration of response
Progression-free survival
Overall Survival
Change in levels of proteins/RNA 
implicated in MAPK/PI3K/EGFR 
pathways in pre- and post-dose 
tumor tissue
2.3.
Part 3: Randomized Phase 2
Objectives
Endpoints
Primary
To evaluate and compare the clinical activity 
of the dabrafenib/panitumumab and 
trametinib/dabrafenib/panitumumab 
combinations as compared to standard of 
care therapy in subjects with KRAS wild-type 
(WT)/BRAF-V600E mutation-positive CRC
PFS
Secondary
To characterize the durability of response to 
dabrafenib/ panitumumab and trametinib/ 
dabrafenib/panitumumab combinations as 
compared to standard of care therapy
To evaluate and compare the clinical activity 
of the trametinib/dabrafenib/panitumumab 
combination as compared to the 
dabrafenib/panitumumab combination with 
Response rate (CR +PR)
Duration of response
OS
PFS


Novartis
Confidential
Page 37
Clinical Study Protocol Version 05
Protocol No. MEK116833
Objectives
Endpoints
respect to PFS
To confirm the safety and tolerability of 
dabrafenib and trametinib dosed orally in 
combination with panitumumab
To confirm the safety and tolerability of 
dabrafenib dosed orally in combination with 
panitumumab
Adverse events and changes 
in laboratory values, vital 
signs and dose modifications 
and discontinuations
2.4.
Part 4A: Dose Escalation
Objectives
Endpoints
Primary 
To determine the safety, tolerability 
and range of tolerated combination 
doses in of the combination of 
panitumumab and trametinib in 
subjects with advanced/metastatic 
CRC 
Adverse events and changes in 
laboratory values, vital signs and 
dose interruptions, modifications and 
discontinuations


Novartis
Confidential
Page 38
Clinical Study Protocol Version 05
Protocol No. MEK116833
Objectives
Endpoints
Secondary
To describe the pharmacokinetics of 
trametinib and panitumumab after 
combination therapy
To determine preliminary clinical 
activity of panitumumab/trametinib 
combination therapy in two patient 
populations:

subjects with BRAF-V600E 
mutation-positive CRC

subjects with CRC that 
developed secondary 
resistance to anti-EGFR 
therapy after initially deriving 
benefit
To evaluate the pharmacodynamic 
response in colorectal tumors 
following combination therapy
Maximum observed concentration 
(Cmax), time of occurrence of Cmax 
(tmax), and area under the 
concentration-time curve from zero 
(pre-dose) the time of the last 
quantifiable concentration (AUC(0-t)), 
pre-dose (trough) concentration at 
the end of the dosing interval (C) of 
trametinib.  Predose (C) and Cmax 
concentrations of panitumumab.
Response rate (complete response 
[CR] + partial response [PR]) 
Progression free survival
Duration of response
Change in levels of proteins/RNA 
implicated in MAPK/PI3K/EGFR 
pathways in pre- and post-dose 
tumor tissue. 


Novartis
Confidential
Page 39
Clinical Study Protocol Version 05
Protocol No. MEK116833
2.5.
Part 4B: Cohort Expansion
Objectives
Endpoints
Primary 
To confirm the safety and tolerability 
of  RP2R of the 
panitumumab/trametinib combination 
in an expansion cohorts of

subjects with BRAF-V600E 
mutation-positive CRC

subjects with CRC that 
developed secondary 
resistance to anti-EGFR 
therapy after initially deriving 
benefit
To determine clinical activity of 
combination therapy in this patient 
population
Adverse events and changes in 
laboratory values, vital signs and 
dose interruptions, modifications and 
discontinuations
Response rate (CR +PR)
Secondary
To characterize the population PK 
parameters of trametinib dosed orally 
in combination with anti-EGFR 
antibody (panitumumab) 
To characterize the durability of 
response with trametinib dosed in 
combination with panitumumab 
To evaluate the pharmacodynamic 
response in colorectal tumors 
following combination treatment
Population PK parameters,  oral 
clearance (CL/F),  oral volume of 
distribution (V/F), and absorption rate 
constant (Ka) 
Duration of response
Progression-free survival 
Overall survival
Change in levels of proteins/RNA 
implicated in MAPK/PI3K/EGFR 
pathways in pre- and post-dose 
tumor tissue


Novartis
Confidential
Page 40
Clinical Study Protocol Version 05
Protocol No. MEK116833
3.
INVESTIGATIONAL PLAN
3.1.
Part 1 Dose Escalation Study Design/Schematic
3.2.
Part 2A: Cohort Expansions Study Design/Schematic


Novartis
Confidential
Page 41
Clinical Study Protocol Version 05
Protocol No. MEK116833
3.3.
Part 2B:  Cohort Expansion
  
BID, twice daily dosing; D, dabrafenib; L, line of therapy; P, panitumumab; T, 
trametinib; Q2W, dosing every 2 weeks; QD, once daily dosing.
3.4.
Part 3: Randomized Phase 2 Study Design//Schematic
The chemotherapy comparator will consist of a standard fluoropyrimidine-containing 
regimen including either irinotecan or oxaliplatin. Selection of the chemotherapy 
comparator arm may be revised based on emerging data from Part 1, Part 2 and Part 4
through a protocol amendment.


Novartis
Confidential
Page 42
Clinical Study Protocol Version 05
Protocol No. MEK116833
3.5.
Part 4A Dose Escalation
a. If the initial combination dose of trametinib and panitumumab in Cohort 1 (starting dose) is not tolerable, the lower 
dose combination defined in de-escalation cohorts (Cohort -1A, -1B and/or -1C) may be evaluated.
3.6.
Part 4B Cohort Expansion
Protocol waivers or exemptions are not allowed. Therefore, adherence to the study design 
requirements, including those specified in the Time and Events Table, is essential.
Supplementary study conduct information not mandated to be present in this protocol is 
provided in the accompanying Study Procedures Manual (SPM).  The SPM will provide 
the site personnel with administrative and detailed technical information that does not 
impact subject safety.
3.7.
Discussion of Design
This four-part Phase 1/2 multi-center study allows for the phased evaluation of safety, 
tolerability, and activity of dabrafenib and/or trametinib in combination with 
panitumumab in subjects with BRAF-V600E mutation-positive CRC and in subjects with 
CRC with secondary resistance to prior anti-EGFR therapy.  The planned number of 
subjects per part is described in Section 4.1.  Dose adjustment and stopping criteria are 
described in Section 3.10.  All study treatments, including investigational products, will 
be referred to as “study treatment(s)” for ease of presentation throughout the protocol, 
except for Section 3.9.


Novartis
Confidential
Page 43
Clinical Study Protocol Version 05
Protocol No. MEK116833
For all parts of the study, assessments throughout are calendar-based starting from 
the first day of dosing (Day 1) in the first treatment period.  Dose interruptions 
should not alter the assessment schedule for any subsequent treatment period.
3.7.1.
Prescreening for KRAS and BRAF Mutation Status
Note: Procedures conducted as part of the subject’s routine clinical management (e.g., 
blood counts, imaging study) and obtained prior to signing of informed consent may be 
utilized for screening or baseline purposes provided these procedures meet the protocol 
requirements.
The conduct of the KRAS- and BRAF-mutation screening prior to the baseline 
assessments is the responsibility of the investigator and must be performed in a CLIA-
approved facility.  Local testing for KRAS and BRAF mutations for enrollment in the 
trial can occur any time prior to dosing.  If KRAS and BRAF mutation status is unknown 
at screening, no biopsy for assessment of mutation status in association with this protocol 
should be taken prior to obtaining consent. Following consent, subjects should be 
screened for KRAS and BRAF mutation status (if not already performed) prior to any 
other study-related screening procedures. For Part 1 and Part 2, a local test result for 
KRAS status is adequate for enrollment.  Enrollment in Part 3 may only occur following 
confirmation of KRAS wild-type cancer, as determined by FDA-approved KRAS test for 
CRC (e.g., Qiagen test) and documented in source.  For patients in Part 4, who have 
acquired secondary resistance to anti-EGFR therapy, repeat testing for RAS mutations is 
not required.
For subjects with known BRAFV600E mutations, confirmation of mutation must occur 
following registration in Parts 1, 2 and 4.  Subjects will not be excluded if centralized 
testing is later found to be discordant or uninformative (e.g., inadequate sample), but 
additional subjects may be enrolled as replacement subjects at the discretion of the 
Sponsor and in consultation with the investigator.  
Enrollment in Part 3 will only occur following centralized determination of BRAFV600E 
mutation.  Testing must be performed in a CLIA certified central laboratory.  The testing 
will be preferably conducted on metastatic tumor tissue or on recently obtained tumor 
tissue.  
Archived tumor tissue sample must be collected from all subjects enrolled in this study at 
screening.  If this has not been done and an archived tumor tissue sample is not available, 
the subject should undergo a biopsy prior to dosing to obtain a tumor tissue sample.  
 
  
3.7.2.
Part 1
In Part 1, a combination dose will be defined for both the dabrafenib/panitumumab 
combination and the dabrafenib/trametinib/panitumumab combination (Table 4).  The 
combination dose will either be the recommended full monotherapy dose for all 
components of the combination or an MTD for the combination (sub-MTD dosing is also 
possible if the MTD is not sufficiently well tolerated with long-term dosing).  Dosing for 


Novartis
Confidential
Page 44
Clinical Study Protocol Version 05
Protocol No. MEK116833
dabrafenib and trametinib will be continuous daily dosing while panitumumab will be 
dosed once every two weeks, and assessments will occur in 28-day intervals.  Subjects 
will be evaluated for dose-limiting toxicities during the first 28 days of treatment. 
Table 4
Part 1 Dosing Cohorts
COHORTS
De-escalation cohorts
Dose escalation cohorts
-1A
-1B
-1C
1
STARTING 
DOSE
2
3Aa
3Ba
4
dabrafenibb
100mg
BID
150mg
BID
100mg
BID
150mg 
BID
RP2D* from 
Cohort 1 b
RP2D
from 
Cohort 
1 b
RP2D
from 
Cohort 
1 b
RP2D
from 
Cohort 
1 b
trametinib
-
-
1.5mg
once daily
2mg
once 
daily
1.5mg
once 
daily
2mg
once 
daily
panitumumabc, d
6mg/kg
Q2W
4.8mg/kg
Q2W
4.8mg/kg
Q2W
6mg/kg
Q2W
one dose level 
below RP2D from 
Cohort 1 c
one 
dose 
level 
below 
RP2D
from 
Cohort 
1 c
RP2D
from 
Cohort 
1 d
RP2D
from 
Cohort 
1 d
*RP2D= Recommended Phase 2 Dose
a. Cohorts that are designated as “A” and “B” may be opened simultaneously once the prior dosing cohort has 
completed the 28-day dose-limiting toxicity (DLT) window and met dose escalation criteria as specified in Table 
5.
b. Cohort will dose at the dabrafenib dose level in the RP2R defined in Cohort 1 (or, -1A, -1B or -1C, depending on 
what combination is tolerable).
c. Cohort will dose at one dose level lower than panitumumab dose level in the RP2R defined in Cohort 1 (or, -
1A, -1B  or -1C, depending on what combination is tolerable).
d. Cohort will dose at the panitumumab dose level in the RP2R defined in Cohort 1 (or, -1A, -1B or -1C, depending 
on what combination is tolerable).
Dose escalation will follow a 3+3 dose escalation procedure as described in Table 5.  
Evaluation of safety data from at least 3 subjects who have completed 28 days of dosing 
on study is required prior to defining a new dose and starting the next cohort.


Novartis
Confidential
Page 45
Clinical Study Protocol Version 05
Protocol No. MEK116833
Table 5
3+3 Cohort Dose Escalation
Number of subjects in cohort 
with DLT
Action
0 out of 3 subjects
Escalate to next dose level according to dose escalation rules 
below.
1 out of 3 subjects
Accrue 3 additional evaluable subjects at current dose level for a 
total of 6 evaluable subjects
1 out of 6 subjects
Escalate to next dose level with an increase of 50% (this 
represents the sum of relative escalation for each of the drugs)
2 or more subjects in a dosing 
cohort (up to 6 subjects )
Maximum tolerated dose has been exceeded.  Either evaluate 
an intermediate dose lower than current dose or expand a prior 
cohort up to 12 subjects. 
Dose escalation decisions will take into consideration all available data, including the 
safety profile of prior cohorts throughout the time subjects are on study, which will be 
reviewed by the investigator(s), Novartis Medical Lead(s), pharmacokineticist and 
statistician.  The dose escalation decision for the subsequent cohort and rationale will be 
documented in writing with copies maintained at each site and the Master Study Files.
Any cohort may be expanded beyond the initial 3 to 6 subjects enrolled during dose 
escalation, to a maximum of 12 subjects, to facilitate additional collection of safety 
data.
3.7.2.1.
Dose-Limiting Toxicity Definitions
An event will be considered a dose limiting toxicity (DLT) if it occurs within the first 
28 days of dosing, if it has a possible causal relationship to the study drug(s) based on 
investigator assessment, and if it meets at least one of the following criteria:


Novartis
Confidential
Page 46
Clinical Study Protocol Version 05
Protocol No. MEK116833
Toxicity
DLT Definition
Hematologic

Grade 4 absolute neutrophil count (ANC) for 5 days

Febrile neutropenia (defined as concurrent Grade 4 neutropenia and fever 
>38.5C and lasting >24 hrs)

Grade 4 anemia of any duration

Grade 4 thrombocytopenia (platelets <25,000/mm3) of any duration
Non-hematologic

Alanine aminotransferase (ALT) >5X upper limit of normal (ULN) OR, ALT >3X 
ULN AND bilirubin >2X ULN (after exclusion of disease progression and/or bile 
duct obstruction)

Grade 4 rash

Grade 4 Squamous Cell Carcinoma, keratoacanthoma or basal cell carcinoma

Grade 3 or greater clinically significant non-hematologic toxicity per NCI-
CTCAE, v 4.0, other than those listed above, with the following exceptions:
o
Grade 3 or greater nausea, vomiting, diarrhea, or 
mucositis/esophagitis that responds to maximal supportive 
treatment(s) within 48 hours
o
Electrolyte disturbances that respond to correction within 24 hours
o
Grade 3 hypertension that is adequately controlled by the addition of 
up to 2 additional antihypertensive medications
o
Grade 3 pyrexia that does not result in study discontinuation
Cardiac

Ejection fraction < lower limit of normal (LLN) with an absolute decrease of 
>20% from baseline 
Other

Inability to receive 75% of scheduled doses in treatment period due to 
toxicity

Grade 2 or higher toxicity that occurs beyond 28 days which in the judgment of 
the investigator and Novartis Medical Lead is considered to be a DLT
3.7.2.2.
Maximum Tolerated Dose and Recommended Phase 2 Dose
The maximum tolerated dose (MTD) is defined as the highest dose at which one or fewer 
of up to 6 subjects experience a DLT during the first 28 days of treatment in Part 1.  Due 
to the heterogeneity of the rash caused by panitumumab and/or trametinib, if any DLTs 
are due to rash, the cohort may be expanded to 12 subjects in order to more fully assess 
the true risk of intolerable rash, in which case DLTs in >3 of 12 subjects defines an 
intolerable dose. The recommended doses in Part 2, Part 3 and Part 4 may include doses 
that are less than or equal to the MTD but demonstrate biological activity and adequate 
tolerability.  
3.7.3.
Part 2
In Part 2, the primary objectives will be to further assess the safety and preliminary 
clinical activity of given doses and regimen(s) in subjects with BRAF-V600E mutation-
positive CRC.  
For Part 2A and 2B, subjects should follow the assessments in Section 3.11.2.
Part 2 will employ a Bayesian design that allows the trial to be monitored more 
frequently at multiple stages.


Novartis
Confidential
Page 47
Clinical Study Protocol Version 05
Protocol No. MEK116833
3.7.3.1.
Part 2A:  Cohort Expansion
Enrollment in Part 2A doublet will be initiated once dose escalation for the doublet 
(dabrafenib in combination with panitumumab) has been completed.  Enrollment in Part 
2A triplet (trametinib plus dabrafenib in combination with panitumumab) will open once 
dose escalation for the triplet has been completed.
Subjects will be enrolled in the expansion cohorts at a selected dose of dabrafenib in 
combination with panitumumab and a selected dose of trametinib plus dabrafenib in 
combination with panitumumab.  Based on the safety data from Part 1, approximately 20 
evaluable subjects with BRAF-V600E mutation-positive CRC will be enrolled at the 
Cohort 4 dose, the full monotherapy dose for all three component of the triplet regimen,
to obtain preliminary data on the safety and efficacy of the combinations. 
Subjects who participated in Part 1 of the study at the doses evaluated in Part 2A will be 
included in Part 2A analysis, and will contribute to the total count of the 20 subjects 
enrolled in Part 2A.  
For Part 2A, subjects should follow the assessments in Section 3.11.2.
3.7.3.2.
Part 2B:  Cohort Expansion
After completion of Part 2A, additional subjects will be enrolled into the triplet 
combination of dabrafenib and trametinib in combination with panitumumab. Based on 
the efficacy (Table 1) and long term tolerability observed in Part 2A, two doses will be 
evaluated in Part 2B.  
Up to ten subjects with no prior treatment and up to 20 subjects with at least one prior 
treatment will be enrolled at the Cohort 3A dose (dabrafenib 150mg BID + trametinib 
2mg QD + panitumumab 4.8mg/kg IV Q2wks).  Up to 10 subjects with no prior 
treatment and up to 20 subjects with at least one prior treatment will be enrolled at the 
Cohort 4 dose (dabrafenib 150mg BID + trametinib 2mg QD + panitumumab 6mg/kg IV 
Q2wks).
Enrolment into two patient populations will be dependent on prior therapy for their 
metastatic disease:
1. First Line Population (1L Population):  No prior treatment is defined as subjects 
with no prior treatment for metastatic disease or metastatic recurrence greater than 
6 months following completion of adjuvant therapy; 
2. Second to Fourth Line Population (2-4L Population):  At least one prior treatment 
is defined as subjects with progression or intolerance to at least one prior 
chemotherapy regimen for metastatic disease or recurrence within 6 months 
following completion of adjuvant therapy. Patients treated with > 4 prior lines of 
therapy for metastatic disease will not be eligible. 
Lines of prior therapy for each subject will be agreed upon by the Meadical Lead and 
investigator at the time of enrolment.  


Novartis
Confidential
Page 48
Clinical Study Protocol Version 05
Protocol No. MEK116833
This would provide safety, efficacy and tolerability data for the triplet regimen in up to 
95 subjects between Part 1, Part 2A and Part 2B. .
For Part 2B subjects should follow the assessments in Section 3.11.2.
Responses will be assessed by patient population, line of therapy, dose cohort and in 
aggregate for a given combination to inform decisions to continue to Part 3.  
Part 2 may be stopped at any time if excessive toxicities with the drug are observed.  For 
additional details about this approach, see Section 5. 
The decision to proceed to Part 3 of the study will take into consideration all available 
data and will be reviewed by the investigator(s), Novartis Medical Lead(s), 
pharmacokineticist and statistician.  Data will include the safety profile 
 
 of all dosing cohorts throughout the time subjects are on 
study.  The decision could be based on analysis of a subgroup of responders, so that a 
single combination arm would be carried forward into Part 3. 
3.7.4.
Part 3
Part 3 of the study will be conducted as a randomized Phase 2 study, enrolling subjects 
with BRAF-V600E mutation-positive CRC who are eligible to receive fluoropyrimidine-
containing chemotherapy regimen that have experienced documented radiographic 
progression on one prior line of fluoropyrimidine-containing chemotherapy  (previous 
anti-EGFR therapy is excluded), and will compare safety, tolerability and efficacy of 
dabrafenib in combination with panitumumab and trametinib plus dabrafenib in 
combination with panitumumab with standard chemotherapy.  The current design reflects 
our current understanding of the biology and clinical management of BRAF mutation-
positive CRC.  However, emerging data (either from this study or others) may necessitate 
a change in the design of Part 3.  Available data from Parts 1 and 2 of this study will 
be provided to ethics review boards, along with any necessary changes to the 
protocol, prior to starting Part 3.  The chemotherapy comparator will be a standard 
fluoropyrimidine-containing regimen that includes either irinotecan or oxaliplatin. The 
addition of a biological therapy in the chemotherapy comparator arm will be allowed, 
based on local practice, and will be restricted to panitumumab or bevacizumab.   Final 
decisions on the experimental combination dose levels and the study population for Part 3 
will be chosen based on emerging PK, PD, and tolerability data from Part 1 and Part 2.  
Interim analyses of Part 3 data will be reviewed for efficacy and safety, as described in 
Section 5.3.7.3. 
Data generated during Part 3 may be reviewed by an independent data monitoring 
committee (IDMC) along with data from Parts 1 and 2, as described in Section 13.9.
In addition to periodic reviews of the safety and efficacy data, one planned interim 
analysis for PFS will be performed when 40% of the progression events are reported 
across either dabrafenib/panitumumab and chemotherapy comparator arms or 
trametinib/dabrafenib/panitumumab and chemotherapy comparator arms.  The interim 
analysis allows a treatment arm to stop early for harm in PFS.  At the interim analysis, if


Novartis
Confidential
Page 49
Clinical Study Protocol Version 05
Protocol No. MEK116833
the enrollment to either of dabrafenib/panitumumab arm or 
trametinib/dabrafenib/panitumumab arm or chemotherapy comparator arm is halted due 
to lack of efficacy, the subjects on the halted arm may be provided the opportunity to 
receive treatment on the ongoing experimental arm(s) depending on the emerging safety 
and efficacy profile.  The details on the interim analysis, including planned stopping 
boundaries and decision rules in terms of hazard ratios of PFS, are described in 
Section 5.3.7.3.
To obtain PFS data, after study treatment is withdrawn, radiographic disease assessments 
(CT or MRI, as appropriate according to the method used at baseline) should continue 
every 8 weeks until documented disease progression, the start of new anti-cancer therapy, 
withdrawal of consent or death.  To obtain overall survival (OS) data, the subject should 
be followed to the date of death due to any cause.  Further details on study completion are 
provided in see Section 9.2.
3.7.5.
Part 4A Dose Escalation
A combination dose will be defined for combination of trametinib and panitumumab as 
shown in Section 3.5).  Once safety data has been collected for at least 3 patients in 
Cohort 1, preliminary data will be evaluated for dose-limiting toxicities (DLTs) during 
the first 28 days of treatment, per table in Section 3.7.5.1.  
Table 6
3+3 Cohort Dose Escalation
Number of subjects in cohort 
with DLT
Action
0 out of 3 subjects
Escalate to next dose level. 
1 out of 3 subjects
Accrue 3 additional evaluable subjects at current dose level for a 
total of 6 evaluable subjects
1 out of 6 subjects
Escalate to next dose level with an increase of 50% (this 
represents the sum of relative escalation for each of the drugs)
2 or more subjects in a dosing 
cohort (up to 6 subjects )
Maximum tolerated dose has been exceeded.  Either evaluate 
an intermediate dose lower than current dose or expand a prior
cohort up to 12 subjects. 
Dose escalation decisions will take into consideration all available data, including the 
safety profile of prior cohorts throughout the time subjects are on study, which will be 
reviewed by the investigator(s), Novartis Medical Lead(s), pharmacokineticist and 
statistician.  The dose escalation decision for the subsequent cohort and rationale will be 
documented in writing with copies maintained at each site and the Master Study Files.
Due to the heterogeneity of the rash caused by panitumumab and/or trametinib, if 
any DLTs are due to rash, the cohort may be expanded to 12 subjects in order to 
more fully assess the true risk of intolerable rash, in which case DLTs in >3 of 12 
subjects defines an intolerable dose.   If the preliminary MTD is below the full dose 
of both agents, re-escalation may be considered ONLY if fewer than 4 DLTs have 


Novartis
Confidential
Page 50
Clinical Study Protocol Version 05
Protocol No. MEK116833
been reported after enrolling at least 12 patients at the preliminary MTD (including 
patients enrolled in the dose escalation and expansion cohorts).
3.7.5.1.
Dose-Limiting Toxicity Definitions
An event will be considered a dose limiting toxicity (DLT) if it occurs within the first 
28 days of dosing, has a possible causal relationship to the study drug(s) based on 
investigator assessment, and meets at least one of the following criteria:
Toxicity
DLT Definition
Hematologic

Grade 4 absolute neutrophil count (ANC) for 5 days

Febrile neutropenia (defined as concurrent Grade 4 
neutropenia and fever >38.5C and lasting >24 hrs)

Grade 4 anemia of any duration

Grade 4 thrombocytopenia (platelets <25,000) of any duration
Non-hematologic

Alanine aminotransferase (ALT) >5X upper limit of normal 
(ULN) OR, ALT >3X ULN AND bilirubin >2X ULN (after 
exclusion of disease progression and/or bile duct obstruction)

Grade 4 rash 

Grade 3 or greater clinically significant non-hematologic toxicity 
per NCI-CTCAE, v 4.0, other than those listed above, with the 
following exceptions:
o
Grade 3 or greater nausea, vomiting, diarrhea, or 
mucositis/esophagitis that responds to maximal 
supportive treatment(s) within 48 hours
o
Electrolyte disturbances that respond to correction 
within 24 hours
o
Grade 3 hypertension that is adequately controlled by 
the addition of up to 2 additional antihypertensive 
medications
o
Grade 3 pyrexia that does not result in study 
discontinuation
Cardiac

Ejection fraction < lower limit of normal (LLN) with an absolute 
decrease of >20% from baseline 
Other

Inability to receive 75% of scheduled doses in treatment 
period due to toxicity

Grade 2 or higher toxicity that occurs beyond 28 days which in 
the judgment of the investigator and Novartis Medical Lead is 
considered to be a DLT
3.7.6.
Part 4B Cohort Expansion
In Part 4B cohort expansion, the primary objectives will be to further assess the safety 
and preliminary clinical activity of trametinib and panitumumab at the MTD determined 
in Part 4A.  Clinical activity will be determined in two patient populations of subjects 
with advanced/metastatic CRC:
1. BRAF mutant population, subjects with BRAF-V600E mutation-positive CRC 
(described above)


Novartis
Confidential
Page 51
Clinical Study Protocol Version 05
Protocol No. MEK116833
2. Anti-EGFR resistant population, subjects with CRC that developed secondary 
resistance to anti-EGFR therapy after initially deriving benefit.  
Enrollment in expansion cohorts will be initiated once dose escalation for the trametinib
and panitumumab combination has been completed.  Up to 20 subjects will be enrolled 
into each population at the starting dose or MTD if lower dose combination is required.
This will include the patients from part 4A.  An additional 20 subjects with
advanced/metastatic CRC with a BRAF mutation and progression or intolerance to one 
line of prior chemotherapy for metastatic disease or recurrence within 6 months of 
adjuvant therapy may be enrolled into BRAF mutant CRC population at a lower dose 
combination defined by the de-escalation cohorts to evaluate the tolerability and efficacy 
of a lower dose of one or both of the investigational products.  The decision to enroll
subjects at a lower dose level(s) and the lower dose(s) selected will be at the discretion of 
the investigators and Novartis Medical Lead. Part 4 may also be stopped at any time if 
excessive toxicities with the study treatment are observed. 
3.8.
Treatment Assignment
All subjects will be assigned to study treatment in accordance with the randomization 
schedule generated by Discovery Biometrics, prior to the start of the study, using 
validated internal software.  In Part 1, subjects will be assigned to a cohort/ dose level 
based on evaluation of safety in subjects enrolled in prior cohorts.  In Part 2, subjects will 
be assigned to expansion cohorts at a dose cohort from Part 1 dabrafenib in combination 
with panitumumab and a dose cohort from Part 1 of trametinib plus dabrafenib in 
combination with panitumumab.  In Part 3, subjects will be randomized to study 
treatment.  In Part 4A dose escalation, subjects will be assigned to a cohort/ dose level 
based on evaluation of safety in subjects enrolled in prior cohorts.  In Part 4B cohort 
expansion, subjects will be assigned to expansion cohorts at the starting dose cohort or 
dose de-escalation cohort from Part 4A of trametinib in combination with panitumumab.


Novartis
Confidential
Page 52
Clinical Study Protocol Version 05
Protocol No. MEK116833
3.9.
Investigational Products and Other Study Treatment 
Dosage/Administration
Product name:
Dabrafenib: GSK2118436
Trametinib: GSK1120212
Formulation 
description:
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dosage form:
Capsule
Tablet
Unit dose 
strength(s)
50mg, 75mg
0.5mg, 2mg
Route/
Regimen
Oral/ 
The initial dosing regimen will be twice daily 
(BID) continuous oral daily dosing. 

Subjects should be encouraged to 
take their doses at 12 hour 
intervals and at similar times every 
day with approximately 200mL of 
water.
Oral/ 
The initial dosing regimen will be once daily 
continuous oral daily dosing. 

Subjects should be encouraged to 
take study medication at 
approximately the same time(s) of 
day each day with approximately 
200mL of water.
Physical 
description:
50 mg strength capsules are Swedish 
orange (dark red) opaque hypromellose size 
2 capsules.
75 mg strength capsules are pink opaque 
hypromellose size 1 capsules/
Both tablet strengths are biconvex film coated 
tablets with a different shape and size to 
facilitate the visual identification. 
0.5mg: Yellow modified oval biconvex film-
coated tablets;: 4.8mm X 8.9mm
2mg: Pink round biconvex film coated 
tablets;7.5  mm in diameter
Product name:
Panitumumab/ Vectibix
Formulation description:
Vectibix (panitumumab) is recombinant, human IgG2 kappa monoclonal 
antibody that binds specifically to the human epidermal growth factor 
receptor (EGFR).  Panitumumab has an approximate molecular weight of 
147kDa.  Panitumumab is produced in genetically engineered mammalian 
(Chinese Hamster Ovary) cells. 
Dosage form:
Single-use vials
Unit dose strength(s)
100mg panitumumab in 5mL (20mg/mL) single-use vial; (NDC 55513-954-
01)
200mg panitumumab in 10mL (20mg/mL) single-use vial; (NDC 55513-955-
01)
400mg panitumumab in 20mL (20mg/mL) single-use vial; (NDC 55513-956-
01).
Route/
Dosing instructions
Intravenous 
The recommended dose of Vectibix is 6mg/kg, administered as an 
intravenous infusion over 60 minutes, every 14 days. Doses higher than 


Novartis
Confidential
Page 53
Clinical Study Protocol Version 05
Protocol No. MEK116833
Product name:
Dabrafenib: GSK2118436
Trametinib: GSK1120212
1000 mg should be administered over 90 minutes.

Infusion of panitumumab should be started within 30 minutes of 
dosing with oral medications dabrafenib and trametinib.
Physical description:
Vectibix is a sterile, colorless, pH 5.6 to 6.0 liquid for intravenous (IV) 
infusion, which may contain a small amount of visible translucent-to-white, 
amorphous, proteinaceous, panitumumab particulates. Each single-use 5 
mL vial contains 100 mg of panitumumab, 29 mg sodium chloride, 34 mg 
sodium acetate, and Water for Injection, USP. Each single-use 10 mL vial 
contains 200 mg of panitumumab, 58 mg sodium chloride, 68 mg sodium 
acetate, and Water for Injection, USP. Each single-use 20 mL vial contains 
400 mg of panitumumab, 117 mg sodium chloride, 136 mg sodium acetate, 
and Water for Injection, USP.
Manufacturer/ source of 
procurement:
Amgen Inc.
Staff should refer to the prescribing information for panitumumab, as appropriate, for a 
detailed description of drug storage, preparation, and administration [VECTIBIX, 2014].
3.10.
Dose Adjustment/Stopping Criteria
3.10.1.
Continuation on Study
In the absence of unacceptable toxicity, disease progression or subject withdrawal of 
consent for continued treatment, subjects may continue on treatment.  
Subjects who have met the criteria for disease progression (PD) according to RECIST v 
1.1 may continue to receive study drug if the Investigator believes the subject is receiving 
clinical benefit and approval to continue is granted by the Novartis Medical Lead. In this 
case, all study procedures would continue per protocol. The following efficacy and safety 
criteria must be met during study treatment prior to disease progression in order for 
investigators to consider continuing study therapy beyond radiographic tumor 
progression:

the subject experienced a confirmed tumor response according to RECIST v 1.1 
while receiving study treatment OR disease under study had remained no worse 
than stable for a period of at least two consecutive scans (approximately 12 
weeks) while receiving study treatment;

absence of signs and symptoms of clinical disease progression despite 
radiographic disease progressive based on RECIST v 1.1 criteria outlined in 
Appendix 4;

no treatment-related AEs of CTCAE Grade 4 or SAEs have occurred during the 
last 4 weeks of study treatment.
Prior to continuing study treatment, Investigators will be required to document that, in 
their opinion, the patient continues to receive clinical benefit and that the patient agreed 
to continue following a discussion of all available treatment options.


Novartis
Confidential
Page 54
Clinical Study Protocol Version 05
Protocol No. MEK116833
If the study treatment(s) is continued beyond disease progression, study procedures will 
be continued according to the Time and Events Table (Section 3.11).  
Table 7
Categories of Dose Modification Guidelines
Adverse Event
Dabrafenib
Trametinib 
Section
General Guidelines for Clinically Significant 
Toxicities
X
X
Section 3.10.4
Guidelines for Specific Adverse Events
Cardiovascular Adverse Eventsa
LVEF
X
Section 3.10.7.1
Hypertension 
X
X
Section 3.10.8
Prolonged QTc
X
X
Section 3.10.9
Skin –Related Adverse Events (Except cuSCC)b
Rash
X
X
Section 3.10.4.2
Hand-Foot Skin Reaction
X
X
Section 3.10.4.2.4
Other Adverse Events
Pyrexia
X
Section 3.10.4.1
Diarrhea
X
X
Section 3.10.5
Renal Insufficiency
X
X
Section 3.10.6
Visual Changes
X
X
Section 3.10.11
Pneumonitis
X
X
Section 3.10.13
Liver Chemistry Stopping Criteria
X
X
Section 3.10.10
a. For subjects enrolled in France, please see Appendix 5  for additional dose modification guidelines.
b. Refer to Section 3.10.4.3 for management of cuSCC
3.10.2.
Dose Adjustment
The severity of adverse events (AEs) will be graded utilizing the National Cancer 
Institute- Common Toxicity Criteria for Adverse Events (NCI-CTCAE), version 4.0.  
Guidelines for dose modifications and interruptions for management of common 
toxicities associated with the study treatment(s) are provided in this section:

general guidelines for clinically significant toxicities related to study treatments
and

specific guidelines for adverse events of special interest, which are events that 
have been observed with higher frequency or severity in subjects receiving 
dabrafenib, trametinib, or a combination of both therapies.
In the event of a DLT (for subjects enrolled in a dose escalation cohort), or other 
clinically significant AE in any part of the study, treatment may be withheld and 
supportive therapy administered as clinically indicated.  If the toxicity or event resolves 
to baseline or Grade 1 in less than or equal to 14 days of stopping therapy, then treatment 
may be restarted.  Dose reduction should be considered as clinically indicated.  Any dose 
adjustment or interruption will be recorded.
If the toxicity does not resolve to at least Grade 1 in less than or equal to 14 days, 
withdrawal from the study drug(s) is recommended.  However, if the investigator and 
Novartis Medical Lead agree that further treatment would benefit the subject, treatment 


Novartis
Confidential
Page 55
Clinical Study Protocol Version 05
Protocol No. MEK116833
can continue with at least one dose level dose reduction, per Table 8.  If toxicity is clearly 
related to one agent, a single agent in the combination may be dose-reduced. 
Table 8
Dose Level Reduction Guidelines
Dose Level
Dabrafenib 
Dose/Schedule
Trametinib 
Dose/Schedule
Panitumumab 
Dose/Schedule
0
150mg BID
2mg once daily
 6 mg/kg every 14 days
-1 (first dose reduction)
100mg BID
1.5mg once daily
4.8 mg/kg every 14 days
-2 (second dose reduction)
75mg BID
1mg once daily
3.6 mg/kg every 14 days
If an AE resolves to Grade 1 or baseline at the reduced dose level, and no additional 
toxicities are seen after 4 weeks of study treatment at the reduced dose, the dose may be 
increased to the previous dose level with approval from the Novartis Medical Lead.
A dose reduction below 75mg BID for dabrafenib, 1mg once daily for trametinib and 
3mg/kg every 14 days for panitumumab is not allowed (per the panitumumab label 
[VECTIBIX, 2014].  If a dose reduction below 75mg BID for dabrafenib is required, 
dabrafenib will be permanently discontinued, but the subjects will be allowed to continue 
trametinib and panitumumab. If a dose reduction below1.0 mg once daily for trametinib 
is required, then trametinib will be permanently discontinued, but these subjects will be 
allowed to continue dabrafenib and panitumumab. If a dose reduction below 3mg/kg 
every 14 days for panitumumab is required, panitumumab will be permanently 
discontinued, but the subjects will be allowed to continue dabrafenib and trametinib.
Note: Approval from the Novartis Medical Lead is required to restart study 
treatment after ≥21 days of interruption.
3.10.3.
Intra-subject Doublet to Triplet Crossover and Dose Escalation: 
Part 1, 2 or 4
For BRAF-mutation positive subjects enrolled in Part 1, 2 or 4 doublet dosing, intra-
subject doublet to triplet crossover is allowed if a patient has not experienced intolerable 
toxicity that could not be managed, and has demonstrated radiographic progression on 
therapy by RECIST v1.1 criteria, and approval will be based on review by the Novartis 
Medical Lead. Subjects must crossover to triplet within 6 weeks of radiographic 
progression. All assessments and samples required at progression as described in Section 
3.11 must be completed even though the subject crosses over to triplet. Dose 
administered must be from among those for which cohorts have been completed and data 
has been reviewed for safety.  
At the time of crossover, certain safety assessments will be repeated prior to start of 
triplet dosing (additional information describing assessments is available in Section 6):

brief physical examination

vital signs 

dermatological examination


Novartis
Confidential
Page 56
Clinical Study Protocol Version 05
Protocol No. MEK116833

ECG (single; repeated with 2 additional ECGs if clinically significant 
abnormalities are observed in the first assessment)

ECHO/ MUGA

disease assessment demonstrating radiographic progression on therapy by 
RECIST v1.1 criteria

ophthalmic examination, repeated at Week 4 after start of dosing with trametinib
Note: Approval from the Novartis Medical Lead is required to restart study 
treatment after ≥21 days of interruption.
All crossover assessments must be completed within 14 days prior to first dose on triplet 
except informed consent, ophthalmology exam, ECHO/MUGA and Disease Assessment, 
which can occur within 35 days prior to the first dose on triplet.  Assessments performed 
as part of the follow-up for the doublet will be acceptable if they are performed within 
these timeframes prior to the first dose on triplet.  
The source documents for these assessments should be provided to Novartis at least 
24 hours in advance to planned start of triplet dosing.  The Medical Lead will review and 
provide approval for crossover from doublet to triplet, and site will be notified via email 
with a signed crossover form (refer to SPM).
Once approved, patients will follow the time and events table in Section 3.11.5, starting 
at the column labelled “Continuation Phase” for continued monitoring of safety and 
efficacy after they receive their first dose on triplet.  The Initial Follow-Up and 
Secondary Follow-Up Assessments should be performed after last dose of triplet.  
Additional details are provided in the SPM.
Subjects are allowed to crossover once during the study.
Additionally, for subjects who have remained on study for 6 months in the triplet 
combination, their dose level for the combination may be increased up to the highest 
combination dose level that has previously been confirmed as not exceeding the MTD for 
the combination. The intra-subject dose escalation must be agreed to by the investigator 
and the Novartis Medical Lead.
3.10.4.
General Guidelines for Clinically Significant Toxicities
General guidelines regarding management and dose reduction for adverse events that are 
considered by the investigator to be related to study treatment and which do not have 
specific guidelines.


Novartis
Confidential
Page 57
Clinical Study Protocol Version 05
Protocol No. MEK116833
Table 9
Dose Modification Algorithms
Non-hematologic and 
hematologic toxicity (except 
fever), CTCAE Grade
Dose modification algorithms a, b, c, d
Grade 1

Continue dabrafenib, trametinib and panitumumab at full dose

Monitor closely

Provide supportive care according to institutional standards
Grade 2

Consider dose de-escalation by 1 dose level or holding dabrafenib, 
trametinib, and/or panitumumab until resolution to Grade 1 or baseline

Provide supportive care as clinically indicated. 

Monitoring of laboratory values should occur as clinically indicated.

For Grade 2 or higher respiratory symptoms (i.e., cough, dyspnea, 
hypoxia, etc), evaluation by CT scan is recommended.
Grade 3

Hold dabrafenib, trametinib, and panitumumab until toxicity resolves to 
Grade 1 or baseline then reduce dose of dabrafenib, trametinib, and/or 
panitumumab by 1 dose level.  

The subject may be continued at the same dose, if in the judgment of 
the investigator, the toxicity is considered unrelated to dabrafenib, 
trametinib, and/or panitumumab or clearly related to a particular 
agent(s).

Continue to monitor as clinically indicated.
Grade 4

Discontinue dabrafenib, trametinib, and panitumumab. Continue to 
monitor as clinically indicated, and provide supportive care as needed.

If in the investigator’s judgment the toxicity is unlikely to recur, hold 
dabrafenib, trametinib, and panitumumab until the toxicity is Grade 1 or 
baseline, then reduce dose of dabrafenib, trametinib, and/or 
panitumumab by 1 dose level. 

If Grade 4 toxicity recurs after dose reduction, discuss continuation of 
study drug(s) with the Novartis Medical Lead.
a.
The minimum dose of dabrafenib is 75mg BID; the minimum dose of trametinib is 1mg once daily; the minimum 
dose of panitumumab is 3.6 mg/kg.  If a subject requires dose reduction below dabrafenib 75mg BID, trametinib 
1mg once daily, or panitumumab 3.6 mg/kg then the subject must be discontinued from study drug(s).
b.
For adverse events of abdominal pain or suspected pancreatitis, amylase and lipase laboratory samples should 
be collected.
c.
If the subject has a Grade 3 or 4 laboratory abnormality that in the judgment of the investigator is not considered 
clinically significant, dose modification is not required.
d.
For subjects who develop symptoms associated with uveitis, including blurry vision, eye pain or erythema, an 
ophthalmologic consult is required.


Novartis
Confidential
Page 58
Clinical Study Protocol Version 05
Protocol No. MEK116833
Table 10
Panitumumab Dose Modification and Management Guidelines for 
Infusion Reactions
Toxicity and Grade
Modification and Management
Infusion reaction:
mild or moderate (Grade 1 or Grade 2) infusion 
reaction

Reduce the infusion rate by 50% for the 
duration of that infusion

Consider premedication with antihistamines 
and/or corticosteroids prior to subsequent 
doses
severe (Grade 3 or Grade 4) infusion reaction

Immediately discontinue panitumumab infusion

If the reaction is particularly severe and/or 
persistent, consider discontinuation of 
panitumumab.

Consider premedication with antihistamines 
and/or corticosteroids prior to subsequent 
doses.
3.10.4.1.
Guidelines for Treatment of Pyrexia
Episodes of pyrexia have been observed in subjects receiving dabrafenib monotherapy 
and is increased in incidence and severity in subjects receiving dabrafenib in combination 
with trametinib (refer to the GSK2118436 IB [GlaxoSmithKline Document Number 
2012N136095_00], the GSK1120212 IB [GlaxoSmithKline Document Number 
HM2009/00151/03] and the GSK1120212 + GSK2118436 Clinical IB [GlaxoSmithKline 
Document Number, 2011N126811_00]). In a minority of cases the pyrexia was 
accompanied by symptoms such as severe chills, dehydration, hypotension, dizziness or 
weakness.
Subjects should be instructed on the importance of immediately reporting febrile episodes. 
In the event of a fever, the subject should be instructed to take anti-pyretics (e.g., 
ibuprofen or acetaminophen/paracetamol) as appropriate to control fever.  The use of oral 
corticosteroids should be considered in those instances in which anti-pyretics are 
insufficient. Monitor serum creatinine and other evidence of renal function during and 
following severe events of pyrexia (see Section 3.10.6).
Guidelines regarding management and dose reduction for pyrexia considered to be 
related to study treatment are provided in Table 11.


Novartis
Confidential
Page 59
Clinical Study Protocol Version 05
Protocol No. MEK116833
Table 11
Management and Dose Modification Guidelines for Pyrexia
Pyrexiaa Management
Action and Dose Modification
All Events:

Clinical evaluation for infection and hypersensitivityc

Laboratory work-upc

Hydration as requiredd
1st Eventb: 
Administer anti-pyretic treatment if clinically indicated 
and continue prophylactic treatmentf if associated with 
rigors, renal failure, dehydration or hypotensione
1st Event:

Interrupt dabrafenib

Continue trametinib and/or panitumumab

Once pyrexia resolves to baseline, restart 
dabrafenib at the same dose level
If fever was associated with dehydration or 
hypotension, reduce dabrafenib by one dose 
level
2nd Eventg:

Within 3 days of onset of pyrexia:
Optimize anti-pyretic therapy
Consider oral cortiocosteroids (i.e., 
prednisone 10mg) for at least 5 days or as 
clinically indicated
2nd Event:

Interrupt dabrafenib

Continue trametinib and/or panitumumab

Once pyrexia resolves to baseline, restart 
dabrafenib at the same dose level
If fever was associated with rigors, renal failure, 
dehydration or hypotension, reduce dabrafenib 
by one dose levelg
Subsequent Events:

Within 3 days of onset of pyrexia:
Optimize oral corticosteroid dose as clinically 
indicated for recalcitrant pyrexia
if corticosteroids have been tapered and pyrexia 
recurs, restart steroids
if corticosteroids cannot be tapered consult the 
Medical Lead
Subsequent Events:

Interrupt dabrafenib

Continue trametinib and/or panitumumab
Once pyrexia resolves to baseline, restart dabrafenib 
reduced by one dose levelg
If dabrafenib must be reduced to <50mg BID, 
permanently discontinue dabrafenib. Trametinib 
may be continued.
a.
Pyrexia is defined as a body temperature equal to or above 38.5 Celsius or 101.3Fahrenheit.
b.
For subjects experiencing pyrexia complicated by rigors, severe chills, etc., a clinical evaluation and 
laboratory work-up is mandatory for each event; anti-pyretic treatment should be started immediately at the 
first occurrence and prophylactic anti-pyretic treatment is recommended
c.
Thorough clinical examination for signs and symptoms of infection or hypersensitivity is required; laboratory 
workup should include full-blood-count, electrolytes, creatinine, blood urea nitrogen (BUN), C-reactive protein 
(CRP), liver-function tests, blood culture, and urine culture.
d.
Oral hydration should be encouraged in subjects without evidence of dehydration. Intravenous hydration is 
recommended in subjects experiencing pyrexia complicated by dehydration/hypotension.
e.
Anti-pyretic treatment may include acetaminophen, ibuprofen, or suitable anti-pyretic medication according to 
institutional standards. Prophylactic anti-pyretic treatment may be discontinued after three days in the 
absence of pyrexia


Novartis
Confidential
Page 60
Clinical Study Protocol Version 05
Protocol No. MEK116833
f.
In subject experiencing pyrexia complicated by rigors, severe chills, etc., which cannot be controlled with 
anti-pyretic medication, oral corticosteroids should be started at the 2nd event and doses should be gradually 
increased for subsequent events.
g.
Dabrafenib should be reduced by one dose level after three episodes of pyrexia complicated by rigors, 
severe chills, etc., which cannot be managed by best supportive care and increasing doses of oral steroids.  
Escalation of dabrafenib is allowed if no episode of pyrexia is observed in the 4 weeks subsequent to dose 
reduction.
3.10.4.2.
Management of Dermatological Adverse Events Skin Toxicity
Treatment of subjects with dabrafenib, panitumumab and /or trametinib may result in 
skin toxicities.  These skin toxicities include acneiform rash, non-acneiform rash and 
hand-foot-skin reaction (HFSR).  Please note that the distinctions between these skin 
toxicities is important as it provides insight into the most likely causative agents and has 
implications in terms of management of the toxicity. In addition, some subjects enrolled 
in study BRF112680 experienced squamous cell carcinoma (SCC), keratoacanthomas 
(KA), and keratotic lesions.  Treatment of SCC, KA and keratotic lesions should occur 
based upon institutional practice.  Dose interruptions or modifications are usually not 
required for SCC/KA.
Management guidelines have been provided for acneiform rash (Section 3.10.4.2.2), non-
acneiform rash (Section 3.10.4.2.3) and HFSR [Section 3.10.4.2.4].  Management can 
differ from the guidelines below based on the clinical judgment of the investigator.  The 
investigator should contact the Novartis Medical Lead to discuss skin toxicity as needed.  
The Sponsor recommends biopsies of any new skin lesions for further study, specifically 
those suspicious for malignancy and pre-malignancy (SCC, actinic keratosis, and 
keratoacanthoma). Copies of pathology reports and slides may be collected by the
sponsor for review.  Photography of any lesions at baseline is recommended with 
photographs of any new or changing lesions recommended at subsequent visits per the 
Time and Events Table (Section 3.11).
3.10.4.2.1. Rash Prophylaxis and Supportive Care
In order to reduce the frequency and severity of skin toxicity (particularly rash), the 
following prophylactic measures are strongly suggested:
General considerations in rash management

Encourage subjects to avoid unnecessary exposure to sunlight.

Employ a proactive approach.  Subjects should have topical steroid and/ or topical 
antibiotic available for prophylactic use at the start of treatment (i.e., prophylactic 
treatment; see below for recommendations).
If a subject develops rash, verify treatment intervention and follow-up steps outlined 
under “Reactive Management”.
Prophylactic treatment (during the first 6 weeks of treatment)


Novartis
Confidential
Page 61
Clinical Study Protocol Version 05
Protocol No. MEK116833
The exact prophylactic regimen should be based on the investigator’s experience; 
however, the following regimen is recommended:
1. Mild strength topical steroid (e.g., hydrocortisone 1% cream), with escalation to 
higher strength and/or oral steroids as detailed below.
2. Offer topical antibiotics (such as clindamycin) or oral antibiotics (such as 
doxycycline 100mg BID or minocycline 100mg BID).  
3. Topical steroids and antibiotics should be applied on a daily basis starting on Day 
1 of study treatment, and more often as needed to areas such as face, chest and 
upper back.
4. Broad-spectrum sunscreen containing titanium dioxide or zinc oxide) with a skin 
protection factor (SPF) 15.
5. Thick, alcohol-free emollient cream (e.g., glycerine and cetomacrogol cream) on 
dry areas of the body.
Reactive Management for Rash
Two types of rash have been seen with the dabrafenib and trametinib combination.
Acneiform rash.  The need for oral or topical antibiotics (e.g., clindamycin cream, 
minocycline, doxycycline, etc) and higher strength topical steroids is a clinical decision 
of the investigator. Prophylactic use of skin emollients, sunscreen, oral doxycycline and 
topical steroids was demonstrated to be more effective than reactive use of the same 
agents after rash developed [Lacouture, 2010].  Oral or topical retinoids are not 
recommended.  Consider the algorithm provided in Table 12 for management of 
acneiform rash.
1. Inflammatory rash, which is often patchy, with sudden onset, and accompanied 
by erythema, pruritus and/ or pain.  If diagnosis is unclear, a biopsy and 
photographs should be obtained.
a.
For Grade 2 or worse inflammatory rash, hold dabrafenib until resolution 
to Grade 1. Dabrafenib may be restarted at full dose while monitoring for 
recurrence of skin reaction. Consider holding trametinib if symptoms are 
troublesome. Consider treatment with systemic steroids, such as a Medrol 
dose pack.  If the reaction occurs a second time, hold until resolution and 
then reduce dose by at least 25%.
It is strongly recommended that subjects who develop rash or other skin toxicities have a 
consultation with a dermatologist to determine appropriate management.

For pruritic lesions, the use of cool compresses and oral antihistamine agents 
may be helpful.


Novartis
Confidential
Page 62
Clinical Study Protocol Version 05
Protocol No. MEK116833

For fissuring, the use of Monsel’s solution, silver nitrate, or zinc oxide cream is 
advised.

For desquamation, thick emollients and mild soap are recommended.

For paronychia, antiseptic bath and local potent corticosteroids, in addition to 
oral antibiotics, are recommended.  If no improvement is seen, a dermatology or 
surgery consultation is recommended.
For infected lesions, bacterial and fungal culturing followed by the appropriate culture-
driving systemic or topical antibiotics is indicated.
3.10.4.2.2. Acneiform Rash
Acneiform rash is a common adverse event associated with trametinib and panitumumab 
and it is expected to be a common adverse event in the current study.  The management 
of acneiform rash is outlined in Table 12.


Novartis
Confidential
Page 63
Clinical Study Protocol Version 05
Protocol No. MEK116833
Table 12
Acneiform Rash Management Guidelines
Step
Rash 
grading
Rash severity
Management of Rash
Dose Modification for 
Trametinib and Panitumumaba
1
Mild
Locallized
Minimally symptomatic
No impact on activities of 
daily living (ADL)
No sign of superinfection
Initiate prophylactic 
regimen, including oral 
antibiotics, if not already 
started (see Section 
3.10.4.2.1).  Consider 
using moderate 
strength topical 
steroidsa
Consider reduction of
panitumumab dose by one dose 
level. 
Reassess after 2 weeks; if rash 
worsens or does not improve, 
proceed to Step 2.
2
Moderate
Generalized
Mild symptoms (e.g., 
pruritus, tenderness)
Minimal impact on ADL
No sign of superinfection
Initiate prophylactic 
regimen, including oral 
antibiotics, if not already 
started (see Section 
3.10.4.2.1), using 
moderate strength 
topical steroidsb
Reduce panitumumab dose by 
one dose level or consider 
interrupting panitumumab until 
resolution of toxicity to Grade 1.  
Reduce trametinib by one dose 
level or consider interrupting 
trametinib until resolution of 
toxicity to Grade 1.  If toxicity 
resolves, then can consider re-
escalation to initial dose level.
Reassess after 2 weeks; if rash 
worsens or does not improve, 
proceed to Step 3.
3
Severe
Generalized
Severe symptoms (e.g., 
pruritus, tenderness)
Significant impact on 
ADL
Sign of or potential for 
superinfection
Initiate prophylactic 
regimen, including oral 
antibiotics, if not already 
started, using moderate 
strength topical 
steroidsb plus 
methylprednisone dose 
pack (see Section 
3.10.4.2.1).
Consider obtaining 
dermatology 
consultation. 
Manage rash per 
dermatologist’s 
recommendation.
Interrupt panitumumab and 
trametinib until rash improves 
(mild), or resolves. 
If rash worsens or does not 
improve after 2 weeks, 
permanently discontinue 
panitumumab and trametinib.
If rash does improve/resolve, 
restart trametinib and 
panitumumab, each reduced by 
a single dose level.
1.
If it is not tolerated, 
hold both agents until 
resolution to Gr1 and 
then restart both 
agents, each reduced 
by another dose level.
a.
Recommendations for modification of panitumumab dosing may deviate from the package insert [VECTIBIX, 
2014].
b.
Hydrocortisone 2.5% cream or fluticasone proprionate 0.5% cream.


Novartis
Confidential
Page 64
Clinical Study Protocol Version 05
Protocol No. MEK116833
3.10.4.2.3. Non-Acneiform Rash
Non-acneiform rashes are also seen following treatment with the dabrafenib/trametinib 
combination and are generally thought to be related to dabrafenib.  Therefore, the 
management guidelines for non-acneiform rash in Table 13 focuses on dabrafenib dose 
interruption/reduction.  However, if the non-acneiform rash is not resolving, 
administration of trametinib and panitumumab may also be interrupted/reduced.
Table 13
Non-acneiform Rash Management Guidelines
Skin Toxicity Grade (NCI CTCAE, 
v4.0)
Guideline for Management
Dabrafenib Dose Reductiona
1
Topical corticosteroids, such as 
mometasone, betamethasone or 
fluocinonide creams
None
2
As for Grade 1, with the addition of 
diphenhydramine oral prednisone 
(short course)b
None: if unacceptable to subject or if 
medically concerning, then hold 
dabrafenib until recovery of toxicity to 
Grade 1. Restart at the same dose.
3
Hold dabrafenib until recovery of 
toxicity to Grade 1. Restart 
dabrafenib with a dose reduction of 1 
dose level.
a. If no recovery after 2 weeks of holding dabrafenib, then subjects must be withdrawn from study drug, unless in 
the opinion of the investigator and the Novartis Medical Lead there is reason to believe that the subject will 
experience clinical benefit from future treatment.
b.
For subjects with Grade 3 or Grade 4 extensive or symptomatic dermatological event, or chronic, persistent or 
recurring lower-grade dermatological events, a dermatology consult is recommended.
3.10.4.2.4. Hand-Foot-Skin Reaction (HFSR)
Episodes of hand-foot skin reaction (HFSR) have been observed in subjects receiving 
dabrafenib. Guidelines for management of HFSR are based on experience with other 
kinase inhibitors [Lacouture, 2008; McClellan, 2011] and are listed in Table 14.


Novartis
Confidential
Page 65
Clinical Study Protocol Version 05
Protocol No. MEK116833
Table 14
Management and Dose Modification Guidelines for Hand-Foot Skin 
Reaction (HFSR)
CTCAE Grade
Adverse Event Management
Action and Dose Modification
Grade 1a
Life-style changes recommendedb
Initiate symptomatic treatmentcif 
clinically appropriate
Continue study treatments at current 
dose level
Grade 2
Life-style changes recommendedb
Initiate symptomatic treatmentc
Interrupt study treatment(s)f until 
recover to Grade 1d
If there is recovery to Grade 1 
within 7 days, restart study 
treatment(s)f at previous dose level.
If not recovered to Grade 1 within 7 
days, or at the 2nd occurrence, restart 
study treatment(s)f with a one dose 
level reduction in dabrafenibe
Grade 3
Life-style changes recommendedb
Initiate symptomatic treatmentc

Consult dermatologist
Interrupt study treatment until recover 
to Grade 1d
Restart study treatment(s)f with a one 
dose level reduction in dabrafenibe
If 3rd occurrence, discontinue study 
treatments permanently
a.
A full-body skin examination and a removal of pre-existing calluses and keratotic skin are recommended prior 
to initiation of study treatment (Section 6.2).
b.
Life-style changes: (1) reduce exposure of hands and feet to hot water, (2) avoid traumatic activity including 
vigorous exercise especially in the first 4 weeks after start of study treatment, (3) avoid constrictive footwear, 
(4) avoid excessive friction on the skin, when applying topical treatments, (5) wear thick cotton socks and 
gloves, and shoes with padded insoles.
c.
Symptomatic Treatments: (1) use moisturizing creams frequently and especially on hands and feet (2) 
consider topical keratolytics: urea 20-40 % cream, or salicylic acid 6%, or tazarotene 0.1% cream, or 
fluorouracil 5% cream; (3) erythrematous areas: clobetasol propionate 0.05% ointment; (4) Pain: topical 
lidocaine 2%, and / or systemic pain medication such as nonsteroidal anti-inflammatory drugs, codeine, and 
pregabalin.
d.
Approval of the Novartis Medical Lead is required to restart study treatment after ≥21 days of interruption.
e.
Escalation of study treatment to the previous dose level is allowed if no HFSR is observed in the 4 weeks 
subsequent to dose reduction.
f.
Modification to study treatment(s) should be discussed with the Novartis Medical Lead.


Novartis
Confidential
Page 66
Clinical Study Protocol Version 05
Protocol No. MEK116833
3.10.4.3.
Guidelines for cuSCC
Cutaneous squamous cell carcinomas have been observed in subjects treated with 
dabrafenib and the combination of dabrafenib and trametinib (see the GSK1120212 + 
GSK2118436 Clinical IB and Supplements [GlaxoSmithKline Document Number, 
2011N126811_00, GlaxoSmithKline Document Number 2012N152310_00, 
GlaxoSmithKline Document Number 2012N152310_01]). These treatment-related 
cuSCC should be surgically removed according to institutional practice.  Dose 
modifications or interruptions of the study treatment are not required for cuSCC.  
Occurrence of cuSCC must be reported as an SAE. Submit cuSCC tumor tissue for 
analysis as directed in the SPM.
3.10.5.
Guidelines for Diarrhea
Episodes of diarrhea have occurred in subjects receiving dabrafenib, panitumumab and 
/or trametinib. 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 15.
Table 15
Management and Dose Modification Guidelines for Diarrhea
CTCAE Grade
Adverse Event Management
Action and Dose Modification
Uncomplicated diarrheaa
  Grade 1 or Grade 2
Diet: Stop all lactose-containing 
products; eat small meals, BRAT diet 
(bananas, rice, apples, toast) is 
recommended.
Hydration: 8 to 10 large glasses of 
clear liquids per day (e.g., Gatorade 
or broth)
Loperamide: initially 4mg, followed by 
2mg every 4 hours or after every 
unformed stool, to a maximum of 
16mg/ day. Continue until diarrhea-
free for 12 hours.
Diarrhea 24 hours: Loperamide 
2mg every two hours to a maximum 
of 16mg/ day. Consider adding oral 
antibiotics.
Diarrhea 48 hours:  Loperamide 
2mg every two hours to a maximum 
of 16mg/ day. Add budesonide or 
other 2nd line therapies (otreotide, or 
Continue study treatments. Consider 
dose reduction of trametinib and 
panitumumab by one dose level.
If diarrhea is Grade 2 for >48 hours, 
interrupt study treatments until 
resolution to Grade 1.
Restart study treatments at the 
current dose level.


Novartis
Confidential
Page 67
Clinical Study Protocol Version 05
Protocol No. MEK116833
CTCAE Grade
Adverse Event Management
Action and Dose Modification
tincture of opium) and oral antibiotics.
Uncomplicated diarrheaa
   Grade 3 or Grade 4
Any complicated diarrheab
Clinical evaluation is mandatory.
Loperamidec: initially 4mg, followed 
by 2mg every 4 hours or after every 
unformed stool, to a maximum of 
16mg/ day. Continue until diarrhea-
free for 12 hours.
Oral antibiotics and 2nd line therapies
should be implemented if clinically 
indicated.
Hydration: intravenous fluids should 
be administered if clinically indicated.
Antibiotics (oral or IV) should be 
administered if clinically indicated.
Interventions should be continued 
until the subject is diarrhea-free 
for 24 hours.
Intervention may require 
hospitalization for subjects at risk 
of life-threatening complications.
Interrupt study treatments until 
diarrhea recovers to Grade 1.
Restart study treatments with a one 
dose level reduction.  
If 3 dose reductions of study 
treatment are clinically indicated, 
permanently discontinue study 
treatments.
a.
Uncomplicated diarrhea is defined by the absence of symptoms such as cramping, nausea/vomiting Grade 2, 
decreased performance status, pyrexia, sepsis, neutropenia Grade 3, frank bleeding, and/or dehydration 
requiring IV fluid substitution.
b.
Complicated diarrhea is defined by the presence of symptoms such as cramping, nausea/vomiting Grade 2, 
decreased performance status, pyrexia, sepsis, neutropenia Grade 3, frank bleeding, and/or dehydration 
requiring IV fluid substitution.
c.
Loperamide should be made available prior to the start of study treatment so that loperamide administration can 
begin at the first signs of diarrhea.
3.10.6.
Guidelines for Renal Insufficiency
Cases of renal insufficiency have occurred in subjects receiving dabrafenib and the 
combination of dabrafenib and trametinib. Prior to start of any study treatment, 
concomitant medications should be reviewed for the potential risk of inducing 
nephrotoxicity and concomitant medications should be modified if clinically possible.
Guidelines regarding management and dose reduction for renal insufficiency considered 
to be related to study treatment by the investigator are provided in Table 16.  


Novartis
Confidential
Page 68
Clinical Study Protocol Version 05
Protocol No. MEK116833
Table 16
Management and Dose Modification Guidelines for Renal 
Insufficiency
Creatinine
Adverse Event Management
Action and Dose Modification
For subjects with serum creatinine 
increase >0.2 mg/dL (18 mol/L) 
but 
0.5 mg/dL (44 mol/L) above 
baseline:

Re-check serum 
creatinine within 1 week

If serum creatinine 
increases > 1 week, contact the 
Novartis Medical Lead

If pyrexia is present, treat 
pyrexia as per guidelinesa
Continue study treatment at the 
same dose level.
For subjects with serum creatinine 
increase >0.5 mg/dL (44 mol/L) 
above baseline 
or 
serum creatinine >2 mg/dL (> 177 
mol/L)

Follow serum creatinine 
at least twice weekly

Consider hospitalization if 
serum creatinine cannot be 
monitored frequently

If pyrexia is present, treat 
pyrexia as per guidelinesa

Consult nephrologist if 
clinically indicated

Perform renal biopsy if 
clinically indicated, for 
example:

Renal 
insufficiency persists despite 
volume repletion

Subject has new 
rash or signs of hypersensitivity 
(such  as elevated eosinophil 
count) 

Interrupt study 
treatment(s)c until serum 
creatinine recovers to 
baseline.

Restart with study 
treatmentbat either the 
same or a reduced dose 
level
a.
Nonsteroidal anti-inflammatory drugs (NSAIDs) can induce renal insufficiency, especially in subjects with 
dehydration.  Encourage oral fluids or consider IV fluids as clinically indicated.  Refer to guidelines for pyrexia in 
Section 3.10.4.1.
b. Investigator may restart at either the same or a reduced dose level. Escalation of study treatment to previous dose 
level may be allowed if another episode of renal insufficiency does NOT occur after 4 weeks at the reduced 
dose level. Consultation with the Novartis Medical Lead is required before restarting treatment if there is 
evidence of thrombotic microangiopathy.
c.
Modification to study treatment(s) should be discussed with the Novartis Medical Lead.  Since panitumumab is 
not associated with renal toxicity and its pharmacokinetics are not altered by renal insufficiency, the 
panitumumab dose should be restarted at the same dose.
3.10.7.
Guidelines for Cardiovascular Adverse Events
Cardiovascular adverse events have been observed in subjects receiving either dabrafenib, 
trametinib, or the two drugs in combination.  Additional information is available in the 
IBs:  GSK2118436 IB [GlaxoSmithKline Document Number 2012N136095_00], the 
GSK1120212 IB [GlaxoSmithKline Document Number HM2009/00151/03] and the 
GSK1120212 + GSK2118436 Clinical IB [GlaxoSmithKline Document Number, 
2011N126811_00].  Guidelines for LVEF decreases, hypertension and prolonged QTc 
are provided in Section 3.10.7.1, Section 3.10.8 and Section 3.10.9, respectively.


Novartis
Confidential
Page 69
Clinical Study Protocol Version 05
Protocol No. MEK116833
3.10.7.1.
Left Ventricular Ejection Fraction (LVEF)
Decreases of the left-ventricular-ejection-fraction (LVEF) have been observed in subjects 
receiving trametinib monotherapy and in combination with dabrafenib. Therefore, 
ECHO/MUGAs must be performed to assess cardiac ejection fraction in regular intervals 
as outlined in the Time and Events Table (Section 3.11).  All assessments for an 
individual patient must be performed with the same modality (i.e., ECHO or MUGA) and, 
preferably, by the same institution/operator, in order to reduce variability.  Copies of all 
LVEF assessments and cardiology consultations performed on subjects who experience a 
>10% decrease in LVEF from baseline and whose cardiac ejection fraction is 
<institution’s LLN will be required by Novartis for review.  Instructions for submitting 
qualifying ECHOs/ MUGAs are provided in the Study Procedures Manual (SPM).
Dose modification guidance and stopping criteria for LVEF decrease are provided in 
Table 17.  Additional guidelines for subjects enrolled at sites in France are provided in 
Appendix 5.


Novartis
Confidential
Page 70
Clinical Study Protocol Version 05
Protocol No. MEK116833
Table 17
Dose Modification Guidelines and Stopping Criteria for LVEF 
Decrease
Clinic Presentation
LVEF decrease (%) or CTCAE grade
Action and Dose Modificationd
Asymptomatic
Absolute decrease of >10% in LVEF 
compared to baseline and ejection 
fraction below the institutional LLN
Interrupt trametinib and repeat ECHO/MUGA within 
2 weeksa
IF LVEF recovers within 4 weeks (defined as LVEF 
LLN and absolute decrease 10% compared to 
baseline):

Consult with the Novartis Medical Lead
and request approval for restart

If approved, restart trametinib reduced by 
one dose levelb

Repeat ECHO/MUGA at 2, 4, 8, and 12 
weeks after re-start; continue in 12 week 
intervals thereafter
If LVEF does not recover within 4 weeks:

Consult with cardiologist

Permanently discontinue trametinib

Report as SAE

Repeat ECHO/MUGA after 2, 4, 8, 12 
and 16 weeks or until resolution

Symptomaticc
Grade 3: resting LVEF 39-20% or >20% 
absolute reduction from baseline
Permanently discontinue trametinib 
Interrupt dabrafenibd
Report as SAE
Consult with cardiologist
Repeat ECHO/MUGA after 2, 4, 8, 12 and 16 
weeks or until resolution.
Grade 4: resting LVEF <20%
Abbreviations:  CTCAE = Common Terminology Criteria for Adverse Events; ECHO = echocardiogram; LLN = lower 
limit of normal; LVEF = left ventricular ejection fraction
a.
If ECHO/MUGA does not show LVEF recovery after 2 weeks, repeat ECHO/MUGA 2 weeks later.
b.
If recurrent episodes of LVEF reduction occur in subjects receiving dabrafenib monotherapy, consult the 
Medical Lead.
c.
Symptoms may include: dyspnea, orthopnea, and other signs and symptoms of pulmonary congestion and 
edema.
d.
Once LVEF recovers to baseline, restarting dabrafenib monotherapy may be considered in consultation with 
the Novartis Medical Lead.
3.10.8.
Monitoring and Management of Hypertension
Increases in blood pressure have been observed in subjects receiving trametinib. 
Recommendations for blood pressure monitoring and management are provided in 
Section 3.10.8.1 and Section 3.10.8.2, respectively.
3.10.8.1.
Monitoring of Hypertension
All blood pressure measurements should be performed under the following optimal 
conditions:


Novartis
Confidential
Page 71
Clinical Study Protocol Version 05
Protocol No. MEK116833

subject has been seated with back support, ensuring that legs are uncrossed and 
both feet are flat on the floor, 

subject has relaxed comfortably for at least 5 minutes prior to measurements, 

preparatory steps, such as removal of restrictive clothing over the cuff area and 
selection of the appropriate cuff size has been ensured, 

the arm is supported so that the middle of the cuff is at heart level, and 

the subject remains quiet and still during the measurement.  
In subjects with an initial blood pressure reading within the hypertensive range, a second 
reading should be taken at least 1 minute after the initial reading, with the average of the 
2 readings averaged to obtain a final blood pressure measurement.  The averaged value 
should be recorded in the electronic Case Report Form (eCRF).
Persistent hypertension is defined as an increase of systolic blood pressure (SBP) to 
>140mm Hg and / or diastolic blood pressure (DBP) to >90mm Hg in up to 3 consecutive 
visits with blood pressure assessments from 2 readings under the optimal conditions 
described above.  Visits to monitor increased blood pressure can be scheduled 
independently from the per-protocol visits outlined in the Time and Events Table 
(Section 3.11). Ideally, subsequent blood pressure assessments should be performed 
within 1 week.
Asymptomatic hypertension is defined as an increase of SBP to >140mm Hg and /or 
DBP to >90mm Hg in the absence of headache, light-headedness, vertigo, tinnitus, 
episodes of fainting or other symptoms indicative of hypertension.
3.10.8.2.
Management of Hypertension
For subjects experiencing an increase in systolic and/or diastolic blood pressure that is 
persistent and may be associated with study drug(s), recommendations for the clinical 
management of hypertension are described in Table 18:


Novartis
Confidential
Page 72
Clinical Study Protocol Version 05
Protocol No. MEK116833
Table 18
Guidelines for Management of Hypertension
Hypertension
Action and Dose Modification
Scenario A:
Asymptomatic and persistenta SBP 140mm Hg and 
<160mm Hg, or DBP 90mm Hg and <100mm Hg, 
or 
a clinically significant increase in DBP of 20mm Hg (but 
DBP still <100 mmHg).
Step 1: Continue study treatments at the current dose.
Step 2: Adjust current or initiate new antihypertensive 
medication(s).
Step 3: Titrate antihypertensive medication(s) during next 
2 weeks as indicated to achieve well-controlledb blood 
pressure.  
If BP is not well-controlled within 2 weeks, consider 
referral to a specialist and follow steps outlined for 
Scenario B.
Scenario B:
Asymptomatic SPB 160mm Hg, or DBP 100mm Hg, 
or 
failure to achieve well-controlled BP within 2 weeks in 
Scenario A
Step 1: Interrupting study treatment(s)d, if clinically 
indicated.
Step 2: Adjust current or initiate new antihypertensive 
medication(s). 
Step 3: Titrate antihypertensive medication(s) during next 
2 weeks as indicated to achieve well-controlled BP. 
Step 4: Once blood pressure (BP) is well-controlledb, 
restart study treatment(s)f with one dose level 
reductionc.
Scenario C:
Symptomatic hypertension 
or 
Persistente SBP 160mm Hg, or DBP 100mm Hg, 
despite modification of antihypertensive medication(s) 
and dose reduction of trametinib
Step 1: Interrupt study treatment(s)f
Step 2: Adjust current or initiate new antihypertensive 
medication(s).
Step 3: Titrate antihypertensive medication(s) during next 
2 weeks as indicated to achieve well-controlled BP. 
Referral to a specialist for further evaluation and follow-up 
is also recommended. 
Step 4: Once BP is well-controlledb, restart study 
treatment(s)f with one dose level reductionc.
Scenario D: 
Refractory hypertension unresponsive to above 
interventions, or having hypertensive crisis
Discontinue administration of study treatment(s)f
Continue follow-up per protocol.
Abbreviations:  BP = blood pressure; DBP = diastolic blood pressure; mmHg = millimetres mercury; SBP = systolic 
blood pressure;
a.
Hypertension detected in two separate readings during up to three subsequent visits.
b.
Blood pressure of SBP 140 mm Hg and DBP 90 mm Hg in two separate readings during up to three 
consecutive visits.
c.
Escalation of trametinib to previous dose level can be considered if BPs remain well-controlled for 4 weeks 
after restarting of trametinib.  Approval from the Novartis Medical Lead is required.
d.
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
e.
Persistent asymptomatic hypertension after initially successful anti-hypertensive intervention.
f.
Modification to study treatment(s) should be discussed with the Novartis Medical Lead.


Novartis
Confidential
Page 73
Clinical Study Protocol Version 05
Protocol No. MEK116833
3.10.9.
Guidelines for Prolonged QTc
Guidelines for dose modification and stopping criteria due to QTc prolongation are 
provided in Table 19.  For subjects enrolled in France, please refer to Appendix 5 for 
QTc prolongation withholding and stopping criteria.
Table 19
Withholding and Stopping Criteria for QTc Prolongation
QTc Prolongationa
Action and Dose Modification
QTcB501msec

Interrupt study treatment until QTcB 
prolongation resolves to Grade 1 or baseline

Test serum potassium, calcium, phosphorus 
and magnesium. If abnormal, correct per 
routine clinical practice to within normal limits.

Review concomitant medication for usage of 
agents that prolonged QTc.

If event resolves, restart study treatment at 
current dose levelb

If event does not resolve, permanently 
discontinue study treatments. Consider 
evaluation with cardiologist.

If event recurs, permanently discontinue 
study treatments.  Consider evalution with 
cardiologist.
Abbreviations:  msec = milliseconds; QTcB = QT interval on electrocardiogram 
a.
Based on an average QTc value of triplicate electrocardiograms (ECGs). For example, if an ECG 
demonstrates a prolonged QT interval, obtain 2 more ECGs over a brief period, and then use the averaged 
QTc values of the 3 ECGs to determine if study treatments should be interrupted or discontinued.
b.
If the QTc prolongation resolves to Grade 1 or baseline, the subject may resume study treatment if the 
investigator and the Novartis Medical Lead agree that the subject will benefit from further treatment.
3.10.10.
Liver Chemistry Stopping Criteria
Liver chemistry threshold stopping criteria have been designed to assure subject 
safety and evaluate liver event etiology during administration of study treatment(s) and 
the follow-up period.  Study treatment(s) will be stopped if any of the following liver 
chemistry stopping criteria is/are met: 
1. Alanine aminotransferase (ALT) 3x upper limit of normal (ULN) AND bilirubin 
≥2xULN (>35% direct bilirubin) (or ALT3xULN and international normalized 
ratio [INR]>1.5, if INR measured and subject not receiving warfarin therapy).

NOTE: If serum bilirubin fractionation is not immediately available, study 
drug should be discontinued if ALT 3xULN and bilirubin 2xULN. 
Serum bilirubin fractionation should be performed if testing is available. If 
testing is unavailable, record presence of detectable urinary bilirubin on 
dipstick, indicating direct bilirubin elevations and suggesting liver injury.


Novartis
Confidential
Page 74
Clinical Study Protocol Version 05
Protocol No. MEK116833
2. ALT 5xULN.
3. ALT 3xULN if associated with the appearance or worsening of symptoms of 
hepatitis or hypersensitivity such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash or eosinophilia.
4. ALT 3xULN persists for 4 weeks.
5. ALT 3xULN and cannot be monitored weekly for 4 weeks.
When any of the 5 liver chemistry stopping criteria is met, do the following:

Immediately discontinue investigational product(s).

Report the event to Novartis within 24 hours of learning its occurrence.

Complete the liver event eCRF and SAE data collection tool if the event also 
meets the criteria for an SAE.

All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) (or 
ALT3xULN and INR>1.5, if INR measured; INR measurement is not required 
and the threshold value stated will not apply to subjects receiving anticoagulants), 
termed ‘Potential Hy’s Law’, must be reported as an SAE (excluding studies of 
hepatic impairment or cirrhosis).

Complete the liver imaging and/or liver biopsy CRFs if these tests are performed.

Perform liver event follow up assessments, and monitor the subject until liver 
chemistries resolve, stabilize, or return to baseline values as described below.

Follow-up for Overall Survival (OS) is required following permanent 
discontinuation from investigational product.

Do not re-challenge with investigational product.
In addition, for criterion 1:

Make every reasonable attempt to have subjects return to clinic within 24 hours 
for repeat liver chemistries, liver event follow up assessments (refer to 
Section 12), and close monitoring.

A specialist or hepatology consultation is recommended.

Monitor subjects twice weekly until liver chemistries (ALT, aspartate 
aminotransferase (AST), alkaline phosphatase, bilirubin) resolve, stabilize or 
return to within baseline values.
In addition, for subjects meeting any of the criteria 2 to 5:


Novartis
Confidential
Page 75
Clinical Study Protocol Version 05
Protocol No. MEK116833

Make every reasonable attempt to have subjects return to clinic within 24 to 72 
hours for repeat liver chemistries and liver event follow up assessments (refer to 
Section 12).

Monitor subjects weekly until liver chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) resolve, stabilize or return to within baseline values.
3.10.11.
Guidelines for Visual Changes or Specified Ophthalmic 
Examination Findings
Episodes of visual changes have been observed in subjects receiving trametinib, 
dabrafenib, and combination therapy. An ophthalmologist should be consulted if changes 
in vision develop.  However, if the visual changes are clearly unrelated to study treatment 
(e.g., allergic conjunctivitis), then monitor closely as it may be reasonable to defer 
ophthalmic examination.
Treatment with dabrafenib has been associated with the development of uveitis, including 
iritis. Monitor patients for visual signs and symptoms (such as, change in vision, 
photophobia and eye pain) during therapy. Special attention should be given to retinal 
findings (e.g., retinal pigment epithelial detachment (RPED) or retinovascular 
abnormalities (i.e., branch or central retinal vein occlusions (RVO).  
For events of visual changes (regardless of severity) for which an ophthalmic 
examination is conducted, a blood sample for PK analysis must be drawn as close as 
possible to the time of the event.
Guidelines regarding management and dose reduction for visual changes considered to be 
related to study treatment are provided in Table 20.


Novartis
Confidential
Page 76
Clinical Study Protocol Version 05
Protocol No. MEK116833
Table 20
Management and Dose Modification Guidelines for Visual Changes
and/or Ophthalmic Examination Findings
CTCAE Gradea
Adverse Event Management
Action and Dose Modification
Grade 1 b
.

Consult ophthalmologist within 7 days 
of onset

If dilated fundus examination cannot be 
performed within 7 days of onset, interrupt 
study treatment until RPED and RVO can be 
excluded by retinal specialist / 
ophthalmologist 

if RPED and RVO excluded, continue (or 
restart) trametinib at same dose level

If RPED is suspected or diagnosed: see 
RPED dose modification Table 21 below;
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.  If subject is 
receiving trametinib/dabrafenib 
combination therapy, dabrafenib may 
be discontinued.

If RPED and RVO excluded, restart 
trametinib at same dose level

If RPED diagnosed: see RPED dose 
modification Table 21 below; report as SAE.

If RVO is diagnosed: Permanently 
discontinue trametinib and report as SAE
Grade 4

Consult ophthalmologist immediately 

Interrupt trametinib. .  If subject is 
receiving trametinib/dabrafenib 
combination therapy, dabrafenib may 
be discontinued.

If RPED and RVO excluded, may consider 
restarting trametinib at same or reduced dose 
after discussion with study the Medical Lead

If RVO or RPED diagnosed, permanently 
discontinue study treatment
Abbreviations:  RPED = Retinal pigment epithelium detachment; CTCAE = Common Terminology Criteria for Adverse 
Events; RVO = retinal vein occlusion; SAE = serious adverse event
a.
Refers to CTCAE Version 4.0 ‘Eye disorders – Other, specify
b.
If visual changes are clearly unrelated to study treatment (e.g., allergic conjunctivitis), monitor closely but 
ophthalmic examination is not required.


Novartis
Confidential
Page 77
Clinical Study Protocol Version 05
Protocol No. MEK116833
Table 21
Recommended dose modifications for trametinib for retinal pigment 
epithelial detachments (RPED)a
CTCAE Grade
Action and Dose Modification
Grade 1 RPED (Asymptomatic; clinical or diagnostic 
observations only)

Continue treatment with retinal evaluation monthly until 
resolution. If RPED worsens follow instructions below 
Grade 2-3 RPED (Symptomatic with mild to moderate 
decrease in visual acuity; limiting instrumental ADL)

Interrupt trametinib 

Retinal evaluation monthly 

If improved to ≤ Grade 1, restart trametinib at lower 
dose (reduced by 0.5 mg) or discontinue in patients 
taking trametinib 1 mg daily
a. Refers to CTCAE Version 4.0 ‘Retinopathy’
3.10.12.
Supportive Care
3.10.12.1. Supportive Measures for Respiratory Symptoms
For Grade 2 or higher respiratory symptoms (i.e., cough, dyspnea, hypoxia, etc), 
evaluation by a CT scan is recommended.
3.10.12.2. Supportive Measures for Abdominal Pain or Suspected Pancreatitis
For adverse events of abdominal pain or suspected pancreatitis, amylase and lipase 
laboratory samples should be collected.
3.10.13.
Pneumonitis/ Interstitial Lung Disease Management Guidelines
Pneumonitis/ILD has been observed in subjects receiving trametinib.  To reduce the risk 
of pneumonitis/ILD, subjects will be monitored closely for symptoms, evaluated with 
imaging and functional tests.  Dose modification and supportive care guidelines for 
pneumonitis/ILD are described in Table 22.


Novartis
Confidential
Page 78
Clinical Study Protocol Version 05
Protocol No. MEK116833
Table 22
Management and Dose Modification Guidelines for Pneumonitis/ILD
CTCAE Grade
Adverse Event Management
Action and Dose Modification
Grade 1
CT scan (high-resolution with lung windows) 
is recommended. 
Clinical evaluation and laboratory work-up 
for infection should be performed. 
Monitoring of oxygenation via pulse-oximetry 
is recommended. 
Consultation by a pulmonologist is 
recommended.
Continue dabrafenib and trametinib at 
current dose.
Permanently discontinue panitumumab.
Grade 2
CT scan (high-resolution with lung windows) 
is recommended.
Clinical evaluation and laboratory work-up 
for infection should be performed.
Consult a pulmonologist.
Pulmonary function testing should be 
performed; if < normal, repeat every 8 
weeks until results are normal.
Bronchoscopy with biopsy and/or 
bronchalveolar lavage (BAL) is 
recommended.
Symptomatic therapy including 
corticosteroids is recommended if clinically 
indicated. 
Interrupt dabrafenib and trametinib until 
recovery to Grade 1.
Permanently discontinue panitumumab.
Restart dabrafenib and trametinib, reduced 
by one dose level.
Escalation to previous dose level after 4 
weeks and after consultation with the
Novartis Medical Lead
If symptoms do not recover to Grade 1 
within 4 weeks, permanently discontinue 
dabrafenib and trametinib.
Grade 3
CT scan (high-resolution with lung windows) 
should be performed.
Clinical evaluation and laboratory work-up 
for infection should be performed.
Consult a pulmonologist.
Pulmonary function testing should be 
performed; if < normal, repeat every 8 
weeks until results are normal.
Bronchoscopy with biopsy and/or BAL if 
possible.
Symptomatic therapy including 
corticosteroids is recommended if clinically 
indicated.
Interrupt dabrafenib and trametinib until 
recovery to Grade 1.
Permanently discontinue panitumumab.
After consultation with the Novartis Medical 
Lead, dabrafenib and trametinib may be 
restarted with a one dose level reduction.
If symptoms do not recover to Grade 1 
within 4 weeks, permanently discontinue 
dabrafenib and trametinib
Grade 4
Same as Grade 3.
Permanently discontinue dabrafenib, 
panitumumab and trametinib


Novartis
Confidential
Page 79
Clinical Study Protocol Version 05
Protocol No. MEK116833
3.11.
Time and Events Tables
3.11.1.
Part 1 Dose Escalation
Screening1
First Treatment Period 
(Day 1 through Day 28)
Continuation Phase2
(7 days)
Initial follow-
up3
(14 days [7 
days] from last 
dose of study 
drugs)
Secondary follow-up3
Day 1
Day 15
(2 days)
Day 21
(2 days)
4 weeks (7 
days) after the 
last dose of 
panitumumab
8 weeks (7 
days) after the 
last dose of 
panitumumab
Informed Consent
X
Archival tumor tissue 
or fresh tumor biopsy 
(BRAF mutation 
confirmation)14
X
Tumor Biopsy 
(mandatory)10
X 
(pre-dose)14
X11
(to be 
collected 
from Day 15 
to Day 18)
X12
(at 
progression)
Demographics
X
Medical history/ Interim 
History
X
X6
At Week 4, then every 4 weeks
X
Concurrent 
medications
X
X6
X
X
At Week 4, then every 4 weeks
X
Serum or urine 
pregnancy test (-
human chorionic 
gonadotropin [hCG]; 
women)4
X
Every 8 to 12 weeks4
X
Complete physical 
examination5
X
X
Brief physical 
examination5
X6
X
At Week 4, then every 4 weeks


Novartis
Confidential
Page 80
Clinical Study Protocol Version 05
Protocol No. MEK116833
Screening1
First Treatment Period 
(Day 1 through Day 28)
Continuation Phase2
(7 days)
Initial follow-
up3
(14 days [7 
days] from last 
dose of study 
drugs)
Secondary follow-up3
Day 1
Day 15
(2 days)
Day 21
(2 days)
4 weeks (7 
days) after the 
last dose of 
panitumumab
8 weeks (7 
days) after the 
last dose of 
panitumumab
Dermatological 
examination7
X
At Week 4, then every 8 weeks
More frequently if there are new or 
changing lesions
X
Height (at screening 
only) and weight
X
X
Weight: At Week 4, 
then every 4 weeks
X
Ophthalmic 
examination
X
At Week 4, 
then as symptomatically warranted
X
Eastern Cooperative 
Oncology Group 
(ECOG) Performance 
Status
X
X6
At Week 4, 
then every 4 weeks
X
Vital signs (BP, HR, 
Body Temperature)
X
X15
X15
X
X15
X
12-lead ECG8
X
X6
X
X
At Week 4, 
then every 4 weeks until Week 24, 
then every 8 weeks
X
Hematology/Clinical 
Chemistry 
X
X6
X
X
At Week 4, 
then every 4 weeks until Week 24, 
then every 8 weeks
X
X3
X3
Coagulation 
Repeat as clinically 
indicated
X
CEA
X
X6
X
X
At Week 4, 
then every 4 weeks until Week 24, 
then every 8 weeks
X
X3
X3
ECHO (or MUGA)18
X
At Week 4,
then at Week 12 
and every 12 weeks thereafter
X


Novartis
Confidential
Page 81
Clinical Study Protocol Version 05
Protocol No. MEK116833
Screening1
First Treatment Period 
(Day 1 through Day 28)
Continuation Phase2
(7 days)
Initial follow-
up3
(14 days [7 
days] from last 
dose of study 
drugs)
Secondary follow-up3
Day 1
Day 15
(2 days)
Day 21
(2 days)
4 weeks (7 
days) after the 
last dose of 
panitumumab
8 weeks (7 
days) after the 
last dose of 
panitumumab
Collection of blood PK 
samples9
X
X 
X
X9
X9
(at 
progression)
Panitumumab dosing15
X
X
X
Every 2  weeks
Dabrafenib and 
trametinib dosing
CONTINUOUS daily dosing; 
Dabrafenib BID and trametinib once daily should be administered under fasting 
conditions, 
either one hour before a meal or 2 hours after a meal.
AE assessment 
CONTINUOUS
Urinalysis
X
X6
X
Disease Assessment13
X
Every 6 weeks until Week 24, 
then every 8 weeks
X13
X17
Long-term survival 
follow-up
X19
AE, Adverse Event; BP, blood pressure; CEA, ; ECHO, echocardiogram; ECG, electrocardiogram; ECOG, Eastern Cooperative Oncology Group; HR, heart rate; 
MUGA, 


Novartis
Confidential
Page 82
Clinical Study Protocol Version 05
Protocol No. MEK116833
1.
SCREENING WINDOW:  All screening assessments must be completed within 14 days prior to first dose except informed consent, ophthalmology exam, dermatology exam. 
ECHO/MUGA and Disease Assessment, which can occur within 35 days prior to the first dose. Note: Procedures conducted as part of the subject’s routine clinical management 
(e.g., blood counts, imaging study) and obtained prior to signing of informed consent may be utilized for screening or baseline purposes provided these procedures meet the 
protocol requirements.
2.
TREATMENT PHASE:  Assessments throughout the study are calendar-based starting from the first day of dosing (Day 1) in the first treatment period.  Dose interruptions should 
not alter the assessment schedule for any subsequent treatment period.  The Continuation Phase starts with Day 29; events in the Continuation Phase are allowed 7 days from 
projected date. Safety lab tests (chemistry/hematology/coag/UA) may be done the day before the visit so that results are ready on the day of the visit, but all assessments should 
be done within the 7 day window.
3.
FOLLOW-UP VISIT:  Initial follow-up visit should be 14 days from last dose of study drugs (7 days). If a subject is unable to return to the clinic due to hospitalization, site staff are 
encouraged to telephone the subject for assessment of AEs.  Secondary follow-up visits should occur at 4 weeks and 8 weeks after the last dose of panitumumab.
4.
PREGNANCY TEST:  Serum pregnancy test should be performed at screening; all subsequent pregnancy tests may be either serum or urine, and performed every 8 to 12 weeks.
5.
PHYSICAL EXAMINATION:  Complete physical examination must include integument and genitalia. Note: pelvic exam in female subjects may be completed up to 24 weeks prior 
to date of first dose.  Complete and brief physical examinations are defined in Section 6.2.
6.
DAY1 ASSESSMENTS:  If within 72 hours of Screening, this assessment does not need to be repeated on Day 1.
7.
DERMALOGICAL EVALUATION:  Baseline skin photography should be performed at Screening.  Photographs should be taken of new skin lesions that occur, or skin lesions that 
change on therapy. Refer to Section 6.2. French sites will perform dermatological exams monthly while on-therapy, and monthly for 6 months following discontinuation of 
dabrafenib or until initiation of another anti-neoplastic therapy, whichever comes first. Refer to Appendix 7 for full information.
8.
ECG:  Single ECGs will be collected prior to dosing.
9.
PHARMACOKINETIC SAMPLES:  Blood samples (4 mL) for PK analysis of dabrafenib and metabolites (hydroxy-dabrafenib and desmethyl-dabrafenib) and trametinib  will be 
collected on Day 1 and on Day 15 predose (within 30 minutes of dosing) and at 1, 2, 4, 6,and 8 hours after administration.  Blood samples (4 mL) for PK analysis of panitumumab 
will be collected on Day 1 and Day 15 predose (within 30 minutes of dosing panitumumab) and at 1 hour (end of infusion of panitumumab).  A single 4 mL blood sample for 
analysis of panitumumab will be collected pre-dose on Day 21 during the clinic visit. During the continuation phase, PK samples will be collected pre-dose at Week 8, Week 12, 
Week 16, and Week 20. PK blood samples for dabrafenib, trametinib, and panitumumab analysis should be collected along with the tumor biopsy taken at progression.  On days 
when serial PK samples are collected, subjects should be instructed to hold doses of dabrafenib and trametinib, report to the clinic for the predose PK blood draw, then dose with 
dabrafenib and trametinib.  Collect PK samples at the time indicated 5 minutes up to 2 hour sample, 20 minutes up to the 8 hour sample. On all days when a PK sample is 
collected, date and time of PK sample, date and time of the last doses of dabrafenib, trametinib, and panitumumab prior to the predose PK samples, and the date and time of the 
doses dabrafenib, trametinib, and panitumumab administered in the clinic  must be recorded
10. BIOPSY:  Pre- and post-dose tumor biopsies are mandatory. If the patient’s tumors are inaccessible for biopsy, permission to enroll must be granted by the Novartis Medical Lead.
11. BIOPSY:  Collection of on-treatment tumor biopsy for subjects with accessible tumors.  On-treatment biopsy may be collected 2 to 4 hours after dosing with oral study 
medication’from Day 15 to Day 18 (+3 days). Biopsies should be performed on non-target lesions when possible. PK samples for dabrafenib, trametinib and panitumumab 
analysis will be collected at the time of the post-dose tumor biopsy (24 hours) (unless the post-dose biopsy occurs on the same day that the Day 15 serial PK samples are 
collected).
12. BIOPSY:  Tumor biopsy at tumor progression in subjects who have had a radiologic response (20% or more) or had a stable disease for 6 months is highly encouraged.  .
13. DISEASE ASSESSMENT:  CT is the preferred method to measure lesions selected for response assessment. Refer to Appendix 4 for additional information regarding Response 
Evaluation Criteria In Solid Tumors (RECIST) version 1.1 methodology and criteria.  Follow-up disease assessment results for subjects who discontinue study medication for any 
other reason than progression or death. Even if study treatment is withdrawn, radiographic disease assessments (computed tomography [CT] or magnetic resonance imaging 


Novartis
Confidential
Page 83
Clinical Study Protocol Version 05
Protocol No. MEK116833
[MRI], as appropriate according to the method used at baseline) should continue every 8 weeks until documented disease progression, the start of new anti-cancer therapy, 
withdrawal of consent or death. 
14. TUMOR TISSUE SAMPLE:  Collection of archived tumor tissue or fresh tumor biopsies and determination of the subject’s tumor BRAF mutation status is required for enrollment; 
if a fresh tumor biopsy is collected during screening and up to prior to dosing on Day 1 for BRAF mutation confirmation, this tissue may be used for the day 1/ predose tumor 
biopsy.  
   The Day 1/predose tumor biopsy may be collected at any point after 
signing consent, after completing wash-out from prior therapies (either 5 half-lives or 14 days from last dose of prior therapy)..
15. VITAL SIGNS:  Vital signs and temperature should be measured within 30 minutes prior to initiation and upon completion of the panitumumab infusion (up to 15 minutes after the 
end of infusion).
 
17. After study treatment is withdrawn, disease assessments (the method used at baseline) should continue every 8 weeks until documented disease progression, the start of new 
anti-cancer therapy, withdrawal of consent, or death.
18. ECHO:  ECHO is preferred.  MUGA may be used only if ECHO is not available.  The same method must be used consistently from screening throughout the study.
19. OVERALL SURVIVAL:  Subjects will be followed for Overall Survival every 8 weeks after last dose of study drugs. See Section 6.3.1.for additional information.


Novartis
Confidential
Page 84
Clinical Study Protocol Version 05
Protocol No. MEK116833
3.11.2.
Part 2 Expansion Cohorts
Screening1
First Treatment Period       
(Day 1 through Day 28)
Continuation Phase2
(7 days)
Initial Follow-
up3
Secondary Follow-up3
Day 1
Day 15
(2 days)
4 weeks (7 
days) after the 
last dose of 
panitumumab
8 weeks (7 
days) after the 
last dose of 
panitumumab
Informed Consent
X
Archival tumor tissue 
or fresh tumor biopsy 
(BRAF mutation 
confirmation)12
X
Tumor tissue biopsy 
(mandatory)9
X (pre-dose)12
X 
(to be collected 
from Day15 to 
Day 18)10
X13(at 
progression)
Demographics
X
Medical history/ 
Interim History
X
X5
At Week 4, 
then every 4 weeks
X
Concurrent 
Medications
X
X5
X
At Week 4, 
then every 4 weeks
X
Serum or urine 
pregnancy test (-
hCG; women)4
X
Every 8 to 12 weeks4
X
Complete physical 
examination6
X
X
Brief physical 
examination6
X5
X
At Week 4, 
then every 4 weeks


Novartis
Confidential
Page 85
Clinical Study Protocol Version 05
Protocol No. MEK116833
Screening1
First Treatment Period       
(Day 1 through Day 28)
Continuation Phase2
(7 days)
Initial Follow-
up3
Secondary Follow-up3
Day 1
Day 15
(2 days)
4 weeks (7 
days) after the 
last dose of 
panitumumab
8 weeks (7 
days) after the 
last dose of 
panitumumab
Dermatological 
examination7
X
At Week 4, 
then every 8 weeks
More frequently if there are new or 
changing lesions
X
Height (at screening 
only) and weight
X
Weight: At Week 4, 
then every 4 weeks
X
Ophthalmic 
examination
X
at Week 4, 
then as symptomatically warranted
X
ECOG Performance 
Status
X
X5
At Week 4, 
then every 4 weeks
X
Vital signs (BP, HR, 
Body Temperature)
X
X15
X15
X15
X
12-lead ECG8
X
X5
X
At Week 4, 
then every 4 weeks until Week 24, 
then every 8 weeks
X
Hematology/Clinical 
Chemistry)
X
X5
X
At Week 4, 
then every 4 weeks until Week 24, 
then every 8 weeks
X3
X3
X3
Coagulation
Repeat as clinically 
indicated
X
CEA
X
At Week 6, 
then every 6 weeks until Week 24, 
then every 8 weeks
X3
X3
X3


Novartis
Confidential
Page 86
Clinical Study Protocol Version 05
Protocol No. MEK116833
Screening1
First Treatment Period       
(Day 1 through Day 28)
Continuation Phase2
(7 days)
Initial Follow-
up3
Secondary Follow-up3
Day 1
Day 15
(2 days)
4 weeks (7 
days) after the 
last dose of 
panitumumab
8 weeks (7 
days) after the 
last dose of 
panitumumab
ECHO (or MUGA)18
X
At Week 4, 
then at Week 12 
and every 12 weeks thereafter
X
Pharmacokinetics 
collection: blood
X11
X10,11
Predose; At Week 411
X11(at 
progression)
Panitumumab 
dosing15
X
X
X
Every 2 weeks
Dabrafenib and 
trametinib dosing
CONTINUOUS daily dosing; 
Dabrafenib BID and trametinib once daily should be administered under 
fasting conditions, either one hour before or 2 hours after a meal.
Urinalysis
X
X5
X
AE assessment 
CONTINUOUS
Disease 
Assessment14
X
Every 6 weeks until Week 24, 
then every 8 weeks
X14
X17


Novartis
Confidential
Page 87
Clinical Study Protocol Version 05
Protocol No. MEK116833
Screening1
First Treatment Period       
(Day 1 through Day 28)
Continuation Phase2
(7 days)
Initial Follow-
up3
Secondary Follow-up3
Day 1
Day 15
(2 days)
4 weeks (7 
days) after the 
last dose of 
panitumumab
8 weeks (7 
days) after the 
last dose of 
panitumumab
Long-term survival 
follow-up
X20
AE, Adverse Event; BP, blood pressure; CEA, ; ECHO, echocardiogram; ECG, electrocardiogram; ECOG, Eastern Cooperative Oncology Group; HR, heart rate; 
MUGA,
1.
SCREENING:  All screening assessments must be completed within 14 days prior to first dose except informed consent, ophthalmic exam, dermatological exam, ECHO/MUGA, 
and Disease Assessment, which can occur within 35 days prior to the first dose. Note: Procedures conducted as part of the subject’s routine clinical management (e.g., blood 
counts, imaging study) and obtained prior to signing of informed consent may be utilized for screening or baseline purposes provided these procedures meet the protocol 
requirements.
2.
TREATMENT PHASE:  Assessments throughout the study are calendar-based starting from the first day of dosing (Day 1) in the first treatment period.  Dose interruptions should 
not alter the assessment schedule for any subsequent treatment period.  The Continuation Phase starts with Day 29; events in the Continuation Phase are allowed 7 days from 
projected date. Safety lab tests (chemistry/hematology/coag/UA) may be done the day before the visit so that results are ready on the day of the visit, but all assessments should 
be done within the 7 day window.
3.
FOLLOW-UP VISIT:  Initial follow-up visit should be 14 days from last dose of study drugs (7 days).  If a subject is unable to return to the clinic due to hospitalization, site staff 
are encouraged to telephone the subject for assessment of AEs. Secondary follow-up visits should occur at 4 weeks and 8 weeks after the last dose of panitumumab.  Subjects 
are to be followed until progression for collection of PFS data and until death for collection of overall survival (OS) data. If a subject who is eligible for crossover to the triplet 
combination has not crossed over by 14 days past the last dose of study treatment, the Initial Follow-Up assessments should be done.  If a subject who is eligible for crossover to 
the triplet combination has not crossed over by 4 weeks past the last dose of panitumumab, the Secondary Follow-Up assessments should be done.
4.
PREGNANCY TEST:  Serum pregnancy test should be performed at screening; all subsequent pregnancy tests may be either serum or urine, and performed every 8 to 12 weeks.
5.
PHYSICAL EXAM:  If within 72 hours of Screening, this assessment does not need to be repeated on Day 1.
6.
PHYSICAL EXAM:  Complete physical examination must include integument and genitalia.  Note: pelvic exam in female subjects may be completed up to 24 weeks prior to date 
of first dose. Complete and brief physical examinations are defined in Section 6.2.
7.
DERMALOGICAL EVALUATION:  Baseline skin photography should be performed at Screening. Photographs should be taken of new skin lesions that occur, or skin lesions that 
change on therapy. Refer to Section 6.2. French sites will perform dermatological exams monthly while on-therapy, and monthly for 6 months following discontinuation of 
dabrafenib or until initiation of another anti-neoplastic therapy, whichever comes first. Refer to Appendix 7 for full information
8.
ECG:  Single ECGs will be collected prior to dosing.
9.
BIOPSY:  Pre- and post-dose tumor biopsies are mandatory. If the patient’s tumors are inaccessible for biopsy, permission to enroll must be granted by the Novartis Medical Lead.
10. BIOPSY:  Collection of on-treatment tumor biopsy for subjects with accessible tumors.  On-treatment biopsy may be collected 2 to 4 hours after dosing with oral study 
medication’from Day 15 to Day 18 (+3 days).  Biopsies should be performed on non-target lesions when possible.  A single PK samples for dabrafenib, trametinib, and 


Novartis
Confidential
Page 88
Clinical Study Protocol Version 05
Protocol No. MEK116833
panitumumab will be collected at the time of the post-dose tumor biopsy (24 hours) (unless the post-dose biopsy occurs on the same day that the Day 15 serial PK samples are 
collected).
11. PHARMACOKINETIC SAMPLES:  Blood samples (4 mL) for PK analysis of dabrafenib and metabolites (hydroxy-dabrafenib and desmethyl-dabrafenib) and trametinib  will be 
collected on Day 1 and Day 15 predose (within 30 minutes of dosing) and at 1, 2, 4, 6,and 8 hours after administration. Blood samples (4 mL) for PK analysis of panitumumab will 
be collected on Day 1 and Day 15 predose (within 30 minutes of dosing panitumumab)  and at 1 hour (end of infusion of panitumumab). A single 4 mL blood sample for analysis of 
panitumumab will be collected predose at the Week 4 clinic visit. On days when serial PK samples are collected, subjects should be instructed to hold doses of dabrafenib and 
trametinib, report to the clinic for the predose PK blood draw, then dose with dabrafenib and trametinib.  Collect PK samples at the time indicated 5 minutes up to 2 hour sample, 
20 minutes up to the 8 hour sample. On all days when PK samples are collected, date and time of the PK sample(s), date and time  of the last doses of dabrafenib, trametinib, 
and panitumumab prior to the predose PK sample, and date and time of the dose of dabrafenib, trametinib, and panitumumab in the clinic must be recorded.  A single blood 
sample for dabrafenib, trametinib, and panitumumab analysis should be collected along with the tumor biopsy taken at progression.
12. TUMOR TISSUE SAMPLE:  Collection of archived tumor tissue or fresh tumor biopsies and determination of the subject’s tumor BRAF mutation status is required for enrollment; 
if a fresh tumor biopsy is collected during screening and up to prior to dosing on Day1 for BRAF mutation confirmation, this tissue may be used for the day 1/ predose tumor 
  The Day 1/predose tumor biopsy may be collected at any point 
after signing consent, after completing wash-out from prior therapies (either 5 half-lives or 14 days from last dose of prior therapy).
13. BIOPSY AT PROGRESSION:  Optional tumor biopsy for subjects who had a radiologic response (20% or more decrease) or had a stable disease for 6 months at disease
progression (if feasible). A single PK sample will be collected at the time of tumor progression Refer to Section 6.7.2.
14. DISEASE ASSESSMENT:  CT is the preferred method to measure lesions selected for response assessment. Refer to Appendix 4 for additional information regarding RECIST 
1.1 methodology and criteria.  Even if study treatment is withdrawn, radiographic disease assessments (CT or MRI, as appropriate according to the method used at baseline) 
should continue every 8 weeks until documented disease progression, the start of new anti-cancer therapy, withdrawal of consent or death.
15. VITAL SIGNS:  Vital signs and temperature should be measured within 30 minutes prior to initiation and upon completion of the panitumumab infusion (up to 15 minutes after the 
end of infusion).
 
17. DISEASE ASSESSMENT:  After study treatment is withdrawn, disease assessments (the method used at baseline) should continue every 8 weeks until documented disease 
progression, the start of new anti-cancer therapy, withdrawal of consent, or death.
18. ECHO:  ECHO is preferred.  MUGA may be used only if ECHO is not available.  The same method must be used consistently from screening throughout the study.
20. OVERALL SURVIVAL:  Subjects will be followed for Overall Survival every 8 weeks after last dose of study drugs. See Section 6.3.1.for additional information.


Novartis
Confidential
Page 89
Clinical Study Protocol Version 05
Protocol No. MEK116833
3.11.3.
Part 3 Randomized Phase 2
Screening1
Treatment
Follow-up3
Day 1
Every 4 weeks2
(3 days)
Every 8 weeks2
(7 days)
Every 12 weeks2
(7 days)
Treatment discontinuation
(7 days)
Informed Consent
X
Archival tissue or 
fresh biopsy9
X
Demographics
X
Medical history/ 
Interim History
X
X5
X
X
Concurrent 
medications
X
X5
X
X
Serum or urine 
pregnancy test (-
hCG; women)4
X
X5
X4
X4
X
Complete physical 
examination6
X
X
Brief physical 
examination6
X5
X
Dermatological 
examination7
X
X7
X7
X
Height (at screening 
only) and weight
X
X5
X
X
X
Ophthalmic 
examination12
X
X12
X
ECOG Performance 
Status
X
X5
X
X
Vital signs (BP, HR, 
Body Temperature)
X
X10
X10
X10
X10
X
12-lead ECG8
X
X5
X
X
X
Hematology/Clinical 
X
X5
X13
X13
X
X3


Novartis
Confidential
Page 90
Clinical Study Protocol Version 05
Protocol No. MEK116833
Screening1
Treatment
Follow-up3
Day 1
Every 4 weeks2
(3 days)
Every 8 weeks2
(7 days)
Every 12 weeks2
(7 days)
Treatment discontinuation
(7 days)
Chemistry 
Coagulation
Repeat as clinically 
indicated
X
CEA
X
X5
X13
X13
X
X3
ECHO14
X
X14
X14
X
Tumor tissue biopsy 
(Optional)16
X (at progression)
Panitumumab dosing
X
X
Every two weeks
X
Every two weeks
X
Every two weeks
Dabrafenib and 
trametinib dosing
CONTINUOUS daily dosing; 
Dabrafenib BID and trametinib once daily should be administered under fasting 
conditions, either one hour before or 2 hours after a meal.
Urinalysis
X
X5
X
AE assessment 
CONTINUOUS
Disease 
Assessment11
X
Every 6 weeks 
until Week 24, 
then every 8 weeks
X11
AE, Adverse Event; BP, blood pressure; CEA, ; ECHO, echocardiogram; ECG, electrocardiogram; ECOG, Eastern Cooperative Oncology Group; HR, heart rate; MUGA, 


Novartis
Confidential
Page 91
Clinical Study Protocol Version 05
Protocol No. MEK116833
1.
All screening assessments must be completed within 14 days prior to first dose except informed consent, ophthalmic exam, dermatological exam, ECHO and Disease 
Assessment, which can occur within 35 days prior to the first dose. Note: Procedures conducted as part of the subject’s routine clinical management (e.g., blood counts, 
imaging study) and obtained prior to signing of informed consent may be utilized for screening or baseline purposes provided these procedures meet the protocol 
requirements.
2.
Assessments throughout the study are calendar-based starting from the first day of dosing (Day 1) in the first treatment period.  Dose interruptions should not alter the 
assessment schedule for any subsequent treatment period.  Events in the continuation phase are allowed 7 days from projected date. Safety lab tests 
(chemistry/hematology/coag/UA) can be done the day before the visit so the results are available on the day of the visit.
3.
Follow-up visit should be 14 days from last dose of study drugs (7 days).  If a subject is unable to return to the clinic due to hospitalization, site staff are encouraged to 
telephone the subject for assessment of AEs. If possible, subjects should return at 8 weeks after the last dose of panitumumab to evaluate for electrolyte disturbances.
4.
Serum pregnancy test should be performed at screening; all subsequent pregnancy tests may be either serum or urine and should be performed every 8 to 12 weeks.
5.
If within 72 hours of Screening, this assessment does not need to be repeated on Day 1.
6.
Complete physical examination must include integument and genitalia.  Note: pelvic exam in female subjects may be completed up to 24 weeks prior to date of first dose. 
Complete and brief physical examinations are defined in Section 6.2. A brief physical examination should be performed every 4 weeks.
7.
Baseline skin photography should be performed at Screening. Photographs should be taken of new skin lesions that occur, or skin lesions that change on therapy. Refer to 
Section 6.2.  The dermatology examination should be performed at Week 4, then every 8 weeks; the examination may be performed more frequently if there are new or 
changing lesions. French sites will perform dermatological exams monthly while on-therapy, and monthly for 6 months following discontinuation of dabrafenib or until initiation 
of another anti-neoplastic therapy, whichever comes first. Refer to Appendix 7 for full information
8.
Single ECGs will be collected at Week 4 then at Week 12, Week 24, and every 12 weeks thereafter.
9.
Collection of archived tumor tissue or fresh tumor biopsies and central confirmation of the subject’s tumor BRAF mutation status is required prior to enrollment.
10. Vital signs and temperature should be measured within 30 minutes prior to initiation and upon completion of the panitumumab infusion (up to 15 minutes after the end of 
infusion).
11. CT is the preferred method to measure lesions selected for response assessment. Refer to Appendix 4 for additional information regarding RECIST 1.1 methodology and 
criteria.  Even if study treatment is withdrawn, radiographic disease assessments (CT or MRI, as appropriate according to the method used at baseline) should continue every 
8 weeks until documented disease progression, the start of new anti-cancer therapy, withdrawal of consent or death. 
12. Subjects are required to have a standard ophthalmic exam (including baseline color fundus photographs) performed by an ophthalmologist at baseline, at Week 4 and as 
clinically warranted per protocol’s guidance (refer to Section 6.2).  The exam will include indirect fundoscopic examination, visual acuity (corrected), visual field examination, 
tonometry, and direct fundoscopy, with special attention to retinal abnormality that are predisposing factors for RVO or RPED.
13. Hematology/Clinical chemistries should be assessed at baseline, then again at Week 4, then every 8 weeks.  
14. LVEF should be assessed by ECHO at Week 4 then at Week 12, Week 24, and every 12 weeks thereafter.  ECHO is the preferred method; MUGA may be used only if 
ECHO is not available.  The same method must be used consistently from screening throughout the study
 
16. Optional tumor biopsy for subjects who had a radiologic response (20% or more decrease) or had a stable disease for 6 months at disease progression.  The biopsy at 
progression is highly encouraged.


Novartis
Confidential
Page 92
Clinical Study Protocol Version 05
Protocol No. MEK116833
3.11.4.
Part 4 Dose Escalation and Cohort Expansion
Day:
Screening1
First treatment period
Day 1 thru Day 28
Continuation phase2
Initial follow-up3
Secondary 
follow-up3
Tertiary 
follow-up3
Visit Window 
(relative to Day 1)
-14 to -1 
days
on 
Day 1
on Day 15
(2 days)
On Day 21
(2 days)
7 days
14 (7) days from 
last dose of 
trametinib
4 weeks (7 
days) after 
the last dose 
of 
panitumumab
8 weeks (7 
days) after 
the last dose 
of 
panitumumab
Informed Consent
X1
Demographics
X
Collection of archival 
tissue14
X1
Complete physical5
X1
X
Brief physical5
X
X
At Week 4, then every 
4 wks
Medical/medication/
drug/alcohol history
X
X6
X
X
Concurrent medications
X
X
X
At Week 4, 
then every 4 weeks
X
X
12-lead ECG7
X
X6
X
X
At Week 4, then every 
4 weeks until Week 
24, then every 8 
weeks
X
Vital signs13 (including 
weight)
X
X
X
X
X13
X
Height
X
Ophthalmic examination
X1
At Week 4, then as 
symptomatically 
warranted
ECOG
X
X6
At Week 4, then every 
4 wks
X


Novartis
Confidential
Page 93
Clinical Study Protocol Version 05
Protocol No. MEK116833
Day:
Screening1
First treatment period
Day 1 thru Day 28
Continuation phase2
Initial follow-up3
Secondary 
follow-up3
Tertiary 
follow-up3
Visit Window 
(relative to Day 1)
-14 to -1 
days
on 
Day 1
on Day 15
(2 days)
On Day 21
(2 days)
7 days
14 (7) days from 
last dose of 
trametinib
4 weeks (7 
days) after 
the last dose 
of 
panitumumab
8 weeks (7 
days) after 
the last dose 
of 
panitumumab
ECHO/MUGA16
X1
At Week 4, then at 
Week 12, then every 
12 weeks
X
Serum or urine 
pregnancy test (-
hCG;women)4
X
Every 8 to 12 weeks4
Hematology/Clinical 
Chemistry
X
X6
At Week 4, 
then every 4 weeks 
until Week 24, then 
every 8 weeks
X
X
Urinalysis
X
X6
X
Coagulation
Repeat as clinically 
indicated
X1
CEA
X
At Week 6, 
then every 6 weeks 
until Week 24, then 
every 8 weeks
X
X
Tumor biopsy9
X (pre-dose)9
X9 (to be 
collected 
from Day 15 
to Day 18)
X11
(at progression)


Novartis
Confidential
Page 94
Clinical Study Protocol Version 05
Protocol No. MEK116833
Day:
Screening1
First treatment period
Day 1 thru Day 28
Continuation phase2
Initial follow-up3
Secondary 
follow-up3
Tertiary 
follow-up3
Visit Window 
(relative to Day 1)
-14 to -1 
days
on 
Day 1
on Day 15
(2 days)
On Day 21
(2 days)
7 days
14 (7) days from 
last dose of 
trametinib
4 weeks (7 
days) after 
the last dose 
of 
panitumumab
8 weeks (7 
days) after 
the last dose 
of 
panitumumab
AE assessment
CONTINUOUS
PK blood sample8
X
X
X
X
Panitumumab Dosing
X
X
X
every 2 weeks 
Trametinib dosing
CONTINUOUS daily dosing; 
Trametinib once daily should be administered under fasting 
conditions, either one hour before or 2 hours after a meal.
Disease assessments12
X1
Every 6 weeks until 
Week 24, 
then every 8 weeks. 15
Long-term survival 
follow-up
X18
AE, Adverse Event; BP, blood pressure; CEA, ; ECHO, echocardiogram; ECG, electrocardiogram; ECOG, Eastern Cooperative Oncology Group; HR, heart rate; MUGA, 


Novartis
Confidential
Page 95
Clinical Study Protocol Version 05
Protocol No. MEK116833
1.
SCREENING ASSESSMENTS:  All screening assessments must be completed within 14 days prior to first dose except informed consent, ophthalmology exam, dermatological 
exam, ECHO/MUGA and Disease Assessment, which can occur within 35 days prior to the first dose. Note: Procedures conducted as part of the subject’s routine clinical 
management (e.g., blood counts, imaging study) and obtained prior to signing of informed consent may be utilized for screening or baseline purposes provided these procedures 
meet the protocol requirements.
2.
TREATMENT PERIOD:  Assessments throughout the study are calendar-based starting from the first day of dosing (Day 1) in the first treatment period.  Dose interruptions should 
not alter the assessment schedule for any subsequent treatment period.  The Continuation Phase starts with Day 29; events in the continuation phase are allowed 7 days from 
projected date.  Safety lab tests (chemistry/hematology/UA) may be done the day before the visit so that results are available on the day of the visit, but all assessments should be 
done within the 7 day window.
3.
FOLLOW-UP VISIT:  Initial follow-up visit should be 14 days (7 days) from last dose of trametinib. If a subject is unable to return to the clinic due to hospitalization, site staff are 
encouraged to telephone the subject for assessment of AEs. Secondary follow-up visits should occur at 4 weeks and 8 weeks after the last dose of panitumumab.  Subjects are to 
be followed until progression for collection of PFS data and until death for collection of overall survival (OS) data.  If a subject who is eligible for crossover to the triplet combination 
has not crossed over by 14 days past the last dose of study treatment, the Initial Follow-Up assessments should be done.  If a subject who is eligible for crossover to the triplet 
combination has not crossed over by 4 weeks past the last dose of panitumumab, the Secondary Follow-Up assessments should be done.
4.
PREGNANCY TEST:  Serum pregnancy test should be performed at screening; all subsequent pregnancy tests may be either serum or urine, and performed every 8 to 12 weeks.
5.
PHYSICAL EXAMINATION:  Complete physical examination must include integument. Note: pelvic exam in female subjects is not required in Part 4. Complete and brief physical 
examinations are defined in Section 6.2.
6.
PHYSICAL EXAMINATION:  If within 72 hours of Screening, this assessment does not need to be repeated on Day 1.
7.
ECG:  Single ECGs will be collected prior to dosing.
8.
PHARMACOKINETIC SAMPLES:  Blood samples (2 mL) for PK analysis of trametinib will be collected on Day 1 and on Day 15 predose (within 30 minutes of dosing) and at 1, 2 
and 4 hours after administration. Blood samples (4 mL) for PK analysis of panitumumab will be collected on Day 1 and on Day 15 predose (within 30 minutes of dosing with 
panitumumab) and at 1 hour ( at the end of infusion of panitumumab). A single 4 mL blood sample for analysis of panitumumab will be collected pre-dose on Day 21 during the 
clinic visit. During the continuation phase, PK samples (for trametinib and panitumumab) will be collected pre-dose at Week 8, Week 12, Week 16, and Week 20. PK blood 
samples for trametinib, and panitumumab analysis should be collected along with the tumor biopsy taken at progression. On days when serial PK samples are collected, subjects 
should be instructed to hold doses of trametinib, report to the clinic for the predose PK blood draw, then dose with trametinib. Collect PK samples at the time indicated 5 minutes 
up to 2 hour sample, 20 minutes up to the 4 hour sample. 
9.
TUMOR TISSUE SAMPLE/DAY1:  Collection of archived tumor tissue or fresh tumor biopsies and determination of the subject’s tumor BRAF mutation status is required for 
enrollment; if a fresh tumor biopsy is collected during screening and up to prior to dosing on Day1 for BRAF mutation confirmation, this tissue may be used for the day 1/ predose 
tumor biopsy. 
  The Day 1/predose tumor biopsy may be collected at any point 
after signing consent, after completing wash-out from prior therapies (either 5 half-lives or 14 days from last dose of prior therapy). Pre- and post-dose tumor biopsies are 
mandatory. If the patient’s tumors are inaccessible for biopsy, permission to enroll must be granted by the Novartis Medical Lead.
10. BIOPSY:  Collection of on-treatment tumor biopsy for subjects with accessible tumors. On-treatment biopsy may be collected 2 to 4 hours after dosing with oral study medication 
from Day 15 to Day 18. Biopsies should be performed on non-target lesions when possible. PK samples for trametinib and panitumumab analysis will be collected at the time of 
the post-dose tumor biopsy (24 hours) (unless the post-dose biopsy occurs on the same day that the Day 15 serial PK samples are collected).
11. BIOPSY:  Tumor biopsy at tumor progression in subjects who have had a response is highly encouraged. PK blood samples for trametinib and panitumumab analysis should be 
collected along with the tumor biopsy taken at progression.
12. DISEASE ASSESSMENT:  CT is the preferred method to measure lesions selected for response assessment. Refer to Appendix 4 for additional information regarding Response 
Evaluation Criteria In Solid Tumors (RECIST) version 1.1 methodology and criteria. Even if study treatment is withdrawn, radiographic disease assessments (computed 


Novartis
Confidential
Page 96
Clinical Study Protocol Version 05
Protocol No. MEK116833
tomography [CT] or magnetic resonance imaging [MRI], as appropriate according to the method used at baseline) should continue every 8 weeks until documented disease 
progression, the start of new anti-cancer therapy, withdrawal of consent or death.
13. VITAL SIGNS: Vital signs and temperature should be measured within 30 minutes prior to initiation and upon completion of the panitumumab infusion (up to 15 minutes after the 
end of infusion).
 
15. DISEASE ASSESSMENT:  After study treatment is withdrawn, disease assessments (the method used at baseline) should continue every 8 weeks until documented disease 
progression, the start of new anti-cancer therapy, withdrawal of consent, or death.
16. ECHO:  ECHO is preferred. MUGA may be used only if ECHO is not available. The same method must be used consistently from screening throughout the study.
18. OVERALL SURVIVAL:  Subjects will be followed for Overall Survival every 8 weeks after last dose of study drugs. See Section 6.3.1.for additional information.


Novartis
Confidential
Page 97
Clinical Study Protocol Version 05
Protocol No. MEK116833
3.11.5.
Intra-subject Doublet to Triplet Crossover
Crossover 
Screening1
Crossover
Day 1
Crossover Treatment Phase2
(7 days)
Initial 
Follow-up3
Secondary Follow-up3
4 weeks (7 
days) after the 
last dose of 
panitumumab
8 weeks (7 
days) after the 
last dose of 
panitumumab
Medical history/ 
Interim History
X
Every 4 weeks 
X
Concurrent 
Medications
X
At Week 4, 
then every 4 weeks 
X
Serum or urine 
pregnancy test (-
hCG; women) 
Every 8 to 12 weeks
X
Physical 
examination4
X
Every 4 weeks 
X4
Dermatological 
examination5
X
At Week 4, 
then every 8 weeks
More frequently if there are new or changing lesions
X
Weight
X
Every 4 weeks 
X
Ophthalmic 
examination
X
at Week 4, 
then as symptomatically warranted
X
ECOG Performance 
Status
X
Every 4 weeks 
X
Vital signs (BP, HR, 
Body Temperature)
X
X6
Before and after panitumumab infusion6
X
12-lead ECG
X
At Week 4, 
then every 4 weeks until Week 24, then every 8 weeks
X
Hematology/Clinical 
Chemistry)
X
At Week 4, 
then every 4 weeks until Week 24, then every 8 weeks
X
X
X
Coagulation
As clinically indicated


Novartis
Confidential
Page 98
Clinical Study Protocol Version 05
Protocol No. MEK116833
Crossover 
Screening1
Crossover
Day 1
Crossover Treatment Phase2
(7 days)
Initial 
Follow-up3
Secondary Follow-up3
4 weeks (7 
days) after the 
last dose of 
panitumumab
8 weeks (7 
days) after the 
last dose of 
panitumumab
CEA
X
At Week 6, 
then every 6 weeks until Week 24, then every 8 weeks
X
X
ECHO (or MUGA)7
X
At Week 4, 
then at Week 12 
and every 12 weeks thereafter
X
Panitumumab 
dosing6
X
Every 2 weeks
Dabrafenib and 
trametinib dosing
CONTINUOUS daily dosing; 
Dabrafenib BID and trametinib once daily should be administered under 
fasting conditions, either one hour before or 2 hours after a meal.
Urinalysis
X
AE assessment 
CONTINUOUS
Disease 
Assessment9
X
Every 6 weeks until Week 24, 
then every 8 weeks
X9
X10
Long-term survival 
follow-up
X11


Novartis
Confidential
Page 99
Clinical Study Protocol Version 05
Protocol No. MEK116833
AE, Adverse Event; BP, blood pressure; CEA, ; ECHO, echocardiogram; ECG, electrocardiogram; ECOG, Eastern Cooperative Oncology Group; HR, heart rate; 
MUGA, 
1.
SCREENING WINDOW:  All screening assessments must be completed within 14 days prior to first crossover dose except ophthalmic exam, dermatological exam, ECHO/MUGA, 
and Disease Assessment, which can occur within 35 days prior to the first dose. Note: Procedures conducted as part of the subject’s initial follow-up assessments may be utilized 
for screening or baseline purposes provided these procedures meet the protocol requirements.
2.
TREATMENT PHASE:  Assessments throughout the study are calendar-based starting from the first day of dosing (Day 1) in the first treatment period.  Dose interruptions should 
not alter the assessment schedule for any subsequent treatment period.  Safety lab tests (chemistry/hematology/coag/UA) may be done the day before the visit so that results are 
ready on the day of the visit, but all assessments should be done within the 7 day window.
3.
FOLLOW_UP VISITS:  Initial follow-up visit should be 14 days from last dose of study drugs (7 days).  If a subject is unable to return to the clinic due to hospitalization, site staff 
are encouraged to telephone the subject for assessment of AEs. Secondary follow-up visits should occur at 4 weeks and 8 weeks after the last dose of panitumumab.  
4.
PHYSICAL EXAM:  A brief physical exam should be conducted at screening and every 4 weeks.  A complete physical examination including integument and genitalia should be 
performed during the initial follow-up visit.  Note: pelvic exam in female subjects may be completed up to 24 weeks prior to date of first dose. Complete and brief physical 
examinations are defined in Section 6.2.
5.
DERMATOLOGICAL EVALUATION:  Baseline skin photography should be performed at Screening. Photographs should be taken of new skin lesions that occur, or skin lesions 
that change on therapy. Refer to Section 6.2. French sites will perform dermatological exams monthly while on-therapy, and monthly for 6 months following discontinuation of 
dabrafenib or until initiation of another anti-neoplastic therapy, whichever comes first. Refer to Appendix 7 for full information.
6.
VITAL SIGNS:  Vital signs and temperature should be measured within 30 minutes prior to initiation and upon completion of the panitumumab infusion (up to 15 minutes after the 
end of infusion).
7.
ECHO:  ECHO is preferred.  MUGA may be used only if ECHO is not available.  The same method must be used consistently from screening throughout the study.
 
9.
DISEASE ASSESSMENT:  CT is the preferred method to measure lesions selected for response assessment. Refer to Appendix 4 for additional information regarding RECIST 
1.1 methodology and criteria.  Even if study treatment is withdrawn, radiographic disease assessments (CT or MRI, as appropriate according to the method used at baseline) 
should continue every 8 weeks until documented disease progression, the start of new anti-cancer therapy, withdrawal of consent or death.
10. DISEASE ASSESSMENT:  After study treatment is withdrawn, disease assessments (the method used at baseline) should continue every 8 weeks until documented disease 
progression, the start of new anti-cancer therapy, withdrawal of consent, or death.
11. OVERALL SURVIVAL:  Subjects will be followed for Overall Survival every 8 weeks after last dose of study drugs. See Section 6.3.1.for additional information.


Novartis
Confidential
Page 100
Clinical Study Protocol Version 05
Protocol No. MEK116833
4.
STUDY POPULATION
4.1.
Number of Subjects
The number of dose levels and the level at which the MTD will be reached cannot be 
determined in advance. An adequate number of subjects will be enrolled into the study to 
establish a recommended dose(s) and schedule(s) for the further study of 
dabrafenib/panitumumab and dabrafenib/trametinib/panitumumab combinations.  
To complete Part 1, it is estimated that 24 evaluable subjects (~4 per cohort) will be 
enrolled.  Part 2 will enroll approximately 100 subjects in total. In order to confirm safety 
in Japanese patients, up to three additional Japanese patients may be enrolled in Japan in 
each expansion cohort.  By the end of Part 2, approximately 30 subjects will be evaluated 
for each dose cohort.  For Part 3, approximately 47 subjects per arm will be enrolled.  For 
Part 4A (dose escalation), it is estimated that up to 18 evaluable subjects (~6 per cohort) 
will be enrolled.  Part 4B will enroll approximately 17 additional subjects in each of two 
expansion populations (n=34). This will be a total of approximately 20 patients at the 
MTD for each patient population, including the subjects enrolled in Part 4A. In order to 
confirm safety in Japanese patients, three additional Japanese patients may be enrolled in 
Japan in each expansion population for Part 4.  Up to an additional 20 subjects with 
BRAF mutant CRC may be enrolled in Part 4 to further explore safety and efficacy of the 
trametinib plus panitumumab doublet.
If subjects discontinue the study before completing Week 4, additional subjects may be 
enrolled at the discretion of the Sponsor in consultation with the investigator.
4.2.
Eligibility Criteria
4.2.1.
Part 1, 2 and 4 Inclusion and Exclusion Criteria
The investigator should refer to the GSK2118436 IB [GlaxoSmithKline Document 
Number 2012N136095_00], the GSK1120212 IB [GlaxoSmithKline Document Number 
HM2009/00151/03]  and the GSK1120212 + GSK2118436 Clinical IB 
[GlaxoSmithKline Document Number, 2011N126811_00] for detailed information 
regarding ongoing clinical studies, pharmacokinetics in the target disease populations, as 
well as observed safety and efficacy findings.
4.2.1.1.
Part 1, 2 and 4 Inclusion Criteria
Specific information regarding warnings, precautions, contraindications, AEs, and other 
pertinent information on the study treatment(s) or panitumumab that may impact subject 
eligibility is provided in the Investigator Brochure (IB) and product label.
Deviations from inclusion criteria are not allowed because they can potentially jeopardize 
the scientific integrity of the study, regulatory acceptability or subject safety. Therefore, 
adherence to the criteria as specified in the protocol is essential.
Subjects eligible for enrolment in this study must meet all of the following criteria:


Novartis
Confidential
Page 101
Clinical Study Protocol Version 05
Protocol No. MEK116833
1.
Provided signed written informed consent, which includes compliance with the 
requirements and restrictions listed in the consent form.
2.
Male or female 18 years of age and able to swallow and retain orally administered 
study treatment and does not have any clinically significant gastrointestinal (GI) 
abnormalities that may alter absorption such as malabsorption syndrome or major 
resection of the stomach and/or bowels.
3.
Part 1 and Part 2: Histologically- or cytologically-confirmed diagnosis of advanced 
or metastatic BRAF V600E mutation positive colorectal cancer (CRC), as 
determined by relevant genetic testing and documented in source.  For subjects 
enrolled based on local mutation testing, confirmation of mutation will occur 
following registration in Part 1 and Part 2.
Note: Subjects will not be excluded if centralized testing is later found to be 
discordant or uninformative (e.g., inadequate sample), but additional subjects may 
be enrolled as replacement subjects at the discretion of the Sponsor and in 
consultation with the investigator. 
4.
Part 4A and 4B ONLY: Histologically- or cytologically-confirmed diagnosis of 
advanced or metastatic colorectal cancer (CRC) that either:

harbours the BRAF V600E –mutation, as determined by relevant genetic testing 
and documented in source, OR 

has developed secondary resistance to anti-EGFR therapy, defined as patients that 
derived benefit (disease control based on investigator assessment for > 6 months 
OR partial response [confirmed or unconfirmed] based on RECIST 1.1) from 
prior anti-EGFR-containing therapy (as defined below) and then subsequently 
progressed on therapy.  The anti-EGFR therapy must have been the most recent 
therapy and the patient must have progressed based on investigator assessment
within 3 months of screening.  Acceptable prior anti-EGFR-containing therapies 
include:
a.
Monotherapy anti-EGFR, including cetuximab or panitumumab OR
b. irinotecan/anti-EGFR combo after previously having disease progression 
(based on investigator assessment) on an irinotecan-containing regimen
5.
Archival tissue is required; if archival tissue is not available or found to not contain 
tumor tissue, a fresh biopsy is required.  
6.
Measurable disease per RECIST version 1.1(Refer to Appendix 4).
7.
ECOG Performance Status of 0 or 1.
8.
Men with a female partner of childbearing potential must have either had a prior 
vasectomy or agree to use one of the contraception methods listed in Section 7.1.2
from 7 days prior to the first dose of study drug(s) and until 6 months after the last 
dose of panitumumab, or 16 weeks following the last dose of dabrafenib or 
trametinib, whichever is later to allow for clearance of any altered sperm.  
9.
Female subjects are eligible if:


Novartis
Confidential
Page 102
Clinical Study Protocol Version 05
Protocol No. MEK116833

Non-childbearing potential defined as pre-menopausal females with a 
documented tubal ligation or hysterectomy; or post-menopausal female defined 
as 12 months of spontaneous amenorrhea to be verified with a follicle-
stimulating hormone (FSH) level >40MIU/mL and estradiol level <40pg/mL.  
Females on hormone replacement therapy (HRT) and whose menopausal status 
is in doubt will be required to use one of the contraception methods in Section 
7.1.1 if they wish to continue their HRT during the study.  Otherwise, they must 
discontinue HRT to allow confirmation of post-menopausal status prior to study 
enrollment.  For most forms of HRT, at least 2 to 4 weeks will elapse between 
the cessation of therapy and the blood draw; this interval depends on the type 
and dosage of HRT. Following confirmation of post-menopausal status, they can 
resume use of HRT during the study without use of a contraceptive method.

Child-bearing potential and agrees to use one of the contraceptive methods listed 
in Section 7.1.1 for an appropriate period of time as determined by the product 
label and applicable IBs) prior to the start of dosing to sufficiently minimize risk 
of pregnancy at that point. 
10. Female subjects must agree to use contraception from 7 days prior to the first dose of 
study drug(s) until 6 months after the last dose of panitumumab, until 4 months after 
the last dose of trametinib, or 4 weeks after the last dose of dabrafenib, whichever is 
longer. Note: oral contraceptives are not reliable due to potential drug-drug 
interactions.  Additionally, women of childbearing potential must have had a 
negative serum pregnancy test within 14 days prior to the first dose of study drug(s).
11. Adequate organ system function as defined in Table 23:


Novartis
Confidential
Page 103
Clinical Study Protocol Version 05
Protocol No. MEK116833
Table 23
Definitions for Adequate Baseline Organ Function
System
Laboratory Values
Hematologic 
Absolute neutrophil count
1.2 × 109/L 
Hemoglobin
9 g/dL or 5.6 mmol/L
Platelets
100 × 109/L  
Coagulation parameters
Prothrombin Time / International 
Normalized Ratio (PT/INR) and Partial 
Thromboplastin Time (PTT)a
≤1.5 x ULN
Chemistry
Mg++
≥ LLN
Hepatic
Albumin
2.5 g/dL or 25 g/L
Total bilirubin
1.5 x ULN
AST and ALT
2.5× ULN 
Renal
Creatinine or
1.5 ULN
Calculated creatinine clearanceb
or 
24-hour urine creatinine clearance
50 mL/min 
Cardiac
Left Ventricular Ejection fraction (LVEF)
≥ LLN by ECHO or multigated acquisition scan 
(MUGA)c
a.
Subjects receiving anticoagulant therapy are eligible if their INR is stable and within the recommended range for 
the desired level of anticoagulation
b.
Calculated by the Cockcroft-Gault formula.
c.
Same method as used at baseline must be use throughout the study, ECHO is the preferred method.
12. Subjects enrolled in France or Italy: In France or Italy, a subject will be eligible for 
inclusion in this study only if either affiliated to, or a beneficiary of, a social security 
category.
4.2.1.2.
Part 1, Part 2, and Part 4 Exclusion Criteria
Deviations from exclusion criteria are not allowed because they can potentially 
jeopardize the scientific integrity of the study, regulatory acceptability or subject safety. 
Therefore, adherence to the criteria as specified in the protocol is essential.
Subjects meeting any of the following criteria must not be enrolled in the study:
1.
History of prior malignancy, other than colorectal cancer.
Exception:  Subjects who have been disease-free for 5 years, or subjects with a history of completely 
resected non-melanoma skin cancer or successfully treated in situ carcinoma are eligible.


Novartis
Confidential
Page 104
Clinical Study Protocol Version 05
Protocol No. MEK116833
2.
Any serious and/or unstable pre-existing medical, psychiatric disorder or other 
conditions that could interfere with subject’s safety, obtaining informed consent or 
compliance to the study procedures.
3.
Current active liver or biliary disease (with the exception of Gilbert's syndrome or 
asymptomatic gallstones, liver metastases or otherwise stable chronic liver disease 
per investigator’s assessment).
4.
History of sensitivity to heparin or heparin-induced thrombocytopenia. 
5.
Currently receiving cancer therapy (chemotherapy, radiation therapy, 
immunotherapy or biologic therapy), as described in Section 8.
6.
Prior exposure to a MEK inhibitor.
7.
Part 1, Part 2 and BRAF-mutant patients in Part 4 ONLY: Prior exposure to a BRAF 
inhibitor.
8.
Part 1, Part 2 and BRAF-mutant patients in Part 4 ONLY: Known presence of
KRAS-mutation based on previous KRAS-testing.
Note: Prospective KRAS testing is not required.  However, if the results of 
previous KRAS testing are known, they must be used in assessing eligibility.  
KRAS testing will be performed retrospectively for all patients.
9.
Part 2B ONLY: Patients treated with > 4 prior lines of therapy for metastatic disease 
will not be eligible.
10. Received an investigational or approved anti-cancer drug within 4 weeks, or within 5 
half-lives (whichever is shorter) of the first dose of study drug(s). At least 14 days 
must have passed between the last dose of prior investigational agent and the first 
dose of study drug(s). 
11. Current use of a prohibited medication or requirement to dose with any of these 
medications during treatment with study drug(s).
12. A history of Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection 
(subjects with laboratory evidence of cleared HBV and/or HCV will be permitted.
13. Any major surgery, radiotherapy or immunotherapy within the 4 weeks prior to first 
dose of study drug(s). Limited radiotherapy with in the 2 weeks prior to first dose of 
study drug(s).
14. Chemotherapy regimens with delayed toxicity within the 3 weeks prior to first dose 
of study drug(s).  Chemotherapy regimens given continuously or on a weekly basis 
with limited potential for delayed toxicity within 2 weeks prior to first dose of study 
drug(s).
15. Unresolved toxicity greater than NCI-CTCAE version 4 Grade 1 from previous anti-
cancer therapy, with the exception of Grade 2 alopecia, Grade 2 neuropathy, or 
laboratory values that are allowed per Table 23.
16. History of retinal vein occlusion (RVO).
17. Presence of active gastrointestinal disease or other condition that will interfere 
significantly with the absorption, distribution, metabolism or excretion of drugs.  
Previous colectomy is acceptable.


Novartis
Confidential
Page 105
Clinical Study Protocol Version 05
Protocol No. MEK116833
18. Subjects with brain metastases are excluded, unless:

All known lesions must be previously treated with surgery or stereotactic 
radiosurgery, and 

Brain lesion(s), if present, must be confirmed stable (i.e., no increase in lesion 
size) for 90 days prior to first dose of study drug(s).  This must be 
documented with two consecutive MRI or CT scans using contrast, and

Asymptomatic with no corticosteroids requirement for 30 days prior to first 
dose of study drug(s), and

No enzyme-inducing anticonvulsants for 14 days prior to first dose of study 
drug(s).

In addition, for subjects that had brain metastases but currently have no 
evidence of disease (NED), NED for 12 weeks is required and must be 
confirmed by two consecutive MRI or CT scans (using contrast) separated by 
6 weeks, prior to randomization. Enrollment of a subject with brain 
metastases who meet the above criteria requires approval of a Novartis Medical
Lead.
19. Psychological, familial, sociological or geographical conditions that do not permit 
compliance with the protocol. 
20. History or evidence of cardiovascular risk including any of the following:

LVEF<LLN

A QT interval corrected for heart rate using the Bazett’s formula (QTcB;) 
480 msec; Appendix 6.

History or evidence of current clinically significant uncontrolled 
arrhythmias.
Exception:  Subjects with controlled atrial fibrillation for >30 days prior 
to randomization are eligible.

History of acute coronary syndromes (including myocardial infarction and 
unstable angina), coronary angioplasty, or stenting within 6 months prior 
to randomization.

History or evidence of current ≥ Class II congestive heart failure as 
defined by New York Heart Association (NYHA).

Treatment refractory hypertension defined as a blood pressure of systolic> 
140 mmHg and/or diastolic > 90 mm Hg which cannot be controlled by 
anti-hypertensive therapy;

Subjects with intra-cardiac defibrillators or permanent pacemakers;

Known cardiac metastases;
21. Unstable pulmonary embolism, deep vein thrombosis, or other significant 
arterial/venous thromboembolic event ≤ 30 days before randomization.  If on 
anticoagulation, subject must be on stable therapeutic dose prior to randomization.


Novartis
Confidential
Page 106
Clinical Study Protocol Version 05
Protocol No. MEK116833
22. Subjects with a history of pneumonitis or interstitial lung disease (ILD).
23. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs 
chemically related to the study drug(s) or their excipients.
24. Pregnant or lactating female.
25. Unwillingness or inability to follow the procedures outlined in the protocol.
26. Uncontrolled diabetes or other medical condition that may interfere with assessment 
of toxicity.
4.2.2.
Part 3 Inclusion and Exclusion Criteria
The investigator should refer to the GSK2118436 IB [GlaxoSmithKline Document 
Number 2012N136095_00], the GSK1120212 IB [GlaxoSmithKline Document Number 
HM2009/00151/03] and the GSK1120212 + GSK2118436 Clinical IB [GlaxoSmithKline 
Document Number, 2011N126811_00] for detailed information regarding ongoing 
clinical studies, pharmacokinetics in the target disease populations, as well as observed 
safety and efficacy findings.
4.2.2.1.
Part 3 Inclusion Criteria
Deviations from inclusion criteria are not allowed because they can potentially jeopardize 
the scientific integrity of the study, regulatory acceptability or subject safety. Therefore, 
adherence to the criteria as specified in the protocol is essential.
A subject will be eligible for inclusion in Part 3 of this study only if all of the following 
criteria apply:
1.
Capable of giving written informed consent, which includes compliance with the 
requirements and restrictions listed in the consent form.
2.
Male or female 18 years of age and able to swallow and retain oral medication.
3.
Histologically- or cytologically-confirmed diagnosis of BRAFV600E mutation 
positive advanced or metastatic colorectal cancer (CRC who are eligible to receive 
fluoropyrimidine-containing chemotherapy regimen that have experienced 
documented radiographic progression on one prior line of fluoropyrimidine-
containing chemotherapy  (previous anti-EGFR therapy is excluded), 
4.
Second-line for advanced/metastatic disease, having failed or been intolerant to at 
least one regimen of fluoropyrimidine-containing chemotherapy including irinotecan 
or oxaliplatin in the advanced/metastatic setting.  
5.
Tumor type criteria: 
BRAF V600E mutation-positive colorectal cancer, as determined by relevant 
genetic testing and documented in source.  Enrollment in Part 3 will require 
prospective testing for BRAF mutation V600E using a CLIA certified BRAF 
mutation assay that will be performed in a central laboratory.  


Novartis
Confidential
Page 107
Clinical Study Protocol Version 05
Protocol No. MEK116833
KRAS wild-type colorectal cancer as determined by relevant genetic testing 
(Codon 12 and 13) and documented in source.  Enrollment in Part 3 may only 
occur following confirmation of KRAS wild-type cancer.
6.
Archival tissue is required; if archival tissue is not available or found to not contain 
tumor tissue, a fresh biopsy is required for prospective central confirmation of BRAF 
mutation status.  
7.
Measurable disease per RECIST version 1.1.
8.
ECOG Performance Status of 0 or 1.
9.
Male subjects must agree to use one of the contraception methods listed in Section 
7.1.2. This criterion must be followed from 7 days prior to the e first dose of study 
drug(s) until 6 months after the last dose of panitumumab, or 16 weeks following the 
last dose of dabrafenib or trametinib, whichever is later.
10. Female subjects are eligible if of:

Non-childbearing potential defined as pre-menopausal females with a 
documented tubal ligation or hysterectomy; or post-menopausal female defined 
as 12 months of spontaneous amenorrhea to be verified with a follicle-
stimulating hormone (FSH) level >40MIU/mL and estradiol level <40pg/mL.  
Females on hormone replacement therapy (HRT) and whose menopausal status 
is in doubt will be required to use one of the contraception methods in Section 
7.1.1 if they wish to continue their HRT during the study.  Otherwise, they must 
discontinue HRT to allow confirmation of post-menopausal status prior to study 
enrollment.  For most forms of HRT, at least 2 to 4 weeks will elapse between 
the cessation of therapy and the blood draw; this interval depends on the type 
and dosage of HRT. Following confirmation of post-menopausal status, they can 
resume use of HRT during the study without use of a contraceptive method.

Child-bearing potential and agrees to use one of the contraceptive methods listed 
in Section 7.1.1 for an appropriate period of time as determined by the product 
label and applicable IBs) prior to the start of dosing to sufficiently minimize risk 
of pregnancy at that point. 
11. Female subjects must agree to use contraception from 7 days prior to the first dose of 
study drug(s) until 6 months after the last dose of panitumumab, until 4 months after 
the last dose of trametinib, or 4 weeks after the last dose of dabrafenib, whichever is 
longer.  Note: oral contraceptives are not reliable due to potential drug-drug 
interactions. Additionally, women of childbearing potential must have had a 
negative serum pregnancy test within 7 days prior to the first dose of study drug(s).
12. Adequate organ system function as defined in Table 24: 


Novartis
Confidential
Page 108
Clinical Study Protocol Version 05
Protocol No. MEK116833
Table 24
Definitions for Adequate Baseline Organ Function
System
Laboratory Values
Hematologic 
Absolute neutrophil count
1.5 × 109/L 
Hemoglobin
9 g/dL or 5.6 mmol/L
Platelets
75 × 109/L  
PT/INR and PTT
≤1.5 x ULN
Chemistry
Mg++
≥ LLN
Hepatic
Albumin
2.5 g/dL or 25 g/L
Total bilirubin
1.5 x ULN
AST and ALT
2.5× ULN 
Renal
Creatinine or
ULN
Calculated creatinine clearancea or
50 mL/min 
   24-hour urine creatinine clearance
≥ 50 mL/min
Cardiac
Left Ventricular Ejection fraction (LVEF)
≥ LLN by ECHO or MUGAb
a.
Calculated by the Cockcroft-Gault formula.
b.
Same method as used at baseline must be use throughout the study, ECHO is the preferred method
13. Subjects enrolled in France: In France, a subject will be eligible for inclusion in this 
study only if either affiliated to, or a beneficiary of, a social security category
4.2.2.2.
Part 3 Exclusion Criteria
Deviations from exclusion criteria are not allowed because they can potentially 
jeopardize the scientific integrity of the study, regulatory acceptability or subject safety. 
Therefore, adherence to the criteria as specified in the protocol is essential.
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply:
1.
History of prior malignancy, other than colorectal cancer.
Exception: Subjects who have been disease-free for 5 years, or subjects with a history of 
completely resected non-melanoma skin cancer or successfully treated in situ carcinoma 
are eligible.
2.
Any serious and/or unstable pre-existing medical, psychiatric disorder or other 
conditions that could interfere with subject’s safety, obtaining informed consent or 
compliance to the study procedures.
3.
Current active liver or biliary disease (with the exception of Gilbert's syndrome or 
asymptomatic gallstones, liver metastases or otherwise stable chronic liver disease 
per investigator’s assessment).


Novartis
Confidential
Page 109
Clinical Study Protocol Version 05
Protocol No. MEK116833
4.
History of sensitivity to heparin or heparin-induced thrombocytopenia 
5.
Currently receiving cancer therapy (chemotherapy, radiation therapy, 
immunotherapy or biologic therapy), as described in Section 8.
6.
Prior exposure to BRAF or MEK inhibitors.
7.
Prior exposure to EGFR inhibitors or an anti-EGFR antibody.
8.
Received an investigational or approved anti-cancer drug within 4 weeks, or within 5 
half-lives (whichever is shorter) of the first dose of study drug(s). At least 14 days 
must have passed between the last dose of prior investigational agent and the first 
dose of study drug(s). 
9.
Received more than one prior anti-cancer therapy in the metastatic setting, exclusive 
of previous adjuvant regimens.  Previous investigational anti-cancer therapy in the 
metastatic setting is prohibited.
10. Current use of a prohibited medication or requirement to dose with any of these 
medications during treatment with study drug(s).
11. Known Hepatitis B, or Hepatitis C infection. 
12. Any major surgery, radiotherapy or immunotherapy within the 4 weeks prior to first 
dose of study drug(s). Limited radiotherapy with in the 2 weeks prior to first dose of 
study drug(s).
13. Unresolved toxicity greater than NCI-CTCAE version 4 Grade 1 from previous anti-
cancer therapy, with the exception of alopecia.
14. History of retinal vein occlusion (RVO).
15. Presence of active gastrointestinal disease or other condition that will interfere 
significantly with the absorption, distribution, metabolism or excretion of drugs. 
Previous colectomy is acceptable.
16. Subjects with brain metastases are excluded, unless:

All known lesions must be previously treated with surgery or stereotactic 
radiosurgery, and 

Brain lesion(s), if present, must be confirmed stable (i.e., no increase in lesion 
size) for 90 days prior to first dose of study drug(s).  This must be documented 
with two consecutive MRI or CT scans using contrast, and

Asymptomatic with no corticosteroids requirement for 30 days prior to first 
dose of study drug(s), and 

No enzyme-inducing anticonvulsants for 14 days prior to first dose of study 
drug(s).

In addition, for subjects that had brain metastases but currently have no evidence 
of disease (NED), NED for 12 weeks is required and must be confirmed by 
two consecutive MRI or CT scans (using contrast) separated by 6 weeks, prior 
to randomization. Enrollment of a subject with brain metastases who meet the 
above criteria requires approval of a Novartis Medical Lead.


Novartis
Confidential
Page 110
Clinical Study Protocol Version 05
Protocol No. MEK116833
17. Subjects with a history of pneumonitis or interstitial lung disease (ILD).
18. History or evidence of cardiovascular risk including any of the following:

LVEF<LLN

A QT interval corrected for heart rate using the Bazett’s formula (QTcB;
Appendix 6) 480 msec;

History or evidence of current clinically significant uncontrolled 
arrhythmias.
Exception:  Subjects with controlled atrial fibrillation for >30 days prior 
to randomization are eligible.

History of acute coronary syndromes (including myocardial infarction and 
unstable angina), coronary angioplasty, or stenting within 6 months prior 
to randomization.

History or evidence of current ≥ Class II congestive heart failure as 
defined by New York Heart Association (NYHA).

Treatment refractory hypertension defined as a blood pressure of systolic> 
140 mmHg and/or diastolic > 90 mm Hg which cannot be controlled by 
anti-hypertensive therapy;

Subjects with intra-cardiac defibrillators or permanent pacemakers;

Known cardiac metastases;
19. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs 
chemically related to the study drug(s) or their excipients.
20. Pregnant or lactating female.
21. Unwillingness or inability to follow the procedures outlined in the protocol.
22. Uncontrolled diabetes, hypertension or other medical condition that may interfere 
with assessment of toxicity.


Novartis
Confidential
Page 111
Clinical Study Protocol Version 05
Protocol No. MEK116833
5.
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS
5.1.
Hypotheses and Treatment Comparisons
5.1.1.
Part 1 and Part 4 Dose Escalation
The primary goals in Part 1 of this study are to determine safety and the recommended 
dose(s) for Part 2 and Part 4 based on available safety, PK and any clinical activity data 
of trametinib when administered in combination with dabrafenib and panitumumab; thus, 
no formal statistical hypotheses will be tested.  Analysis will be descriptive 
 
  
5.1.2.
Part 2 and Part 4 Cohort Expansion
For Part 2 and Part 4 cohort expansion, efficacy will be evaluated for each cohort to 
decide whether to proceed with further development based on the clinical activity seen in 
Part 1 and Part 4A.  Analyses will be descriptive 
.  Subjects treated with 
the same starting dose will be analyzed together.  
The Part 2 and Part 4B portion of the study will employ a Bayesian predictive adaptive 
design [Lee, 2008] that allows the trial to be monitored more frequently at multiple stages. 
The criteria will be based on a historically unimportant response rate of 15% versus a 
response rate of interest of 30%.  Bayesian statistics will be employed to calculate the 
predictive probability that the response rate ≥30% and ≥15% at interim assuming a Beta 
prior for the Binomial distributed data.  Predictive probability calculates the probability 
that the response rate ≥30% or ≥15% at the end of Part 2 or Part 4 given the responses 
have already been observed.  It predicts what is likely to happen at the end of Part 2 or 
Part 4 so is more meaningful and straightforward than posterior probability.  A weak 
prior Beta (0.003, 0.007) is used, which is equivalent to the information present in 0.01
subject. The first interim analysis may be conducted when at least 10 subjects are 
recruited for each analysis cohort specified in Table 25. Futility interim analysis decision 
rules for the 10th to 54th evaluable subjects, specifying the number of subjects with a 
confirmed response needed for continuing enrolment or stopping for futility when total 
sample size is up to 54 is presented in Table 26. These rules are intended as a guideline.  
Actual decisions will depend on the totality of the data.


Novartis
Confidential
Page 112
Clinical Study Protocol Version 05
Protocol No. MEK116833
Table 25
Sample sizes for different analysis cohorts using Bayesian 
predictive adaptive design.
Part
Cohorts/Population
Target 
sample size
Minimum sample 
size needed for first 
interim analysis
Part 1 and Part 2
D 150mg BID+P 6mg/kg
20
10
Part 1 and Part 2
D 150mg BID+ T 2mg QD +P 6mg/kg
54
10
Part 1 and Part 2
D 150mg BID+T 2mg QD+P 6mg/kg 1L
10-15
10
Part 1 and Part 2
D 150mg BID+T 2mg QD+P 6mg/kg 2L-4L
40-44
10
Part 1 and Part 2
D 150mg BID+T 2mg QD+P 4.8mg/kg
34
10
Part 1 and Part 2
D 150mg BID+T 2mg QD+P 4.8mg/kg 1L
10-14
10
Part 1 and Part 2
D 150mg BID+T 2mg QD+P 4.8mg/kg 2L-4L
20-24
10
Part 4
T+P Anti-EGFR CRC population
20
10
Part 4
T+ P BRAF+ CRC population
20-40
10
Table 26
Decision Making Criteria for Futility
Number of Evaluable 
Subjects 
This Number of Confirmed 
Responses  to Stop Early 
for Futility
Probability of continuing 
enrolling when ORR=0.15 
Probability of continuing 
enrolling when ORR=0.3 
10
0
0.8031
0.9718
11
0
0.8031
0.9718
12
0
0.8031
0.9718
13
0
0.8031
0.9718
14
0
0.8031
0.9718
15
0
0.8031
0.9718
16
1
0.6721
0.9575
17
1
0.6721
0.9575
18
1
0.6721
0.9575
19
1
0.6721
0.9575
20
1
0.6721
0.9575
24
2
0.5805
0.9500
25
2
0.5805
0.9500
30
3
0.5126
0.9457
34
4
0.4506
0.9422
35
4
0.4506
0.9422
40
5
0.3875
0.9381
45
7
0.2785
0.9299
50
8
0.2268
0.9243
53
10
0.1345
0.9063
54 
11
0 
0
For the separate interim looks in each cohort, the enrollment for that cohort may be 
stopped due to futility if the predictive probability that the confirmed response rate ≥15% 


Novartis
Confidential
Page 113
Clinical Study Protocol Version 05
Protocol No. MEK116833
(historical control) is small (e.g., less than 10% chance for a total sample size of 20 
subjects or less than a 2% chance for a total sample size of 54 subjects). Enrollment may 
also be stopped due to futility if the equivalent of no confirmed response is observed in 
the first 10-15 enrolled evaluable subjects in that cohort or less than 1 confirmed response 
is observed in the first 16-19 evaluable subjects.  For example, if all (10-15) or all but one 
(16-19) of the subjects have either progressed, withdrew from the study, were lost to 
follow-up, or are ongoing and have completed at least one post treatment disease 
assessment without a confirmed response then the cohort may be stopped for futility.
Otherwise, the enrolment of the respective cohort will continue to the target sample size. 
If the predictive probability that the response rate of ≥30% is large (i.e., greater than 80% 
chance) is observed during the interim looks, strong statistical evidence has been 
provided in favor of further development of the treatment for the target population.
When the total sample size in a treatment arm/cohort is 20 and at least 2 confirmed 
responders out of 20 subjects are observed, further development of the corresponding 
treatment in Part 3 may follow.  
When the total sample size in a cohort is 54 and at least 12 confirmed responders out of 
54 subjects are observed, further development of the corresponding treatment in Part 3 
may follow.  
5.1.3.
Part 3
The primary objective of Part 3 is to compare progression free survival (PFS) and of the 
combinations of trametinib plus dabrafenib plus panitumumab and/or dabrafenib plus 
panitumumab versus standard of care in subjects with BRAF-V600E mutation positive 
CRC.  There will be two primary comparisons of interest in this study based on 
comparing each of the panitumumab combination arms with chemotherapy comparator.  
Specifically, the study is designed to provide evidence with regard to PFS to support the 
null hypothesis: 
H01: λ1 = 1
or to reject it in favor of the alternative hypothesis: 
HA1: λ1 ≠ 1,
where λ1 is the hazard ratio: dabrafenib plus panitumumab / chemotherapy comparator 
and further to support the null hypothesis:
H02: λ2 = 1
or to reject it in favor of the alternative hypothesis 
HA2: λ2 ≠ 1,
where λ2 is the hazard ratio: trametinib plus dabrafenib plus panitumumab/ chemotherapy 
comparator. 


Novartis
Confidential
Page 114
Clinical Study Protocol Version 05
Protocol No. MEK116833
The study will have 80% power to detect a hazard ratio (HR) of 0.5 with a two-sided 0.05 
level test. Under the assumption of exponential PFS, this HR is equivalent to 100% 
increase in median progression-free survival for dabrafenib/panitumumab versus 
chemotherapy comparator or dabrafenib/trametinib/panitumumab versus the 
chemotherapy comparator (6 months vs. 3 months).  An additional secondary comparison 
of interest for PFS may be between the dabrafenib/panitumumab and the 
dabrafenib/trametinib/panitumumab arm.
5.2.
Sample Size Considerations
5.2.1.
Sample Size Assumptions
5.2.1.1.
Part 1 and Part 4 Dose Escalation
The total number of subjects in Part 1 and Part 4 dose escalation will depend on the 
number of dose escalations needed. However, the maximum anticipated number of 
subjects will be approximately 24 in Part 1 and approximately 22 in Part 4 dose 
escalation. 
Table 27
Statistical Basis for Phase 1 Dose Escalation
True incidence of dose-limiting toxicity
10%
20%
30%
40%
50%
60%
Probability of escalating the dose
0.91
0.71
0.49
0.31
0.17
0.08
5.2.1.2.
Part 2 and Part 4 Cohort Expansions
Part 2 will enroll up to 90 subjects in total.  Part 4 cohort expansion will enroll 40-60 
subjects in total (20 subjects in the anti-EGFR acquired resistance CRC population and 
20-40 subjects in the BRAF mutant CRC population).  Subjects will be evaluated 
separately by dose cohort and population at the end of Part 2 and Part 4.
To determine the sample size for dabrafenib in combination with panitumumab
expansion cohort, and trametinib in combination with panitumumab expansion cohort, a 
traditional, 2-stage Green-Dahlberg design [Green, 1992] was evaluated and the sample 
size for the first stage will be used for the futility analysis. To test the hypotheses 
(RR=30% vs. RR=15%), using a Green-Dahlberg design, 20 subjects per arm would be 
needed for Stage 1 (assuming a type 1 error of 10% and power of 80%).  The chance to 
effectively terminate the trial after 20 subjects due to futility (true RR=15%) is 33%; the 
risk to incorrectly stop the trial after 20 subjects if the treatment is effective (true RR 
=40%) is less than 2% (Table 28).  To determine the maximum sample size for any 
cohort or patient population in trametinib plus dabrafenib in combination with 
panitumumab, Bayesian predictive adaptive design will be used for testing hypotheses:
H0: RR≤15%
HA:RR≥30%


Novartis
Confidential
Page 115
Clinical Study Protocol Version 05
Protocol No. MEK116833
When maximum sample size is 54, the design will have a Type I error () of 0.089 and 
88% power with the probability of termination is 0.911 when the treatment is futile and 
probability of early termination 0.116 when the treatment is effective (true RR=0.3).
Table 28
Futility Analysis Design Performance
True 
RR
Probability of 
Termination, after 20 pts 
Probability of 
Termination, after 
34 pts
Probability of 
Termination, after 40 
pts
Probability of 
Termination, after 54 pts
15%
0.329
0.548
0.603
0.911
20%
0.180
0.288
0.324
0.641
30%
0.044
0.054
0.057
0.116
40%
0.007
0.011
0.011
0.013
A Bayesian posterior probability will also be calculated to further inform decision 
making.   Since neither dabrafenib in combination with panitumumab, trametinib in 
combination with panitumumab, nor trametinib in combination with dabrafenib and 
panitumumab has been tested previously in the clinic in CRC subjects, a Beta (0.003, 
0.007) prior is assumed.  This prior is equivalent to the information from 0.01 subject.  
The posterior probabilities of ORR exceeding 20%, 30% and 40% based on 20 subjects 
and the posterior probabilities of ORR exceeding 20%, 30% and 40% based on 54 
subjects are shown in Table 29.


Novartis
Confidential
Page 116
Clinical Study Protocol Version 05
Protocol No. MEK116833
Table 29
Bayesian Posterior Probabilities of Response Rate for Given 
Number of Observed Responses
# of Responses Observed out 
of 20 Subjects
Posterior Probability 
RR ≥20%
Posterior Probability 
RR ≥30%
Posterior Probability RR 
≥40%
4
0.45
0.14
0.024
5
0.69
0.29
0.075
6
0.83
0.48
0.17
7
0.93
0.66
0.31
8
0.97
0.81
0.49
# of Responses Observed out 
of 34 Subjects
Posterior Probability 
RR ≥20%
Posterior Probability 
RR ≥30%
Posterior Probability RR 
≥40%
5
0.18
0.01
0.000
6
0.33
0.04
0.002
7
0.50
0.09
0.007
8
0.67
0.18
0.019
9
0.80
0.30
0.044
10
0.89
0.45
0.092
11
0.95
0.60
0.169
12
0.98
0.73
0.276
# of Responses Observed out 
of 40 Subjects
Posterior Probability 
RR ≥20%
Posterior Probability 
RR ≥30%
Posterior Probability RR 
≥40%
6
0.18
0.01
0.000
7
0.31
0.03
0.001
8
0.47
0.07
0.003
9
0.62
0.13
0.008
10
0.76
0.22
0.020
11
0.86
0.35
0.045
12
0.93
0.48
0.088
13
0.96
0.62
0.155
# of Responses Observed out 
of 54 Subjects
Posterior Probability 
RR ≥20%
Posterior Probability 
RR ≥30%
Posterior Probability RR 
≥40%
11
0.50
0.05
0.001
12
0.63
0.09
0.002
13
0.75
0.15
0.006
14
0.84
0.24
0.014
15
0.91
0.34
0.028
16
0.95
0.46
0.053
17
0.97
0.58
0.092
Using these sample sizes, a Bayesian design that allows the trial to be monitored more 
frequently at multiple stages was evaluated. A Bayesian analysis expresses uncertainty 
about a parameter in terms of probability. A prior is defined to characterize the level of 


Novartis
Confidential
Page 117
Clinical Study Protocol Version 05
Protocol No. MEK116833
knowledge about a parameter before the data are collected. Once the data are collected, a 
posterior distribution is formed using the prior and the likelihood (i.e., the data). Since 
none of the treatment has been tested previously in the clinic in the target population, a 
weak prior Beta (0.003, 0.007) is assumed. Thus, the posterior distribution for the 
response rate will be primarily driven by the data and can be derived as follows: Let p 
denote the response rate for the treatment, the number of responses in the current n 
patients, x, follows a binomial distribution, Binomial (n, p). Taking the Bayesian method 
and combining the weak prior and the likelihood of the observed data x, the posterior 
distribution of the response rate follows a beta distribution, i.e., p Beta (0.003 + x, 
0.007 + n-x) with the posterior mean (0.003 + x)/(0.01 + n). 
Based on this posterior distribution of the response rate, the predictive probability that the 
response rate >15% or ≥30% after 19 or 53 subjects will be calculated for decision-
making as described in the Section 5.1.2 (Hypotheses). The decision rule and a minimal 
required sample size of 10 patients for the first interim look are determined to generate 
the design that leads to a reasonable chance of early termination due to futility.
The design property, by utilizing the decision rule specified in Section 5.1.2, and sample 
size of 20 subjects or 54 subjects are shown (Table 30). The probability of early 
termination of the trial is calculated by simulations. The probability of early termination 
after the first 19 evaluable subjects is 33% under the null hypothesized response rate, and 
the risk to incorrectly stop the trial early if the drug is effective is approximately 5%. 
Thus, the study will employ the Bayesian design that allows the trial to be monitored 
more frequently at multiple stages with the constraint of satisfactory stop for futility rate
Table 30
Bayesian Design Performance by Response Rate
If True Response Rate to the 
Treatment is: (%) 
Probability (early stop for futility) 
after 19 subjects
Probability (early stop for futility) after 
53 subjects
0.15
0.326
0.853
0.2
0.180
0.483
0.3
0.043
0.086
5.2.1.3.
Part 3
Based on available published data and input from experts in treatment of BRAF-mutant 
colorectal cancer, the median PFS assumed for the SOC is approximately 3 months 
[Loupakis, 2009; Di Nicolantonio, 2008; Laurent-Puig, 2009; unpublished data].
The following assumptions were made in the estimation of sample size and the required 
number of events for PFS for each of the two primary comparisons:

Exponential distributions

Constant accrual rate of 12 subjects per month 

20% loss-to-follow-up rate


Novartis
Confidential
Page 118
Clinical Study Protocol Version 05
Protocol No. MEK116833

A 1:1:1 randomization scheme

Power for each comparison of 80% 
An overall of 5% two-sided risk of erroneously claiming difference between the 
experimental arms and the control arm (chemotherapy comparator) in the case of no 
underlying difference between the two arms (overall type I error for each comparison). 
Forty-seven (47) subjects per arm will be enrolled, leading to approximately 12 months 
of accrual.  The first interim analysis for PFS and OS will be performed (at the same time, 
for all three arms) when at least 29 PFS events (per RECIST v1.1) have occurred across 
either dabrafenib/panitumumab and chemotherapy comparator arms or 
trametinib/dabrafenib/panitumumab  and chemotherapy comparator arms (around 9 
months after the first subject enrolled).  The final analysis on PFS will be conducted 
when at least 72 PFS events (per RECIST) have been reported in 
dabrafenib/panitumumab and chemotherapy comparator arms and at least 72 PFS events 
have been reported in trametinib/dabrafenib/panitumumab and chemotherapy comparator 
arms.
5.2.2.
Sample Size Sensitivity
Table 31 shows the sensitivity of PFS events to smaller median PFS in the dabrafenib 
plus panitumumab or trametinib plus dabrafenib plus panitumumab treatment arms.
Table 31
PFS Sample Size Sensitivity
Median Progression-Free Survival (months)
Percent of 
Improvement 
Statistical Powera
comparator
Dabrafenib plus panitumumab / 
Trametinib plus dabrafenib plus panitumumab
3
5.4 
80 
69%
3
5.6 
90 
75%
3
6 
100 
80%
a.
Overall power is defined as to detect a 100% increase in median progression free survival in subjects who 
receive dabrafenib plus panitumumab vs. chemotherapy comparator or in subjects who receive trametinib plus 
dabrafenib plus panitumumab compared vs. chemotherapy comparator.
5.2.3.
Analysis Populations
The Intent-to-Treat (ITT) population will comprise all randomized subjects regardless 
of whether or not treatment was administered.  This population will be based on the 
treatment to which the subject was randomized and will be the primary population for the 
analysis of efficacy data in Part 3.
The All Treated Population will consist of all subjects that received at least one dose of 
investigational product.  Safety and clinical activity data for Parts 1, 2 and 4 will be 
evaluated based on this population.
The PK Population will consist of those subjects in All Treated Population and for 
whom a PK sample is obtained and analyzed.


Novartis
Confidential
Page 119
Clinical Study Protocol Version 05
Protocol No. MEK116833
The Crossover Population will comprise the subset of subjects in Part 1, Part 2 and Part 
4 who had intra-subject dose escalation or intra-subject doublet to triplet crossover. It will 
be the primary population when summarizing data in Part 1, Part 2 and Part 4 crossover 
phase.
5.2.4.
Analysis Data Sets
The construction of analysis data sets will be performed in accordance with all applicable 
Novartis standards and procedures.
5.2.5.
Sample Size Re-estimation
No sample size re-estimation will be performed.
5.3.
Data Analysis Considerations
Data will be listed and summarized according to the Novartis reporting standards, where 
applicable.  Complete details will be documented in the Reporting and Analysis Plan 
(RAP).
5.3.1.
Withdrawal
Reason for subject withdrawal will be listed.
5.3.2.
Missing Data
Missing data will not be imputed.  Where appropriate, available data will be summarized 
over specified intervals (e.g., from start of treatment until withdrawal from study) using 
suitable summary statistics.
5.3.3.
Protocol Violations
A summary and listing of protocol violations will be provided.
5.3.4.
Derived and Transformed Data
The PK parameters, AUC, Cmax, and terminal half-life will be log-transformed prior to 
analysis when needed.


Novartis
Confidential
Page 120
Clinical Study Protocol Version 05
Protocol No. MEK116833
5.3.5.
Assessment Windows
Safety assessments that occur prior to the administration of study drug will be considered 
screening assessments.  Safety assessments that occur after dosing has begun will be 
considered as having occurred while on treatment.
Disease assessments will be distinguished as belonging to either screening, continued 
therapy or post-study phases of the study.
5.3.6.
Other Issues
Data from participating centers will be pooled prior to analysis. It is anticipated that 
subject accrual may be limited across centers and summaries of data by center would 
likely not be informative. Therefore, these summaries will not be provided. 
Demographic and baseline characteristics will be summarized.
For pharmacokinetics analyses, assay values below quantifiable limits (BQL) will be 
handled according to Novartis procedures.
5.3.7.
Interim Analysis
5.3.7.1.
Part 1 and Part 4 Dose Escalation
No formal interim analysis will be performed.  Review of all available safety and 
pharmacokinetic data will be performed after completion of each dosing cohort. 
 
In Part 1, to further facilitate dose escalation/de-escalation decisions, an adaptive 
Bayesian logistic regression model (BLRM) may be utilized to predict the probability of 
DLT at the dose levels yet to be tested. Specifically, an 8-parameter BLRM for 
combination treatment [Bailey, 2009] will be fitted on the dose limiting toxicity data (i.e., 
absence or presence of DLT) accumulated throughout the dose-escalation to model the 
dose-toxicity relationship of trametinib and dabrafenib and panitumumab when given in 
combination. 
Prior distributions of two parameters for trametinib will be calculated based on the 
toxicity data observed in the first time in human (FTIH) study MEK111054 where 
trametinib is administered alone; similarly, prior distributions of two parameters for 
dabrafenib will be determined based on data observed in the FTIH study BRF112680
where dabrafenib is administered alone; prior distributions of the parameter for 
trametinib- dabrafenib interaction based on the data observed in study BRF113220 where 
trametinib and dabrafenib are administered in combination; a non-informative prior will 
be assumed for the other parameters which accounts for the combination of the two or 
three compounds.  The model will be used only as a guide for what further doses to study 
in the presence of DLTs.  The primary considerations for dose escalation/de-escalation 
will be based on the rules described in Section 3.7.2.  Further details on the model as well 
as prior distributions will be included in the Reporting and Analysis Plan (RAP).


Novartis
Confidential
Page 121
Clinical Study Protocol Version 05
Protocol No. MEK116833
5.3.7.2.
Part 2 and Part 4 Cohort Expansion
No formal interim analysis will be performed.  Review of all available safety and 
pharmacokinetic data will be performed after completion of each dosing cohort.
In the expansion cohorts in Part 2, if an increased incidence of clinically significant 
toxicity i.e., ≥4 subjects of the first 10 subjects enrolled) is observed, the dosing regimen 
may be adjusted for all future subjects in a specific cohort or for the whole study 
population.
5.3.7.3.
Part 3
An IDMC will be utilized in this study to ensure external objective medical and statistical 
review of efficacy and safety data in order to protect the ethical and safety interests of 
subjects and to protect the scientific validity of the study. The schedule of IDMC data 
reviews and the scope of the IDMC reviews are described in the IDMC charter, which is 
available upon request.
Planned Interim Analyses for Progression Free Survival
In addition to periodic reviews of the safety and efficacy data, one planned interim 
analysis for PFS will be performed. The interim analysis will be performed when 29 PFS 
events (per RECIST v1.1 criteria; 40% of required number of events for the final PFS
analysis for each comparison) are reported across either dabrafenib/panitumumab and 
chemotherapy comparator arms or trametinib/dabrafenib/panitumumab and 
chemotherapy comparator arms. 
The interim analyses for PFS will be performed for the purpose of evaluating whether to 
stop the trial early for “harm” in PFS.
"Harm" would correspond to declaring the dabrafenib plus panitumumab arm or 
trametinib plus dabrafenib plus panitumumab arm to be worse than the chemotherapy 
comparator arm in PFS.
For the purpose of evaluating whether to stop the trial due to harm/futility, a Gamma 
family beta spending function with a parameter of -0.5 will be utilized. The boundary 
does not represent a binding decision to stop the trial should this boundary be crossed. 
The boundaries are defined in East to preserve Type I error at 5% under the assumption 
of a non-binding futility rule. 
The EAST software package will be used to calculate the appropriate bounds at the time 
of the analyses, given the fraction of information available.  Assuming an accrual time of 
12 months and a follow-up time of 6 months and the accrual rate is constant, the time 
point of interim analyses is around 9 months. An example of the nominal significance 
levels corresponding to the error spending functions as well as planned stopping 
boundaries and decision rules in terms of hazard ratios for the analysis time points of 
progression free survival, are as follows:


Novartis
Confidential
Page 122
Clinical Study Protocol Version 05
Protocol No. MEK116833

40% of expected events:, stop for harm if HR>3.537

100% of expected events: α=0.05, claim superiority of the experimental arm if 
HR<0.630 or claim harm if HR>1.587. 
At the interim analysis, if either the trametinib/dabrafenib/panitumumab arm or 
dabrafenib/panitumumab arm demonstrates harm, enrollment to that arm may be halted. 
The IDMC may also recommend halting the trial or arms within the trial based on 
accruing safety information. If one of the experimental arms is halted due to either harm 
or safety, subjects on that arm may be provided the opportunity to receive treatment on 
the other experimental arm depending in the emerging safety and efficacy profile. 
5.3.8.
Final Analyses
Analyses of the data captured in Part 1 and Part 2 will be undertaken after each subject
has been followed at least 12 weeks. Data from the two parts may be combined for some 
analyses at the end of the trial, as appropriate.
For Part 3, final analyses may be conducted when sufficient PFS events (72) have 
accrued for each pairwise comparison of the combination arms with the chemotherapy 
comparator.  Analysis of OS will be conducted when 99 deaths have been reported across 
all three arms.
5.3.8.1.
Safety Analyses
Safety data for Parts 1, 2 and 3 will be presented in tabular and/or graphical format and 
summarized descriptively according to Novartis standards.
5.3.8.2.
Extent of Exposure
Extent of exposure of trametinib, dabrafenib and panitumumab will depend on 
tolerability of the subjects to the doses administered and the course of their disease.  The 
number of subjects exposed to the combination of trametinib and dabrafenib and 
panitumumab will be summarized for each dose level administered.
5.3.8.3.
Adverse Events
Adverse events (AEs) will be coded using the standard Medical Dictionary for 
Regulatory Activities (MedDRA) and grouped by system organ class.  Adverse events 
(AEs) will be graded by the investigator according to the NCI CTCAE, version 4.0.
Events will be summarized by frequency and proportion of total subjects, by system 
organ class and preferred term.  Separate summaries will be given for all AEs, drug-
related AEs, SAEs and AEs leading to treatment discontinuation.
If the AE is listed in the NCI CTCAE (version 4.0) table, the maximum Grade will be 
summarized.


Novartis
Confidential
Page 123
Clinical Study Protocol Version 05
Protocol No. MEK116833
Any AEs of special interest (including SCC and other proliferative diseases) will be 
summarized as detailed in the RAP.
The incidence of deaths and the primary cause of death will be summarized.
5.3.8.4.
Clinical Laboratory Evaluations
Hematology and clinical chemistry data will be summarized at each scheduled 
assessment according to NCI CTCAE (version 4.0) Grade.  The proportion of values 
lying outside the reference range will also be presented for laboratory tests that are not 
graded because there are no associated NCI CTCAE criteria.  Summaries by visit will 
include data from scheduled assessments only, and all data will be reported according to 
the nominal visit date for which it was recorded (i.e., no visit windows will be applied).  
Unscheduled data will be included in ‘worse case post baseline’ summaries which will 
capture a worst case across all scheduled and unscheduled visits after the first dose of 
study treatment.  Further details will be provided in the RAP.
5.3.8.5.
Other Safety Measures
The results of scheduled assessments of vital signs, ECOG performance status, 12-lead 
ECG, and ECHO/ MUGA will be summarized.  Summaries by visit will include data 
from scheduled assessments only.  All data will be reported according to the nominal 
visit date for which it was recorded (i.e., no visit windows will be applied).  Unscheduled 
data will be included in ‘worse case’ summaries which will capture a worst case across 
all scheduled and unscheduled visits after the first dose of study treatment.  All data will 
be listed.  Further details will be provided in the RAP.
5.3.8.6.
Pharmacokinetic Analyses
Pharmacokinetic analysis will be the responsibility of Novartis.  Plasma dabrafenib and 
metabolites including hydroxy- and desmethyl-dabrafenib and trametinib concentration-
time data from subjects enrolled in the dose escalation phase of the study will be 
analyzed by non-compartmental methods with WinNonlin Version 5.2 or higher.  
Calculations will be based on the actual sampling times recorded during the study.  From 
the plasma concentration-time data, the following pharmacokinetic parameters will be 
determined for trametinib and dabrafenib and metabolites, as data permit: pre-dose 
concentration (C), maximum observed plasma concentration (Cmax), time to Cmax 
(tmax), area under the plasma concentration-time curve [AUC(0-t) and AUC(0-8)], and 
apparent terminal phase half-life (t1/2).  The metabolite to parent ratio for AUC(0-t) will 
be calculated for each metabolite of dabrafenib.  C(predose concentration) and Cmax 
(end of infusion) for panitumumab will be determined. 
Mixed-effects pharmacokinetic models developed previously for trametinib, dabrafenib, 
and dabrafenib metabolites will be fit to the dabrafenib and trametinib concentration-time 
data observed after administration with panitumumab in the expanded cohort using 
NONMEM VII.  Post-hoc estimates of population pharmacokinetic parameters CL/F, V/F, 
and Ka will be determined for trametinib and dabrafenib metabolites after administration 
with panitumumab.  


Novartis
Confidential
Page 124
Clinical Study Protocol Version 05
Protocol No. MEK116833
Descriptive statistics for panitumumab predose concentration and Cmax (end of infusion 
concentration) by visit will generated.  
Pharmacokinetic data will be presented in graphical and/or tabular form and will be 
summarized descriptively. All pharmacokinetic data will be stored by Novartis.
Statistical analyses of the pharmacokinetic parameter data will be the responsibility of 
Novartis.
If more than two dose cohorts are required to reach MTD (or recommended dose based 
on available safety, PK and response data), dose proportionality of dabrafenib, trametinib 
and panitumumab AUC(0-), Cmax and Cfollowing repeat dose administration will be
evaluated graphically and using the power model as described below:
log(PK parameter) = a + b * log(dose)
where a is the intercept and b is the slope.
The power model will be fitted by restricted maximum likelihood (REML) using SAS 
procedure MIXED (SAS Proc Mixed).  Both the intercept and slope will be fitted as fixed 
effects.  If there is sufficient data, then the model may also be fit with the intercept and/or 
slope as random effects.  The mean slope will be estimated from the power model and the 
corresponding 90% confidence interval (CI) calculated.
5.3.8.7.
Efficacy Analyses
5.3.8.7.1.
Part 1, Part 2 and Part 4
The ORR endpoint will be tabulated based on number and percentage of subjects 
attaining either a confirmed or unconfirmed overall best response of CR or PR in the all 
treated population.  Per RECIST, version 1.1, confirmation of response is not required.  
Subjects with unknown or missing response data, including those who withdraw from the 
study without an assessment, will be treated as non-responders (i.e., they will be included 
in the denominator when calculating the percentage).  No imputation will be performed 
for missing lesion assessment or tumour response data.  
All responses are investigator-assessed.  Independent central review may be performed.
PFS will be estimated using the Kaplan Meier method.  PFS will be defined as the time 
from study treatment start until the first date of either disease progression or death due to 
any cause.  The date of objective disease progression will be defined as the earliest date 
of disease progression as assessed by the investigator using RECIST, version 1.1.  For 
subjects who have not progressed or died at the time of the PFS analysis, censoring will 
be performed using the date of the last adequate disease assessment.  In addition, subjects 
with an extended loss to follow-up or who start a new anti-cancer therapy prior to a PFS 
event will be censored at the date of the last adequate disease assessment prior to the 
extended loss to follow-up or start of new anti-cancer therapy, respectively.  Further 
details on censoring rules will be outlined in the RAP.


Novartis
Confidential
Page 125
Clinical Study Protocol Version 05
Protocol No. MEK116833
For Part 1 and Part 2, anti-tumor activities will be evaluated based on clinical evidence 
and response criteria. If the data warrant, the response data from both parts will be
combined and summarized by dose level. The efficacy data collected after crossover for 
those subjects who crossover from dabrafenib/panitumumab combination or 
trametinib/panitumumab to dabrafenib/trametinib/panitumumab combination will not be 
included in the main efficacy analysis for dabrafenib/trametinib/panitumumab 
combinations. The crossover efficacy data for these subjects will be summarized 
separately.
5.3.8.7.2.
Part 3
PFS along with 95% confidence interval for each treatment will be estimated using the 
Kaplan Meier method and treatment comparisons will be made using a log-rank test 
(defined in Section 5.1.3).  The median PFS for each treatment, the hazard ratio for each 
comparison along with 95% confidence intervals will be reported.
PFS will be defined as the time from randomization until the first date of either disease 
progression or death due to any cause and will be evaluated for the combination versus 
the chemotherapy comparator.  The date of objective disease progression will be defined 
as the earliest date of disease progression as assessed by the investigator using RECIST, 
version 1.1.  For subjects who have not progressed or died at the time of the PFS analysis, 
censoring will be performed using the date of the last adequate disease assessment.  In 
addition, subjects with an extended loss to follow-up or who start a new anti-cancer 
therapy prior to a PFS event will be censored at the date of the last adequate disease 
assessment prior to the extended loss to follow-up or start of new anti-cancer therapy, 
respectively.  Further details on censoring rules will be outlined in the RAP.
Additional sensitivity and/or subgroup analyses for PFS may be pre-specified in the RAP, 
if appropriate.
The ORR endpoint will be tabulated based on number and percentage of subjects 
attaining either a confirmed or unconfirmed overall best response of CR or PR in the ITT 
population.  Per RECIST, version 1.1, confirmation of response is not required.  Subjects
with unknown or missing response data, including those who withdraw from the study 
without an assessment, will be treated as non-responders (i.e., they will be included in the 
denominator when calculating the percentage).  No imputation will be performed for 
missing lesion assessment or tumour response data.  
OS along with 95% confidence interval for each treatment will be estimated using the 
Kaplan Meier method and treatment comparisons will be made using a log-rank test.  All 
cause mortality will be used and censoring will be performed using the date of last known 
contact for those who are alive or lost to follow-up at the time of analysis.  The hazard 
ratio along with 95% confidence intervals will be provided for each of the pairwise 
comparisons described in Section 5.3.8. Sensitivity analyses to ascertain the effect of 
baseline prognostic factors may be performed.  Details will be provided in the RAP.
Overall response rates (ORR) for each treatment group as well as for differences between 
each of the three arms will be provided along with corresponding 95% CI.  A chi-square 


Novartis
Confidential
Page 126
Clinical Study Protocol Version 05
Protocol No. MEK116833
test will be used for each pairwise comparison to test for differences between treatment 
arms.
Duration of response will include subjects from the ITT population who achieve a 
confirmed best response of CR or PR and will only be analyzed provided a sufficient 
number of subjects respond to warrant such an analysis.  Censoring rules for duration of 
response will follow the rules for PFS and will be outlined in detail in the RAP.
6.
STUDY ASSESSMENTS AND PROCEDURES
This section lists the parameters of each planned study assessment.  The exact timing of 
each assessment is listed in the Time and Events Table (Section 3.11).  Detailed 
procedures for obtaining each assessment are provided in the Study Procedures Manual 
(SPM).  Whenever vital signs, 12-lead ECGs and blood draws are scheduled for the same 
nominal time, the assessments should occur in the following order: 12-lead ECG, vital 
signs, blood draws.  The timing of the assessments should allow the blood draw to occur 
at the exact nominal time.
In Part 1 and Part 2, the timing and number of planned study assessments, including: 
safety, pharmacokinetic, pharmacodynamic
r other assessments may be 
altered during the course of the study based on newly available data (e.g. to obtain data 
closer to the time of peak plasma concentrations) to ensure appropriate monitoring. The 
change in timing or addition of time points for any planned study assessments must be 
approved and documented by Novartis, but this will not constitute a protocol amendment. 
The Institutional Review Board (IRB)/ Independent Ethics Committee (IEC) will be 
informed of any safety issues that require alteration of the safety monitoring scheme; and 
an updated informed consent form will be presented to ongoing subjects. No more than 
500 mL of blood will be collected over the duration of the study, including any extra 
assessments that may be required.
6.1.
Demographic/Medical History Assessments
The following demographic parameters will be captured: date of birth, gender, race and 
ethnicity.
Medical, surgical, and treatment history including date (month and year) of first diagnosis 
and histology, as well as cardiovascular medical history and risk factors, alcohol and 
tobacco history, plus family history will be taken as part of the medical history and 
disease status.  Additional information may be requested to evaluate eligibility per 
Section 4.2.
6.2.
Safety
Planned time points for all safety assessments are listed in the Time and Events Table 
(Section 3.11).  Additional time points for safety tests such as vital signs, physical exams 
and laboratory safety tests may be added during the course of the study based on newly 
available data to ensure appropriate safety monitoring.


Novartis
Confidential
Page 127
Clinical Study Protocol Version 05
Protocol No. MEK116833
Physical Exams/ Dermatological Exams
A complete physical examination will be performed by a qualified physician according to 
local practices.  At minimum, the examination should include assessments of the head 
and neck, skin, neurological, lungs, cardiovascular, abdomen (liver and spleen), thyroid, 
lymph nodes and extremities.  For subjects treated with dabrafenib in Part 1, 2, and 3, 
complete physical examinations will also include thorough genitourinary (pelvic) and 
rectal exams to assess secondary malignancies. In females, the pelvic exam must 
visualize the cervix for subjects in Parts 1, 2 and 3. (Pap smear and colposcopy are not 
required unless clinically indicated.) Rectal exam must include digital rectal exam and 
visual inspection of the anus and perianal area.  Height (at baseline only) and weight will 
also be measured and recorded.
A brief physical examination will include assessments of the skin, lungs, cardiovascular 
system and abdomen (liver and spleen); these may be performed at time points indicated 
in the Time and Events tables (Section 3.11).
The baseline skin examination must be performed by a dermatologist, and removal of 
pre-existing calluses and keratotic skin is recommended.  Baseline skin photographs 
should be submitted electronically as described in the SPM.
Referral to a dermatologist for follow-up skin exam should be done as clinically indicated. 
Skin lesions that emerge during therapy or change on therapy should be photographed.  
Photographs should be forwarded electronically for central review as described in the 
SPM.  Any pathology samples collected must be sent for central review.
Assessment of Skin Changes
Biopsy of skin lesions related to treatment may be performed as clinically indicated.  
 
 
 
Vital Signs
Vital sign measurements will include systolic and diastolic blood pressure, pulse rate and 
temperature.  Vital signs should be assessed under optimal conditions as described in 
Section 3.10.8.1.  
Vital signs should be measured within 30 minutes prior to initiation and upon completion 
of panitumumab infusion (up to 15 minutes after the end of infusion).  On other study 
days where vital signs are measured multiple times, temperature does not need to be 
repeated, unless clinically indicated.
Ophthalmic Exam
At certain time points in the trial and if visual changes develop, an eye exam is indicated 
(refer to Visual Changes Stopping Criteria, Section 3.10.11).  The exam will include best 
corrected visual acuity, tonometry, slit lamp biomicroscopic examination, visual field 
examination, and dilated indirect fundoscopy with special attention to retinal 
abnormalities. Optical coherence tomography is strongly recommended at scheduled 


Novartis
Confidential
Page 128
Clinical Study Protocol Version 05
Protocol No. MEK116833
visits, and if retinal abnormalities are suspected. Other types of ancillary testing including 
color fundus photography and fluorescein angiography are also recommended if 
clinically indicated.
In addition, it is recommended that subjects have baseline color fundus photographs 
taken at screening to document baseline appearance.  
Electrocardiogram (ECG)
Twelve-lead ECGs will be obtained as indicated in the Time and Events table 
(Section 3.11) using an ECG machine that automatically calculates the heart rate and 
measures PR, QRS, QT, and QTc intervals.  Results of the ECG will be transmitted to a 
central storage facility. At each assessment, a 12-lead ECG will be performed by 
qualified personnel at the site after the subject has rested at least 5 minutes in a semi-
recumbent or supine position.  Those QTc values greater than 480msec as calculated by 
the machine must be confirmed manually using Bazett’s formula [Bazett, 1920] given 
below:
RR
QT
QTcB 
If there are any clinically significant abnormalities including but not limited to a 
QTcF>500msec, confirm with 2 additional ECGs taken at least 5 minutes apart.
Refer to Section 3.10.9 for QTc withdrawal criteria and additional QTc readings that may 
be necessary.
Echocardiogram (ECHO) or Multiple Gated Acquisition (MUGA)
ECHO is the preferred method to assess cardiac ejection fraction and cardiac valve 
abnormalities; MUGA is acceptable only if ECHO is not available.  Assessments should 
be performed as indicated in the Time and Events table (Section 3.11). Results will be 
transmitted to a central storage facility. Echocardiography should include an evaluation 
for left ventricular ejection fraction (LVEF) and both right- and left-sided valvular lesions. 
For each subject the same procedure should be performed at screening and any following 
visit to allow direct comparison. Additional ECHO/ MUGA assessments may be 
performed as clinically indicated.


Novartis
Confidential
Page 129
Clinical Study Protocol Version 05
Protocol No. MEK116833
Clinical Laboratory Assessments
Hematology, clinical chemistry, urinalysis and additional parameters to be tested are 
listed below:
Hematology
Platelet Count
RBC Indices:
Automated WBC Differential:
Red blood cell (RBC) Count
Mean corpuscular 
volume (MCV)
Neutrophils
White blood cell (WBC) Count 
(absolute) 
Mean corpuscular 
hemoglobin (MCH)
Lymphocytes
Hemoglobin
Mean corpuscular 
hemoglobin 
concentration 
(MCHC)
Monocytes
Hematocrit
Eosinophils
Basophils
Clinical Chemistry
Albumin
Sodium
AST (SGOT)
Magnesium
BUN
Potassium
ALT (SGPT)
Total and direct bilirubin1
Creatinine
Chloride
Gamma glutamyl transferase 
(GGT)
Uric Acid
Glucose
      fasting glucose 
at screening only; 
all other glucose 
measurements may 
be non-fasting
Total carbon 
dioxide (CO2)
Alkaline phosphatase
Inorganic phosphorus
Lactacte 
dehydrogenase 
(LDH)
Calcium
Total Protein
1. Direct bilirubin is only required when total bilirubin is above the upper limit of normal.
Routine Urinalysis
Color, appearance, pH, specific gravity, glucose, protein, blood, ketones, WBC esterase, urobiligen
Microscopic examination (if blood or protein is abnormal)
Other screening tests
FSH and estradiol (as needed in women of non-child bearing potential only)
Coagulation (at screening, repeated only if clinically indicated)
Progressively decreasing serum magnesium levels leading to severe (grade 3-4) 
hypomagnesemia occurred in up to 7% (in Study 2) of patients across clinical trials. 
Monitor patients for hypomagnesemia and hypocalcemia prior to initiating panitumumab
treatment, periodically during panitumumab treatment, and for up to 8 weeks after the 
completion of treatment. Other electrolyte disturbances, including hypokalemia, have 
also been observed. Replete magnesium and other electrolytes as appropriate.


Novartis
Confidential
Page 130
Clinical Study Protocol Version 05
Protocol No. MEK116833
Eastern Cooperative Oncology Group (ECOG) Performance Status
The performance status assessment is based on the ECOG scale [Oken, 1982]:
0. Fully active, able to carry on all pre-disease performance without restriction.
1. Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature (e.g., light house work, office work).
2. Ambulatory and capable of all self-care but unable to carry out any work activities.  
Up and about more than 50% of waking hours.
3. Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours.
4. Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair.
6.3.
Disease Assessments
Disease assessment will include imaging of the chest, abdomen and pelvis (e.g., 
computed tomography [CT], magnetic resonance imaging, bone scan, plain radiograph) 
and physical examination (as indicated for palpable or superficial lesions).  CT is the 
preferred method to measure lesions selected for response assessment.  To ensure 
comparability between baseline and subsequent assessments, the same method of 
assessment and the same technique will be used when assessing response [Eisenhauer, 
2009]. Refer to Appendix 4 for additional information regarding RECIST 1.1 
methodology and criteria.  The screening disease assessment will be completed within 35 
days prior to the first dose of study drug(s); for subjects with known brain metastases, 
MRI of the head is required to determine stability of lesions as part of screening.  
Subsequent timings of disease assessments are detailed in the time and event tables for 
Part 1 (Section 3.11.1), Part 2 (Section 3.11.2) and Part 3 (Section 3.11.3).  Disease 
assessments throughout the study are calendar-based, starting from the first day of dosing 
(Day 1) in the first treatment period, and irrespective of dose interruptions or delays.  
More frequent disease assessments may be performed at the discretion of the investigator.  
Subjects who discontinue study drug(s) for any reason other than progression or death 
should have a disease assessment performed at the follow-up visit, and results recorded in 
the eCRF.
 
Disease response will be recorded on the electronic case report form (eCRF) as complete 
response (CR), partial response (PR), stable disease (SD) or progressive disease (PD), 
according to RECIST v 1.1 criteria (Appendix 4).  Subjects whose disease responds 
(either CR or PR), should have a confirmatory disease assessment performed at least 
4 weeks after the date of the assessment during which the response was demonstrated.  
Response will be characterized by best overall response rate (BORR), duration of 
response, progression-free survival (PFS) and overall survival (OS) [Eisenhauer, 2009].  


Novartis
Confidential
Page 131
Clinical Study Protocol Version 05
Protocol No. MEK116833

BORR: Defined as the best response recorded from the start of study treatment 
until the end of treatment.  

Duration of response:  Defined as the interval between the time criteria are first 
met for CR/ PR (whichever is first recorded) until the first date that recurrence of 
progressive disease is objectively documented.

PFS: Defined as the interval between the randomization date (Part 3) or the start 
of study treatment (Parts 1, 2 and 4) until progressive disease is objectively 
documented.

OS: Defined as the interval between the randomization date (Part 3) or the start of 
study treatment (Parts 1, 2 and 4) until date of death due to any cause.
Even if study treatment is withdrawn, radiographic disease assessments (CT or MRI, as 
appropriate according to the method used at baseline) should continue every 8 weeks 
until documented disease progression, the start of new anti-cancer therapy, withdrawal of 
consent or death.
6.3.1.
Follow-up Assessments for Subjects Permanently Discontinued 
from Study Treatment
Subjects will be followed for progression, survival and new anti-cancer therapy 
(including radiotherapy) every 8 weeks. If subjects are unable or unwilling to attend 
clinic visits during follow-up, contact to assess survival may be made via another 
form of communication (e.g., phone, email, etc.).
Subjects who permanently discontinue study treatment without disease progression will 
have radiographic disease assessments performed as indicated in the Time and Events 
Table (Section 3.11) until disease progression, new anti-cancer therapy start, or death is 
documented.
Subjects are to be followed until progression for collection of PFS data and until death 
for collection of overall survival (OS) data.  
6.4.
Blood Requirements
The approximate amount of blood collected from subjects completing screening, a 4 
week treatment period and follow-up assessments is listed for each part of the study in 
Appendix 2. 
6.5.
Pregnancy
6.5.1.
Time period for collecting pregnancy information
All pregnancies in female subjects and/or female partners of male subjects will be 
collected after the start of dosing and until 6 months after the last dose of panitumumab, 
or 16 weeks following the last dose of dabrafenib or trametinib, whichever is later.


Novartis
Confidential
Page 132
Clinical Study Protocol Version 05
Protocol No. MEK116833
6.5.2.
Action to be taken if pregnancy occurs
The investigator will collect pregnancy information on any female subject who becomes 
pregnant while participating in this study.  The investigator will record pregnancy 
information on the appropriate form and submit it to Novartis within 24 hours of learning 
of a subject's pregnancy.  The subject will also be followed to determine the outcome of 
the pregnancy.  Information on the status of the mother and child will be forwarded to 
Novartis.  Generally, follow-up will be no longer than 6 to 8 weeks following the 
estimated delivery date.  Any premature termination of the pregnancy will be reported.
While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be recorded 
as an AE or SAE.
A spontaneous abortion is always considered to be an SAE and will be reported as such.  
Furthermore, any SAE occurring as a result of a post-study pregnancy and that is 
considered reasonably related to the study treatment by the investigator, will be reported 
to Novartis as described in Section 11. While the investigator is not obligated to actively 
seek this information in former study participants, he or she may learn of an SAE through 
spontaneous reporting.
Any female subject who becomes pregnant while participating will discontinue study 
medication or be withdrawn from the study.
6.5.3.
Action to be taken if pregnancy occurs in a female partner of a 
male study subject
The investigator will attempt to collect pregnancy information on any female partner of a 
male study subject who becomes pregnant while participating in this study.  The 
investigator will record pregnancy information on the appropriate form and submit it to 
Novartis within 24 hours of learning of the partner’s pregnancy.  The partner will also be 
followed to determine the outcome of the pregnancy.  Information on the status of the 
mother and child will be forwarded to Novartis.  Generally, follow-up will be no longer 
than 6 to 8 weeks following the estimated delivery date.  Any premature termination of 
the pregnancy will be reported.
6.6.
Pharmacokinetics
6.6.1.
Blood Sample Collection
Blood samples for pharmacokinetic analysis of dabrafenib and metabolites (hydroxy- and 
desmethyl-dabrafenib), trametinib, and panitumumab will be collected at the time points 
indicated in the Time and Events table (Section 3.11).  The actual date and time of each 
blood sample collection will be recorded.  The timing of PK samples may be altered 
and/or PK samples may be obtained at additional time points to ensure thorough PK 
monitoring.  
Details of PK blood sample collection (including volume to be collected), processing, 
storage and shipping procedures are provided in the Study Procedures Manual (SPM).


Novartis
Confidential
Page 133
Clinical Study Protocol Version 05
Protocol No. MEK116833
6.6.2.
Sample Analysis
Plasma analysis will be performed under the management of Novartis.  Concentrations of 
dabrafenib and its metabolites (hydroxy- and desmethyl -dabrafenib) and trametinib will 
be determined in plasma samples using the currently approved analytical methodology.  
Concentrations of panitumumab will be determined in serum samples using a validated 
method.  Raw data will be stored by Novartis.    
6.7.
Pharmacodynamic 
6.7.1.
Fresh Pre-and Post-dose Tumor Tissues
Tumor specimens that are accessible and can be sampled easily will be requested in Part 
1, Part 2 and Part 4.  These biopsies will be taken during the screening period, e.g., within 
14 days before treatment, and within 2 to 4 hrs after dosing on Day 15 (+3 days) in those 
subjects who have signed the corresponding section of the informed consent.  Details of 
the tumor biopsy collection including processing, storage and shipping procedures will be 
provided in the SPM.
6.7.2.
Fresh Tumor Tissue at Progression
Tumor specimens that are accessible and can be sampled easily will be requested from 
subjects at time of demonstrated progression on therapy from all parts of the study, as 
determined by RECIST v1.1 criteria.  Subjects of interest will be those who have had 
meaningful clinical response in target lesions (20% reduction, or stable disease for 6 
months) and then progressed on existing target lesions or if a new lesion emerged. The 
guidance on the lesion selection for the progression biopsy are:

if subject has new lesions only, preferably biopsy a new lesion if feasible

if a subject has growth of existing lesions only, biopsy a growing lesion if feasible 
if a subject has both emergence of new lesions and growth of existing lesions, 
then biopsy both a new lesion and existing lesions, if feasible. 

If above criteria based lesions are not feasible to be biopsied, selection of lesion 
will be at the discretion of the interventional radiologist.
 
 
 
 
 


Novartis
Confidential
Page 134
Clinical Study Protocol Version 05
Protocol No. MEK116833
 
 
 
  
 
 
6.7.4.
Archival tumor tissue
Collection of archival primary tumor tissue is required. These samples will be used to 
confirm or determine the BRAF or KRAS mutation status of subjects.
 
 
 
 
Samples will be collected as indicated in the Time and Events table (Section 3.11).  The 
timing of the collections may be adjusted on the basis of emerging pharmacokinetic or 
pharmacodynamic data from this study or other new information in order to ensure 
optimal evaluation of the pharmacodynamic endpoints.
All samples will be retained for a maximum of 15 years after the last subject completes 
the trial.
 
 
  


Novartis
Confidential
Page 135
Clinical Study Protocol Version 05
Protocol No. MEK116833
7.
LIFESTYLE AND/OR DIETARY RESTRICTIONS
7.1.
Contraception Requirements
7.1.1.
Female Subjects
The need for a screening pregnancy test depends on whether a female subject is of 
childbearing potential or non-childbearing potential.
A female of non-childbearing potential (i.e., physiologically incapable of becoming 
pregnant) is defined as any female who has had a hysterectomy, bilateral oophorectomy 
(ovariectomy) or bilateral tubal ligation, or is post-menopausal.
A practical definition accepts menopause after 1 year without menses with an appropriate 
clinical profile, e.g., age appropriate, >45 years in the absence of hormone replacement 
therapy (HRT).  In questionable cases, the subject must have a follicular stimulating 
hormone (FSH) value >40 mIU/mL and an estradiol value < 40pg/mL (<140 pmol/L).
A female of childbearing potential is defined as any female who does not meet the 
criteria of non-childbearing potential as described in the previous paragraph.
Female subjects of childbearing potential must not become pregnant and so must be 
sexually inactive by abstinence or use contraceptive methods with a failure rate of < 1% 
from start of dosing and.

for 6 months after the last dose of panitumumab (Vectibix)

for 4 months after the last dose of trametinib in combination with dabrafenib 

for 4 weeks after the last dose of dabrafenib  


Novartis
Confidential
Page 136
Clinical Study Protocol Version 05
Protocol No. MEK116833

for 4 months after the last dose of trametinib.
Abstinence
Sexual inactivity by abstinence must be consistent with the preferred and usual lifestyle 
of the subject.  Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of contraception. 
Complete abstinence from sexual intercourse for 14 days prior to first dose of study 
treatment, through the dosing period, and from the first dose of study drug(s) until 60 
days after the last dose of any study drug.
Novartis acceptable contraceptive methods, when used consistently and in accordance 
with both the product label and the instructions of the physician, are as follows:
Contraceptive Methods with a Failure Rate of 1%

Intrauterine device (IUD) or intrauterine system (IUS) that meets the <1% 
failure rate as stated in the product label

Male partner sterilization (vasectomy with documentation of azoospermia) 
prior to the female subject's entry into the study, and this male is the sole 
partner for that subject.  For this definition, “documented” refers to the 
outcome of the investigator's/designee’s medical examination of the subject or 
review of the subject's medical history for study eligibility, as obtained via a 
verbal interview with the subject or from the subject’s medical records.

Double-barrier method: condom and occlusive cap (diaphragm or cervical/vault 
caps) plus vaginal spermicidal agent (foam/gel/film/cream/suppository)

Note: Hormonal-based methods (e.g., oral contraceptives) are not permitted as 
contraception due to potential drug-drug interactions with dabrafenib.  
These allowed methods of contraception are only effective when used consistently, 
correctly and in accordance with the product label.  The investigator is responsible 
for ensuring subjects understand how to properly use these methods of 
contraception.
7.1.2.
Male Subjects
To prevent pregnancy in a female partner or to prevent exposure of any partner to the 
study treatment from a male subject’s semen, male subjects must use one of the following 
contraceptive methods from 7 days prior to the first dose and until 6 months after the last 
dose of panitumumab, or 16 weeks following the last dose of dabrafenib or trametinib, 
whichever is later to allow for clearance of any altered sperm:

Condom (during non-vaginal intercourse with any partner - male or female) 
plus partner use of a highly effective contraceptive (see list in Section 7.1.1). 


Novartis
Confidential
Page 137
Clinical Study Protocol Version 05
Protocol No. MEK116833

Abstinence, defined as sexual inactivity consistent with the preferred and usual 
lifestyle of the subject. Periodic abstinence (e.g. calendar, ovulation, 
symptothermal, post-ovulation methods) and withdrawal are not acceptable 
methods of contraception
7.2.
Meals and Dietary Restrictions
Dabrafenib and trametinib should be administered in the morning at approximately the 
same time every day.  The second dose of dabrafenib (150 mg) should be administered 
approximately 12 hours after the morning dose.  Study medication should be taken orally 
with approximately 200 mL of water under fasting conditions, either 1 hour before or 2 
hours after a meal.
If a subject vomits after taking study medication, the subject should be instructed not to 
retake the dose and should take the next dose as originally scheduled.  
If a subject misses a dabrafenib dose, the subject may take the dose immediately if the 
next dose is scheduled for at least 6 hours later. If the next scheduled dabrafenib dose is 
due in less than 6 hours, the subject should skip the dose and resume dosing at the next 
scheduled dose.  If a subject misses a trametinib dose, the subject may take the dose 
immediately if the next dose is scheduled for at least 12 hours later.  If the next scheduled 
trametinib dose is within 12 hours, skip the missed dose.
8.
CONCOMITANT MEDICATIONS AND NON-DRUG 
THERAPIES
8.1.
Permitted Medications
The investigator must be informed as soon as possible about any medication taken from 
the time of screening until 30 days after the last dose of study treatment.  Any 
concomitant medication(s), including dietary supplements,) taken during the study will be 
recorded in the eCRF.  The minimum requirement is that drug name, dose, and the dates 
of administration are to be recorded.  Additionally, a complete list of all prior cancer 
therapies will be recorded in the eCRF.
Subjects should receive full supportive care during the study, including transfusions of 
blood and blood products, and treatment with antibiotics, anti-emetics, anti-diarrheals, 
and analgesics, and other care as deemed appropriate, and in accordance with their 
institutional guidelines.  Growth factors and bisphosphonates are allowed but must not be 
initiated during the first 4 weeks of treatment. Use of anticoagulants such as warfarin is 
permitted however, caution should be exercised and additional International Normalized 
Ratio (INR) monitoring is recommended when dabrafenib is used concomitantly with 
warfarin.
While patients are on study treatment, palliative radiation therapy is permitted for non-
target lesions that are either new or present at baseline.
Radiation skin injury has been reported with concurrent use of dabrafenib and radiation. 
It is recommended that dabrafenib be held for seven days before and two days after XRT 


Novartis
Confidential
Page 138
Clinical Study Protocol Version 05
Protocol No. MEK116833
in subjects receiving dabrafenib monotherapy or in combination with trametinib. These 
recommendations can be modified based on the physician’s assessment of the risk of 
radiation skin injury.
8.2.
Prohibited Medications
The use of certain medications, and illicit drugs within 5 half-lives or 28 days, whichever 
is shorter prior to the first dose of study drug and for the duration of the trial will not be 
allowed.  If a prohibited medication is required for single use (such as for a procedure) 
while study drug is held, the Novartis Medical Lead can approve such use.
The following medications or non-drug therapies are prohibited:

Other anti-cancer therapy while on treatment in this study.

Antiretroviral drugs.

Herbal remedies (e.g., St. John’s wort).

Dabrafenib is metabolized primarily by Cytochrome P450 (CYP) 2C8 and 
CYP3A4.  Co-administration of dabrafenib with ketoconazole, a CYP3A4 
inhibition, or with gemfibrozil, a CYP2C8 inhibitor, resulted in increases in 
dabrafenib AUC of 71% and 47%, respectively.  Drugs that are strong 
inhibitors or inducers of CYP3A and CYP2C8 (see list in Table 32) may only 
be used under special circumstances (e.g. as a single use for a procedure) while 
treatment with study drug is interrupted as they may alter dabrafenib 
concentrations; consider therapeutic substitutions for these medications.  
Approval of the Novartis Medical Lead is required in these situations. The list 
may be modified based on emerging data. 

Oral contraceptives (either combined or progesterone only), estrogenic vaginal 
ring/percutaneous contraceptive patches, or implants of 
levonorgestrel/Injectable progesterone is prohibited in this study as it is not 
known if there is the potential of inhibition/induction of enzymes that affect the 
metabolism of estrogens and/or progestins.  HRT is permitted.


Novartis
Confidential
Page 139
Clinical Study Protocol Version 05
Protocol No. MEK116833
Table 32
Prohibited Medications
PROHIBITED – strong inducers of CYP3A or CYP2C8, since concentrations of dabrafenib may be decreased
Class/Therapeutic Area
Drugs/Agents
Oral Antibioticsa
Rifamycin class agents (e.g.,  rifampin, rifabutin, rifapentine), 
Anticonvulsant
Carbamazepine, oxcarbazepine phenobarbital, phenytoin, s-mephenytoin 
Miscellaneous
bosentan, St John’s wort
PROHIBITED – Strong inhibitors of CYP3A, or CYP2C8 since concentrations of dabrafenib may be increased
Class/Therapeutic Area
Drugs/Agents
Oral Antibioticsa
Clarithromycin, telithromycin, troleandomycin
Antidepressant
Nefazodone
Oral Antifungalsa
Itraconazole, ketoconazole, posaconazole, voriconazole
Hyperlipidemia
Gemfibrozil
Antiretroviral
ritonavir, saquinavir, atazanavir
Miscellaneous
Conivaptan 
a.
Topical formulations of these drugs/agents can be used.
8.3.
Cautionary Medications
The following medications should be used with caution as their concentrations may be 
altered by dabrafenib or they may alter dabrafenib concentrations:

Drugs that are moderate inhibitors or inducers of CYP3A, CYP2C8, or Pgp or 
Bcrp transporter because they may alter dabrafenib concentrations.

Dabrafenib has been shown to induce CYP3A4 and CYP2C9 in vivo using 
midazolam (CYP3A4 substrate) and S-warfarin (CYP2C9 substrate).  
Dabrafenib is an in vitro inducer of CYP2B6 and other enzymes such as 
CYP2C8, CYP2C19, UDP-glucuronyl transferases, and transporters may also 
be affected. Co-administration of dabrafenib and medications which are 
affected by the induction of these enzymes (including warfarin) may result in 
loss of efficacy. If co-administration of these medications is necessary, 
investigators should monitor subjects for loss of efficacy or consider 
substitutions of these medications. 

Therapeutic level dosing of warfarin can be used with approval by the Novartis 
Medical Lead and close monitoring of PT/INR by the site. Exposure decreased 
by 37% due to enzyme induction when on treatment, thus warfarin dosing may 
need to be adjusted based upon PT/INR. Consequently, when discontinuing 
dabrafenib, warfarin exposure may be increased and thus close monitoring via 
PT/INR and warfarin dose adjustments must be made as clinically appropriate. 
Prophylactic low dose warfarin may be given to maintain central catheter 
patency.

Dabrafenib solubility is pH-dependent with decreased solubility at higher pH. 
Drugs such as proton pump inhibitors that inhibit gastric acid secretion to 
elevate gastric pH may decrease the solubility of dabrafenib and reduce its 
bioavailability. No clinical study has been conducted to evaluate the effect of 


Novartis
Confidential
Page 140
Clinical Study Protocol Version 05
Protocol No. MEK116833
pH on dabrafenib pharmacokinetics. In an ad-hoc analysis, no differences in 
Cmax and AUC were noted between subjects who reported taking pH-elevating 
products relative to other subjects. Due to the theoretical risk that pH-elevating 
agents may decrease oral bioavailability and exposure to dabrafenib, these 
medicinal products that increase gastric pH should be used with caution when 
administered with dabrafenib.
These include but are not limited to those listed in Table 33.
Table 33
Cautionary Medications
USE WITH CAUTION:  Moderate inhibitors of CYP3A, or CYP2C8 since concentrations of dabrafenib may be 
increased
Class/Therapeutic Area 
Moderate CYP3A and CYP2C8 Inhibitors 
Antiarrhythmics 
Diltiazem, verapamil 
Oral Antibiotic
Erythromycin 
Oral Antifungal
Fluconazole 
Miscellaneous 
Aprepitant, 
USE WITH CAUTION: Co-administration of these drugs with study treatment may result in loss of efficacy.  
Monitor subjects for loss of efficacy or substitute with another medication. 
Class/Therapeutic Area 
CYP3A4, CYP2B6, CYP2C8, CYP2C9, CYP2C19 or Transporter Substrates 
that May be Affected by Induction  
Analgesics 
Alfentanil, buprenorphine, celecoxib, codeine, fentanyl, methadone, oxycodone 
Antiarrhythmics 
Disopyramide, dronedarone, mexiletine, propafenone, quinidine 
USE WITH CAUTION: Co-administration of these drugs with study treatment may result in 
loss of efficacy.  Monitor subjects for loss of efficacy or substitute with another 
medication. 
Class/Therapeutic Area 
CYP3A4, CYP2B6, CYP2C8, CYP2C9, CYP2C19 or Transporter 
Substrates that May be Affected by Induction  
Oral Antibiotics
Chloramphenicol, doxycycline, erythromycin, moxifloxacin 
Anticoagulants/ 
Antiplatelets 
Cilostazole, warfarin 
Anticonvulsants 
Divalproex, lamotrigine, valproate, zonisamide 
Antidepressants and 
Antipsychotics 
Aripiprazole, bupropion, buspirone, desipramine, haloperidol, 
mirtazapine, pimozide, quetiapine, trazodone, amitriptyline, 
clomipramine, imipramine 
Antidiabetics 
Glyburide, saxagliptin, tolbutamide, nateglinide, pioglitazone, 
repaglinide, rosiglitazone 
Oral Antifungals
Caspofungin, fluconazole, terbinafine 


Novartis
Confidential
Page 141
Clinical Study Protocol Version 05
Protocol No. MEK116833
USE WITH CAUTION: Co-administration of these drugs with study treatment may result in 
loss of efficacy.  Monitor subjects for loss of efficacy or substitute with another 
medication. 
Class/Therapeutic Area 
CYP3A4, CYP2B6, CYP2C8, CYP2C9, CYP2C19 or Transporter 
Substrates that May be Affected by Induction  
Antihistamines
Astemizole, chlorpheniramine, ebastine 
Antihypertensives 
Amlodipine, diltiazem, felodipine, nifedipine, nilvadipine, nisoldipine, 
verapamil 
Antimigraine Agents 
Diergotamine, eletriptan, ergotamine 
Corticosteroids 
Dexamethasone, methylprednisolone, oral budesonide 
Erectile Dysfunction 
Agents 
Sildenafil, tadalafil, vardenafil 
HMG-CoA Reductase 
Inhibitors 
Atorvastatin, lovastatin, simvastatin, rosuvastatin, pravastatin 
Hypnotics and Sedatives 
Alprazolam, brotizolam, diazepam, estazolam, midazolam, 
triazolam, zolpidem, zopiclone 
Immunosuppressants 
Everolimus, sirolimus, tacrolimus 
Miscellaneous 
Aprepitant, cisapride, darifenacin, disopyramide, leflunomide, 
methohexital, oral contraceptives, quinine, ranitidine, solifenacin, 
sulfasalazine, tramadol, tolvaptan, chloroquine, zopiclone 
Selective Aldosterone 
Blockers 
Eplerenone 
USE WITH CAUTION: Co-administration of drugs that increase gastric pH should be used 
with caution when administered with dabrafenib.
pH altering agents
dexlansoprazole. esomeprazole, famotidine, ilaprazole, 
lansoprazole, omeprazole, pantoprazole, rabeprazole, ranitidine
Abbreviations: CYP = cytochrome P450; HMG-CoA = 3-hydroxy-3-methylglutaryl-coenzyme A
Questions regarding concomitant medications should be directed to the Novartis Medical 
Lead for clarification.
8.4.
Non-Drug Therapies
Subjects must abstain from taking any vitamins, herbal and dietary supplements within 
7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is 
longer) prior to the first dose of study medication until completion of the follow-up visit, 
unless in the opinion of the investigator and sponsor the medication will not interfere 
with the study.


Novartis
Confidential
Page 142
Clinical Study Protocol Version 05
Protocol No. MEK116833
9.
COMPLETION OR EARLY WITHDRAWAL OF SUBJECTS
9.1.
Screen and Baseline Failures
Data for screen and baseline failures will be collected in source documentation at the site 
but will not be transmitted to Novartis.
9.2.
Subject Completion Criteria
A completed subject is one who has discontinued study treatment for reasons listed in 
Section 3.10 and was followed to death or has died while receiving study treatment.  
Subjects will be considered to have completed the study if they died or were ongoing at 
the time the study has completed.  Subjects who have not died, and are no longer being 
followed for survival are considered to have discontinued the study.  The End of Study 
eCRF should only be completed when a subject is no longer being followed.  The study 
will be considered completed for purposes of a final analysis when a total of 99 deaths 
have occurred (70% of subjects enrolled have died).  If available, subjects continuing on 
treatment at the time 70% of deaths have been observed may be offered the option to 
continue in a rollover trial.
9.3.
Permanent Discontinuation from Study Treatment
Subjects will receive study treatment until disease progression, death or unacceptable 
toxicity, including meeting stopping criteria for liver chemistry defined in Section 3.10.  
In addition, study treatment may be permanently discontinued for any of the following 
reasons:

deviation(s) from the protocol

investigator’s discretion

intercurrent illness that prevents further administration of study treatment(s)

subject is lost to follow-up study is closed or terminated.

Disease progression.  Note: Continuation of study treatment beyond 
radiographic disease progression (as defined by RECIST 1.1) may be possible if 
the investigator determines that subject has clear evidence of clinical benefit 
from study treatment, continuing study drug(s) may be in the best interest for the 
subject and the subject is willing to continue on study drug(s). In this case, 
consultation between the investigator and the Novartis Medical Lead is 
mandatory. If continuing the subject on study treatment is agreed then all study 
procedures, including tumor assessments, must be followed as scheduled 
(Section 3.11). In addition, after each tumor assessment, the investigators must 
confirm with the Novartis Medical Lead that the subject is still benefitting from 
study treatment and therefore can continue receiving study treatment.

Female subject becomes pregnant;

Adverse event that is considered by the investigator or a Novartis Medical Lead
to warrant permanent discontinuation of the study drug;


Novartis
Confidential
Page 143
Clinical Study Protocol Version 05
Protocol No. MEK116833

A clinically significant AE leading to an interruption of treatment for >14 
consecutive days.  If the investigator and the Novartis Medical Lead conclude 
that continued treatment will benefit a subject who has had a >14 day treatment 
delay, then the subject may continue therapy with the approval of the Novartis 
Medical Lead.

Subject withdraws consent for further treatment or data collection:

If the subject withdraws consent for further treatment, follow-up visit 
assessments should be completed (as indicated in the Time and Events table 
(Section 3.11).

If the subject withdraws consent for further treatment and data collection, 
then no additional study visits or data collection should occur.

Subject is withdrawn at the discretion of the investigator for safety, behavioral, 
or administrative reasons.
The primary reason study treatment was permanently discontinued must be documented 
in the subject’s medical records and electronic case report form (eCRF). 
9.4.
Subject Withdrawal Procedures
9.4.1.
Subject Withdrawal from Study
Following permanent discontinuation of study treatment, every effort should be made for 
subjects to complete the follow-up visit as described in the Time and Events Table 
(Section 3.11). The follow-up visit should occur approximately 14 days from last dose of 
study drugs (7 days) and prior to initiating further anti-cancer therapy or dosing of a 
different investigational agent.  The reason for discontinuing treatment with study drug 
will be clearly documented in the subject’s medical record and on the Study Conclusion 
eCRF page.  If the subject withdraws from treatment due to toxicity, ‘Adverse Event’ will 
be recorded as the primary reason for withdrawal.
9.4.2.
Subject Withdrawal from Study Treatment
If the subject withdraws consent for further treatment, final study visit should be 
completed (see Time and Events Tables in Section 3.11).  If the subject withdraws 
consent for further treatment and data collection, then no additional study visits or data 
collection should occur.  The investigator may also, at his or her discretion, discontinue a 
subject from participating in this study at any time.
In the event that a subject is prematurely discontinued from the study at any time due to 
an AE (as defined in Section 0, “Definition of an AE”) or SAE (as defined in Section 
11.1 “Definition of a SAE”), the procedures stated in Section 11.4, (“AEs and SAEs”)
must be followed.  All subjects who have a Grade 3 or 4 clinical or laboratory 
abnormality at the time of withdrawal from the study must be followed until resolution to 
Grade 2 or less, unless it is unlikely to improve because of underlying disease.


Novartis
Confidential
Page 144
Clinical Study Protocol Version 05
Protocol No. MEK116833
9.5.
Treatment After the End of the Study
The investigator is responsible for ensuring that consideration has been given to the 
post-study care of the subject’s medical condition, whether or not Novartis is providing 
specific post-study treatment.
Subjects will receive standard of care treatment as determined by their health care 
provider after discontinuation from the study.
10.
STUDY TREATMENT
Study treatment dosage and administration details are listed in Section 3.9.
Supplies of the investigational products will be provided to sites by Novartis, with the 
exception of sites in China (if applicable) where GSK will continue to provide supplies.
10.1.
Blinding
This will be an open-label study.
10.2.
Packaging and Labeling
The contents of the label will be in accordance with all applicable regulatory 
requirements.
10.3.
Preparation/Handling/Storage/Accountability
Investigational products (dabrafenib and trametinib) must be dispensed or administered 
according to procedures described herein.  Only subjects enrolled in the study may 
receive investigational product.  Only authorized site staff may supply or administer 
investigational product.  
10.3.1.
Preparation
No special preparation of dabrafenib and trametinib is required.  Refer to the 
GSK2118436 IB [GlaxoSmithKline Document Number 2012N136095_00], the 
GSK1120212 IB [GlaxoSmithKline Document Number HM2009/00151/03] and the 
GSK1120212 + GSK2118436 Clinical IB [GlaxoSmithKline Document Number, 
2011N126811_00] for detailed information regarding dabrafenib and trametinib.  
Please refer to the FDA approved label and/or EU SmPC for panitumumab for updated 
detailed information.  The following text is summarized from the approved FDA label 
[VECTIBIX, 2014].
Prepare the solution for infusion, using aseptic technique, as follows:

Parenteral drug products should be inspected visually for particulate matter and 
discoloration prior to administration. Although panitumumab should be colorless, 
the solution may contain a small amount of visible translucent-to-white, 


Novartis
Confidential
Page 145
Clinical Study Protocol Version 05
Protocol No. MEK116833
amorphous, proteinaceous, panitumumab particulates (which will be removed by 
filtration; see below). Do not shake. Do not administer if discoloration is observed.

Withdraw the necessary amount of panitumumab for the study- prescribed dose.

Dilute to a total volume of 100 mL with 0.9% sodium chloride injection, USP. 
Doses higher than 1000 mg should be diluted to 150 mL with 0.9% sodium 
chloride injection, USP. Do not exceed a final concentration of 10 mg/mL.

Mix diluted solution by gentle inversion. Do not shake.

Administer using a low-protein-binding 0.2m or 0.22m in-line filter.

Vectibix must be administered via infusion pump.
o
Flush line before and after Vectibix administration with 0.9% sodium 
chloride injection, USP, to avoid mixing with other drug products or 
intravenous solutions.  Do not mix Vectibix with, or administer as an 
infusion with, other medicinal products. Do not add other medications to 
solutions containing panitumumab.
o
Infuse over 60 minutes through a peripheral intravenous line or indwelling 
intravenous catheter. Doses higher than 1000mg should be infused over 90 
minutes. 
10.3.2.
Handling and Storage of Study Treatments
Precaution will be taken to avoid direct contact with the investigational product.  Material 
Safety Data Sheets (MSDS) for dabrafenib and trametinib describing occupational 
hazards and recommended handling precautions will be provided to the investigator.
Please refer to the FDA approved label and/or EU SmPC for panitumumab for updated 
detailed information [VECTIBIX, 2014].
However, precautions are to be taken to avoid direct skin contact, eye contact, and 
generating aerosols or mists.  In the case of unintentional occupational exposure notify 
the Medical Lead and/or study manager.
Precaution will be taken to avoid direct contact with the investigational product.  A 
Material Safety Data Sheet (MSDS) describing occupational hazards and recommended 
handling precautions will be provided to the investigator.
Dabrafenib and trametinib must be dispensed and administered in accordance with the 
protocol, and only to subjects enrolled in the study.  Dabrafenib and trametinib must be 
stored in a secure area under the appropriate physical conditions for the product.  Study 
medication is to be stored at the temperature specified on the label.  Maintenance of a 
temperature log (manual or automated) is required.  Access to and administration of 
dabrafenib and trametinib will be limited to the investigator and authorized site staff.  


Novartis
Confidential
Page 146
Clinical Study Protocol Version 05
Protocol No. MEK116833
Please refer to the FDA approved label and/or EU SmPC for panitumumab for updated 
detailed information.  The following text is summarized from the approved FDA label 
[VECTIBIX, 2014].  Store vials in the original carton under refrigeration at 2° to 8°C 
(36° to 46°F) until time of use. Protect from direct sunlight. DO NOT FREEZE. Since 
panitumumab does not contain preservatives, any unused portion remaining in the vial 
must be discarded.
Procedures for final disposition of unused study treatments will be provided in the Study 
Procedures Manual (SPM).  
10.3.3.
Accountability
In accordance with local regulatory requirements, the investigator, designated site staff, 
or head of the medical institution (where applicable) must document the amount of 
investigational product (IP) dispensed and/or administered to study subjects, the amount 
returned by study subjects, and the amount received from and returned to Novartis, when 
applicable.  Product accountability records must be maintained throughout the course of 
the study.  
The required accountability unit for this study will be tablet (trametinib), capsule 
(dabrafenib) and vial (panitumumab).  Discrepancies are to be reconciled or resolved.  
Refer to the SPM for further detailed instructions on product accountability. Procedures 
for final disposition of unused investigational product are listed in the SPM.
10.4.
Assessment of Compliance
When subjects are dosed at the study site, they will receive study treatment(s) directly 
from the investigator or designee, under medical supervision.  The date and time of each 
dose administered in the clinic will be recorded in the source documents, including a 
supplied subject dosing diary.  When subjects are dosed at the study site, the dose of 
study treatment and study participant identification will be confirmed at the time of 
dosing by a member of the study site staff other than the person administering the study 
treatment.  
When subjects self-administer study treatment(s) at home, compliance with dabrafenib 
and/or trametinib dosing will be assessed through querying the subject during the site 
visits, review of the subject dosing diary and documented in the source documents and 
electronic case report form (eCRF).  A record of the number of dabrafenib capsules 
and/or trametinib tablets dispensed to and taken by each subject must be maintained and 
reconciled with study treatment and compliance records.  Treatment start and stop dates, 
including dates for treatment delays and/or dose reductions will also be recorded in the 
eCRF.
Panitumumab will be intravenously administered to subjects at the study site.  
Administration will be documented in the source documents and reported in the electric 
case report form (eCRF).


Novartis
Confidential
Page 147
Clinical Study Protocol Version 05
Protocol No. MEK116833
10.5.
Treatment of Study Treatment Overdose
In the event of a dabrafenib overdose, defined as administration of more than 300mg as a 
single dose or 600mg daily (the highest dose tested in clinical studies to date), or in the 
event of a trametinib overdose defined as administration of more than 3.0 mg once daily 
(the maximum tolerated dose defined in the MEK111054 Study), the investigator should 
contact the Novartis Medical Lead immediately and closely monitor the subject for 
AEs/SAEs and laboratory abnormalities.  Novartis does not recommend specific 
treatment.  The investigator will use clinical judgment to treat any overdose.  
Haemodialysis is not expected to enhance the elimination of either dabrafenib or 
trametinib as both are highly bound to plasma proteins.
In the event of an overdose of panitumumab, refer to the package insert [VECTIBIX, 
2014].
Decisions regarding dose interruptions or modifications should be made by the 
investigator in consultation with the Novartis Medical Lead based on the clinical 
evaluation of the subject.
A plasma sample for PK analysis may be requested by the Novartis Medical Lead on a 
case-by-case basis.  This plasma sample should be collected as soon as possible, but 
within 10 days from the date of the last dose of on-study dosing.
Information regarding the quantity of the excess dose as well as the duration of the 
overdosing should be documented in the eCRF.
11.
ADVERSE EVENTS (AE) AND SERIOUS ADVERSE 
EVENTS (SAE)
The investigator or site staff is responsible for detecting, documenting and reporting 
events that meet the definition of an AE or SAE. The severity of adverse events (AEs) 
will be graded utilizing the National Cancer Institute- Common Toxicity Criteria for 
Adverse Events (NCI-CTCAE), version 4.0.  
AEs will be collected from the time a subject consents to participate in and completes the
study (See Section 9.2), all SAEs assessed as related to study participation (e.g., 
protocol-mandated procedures, invasive tests, or change in existing therapy), will be 
reported promptly to Novartis, as indicated in Section 11.5 from the start of Study 
Treatment and until the follow-up contact.  
SAEs will be collected over the same time period as stated above for AEs.  In addition, 
any SAEs assessed as related to study participation (e.g. protocol-mandated procedures, 
invasive tests, or change in existing therapy, study treatment[s]) will be recorded from the 
time a subject consents to participate in the study up to and including any follow-up 
contact.  All SAEs will be recorded.  Only SAEs relating to study procedures should be 
reported to Novartis within 24 hours, as indicated in Section 11.4.


Novartis
Confidential
Page 148
Clinical Study Protocol Version 05
Protocol No. MEK116833
After discontinuation of study treatment, the investigator will monitor all AEs/SAEs that 
are ongoing until resolution or stabilization of the event or until the subject is lost to 
follow-up.  At any time after at least 5 terminal half lives or 30 days the investigator may 
report any AE that they believe possibly related to study treatment.
Definition of Adverse Events
An AE is any untoward medical occurrence in a subject or clinical investigation subject, 
temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product.
Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal product.  For marketed medicinal products, this 
also includes failure to produce expected benefits, abuse, or misuse.
Examples of events meeting the definition of an AE include:

Exacerbation of a chronic or intermittent pre-existing condition including either 
an increase in frequency and/or grade of the condition

New conditions detected or diagnosed after study treatment administration 
even though it may have been present prior to the start of the study

Signs, symptoms, or the clinical sequelae of a suspected interaction

Signs, symptoms, or the clinical sequelae of a suspected overdose of either 
study treatment or a concomitant medication (overdose per se will not be 
reported as an AE/serious adverse event [SAE]). 

Any abnormal laboratory test results (hematology, clinical chemistry, or 
urinalysis) or other safety assessments (e.g., ECGs, radiological scans, vital 
signs measurements), including those that worsen from baseline, and felt to be 
clinically significant in the medical and scientific judgment of the investigator.
“Lack of efficacy” or “failure of expected pharmacological action” per se is not to be 
reported as an AE or SAE.  However, any signs and symptoms and/or clinical sequelae 
resulting from “lack of efficacy” will be reported as an AE or SAE, if they fulfill the 
definition of an AE or SAE. 
Events that do not meet the definition of an AE include:

Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition 
that leads to the procedure is an AE.

Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen.


Novartis
Confidential
Page 149
Clinical Study Protocol Version 05
Protocol No. MEK116833

The disease/disorder being studied, or expected progression, signs, or 
symptoms of the disease/disorder being studied, unless more severe than 
expected for the subject’s condition. 
11.1.
Definition of Serious Adverse Events
If an event is not an AE per Section 0, then it cannot be an SAE even if serious conditions 
are met (e.g., hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease, etc).
An SAE is any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life-threatening
NOTE:  The term 'life-threatening' in the definition of 'serious' refers to an event in 
which the subject was at risk of death at the time of the event.  It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
c.
Requires hospitalization or prolongation of existing hospitalization
NOTE:  In general, hospitalization signifies that the subject has been detained 
(usually involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or out-patient setting.  Complications that occur during hospitalization are AEs.  
If a complication prolongs hospitalization or fulfills any other serious criteria, the 
event is serious.  When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.
d.
Results in disability/incapacity, or
NOTE:  The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions.  This definition is not intended to include experiences 
of relatively minor medical significance such as uncomplicated headache, nausea, 
vomiting, diarrhea, influenza, and accidental trauma (e.g. sprained ankle) which may 
interfere or prevent everyday life functions but do not constitute a substantial 
disruption.
e.
Is a congenital anomaly/birth defect
f.
Medical or scientific judgment should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definition.  These should also be considered 
serious.  Examples of such events are invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization, or development of 
drug dependency or drug abuse.


Novartis
Confidential
Page 150
Clinical Study Protocol Version 05
Protocol No. MEK116833
g.
Is associated with liver injury and impaired liver function defined as:

ALT 3xULN and total bilirubin* 2xULN (>35% direct), or

ALT 3xULN and INR** > 1.5. 
* Serum bilirubin fractionation should be performed if testing is available; if 
unavailable, measure urinary bilirubin via dipstick.  If fractionation is unavailable 
and ALT 3xULN and total bilirubin 2xULN, then the event is still to be reported 
as an SAE.
** INR testing not required per protocol and the threshold value does not apply to 
subjects receiving anticoagulants.  If INR measurement is obtained, the value is to be 
recorded on the SAE form.

Refer to Section 12 for the required liver chemistry follow-up instructions.
h.
All grade 4 laboratory abnormalities.
i.
Protocol-specific SAEs: 

All events of possible drug-induced liver injury with hyperbilirubinemia defined 
as ALT ≥3 x ULN and total bilirubin ≥2 x ULN (>35% direct) or ALT ≥3 x ULN 
and INR >1.5 (if INR is measured) or termed ‘Hy’s Law’ events (INR 
measurement is not required and the threshold value stated will not apply to 
subjects receiving anticoagulants).
Note: Bilirubin fractionation is performed if testing is available. If testing is 
unavailable, record presence of detectable urinary bilirubin on dipstick indicating 
direct bilirubin elevations and suggesting liver injury. If testing is unavailable and 
a subject meets the criterion of total bilirubin ≥2 x ULN, then the event is still 
reported as an SAE. If INR is obtained, include values on the SAE form. 
International normalized ratio (INR) elevations >1.5 suggest severe liver injury.

Any new malignancy with a histology different from the primary tumor, including 
cutaneous squamous cell carcinoma, basal cell carcinoma, and secondary 
melanoma

Symptomatic LVEF decrease that meets stopping criteria or asymptomatic LVEF 
decrease that does not recover, as outlined as LVEF guidance Section 3.10.7.1.

RPED or RVO.
11.2.1.
Sentinel Events
A Sentinel Event is a Novartis -defined SAE that is not necessarily drug-related but has 
been associated historically with adverse reactions for other drugs and is therefore worthy 
of heightened pharmacovigilance.  The Novartis Medical Lead is accountable for 
reviewing all SAEs for possible Sentinel Events which is mandated at Novartis.  The 
Novartis Medical Lead may request additional clinical information on an urgent basis if a 
possible Sentinel Event is identified on SAE review.  The current Novartis -defined 
Sentinel Events are listed below:


Novartis
Confidential
Page 151
Clinical Study Protocol Version 05
Protocol No. MEK116833

Acquired Long QT Syndrome

Agranulocytosis/Severe Neutropenia 

Anaphylaxis & Anaphylactoid Reactions 

Hepatotoxicity

Acute Renal Failure

Seizure

Stevens Johnson syndrome/Toxic epidermal necrosis
11.2.
Laboratory and Other Safety Assessment Abnormalities 
Reported as AEs and SAEs
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis), or 
other safety assessments (e.g., electrocardiogram [ECGs], radiological scans, vital signs
measurements) including those that worsen from baseline, and events felt to be clinically 
significant in the medical and scientific judgment of the investigator are to be recorded as 
an adverse event (AE) or serious adverse event (SAE), in accordance with the definitions 
provided.
In addition, an associated AE or SAE is to be recorded for any laboratory test result or 
other safety assessment that led to an intervention, including permanent discontinuation 
of study treatment, dose reduction, and/or dose interruption/delay.
Any new primary cancer must be reported as a SAE. 
However, any clinically significant safety assessments that are associated with the 
underlying disease, unless judged by the investigator to be more severe than expected for 
the subject's condition, are not to be reported as AEs or SAEs.
11.3.1.
Cardiovascular Events
Investigators will be required to fill out event specific data collection tools for the 
following AEs and SAEs:  

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularisation


Novartis
Confidential
Page 152
Clinical Study Protocol Version 05
Protocol No. MEK116833
This information should be recorded in the specific cardiovascular eCRF within one week 
of when the AE/SAE(s) are first reported.
11.3.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrence.  Appropriate questions include:

“How are you feeling?” 

“Have you had any (other) medical problems since your last visit/contact?” 

“Have you taken any new medicines, other than those provided in this study, 
since your last visit/contact?” 
11.4.1.
Assessment of Causality
The investigator is obligated to assess the relationship between study treatment and the 
occurrence of each AE/SAE.  A "reasonable possibility" is meant to convey that there are 
facts/evidence or arguments to suggest a causal relationship, rather than a relationship 
cannot be ruled out.  The investigator will use clinical judgment to determine the 
relationship.  Alternative causes, such as natural history of the underlying diseases, 
concomitant therapy, other risk factors, and the temporal relationship of the event to the 
study treatment will be considered and investigated.  The investigator will also consult 
the Investigator Brochure (IB), IB Supplement(s) and/or Product Information, for 
marketed products, in the determination of his/her assessment.
For each AE/SAE the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
There may be situations when an SAE has occurred and the investigator has minimal 
information to include in the initial report to Novartis.  However, it is very important 
that the investigator always make an assessment of causality for every event prior to 
the initial transmission of the SAE data to Novartis.  The investigator may change 
his/her opinion of causality in light of follow-up information, amending the SAE data 
collection tool accordingly.  The causality assessment is one of the criteria used when 
determining regulatory reporting requirements.
11.4.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject at subsequent visits/contacts.  All AEs and SAEs will be followed until resolution, 
until the condition stabilizes, until the event is otherwise explained, or until the subject is 
lost to follow-up.
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as may be indicated or as requested by Novartis to 
elucidate as fully as possible the nature and/or causality of the AE or SAE.   The 


Novartis
Confidential
Page 153
Clinical Study Protocol Version 05
Protocol No. MEK116833
investigator is obligated to assist.  This may include additional laboratory tests or 
investigations, histopathological examinations or consultation with other health care 
professionals.  If a subject dies during participation in the study or during a recognized 
follow-up period, the investigator will provide Novartis with a copy of any post-mortem 
findings, including histopathology. 
New or updated information will be recorded in the originally completed data collection 
tool.  The investigator will submit any updated SAE data to Novartis within the 
designated reporting time frames.
11.5.
Prompt Reporting of SAEs to Novartis
Serious adverse events (SAEs), pregnancies, liver function abnormalities and any other 
events meeting pre-defined criteria will be reported promptly by the investigator to 
Novartis as described in the following table once the investigator determines the event 
meets the protocol definition for that event.


Novartis
Confidential
Page 154
Clinical Study Protocol Version 05
Protocol No. MEK116833
Initial Reports
Follow-up Information on a Previous 
Report
Type of Event
Time Frame
Documents
Time Frame
Documents
All SAEs
24 hours
SAE data collection 
tool
24 hours
Updated SAE data 
collection tool 
“CV events” and/or 
“death”
Initial and 
follow up 
reports to be 
completed 
within one 
week of when 
the 
cardiovascular 
event or death 
is reported
“CV events” 
and/or “death” 
data collection 
tool(s) if 
applicable
Initial and follow 
up reports to be 
completed within 
one week of when 
the cardiovascular 
event or death is 
reported
Updated “CV 
events” and/or 
“death” data 
collection tool(s) if 
applicable
Pregnancy
24 hours
Pregnancy 
Notification Form
2 Weeks
Pregnancy 
Follow-up Form
Liver chemistry abnormalities:
ALT 3 times ULN and 
bilirubin 2 times ULN 
(>35% direct) (or ALT 
3 times ULN and INR 
>1.5, if INR is 
measured)c
24 hoursa
SAE data collection 
tool;
Liver Event eCRF 
and liver imaging 
and/or biopsy 
eCRFs if 
applicableb
24 hours
Updated SAE data 
collection tool. 
Updated Liver Event 
eCRFb
ALT 5 times ULN; ALT 
3 times ULN with 
hepatitis or rash or 3 
times ULN 4 weeks
24 hoursa
Liver Event eCRFb
24 hours
Updated Liver Event 
eCRFb
ALT 3 times ULN and 
<5 times ULN and 
bilirubin <2 times ULN
24 hoursa
Liver Event eCRF 
does not need to be 
completed unless 
elevations persist 
for 4 weeks or 
subject cannot be 
monitored weekly 
for 4 weeksb
a.
Novartis to be notified at onset of liver chemistry elevations to discuss subject safety.
b.
Liver event documents should be completed as soon as possible
c.
INR measurement is not required; if measured, the threshold value stated will not apply to subjects receiving 
anticoagulants.
Methods for detecting, recording, evaluating, and following up on adverse events (AEs) 
and serious adverse events (SAEs) are provided in the Study Procedures Manual (SPM).


Novartis
Confidential
Page 155
Clinical Study Protocol Version 05
Protocol No. MEK116833
11.6.
Regulatory Reporting Requirements for SAEs
Prompt notification of SAEs by the investigator to Novartis is essential so that legal 
obligations and ethical responsibilities towards the safety of subjects are met.
Novartis have a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation.  Novartis
will comply with country specific regulatory requirements relating to safety reporting to 
regulatory authorities, IRBs/IECs and investigators.  
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and Novartis policy and are 
forwarded to investigators as necessary.  An investigator who receives an investigator 
safety report describing an SAE(s) or other specific safety information (e.g., summary or 
listing of SAEs) from Novartis will file it with the IB and will notify the IRB/IEC, if 
appropriate according to local requirements.
12.
LIVER CHEMISTRY FOLLOW-UP PROCEDURES
12.1.
Liver Chemistry Testing Procedures
For subjects meeting any of the liver chemistry stopping criteria in Section 3.10.10, make 
every attempt to carry out the liver event follow-up assessments described below:

Viral hepatitis serology, including:

Hepatitis A IgM antibody

Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM)

Hepatitis C RNA

Cytomegalovirus IgM antibody

Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, then obtain 
heterophile antibody or monospot testing)

Blood sample for pharmacokinetic (PK) analysis, obtained within 10 days of the 
last dose of study drug(s). Record the date and time of the PK blood sample 
draw and the date and time of the last dose of study drug(s) prior the blood 
sample draw on the eCRF.  If the date or time of the last dose is unclear, provide 
the subject’s best approximation.  If the date or time of the last dose cannot be 
approximated, or if a PK sample cannot be collected within the 10-day period 
following the last dose, do not obtain a PK sample.  Instructions for sample 
handling and shipping are found in the Study Procedures Manual (SPM).

Serum creatinine phosphokinase (CPK) and lactate dehydrogenase (LDH).

Fractionate bilirubin, if total bilirubin 2 X upper limit of normal (ULN).

Obtain a complete blood count (CBC) with differential to assess eosinophilia.


Novartis
Confidential
Page 156
Clinical Study Protocol Version 05
Protocol No. MEK116833

Record the appearance or worsening of clinical symptoms indicative of hepatitis 
or hypersensitivity, such as fatigue, nausea, vomiting, right upper quadrant pain 
or tenderness, fever, rash or eosinophilia as relevant on the AE eCRF.

Record the use of concomitant medications, including acetaminophen, herbal 
remedies or any other over the counter (OTC) medications, or any putative 
hepatotoxins, on the concomitant medication eCRF.

Record alcohol use on the liver event alcohol intake eCRF.
The following assessments are required for subjects with ALT 3 X ULN and bilirubin 
2X ULN (>35% direct) but are optional for other abnormal liver chemistries:

Anti-nuclear antibody, anti-smooth muscle antibody, and Type 1 anti-liver 
kidney microsomal antibodies.

Liver imaging (ultrasound, magnetic resonance imaging [MRI] or computed 
tomography [CT]) to evaluate liver disease.
12.2.
Liver Chemistry Monitoring Criteria
For subjects with ALT 3 X ULN but <5X ULN and bilirubin <2 X ULN, without 
symptoms indicative of hepatitis or rash, and who can be monitored safety for 4 weeks, 
the following actions should be taken:

Notify the Novartis Medical Lead within 24 hours of learning of the abnormality 
to discuss subject safety.

Continue administration of study drug(s).

Evaluate liver chemistries (ALT, AST, alkaline phosphatase, bilirubin) weekly 
until they resolve, stabilize or return to within baseline levels.

If at any time the subject meets any of the liver chemistry stopping criteria 1 to 5 
(Section 3.10.10), then proceed as described in Section 12).

If, after 4 weeks of monitoring, ALT <3X ULN and bilirubin <2 X ULN, then 
monitor subjects twice monthly until liver chemistries normalize or return to 
within baseline values.
12.3.
Drug Restart/Rechallenge Following Liver Events that are 
Possibly Related to Study Drug(s)
Approval by the Novartis Medical Lead to restart/rechallenge study drug(s) may be 
considered where:

The subject is receiving compelling benefit, the benefit exceeds the risk, and no 
effective alternative therapy is available.  Approval of restart/rechallenge by the 
Institutional Review Board (IRB) or Independent Ethics Committee (IEC) must 
be obtained, as required.  

If the restart/rechallenge is approved by Novartis in writing, then the subject 
must be provided with a clear description of the possible benefits and risks of 


Novartis
Confidential
Page 157
Clinical Study Protocol Version 05
Protocol No. MEK116833
administration of study drug(s), including the possibility of a recurrence, a more 
severe liver injury or death.

The subject must also provide signed informed consent specifically for the study 
drug(s) restart/rechallenge.  Documentation of the informed consent must be 
recorded in the subject’s study chart.

Study drug(s) must be administered at the dose specified by the Novartis 
Medical Lead.

Subjects approved by Novartis for restart/rechallenge of study drug(s) must 
return to the clinic twice a week for evaluation of liver chemistry tests until 
stable liver chemistries have been demonstrated and laboratory monitoring may 
resume per protocol.
12.4.
Drug Restart Following Transient, Resolving Liver Events 
Not Related to Study Drug(s)
Approval by the Novartis Medical Lead to restart study drug(s) may be considered 
where:

Liver chemistry abnormalities have a clear underlying cause (e.g., biliary 
obstruction, hypotension) and liver chemistries have improved to normal or are 
within 1.5 X baseline and ALT <3X ULN.  Approval of restart by the 
Institutional Review Board (IRB) or Independent Ethics Committee (IEC) may 
be required.  

If the restart/rechallenge is approved by Novartis in writing, then the subject 
must be provided with a clear description of the possible benefits and risks of 
administration of study drug(s), including the possibility of a recurrence, a more 
severe liver injury or death.

The subject must also provide signed informed consent specifically for the study 
drug(s) restart/rechallenge.  Documentation of the informed consent must be 
recorded in the subject’s study chart.

Study drug(s) must be administered at the dose specified by the Novartis 
Medical Lead.

Subjects approved by Novartis for restart/rechallenge of study drug(s) must 
return to the clinic once a week for evaluation of liver chemistry tests until 
stable liver chemistries have been demonstrated and laboratory monitoring may 
resume per protocol.

If protocol-defined stopping criteria for liver chemistry abnormalities are met, 
study drug(s) administration must stop.


Novartis
Confidential
Page 158
Clinical Study Protocol Version 05
Protocol No. MEK116833
13.
STUDY CONDUCT CONSIDERATIONS
13.1.
Posting of Information on Publicly Available Clinical Trial 
Registers
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrollment of subjects begins.
13.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Novartis will obtain favorable opinion/approval to conduct the study from the appropriate 
regulatory agency in accordance with any applicable country-specific regulatory 
requirements prior to a site initiating the study in that country.
The study will be conducted in accordance with all applicable regulatory requirements.
The study will also be conducted in accordance with ICH Good Clinical Practice (GCP), 
all applicable subject privacy requirements, and, the guiding principles of the 2008 
Declaration of Helsinki.  This includes, but is not limited to, the following:

IRB/IEC review and favorable opinion/approval to conduct the study and of 
any subsequent relevant amended documents

Written informed consent (and any amendments) to be obtained for each 
subject before participation in the study

Investigator reporting requirements (e.g. reporting of AEs/SAEs/protocol 
deviations to IRB/IEC)
Written informed consent must be obtained from each subject prior to participation in the 
study.
In approving the clinical protocol the IEC/IRB and, where required, the applicable 
regulatory agency are also approving the optional assessments, 
 
, unless otherwise indicated.  Where permitted by regulatory 
authorities, approval of the optional assessments can occur after approval is obtained for 
the rest of the study.  If so, then the written approval will clearly indicate approval of the 
optional assessments is being deferred and the study, except for the optional assessments, 
can be initiated.  When the optional assessments are not approved, then the approval for 
the rest of the study will clearly indicate this and therefore, the optional assessments will 
not be conducted.
13.2.1.
Urgent Safety Measures
If an event occurs that is related to the conduct of the study or the development of the 
study treatment, and this new event is likely to affect the safety of subjects, the sponsor 
and the investigator will take appropriate urgent safety measures to protect subjects 
against any immediate hazard.


Novartis
Confidential
Page 159
Clinical Study Protocol Version 05
Protocol No. MEK116833
The sponsor will work with the investigator to ensure the IEC/IRB is notified.
13.3.
Quality Control (Study Monitoring)
In accordance with applicable regulations including GCP, and Novartis procedures, 
Novartis personnel (or designated Clinical Research Organization [CRO]) will contact 
the site prior to the start of the study to review with the site staff the protocol, study 
requirements, and their responsibilities to satisfy regulatory, ethical, and Novartis 
requirements.  When reviewing data collection procedures, the discussion will also 
include identification, agreement and documentation of data items for which the CRF 
will serve as the source document.
Novartis (or designated CRO) personnel will monitor the study and site activity to verify 
that the:

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol and any 
other study agreements, GCP, and all applicable regulatory requirements.
The investigator and the head of the medical institution (where applicable) agrees to 
allow the Medical Lead direct access to all relevant documents
13.4.
Quality Assurance
To ensure compliance with GCP and all applicable regulatory requirements, Novartis 
may conduct a quality assurance assessment and/or audit of the site records, and the 
regulatory agencies may conduct a regulatory inspection at any time during or after 
completion of the study. In the event of an assessment, audit or inspection, the 
investigator (and institution) must agree to grant the advisor(s), auditor(s) and 
inspector(s) direct access to all relevant documents and to allocate their time and the time 
of their staff to discuss the conduct of the study, any findings/relevant issues and to 
implement any corrective and/or preventative actions to address any findings/issues 
identified.
13.5.
Study and Site Closure
Upon completion or premature discontinuation of the study, Novartis personnel (or 
designated CRO)will conduct site closure activities with the investigator or site staff, as 
appropriate, in accordance with applicable regulations including GCP, and Novartis
procedures.
In addition, Novartis reserves the right to temporarily suspend or prematurely discontinue 
this study at any time for reasons including, but not limited to, safety or ethical issues or 
severe non-compliance.  For multicenter studies, this can occur at one or more or at all 
sites.  If Novartis determines such action is needed, Novartis will discuss this with the 
investigator or the head of the medical institution (where applicable), including the 
reasons for taking such action.  When feasible, Novartis will provide advance notification 


Novartis
Confidential
Page 160
Clinical Study Protocol Version 05
Protocol No. MEK116833
to the investigator or the head of the medical institution, where applicable, of the 
impending action prior to it taking effect.
If the study is suspended or prematurely discontinued for safety reasons, Novartis will 
promptly inform investigators or the head of the medical institution (where applicable) 
and the regulatory authorities of the suspension or premature discontinuation of the study 
and the reason(s) for the action.  If required by applicable regulations, the investigator or 
the head of the medical institution (where applicable) must inform the IRB/IEC promptly 
and provide the reason for the suspension or premature discontinuation.
13.6.
Records Retention
Following closure of the study, the investigator or the head of the medical institution 
(where applicable) must maintain all site study records, except for those required by local 
regulations to be maintained by someone else, in a safe and secure location.  The records 
must be maintained to allow easy and timely retrieval, when needed (e.g., audit or 
inspection), and, whenever feasible, to allow any subsequent review of data in 
conjunction with assessment of the facility, supporting systems, and staff.  Where 
permitted by local laws/regulations or institutional policy, some or all of these records 
can be maintained in a format other than hard copy (e.g., microfiche, scanned, 
electronic); however, caution needs to be exercised before such action is taken.  The 
investigator must assure that all reproductions are legible and are a true and accurate copy 
of the original, and meet accessibility and retrieval standards, including re-generating a 
hard copy, if required.  Furthermore, the investigator must ensure there is an acceptable 
back-up of these reproductions and that an acceptable quality control process exists for 
making these reproductions.
Essential documents (written and electronic) should be retained for a period of not less 
than fifteen (15) years from the completion of the Clinical Trial unless the Sponsor 
provides written permission to dispose of them or, requires their retention for an 
additional period of time because of applicable laws, regulations and/or guidelines.The 
investigator must notify Novartis of any changes in the archival arrangements, including, 
but not limited to, archival at an off-site facility or transfer of ownership of the records in 
the event the investigator leaves the site.
13.7.
Provision of Study Results to Investigators, Posting of 
Information on Publically Available Clinical Trials Registers 
and Publication
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report.  Investigators will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a Novartis site or other 
mutually-agreeable location.
Novartis will also provide investigators with the full summary of the study results.  
Investigators are encouraged to share the summary results with the study subjects, as 
appropriate.


Novartis
Confidential
Page 161
Clinical Study Protocol Version 05
Protocol No. MEK116833
Novartis will provide the investigator with the randomization codes for their site after 
completion of the full statistical analysis and finalization of the clinical study report 
(CSR).
Novartis aims to post a results summary to the Novartis Clinical Trial Results website 
(www.novartisclinicaltrials.com) and other publicly available registers no later than 
12 months after the last subject’s last visit (LSLV).  In addition, upon study completion 
and finalization of study report, Novartis aims to submit results of the study for 
publication.  
When publication is not feasible, please refer to the Novartis Clinical Trial Results 
website (www.novartisclinicaltrials.com) for a summary of the trial results.
13.8.
Data Management
For this study subject data will be entered into the electronic case report forms (eCRFs), 
transmitted electronically to the sponsor (or designee) and be combined with data 
provided from other sources in a validated data system.
Management of clinical data will be performed in accordance with applicable Novartis
standards and data cleaning procedures to ensure the integrity of the data, e.g., resolving 
errors and inconsistencies in the data.  Adverse events and concomitant medications 
terms will be coded using the Medical Dictionary for Regulatory Activities (MedDRA)
and a custom drug dictionary.  eCRFs (including queries and audit trails) will be retained 
by Novartis, and copies will be sent to the investigator to maintain as the investigator 
copy.  
13.9.
Independent Data Monitoring Committee (IDMC)
An IDMC will be utilized during the conduct of this study to review all available data in 
Part 3.  An IDMC is generally assembled when there are significant safety or efficacy 
issues that warrant external objective medical and/or statistical review in order to protect 
the ethical and safety interests of subjects and to protect the scientific validity of the 
study. The schedule of any planned interim analysis and the analysis plan for IDMC 
review is described in the charter.  A copy of the IDMC charter will be available from 
Novartis, prior to start of Part 3, upon request.


Novartis
Confidential
Page 162
Clinical Study Protocol Version 05
Protocol No. MEK116833
14.
REFERENCES
Bailey S, Neuenschwander B, Laird G, Branson M. A Bayesian case study in oncology 
phase I combination dose-finding using logisitic regression with covariates. J Biopharm 
Stats. 2009; 19 (3):469-484.
Bazett HC. An analysis of the time-relations of electrocardiograms. Heart 1920; 7:353-
370.
Benson AB, Ajani JA, Catalano RB, Engelking C, Kornblau SM, Martenson Jr JA, 
McCallum R, Mitchel EP, O’Dorisio TM, Vokes EE, & Wadler S. Recommended 
guidelines for the treatment of cancer treatment-induced diarrhea. J Clin Oncol. 
2004;22:2918- 2926.
Bokemeyer C, Bondarenko I, Makhson A, et al. Fluorouracil, leucovorin, and oxaliplatin 
with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J 
Clin Oncol 2009; 27(5):663-671.
Bokemeyer C, Van Cutsem E, Rougier P, et al. Addition of cetuximab to chemotherapy 
as first-line treatment for KRAS wild-type metastatic colorectal cancer: pooled analysis 
of the CRYSTAL and OPUS randomized clinical trials. Eur J Cancer 2012; 48(10):1466-
1475.
Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in 
melanoma with BRAF V600E mutation. N Engl J Med 2011;364:2507-16.
Claret L., Girard P., Hoff PM, et al. Model-based prediction of Phase III overall survival 
in colorectal cancer on the basis of Phase II tumor dynamics. J Clin Oncol 2009. 
27:4103-4108.
Corcoran RB, Hiromichi E, Turke AB, et al. EGFR-mediated reactivation of MAPK 
signaling contributes to insensitivity of BRAF-mutant colorectal cancers to RAF 
inhibition with vemurafenib. Cancer Discovery 2012; 2:193-195. 
Davies H, Bignell GR, Cox C, Stephens P, Edkins S, et al. Mutations of the BRAF gene 
in human cancer. Nature. 2002;417:949-954.
Davis CG, Gallo ML, Corvalan JRF. Transgenic mice as a source of fully human 
antibodies for the treatment of cancer. Cancer Metastasis Rev. 1999. 18(4):421-425.
Deming DA, Schelman WR, Lubner SJ, et al. A phase I study of selumetinib 
(AZD6244/ARRY-142866) in combination with cetuximab (cet) in refractory solid 
tumors and KRAS mutant colorectal cancer.  J Clin Oncol 2012; 30 (suppl): abstract 
3013.
DeRoock W, Jonker DJ, Di Nicolantonio F, et al. Association of KRAS p.G13D mutation 
with outcome in patients with chemotherapy-refractory metastatic colorectal cancer 
treated with cetuximab. JAMA 2010; 304 (16):1812-1820.


Novartis
Confidential
Page 163
Clinical Study Protocol Version 05
Protocol No. MEK116833
Di Nicolantonio F, Martini M, Molinari F, et al. Wild-type BRAF is required for response 
to panitumuab or cetuximab in metastatic colorectal cancer. J Clin Oncol 2008; 10:5705-
5712. 
Douillard J-Y, Oliner KS, Siena S, et al. Panitumumab-FOLFOX4 treatment and RAS 
mutations in colorectal cancer. NEJM 2013; 369:1023-1034.
Douillard J-Y, Siena S, Cassidy J, et al. Randomized, phase III trial of panitumumab with 
infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone 
as first-line treatment in patients with previously untreated metastatic colorectal cancer: 
the PRIME study. J Clin Oncol 2010; 28(31):4697-4705.
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, et al. New response 
evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J 
Cancer. 2009;45:228-247.
Falchook GS, Lewis KD, Infante JR, et al. Activity of the oral MEK inhibitor trametinib 
in patients with advanced melanoma: a phase 1 dose-escalation trial. The Lancet 
Oncology; Early Online Publication, 16 July 2012 doi:10.1016/S1470-2045(12)70269-3.
Flaherty KT, Robert C, Hersey P, et al. Improved survival with MEK inhibition in 
BRAF-mutated melanoma. N Engl J Med 2012 367:107-14.
Gilmartin AG, Bleam MR, Groy A, et al. GSK1120212 (JTP-74057) is an inhibitor of 
MEK activity and activation with favorable pharmacokinetic properties for sustained in 
vivo pathway inhibition. Clin Cancer Res 2011; 17:989-1000.
 
 
 
 
 
 
Green SJ, Dahlberg S. Planned versus attained design in phase II clinical trials. Stat Med; 
1992. 11(7):853-862.


Novartis
Confidential
Page 164
Clinical Study Protocol Version 05
Protocol No. MEK116833
Hauschild A, Grob J-J, Demidov LV, et al. Dabrafenib in BRAF-mutated metastatic 
melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet 2012. 
www.thelancet.com Published online June 25, 2012 http://dx.doi.org/10.1016/S0140-
6736(12)60868-X.
James LP. 2009. Pharmacokinetics of Acetaminophen - Protein Adducts ... Liver Failure. 
Drug Metab Disp, 37:1779-1784. 
Jonker DJ, O’Callaghan CJ, Karapetis CS, et al. Cetuximab for the treatment of 
colorectal cancer. N Engl J Med 2007; 357:2040-2048.
Karapetis CS, Khambata-Ford S, Jonker DJ, et al. K-ras mutations and benefit from 
cetuximab in advanced colorectal cancer. N Engl J Med 2008; 359:1757-1765.
Kopetz S., Desai E., Chan J. R., et al. PLX4032 in metastatic colorectal patients with 
mutant BRAF tumors. J Clin Oncol 2010; 28:15s (suppl; abstr 3534).
Lacouture ME, Mitchell EP, Piperdi B, et al. Skin toxicity evaluation protocol with 
panitumumab (STEPP), a Phase II, open-label, randomized trial evaluating the impact ofa 
pre-emptive skin treatment regimen on skin toxicities and quality of life in patients with 
metastatic colorectal cancer. J Clin Oncol 2010 28(6):1351-1357.
Lacouture ME. Mechanisms of cutaneous toxiticites to EGFR inhibitors. Nat Rev Cancer
2008. 6:803-812.
Laurent-Puig P, Cayre A, Manceau G, et al. Analysis of PTEN, BRAF, and EGFR status 
in determining benefit from cetuximab therapy in wild-type KRAS metastatic colon 
cancer. J Clin Oncol 2009; 10:5924-5930.
Lee JJ, Liu DD. A predictive probability design for Phase II cancer clinical trials. Clin 
Trials. 2008. 5(2):93-106.
Lievre A. Blons H, Laurent-Puig P. Oncogenic mutations as predictive factors in 
colorectal cancer. Oncogene 2010; 29:3033-3043.
Lipworth AD, Robert C, Zhu AX. Hand-foot syndrome (hand-foot skin reaction, palmar-
plantar erythrodysesthesia); focus on sorafenib and sunitinib. Oncology. 2009;77:257-71.
Loupakis F, Ruzzo A, Cremolini C et al. KRAS codon 61, 146 and BRAF mutations 
predict resistance to cetuximab plus irinotecan in KRAS codon 12 and 13 wild-type 
metastatic colorectal cancer. Br J Cancer 2009; 101(4):715-721.
Maughan TS, Adams RA, Smith CG, et al., Addition of cetuximab to oxaliplatin-based 
first-line combination chemotherapy for treatment of advanced colorectal cancer: results 
of the randomized phase 3 MRC COIN trial. The Lancet 2011; 377(9783):2103-2114.
McClellan B, Kerr H. Cutaneous toxicities of the multikinase inhibitors sorafenib and 
sunitinib. 2011. Derm Therapy 24(4):396-400.


Novartis
Confidential
Page 165
Clinical Study Protocol Version 05
Protocol No. MEK116833
Misale S, Arena S, Lamba S et al. Blockade of EGFR and MEK intercepts heterogenous 
mechanisms of acquired resistance to anti-EGFR therapies in colorectal cancer. Sci 
Transl Med 2014; 6 (224):224-226.
Misale S, Yaeger R, Hobor S et al. Emergence of KRAS mutations and acquired 
resistance to anti-EGFR therapy in colorectal cancer. Nature 2012; 486 (7404):532-536.
Oken MM, Creech RH, Tormey DC, Horton J, et al. Toxicity and response criteria of the 
Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982;5:649-655.
Peeters M, Price TJ, Cervantes A, et al. Randomized phase III study of panitumumab 
with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone 
as second-line treatment in patients with metastatic colorectal cancer. J Clin Oncol 2010; 
28(31): 4706-4713.
Prahallad A, Chong S, Huang S, et al. Unresponsiveness of colon cancer to BRAF 
(V600E) inhibition through feedback activation of EGFR. Nature 2012; 483:100-103.
Richman SD, Seymour MT, Chambers P, et al. KRAS and BRAF mutations in advanced 
colorectal cancer are associated with poor prognosis but do not preclude benefit from 
oxaliplatin or irinotecan: results from the MRC FOCUS Trial. J Clin Oncol 2009; 27(35): 
5931-5937.
Rowinsky EK, Schwartz, GH, Gollob JA, et al. Safety, pharmacokinetics, and activity of 
ABX-EGF, a fully human anti-epidermal growth factor receptor monoclonal antibody in 
patients with metastatic renal cell cancer. J Clin Oncol 2004;22:3003-3015.
Schwartzberg LS, Rivera F, Karthaus M et al. PEAK: a randomized, multicenter Phase II 
study of panitumumab plus modified fluorouracil, leucovorin, an oxaliplatin 
(mFOLFOX6) or bevacizumab plus mFOLFOX6 in patients with previously untreated, 
unresectable, wild-type KRAS exon 2 metastatic colorectal cancer. J Clin Oncol
Published online JCO.2013.53.2473; March 31, 2014.
Souglakos J, Phillips J, Wang R, et al. Prognostic and predictive value of common 
mutations for treatment response and survival in patients with metastatic colorectal 
cancer. Br J Cancer 2009; 101(3):465-472.
Stein WD, Gulley JL, Schlorn J, et al. Tumor regression and growth rates determined in 
five intramural NCI prostate cancer trials: the growth rate constant as an indicator of 
therapeutic efficacy. Clin Cancer Res 2011; 17:907-917.
Stein WD, Wilkerson J, Kim ST, et al. Analyzing the pivotal trial that compared sunitinib 
and INF-in renal cell carcinoma, using a method that assesses tumor regression and 
growth. Clin Cancer Res. 2012; 18:2374-2381.
Steinijans VW and E Diletti. Statistical analysis of bioavailability studies: parametric and 
nonparametric confidence intervals. Eur J Clin Pharm. 1983. 24(1):127-136.
TAFINLAR (dabrafenib) prescribing information. January 2014.


Novartis
Confidential
Page 166
Clinical Study Protocol Version 05
Protocol No. MEK116833
Tie J, Gibbs P, Upton L, et al. Optimizing targeted therapeutic development: analysis of a 
colorectal cancer patient population with the BRAF V600E mutation. Int J Cancer 2011; 
128:2075-2084.
Tran B, Kopetz S, Tie J, et al. Impact of BRAF mutation and microsatellite instability on 
the pattern of metastatic spread and prognosis in metastatic colorectal cancer. Cancer
2011; 117(20):4623-4632.
Tveit KM, Guren T, Glimelius B, et al. Phase III trial of cetuximab with continuous or 
intermittent fluorouracil, leucovorin, and oxaliplatin (Nordic FLOX) versus FLOX alone 
in first-line treatment of metastatic colorectal cancer: the NORDIC-VII study. J Clin 
Oncol 2012; 30(15):1755-1762.
Van Cutsem E, Köhne C-H, Hitre E, et al. Cetuximab and chemotherapy as initial 
treatment for metastatic colorectal cancer. N Engl J Med 2009; 360:1408-1417.
VECTIBIX (panitumumab) Product Information. October 2014.
Wan PT, Garnett MJ, Roe SM, Lee S, et al. Mechanism of activation of the RAF-ERK 
signaling pathway by oncogenic mutations of B-RAF. Cell. 2004;116:855-867.
Weber JS, Flaherty KT, Infante JR, et al. Updated safety and efficacy results from a 
phase I/II study of the oral BRAF inhibitor dabrafenib (GSK2118436) combined with the 
oral MEK1/2 inhibitor trametinib (GSK1120212) in patients with BRAF-naïve metastatic 
melanoma. J Clin Oncol 2012; 30(suppl): abstract 8510.  
Weiner LM, Belldegrun AS, Crawford J, et al. Dose and schedule study of panitumumab 
monotherapy in patients with advanced solid malignancies. Clin Cancer Res
2008;14:502-508
Wellbrock C, Karasaides M, Marais R. The RAF proteins take center stage. Nature 
Reviews Mol Cell Biol. 2004;5:875-885.
Yang X-D, Jia X-C, Corvalan JRF, et al. Eradication of established tumors by a fully 
human monoclonal antibody to the epidermal growth factor receptor without concomitant 
hemotherapy. Cancer Res. 1999; 59:1236-1243.
Yokota T, Ura T, Shibata N, et al. BRAF mutation is a powerful prognostic factor in 
advanced and recurrent colorectal cancer. Br J Cancer. 2011;104:392-398.


Novartis
Confidential
Page 167
Clinical Study Protocol Version 05
Protocol No. MEK116833
Appendices
Appendix 1: Liver Safety Algorithms
Part 1, Part 2 and Part 4
ALT?3xULN ?
Bilirubin ? 2xULN
(>35% direct) or 
INR > 1.5 (if 
measured)* ?
No
No
Yes
Yes
Continue investigational product (IP)
Instruct subject to stop IP
Notify Novartis within 24 hrs
Obtain weekly liver chemistries until resolved, stabilized or returned 
to baseline values
Perform liver event follow up assessments(serology, PK sample, etc
as in protocol) 
Complete liver event CRF
Withdraw subject from study after liver chemistry monitoring 
complete (unless protocol offers option to restart drug).
Instruct subject to stop IP
Notify Novartis and arrange clinical followup within 24 hrs
Perform liver event follow up assessments(serology, PK sample etc 
as in protocol) 
Report as SAE(excl. hepatic impairment or cirrhosis studies); 
complete SAE & liver event CRF + liver imaging 
and biopsy CRFs (if these tests are performed)
Obtain twice weekly liver chemistries until resolved, stabilized or 
returned to baseline values 
Consultation with hepatologist/specialist recommended
Withdraw subject from study after liver chemistry monitoring 
complete (unless protocol offers option to restart drug).
*INR threshold does not apply to 
subjects receiving anticoagulants.


Novartis
Confidential
Page 168
Clinical Study Protocol Version 05
Protocol No. MEK116833
Part 3
ALT?3xULN ?
Bilirubin ? 2xULN 
(>35% direct);
or, INR >1.5 if 
measured* ?
No
Yes
Yes
Instruct subject to stop IP 
Notify Novartis+ arrange clinical followup within 24-72h
Obtain weekly liver chemistries (*if possible) until 
resolved, stabilized or returned to baseline values
Perform liver event follow up assessments (serology,
PK sample, etc as in protocol) 
Complete liver event CRF & if appropriate liver 
imaging and biopsy CRFs (if these tests performed)
Withdraw subject from study after liver chemistry
monitoring complete (unless protocol has
option to restart drug).
Instruct subject to stop investigational product (IP)
Notify Novartis and arrange clinical followup within 24 hrs
Perform liver event f/u assessments (serology, PK, etc)
Report as an SAE (exc. hepatic impairment or cirrhosis 
studies); complete SAE & liver event CRF + 
liver imaging and biopsy CRFs (if tests performed).
Obtain twice weekly liver chemistries until resolved, 
stabilized or returned to baseline values 
Consultation with hepatologist/specialist recommended
Withdraw subject from study after monitoring 
complete unless protocol has option to restart drug.
ALT?5xULN ?
Hepatitis 
symptoms
or rash ? 
No
Able to 
monitor weekly
for 4 wks ?
No
Notify Novartis within 24 hrs
Continue IP
Check liver chem weekly 
for 4 wks
No
No*
Yes
Yes
Yes
Yes
ALT?3xULN or 
bilirubin ? 2xULN 
after 4 weeks?
Continue IP
Monitor liver chemistries 
2X/month until values normalize 
or return to baseline
*INR threshold does not apply to 
subjects receiving anticoagulants.


Novartis
Confidential
Page 169
Clinical Study Protocol Version 05
Protocol No. MEK116833
Appendix 2: Blood Requirements
Part 1: Dose Escalation Cohorts
Test
Sample Volume
Total Volume for Screening, One 4-wk treatment period 
and Follow-up 
Hematology/Clin Chem
5 mL
30
Coagulation
5 mL
5
PK Analysis (panitumumab)
4 mL
20
PK & Metabolite Analysis 
(dabrafenib, trametinib)
4 mL
48
Serum Pregnancy Test
1 mL
1
CEA
2 mL
12
Total
167mL/subject
plus any wasteage associated with collection
Part 2: Expansion Cohorts
Test
Sample Volume
Total Volume for Screening, One 4-wk treatment period 
and Follow-up 
Hematology/Clin Chem
5 mL
25
Coagulation
5 mL
5
PK Analysis (panitumumab)
4 mL
16
PK & Metabolite Analysis 
(dabrafenib, trametinib)
4 mL
48
Serum Pregnancy Test
1 mL
1
CEA
2
10
Total
187mL/subject 
plus any wasteage associated with collection
Part 3: Randomized Phase II Study
Test
Sample Volume
Total Volume for Screening, One 4-wk treatment 
period and Follow-up 
Hematology/Clin Chem
5 mL
20
Coagulation
5 mL
5
Serum Pregnancy Test
1 mL
1
Total
82/subject 
plus any wasteage associated with collection


Novartis
Confidential
Page 170
Clinical Study Protocol Version 05
Protocol No. MEK116833
Part 4A and 4B: Dose Escalation and Expansion Cohorts
Test
Sample Volume
Total Volume for Screening, One 4-wk treatment period 
and Follow-up 
Hematology/Clin Chem
5 mL
20
Coagulation
5 mL
5
PK Analysis (panitumumab)
4 mL
16
PK & Metabolite Analysis 
(dabrafenib, trametinib)
4 mL
48
Serum Pregnancy Test
1 mL
1
CEA
2
10
Total
182mL/subject 
plus any wasteage associated with collection


Novartis
Confidential
Page 171
Clinical Study Protocol Version 05
Protocol No. MEK116833
Appendix 3: Liver Safety Drug Restart Guidelines
Drug restart may be considered for a subject exhibiting compelling benefit for a critical 
medicine following drug-induced liver injury, if there is favorable benefit: risk ratio and 
no alternative medicine available.
Background Information on Drug Restart/Rechallenge
Following drug-induced liver injury, drug restart or rechallenge is associated with a 
13% mortality across all drugs in prospective studies.1  Clinical outcomes vary by 
drug, with nearly 50% fatality with halothane readministered in one month of initial 
injury. However, some drugs seldom result in recurrent liver injury or fatality.  Risk 
factors for a fatal drug restart/rechallenge outcome include: hypersensitivity1 with initial 
liver injury (e.g. fever, rash, eosinophilia), jaundice or bilirubin 2xULN or INR>1.5 
suggesting severe liver injury, prior IP-related severe or fatal drug restart/rechallenge2,3 or 
evidence of drug-related preclinical liability / mitochondrial impairment3.
Drug Restart/Rechallenge Process (also see Figure 1)
1.
Principal Investigator (PI) requests consideration of drug restart for a subject 
receiving compelling benefit from a critical or life-saving drug, who exhibits liver 
chemistry elevation meeting subject stopping criteria, with no alternative treatment.
2.
Novartis Safety Monitoring Team (SMT) to review the subject’s restart/rechallenge 
risk factors and complete checklist (Table 34).
Table 34
Checklist for drug restart/rechallenge for critical medicine
(Following drug-induced liver injury, drug rechallenge is associated with 13% mortality across all 
drugs in prospective studies)
Yes
No
Compelling benefit of the investigational product (IP) for this subject and
no alternative therapy.  Provide brief explanation:
Relative benefit-risk favorable for drug restart/rechallenge, after 
considering the following high risk factors:
•
Initial liver injury event included: 
–
fever, rash, eosinophilia, or hypersensitivity
–
or bilirubin 2xULN (direct bilirubin >35% of total)
•
Subject currently exhibits ALT 3xULN, bilirubin 2xULN (direct 
bilirubin >35% of total, if available), or INR 1.5
•
Severe or fatal restart/rechallenge has earlier been observed with IP 
If yes, please provide brief explanation:
•
IP associated with known preclinical hepatic liability/ injury   


Novartis
Confidential
Page 172
Clinical Study Protocol Version 05
Protocol No. MEK116833
3.
If Novartis provides written approval for restart/rechallenge following the above 
review, the Principal Investigator (PI) must ensure the following:

The PI is to obtain Ethics Committee or Institutional Review Board review of 
drug re-initiation, as required. 

PI must discuss the possible benefits and risks of drug re-initiation with the 
subject.

The subject must sign informed consent with a clear description of possible 
benefits and risks of drug administration, including recurrent liver injury or death. 
Consent specifically for the IP restart must be recorded in the study chart.

The drug must be reinitiated at Novartis approved dose(s). 

Subjects approved by Novartis for restart of IP must return to the clinic twice a 
week for liver chemistry tests until stable, liver chemistries have been 
demonstrated and then laboratory monitoring may resume as per protocol.  If 
protocol defined stopping criteria for liver chemistry elevations are met, study 
drug must be stopped.

The Ethics Committee or Institutional Review Board is to be informed of the 
subject’s outcome, as required.

Novartis is to be notified of any adverse events, as per Section 11.


Novartis
Confidential
Page 173
Clinical Study Protocol Version 05
Protocol No. MEK116833
Figure 1
Novartis process for drug restart after possible drug-induced liver 
injury
References:
1.
Andrade RJ, Robles M, Lucena MI. Rechallenge in drug-induced liver injury:  the attractive hazard. Expert Opin 
Drug Saf 2009;8:709–714.
2.
Hunt CM. Mitochondrial and immunoallergic injury increase risk of positive drug rechallenge after drug-induced 
liver injury: a systematic review. Hepatology 2010;52:2216–2222
3.
Papay JI, Clines D, Rafi R, Yuen N, Britt SD, Walsh JS, et al. Drug-induced liver injury following positive drug 
rechallenge. Regul Toxicol Pharmacol 2009;54:84-90.


Novartis
Confidential
Page 174
Clinical Study Protocol Version 05
Protocol No. MEK116833
Appendix 4: RECIST 1.1 Criteria
[Eisenhauer, 2009]
Measurability of tumor lesions at baseline
Measurable lesion:
A non nodal lesion that can be accurately measured in at least one dimension (longest 
dimension) of

10 mm with MRI or CT when the scan slice thickness is no greater than 5mm.  
If the slice thickness is greater than 5mm, the minimum size of a measurable 
lesion must be at least double the slice thickness (e.g., if the slice thickness is 
10 mm, a measurable lesion must be 20 mm).

10 mm calliper/ruler measurement by clinical exam or medical photography. 

20 mm by chest x-ray.
Additionally lymph nodes can be considered pathologically enlarged and measurable if

15mm in the short axis when assessed by CT or MRI (slice thickness 
recommended to be no more than 5mm).  At baseline and follow-up, only the 
short axis will be measured [Eisenhauer, 2009].
Non-measurable lesion:
All other lesions including lesions too small to be considered measurable (longest 
diameter <10 mm or pathological lymph nodes with ≥ 10 mm and <15 mm short axis) as 
well as truly non-measurable lesions, which include: leptomeningeal disease, ascites, 
pleural or pericardial effusions, inflammatory breast disease, lymphangitic involvement 
of the skin or lung, abdominal masses/abdominal organomegaly identified by physical 
exam that is not measurable by reproducible imaging techniques [Eisenhauer, 2009].
Measurable disease: The presence of at least one measurable lesion.  Palpable lesions 
that are not measurable by radiologic or photographic evaluations may not be utilized as 
the only measurable lesion.
Non-Measurable only disease: The presence of only non-measurable lesions. 
Specifications by methods of measurements

The same diagnostic method, including use of contrast when applicable, must 
be used throughout the study to evaluate a lesion.

All measurements should be taken and recorded in millimeters (mm), using a 
ruler or calipers.

Ultrasound is not a suitable modality of disease assessment.  If new lesions are 
identified by ultrasound, confirmation by CT or MRI is required.


Novartis
Confidential
Page 175
Clinical Study Protocol Version 05
Protocol No. MEK116833

Fluorodeoxyglucose (FDG)-PET is generally not suitable for ongoing 
assessments of disease.  However FDG-PET can be useful in confirming new 
sites of disease where a positive FDG-PET scans correlates with the new site of 
disease present on CT/MRI or when a baseline FDG-PET was previously 
negative for the site of the new lesion. FDG-PET may also be used in lieu of a 
standard bone scan providing coverage allows interrogation of all likely sites of 
bone disease and FDG-PET is performed at all assessments.

If PET/CT is performed then the CT component can only be used for standard 
response assessments if performed to diagnostic quality, which includes the 
required anatomical coverage and prescribed use of contrast.  The method of 
assessment should be noted as CT on the CRF.
Clinical Examination: Clinically detected lesions will only be considered measurable 
when they are superficial (e.g., skin nodules).  In the case of skin lesions, documentation 
by color photography, including a ruler/calipers to measure the size of the lesion, is 
required. [Eisenhauer, 2009]
CT and MRI: Contrast enhanced CT with 5mm contiguous slices is recommended.
Minimum size of a measurable baseline lesion should be twice the slice thickness, with a 
minimum lesion size of 10 mm when the slice thickness is 5 mm. MRI is acceptable, but 
when used, the technical specification of the scanning sequences should be optimised for 
the evaluation of the type and site of disease and lesions must be measured in the same 
anatomic plane by use of the same imaging examinations.  Whenever possible the same 
scanner should be used. [Eisenhauer, 2009].
X-ray: Should not be used for target lesion measurements owing to poor lesion definition.  
Lesions on chest X-ray may be considered measurable if they are clearly defined and 
surrounded by aerated lung; however chest CT is preferred over chest X-ray 
[Eisenhauer, 2009].
Evaluation of target lesions
Definitions for assessment of response for target lesion(s) are as follows:

Complete Response (CR):  Disappearance of all target lesions.  Any 
pathological lymph nodes must be <10mm in the short axis.

Partial Response (PR):  At least a 30% decrease in the sum of the diameters of 
target lesions, taking as a reference, the baseline sum of the diameters (e.g. 
percent change from baseline).

Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for progressive disease.


Novartis
Confidential
Page 176
Clinical Study Protocol Version 05
Protocol No. MEK116833

Progressive Disease (PD): At least a 20% increase in the sum of the diameters 
of target lesions, taking as a reference, the smallest sum of diameters recorded 
since the treatment started (e.g. percent change from nadir, where nadir is 
defined as the smallest sum of diameters recorded since treatment start). In 
addition, the sum must have an absolute increase from nadir of 5mm.

Not Applicable (NA):  No target lesions at baseline.

Not Evaluable (NE):  Cannot be classified by one of the five preceding 
definitions.
Note:

If lymph nodes are documented as target lesions the short axis is added into the 
sum of the diameters (e.g. sum of diameters is the sum of the longest diameters 
for non-nodal lesions and the short axis for nodal lesions).  When lymph nodes 
decrease to non-pathological size (short axis <10mm) they should still have a 
measurement reported in order not to overstate progression.

If at a given assessment time point all target lesions identified at baseline are 
not assessed, sum of the diameters cannot be calculated for purposes of 
assessing CR, PR, or SD, or for use as the nadir for future assessments.  
However, the sum of the diameters of the assessed lesions and the percent 
change from nadir should be calculated to ensure that progression has not been 
documented.  If an assessment of PD cannot be made, the response assessment 
should be NE.

All lesions (nodal and non-nodal) should have their measurements recorded 
even when very small (e.g., 2 mm).  If lesions are present but too small to 
measure, 5 mm should be recorded and should contribute to the sum of the 
diameters, unless it is likely that the lesion has disappeared in which case 0 mm 
should be reported.

If a lesion disappears and reappears at a subsequent time point it should 
continue to be measured.  The response at the time when the lesion reappears 
will depend upon the status of the other lesions.  For example, if the disease 
had reached a CR status then PD would be documented at the time of 
reappearance.  However, if the response status was PR or SD, the diameter of 
the reappearing lesion should be added to the remaining diameters and 
response determined based on percent change from baseline and percent 
change from nadir.
Evaluation of non-target lesions
Definitions for assessment of response for non-target lesions are as follows:

Complete Response (CR):  The disappearance of all non-target lesions. All 
lymph nodes identified as a site of disease at baseline must be non-pathological 
(e.g. <10 mm short axis).

Non-CR/Non-PD:  The persistence of 1 or more non-target lesion(s) or lymph 
nodes identified as a site of disease at baseline ≥ 10 mm short axis.


Novartis
Confidential
Page 177
Clinical Study Protocol Version 05
Protocol No. MEK116833

Progressive Disease (PD): Unequivocal progression of existing non-target 
lesions. 

Not Applicable (NA):  No non-target lesions at baseline.

Not Evaluable (NE):  Cannot be classified by one of the four preceding 
definitions.
Note:

In the presence of measurable disease, progression on the basis of solely non-
target disease requires substantial worsening such that even in the presence of 
SD or PR in target disease, the overall tumour burden has increased sufficiently 
to merit discontinuation of therapy.

In the presence of non-measurable only disease consideration should be given 
to whether or not the increase in overall disease burden is comparable in 
magnitude to the increase that would be required to declare PD for measurable 
disease.

Sites of non-target lesions, which are not assessed at a particular timepoint 
based on the assessment schedule, should be excluded from the response 
determination (e.g. non-target response does not have to be "Not Evaluable"). 
Frequency of tumor re-evaluation
Target and non-target lesions will be re-evaluated every 6 weeks for the first 24 weeks 
and every 8 weeks thereafter, or more frequently, based on clinical judgment.
Confirmation of response
To be assigned a status of PR or CR, a confirmatory disease assessment should be 
performed no less than 4 weeks (28 days) after the criteria for response are first met.
Overall response criteria
Table 35 presents the overall response at an individual time point for all possible 
combinations of tumor responses in target and non-target lesions with or without the 
appearance of new lesions for subjects with measurable disease at baseline.


Novartis
Confidential
Page 178
Clinical Study Protocol Version 05
Protocol No. MEK116833
Table 35
Evaluation of Overall Response for Subjects with Measurable 
Disease at Baseline
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
CR
CR or NA
No
CR
CR
Non-CR/Non-PD or NE
No
PR
PR
Non-PD or NA or NE
No
PR
SD
Non-PD or NA or NE
No
SD
NE
Non-PD or NA or NE
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
1.
CR=complete response, PR = partial response, SD=stable disease, PD=progressive disease, NA= Not applicable, 
and 
2.
NE=Not Evaluable
Note:

Subjects with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should 
be classified as having "symptomatic deterioration." Objective response status is 
determined by evaluations of disease burden. Every effort should be made to 
document the objective progression even after discontinuation of treatment.  

In some circumstances, it may be difficult to distinguish residual disease from 
normal tissue. When the evaluation of CR depends on this determination, it is 
recommended that the residual lesion be investigated (fine needle 
aspirate/biopsy) to confirm the CR.


Novartis
Confidential
Page 179
Clinical Study Protocol Version 05
Protocol No. MEK116833
Appendix 5: Withholding and Stopping Criteria for QTc Prolongation for 
Subjects Enrolled in France
QTc-Prolongationa
Action and Dose Modification

QTcB ≥501 msec 

Interrupt study treatment until QTcB prolongation 
resolves to grade 1 or baseline

Restart at current dose levelb

If event recurs, permanently discontinue study 
treatment
Abbreviations:  msec = milliseconds; QTcB = QT interval on electrocardiogram corrected using the Bazett’s formula 
[Bazett, 1920]
a.
Based on average QTc value of triplicate ECGs.  For example, if an ECG demonstrates a prolonged QT interval, 
obtain two or more ECGs over a brief period, and then use the averaged QTc values of the three ECGs to 
determine if study treatments should be interrupted or discontinued.
b. If the QTc prolongation resolves to grade 1 or baseline, the subject may resume study treatment if the investigator 
and Novartis Medical Lead agree that the subject will benefit from further treatment.
Guidelines for Valvular Toxicity for Subjects Enrolled in France

Subjects who have an asymptomatic, moderate regurgitation or stenosis by 
ECHO (Grade 2 mitral/tricuspid/aortic valvular toxicity per CTCAE v4.0) 
should temporarily discontinue dabrafenib and have a repeat evaluation by 
ECHO within 1 week.  ECHO should be repeated every 1-2 weeks for 4 weeks 
or until valve recovery to baseline. 
o
If the valve recovers to baseline any time during the next 4 weeks, after 
consultation and approval of the Novartis Medical Lead, the subject may 
be restarted on dabrafenib at a reduced dose(s). For such subjects, 
monitoring of the valve via ECHO will then be performed 2 and 4 weeks 
after rechallenge, and every 4 weeks thereafter for 12 weeks and then per 
protocol.
o
If repeat ECHO does not reveal valve recovery to baseline within 4 weeks, 
then the subject should permanently discontinue dabrafenib.  The valve 
should continue to be monitored via ECHO every 4 weeks for 16 weeks or 
until resolution. 

Subjects with a Grade 3 or 4 (symptomatic, severe regurgitation/stenosis by 
imaging, with symptoms controlled by medical intervention) valvular toxicity 
must discontinue dabrafenib.  Valvular toxicity should continue to be monitored 
every 4 weeks for 16 weeks or until resolution.  If recovery occurs (return to 
baseline via imaging AND symptom resolution) within 4 weeks, the subject may 
restart dabrafenib at a reduced dose after consultation and approval of the
Novartis Medical Lead. For such subjects, monitoring of the valve via ECHO 
will then be performed 2 and 4 weeks after rechallenge, and every 4 weeks 
thereafter for 12 weeks and then per protocol.
ECHO must be performed at baseline and at follow-up visit(s).  Copies of all ECHO(s) 
and cardiology consultations performed on subjects who experience a valvular toxicity 
will be required by Novartis and its authorized agents for review.


Novartis
Confidential
Page 180
Clinical Study Protocol Version 05
Protocol No. MEK116833
Appendix 6: Bazett’s Correction
Bazett's formula used to correct QT interval for heart rate is:
RR
QT
QTcB 
where QTcB is the QT interval corrected for heart rate, RR is the interval from the onset 
of one QRS complex to the onset of the next QRS complex, measured in seconds, often 
derived from the heart rate (HR) as 60/HR, and QT is the QT interval measured in 
milliseconds.  
Reference
Bazett HC.  An analysis of the time-relations of electrocardiograms.  Heart 1920; 7: 353-
370.  


Novartis
Confidential
Page 181
Clinical Study Protocol Version 05
Protocol No. MEK116833


Novartis
Confidential
Page 182
Clinical Study Protocol Version 05
Protocol No. MEK116833


Novartis
Confidential
Page 183
Clinical Study Protocol Version 05
Protocol No. MEK116833


Novartis
Confidential
Page 184
Clinical Study Protocol Version 05
Protocol No. MEK116833
Appendix 8: Protocol Amendment Changes
AMENDMENT 05
Where the Amendment Applies
This amendment applies to all study sites in all countries.
Amendment Summary of Main Changes
Section
Change
Rationale
Multiple
Delete or replace references 
to GlaxoSmithKline (GSK) or 
its staff with that of Novartis 
To align with the change of sponsorship from 
GSK to Novartis
Multiple
Make administrative changes To align with the change of sponsorship from 
GSK to Novartis.
Multiple
Style and typographical 
updates have been made 
throughout the document but 
not listed individually
To align with the change of sponsorship from 
GSK to Novartis
Multiple 
Change from medical 
monitor [or GSK medical 
monitor] to Medical Lead
To align with the change of sponsorship from 
GSK to Novartis.
Amendment Details:
Bolded text indicates added text and strikethrough indicates deleted text.
Section: Title Page 
Text changed:
The title page was replaced as per Novartis requirements. 
Section: Sponsor Information Page
Text changed:
The GSK contact information was removed.
The term medical monitor was replaced by clinical leader and the contact details were 
updated.
Details of the clinical trial head of Novartis were added. 
Section 5.3.6: Other Issues
Text changed:


Novartis
Confidential
Page 185
Clinical Study Protocol Version 05
Protocol No. MEK116833
For pharmacokinetics analyses, assay values below quantifiable limits (BQL) will be 
handled as described in the GSK Clinical Pharmacokinetics/ Modeling & Simulation 
Pharmacokinetic (CPK/M&S PK) Methods according to Novartis procedures.
Section 5.3.8.1: Safety Analyses
Text changed:
Safety data for Parts 1, 2 and 3 will be presented in tabular and/or graphical format and 
summarized descriptively according to GSK’s Integrated Data Standards Library (IDSL)
Novartis standards.
Section 6.5.1 Time Period for Collecting Pregnancy Information
Text changed:
The investigator will record pregnancy information on the appropriate form and submit it 
to GSKNovartis within 2 weeks 24 hours of learning of a subject's pregnancy.  
Section 6.5.2: Action to be taken if pregnancy occurs
Text changed:
The investigator will record pregnancy information on the appropriate form and submit it 
to GSK Novartis within 2 weeks 24 hours of learning of a subject's pregnancy.  The 
subject will also be followed to determine the outcome of the pregnancy.  Information on 
the status of the mother and child will be forwarded to GSK Novartis.
Section 6.5.3: Action to be taken if pregnancy occurs in a female partner of a male study 
subject
Text changed:
The investigator will record pregnancy information on the appropriate form and submit it 
to GSK Novartis within 2 weeks 24 hours of learning of the partner’s pregnancy.  The 
partner will also be followed to determine the outcome of the pregnancy.  Information on 
the status of the mother and child will be forwarded to GSK Novartis.
Section 6.6.2: Sample Analysis
Text changed:
Plasma analysis will be performed under the management of Bioanalytical Science and 
Toxicokinetic (BST), Drug Metabolism and Pharmacokinetics, Platform Technology and 
Sciences, GSK Novartis.
Raw data will be stored in the Good Laboratory Practice (GLP) Archives, 
GlaxoSmithKline by Novartis.


Novartis
Confidential
Page 186
Clinical Study Protocol Version 05
Protocol No. MEK116833
Section 10
Study Treatment
Text changed:
Supplies of the investigational products will be provided to sites by Novartis, with 
the exception of sites in China (if applicable) where GSK will continue to provide 
supplies.
Section 11: Adverse Events (AE) and Serious Adverse Events (SAE)
Text changed:
AEs will be collected from the time a subject consents to participate in and 
completes the study (See Section 9.2), all SAEs assessed as related to study 
participation (e.g., protocol-mandated procedures, invasive tests, or change in 
existing therapy), will be reported promptly to Novartis, as indicated in Section 11.5
from the start of Study Treatment and until the follow-up contact.
Only SAEs relating to study procedures should be reported to GKSNovartis within 
24 hours, as indicated in Section 11.4.
Section 13.3: Quality Control (Study Monitoring)
Text changed:
In accordance with applicable regulations including GCP, and GSKNovartis procedures, 
Novartis personnel (or designated Clinical Research Organization [CRO])
procedures, Novartis study monitors will contact the site prior to the start of the study to 
review with the site staff the protocol, study requirements, and their responsibilities to 
satisfy regulatory, ethical, and Novartis requirements.  When reviewing data collection 
procedures, the discussion will also include identification, agreement and documentation 
of data items for which the CRF will serve as the source document.
GSKNovartis (or designated CRO) personnel will monitor the study and site activity to 
verify that the:
Section 13.5
Study and Site Closure
Text changed:
Upon completion or premature discontinuation of the study, Novartis personnel (or 
designated CRO)the monitor will conduct site closure activities with the investigator or 
site staff, as appropriate, in accordance with applicable regulations including GCP, and 
GSKNovartis procedures.
Section 13.6
Records Retention
Text changed:


Novartis
Confidential
Page 187
Clinical Study Protocol Version 05
Protocol No. MEK116833
GSK will inform the investigator of the time period for retaining these records to comply 
with all applicable regulatory requirements.  The minimum retention time will meet the 
strictest standard applicable to that site for the study, as dictated by any institutional 
requirements or local laws or regulations, or GSKNovartis standards/procedures; 
otherwise, the retention period will default to 15 years. Essential documents (written 
and electronic) should be retained for a period of not less than fifteen (15) years 
from the completion of the Clinical Trial unless the Sponsor provides written 
permission to dispose of them or, requires their retention for an additional period of 
time because of applicable laws, regulations and/or guidelines.
Section 13.7
Provision of Study Results to Investigators, Posting of Information on 
Publically Available Clinical Trials Registers and Publication
Text changed:
GSKNovartis aims to post a results summary to the GSKNovartis Clinical Trial Results 
website (www.novartisclinicaltrials.com) and other publicly available registers no later 
than 812 months after the last subjects last visit (LSLV) [this applies to each data analysis 
phase for studies with multiple phases, e.g., primary analysis, follow up analysis etc]).  In 
addition, the aim is to submit a manuscript to a peer-reviewed journal for publication 
within 18 months of LSLV.  GSK alsoupon study completion and finalization of study 
report, Novartis aims to publish the full study protocol on the GSK Clinical Study 
Register at the time the submit results of the study are published as a manuscript in the 
scientific literature for publication.  
When manuscript publication in a peer reviewed journal is not feasible, further study 
information will be posted please refer to the GSKNovartis Clinical Trial Results 
website (www.novartisclinicaltrials.com) for a summary of the trial results.
Section 13.8
Data Management
Text changed:
For this study subject data will be entered into GSK defined the electronic case report 
forms (eCRFs), transmitted electronically to GSK the sponsor (or designee) and be
combined with data provided from other sources in a validated data system.
Management of clinical data will be performed in accordance with applicable
GSKNovartis standards and data cleaning procedures to ensure the integrity of the data, 
e.g., removingresolving errors and inconsistencies in the data.  Adverse events and 
concomitant medications terms will be coded using the MedDRA (the Medical 
Dictionary for Regulatory Activities (MedDRA) and an internal validated medicationa 
custom drug dictionary.  eCRFs (including queries and audit trails) will be retained by 
GSKNovartis, and copies will be sent to the investigator to maintain as the investigator 
copy.  Subject initials will not be collected or transmitted to GSKNovartis according to 
GSK policy.


Novartis
Confidential
Page 188
Clinical Study Protocol Version 05
Protocol No. MEK116833
AMENDMENT 4
Where the Amendment Applies
This amendment applies to all sites in all countries.
Summary of Amendment Changes with Rationale
Major revisions in this amendment include the additional of Part 2B with revisions to 
data analysis and statistical considerations; modifications to dose management 
guidelines; the inclusion of a crossover Time and Event Table; and addition of overall 
survival to the time and events tables for all Parts of the study.
Throughout the protocol, minor edits have been made to clarify text, including changing 
of Recommend to Phase 2 Dose (RP2D) to Recommend to Phase 2 Regimen (RP2R), 
using BRAF mutant and anti-EGFR resistant population in Part 4B
List of Specific Changes
Original text displayed strikethrough indicates replaced or removed text. New text is 
displayed as underline. Revisions within figures will be displayed first by the original 
figure, and then followed by the new figure. Revisions within tables will be displayed as 
text. Formatting changes, corrections to grammatical errors or misspelled words, added 
abbreviations or references, and changes to Table numbering will not be included in the 
Summary of Changes for Amendment 4.
SPONSOR SIGNATORY
PREVIOUS TEXT
 MD, PhD
GlaxoSmithKline
REVISED TEXT
, MD
GlaxoSmithKline
SPONSOR/MEDICAL MONITOR INFORMATION PAGE


Novartis
Confidential
Page 189
Clinical Study Protocol Version 05
Protocol No. MEK116833
PREVIOUS TEXT
Medical Monitor and Sponsor Contact Information:
Role
Name
Day Time 
Phone 
Number
After-hours 
Phone/Cell/
Pager 
Number
Fax 
Number
GSK Address
Medical 
Monitor
MD, PhD
GlaxoSmithKline
Five Moore Drive
Mailstop 5.4300.4B
Research Triangle Park, NC 
27709
Medical 
Monitor
MD, PhD
GlaxoSmithKline
1250 Collegeville Road
Mailstop UP4310
Collegeville, PA USA
Medical 
Monitor
PhD
GlaxoSmithKline
1250 Collegeville Road
Mailstop UP4-4210
Collegeville, PA USA
SAE fax 
number 
REVISED TEXT
Medical Monitor and Sponsor Contact Information:
Role
Name
Day Time 
Phone 
Number
After-hours 
Phone/Cell/
Pager 
Number
Fax 
Number
GSK Address
Medical 
Monitor
MD, PhD
GlaxoSmithKline
Five Moore Drive
Mailstop 5.4300.4B
Research Triangle Park, NC 
27709
Medical 
Monitor
MD, PhD
GlaxoSmithKline
1250 Collegeville Road
Mailstop UP4310
Collegeville, PA USA


Novartis
Confidential
Page 190
Clinical Study Protocol Version 05
Protocol No. MEK116833
Role
Name
Day Time 
Phone 
Number
After-hours 
Phone/Cell/
Pager 
Number
Fax 
Number
GSK Address
Medical 
Monitor
MD, PhD
GlaxoSmithKline
1250 Collegeville Road
Mailstop UP4-4210
Collegeville, PA USA
SAE fax 
number 
RATIONALE:  Update to medical monitor contact information
SECTION 1.1.4
Panitumumab, Vectibix
PREVIOUS TEXT
Panitumumab is a high-affinity (kd 5 x 10-11 M), human immunoglobulin G2 (IgG2) 
monoclonal antibody directed against human EGFR [Davis, 1999; Yang, 1999].  
Panitumumab blocks EGFR binding of epidermal growth factor (EGF), transforming 
growth factor-alpha (TGF), amphiregulin, betacellulin, epiregulin, and heparin-binding 
EGF.  Panitumumab [VECTIBIX, 2013] is currently licensed in the United States by the 
Food and Drug administration (FDA) for single agent use in patients with mCRC that 
expresses EGFR and is refractory to fluoropyrimidine-, irinotecan-, and oxaliplatin-
containing regimens.  Use of panitumumab is not recommended for the treatment of 
colorectal cancer with KRAS mutations in codon 12 or 13.  Further, panitumumab is 
approved in the European Union, Canada, Australia, and other regions for use in the 
treatment of chemotherapy-refractory mCRC that expresses EGFR and wild-type form of 
the KRAS gene.  In Japan, panitumumab is approved for treatment of patient with 
unresectable, advanced or recurrent CRC with wild-type KRAS.  Panitumumab is 
administered as an intravenous infusion.  The most common adverse events of 
panitumumab are skin rash, hypomagnesemia, paronychia, fatigue, abdominal pain, 
nausea and diarrhea.  
Refer to the current panitumumab approved labelling for further details [VECTIBIX, 
2013]. Please also reference Section 1.4.3 for additional information on the safety profile 
and the Summary of Risk Mitigation.
REVISED TEXT
Panitumumab is a high-affinity (kd 5 x 10-11 M), human immunoglobulin G2 (IgG2) 
monoclonal antibody directed against human EGFR [Davis, 1999; Yang, 1999].  
Panitumumab blocks EGFR binding of epidermal growth factor (EGF), transforming 
growth factor-alpha (TGF), amphiregulin, betacellulin, epiregulin, and heparin-binding 
EGF.  Panitumumab [VECTIBIX, 20132014] is currently licensed in the United States by 
the Food and Drug administration (FDA) for the treatment of patients with wild-type 
KRAS mCRC as determined by an FDA-approved test for this use as first-line therapy in 
combination with FOLFOX in previously untreated mCRC and for as monotherapy a 


Novartis
Confidential
Page 191
Clinical Study Protocol Version 05
Protocol No. MEK116833
single agent use in patients with mCRC that expresses EGFR and is refractory to 
following disease progression after prior treatment with fluoropyrimidine-, oxaliplatin-, 
and irinotecan-, and oxaliplatin-containing regimens.  Use of panitumumab is not 
indicated for the treatment of patients with KRAS–mutant mCRC or for whom KRAS 
mutation status is unknown.  not recommended for the treatment of colorectal cancer with 
KRAS mutations in codon 12 or 13.  Further, panitumumab is approved in the European 
Union, Canada, Australia, and other regions for use in the treatment of chemotherapy-
refractory mCRC that expresses EGFR and wild-type form of the KRAS gene.  In Japan, 
panitumumab is approved for treatment of patient with unresectable, advanced or 
recurrent CRC with wild-type KRAS.  However in the European Union and Australia, 
panitumumab is indicated for the treatment of adult patients with wild-type RAS mCRC 
in first- and second-lines as well as monotherapy.  Refer to the current regionally-
approved labelling for further details.
Panitumumab is administered as an intravenous infusion.  The most common adverse 
events of panitumumab are skin rash, hypomagnesemia, paronychia, fatigue, abdominal 
pain, nausea and diarrhea.  
Refer to the current panitumumab approved labelling for further details [VECTIBIX, 
2013]. Please also reference Section 1.4.3 for additional information on the safety profile 
and the Summary of Risk Mitigation.
RATIONALE:  Updated information from the 2014 Vectibix label
SECTION 1.3
Study Rationale for Parts 1, 2, 3, 4
PREVIOUS TEXT
BRAF-mutation V600E positive CRC is more aggressive than KRAS-mutation positive-
or KRAS/BRAF- wild-type colorectal cancer, with a lower overall response rate (ORR), 
reduced progression-free (PFS) and overall survival (OS) [Di Nicolantonio, 2008; 
Laurent-Puig, 2009; Maughan, 2011; Souglakos, 2009; Bokemeyer, 2012; Tveit, 2012; 
Richman, 2009; Tran, 2011; Yokota, 2011; Tie, 2011].  Efforts to target BRAF-mutant 
CRC with BRAF inhibitors and MEK inhibitors as monotherapies have not been 
successful to date [Falchook, 2012; Kopetz 2010].  Recently published nonclinical data 
suggest a role for receptor tyrosine kinase activation (particularly EGFR) in the resistance 
mechanism and have demonstrated synergistic activity of the combination of a BRAF 
inhibitor and an EGFR inhibitor in in vitro and in vivo models of BRAF-mutant CRC 
[Prahallad, 2012; Corcoran, 2012].  Therefore, the combination of potent inhibition of the 
BRAF pathway (with dabrafenib alone or dabrafenib/trametinib) with an anti-EGFR 
agent to prevent EGFR-mediated resistance is a rational and promising approach to treat 
BRAF-mutant CRC.
The study is designed to identify the recommended Phase 2 dose/regimen for the doublet 
(dabrafenib/panitumumab) and the triplet (dabrafenib/trametinib/panitumumab) in Part 1, 
identify an initial signal of clinical activity in Part 2 and to perform a randomized 
comparison of the experimental arms to a chemotherapy comparator arm (a regimen of 
FOLFOX or FOLFIRI with or without panitumumab or bevacizumab) in Part 3.  
Extrapolating from the experience in BRAF V600E/V600K -mutation positive melanoma, 


Novartis
Confidential
Page 192
Clinical Study Protocol Version 05
Protocol No. MEK116833
it is expected that the triple combination is likely to provide the greatest benefit to 
subjects, in which case the inclusion of the double combination serves as a control to 
assess the important “contribution of components” question.  However, another possible 
outcome is that the double combination is superior (e.g., due to poor tolerability of the 
triple combination), an outcome that this study design will also adequately evaluate.
REVISED TEXT
BRAF-mutation V600E positive CRC is more aggressive than KRAS-mutation positive-
or KRAS/BRAF- wild-type colorectal cancer, with a lower overall response rate (ORR), 
reduced progression-free (PFS) and overall survival (OS) [Di Nicolantonio, 2008; 
Laurent-Puig, 2009; Maughan, 2011; Souglakos, 2009; Bokemeyer, 2012; Tveit, 2012; 
Richman, 2009; Tran, 2011; Yokota, 2011; Tie, 2011].  Efforts to target BRAF-mutant 
CRC with BRAF inhibitors and MEK inhibitors as monotherapies have not been 
successful to date [Falchook, 2012; Kopetz 2010].  Recently published nonclinical data 
suggest a role for receptor tyrosine kinase activation (particularly EGFR) in the resistance 
mechanism and have demonstrated synergistic activity of the combination of a BRAF 
inhibitor and an EGFR inhibitor in in vitro and in vivo models of BRAF-mutant CRC 
[Prahallad, 2012; Corcoran, 2012].  Therefore, the combination of potent inhibition of the 
BRAF pathway (with dabrafenib alone or dabrafenib/trametinib) with an anti-EGFR 
agent to prevent EGFR-mediated resistance is a rational and promising approach to treat 
BRAF-mutant CRC.
Thus, this study is designed to identify the recommended Phase 2 dose/regimen (RP2R)
for the dabrafenib/panitumumab doublet (dabrafenib/panitumumab) and the
dabrafenib/trametinib/panitumumab triplet (dabrafenib/trametinib/panitumumab) in Part 
1 and for the trametinib/panitumumab doublet in Part 4A. In part 2 and 4B, the study will 
identify an initial signal of clinical activity for these combinations.in Part 2 In part 3, and 
to perform a randomized comparison of the experimental arms to a chemotherapy 
comparator arm (a regimen of FOLFOX or FOLFIRI with or without panitumumab or 
bevacizumab) will be performedin Part 3.  
RATIONALE:  Added rationale for evaluation of trametinib and panitumumab 
combination in Part 4.
SECTION 1.3.2
Study Rationale for Part 4
PREVIOUS TEXT
Anti-EGFR therapies, either in combination with chemotherapy or as monotherapy, are 
approved therapy for KRAS wild-type (wt) colorectal cancer.  Although a significant 
proportion of patients with KRAS wt CRC derive benefit from anti-EGFR therapy, they 
inevitably become resistant to this therapy.  In a large proportion of cases, the mechanism 
of resistance to anti-EGFR therapy involves the reactivation of the RAS/MEK/ERK 
pathway, often through acquisition of mutations to RAS genes (KRAS or NRAS) 
converging on activation of the RAS/MEK/ERK pathway [Misale, 2012; Misale, 2014].  
This is similar to the example of BRAF mutant melanoma in which a frequent 
mechanism of resistance involves the reactivation of this pathway [Flaherty, 2012].


Novartis
Confidential
Page 193
Clinical Study Protocol Version 05
Protocol No. MEK116833
REVISED TEXT
Part 4 of the study is designed to identify the RP2R for trametinib dosed orally in 
combination with IV infusions of panitumumab in dose escalation and to identify an 
initial signal of clinical activity in two populations, subjects with BRAF-V600E 
mutation-positive CRC (described above) and subjects with CRC that developed 
secondary resistance to anti-EGFR therapy after initially deriving benefit.   
It is also important to understand whether dabrafenib is contributing to the clinical 
activity that has been seen with the triplet.  Therefore, patients with BRAF-mutant CRC 
will be included in the dose escalation of the trametinib/panitumumab doublet (Part 4A) 
and an expansion cohort (Part 4B) further evaluating safety and efficacy of the 
trametinib/panitumumab doublet.
Anti-EGFR therapies, either in combination with chemotherapy or as monotherapy, are 
approved therapy for KRAS wild-type (wt) colorectal cancer.  Although a significant 
proportion of patients with KRAS wt CRC derive benefit from anti-EGFR therapy, they 
inevitably become resistant to this therapy.  In a large proportion of cases, the mechanism 
of resistance to anti-EGFR therapy involves the reactivation of the RAS/MEK/ERK 
pathway, often through acquisition of mutations to RAS genes (KRAS or NRAS) 
converging on activation of the RAS/MEK/ERK pathway [Misale, 2012; Misale, 2014].  
This is similar to the example of BRAF mutant melanoma in which a frequent 
mechanism of resistance involves the reactivation of this pathway [Flaherty, 2012].
RATIONALE:  Added rationale for evaluation of trametinib and panitumumab 
combination in Part 4.
SECTION 1.3.2.1
Preliminary data from ongoing MEK116833 study
PREVIOUS TEXT
Preliminary clinical data from Parts 1 and 2 of this ongoing study suggest that the triplet 
combination of dabrafenib/trametinib/panitumumab is more efficacious than the 
dabrafenib/panitumumab doublet in the BRAF-mutant patient population (see Table 1).   
Enrollment in this dose combination has been limited to 20 patients, including those 
enrolled in Part 1 Cohort 1 and those enrolled in Part 2 doublet cohort.   Given the 
difference in activity, it is important to understand whether dabrafenib is contributing to 
the clinical activity that has been seen with the triplet.  Therefore, patients with BRAF-
mutant CRC will be included in the dose escalation of the trametinib/panitumumab 
doublet and an expansion cohort further evaluating safety and efficacy of the 
trametinib/panitumumab doublet will be included in Part 4 of the study.


Novartis
Confidential
Page 194
Clinical Study Protocol Version 05
Protocol No. MEK116833
Table 1
Best unconfirmed response, Part 1 and Part 2 (preliminary data)
Best unconfirmed response
Doublet Cohorta, 
n=13
Triplet Cohorts
Cohort 2b,
n=3
Cohort 3Ac
n=4
Cohort 3Bd
n=4
PD
2
0
0
0
SD
9
1
1
3
PR
2
2
2
0
CR
0
0
1
0
a. Doublet cohort combines patients enrolled in Part 1 Cohort 1 and Part 2 doublet expansion cohort; all dosed with 
Dabrafenib 150mg BID + Panitumumab 6mg/kg/Q2W
b. Dabrafenib 150mg BID + Panitumumab 4.8mg/kg/Q2W + Trametinib 1.5mg QD
c. Dabrafenib 150mg BID + Panitumumab 4.8mg/kg/Q2W + Trametinib 2mg QD
d. Dabrafenib 150mg BID + Panitumumab 6mg/kg/Q2W + Trametinib 1.5mg QD
Part 4 of the study is designed to identify the recommended Phase 2 dose/regimen for 
trametinib dosed orally in combination with IV infusions of panitumumab in dose 
escalation and to identify an initial signal of clinical activity in expansion cohorts:
1. subjects with BRAF-V600E mutation-positive CRC
2. subjects with CRC that developed secondary resistance to anti-EGFR therapy 
after initially deriving benefit.   
REVISED TEXT
Preliminary clinical data from Parts 1 and 2A of this ongoing study suggest that the 
triplet combination of dabrafenib/trametinib/panitumumab is more efficacious than the 
dabrafenib/panitumumab doublet in the BRAF-mutant patient population (see Table 1).  
Enrollment in this dose combination has been limited to 20 patients, including those 
enrolled in Part 1 Cohort 1 and those enrolled in Part 2 doublet cohort. 
Table 1
Summary of investigator-assessed best unconfirmed response, 
Part 1 and Part 2A (preliminary data)
Best 
unconfirmed 
response, n (%)
Doublet 
Cohorta, 
n=2013
Triplet Cohorts
Cohort 2b,
n=3
Cohort 3Ac
n=4
Cohort 3Bd
n=4
Cohort 4e
N=24
Not evaluable
0
0
0
0
1 (4%)
PD
2 (10%)
0
0
2 (50%)0
3 (13%)
SD
16 (80%)9
1 (33%)
2 (50%)1
2 (50%)3
16 (67%)
PR
1 (5%)2
2 (67%)
1 (25%)2
0
4 (17%)
CR
1 (5%)0
0
1 (25%)
0
0
PR+CR,  n (%)
(95% CI)
2 (10%) 
(1.2%, 31.7%)
2 (66%) 
(9.4%, 99.2%)
2 (50%) 
(6.8%, 93.2%)
0 (0%) 
(0%, 60.2%)
4 (16.7%) 
(4.7%, 37.4%)
From 20 October 2014 data cut-off
a. Doublet cohort combines patients enrolled in Part 1 Cohort 1 and Part 2 doublet expansion cohort; all dosed with 
Dabrafenib 150mg BID + Panitumumab 6mg/kg/Q2W
b. Dabrafenib 150mg BID + Panitumumab 4.8mg/kg/Q2W + Trametinib 1.5mg QD
c. Dabrafenib 150mg BID + Panitumumab 4.8mg/kg/Q2W + Trametinib 2mg QD


Novartis
Confidential
Page 195
Clinical Study Protocol Version 05
Protocol No. MEK116833
d. Dabrafenib 150mg BID + Panitumumab 6mg/kg/Q2W + Trametinib 1.5mg QD
e. Dabrafenib 150mg BID + Panitumumab 6mg/kg/Q2W + Trametinib 2mg QD
The safety and tolerability of the triplet at multiple doses will be further explored in Part 
2B.  This will stratify subjects based on prior lines of therapy to obtain a more 
homogeneous patient population.
Given the difference in activity, it is important to understand whether dabrafenib is 
contributing to the clinical activity that has been seen with the triplet.  Therefore, patients 
with BRAF-mutant CRC will be included in the dose escalation of the 
trametinib/panitumumab doublet and an expansion cohort further evaluating safety and 
efficacy of the trametinib/panitumumab doublet will be included in Part 4 of the study.
Part 4 of the study is designed to identify the recommended Phase 2 dose/regimen for 
trametinib dosed orally in combination with IV infusions of panitumumab in dose 
escalation and to identify an initial signal of clinical activity in expansion cohorts:
3. subjects with BRAF-V600E mutation-positive CRC
subjects with CRC that developed secondary resistance to anti-EGFR therapy after 
initially deriving benefit.   RATIONALE:  Updated data from 20 Oct 2014 data cut-off.
SECTION 1.3.3
Dose Rational
PREVIOUS TEXT
This study will evaluate the safety, tolerability and efficacy of the doublet 
dabrafenib/panitumumab and triplet trametinib/dabrafenib/panitumumab combinations in subjects 
with BRAF- mutation V600E positive CRC.  Part 1 includes a 3+3 dose escalation that will 
identify tolerable combination doses for the two combinations.  The safety and tolerability of 
these combination doses will be confirmed in expansion cohorts in Part 2, followed by a 
randomized evaluation of the efficacy and safety of the combinations in Part 3.
Part 4 of the study includes a 3+3 dose escalation that will identify tolerable combination doses 
for trametinib dosed orally in combination with IV infusions of panitumumab.  The safety and 
tolerability of the RP2D will be confirmed in the expansion cohorts.
REVISED TEXT
Parts 1-3 of this study will evaluate the safety, tolerability and efficacy of the doublet 
dabrafenib/panitumumab and triplet trametinib/dabrafenib/panitumumab combinations in subjects 
with BRAF- mutation V600E mutation positive CRC.  Part 1 includes a 3+3 dose escalation that 
will identify tolerable combination doses for the two combinations.  The safety and tolerability of 
these combination doses will be confirmed in expansion cohorts in Part 2, followed by a 
randomized evaluation of the efficacy and safety of the combinations in Part 3.
Part 4 of the study includes a 3+3 dose escalation that will identify tolerable combination doses 
for trametinib dosed orally in combination with IV infusions of panitumumab.  The safety and 
tolerability of the RP2DR will be confirmed in the expansion cohorts.
RATIONALE FOR CHANGE:  Clarify the goals for the specific part of the study


Novartis
Confidential
Page 196
Clinical Study Protocol Version 05
Protocol No. MEK116833
SECTION 1.3.3.2
Potential for Overlapping Toxicities
PREVIOUS TEXT
Fatigue, diarrhea, and nausea are common adverse reactions observed after administration of 
dabrafenib, trametinib, or panitumumab.  In addition, dermatologic toxicities are common after 
administration of trametinib or panitumumab with severe (National Cancer Institute Common 
Terminology Criteria for Adverse Events NCI-CTCAE Grade 3 or higher) dermatologic toxicities 
reported in 16% of all subjects (and ~25% of subjects with KRAS wild-type CRC) with 
metastatic carcinoma of the colon or rectum after administration of panitumumab alone.  In 
addition, there is an apparent small risk for pneumonitis/interstitial lung disease (ILD) with both 
trametinib and panitumumab, respectively.
REVISED TEXT
Fatigue, diarrhea, and nausea are common adverse reactions observed after administration of 
dabrafenib, trametinib, or panitumumab.  In addition, dermatologic toxicities are common after 
administration of trametinib or panitumumab. with Ssevere (National Cancer Institute Common 
Terminology Criteria for Adverse Events NCI-CTCAE Grade 3 or higher) dermatologic toxicities 
have been reported in 16% of all subjects (and ~25% of subjects with KRAS wild-type CRC) 
with metastatic carcinoma of the colon or rectum after administration of panitumumab alone.  In 
addition, there is an apparent small risk for pneumonitis/interstitial lung disease (ILD) with both 
trametinib and panitumumab, respectively.
RATIONALE FOR CHANGE:  Clarify the toxicity attributed to panitumumab in the sentence.
SECTION 1.3.3.3
Part 1
PREVIOUS TEXT
The maximum tolerated dose (MTD)/Recommended Phase 2 Regimen (RP2R) of 
dabrafenib plus panitumumab will be defined first in Part 1.  The starting dose of 
dabrafenib will be the recommended monotherapy dose of 150mg twice daily (BID).  
Panitumumab will be administered at the recommended dose of 6mg/kg, administered as 
an intravenous infusion over 60 minutes, every 14 days.  (Additional details regarding 
dose escalation are provided in Section 3.6.2.)  These doses are clinically active with 
manageable toxicity with prolonged dosing and the potential for overlapping toxicities 
appears relatively low.  However, if unexpected toxicities are observed in Cohort 1, 
subjects will be enrolled in Cohort -1, in which the dose of one or both agents (depending 
on the toxicities observed) will be reduced. 
Upon definition of a tolerable dose of dabrafenib plus panitumumab, trametinib will be 
added to the combination in Cohort 2 (see Section 3.1).  Dabrafenib will be administered 
in the triple combination at the dose that was tolerated in combination with panitumumab 
in Cohort 1.  Due to overlapping dermatologic toxicities, the starting doses of 
panitumumab and trametinib will be reduced.  The starting dose of trametinib will be 
1.5mg once daily, which is below the current recommended monotherapy dose of 2mg 
once daily, but is a dose that has demonstrated both pharmacodynamic and clinical 
activity in subjects with melanoma.  The starting dose for panitumumab will be one dose 
level below the dose that was tolerated in combination with dabrafenib in Cohort 1, 
administered as an intravenous infusion over 60 minutes, every 14 days.  It should be 


Novartis
Confidential
Page 197
Clinical Study Protocol Version 05
Protocol No. MEK116833
noted that a recent clinical study of the combination of the MEK inhibitor selumetinib 
and the chimeric anti-EGFR agent cetuximab were able to achieve the full monotherapy 
dose for both agents in combination, although there was an increased rate of skin toxicity 
and an episode of Grade 4 hypomagnesemia [Deming, 2012].  Also of note, 
panitumumab has demonstrated pharmacodynamic and clinical activity at doses as low as 
1 to 2.5 mg/kg weekly [Rowinsky, 2004; Weiner, 2008].  (Dose escalation details are 
provided in Section 3.6.2, and dose adjustment/ stopping criteria are described in Section 
3.9).  Doses in combination will not exceed the monotherapy top dose for any single 
agent.
REVISED TEXT
The maximum tolerated dose (MTD)/Recommended Phase 2 Regimen (RP2R) of 
dabrafenib plus panitumumab will bewas defined first in Part 1.  The starting dose of 
dabrafenib will bewas the recommended monotherapy dose of 150mg twice daily (BID).  
Panitumumab waswill be administered at the recommended dose of 6mg/kg, 
administered as an intravenous infusion over 60 minutes, every 14 days.  (Additional 
details regarding dose escalation are provided in Section 3.6.2.)  These doses are 
clinically active with manageable toxicity with prolonged dosing and the potential for 
overlapping toxicities appears relatively low.  However, if unexpected toxicities were to 
have beenare observed in Cohort 1, subjects would have beenill be enrolled in Cohort -1, 
in which the dose of one or both agents (depending on the toxicities observed) wouldill
be reduced. 
Upon definition of a tolerable dose of dabrafenib plus panitumumab, trametinib wasill be
added to the combination in Cohort 2 (see Section 3.1).  Dabrafenib wasill be
administered in the triple combination at the dose that was tolerated in combination with 
panitumumab in Cohort 1.  Due to overlapping dermatologic toxicities, the starting doses 
of panitumumab and trametinib wereill be reduced.  The starting dose of trametinib wasill 
be 1.5mg once daily, which is below the current recommended monotherapy dose of 2mg 
once daily, but is a dose that has demonstrated both pharmacodynamic and clinical 
activity in subjects with melanoma.  The starting dose for panitumumab wasill be one
dose level below the dose that was tolerated in combination with dabrafenib in Cohort 1, 
administered as an intravenous infusion over 60 minutes, every 14 days.  It should be 
noted that a recent clinical study of the combination of the MEK inhibitor selumetinib 
and the chimeric anti-EGFR agent cetuximab wasere able to achieve the full 
monotherapy dose for both agents in combination, although there was an increased rate of 
skin toxicity and an episode of Grade 4 hypomagnesemia [Deming, 2012].  Also of note,
panitumumab has demonstrated pharmacodynamic and clinical activity at doses as low as 
1 to 2.5 mg/kg weekly [Rowinsky, 2004; Weiner, 2008].  
(Dose escalation is permitted, details are provided in Section 3.6.2, and dose adjustment/ 
stopping criteria are described in Section 3.9).  Doses in combination will not exceed the 
monotherapy top dose for any single agent.
RATIONALE:  Updated text based on the results of the 20 October 2014 data cut.


Novartis
Confidential
Page 198
Clinical Study Protocol Version 05
Protocol No. MEK116833
SECTION 1.3.3.4
Part 2
PREVIOUS TEXT
For each combination (dabrafenib/panitumumab and 
dabrafenib/trametinib/panitumumab), the optimal safe and tolerable dose combinations 
defined in Part 1 will be brought forward into Part 2.  This will likely be the maximal 
dose from Part 1 for each combination, although a lower dose combination may be 
selected if significant delayed or prolonged toxicities require frequent dose modifications.  
In Part 2, expansion cohorts of approximately 20 subjects with BRAF- mutation V600E 
positive CRC (including the subjects enrolled at this dose in Part 1) will be enrolled to 
confirm safety and tolerability, and to generate signals of activity.  Based on the safety 
and tolerability of these combinations, these doses may be modified during Part 2 of the 
study.
REVISED TEXT
For each combination (dabrafenib/panitumumab and 
dabrafenib/trametinib/panitumumab), the optimal safe and tolerable dose combinations 
defined in Part 1 wereill be brought forward into Part 2A.  This wasill likely be the 
maximal dose from Part 1 for each combination, although a lower dose combination
could mayhave been selected if significant delayed or prolonged toxicities required 
frequent dose modifications.  In Part 2A, expansion cohorts of approximately 20 20 and
35 subjects with BRAF- mutation V600E mutation positive CRC (including the subjects 
enrolled at this dose in Part 1) were will be enrolled to confirm safety and tolerability, 
and to generate signals of activity of the doublet and triplet regimens, respectively (See 
Table 1 for clinical data from Parts 1 and 2A).  
Preliminary data from Part 2A suggested that compliance of dabrafenib, trametinib and 
panitumumab was similar between dose cohorts in Weeks 1 to Week4.  However, during 
Weeks 5 to 8, the compliance of dabrafenib, trametinib and panitumumab decreased to 
70-80% of the expected dose amounts in Cohort 3B and Cohort 4 compared to Cohort 2 
and Cohort 3A.  Adverse events leading to dose modifications were greater in the Cohort 
3B and Cohort 4 compared to Cohort 2 and Cohort 3A as shown in Table 2. 
Table 2
AEs Leading to Dose Modification (Triplet Cohorts)
Preferred Term
Cohort 2
N=3
Cohort 3A
N=4
Cohort 3B
N=4
Cohort 4
N=24
Total Triplet
N=35
AEs Leading to Investigational Product Discontinuation of any Study Treatment 
Any event 
0
1 (25%)
0
0
1 (3%)
Subdural haematoma 
0
1 (25%)
0
0
1 (3%)
AEs Leading to Dose Reduction of any Study Treatment 
Any event 
2 (67%)
1 (25%)
2 (50%)
9 (38%)
14 (40%)
Dermatitis acneiform 
0
1 (25%)
2 (50%)
2 (8%)
5 (14%)
Rash 
0
1 (25%)
0
1 (4%)
2 (6%)
AEs Leading to Dose Interruption/Delay of any Study Treatment 


Novartis
Confidential
Page 199
Clinical Study Protocol Version 05
Protocol No. MEK116833
Preferred Term
Cohort 2
N=3
Cohort 3A
N=4
Cohort 3B
N=4
Cohort 4
N=24
Total Triplet
N=35
Any event 
2 (67%)
3 (75%)
4 (100%)
20 (83%)
29 (83%)
Dermatitis acneiform 
0
1 (25%)
2 (50%)
2 (8%)
5 (14%)
Vomiting 
1 (33%)
0
3 (75%)
1 (4%)
5 (14%)
Dehydration 
0
1 (25%)
1 (25%)
2 (8%)
4 (11%)
Dry skin 
0
0
1 (25%)
3 (13%)
4 (11%)
Fatigue 
0
0
0
4 (17%)
4 (11%)
Nausea 
0
0
3 (75%)
1 (4%)
4 (11%)
ALT increased 
0
0
0
3 (13%)
3 (9%)
AST increased 
0
0
0
3 (13%)
3 (9%)
Diarrhoea 
0
0
2 (50%)
1 (4%)
3 (9%)
Rash 
0
1 (25%)
0
2 (8%)
3 (9%)
Based on data from 20 Oct 2014 cut-off
The dose of panitumumab in Cohort 3B and Cohort 4 was 6mg/kg every two weeks. In 
Part 2B, an additional 60 subjects will be enrolled into 1 of 2 dose cohorts.  Subjects will 
be enrolled at the Cohort 3A dose (Dabrafenib 150mg BID + Panitumumab 
4.8mg/kg/Q2W + Trametinib 2mg QD) and Cohort 4 dose (Dabrafenib 150mg BID 
+Panitumumab 6mg/kg Q2W + Trametinib 2mg QD) to further explore safety, 
tolerability and clinical activity at the two dose levels. In addition, subjects will be 
enrolled by lines of therapy in order to provide a more homogeneous patient population. 
As the dose of panitumumab was the same in Cohort 3B and Cohort 4 (6 mg/kg every 2 
weeks), a lower dose panitumumab as used in Cohort 3A (4.8 mg/kg every 2 weeks) will 
be included in Part 2.  
After the analysis of the preliminary data on the 35 subjects administered the triplet 
regimen, an additional 60 subjects will be enrolled into 1 of 2 sub-cohorts based on line 
of therapy.  This will provide a more homoegeneous patient population.  In addition, the 
subjects will be enrolled at the Cohort 4 dose and the Cohort 3A dose to further evaluate 
long-term safety and tolerability of the triplet regimen.  Based on the safety and 
tolerability of these combinations these doses may be modified during Part 2 of the study.
RATIONALE:  Updated results from 20 October 2014 data cut and inclusion of AEs 
leading to dose modifications.
SECTION 1.3.3.6
Part 4
PREVIOUS TEXT
Data from Parts 1 and 2 of this ongoing study have demonstrated that both the 
dabrafenib/panitumumab doublet and the dabrafenib/trametinib/panitumumab triplet are 
well-tolerated by patients (see Table 2). The triplet combination studies in Cohorts 3A 
and 3B, in which dabrafenib is dosed at the full marketed dose (150mg po BID) and 
either trametinib or panitumumab is also dosed at the full marketed dose (2mg po QD or 
6 mg/kg IV Q2W, respectively), with the other agent dosed at one dose level lower 


Novartis
Confidential
Page 200
Clinical Study Protocol Version 05
Protocol No. MEK116833
(1.5mg po QD or 4.8mg/kg IV Q2W, respectively) have been well tolerated to date, with 
no DLTs being identified.  The highest triplet combination (all three agents at full dose) 
is currently being evaluated in Cohort 4 of the dose escalation.  Based on the tolerability 
of the triplet in Part 1, the two starting dose trametinib/panitumumab combinations that 
will be studied in the initial dose escalation cohort of Part 4 will include the doses of 
trametinib and panitumumab that were tolerated in combination with dabrafenib in 
Cohorts 3A and 3B of Part 1.  If these are well tolerated, the dose will be escalated to the 
full dose of both agents. If neither of these is well tolerated, there will be an option to 
dose reduce (see Section 3.4). The optimal safe and tolerable dose combinations defined 
in dose escalation will be brought forward into expansion cohorts.  This will likely be the 
maximal dose for each combination in dose escalation, although a lower dose 
combination may be selected if significant delayed or prolonged toxicities require 
frequent dose modifications.  Expansion cohorts of approximately 20 subjects with 
KRAS wt CRC who progressed on previous anti-EGFR will be enrolled to confirm safety 
and tolerability, and to generate signals of activity.  
Table 2
DLTs, Related AEs ≥Gr 3, and Related SAEs in Part 1 and Part 2 
(preliminary data)
Doublet Cohorta, 
n=13
Triplet Cohorts
Cohort 2b,
n=3
Cohort 3Ac
n=4
Cohort 3Bd
n=4
DLTs
None
None
None
None
Related SAEs
5
1
None
None
Related AEs 
≥Grade 3
1
2
1
2
a. Doublet cohort combines patients enrolled in Part 1 Cohort 1 and Part 2 doublet expansion cohort; all dosed with 
dabrafenib 150mg BID + panitumumab 6mg/kg/Q2W.
b. Part 1 Cohort 2 dose dabrafenib 150mg BID + panitumumab 4.8mg/kg/Q2W + trametinib 1.5mg QD 
c. Part 1 Cohort 3A dose dabrafenib 150mg BID + panitumumab 4.8mg/kg/Q2W + trametinib 2mg QD
d. Part 1 Cohort 3B dose dabrafenib 150mg BID + panitumumab 6mg/kg/Q2W + trametinib 1.5mg QD
REVISED TEXT
Data from Parts 1 and 2A of this ongoing study have demonstrated that both the 
dabrafenib/panitumumab doublet and the dabrafenib/trametinib/panitumumab triplet are 
well-tolerated by patients (see Table 3Table 2). The triplet combination studies in 
Cohorts 3A and 3B, in which dabrafenib is dosed at the full marketed dose (150mg po 
BID) and either trametinib or panitumumab is also dosed at the full marketed dose (2mg 
po QD or 6 mg/kg IV Q2W, respectively), with the other agent dosed at one dose level 
lower (1.5mg po QD or 4.8mg/kg IV Q2W, respectively) have been well tolerated to date, 
with no DLTs being identified.  The highest triplet combination (all three agents at full 
dose) also has is currently beening evaluated in Cohort 4 of the dose escalation with no 
DLTs and an additional 20 patients has been enrolled in the expansion cohort at the full 
dose of all three agents.  Based on the tolerability of the triplet at full dose in Part 1, the 
two starting dose trametinib/panitumumab combinations that is beingwill be studied in 
the initial dose escalation cohort of Part 4 will include the doses of trametinib and 
panitumumab that were tolerated in combination with dabrafenib in Cohorts 3A and 3B 
of Part 1.  If these are well tolerated, the dose will be escalated to the full dose of both 


Novartis
Confidential
Page 201
Clinical Study Protocol Version 05
Protocol No. MEK116833
agents. If these doses neither of these is are not well tolerated, there will be an option to 
dose reduce (see Section 3.4). The optimal safe and tolerable dose combinations defined 
in dose escalation will be brought forward into expansion cohorts.  This will likely be the 
maximal dose for each combination in dose escalation, although a lower dose 
combination may be selected if significant delayed or prolonged toxicities require 
frequent dose modifications.  Expansion cohorts of approximately 20 subjects with 
BRAF V600E mutant mCRC or advanced CRC/metastatic mCRC who progressed on 
previous anti-EGFR will be enrolled to confirm safety and tolerability, and to generate 
signals of activity.  
Table 32 DLTs, Related AEs ≥Gr 3, and Related SAEs in Part 1 and Part 2 
(preliminary data)
Doublet 
Cohorta, 
n=1320
Triplet Cohorts
Cohort 2b,
n=3
Cohort 3Ac
n=4
Cohort 3Bd
n=4
Cohort 4e
N=24
DLTs
None
None
None
None
None
Related SAEs
56
1
None
None1
6
Related AEs 
≥Grade 3
13
2
12
2
11
From 20 October 2014 data cut-off
a. Doublet cohort combines patients enrolled in Part 1 Cohort 1 and Part 2 doublet expansion cohort; all dosed with 
dabrafenib 150mg BID + panitumumab 6mg/kg/Q2W.
b. Part 1 Cohort 2 dose dabrafenib 150mg BID + panitumumab 4.8mg/kg/Q2W + trametinib 1.5mg QD 
c. Part 1 Cohort 3A dose dabrafenib 150mg BID + panitumumab 4.8mg/kg/Q2W + trametinib 2mg QD
d. Part 1 Cohort 3B dose dabrafenib 150mg BID + panitumumab 6mg/kg/Q2W + trametinib 1.5mg QD
e. Dabrafenib 150mg BID + Panitumumab 6mg/kg/Q2W + Trametinib 2mg QD
RATIONALE:  Updated safety information related to the 20 October 2014
SECTION 3.2
Part 2A: Cohort Expansions Study 
Design/Schematic
PREVIOUS TEXT
Part 2: Cohort Expansions Study Design/Schematic


Novartis
Confidential
Page 202
Clinical Study Protocol Version 05
Protocol No. MEK116833
REVISED TEXT
Part 2A: Cohort Expansions Study Design/Schematic
RATIONALE:  Updated Schematic to include actual data from the 20 October 2014 
data cut and the inclusion of the Part 2B.
ADDITIONAL TEXT
Section 3.3 Part 2B:  Cohort Expansion
BID, twice daily dosing; D, dabrafenib; L, line of therapy; P, panitumumab; T, 
trametinib; Q2W, dosing every 2 weeks; QD, once daily dosing;
RATIONALE:  Addition of Part 2B to further evaluate the triplet combination at the 
doses used in Cohort 3A and Cohort 4.


Novartis
Confidential
Page 203
Clinical Study Protocol Version 05
Protocol No. MEK116833
SECTION 3.6 Cohort Expansion
PREVIOUS TEXT
14.1
Part 4B Cohort Expansion
REVISED TEXT
14.2
Part 4B Cohort Expansion
RATIONALE:  Schema updated to change from cohort to population for the two 
populations evaluated in Part 4B
SECTION 3.7.1
Prescreening for KRAS and BRAF Mutation Status
PREVIOUS TEXT
The conduct of the KRAS- and BRAF-mutation screening prior to the baseline 
assessments is the responsibility of the investigator and must be performed in a CLIA-
approved facility.  Local testing for KRAS and BRAF mutations for enrollment in the 
trial can occur any time prior to dosing.  If KRAS and BRAF mutation status is unknown 
at screening, no biopsy for assessment of mutation status in association with this protocol 
should be taken prior to obtaining consent. Following consent, subjects should be 


Novartis
Confidential
Page 204
Clinical Study Protocol Version 05
Protocol No. MEK116833
screened for KRAS and BRAF mutation status (if not already performed) prior to any 
other study-related screening procedures. The BRAFV600E mutation status will be 
confirmed centrally using the GSK selected assay.  For Part 1 and Part 2, a local test 
result for KRAS status is adequate for enrollment.  Enrollment in Part 3 may only occur 
following confirmation of KRAS wild-type cancer, as determined by FDA-approved 
KRAS test for CRC (e.g., Qiagen test) and documented in source.  For patients in Part 4 
who have acquired secondary resistance to anti-EGFR therapy, repeat testing for RAS 
mutations is not required.
REVISED TEXT
The conduct of the KRAS- and BRAF-mutation screening prior to the baseline 
assessments is the responsibility of the investigator and must be performed in a CLIA-
approved facility.  Local testing for KRAS and BRAF mutations for enrollment in the 
trial can occur any time prior to dosing.  If KRAS and BRAF mutation status is unknown 
at screening, no biopsy for assessment of mutation status in association with this protocol 
should be taken prior to obtaining consent. Following consent, subjects should be 
screened for KRAS and BRAF mutation status (if not already performed) prior to any 
other study-related screening procedures. The BRAFV600E mutation status will be 
confirmed centrally using the GSK selected assay.  For Part 1 and Part 2, a local test 
result for KRAS status is adequate for enrollment.  Enrollment in Part 3 may only occur 
following confirmation of KRAS wild-type cancer, as determined by FDA-approved 
KRAS test for CRC (e.g., Qiagen test) and documented in source.  For patients in Part 4 
who have acquired secondary resistance to anti-EGFR therapy, repeat testing for RAS 
mutations is not required.
RATIONALE:  Deleted sentence as central confirmation of BRAF mutation status is 
discussed in the paragraph below.
SECTION 3.7.2
Part 1
PREVIOUS TEXT
If the initial combination dose of dabrafenib and panitumumab in Cohort 1 (starting dose) 
is not tolerable, lower dose combination(s) defined in de-escalation cohorts (Cohort -1A, 
-1B and/or -1C) may be evaluated.  The actual de-escalation cohorts that are opened will 
be based on the agent(s) that are most likely causing the intolerance.  Once the 
dabrafenib/panitumumab combination dose is defined, subsequent cohorts in which 
trametinib is added will be based on the dabrafenib/panitumumab dose defined in Cohort 
1 or -1 (e.g., if the maximally tolerated panitumumab dose in the 
dabrafenib/panitumumab combination is 4.8mg/kg, the panitumumab dose in Cohort 2 
will be one dose level lower, or 3.6mg/kg.  Cohorts that are designated as “3A” and “3B” 
may be opened simultaneously once the prior dosing cohort has completed the 28-day 
DLT window and met dose escalation criteria as specified in Table 4.  If the combination 
doses in both Cohort 3A and Cohort 3B are well-tolerated, available safety and response 
data will be evaluated to determine the appropriate dose to evaluate in Part 2.


Novartis
Confidential
Page 205
Clinical Study Protocol Version 05
Protocol No. MEK116833
REVISED TEXT
If the initial combination dose of dabrafenib and panitumumab in Cohort 1 (starting dose) 
is not tolerable, lower dose combination(s) defined in de-escalation cohorts (Cohort -1A, 
-1B and/or -1C) may be evaluated.  The actual de-escalation cohorts that are opened will 
be based on the agent(s) that are most likely causing the intolerance.  Once the 
dabrafenib/panitumumab combination dose is defined, subsequent cohorts in which 
trametinib is added will be based on the dabrafenib/panitumumab dose defined in Cohort 
1 or -1 (e.g., if the maximally tolerated panitumumab dose in the 
dabrafenib/panitumumab combination is 4.8mg/kg, the panitumumab dose in Cohort 2 
will be one dose level lower, or 3.6mg/kg.  Cohorts that are designated as “3A” and “3B” 
may be opened simultaneously once the prior dosing cohort has completed the 28-day 
DLT window and met dose escalation criteria as specified in Table 4.  If the combination 
doses in both Cohort 3A and Cohort 3B are well-tolerated, available safety and response 
data will be evaluated to determine the appropriate dose to evaluate in Part 2.
RATIONALE:  Paragraph deleted as de-escalation cohorts were not used in Part 1
SECTION 3.7.3
Part 2
PREVIOUS TEXT
In Part 2, the primary objectives will be to further assess the safety and preliminary 
clinical activity of given doses and regimen(s) in subjects with BRAF-V600E mutation-
positive CRC.  Enrollment in Part 2 doublet will be initiated once dose escalation for the 
doublet (dabrafenib in combination with panitumumab) has been completed.  Enrollment 
in Part 2 triplet (trametinib plus dabrafenib in combination with panitumumab) will open 
once dose escalation for the triplet has been completed.
Subjects will be enrolled in the expansion cohorts at a selected dose of dabrafenib in 
combination with panitumumab and a selected dose of trametinib plus dabrafenib in 
combination with panitumumab.  For each combination, up to 20 evaluable subjects with 
BRAF-V600E mutation-positive CRC will be enrolled (inclusive of those subjects
enrolled at the same dose level in Part 1).  
Subjects who participated in Part 1 of the study at the recommended doses will be 
included in Part 2 analysis, and will contribute to the goal of 15 to 20 subjects enrolled in 
each arm in Part 2.  For this cohort, subjects should follow the assessments in Section 
3.10.2.
The responses will be assessed and decisions to continue to Part 3 will be made based on 
response data are available for up to 20 subjects for each cohort.  In order to proceed to 
Part 3, sufficient evidence of clinical activity (e.g. observing 4 responses out of up to 
20 subjects) should be observed to warrant further development. Meanwhile, the Part 
2 portion of the study will employ a Bayesian design that allows the trial to be monitored 
more frequently at multiple stages.
The trial may also be stopped at any time if excessive toxicities with the drug are 
observed.  For additional details about this approach, see Section 5. 


Novartis
Confidential
Page 206
Clinical Study Protocol Version 05
Protocol No. MEK116833
The decision to proceed to Part 3 of the study will take into consideration all available 
data and will be reviewed by the investigator(s), GSK medical monitor(s), 
pharmacokineticist and statistician.  Data will include the safety profile 
 
 of all dosing cohorts throughout the time subjects are on 
study.  The decision could be based on analysis of a subgroup of responders, so that a 
single combination arm would be carried forward into Part 3. 
REVISED TEXT
In Part 2, the primary objectives will be to further assess the safety and preliminary 
clinical activity of given doses and regimen(s) in subjects with BRAF-V600E mutation-
positive CRC.  
For Part 2A and 2B, subjects should follow the assessments in Section 3.10.2.
Part 2 will employ a Bayesian design that allows the trial to be monitored more 
frequently at multiple stages.
3.7.3.1 Part 2A:  Cohort Expansion
Enrollment in Part 2A doublet will be initiated once dose escalation for the doublet 
(dabrafenib in combination with panitumumab) has been completed.  Enrollment in Part 
2A triplet (trametinib plus dabrafenib in combination with panitumumab) will open once 
dose escalation for the triplet has been completed.
Subjects will be enrolled in the expansion cohorts at a selected dose of dabrafenib in 
combination with panitumumab and a selected dose of trametinib plus dabrafenib in 
combination with panitumumab.  For each combination, Approximately up to 20 
evaluable subjects with BRAF-V600E mutation-positive CRC will be enrolled at the 
Cohort 4 dose, the full monotherapy dose for all three component of the triplet 
regimen,RP2R to obtain preliminary data on the safety and efficacy of the combinations.  
Subjects who participated in Part 1 of the study at the doses evaluated in Part 2A will be 
included in Part 2A analysis, and will contribute to the total count of the 20 subjects 
enrolled in Part 2A.  
For Part 2A, subjects should follow the assessments in Section 3.10.2.
3.7.3.2 Part 2B:  Cohort Expansion
After completion of Part 2A, additional subjects will be enrolled into dose cohorts for the 
triplet of dabrafenib + trametinib +panitumumab.  Based on the efficacy (Table 1) and 
long term tolerability observed in Part 2A, two doses will be evaluated in Part 2B.  
Enrollement will be. Up to ten subjects with no prior treatment and up to 20 subjects with 
at least one prior treatment will be enrolled at the Cohort 3A dose (dabrafenib 150mg 
BID + trametinib 2mg QD + panitumumab 4.8mg/kg IV Q2wks). .  Up to 10 subjects 
with no prior treatment and up to 20 subjects with at least one prior treatment will be 


Novartis
Confidential
Page 207
Clinical Study Protocol Version 05
Protocol No. MEK116833
enrolled at the Cohort 4 dose (dabrafenib 150mg BID + trametinib 2mg QD + 
panitumumab 6mg/kg IV Q2wks).
Enrolment into two patient populations will be dependent on prior therapy for their 
metastatic disease. 
3. First Line Population (1L Population):  No prior treatment is defined as subjects 
with no prior treatment for metastatic disease or metastatic recurrence greater than 
6 months following completion of adjuvant therapy; 
4. Second to Fourth Line Population (2-4L Population):  At least one prior treatment 
is defined as subjects with progression or intolerance to at least one prior 
chemotherapy regimen for metastatic disease or recurrence within 6 months 
following completion of adjuvant therapy. Patients treated with > 4 prior lines of 
therapy for metastatic disease will not be eligible. 
Lines of prior therapy for each subject will be agreed upon by the medical monitor and
investigator at the time of enrolment.  
This would provide safety, efficacy and tolerability data for the triplet regimen in up to 
95 subjects between Part 1, Part 2A and Part 2B. .
For thisPart 2B subjects should follow the assessments in Section 3.10.2.
The Responses will be assessed by patient population, line of therapy, dose cohort and in 
aggregate for a given combination to informand decisions to continue to Part 3 will be 
made based on response data are available for up to 20 subjects for each cohort.  In order 
to proceed to Part 3, sufficient evidence of clinical activity (e.g. observing 4 
responses out of up to 20 subjects) should be observed to warrant further 
development. Meanwhile, the Part 2 portion of the study will employ a Bayesian design 
that allows the trial to be monitored more frequently at multiple stages.
The trial Part 2 may also be stopped at any time if excessive toxicities with the drug are 
observed.  For additional details about this approach, see Section 5. 
The decision to proceed to Part 3 of the study will take into consideration all available 
data and will be reviewed by the investigator(s), GSK medical monitor(s), 
pharmacokineticist and statistician.  Data will include the safety profile 
 
 of all dosing cohorts throughout the time subjects are on 
study.  The decision could be based on analysis of a subgroup of responders, so that a 
single combination arm would be carried forward into Part 3. 
RATIONALE:  Addition of Part 2B to further evaluate the efficacy, safety and long-
term tolerability of the triplet regimen using the doses evaluated in Cohort 3A and Cohort 
4 as well as adding subjects based on line of therapy to ensure a more homogenous 
patient population.


Novartis
Confidential
Page 208
Clinical Study Protocol Version 05
Protocol No. MEK116833
SECTION 3.7.6
Part 4B Cohort Expansion
PREVIOUS TEXT
In Part 4B cohort expansion, the primary objectives will be to further assess the safety 
and preliminary clinical activity of given doses and regimen(s) in subjects with 
advanced/metastatic CRC with either a BRAF-mutation (Cohort 1E ) or who developed 
secondary resistance to prior anti-EGFR therapy (Cohort 2E).  Enrollment in expansion 
cohorts will be initiated once dose escalation for the trametinib /panitumumab 
combination has been completed.
The trial may also be stopped at any time if excessive toxicities with the study treatment 
are observed. 
REVISED TEXT
In Part 4B cohort expansion, the primary objectives will be to further assess the safety 
and preliminary clinical activity of trametinib and panitumumab at the MTD determined 
in Part 4A.  Clinical activity will be determined in two patient populations of subjects
with advanced/metastatic CRC:
3. BRAF mutant population, subjects with BRAF-V600E mutation-positive CRC 
(described above)
4. Anti-EGFR resistant population, subjects with CRC that developed secondary 
resistance to anti-EGFR therapy after initially deriving benefit.   
given doses and regimen(s) in subjects with advanced/metastatic CRC with either a 
BRAF-mutation (Cohort 1E ) or who developed secondary resistance to prior anti-EGFR 
therapy (Cohort 2E).    Enrollment in expansion cohorts will be initiated once dose 
escalation for the trametinib /panitumumab combination has been completed.  Up to 20 
subjects will be enrolled into each population at the starting dose or MTD if lower dose 
combination is required. This will include the patients from part 4A.  An additional 20 
subjects with advanced/metastatic CRC with a BRAF mutation and progression or 
intolerance to one line of prior chemotherapy for metastatic disease or recurrence within 
6 months of adjuvant therapy may be enrolled into BRAF mutant CRC population at a 
lower dose combination defined by the de-escalation cohorts to evaluate the tolerability 
and efficacy of a lower dose of one or both of the investigational products.  The decision 
to enroll subjects at a lower dose level(s) and the lower dose(s) selected will be at the 
discretion of the investigators and GSK medical monitor. The trialPart 4 may also be 
stopped at any time if excessive toxicities with the study treatment are observed. 
RATIONALE:  Change from cohort to population to describe the patients that will 
be enrolled in Part 4B as well as to add an additional 20 subjects with BRAF mutant 
disease to be enrolled if evaluation of a lower dose combination of trametinib and 
panitumumab is undertaken.


Novartis
Confidential
Page 209
Clinical Study Protocol Version 05
Protocol No. MEK116833
SECTION 3.8
Treatment Assignment
PREVIOUS TEXT
All subjects will be assigned to study treatment in accordance with the randomization 
schedule generated by Discovery Biometrics, prior to the start of the study, using 
validated internal software.  In Part 1, subjects will be assigned to a cohort/ dose level 
based on evaluation of safety in subjects enrolled in prior cohorts.  In Part 2, subjects will 
be assigned to expansion cohorts at a selected dose of dabrafenib in combination with 
panitumumab and a selected dose of trametinib plus dabrafenib in combination with 
panitumumab.  In Part 3, subjects will be randomized to study treatment.  In Part 4A dose 
escalation, subjects will be assigned to a cohort/ dose level based on evaluation of safety 
in subjects enrolled in prior cohorts.  In Part 4B cohort expansion, subjects will be 
assigned to expansion cohorts at a selected dose of trametinib in combination with 
panitumumab
REVISED TEXT
All subjects will be assigned to study treatment in accordance with the randomization 
schedule generated by Discovery Biometrics, prior to the start of the study, using 
validated internal software.  In Part 1, subjects will be assigned to a cohort/ dose level 
based on evaluation of safety in subjects enrolled in prior cohorts.  In Part 2, subjects will 
be assigned to expansion cohorts at a dose cohort from Part 1selected dose of dabrafenib
in combination with panitumumab and a selected dosedose cohort from Part 1 of 
trametinib plus dabrafenib in combination with panitumumab.  In Part 3, subjects will be 
randomized to study treatment.  In Part 4A dose escalation, subjects will be assigned to a 
cohort/ dose level based on evaluation of safety in subjects enrolled in prior cohorts.  In 
Part 4B cohort expansion, subjects will be assigned to expansion cohorts at a selected 
dosethe starting dose cohort or dose de-escalation cohort from Part 4A of trametinib in 
combination with panitumumab
RATIONALE:  Update text to allow for a dose cohort evaluated in Part 1 to be further 
evaluated in Part 2
SECTION 3.10.1
Continuation on Study
PREVIOUS TEXT
Subjects who have met the criteria for disease progression (PD) according to RECIST v 
1.1 may continue to receive study drug if the Investigator believes the subject is receiving 
clinical benefit and approval to continue is granted by the GSK Medical Monitor. In this 
case, all study procedures would continue per protocol. The following efficacy and safety 
criteria must be met during study treatment prior to disease progression in order for 
investigators to consider continuing study therapy beyond radiographic tumor 
progression:

the subject experienced a confirmed tumor response according to RECIST v 1.1 
while receiving study treatment OR disease under study had remained no worse 
than stable for a period of at least 6 months while receiving dabrafenib;


Novartis
Confidential
Page 210
Clinical Study Protocol Version 05
Protocol No. MEK116833

absence of signs and symptoms of clinical disease progression despite 
radiographic disease progressive based on RECIST v 1.1 criteria outlined in 
Appendix 4;

no treatment-related AEs of CTCAE Grade 4 or SAEs have occurred during the 
last 4 weeks of dabrafenib treatment.
REVISED TEXT
Subjects who have met the criteria for disease progression (PD) according to RECIST v 
1.1 may continue to receive study drug if the Investigator believes the subject is receiving 
clinical benefit and approval to continue is granted by the GSK Medical Monitor. In this 
case, all study procedures would continue per protocol. The following efficacy and safety 
criteria must be met during study treatment prior to disease progression in order for 
investigators to consider continuing study therapy beyond radiographic tumor 
progression:

the subject experienced a confirmed tumor response according to RECIST v 1.1 
while receiving study treatment OR disease under study had remained no worse 
than stable for a period of at least 6two consecutive scans (approximately 12 
weeks)months while receiving study treatmentdabrafenib;

absence of signs and symptoms of clinical disease progression despite 
radiographic disease progressive based on RECIST v 1.1 criteria outlined in 
Appendix 4;
no treatment-related AEs of CTCAE Grade 4 or SAEs have occurred during the last 4 
weeks of dabrafenib study treatment.
RATIONALE:  Changed continuation past progression to account for Part 4, which does 
not contain trametinib, and allow for continuation past progression after a more modest 
response to study treatment at the discretion of the investigator and GSK medical monitor.
SECTION 3.10.2
Dose Adjustments
PREVIOUS TEXT
In the event of a DLT (for subjects enrolled in Part 1), or other clinically significant AE 
in any part of the study, treatment may be withheld and supportive therapy administered 
as clinically indicated.  If the toxicity or event resolves to baseline or Grade 1 in less than 
or equal to 14 days of stopping therapy, then treatment may be restarted.  Dose reduction 
should be considered as clinically indicated.  Any dose adjustment or interruption will be 
recorded.
REVISED TEXT
In the event of a DLT (for subjects enrolled in Part 1a dose escalation cohort), or other 
clinically significant AE in any part of the study, treatment may be withheld and 
supportive therapy administered as clinically indicated.  If the toxicity or event resolves 


Novartis
Confidential
Page 211
Clinical Study Protocol Version 05
Protocol No. MEK116833
to baseline or Grade 1 in less than or equal to 14 days of stopping therapy, then treatment 
may be restarted.  Dose reduction should be considered as clinically indicated.  Any dose 
adjustment or interruption will be recorded. 
RATIONALE FOR CHANGE:  Clarify DLTs from any dose escalation cohort.
SECTION 3.10.2
Dose Adjustments
PREVIOUS TEXT
Table 7
Dose Level Reduction Guidelines
Dose Level
Dabrafenib 
Dose/Schedule
Trametinib 
Dose/Schedule
Panitumumab 
Dose/Schedulea
0
150mg BID
2mg once daily
 6 mg/kg every 14 days
-1 (first dose reduction)
100mg BID
1.5mg once daily
4.8 mg/kg every 14 days
-2 (second dose reduction)
75mg BID
1mg once daily
3.6 mg/kg every 14 days
a.
In the case of acneiform rash, panitumumab dose may be reduced 50% of the previous dose per Table 11.
REVISED TEXT
Table 87
Dose Level Reduction Guidelines
Dose Level
Dabrafenib 
Dose/Schedule
Trametinib 
Dose/Schedule
Panitumumab 
Dose/Schedulea
0
150mg BID
2mg once daily
 6 mg/kg every 14 days
-1 (first dose reduction)
100mg BID
1.5mg once daily
4.8 mg/kg every 14 days
-2 (second dose reduction)
75mg BID
1mg once daily
3.6 mg/kg every 14 days
a.
In the case of acneiform rash, panitumumab dose may be reduced 50% of the previous dose per Table 11.
RATIONALE:  Reduction of panitumumab dose by 50% was modified to “by one dose 
level”
SECTION 3.10.3
Intra-subject Doublet to Triplet Crossover and Dose 
Escalation: Part 1, 2 or 4
PREVIOUS TEXT
For BRAF-mutation positive subjects enrolled in Part 1, 2 or 4 doublet dosing, intra-
subject doublet to triplet crossover is allowed if a patient has not experienced intolerable 
toxicity that could not be managed, and has demonstrated radiographic progression on 
therapy by RECIST v1.1 criteria, and approval will be based on review by GSK Medical 
Monitor. Dose administered must be from among those for which cohorts have been 
completed and data has been reviewed for safety.  
At the time of crossover, certain safety assessments will be repeated prior to start of 
triplet dosing (additional information describing assessments is available in Section 6):


Novartis
Confidential
Page 212
Clinical Study Protocol Version 05
Protocol No. MEK116833

brief physical examination

vital signs 

dermatological examination

ECG (single; repeated with 2 additional ECGs if clinically significant 
abnormalities are observed in the first assessment)

ECHO/ MUGA

disease assessment demonstrating radiographic progression on therapy by 
RECIST v1.1 criteria

ophthalmic examination, repeated at Week 4 after start of dosing with trametinib
Note: Approval from the GSK Medical Monitor is required to restart study 
treatment after ≥21 days of interruption.
All crossover assessments must be completed within 14 days prior to first dose on triplet 
except informed consent, ophthalmology exam, ECHO/MUGA and Disease Assessment, 
which can occur within 35 days prior to the first dose on triplet.
The source documents for these assessments should be provided to GSK at least 24 hours 
in advance to planned start of triplet dosing.  The medical monitor will review and 
provide approval for crossover from doublet to triplet, and site will be notified via email 
with a signed crossover form (refer to SPM).
Once approved, patients will follow the time and events table for Part 2 Expansion 
Cohorts, in Section 3.10.3, starting at the column labelled “Continuation Phase” for 
continued monitoring of safety and efficacy.
Subjects are allowed to crossover once during the study.
Additionally, for subjects who have remained on study for 6 months in the triplet 
combination, their dose level for the combination may be increased up to the highest 
combination dose level that has previously been confirmed as not exceeding the MTD for 
the combination. The intra-subject dose escalation must be agreed to by the investigator 
and the GSK Medical Monitor.
REVISED TEXT
For BRAF-mutation positive subjects enrolled in Part 1, 2 or 4 doublet dosing, intra-
subject doublet to triplet crossover is allowed if a patient has not experienced intolerable 
toxicity that could not be managed, and has demonstrated radiographic progression on 
therapy by RECIST v1.1 criteria, and approval will be based on review by GSK Medical 
Monitor. Subjects must crossover to triplet within 6 weeks of radiographic progression. 
All assessments and samples required at progression as described in Section 3.10 must be 
completed even though the subject crosses over to triplet.  Dose administered must be 
from among those for which cohorts have been completed and data has been reviewed for 
safety.  


Novartis
Confidential
Page 213
Clinical Study Protocol Version 05
Protocol No. MEK116833
At the time of crossover, certain safety assessments will be repeated prior to start of 
triplet dosing (additional information describing assessments is available in Section 6):

brief physical examination

vital signs 

dermatological examination

ECG (single; repeated with 2 additional ECGs if clinically significant 
abnormalities are observed in the first assessment)

ECHO/ MUGA

disease assessment demonstrating radiographic progression on therapy by 
RECIST v1.1 criteria

ophthalmic examination, repeated at Week 4 after start of dosing with trametinib
Note: Approval from the GSK Medical Monitor is required to restart study 
treatment after ≥21 days of interruption.
All crossover assessments must be completed within 14 days prior to first dose on triplet 
except informed consent, ophthalmology exam, ECHO/MUGA and Disease Assessment, 
which can occur within 35 days prior to the first dose on triplet.  Assessments performed 
as part of the initial follow-up for the doublet will be acceptable if they are performed 
within these timeframes prior to the first dose on triplet.  
The source documents for these assessments should be provided to GSK at least 24 hours 
in advance to planned start of triplet dosing.  The medical monitor will review and 
provide approval for crossover from doublet to triplet, and site will be notified via email 
with a signed crossover form (refer to SPM).
Once approved, patients will follow the time and events table for Part 2 Expansion 
Cohorts, in Section 3.10.23.11.5, starting at the column labelled “Continuation Phase” for 
continued monitoring of safety and efficacy after they receive their first dose on triplet.  
The Initial Follow-Up and Secondary Follow-Up Assessments should be performed after 
last dose of triplet.  Additional details are provided in the SPM.
Subjects are allowed to crossover once during the study.
Additionally, for subjects who have remained on study for 6 months in the triplet 
combination, their dose level for the combination may be increased up to the highest 
combination dose level that has previously been confirmed as not exceeding the MTD for 
the combination. The intra-subject dose escalation must be agreed to by the investigator 
and the GSK Medical Monitor.
RATIONALE:  Clarification of assessments to be performed at time of intra-subject 
crossover and cross reference to inserted crossover time and event table.
SECTION 3.10.4 General Guidelines for Clinical Significant Toxicities
PREVIOUS TEXT


Novartis
Confidential
Page 214
Clinical Study Protocol Version 05
Protocol No. MEK116833
General guidelines regarding management and dose reduction for adverse events that are 
considered by the investigator to be related to study treatment and which do not have 
specific guidelines.
Table 8
Dose Modification Algorithms
Non-hematologic and 
hematologic toxicity (except 
neutropenia and fever), CTCAE 
Grade
Dose modification algorithms a, b, c, d
Grade 1

Continue dabrafenib, trametinib and panitumumab at full dose

Monitor closely

Provide supportive care according to institutional standards
Grade 2

Consider holding dabrafenib, trametinib, and/or panitumumab until 
resolution to Grade 1 or baseline

Provide supportive care as clinically indicated. 

Monitoring of laboratory values should occur as clinically indicated.

For Grade 2 or higher respiratory symptoms (i.e., cough, dyspnea, 
hypoxia, etc), evaluation by CT scan is recommended.
Grade 3

Hold dabrafenib, trametinib, and panitumumab until toxicity resolves to 
Grade 1 or baseline then reduce dose of dabrafenib, trametinib, and/or 
panitumumab by 1 dose level.  

The subject may be continued at the same dose, if in the judgment of 
the investigator, the toxicity is considered unrelated to dabrafenib, 
trametinib, and/or panitumumab.  

Continue to monitor as clinically indicated.
Grade 4

Discontinue dabrafenib, trametinib, and panitumumab. Continue to 
monitor as clinically indicated, and provide supportive care as needed.

If, in the investigator’s judgment the toxicity is unlikely to recur, then 
hold dabrafenib, trametinib, and panitumumab until the toxicity is Grade 
1 or baseline, then reduce dose of dabrafenib, trametinib, and/or 
panitumumab by 1 dose level. 

If Grade 4 toxicity recurs after dose reduction, discuss continuation of 
study drug(s) with the GSK Medical Monitor.
a.
The minimum dose of dabrafenib is 75mg BID; the minimum dose of trametinib is 1mg once daily; the minimum 
dose of panitumumab is 3.6 mg/kg.  If a subject requires dose reduction below dabrafenib 75mg BID, trametinib 
1mg once daily, or panitumumab 3.6 mg/kg then the subject must be discontinued from study drug(s).
b.
For adverse events of abdominal pain or suspected pancreatitis, amylase and lipase laboratory samples should 
be collected.
c.
If the subject has a Grade 3 or 4 laboratory abnormality, that in the judgment of the investigator is not considered 
clinically significant, dose modification is not required.
d.
For subjects who develop symptoms associated with uveitis, including blurry vision, eye pain or erythema, an 
ophthalmologic consult is required.
REVISED TEXT


Novartis
Confidential
Page 215
Clinical Study Protocol Version 05
Protocol No. MEK116833
General guidelines regarding management and dose reduction for adverse events that are 
considered by the investigator to be related to study treatment and which do not have 
specific guidelines.
Table 98
Dose Modification Algorithms
Non-hematologic and 
hematologic toxicity (except 
neutropenia and fever), CTCAE 
Grade
Dose modification algorithms a, b, c, d
Grade 1

Continue dabrafenib, trametinib and panitumumab at full dose

Monitor closely

Provide supportive care according to institutional standards
Grade 2

Consider dose de-escalation by 1 dose level or holding dabrafenib, 
trametinib, and/or panitumumab until resolution to Grade 1 or baseline

Provide supportive care as clinically indicated. 

Monitoring of laboratory values should occur as clinically indicated.

For Grade 2 or higher respiratory symptoms (i.e., cough, dyspnea, 
hypoxia, etc), evaluation by CT scan is recommended.
Grade 3

Hold dabrafenib, trametinib, and panitumumab until toxicity resolves to 
Grade 1 or baseline then reduce dose of dabrafenib, trametinib, and/or 
panitumumab by 1 dose level.  

The subject may be continued at the same dose, if in the judgment of 
the investigator, the toxicity is considered unrelated to dabrafenib, 
trametinib, and/or panitumumab or clearly related to a particular 
agent(s).

Continue to monitor as clinically indicated.
Grade 4

Discontinue dabrafenib, trametinib, and panitumumab. Continue to 
monitor as clinically indicated, and provide supportive care as needed.

If, in the investigator’s judgment the toxicity is unlikely to recur, then 
hold dabrafenib, trametinib, and panitumumab until the toxicity is Grade 
1 or baseline, then reduce dose of dabrafenib, trametinib, and/or 
panitumumab by 1 dose level. 

If Grade 4 toxicity recurs after dose reduction, discuss continuation of 
study drug(s) with the GSK Medical Monitor.
a.
The minimum dose of dabrafenib is 75mg BID; the minimum dose of trametinib is 1mg once daily; the minimum 
dose of panitumumab is 3.6 mg/kg.  If a subject requires dose reduction below dabrafenib 75mg BID, trametinib 
1mg once daily, or panitumumab 3.6 mg/kg then the subject must be discontinued from study drug(s).
b.
For adverse events of abdominal pain or suspected pancreatitis, amylase and lipase laboratory samples should 
be collected.
c.
If the subject has a Grade 3 or 4 laboratory abnormality that in the judgment of the investigator is not considered 
clinically significant, dose modification is not required.
d.
For subjects who develop symptoms associated with uveitis, including blurry vision, eye pain or erythema, an 
ophthalmologic consult is required.
RATIONALE:  Update guidelines to provide revised guidance on dose modifications.


Novartis
Confidential
Page 216
Clinical Study Protocol Version 05
Protocol No. MEK116833
SECTION 3.10.4.1
Guidelines for Treatment of Pyrexia
PREVIOUS TEXT
Table 1110
Management and Dose Modification Guidelines for Pyrexia
Pyrexiaa Management
Action and Dose Modification
All Events:

Clinical evaluation for infection and hypersensitivityc

Laboratory work-upc

Hydration as requiredd
1st Eventb: 
Administer anti-pyretic treatment if clinically indicated 
and continue prophylactic treatmentf if associated with 
rigors, renal failure, dehydration or hypotensione
1st Event:

Interrupt dabrafenib

Continue trametinib and/or panitumumab

Once pyrexia resolves to baseline, restart
dabrafenib at the same dose level
If fever was associated with dehydration or 
hypotension, reduce dabrafenib by one dose level
2nd Eventg:

Within 3 days of onset of pyrexia:
Optimize anti-pyretic therapy
Consider oral cortiocosteroids (i.e., 
prednisone 10mg) for at least 5 days or as clinically 
indicated
2nd Event:

Interrupt dabrafenib

Continue trametinib and/or panitumumab

Once pyrexia resolves to baseline, restart 
dabrafenib at the same dose level
If fever was associated with rigors, renal 
failure, dehydration or hypotension, reduce dabrafenib 
by one dose level
Subsequent Events:

Within 3 days of onset of pyrexia:
Optimize oral corticosteroid dose as clinically 
indicated for recalcitrant pyrexia
if corticosteroids have been tapered and 
pyrexia recurs, restart steroids
if corticosteroids cannot be tapered consult 
medical monitor
Subsequent Events:

Interrupt dabrafenib

Continue trametinib and/or panitumumab
Once pyrexia resolves to baseline, restart dabrafenib 
reduced by one dose levelh
If dabrafenib must be reduced to <50mg BID, 
permanently discontinue dabrafenib. Trametinib may 
be continued.
h.
Pyrexia is defined as a body temperature equal to or above 38.5 Celsius or 101.3Fahrenheit.
i.
For subjects experiencing pyrexia complicated by rigors, severe chills, etc., a clinical evaluation and 
laboratory work-up is mandatory for each event; anti-pyretic treatment should be started immediately at the 
first occurrence and prophylactic anti-pyretic treatment is recommended
j.
Thorough clinical examination for signs and symptoms of infection or hypersensitivity is required; laboratory 
workup should include full-blood-count, electrolytes, creatinine, blood urea nitrogen (BUN), C-reactive protein 
(CRP), liver-function tests, blood culture, and urine culture.
k.
Oral hydration should be encouraged in subjects without evidence of dehydration. Intravenous hydration is 
recommended in subjects experiencing pyrexia complicated by dehydration/hypotension.
l.
Anti-pyretic treatment may include acetaminophen, ibuprofen, or suitable anti-pyretic medication according to 
institutional standards. Prophylactic anti-pyretic treatment may be discontinued after three days in the 
absence of pyrexia


Novartis
Confidential
Page 217
Clinical Study Protocol Version 05
Protocol No. MEK116833
REVISED TEXT
Table 1110
Management and Dose Modification Guidelines for Pyrexia
Pyrexiaa Management
Action and Dose Modification
All Events:

Clinical evaluation for infection and hypersensitivityc

Laboratory work-upc

Hydration as requiredd
1st Eventb: 
Administer anti-pyretic treatment if clinically indicated 
and continue prophylactic treatmentf if associated with 
rigors, renal failure, dehydration or hypotensione
1st Event:

Interrupt dabrafenib

Continue trametinib and/or panitumumab

Once pyrexia resolves to baseline, restart 
dabrafenib at the same dose level
If fever was associated with dehydration or 
hypotension, reduce dabrafenib by one dose level
2nd Eventg:

Within 3 days of onset of pyrexia:
Optimize anti-pyretic therapy
Consider oral cortiocosteroids (i.e., 
prednisone 10mg) for at least 5 days or as clinically 
indicated
2nd Event:

Interrupt dabrafenib

Continue trametinib and/or panitumumab

Once pyrexia resolves to baseline, restart 
dabrafenib at the same dose level
If fever was associated with rigors, renal 
failure, dehydration or hypotension, reduce dabrafenib 
by one dose level
Subsequent Events:

Within 3 days of onset of pyrexia:
Optimize oral corticosteroid dose as clinically 
indicated for recalcitrant pyrexia
if corticosteroids have been tapered and 
pyrexia recurs, restart steroids
if corticosteroids cannot be tapered consult 
medical monitor
Subsequent Events:

Interrupt dabrafenib

Continue trametinib and/or panitumumab
Once pyrexia resolves to baseline, restart dabrafenib 
reduced by one dose levelh
If dabrafenib must be reduced to <50mg BID, 
permanently discontinue dabrafenib. Trametinib may 
be continued.
a.
Pyrexia is defined as a body temperature equal to or above 38.5 Celsius or 101.3Fahrenheit.
b.
For subjects experiencing pyrexia complicated by rigors, severe chills, etc., a clinical evaluation and 
laboratory work-up is mandatory for each event; anti-pyretic treatment should be started immediately at the 
first occurrence and prophylactic anti-pyretic treatment is recommended
c.
Thorough clinical examination for signs and symptoms of infection or hypersensitivity is required; laboratory 
workup should include full-blood-count, electrolytes, creatinine, blood urea nitrogen (BUN), C-reactive protein 
(CRP), liver-function tests, blood culture, and urine culture.
d.
Oral hydration should be encouraged in subjects without evidence of dehydration. Intravenous hydration is 
recommended in subjects experiencing pyrexia complicated by dehydration/hypotension.
e.
Anti-pyretic treatment may include acetaminophen, ibuprofen, or suitable anti-pyretic medication according to 
institutional standards. Prophylactic anti-pyretic treatment may be discontinued after three days in the 
absence of pyrexia
f.
In subject experiencing pyrexia complicated by rigors, severe chills, etc., which cannot be controlled with 
anti-pyretic medication, oral corticosteroids should be started at the 2nd event and doses should be gradually 
increased for subsequent events.
g.
Dabrafenib should be reduced by one dose level after three episodes of pyrexia complicated by rigors, 
severe chills, etc., which cannot be managed by best supportive care and increasing doses of oral steroids.  
Escalation of dabrafenib is allowed if no episode of pyrexia is observed in the 4 weeks subsequent to dose 
reduction.


Novartis
Confidential
Page 218
Clinical Study Protocol Version 05
Protocol No. MEK116833
RATIONALE:  Updated text to include missing footnotes.
SECTION 3.10.4.2.2 Acneiform Rash
PREVIOUS TEXT
Table 11
Acneiform Rash Management Guidelines
Step
Rash 
grading
Rash severity
Management of Rash
Dose Modification for 
Trametinib and Panitumumaba
1
Mild
Locallized
Minimally symptomatic
No impact on activities of 
daily living (ADL)
No sign of superinfection
Initiate prophylactic 
regimen, including oral 
antibiotics, if not already 
started (see Section 
3.9.4.2.1).  Consider 
using moderate 
strength topical 
steroidsa
Continue current doses.
Reassess after 2 weeks; if rash 
worsens or does not improve, 
proceed to Step 2.
2
Moderate
Generalized
Mild symptoms (e.g., 
pruritus, tenderness)
Minimal impact on ADL
No sign of superinfection
Initiate prophylactic 
regimen, including oral 
antibiotics, if not already 
started (see Section 
3.9.4.2.1), using 
moderate strength 
topical steroidsa
Reduce panitumumab dose by 
50% or consider interrupting 
panitumumab until resolution of 
toxicity to Grade 1.  If applicable, 
reduce trametinib by one dose 
level or consider interrupting 
trametinib until resolution of 
toxicity to Grade 1.  If toxicity 
resolves, then can consider re-
escalation to initial dose level.
Reassess after 2 weeks; if rash 
worsens or does not improve, 
proceed to Step 3.
3
Severe
Generalized
Severe symptoms (e.g., 
pruritus, tenderness)
Significant impact on 
ADL
Sign of or potential for 
superinfection
Initiate prophylactic 
regimen, including oral 
antibiotics, if not already 
started, using moderate 
strength topical 
steroidsb plus 
methylprednisone dose 
pack (see Section 
3.9.4.2.1).
Consider obtaining 
dermatology 
consultation. 
Manage rash per 
dermatologist’s 
recommendation.
Interrupt panitumumab and 
trametinib until rash improves 
(moderate or mild), or resolves. 
If rash worsens or does not 
improve after 2 weeks, 
permanently discontinue 
panitumumab and trametinib.
If rash does improve/resolve, 
restart trametinib and 
panitumumab, each reduced by 
a single dose level.
2.
If the combination is 
tolerated for two 
weeks, consider dose 
escalating one or both 
agents to the prior 
dose level.
3.
If it is not tolerated, 
hold both agents until 
resolution to Gr1 and 


Novartis
Confidential
Page 219
Clinical Study Protocol Version 05
Protocol No. MEK116833
Step
Rash 
grading
Rash severity
Management of Rash
Dose Modification for 
Trametinib and Panitumumaba
then restart both 
agents, each reduced
by another dose level.
c.
Recommendations for modification of panitumumab dosing may deviate from the package insert [VECTIBIX, 
2012].
d.
Hydrocortisone 2.5% cream or fluticasone proprionate 0.5% cream.
REVISED TEXT
Table 1211
Acneiform Rash Management Guidelines
Step
Rash 
grading
Rash severity
Management of Rash
Dose Modification for 
Trametinib and Panitumumaba
1
Mild
Locallized
Minimally symptomatic
No impact on activities of 
daily living (ADL)
No sign of superinfection
Initiate prophylactic 
regimen, including oral 
antibiotics, if not already 
started (see Section 
3.9.4.2.1).  Consider 
using moderate 
strength topical 
steroidsab
Consider reduction of 
panitumumab dose by one dose 
level . Continue current doses.
Reassess after 2 weeks; if rash 
worsens or does not improve, 
proceed to Step 2.
2
Moderate
Generalized
Mild symptoms (e.g., 
pruritus, tenderness)
Minimal impact on ADL
No sign of superinfection
Initiate prophylactic 
regimen, including oral 
antibiotics, if not already 
started (see Section 
3.9.4.2.1), using 
moderate strength 
topical steroidsab
Reduce panitumumab dose by 
one dose level 50% or consider 
interrupting panitumumab until 
resolution of toxicity to Grade 1.  
If applicable, Rreduce trametinib 
by one dose level or consider 
interrupting trametinib until 
resolution of toxicity to Grade 1.  
If toxicity resolves, then can 
consider re-escalation to initial 
dose level.
Reassess after 2 weeks; if rash 
worsens or does not improve, 
proceed to Step 3.
3
Severe
Generalized
Severe symptoms (e.g., 
pruritus, tenderness)
Significant impact on 
ADL
Sign of or potential for 
superinfection
Initiate prophylactic 
regimen, including oral 
antibiotics, if not already 
started, using moderate 
strength topical 
steroidsb plus 
methylprednisone dose 
pack (see Section 
3.9.4.2.1).
Consider obtaining 
dermatology 
Interrupt panitumumab and 
trametinib until rash improves 
(moderate or mild), or resolves. 
If rash worsens or does not 
improve after 2 weeks, 
permanently discontinue 
panitumumab and trametinib.
If rash does improve/resolve, 
restart trametinib and 
panitumumab, each reduced by 
a single dose level.


Novartis
Confidential
Page 220
Clinical Study Protocol Version 05
Protocol No. MEK116833
Step
Rash 
grading
Rash severity
Management of Rash
Dose Modification for 
Trametinib and Panitumumaba
consultation. 
Manage rash per 
dermatologist’s 
recommendation.
4.
If the combination is 
tolerated for two 
weeks, consider dose
escalating one or both 
agents to the prior 
dose level.
5.
If it is not tolerated, 
hold both agents until 
resolution to Gr1 and 
then restart both 
agents, each reduced 
by another dose level.
e.
Recommendations for modification of panitumumab dosing may deviate from the package insert [VECTIBIX, 
20124].
Hydrocortisone 2.5% cream or fluticasone proprionate 0.5% cream.
RATIONALE:  Updated dose modification guidelines to attempt to better control 
acneiform rash.
SECTION 3.10.5
Management and Dose Modification Guidelines for 
Diarrhea
PREVIOUS TEXT
Episodes of diarrhea have occurred in subjects receiving dabrafenib, panitumumab and 
/or trametinib. 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 14.
Table 14
Management and Dose Modification Guidelines for Diarrhea
CTCAE Grade
Adverse Event Management
Action and Dose Modification
Uncomplicated diarrheaa
  Grade 1 or Grade 2
Diet: Stop all lactose-containing 
products; eat small meals, BRAT diet 
(bananas, rice, apples, toast) is 
recommended.
Hydration: 8 to 10 large glasses of 
clear liquids per day (e.g., Gatorade 
or broth)
Loperamide: initially 4mg, followed by 
2mg every 4 hours or after every 
unformed stool, to a maximum of 
16mg/ day. Continue until diarrhea-
Continue study treatments 
If diarrhea is Grade 2 for >48 hours, 
interrupt study treatments until 
resolution to Grade 1.
Restart study treatments at the 
current dose level.


Novartis
Confidential
Page 221
Clinical Study Protocol Version 05
Protocol No. MEK116833
CTCAE Grade
Adverse Event Management
Action and Dose Modification
free for 12 hours.
Diarrhea 24 hours: Loperamide 
2mg every two hours to a maximum 
of 16mg/ day. Consider adding oral 
antibiotics.
Diarrhea 48 hours:  Loperamide 
2mg every two hours to a maximum 
of 16mg/ day. Add budesonide or 
other 2nd line therapies (otreotide, or 
tincture of opium) and oral antibiotics.
Uncomplicated diarrheaa
   Grade 3 or Grade 4
Any complicated diarrheab
Clinical evaluation is mandatory.
Loperamidec: initially 4mg, followed 
by 2mg every 4 hours or after every 
unformed stool, to a maximum of 
16mg/ day. Continue until diarrhea-
free for 12 hours.
Oral antibiotics and 2nd line therapies
should be implemented if clinically 
indicated.
Hydration: intravenous fluids should 
be administered if clinically indicated.
Antibiotics (oral or IV) should be 
administered if clinically indicated.
Interventions should be continued 
until the subject is diarrhea-free 
for 24 hours.
Intervention may require 
hospitalization for subjects at risk 
of life-threatening complications.
Interrupt study treatments until 
diarrhea recovers to Grade 1.
Restart study treatments with a one 
dose level reduction.  
If diarrhea does not recur with 
this one-level dose reduction, 
consider re-escalationd of study 
treatment with the following 
order of priority:
1.
Dabrafenib
2.
Panitumumab
3.
Trametinib
If 3 dose reductions of study 
treatment are clinically indicated, 
permanently discontinue study 
treatments.
f.
Uncomplicated diarrhea is defined by the absence of symptoms such as cramping, nausea/vomiting Grade 2, 
decreased performance status, pyrexia, sepsis, neutropenia Grade 3, frank bleeding, and/or dehydration 
requiring IV fluid substitution.
g.
Complicated diarrhea is defined by the presence of symptoms such as cramping, nausea/vomiting Grade 2, 
decreased performance status, pyrexia, sepsis, neutropenia Grade 3, frank bleeding, and/or dehydration 
requiring IV fluid substitution.
h.
Loperamide should be made available prior to the start of study treatment so that loperamide administration can 
begin at the first signs of diarrhea.


Novartis
Confidential
Page 222
Clinical Study Protocol Version 05
Protocol No. MEK116833
Escalation of study treatment to the previous dose level is allowed after consultation with 
the GSK Medical Monitor and in the absence of another episode of complicated or severe 
diarrhea in the 4 weeks subsequent to dose reduction.
REVISED TEXT
Episodes of diarrhea have occurred in subjects receiving dabrafenib, panitumumab and 
/or trametinib. 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 15Table 14.
Table 1514
Management and Dose Modification Guidelines for Diarrhea
CTCAE Grade
Adverse Event Management
Action and Dose Modification
Uncomplicated diarrheaa
  Grade 1 or Grade 2
Diet: Stop all lactose-containing 
products; eat small meals, BRAT diet 
(bananas, rice, apples, toast) is 
recommended.
Hydration: 8 to 10 large glasses of 
clear liquids per day (e.g., Gatorade 
or broth)
Loperamide: initially 4mg, followed by 
2mg every 4 hours or after every 
unformed stool, to a maximum of 
16mg/ day. Continue until diarrhea-
free for 12 hours.
Diarrhea 24 hours: Loperamide 
2mg every two hours to a maximum 
of 16mg/ day. Consider adding oral 
antibiotics.
Diarrhea 48 hours:  Loperamide 
2mg every two hours to a maximum 
of 16mg/ day. Add budesonide or 
other 2nd line therapies (otreotide, or 
tincture of opium) and oral antibiotics.
Continue study treatments. Consider 
dose reduction of trametinib and 
panitumumab by one dose level.
If diarrhea is Grade 2 for >48 hours, 
interrupt study treatments until 
resolution to Grade 1.
Restart study treatments at the 
current dose level.
Uncomplicated diarrheaa
   Grade 3 or Grade 4
Any complicated diarrheab
Clinical evaluation is mandatory.
Loperamidec: initially 4mg, followed 
by 2mg every 4 hours or after every 
unformed stool, to a maximum of 
16mg/ day. Continue until diarrhea-
free for 12 hours.
Interrupt study treatments until 
diarrhea recovers to Grade 1.
Restart study treatments with a one 
dose level reduction.  
If diarrhea does not recur with 


Novartis
Confidential
Page 223
Clinical Study Protocol Version 05
Protocol No. MEK116833
CTCAE Grade
Adverse Event Management
Action and Dose Modification
Oral antibiotics and 2nd line therapies
should be implemented if clinically 
indicated.
Hydration: intravenous fluids should 
be administered if clinically indicated.
Antibiotics (oral or IV) should be 
administered if clinically indicated.
Interventions should be continued 
until the subject is diarrhea-free 
for 24 hours.
Intervention may require 
hospitalization for subjects at risk 
of life-threatening complications.
this one-level dose reduction, 
consider re-escalationd of study 
treatment with the following 
order of priority:
4.
Dabrafenib
5.
Panitumumab
6.
Trametinib
If 3 dose reductions of study 
treatment are clinically indicated, 
permanently discontinue study 
treatments.
i.
Uncomplicated diarrhea is defined by the absence of symptoms such as cramping, nausea/vomiting Grade 2, 
decreased performance status, pyrexia, sepsis, neutropenia Grade 3, frank bleeding, and/or dehydration 
requiring IV fluid substitution.
j.
Complicated diarrhea is defined by the presence of symptoms such as cramping, nausea/vomiting Grade 2, 
decreased performance status, pyrexia, sepsis, neutropenia Grade 3, frank bleeding, and/or dehydration 
requiring IV fluid substitution.
k.
Loperamide should be made available prior to the start of study treatment so that loperamide administration can 
begin at the first signs of diarrhea.
l.
Escalation of study treatment to the previous dose level is allowed after consultation with the GSK Medical 
Monitor and in the absence of another episode of complicated or severe diarrhea in the 4 weeks subsequent to 
dose reduction.
RATIONALE:  Update dose modification guidelines for management of diarrhea
SECTION 3.10.7.1
Left Ventricular Ejection Fraction (LVEF)
PREVIOUS TEXT
Table 16 Dose Modification Guidelines and Stopping Criteria for LVEF 
Decrease
Clinic Presentation
LVEF decrease (%) or CTCAE grade
Action and Dose Modificationd
Asymptomatic
Absolute decrease of >10% in LVEF 
compared to baseline and ejection 
fraction below the institutional LLN
Interrupt study treatment with dabrafenib and 
trametinib and repeat ECHO/MUGA within 2 
weeksa
IF LVEF recovers within 4 weeks (defined as LVEF 
LLN and absolute decrease 10% compared to 
baseline):

Consult with the GSK Medical Monitor 
and request approval for restart


Novartis
Confidential
Page 224
Clinical Study Protocol Version 05
Protocol No. MEK116833

Restart trametinib reduced by one dose 
levelb

Restart dabrafenib at previous dose level

Repeat ECHO/MUGA at 2, 4, 8, and 12 
weeks after re-start; continue in 12 week 
intervals thereafter
If LVEF does not recover within 4 weeks:
e.
Consult with cardiologist
f.
Permanently discontinue dabrafenib 
and trametinib
g.
Report as SAE
h.
Repeat ECHO/MUGA after 2, 4, 8, 12 
and 16 weeks or until resolution
i.
Consult with GSK Medical Monitord
Symptomaticc
Grade 3: resting LVEF 39-20% or >20% 
absolute reduction from baseline
Permanently discontinue study treatment with 
dabrafenib and trametinib 
Report as SAE
Consult with cardiologist
Repeat ECHO/MUGA after 2, 4, 8, 12 and 16 
weeks or until resolution.
Grade 4: resting LVEF <20%
a.
Abbreviations:  CTCAE = Common Terminology Criteria for Adverse Events; ECHO = echocardiogram; GSK 
= GlaxoSmithKline; LLN = lower limit of normal; LVEF = left ventricular ejection fraction If ECHO/MUGA does 
not show LVEF recovery after 2 weeks, repeat ECHO/MUGA 2 weeks later.
b.
Escalation of trametinib to previous dose level can be considered if LVEF remains stable for 4 weeks after 
restarting of trametinib.  Approval from GSK Medical Monitor is required
c.
Symptoms may include: dyspnea, orthopnea, and other signs and symptoms of pulmonary congestion and 
edema.
d.
Once LVEF recovers to baseline, restarting dabrafenib monotherapy may be considered in consultation with 
the GSK Medical Monitor.
REVISED TEXT
Table 1716
Dose Modification Guidelines and Stopping Criteria for LVEF 
Decrease
Clinic Presentation
LVEF decrease (%) or CTCAE grade
Action and Dose Modificationd
Asymptomatic
Absolute decrease of >10% in LVEF 
compared to baseline and ejection 
fraction below the institutional LLN
Interrupt study treatment with dabrafenib and 
trametinib and repeat ECHO/MUGA within 2 
weeksa
IF LVEF recovers within 4 weeks (defined as LVEF 
LLN and absolute decrease 10% compared to 
baseline):

Consult with the GSK Medical Monitor 
and request approval for restart

If approved, Rrestart trametinib reduced 
by one dose levelb

Restart dabrafenib at previous dose level

Repeat ECHO/MUGA at 2, 4, 8, and 12 
weeks after re-start; continue in 12 week 
intervals thereafter
If LVEF does not recover within 4 weeks:


Novartis
Confidential
Page 225
Clinical Study Protocol Version 05
Protocol No. MEK116833
e.
Consult with cardiologist
f.
Permanently discontinue dabrafenib 
and trametinib
g.
Report as SAE
h.
Repeat ECHO/MUGA after 2, 4, 8, 12 
and 16 weeks or until resolution
i.
Consult with GSK Medical Monitord
Symptomaticc
Grade 3: resting LVEF 39-20% or >20% 
absolute reduction from baseline
Permanently discontinue study treatment with 
dabrafenib and trametinib 
Interrupt dabrafenibd
Report as SAE
Consult with cardiologist
Repeat ECHO/MUGA after 2, 4, 8, 12 and 16 
weeks or until resolution.
Grade 4: resting LVEF <20%
Abbreviations:  CTCAE = Common Terminology Criteria for Adverse Events; ECHO = echocardiogram; GSK = 
GlaxoSmithKline; LLN = lower limit of normal; LVEF = left ventricular ejection fraction
a.
If ECHO/MUGA does not show LVEF recovery after 2 weeks, repeat ECHO/MUGA 2 weeks later.
b.
Escalation of trametinib to previous dose level can be considered if LVEF remains stable for 4 weeks after 
restarting of trametinib.  Approval from GSK Medical Monitor is required
c.
Symptoms may include: dyspnea, orthopnea, and other signs and symptoms of pulmonary congestion and 
edema.
d.
Once LVEF recovers to baseline, restarting dabrafenib monotherapy may be considered in consultation with 
the GSK Medical Monitor.
RATIONALE:  Update to align with current guidance for the dabrafenib and trametinib 
combination.


Novartis
Confidential
Page 226
Clinical Study Protocol Version 05
Protocol No. MEK116833
SECTION 3.10.10
Liver Stopping Criteria
PREVIOUS TEXT
Liver chemistry threshold stopping criteria have been designed to assure subject safety and evaluate liver event etiology during 
administration of study treatment(s) and the follow-up period.  Study treatment(s) will be stopped if any of the following liver chemistry 
stopping criteria is/are met: 

Alanine aminotransferase (ALT) 3x upper limit of normal (ULN) AND bilirubin ≥2xULN (>35% direct bilirubin) (or 
ALT3xULN and international normalized ratio [INR]>1.5, if INR measured and subject not receiving warfarin therapy).
NOTE: If serum bilirubin fractionation is not immediately available, study drug should be discontinued if ALT 3xULN and 
bilirubin 2xULN. Serum bilirubin fractionation should be performed if testing is available. If testing is unavailable, record 
presence of detectable urinary bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury.

ALT 5xULN.

ALT 3xULN if associated with the appearance or worsening of symptoms of hepatitis or hypersensitivity such as fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash or eosinophilia.

ALT 3xULN persists for 4 weeks.

ALT 3xULN and cannot be monitored weekly for 4 weeks.
When any of the 5 liver chemistry stopping criteria is met, do the following:

Immediately discontinue investigational product(s).

Report the event to GSK within 24 hours of learning its occurrence.

Complete the liver event eCRF and SAE data collection tool if the event also meets the criteria for an SAE.


Novartis
Confidential
Page 227
Clinical Study Protocol Version 05
Protocol No. MEK116833

All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) (or ALT3xULN and INR>1.5, if INR measured; 
INR measurement is not required and the threshold value stated will not apply to subjects receiving anticoagulants), termed ‘Hy’s 
Law’, must be reported as an SAE (excluding studies of hepatic impairment or cirrhosis).

Complete the liver imaging and/or liver biopsy CRFs if these tests are performed.

Perform liver event follow up assessments, and monitor the subject until liver chemistries resolve, stabilize, or return to baseline 
values as described below.

Follow-up for Overall Survival (OS) is required following permanent discontinuation from investigational product.

Do not re-challenge with investigational product.
REVISED TEXT
Liver chemistry threshold stopping criteria have been designed to assure subject safety and evaluate liver event etiology during 
administration of study treatment(s) and the follow-up period.  Study treatment(s) will be stopped if any of the following liver chemistry 
stopping criteria is/are met: 
1. Alanine aminotransferase (ALT) 3x upper limit of normal (ULN) AND bilirubin ≥2xULN (>35% direct bilirubin) (or 
ALT3xULN and international normalized ratio [INR]>1.5, if INR measured and subject not receiving warfarin therapy).

NOTE: If serum bilirubin fractionation is not immediately available, study drug should be discontinued if ALT 3xULN 
and bilirubin 2xULN. Serum bilirubin fractionation should be performed if testing is available. If testing is unavailable, 
record presence of detectable urinary bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury.
2. ALT 5xULN.
3. ALT 3xULN if associated with the appearance or worsening of symptoms of hepatitis or hypersensitivity such as fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash or eosinophilia.
4. ALT 3xULN persists for 4 weeks.
5. ALT 3xULN and cannot be monitored weekly for 4 weeks.


Novartis
Confidential
Page 228
Clinical Study Protocol Version 05
Protocol No. MEK116833
When any of the 5 liver chemistry stopping criteria is met, do the following:

Immediately discontinue investigational product(s).

Report the event to GSK within 24 hours of learning its occurrence.

Complete the liver event eCRF and SAE data collection tool if the event also meets the criteria for an SAE.

All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) (or ALT3xULN and INR>1.5, if INR measured; 
INR measurement is not required and the threshold value stated will not apply to subjects receiving anticoagulants), termed 
‘Potential Hy’s Law’, must be reported as an SAE (excluding studies of hepatic impairment or cirrhosis).

Complete the liver imaging and/or liver biopsy CRFs if these tests are performed.

Perform liver event follow up assessments, and monitor the subject until liver chemistries resolve, stabilize, or return to baseline 
values as described below.

Follow-up for Overall Survival (OS) is required following permanent discontinuation from investigational product.

Do not re-challenge with investigational product.
RATIONALE FOR CHANGE:  Clarify liver criteria
SECTION 3.11.1 
Part 1 Dose Escalation Time and Event Tables
PREVIOUS TEXT
Screening1
First Treatment Period 
(Day 1 through Day 28)
Continuation Phase2
(7 days)
Initial follow-up3
(14 days [7 
days] from last 
dose of study 
drugs)
Secondary follow-up3
Day 1
Day 15
(2 days)
Day 21
(2 
days)
4 weeks (7 days) 
after the last dose 
of panitumumab
8 weeks (7 days) 
after the last dose 
of panitumumab
Informed Consent
X
Archival tumor tissue or 
fresh tumor biopsy (BRAF 
mutation confirmation)13
X


Novartis
Confidential
Page 229
Clinical Study Protocol Version 05
Protocol No. MEK116833
Screening1
First Treatment Period 
(Day 1 through Day 28)
Continuation Phase2
(7 days)
Initial follow-up3
(14 days [7 
days] from last 
dose of study 
drugs)
Secondary follow-up3
Day 1
Day 15
(2 days)
Day 21
(2 
days)
4 weeks (7 days) 
after the last dose 
of panitumumab
8 weeks (7 days) 
after the last dose 
of panitumumab
Tumor Biopsy 
(mandatory)16
X 
(pre-dose) 13
X10
(to be 
collected 
from Day15 
to Day 18)
X11
(at progression)
Demographics
X
Medical history/ Interim 
History
X
X6
At Week 4, then every 
4 weeks
X
Concurrent medications
X
X6
X
X
At Week 4, then every 
4 weeks
X
Serum or urine pregnancy 
test (-human chorionic 
gonadotropin [hCG]; 
women)4
X
Every 8 to 12 weeks 4
X
Complete physical 
examination5
X
X
Brief physical examination5
X6
X
At Week 4, then every 
4 weeks
Dermatological 
examination7
X
At Week 4, then every 
8 weeks
More frequently if 
there are new or 
changing lesions
X
Height (at screening only) 
and weight
X
X
Weight: At Week 4, 
then every 4 weeks
X
Ophthalmic examination
X
At Week 4, 
then as 
symptomatically 
warranted
X


Novartis
Confidential
Page 230
Clinical Study Protocol Version 05
Protocol No. MEK116833
Screening1
First Treatment Period 
(Day 1 through Day 28)
Continuation Phase2
(7 days)
Initial follow-up3
(14 days [7 
days] from last 
dose of study 
drugs)
Secondary follow-up3
Day 1
Day 15
(2 days)
Day 21
(2 
days)
4 weeks (7 days) 
after the last dose 
of panitumumab
8 weeks (7 days) 
after the last dose 
of panitumumab
Eastern Cooperative 
Oncology Group (ECOG) 
Performance Status
X
X6
At Week 4, 
then every 4 weeks
X
Vital signs (BP, HR, Body 
Temperature)
X
X14
X14
X
X14
X
12-lead ECG8
X
X6
X
X
At Week 4, 
then every 4 weeks 
until Week 24, 
then every 8 weeks
X
Hematology/Clinical 
Chemistry 
X
X6
X
X
At Week 4, 
then every 4 weeks 
until Week 24, 
then every 8 weeks
X
X3
X3
Coagulation 
Repeat as clinically 
indicated
X
CEA
X
X6
X
X
At Week 4, 
then every 4 weeks 
until Week 24, 
then every 8 weeks
X
X3
X3
ECHO (or MUGA)18
X
At Week 4,
then at Week 12 
and every 12 weeks 
thereafter
X
Collection of blood PK 
samples9
X
X 
X
X9
X9 
(at progression)


Novartis
Confidential
Page 231
Clinical Study Protocol Version 05
Protocol No. MEK116833
Screening1
First Treatment Period 
(Day 1 through Day 28)
Continuation Phase2
(7 days)
Initial follow-up3
(14 days [7 
days] from last 
dose of study 
drugs)
Secondary follow-up3
Day 1
Day 15
(2 days)
Day 21
(2 
days)
4 weeks (7 days) 
after the last dose 
of panitumumab
8 weeks (7 days) 
after the last dose 
of panitumumab
Panitumumab dosing14
X
X
X
Every 2  weeks
Dabrafenib and trametinib 
dosing
CONTINUOUS daily dosing; 
Dabrafenib BID and trametinib once daily should be administered 
under fasting conditions, 
either one hour before a meal or 2 hours after a meal.
AE assessment 
CONTINUOUS
Urinalysis
X
X6
X
Disease Assessment12
X
Every 6 weeks until 
Week 24, 
then every 8 weeks
X12
X17


Novartis
Confidential
Page 232
Clinical Study Protocol Version 05
Protocol No. MEK116833
1.
All screening assessments must be completed within 14 days prior to first dose except informed consent, ophthalmology exam, dermatology exam. ECHO/MUGA and Disease 
Assessment, which can occur within 35 days prior to the first dose. Note: Procedures conducted as part of the subject’s routine clinical management (e.g., blood counts, imaging 
study) and obtained prior to signing of informed consent may be utilized for screening or baseline purposes provided these procedures meet the protocol requirements.
2.
Assessments throughout the study are calendar-based starting from the first day of dosing (Day 1) in the first treatment period.  Dose interruptions should not alter the assessment 
schedule for any subsequent treatment period.  The Continuation Phase starts with Day 29; events in the Continuation Phase are allowed 7 days from projected date. Safety lab 
tests (chemistry/hematology/coag/UA) may be done the day before the visit so that results are ready on the day of the visit, but all assessments should be done within the 7 day 
window.
3.
Initial follow-up visit should be 14 days from last dose of study drugs (7 days). If a subject is unable to return to the clinic due to hospitalization, site staff are encouraged to 
telephone the subject for assessment of AEs.  Secondary follow-up visits should occur at 4 weeks and 8 weeks after the last dose of panitumumab.
4.
Serum pregnancy test should be performed at screening; all subsequent pregnancy tests may be either serum or urine, and performed every 8 to 12 weeks.
5.
Complete physical examination must include integument and genitalia. Note: pelvic exam in female subjects may be completed up to 24 weeks prior to date of first dose.  
Complete and brief physical examinations are defined in Section 6.2.
6.
If within 72 hours of Screening, this assessment does not need to be repeated on Day 1.
7.
Baseline skin photography should be performed at Screening.  Photographs should be taken of new skin lesions that occur, or skin lesions that change on therapy. Refer to 
Section 6.2. French sites will perform dermatological exams monthly while on-therapy, and monthly for 6 months following discontinuation of dabrafenib or until initiation of another 
anti-neoplastic therapy, whichever comes first. Refer to Appendix 7 for full information.
8.
Single ECGs will be collected prior to dosing.
9.
Blood samples (4 mL) for PK analysis of dabrafenib and metabolites (hydroxy-dabrafenib and desmethyl-dabrafenib) and trametinib  will be collected on Day 1 and on Day 15 
predose (within 30 minutes of dosing) and at 1, 2, 4, 6,and 8 hours after administration.  Blood samples (4 mL) for PK analysis of panitumumab will be collected on Day 1 and Day 
15 predose (within 30 minutes of dosing panitumumab) and at 1 hour (end of infusion of panitumumab).  A single 4 mL blood sample for analysis of panitumumab will be collected 
pre-dose on Day 21 during the clinic visit. During the continuation phase, PK samples will be collected pre-dose at Week 8, Week 12, Week 16, and Week 20. PK blood samples 
for dabrafenib, trametinib, and panitumumab analysis should be collected along with the tumor biopsy taken at progression.  On days when serial PK samples are collected, 
subjects should be instructed to hold doses of dabrafenib and trametinib, report to the clinic for the predose PK blood draw, then dose with dabrafenib and trametinib.  Collect PK 
samples at the time indicated 5 minutes up to 2 hour sample, 20 minutes up to the 8 hour sample. On all days when a PK sample is collected, date and time of PK sample, 
date and time of the last doses of dabrafenib, trametinib, and panitumumab prior to the predose PK samples, and the date and time of the doses dabrafenib, trametinib, and 
panitumumab administered in the clinic  must be recorded
10. Collection of on-treatment tumor biopsy for subjects with accessible tumors.  On-treatment biopsy may be collected 2 to 4 hours after dosing with oral study medication’from Day 
15 to Day 18 (+3 days). Biopsies should be performed on non-target lesions when possible. PK samples for dabrafenib, trametinib and panitumumab analysis will be collected at 
the time of the post-dose tumor biopsy (24 hours) (unless the post-dose biopsy occurs on the same day that the Day 15 serial PK samples are collected).
11. Tumor biopsy at tumor progression in subjects who have had a radiologic response (20% or more) or had a stable disease for 6 months is highly encouraged.  .
12. CT is the preferred method to measure lesions selected for response assessment. Refer to Appendix 4 for additional information regarding Response Evaluation Criteria In Solid 
Tumors (RECIST) version 1.1 methodology and criteria.  Follow-up disease assessment results for subjects who discontinue study medication for any other reason than 
progression or death. Even if study treatment is withdrawn, radiographic disease assessments (computed tomography [CT] or magnetic resonance imaging [MRI], as appropriate 
according to the method used at baseline) should continue every 8 weeks until documented disease progression, the start of new anti-cancer therapy, withdrawal of consent or 
death. 
13. Collection of archived tumor tissue or fresh tumor biopsies and determination of the subject’s tumor BRAF mutation status is required for enrollment; if a fresh tumor biopsy is 
collected during screening and up to prior to dosing on Day 1 for BRAF mutation confirmation, this tissue may be used for the day 1/ predose tumor biopsy.  
 


Novartis
Confidential
Page 233
Clinical Study Protocol Version 05
Protocol No. MEK116833
   The Day 1/predose tumor biopsy may be collected at any point after signing consent, after 
completing wash-out from prior therapies (either 5 half-lives or 14 days from last dose of prior therapy)..
14. Vital signs and temperature should be measured within 30 minutes prior to initiation and upon completion of the panitumumab infusion (up to 15 minutes after the end of infusion).
 
16. Pre- and post-dose tumor biopsies are mandatory. If the patient’s tumors are inaccessible for biopsy, permission to enroll must be granted by the GSK Medical Monitor.
17. After study treatment is withdrawn, disease assessments (the method used at baseline) should continue every 8 weeks until documented disease progression, the start of new 
anti-cancer therapy, withdrawal of consent, or death.
18. ECHO is preferred.  MUGA may be used only if ECHO is not available.  The same method must be used consistently from screening throughout the study.
REVISED TEXT
SECTION 3.11.1
Part 1 Dose Escalation
Screening1
First Treatment Period 
(Day 1 through Day 28)
Continuation Phase2
(7 days)
Initial follow-
up3
(14 days [7 
days] from last 
dose of study 
drugs)
Secondary follow-up3
Day 1
Day 15
(2 days)
Day 21
(2 days)
4 weeks (7 
days) after the 
last dose of 
panitumumab
8 weeks (7 
days) after the 
last dose of 
panitumumab
Informed Consent
X
Archival tumor tissue 
or fresh tumor biopsy 
(BRAF mutation 
confirmation)14
X
Tumor Biopsy 
(mandatory)10
X 
(pre-dose)14
X11
(to be 
collected 
from Day15 
to Day 18)
X12
(at 
progression)
Demographics
X
Medical history/ Interim 
History
X
X6
At Week 4, then every 4 weeks
X
Concurrent 
medications
X
X6
X
X
At Week 4, then every 4 weeks
X


Novartis
Confidential
Page 234
Clinical Study Protocol Version 05
Protocol No. MEK116833
Screening1
First Treatment Period 
(Day 1 through Day 28)
Continuation Phase2
(7 days)
Initial follow-
up3
(14 days [7 
days] from last 
dose of study 
drugs)
Secondary follow-up3
Day 1
Day 15
(2 days)
Day 21
(2 days)
4 weeks (7 
days) after the 
last dose of 
panitumumab
8 weeks (7 
days) after the 
last dose of 
panitumumab
Serum or urine 
pregnancy test (-
human chorionic 
gonadotropin [hCG]; 
women)4
X
Every 8 to 12 weeks4
X
Complete physical 
examination5
X
X
Brief physical 
examination5
X6
X
At Week 4, then every 4 weeks
Dermatological 
examination7
X
At Week 4, then every 8 weeks
More frequently if there are new or 
changing lesions
X
Height (at screening 
only) and weight
X
X
Weight: At Week 4, 
then every 4 weeks
X
Ophthalmic 
examination
X
At Week 4, 
then as symptomatically warranted
X
Eastern Cooperative 
Oncology Group 
(ECOG) Performance 
Status
X
X6
At Week 4, 
then every 4 weeks
X
Vital signs (BP, HR, 
Body Temperature)
X
X15
X15
X
X15
X
12-lead ECG8
X
X6
X
X
At Week 4, 
then every 4 weeks until Week 24, 
then every 8 weeks
X
Hematology/Clinical 
Chemistry 
X
X6
X
X
At Week 4, 
then every 4 weeks until Week 24, 
then every 8 weeks
X
X3
X3


Novartis
Confidential
Page 235
Clinical Study Protocol Version 05
Protocol No. MEK116833
Screening1
First Treatment Period 
(Day 1 through Day 28)
Continuation Phase2
(7 days)
Initial follow-
up3
(14 days [7 
days] from last 
dose of study 
drugs)
Secondary follow-up3
Day 1
Day 15
(2 days)
Day 21
(2 days)
4 weeks (7 
days) after the 
last dose of 
panitumumab
8 weeks (7 
days) after the 
last dose of 
panitumumab
Coagulation 
Repeat as clinically 
indicated
X
CEA
X
X6
X
X
At Week 4, 
then every 4 weeks until Week 24, 
then every 8 weeks
X
X3
X3
ECHO (or MUGA)18
X
At Week 4,
then at Week 12 
and every 12 weeks thereafter
X
Collection of blood PK 
samples9
X
X 
X
X9
X9 
(at 
progression)
Panitumumab dosing15
X
X
X
Every 2  weeks
Dabrafenib and 
trametinib dosing
CONTINUOUS daily dosing; 
Dabrafenib BID and trametinib once daily should be administered under fasting 
conditions, 
either one hour before a meal or 2 hours after a meal.
AE assessment 
CONTINUOUS
Urinalysis
X
X6
X


Novartis
Confidential
Page 236
Clinical Study Protocol Version 05
Protocol No. MEK116833
Screening1
First Treatment Period 
(Day 1 through Day 28)
Continuation Phase2
(7 days)
Initial follow-
up3
(14 days [7 
days] from last 
dose of study 
drugs)
Secondary follow-up3
Day 1
Day 15
(2 days)
Day 21
(2 days)
4 weeks (7 
days) after the 
last dose of 
panitumumab
8 weeks (7 
days) after the 
last dose of 
panitumumab
Disease Assessment12
X
Every 6 weeks until Week 24, 
then every 8 weeks
X12
X17
Long-term survival 
follow-up
X19
AE, Adverse Event; BP, blood pressure; CEA, ; ECHO, echocardiogram; ECG, electrocardiogram; ECOG, Eastern Cooperative Oncology Group; HR, heart rate; 
MUGA, 
1.
SCREENING WINDOW:  All screening assessments must be completed within 14 days prior to first dose except informed consent, ophthalmology exam, dermatology exam. 
ECHO/MUGA and Disease Assessment, which can occur within 35 days prior to the first dose. Note: Procedures conducted as part of the subject’s routine clinical management 
(e.g., blood counts, imaging study) and obtained prior to signing of informed consent may be utilized for screening or baseline purposes provided these procedures meet the 
protocol requirements.
2.
TREATMENT PHASE:  Assessments throughout the study are calendar-based starting from the first day of dosing (Day 1) in the first treatment period.  Dose interruptions should 
not alter the assessment schedule for any subsequent treatment period.  The Continuation Phase starts with Day 29; events in the Continuation Phase are allowed 7 days from 
projected date. Safety lab tests (chemistry/hematology/coag/UA) may be done the day before the visit so that results are ready on the day of the visit, but all assessments should 
be done within the 7 day window.
3.
FOLLOW-UP VISIT:  Initial follow-up visit should be 14 days from last dose of study drugs (7 days). If a subject is unable to return to the clinic due to hospitalization, site staff are 
encouraged to telephone the subject for assessment of AEs.  Secondary follow-up visits should occur at 4 weeks and 8 weeks after the last dose of panitumumab.
4.
PREGNANCY TEST:  Serum pregnancy test should be performed at screening; all subsequent pregnancy tests may be either serum or urine, and performed every 8 to 12 weeks.
5.
PHYSICAL EXAMINATION:  Complete physical examination must include integument and genitalia. Note: pelvic exam in female subjects may be completed up to 24 weeks prior 
to date of first dose.  Complete and brief physical examinations are defined in Section 6.2.
6.
DAY1 ASSESSMENTS:  If within 72 hours of Screening, this assessment does not need to be repeated on Day 1.
7.
DERMALOGICAL EVALUATION:  Baseline skin photography should be performed at Screening.  Photographs should be taken of new skin lesions that occur, or skin lesions that 
change on therapy. Refer to Section 6.2. French sites will perform dermatological exams monthly while on-therapy, and monthly for 6 months following discontinuation of 
dabrafenib or until initiation of another anti-neoplastic therapy, whichever comes first. Refer to Appendix 7 for full information.
8.
ECG:  Single ECGs will be collected prior to dosing.
9.
PHARMACOKINETIC SAMPLES:  Blood samples (4 mL) for PK analysis of dabrafenib and metabolites (hydroxy-dabrafenib and desmethyl-dabrafenib) and trametinib  will be 
collected on Day 1 and on Day 15 predose (within 30 minutes of dosing) and at 1, 2, 4, 6,and 8 hours after administration.  Blood samples (4 mL) for PK analysis of panitumumab 
will be collected on Day 1 and Day 15 predose (within 30 minutes of dosing panitumumab) and at 1 hour (end of infusion of panitumumab).  A single 4 mL blood sample for 
analysis of panitumumab will be collected pre-dose on Day 21 during the clinic visit. During the continuation phase, PK samples will be collected pre-dose at Week 8, Week 12, 
Week 16, and Week 20. PK blood samples for dabrafenib, trametinib, and panitumumab analysis should be collected along with the tumor biopsy taken at progression.  On days 
when serial PK samples are collected, subjects should be instructed to hold doses of dabrafenib and trametinib, report to the clinic for the predose PK blood draw, then dose with 


Novartis
Confidential
Page 237
Clinical Study Protocol Version 05
Protocol No. MEK116833
dabrafenib and trametinib.  Collect PK samples at the time indicated 5 minutes up to 2 hour sample, 20 minutes up to the 8 hour sample. On all days when a PK sample is 
collected, date and time of PK sample, date and time of the last doses of dabrafenib, trametinib, and panitumumab prior to the predose PK samples, and the date and time of the 
doses dabrafenib, trametinib, and panitumumab administered in the clinic  must be recorded
10. BIOPSY:  Pre- and post-dose tumor biopsies are mandatory. If the patient’s tumors are inaccessible for biopsy, permission to enroll must be granted by the GSK Medical Monitor.
11. BIOPSY:  Collection of on-treatment tumor biopsy for subjects with accessible tumors.  On-treatment biopsy may be collected 2 to 4 hours after dosing with oral study 
medication’from Day 15 to Day 18 (+3 days). Biopsies should be performed on non-target lesions when possible. PK samples for dabrafenib, trametinib and panitumumab 
analysis will be collected at the time of the post-dose tumor biopsy (24 hours) (unless the post-dose biopsy occurs on the same day that the Day 15 serial PK samples are 
collected).
12. BIOPSY:  Tumor biopsy at tumor progression in subjects who have had a radiologic response (20% or more) or had a stable disease for 6 months is highly encouraged.  .
13. DISEASE ASSESSMENT:  CT is the preferred method to measure lesions selected for response assessment. Refer to Appendix 4 for additional information regarding Response 
Evaluation Criteria In Solid Tumors (RECIST) version 1.1 methodology and criteria.  Follow-up disease assessment results for subjects who discontinue study medication for any 
other reason than progression or death. Even if study treatment is withdrawn, radiographic disease assessments (computed tomography [CT] or magnetic resonance imaging 
[MRI], as appropriate according to the method used at baseline) should continue every 8 weeks until documented disease progression, the start of new anti-cancer therapy, 
withdrawal of consent or death. 
14. TUMOR TISSUE SAMPLE:  Collection of archived tumor tissue or fresh tumor biopsies and determination of the subject’s tumor BRAF mutation status is required for enrollment; 
if a fresh tumor biopsy is collected during screening and up to prior to dosing on Day 1 for BRAF mutation confirmation, this tissue may be used for the day 1/ predose tumor 
biopsy.  
The Day 1/predose tumor biopsy may be collected at any point after 
signing consent, after completing wash-out from prior therapies (either 5 half-lives or 14 days from last dose of prior therapy)..
15. VITAL SIGNS:  Vital signs and temperature should be measured within 30 minutes prior to initiation and upon completion of the panitumumab infusion (up to 15 minutes after the 
end of infusion).
 
17. After study treatment is withdrawn, disease assessments (the method used at baseline) should continue every 8 weeks until documented disease progression, the start of new 
anti-cancer therapy, withdrawal of consent, or death.
18. ECHO:  ECHO is preferred.  MUGA may be used only if ECHO is not available.  The same method must be used consistently from screening throughout the study.
19. OVERALL SURVIVAL:  Subjects will be followed for Overall Survival every 8 weeks after last dose of study drugs. See Section 6.3.1.for additional information.


Novartis
Confidential
Page 238
Clinical Study Protocol Version 05
Protocol No. MEK116833
RATIONALE:  Update Time and Events Table footnote with label and include Overall Survival follow up.
SECTION 3.11.2
Part 2 Dose Escalation Time and Event Tables
PREVIOUS TEXT
Screening1
First Treatment Period    
(Day 1 through Day 28)
Continuation Phase2
(7 days)
Initial Follow-
up3
Secondary Follow-up3
Day 1
Day 15
(2 days)
4 weeks (7 days) 
after the last dose 
of panitumumab
8 weeks (7 days) 
after the last dose 
of panitumumab
Informed Consent
X
Archival tumor tissue or 
fresh tumor biopsy (BRAF 
mutation confirmation)11
X
Tumor tissue biopsy 
(mandatory)16
X (pre-dose)11
X 
(to be 
collected 
from Day15 
to Day 18) 9
X12 (at 
progression)
Demographics
X
Medical history/ Interim 
History
X
X5
At Week 4, 
then every 4 weeks
X
Concurrent Medications
X
X5
X
At Week 4, 
then every 4 weeks
X
Serum or urine pregnancy 
test (-hCG; women)4
X
Every 8 to 12 weeks 4
X
Complete physical 
examination6
X
X
Brief physical examination6
X5
X
At Week 4, 
then every 4 weeks


Novartis
Confidential
Page 239
Clinical Study Protocol Version 05
Protocol No. MEK116833
Screening1
First Treatment Period    
(Day 1 through Day 28)
Continuation Phase2
(7 days)
Initial Follow-
up3
Secondary Follow-up3
Day 1
Day 15
(2 days)
4 weeks (7 days) 
after the last dose 
of panitumumab
8 weeks (7 days) 
after the last dose 
of panitumumab
Dermatological 
examination7
X
At Week 4, 
then every 8 weeks
More frequently if 
there are new or 
changing lesions
X
Height (at screening only) 
and weight
X
Weight: At Week 4, 
then every 4 weeks
X
Ophthalmic examination
X
at Week 4, 
then as 
symptomatically 
warranted
X
ECOG Performance 
Status
X
X5
At Week 4, 
then every 4 weeks
X
Vital signs (BP, HR, Body 
Temperature)
X
X14
X14
X14
X
12-lead ECG8
X
X5
X
At Week 4, 
then every 4 weeks 
until Week 24, then 
every 8 weeks
X
Hematology/Clinical 
Chemistry)
X
X5
X
At Week 4, 
then every 4 weeks 
until Week 24, then 
every 8 weeks
X3
X3
X3
Coagulation
Repeat as clinically 
indicated
X


Novartis
Confidential
Page 240
Clinical Study Protocol Version 05
Protocol No. MEK116833
Screening1
First Treatment Period    
(Day 1 through Day 28)
Continuation Phase2
(7 days)
Initial Follow-
up3
Secondary Follow-up3
Day 1
Day 15
(2 days)
4 weeks (7 days) 
after the last dose 
of panitumumab
8 weeks (7 days) 
after the last dose 
of panitumumab
CEA
X
X5
X
At Week 4, 
then every 4 weeks 
until Week 24, then 
every 8 weeks
X3
X3
X3
ECHO (or MUGA)18
X
At Week 4, 
then at Week 12 
and every 12 weeks 
thereafter
X
Pharmacokinetics 
collection: blood
X10
X9,10
Predose; At Week 410
X10 (at 
progression)
Panitumumab dosing14
X
X
X
Every 2 weeks
Dabrafenib and trametinib 
dosing
CONTINUOUS daily dosing; 
Dabrafenib BID and trametinib once daily should 
be administered under fasting conditions, either 
one hour before or 2 hours after a meal.
Urinalysis
X
X5
X


Novartis
Confidential
Page 241
Clinical Study Protocol Version 05
Protocol No. MEK116833
Screening1
First Treatment Period    
(Day 1 through Day 28)
Continuation Phase2
(7 days)
Initial Follow-
up3
Secondary Follow-up3
Day 1
Day 15
(2 days)
4 weeks (7 days) 
after the last dose 
of panitumumab
8 weeks (7 days) 
after the last dose 
of panitumumab
AE assessment 
CONTINUOUS
Disease Assessment13
X
Every 6 weeks until 
Week 24, 
then every 8 weeks
X13
X17
1.
All screening assessments must be completed within 14 days prior to first dose except informed consent, ophthalmic exam, dermatological exam, ECHO/MUGA, and Disease 
Assessment, which can occur within 35 days prior to the first dose. Note: Procedures conducted as part of the subject’s routine clinical management (e.g., blood counts, imaging 
study) and obtained prior to signing of informed consent may be utilized for screening or baseline purposes provided these procedures meet the protocol requirements.
2.
Assessments throughout the study are calendar-based starting from the first day of dosing (Day 1) in the first treatment period.  Dose interruptions should not alter the assessment 
schedule for any subsequent treatment period.  The Continuation Phase starts with Day 29; events in the Continuation Phase are allowed 7 days from projected date. Safety lab 
tests (chemistry/hematology/coag/UA) may be done the day before the visit so that results are ready on the day of the visit, but all assessments should be done within the 7 day 
window.
3.
Initial follow-up visit should be 14 days from last dose of study drugs (7 days).  If a subject is unable to return to the clinic due to hospitalization, site staff are encouraged to 
telephone the subject for assessment of AEs. Secondary follow-up visits should occur at 4 weeks and 8 weeks after the last dose of panitumumab.
4.
Serum pregnancy test should be performed at screening; all subsequent pregnancy tests may be either serum or urine, and performed every 8 to 12 weeks.
5.
If within 72 hours of Screening, this assessment does not need to be repeated on Day 1.
6.
Complete physical examination must include integument and genitalia.  Note: pelvic exam in female subjects may be completed up to 24 weeks prior to date of first dose. 
Complete and brief physical examinations are defined in Section 6.2.
7.
Baseline skin photography should be performed at Screening. Photographs should be taken of new skin lesions that occur, or skin lesions that change on therapy. Refer to 
Section 6.2. French sites will perform dermatological exams monthly while on-therapy, and monthly for 6 months following discontinuation of dabrafenib or until initiation of another 
anti-neoplastic therapy, whichever comes first. Refer to Appendix 7 for full information
8.
Single ECGs will be collected prior to dosing.
9.
Collection of on-treatment tumor biopsy for subjects with accessible tumors.  On-treatment biopsy may be collected 2 to 4 hours after dosing with oral study medication’from Day 
15 to Day 18 (+3 days).  Biopsies should be performed on non-target lesions when possible.  A single PK samples for dabrafenib, trametinib, and panitumumab will be collected at 
the time of the post-dose tumor biopsy (24 hours) (unless the post-dose biopsy occurs on the same day that the Day 15 serial PK samples are collected).
10. Blood samples (4 mL) for PK analysis of dabrafenib and metabolites (hydroxy-dabrafenib and desmethyl-dabrafenib) and trametinib  will be collected on Day 1 and Day 15 
predose (within 30 minutes of dosing) and at 1, 2, 4, 6,and 8 hours after administration. Blood samples (4 mL) for PK analysis of panitumumab will be collected on Day 1 and Day 


Novartis
Confidential
Page 242
Clinical Study Protocol Version 05
Protocol No. MEK116833
15 predose (within 30 minutes of dosing panitumumab)  and at 1 hour (end of infusion of panitumumab). A single 4 mL blood sample for analysis of panitumumab will be collected 
predose at the Week 4 clinic visit. On days when serial PK samples are collected, subjects should be instructed to hold doses of dabrafenib and trametinib, report to the clinic for 
the predose PK blood draw, then dose with dabrafenib and trametinib.  Collect PK samples at the time indicated 5 minutes up to 2 hour sample, 20 minutes up to the 8 hour 
sample. On all days when PK samples are collected, date and time of the PK sample(s), date and time  of the last doses of dabrafenib, trametinib, and panitumumab prior to the 
predose PK sample, and date and time of the dose of dabrafenib, trametinib, and panitumumab in the clinic must be recorded.  A single blook sample for dabrafenib, trametinib, 
and panitumumab analysis should be collected along with the tumor biopsy taken at progression.
11. Collection of archived tumor tissue or fresh tumor biopsies and determination of the subject’s tumor BRAF mutation status is required for enrollment; if a fresh tumor biopsy is 
collected during screening and up to prior to dosing on Day1 for BRAF mutation confirmation, this tissue may be used for the day 1/ predose tumor biopsy. 
 
  The Day 1/predose tumor biopsy may be collected at any point after signing consent, 
after completing wash-out from prior therapies (either 5 half-lives or 14 days from last dose of prior therapy).
12. Optional tumor biopsy for subjects who had a radiologic response (20% or more decrease) or had a stable disease for 6 months at disease progression (if feasible). A single PK 
sample will be collected at the time of tumor progression Refer to Section 6.7.2.
13. CT is the preferred method to measure lesions selected for response assessment. Refer to Appendix 4 for additional information regarding RECIST 1.1 methodology and criteria.  
Even if study treatment is withdrawn, radiographic disease assessments (CT or MRI, as appropriate according to the method used at baseline) should continue every 8 weeks 
until documented disease progression, the start of new anti-cancer therapy, withdrawal of consent or death.
14. Vital signs and temperature should be measured within 30 minutes prior to initiation and upon completion of the panitumumab infusion (up to 15 minutes after the end of infusion).
 
16. Pre- and post-dose tumor biopsies are mandatory. If the patient’s tumors are inaccessible for biopsy, permission to enroll must be granted by the GSK Medical Monitor.
17. After study treatment is withdrawn, disease assessments (the method used at baseline) should continue every 8 weeks until documented disease progression, the start of new 
anti-cancer therapy, withdrawal of consent, or death.
18. ECHO is preferred.  MUGA may be used only if ECHO is not available.  The same method must be used consistently from screening throughout the study.


Novartis
Confidential
Page 243
Clinical Study Protocol Version 05
Protocol No. MEK116833
REVISED TEXT
SECTION 3.11.2
Part 2 Expansion Cohorts
Screening1
First Treatment Period      
(Day 1 through Day 28)
Continuation Phase2
(7 days)
Initial Follow-
up3
Secondary Follow-up3
Day 1
Day 15
(2 days)
4 weeks (7 
days) after the 
last dose of 
panitumumab
8 weeks (7 
days) after the 
last dose of 
panitumumab
Informed Consent
X
Archival tumor tissue 
or fresh tumor biopsy 
(BRAF mutation 
confirmation)12
X
Tumor tissue biopsy 
(mandatory)9
X (pre-dose)12
X 
(to be collected 
from Day15 to 
Day 18)10
X13 (at 
progression)
Demographics
X
Medical history/ 
Interim History
X
X5
At Week 4, 
then every 4 weeks 
X
Concurrent 
Medications
X
X5
X
At Week 4, 
then every 4 weeks 
X
Serum or urine 
pregnancy test (-
hCG; women)4
X
Every 8 to 12 weeks4
X
Complete physical 
examination6
X
X
Brief physical 
examination6
X5
X
At Week 4, 
then every 4 weeks 


Novartis
Confidential
Page 244
Clinical Study Protocol Version 05
Protocol No. MEK116833
Screening1
First Treatment Period      
(Day 1 through Day 28)
Continuation Phase2
(7 days)
Initial Follow-
up3
Secondary Follow-up3
Day 1
Day 15
(2 days)
4 weeks (7 
days) after the 
last dose of 
panitumumab
8 weeks (7 
days) after the 
last dose of 
panitumumab
Dermatological 
examination7
X
At Week 4, 
then every 8 weeks
More frequently if there are new or 
changing lesions
X
Height (at screening 
only) and weight
X
Weight: At Week 4, 
then every 4 weeks 
X
Ophthalmic 
examination
X
at Week 4, 
then as symptomatically warranted
X
ECOG Performance 
Status
X
X5
At Week 4, 
then every 4 weeks 
X
Vital signs (BP, HR, 
Body Temperature)
X
X15
X15
X15
X
12-lead ECG8
X
X5
X
At Week 4, 
then every 4 weeks until Week 24, 
then every 8 weeks
X
Hematology/Clinical 
Chemistry)
X
X5
X
At Week 4, 
then every 4 weeks until Week 24, 
then every 8 weeks
X3
X3
X3
Coagulation
Repeat as clinically 
indicated
X
CEA
X
X5
X
At Week 46, 
then every 4 6 weeks until Week 24, 
then every 8 weeks
X3
X3
X3


Novartis
Confidential
Page 245
Clinical Study Protocol Version 05
Protocol No. MEK116833
Screening1
First Treatment Period      
(Day 1 through Day 28)
Continuation Phase2
(7 days)
Initial Follow-
up3
Secondary Follow-up3
Day 1
Day 15
(2 days)
4 weeks (7 
days) after the 
last dose of 
panitumumab
8 weeks (7 
days) after the 
last dose of 
panitumumab
ECHO (or MUGA)18
X
At Week 4, 
then at Week 12 
and every 12 weeks thereafter
X
Pharmacokinetics 
collection: blood
X11
X10,11
Predose; At Week 410
X11(at 
progression)
Panitumumab 
dosing15
X
X
X
Every 2 weeks
Dabrafenib and 
trametinib dosing
CONTINUOUS daily dosing; 
Dabrafenib BID and trametinib once daily should be administered under 
fasting conditions, either one hour before or 2 hours after a meal.
Urinalysis
X
X5
X
AE assessment 
CONTINUOUS
Disease 
Assessment13
X
Every 6 weeks until Week 24, 
then every 8 weeks
X14
X17


Novartis
Confidential
Page 246
Clinical Study Protocol Version 05
Protocol No. MEK116833
Screening1
First Treatment Period      
(Day 1 through Day 28)
Continuation Phase2
(7 days)
Initial Follow-
up3
Secondary Follow-up3
Day 1
Day 15
(2 days)
4 weeks (7 
days) after the 
last dose of 
panitumumab
8 weeks (7 
days) after the 
last dose of 
panitumumab
Long-term survival 
follow-up
X20
AE, Adverse Event; BP, blood pressure; CEA, ; ECHO, echocardiogram; ECG, electrocardiogram; ECOG, Eastern Cooperative Oncology Group; HR, heart rate; 
MUGA,
1.
SCREENING:  All screening assessments must be completed within 14 days prior to first dose except informed consent, ophthalmic exam, dermatological exam, ECHO/MUGA, 
and Disease Assessment, which can occur within 35 days prior to the first dose. Note: Procedures conducted as part of the subject’s routine clinical management (e.g., blood 
counts, imaging study) and obtained prior to signing of informed consent may be utilized for screening or baseline purposes provided these procedures meet the protocol 
requirements.
2.
TREATMENT PHASE:  Assessments throughout the study are calendar-based starting from the first day of dosing (Day 1) in the first treatment period.  Dose interruptions should 
not alter the assessment schedule for any subsequent treatment period.  The Continuation Phase starts with Day 29; events in the Continuation Phase are allowed 7 days from 
projected date. Safety lab tests (chemistry/hematology/coag/UA) may be done the day before the visit so that results are ready on the day of the visit, but all assessments should 
be done within the 7 day window.
3.
FOLLOW-UP VISIT:  Initial follow-up visit should be 14 days from last dose of study drugs (7 days).  If a subject is unable to return to the clinic due to hospitalization, site staff 
are encouraged to telephone the subject for assessment of AEs. Secondary follow-up visits should occur at 4 weeks and 8 weeks after the last dose of panitumumab.  Subjects 
are to be followed until progression for collection of PFS data and until death for collection of overall survival (OS) data.  If a subject who is eligible for crossover to the triplet 
combination has not crossed over by 14 days past the last dose of study treatment, the Initial Follow-Up assessments should be done.  If a subject who is eligible for crossover to 
the triplet combination has not crossed over by 4 weeks past the last dose of panitumumab, the Secondary Follow-Up assessments should be done.
4.
PREGNANCY TEST:  Serum pregnancy test should be performed at screening; all subsequent pregnancy tests may be either serum or urine, and performed every 8 to 12 weeks.
5.
PHYSICAL EXAM:  If within 72 hours of Screening, this assessment does not need to be repeated on Day 1.
6.
PHYSICAL EXAM:  Complete physical examination must include integument and genitalia.  Note: pelvic exam in female subjects may be completed up to 24 weeks prior to date 
of first dose. Complete and brief physical examinations are defined in Section 6.2.
7.
DERMALOGICAL EVALUATION:  Baseline skin photography should be performed at Screening. Photographs should be taken of new skin lesions that occur, or skin lesions that 
change on therapy. Refer to Section 6.2. French sites will perform dermatological exams monthly while on-therapy, and monthly for 6 months following discontinuation of 
dabrafenib or until initiation of another anti-neoplastic therapy, whichever comes first. Refer to Appendix 7 for full information
8.
ECG:  Single ECGs will be collected prior to dosing.
9.
BIOPSY:  Pre- and post-dose tumor biopsies are mandatory. If the patient’s tumors are inaccessible for biopsy, permission to enroll must be granted by the GSK Medical Monitor.
10. BIOPSY:  Collection of on-treatment tumor biopsy for subjects with accessible tumors.  On-treatment biopsy may be collected 2 to 4 hours after dosing with oral study 
medication’from Day 15 to Day 18 (+3 days).  Biopsies should be performed on non-target lesions when possible.  A single PK samples for dabrafenib, trametinib, and 


Novartis
Confidential
Page 247
Clinical Study Protocol Version 05
Protocol No. MEK116833
panitumumab will be collected at the time of the post-dose tumor biopsy (24 hours) (unless the post-dose biopsy occurs on the same day that the Day 15 serial PK samples are 
collected).
11. PHARMACOKINETIC SAMPLES:  Blood samples (4 mL) for PK analysis of dabrafenib and metabolites (hydroxy-dabrafenib and desmethyl-dabrafenib) and trametinib  will be 
collected on Day 1 and Day 15 predose (within 30 minutes of dosing) and at 1, 2, 4, 6,and 8 hours after administration. Blood samples (4 mL) for PK analysis of panitumumab will 
be collected on Day 1 and Day 15 predose (within 30 minutes of dosing panitumumab)  and at 1 hour (end of infusion of panitumumab). A single 4 mL blood sample for analysis of 
panitumumab will be collected predose at the Week 4 clinic visit. On days when serial PK samples are collected, subjects should be instructed to hold doses of dabrafenib and 
trametinib, report to the clinic for the predose PK blood draw, then dose with dabrafenib and trametinib.  Collect PK samples at the time indicated 5 minutes up to 2 hour sample, 
20 minutes up to the 8 hour sample. On all days when PK samples are collected, date and time of the PK sample(s), date and time  of the last doses of dabrafenib, trametinib, 
and panitumumab prior to the predose PK sample, and date and time of the dose of dabrafenib, trametinib, and panitumumab in the clinic must be recorded.  A single blookd
sample for dabrafenib, trametinib, and panitumumab analysis should be collected along with the tumor biopsy taken at progression.
12. TUMOR TISSUE SAMPLE:  Collection of archived tumor tissue or fresh tumor biopsies and determination of the subject’s tumor BRAF mutation status is required for enrollment; 
if a fresh tumor biopsy is collected during screening and up to prior to dosing on Day1 for BRAF mutation confirmation, this tissue may be used for the day 1/ predose tumor 
  The Day 1/predose tumor biopsy may be collected at any point 
after signing consent, after completing wash-out from prior therapies (either 5 half-lives or 14 days from last dose of prior therapy).
13. BIOPSY AT PROGRESSION:  Optional tumor biopsy for subjects who had a radiologic response (20% or more decrease) or had a stable disease for 6 months at disease
progression (if feasible). A single PK sample will be collected at the time of tumor progression Refer to Section 6.7.2.
14. DISEASE ASSESSMENT:  CT is the preferred method to measure lesions selected for response assessment. Refer to Appendix 4 for additional information regarding RECIST 
1.1 methodology and criteria.  Even if study treatment is withdrawn, radiographic disease assessments (CT or MRI, as appropriate according to the method used at baseline) 
should continue every 8 weeks until documented disease progression, the start of new anti-cancer therapy, withdrawal of consent or death.
15. VITAL SIGNS:  Vital signs and temperature should be measured within 30 minutes prior to initiation and upon completion of the panitumumab infusion (up to 15 minutes after the 
end of infusion).
 
17. DISEASE ASSESSMENT:  After study treatment is withdrawn, disease assessments (the method used at baseline) should continue every 8 weeks until documented disease 
progression, the start of new anti-cancer therapy, withdrawal of consent, or death.
18. ECHO:  ECHO is preferred.  MUGA may be used only if ECHO is not available.  The same method must be used consistently from screening throughout the study.
20. OVERALL SURVIVAL:  Subjects will be followed for Overall Survival every 8 weeks after last dose of study drugs. See Section 6.3.1.for additional information.


Novartis
Confidential
Page 248
Clinical Study Protocol Version 05
Protocol No. MEK116833
RATIONALE:  Update Time and Events Table footnote with label and include Overall Survival follow up.
SECTION 3.11.4
Part 4 Dose Escalation Time and Event Tables
PREVIOUS TEXT
Day:
Screening1
Screening1
First treatment period, 
Day 1 thru Day 28/end of Week 
4
Continuation 
phase 
Day 29/start of 
Week 52
Initial follow-
up3
Secondary 
follow-up3
Tertiary follow-
up3
Visit Window 
(relative to Day 1)
-35 to -1 days
-14 to -1 days
on Day 
1
on Day 15
(2 days)
on Day 
21
(2 
days)
14 (7) days 
from last dose 
of trametinib
4 weeks (7 
days) after the 
last dose of 
panitumumab
8 weeks (7 
days) after the 
last dose of 
panitumumab
Informed Consent
X
Demographics
X
Collection of archival 
tissue12
X
Complete physical5
X
X
Brief physical5
X
X
At Week 4, then 
every 4 wks
Medical/medication/
drug/alcohol history
X
X6
X
X
Concurrent medications
X
X
X
At Week 4, 
then every 4 weeks
X
12-lead ECG7
X
X6
X
X
At Week 4, then 
every 4 weeks until 
Week 24, then 
every 8 weeks
X
Vital signs 13 (including 
weight)
X
X
X
X
X
X
Height
X
Ophthalmic examination
X
At Week 4, then as 
symptomatically 
warranted
ECOG
X
X6
At Week 4, then 
every 4 wks
X


Novartis
Confidential
Page 249
Clinical Study Protocol Version 05
Protocol No. MEK116833
Day:
Screening1
Screening1
First treatment period, 
Day 1 thru Day 28/end of Week 
4
Continuation 
phase 
Day 29/start of 
Week 52
Initial follow-
up3
Secondary 
follow-up3
Tertiary follow-
up3
Visit Window 
(relative to Day 1)
-35 to -1 days
-14 to -1 days
on Day 
1
on Day 15
(2 days)
on Day 
21
(2 
days)
14 (7) days 
from last dose 
of trametinib
4 weeks (7 
days) after the 
last dose of 
panitumumab
8 weeks (7 
days) after the 
last dose of 
panitumumab
ECHO/MUGA17
X
At Week 4, then at 
Week 12, then 
every 12 weeks
X
Serum or urine pregnancy 
test (-hCG;women)4
X
Every 8 to 12 
weeks 4
Hema/Chem/Urinalysis 
tests
X
X6
At Week 4, 
then every 4 weeks 
until Week 24, then 
every 8 weeks
X
X
Coagulation
Repeat as clinically 
indicated
X
CEA
X
X
At Week 4, 
then every 4 weeks 
until Week 24, then 
every 8 weeks
X
X
Tumor biopsy15
X (pre-dose)15
X9 (to be 
collected 
from Day 
15 to Day 
18)
X10
(at 
progression)


Novartis
Confidential
Page 250
Clinical Study Protocol Version 05
Protocol No. MEK116833
Day:
Screening1
Screening1
First treatment period, 
Day 1 thru Day 28/end of Week 
4
Continuation 
phase 
Day 29/start of 
Week 52
Initial follow-
up3
Secondary 
follow-up3
Tertiary follow-
up3
Visit Window 
(relative to Day 1)
-35 to -1 days
-14 to -1 days
on Day 
1
on Day 15
(2 days)
on Day 
21
(2 
days)
14 (7) days 
from last dose 
of trametinib
4 weeks (7 
days) after the 
last dose of 
panitumumab
8 weeks (7 
days) after the 
last dose of 
panitumumab
AE assessment
CONTINUOUS
PK blood sample8
X
X
X
X
Panitumumab Dosing
X
X
X
every 2 weeks 
from Day 1
Trametinib dosing
X
X
X
X
Disease assessments11
x
Every 6 weeks until 
Week 24, 
then every 8 
weeks. 16
1.
All screening assessments must be completed within 14 days prior to first dose except informed consent, ophthalmology exam, dermatological exam, ECHO/MUGA and Disease 
Assessment, which can occur within 35 days prior to the first dose. Note: Procedures conducted as part of the subject’s routine clinical management (e.g., blood counts, imaging 
study) and obtained prior to signing of informed consent may be utilized for screening or baseline purposes provided these procedures meet the protocol requirements.
2.
Assessments throughout the study are calendar-based starting from the first day of dosing (Day 1) in the first treatment period.  Dose interruptions should not alter the assessment 
schedule for any subsequent treatment period.  The continuation phase starts with Day 29; events in the continuation phase are allowed 7 days from projected date.  Safety lab 
tests (chemistry/hematology/UA) may be done the day before the visit so that results are available on the day of the visit, but all assessments should be done within the 7 day 
window.
3.
Initial follow-up visit should be 14 days (7 days) from last dose of trametinib. If a subject is unable to return to the clinic due to hospitalization, site staff are encouraged to 
telephone the subject for assessment of AEs. Secondary follow-up visits should occur at 4 weeks and 8 weeks after the last dose of panitumumab.
4.
Serum pregnancy test should be performed at screening; all subsequent pregnancy tests may be either serum or urine, and performed every 8 to 12 weeks.
5.
Complete physical examination must include integument and genitalia. Note: pelvic exam in female subjects may be completed up to 24 weeks prior to date of first dose. 
Complete and brief physical examinations are defined in Section 6.2.
6.
If within 72 hours of Screening, this assessment does not need to be repeated on Day 1.


Novartis
Confidential
Page 251
Clinical Study Protocol Version 05
Protocol No. MEK116833
7.
Single ECGs will be collected prior to dosing.
8.
Blood samples (2 mL) for PK analysis of trametinib will be collected on Day 1 and on Day 15 predose (within 30 minutes of dosing) and at 1, 2 and 4 hours after administration. 
Blood samples (4 mL) for PK analysis of panitumumab will be collected on Day 1 and on Day 15 predose (within 30 minutes of dosing with panitumumab) and at 1 hour ( at the 
end of infusion of panitumumab). A single 4 mL blood sample for analysis of panitumumab will be collected pre-dose on Day 21 during the clinic visit. During the continuation 
phase, PK samples (for trametinib and panitumumab) will be collected pre-dose at Week 8, Week 12, Week 16, and Week 20. PK blood samples for trametinib, and panitumumab 
analysis should be collected along with the tumor biopsy taken at progression. On days when serial PK samples are collected, subjects should be instructed to hold doses of 
trametinib, report to the clinic for the predose PK blood draw, then dose with trametinib. Collect PK samples at the time indicated 5 minutes up to 2 hour sample, 20 minutes up 
to the 4 hour sample. 
9.
Collection of on-treatment tumor biopsy for subjects with accessible tumors. On-treatment biopsy may be collected 2 to 4 hours after dosing with oral study medication from Day 
15 to Day 18. Biopsies should be performed on non-target lesions when possible. PK samples for trametinib and panitumumab analysis will be collected at the time of the post-
dose tumor biopsy (24 hours) (unless the post-dose biopsy occurs on the same day that the Day 15 serial PK samples are collected).
10. Tumor biopsy at tumor progression in subjects who have had a response is highly encouraged. PK blood samples for trametinib, and panitumumab analysis should be collected 
along with the tumor biopsy taken at progression.
11. CT is the preferred method to measure lesions selected for response assessment. Refer to Appendix 4 for additional information regarding Response Evaluation Criteria In Solid 
Tumors (RECIST) version 1.1 methodology and criteria. Even if study treatment is withdrawn, radiographic disease assessments (computed tomography [CT] or magnetic 
resonance imaging [MRI], as appropriate according to the method used at baseline) should continue every 8 weeks until documented disease progression, the start of new anti-
cancer therapy, withdrawal of consent or death.
12. Collection of archived tumor tissue or fresh tumor biopsies is required for enrollment; if a fresh tumor biopsy is collected at screening, this tissue may be used for the day 1/ 
predose tumor biopsy. 
The Day 1/predose tumor biopsy may be collected 
at any point after signing consent, up to 14 days prior to first dose.
13. Vital signs and temperature should be measured within 30 minutes prior to initiation and upon completion of the panitumumab infusion (up to 15 minutes after the end of infusion).
 
15. Collection of archived tumor tissue or fresh tumor biopsies and determination of the subject’s tumor BRAF mutation status is required for enrollment; if a fresh tumor biopsy is 
collected during screening and up to prior to dosing on Day1 for BRAF mutation confirmation, this tissue may be used for the day 1/ predose tumor biopsy. 
 
  The Day 1/predose tumor biopsy may be collected at any point after signing consent, 
after completing wash-out from prior therapies (either 5 half-lives or 14 days from last dose of prior therapy). Pre- and post-dose tumor biopsies are mandatory. If the patient’s 
tumors are inaccessible for biopsy, permission to enroll must be granted by the GSK Medical Monitor
16. After study treatment is withdrawn, disease assessments (the method used at baseline) should continue every 8 weeks until documented disease progression, the start of new
anti-cancer therapy, withdrawal of consent, or death
17. ECHO is preferred. MUGA may be used only if ECHO is not available. The same method must be used consistently from screening throughout the study.


Novartis
Confidential
Page 252
Clinical Study Protocol Version 05
Protocol No. MEK116833
REVISED TEXT
SECTION 3.11.4
Part 4 Dose Escalation and Cohort Expansion
Day:
Screening1
Screening1
First treatment period,
Day 1 thru Day 28/end of 
Week 4
Continuation 
phase 
Day 29/start of 
Week 52
(7 Days)
Initial 
follow-up3
Secondary follow-
up3
Tertiary follow-up3
Visit Window 
(relative to Day 1)
-35 to -1 
days
-14 to -1 
days
on Day 1
on Day 
15
(2 
days)
on 
Day 
21
(2 
days)
14 (7) 
days from 
last dose of 
trametinib
4 weeks (7 days) 
after the last dose 
of panitumumab
8 weeks (7 days) 
after the last dose 
of panitumumab
Informed Consent
X
Demographics
X
Collection of archival tissue14
X
Complete physical5
X
X
Brief physical5
X
X
At Week 4, then 
every 4 wks
Medical/medication/
drug/alcohol history
X
X6
X
X
Concurrent medications
X
X
X
X
X
At Week 4, 
then every 4 
weeks
X
X
12-lead ECG7
X
X6
X
X
At Week 4, then 
every 4 weeks 
until Week 24, 
then every 8 
weeks
X
Vital signs 12 (including weight)
X
X
X
X
X13
X
Height
X
Ophthalmic examination
X
At Week 4, then 
as 
symptomatically 
warranted
ECOG
X
X6
At Week 4, then 
every 4 wks
X


Novartis
Confidential
Page 253
Clinical Study Protocol Version 05
Protocol No. MEK116833
Day:
Screening1
Screening1
First treatment period,
Day 1 thru Day 28/end of 
Week 4
Continuation 
phase 
Day 29/start of 
Week 52
(7 Days)
Initial 
follow-up3
Secondary follow-
up3
Tertiary follow-up3
Visit Window 
(relative to Day 1)
-35 to -1 
days
-14 to -1 
days
on Day 1
on Day 
15
(2 
days)
on 
Day 
21
(2 
days)
14 (7) 
days from 
last dose of 
trametinib
4 weeks (7 days) 
after the last dose 
of panitumumab
8 weeks (7 days) 
after the last dose 
of panitumumab
ECHO/MUGA16
X
At Week 4, then 
at Week 12, then 
every 12 weeks
X
Serum or urine pregnancy test 
(-hCG;women)4
X
Every 8 to 12 
weeks4
Hematology/Clinical 
ChemistryHema/Chem/Urinalysis 
tests
X
X6
At Week 4,
then every 4 
weeks until Week 
24, then every 8 
weeks
X
X
Urinalysis
X
X6
X
Coagulation
Repeat as clinically indicated
X
CEA
X
X
At Week 64, 
then every 64
weeks until Week 
24, then every 8 
weeks
X
X
Tumor biopsy159
X (pre-dose)159
X9 (to be 
collected 
from 
Day 15 
to Day 
18)
X11
(at 
progression)


Novartis
Confidential
Page 254
Clinical Study Protocol Version 05
Protocol No. MEK116833
Day:
Screening1
Screening1
First treatment period,
Day 1 thru Day 28/end of 
Week 4
Continuation 
phase 
Day 29/start of 
Week 52
(7 Days)
Initial 
follow-up3
Secondary follow-
up3
Tertiary follow-up3
Visit Window 
(relative to Day 1)
-35 to -1 
days
-14 to -1 
days
on Day 1
on Day 
15
(2 
days)
on 
Day 
21
(2 
days)
14 (7) 
days from 
last dose of 
trametinib
4 weeks (7 days) 
after the last dose 
of panitumumab
8 weeks (7 days) 
after the last dose 
of panitumumab
AE assessment
CONTINUOUS
PK blood sample8
X
X
X
Predose, at Week 
4
Panitumumab Dosing
X
X
X
every 2 weeks 
from Day 1
Trametinib dosing
X
X
X
XCONTINUOUS 
daily dosing; 
Trametinib once 
daily should be 
administered 
under fasting 
conditions, 
either one hour 
before or 2 
hours after a 
meal.


Novartis
Confidential
Page 255
Clinical Study Protocol Version 05
Protocol No. MEK116833
Day:
Screening1
Screening1
First treatment period,
Day 1 thru Day 28/end of 
Week 4
Continuation 
phase 
Day 29/start of 
Week 52
(7 Days)
Initial 
follow-up3
Secondary follow-
up3
Tertiary follow-up3
Visit Window 
(relative to Day 1)
-35 to -1 
days
-14 to -1 
days
on Day 1
on Day 
15
(2 
days)
on 
Day 
21
(2 
days)
14 (7) 
days from 
last dose of 
trametinib
4 weeks (7 days) 
after the last dose 
of panitumumab
8 weeks (7 days) 
after the last dose 
of panitumumab
Disease assessments12
x
Every 6 weeks 
until Week 24,
then every 8 
weeks. 15
Long-term survival follow-up
X18
AE, Adverse Event; BP, blood pressure; CEA, ; ECHO, echocardiogram; ECG, electrocardiogram; ECOG, Eastern Cooperative Oncology Group; HR, heart rate; MUGA, 
1.
SCREENING ASSESSMENTS:  All screening assessments must be completed within 14 days prior to first dose except informed consent, ophthalmology exam, dermatological 
exam, ECHO/MUGA and Disease Assessment, which can occur within 35 days prior to the first dose. Note: Procedures conducted as part of the subject’s routine clinical 
management (e.g., blood counts, imaging study) and obtained prior to signing of informed consent may be utilized for screening or baseline purposes provided these procedures 
meet the protocol requirements.
2.
TREATMENT PERIOD:  Assessments throughout the study are calendar-based starting from the first day of dosing (Day 1) in the first treatment period.  Dose interruptions should 
not alter the assessment schedule for any subsequent treatment period.  The continuation phase starts with Day 29; eEvents in the continuation phase are allowed 7 days from 
projected date.  Safety lab tests (chemistry/hematology/UA) may be done the day before the visit so that results are available on the day of the visit, but all assessments should be 
done within the 7 day window.
3.
FOLLOW-UP VISIT:  Initial follow-up visit should be 14 days (7 days) from last dose of trametinib. If a subject is unable to return to the clinic due to hospitalization, site staff are 
encouraged to telephone the subject for assessment of AEs. Secondary follow-up visits should occur at 4 weeks and 8 weeks after the last dose of panitumumab.  Subjects are to 
be followed until progression for collection of PFS data and until death for collection of overall survival (OS) data.  If a subject who is eligible for crossover to the triplet combination 
has not crossed over by 14 days past the last dose of study treatment, the Initial Follow-Up assessments should be done.  If a subject who is eligible for crossover to the triplet 
combination has not crossed over by 4 weeks past the last dose of panitumumab, the Secondary Follow-Up assessments should be done.
4.
PREGNANCY TEST:  Serum pregnancy test should be performed at screening; all subsequent pregnancy tests may be either serum or urine, and performed every 8 to 12 weeks.
5.
PHYSICAL EXAMINATION:  Complete physical examination must include integument and genitalia. Note: pelvic exam in female subjects is not required in Part 4 may be 
completed up to 24 weeks prior to date of first dose. Complete and brief physical examinations are defined in Section 6.2.
6.
PHYSICAL EXAMINATION:  If within 72 hours of Screening, this assessment does not need to be repeated on Day 1.
7.
ECG:  Single ECGs will be collected prior to dosing.
8.
PHARMACOKINETIC SAMPLES:  Blood samples (2 mL) for PK analysis of trametinib will be collected on Day 1 and on Day 15 predose (within 30 minutes of dosing) and at 1, 2 
and 4 hours after administration. Blood samples (4 mL) for PK analysis of panitumumab will be collected on Day 1 and on Day 15 predose (within 30 minutes of dosing with 
panitumumab) and at 1 hour ( at the end of infusion of panitumumab). A single 4 mL blood sample for analysis of panitumumab will be collected pre-dose on Day 21 during the 


Novartis
Confidential
Page 256
Clinical Study Protocol Version 05
Protocol No. MEK116833
clinic visit. During the continuation phase, PK samples (for trametinib and panitumumab) will be collected pre-dose at Week 8, Week 12, Week 16, and Week 20. PK blood 
samples for trametinib, and panitumumab analysis should be collected along with the tumor biopsy taken at progression. On days when serial PK samples are collected, subjects 
should be instructed to hold doses of trametinib, report to the clinic for the predose PK blood draw, then dose with trametinib. Collect PK samples at the time indicated 5 minutes 
up to 2 hour sample, 20 minutes up to the 4 hour sample. 
9.
TUMOR TISSUE SAMPLE/DAY1:  Collection of archived tumor tissue or fresh tumor biopsies and determination of the subject’s tumor BRAF mutation status is required for 
enrollment; if a fresh tumor biopsy is collected during screening and up to prior to dosing on Day1 for BRAF mutation confirmation, this tissue may be used for the day 1/ predose 
tumor biopsy. 
  The Day 1/predose tumor biopsy may be collected at any point 
after signing consent, after completing wash-out from prior therapies (either 5 half-lives or 14 days from last dose of prior therapy). Pre- and post-dose tumor biopsies are 
mandatory. If the patient’s tumors are inaccessible for biopsy, permission to enroll must be granted by the GSK Medical Monitor
10. BIOPSY:  Collection of on-treatment tumor biopsy for subjects with accessible tumors. On-treatment biopsy may be collected 2 to 4 hours after dosing with oral study medication 
from Day 15 to Day 18. Biopsies should be performed on non-target lesions when possible. PK samples for trametinib and panitumumab analysis will be collected at the time of 
the post-dose tumor biopsy (24 hours) (unless the post-dose biopsy occurs on the same day that the Day 15 serial PK samples are collected).
11. BIOPSY:  Tumor biopsy at tumor progression in subjects who have had a response is highly encouraged. PK blood samples for trametinib and panitumumab analysis should be 
collected along with the tumor biopsy taken at progression.
12. DISEASE ASSESSMENT:  CT is the preferred method to measure lesions selected for response assessment. Refer to Appendix 4 for additional information regarding Response 
Evaluation Criteria In Solid Tumors (RECIST) version 1.1 methodology and criteria. Even if study treatment is withdrawn, radiographic disease assessments (computed 
tomography [CT] or magnetic resonance imaging [MRI], as appropriate according to the method used at baseline) should continue every 8 weeks until documented disease 
progression, the start of new anti-cancer therapy, withdrawal of consent or death.
13. Collection of archived tumor tissue or fresh tumor biopsies is required for enrollment; if a fresh tumor biopsy is collected at screening, this tissue may be used for the day 1/ 
predose tumor biopsy. 
 The Day 1/predose tumor biopsy may be collected 
at any point after signing consent, up to 14 days prior to first dose.
14. VITAL SIGNS:  Vital signs and temperature should be measured within 30 minutes prior to initiation and upon completion of the panitumumab infusion (up to 15 minutes after the 
end of infusion).
 
16. Collection of archived tumor tissue or fresh tumor biopsies and determination of the subject’s tumor BRAF mutation status is required for enrollment; if a fresh tumor biopsy is 
collected during screening and up to prior to dosing on Day1 for BRAF mutation confirmation, this tissue may be used for the day 1/ predose tumor biopsy. 
 
  The Day 1/predose tumor biopsy may be collected at any point 
after signing consent, after completing wash-out from prior therapies (either 5 half-lives or 14 days from last dose of prior therapy). Pre- and post-dose tumor biopsies are 
mandatory. If the patient’s tumors are inaccessible for biopsy, permission to enroll must be granted by the GSK Medical Monitor
17. DISEASE ASSESSMENT:  After study treatment is withdrawn, disease assessments (the method used at baseline) should continue every 8 weeks until documented disease 
progression, the start of new
anti-cancer therapy, withdrawal of consent, or death
18. ECHO:  ECHO is preferred. MUGA may be used only if ECHO is not available. The same method must be used consistently from screening throughout the study.
20. OVERALL SURVIVAL:  Subjects will be followed for Overall Survival every 8 weeks after last dose of study drugs. See Section 6.3.1.for additional information.
RATIONALE:  Update Time and Events Table footnote with label and include Overall Survival follow up.


Novartis
Confidential
Page 257
Clinical Study Protocol Version 05
Protocol No. MEK116833
SECTION 3.11.5
Intra-Subject Crossover Time and Event Tables
ADDITIONAL TEXT
3.11.5.1
Intra-subject Doublet to Triplet Crossover
Crossover 
Screening1
Crossover
Day 1
Crossover Treatment Phase2
(7 days)
Initial 
Follow-up3
Secondary Follow-up3
4 weeks (7 
days) after the 
last dose of 
panitumumab
8 weeks (7 
days) after the 
last dose of 
panitumumab
Medical history/ 
Interim History
X
Every 4 weeks 
X
Concurrent
Medications
X
At Week 4, 
then every 4 weeks 
X
Serum or urine 
pregnancy test (-
hCG; women) 
Every 8 to 12 weeks
X
Physical 
examination4
X
Every 4 weeks 
X4
Dermatological 
examination5
X
At Week 4, 
then every 8 weeks
More frequently if there are new or changing lesions
X
Weight
X
Every 4 weeks 
X
Ophthalmic 
examination
X
at Week 4, 
then as symptomatically warranted
X
ECOG Performance 
Status
X
Every 4 weeks 
X
Vital signs (BP, HR, 
Body Temperature)
X
X6
Before and after panitumumab infusion6
X
12-lead ECG
X
At Week 4, 
then every 4 weeks until Week 24, then every 8 weeks
X


Novartis
Confidential
Page 258
Clinical Study Protocol Version 05
Protocol No. MEK116833
Crossover 
Screening1
Crossover
Day 1
Crossover Treatment Phase2
(7 days)
Initial 
Follow-up3
Secondary Follow-up3
4 weeks (7 
days) after the 
last dose of 
panitumumab
8 weeks (7 
days) after the 
last dose of 
panitumumab
Hematology/Clinical 
Chemistry)
X
At Week 4, 
then every 4 weeks until Week 24, then every 8 weeks
X
X
X
Coagulation
As clinically indicated
CEA
X
At Week 6, 
then every 6 weeks until Week 24, then every 8 weeks
X
X
ECHO (or MUGA)7
X
At Week 4, 
then at Week 12 
and every 12 weeks thereafter
X
Panitumumab 
dosing6
X
Every 2 weeks
Dabrafenib and 
trametinib dosing
CONTINUOUS daily dosing; 
Dabrafenib BID and trametinib once daily should be administered under 
fasting conditions, either one hour before or 2 hours after a meal.
Urinalysis
X
AE assessment 
CONTINUOUS
Disease 
Assessment9
X
Every 6 weeks until Week 24, 
then every 8 weeks
X9
X10


Novartis
Confidential
Page 259
Clinical Study Protocol Version 05
Protocol No. MEK116833
Crossover 
Screening1
Crossover
Day 1
Crossover Treatment Phase2
(7 days)
Initial 
Follow-up3
Secondary Follow-up3
4 weeks (7 
days) after the 
last dose of 
panitumumab
8 weeks (7 
days) after the 
last dose of 
panitumumab
Long-term survival 
follow-up
X11
AE, Adverse Event; BP, blood pressure; CEA, ; ECHO, echocardiogram; ECG, electrocardiogram; ECOG, Eastern Cooperative Oncology Group; HR, heart rate; 
MUGA, 
1.
SCREENING ASSESSMENTS:  All screening assessments must be completed within 14 days prior to first crossover dose except ophthalmic exam, dermatological exam, 
ECHO/MUGA, and Disease Assessment, which can occur within 35 days prior to the first dose. Note: Procedures conducted as part of the subject’s initial follow-up assessments 
may be utilized for screening or baseline purposes provided these procedures meet the protocol requirements.
2.
TREATMENT PHASE:  Assessments throughout the study are calendar-based starting from the first day of dosing (Day 1) in the first treatment period.  Dose interruptions should 
not alter the assessment schedule for any subsequent treatment period.  Safety lab tests (chemistry/hematology/coag/UA) may be done the day before the visit so that results are 
ready on the day of the visit, but all assessments should be done within the 7 day window.
3.
FOLLOW_UP VISITS:  Initial follow-up visit should be 14 days from last dose of study drugs (7 days).  If a subject is unable to return to the clinic due to hospitalization, site staff 
are encouraged to telephone the subject for assessment of AEs. Secondary follow-up visits should occur at 4 weeks and 8 weeks after the last dose of panitumumab.  
4.
PHYSICAL EXAM:  A brief physical exam should be conducted at screening and every 4 weeks.  A complete physical examination including integument and genitalia should be 
performed during the initial follow-up visit.  Note: pelvic exam in female subjects may be completed up to 24 weeks prior to date of first dose. Complete and brief physical 
examinations are defined in Section 6.2.
5.
DERMATOLOGICAL EVALUATION:  Baseline skin photography should be performed at Screening. Photographs should be taken of new skin lesions that occur, or skin lesions 
that change on therapy. Refer to Section 6.2. French sites will perform dermatological exams monthly while on-therapy, and monthly for 6 months following discontinuation of 
dabrafenib or until initiation of another anti-neoplastic therapy, whichever comes first. Refer to Appendix 7 for full information.
6.
VITAL SIGNS:  Vital signs and temperature should be measured within 30 minutes prior to initiation and upon completion of the panitumumab infusion (up to 15 minutes after the 
end of infusion).
7.
ECHO:  ECHO is preferred.  MUGA may be used only if ECHO is not available.  The same method must be used consistently from screening throughout the study.
 
.
9.
DISEASE ASSESSMENT:  CT is the preferred method to measure lesions selected for response assessment. Refer to Appendix 4 for additional information regarding RECIST 
1.1 methodology and criteria.  Even if study treatment is withdrawn, radiographic disease assessments (CT or MRI, as appropriate according to the method used at baseline) 
should continue every 8 weeks until documented disease progression, the start of new anti-cancer therapy, withdrawal of consent or death.
10. DISEASE ASSESSMENT:  After study treatment is withdrawn, disease assessments (the method used at baseline) should continue every 8 weeks until documented disease 
progression, the start of new anti-cancer therapy, withdrawal of consent, or death.
11. OVERALL SURVIVAL:  Subjects will be followed for Overall Survival every 8 weeks after last dose of study drugs. See Section 6.3.1.for additional information.


Novartis
Confidential
Page 260
Clinical Study Protocol Version 05
Protocol No. MEK116833
SECTION 4.1
Number of Subjects
PREVIOUS TEXT
The number of dose levels and the level at which the MTD will be reached cannot be 
determined in advance. An adequate number of subjects will be enrolled into the study to 
establish a recommended dose(s) and schedule(s) for the further study of 
dabrafenib/panitumumab and dabrafenib/trametinib/panitumumab combinations.  
To complete Part 1, it is estimated that 24 evaluable subjects (~4 per cohort) will be 
enrolled.  Part 2 will enroll approximately 30 subjects in total. In order to confirm safety 
in Japanese patients, up to three additional Japanese patients may be enrolled in Japan in 
each expansion cohort.  Approximately 20 subjects will be evaluated at the RP2D/R for 
each combination tested by the end of Part 2, including those subjects enrolled at the 
RP2D/R in Part 1. For Part 3, approximately 47 subjects per arm will be enrolled.  For 
Part 4A (dose escalation), it is estimated that up to 18 evaluable subjects (~6 per cohort) 
will be enrolled.  Part 4B (expansion cohorts 1E and 2E) will enroll approximately 17 
additional subjects in each of two expansion cohorts (n=34). This will be a total of 
approximately 20 patients at the RP2D/R for each patient population, including the 
subjects enrolled in Part 4A.
If subjects discontinue the study before completing Week 4, additional subjects may be 
enrolled at the discretion of the Sponsor in consultation with the investigator.
REVISED TEXT
The number of dose levels and the level at which the MTD will be reached cannot be 
determined in advance. An adequate number of subjects will be enrolled into the study to 
establish a recommended dose(s) and schedule(s) for the further study of 
dabrafenib/panitumumab and dabrafenib/trametinib/panitumumab combinations.  
To complete Part 1, it is estimated that 24 evaluable subjects (~4 per cohort) will be 
enrolled.  Part 2 will enroll approximately 30120 subjects in total. In order to confirm 
safety in Japanese patients, up to three additional Japanese patients may be enrolled in 
Japan in each expansion cohort.  By the end of Part 2, approximately 30 subjects will be 
evaluated for each dose cohort.  Approximately 20 subjects will be evaluated at the 
RP2D/R for each combination tested by the end of Part 2, including those subjects 
enrolled at the RP2R in Part 1. For Part 3, approximately 47 subjects per arm will be 
enrolled.  For Part 4A (dose escalation), it is estimated that up to 18 evaluable subjects 
(~6 per cohort) will be enrolled.  Part 4B (expansion cohorts 1E and 2E) will enroll 
approximately 17 additional subjects in each of two expansion cohorts populations 
(n=34). This will be a total of approximately 20 patients at the RP2D/RMTD for each 
patient population, including the subjects enrolled in Part 4A.  In order to confirm safety 
in Japanese patients, three additional Japanese patients may be enrolled in Japan in each 
expansion population for Part 4. Up to an additional 20 subjects with BRAF mutant CRC 
may be enrolled in Part 4 to further explore safety and efficacy of the trametinib plus 
panitumumab doublet.


Novartis
Confidential
Page 261
Clinical Study Protocol Version 05
Protocol No. MEK116833
If subjects discontinue the study before completing Week 4, additional subjects may be 
enrolled at the discretion of the Sponsor in consultation with the investigator.
RATIONALE:  Enrolment updated to include the additional subjects of Part 2B and 
allow for additional subjects from Japan to be enrolled in Part 4B.
SECTION 4.2.1.2
Part 1, Part 2, and Part 4 Exclusion Criteria
ADDITIONAL TEXT
9.
Part 2B ONLY: Patients treated with > 4 prior lines of therapy for metastatic 
disease will not be eligible.
RATIONALE:  Additional exclusion criteria to limit the number of prior lines of 
therapy for subjects enrolled into Part 2B to collect data on a more homogeneous patient 
population.
SECTION 5.2.1.1
Part 1 and Part 4 Dose Escalation
PREVIOUS TEXT
The total number of subjects in Part 1 and Part 4 dose escalation will depend on the 
number of dose escalations needed. However, the maximum anticipated number of 
subjects will be approximately 24 in Part 1 and approximately 12 in Part 4 dose 
escalation. 
REVISED TEXT
The total number of subjects in Part 1 and Part 4 dose escalation will depend on the 
number of dose escalations needed. However, the maximum anticipated number of 
subjects will be approximately 24 in Part 1 and approximately 12 22 in Part 4 dose 
escalation. 
RATIONALE:  Change to allow for dose de-escalation in Part 4A.
SECTION 5.1.2
Part 2 and Part 4 Cohort Expansion
PREVIOUS TEXT
For Part 2 and Part 4 cohort expansion, efficacy will be evaluated for each cohort to 
decide whether to proceed with further development based on the clinical activity seen in 
Part 1. Futility analysis criteria at the end of Part 2 and Part 4 will be based on 2-stage 
Green-Dahlberg design’s [Green, 1992] interim analysis criteria.  The criteria will be 
based on a historically unimportant response rate of 15% versus a response rate of 
interest of 30%. The Part 2 and Part 4B portion of the study will employ a Bayesian 
design that allows the trial to be monitored more frequently at multiple stages. Bayesian 
statistics will be employed to calculate the predictive probability that the response rate 
≥30% and ≥15% at interim assuming a Beta prior for the Binomial distributed data.  
Predictive probability calculates the probability that the response rate ≥30% or ≥15% at 
the end of Part 2 (after 20 subjects) given the responses have already been observed.  It 


Novartis
Confidential
Page 262
Clinical Study Protocol Version 05
Protocol No. MEK116833
predicts what is likely to happen at the end of Part 2 and Part 4 so is more meaningful and 
straightforward than posterior probability.  A weak prior Beta (0.003, 0.007) is used, 
which is equivalent to the information present in 0.01 subject. Futility analysis criteria 
based on 2-stage Green-Dahlberg design’s are only used at the end of Part 2 and Part 4B 
when all subjects are enrolled. Bayesian design based criteria are only used for interim 
data monitoring before the end of Part 2 or Part 4B data analysis allowing early stop for 
futility.  An initial total of 10 subjects will be recruited at a dose level based on the 
recommended dose for each treatment/cohort (including the subjects treated in Part 1 or 
Part 4A at the same dose with the same mutation status).  The number of subjects will be 
increased up to a total of 20 per treatment cohort depending on the results observed.  The 
tables below show the decision rules for the 10th to 19th evaluable subjects, specifying the 
number of subjects with a confirmed response needed for continuing enrolment or 
stopping for futility.  The methodology is based on the predictive probability of success if 
enrolment continues to 20 subjects [Lee, 2008].  These rules are intended as a guideline.  
Actual decisions will depend on the totality of the data.
Table 24 Decision Making Criteria at Interim Analysis for Futility and 
Efficacy
Number of Evaluable 
Patients 
This Number of Confirmed 
Responses  to Stop Early for 
Futility
This Number of Confirmed 
Responses to Declare 
ORR≥0.3
10
0
5
11
0
5
12
0
6
13
0
6
14
0
6
15
0
7
16
1
7
17
1
7
18
1
8
19
1
8
For the interim looks in each cohort separately, if the predictive probability that the 
confirmed response rate ≥15% (historical control) is small (i.e., less than 10% chance), or 
equivalent to observe no confirmed response in the first enrolled 10-15 evaluable subjects 
in that cohort (e.g., after they have either progressed, or withdrew from the study, or lost 
to follow-up, or ongoing but have completed at least one post treatment disease 
assessment) and observe less than 1 confirmed response in the first 16-19 evaluable 
subjects, the enrollment for that cohort may be stopped due to futility. Otherwise, the 
enrolment of the respective cohort will continue to the target sample size of 20. If the 
predictive probability that the response rate of ≥30% is large (i.e., greater than 80% 
chance), strong statistical evidence has been provided in favor of further development of 
the treatment for the target population.
When at least 4 responders out of 20 subjects are observed in a treatment arm, after each 
subject has been followed at least 12 weeks, further development of the corresponding 


Novartis
Confidential
Page 263
Clinical Study Protocol Version 05
Protocol No. MEK116833
treatment in Part 3 will follow.  If less than 4 responders are observed, the accrued 
efficacy data will be evaluated for possibility of further development to Part 3.
The final decision with respect to continuation of the trial to Part 3 will be made by the 
Sponsor based on safety considerations as well as available efficacy data with input from 
participating investigators.
REVISED TEXT
For Part 2 and Part 4 cohort expansion, efficacy will be evaluated for each cohort to 
decide whether to proceed with further development based on the clinical activity seen in 
Part 1 and Part 4.  Analyses will be descriptive 
  Subjects treated with the 
same starting dose will be analysed together.  
Futility analysis criteria at the end of Part 2 and Part 4 will be based on 2-stage Green-
Dahlberg design’s [Green, 1992] interim analysis criteriabased on Bayesian predictive 
adaptive design [Lee, 2008].  The criteria will be based on a historically unimportant 
response rate of 15% versus a response rate of interest of 30%.  The Part 2 and Part 4B
portion of the study will employ a Bayesian design that allows the trial to be monitored 
more frequently at multiple stages. Bayesian statistics will be employed to calculate the 
predictive probability that the response rate ≥30% and ≥15% at interim assuming a Beta 
prior for the Binomial distributed data.  Predictive probability calculates the probability 
that the response rate ≥30% or ≥15% at the end of Part 2 (after 20 subjects) given the 
responses have already been observed.  It predicts what is likely to happen at the end of 
Part 2 and Part 4 so is more meaningful and straightforward than posterior probability.  A 
weak prior Beta (0.003, 0.007) is used, which is equivalent to the information present in 
0.01 subject. Futility analysis criteria based on 2-stage Green-Dahlberg design’s are only 
used at the end of Part 2 and Part 4B when all subjects are enrolled. Bayesian design 
based criteria are only used for interim data monitoring before the end of Part 2 or Part 
4B data analysis allowing early stop for futility.  An initial total of 10 subjects will be 
recruited at a dose level based on the recommended dose for each treatment/cohort 
(including the subjects treated in Part 1 or Part 4A at the same dose with the same 
mutation status).  The number of subjects will be increased by 30up to a total of 20 10055
per treatment cohort depending on the results observed.  Table 25The tables below shows
the decision rules for the 10th to 19th evaluable subjects, specifying the number of subjects 
with a confirmed response needed for continuing enrolment or stopping for futility when 
total sample size is 20.  The methodology is based on the predictive probability of 
success if enrolment continues to 20 subjects [Lee, 2008].   Table 26 shows the decision 
rules for the 10th to 54th evaluable subjects, specifying the number of subjects with a 
confirmed response needed for continuing enrolment or stopping for futility when total 
sample size is 55.  These rules are intended as a guideline.  Actual decisions will depend 
on the totality of the data.


Novartis
Confidential
Page 264
Clinical Study Protocol Version 05
Protocol No. MEK116833
Table 2524
Decision Making Criteria at Interim Analysis for Futility and 
Efficacy when enrolling up to 20 subjects
Number of Evaluable 
Patients 
This Number of Confirmed 
Responses  to Stop Early for 
Futility
This Number of Confirmed 
Responses to Declare 
ORR≥0.3
10
0
5
11
0
5
12
0
6
13
0
6
14
0
6
15
0
7
16
1
7
17
1
7
18
1
8
19
1
8
Table 25 Sample sizes for different analysis cohorts using Bayesian 
predictive adaptive design.
Part
Cohorts/Population
Target 
sample size
Minimum sample 
size needed for first 
interim analysis
Part 1 and Part 2
D 150mg BID+P 6mg/kg
20
10
Part 1 and Part 2
D 150mg BID+ T 2mg QD +P 6mg/kg
54
10
Part 1 and Part 2
D 150mg BID+T 2mg QD+P 6mg/kg 1L
10-15
10
Part 1 and Part 2
D 150mg BID+T 2mg QD+P 6mg/kg 2L-4L
40-44
10
Part 1 and Part 2
D 150mg BID+T 2mg QD+P 4.8mg/kg
34
10
Part 1 and Part 2
D 150mg BID+T 2mg QD+P 4.8mg/kg 1L
10-14
10
Part 1 and Part 2
D 150mg BID+T 2mg QD+P 4.8mg/kg 2L-4L
20-24
10
Part 4
T+P Anti-EGFR CRC population
20
10
Part 4
T+ P BRAF+ CRC population
20-40
10
Table 26 Decision Making Criteria at Interim Analysis for Futility when 
enrolling up to 55 subjects
Number of Evaluable 
Subjects 
This Number of 
Confirmed Responses  
to Stop Early for 
Futility
Probability of 
continuing when 
ORR=0.15 
Probability of 
continuing when 
ORR=0.3 
10
0
0.8031
0.9718
11
0
0.8031
0.9718
12
0
0.8031
0.9718
13
0
0.8031
0.9718
14
0
0.8031
0.9718


Novartis
Confidential
Page 265
Clinical Study Protocol Version 05
Protocol No. MEK116833
Number of Evaluable 
Subjects 
This Number of 
Confirmed Responses  
to Stop Early for 
Futility
Probability of 
continuing when 
ORR=0.15 
Probability of 
continuing when 
ORR=0.3 
15
0
0.8031
0.9718
16
1
0.6721
0.9575
17
1
0.6721
0.9575
18
1
0.6721
0.9575
19
1
0.6721
0.9575
20
1
0.6721
0.9575
25
2
0.5943
0.9522
30
3
0.5203
0.9476
35
4
0.4559
0.9439
40
5
0.4009
0.941
45
6
0.3457
0.9378
50
8
0.2430
0.9298
54 
10 
0.1471 
0.9144 
For the interim looks in each cohort separately, if the predictive probability that the 
confirmed response rate ≥15% (historical control) is small (i.e., less than 10% chance), or 
equivalent to observe no confirmed response in the first enrolled 10-15 evaluable subjects 
in that cohort (e.g., after they have either progressed, or withdrew from the study, or lost 
to follow-up, or ongoing but have completed at least one post treatment disease 
assessment) and observe less than 1 confirmed response in the first 16-19 evaluable 
subjects, the enrollment for that cohort may be stopped due to futility.For the separate 
interim looks in each cohort, the enrollment for that cohort may be stopped due to futility 
if the predictive probability that the confirmed response rate ≥15% (historical control) is 
small (e.g., less than 10% chance for a total sample size of 20 subjects or less than a 2% 
chance for a total sample size of 54 subjects). Enrollment may also be stopped due to 
futility if the equivalent of no confirmed response is observed in the first 10-15 enrolled 
evaluable subjects in that cohort or less than 1 confirmed response is observed in the first 
16-19 evaluable subjects. For example, if all (10-15) or all but one (16-19) of the 
subjects have either progressed, withdrew from the study, were lost to follow-up, or are 
ongoing and have completed at least one post treatment disease assessment without a 
confirmed response then the cohort may be stopped for futility.  Otherwise, the enrolment 
of the respective cohort will continue to the target sample sizeof 20. If the predictive 
probability that the response rate of ≥30% is large (i.e., greater than 80% chance) is 
observed during the interim looks, strong statistical evidence has been provided in favor 
of further development of the treatment for the target population.
When the total sample size in a treatment arm/cohort is 20 and at least 4 2 confirmed 
responders out of 20 subjects are observed in a treatment arm, after each subject has been 
followed at least 12 weeks, further development of the corresponding treatment in Part 3 
maywill follow.  If less than 4 responders are observed, the accrued efficacy data will be 
evaluated for possibility of further development to Part 3.


Novartis
Confidential
Page 266
Clinical Study Protocol Version 05
Protocol No. MEK116833
When the total sample size in a cohort is 55 and at least 12 confirmed responders out of 
55 subjects are observed, after each subject has been followed at least 12 weeks, further 
development of the corresponding treatment in Part 3 may follow. 
RATIONALE:  Update sample size to add Part 2B and update decision making criteria 
rules based on the addition of Part 2B subjects
SECTION 5.2.1.2
Part 2 and Part 4 Cohort Expansions
PREVIOUS TEXT
Part 2 will enroll approximately 30 subjects in total.  Approximately 40 subjects will be 
evaluated at the end of Part 2, including those enrolled in Part 1 at the same dose levels. 
Part 4 cohort expansion will enroll approximately 40 subjects in total (20 subjects in 
Cohort 1E and 20 subjects in Cohort 2E). For each cohort, approximately 20 subjects will 
be evaluated separately at the end of Part 4, including those enrolled in dose escalation at 
the same dose levels and the same mutation status.
To determine the maximum sample size for each cohort, a traditional, 2-stage Green-
Dahlberg design [Green, 1992] was evaluated and the sample size for the first stage will 
be used for the futility analysis.  To test the hypotheses (RR=30% vs RR=15%), using a 
Green-Dahlberg design, 20 subjects per arm would be needed for Stage 1 (assuming a 
type 1 error of 5% and power of 95%). The chance to effectively terminate the trial after 
20 subjects due to futility (true RR=15%) is 65%; the risk to incorrectly stop the trial 
after 20 subjects if the treatment is effective (true RR =40%) is less than 2% (Table 26).
Table 26
Futility Analysis Design Performance
True RR
Probability of Early Termination, after 20 pts 
15%
0.648
20%
0.411
30%
0.107
40%
0.016
A Bayesian posterior probability will also be calculated to further inform decision 
making.   Since neither BRAF in combination with panitumumab nor MEK in 
combination with BRAF and panitumumab has been tested previously in the clinic in 
CRC subjects, a Beta (0.003, 0.007) prior is assumed.  This prior is equivalent to the prior 
information from 0.01 subject.  The posterior probabilities of RR exceeding 20%, 30% 
and 40% based on 20 subjects are shown in Table 27.


Novartis
Confidential
Page 267
Clinical Study Protocol Version 05
Protocol No. MEK116833
Table 27 Bayesian Posterior Probabilities of Response Rate for Given 
Number of Observed Responses
# of Responses Observed out 
of 20 Subjects
Posterior Probability 
RR ≥20%
Posterior Probability 
RR ≥30%
Posterior Probability RR 
≥40%
4
0.45
0.14
0.024
5
0.69
0.29
0.075
6
0.83
0.48
0.17
7
0.93
0.66
0.31
8
0.97
0.81
0.49
Using this sample size, a Bayesian design that allows the trial to be monitored more 
frequently at multiple stages was evaluated. A Bayesian analysis expresses uncertainty 
about a parameter in terms of probability. A prior is defined to characterize the level of 
knowledge about a parameter before the data are collected. Once the data are collected, a 
posterior distribution is formed using the prior and the likelihood (i.e., the data). Since 
none of the treatment has been tested previously in the clinic in the target population, a 
weak prior Beta (0.003, 0.007) is assumed. Thus, the posterior distribution for the 
response rate will be primarily driven by the data and can be derived as follows: Let p 
denote the response rate for the treatment, the number of responses in the current n 
patients, x, follows a binomial distribution, Binomial (n, p). Taking the Bayesian method 
and combining the weak prior and the likelihood of the observed data x, the posterior 
distribution of the response rate follows a beta distribution, i.e., p Beta (0.003 + x, 
0.007 + n-x) with the posterior mean (0.003 + x)/(0.01 + n). 
Based on this posterior distribution of the response rate, the predictive probability that the 
response rate >15% or ≥30% after 19 subjects will be calculated for decision-making as 
described in the Section 5.1.2 (Hypotheses). The decision rule and a minimal required 
sample size of 10 patients for the first interim look is determined to generate the design 
that leads to a reasonable chance of early termination due to futility.
The design property, by utilizing the decision rule specified in Section 5.1.2, and sample 
size of 20 patients are shown (Table 28). The probability of early termination of the trial 
is calculated by simulations. The probability of early termination after the first 19 
evaluable subjects is 33% under the null hypothesized response rate, and the risk to 
incorrectly stop the trial early if the drug is effective is approximately 5%. Thus, the 
study will employ the Bayesian design that allows the trial to be monitored more 
frequently at multiple stages with the constraint of satisfactory stop for futility rate.
Table 28
Bayesian Design Performance by Response Rate
If True Response Rate to
The Treatment is: (%) 
Prob (early stop for futility) 
0.15
0.326
0.2
0.180
0.3
0.047


Novartis
Confidential
Page 268
Clinical Study Protocol Version 05
Protocol No. MEK116833
REVISED TEXT
Part 2 will enroll approximately 30up to 115 subjects in total.  Approximately 40 subjects
will be evaluated at the end of Part 2, includingThis will include those enrolled in Part 1 
at the same dose levels. Each population and dose cohort will be evaluated separately.  
Part 4 cohort expansion will enroll approximately 40-60 subjects in total (20 subjects in 
Cohort 1Ethe anti-EGFR acquired resistance CRC population and 20-40 subjects in the 
BRAF mutant CRC populationCohort 2E). Subjects will be evaluated separately by dose 
cohort and population at the end of Part 4For each cohort, approximately 20 subjects will 
be evaluated separately at the end of Part 4, including those enrolled in dose escalation at 
the same dose levels and the same mutation status.
To determine the maximum sample size for each dabrafenib in combination with 
panitumumab expansion cohort, cohort1E and cohort 2E in cohort 4and trametinib in 
combination with panitumumab expansion cohort, a traditional, 2-stage Green-Dahlberg 
design [Green, 1992] was evaluated and the sample size for the first stage will be used for 
the futility analysis. To test the hypotheses (RR=30% vs RR=15%), using a Green-
Dahlberg design, 20 subjects per arm would be needed for Stage 1 (assuming a type 1 
error of 105% and power of 8095%).  The chance to effectively terminate the trial after 
20 subjects due to futility (true RR=15%) is 3365%; the risk to incorrectly stop the trial 
after 20 subjects if the treatment is effective (true RR =40%) is less than 12% (Table 
28Table 26).  To determine the maximum sample size for any cohort or population in 
trametinib plus dabrafenib in combination with panitumumab, Bayesian predictive 
adaptive design will be used for testing hypotheses:
H0: RR≤15%
HA:RR≥30%
When maximum sample size is 55, the design will have a Type I error () of 0.10 and 
89% power with the probability of termination is 0.898 when the treatment is futile and 
probability of early termination 0.104 when the treatment is effective (true RR=0.3).
Table 2826
Futility Analysis Design Performance
True RR
Probability of Early Termination, after 20 pts 
Probability of Termination, after 55 pts
15%
0.3290.648
0.898
20%
0.1800.411
0.619
30%
0.0440.107
0.104
40%
0.0070.016
0.010
A Bayesian posterior probability will also be calculated to further inform decision 
making.   Since neither BRAF dabrafenib in combination with panitumumab, trametinib 
in combination with panitumumab, nor MEK trametinib in combination with BRAF 
dabrafenib and panitumumab has been tested previously in the clinic in CRC subjects, a 
Beta (0.003, 0.007) prior is assumed.  This prior is equivalent to the prior information 
from 0.01 subject.  The posterior probabilities of RR exceeding 20%, 30% and 40%


Novartis
Confidential
Page 269
Clinical Study Protocol Version 05
Protocol No. MEK116833
based on 20 subjects and the posterior probabilities of RR exceeding 20%, 30% and 40%
based on 55 subjects are shown in Table 29Table 27.
Table 2927
Bayesian Posterior Probabilities of Response Rate for Given 
Number of Observed Responses
# of Responses Observed out 
of 20 Subjects
Posterior Probability 
RR ≥20%
Posterior Probability 
RR ≥30%
Posterior Probability RR 
≥40%
4
0.45
0.14
0.024
5
0.69
0.29
0.075
6
0.83
0.48
0.17
7
0.93
0.66
0.31
8
0.97
0.81
0.49
# of Responses Observed out 
of 55 Subjects
Posterior Probability 
RR ≥20%
Posterior Probability 
RR ≥30%
Posterior Probability RR 
≥40%
11
0.47
0.04
0.001
12
0.61
0.08
0.002
13
0.73
0.13
0.005
14
0.82
0.21
0.011
15
0.89
0.31
0.022
16
0.94
0.43
0.043
17
0.97
0.54
0.076
Using thesethis sample sizes, a Bayesian design that allows the trial to be monitored more 
frequently at multiple stages was evaluated. A Bayesian analysis expresses uncertainty 
about a parameter in terms of probability. A prior is defined to characterize the level of 
knowledge about a parameter before the data are collected. Once the data are collected, a 
posterior distribution is formed using the prior and the likelihood (i.e., the data). Since 
none of the treatment has been tested previously in the clinic in the target population, a 
weak prior Beta (0.003, 0.007) is assumed. Thus, the posterior distribution for the 
response rate will be primarily driven by the data and can be derived as follows: Let p 
denote the response rate for the treatment, the number of responses in the current n 
patients, x, follows a binomial distribution, Binomial (n, p). Taking the Bayesian method 
and combining the weak prior and the likelihood of the observed data x, the posterior 
distribution of the response rate follows a beta distribution, i.e., p Beta (0.003 + x, 
0.007 + n-x) with the posterior mean (0.003 + x)/(0.01 + n). 
Based on this posterior distribution of the response rate, the predictive probability that the 
response rate >15% or ≥30% after 19 or 54 subjects will be calculated for decision-
making as described in the Section 5.1.2 (Hypotheses). The decision rule and a minimal 
required sample size of 10 patients for the first interim look is determined to generate the 
design that leads to a reasonable chance of early termination due to futility.
The design property, by utilizing the decision rule specified in Section 5.1.2, and sample 
size of 20 patients subjects or 55 subjects are shown (Table 30Table 28). The probability 


Novartis
Confidential
Page 270
Clinical Study Protocol Version 05
Protocol No. MEK116833
of early termination of the trial is calculated by simulations. The probability of early 
termination after the first 19 evaluable subjects is 33% under the null hypothesized 
response rate, and the risk to incorrectly stop the trial early if the drug is effective is 
approximately 5%. Thus, the study will employ the Bayesian design that allows the trial 
to be monitored more frequently at multiple stages with the constraint of satisfactory stop 
for futility rate
Table 3028
Bayesian Design Performance by Response Rate
If True Response Rate to
The Treatment is: (%) 
Prob (early stop for futility) after 19 
subjects
Prob (early stop for futility) after 54 
subjects
0.15
0.326
0.853
0.2
0.180
0.483
0.3
0.0437
0.086
RATIONALE:  Update sample size in the Bayesian design to accommodate the 
additional subjects in Part 2B
SECTION 5.2.3
Analysis Populations
PREVIOUS TEXT
The Intent-to-Treat (ITT) population will comprise all randomized subjects regardless 
of whether or not treatment was administered.  This population will be based on the 
treatment to which the subject was randomized and will be the primary population for the 
analysis of efficacy data in Part 3.
The All Treated Population will consist of all subjects that received at least one dose of 
investigational product.  Safety and clinical activity data will be evaluated based on this 
population.
The PK Population will consist of those subjects in All Treated Population and for 
whom a PK sample is obtained and analyzed.
The Crossover Population will comprise the subset of subjects in Part 1, Part 2 and Part 
4 who had intra-subject dose escalation or intra-subject doublet to triplet crossover. It will 
be the primary population when summarizing data in Part 1, Part 2 and Part 4 crossover 
phase.
REVISED TEXT
The Intent-to-Treat (ITT) population will comprise all randomized subjects regardless 
of whether or not treatment was administered.  This population will be based on the 
treatment to which the subject was randomized and will be the primary population for the 
analysis of efficacy data in Part 3.


Novartis
Confidential
Page 271
Clinical Study Protocol Version 05
Protocol No. MEK116833
The All Treated Population will consist of all subjects that received at least one dose of 
investigational product.  Safety and clinical activity data for Parts 1, 2 and 4 will be 
evaluated based on this population.
The PK Population will consist of those subjects in All Treated Population and for 
whom a PK sample is obtained and analyzed.
The Crossover Population will comprise the subset of subjects in Part 1, Part 2 and Part 
4 who had intra-subject dose escalation or intra-subject doublet to triplet crossover. It will 
be the primary population when summarizing data in Part 1, Part 2 and Part 4 crossover 
phase.
RATIONALE:  To clarify that Part 1, Part 2 and Part 4 will use all subjects that were 
treated with one dose of either doublet or triplet regimen will be included in the efficacy 
and safety populations.
SECTION 5.3.8.7.1
Part 1, Part 2 and Part 4
PREVIOUS TEXT
The ORR endpoint will be tabulated based on number and percentage of subjects 
attaining either a confirmed or unconfirmed overall best response of CR or PR in the ITT 
population.  Per RECIST, version 1.1, confirmation of response is not required.  Subjects 
with unknown or missing response data, including those who withdraw from the study 
without an assessment, will be treated as non-responders (i.e., they will be included in the 
denominator when calculating the percentage).  No imputation will be performed for 
missing lesion assessment or tumour response data.
PFS will be estimated using the Kaplan Meier method.  PFS will be defined as the time 
from randomization until the first date of either disease progression or death due to any 
cause.  The date of objective disease progression will be defined as the earliest date of 
disease progression as assessed by the investigator using RECIST, version 1.1.  For 
subjects who have not progressed or died at the time of the PFS analysis, censoring will 
be performed using the date of the last adequate disease assessment.  In addition, subjects 
with an extended loss to follow-up or who start a new anti-cancer therapy prior to a PFS 
event will be censored at the date of the last adequate disease assessment prior to the 
extended loss to follow-up or start of new anti-cancer therapy, respectively.  Further 
details on censoring rules will be outlined in the RAP.
For Part 1 and Part 2, anti-tumor activities will be evaluated based on clinical evidence 
and response criteria.  If the data warrant, the response data from both parts will be 
combined and summarized by dose level.  Subjects who crossover from 
dabrafenib/panitumumab combination or trametinib/panitumumab to 
dabrafenib/trametinib/panitumumab combination will not be included in the main 
efficacy analysis for dabrafenib/trametinib/panitumumab combinations. The efficacy for 
these subjects will be summarized separately.


Novartis
Confidential
Page 272
Clinical Study Protocol Version 05
Protocol No. MEK116833
REVISED TEXT
The ORR endpoint will be tabulated based on number and percentage of subjects 
attaining either a confirmed or unconfirmed overall best response of CR or PR in the ITT
all treated population.  Per RECIST, version 1.1, confirmation of response is not required.  
Subjects with unknown or missing response data, including those who withdraw from the 
study without an assessment, will be treated as non-responders (i.e., they will be included 
in the denominator when calculating the percentage).  No imputation will be performed 
for missing lesion assessment or tumour response data.  
All responses are investigator-assessed.  Independent central review may be performed.
PFS will be estimated using the Kaplan Meier method.  PFS will be defined as the time 
from randomizationstudy treatment start until the first date of either disease progression 
or death due to any cause.  The date of objective disease progression will be defined as 
the earliest date of disease progression as assessed by the investigator using RECIST, 
version 1.1.  For subjects who have not progressed or died at the time of the PFS analysis, 
censoring will be performed using the date of the last adequate disease assessment.  In 
addition, subjects with an extended loss to follow-up or who start a new anti-cancer 
therapy prior to a PFS event will be censored at the date of the last adequate disease 
assessment prior to the extended loss to follow-up or start of new anti-cancer therapy, 
respectively.  Further details on censoring rules will be outlined in the RAP.
For Part 1 and Part 2, anti-tumor activities will be evaluated based on clinical evidence 
and response criteria.  If the data warrant, the response data from both parts will be 
combined and summarized by dose level.  The efficacy data collected after crossover for 
those subjects who crossover from dabrafenib/panitumumab combination or 
trametinib/panitumumab to dabrafenib/trametinib/panitumumab combination will not be 
included in the main efficacy analysis for dabrafenib/trametinib/panitumumab 
combinations. The crossover efficacy data for these subjects will be summarized 
separately.
RATIONALE:  Added to allow for independent review of scans as well as clarify PFS 
definition and handling of crossover data.
Section 6.2 
Safety
PREVIOUS TEXT
Physical Exams/ Dermatological Exams
A complete physical examination will be performed by a qualified physician according to 
local practices.  At minimum, the examination should include assessments of the head 
and neck, skin, neurological, lungs, cardiovascular, abdomen (liver and spleen), thyroid, 
lymph nodes and extremities.  Complete physical examinations will also include 
thorough genitourinary (pelvic) and rectal exams to assess secondary malignancies. In 
females, the pelvic exam must visualize the cervix. (Pap smear and colposcopy are not 
required unless clinically indicated.) Rectal exam must include digital rectal exam and 


Novartis
Confidential
Page 273
Clinical Study Protocol Version 05
Protocol No. MEK116833
visual inspection of the anus and perianal area.  Height (at baseline only) and weight will 
also be measured and recorded.
UPDATED TEXT
Physical Exams/ Dermatological Exams
A complete physical examination will be performed by a qualified physician according to 
local practices.  At minimum, the examination should include assessments of the head 
and neck, skin, neurological, lungs, cardiovascular, abdomen (liver and spleen), thyroid, 
lymph nodes and extremities.  For subjects treated with dabrafenib in Part 1, 2, and 3,
Ccomplete physical examinations will also include thorough genitourinary (pelvic) and 
rectal exams to assess secondary malignancies. In females, the pelvic exam must 
visualize the cervix for subjects in Parts 1, 2 and 3. (Pap smear and colposcopy are not 
required unless clinically indicated.) Rectal exam must include digital rectal exam and 
visual inspection of the anus and perianal area.  Height (at baseline only) and weight will 
also be measured and recorded.
RATIONALE:  Removal of dabrafenib specific monitoring from Part 4.
SECTION 6.2 Safety
PREVIOUS TEXT
Clinical Chemistry
Albumin
Sodium
AST (SGOT)
Magnesium
BUN
Potassium
ALT (SGPT)
Total and direct bilirubin
Creatinine
Chloride
Gamma glutamyl transferase 
(GGT)
Uric Acid
Glucose
      fasting glucose 
at screening only; 
all other glucose 
measurements may 
be non-fasting
Total carbon 
dioxide (CO2)
Alkaline phosphatase
Inorganic phosphorus
Lactacte 
dehydrogenase 
(LDH)
Calcium
Total Protein
Routine Urinalysis
Color, appearance, pH, specific gravity, glucose, protein, blood, ketones, WBC esterase, urobiligen
Microscopic examination (if blood or protein is abnormal)
Other screening tests
FSH and estradiol (as needed in women of non-child bearing potential only)
Coagulation (at screening, repeated only if clinically indicated)


Novartis
Confidential
Page 274
Clinical Study Protocol Version 05
Protocol No. MEK116833
REVISED TEXT
Clinical Chemistry
Albumin
Sodium
AST (SGOT)
Magnesium
BUN
Potassium
ALT (SGPT)
Total and direct bilirubin1
Creatinine
Chloride
Gamma glutamyl transferase 
(GGT)
Uric Acid
Glucose
fasting glucose 
at screening only; 
all other glucose 
measurements may 
be non-fasting
Total carbon 
dioxide (CO2)
Alkaline phosphatase
Inorganic phosphorus
Lactacte 
dehydrogenase 
(LDH)
Calcium
Total Protein
1.
Direct bilirubin is only required when total bilirubin is above the upper limit of normal.
Routine Urinalysis
Color, appearance, pH, specific gravity, glucose, protein, blood, ketones, WBC esterase, urobiligen
Microscopic examination (if blood or protein is abnormal)
Other screening tests
FSH and estradiol (as needed in women of non-child bearing potential only)
Coagulation (at screening, repeated only if clinically indicated)
Progressively decreasing serum magnesium levels leading to severe (grade 3-4) 
hypomagnesemia occurred in up to 7% (in Study 2) of patients across clinical trials. 
Monitor patients for hypomagnesemia and hypocalcemia prior to initiating panitumumab 
treatment, periodically during panitumumab treatment, and for up to 8 weeks after the 
completion of treatment. Other electrolyte disturbances, including hypokalemia, have 
also been observed. Replete magnesium and other electrolytes as appropriate.
RATIONALE:  Clarification that direct bilirubin is only necessary to test as part of the 
clinical chemistry panel if total bilirubin is above the upper limit of normal per standard 
clinical practice.  Added language around hypomagnesemia and hypocalcemia from 
panitumumab.
SECTION 6.7.1
Fresh Pre- and Post-dose Tumour Tissues
PREVIOUS TEXT
Tumor specimens that are accessible and can be sampled easily will be requested in Part 
1 and Part 2.  These biopsies will be taken during the screening period, e.g., within 14 
days before treatment, and within 2 to 4 hrs after dosing on Day 15 (+3 days) in those 
subjects who have signed the corresponding section of the informed consent.  Details of 
the tumor biopsy collection including processing, storage and shipping procedures will be 
provided in the SPM.


Novartis
Confidential
Page 275
Clinical Study Protocol Version 05
Protocol No. MEK116833
REVISED TEXT
Tumor specimens that are accessible and can be sampled easily will be requested in Part 
1and, Part 2 and Part 4.  These biopsies will be taken during the screening period, e.g., 
within 14 days before treatment, and within 2 to 4 hrs after dosing on Day 15 (+3 days) in 
those subjects who have signed the corresponding section of the informed consent.  
Details of the tumor biopsy collection including processing, storage and shipping 
procedures will be provided in the SPM.
RATIONALE:  Include Part 4 to be consistent with Time and Event Table
SECTION 6.7.4
Archival tissue collection
PREVIOUS TEXT
Collection of archival primary tumor tissue is required. These samples will be used to 
confirm or determine the BRAF or KRAS mutation status of subjects. 
 
 
 


Novartis
Confidential
Page 276
Clinical Study Protocol Version 05
Protocol No. MEK116833
REVISED TEXT
Collection of archival primary tumor tissue is required. These samples will be used to 
confirm or determine the BRAF or KRAS mutation status of subjects. 
 
 
 
 
SECTION 8.2
Prohibited Medications
PREVIOUS TEXT
The use of certain medications, and illicit drugs within 5 half-lives or 28 days, whichever 
is shorter prior to the first dose of study drug and for the duration of the trial will not be 
allowed.  If a prohibited medication is required for single use (such as for a procedure) 
while study drug is held, the GSK medical monitor can approve such use.
The following medications or non-drug therapies are prohibited:

Other anti-cancer therapy while on treatment in this study.

Antiretroviral drugs.

Herbal remedies (e.g., St. John’s wort).

Dabrafenib is metabolized primarily by Cytochrome P450 (CYP) 2C8 and 
CYP3A4.  Co-administration of dabrafenib with ketoconazole, a CYP3A4 
inhibition, or with gemfibrozil, a CYP2C8 inhibitor, resulted in increases in 
dabrafenib AUC of 71% and 47%, respectively.  Drugs that are strong 
inhibitors or inducers of CYP3A and CYP2C8 (see list in Tablel 30) may only 
be used under special circumstances (e.g. as a single use for a procedure) while 
treatment with study drug is interrupted as they may alter dabrafenib 
concentrations; consider therapeutic substitutions for these medications.  
Approval of the GSK medical monitor is required in these situations. The list 
may be modified based on emerging data. 
Oral contraceptives (either combined or progesterone only), estrogenic vaginal 
ring/percutaneous contraceptive patches, or implants of levonorgestrel/Injectable 
progesterone is prohibited in this study as it is not known if there is the potential of 
inhibition/induction of enzymes that affect the metabolism of estrogens and/or progestins.


Novartis
Confidential
Page 277
Clinical Study Protocol Version 05
Protocol No. MEK116833
Table 30
Prohibited Medications
PROHIBITED – strong inducers of CYP3A or CYP2C8, since concentrations of dabrafenib may be decreased
Class/Therapeutic Area
Drugs/Agents
Antibiotics
Rifamycin class agents (e.g.,  rifampin, rifabutin, rifapentine), 
Anticonvulsant
Carbamazepine, oxcarbazepine phenobarbital, phenytoin, s-mephenytoin 
Miscellaneous
bosentan, St John’s wort
PROHIBITED – Strong inhibitors of CYP3A, or CYP2C8 since concentrations of dabrafenib may be increased
Class/Therapeutic Area
Drugs/Agents
Antibiotics
Clarithromycin, telithromycin, troleandomycin
Antidepressant
Nefazodone
Antifungals
Itraconazole, ketoconazole, posaconazole, voriconazole
Hyperlipidemia
Gemfibrozil
Antiretroviral
ritonavir, saquinavir, atazanavir
Miscellaneous
Conivaptan 
REVISED TEXT
The use of certain medications, and illicit drugs within 5 half-lives or 28 days, whichever 
is shorter prior to the first dose of study drug and for the duration of the trial will not be 
allowed.  If a prohibited medication is required for single use (such as for a procedure) 
while study drug is held, the GSK medical monitor can approve such use.
The following medications or non-drug therapies are prohibited:

Other anti-cancer therapy while on treatment in this study.

Antiretroviral drugs.

Herbal remedies (e.g., St. John’s wort).

Dabrafenib is metabolized primarily by Cytochrome P450 (CYP) 2C8 and 
CYP3A4.  Co-administration of dabrafenib with ketoconazole, a CYP3A4 
inhibition, or with gemfibrozil, a CYP2C8 inhibitor, resulted in increases in 
dabrafenib AUC of 71% and 47%, respectively.  Drugs that are strong 
inhibitors or inducers of CYP3A and CYP2C8 (see list in Table 3230) may 
only be used under special circumstances (e.g. as a single use for a procedure) 
while treatment with study drug is interrupted as they may alter dabrafenib 
concentrations; consider therapeutic substitutions for these medications.  
Approval of the GSK medical monitor is required in these situations. The list 
may be modified based on emerging data. 
Oral contraceptives (either combined or progesterone only), estrogenic vaginal 
ring/percutaneous contraceptive patches, or implants of 
levonorgestrel/Injectable progesterone is prohibited in this study as it is not 
known if there is the potential of inhibition/induction of enzymes that affect the 
metabolism of estrogens and/or progestins.  HRT is permitted.


Novartis
Confidential
Page 278
Clinical Study Protocol Version 05
Protocol No. MEK116833
Table 3230
Prohibited Medications
PROHIBITED – strong inducers of CYP3A or CYP2C8, since concentrations of dabrafenib may be decreased
Class/Therapeutic Area
Drugs/Agents
Oral Antibioticsa
Rifamycin class agents (e.g.,  rifampin, rifabutin, rifapentine), 
Anticonvulsant
Carbamazepine, oxcarbazepine phenobarbital, phenytoin, s-mephenytoin 
Miscellaneous
bosentan, St John’s wort
PROHIBITED – Strong inhibitors of CYP3A, or CYP2C8 since concentrations of dabrafenib may be increased
Class/Therapeutic Area
Drugs/Agents
Oral Antibioticsa
Clarithromycin, telithromycin, troleandomycin
Antidepressant
Nefazodone
Oral Antifungalsa
Itraconazole, ketoconazole, posaconazole, voriconazole
Hyperlipidemia
Gemfibrozil
Antiretroviral
ritonavir, saquinavir, atazanavir
Miscellaneous
Conivaptan 
a.
Topical formulations of these drugs/agents can be used.
RATIONALE FOR CHANGE:  Updated to allow HRT for female patients and topical 
formulation of certain drugs.
SECTION 9.2
Subject Completion Criteria
PREVIOUS TEXT
For Part 1 (dose-escalation phase) subjects who are not treated with the RP2D, a 
completed subject is one who has discontinued study treatment for reasons listed in 
Section 3.9 and was followed to progression, or to death.  
For Part 1 subjects who are treated at RP2D, for Part 2 (expansion cohorts) subjects and 
for Part 3 (randomized Phase 2) subjects, a completed subject is one who has 
discontinued study treatment for reasons listed in Section 3.9 and was followed to death 
or has died while receiving study treatment.  
REVISED TEXT
For Part 1 (dose-escalation phase) subjects who are not treated with the RP2D, a 
completed subject is one who has discontinued study treatment for reasons listed in 
Section 3.9 and was followed to progression, or to death.  
For Part 1 subjects who are treated at RP2D, for Part 2 (expansion cohorts) subjects and 
for Part 3 (randomized Phase 2) subjects, aA completed subject is one who has 
discontinued study treatment for reasons listed in Section 3.9 and was followed to death 
or has died while receiving study treatment.  
RATIONALE:  Updated to collect overall survival on all subjects in the study regardless 
of Part or dose cohort.


Novartis
Confidential
Page 279
Clinical Study Protocol Version 05
Protocol No. MEK116833
APPENDIX 4
RECIST 1.1
PREVIOUS TEXT
Frequency of tumor re-evaluation
Target and non-target lesions will be re-evaluated every 8 weeks, or more frequently, 
based on clinical judgment.
REVISED TEXT
Frequency of tumor re-evaluation
Target and non-target lesions will be re-evaluated every 6 weeks for the first 24 weeks 
and every 8 weeks thereafter, or more frequently, based on clinical judgment.
RATIONALE:  Update to match the Time and Event Table.
AMENDMENT 3
Where the Amendment Applies
This protocol amendment applies to all participating sites in all countries.
Summary of Amendment Changes with Rationale
List of Specific Changes
TITLE PAGE
PREVIOUS TITLE
An Open-Label, Three-Part, Phase I/II Study to Investigate the Safety, Pharmacokinetics, 
Pharmacodynamics, and Clinical Activity of the MEK Inhibitor GSK1120212, BRAF 
Inhibitor GSK2118436 and the anti-EGFR Antibody Panitumumab in Combination in 
Subjects with BRAF-mutation V600E Positive Colorectal Cancer 
REVISED TITLE
An Open-Label, ThreeFour-Part, Phase I/II Study to Investigate the Safety, 
Pharmacokinetics, Pharmacodynamics, and Clinical Activity of the MEK Inhibitor 
GSK1120212, BRAF Inhibitor GSK2118436 and the anti-EGFR Antibody Panitumumab 
in Combination in Subjects with BRAF-mutation V600E Positive Colorectal Cancer and 
in Subjects with CRC With Secondary Resistance to Prior Anti-EGFR Therapy
PREVIOUS TEXT
This is an open-label, three-part Phase I/II study to investigate the safety, 
pharmacokinetics, pharmacodynamics and clinical activity of trametinib (GSK1120212) 
and dabrafenib (GSK2118436) when administered in combination with the anti-EGFR 


Novartis
Confidential
Page 280
Clinical Study Protocol Version 05
Protocol No. MEK116833
antibody panitumumab in subjects with BRAF-mutation V600E positive colorectal 
cancer (CRC).  Part 1 of the study will consist of dose-escalation cohorts, following a 3 
+ 3 enrollment scheme.  Part 2 of the study will consist of expansion cohorts to 
investigate safety and clinical activity of dabrafenib in combination with panitumumab 
and trametinib plus dabrafenib in combination with panitumumab.  Part 3 of the study 
will be a randomized Phase II study comparing dosing with dabrafenib in combination 
with panitumumab and trametinib plus dabrafenib in combination with panitumumab as 
compared to the chemotherapy comparator (a regimen of FOLFOX, FOLFIRI or
irinotecan with or without panitumumab or bevacizumab).  Subjects will be assigned to 
treatment groups in a randomized fashion to compare safety and clinical activity. 
REVISED TEXT
This is an open-label, threefour-part Phase I/II study to investigate the safety, 
pharmacokinetics, pharmacodynamics and clinical activity of trametinib (GSK1120212) 
and dabrafenib (GSK2118436) when administered in combination with the anti-EGFR 
antibody panitumumab in subjects with BRAF-mutation V600E positive colorectal 
cancer (CRC) and in subjects with CRC with secondary resistance to prior anti-EGFR 
therapy.  Part 1 of the study will consist of dose-escalation cohorts, following a 3 + 3 
enrollment scheme.  Part 2 of the study will consist of expansion cohorts to investigate 
safety and clinical activity of dabrafenib in combination with panitumumab and 
trametinib plus dabrafenib in combination with panitumumab.  Part 3 of the study will be 
a randomized Phase II study comparing dosing with dabrafenib in combination with 
panitumumab and trametinib plus dabrafenib in combination with panitumumab as 
compared to the chemotherapy comparator (a regimen of FOLFOX, FOLFIRI or 
irinotecan with or without panitumumab or bevacizumab).  Subjects will be assigned to 
treatment groups in a randomized fashion to compare safety and clinical activity. Part 4
of the study will investigate the trametinib/panitumumab combination, including dose 
escalation and subsequent cohort expansion in two patient populations: 1) BRAF-
mutation V600E positive CRC and 2) subjects with CRC who developed secondary 
resistance to prior anti-EGFR therapy.   The objective of Part 4 is to identify the 
recommended Phase 2 dose/regimen for trametinib dosed in combination with 
panitumumab in dose escalation and to identify an initial signal of clinical activity in 
expansion cohorts.
RATIONALE:  Additional text describes subject population and dosing 
regimen for Part 4.
SPONSOR SIGNATORY
PREVIOUS TEXT
 MD, PhD
GlaxoSmithKline


Novartis
Confidential
Page 281
Clinical Study Protocol Version 05
Protocol No. MEK116833
REVISED TEXT
 MD, PhD
GlaxoSmithKline
Section 1.1.1, Paragraph 2
PREVIOUS TEXT
One improvement in CRC therapy has been the inclusion of anti-epidermal growth factor 
receptor (EGFR) therapy.  Cetuximab, the first anti-EGFR therapy approved for the 
treatment of CRC, was demonstrated to have a benefit on progression free survival (PFS) 
and overall survival (OS) as a single agent in subjects with CRC that was resistant to 
standard chemotherapy [Jonker, 2007].  Subsequently it was demonstrated that cetuximab 
also demonstrated improvement in PFS when combined with standard chemotherapy 
(leucovorin calcium, fluorouracil, irinotecan hydrochloride; FOLFIRI) in previously 
untreated CRC subjects [Van Cutsem, 2009].  However, subsequent analyses of these 
studies, and a randomized Phase 2 evaluation of cetuximab with FOLFOX (leucovorin 
calcium, fluorouracil, oxaliplatin) demonstrated that the improvement in PFS was limited 
to cancers that harboured the wild-type version of the proto-oncogene KRAS [Karapetis, 
2008; Bokemeyer, 2009; Van Cutsem, 2009].  Furthermore, a benefit in overall survival 
could also be demonstrated in wild-type KRAS subjects.  More recently, the fully 
humanized anti-EGFR antibody panitumumab (Vectibix) was demonstrated to have very 
similar efficacy in the first line and second line settings with less frequent dosing (once 
every two weeks) and a lower rate of infusion reactions [VECTIBIX, 2013; Douillard, 
2010; Peeters, 2010].  Again, the therapeutic benefit was limited to the KRAS wild-type 
population.  Subsequent meta-analyses of studies that have investigated anti-EGFR 
therapy (cetuximab and panitumumab) in CRC have confirmed that the clinical benefit of 
these therapies is limited to subjects with wild-type KRAS CRC [DeRoock, 2010]. 
REVISED TEXT
One improvement in CRC therapy has been the inclusion of anti-epidermal growth factor 
receptor (EGFR) therapy.  Cetuximab, the first anti-EGFR therapy approved for the 
treatment of CRC, was demonstrated to have a benefit on progression free survival (PFS) 
and overall survival (OS) as a single agent in subjects with CRC that was resistant to 
standard chemotherapy [Jonker, 2007].  Subsequently it was demonstrated that cetuximab 
also demonstrated improvement in PFS when combined with standard chemotherapy 
(leucovorin calcium, fluorouracil, irinotecan hydrochloride; FOLFIRI) in previously 
untreated CRC subjects [Van Cutsem, 2009].  However, subsequent analyses of these 
studies, and a randomized Phase 2 evaluation of cetuximab with FOLFOX (leucovorin 
calcium, fluorouracil, oxaliplatin) demonstrated that the improvement in PFS was limited 
to cancers that harboured the wild-type version of the proto-oncogene KRAS [Karapetis, 
2008; Bokemeyer, 2009; Van Cutsem, 2009].  Furthermore, a benefit in overall survival 
could also be demonstrated in wild-type KRAS subjects.  More recently, the fully 
humanized anti-EGFR antibody panitumumab (Vectibix) was demonstrated to have very 
similar efficacy in the first line and second line settings with less frequent dosing (once 
every two weeks) and a lower rate of infusion reactions [VECTIBIX, 2013; Douillard, 


Novartis
Confidential
Page 282
Clinical Study Protocol Version 05
Protocol No. MEK116833
2010; Peeters, 2010].  Again, the therapeutic benefit was limited to the KRAS wild-type 
population.  Subsequent meta-analyses of studies that have investigated anti-EGFR 
therapy (cetuximab and panitumumab) in CRC have confirmed that the clinical benefit of 
these therapies is limited to subjects with wild-type KRAS CRC/NRAS [DeRoock, 2010, 
Schwartzberg 2014; Douillard 2013]. 
RATIONALE:  Additional documentation in support of the ongoing study.
Section 1.1.1, Paragraph 9
PREVIOUS TEXT
The current study is designed to test the hypothesis that the combination of an anti-EGFR 
antibody with either a BRAF inhibitor (dabrafenib; GSK2118436) alone or with the 
combination of a BRAF inhibitor and a MEK inhibitor (trametinib; GSK1120212) will 
result in clinically meaningful anti-tumor activity that represents an improvement over 
the chemotherapy comparator (a regimen of FOLFOX, FOLFIRI or irinotecan with or 
without panitumumab or bevacizumab) for BRAF-mutant CRC.  This will include the 
evaluation of the safety and tolerability of the two combinations, a preliminary 
assessment of clinical activity and then a randomized evaluation relative to the 
chemotherapy comparator therapy.  
REVISED TEXT
The current study is designed to test the hypothesis that the combination of an anti-EGFR 
antibody with either a BRAF inhibitor (dabrafenib; GSK2118436) alone or with the 
combination of a BRAF inhibitor and a MEK inhibitor (trametinib; GSK1120212) will 
result in clinically meaningful anti-tumor activity that represents an improvement over 
the chemotherapy comparator (a regimen of FOLFOX, FOLFIRI or irinotecan with or 
without panitumumab or bevacizumab) for BRAF-mutant CRC.  This will include the 
evaluation of the safety and tolerability of the two combinations, a preliminary 
assessment of clinical activity and then a randomized evaluation relative to the 
chemotherapy comparator therapy.  In addition, the study will test the hyposthesis that 
the combination of panitumumab and trametinib can overcome secondary resistance to an 
abti-EGFR therapy in patients that initially derived benefit from the anti-EGFR therapy 
(further rationale in Section1.3.2).
RATIONALE:  Additional documentation in support of the ongoing study.
Section 1.3.1, Heading
PREVIOUS TEXT
Study Rationale
REVISED TEXT
Study Rationale for Parts 1, 2 3


Novartis
Confidential
Page 283
Clinical Study Protocol Version 05
Protocol No. MEK116833
Section 1.3.2: Added Section
RATIONALE:  Addition of text describing incorporation of Part 4 in the 
ongoing study.
1.3.2. Study Rationale for Part 4
Anti-EGFR therapies, either in combination with chemotherapy or as monotherapy, are 
approved therapy for KRAS wild-type (wt) colorectal cancer.  Although a significant 
proportion of patients with KRAS wt CRC derive benefit from anti-EGFR therapy, they 
inevitably become resistant to this therapy.  In a large proportion of cases, the mechanism 
of resistance to anti-EGFR therapy involves the reactivation of the RAS/MEK/ERK 
pathway, often through acquisition of mutations to RAS genes (KRAS or NRAS) 
converging on activation of the RAS/MEK/ERK pathway [Misale 2012; Misale 2014].  
This is similar to the example of BRAF mutant melanoma in which a frequent 
mechanism of resistance involves the reactivation of this pathway [Flaherty 2012].
Vertical pathway inhibition can be an effective therapeutic strategy in tumors that are 
highly dependent on a single signaling pathway [Flaherty 2012]. The addition of a MEK 
inhibitor, trametinib, to the BRAF inhibitor dabrafenib results in a significant 
improvement in both the depth and durability of responses in preclinical models of or in 
patients with BRAF mutant melanoma [TAFINLAR prescribing information January 
2014].  Using a similar rationale, the combination of an anti-EGFR agent and a MEK 
inhibitor demonstrated efficacy in preclinical models of CRC that had developed 
resistance to anti-EGFR therapy [Misale 2014].
Based on above data, the combination of the anti-EGFR agent panitumumab with the 
MEK inhibitor trametinib is of great interest to study in patients who were eligible for 
and derived benefit from anti-EGFR therapy and have subsequenty developed secondary 
resistance to anti-EGFR therapy. 
1.3.2.1.
Preliminary data from ongoing MEK116833 study
Preliminary clinical data from Parts 1 and 2 of this ongoing study suggest that the triplet 
combination of dabrafenib/trametinib/panitumumab is more efficacious than the 
dabrafenib/panitumumab doublet in the BRAF-mutant patient population (see Table 1).   
Enrollment in this dose combination has been limited to 20 patients, including those 
enrolled in Part 1 Cohort 1 and those enrolled in Part 2 doublet cohort.   Given the 
difference in activity, it is important to understand whether dabrafenib is contributing to 
the clinical activity that has been seen with the triplet.  Therefore, patients with BRAF-
mutant CRC will be included in the dose escalation of the trametinib/panitumumab 
doublet and an expansion cohort further evaluating safety and efficacy of the 
trametinib/panitumumab doublet will be included in Part 4 of the study.


Novartis
Confidential
Page 284
Clinical Study Protocol Version 05
Protocol No. MEK116833
Table 1
Best unconfirmed response, Part 1 and Part 2 (preliminary data)
Best unconfirmed response
Doublet Cohorta, 
n=13
Triplet Cohorts
Cohort 2b,
n=3
Cohort 3Ac
n=4
Cohort 3Bd
n=4
PD
2
0
0
0
SD
9
1
1
3
PR
2
2
2
0
CR
0
0
1
0
a. Doublet cohort combines patients enrolled in Part 1 Cohort 1 and Part 2 doublet expansion cohort; all dosed with 
Dabrafenib 150mg BID + Panitumumab 6mg/kg/Q2W
b.
Dabrafenib 150mg BID + Panitumumab 4.8mg/kg/Q2W + Trametinib 1.5mg QD
c.
Dabrafenib 150mg BID + Panitumumab 4.8mg/kg/Q2W + Trametinib 2mg QD
d.
Dabrafenib 150mg BID + Panitumumab 6mg/kg/Q2W + Trametinib 1.5mg QD
Part 4 of the study is designed to identify the recommended Phase 2 dose/regimen for 
trametinib dosed orally in combination with IV infusions of panitumumab in dose 
escalation and to identify an initial signal of clinical activity in expansion cohorts:
1. subjects with BRAF-V600E mutation-positive CRC
2. subjects with CRC that developed secondary resistance to anti-EGFR therapy 
after initially deriving benefit.   
Section 1.3.3 Dose Rationale: Added Paragraph 2
Part 4 of the study includes a 3+3 dose escalation that will identify tolerable combination 
doses for trametinib dosed orally in combination with IV infusions of panitumumab.  The 
safety and tolerability of the RP2D will be confirmed in the expansion cohorts.
RATIONALE:  Addition of text describing incorporation of Part 4 in the 
ongoing study
Section 1.3.3.6 Dose Rationale, Part 4: Added Section
RATIONALE:  Addition of text describing incorporation of Part 4 in the 
ongoing study
1.3.3.6 Part 4
Data from Parts 1 and 2 of this ongoing study have demonstrated that both the 
dabrafenib/panitumumab doublet and the dabrafenib/trametinib/panitumumab triplet are 
well-tolerated by patients (see Table 2). The triplet combination studies in Cohorts 3A 
and 3B, in which dabrafenib is dosed at the full marketed dose (150mg po BID) and 
either trametinib or panitumumab is also dosed at the full marketed dose (2mg po QD or 
6 mg/kg IV Q2W, respectively), with the other agent dosed at one dose level lower 
(1.5mg po QD or 4.8mg/kg IV Q2W, respectively) have been well tolerated to date, with 
no DLTs being identified.  The highest triplet combination (all three agents at full dose) 
is currently being evaluated in Cohort 4 of the dose escalation.  Based on the tolerability 
of the triplet in Part 1, the two starting dose trametinib/panitumumab combinations that 
will be studied in the initial dose escalation cohort of Part 4 will include the doses of 


Novartis
Confidential
Page 285
Clinical Study Protocol Version 05
Protocol No. MEK116833
trametinib and panitumumab that were tolerated in combination with dabrafenib in 
Cohorts 3A and 3B of Part 1.  If these are well tolerated, the dose will be escalated to the 
full dose of both agents. If neither of these is well tolerated, there will be an option to 
dose reduce (see Section 3.4). The optimal safe and tolerable dose combinations defined 
in dose escalation will be brought forward into expansion cohorts.  This will likely be the 
maximal dose for each combination in dose escalation, although a lower dose 
combination may be selected if significant delayed or prolonged toxicities require 
frequent dose modifications.  Expansion cohorts of approximately 20 subjects with 
KRAS wt CRC who progressed on previous anti-EGFR will be enrolled to confirm safety 
and tolerability, and to generate signals of activity.  
Table 2
DLTs, Related AEs ≥Gr 3, and Related SAEs in Part 1 and Part 2 
(preliminary data)
Doublet Cohorta, 
n=13
Triplet Cohorts
Cohort 2b,
n=3
Cohort 3Ac
n=4
Cohort 3Bd
n=4
DLTs
None
None
None
None
Related SAEs
5
1
None
None
Related AEs 
≥Grade 3
1
2
1
2
a. Doublet cohort combines patients enrolled in Part 1 Cohort 1 and Part 2 doublet expansion cohort; all dosed with 
dabrafenib 150mg BID + panitumumab 6mg/kg/Q2W.
b. Part 1 Cohort 2 dose dabrafenib 150mg BID + panitumumab 4.8mg/kg/Q2W + trametinib 1.5mg QD 
c. Part 1 Cohort 3A dose dabrafenib 150mg BID + panitumumab 4.8mg/kg/Q2W + trametinib 2mg QD
d. Part 1 Cohort 3B dose dabrafenib 150mg BID + panitumumab 6mg/kg/Q2W + trametinib 1.5mg QD
Section 2.4 Part 4A Dose Escalation: Added Section
RATIONALE:  Addition of text describing objectives and endpoints 
associated with Part 4 in the ongoing study
Objectives
Endpoints
Primary 
To determine the safety, tolerability 
and range of tolerated combination 
doses in of the combination of 
panitumumab and trametinib in 
subjects with advanced/metastatic 
CRC 
Adverse events and changes in 
laboratory values, vital signs and 
dose interruptions, modifications and 
discontinuations
Secondary
To describe the pharmacokinetics of 
trametinib and panitumumab after 
combination therapy
To determine preliminary clinical 
activity of panitumumab/trametinib 
Maximum observed concentration 
(Cmax), time of occurrence of Cmax 
(tmax), and area under the 
concentration-time curve from zero 
(pre-dose) the time of the last 
quantifiable concentration (AUC(0-
t)), pre-dose (trough) concentration 
at the end of the dosing interval (C) 
of trametinib.  Predose (C) and 
Cmax concentrations of 
panitumumab.


Novartis
Confidential
Page 286
Clinical Study Protocol Version 05
Protocol No. MEK116833
Objectives
Endpoints
combination therapy in two patient 
populations:

subjects with BRAF-V600E 
mutation-positive CRC

subjects with CRC that 
developed secondary 
resistance to anti-EGFR 
therapy after initially deriving 
benefit
To evaluate the pharmacodynamic 
response in colorectal tumors 
following combination therapy
Response rate (complete response 
[CR] + partial response [PR]) 
Progression free survival
Duration of response
Change in levels of proteins/RNA 
implicated in MAPK/PI3K/EGFR 
pathways in pre- and post-dose 
tumor tissue. 


Novartis
Confidential
Page 287
Clinical Study Protocol Version 05
Protocol No. MEK116833
Section 2.5 Part 4B Cohort Expansion: Added Section
Objectives
Endpoints
Primary 
To confirm the safety and tolerability 
of  RP2D/R of the 
panitumumab/trametinib combination 
in an expansion cohorts of

subjects with BRAF-V600E 
mutation-positive CRC

subjects with CRC that 
developed secondary 
resistance to anti-EGFR 
therapy after initially deriving 
benefit
To determine clinical activity of 
combination therapy in this patient 
population
Adverse events and changes in 
laboratory values, vital signs and 
dose interruptions, modifications and 
discontinuations
Response rate (CR +PR)
Secondary
To characterize the population PK 
parameters of trametinib dosed orally 
in combination with anti-EGFR 
antibody (panitumumab) 
To characterize the durability of 
response with trametinib dosed in 
combination with panitumumab 
To evaluate the pharmacodynamic 
response in colorectal tumors 
following combination treatment
Population PK parameters,  oral 
clearance (CL/F),  oral volume of 
distribution (V/F), and absorption rate 
constant (Ka) 
Duration of response
Progression-free survival 
Overall survival
Change in levels of proteins/RNA 
implicated in MAPK/PI3K/EGFR 
pathways in pre- and post-dose 
tumor tissue


Novartis
Confidential
Page 288
Clinical Study Protocol Version 05
Protocol No. MEK116833
Section 3.4 Part 4A Dose Escalation: Added Schematic
a. If the initial combination dose of trametinib and panitumumab in Cohort 1 (starting dose) is not tolerable, the lower 
dose combination defined in de-escalation cohorts (Cohort -1A, -1B and/or -1C) may be evaluated.
Section 3.5 Part 4B Cohort Expansion: Added Schematic
Section 3.6 Discussion of Design
PREVIOUS TEXT
This three-part Phase 1/2 multi-center study allows for the phased evaluation of safety, 
tolerability, and activity of dabrafenib and trametinib in combination with panitumumab 
in subjects with BRAF-V600E mutation-positive CRC.  The planned number of subjects 
per part is described in Section 4.1.  Dose adjustment and stopping criteria are described 
in Section 3.9.  All study treatments, including investigational products, will be referred 
to as “study treatment(s)” for ease of presentation throughout the protocol, except for 
Section 3.8.
REVISED TEXT
This threefour-part Phase 1/2 multi-center study allows for the phased evaluation of 
safety, tolerability, and activity of dabrafenib and/or trametinib in combination with 
panitumumab in subjects with BRAF-V600E mutation-positive CRC and in subjects with 


Novartis
Confidential
Page 289
Clinical Study Protocol Version 05
Protocol No. MEK116833
CRC with secondary resistance to prior anti-EGFR therapy.  The planned number of 
subjects per part is described in Section 4.1.  Dose adjustment and stopping criteria are 
described in Section 3.9.  All study treatments, including investigational products, will be 
referred to as “study treatment(s)” for ease of presentation throughout the protocol, 
except for Section 3.8.
RATIONALE:  Addition of text describing population enrolling into Part 4 in 
the ongoing study
Section 3.6.1 Prescreening for KRAS and BRAF Mutation Status, Paragraph 
2 & 3
PREVIOUS TEXT
The conduct of the KRAS- and BRAF-mutation screening prior to the baseline 
assessments is the responsibility of the investigator and must be performed in a CLIA-
approved facility.  Local testing for KRAS and BRAF mutations for enrollment in the 
trial can occur any time prior to dosing.  If KRAS and BRAF mutation status is unknown 
at screening, no biopsy for assessment of mutation status in association with this protocol 
should be taken prior to obtaining consent. Following consent, subjects should be 
screened for KRAS and BRAF mutation status (if not already performed) prior to any 
other study-related screening procedures. The BRAFV600E mutation status will be 
confirmed centrally using the GSK selected assay.  For Part 1 and Part 2, a local test 
result for KRAS status is adequate for enrollment.  Enrollment in Part 3 may only occur 
following confirmation of KRAS wild-type cancer, as determined by FDA-approved 
KRAS test for CRC (e.g., Qiagen test) and documented in source.  
For subjects with known BRAFV600E mutations, confirmation of mutation must occur 
following registration in Part 1 and Part 2.  Subjects will not be excluded if centralized 
testing is later found to be discordant or uninformative (e.g., inadequate sample), but 
additional subjects may be enrolled as replacement subjects at the discretion of the 
Sponsor and in consultation with the investigator.  
REVISED TEXT
The conduct of the KRAS- and BRAF-mutation screening prior to the baseline 
assessments is the responsibility of the investigator and must be performed in a CLIA-
approved facility.  Local testing for KRAS and BRAF mutations for enrollment in the 
trial can occur any time prior to dosing.  If KRAS and BRAF mutation status is unknown 
at screening, no biopsy for assessment of mutation status in association with this protocol 
should be taken prior to obtaining consent. Following consent, subjects should be 
screened for KRAS and BRAF mutation status (if not already performed) prior to any 
other study-related screening procedures. The BRAFV600E mutation status will be 
confirmed centrally using the GSK selected assay.  For Part 1 and Part 2, a local test 
result for KRAS status is adequate for enrollment.  Enrollment in Part 3 may only occur 
following confirmation of KRAS wild-type cancer, as determined by FDA-approved 
KRAS test for CRC (e.g., Qiagen test) and documented in source.  For patients in Part 4 
who have acquired secondary resistance to anti-EGFR therapy, repeat testing for RAS 
mutations is not required.


Novartis
Confidential
Page 290
Clinical Study Protocol Version 05
Protocol No. MEK116833
For subjects with known BRAFV600E mutations, confirmation of mutation must occur 
following registration in Parts 1, 2 and 4.  Subjects will not be excluded if centralized 
testing is later found to be discordant or uninformative (e.g., inadequate sample), but 
additional subjects may be enrolled as replacement subjects at the discretion of the 
Sponsor and in consultation with the investigator.  
RATIONALE:  Addition of text describing population enrolling into Part 4 in 
the ongoing study
Section 3.6.2.1 Dose-Limiting Toxicity Definitions
PREVIOUS TEXT
Toxicity
DLT Definition
Hematologic

Grade 4 absolute neutrophil count (ANC) for 5 days

Febrile neutropenia (defined as concurrent Grade 4 neutropenia and fever 
>38.5C and lasting >24 hrs)

Grade 4 anemia of any duration

Grade 4 thrombocytopenia (platelets <25,000) of any duration
Non-hematologic

Alanine aminotransferase (ALT) >5X upper limit of normal (ULN) OR, ALT >3X 
ULN AND bilirubin >2X ULN (after exclusion of disease progression and/or bile 
duct obstruction)

Grade 4 rash

Grade 4 Squamous Cell Carcinoma, keratoacanthoma or basal cell carcinoma

Grade 3 or greater clinically significant non-hematologic toxicity per NCI-
CTCAE, v 4.0, other than those listed above, with the following exceptions:
o
Grade 3 or greater nausea, vomiting, diarrhea, or 
mucositis/esophagitis that responds to maximal supportive 
treatment(s) within 48 hours
o
Electrolyte disturbances that respond to correction within 24 hours
o
Grade 3 hypertension that is adequately controlled by the addition of 
up to 2 additional antihypertensive medications
o
Grade 3 pyrexia that does not result in study discontinuation
Cardiac

Ejection fraction < lower limit of normal (LLN) with an absolute decrease of 
>20% from baseline 
Other

Inability to received >75% of scheduled doses in treatment period due to 
toxicity

Grade 2 or higher toxicity that occurs beyond 28 days which in the judgment of 
the investigator and GSK Medical Monitor is considered to be a DLT


Novartis
Confidential
Page 291
Clinical Study Protocol Version 05
Protocol No. MEK116833
REVISED TEXT
Toxicity
DLT Definition
Hematologic

Grade 4 absolute neutrophil count (ANC) for 5 days

Febrile neutropenia (defined as concurrent Grade 4 neutropenia and fever 
>38.5C and lasting >24 hrs)

Grade 4 anemia of any duration

Grade 4 thrombocytopenia (platelets <25,000) of any duration
Non-hematologic

Alanine aminotransferase (ALT) >5X upper limit of normal (ULN) OR, ALT >3X 
ULN AND bilirubin >2X ULN (after exclusion of disease progression and/or bile 
duct obstruction)

Grade 4 rash

Grade 4 Squamous Cell Carcinoma, keratoacanthoma or basal cell carcinoma

Grade 3 or greater clinically significant non-hematologic toxicity per NCI-
CTCAE, v 4.0, other than those listed above, with the following exceptions:
o
Grade 3 or greater nausea, vomiting, diarrhea, or 
mucositis/esophagitis that responds to maximal supportive 
treatment(s) within 48 hours
o
Electrolyte disturbances that respond to correction within 24 hours
o
Grade 3 hypertension that is adequately controlled by the addition of 
up to 2 additional antihypertensive medications
o
Grade 3 pyrexia that does not result in study discontinuation
Cardiac

Ejection fraction < lower limit of normal (LLN) with an absolute decrease of 
>20% from baseline 
Other

Inability to received >receive 75% of scheduled doses in treatment period 
due to toxicity

Grade 2 or higher toxicity that occurs beyond 28 days which in the judgment of 
the investigator and GSK Medical Monitor is considered to be a DLT
RATIONALE: Correction to clarify subjects must have received greater than 
or equal to 75% of scheduled doses during the DLT period
Section 3.6.2.2 Maximum Tolerated Dose and Recommended Phase 2 Dose
PREVIOUS TEXT
The maximum tolerated dose (MTD) is defined as the highest dose at which one or fewer 
of up to 6 subjects experience a DLT during the first 28 days of treatment in Part 1.  Due 
to the heterogeneity of the rash caused by panitumumab, if any DLTs are due to rash, the 
cohort may be expanded to 12 subjects in order to more fully assess the true risk of 
intolerable rash, in which case DLTs in >3 of 12 subjects defines an intolerable dose. The 
recommended doses in Part 2 and Part 3 may include doses that are less than or equal to 
the MTD but demonstrate biological activity and adequate tolerability.
REVISED TEXT
The maximum tolerated dose (MTD) is defined as the highest dose at which one or fewer 
of up to 6 subjects experience a DLT during the first 28 days of treatment in Part 1.  Due 
to the heterogeneity of the rash caused by panitumumab and/or trametinib, if any DLTs 
are due to rash, the cohort may be expanded to 12 subjects in order to more fully assess 


Novartis
Confidential
Page 292
Clinical Study Protocol Version 05
Protocol No. MEK116833
the true risk of intolerable rash, in which case DLTs in >3 of 12 subjects defines an 
intolerable dose. The recommended doses in Part 2 and Part 3 may include doses that are 
less than or equal to the MTD but demonstrate biological activity and adequate 
tolerability.
RATIONALE:  Addition of text describing management of rash for patients 
enrolling into Part 4 in the ongoing study
Section 3.6.5 Part 4A Dose Escalation: Added Section
RATIONALE:  Addition of text describing dose escalation and DLT 
evaluation for patients enrolling into Part 4 in the ongoing study
A combination dose will be defined for combination of trametinib and panitumumab as 
shown in Section3.4). Once safety data has been collected for at least 3 patients in 
Cohort 1, preliminary data will be evaluated for dose-limiting toxicities (DLTs) during 
the first 28 days of treatment, per table in Section 3.6.5.1.  
Table 5
3+3 Cohort Dose Escalation
Number of subjects in cohort 
with DLT
Action
0 out of 3 subjects
Escalate to next dose level. 
1 out of 3 subjects
Accrue 3 additional evaluable subjects at current dose level for a 
total of 6 evaluable subjects
1 out of 6 subjects
Escalate to next dose level with an increase of 50% (this 
represents the sum of relative escalation for each of the drugs)
2 or more subjects in a dosing 
cohort (up to 6 subjects )
Maximum tolerated dose has been exceeded.  Either evaluate 
an intermediate dose lower than current dose or expand a prior 
cohort up to 12 subjects. 
Dose escalation decisions will take into consideration all available data, including the 
safety profile of prior cohorts throughout the time subjects are on study, which will be 
reviewed by the investigator(s), GSK medical monitor(s), pharmacokineticist and 
statistician.  The dose escalation decision for the subsequent cohort and rationale will be 
documented in writing with copies maintained at each site and the Master Study Files.
Due to the heterogeneity of the rash caused by panitumumab and/or trametinib, if 
any DLTs are due to rash, the cohort may be expanded to 12 subjects in order to 
more fully assess the true risk of intolerable rash, in which case DLTs in >3 of 12 
subjects defines an intolerable dose.   If the preliminary MTD is below the full dose 
of both agents, re-escalation may be considered ONLY if fewer than 4 DLTs have 
been reported after enrolling at least 12 patients at the preliminary MTD (including 
patients enrolled in the dose escalation and expansion cohorts).


Novartis
Confidential
Page 293
Clinical Study Protocol Version 05
Protocol No. MEK116833
14.1.1.1.
Dose-Limiting Toxicity Definitions
An event will be considered a dose limiting toxicity (DLT) if it occurs within the first
28 days of dosing, has a possible causal relationship to the study drug(s) based on 
investigator assessment, and meets at least one of the following criteria:
Toxicity
DLT Definition
Hematologic

Grade 4 absolute neutrophil count (ANC) for 5 days

Febrile neutropenia (defined as concurrent Grade 4 neutropenia and 
fever >38.5C and lasting >24 hrs)

Grade 4 anemia of any duration

Grade 4 thrombocytopenia (platelets <25,000) of any duration
Non-hematologic

Alanine aminotransferase (ALT) >5X upper limit of normal (ULN) OR, 
ALT >3X ULN AND bilirubin >2X ULN (after exclusion of disease 
progression and/or bile duct obstruction)

Grade 4 rash 

Grade 3 or greater clinically significant non-hematologic toxicity per 
NCI-CTCAE, v 4.0, other than those listed above, with the following 
exceptions:
o
Grade 3 or greater nausea, vomiting, diarrhea, or 
mucositis/esophagitis that responds to maximal supportive 
treatment(s) within 48 hours
o
Electrolyte disturbances that respond to correction within 24 
hours
o
Grade 3 hypertension that is adequately controlled by the 
addition of up to 2 additional antihypertensive medications
o
Grade 3 pyrexia that does not result in study discontinuation
Cardiac

Ejection fraction < lower limit of normal (LLN) with an absolute 
decrease of >20% from baseline 
Other

Inability to receive 75% of scheduled doses in treatment period due to 
toxicity

Grade 2 or higher toxicity that occurs beyond 28 days which in the 
judgment of the investigator and GSK Medical Monitor is considered to 
be a DLT
Section 3.6.6 Part 4B Cohort Expansion: Added Section
In Part 4B cohort expansion, the primary objectives will be to further assess the safety 
and preliminary clinical activity of given doses and regimen(s) in subjects with 
advanced/metastatic CRC with either a BRAF-mutation (Cohort 1E ) or who developed 
secondary resistance to prior anti-EGFR therapy (Cohort 2E).    Enrollment in expansion 
cohorts will be initiated once dose escalation for the trametinib /panitumumab 
combination has been completed.
The trial may also be stopped at any time if excessive toxicities with the study treatment 
are observed. 
RATIONALE: Addition of text rationale for cohort expansion in Part 4 of the 
ongoing study


Novartis
Confidential
Page 294
Clinical Study Protocol Version 05
Protocol No. MEK116833
Section 3.8 Treatment Assignment
PREVIOUS TEXT
All subjects will be assigned to study treatment in accordance with the randomization 
schedule generated by Discovery Biometrics, prior to the start of the study, using 
validated internal software.  In Part 1, subjects will be assigned to a cohort/ dose level 
based on evaluation of safety in subjects enrolled in prior cohorts.  In Part 2, subjects will 
be assigned to expansion cohorts at a selected dose of dabrafenib in combination with 
panitumumab and a selected dose of trametinib plus dabrafenib in combination with 
panitumumab.  In Part 3, subjects will be randomized to study treatment.  
REVISED TEXT
All subjects will be assigned to study treatment in accordance with the randomization 
schedule generated by Discovery Biometrics, prior to the start of the study, using 
validated internal software.  In Part 1, subjects will be assigned to a cohort/ dose level 
based on evaluation of safety in subjects enrolled in prior cohorts.  In Part 2, subjects will 
be assigned to expansion cohorts at a selected dose of dabrafenib in combination with 
panitumumab and a selected dose of trametinib plus dabrafenib in combination with 
panitumumab.  In Part 3, subjects will be randomized to study treatment.  In Part 4A dose 
escalation, subjects will be assigned to a cohort/ dose level based on evaluation of safety 
in subjects enrolled in prior cohorts.  In Part 4B cohort expansion, subjects will be 
assigned to expansion cohorts at a selected dose of trametinib in combination with 
panitumumab.
RATIONALE: Addition of text explaining dose assignment in Part 4 of the 
ongoing study
Section 3.9.3 Intra-Subject Doublet to Triplet Crossover and Dose 
Escalation: Part 1 and Part 2, 2 or 4
PREVIOUS TEXT
For subjects enrolled in Part 1 or Part 2, intra-subject doublet to triplet crossover is 
allowed if a patient has not experienced intolerable toxicity that could not be managed, 
and has demonstrated radiographic progression on therapy by RECIST v1.1 criteria, and 
approval will be based on review by GSK Medical Monitor. Dose administered must be 
from among those for which cohorts have been completed and data has been reviewed for 
safety.  
Subjects are allowed to crossover once during the study.
Additionally, for subjects who have remained on study for 6 months in the triplet 
combination, their dose level for the combination may be increased up to the highest 
combination dose level that has previously been confirmed as not exceeding the MTD for 
the combination. The intra-subject dose escalation must be agreed to by the investigator 
and the GSK Medical Monitor.


Novartis
Confidential
Page 295
Clinical Study Protocol Version 05
Protocol No. MEK116833
REVISED TEXT
For BRAF-mutation positive subjects enrolled in Part 1, 2 or Part 2 4 doublet dosing, 
intra-subject doublet to triplet crossover is allowed if a patient has not experienced 
intolerable toxicity that could not be managed, and has demonstrated radiographic 
progression on therapy by RECIST v1.1 criteria, and approval will be based on review by 
GSK Medical Monitor. Dose administered must be from among those for which cohorts 
have been completed and data has been reviewed for safety.  
At the time of crossover, certain safety assessments will be repeated prior to start of 
triplet dosing (additional information describing assessments is available in Section 6):

brief physical examination

vital signs 

dermatological examination

ECG (single; repeated with 2 additional ECGs if clinically significant 
abnormalities are observed in the first assessment)

ECHO/ MUGA

disease assessment demonstrating radiographic progression on therapy by 
RECIST v1.1 criteria

ophthalmic examination, repeated at Week 4 after start of dosing with trametinib
Note: Approval from the GSK Medical Monitor is required to restart study 
treatment after ≥21 days of interruption.
All crossover assessments must be completed within 14 days prior to first dose on triplet 
except informed consent, ophthalmology exam, ECHO/MUGA and Disease Assessment, 
which can occur within 35 days prior to the first dose on triplet.
The source documents for these assessments should be provided to GSK at least 24 hours 
in advance to planned start of triplet dosing.  The medical monitor will review and 
provide approval for crossover from doublet to triplet, and site will be notified via email 
with a signed crossover form (refer to SPM).
Once approved, patients will follow the time and events table for Part 2 Expansion 
Cohorts, in Section 3.10.3, starting at the column labelled “Continuation Phase” for 
continued monitoring of safety and efficacy.
Subjects are allowed to crossover once during the study.
Additionally, for subjects who have remained on study for 6 months in the triplet 
combination, their dose level for the combination may be increased up to the highest 
combination dose level that has previously been confirmed as not exceeding the MTD for 
the combination. The intra-subject dose escalation must be agreed to by the investigator 
and the GSK Medical Monitor.
RATIONALE: Addition of evaluations required at time of crossover to 
evaluate risk/benefit


Novartis
Confidential
Page 296
Clinical Study Protocol Version 05
Protocol No. MEK116833
Section 3.9.4.1 Guidelines for Treatment of Pyrexia
PREVIOUS TEXT
Episodes of pyrexia have been observed in subjects receiving dabrafenib monotherapy or
in combination with trametinib (refer to the GSK2118436 IB [GlaxoSmithKline 
Document Number 2012N136095_00], the GSK1120212 IB [GlaxoSmithKline 
Document Number HM2009/00151/03] and the GSK1120212 + GSK2118436 Clinical 
IB [GlaxoSmithKline Document Number, 2011N126811_00]). In a minority of cases the 
pyrexia was accompanied by symptoms such as severe chills, dehydration, hypotension, 
dizziness or weakness.
Pyrexia accompanied by hypotension, or dehydration requiring IV fluids, or severe 
rigors/chills should be reported as a serious adverse event (SAE) per Section 11.2.
Subjects should be instructed on the importance of immediately reporting febrile episodes. 
In the event of a fever, the subject should be instructed to take non-steroidal anti-pyretics 
as appropriate to control fever. In subjects experiencing pyrexia associated with rigors, 
severe chills, dehydration, hypotension, etc., renal function should be monitored carefully 
(see Section 3.9.6).
Guidelines regarding management and dose reduction for pyrexia considered to be 
related to study treatment are provided in Table 10.
Table 10
Management and Dose Modification Guidelines for Pyrexia
Pyrexiaa Management
Action and Dose Modification
1st Eventb: 
Clinical evaluation for infection and hypersensitivityc
Laboratory work-upc
Hydration as requiredd
Blood sample for cytokine analysise
Administer anti-pyretic treatment if clinically indicated 
and continue prophylactic treatmentf 
1st Event:

Interrupt dabrafenib

Continue trametinib and/or panitumumab

Once pyrexia resolves to baseline, restart 
dabrafenib at the same dose level
If fever was associated with dehydration or 
hypotension, reduce dabrafenib by one dose level
2nd Eventg:
Clinical evaluation for infection and hypersensitivityc
Laboratory work-upc
Hydration as requiredd
Blood sample for cytokine analysise

Within 3 days of onset of pyrexia:
2nd Event:

Interrupt dabrafenib

Continue trametinib and/or panitumumab

Once pyrexia resolves to baseline, restart 
dabrafenib at the same dose level
If fever was associated with dehydration or 
hypotension, reduce dabrafenib by one dose level


Novartis
Confidential
Page 297
Clinical Study Protocol Version 05
Protocol No. MEK116833
Pyrexiaa Management
Action and Dose Modification
Optimize anti-pyretic therapy
Consider oral cortiocosteroids (i.e., 
prednisone 10mg) for at least 5 days or as clinically 
indicated
Subsequent Events:
Clinical evaluation for infection and hypersensitivityc
Laboratory work-upc
Hydration as requiredd
Blood sample for cytokine analysise

Within 3 days of onset of pyrexia:
Optimize oral corticosteroid dose as clinically 
indicated for recalcitrant pyrexia
if corticosteroids have been tapered and 
pyrexia recurs, restart steroids
if corticosteroids cannot be tapered consult 
medical monitor
Subsequent Events:

Interrupt dabrafenib

Continue trametinib and/or panitumumab
Once pyrexia resolves to baseline, restart dabrafenib 
reduced by one dose levelh
If dabrafenib must be reduced to <75mg BID, 
permanently discontinue dabrafenib. 
a.
Pyrexia is defined as a body temperature equal to or above 38.5 Celsius or 101.3Fahrenheit.
b.
For subjects experiencing pyrexia complicated by rigors, severe chills, etc., a clinical evaluation and 
laboratory work-up is mandatory for each event; anti-pyretic treatment should be started immediately at the 
first occurrence and prophylactic anti-pyretic treatment is recommended
c.
Thorough clinical examination for signs and symptoms of infection or hypersensitivity is required; laboratory 
workup should include full-blood-count, electrolytes, creatinine, blood urea nitrogen (BUN), C-reactive protein 
(CRP), liver-function tests, blood culture, and urine culture.
d.
Oral hydration should be encouraged in subjects without evidence of dehydration. Intravenous hydration is 
recommended in subjects experiencing pyrexia complicated by dehydration/hypotension.
e.
Blood sample for cytokine analysis must be sent to the central laboratory
f.
Anti-pyretic treatment may include acetaminophen, ibuprofen, or suitable anti-pyretic medication according to 
institutional standards. Prophylactic anti-pyretic treatment may be discontinued after three days in the 
absence of pyrexia
g.
In subject experiencing pyrexia complicated by rigors, severe chills, etc., which cannot be controlled with 
antipyretic medication, oral corticosteroids should be started at the 2nd event and doses should be gradually 
increased for subsequent events.
h.
Dabrafenib should be reduced by one dose level after three episodes of pyrexia complicated by rigors, 
severe chills, etc., which cannot be managed by best supportive care and increasing doses of oral steroids. 
Escalation of dabrafenib is allowed if no episode of pyrexia is observed in the 4 weeks subsequent to dose 
reduction.
REVISED TEXT
Episodes of pyrexia have been observed in subjects receiving dabrafenib monotherapy or
and is increased in incidence and severity in subjects receiving dabrafenib in combination 
with trametinib (refer to the GSK2118436 IB [GlaxoSmithKline Document Number 
2012N136095_00], the GSK1120212 IB [GlaxoSmithKline Document Number 
HM2009/00151/03] and the GSK1120212 + GSK2118436 Clinical IB [GlaxoSmithKline 
Document Number, 2011N126811_00]). In a minority of cases the pyrexia was 
accompanied by symptoms such as severe chills, dehydration, hypotension, dizziness or 
weakness.


Novartis
Confidential
Page 298
Clinical Study Protocol Version 05
Protocol No. MEK116833
Pyrexia accompanied by hypotension, or dehydration requiring IV fluids, or severe 
rigors/chills should be reported as a serious adverse event (SAE) per Section .
Subjects should be instructed on the importance of immediately reporting febrile episodes. 
In the event of a fever, the subject should be instructed to take non-steroidal anti-pyretics 
(e.g., ibuprofen or acetaminophen/paracetamol) as appropriate to control fever. In 
subjects experiencing pyrexia associated with rigors, severe chills, dehydration, 
hypotension, etc.,The use of oral corticosteroids should be considered in those instances 
in which anti-pyretics are insufficient. Monitor serum creatinine and other evidence of
renal function should be monitored carefully during and following severe events of 
pyrexia (see Section 3.9.6).
Guidelines regarding management and dose reduction for pyrexia considered to be 
related to study treatment are provided in Table 10.
Table 10
Management and Dose Modification Guidelines for Pyrexia
Pyrexiaa Management
Action and Dose Modification
All Events:

Clinical evaluation for infection and hypersensitivityc

Laboratory work-upc

Hydration as requiredd
1st Eventb: 
Clinical evaluation for infection and hypersensitivityc
Laboratory work-upc
Hydration as requiredd
Blood sample for cytokine analysise
Administer anti-pyretic treatment if clinically indicated 
and continue prophylactic treatmentf if associated with 
rigors, renal failure, dehydration or hypotensione
1st Event:

Interrupt dabrafenib

Continue trametinib and/or panitumumab

Once pyrexia resolves to baseline, restart 
dabrafenib at the same dose level
If fever was associated with dehydration or 
hypotension, reduce dabrafenib by one dose level
2nd Eventg:
Clinical evaluation for infection and hypersensitivityc
Laboratory work-upc
Hydration as requiredd
Blood sample for cytokine analysise

Within 3 days of onset of pyrexia:
Optimize anti-pyretic therapy
Consider oral cortiocosteroids (i.e., 
2nd Event:

Interrupt dabrafenib

Continue trametinib and/or panitumumab

Once pyrexia resolves to baseline, restart 
dabrafenib at the same dose level
If fever was associated with rigors, renal 
failure, dehydration or hypotension, reduce dabrafenib 
by one dose level


Novartis
Confidential
Page 299
Clinical Study Protocol Version 05
Protocol No. MEK116833
Pyrexiaa Management
Action and Dose Modification
prednisone 10mg) for at least 5 days or as clinically 
indicated
Subsequent Events:
Clinical evaluation for infection and hypersensitivityc
Laboratory work-upc
Hydration as requiredd
Blood sample for cytokine analysise

Within 3 days of onset of pyrexia:
Optimize oral corticosteroid dose as clinically 
indicated for recalcitrant pyrexia
if corticosteroids have been tapered and 
pyrexia recurs, restart steroids
if corticosteroids cannot be tapered consult 
medical monitor
Subsequent Events:

Interrupt dabrafenib

Continue trametinib and/or panitumumab
Once pyrexia resolves to baseline, restart dabrafenib 
reduced by one dose levelh
If dabrafenib must be reduced to <75mg
50mg BID, permanently discontinue dabrafenib. 
Trametinib may be continued.
i.
Pyrexia is defined as a body temperature equal to or above 38.5 Celsius or 101.3Fahrenheit.
j.
For subjects experiencing pyrexia complicated by rigors, severe chills, etc., a clinical evaluation and 
laboratory work-up is mandatory for each event; anti-pyretic treatment should be started immediately at the 
first occurrence and prophylactic anti-pyretic treatment is recommended
k.
Thorough clinical examination for signs and symptoms of infection or hypersensitivity is required; laboratory 
workup should include full-blood-count, electrolytes, creatinine, blood urea nitrogen (BUN), C-reactive protein 
(CRP), liver-function tests, blood culture, and urine culture.
l.
Oral hydration should be encouraged in subjects without evidence of dehydration. Intravenous hydration is 
recommended in subjects experiencing pyrexia complicated by dehydration/hypotension.
m.
Blood sample for cytokine analysis must be sent to the central laboratory
n.
Anti-pyretic treatment may include acetaminophen, ibuprofen, or suitable anti-pyretic medication according to 
institutional standards. Prophylactic anti-pyretic treatment may be discontinued after three days in the 
absence of pyrexia
o.
In subject experiencing pyrexia complicated by rigors, severe chills, etc., which cannot be controlled with 
antipyretic medication, oral corticosteroids should be started at the 2nd event and doses should be gradually 
increased for subsequent events.
p.
Dabrafenib should be reduced by one dose level after three episodes of pyrexia complicated by rigors, 
severe chills, etc., which cannot be managed by best supportive care and increasing doses of oral steroids. 
Escalation of dabrafenib is allowed if no episode of pyrexia is observed in the 4 weeks subsequent to dose 
reduction.
RATIONALE: Clarification of safety management guidelines based on 
revisions to accepted asset-specific text
Section 3.9.4.2.1 Rash Prophylaxis and Supportive Care
PREVIOUS TEXT
Acneiform rash.  The need for oral or topical antibiotics (e.g., clindamycin cream, 
minocycline, doxycycline, etc) and higher strength topical steroids is a clinical decision 
of the investigator.  Oral or topical retinoids are not recommended.  Consider the 
algorithm provided in Table 11 for management of acneiform rash.


Novartis
Confidential
Page 300
Clinical Study Protocol Version 05
Protocol No. MEK116833
REVISED TEXT
Acneiform rash.  The need for oral or topical antibiotics (e.g., clindamycin cream, 
minocycline, doxycycline, etc) and higher strength topical steroids is a clinical decision 
of the investigator. Prophylactic use of skin emollients, sunscreen, oral doxycycline and 
topical steroids was demonstrated to be more effective than reactive use of the same 
agents after rash developed [Lacouture 2010].  Oral or topical retinoids are not 
recommended.  Consider the algorithm provided in Table 11 for management of 
acneiform rash.
Table 11 Acneiform Rash Management Guidelines
PREVIOUS TEXT
Step
Rash 
grading
Rash severity
Management of Rash
Dose Modification for 
Trametinib and Panitumumaba
1
Mild
Locallized
Minimally symptomatic
No impact on activities of 
daily living (ADL)
No sign of superinfection
Initiate prophylactic 
regimen, including oral 
antibiotics, if not already 
started (see Section 
3.9.4.2.1).  Consider 
using moderate 
strength topical 
steroidsa
Continue current doses.
Reassess after 2 weeks; if rash 
worsens or does not improve, 
proceed to Step 2.
2
Moderate
Generalized
Mild symptoms (e.g., 
pruritus, tenderness)
Minimal impact on ADL
No sign of superinfection
Initiate prophylactic 
regimen, including oral 
antibiotics, if not already 
started (see Section 
3.9.4.2.1), using 
moderate strength 
topical steroidsa
Reduce panitumumab dose by 
50% or consider interrupting 
panitumumab until resolution of 
toxicity to Grade 1.  If applicable, 
reduce trametinib by one dose 
level or consider interrupting 
trametinib until resolution of 
toxicity to Grade 1.  If toxicity 
resolves, then can consider re-
escalation to initial dose level.
Reassess after 2 weeks; if rash 
worsens or does not improve, 
proceed to Step 3.
3
Severe
Generalized
Severe symptoms (e.g., 
pruritus, tenderness)
Significant impact on 
ADL
Sign of or potential for 
superinfection
Initiate prophylactic 
regimen, including oral 
antibiotics, if not already 
started, using moderate 
strength topical 
steroidsb plus 
methylprednisone dose 
pack (see Section 
3.9.4.2.1).
Consider obtaining 
dermatology 
consultation. 
Manage rash per 
Interrupt panitumumab and 
trametinib until rash improves 
(moderate or mild), or resolves. 
If rash worsens or does not 
improve after 2 weeks, 
permanently discontinue 
panitumumab and trametinib.
If rash does improve/resolve, 
restart panitumumab ONLY at 
full.
1.
If panitumumab is 
tolerated for two 
weeks, consider 


Novartis
Confidential
Page 301
Clinical Study Protocol Version 05
Protocol No. MEK116833
Step
Rash 
grading
Rash severity
Management of Rash
Dose Modification for 
Trametinib and Panitumumaba
dermatologist’s 
recommendation.
restarting trametinib at 
a lower dose level.
2.
If it is not tolerated, 
hold panitumumab 
until resolution and 
restart at 50% of the 
previous dose.  If the 
lower dose is tolerated, 
consider restarting 
trametinib at a lower 
dose level.
REVISED TEXT
Step
Rash 
grading
Rash severity
Management of Rash
Dose Modification for 
Trametinib and Panitumumaba
1
Mild
Locallized
Minimally symptomatic
No impact on activities of 
daily living (ADL)
No sign of superinfection
Initiate prophylactic 
regimen, including oral 
antibiotics, if not already 
started (see Section 
3.9.4.2.1).  Consider 
using moderate 
strength topical 
steroidsa
Continue current doses.
Reassess after 2 weeks; if rash 
worsens or does not improve, 
proceed to Step 2.
2
Moderate
Generalized
Mild symptoms (e.g., 
pruritus, tenderness)
Minimal impact on ADL
No sign of superinfection
Initiate prophylactic 
regimen, including oral 
antibiotics, if not already 
started (see Section 
3.9.4.2.1), using 
moderate strength 
topical steroidsa
Reduce panitumumab dose by 
50% or consider interrupting 
panitumumab until resolution of 
toxicity to Grade 1.  If applicable, 
reduce trametinib by one dose 
level or consider interrupting 
trametinib until resolution of 
toxicity to Grade 1.  If toxicity 
resolves, then can consider re-
escalation to initial dose level.
Reassess after 2 weeks; if rash 
worsens or does not improve, 
proceed to Step 3.
3
Severe
Generalized
Severe symptoms (e.g., 
pruritus, tenderness)
Significant impact on 
ADL
Sign of or potential for 
superinfection
Initiate prophylactic 
regimen, including oral 
antibiotics, if not already 
started, using moderate 
strength topical 
steroidsb plus 
methylprednisone dose 
pack (see Section 
3.9.4.2.1).
Consider obtaining 
Interrupt panitumumab and 
trametinib until rash improves 
(moderate or mild), or resolves. 
If rash worsens or does not 
improve after 2 weeks, 
permanently discontinue 
panitumumab and trametinib.
If rash does improve/resolve, 
restart trametinib and
panitumumab ONLY at full, each 


Novartis
Confidential
Page 302
Clinical Study Protocol Version 05
Protocol No. MEK116833
Step
Rash 
grading
Rash severity
Management of Rash
Dose Modification for 
Trametinib and Panitumumaba
dermatology 
consultation. 
Manage rash per 
dermatologist’s 
recommendation.
reduced by a single dose level.
1.
If panitumumab the 
combination is 
tolerated for two 
weeks, consider 
restarting trametinib at 
a lower dose 
escalating one or both 
agents to the prior
dose level.
2.
If it is not tolerated, 
hold panitumumab
both agents until 
resolution to Gr1 and 
then restart at 50% of 
the previous dose.  If 
the lower dose is 
tolerated, consider 
restarting trametinib at 
a lower both agents, 
each reduced by 
another dose level.
RATIONALE: Clarification of safety management guidelines based on 
revisions to accepted asset-specific text
Table 15 Management and Dose Modification Guidelines for Renal 
Insufficiency
PREVIOUS TEXT
Creatinine
Adverse Event Management
Action and Dose Modifcation
For subjects with serum creatinine 
increase >0.2 mg/dL (18 mol/L) 
but 
0.5 mg/dL (44 mol/L) above 
baseline:

Re-check serum 
creatinine within 1 week

If serum creatinine 
increases > 1 week, 
contact GSK Medical 
Monitor

If  subject has fever 
(38.5C), treat pyrexia 
as per guidelinesa
Continue study treatment at the 
same dose level.
For subjects with serum creatinine 
rise>0.5 mg/dL (44 mol/L) above 
baseline 
or 
serum creatinine >2 mg/dL (> 177 

Follow serum creatinine 
at least twice weekly

Consider hospitalization if 
serum creatinine cannot 
be monitored frequently

If subject has fever 
(38.5C), treat pyrexia 

Interrupt study 
treatment(s)c until serum 
creatinine recovers to 
baseline.

Restart wtih study 
treatmentb at either the 
same or a reduced dose 


Novartis
Confidential
Page 303
Clinical Study Protocol Version 05
Protocol No. MEK116833
Creatinine
Adverse Event Management
Action and Dose Modifcation
mol/L)
as per guidelinesa

Consult nephrologist if 
clinically indicated

Perform renal biopsy if 
clinically indicated, for 
example:

Renal 
insufficiency persists 
despite volume repletion

Subject has new 
rash or signs of 
hypersensitivity (such  as 
elevated eosinophil 
count) 
level
REVISED TEXT
Creatinine
Adverse Event Management
Action and Dose Modifcation
For subjects with serum creatinine 
increase >0.2 mg/dL (18 mol/L) 
but 
0.5 mg/dL (44 mol/L) above 
baseline:

Re-check serum 
creatinine within 1 week

If serum creatinine 
increases > 1 week, 
contact GSK Medical 
Monitor

If  subject has fever 
(38.5C):pyrexia is 
present, treat pyrexia as 
per guidelinesa
Continue study treatment at the 
same dose level.
For subjects with serum creatinine 
rise increase >0.5 mg/dL (44 mol/L) 
above baseline 
or 
serum creatinine >2 mg/dL (> 177 
mol/L)

Follow serum creatinine 
at least twice weekly

Consider hospitalization if 
serum creatinine cannot 
be monitored frequently

If subject has fever 
(38.5C):pyrexia is 
present, treat pyrexia as 
per guidelinesa

Consult nephrologist if 
clinically indicated

Perform renal biopsy if 
clinically indicated, for 
example:

Renal 
insufficiency persists 
despite volume repletion

Subject has new 

Interrupt study 
treatment(s)c until serum 
creatinine recovers to 
baseline.

Restart wtih study 
treatmentb at either the 
same or a reduced dose 
level


Novartis
Confidential
Page 304
Clinical Study Protocol Version 05
Protocol No. MEK116833
Creatinine
Adverse Event Management
Action and Dose Modifcation
rash or signs of 
hypersensitivity (such  as 
elevated eosinophil 
count) 
RATIONALE: Clarification of safety management guidelines based on 
revisions to accepted asset-specific text
Section 3.9.7 Guidelines for Cardiovascular Adverse Events
PREVIOUS TEXT
Cardiovascular adverse events have been observed in subjects receiving either dabrafenib, 
trametinib, or the two drugs in combination.  Additional information is available in the 
IBs:  GSK2118436 IB [GlaxoSmithKline Document Number 2012N136095_00], the 
GSK1120212 IB [GlaxoSmithKline Document Number HM2009/00151/03] and the 
GSK1120212 + GSK2118436 Clinical IB [GlaxoSmithKline Document Number, 
2011N126811_00].  
REVISED TEXT
Cardiovascular adverse events have been observed in subjects receiving either dabrafenib, 
trametinib, or the two drugs in combination.  Additional information is available in the 
IBs:  GSK2118436 IB [GlaxoSmithKline Document Number 2012N136095_00], the 
GSK1120212 IB [GlaxoSmithKline Document Number HM2009/00151/03] and the 
GSK1120212 + GSK2118436 Clinical IB [GlaxoSmithKline Document Number, 
2011N126811_00].  Guidelines for LVEF decreases, hypertension and prolonged QTc 
are provided in Section 3.9.7.1, Section 3.9.8 and Section 3.9.9, respectively.
Section 3.9.7.1 Left Ventricular Ejection Fraction (LVEF) Decreases
PREVIOUS TEXT
Section 3.9.7.1 Left Ventricular Ejection Fraction (LVEF) Decreases
Cardiac ejection fraction function assessments (ECHO or MUGA; ECHO is preferred) 
must be performed at Screening and at the post-treatment follow-up visit as outlined in 
the Time and Events Tables (Section 3.8). All assessments for an individual patient must 
be performed in the same modality (i.e., ECHO or MUGA), and preferably, by the same 
institution/operator, in order to reduce variability. Decreases of the left ventricular 
ejection fraction (LVEF) have been observed in subjects receiving trametinib 
monotherapy and in combination with dabrafenib. Therefore, cardiac ejection fraction 
must be assessed at regular intervals as outlined in the Time and Events Table (Section 
3.8).  Copies of all LVEF assessments and cardiology consultations performed on 
subjects who experience a >10% decrease in LVEF from baseline and whose cardiac 
ejection fraction is <institution’s LLN will be required by GSK for review.  Instructions 


Novartis
Confidential
Page 305
Clinical Study Protocol Version 05
Protocol No. MEK116833
for submitting qualifying ECHOs/ MUGAs are provided in the Study Procedures Manual 
(SPM).
Dose modification guidance and stopping criteria for LVEF decrease are provided in 
Table 16.  Additional guidelines for subjects enrolled at sites in France are provided in 
Appendix 5.
REVISED TEXT
Section 3.9.7.1 Left Ventricular Ejection Fraction (LVEF) Decreases 
Cardiac ejection fraction function assessments (ECHO or MUGA; ECHO is preferred) 
must be performed at Screening and at the post-treatment follow-up visit as outlined in 
the Time and Events Tables (Section Decreases of the left-ventricular-ejection- Decreases 
of the left ventricular ejection fraction (LVEF) have been observed in subjects receiving 
trametinib monotherapy and in combination with dabrafenib. Therefore, ECHO/MUGAs 
must be performed to assess cardiac ejection fraction must be assessed at in regular 
intervals as outlined in the Time and Events Table (Section 3.10).  All assessments for an 
individual patient must be peformed with the same modality (i.e., ECHO or MUGA) and, 
preferably, by the same institution/operator, in order to reduce variability.  Copies of all 
LVEF assessments and cardiology consultations performed on subjects who experience a 
>10% decrease in LVEF from baseline and whose cardiac ejection fraction is 
<institution’s LLN will be required by GSK for review.  Instructions for submitting 
qualifying ECHOs/ MUGAs are provided in the Study Procedures Manual (SPM).
Dose modification guidance and stopping criteria for LVEF decrease are provided in 
Table 16.  Additional guidelines for subjects enrolled at sites in France are provided in 
Appendix 5.
Table 16 Dose Modification Guidelines and Stopping Criteria for LVEF 
Decrease
PREVIOUS TEXT
Clinic Presentation
LVEF decrease (%) or CTCAE grade
Action and Dose Modificationd
Asymptomatic
Absolute decrease of >10% in LVEF 
compared to baseline and ejection 
fraction below the institutional LLN
Interrupt study treatment with dabrafenib and 
trametinib and repeat ECHO/MUGA within 2 
weeksa
IF LVEF recovers within 4 weeks (defined as LVEF 
LLN and absolute decrease 10% compared to 
baseline):

Consult with the GSK Medical Monitor 
and request approval for restart

Restart trametinib reduced by one dose 
level

Restart dabrafenib at previous dose level

Repeat ECHO/MUGA at 2, 4, 8, and 12 
weeks after re-start; continue in 12 week 
intervals thereafter


Novartis
Confidential
Page 306
Clinical Study Protocol Version 05
Protocol No. MEK116833
Clinic Presentation
LVEF decrease (%) or CTCAE grade
Action and Dose Modificationd
If LVEF does not recover within 4 weeks:
e.
Consult with cardiologist
f.
Permanently discontinue dabrafenib 
and trametinib
g.
Repeat ECHO/MUGA after 2, 4, 8, 12 
and 16 weeks or until resolution
h.
Consult with GSK Medical Monitord
Symptomaticc
Grade 3: resting LVEF 39-20% or >20% 
absolute reduction from baseline
Permanently discontinue study treatment with 
dabrafenib and trametinib 
Consult with cardiologist
Repeat ECHO/MUGA after 2, 4, 8, 12 and 16 
weeks or until resolution.
Grade 4: resting LVEF <20%
a.
If ECHO/MUGA does not show LVEF recovery after 2 weeks, repeat ECHO/MUGA 2 weeks later.
b.
Symptoms may include: dyspnea, orthopnea, and other signs and symptoms of pulmonary congestion and 
edema.
c.
Once LVEF recovers to baseline, restarting dabrafenib monotherapy may be considered in consultation with 
the GSK Medical Monitor.
REVISED TEXT
Clinic Presentation
LVEF decrease (%) or CTCAE grade
Action and Dose Modificationd
Asymptomatic
Absolute decrease of >10% in LVEF 
compared to baseline and ejection 
fraction below the institutional LLN
Interrupt study treatment with dabrafenib and 
trametinib and repeat ECHO/MUGA within 2 
weeksa
IF LVEF recovers within 4 weeks (defined as LVEF 
LLN and absolute decrease 10% compared to 
baseline):

Consult with the GSK Medical Monitor 
and request approval for restart

Restart trametinib reduced by one dose 
levelb

Restart dabrafenib at previous dose level

Repeat ECHO/MUGA at 2, 4, 8, and 12 
weeks after re-start; continue in 12 week 
intervals thereafter
If LVEF does not recover within 4 weeks:
i.
Consult with cardiologist
j.
Permanently discontinue dabrafenib 
and trametinib
k.
Report as SAE
l.
Repeat ECHO/MUGA after 2, 4, 8, 12 
and 16 weeks or until resolution
m.
Consult with GSK Medical Monitord
Symptomaticc
Grade 3: resting LVEF 39-20% or >20% 
absolute reduction from baseline
Permanently discontinue study treatment with 
dabrafenib and trametinib 
Report as SAE
Consult with cardiologist
Repeat ECHO/MUGA after 2, 4, 8, 12 and 16 
weeks or until resolution.
Grade 4: resting LVEF <20%


Novartis
Confidential
Page 307
Clinical Study Protocol Version 05
Protocol No. MEK116833
Abbreviations:  CTCAE = Common Terminology Criteria for Adverse Events; ECHO = echocardiogram; GSK = 
GlaxoSmithKline; LLN = lower limit of normal; LVEF = left ventricular ejection fraction
a.
If ECHO/MUGA does not show LVEF recovery after 2 weeks, repeat ECHO/MUGA 2 weeks later.
b.
Escalation of trametinib to previous dose level can be considered if LVEF remains stable for 4 weeks after 
restarting of trametinib.  Approval from GSK Medical Monitor is required
c.
Symptoms may include: dyspnea, orthopnea, and other signs and symptoms of pulmonary congestion and 
edema.
d.
Once LVEF recovers to baseline, restarting dabrafenib monotherapy may be considered in consultation with 
the GSK Medical Monitor.
RATIONALE: Clarification of safety management guidelines based on 
revisions to accepted asset-specific text
Section 3.9.8.1 Monitoring of Hypertension
PREVIOUS TEXT
All blood pressure measurements should be performed under optimal conditions, ie after:

subject has been seated with back support, ensuring that legs are uncrossed and 
both feet are flat on the floor, 

subject has relaxed comfortably for at least 5 minutes prior to measurements, 

preparatory steps, such as removal of restrictive clothing over the cuff area and 
selection of the appropriate cuff size has been ensured, 

the arm is supported so that the middle of the cuff is at heart level, and 

the subject remains quiet and still during the measurement.  
In subjects with an initial blood pressure reading within the hypertensive range, a second 
reading should be taken at least 1 minute after the initial reading, with the average of the 
2 readings averaged to obtain a final blood pressure measurement.  The averaged value 
should be recorded in the electronic Case Report Form (eCRF).
Persistent hypertension is defined as an increase of systolic blood pressure (SBP) to 
>140mm Hg and / or diastolic blood pressure (DBP) to >90mm Hg in up to 3 subsequent 
visits with blood pressure assessments from 2 readings under the optimal conditions 
described above.  Visits to monitor increased blood pressure should be scheduled 
independently from the per-protocol visits outlined in the Time and Events Table 
(Section 3.8). Ideally, subsequent blood pressure assessments should be performed within 
1 week.
Asymptomatic hypertension is defined as an increase of SBP to >140mm Hg and /or 
DBP to >90mm Hg in the absence of headache, light-headedness, vertigo, tinnitus, 
episodes of fainting or other symptoms indicative of hypertension which would disappear 
after the blood pressure is controlled within normal range.


Novartis
Confidential
Page 308
Clinical Study Protocol Version 05
Protocol No. MEK116833
REVISED TEXT
All blood pressure measurements should be performed under the following optimal 
conditions, ie after:

subject has been seated with back support, ensuring that legs are uncrossed and 
both feet are flat on the floor, 

subject has relaxed comfortably for at least 5 minutes prior to measurements, 

preparatory steps, such as removal of restrictive clothing over the cuff area and 
selection of the appropriate cuff size has been ensured, 

the arm is supported so that the middle of the cuff is at heart level, and 

the subject remains quiet and still during the measurement.  
In subjects with an initial blood pressure reading within the hypertensive range, a second 
reading should be taken at least 1 minute after the initial reading, with the average of the 
2 readings averaged to obtain a final blood pressure measurement.  The averaged value 
should be recorded in the electronic Case Report Form (eCRF).
Persistent hypertension is defined as an increase of systolic blood pressure (SBP) to 
>140mm Hg and / or diastolic blood pressure (DBP) to >90mm Hg in up to 3 
subsequentconsecutive visits with blood pressure assessments from 2 readings under the 
optimal conditions described above.  Visits to monitor increased blood pressure 
shouldcan be scheduled independently from the per-protocol visits outlined in the Time 
and Events Table (Section 3.8). Ideally, subsequent blood pressure assessments should be 
performed within 1 week.
Asymptomatic hypertension is defined as an increase of SBP to >140mm Hg and /or 
DBP to >90mm Hg in the absence of headache, light-headedness, vertigo, tinnitus, 
episodes of fainting or other symptoms indicative of hypertension which would disappear 
after the blood pressure is controlled within normal range.
Table 17 Guidelines for Management of Hypertension
PREVIOUS TEXT
Hypertension
Action and Dose Modification
Scenario A:
Asymptomatic and persistenta SBP 140mm Hg and 
<160mm Hg, or DBP 90mm Hg and <100mm Hg, 
or 
a clinically significant increase in DBP of 20mm Hg, with 
an overall reading <100mm Hg 
Step 1: Continue study treatments at the current dose.
Step 2: Adjust current or initiate new antihypertensive 
medication(s).
Step 3: Titrate antihypertensive medication(s) during next 
2 weeks as indicated to achieve well-controlledb blood 
pressure.  
If BP is not well-controlled within 2 weeks, consider 
referral to a specialist and follow steps outlined for 
Scenario B.
Scenario B:


Novartis
Confidential
Page 309
Clinical Study Protocol Version 05
Protocol No. MEK116833
Hypertension
Action and Dose Modification
Asymptomatic SPB 160mm Hg, or DBP 100mm Hg, 
or 
failure to achieve well-controlled BP within 2 weeks in 
Scenario A
Step 1: Interrupting study treatment(s)d, if clinically 
indicated.
Step 2: Adjust current or initiate new antihypertensive 
medication(s). 
Step 3: Titrate antihypertensive medication(s) during next 
2 weeks as indicated to achieve well-controlled BP. 
Step 4: Once blood pressure (BP) is well-controlled, 
restart study treatment(s)df with one dose level 
reduction.
Scenario C:
Symptomatic hypertension or recurringc SBP 160mm 
Hg, or DBP 100mm Hg, despite modification of 
antihypertensive medication(s) 
Step 1: Interrupt study treatment(s)df
Step 2: Adjust current or initiate new antihypertensive 
medication(s).
Step 3: Titrate antihypertensive medication(s) during next 
2 weeks as indicated to achieve well-controlled BP. 
Referral to a specialist for further evaluation and follow-up 
is also recommended. 
Step 4: Once BP is well-controlled, restart study 
treatment(s)df with one dose level reduction.
Scenario D: 
Refractory hypertension unresponsive to above 
interventions
Discontinue administration of study treatment(s)d and 
continuef follow-up per protocol.
a.
Hypertension detected in two separate readings during up to three subsequent visits.
b.
Blood pressure of SBP < 140 mm Hg and DBP < 90 mm Hg in two separate readings during up to three 
subsequent visits.
c.
Persistent asymptomatic hypertension after initially successful anti-hypertensive intervention.
d.
Modification to study treatment(s) should be discussed with the GSK Medical Monitor.
REVISED TEXT
Hypertension
Action and Dose Modification
Scenario A:
Asymptomatic and persistent apersistenta SBP 140mm 
Hg and <160mm Hg, or DBP 90mm Hg and <100mm 
Hg, 
or 
a clinically significant increase in DBP of 20mm Hg, with
an overall reading <100mm Hg(but DBP still <100 
mmHg).
Step 1: Continue study treatments at the current dose.
Step 2: Adjust current or initiate new antihypertensive 
medication(s).
Step 3: Titrate antihypertensive medication(s) during next 
2 weeks as indicated to achieve well-controlledb blood 
pressure.  
If BP is not well-controlled within 2 weeks, consider 
referral to a specialist and follow steps outlined for 
Scenario B.
Scenario B:
Asymptomatic SPB 160mm Hg, or DBP 100mm Hg, 
or 
failure to achieve well-controlled BP within 2 weeks in 
Step 1: Interrupting study treatment(s)d, if clinically 
indicated.
Step 2: Adjust current or initiate new antihypertensive 
medication(s). 
Step 3: Titrate antihypertensive medication(s) during next 


Novartis
Confidential
Page 310
Clinical Study Protocol Version 05
Protocol No. MEK116833
Hypertension
Action and Dose Modification
Scenario A
2 weeks as indicated to achieve well-controlled BP. 
Step 4: Once blood pressure (BP) is well-
controlledcontrolledb, restart study treatment(s)df with one 
dose level reduction.
Scenario C:
Symptomatic hypertension 
or recurringc
Persistente SBP 160mm Hg, or DBP 100mm Hg, 
despite modification of antihypertensive medication(s) 
and dose reduction of trametinib
Step 1: Interrupt study treatment(s)df
Step 2: Adjust current or initiate new antihypertensive 
medication(s).
Step 3: Titrate antihypertensive medication(s) during next 
2 weeks as indicated to achieve well-controlled BP. 
Referral to a specialist for further evaluation and follow-up 
is also recommended. 
Step 4: Once BP is well-controlledcontrolledb, restart 
study treatment(s)df with one dose level reduction.
Scenario D: 
Refractory hypertension unresponsive to above 
interventions, or having hypertensive crisis
Discontinue administration of study treatment(s)d and 
continuef
Continue follow-up per protocol.
Abbreviations:  BP = blood pressure; DBP = diastolic blood pressure; mmHg = millimetres mercury; SBP = systolic 
blood pressure;
a.
Hypertension detected in two separate readings during up to three subsequent visits.
b.
Blood pressure of SBP < 140 mm Hg and DBP <90 mm Hg in two separate readings during up to three 
subsequentconsecutive visits.
c.
Escalation of trametinib to previous dose level can be considered if BPs remain well-controlled for 4 weeks 
after restarting of trametinib.  Approval from GSK Medical Monitor is required.
d.
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
e.
Persistent asymptomatic hypertension after initially successful anti-hypertensive intervention.
f.
Modification to study treatment(s) should be discussed with the GSK Medical Monitor.
RATIONALE: Clarification of safety management guidelines based on 
revisions to accepted asset-specific text
Section 3.9.9 Guidelines for Prolonged QTc
PREVIOUS TEXT
Guidelines for dose modification and stopping criteria due to QTc prolongation are 
provided in Table 18.


Novartis
Confidential
Page 311
Clinical Study Protocol Version 05
Protocol No. MEK116833
Table 18
Withholding and Stopping Criteria for QTc Prolongation
QTc Prolongationa
Action and Dose Modification
QTcB501msec

Interrupt study treatment until QTcB 
prolongation resolves to Grade 1 or baseline

Test serum potassium, calcium, phosphorus 
and magnesium. If <LLN, correct with 
supplements to within normal limits.

Review concomitant medication usage for a 
prolonged QTc.

If event resolves, restart  study treatment at 
current dose levelb

If event does not resolve, permanently 
discontinue study treatments. 

If event recurs, permanently discontinue 
study treatments
REVISED TEXT
Guidelines for dose modification and stopping criteria due to QTc prolongation are 
provided in Table 18. For subjects enrolled in France, please refer to Appendix 5 for QTc 
prolongation withholding and stopping criteria.
Table 18
Withholding and Stopping Criteria for QTc Prolongation
QTc Prolongationa
Action and Dose Modification
QTcB501msec
or
uncorrected QT>600msec 
or
QTcB>530msec for subjects with bundle branch block

Interrupt study treatment until QTcB 
prolongation resolves to Grade 1 or baseline

Test serum potassium, calcium, phosphorus 
and magnesium. If <LLN abnormal, correct with 
supplements per routine clinical practice to 
within normal limits.

Review concomitant medication usage for a 
prolonged QTc.

If event resolves, restart  Restart study 
treatment at current dose levelb

If event does not resolve, permanently 
discontinue study treatments. Consider 
evaluation with cardiologist.

If event recurs, permanently discontinue 
study treatments
RATIONALE: Clarification of safety management guidelines based on 
revisions to accepted asset-specific text


Novartis
Confidential
Page 312
Clinical Study Protocol Version 05
Protocol No. MEK116833
Section 3.9.11 Guidelines for Visual Changes or Specified Ophthalmic 
Examination Findings
PREVIOUS TEXT
Section 3.9.11 Visual Changes Stopping Criteria
Episodes of visual changes have been observed in subjects receiving dabrafenib, 
trametinib or the combination of both therapies. The causal relationship between a 
change in vision and the study treatment should be carefully explored and and an 
ophthalmologist should be consulted. Special attention should be given to retinal (e.g., 
RPED) or retinal vein abnormalities (e.g., RVO).  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.
Guidelines regarding management and dose reduction for visual changes considered to be 
related to study treatment are provided in Table 19.
Table 19
Management and Dose Modification Guidelines for Visual 
Changes
CTCAE Gradea
Adverse Event Management
Action and Dose Modification
Grade 1
Asymptomatic or 
mild symptoms; 
clinical or 
diagnostic 
observations 
only; intervention 
not indicated.

Consult ophthalmologist within 7 days 
of onset

Exclude RPED or RVO

Consult retinal specialist in case of 
RPED or RVO

Report RPED and RVO as SAE

Continue follow up examination(s) by 
retinal specialist for RPED and RVO

Continue study treatment at the same dose 
level until ophthalmic examination can be 
conductedb

If ophthalmic examination cannot be 
performed within 7 days of onset, interrupt 
study treatment until CSR and RVO can be 
excluded and symptoms resolve.  

Restart study treatment at same dose level

If RPED is diagnosed: Interrupt study 
treatment until symptoms resolve and exam 
by retinal specialist shows resolution. 

Restart with study treatment reduced by one 
dose level

If RVO is diagnosed:  Permanently 
discontinue study treatment


Novartis
Confidential
Page 313
Clinical Study Protocol Version 05
Protocol No. MEK116833
CTCAE Gradea
Adverse Event Management
Action and Dose Modification
Grade 2 
Moderate, 
minimal, local or 
noninvasive 
intervention 
indicated; limiting 
age-appropriate 
instrumental 
ADL.
and
Grade 3
Severe or 
medically 
significant but not 
immediately 
sight-threatening; 
hospitalization or 
prolongation of 
existing 
hospitalization 
indicated; 
disabling; limiting 
self-care ADL

Consult ophthalmologist immediately 

Exclude RPED and RVO

Consult retinal specialist in case of 
RVO or RPED for follow-up exam

Report RPED and RVO as SAE

Continue follow up examination(s) by 
retinal specialist for RPED and RVO

Interrupt study treatmentuntil signs and 
symptoms have resolved to baseline

Restart with study treatment reduced by one 
dose level

If RPED is diagnosed: Interrupt study 
treatment until symptoms resolve and exam 
by retinal specialist shows resolution.

Restart study treatment reduced by one 
dose level

If RVO is diagnosed: Permanently 
discontinue study treatment
Grade 4
Sight-threatening 
consequences; 
urgent 
intervention 
indicated; 
blindness 
(20/200 or worse) 
in the affected 
eye.

Consult ophthalmologist immediately 

Exclude RPED and RVO

Report RPED and RVO as SAE

Continue follow up examination(s) by 
retinal specialist for RPED and RVO

Permanently discontinue study treatment
Abbreviations:  RPED = Retinal pigment epithelium detachment; CTCAE = Common Terminology Criteria for Adverse 
Events; RVO = retinal vein occlusion; SAE = serious adverse event
a. Refers to CTCAE Version 4.0 ‘Eye disorders – Other, specify
b. If visual changes are clearly unrelated to study treatment (e.g., allergic conjunctivitis), monitor closely but 
ophthalmic examination is not required.
For all visual changes, regardless of grade, a blood sample for pharmacokinetic analysis 
must be drawn as close as possible to the time of onset of the event.
REVISED TEXT
Section 3.9.11 Visual Changes Stopping Criteria Guidelines for Visual 
Changes or Specified Ophthalmic Examination Findings
Episodes of visual changes have been observed in subjects receiving trametinib,
dabrafenib, trametinib or the  and combination of both therapies. The causal relationship 
between a change in vision and the study treatment should be carefully explored and 
antherapy. An ophthalmologist should be consulted if changes in vision develop.  
However, if the visual changes are clearly unrelated to study treatment (e.g., allergic 


Novartis
Confidential
Page 314
Clinical Study Protocol Version 05
Protocol No. MEK116833
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 patients for visual signs and symptoms (such as, change in vision, 
photophobia and eye pain) during therapy. Special attention should be given to retinal 
(e.g., findings (e.g., retinal pigment epithelial detachment (RPED) or retinal vein
retinovascular abnormalities (e.g., i.e., branch or central retinal vein occlusions (RVO).  
For events of visual changes (regardless of severity) for which an ophthalmic 
examination is conducted, a blood sample for PK analysis must be drawn as close as 
possible to the time of the event.
Guidelines regarding management and dose reduction for visual changes considered to be 
related to study treatment are provided in Table 19.
Table 19 Management and Dose Modification Guidelines for Visual 
Changes and/or Ophthalmic Examination Findings
CTCAE Gradea
Adverse Event Management
Action and Dose Modification
Grade 1
Asymptomatic or 
mild symptoms; 
clinical or 
diagnostic 
observations 
only; intervention 
not indicated..

Consult ophthalmologist within 7 days 
of onset

Exclude RPED or RVO

Consult retinal specialist in case of 
RPED or RVO

Report RPED and RVO as SAE

Continue follow up examination(s) by 
retinal specialist for RPED and RVO

Continue study treatment at the same dose 
level until ophthalmic examination can be 
conductedb

If ophthalmic dilated fundus examination 
cannot be performed within 7 days of onset, 
interrupt study treatment until CSR RPED
and RVO can be excluded by retinal 
specialist / ophthalmologist

if RPED and symptoms resolve.  

Restart study treatment RVO excluded, 
continue (or restart) trametinib at same dose 
level

If RPED is suspected or diagnosed: see 
RPED dose modification Table 20 Interrupt 
study treatment until symptoms resolve and 
exam by retinal specialist shows resolution.

Restart with study treatment reduced by one 
dose level

If RVO is below; report as SAE if 
diagnosed.

If RVO diagnosed, Permanently 
discontinue study treatment trametinib 
and report as SAE.


Novartis
Confidential
Page 315
Clinical Study Protocol Version 05
Protocol No. MEK116833
CTCAE Gradea
Adverse Event Management
Action and Dose Modification
Grade 2 
Moderate, 
minimal, local or 
noninvasive 
intervention 
indicated; limiting 
age-appropriate 
instrumental 
ADL.
and
Grade 3
Severe or 
medically 
significant but not 
immediately 
sight-threatening; 
hospitalization or 
prolongation of 
existing 
hospitalization 
indicated; 
disabling; limiting 
self-care ADL

Consult ophthalmologist immediately 

Exclude RPED and RVO

Consult retinal specialist in case of 
RVO or RPED for follow-up exam

Report RPED and RVO as SAE
Continue follow up examination(s) by 
retinal specialist for RPED and RVO

Interrupt trametinib.  If subject is 
receiving trametinib/dabrafenib 
combination therapy, dabrafenib may 
be discontinued.

Interrupt study treatmentuntil signs If RPED
and symptoms have resolved to baseline

Restart with study treatment reduced by one
RVO excluded, restart trametinib at same
dose level

If RPED diagnosed: see RPED dose 
modification Table 20 is diagnosed: Interrupt 
study treatment until symptoms resolve and 
exam by retinal specialist shows resolution
below; report as SAE.

Restart study treatment reduced by one 
dose level

If RVO is diagnosed: Permanently 
discontinue study treatment trametinib 
and report as SAE
Grade 4
Sight-threatening 
consequences; 
urgent 
intervention 
indicated; 
blindness 
(20/200 or worse) 
in the affected 
eye.

Consult ophthalmologist immediately 

Exclude RPED and RVO

Report RPED and RVO as SAE

Continue follow up examination(s) by 
retinal specialist for RPED and RVO 
Interrupt trametinib. .  If subject is 
receiving trametinib/dabrafenib 
combination therapy, dabrafenib may 
be discontinued.

Permanently If RPED and RVO excluded,
may consider restarting trametinib at same or 
reduced dose after discussion with study 
medical monitor 

If RVO or RPED diagnosed, permanently 
discontinue study treatment
Abbreviations:  RPED = Retinal pigment epithelium detachment; CTCAE = Common Terminology Criteria for Adverse 
Events; RVO = retinal vein occlusion; SAE = serious adverse event
c.
Refers to CTCAE Version 4.0 ‘Eye disorders – Other, specify
d. If visual changes are clearly unrelated to study treatment (e.g., allergic conjunctivitis), monitor closely but 
ophthalmic examination is not required.
For all visual changes, regardless of grade, a blood sample for pharmacokinetic analysis 
must be drawn as close as possible to the time of onset of the event.


Novartis
Confidential
Page 316
Clinical Study Protocol Version 05
Protocol No. MEK116833
Table 20 Recommended dose modifications for trametinib for retinal
pigment epithelial detachments (RPED)a
CTCAE Grade
Action and Dose Modification
Grade 1 RPED (Asymptomatic; clinical or 
diagnostic observations only)

Continue treatment with retinal evaluation 
monthly until resolution. If RPED worsens 
follow instructions below 
Grade 2-3 RPED (Symptomatic with mild to 
moderate decrease in visual acuity; limiting 
instrumental ADL)

Interrupt trametinib 

Retinal evaluation monthly 

If improved to ≤ Grade 1, restart trametinib at 
lower dose (reduced by 0.5 mg) or 
discontinue in patients taking trametinib 1 mg 
daily
a. Refers to CTCAE Version 4.0 ‘Retinopathy’
RATIONALE: Clarification of safety management guidelines based on 
revisions to accepted asset-specific text
Table 21 Management and Dose Modification Guidelines for 
Pneumonitis/ILD
PREVIOUS TEXT
CTCAE Grade
Adverse Event Management
Action and Dose Modification
Grade 1
CT scan (high-resolution with lung windows) 
is recommended. 
Clinical evaluation and laboratory work-up 
for infection should be performed. 
Monitoring of oxygenation via pulse-oximetry 
is recommended. 
Consultation by a pulmonologist is 
recommended.
Continue dabrafenib and trametinib at 
current dose.
Permanently discontinue panitumumab.
Grade 2
CT scan (high-resolution with lung windows) 
is recommended.
Clinical evaluation and laboratory work-up 
for infection should be performed.
Consult a pulmonologist.
Pulmonary function testing should be 
performed; if < normal, repeat every 8 
weeks until results are normal.
Bronchoscopy with biopsy and/or 
Interrupt dabrafenib and trametinib until 
recovery to Grade 1.
Permanently discontinue panitumumab.
Restart dabrafenib and trametinib, reduced 
by one dose level.
Escalation to previous dose level after 4 
weeks and after consultation with the GSK 
Medical Monitor
If symptoms do not recover to Grade 1 


Novartis
Confidential
Page 317
Clinical Study Protocol Version 05
Protocol No. MEK116833
CTCAE Grade
Adverse Event Management
Action and Dose Modification
bronchalveolar lavage (BAL) is 
recommended.
Symptomatic therapy including 
corticosteroids is recommended if clinically 
indicated. 
within 4 weeks, permanently discontinue 
dabrafenib and trametinib.
Grade 3
CT scan (high-resolution with lung windows) 
should be performed.
Clinical evaluation and laboratory work-up 
for infection should be performed.
Consult a pulmonologist.
Pulmonary function testing should be 
performed; if < normal, repeat every 8 
weeks until results are normal.
Bronchoscopy with biopsy and/or BAL if 
possible.
Symptomatic therapy including 
corticosteroids is recommended if clinically 
indicated.
Interrupt dabrafenib and trametinib until 
recovery to Grade 1.
Permanently discontinue panitumumab.
After consultation with GSK Medical Monitor, 
dabrafenib and trametinib may be restarted 
with a one dose level reduction.
If symptoms do not recover to Grade 1 
within 4 weeks, permanently discontinue 
dabrafenibtrametinib
Grade 4
CT scan (high-resolution with lung windows) 
should be performed.
Clinical evaluation and laboratory work-up 
for infection should be performed.
Consult a pulmonologist.
Pulmonary function testing should be 
performed; if < normal, repeat every 8 
weeks until results are normal.
Bronchoscopy with biopsy and/or BAL if 
possible.
Symptomatic therapy including
corticosteroids is recommended if clinically 
indicated.
Permanently discontinue dabrafenib, 
panitumumab and trametinib


Novartis
Confidential
Page 318
Clinical Study Protocol Version 05
Protocol No. MEK116833
REVISED TEXT
CTCAE Grade
Adverse Event Management
Action and Dose Modification
Grade 1
CT scan (high-resolution with lung windows) 
is recommended. 
Clinical evaluation and laboratory work-up 
for infection should be performed. 
Monitoring of oxygenation via pulse-oximetry 
is recommended. 
Consultation by a pulmonologist is 
recommended.
Continue dabrafenib and trametinib at 
current dose.
Permanently discontinue panitumumab.
Grade 2
CT scan (high-resolution with lung windows) 
is recommended.
Clinical evaluation and laboratory work-up 
for infection should be performed.
Consult a pulmonologist.
Pulmonary function testing should be 
performed; if < normal, repeat every 8 
weeks until results are normal.
Bronchoscopy with biopsy and/or 
bronchalveolar lavage (BAL) is 
recommended.
Symptomatic therapy including 
corticosteroids is recommended if clinically 
indicated. 
Interrupt dabrafenib and trametinib until 
recovery to Grade 1.
Permanently discontinue panitumumab.
Restart dabrafenib and trametinib, reduced 
by one dose level.
Escalation to previous dose level after 4 
weeks and after consultation with the GSK 
Medical Monitor
If symptoms do not recover to Grade 1 
within 4 weeks, permanently discontinue 
dabrafenib and trametinib.
Grade 3
CT scan (high-resolution with lung windows) 
should be performed.
Clinical evaluation and laboratory work-up 
for infection should be performed.
Consult a pulmonologist.
Pulmonary function testing should be 
performed; if < normal, repeat every 8 
weeks until results are normal.
Bronchoscopy with biopsy and/or BAL if 
possible.
Symptomatic therapy including 
corticosteroids is recommended if clinically 
indicated.
Interrupt dabrafenib and trametinib until 
recovery to Grade 1.
Permanently discontinue panitumumab.
After consultation with GSK Medical Monitor, 
dabrafenib and trametinib may be restarted 
with a one dose level reduction.
If symptoms do not recover to Grade 1 
within 4 weeks, permanently discontinue 
dabrafenibtrametinib
Grade 4
CT scan (high-resolution with lung windows) 
should be performed.
Clinical evaluation and laboratory work-up 
for infection should be performed.
Permanently discontinue dabrafenib, 
panitumumab and trametinib


Novartis
Confidential
Page 319
Clinical Study Protocol Version 05
Protocol No. MEK116833
CTCAE Grade
Adverse Event Management
Action and Dose Modification
Consult a pulmonologist.
Pulmonary function testing should be 
performed; if < normal, repeat every 8 
weeks until results are normal.
Bronchoscopy with biopsy and/or BAL if 
possible.
Symptomatic therapy including 
corticosteroids is recommended if clinically 
indicated.Same as Grade 3.
RATIONALE: Clarification of safety management guidelines based on 
revisions to accepted asset-specific text
Section 3.10.1 Part 1 Dose Escalation Time and Events Table
PREVIOUS TEXT
Hematology/Clinical Chemistry (including Screening assessment of adequate baseline 
organ function as noted in Table 18)
Footnote 1: All screening assessments must be completed within 14 days prior to first 
dose except informed consent, ophthalmology exam, ECHO/MUGA and Disease 
Assessment, which can occur within 35 days prior to the first dose. Note: Procedures 
conducted as part of the subject’s routine clinical management (e.g., blood counts,
imaging study) and obtained prior to signing of informed consent may be utilized for 
screening or baseline purposes provided these procedures meet the protocol requirements.
Footnote 14: Vital signs and temperature should be measured within 30 minutes prior to 
initiation and upon completion of the panitumumab infusion 
REVISED TEXT
Hematology/Clinical Chemistry (including Screening assessment of adequate baseline 
organ function as noted in Table 18)
Coagulation; Repeat as clinically indicated: at Screening
CEA: at Screening, Day 1, Day 15, Day 21, in Continuation Phase: At Week 4, then 
every 4 weeks until Week 24, then every 8 weeks, at Initial Follow-up and at Secondary 
Follow-up Visits
Footnote 1: All screening assessments must be completed within 14 days prior to first 
dose except informed consent, ophthalmology exam, dermatology exam, ECHO/MUGA 
and Disease Assessment, which can occur within 35 days prior to the first dose. Note: 
Procedures conducted as part of the subject’s routine clinical management (e.g., blood 


Novartis
Confidential
Page 320
Clinical Study Protocol Version 05
Protocol No. MEK116833
counts, imaging study) and obtained prior to signing of informed consent may be utilized 
for screening or baseline purposes provided these procedures meet the protocol 
requirements.
Footnote 14: Vital signs and temperature should be measured within 30 minutes prior to 
initiation and upon completion of the panitumumab infusion (up to 15 minutes after the 
end of infusion).
RATIONALE:  Clarification of previous assessments, addition of CEA 
collection timepoints
Section 3.10.2 Part 2 Expansion Cohorts Time and Events Table
PREVIOUS TEXT
Hematology/Clinical Chemistry (including Screening assessment of adequate baseline 
organ function as noted in Table 18)
Footnote 1: All screening assessments must be completed within 14 days prior to first 
dose except informed consent, ophthalmology exam, ECHO/MUGA and Disease 
Assessment, which can occur within 35 days prior to the first dose. Note: Procedures 
conducted as part of the subject’s routine clinical management (e.g., blood counts, 
imaging study) and obtained prior to signing of informed consent may be utilized for 
screening or baseline purposes provided these procedures meet the protocol requirements.
Footnote 14: Vital signs and temperature should be measured within 30 minutes prior to 
initiation and upon completion of the panitumumab infusion 
REVISED TEXT
Hematology/Clinical Chemistry (including Screening assessment of adequate baseline 
organ function as noted in Table 18)
Coagulation; Repeat as clinically indicated: at Screening
CEA: at Screening, Day 1, Day 15,  in Continuation Phase: At Week 4, then every 4 
weeks until Week 24, then every 8 weeks, at Initial Follow-up and at Secondary Follow-
up Visits
  
 
 
 
Footnote 1: All screening assessments must be completed within 14 days prior to first 
dose except informed consent, ophthalmology exam, dermatology exam, ECHO/MUGA 
and Disease Assessment, which can occur within 35 days prior to the first dose. Note: 
Procedures conducted as part of the subject’s routine clinical management (e.g., blood 


Novartis
Confidential
Page 321
Clinical Study Protocol Version 05
Protocol No. MEK116833
counts, imaging study) and obtained prior to signing of informed consent may be utilized 
for screening or baseline purposes provided these procedures meet the protocol 
requirements.
Footnote 14: Vital signs and temperature should be measured within 30 minutes prior to 
initiation and upon completion of the panitumumab infusion (up to 15 minutes after the 
end of infusion).
RATIONALE:  Clarification of previous assessments, addition of CEA 
collection timepoints and collection of blood sample 
Section 3.10.3 Part 3 Randomized Phase 2 Time and Events Table
PREVIOUS TEXT
Hematology/Clinical Chemistry (including Screening assessment of adequate baseline 
organ function as noted in Table 18)
Footnote 1: All screening assessments must be completed within 14 days prior to first 
dose except informed consent, ophthalmology exam, ECHO/MUGA and Disease 
Assessment, which can occur within 35 days prior to the first dose. Note: Procedures 
conducted as part of the subject’s routine clinical management (e.g., blood counts, 
imaging study) and obtained prior to signing of informed consent may be utilized for 
screening or baseline purposes provided these procedures meet the protocol requirements.
Footnote 10: Vital signs and temperature should be measured within 30 minutes prior to 
initiation and upon completion of the panitumumab infusion 
REVISED TEXT
Hematology/Clinical Chemistry (including Screening assessment of adequate baseline 
organ function as noted in Table 18)
Coagulation; Repeat as clinically indicated: at Screening
CEA: at Screening, Day 1, Day 15, every 4 weeks, every 8 weeks, every 12 weeks and at 
Follow-up visit
 
 
Footnote 10: Vital signs and temperature should be measured within 30 minutes prior to 
initiation and upon completion of the panitumumab infusion (up to 15 minutes after the 
end of infusion).
RATIONALE:  Clarification of previous assessments, addition of CEA 
collection timepoints and collection of blood sample for 


Novartis
Confidential
Page 322
Clinical Study Protocol Version 05
Protocol No. MEK116833
Section 3.10.4 Part 4 Dose Escalation and Cohort Expansion Time and 
Events Table, Added Section
Day:
Scree
ning1
Scree
ning1
First treatment 
period, 
Day 1 thru Day 
28/end of Week 
4
Continuat
ion phase 
Day 
29/start of 
Week 52
Initial 
follow-
up3
Secondary 
follow-up3
Tertiary 
follow-up3
Visit 
Window 
(relative to 
Day 1)
-35 to 
-1 
days
-14 to 
-1 
days
on 
Da
y 1
on 
Da
y 
15
(
2 
day
s)
on 
Da
y 
21
(
2 
day
s)
14 (7) 
days 
from last 
dose of 
trametini
b
4 weeks (7 
days) after 
the last dose 
of 
panitumumab
8 weeks (7 
days) after 
the last 
dose of 
panitumum
ab
Informed 
Consent
X
Demograph
ics
X
Collection 
of archival 
tissue12
X
Complete 
physical5
X
X
Brief 
physical5
X
X
At Week 4, 
then every 
4 wks
Medical/me
dication/
drug/alcoh
ol history
X
X6
X
X
12-lead 
ECG7
X
X6
X
X
At Week 4, 
then every 
4 weeks 
until Week 
24, then 
every 8 
weeks
X
Vital signs 
13 (including 
weight)
X
X
X
X
X
X
Height
X
Ophthalmic 
examinatio
n
X
At Week 4, 
then as 
symptomat
ically 
warranted
ECOG
X
X6
At Week 4, 
then every 
4 wks
X
ECHO/MUG
A17
X
At Week 4, 
then at 
Week 12, 
then every 
12 weeks
X


Novartis
Confidential
Page 323
Clinical Study Protocol Version 05
Protocol No. MEK116833
Day:
Scree
ning1
Scree
ning1
First treatment 
period, 
Day 1 thru Day 
28/end of Week 
4
Continuat
ion phase 
Day 
29/start of 
Week 52
Initial 
follow-
up3
Secondary 
follow-up3
Tertiary 
follow-up3
Visit 
Window 
(relative to 
Day 1)
-35 to 
-1 
days
-14 to 
-1 
days
on 
Da
y 1
on 
Da
y 
15
(
2 
day
s)
on 
Da
y 
21
(
2 
day
s)
14 (7) 
days 
from last 
dose of 
trametini
b
4 weeks (7 
days) after 
the last dose 
of 
panitumumab
8 weeks (7 
days) after 
the last 
dose of 
panitumum
ab
Serum or 
urine 
pregnancy 
test (-
hCG;wome
n)4
X
Every 8 to 
12 weeks 4
Hema/Che
m/Urinalysi
s tests
X
X6
At Week 4, 
then every 
4 weeks 
until Week 
24, then 
every 8 
weeks
X
X
Coagulatio
n
Repeat as 
clinically 
indicated
X
CEA
X
X
At Week 4, 
then every 
4 weeks 
until Week 
24, then 
every 8 
weeks
X
X
Tumor 
biopsy15
X (pre-dose)15
X9
(to 
be 
coll
ect
ed 
fro
m 
Day 
15 
to 
Day 
18)
X10
(at 
progressi
on)


Novartis
Confidential
Page 324
Clinical Study Protocol Version 05
Protocol No. MEK116833
Day:
Scree
ning1
Scree
ning1
First treatment 
period, 
Day 1 thru Day 
28/end of Week 
4
Continuat
ion phase 
Day 
29/start of 
Week 52
Initial 
follow-
up3
Secondary 
follow-up3
Tertiary 
follow-up3
Visit 
Window 
(relative to 
Day 1)
-35 to 
-1 
days
-14 to 
-1 
days
on 
Da
y 1
on 
Da
y 
15
(
2 
day
s)
on 
Da
y 
21
(
2 
day
s)
14 (7) 
days 
from last 
dose of 
trametini
b
4 weeks (7 
days) after 
the last dose 
of 
panitumumab
8 weeks (7 
days) after 
the last 
dose of 
panitumum
ab
Collection 
of blood 
sample for 
immunogen
icity  
analysis
X 
(pr
e-
do
se)
Predose at 
Week 8
X14
X14
AE 
assessmen
t
PK blood 
sample8
X
X
X
Panitumum
ab Dosing
X
X
X
every 2 
weeks 
from Day 1
Trametinib 
dosing
X
X
X
X
Disease 
assessmen
ts11
x
Every 6 
weeks 
until Week 
24, 
then every 
8 weeks. 16


Novartis
Confidential
Page 325
Clinical Study Protocol Version 05
Protocol No. MEK116833
19. All screening assessments must be completed within 14 days prior to first dose except informed consent, 
ophthalmology exam, dermatological exam, ECHO/MUGA and Disease Assessment, which can occur within 35 
days prior to the first dose. Note: Procedures conducted as part of the subject’s routine clinical management (e.g., 
blood counts, imaging study) and obtained prior to signing of informed consent may be utilized for screening or 
baseline purposes provided these procedures meet the protocol requirements.
20. Assessments throughout the study are calendar-based starting from the first day of dosing (Day 1) in the first 
treatment period.  Dose interruptions should not alter the assessment schedule for any subsequent treatment 
period.  The continuation phase starts with Day 29; events in the continuation phase are allowed 7 days from 
projected date.  Safety lab tests (chemistry/hematology/UA) may be done the day before the visit so that results 
are available on the day of the visit, but all assessments should be done within the 7 day window.
21. Initial follow-up visit should be 14 days (7 days) from last dose of trametinib. If a subject is unable to return to 
the clinic due to hospitalization, site staff are encouraged to telephone the subject for assessment of AEs. 
Secondary follow-up visits should occur at 4 weeks and 8 weeks after the last dose of panitumumab.
22. Serum pregnancy test should be performed at screening; all subsequent pregnancy tests may be either serum or 
urine, and performed every 8 to 12 weeks.
23. Complete physical examination must include integument and genitalia. Note: pelvic exam in female subjects may 
be completed up to 24 weeks prior to date of first dose. Complete and brief physical examinations are defined in 
Section 6.2.
24. If within 72 hours of Screening, this assessment does not need to be repeated on Day 1.
25. Single ECGs will be collected prior to dosing.
26. Blood samples (2 mL) for PK analysis of trametinib will be collected on Day 1 and on Day 15 predose (within 30 
minutes of dosing) and at 1, 2 and 4 hours after administration. Blood samples (4 mL) for PK analysis of 
panitumumab will be collected on Day 1 and on Day 15 predose (within 30 minutes of dosing with panitumumab) 
and at 1 hour ( at the end of infusion of panitumumab). A single 4 mL blood sample for analysis of panitumumab 
will be collected pre-dose on Day 21 during the clinic visit. During the continuation phase, PK samples (for 
trametinib and panitumumab) will be collected pre-dose at Week 8, Week 12, Week 16, and Week 20. PK blood 
samples for trametinib, and panitumumab analysis should be collected along with the tumor biopsy taken at 
progression. On days when serial PK samples are collected, subjects should be instructed to hold doses of 
trametinib, report to the clinic for the predose PK blood draw, then dose with trametinib. Collect PK samples at the 
time indicated 5 minutes up to 2 hour sample, 20 minutes up to the 4 hour sample. 
27. Collection of on-treatment tumor biopsy for subjects with accessible tumors. On-treatment biopsy may be 
collected 2 to 4 hours after dosing with oral study medication from Day 15 to Day 18. Biopsies should be 
performed on non-target lesions when possible. PK samples for trametinib and panitumumab analysis will be 
collected at the time of the post-dose tumor biopsy (24 hours) (unless the post-dose biopsy occurs on the same 
day that the Day 15 serial PK samples are collected).
28. Tumor biopsy at tumor progression in subjects who have had a response is highly encouraged. PK blood samples 
for trametinib, and panitumumab analysis should be collected along with the tumor biopsy taken at progression.
29. CT is the preferred method to measure lesions selected for response assessment. Refer to Appendix 4 for 
additional information regarding Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1 methodology 
and criteria. Even if study treatment is withdrawn, radiographic disease assessments (computed tomography [CT] 
or magnetic resonance imaging [MRI], as appropriate according to the method used at baseline) should continue 
every 8 weeks until documented disease progression, the start of new anti-cancer therapy, withdrawal of consent 
or death.
30. Collection of archived tumor tissue or fresh tumor biopsies is required for enrollment; if a fresh tumor biopsy is 
collected at screening, this tissue may be used for the day 1/ predose tumor biopsy. 
 
The Day 1/predose tumor biopsy 
may be collected at any point after signing consent, up to 14 days prior to first dose.
31. Vital signs and temperature should be measured within 30 minutes prior to initiation and upon completion of the 
panitumumab infusion (up to 15 minutes after the end of infusion).
 
33. Collection of archived tumor tissue or fresh tumor biopsies and determination of the subject’s tumor BRAF 
mutation status is required for enrollment; if a fresh tumor biopsy is collected during screening and up to prior to 
dosing on Day1 for BRAF mutation confirmation, this tissue may be used for the day 1/ predose tumor biopsy. 
  The 
Day 1/predose tumor biopsy may be collected at any point after signing consent, after completing wash-out from 


Novartis
Confidential
Page 326
Clinical Study Protocol Version 05
Protocol No. MEK116833
prior therapies (either 5 half-lives or 14 days from last dose of prior therapy). Pre- and post-dose tumor biopsies 
are mandatory. If the patient’s tumors are inaccessible for biopsy, permission to enroll must be granted by the 
GSK Medical Monitor
17. After study treatment is withdrawn, disease assessments (the method used at baseline) should continue every 8 
weeks until documented disease progression, the start of new
anti-cancer therapy, withdrawal of consent, or death.
1.
ECHO is preferred. MUGA may be used only if ECHO is not available. The same method must be used 
consistently from screening throughout the study.
 
RATIONALE: Time and events table describing assessments associated 
with addition of Part 4
Section 4.1 Number of Subjects, Paragraph 2
PREVIOUS TEXT
To complete Part 1, it is estimated that 24 evaluable subjects (~4 per cohort) will be 
enrolled.  Part 2 will enroll approximately 30 subjects in total. Approximately 40 subjects 
will be evaluated at the end of Part 2, including those enrolled in Part 1 at the same dose 
levels. For Part 3, approximately 47 subjects per arm will be enrolled.  .
REVISED TEXT
To complete Part 1, it is estimated that 24 evaluable subjects (~4 per cohort) will be 
enrolled.  Part 2 will enroll approximately 30 subjects in total. In order to confirm safety 
in Japanese patients, up to three additional Japanese patients may be enrolled in Japan in 
each expansion cohort.  Approximately 40 20 subjects will be evaluated at the RP2D/R 
for each combination tested by the end of Part 2, including those subjects enrolled in Part 
1 at the same dose levels RP2D/R in Part 1. For Part 3, approximately 47 subjects per 
arm will be enrolled.  For Part 4A (dose escalation), it is estimated that up to 18 evaluable 
subjects (~6 per cohort) will be enrolled.  Part 4B (expansion cohorts 1E and 2E) will 
enroll approximately 17 additional subjects in each of two expansion cohorts (n=34). 
This will be a total of approximately 20 patients at the RP2D/R for each patient 
population, including the subjects enrolled in Part 4A.
RATIONALE: Addition of number of subjects to be enrolled with addition of 
Part 4
PREVIOUS TEXT
Section 4.2.1 Part 1 and Part 2 Inclusion Criteria
REVISED TEXT
Section 4.2.1 Part 1, 2 and Part 24 Inclusion and Exclusion Criteria
Section 4.2.1.1 Part 1, 2 and Part 4 Inclusion Criteria


Novartis
Confidential
Page 327
Clinical Study Protocol Version 05
Protocol No. MEK116833
PREVIOUS TEXT
Inclusion criterion 3:
Histologically- or cytologically-confirmed diagnosis of advanced or metastatic BRAF 
V600E mutation positive colorectal cancer (CRC), as determined by relevant genetic 
testing and documented in source.  For subjects enrolled based on local mutation testing, 
confirmation of mutation will occur following registration in Part 1 and Part 2.
Note: Subjects will not be excluded if centralized testing is later found to be discordant or 
uninformative (e.g., inadequate sample), but additional subjects may be enrolled as 
replacement subjects at the discretion of the Sponsor and in consultation with the 
investigator
Table 22 Definitions for Adequate Baseline Organ Function
System
Laboratory Values
Hematologic 
Absolute neutrophil count
1.2 × 109/L 
Hemoglobin
9 g/dL or 5.6 mmol/L
Platelets
75 × 109/L  
Prothrombin Time / International 
Normalized Ratio (PT/INR) and Partial 
Thromboplastin Time (PTT)
≤1.5 x ULN
Chemistry
Mg++
≥ LLN
Hepatic
Albumin
2.5 g/dL or 25 g/L
Total bilirubin
1.5 x ULN
AST and ALT
2.5× ULN 
Renal
Creatinine or
1.5 ULN
Calculated creatinine clearancea 
or 
24-hour urine creatinine clearance
50 mL/min 
Cardiac
Left Ventricular Ejection fraction (LVEF)
≥ LLN by ECHO or multigated acquisition scan 
(MUGA)b
d.
Calculated by the Cockcroft-Gault formula.
e.
Same method as used at baseline must be use throughout the study, ECHO is the preferred method
Inclusion criterion 12:
Subjects enrolled in France: In France, a subject will be eligible for inclusion in this study 
only if either affiliated to, or a beneficiary of, a social security category


Novartis
Confidential
Page 328
Clinical Study Protocol Version 05
Protocol No. MEK116833
REVISED TEXT
Inclusion criterion 3:
Part 1 and Part 2: Histologically- or cytologically-confirmed diagnosis of advanced or 
metastatic BRAF V600E mutation positive colorectal cancer (CRC), as determined by 
relevant genetic testing and documented in source.  For subjects enrolled based on local 
mutation testing, confirmation of mutation will occur following registration in Part 1 and 
Part 2.
Note: Subjects will not be excluded if centralized testing is later found to be discordant or 
uninformative (e.g., inadequate sample), but additional subjects may be enrolled as 
replacement subjects at the discretion of the Sponsor and in consultation with the 
investigator
Inclusion criterion 4:
Part 4A and 4B ONLY: Histologically- or cytologically-confirmed diagnosis of advanced 
or metastatic colorectal cancer (CRC) that either:

harbours the BRAF V600E –mutation, as determined by relevant genetic testing 
and documented in source, OR 

has developed secondary resistance to anti-EGFR therapy, defined as patients that 
derived benefit (disease control based on investigator assessment for > 6 months 
OR partial response [confirmed or unconfirmed] based on RECIST 1.1) from 
prior anti-EGFR-containing therapy (as defined below) and then subsequently 
progressed on therapy.  The anti-EGFR therapy must have been the most recent 
therapy and the patient must have progressed based on investigator assessment 
within 3 months of screening.  Acceptable prior anti-EGFR-containing therapies 
include:
a.
Monotherapy anti-EGFR, including cetuximab or panitumumab OR
b. irinotecan/anti-EGFR combo after previously having disease progression 
(based on investigator assessment) on an irinotecan-containing regimen
System
Laboratory Values
Hematologic 
Absolute neutrophil count
1.2 × 109/L 
Hemoglobin
9 g/dL or 5.6 mmol/L
Platelets
75 × 109/L  
Coagulation parameters
Prothrombin Time / International 
Normalized Ratio (PT/INR) and 
Partial Thromboplastin Time (PTT)a
≤1.5 x ULN
Chemistry
Mg++
≥ LLN
Hepatic
Albumin
2.5 g/dL or 25 g/L
Total bilirubin
1.5 x ULN
AST and ALT
2.5× ULN 


Novartis
Confidential
Page 329
Clinical Study Protocol Version 05
Protocol No. MEK116833
Renal
Creatinine or
1.5 ULN
Calculated creatinine clearanceab
or 
24-hour urine creatinine clearance
50 mL/min 
Cardiac
Left Ventricular Ejection fraction 
(LVEF)
≥ LLN by ECHO or multigated acquisition scan 
(MUGA)bc
a.
Subjects receiving anticoagulant therapy are eligibile if their INR is stable and within the recommended range 
for the desired level of anticoagulation
b.
Calculated by the Cockcroft-Gault formula.
c.
Same method as used at baseline must be use throughout the study, ECHO is the preferred method.
Inclusion criterion 12:
Subjects enrolled in France or Italy: In France or Italy, a subject will be eligible for 
inclusion in this study only if either affiliated to, or a beneficiary of, a social security 
category
RATIONALE: Addition inclusion criteria to define eligibility for subjects to 
be enrolled with addition of Part 4
Section 4.2.1.2 Part 1, 2 and Part 4 Exclusion Criteria
PREVIOUS TEXT
Exclusion criterion 6:
Prior exposure to BRAF or MEK inhibitors.
Exclusion criterion 7:
Prior exposure to EGFR inhibitors, including anti-EGFR antibodies (Part 2 ONLY)
Exclusion criterion 8:
Known presence of KRAS-mutation based on previous KRAS-testing.
Note: Propsective KRAS testing is not required.  However, if the results of previous 
KRAS testing are known, they must be used in assessing eligibility.  KRAS testing will 
be performed retrospectively for all patients.
Exclusion criterion 11:
Known Human Immunodeficiency Virus (HIV), Hepatitis B, or Hepatitis C infection.
Exclusion criteria 15 & 16:
History of retinal vein occlusion (RVO) or Retinal pigment epithelium detachment
(RPED), predisposing factors to RVO or RPED (e.g., uncontrolled glaucoma or ocular 


Novartis
Confidential
Page 330
Clinical Study Protocol Version 05
Protocol No. MEK116833
hypertension, uncontrolled systemic disease such as hypertension, diabetes mellitus, or a 
history of hyperviscosity or hypercoagulability syndromes).
Visible retinal pathology as assessed by ophthalmic examination that is considered a risk 
for RVO or RPED, such as:

Evidence of new optic disc cupping.

Evidence of new visual field defects.
Intraocular pressure >21mm Hg as measured by tonography
REVISED TEXT
Exclusion criterion 6:
Prior exposure to BRAF or a MEK inhibitors inhibitor.
Exclusion criterion 7:
Part 1, Part 2 and BRAF-mutant patients in Part 4 ONLY: Prior exposure to EGFR 
inhibitors, including anti-EGFR antibodies (Part 2 ONLY)a BRAF inhibitor.
Exclusion criterion 8:
Part 1, Part 2 and BRAF-mutant patients in Part 4 ONLY: Known presence of KRAS-
mutation based on previous KRAS-testing.
Note: Propsective KRAS testing is not required.  However, if the results of previous 
KRAS testing are known, they must be used in assessing eligibility.  KRAS testing will 
be performed retrospectively for all patients.
Exclusion criterion 11:
Known Human Immunodeficiency Virus (HIV), Hepatitis B, or Hepatitis C infection.
Exclusion criteria 17:
History of retinal vein occlusion (RVO) or Retinal pigment epithelium detachment
(RPED), predisposing factors to RVO or RPED (e.g., uncontrolled glaucoma or ocular 
hypertension, uncontrolled systemic disease such as hypertension, diabetes mellitus, or a 
history of hyperviscosity or hypercoagulability syndromes).
Visible retinal pathology as assessed by ophthalmic examination that is considered a risk 
for RVO or RPED, such as:

Evidence of new optic disc cupping.

Evidence of new visual field defects.

Intraocular pressure >21mm Hg as measured by tonography.
History of retinal vein occlusion (RVO).
RATIONALE: Revision of eligibility criteria to reflect revised safety 


Novartis
Confidential
Page 331
Clinical Study Protocol Version 05
Protocol No. MEK116833
management guidelines based on accepted asset-specific text
Section 4.2.2.2 Part 3 Exclusion Criteria
PREVIOUS TEXT
Exclusion criteria 14 & 15:
History of retinal vein occlusion (RVO) or Retinal pigment epithelium detachment
(RPED), predisposing factors to RVO or RPED (e.g., uncontrolled glaucoma or ocular 
hypertension, uncontrolled systemic disease such as hypertension, diabetes mellitus, or a 
history of hyperviscosity or hypercoagulability syndromes).
Visible retinal pathology as assessed by ophthalmic examination that is considered a risk 
for RVO or RPED, such as:

Evidence of new optic disc cupping.

Evidence of new visual field defects.
Intraocular pressure >21mm Hg as measured by tonography.
REVISED TEXT
Exclusion criterion 14:
History of retinal vein occlusion (RVO) or Retinal pigment epithelium detachment
(RPED), predisposing factors to RVO or RPED (e.g., uncontrolled glaucoma or ocular 
hypertension, uncontrolled systemic disease such as hypertension, diabetes mellitus, or a 
history of hyperviscosity or hypercoagulability syndromes).
Visible retinal pathology as assessed by ophthalmic examination that is considered a risk 
for RVO or RPED, such as:

Evidence of new optic disc cupping.

Evidence of new visual field defects.

Intraocular pressure >21mm Hg as measured by tonography.
History of retinal vein occlusion (RVO).
RATIONALE: Revision of eligibility criteria to reflect revised safety 
management guidelines based on accepted asset-specific text
Section 5.1 Hypotheses and Treatment Comparisons
PREVIOUS TEXT
Section 5.1.1 Part 1
The primary goals in Part 1 of this study are to determine safety and the recommended 
dose(s) for Part 2 based on available safety, PK and any clinical activity data of 
trametinib when administered in combination with dabrafenib and panitumumab; thus, no 


Novartis
Confidential
Page 332
Clinical Study Protocol Version 05
Protocol No. MEK116833
formal statistical hypotheses will be tested.  Analysis will be descriptive 
Section 5.1.2 Part 2, Paragraphs 1 and 2
For Part 2, efficacy will be evaluated to decide whether to proceed with further 
development based on the clinical activity seen in Part 1 and Part 2. Futility analysis 
criteria at the end of Part 2 will be based on 2-stage Green-Dahlberg design’s [Green, 
1992] interim analysis criteria.  The criteria will be based on a historically unimportant 
response rate of 15% versus a response rate of interest of 30%. The Part 2 portion of the 
study will employ a Bayesian design that allows the trial to be monitored more frequently 
at multiple stages. Bayesian statistics will be employed to calculate the predictive 
probability that the response rate ≥30% and ≥15% at interim assuming a Beta prior for 
the Binomial distributed data.  Predictive probability calculates the probability that the 
response rate ≥30% or ≥15% at the end of Part 2 (after 20 subjects) given the responses 
have already been observed.  It predicts what is likely to happen at the end of Part 2 so is 
more meaningful and straightforward than posterior probability.  A weak prior Beta 
(0.003, 0.007) is used, which is equivalent to the information present in 0.01 subject.
An initial total of 10 subjects will be recruited at a dose level based on the recommended 
dose for each treatment (including the subjects treated in Part 1 at the same dose).  The 
number of subjects will be increased up to a total of 20 depending on the results observed.  
The tables below show the decision rules for the 10th to 19th evaluable subjects, 
specifying the number of subjects with a confirmed response needed for continuing 
enrolment or stopping for futility.  The methodology is based on the predictive 
probability of success if enrolment continues to 20 subjects [Lee, 2008].  These rules are 
intended as a guideline.  Actual decisions will depend on the totality of the data.
REVISED TEXT
Section 5.1.1 Part 1 and Part 4 Dose Escalation
The primary goals in Part 1 of this study are to determine safety and the recommended 
dose(s) for Part 2 and Part 4 based on available safety, PK and any clinical activity data 
of trametinib when administered in combination with dabrafenib and panitumumab; thus, 
no formal statistical hypotheses will be tested.  Analysis will be descriptive 
 
Section 5.1.2 Part 2 and Part 4 Cohort Expansion, Paragraphs 1 and 2
For Part 2 and Part 4 cohort expansion, efficacy will be evaluated for each cohort to 
decide whether to proceed with further development based on the clinical activity seen in 
Part 1 and Part 2. Futility analysis criteria at the end of Part 2 and Part 4 will be based on 
2-stage Green-Dahlberg design’s [Green, 1992] interim analysis criteria.  The criteria will 
be based on a historically unimportant response rate of 15% versus a response rate of 
interest of 30%. The Part 2 and Part 4B portion of the study will employ a Bayesian 
design that allows the trial to be monitored more frequently at multiple stages. Bayesian 
statistics will be employed to calculate the predictive probability that the response rate 
≥30% and ≥15% at interim assuming a Beta prior for the Binomial distributed data.  
Predictive probability calculates the probability that the response rate ≥30% or ≥15% at 


Novartis
Confidential
Page 333
Clinical Study Protocol Version 05
Protocol No. MEK116833
the end of Part 2 (after 20 subjects) given the responses have already been observed.  It 
predicts what is likely to happen at the end of Part 2 and Part 4 so is more meaningful and 
straightforward than posterior probability.  A weak prior Beta (0.003, 0.007) is used, 
which is equivalent to the information present in 0.01 subject. Futility analysis criteria 
based on 2-stage Green-Dahlberg design’s are only used at the end of Part 2 and Part 4B 
when all subjects are enrolled. Bayesian design based criteria are only used for interim 
data monitoring before the end of Part 2 or Part 4B data analysis allowing early stop for 
futility.  An initial total of 10 subjects will be recruited at a dose level based on the 
recommended dose for each treatment/cohort (including the subjects treated in Part 1 or 
Part 4A at the same dose). with the same mutation status).  The number of subjects will 
be increased up to a total of 20 per treatment cohort depending on the results observed.  
The tables below show the decision rules for the 10th to 19th evaluable subjects, 
specifying the number of subjects with a confirmed response needed for continuing 
enrolment or stopping for futility.  The methodology is based on the predictive 
probability of success if enrolment continues to 20 subjects [Lee, 2008].  These rules are 
intended as a guideline.  Actual decisions will depend on the totality of the data.
RATIONALE: Revisions to incorporate analysis of Part 4 data
Section 5.2.1 Sample Size Assumptions
PREVIOUS TEXT
Section 5.2.1.1 Part 1
The total number of subjects in Part 1 will depend on the number of dose escalations 
needed. However, the maximum anticipated number of subjects will be approximately 24. 
Table 21
Statistical Basis for Phase 1 Dose Escalation
True incidence of dose-limiting toxicity
10%
20%
30%
40%
50%
60%
Probability of escalating the dose
0.91
0.71
0.49
0.31
0.17
0.08
REVISED TEXT
Section 5.2.1.1 Part 1 and Part 4 Dose Escalation
The total number of subjects in Part 1 and Part 4 dose escalation will depend on the 
number of dose escalations needed. However, the maximum anticipated number of 
subjects will be approximately 24 in Part 1 and approximately 12 in Part 4 dose 
escalation. 
Table 25
Statistical Basis for Phase 1 Dose Escalation
True incidence of dose-limiting toxicity
10%
20%
30%
40%
50%
60%
Probability of escalating the dose
0.91
0.71
0.49
0.31
0.17
0.08
RATIONALE: Revisions to incorporate analysis of Part 4 data.


Novartis
Confidential
Page 334
Clinical Study Protocol Version 05
Protocol No. MEK116833
PREVIOUS TEXT
Section 5.2.1.2 Part 2, Paragraph 1
Part 2 will enroll approximately 30 subjects in total.  Approximately 40 subjects will be 
evaluated at the end of Part 2, including those enrolled in Part 1 at the same dose levels.
REVISED TEXT
Part 2 will enroll approximately 30 subjects in total.  Approximately 40 subjects will be 
evaluated at the end of Part 2, including those enrolled in Part 1 at the same dose levels. 
Part 4 cohort expansion will enroll approximately 40 subjects in total (20 subjects in 
Cohort 1E and 20 subjects in Cohort 2E). For each cohort, approximately 20 subjects will 
be evaluated separately at the end of Part 4, including those enrolled in dose escalation at 
the same dose levels and the same mutation status.
RATIONALE: Revisions to incorporate enrolment of subjects into Part 4.
Section 5.2.3 Analysis Populations, Paragraph 4
PREVIOUS TEXT
The Crossover Population will comprise the subset of subjects in Part 1 and Part 2 who 
had intra-subject dose escalation. It will be the primary population when summarizing 
data in Part 1 and Part 2 crossover phase.
REVISED TEXT
The Crossover Population will comprise the subset of subjects in Part 1, Part 2 and Part 
24 who had intra-subject dose escalation or intra-subject doublet to triplet crossover. It 
will be the primary population when summarizing data in Part 1, Part 2 and Part 24
crossover phase.
RATIONALE: Revisions to incorporate analysis of subjects who crossover 
from doublet to triplet dosing
Section 5.3.7 Interim Analysis
PREVIOUS TEXT
Section 5.3.7.1 Part 1
Section 5.3.7.2 Part 2
REVISED TEXT


Novartis
Confidential
Page 335
Clinical Study Protocol Version 05
Protocol No. MEK116833
Section 5.3.7.1 Part 1 and Part 4 Dose Escalation
Section 5.3.7.2 Part 2 and Part 4 Cohort Expansion
Section 5.3.8.7 Efficacy Analyses
PREVIOUS TEXT
Section 5.3.8.7.1 Part 1 and Part 2
The ORR endpoint will be tabulated based on number and percentage of subjects 
attaining either a confirmed or unconfirmed overall best response of CR or PR in the ITT 
population.  Per RECIST, version 1.1, confirmation of response is not required.  Subjects 
with unknown or missing response data, including those who withdraw from the study 
without an assessment, will be treated as non-responders (i.e., they will be included in the 
denominator when calculating the percentage).  No imputation will be performed for 
missing lesion assessment or tumour response data.  
PFS will be estimated using the Kaplan Meier method.  PFS will be defined as the time 
from randomization until the first date of either disease progression or death due to any 
cause.  The date of objective disease progression will be defined as the earliest date of 
disease progression as assessed by the investigator using RECIST, version 1.1.  For 
subjects who have not progressed or died at the time of the PFS analysis, censoring will 
be performed using the date of the last adequate disease assessment.  In addition, subjects 
with an extended loss to follow-up or who start a new anti-cancer therapy prior to a PFS 
event will be censored at the date of the last adequate disease assessment prior to the 
extended loss to follow-up or start of new anti-cancer therapy, respectively.  Further 
details on censoring rules will be outlined in the RAP.
For Part 1 and Part 2, anti-tumor activities will be evaluated based on clinical evidence 
and response criteria. If the data warrant, the response data from both parts will be 
combined and summarized by dose level. Subjects who crossover from 
dabrafenib/panitumumab combination to dabrafenib/trametinib/panitumumab 
combination will not be included in the main efficacy analysis for 
dabrafenib/trametinib/panitumumab combinations. The efficacy for these subjects will be 
summarized separately.
REVISED TEXT
Section 5.3.8.7.1 Part 1, Part 2 and Part 24
The ORR endpoint will be tabulated based on number and percentage of subjects 
attaining either a confirmed or unconfirmed overall best response of CR or PR in the ITT 
population.  Per RECIST, version 1.1, confirmation of response is not required.  Subjects 
with unknown or missing response data, including those who withdraw from the study 
without an assessment, will be treated as non-responders (i.e., they will be included in the 
denominator when calculating the percentage).  No imputation will be performed for 
missing lesion assessment or tumour response data.  


Novartis
Confidential
Page 336
Clinical Study Protocol Version 05
Protocol No. MEK116833
PFS will be estimated using the Kaplan Meier method.  PFS will be defined as the time 
from randomization until the first date of either disease progression or death due to any 
cause.  The date of objective disease progression will be defined as the earliest date of 
disease progression as assessed by the investigator using RECIST, version 1.1.  For 
subjects who have not progressed or died at the time of the PFS analysis, censoring will 
be performed using the date of the last adequate disease assessment.  In addition, subjects 
with an extended loss to follow-up or who start a new anti-cancer therapy prior to a PFS 
event will be censored at the date of the last adequate disease assessment prior to the 
extended loss to follow-up or start of new anti-cancer therapy, respectively.  Further 
details on censoring rules will be outlined in the RAP.
For Part 1 and Part 2, anti-tumor activities will be evaluated based on clinical evidence 
and response criteria. If the data warrant, the response data from both parts will be 
combined and summarized by dose level. Subjects who crossover from 
dabrafenib/panitumumab combination or trametinib/panitumumab to 
dabrafenib/trametinib/panitumumab combination will not be included in the main 
efficacy analysis for dabrafenib/trametinib/panitumumab combinations. The efficacy for 
these subjects will be summarized separately.
RATIONALE: Revisions to incorporate analysis of Part 4 data
Section 6.2 Safety
PREVIOUS TEXT
Vital Signs
Vital sign measurements will include systolic and diastolic blood pressure, pulse rate and 
temperature.  Vital signs should be assessed under optimal conditions as described in 
Section 3.9.8.1.  
Vital signs should be measured within 30 minutes prior to initiation and upon completion 
of panitumumab infusion.  On other study days where vital signs are measured multiple 
times, temperature does not need to be repeated, unless clinically indicated.
Ophthalmic Exam
Subjects are required to have a standard ophthalmic exam performed by an 
ophthalmologist at baseline and as clinically warranted per protocol’s guidance (refer to 
Visual Changes Stopping Criteria, Section 3.9.11).  The exam will include indirect 
fundoscopic examination, visual acuity (corrected), visual field examination, tonometry, 
and direct fundoscopy, with special attention to retinal abnormalities that are 
predisposing factors for RVO or RPED. 
In addition, it is recommended that subjects have baseline color fundus photographs 
taken at screening to document baseline appearance.  In subjects with clinical suspicion 
of RVO or RPED, additional color fundus photographs are recommended, and 
fluorescein angiography and/or optical coherence tomography are recommended.


Novartis
Confidential
Page 337
Clinical Study Protocol Version 05
Protocol No. MEK116833
Clinical Laboratory Assessments
Clinical Chemistry
Albumin
Sodium
AST (SGOT)
Magnesium
BUN
Potassium
ALT (SGPT)
Total and direct bilirubin
Creatinine
Chloride
Gamma glutamyl transferase 
(GGT)
Uric Acid
Glucose
      fasting glucose 
at screening only
Total carbon 
dioxide (CO2)
Alkaline phosphatase
Inorganic phosphorus
Lactacte 
dehydrogenase 
(LDH)
Calcium
Total Protein
REVISED TEXT
Vital Signs
Vital sign measurements will include systolic and diastolic blood pressure, pulse rate and 
temperature.  Vital signs should be assessed under optimal conditions as described in 
Section 3.9.8.1.  
Vital signs should be measured within 30 minutes prior to initiation and upon completion 
of panitumumab infusion (up to 15 minutes after the end of infusion).  On other study 
days where vital signs are measured multiple times, temperature does not need to be 
repeated, unless clinically indicated.
Ophthalmic Exam
Subjects are required to have a standard ophthalmic At certain time points in the trial and 
if visual changes develop, an eye exam performed by an ophthalmologist at baseline and 
as clinically warranted per protocol’s guidance is indicated (refer to Visual Changes 
Stopping Criteria, Section 3.9.11).  The exam will include indirect fundoscopic best 
corrected visual acuity, tonometry, slit lamp biomicroscopic examination, visual acuity 
(corrected), visual field examination, tonometry, and direct dilated indirect fundoscopy,
with special attention to retinal abnormalities that. Optical coherence tomography is 
strongly recommended at scheduled visits, and if retinal abnormalities are suspected. 
Other types of ancillary testing including color fundus photography and fluorescein 
angiography are predisposing factors for RVO or RPED. also recommended if clinically 
indicated.
In addition, it is recommended that subjects have baseline color fundus photographs 
taken at screening to document baseline appearance.    In subjects with clinical suspicion 
of RVO or RPED, additional color fundus photographs are recommended, and 
fluorescein angiography and/or optical coherence tomography are recommended.


Novartis
Confidential
Page 338
Clinical Study Protocol Version 05
Protocol No. MEK116833
Clinical Laboratory Assessments
Clinical Chemistry
Albumin
Sodium
AST (SGOT)
Magnesium
BUN
Potassium
ALT (SGPT)
Total and direct bilirubin
Creatinine
Chloride
Gamma glutamyl transferase 
(GGT)
Uric Acid
Glucose
      fasting glucose 
at screening only; 
all other glucose 
measurements may 
be non-fasting
Total carbon 
dioxide (CO2)
Alkaline phosphatase
Inorganic phosphorus
Lactacte 
dehydrogenase 
(LDH)
Calcium
Total Protein
RATIONALE: Revision of safety assessment text to reflect revised asset-
specific text
Section 6.7.1 Fresh Pre- and Post- dose Tumor Tissues
PREVIOUS TEXT
Tumor specimens that are accessible and can be sampled easily will be requested in Part 
1 and Part 2.  These biopsies will be taken during the screening period, e.g., within 14 
days before treatment, and within 2 to 4 hrs after dosing on Day 15 (+3 days) in those 
subjects who have signed the corresponding section of the informed consent.  Details of 
the tumor biopsy collection including processing, storage and shipping procedures will be 
provided in the SPM.
 
 
 
 
REVISED TEXT
Tumor specimens that are accessible and can be sampled easily will be requested in Part 
1 and Part 2.  These biopsies will be taken during the screening period, e.g., within 14 
days before treatment, and within 2 to 4 hrs after dosing on Day 15 (+3 days) in those 
subjects who have signed the corresponding section of the informed consent.  Details of 
the tumor biopsy collection including processing, storage and shipping procedures will be 
provided in the SPM.


Novartis
Confidential
Page 339
Clinical Study Protocol Version 05
Protocol No. MEK116833
 
 
 
 
RATIONALE: Clarification
Section 6.7.2 Fresh Tumor Tissue at Progression, Paragraph 1
PREVIOUS TEXT
Tumor specimens that are accessible and can be sampled easily will be requested from 
some subjects at time of demonstrated progression on therapy, as determined by RECIST 
v1.1 criteria.  Subjects of interest will be those who have had meaningful clinical 
response in target lesions (20% reduction, or stable disease for 6 months) and then 
progressed on existing target lesions or if a new lesion emerged. The guidance on the 
lesion selection for the progression biopsy are:
REVISED TEXT
Tumor specimens that are accessible and can be sampled easily will be requested from 
some subjects at time of demonstrated progression on therapy from all parts of the study, 
as determined by RECIST v1.1 criteria.  Subjects of interest will be those who have had 
meaningful clinical response in target lesions (20% reduction, or stable disease for 6 
months) and then progressed on existing target lesions or if a new lesion emerged. The 
guidance on the lesion selection for the progression biopsy are:
RATIONALE: Clarification
Section 6.7.4 Archival Tumor Tissue, Paragraph 1
PREVIOUS TEXT
Collection of archival primary tumor tissue is required when it is available. These 
samples will be used to confirm or determine the BRAF mutation status of subjects for 
study enrolment. 
 
 
REVISED TEXT
Collection of archival primary tumor tissue is required when it is available. These 
samples will be used to confirm or determine the BRAF or KRAS mutation status of 


Novartis
Confidential
Page 340
Clinical Study Protocol Version 05
Protocol No. MEK116833
subjects for study enrolment.  
 
 
 
Section 7.1.1 Female Subjects 
PREVIOUS TEXT
A female of non-childbearing potential (i.e., physiologically incapable of becoming 
pregnant) is defined as any female who has had a hysterectomy, bilateral oophorectomy 
(ovariectomy) or bilateral tubal ligation, or is post-menopausal.
A practical definition accepts menopause after 1 year without menses with an appropriate 
clinical profile, e.g., age appropriate, >45 years in the absence of hormone replacement 
therapy (HRT).  In questionable cases, the subject must have a follicular stimulating 
hormone (FSH) value >40 mIU/mL and an estradiol value < 40pg/mL (<140 pmol/L).
A female of childbearing potential is defined as any female who does not meet the 
criteria of non-childbearing potential as described in the previous paragraph.
Female subjects of childbearing potential must not become pregnant and so must be 
sexually inactive by abstinence or use contraceptive methods with a failure rate of < 1% 
from start of dosing and.

for 6 months after the last dose of panitumumab (Vectibix)

for 4 months after the last dose oftrametinib in combination with dabrafenib 

for 4 weeks after the last dose of dabrafenib.  
Abstinence
Sexual inactivity by abstinence must be consistent with the preferred and usual lifestyle 
of the subject.  Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of contraception. 
Complete abstinence from sexual intercourse for 14 days prior to first dose of study 
treatment, through the dosing period, and from the first dose of study drug(s) until 60 
days after the last dose of any study drug.


Novartis
Confidential
Page 341
Clinical Study Protocol Version 05
Protocol No. MEK116833
Contraceptive Methods with a Failure Rate of 1%

Intrauterine device (IUD) or intrauterine system (IUS) that meets the <1% 
failure rate as stated in the product label

Male partner sterilization (vasectomy with documentation of azoospermia) 
prior to the female subject's entry into the study, and this male is the sole 
partner for that subject.  For this definition, “documented” refers to the 
outcome of the investigator's/designee’s medical examination of the subject or 
review of the subject's medical history for study eligibility, as obtained via a 
verbal interview with the subject or from the subject’s medical records.

Double-barrier method: condom and occlusive cap (diaphragm or cervical/vault 
caps) plus vaginal spermicidal agent (foam/gel/film/cream/suppository)
These allowed methods of contraception are only effective when used consistently, 
correctly and in accordance with the product label.  The investigator is responsible 
for ensuring subjects understand how to properly use these methods of 
contraception.
REVISED TEXT
The need for a screening pregnancy test depends on whether a female subject is of 
childbearing potential or non-childbearing potential.
A female of non-childbearing potential (i.e., physiologically incapable of becoming 
pregnant) is defined as any female who has had a hysterectomy, bilateral oophorectomy 
(ovariectomy) or bilateral tubal ligation, or is post-menopausal.
A practical definition accepts menopause after 1 year without menses with an appropriate 
clinical profile, e.g., age appropriate, >45 years in the absence of hormone replacement 
therapy (HRT).  In questionable cases, the subject must have a follicular stimulating 
hormone (FSH) value >40 mIU/mL and an estradiol value < 40pg/mL (<140 pmol/L).
A female of childbearing potential is defined as any female who does not meet the 
criteria of non-childbearing potential as described in the previous paragraph.
Female subjects of childbearing potential must not become pregnant and so must be 
sexually inactive by abstinence or use contraceptive methods with a failure rate of < 1% 
from start of dosing and.

for 6 months after the last dose of panitumumab (Vectibix)

for 4 months after the last dose of trametinib in combination with dabrafenib 

for 4 weeks after the last dose of dabrafenib  

for 4 months after the last dose of trametinib.


Novartis
Confidential
Page 342
Clinical Study Protocol Version 05
Protocol No. MEK116833
Abstinence
Sexual inactivity by abstinence must be consistent with the preferred and usual lifestyle 
of the subject.  Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of contraception. 
Complete abstinence from sexual intercourse for 14 days prior to first dose of study 
treatment, through the dosing period, and from the first dose of study drug(s) until 60 
days after the last dose of any study drug.
GSK acceptable contraceptive methods, when used consistently and in accordance with 
both the product label and the instructions of the physician, are as follows:
Contraceptive Methods with a Failure Rate of 1%

Intrauterine device (IUD) or intrauterine system (IUS) that meets the <1% 
failure rate as stated in the product label

Male partner sterilization (vasectomy with documentation of azoospermia) 
prior to the female subject's entry into the study, and this male is the sole 
partner for that subject.  For this definition, “documented” refers to the 
outcome of the investigator's/designee’s medical examination of the subject or 
review of the subject's medical history for study eligibility, as obtained via a 
verbal interview with the subject or from the subject’s medical records.

Double-barrier method: condom and occlusive cap (diaphragm or cervical/vault 
caps) plus vaginal spermicidal agent (foam/gel/film/cream/suppository)

Note: Hormonal-based methods (e.g., oral contraceptives) are not permitted as 
contraception due to potential drug-drug interactions with dabrafenib.  
These allowed methods of contraception are only effective when used consistently, 
correctly and in accordance with the product label.  The investigator is responsible 
for ensuring subjects understand how to properly use these methods of 
contraception.
RATIONALE: Clarification of requirements for female contraception
Section 8.1 Permitted Medications
PREVIOUS TEXT
The investigator must be informed as soon as possible about any medication taken from 
the time of screening until 30 days after the last dose of study treatment.  Any 
concomitant medication(s), including herbal preparations, taken during the study will be 
recorded in the eCRF.  The minimum requirement is that drug name, dose, and the dates 
of administration are to be recorded.  Additionally, a complete list of all prior cancer 
therapies will be recorded in the eCRF.


Novartis
Confidential
Page 343
Clinical Study Protocol Version 05
Protocol No. MEK116833
Subjects should receive full supportive care during the study, including transfusions of 
blood and blood products, and treatment with antibiotics, anti-emetics, anti-diarrheals, 
and analgesics, and other care as deemed appropriate, and in accordance with their 
institutional guidelines.  Growth factors and bisphosphonates are allowed but must not be 
initiated durof ing the first 4 weeks of treatment.
REVISED TEXT
The investigator must be informed as soon as possible about any medication taken from 
the time of screening until 30 days after the last dose of study treatment.  Any 
concomitant medication(s), including herbal preparations,dietary supplements,) taken 
during the study will be recorded in the eCRF.  The minimum requirement is that drug 
name, dose, and the dates of administration are to be recorded.  Additionally, a complete 
list of all prior cancer therapies will be recorded in the eCRF.
Subjects should receive full supportive care during the study, including transfusions of 
blood and blood products, and treatment with antibiotics, anti-emetics, anti-diarrheals, 
and analgesics, and other care as deemed appropriate, and in accordance with their 
institutional guidelines.  Growth factors and bisphosphonates are allowed but must not be 
initiated during the first 4 weeks of treatment. Use of anticoagulants such as warfarin is 
permitted however, caution should be exercised and additional International Normalized 
Ratio (INR) monitoring is recommended when dabrafenib is used concomitantly with 
warfarin.
While patients are on study treatment, palliative radiation therapy is permitted for non-
target lesions that are either new or present at baseline.
Radiation skin injury has been reported with concurrent use of dabrafenib and radiation. 
It is recommended that dabrafenib be held for seven days before and two days after XRT 
in subjects receiving dabrafenib monotherapy or in combination with trametinib. These 
recommendations can be modified based on the physician’s assessment of the risk of 
radiation skin injury.
RATIONALE: Clarification of permitted medications, and additional 
information regarding use of anti-coagulants and palliative radiation 
therapy
Section 8.2 Prohibited Medications
PREVIOUS TEXT
The use of certain medications, and illicit drugs within 5 half-lives or 28 days, whichever 
is shorter prior to the first dose of study drug and for the duration of the trial will not be 
allowed.  If a prohibited medication is required for single use (such as for a procedure) 
while study drug is held, the GSK medical monitor can approve such use.
The following medications or non-drug therapies are prohibited:

Other anti-cancer therapy while on treatment in this study.


Novartis
Confidential
Page 344
Clinical Study Protocol Version 05
Protocol No. MEK116833

Antiretroviral drugs (subjects with known HIV are ineligible for study 
participation).

Herbal remedies (e.g., St. John’s wort).

Dabrafenib is metabolized primarily by Cytochrome P450 (CYP) 2C8 and 
CYP3A4.  Co-administration of dabrafenib with ketoconazole, a CYP3A4 
inhibition, or with gemfibrozil, a CYP2C8 inhibitor, resulted in increases in 
dabrafenib AUC of 71% and 47%, respectively.  Drugs that are strong 
inhibitors or inducers of CYP3A and CYP2C8 (see list in Table 26) may only 
be used under special circumstances (e.g. as a single use for a procedure) while 
treatment with study drug is interrupted as they may alter dabrafenib 
concentrations; consider therapeutic substitutions for these medications.  
Approval of the GSK medical monitor is required in these situations. The list 
may be modified based on emerging data. 

Oral contraceptives (either combined or progesterone only), estrogenic vaginal 
ring/percutaneous contraceptive patches, or implants of 
levonorgestrel/Injectable progesterone is prohibited in this study as it is not 
known if there is the potential of inhibition/induction of enzymes that affect the 
metabolism of estrogens and/or progestins.
REVISED TEXT
The use of certain medications, and illicit drugs within 5 half-lives or 28 days, whichever 
is shorter prior to the first dose of study drug and for the duration of the trial will not be 
allowed.  If a prohibited medication is required for single use (such as for a procedure) 
while study drug is held, the GSK medical monitor can approve such use.
The following medications or non-drug therapies are prohibited:

Other anti-cancer therapy while on treatment in this study.

Antiretroviral drugs (subjects with known HIV are ineligible for study 
participation)..

Herbal remedies (e.g., St. John’s wort).

Dabrafenib is metabolized primarily by Cytochrome P450 (CYP) 2C8 and 
CYP3A4.  Co-administration of dabrafenib with ketoconazole, a CYP3A4 
inhibition, or with gemfibrozil, a CYP2C8 inhibitor, resulted in increases in 
dabrafenib AUC of 71% and 47%, respectively.  Drugs that are strong 
inhibitors or inducers of CYP3A and CYP2C8 (see list in Table 30) may only 
be used under special circumstances (e.g. as a single use for a procedure) while 
treatment with study drug is interrupted as they may alter dabrafenib 
concentrations; consider therapeutic substitutions for these medications.  
Approval of the GSK medical monitor is required in these situations. The list 
may be modified based on emerging data. 

Oral contraceptives (either combined or progesterone only), estrogenic vaginal 
ring/percutaneous contraceptive patches, or implants of 
levonorgestrel/Injectable progesterone is prohibited in this study as it is not 


Novartis
Confidential
Page 345
Clinical Study Protocol Version 05
Protocol No. MEK116833
known if there is the potential of inhibition/induction of enzymes that affect the 
metabolism of estrogens and/or progestins.
RATIONALE: Clarification of prohibited medications
Section 10.3.1 Preparation
PREVIOUS TEXT
No special preparation of dabrafenib and trametinib is required.  Refer to the 
GSK2118436 IB [GlaxoSmithKline Document Number 2012N136095_00], the 
GSK1120212 IB [GlaxoSmithKline Document Number HM2009/00151/03] and the 
GSK1120212 + GSK2118436 Clinical IB [GlaxoSmithKline Document Number, 
2011N126811_00] for detailed information regarding dabrafenib and trametinib.  
Please refer to the FDA approved label and/or EU SmPC for panitumumab for updated 
detailed information.  The following text is summarized from the approved FDA label 
[VECTIBIX (panitumumab) Injection for Intravenous Use, Revised August 2012].
Prepare the solution for infusion, using aseptic technique, as follows:

Parenteral drug products should be inspected visually for particulate matter and 
discoloration prior to administration. Although panitumumab should be colorless, 
the solution may contain a small amount of visible translucent-to-white, 
amorphous, proteinaceous, panitumumab particulates (which will be removed by 
filtration; see below). Do not shake. Do not administer if discoloration is observed.

Withdraw the necessary amount of panitumumab for the study- prescribed dose.

Dilute to a total volume of 100 mL with 0.9% sodium chloride injection, USP. 
Doses higher than 1000 mg should be diluted to 150 mL with 0.9% sodium 
chloride injection, USP. Do not exceed a final concentration of 10 mg/mL.

Mix diluted solution by gentle inversion. Do not shake.
REVISED TEXT
No special preparation of dabrafenib and trametinib is required.  Refer to the 
GSK2118436 IB [GlaxoSmithKline Document Number 2012N136095_00], the 
GSK1120212 IB [GlaxoSmithKline Document Number HM2009/00151/03] and the 
GSK1120212 + GSK2118436 Clinical IB [GlaxoSmithKline Document Number, 
2011N126811_00] for detailed information regarding dabrafenib and trametinib.  
Please refer to the FDA approved label and/or EU SmPC for panitumumab for updated 
detailed information.  The following text is summarized from the approved FDA label 
[VECTIBIX (panitumumab) Injection for Intravenous Use, Revised August 2012].
Prepare the solution for infusion, using aseptic technique, as follows:


Novartis
Confidential
Page 346
Clinical Study Protocol Version 05
Protocol No. MEK116833

Parenteral drug products should be inspected visually for particulate matter and 
discoloration prior to administration. Although panitumumab should be colorless, 
the solution may contain a small amount of visible translucent-to-white, 
amorphous, proteinaceous, panitumumab particulates (which will be removed by 
filtration; see below). Do not shake. Do not administer if discoloration is observed.

Withdraw the necessary amount of panitumumab for the study- prescribed dose.

Dilute to a total volume of 100 mL with 0.9% sodium chloride injection, USP. 
Doses higher than 1000 mg should be diluted to 150 mL with 0.9% sodium 
chloride injection, USP. Do not exceed a final concentration of 10 mg/mL.

Mix diluted solution by gentle inversion. Do not shake.

Administer using a low-protein-binding 0.2m or 0.22m in-line filter.

Vectibix must be administered via infusion pump.
o
Flush line before and after Vectibix administration with 0.9% sodium 
chloride injection, USP, to avoid mixing with other drug products or 
intravenous solutions.  Do not mix Vectibix with, or administer as an 
infusion with, other medicinal products. Do not add other medications to 
solutions containing panitumumab.
o
Infuse over 60 minutes through a peripheral intravenous line or indwelling 
intravenous catheter. Doses higher than 1000mg should be infused over 90 
minutes. 
RATIONALE: Additional text on preparation of Vectibix as noted in the 
approved product label
Section 10.3.2 Handling
Section 10.3.3 Storage
PREVIOUS TEXT
Section 10.3.2 Handling
Precaution will be taken to avoid direct contact with the investigational product.  Material 
Safety Data Sheets (MSDS) for dabrafenib and trametinib describing occupational 
hazards and recommended handling precautions will be provided to the investigator.
Please refer to the FDA approved label and/or EU SmPC for panitumumab for updated 
detailed information [VECTIBIX (panitumumab) Injection for Intravenous Use, Revised 
August 2012].


Novartis
Confidential
Page 347
Clinical Study Protocol Version 05
Protocol No. MEK116833
However, precautions are to be taken to avoid direct skin contact, eye contact, and 
generating aerosols or mists.  In the case of unintentional occupational exposure notify 
the monitor, medical monitor and/or study manager.
Precaution will be taken to avoid direct contact with the investigational product.  A 
Material Safety Data Sheet (MSDS) describing occupational hazards and recommended 
handling precautions will be provided to the investigator.
Section 10.3.3 Storage
All investigational products must be stored in original bottles supplied by GSK and in a 
secure area with access limited to the investigator and authorized site staff.  Dabrafenib is 
to be stored up to 30C (86F) in an opaque bottle, as supplied by GSK.  Trametinib is to 
be stored at 2 to 8°C (36 to 46°F), protected from moisture and light, and stored and 
dispensed in the original cartons supplied by GSK.  Please ensure that the bottles have 
equilibrated back to room temperature before opening them to avoid moisture 
condensation on the tablets.  Whole bottles of investigational products are dispensed at 
each 4 week visit. Maintenance of a temperature log (manual or automated) is required.
Please refer to the FDA approved label and/or EU SmPC for panitumumab for updated 
detailed information.  The following text is summarized from the approved FDA label 
[VECTIBIX (panitumumab) Injection for Intravenous Use, Revised August 2012].  Store 
vials in the original carton under refrigeration at 2° to 8°C (36° to 46°F) until time of use. 
Protect from direct sunlight. DO NOT FREEZE. Since panitumumab does not contain 
preservatives, any unused portion remaining in the vial must be discarded.
REVISED TEXT
Section 10.3.2 Handling and Storage of Study Treatments
Precaution will be taken to avoid direct contact with the investigational product.  Material 
Safety Data Sheets (MSDS) for dabrafenib and trametinib describing occupational 
hazards and recommended handling precautions will be provided to the investigator.
Please refer to the FDA approved label and/or EU SmPC for panitumumab for updated 
detailed information [VECTIBIX (panitumumab) Injection for Intravenous Use, Revised 
March 2013].
However, precautions are to be taken to avoid direct skin contact, eye contact, and 
generating aerosols or mists.  In the case of unintentional occupational exposure notify 
the monitor, medical monitor and/or study manager.
Precaution will be taken to avoid direct contact with the investigational product.  A 
Material Safety Data Sheet (MSDS) describing occupational hazards and recommended 
handling precautions will be provided to the investigator.


Novartis
Confidential
Page 348
Clinical Study Protocol Version 05
Protocol No. MEK116833
Section 10.3.3 Storage
All investigational products Dabrafenib and trametinib must be dispensed and 
administered in accordance with the protocol, and only to subjects enrolled in the study.  
Dabrafenib and trametinib must be stored in original bottles supplied by GSK and in a 
secure area with access limited to the investigator and authorized site staff.  Dabrafenib is 
to be stored up to 30C (86F) in an opaque bottle, as supplied by GSK.  Trametinib
under the appropriate physical conditions for the product.  Study medication is to be 
stored at 2 to 8°C (36 to 46°F), protected from moisture and light, and stored and 
dispensed in the original cartons supplied by GSK.  Please ensure that the bottles have 
equilibrated back to roomthe temperature before opening them to avoid moisture 
condensationspecified on the tablets.  Whole bottles of investigational products are 
dispensed at each 4 week visit.label.  Maintenance of a temperature log (manual or 
automated) is required.  Access to and administration of dabrafenib and trametinib will be 
limited to the investigator and authorized site staff.  
Please refer to the FDA approved label and/or EU SmPC for panitumumab for updated 
detailed information.  The following text is summarized from the approved FDA label 
[VECTIBIX (panitumumab) Injection for Intravenous Use, Revised March 2013; 
VECTIBIX (panitumumab) Injection for Intravenous Use, Revised August 2012].  Store 
vials in the original carton under refrigeration at 2° to 8°C (36° to 46°F) until time of use. 
Protect from direct sunlight. DO NOT FREEZE. Since panitumumab does not contain 
preservatives, any unused portion remaining in the vial must be discarded.
Procedures for final disposition of unused study treatments will be provided in the Study 
Procedures Manual (SPM).  
RATIONALE: Updated text concerning handling and storage requirements 
for study treatments
Section 10.5 Treatment of Study Treatment Overdose 
PREVIOUS TEXT
In the event of a dabrafenib overdose, defined as administration of more than 300mg as a 
single dose or 600mg daily (the highest dose tested in clinical studies to date), or in the 
event of a trametinib overdose (defined as administration of more than the prescribed 
dose), the investigator should contact the GSK Medical Monitor immediately and closely 
monitor the subject for AEs/SAEs and laboratory abnormalities.  In the event of an 
overdose of panitumumab, refer to the package insert [VECTIBIX, 2012].
Decisions regarding dose interruptions or modifications should be made by the 
investigator in consultation with the GSK Medical Monitor based on the clinical 
evaluation of the subject.
A plasma sample for PK analysis may be requested by the GSK Medical Monitor on a 
case-by-case basis.  This plasma sample should be collected as soon as possible.


Novartis
Confidential
Page 349
Clinical Study Protocol Version 05
Protocol No. MEK116833
Information regarding the quantity of the excess dose as well as the duration of the 
overdosing should be documented in the eCRF.
REVISED TEXT
In the event of a dabrafenib overdose, defined as administration of more than 300mg as a 
single dose or 600mg daily (the highest dose tested in clinical studies to date), or in the 
event of a trametinib overdose (defined as administration of more than 3.0 mg once daily
(the prescribed maximum tolerated dose defined in the MEK111054 Study), the 
investigator should contact the GSK Medical Monitor immediately and closely monitor 
the subject for AEs/SAEs and laboratory abnormalities.  In the event of an overdose of 
panitumumab, refer to the package insert [, 2012].  GSK does not recommend specific 
treatment.  The investigator will use clinical judgment to treat any overdose.  
Haemodialysis is not expected to enhance the elimination of either 
dabrafenib or trametinib as both are highly bound to plasma proteins.
In the event of an overdose of panitumumab, refer to the package insert [VECTIBIX, 
2013; VECTIBIX, 2012].
Decisions regarding dose interruptions or modifications should be made by the 
investigator in consultation with the GSK Medical Monitor based on the clinical 
evaluation of the subject.
A plasma sample for PK analysis may be requested by the GSK Medical Monitor on a 
case-by-case basis.  This plasma sample should be collected as soon as possible, but 
within 10 days from the date of the last dose of on-study dosing.
Information regarding the quantity of the excess dose as well as the duration of the 
overdosing should be documented in the eCRF.
RATIONALE: Clarification of treatment of overdose with study drugs
Section 11.2 Definition of Serious Adverse Events, Item I
PREVIOUS TEXT
j.
Protocol-specific SAEs: 

All events of possible drug-induced liver injury with hyperbilirubinemia defined 
as ALT ≥3 x ULN and total bilirubin ≥2 x ULN (>35% direct) or ALT ≥3 x ULN 
and INR >1.5 (if INR is measured) or termed ‘Hy’s Law’ events (INR 
measurement is not required and the threshold value stated will not apply to 
subjects receiving anticoagulants).
Note: Bilirubin fractionation is performed if testing is available. If testing is 
unavailable, record presence of detectable urinary bilirubin on dipstick indicating 
direct bilirubin elevations and suggesting liver injury. If testing is unavailable and 
a subject meets the criterion of total bilirubin ≥2 x ULN, then the event is still 


Novartis
Confidential
Page 350
Clinical Study Protocol Version 05
Protocol No. MEK116833
reported as an SAE. If INR is obtained, include values on the SAE form. 
International normalized ratio (INR) elevations >1.5 suggest severe liver injury.

Any new malignancy with a histology different from the primary tumor, including 
cutaneous squamous cell carcinoma, basal cell carcinoma, and secondary 
melanoma

Laboratory abnormalities as referenced in Section 1111.

LVEF that meets stopping criteria Section 3.7.7.1.

RPED or RVO.

Pyrexia accompanied by hypotension, or dehydration requiring IV fluids, or 
severe rigors/chills.
REVISED TEXT
k.
Protocol-specific SAEs: 

All events of possible drug-induced liver injury with hyperbilirubinemia defined 
as ALT ≥3 x ULN and total bilirubin ≥2 x ULN (>35% direct) or ALT ≥3 x ULN 
and INR >1.5 (if INR is measured) or termed ‘Hy’s Law’ events (INR 
measurement is not required and the threshold value stated will not apply to 
subjects receiving anticoagulants).
Note: Bilirubin fractionation is performed if testing is available. If testing is 
unavailable, record presence of detectable urinary bilirubin on dipstick indicating 
direct bilirubin elevations and suggesting liver injury. If testing is unavailable and 
a subject meets the criterion of total bilirubin ≥2 x ULN, then the event is still 
reported as an SAE. If INR is obtained, include values on the SAE form. 
International normalized ratio (INR) elevations >1.5 suggest severe liver injury.

Any new malignancy with a histology different from the primary tumor, including 
cutaneous squamous cell carcinoma, basal cell carcinoma, and secondary 
melanoma

Laboratory abnormalities as referenced in Section 11.

Symptomatic LVEF decrease that meets stopping criteria or asymptomatic LVEF 
decrease that does not recover, as outlined as LVEF guidance Section 3.9.7.1.

RPED or RVO.

Pyrexia accompanied by hypotension, or dehydration requiring IV fluids, or 
severe rigors/chills.
RATIONALE:  Revisions to text reflect updated asset-specific safety 
guidelines


Novartis
Confidential
Page 351
Clinical Study Protocol Version 05
Protocol No. MEK116833
Section 13.2 Regulatory and Ethical Considerations, Including the 
Informed Consent Process, Paragraph 6
PREVIOUS TEXT
In approving the clinical protocol the IEC/IRB and, where required, the applicable 
regulatory agency are also approving the optional assessments.  Where permitted by 
regulatory authorities, approval of the optional assessments can occur after approval is 
obtained for the rest of the study.  If so, then the written approval will clearly indicate 
approval of the optional assessments is being deferred and the study, except for the 
optional assessments, can be initiated.  When the optional assessments are not approved, 
then the approval for the rest of the study will clearly indicate this and therefore, the 
optional assessments will not be conducted.
REVISED TEXT
In approving the clinical protocol the IEC/IRB and, where required, the applicable 
regulatory agency are also approving the optional assessments, 
 
  Where permitted by regulatory 
authorities, approval of the optional assessments can occur after approval is obtained for 
the rest of the study.  If so, then the written approval will clearly indicate approval of the 
optional assessments is being deferred and the study, except for the optional assessments, 
can be initiated.  When the optional assessments are not approved, then the approval for 
the rest of the study will clearly indicate this and therefore, the optional assessments will 
not be conducted.
 
Section 14 References
Douillard J-Y, Oliner KS, Siena S, et al. Panitumumab-FOLFOX4 treatment and RAS 
mutations in colorectal cancer. NEJM 2013; 369:1023-1034.
Lacouture ME, Mitchell EP, Piperdi B, et al. Skin toxicity evaluation protocol with 
panitumumab (STEPP), a Phase II, open-label, randomized trial evaluating the impact ofa 
pre-emptive skin treatment regimen on skin toxicities and quality of life in patients with 
metastatic colorectal cancer. J Clin Oncol 2010 28(6):1351-1357.
Misale S, Arena S, Lamba S et al. Blockade of EGFR and MEK intercepts heterogenous 
mechanisms of acquired resistance to anti-EGFR therapies in colorectal cancer. Sci 
Transl Med 2014; 6 (224):224-226.
Misale S, Yaeger R, Hobor S et al. Emergence of KRAS mutations and acquired 
resistance to anti-EGFR therapy in colorectal cancer. Nature 2012; 486 (7404):532-536.
Schwartzberg LS, Rivera F, Karthaus M et al. PEAK: a randomized, multicenter Phase II 
study of panitumumab plus modified fluorouracil, leucovorin, an oxaliplatin 
(mFOLFOX6) or bevacizumab plus mFOLFOX6 in patients with previously untreated, 


Novartis
Confidential
Page 352
Clinical Study Protocol Version 05
Protocol No. MEK116833
unresectable, wild-type KRAS exon 2 metastatic colorectal cancer. J Clin Oncol
Published online JCO.2013.53.2473; March 31, 2014.
TAFINLAR (dabrafenib) prescribing information. January 2014.
VECTIBIX (panitumumab) Product Information. March 2013.
Appendix 1: Liver Safety Algorithms
PREVIOUS TEXT
Part 1 and Part 2
REVISED TEXT
Part 1, Part 2 and Part 24
Appendix 2: Blood Requirements
PREVIOUS TEXT
Part 1: Dose Escalation Cohorts
Test
Sample Volume
Total Volume for Screening, One 4-wk treatment period 
and Follow-up 
Hematology/Clin Chem
5 mL
25
Coagulation
5 mL
5
PK Analysis (panitumumab)
4 mL
20
PK & Metabolite Analysis 
(dabrafenib, trametinib)
4 mL
48
Serum Pregnancy Test
1 mL
1
Total
155mL/subject
plus any wasteage associated with collection
Part 2: Expansion Cohorts
Test
Sample Volume
Total Volume for Screening, One 4-wk treatment period 
and Follow-up 
Hematology/Clin Chem
5 mL
20
Coagulation
5 mL
5
PK Analysis (panitumumab)
4 mL
16
PK & Metabolite Analysis 
(dabrafenib, trametinib)
4 mL
48
Serum Pregnancy Test
1 mL
1
Total
146mL/subject 
plus any wasteage associated with collection


Novartis
Confidential
Page 353
Clinical Study Protocol Version 05
Protocol No. MEK116833
Part 3: Randomized Phase II Study
Test
Sample Volume
Total Volume for Screening, One 4-wk treatment 
period and Follow-up 
Hematology/Clin Chem
5 mL
20
Coagulation
5 mL
5
Serum Pregnancy Test
1 mL
1
Total
82/subject 
plus any wasteage associated with collection
REVISED TEXT
Part 1: Dose Escalation Cohorts
Test
Sample Volume
Total Volume for Screening, One 4-wk treatment period 
and Follow-up 
Hematology/Clin Chem
5 mL
30
Coagulation
5 mL
5
PK Analysis (panitumumab)
4 mL
20
PK & Metabolite Analysis 
(dabrafenib, trametinib)
4 mL
48
Serum Pregnancy Test
1 mL
1
CEA
2 mL
12
Total
167mL/subject
plus any wasteage associated with collection
Part 2: Expansion Cohorts
Test
Sample Volume
Total Volume for Screening, One 4-wk treatment period 
and Follow-up 
Hematology/Clin Chem
5 mL
25
Coagulation
5 mL
5
PK Analysis (panitumumab)
4 mL
16
PK & Metabolite Analysis 
(dabrafenib, trametinib)
4 mL
48
Serum Pregnancy Test
1 mL
1
CEA
2
10
Total
187mL/subject 
plus any wasteage associated with collection


Novartis
Confidential
Page 354
Clinical Study Protocol Version 05
Protocol No. MEK116833
Part 3: Randomized Phase II Study
Test
Sample Volume
Total Volume for Screening, One 4-wk treatment 
period and Follow-up 
Hematology/Clin Chem
5 mL
20
Coagulation
5 mL
5
Serum Pregnancy Test
1 mL
1
Total
82/subject 
plus any wasteage associated with collection
Part 4A and 4B: Dose Escalation and Expansion Cohorts
Test
Sample Volume
Total Volume for Screening, One 4-wk treatment period 
and Follow-up 
Hematology/Clin Chem
5 mL
20
Coagulation
5 mL
5
PK Analysis (panitumumab)
4 mL
16
PK & Metabolite Analysis 
(dabrafenib, trametinib)
4 mL
48
Serum Pregnancy Test
1 mL
1
CEA
2
10
Total
182mL/subject 
plus any wasteage associated with collection
RATIONALE: Blood draw requirements updated based on updated time and 
events tables and addition of Part 4


Novartis
Confidential
Page 355
Clinical Study Protocol Version 05
Protocol No. MEK116833


Novartis
Confidential
Page 356
Clinical Study Protocol Version 05
Protocol No. MEK116833


Novartis
Confidential
Page 357
Clinical Study Protocol Version 05
Protocol No. MEK116833
AMENDMENT 2
Where the amendment applies

French sites will follow revised schedule for dermatological examinations and 
assessment for non-cutaneous secondary/recurrent malignancy as noted below, 
per request of Agence Nationale de Securite du Medicament et des Produits de 
Sante (ANSM).
Cutaneous Squamous Cell Carcinoma (cuSCC) and New Primary Melanoma 
Dermatological examinations should be performed prior to initiation of therapy with 
dabrafenib, monthly throughout treatment, and monthly for 6 months following 
discontinuation of dabrafenib or until initiation of another anti-neoplastic therapy, 
whichever comes first. Cases should be managed by dermatological excision and 
dabrafenib treatment should be continued without any dose adjustment. Subjects should 
be instructed to immediately inform their physician if new lesions develop.
Non-cutaneous Secondary/Recurrent Malignancy
Prior to initiation of dabrafenib treatment subjects should undergo a head and neck 
examination with minimally visual inspection of oral mucosa and lymph node palpation, 
as well as chest/abdomen Computerised Tomography (CT) scan. During treatment 
subjects should be monitored as clinically appropriate which may include a head and 
neck examination every 3 months and a chest/abdomen CT scan every 6 months. Anal 
examinations and pelvic examinations (for women) are recommended before and at the 
end of treatment or when considered clinically indicated. Complete blood cell counts 
should be performed as clinically indicated. Following discontinuation of dabrafenib 
monitoring for non-cutaneous secondary/recurrent malignancies should continue for up to 
6 months or until initiation of another anti-neoplastic therapy, whichever comes first. 
Abnormal findings should be reported as protocol-specific SAEs and managed according 
to clinical practices.
Amendment applies to all sites and all countries with changes to:
Throughout the protocol, central serous retinopathy (CSR) was changed to retinal 
pigment epithelium detachment (RPED. 


Novartis
Confidential
Page 358
Clinical Study Protocol Version 05
Protocol No. MEK116833
Sponsor/Medical Monitor Information Page
PREVIOUS TEXT:
SPONSOR/MEDICAL MONITOR INFORMATION PAGE
Medical Monitor and Sponsor Contact Information:
Role
Name
Day Time 
Phone 
Number
After-hours 
Phone/Cell/
Pager 
Number
Fax Number
GSK Address
Monitor
 MD, 
PhD
GlaxoSmithKline
1250 Collegeville Road
Mailstop UP4310
Collegeville, PA
USA
Medical 
Monitor
 
MD
GlaxoSmithKline
1250 Collegeville Road
Mailstop UP4410
Collegeville, PA
USA
Medical 
Monitor
MD, PhD
GlaxoSmithKline
1250 Collegeville Road
Mailstop UP4340
Collegeville, PA
USA
SAE fax 
number 


Novartis
Confidential
Page 359
Clinical Study Protocol Version 05
Protocol No. MEK116833
REVISED TEXT
SPONSOR/MEDICAL MONITOR INFORMATION PAGE
Medical Monitor and Sponsor Contact Information:
Role
Name
Day Time 
Phone 
Number
After-hours 
Phone/Cell/
Pager 
Number
Fax 
Number
GSK Address
Medical 
Monitor
 
MD, PhD
GlaxoSmithKline
1250 Collegeville Road
Mailstop UP4310
Collegeville, PA
USA
Medical 
Monitor
MD
GlaxoSmithKline
1250 Collegeville Road
Mailstop UP4410
Collegeville, PA
USA
Medical 
Monitor
MD, PhD
GlaxoSmithKline
1250 Collegeville Road
Mailstop UP4340
Collegeville, PA
USA
SAE fax 
number 
Section 3.4.2, Table 1
PREVIOUS TEXT
Table 1
Part 1 Dosing Cohorts
COHORTS
-1A
-1B
-1C
1
STARTING 
DOSE
2
3Aa
3Ba
4
dabrafenibb
100mg
BID
150mg
BID
100mg
BID
150mg 
BID
RP2R* 
from 
Cohort 1 b
RP2R 
from 
Cohort 1 b 
RP2R 
from 
Cohort 1 
b
RP2R 
from 
Cohort 1 
b
trametinib
-
-
1.5mg
once daily
2mg
once daily
1.5mg
once 
daily
2mg
once 
daily
panitumumab 
c, d
6mg/kg
Q2W
4.8mg/kg
Q2W
4.8mg/kg
Q2W
6mg/kg
Q2W
one dose 
level 
below 
RP2R 
from 
Cohort 1 c
one dose 
level 
below 
RP2R 
from 
Cohort 1 c
RP2R 
from 
Cohort 1 
d
RP2R 
from 
Cohort 1 
d


Novartis
Confidential
Page 360
Clinical Study Protocol Version 05
Protocol No. MEK116833
REVISED TEXT
Table 1
Part 1 Dosing Cohorts
COHORTS
De-escalation cohorts
Dose escalation cohorts
-1A
-1B
-1C
1
STARTING 
DOSE
2
3Aa
3Ba
4
dabrafenibb
100mg
BID
150mg
BID
100mg
BID
150mg 
BID
RP2R* from 
Cohort 1 b
RP2R 
from 
Cohort 
1 b 
RP2R 
from 
Cohort 
1 b
RP2R 
from 
Cohort 
1 b
trametinib
-
-
1.5mg
once daily
2mg
once 
daily
1.5mg
once 
daily
2mg
once 
daily
panitumumab c, 
d
6mg/kg
Q2W
4.8mg/kg
Q2W
4.8mg/kg
Q2W
6mg/kg
Q2W
one dose level 
below RP2R from 
Cohort 1 c
one 
dose 
level 
below 
RP2R 
from 
Cohort 
1 c
RP2R 
from 
Cohort 
1 d
RP2R 
from 
Cohort 
1 d
Rationale: to distinguish between de-escalation and dose escalation cohorts.
Section 3.4.2, paragraph following Table 1
PREVIOUS TEXT
If the initial combination dose of dabrafenib and panitumumab in Cohort 1 (starting dose) 
is not tolerable, lower dose combination(s) defined in Cohort -1A, -1B and/or -1C may be 
evaluated.  The actual Cohort -1 combination(s) that are opened will be based on the 
agent(s) that are most likely causing the intolerance.  Once the dabrafenib/panitumumab 
combination dose is defined, subsequent cohorts in which trametinib is added will be 
based on the dabrafenib/panitumumab dose defined in Cohort 1 or -1 (e.g., if the 
maximally tolerated panitumumab dose in the dabrafenib/panitumumab combination is 
4.8mg/kg, the panitumumab dose in Cohort 2 will be one dose level lower, or 3.6mg/kg.  
Cohorts that are designated as “3A” and “3B” may be opened simultaneously once the 
prior dosing cohort has completed the 28-day DLT window and met dose escalation 
criteria as specified in Table 2.  If the combination doses in both Cohort 3A and Cohort 
3B are well-tolerated, available safety and response data will be evaluated to determine 
the appropriate dose to evaluate in Part 2.
REVISED TEXT
If the initial combination dose of dabrafenib and panitumumab in Cohort 1 (starting dose) 
is not tolerable, lower dose combination(s) defined in de-escalation cohorts (Cohort -1A, 
-1B and/or -1C may be evaluated.  The actual Cohort -1 combination(s) de-escalation 
cohorts that are opened will be based on the agent(s) that are most likely causing the 
intolerance.  Once the dabrafenib/panitumumab combination dose is defined, subsequent 


Novartis
Confidential
Page 361
Clinical Study Protocol Version 05
Protocol No. MEK116833
cohorts in which trametinib is added will be based on the dabrafenib/panitumumab dose 
defined in Cohort 1 or -1 (e.g., if the maximally tolerated panitumumab dose in the 
dabrafenib/panitumumab combination is 4.8mg/kg, the panitumumab dose in Cohort 2 
will be one dose level lower, or 3.6mg/kg.  Cohorts that are designated as “3A” and “3B” 
may be opened simultaneously once the prior dosing cohort has completed the 28-day 
DLT window and met dose escalation criteria as specified in Table 2.  If the combination 
doses in both Cohort 3A and Cohort 3B are well-tolerated, available safety and response 
data will be evaluated to determine the appropriate dose to evaluate in Part 2.
Rationale: to distinguish between de-escalation and dose escalation cohorts.
Section 3.4.3 Part 2, paragraph 1
PREVIOUS TEXT:
In Part 2, the primary objectives will be to further assess the safety and preliminary 
clinical activity of given doses and regimen(s) in subjects with BRAF-V600E mutation-
positive CRC.  Enrollment in Part 2 will be initiated once dose escalation for both 
dabrafenib in combination with panitumumab and a trametinib plus dabrafenib in 
combination with panitumumab has been completed.
REVISED TEXT:
In Part 2, the primary objectives will be to further assess the safety and preliminary 
clinical activity of given doses and regimen(s) in subjects with BRAF-V600E mutation-
positive CRC.  Enrollment in Part 2 doublet will be initiated once dose escalation for the 
doublet both (dabrafenib in combination with panitumumab) and a trametinib plus 
dabrafenib in combination with panitumumab has been completed.  Enrollment in Part 2 
triplet (trametinib plus dabrafenib in combination with panitumumab) will open once 
dose escalation for the triplet has been completed.
Rationale: to clarify timing of opening Part 2 doublet and Part 2 triplet cohorts.
Section 3.7.3 Intra-subject Dose Escalations
PREVIOUS TEXT
In Part 1, intra-subject dose escalation will be allowed for patients enrolling in the triplet 
cohorts provided that the subject has completed at least two 28-day periods on treatment.  
A subject’s dose level for the combination may be increased up to the highest 
combination dose level that has previously been confirmed as not exceeding the MTD for 
the combination.  The intra-subject dose escalation must be agreed to by the investigator 
and the GSK Medical Monitor.
REVISED TEXT
Section 3.7.3 Intra-subject Doublet to Triplet Crossover and Dose Escalation: Part 1 and 
Part 2


Novartis
Confidential
Page 362
Clinical Study Protocol Version 05
Protocol No. MEK116833
In Part 1, intra-subject dose escalation will be allowed for patients enrolling in the triplet 
cohorts provided that the subject has completed at least two 28-day periods on treatment.  
A subject’s dose level for the combination may be increased up to the highest 
combination dose level that has previously been confirmed as not exceeding the MTD for 
the combination.  The intra-subject dose escalation must be agreed to by the investigator 
and the GSK Medical Monitor.
For subjects enrolled in Part 1 or Part 2, intra-subject doublet to triplet crossover is 
allowed if a patient has not experienced intolerable toxicity that could not be managed, 
and has demonstrated radiographic progression on therapy by RECIST v1.1 criteria, and 
approval will be based on review by GSK Medical Monitor. Dose administered must be 
from among those for which cohorts have been completed and data has been reviewed for 
safety.  
Subjects are allowed to crossover once during the study.
Additionally, for subjects who have remained on study for 6 months in the triplet 
combination, their dose level for the combination may be increased up to the highest 
combination dose level that has previously been confirmed as not exceeding the MTD for 
the combination. The intra-subject dose escalation must be agreed to by the investigator 
and the GSK Medical Monitor.
Rationale: To include text allowing subjects who enrolled in Part 1 or Part 2 doublet 
cohort to crossover to a triplet cohort, or to allow those enrolled at a lower than MTD 
cohort to dose-escalate.
Section 3.7.9, Table 15 Withholding and Stopping Criteria for QTc 
Prolongation
PREVIOUS TEXT
QTc Prolongationa
Action and Dose Modification
QTcB501msec
Interrupt study treatment until QTcB prolongation 
resolves to Grade 1 or baseline
Restart at current dose levelb
If event recurs, permanently discontinue study 
treatment


Novartis
Confidential
Page 363
Clinical Study Protocol Version 05
Protocol No. MEK116833
REVISED TEXT
QTc Prolongationa
Action and Dose Modification
QTcB501msec

Interrupt study treatment until QTcB 
prolongation resolves to Grade 1 or baseline

Test serum potassium, calcium, phosphorus 
and magnesium. If <LLN correct with 
supplements to within normal limits.

Review concomitant medication usage for a 
prolonged QTc.

If event resolves, restart study treatment at 
current dose levelb

If event does not resolve, permanently 
discontinue study treatments

If event recurs, permanently discontinue 
study treatments
Abbreviations:  msec = milliseconds; QTcB = QT interval on electrocardiogram corrected using the Bazett’s formula
Rationale: to clarify text based on updated standardized safety text for dabrafenib and 
trametinib assets.
Section 3.8.1, Time and Events Table, Part 1 Dose Escalation
Added text:
Hematology/Clinical Chemistry (including Screening assessment of adequate 
baseline organ function as noted in Table 18)
Footnote 7: French sites will perform dermatological exams monthly while on-therapy, 
and monthly for 6 months following discontinuation of dabrafenib or until initiation of 
another anti-neoplastic therapy, whichever comes first. Refer to Appendix 7 for full 
information.
Footnote 11: Tumor biopsy at tumor progression in subjects who have had a 
radiologic response (20% or more) or had stable disease for 6 months is highly 
encouraged.
Footnote 13: Collection of archived tumor tissue or fresh tumor biopsies and 
determination of the subject’s tumor BRAF mutation status is required for enrollment; if 
a fresh tumor biopsy is collected at during screening and up to prior to dosing on Day 1
for BRAF mutation confirmation, this tissue may be used for the day 1/ predose tumor 
biopsy. 
 
  The Day 1/predose tumor biopsy may be collected at any 
point after signing consent, after completing washout from prior therapies (either 5 half-
lives or 14 days from last dose of prior therapy) up to 14 days prior to first dose.
Rationale: to indicate that subjects should have all assessments performed to meet 
inclusion/exclusion requirements at screening; to point out requirements for French sites 


Novartis
Confidential
Page 364
Clinical Study Protocol Version 05
Protocol No. MEK116833
in timing of dermatological exams; and to clarify which subjects should have tumor 
biopsy at progression.
Section 3.8.2, Time and Events Table, Part 2 Cohort Expansion
Added text:
Hematology/Clinical Chemistry (including Screening assessment of adequate 
baseline organ function as noted in Table 18)
Footnote 7: French sites will perform dermatological exams monthly while on-
therapy, and monthly for 6 months following discontinuation of dabrafenib or until 
initiation of another anti-neoplastic therapy, whichever comes first. Refer to Appendix 7 
for full information.
Footnote 11: Tumor biopsy at tumor progression in subjects who have had a 
radiologic response (20% or more) or had stable disease for 6 months is highly 
encouraged.
Footnote 12: Optional biopsy for subjects who had a radiologic response (20% or 
more decrease) or had a stable disease for 6 months at disease progression (if feasible).  
Mandatory tumor biopsy at tumor progression. A single PK sample will be collected at 
the time of tumor progression.  Refer to Section 6.7.2.
Footnote 13: Collection of archived tumor tissue or fresh tumor biopsies and 
determination of the subject’s tumor BRAF mutation status is required for enrollment; if 
a fresh tumor biopsy is collected at during screening and up to prior to dosing on Day 1
for BRAF mutation confirmation, this tissue may be used for the day 1/ predose tumor 
biopsy. 
 
   The Day 1/predose tumor biopsy may be collected at any 
point after signing consent, after completing washout from prior therapies (either 5 half-
lives or 14 days from last dose of prior therapy) up to 14 days prior to first dose.
Rationale: to indicate that subjects should have all assessments performed to meet 
inclusion/exclusion requirements at screening; to point out requirements for French sites 
in timing of dermatological exams; and to clarify which subjects should have tumor 
biopsy at progression.
Section 3.8.3, Time and Events Table, Part 3 Randomized Phase II
Added text:
Hematology/Clinical Chemistry (including Screening assessment of adequate 
baseline organ function as noted in Table 19)
Tumor tissue biopsy (optional) at progression
Footnote 7: French sites will perform dermatological exams monthly while on-
therapy, and monthly for 6 months following discontinuation of dabrafenib or until 


Novartis
Confidential
Page 365
Clinical Study Protocol Version 05
Protocol No. MEK116833
initiation of another anti-neoplastic therapy, whichever comes first. Refer to Appendix 7 
for full information.
Footnote 16: Optional biopsy for subjects who had a radiologic response (20% or 
more decrease) or had a stable disease for 6 months at disease progression.  The biopsy at 
progression is highly encouraged.
Rationale: to indicate that subjects should have all assessments performed to meet 
inclusion/exclusion requirements at screening; to add an optional tumor biopsy at 
progression; to point out requirements for French sites in timing of dermatological 
exams; and to clarify which subjects should have tumor biopsy at progression.
Section 4.2.1.1 Part 1 and Part 2 Inclusion Criteria
PREVIOUS TEXT
7. Men with a female partner of childbearing potential must have either had a prior 
vasectomy or agree to use one of the contraception methods listed in Section 7.1.2 from
the time of the first dose of study drug(s) and until 6 months after the last dose of 
panitumumab, or 16 weeks following the last dose of dabrafenib or trametinib, whichever 
is later to allow for clearance of any altered sperm.
9. Female subjects must agree to use contraception from the time of the first dose of 
study drug(s) until 60 days after the last dose of any study drug. Note: oral contraceptives 
are not reliable due to potential drug-drug interactions.  Additionally, women of 
childbearing potential must have had a negative serum pregnancy test within 7 days prior 
to the first dose of study drug(s).
REVISED TEXT
7. Men with a female partner of childbearing potential must have either had a prior 
vasectomy or agree to use one of the contraception methods listed in Section 7.1.2 from 
the time of 7 days prior to the first dose of study drug(s) and until 6 months after the last 
dose of panitumumab, or 16 weeks following the last dose of dabrafenib or trametinib, 
whichever is later to allow for clearance of any altered sperm.
9. Female subjects must agree to use contraception from the time of 7 days prior to the 
first dose of study drug(s) until 60 days after the last dose of any study drug 6 months 
after the last dose of panitumumab, until 4 months after the last dose of trametinib, or 4 
weeks after the last dose of dabrafenib, whichever is longer. Note: oral contraceptives 
are not reliable due to potential drug-drug interactions.  Additionally, women of 
childbearing potential must have had a negative serum pregnancy test within 7 days prior 
to the first dose of study drug(s).
Rationale: update to contraception requirements per updated standardized safety text for 
dabrafenib and trametinib assets.


Novartis
Confidential
Page 366
Clinical Study Protocol Version 05
Protocol No. MEK116833
Section 4.2.2.1 Part 3 Inclusion Criteria
PREVIOUS TEXT
9. Men with a female partner of childbearing potential must have either had a prior 
vasectomy or agree to use one of the contraception methods listed in Section 7.1.2 from 
the time of the first dose of study drug(s) and until 6 months after the last dose of 
panitumumab, or 16 weeks following the last dose of dabrafenib or trametinib, whichever 
is later to allow for clearance of any altered sperm.
11. Female subjects must agree to use contraception from the time of the first dose of 
study drug(s) until 60 days after the last dose of any study drug. Note: oral contraceptives 
are not reliable due to potential drug-drug interactions.  Additionally, women of 
childbearing potential must have had a negative serum pregnancy test within 7 days prior 
to the first dose of study drug(s).
REVISED TEXT
9. Men with a female partner of childbearing potential must have either had a prior 
vasectomy or agree to use one of the contraception methods listed in Section 7.1.2 from 
the time of 7 days prior to the first dose of study drug(s) and until 6 months after the last 
dose of panitumumab, or 16 weeks following the last dose of dabrafenib or trametinib, 
whichever is later to allow for clearance of any altered sperm.
11. Female subjects must agree to use contraception from the time of 7 days prior to the 
first dose of study drug(s) until 60 days after the last dose of any study drug 6 months 
after the last dose of panitumumab, until 4 months after the last dose of trametinib, or 4 
weeks after the last dose of dabrafenib, whichever is longer. Note: oral contraceptives 
are not reliable due to potential drug-drug interactions.  Additionally, women of 
childbearing potential must have had a negative serum pregnancy test within 7 days prior 
to the first dose of study drug(s).
Rationale: update to contraception requirements per updated standardized safety text for 
dabrafenib and trametinib assets.
Section 5.2.3 Analysis Populations, added paragraph
The Crossover Population will comprise the subset of subjects in Part 1 and Part 2 who 
had intra-subject dose escalation. It will be the primary population when summarizing 
data in Part 1 and Part 2 crossover phase.
Rationale: to address how subjects who crossover from doublet to triplet dosing will be 
analysed.
Section 5.3.7.8.1 Efficacy Analyses, Part 1 and Part 2, added text to last paragraph
For Part 1 and Part 2, anti-tumor activities will be evaluated based on clinical evidence 
and response criteria. If the data warrant, the response data from both parts will be 
combined and summarized by dose level. Subjects who crossover from 


Novartis
Confidential
Page 367
Clinical Study Protocol Version 05
Protocol No. MEK116833
dabrafenib/panitumumab combination to dabrafenib/trametinib/panitumumab 
combination will not be included in the main efficacy analysis for 
dabrafenib/trametinib/panitumumab combinations. The efficacy for these subjects will be 
summarized separately.
Rationale: to address how subjects who crossover from doublet to triplet dosing will be 
analysed.
Section 6.7.2 Fresh Tumor Tissue at Progression, added section
Tumor specimens that are accessible and can be sampled easily will be requested from 
some subjects at time of demonstrated progression on therapy, as determined by RECIST 
v1.1 criteria.  Subjects of interest will be those who have had meaningful clinical 
response in target lesions (20% reduction, or stable disease for 6 months) and then 
progressed on existing target lesions or if a new lesion emerged. The guidance on the 
lesion selection for the progression biopsy are:

if subject has new lesions only, preferably biopsy a new lesion if feasible

if a subject has growth of existing lesions only, biopsy a growing lesion if feasible 
if a subject has both emergence of new lesions and growth of existing lesions, 
then biopsy both a new lesion and existing lesions, if feasible. 

If above criteria based lesions are not feasible to be biopsied, selection of lesion 
will be at the discretion of the interventional radiologist.
 
 
 
 
 
Details of the tumor biopsy collection including processing, storage and shipping 
procedures will be provided in the SPM.
Rationale: to provide clarity on collection of tumor biopsy at progression
Section 7.1.1 Contraception Requirements, Female Subjects
PREVIOUS TEXT
Female subjects of childbearing potential must not become pregnant and so must be 
sexually inactive by abstinence or use contraceptive methods with a failure rate of < 1% 
from start of dosing and until 60 days after the last dose of any study drug.


Novartis
Confidential
Page 368
Clinical Study Protocol Version 05
Protocol No. MEK116833
REVISED TEXT
Female subjects of childbearing potential must not become pregnant and so must be 
sexually inactive by abstinence or use contraceptive methods with a failure rate of < 1% 
from start of dosing and until 60 days after the last dose of any study drug.

for 6 months after the last dose of panitumumab (Vectibix)

for 4 months after the last dose oftrametinib in combination with dabrafenib 

for 4 weeks after the last dose of dabrafenib.  
Rationale: update to contraception requirements per updated standardized safety text for 
dabrafenib and trametinib assets.
Section 7.1.2 Contraception Requirements, Male Subjects
PREVIOUS TEXT
To prevent pregnancy in a female partner or to prevent exposure of any partner to the 
study treatment from a male subject’s semen, male subjects must use one of the following 
contraceptive methods after the start of dosing and until 6 months after the last dose of 
panitumumab, or 16 weeks following the last dose of dabrafenib or trametinib, whichever 
is later to allow for clearance of any altered sperm:
REVISED TEXT
To prevent pregnancy in a female partner or to prevent exposure of any partner to the 
study treatment from a male subject’s semen, male subjects must use one of the following 
contraceptive methods after the start of dosing from 7 days prior to the first dose and until 
6 months after the last dose of panitumumab, or 16 weeks following the last dose of 
dabrafenib or trametinib, whichever is later to allow for clearance of any altered sperm:
Rationale: update to contraception requirements per updated standardized safety text for 
dabrafenib and trametinib assets.
Section 7.2 Meals and Dietary Restrictions
PREVIOUS TEXT
Dabrafenib and trametinib should be administered under fasting conditions, either one 
hour before or 2 hours after a meal.  If a subject vomits within 4 hours after taking study 
medication, the subject should be instructed not to retake the dose and should take the 
next scheduled dose.  These subjects will be excluded from PK analysis, but not replaced.
REVISED TEXT
Dabrafenib and trametinib should be administered in the morning at approximately the 
same time every day.  The second dose of dabrafenib (150 mg) should be administered 
approximately 12 hours after the morning dose.  Study medication should be taken orally 


Novartis
Confidential
Page 369
Clinical Study Protocol Version 05
Protocol No. MEK116833
with approximately 200 mL of water under fasting conditions, either 1 hour before or 2 
hours after a meal.
If a subject vomits after taking study medication, the subject should be instructed not to 
retake the dose and should take the next dose as originally scheduled.  
Rationale: to provide clarity on timing of dosing
Section 10.3.3 Storage
PREVIOUS TEXT
All investigational products must be stored in original bottles supplied by GSK and in a 
secure area with access limited to the investigator and authorized site staff.  Dabrafenib is 
to be stored up to 30C (86F) in an opaque bottle, as supplied by GSK.  Trametinib is to 
be stored at 25C (77°F), protected from moisture and light, and stored and dispensed in 
the original cartons supplied by GSK.  Whole bottles of investigational products are 
dispensed at each 4 week visit. Maintenance of a temperature log (manual or automated) 
is required.
REVISED TEXT
All investigational products must be stored in original bottles supplied by GSK and in a 
secure area with access limited to the investigator and authorized site staff.  Dabrafenib is 
to be stored up to 30C (86F) in an opaque bottle, as supplied by GSK.  Trametinib is to 
be stored at 2 to 8°C (36 to 46°F) 25C (77°F), protected from moisture and light, and 
stored and dispensed in the original cartons supplied by GSK.  Please ensure that the 
bottles have equilibrated back to room temperature before opening them to avoid 
moisture condensation on the tablets. Whole bottles of investigational products are 
dispensed at each 4 week visit. Maintenance of a temperature log (manual or automated) 
is required.
Rationale: new storage specifications for trametinib have been provided.
AMENDMENT 1
Where the amendment applies
This amendment applies to all sites in all countries.
Summary of Amendment Changes with Rationale
Major revisions in this amendment restricts enrollment to V600E mutation positive CRC; 
formerly allowed V600E or V600K mutations; allows use of MUGA to evaluate LVEF if 
ECHO is not available; allows use of therapeutic warfarin (previously exclusionary); 
adds text on Bayesian design for Part 2; clarifies follow-up (PFS, OS) for subjects who 
discontinue study treatment for any reason other than disease progression; addresses 
cardiac monitoring assessments as requested by the ANSM.


Novartis
Confidential
Page 370
Clinical Study Protocol Version 05
Protocol No. MEK116833
Throughout the protocol, minor edits have been made to clarify text, including removal 
of references to V600K mutation specific to enrollment in this study, clarification of 
supporting documents (Investigator Brochures, supplements to the Investigator 
Brochures) and reformatting of the study schematic for Part 1 to be more easily 
understood. 
Title
Previous text: An Open-Label, Three-Part, Phase I/II Study to Investigate the Safety, 
Pharmacokinetics, Pharmacodynamics, and Clinical Activity of the MEK Inhibitor 
GSK1120212, BRAF Inhibitor GSK2118436 and the anti-EGFR Antibody Panitumumab 
in Combination in Subjects with BRAF-mutation V600E or V600K Positive Colorectal 
Cancer
Revised text: An Open-Label, Three-Part, Phase I/II Study to Investigate the Safety, 
Pharmacokinetics, Pharmacodynamics, and Clinical Activity of the MEK Inhibitor 
GSK1120212, BRAF Inhibitor GSK2118436 and the anti-EGFR Antibody Panitumumab 
in Combination in Subjects with BRAF-mutation V600E or V600K Positive Colorectal 
Cancer
Rationale: The studypopulation was revised to clearly reflect the majority of patients 
with BRAF-mutation positive colorectal cancer will have the BRAF V600E mutation.
Synopsis
Previous text: 
Part 2 of the study will consist of expansion cohorts to enroll subjects with BRAF-
mutation V600E or V600K positive CRC, and investigate safety and clinical activity of 
dabrafenib in combination with panitumumab and trametinib plus dabrafenib in 
combination with panitumumab
Revised text:
Part 2 of the study will consist of expansion cohorts to enroll subjects with BRAF-
mutation V600E or V600K positive CRC, and investigate safety and clinical activity of 
dabrafenib in combination with panitumumab and trametinib plus dabrafenib in 
combination with panitumumab.
Rationale: Clarification of text; the population enrolled for all parts of the study will be 
subjects with BRAF-mutation-positive CRC.


Novartis
Confidential
Page 371
Clinical Study Protocol Version 05
Protocol No. MEK116833
SPONSOR/MEDICAL MONITOR INFORMATION PAGE
Medical Monitor and Sponsor Contact Information:
Previous text: 
Role
Name
Day Time 
Phone 
Number
After-hours 
Phone/Cell/
Pager 
Number
Fax 
Number
GSK Address
Medical 
Monitor
 
, MD
GlaxoSmithKline
1250 Collegeville Road
Mailstop UP4210
Collegeville, PA
USA
Revised text:
Role
Name
Day Time 
Phone 
Number
After-hours 
Phone/Cell/
Pager 
Number
Fax 
Number
GSK Address
Medical 
Monitor
MD
GlaxoSmithKline
1250 Collegeville Road
Mailstop UP4410
Collegeville, PA
USA
Rationale:  Revision to Secondary Medical Monitor contact information to reflect 
changes in staffing.
Previous text:
Regulatory Agency Identifying Number(s); IND#113557
Revised text:
Regulatory Agency Identifying Number(s): IND# 113557, EUDRACT# 2012-004802-81, 
NCT# 01750918
Rationale:  Addition of EUDRACT # and NCT# once available.


Novartis
Confidential
Page 372
Clinical Study Protocol Version 05
Protocol No. MEK116833
Abbreviations:
Added text:
CuSCC
Cutaneous squamous cell carcinoma
Rationale: Addition of abbreviation used in added text in body of protocol.
Section 1.4.2 GSK1120212: Trametinib, paragraph 4:
Previous text:
Cardiac function: A reduction in cardiac function in a fraction of subjects (specifically, 
left ventricular ejection fraction) is a known class effect of MEK inhibitors and have been 
seen with trametinib.  Subjects with pre-existing heart failure will be excluded from this 
study.  To monitor cardiac function, echocardiogram (ECHO) exams will be performed.  
In addition, withholding criteria for left ventricular ejection fraction decreases will be 
implemented.
Revised text:
Cardiac function: A reduction in cardiac function in a fraction of subjects (specifically, 
left ventricular ejection fraction) is a known class effect of MEK inhibitors and have been 
seen with trametinib.  Subjects with pre-existing heart failure will be excluded from this 
study.  To monitor Cardiac function, echocardiogram (ECHO) exams will be performed. 
assessed prior to enrollment, and will be monitored on study. In addition, withholding 
criteria for left ventricular ejection fraction decreases will be implemented.
Rationale: Revised text to allow either ECHO or MUGA for evaluation of cardiac 
function prior to start of study and allow for ECHO or MUGA for on study evaluation of 
changes.  ECHO is the preferred method; MUGA will be allowed only at sites which 
cannot perform ECHO.
Section 2.1 Part 1: Phase I Dose Escalation
Previous text:
Secondary
To describe the pharmacokinetics of 
dabrafenib, trametinib and 
panitumumab after combination 
therapy
To determine preliminary clinical 
activity of dabrafenib dosed orally in 
combination with panitumumab 
To determine clinical activity of 
trametinib dosed orally in 
combination with dabrafenib and 
Maximum observed concentration 
(Cmax), time of occurrence of Cmax 
(tmax), and area under the 
concentration-time curve from zero 
(pre-dose) 8 hours (AUC(0-8)), pre-
dose (trough) concentration at the 
end of the dosing interval (C) of 
trametinib and dabrafenib.  Predose 
(C) and Cmax concentrations of 
panitumumab.
Response rate (complete response 
[CR] + partial response [PR]) 


Novartis
Confidential
Page 373
Clinical Study Protocol Version 05
Protocol No. MEK116833
panitumumab
Progression free survival
Duration of response
Response rate (CR +PR)
Progression free survival
Duration of response
Revised text:
Secondary
To describe the pharmacokinetics of 
dabrafenib, trametinib and 
panitumumab after combination 
therapy
To determine preliminary clinical 
activity of dabrafenib dosed orally in 
combination with panitumumab 
To determine clinical activity of 
trametinib dosed orally in 
combination with dabrafenib and 
panitumumab
Maximum observed concentration 
(Cmax), time of occurrence of Cmax 
(tmax), and area under the 
concentration-time curve from zero 
(pre-dose) 8 hours (AUC(0-8)), pre-
dose (trough) concentration at the 
end of the dosing interval (C) of 
trametinib and dabrafenib.  Predose 
(C) and Cmax concentrations of 
panitumumab.
Response rate (complete response 
[CR] + partial response [PR]) 
Progression free survival
Duration of response


Novartis
Confidential
Page 374
Clinical Study Protocol Version 05
Protocol No. MEK116833
To evaluate the pharmacodynamic 
response in colorectal tumors 
following combination treatment
Response rate (CR +PR)
Progression free survival
Duration of response
Change in levels of proteins/RNA 
implicated in MAPK/PI3K/EGFR 
pathways in pre- and post-dose 
tumor tissue. 
Section 2.2 Part 2: Cohort Expansions
Previous text:
Secondary
To characterize the population PK 
parameters of dabrafenib and 
trametinib dosed orally in 
combination with anti-EGFR antibody 
(panitumumab) 
To characterize the durability of 
response with dabrafenib dosed 
orally in combination with 
panitumumab 
To characterize the durability of 
response with trametinib dosed orally 
Population PK parameters,  oral 
clearance (CL/F),  oral volume of 
distribution (V/F), and absorption rate 
constant (Ka) 
Duration of response
Progression-free survival 
Overall survival
Duration of response
Progression-free survival


Novartis
Confidential
Page 375
Clinical Study Protocol Version 05
Protocol No. MEK116833
in combination with dabrafenib and 
panitumumab 
Overall Survival
Revised text:
Secondary
To characterize the population PK 
parameters of dabrafenib and 
trametinib dosed orally in 
combination with anti-EGFR antibody 
(panitumumab) 
To characterize the durability of
response with dabrafenib dosed 
orally in combination with 
panitumumab 
To characterize the durability of 
response with trametinib dosed orally 
in combination with dabrafenib and 
panitumumab 
Population PK parameters,  oral 
clearance (CL/F),  oral volume of 
distribution (V/F), and absorption rate 
constant (Ka) 
Duration of response
Progression-free survival 
Overall survival
Duration of response
Progression-free survival
Overall Survival


Novartis
Confidential
Page 376
Clinical Study Protocol Version 05
Protocol No. MEK116833
To evaluate the pharmacodynamic 
response in colorectal tumors
following combination treatment
Change in levels of proteins/RNA 
implicated in MAPK/PI3K/EGFR 
pathways in pre- and post-dose 
tumor tissue
Rationale: Given that pharmacodynamics will be investigated during the course of the 
study, the pharmacodynamics objective and endpoint was moved from 
 
secondary for both Part 1 (Section 2.1) and Part 2 (Section 2.2).


Novartis
Confidential
Page 377
Clinical Study Protocol Version 05
Protocol No. MEK116833
Section 3.1 Part 1 Dose Escalation Study Design/Schematic
Previous schematic:
Revised schematic:


Novartis
Confidential
Page 378
Clinical Study Protocol Version 05
Protocol No. MEK116833
Rationale: Clarification of schematic; no revision to study design.
Section 3.4.1 Prescreening for KRAS and BRAF Mutation Status, 
paragraphs 4 and 5
Previous text:
Enrollment in Part 3 will only occur following centralized determination of BRAFV600E 
or V600K mutation.
Archived tumor tissue sample must be collected from all subjects enrolled in this study at 
screening.  If this has not been done and an archived tumor tissue sample is not available, 
the subject should undergo a biopsy to obtain a tumor tissue sample. 
 
Revised text:
Enrollment in Part 3 will only occur following centralized determination of BRAFV600E 
or V600K mutation.  Testing must be performed in a CLIA certified central laboratory.  
The testing will be preferably conducted on metastatic tumor tissue or on recently 
obtained tumor tissue.  
Archived tumor tissue sample must be collected from all subjects enrolled in this study at 
screening.  If this has not been done and an archived tumor tissue sample is not available, 
the subject should undergo a biopsy prior to dosing to obtain a tumor tissue sample.  
 
  
Rationale:  Addition of specific requirements for central laboratory testing, and type of 
tissue to be tested.  
Section 3.4.2 Part 1, paragraph 2 (following Table 1)
Previous text:
If the initial combination dose of dabrafenib and panitumumab in Cohort 1 is not 
tolerable, lower dose combination(s) defined in Cohort -1 will be evaluated.  
Revised text:
If the initial combination dose of dabrafenib and panitumumab in Cohort 1 (starting dose)
is not tolerable, lower dose combination(s) defined in Cohort -1 will 1A, -1B and/or -1C 
may be evaluated.  
Rationale:  Clarification regarding inclusion of Cohort -1A, -1B and/or -1C.  These 
cohorts will be opened only if toxicity emerges in Cohort 1.


Novartis
Confidential
Page 379
Clinical Study Protocol Version 05
Protocol No. MEK116833
Section 3.4.2 Part 1, paragraph 5 (following Table 2)
Previous text:
Any cohort may be expanded beyond the 3 to 6 subjects enrolled during dose escalation, 
to a maximum of 12 subjects, to facilitate additional collection of safety data.
Revised text:
Any cohort may be expanded beyond the initial 3 to 6 subjects enrolled during dose 
escalation, to a maximum of 12 subjects, to facilitate additional collection of safety data.
Rationale: Clarification of the number of subjects that may be enrolled.
Section 3.4.2.1 Dose-Limiting Toxicity Definitions
Previous text:
Toxicity
DLT Definition
Hematologic

Grade 4 absolute neutrophil count (ANC) for 5 days

Febrile neutropenia (defined as concurrent Grade 4 neutropenia and fever 
>38.5C and lasting >24 hrs)

Grade 4 anemia of any duration

Grade 4 thrombocytopenia (platelets <25,000) of any duration
Non-hematologic
Alanine aminotransferase (ALT) >5X upper limit of normal (ULN) OR, ALT >3X ULN 
AND bilirubin >2X ULN (after exclusion of disease progression and/or bile duct 
obstruction)

Grade 4 rash 

Grade 4 Squamous Cell Carcinoma, keratoacanthoma or basal cell carcinoma
Grade 3 or greater clinically significant non-hematologic toxicity per NCI-CTCAE, v 4.0, 
other than those listed above, with the following exceptions:
o
Grade 3 or greater nausea, vomiting, diarrhea, or 
mucositis/esophagitis that responds to maximal supportive 
treatment(s) within 48 hours
o
Electrolyte disturbances that respond to correction within 24 hours
o
Grade 3 hypertension that is adequately controlled by the addition of 
up to 2 additional antihypertensive medications

Grade 3 pyrexia that does not result in study discontinuation
Cardiac

Ejection fraction < lower limit of normal (LLN) with an absolute decrease of 
>10% from baseline with confirming assessment within 7 days.
Other

Inability to received >75% of scheduled doses in treatment period due to 
toxicity

Grade 2 or higher toxicity that occurs beyond 21 days which in the judgment of 
the investigator and GSK Medical Monitor is considered to be a DLT


Novartis
Confidential
Page 380
Clinical Study Protocol Version 05
Protocol No. MEK116833
Revised text:
Toxicity
DLT Definition
Hematologic

Grade 4 absolute neutrophil count (ANC) for 5 days

Febrile neutropenia (defined as concurrent Grade 4 neutropenia and fever 
>38.5C and lasting >24 hrs)

Grade 4 anemia of any duration

Grade 4 thrombocytopenia (platelets <25,000) of any duration
Non-hematologic
Alanine aminotransferase (ALT) >5X upper limit of normal (ULN) OR, ALT >3X ULN 
AND bilirubin >2X ULN (after exclusion of disease progression and/or bile duct 
obstruction)

Grade 4 rash 

Grade 4 Squamous Cell Carcinoma, keratoacanthoma or basal cell carcinoma
Grade 3 or greater clinically significant non-hematologic toxicity per NCI-CTCAE, v 4.0, 
other than those listed above, with the following exceptions:
o
Grade 3 or greater nausea, vomiting, diarrhea, or 
mucositis/esophagitis that responds to maximal supportive 
treatment(s) within 48 hours
o
Electrolyte disturbances that respond to correction within 24 hours
o
Grade 3 hypertension that is adequately controlled by the addition of 
up to 2 additional antihypertensive medications
o
Grade 3 pyrexia that does not result in study discontinuation
Cardiac

Ejection fraction < lower limit of normal (LLN) with an absolute decrease of 
>10 20% from baseline with confirming assessment within 7 days.
Other

Inability to received >75% of scheduled doses in treatment period due to 
toxicity

Grade 2 or higher toxicity that occurs beyond 21 28 days which in the 
judgment of the investigator and GSK Medical Monitor is considered to be a 
DLT
Rationale: Clarification that: Grade 3 pyrexia that does not result in study 
discontinuation” is a sub-bullet to “Grade 3 or greater clinically significant non-
hematologic toxicity per NCI-CTCAE, v 4.0, other than those listed above, with the 
following exceptions:’.  Revising the ejection fraction criteria per safety data. Correcting 
the period of time for DLT evaluation from 21 to 28 days.
Section 3.4.3 Part 2, paragraph 4
Previous text:
The responses will be assessed and decisions to continue to Part 3 will be made based on 
response data are available for up to 20 subjects for each cohort.  In order to proceed to 
Part 3, sufficient evidence of clinical activity (e.g. observing 4 responses out of up to 
20 subjects) should be observed to warrant further development.


Novartis
Confidential
Page 381
Clinical Study Protocol Version 05
Protocol No. MEK116833
Revised text:
The responses will be assessed and decisions to continue to Part 3 will be made based on 
response data are available for up to 20 subjects for each cohort.  In order to proceed to 
Part 3, sufficient evidence of clinical activity (e.g. observing 4 responses out of up to 
20 subjects) should be observed to warrant further development. Meanwhile, the Part 
2 portion of the study will employ a Bayesian design that allows the trial to be monitored 
more frequently at multiple stages.
Rationale:  Additional text to define use of Bayesian design in Part 2/Cohort Expansion.
Section 3.6 Investigational Products and Other Study Treatment 
Dosage/Administration
Previous text:
Trametinib: GSK1120212
Each tablet contains 0.5mg or 2.0 mg GSK1120212 
 
 
Revised text:
Trametinib: GSK1120212
Each tablet contains 0.5mg or 2.0 mg GSK1120212
 
 
Rationale: Correction to indicate that the film coating will contain yellow or pink, not 
both yellow and pink.


Novartis
Confidential
Page 382
Clinical Study Protocol Version 05
Protocol No. MEK116833
Section 3.7.1, Table 3 Categories of Dose Modification Guidelines
Added table:
Adverse Event
Dabrafenib
Trametinib 
Section
General Guidelines for Clinically Significant 
Toxicities
X
X
Section 3.7.4
Guidelines for Specific Adverse Events
Cardiovascular Adverse Eventsa
LVEF
X
Section 3.7.7.1
Hypertension 
X
X
Section 3.7.8
Prolonged QTc
X
X
Section 3.7.9
Skin –Related Adverse Events (Except cuSCC)b
Rash
X
X
Section 3.7.4.2
Hand-Foot Skin Reaction
X
X
Section 3.7.4.2.4
Other Adverse Events
Pyrexia
X
Section 3.7.4.1
Diarrhea
X
X
Section 3.7.5
Renal Insufficiency
X
X
Section 3.7.6
Visual Changes
X
X
Section 3.7.11
Pneumonitis
X
X
Section 3.7.13
Liver Chemistry Stopping Criteria
X
X
Section 3.7.10
a.
For subjects enrolled in France, please see Appendix 5  for additional dose modification guidelines.
b.
Refer to Section 3.7.4.3 for management of cuSCC
Rationale: Table was added to summarize dose modification guidelines and to ease 
navigation through the text.
Section 3.7.2 Dose Adjustment, paragraphs 4 and 5
Previous text:
If an AE resolves to grade 1 or baseline at the reduced dose level, and no additional 
toxicities are seen after 4 weeks of study treatment at the reduced dose, the dose may be 
increased to the previous dose level with approval from the GSK Medical Monitor.
A dose reduction below 75mg BID for dabrafenib, 1mg once daily for trametinib and 
3mg/kg every 14 days for panitumumab is not allowed.  If a dose reduction below 75 mg 
BID for dabrafenib is required, dabrafenib will be permanently discontinued, but the 
subjects will be allowed to continue trametinib and panitumumab. If a dose reduction 
below1.0 mg once daily for trametinib is required, then trametinib will be permanently 
discontinued, but these subjects will be allowed to continue dabrafenib and panitumumab. 
If a dose reduction below 3mg/kg every 14 days for panitumumab is required, 
panitumumab will be permanently discontinued, but the subjects will be allowed to 
continue dabrafenib and trametinib.
Revised text:
If an AE resolves to grade 1 or baseline at the reduced dose level, and no additional 
toxicities are seen after 4 weeks of study treatment at the reduced dose, the dose may be 
increased to the previous dose level with approval from the GSK Medical Monitor.


Novartis
Confidential
Page 383
Clinical Study Protocol Version 05
Protocol No. MEK116833
A dose reduction below 75mg BID for dabrafenib, 1mg once daily for trametinib and 
3mg/kg every 14 days for panitumumab is not allowed (per the panitumumab label 
[VECTIBIX, 2012].  If a dose reduction below 75 mg BID for dabrafenib is required, 
dabrafenib will be permanently discontinued, but the subjects will be allowed to continue 
trametinib and panitumumab. If a dose reduction below1.0 mg once daily for trametinib 
is required, then trametinib will be permanently discontinued, but these subjects will be 
allowed to continue dabrafenib and panitumumab. If a dose reduction below 3mg/kg 
every 14 days for panitumumab is required, panitumumab will be permanently 
discontinued, but the subjects will be allowed to continue dabrafenib and trametinib.
Rationale: Dose re-escalation may occur only after discussion between the investigator 
and the GSK medical monitor.  Panitumumab dosing may not be decreased below label 
parameters.
Section 3.7.3 Intra-subject Dose Escalations
Previous text:
In Part 1, intra-subject dose escalation will be allowed provided that the subject has 
completed at least two 28-day periods on treatment.  
Revised text:
In Part 1, intra-subject dose escalation will be allowed for patients enrolling in the triplet 
cohorts provided that the subject has completed at least two 28-day periods on treatment.  
Rationale: Patients enrolling in the doublet cohort, dosing with dabrafenib plus 
panitumumab, are receiving the maximum approved dose.  
Section 3.7.4 Dose Adjustment/Stopping Safety Criteria
Revised section title to: General Guidelines for Clinically Significant Toxicities
Added text: General guidelines regarding management and dose reduction for adverse 
events that are considered by the investigator to be related to study treatment and which 
do not have specific guidelines.
Revised Table 5:
Non-hematologic and 
hematologic toxicity (except 
neutropenia and fever), CTCAE 
Grade
Dose modification algorithms a, b, c, d
Grade 1
Continue dabrafenib, trametinib and panitumumab at full dose; monitor as 
clinically indicated

Monitor closely
Provide supportive care according to institutional standards
Rationale: Clarification that text in this section refers to toxicities not specifically 
addressed elsewhere in the protocol.


Novartis
Confidential
Page 384
Clinical Study Protocol Version 05
Protocol No. MEK116833
Section 3.7.4.3 Guidelines for cuSCC, added section
Cutaneous squamous cell carcinomas have been observed in subjects treated with 
dabrafenib and the combination of dabrafenib and trametinib (see the GSK1120212 + 
GSK2118436 Clinical IB and Supplements [GlaxoSmithKline Document Number, 
2011N126811_00, GlaxoSmithKline Document Number 2012N1523310_00. 
GlaxoSmithKline Document Number 2012N152310_01]). These treatment-related 
cuSCC should be surgically removed according to institutional practice.  Dose 
modifications or interruptions of the study treatment are not required for cuSCC.  
Occurrence of cuSCC must be reported as an SAE. Submit cuSCC tumor tissue for 
analysis as directed in the SPM.
Rationale: New section added to address toxicity specific to dabrafenib and the 
combination of dabrafenib and trametinib.
Section 3.7.7.1 Left Ventricular Ejection Fraction (LVEF) Decreases
Previous text: 
Echocardiography must be performed at Screening and at the post-treatment follow-up 
visit as outlined in the Time and Events Tables (Section 3.8).  .  Decreases of the left
ventricular ejection fraction (LVEF) have been observed in subjects receiving trametinib 
monotherapy and in combination with dabrafenib. Therefore, ECHOs must be performed 
to assess cardiac ejection fraction at regular intervals as outlined in the Time and Events 
Table (Section 3.8). Copies of all ECHOs and cardiology consultations performed on 
subjects who experience a >10% decrease in LVEF from baseline and whose cardiac 
ejection fraction is <institution’s LLN will be required by GSK for review.  Instructions 
for submitting qualifying ECHOs are provided in the Study Procedures Manual (SPM).
Dose modification guidance and stopping criteria for LVEF decrease are provided in 
Table 13.
Revised text:
Echocardiography Cardiac ejection fraction function assessments (ECHO or MUGA; 
ECHO is preferred) must be performed at Screening and at the post-treatment follow-up 
visit as outlined in the Time and Events Tables (Section 3.8).  All assessments for an 
individual patient must be peformed with the same modality (i.e., ECHO or MUGA) and, 
preferably, by the same institution/operator, in order to reduce variability.  Decreases of 
the left ventricular ejection fraction (LVEF) have been observed in subjects receiving 
trametinib monotherapy and in combination with dabrafenib. Therefore, ECHOs must be 
performed to assess cardiac ejection fraction must be assessed at regular intervals as 
outlined in the Time and Events Table (Section 3.8). Copies of all ECHOs LVEF 
assessments and cardiology consultations performed on subjects who experience a >10% 
decrease in LVEF from baseline and whose cardiac ejection fraction is <institution’s 
LLN will be required by GSK for review.  Instructions for submitting qualifying ECHOs/ 
MUGAs are provided in the Study Procedures Manual (SPM).


Novartis
Confidential
Page 385
Clinical Study Protocol Version 05
Protocol No. MEK116833
Dose modification guidance and stopping criteria for LVEF decrease are provided in 
Table 13.  Additional guidelines for subjects enrolled at sites in France are provided in 
Appendix 5.
Rationale: Text was revised to allow use of MUGA for institutions that cannot perform 
ECHOs.
Table 13: Dose Modification Guidelines and Stopping Criteria for LVEF 
Decrease
Previous table:
Clinic Presentation
LVEF decrease (%) or CTCAE grade
Action and Dose Modification
Asymptomatic
Absolute decrease of >10% in LVEF 
compared to baseline and ejection 
fraction below the institutional LLN
Interrupt study treatment with dabrafenib and 
trametinib and repeat ECHO within 2 weeksa
IF LVEF recovers within 4 weeks (defined as LVEF 
LLN and absolute decrease 10% compared to 
baseline):

Consult with the GSK Medical Monitor 
and request approval for restart

Restart with dabrafenib and trametinib at 
previous dose level

Repeat ECHO at 2, 4, 8, and 12 weeks 
after re-start; continue in 12 week 
intervals thereafter
If LVEF does not recover within 4 weeks:
n.
Consult with cardiologist
o.
Permanently discontinue dabrafenib 
and trametinib
p.
Repeat ECHO after 2, 4, 8, 12 and 16 
weeks or until resolution
q.
Consult with GSK Medical Monitorc
Symptomaticb
Grade 3: resting LVEF 39-20% or >20%
absolute reduction from baseline
Permanently discontinue study treatment with 
dabrafenib and trametinib 
Consult with cardiologist
Repeat ECHO after 2, 4, 8, 12 and 16 weeks or 
until resolution.
Grade 4: resting LVEF <20%
a. If ECHO does not show LVEF recovery after 2 weeks, repeat ECHO 2 weeks later.
b. Symptoms may include: dyspnea, orthopnea, and other signs and symptoms of pulmonary congestion and 
edema.
c. Once LVEF recovers to baseline, restarting dabrafenib monotherapy may be considered in consultation with the 
GSK Medical Monitor.


Novartis
Confidential
Page 386
Clinical Study Protocol Version 05
Protocol No. MEK116833
Revised table:
Clinic Presentation
LVEF decrease (%) or CTCAE grade
Action and Dose Modification
Asymptomatic
Absolute decrease of >10% in LVEF 
compared to baseline and ejection 
fraction below the institutional LLN
Interrupt study treatment with dabrafenib and 
trametinib and repeat ECHO/MUGA within 2 
weeksa
IF LVEF recovers within 4 weeks (defined as LVEF 
LLN and absolute decrease 10% compared to 
baseline):

Consult with the GSK Medical Monitor 
and request approval for restart

Restart with trametinib reduced by one 
dose level

Restart dabrafenib and trametinib at 
previous dose level

Repeat ECHO/MUGA at 2, 4, 8, and 12 
weeks after re-start; continue in 12 week 
intervals thereafter
If LVEF does not recover within 4 weeks:
r.
Consult with cardiologist
s.
Permanently discontinue dabrafenib 
and trametinib
t.
Repeat ECHO/MUGA after 2, 4, 8, 12 
and 16 weeks or until resolution
u.
Consult with GSK Medical Monitorc
Symptomaticb
Grade 3: resting LVEF 39-20% or >20% 
absolute reduction from baseline
Permanently discontinue study treatment with 
dabrafenib and trametinib 
Consult with cardiologist
Repeat ECHO/MUGA after 2, 4, 8, 12 and 16 
weeks or until resolution.
Grade 4: resting LVEF <20%
a. If ECHO/MUGA does not show LVEF recovery after 2 weeks, repeat ECHO/MUGA 2 weeks later.
b. Symptoms may include: dyspnea, orthopnea, and other signs and symptoms of pulmonary congestion and 
edema.
c. Once LVEF recovers to baseline, restarting dabrafenib monotherapy may be considered in consultation with the 
GSK Medical Monitor.
Rationale: Revisions incorporate safety text for restarting trametinib at a dose reduction, 
and allow for use of MUGA at institutions that cannot perform ECHO.
Table 15: Withholding and Stopping Criteria for QTc Prolongation
Previous table:
QTc Prolongationa
Action and Dose Modification
QTcB501msec
Uncorrected QT >600msec
QTcB >530msec for subjects with bundle branch block 
(BBB)
Interrupt study treatment until QTcB prolongation resolves 
to Grade 1 or baseline
Restart at current dose levelb
If event recurs, permanently discontinue study treatment


Novartis
Confidential
Page 387
Clinical Study Protocol Version 05
Protocol No. MEK116833
Revised table:
QTc Prolongationa
Action and Dose Modification
QTcB501msec
Uncorrected QT >600msec
QTcB >530msec for subjects with bundle branch block 
(BBB)
Interrupt study treatment until QTcB prolongation resolves 
to Grade 1 or baseline
Restart at current dose levelb
If event recurs, permanently discontinue study treatment
Rationale: Revisions to stopping criteria for clarification.
Section 3.7.11 Visual Changes Stopping Criteria
Added introductory paragraph:
Episodes of visual changes have been observed in subjects receiving dabrafenib, 
trametinib or the combination of both therapies. The causal relationship between a 
change in vision and the study treatment should be carefully explored and an 
ophthalmologist should be consulted. Special attention should be given to retinal 
(e.g., CSR) or retinal vein abnormalities (e.g., RVO). 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.
Guidelines regarding management and dose reduction for visual changes considered to be 
related to study treatment are provided in Table 16.
*Note, the remaining text in this section was reformatted from bullets to a tabular 
presentation for ease of understanding.
Section 3.8.1 Part 1 Dose Escalation (Time and Events Table)
Revisions with rationale:

in column header “First Treatment Period”, added “(Day 1 through Day 28)” to 
clarify duration of the first treatment period.

added columns, “Initial follow-up”, “Secondary follow-up”:   separation of 
follow-up into initial follow-up and secondary follow-up to clarify procedures that 
were needed within 14 7 days of last dose of study drugs, within 4 weeks 7 
days of last dose of panitumumab, and within 8 weeks 7 days of last dose of 
panitumumab.

revised timing to allow the complete physical examination to be completed in 
screening, then a brief physical examination to be performed on Day 1.

Tumor tissue biopsy (mandatory): added note “to be collected from Day 15 to 
Day 18” to clarify window of collection.


Novartis
Confidential
Page 388
Clinical Study Protocol Version 05
Protocol No. MEK116833

added “At Week 4, then” to indicate that medical history/interim medical history, 
concurrent medication review, brief physical examination, weight and ECOG 
were to be performed at Week 4, then every 4 weeks in Continuation Phase.

added “At Week 4, then” to clarify timing of ECGs and hematology/ clinical 
chemistry in Continuation Phase.

added “or MUGA”, with corresponding footnote 18 (“ECHO is preferred.  
MUGA may be used only if ECHO is not available.  The same method must be 
used consistently from screening throughout the study”), to allow use of MUGA 
for institutions that cannot perform ECHO.

revised formatting to clarify that dosing of dabrafenib and trametinib does not 
continue into follow-up.

Day 1 visit: revised to allow for brief physical examination instead of complete 
physical examination.

Day 15 visit: eliminated requirement for repeated measurement of height.

Initial follow-up visit: added urinalysis (post-treatment)

revised footnote 1 to allow informed consent to be completed within 35 days prior 
to first dose (previously, 14 days prior)

added text to footnote 2: “The Continuation Phase starts with Day 29; …. Safety 
lab tests (chemistry/hematology/coag/UA) may be done the day before the visit so 
that results are ready on the day of the visit, but all assessments should be done 
within the 7 day window.” to indicate start of the Continuation Phase and to 
allow a window for completion of assessments in continuation.

revised footnote 3 to clarify initial follow-up visit and secondary follow-up visit 
timings and to allow a visit window for completion of assessments.

added text to footnote 5: “Note: pelvic exam in female subjects may be completed 
up to 24 weeks prior to date of first dose.” to allow an appropriate window for 
completion of pelvic examination.

added text to footnote 9: “During the continuation phase, PK samples will be 
collected pre-dose at Week 8, Week 12, Week 16, and Week 20.” to indicate a 
stopping point for collection of PK samples in continuation.

added and revised text in footnote 10 to allow patients with few lesions to enroll:
o
Added text: “Collection of on-treatment biopsy for subjects with 
accessible tumors.”
o
Previous text: “Biopsy should not be done on target lesions.”


Novartis
Confidential
Page 389
Clinical Study Protocol Version 05
Protocol No. MEK116833
o
Revised text: “Biopsies should be performed on non-target lesions when 
possible.”

added text to footnote 13: “The Day 1/predose tumor biopsy may be collected at
any point after signing consent, up to 14 days prior to first dose.” to indicate 
allowable window for collection of the predose tumor biopsy.

added footnote 16: “Pre- and post-dose tumor biopsies are mandatory. If the 
patient’s tumors are inaccessible for biopsy, permission to enroll must be granted 
by the GSK Medical Monitor.” to ensure clarity of requirements for enrolment

added footnote 17: “After study treatment is withdrawn, disease assessments (the 
method used at baseline) should continue every 8 weeks until documented disease 
progression, the start of new anti-cancer therapy, withdrawal of consent, or 
death.” to define follow-up after discontinuation of study treatment.

added footnote 18: “ECHO is preferred.  MUGA may be used only if ECHO is 
not available.  The same method must be used consistently from screening 
throughout the study.” to allow for use of MUGA at institutions that cannot 
perform ECHO
Section 3.8.2 Part 2 Expansion Cohorts (Time and Events Table)
Revisions with rationale:

in column header “First Treatment Period”, added “(Day 1 through Day 28)” to 
clarify duration of the first treatment period.

added columns, “Initial follow-up”, “Secondary follow-up”:   separation of 
follow-up into initial follow-up and secondary follow-up to clarify procedures that 
were needed within 14 7 days of last dose of study drugs, within 4 weeks 7 
days of last dose of panitumumab, and within 8 weeks 7 days of last dose of 
panitumumab.

revised timing to allow the complete physical examination to be completed in 
screening, then a brief physical examination to be performed on Day 1.

added “At Week 4, then” to indicate that medical history/interim medical history, 
concurrent medication review, brief physical examination, weight and ECOG 
were to be performed at Week 4, then every 4 weeks in Continuation Phase.

added “or MUGA”, with corresponding footnote 18 (“ECHO is preferred.  
MUGA may be used only if ECHO is not available.  The same method must be 
used consistently from screening throughout the study”), to allow use of MUGA 
for institutions that cannot perform ECHO.

Day 1 visit: revised to allow for brief physical examination instead of complete 
physical examination.


Novartis
Confidential
Page 390
Clinical Study Protocol Version 05
Protocol No. MEK116833

Day 1 visit: 
 (predose); previously collected 
during Screening visit

revised timing of ECG collection for consistency of assessments (in comparison 
to Part 1):
o
previous text: At Week 4 then at Week 12, Week 24 and every 12 weeks 
thereafter
o
revised text: At Week 4, then every 4 weeks until Week 24, then every 8 
weeks

added “At Week 4, then” to clarify timing of hematology/ clinical chemistry in 
Continuation Phase.

revised footnote 1 to allow informed consent to be completed within 35 days prior 
to first dose (previously, 14 days prior)

added text to footnote 2: “The Continuation Phase starts with Day 29; …. Safety 
lab tests (chemistry/hematology/coag/UA) may be done the day before the visit so 
that results are ready on the day of the visit, but all assessments should be done 
within the 7 day window.” to indicate start of the Continuation Phase and to 
allow a window for completion of assessments in continuation.

revised footnote 3 to clarify initial follow-up visit and secondary follow-up visit 
timings and to allow a visit window for completion of assessments.

added text to footnote 6: “Note: pelvic exam in female subjects may be completed 
up to 24 weeks prior to date of first dose.” to allow an appropriate window for 
completion of pelvic examination.

added and revised text in footnote 9 to allow patients with few lesions to enroll:
o
Added text: “Collection of on-treatment biopsy for subjects with 
accessible tumors.”
o
Previous text: “Biopsy should not be done on target lesions.”
o
Revised text: “Biopsies should be performed on non-target lesions when 
possible.”

added text to footnote 11: “The Day 1/predose tumor biopsy may be collected at 
any point after signing consent, up to 14 days prior to first dose.” to indicate 
allowable window for collection of the predose tumor biopsy.

Tumor tissue biopsy (mandatory): added note “to be collected from Day 15 to 
Day 18” to clarify window of collection.

Initial follow-up visit: added urinalysis (post-treatment)


Novartis
Confidential
Page 391
Clinical Study Protocol Version 05
Protocol No. MEK116833

added footnote 16: “Pre- and post-dose tumor biopsies are mandatory. If the 
patient’s tumors are inaccessible for biopsy, permission to enroll must be granted 
by the GSK Medical Monitor.” to ensure clarity of requirements for enrolment

added footnote 17: “After study treatment is withdrawn, disease assessments (the 
method used at baseline) should continue every 8 weeks until documented disease 
progression, the start of new anti-cancer therapy, withdrawal of consent, or 
death.” to define follow-up after discontinuation of study treatment.

added footnote 18: “ECHO is preferred.  MUGA may be used only if ECHO is 
not available. The same method must be used consistently from screening 
throughout the study.” to allow for use of MUGA at institutions that cannot 
perform ECHO
Section 4.2.1.1 Part 1 and Part 2 Inclusion Criteria
Previous text, inclusion criterion 3:
3. Histologically- or cytologically-confirmed diagnosis of advanced or metastatic BRAF 
V600E or V600K mutation positive colorectal cancer (CRC), as determined by relevant 
genetic testing and documented in source.  For subjects enrolled based on local mutation 
testing, confirmation of mutation will occur following registration in Part 1 and Part 2.
Revised text, inclusion criterion 3:
3. Histologically- or cytologically-confirmed diagnosis of advanced or metastatic BRAF 
V600Eor V600K mutation positive colorectal cancer (CRC), as determined by relevant 
genetic testing and documented in source.  For subjects enrolled based on local mutation 
testing, confirmation of mutation will occur following registration in Part 1 and Part 2.
Rationale:  The majority of mutations observed in BRAF-mutation-positive colorectal 
patients are BRAF V600E; this revision is to more accurately reflect the study population.
Section 4.2.1.1 Part 1 and Part 2 Inclusion Criteria, Addition to Table 18 Definitions 
for Adequate Baseline Organ Function
Previous table:
System
Laboratory Values
Hematologic 
Absolute neutrophil count
1.2 × 109/L 
Hemoglobin
9 g/dL or 5.6 mmol/L
Platelets
75 × 109/L  
Prothrombin Time / International 
Normalized Ratio (PT/INR) and Partial 
Thromboplastin Time (PTT)
≤1.5 x ULN
Chemistry
Mg++
≥ LLN
Hepatic


Novartis
Confidential
Page 392
Clinical Study Protocol Version 05
Protocol No. MEK116833
System
Laboratory Values
Albumin
2.5 g/dL or 25 g/L
Total bilirubin
1.5 x ULN
AST and ALT
2.5× ULN 
Renal
Creatinine or
1.5 ULN
Calculated creatinine clearancea or
50 mL/min 
Cardiac
Left Ventricular Ejection fraction (LVEF)
≥ LLN by ECHO or multigated acquisition scan 
(MUGA)b
b.
Calculated by the Cockcroft-Gault formula.
c.
Same method as used at baseline must be use throughout the study, ECHO is the preferred method
Revised table:
System
Laboratory Values
Hematologic 
Absolute neutrophil count
1.2 × 109/L 
Hemoglobin
9 g/dL or 5.6 mmol/L
Platelets
75 × 109/L  
Prothrombin Time / International 
Normalized Ratio (PT/INR) and Partial 
Thromboplastin Time (PTT)
≤1.5 x ULN
Chemistry
Mg++
≥ LLN
Hepatic
Albumin
2.5 g/dL or 25 g/L
Total bilirubin
1.5 x ULN
AST and ALT
2.5× ULN 
Renal
Creatinine or
1.5 ULN
Calculated creatinine clearancea 
or 
24-hour urine creatinine clearance
50 mL/min 
Cardiac
Left Ventricular Ejection fraction (LVEF)
≥ LLN by ECHO or multigated acquisition scan 
(MUGA)b
d.
Calculated by the Cockcroft-Gault formula.
e.
Same method as used at baseline must be use throughout the study, ECHO is the preferred method
Rationale: Correction; previous version inadvertently omitted “24-hour urine creatinine 
clearance”


Novartis
Confidential
Page 393
Clinical Study Protocol Version 05
Protocol No. MEK116833
Section 4.2.1.1 Part 1 and Part 2 Inclusion Criteria, Addition of inclusion criterion 
11:
11. Subjects enrolled in France: In France, a subject will be eligible for inclusion in this 
study only if either affiliated to, or a beneficiary of, a social security category.
Rationale: The inclusion criterion was added to clarify enrollment at French sites.
Section 4.2.1.2 Part 1 and Part 2 Exclusion Criteria, exclusion criterion 7:
Previous text:
7. Prior exposure to EGFR inhibitors, including anti-EGFR antibodies or EGFR (Part 2 
ONLY)
Revised text:
7. Prior exposure to EGFR inhibitors, including anti-EGFR antibodies or EGFR (Part 2 
ONLY)
Rationale: To clarify excluded prior therapies.
Section 4.2.1.2 Part 1 and Part 2 Exclusion Criteria, exclusion criterion 11:
Previous text:
11. Known Human Immunodeficiency Virus (HIV), Hepatitis B, or Hepatitis C infection. 
Subjects who have evidence of clearance of Hepatitis B or Hepatitis C infection can be 
enrolled with approval of the GSK Medical Monitor.
Revised text:
11. Known Human Immunodeficiency Virus (HIV), Hepatitis B, or Hepatitis C infection. 
Subjects who have evidence of clearance of Hepatitis B or Hepatitis C infection can be 
enrolled with approval of the GSK Medical Monitor.
Rationale: There are potential safety issues with enrollment of patients with Hepatitis B 
or C infection; revised for safety reasons.
Section 4.2.1.2 Part 1 and Part 2 Exclusion Criteria, deletion of exclusion criterion 
12:
Deleted exclusion criterion 12:
Current use of therapeutic warfarin.  Therapeutic dosing of warfarin is defined as 
resulting in an INR >1.3.  Low molecular weight heparin (LMWH) is permitted provided 
that the subject’s PT and PTT meet entry criteria. Subjects requiring therapeutic levels of 
LMWH must receive approval from GSK Medical Monitor and must be monitored 
appropriately as clinically indicated.


Novartis
Confidential
Page 394
Clinical Study Protocol Version 05
Protocol No. MEK116833
Rationale: Emerging data from ongoing clinical studies shows that therapeutic warfarin 
may be used with approval of GSK Medical Monitor and with close monitoring of 
PT/INR.
Section 4.2.2.1 Part 3 Inclusion Criteria, inclusion criterion 3:
Previous text:
3. Histologically- or cytologically-confirmed diagnosis of BRAFV600E or V600K 
mutation positive advanced or metastatic colorectal cancer (CRC who are eligible to 
receive fluoropyrimidine-containing chemotherapy regimen that have experienced 
documented radiographic progression on one prior line of fluoropyrimidine-containing 
chemotherapy (previous anti-EGFR therapy is excluded),
Revised text:
3. Histologically- or cytologically-confirmed diagnosis of BRAFV600E or V600K
mutation positive advanced or metastatic colorectal cancer (CRC who are eligible to 
receive fluoropyrimidine-containing chemotherapy regimen that have experienced 
documented radiographic progression on one prior line of fluoropyrimidine-containing 
chemotherapy (previous anti-EGFR therapy is excluded),
Rationale:  The majority of mutations observed in BRAF-mutation-positive colorectal 
patients are BRAF V600E; this revision is to more accurately reflect the study population.
Section 4.2.2.1 Part 3 Inclusion Criteria, inclusion criterion 5:
Previous text:
5. Tumor type criteria: 
BRAF mutation-positive colorectal cancer (i.e., BRAFV600E or V600K), as 
determined by relevant genetic testing and documented in source.  Enrollment in 
Part 3 will only occur following centralized determination of BRAFV600E or 
V600K mutation.
5. Tumor type criteria: 
BRAF V600E mutation-positive colorectal cancer (i.e., BRAFV600E or V600K),
as determined by relevant genetic testing and documented in source.  Enrollment 
in Part 3 will only occur following centralized determination of BRAFV600E or 
V600K require prospective testing for BRAF mutation. V600E using a CLIA 
certified BRAF mutation assay that will be performed in a central laboratory.  
Rationale:  The majority of mutations observed in BRAF-mutation-positive colorectal 
patients are BRAF V600E; this revision is to more accurately reflect the study population.
Section 4.2.2.1 Part 3 Inclusion Criteria, Addition of inclusion criterion 14:
14. Subjects enrolled in France: In France, a subject will be eligible for inclusion in this 
study only if either affiliated to, or a beneficiary of, a social security category.


Novartis
Confidential
Page 395
Clinical Study Protocol Version 05
Protocol No. MEK116833
Rationale: The inclusion criterion was added to clarify enrollment at French sites.
Section 4.2.2.2 Part 3 Exclusion Criteria, exclusion criterion 10:
Previous text:
10. Known Human Immunodeficiency Virus (HIV), Hepatitis B, or Hepatitis C infection. 
Subjects who have evidence of clearance of Hepatitis B or Hepatitis C infection can be 
enrolled with approval of the GSK Medical Monitor.
Revised text:
10. Known Human Immunodeficiency Virus (HIV), Hepatitis B, or Hepatitis C infection. 
Subjects who have evidence of clearance of Hepatitis B or Hepatitis C infection can be 
enrolled with approval of the GSK Medical Monitor.
Rationale: There are potential safety issues with enrollment of patients with Hepatitis B 
or C infection; revised for safety reasons.
Section 4.2.2.2 Part 3 Exclusion Criteria, deletion of exclusion criterion 11:
Deleted exclusion criterion 11:
11. Current use of therapeutic warfarin.  Therapeutic dosing of warfarin is defined as 
resulting in an INR >1.3.  Low molecular weight heparin (LMWH) is permitted provided 
that the subject’s PT and PTT meet entry criteria. Subjects requiring therapeutic levels of 
LMWH must receive approval from GSK Medical Monitor and must be monitored 
appropriately as clinically indicated.
Rationale: Emerging data from ongoing clinical studies shows that therapeutic warfarin 
may be used with approval of GSK Medical Monitor and with close monitoring of 
PT/INR.
Section 5.1.2 Part 2
Previous text:
For Part 2, efficacy will be evaluated to decide whether to proceed with further 
development based on the clinical activity seen in Part 1 and Part 2. Futility analysis 
criteria will be based on 2-stage Green-Dahlberg design’s [Green, 1992] interim analysis 
criteria.  The criteria will be based on a historically unimportant response rate of 15% 
versus a response rate of interest of 30%.
When at least 4 responders out of 20 subjects are observed in a treatment arm, after each 
subject has been followed at least 12 weeks, further development of the corresponding 
treatment in Part 3 will follow.  If less than 4 responders are observed, the accrued 
efficacy data will be evaluated for possibility of further development to Part 3.
The final decision with respect to continuation of the trial to Part 3 will be made by the 
Sponsor based on safety considerations as well as available efficacy data with input from 
participating investigators.


Novartis
Confidential
Page 396
Clinical Study Protocol Version 05
Protocol No. MEK116833
Revised text:
For Part 2, efficacy will be evaluated to decide whether to proceed with further 
development based on the clinical activity seen in Part 1 and Part 2. Futility analysis 
criteria at the end of Part 2 will be based on 2-stage Green-Dahlberg design’s [Green, 
1992] interim analysis criteria.  The criteria will be based on a historically unimportant 
response rate of 15% versus a response rate of interest of 30%. The Part 2 portion of the 
study will employ a Bayesian design that allows the trial to be monitored more frequently 
at multiple stages. Bayesian statistics will be employed to calculate the predictive 
probability that the response rate ≥30% and ≥15% at interim assuming a Beta prior for 
the Binomial distributed data.  Predictive probability calculates the probability that the 
response rate ≥30% or ≥15% at the end of Part 2 (after 20 subjects) given the responses 
have already been observed.  It predicts what is likely to happen at the end of Part 2 so is 
more meaningful and straightforward than posterior probability.  A weak prior Beta 
(0.003, 0.007) is used, which is equivalent to the information present in 0.01 subject.
An initial total of 10 subjects will be recruited at a dose level based on the recommended 
dose for each treatment (including the subjects treated in Part 1 at the same dose).  The 
number of subjects will be increased up to a total of 20 depending on the results observed.  
The tables below show the decision rules for the 10th to 19th evaluable subjects, 
specifying the number of subjects with a confirmed response needed for continuing 
enrolment or stopping for futility.  The methodology is based on the predictive 
probability of success if enrolment continues to 20 subjects [Lee, 2008].  These rules are 
intended as a guideline.  Actual decisions will depend on the totality of the data.
Table 20
Decision Making Criteria at Interim Analysis for Futility and Efficacy
Number of Evaluable 
Patients 
This Number of 
Confirmed Responses  to 
Stop Early for Futility
This Number of 
Confirmed Responses to 
Declare ORR≥0.3
10
0
5
11
0
5
12
0
6
13
0
6
14
0
6
15
0
7
16
1
7
17
1
7
18
1
8
19
1
8
For the interim looks in each cohort separately, if the predictive probability that the 
confirmed response rate ≥15% (historical control) is small (i.e., less than 10% chance), or 
equivalent to observe no confirmed response in the first enrolled 10-15 evaluable subjects 
in that cohort (e.g., after they have either progressed, or withdrew from the study, or lost 
to follow-up, or ongoing but have completed at least one post treatment disease 
assessment) and observe less than 1 confirmed response in the first 16-19 evaluable 
subjects, the enrollment for that cohort may be stopped due to futility. Otherwise, the 


Novartis
Confidential
Page 397
Clinical Study Protocol Version 05
Protocol No. MEK116833
enrolment of the respective cohort will continue to the target sample size of 20. If the 
predictive probability that the response rate of ≥30% is large (i.e., greater than 80% 
chance), strong statistical evidence has been provided in favor of further development of 
the treatment for the target population.
When at least 4 responders out of 20 subjects are observed in a treatment arm, after each 
subject has been followed at least 12 weeks, further development of the corresponding 
treatment in Part 3 will follow.  If less than 4 responders are observed, the accrued 
efficacy data will be evaluated for possibility of further development to Part 3. 
The final decision with respect to continuation of the trial to Part 3 will be made by the 
Sponsor based on safety considerations as well as available efficacy data with input from 
participating investigators.
Rationale: Text was revised to incorporate a Bayesian design in Part 2.
Section 5.1.3 Part 3, first paragraph
Previous text:
The primary objective of Part 3 is to compare progression free survival (PFS) and of the 
combinations of trametinib plus dabrafenib plus panitumumab and/or dabrafenib plus 
panitumumab versus standard of care in subjects with BRAF-V600E or V600K mutation 
positive CRC.  There will be two primary comparisons of interest in this study based on 
comparing each of the panitumumab combination arms with chemotherapy comparator
Revised text: 
The primary objective of Part 3 is to compare progression free survival (PFS) and of the 
combinations of trametinib plus dabrafenib plus panitumumab and/or dabrafenib plus 
panitumumab versus standard of care in subjects with BRAF-V600E or V600K mutation 
positive CRC.  There will be two primary comparisons of interest in this study based on 
comparing each of the panitumumab combination arms with chemotherapy comparator.
Rationale:  The majority of mutations observed in BRAF-mutation-positive colorectal 
patients are BRAF V600E; this revision is to more accurately reflect the study population.


Novartis
Confidential
Page 398
Clinical Study Protocol Version 05
Protocol No. MEK116833
Section 5.2.1.2 Part 2
Previous text:
Part 2 will enroll approximately 30 subjects in total.  Approximately 40 subjects will be 
evaluated at the end of Part 2, including those enrolled in Part 1 at the same dose levels.
To determine the sample size for each cohort, a traditional, 2-stage Green-Dahlberg 
design [Green, 1992] was evaluated and the sample size for the first stage will be used for 
the futility analysis.  To test the hypotheses (RR=30% vs RR=15%), using a Green-
Dahlberg design, 20 subjects per arm would be needed for Stage 1 (assuming a type 1 
error of 5% and power of 95%). The chance to effectively terminate the trial after 20 
subjects due to futility (true RR=15%) is 65%; the risk to incorrectly stop the trial after 
20 subjects if the treatment is effective (true RR =40%) is less than 2% (Table 20).
Table 20
Futility Analysis Design Performance
True RR
Probability of Early Termination, after 20 pts 
15%
0.648
20%
0.411
30%
0.107
40%
0.016
A Bayesian posterior probability will also be calculated to further inform decision 
making.   Since neither BRAF in combination with panitumumab nor MEK in 
combination with BRAF and panitumumab has been tested previously in the clinic in 
CRC subjects, a Beta (0.005, 0.005) prior is assumed. The posterior probabilities of RR 
exceeding 20%, 30% and 40% based on 20 subjects are shown in Table 21.
Table 21 Bayesian Posterior Probabilities of Response Rate for Given 
Number of Observed Responses
# of Responses Observed out 
of 20 Subjects
Posterior Probability 
RR ≥20%
Posterior Probability 
RR ≥30%
Posterior Probability RR 
≥40%
4
0.45
0.14
0.024
5
0.69
0.29
0.075
6
0.83
0.48
0.17
7
0.93
0.66
0.31
8
0.97
0.81
0.49
Revised text:
Part 2 will enroll approximately 30 subjects in total.  Approximately 40 subjects will be 
evaluated at the end of Part 2, including those enrolled in Part 1 at the same dose levels.


Novartis
Confidential
Page 399
Clinical Study Protocol Version 05
Protocol No. MEK116833
To determine the maximum sample size for each cohort, a traditional, 2-stage Green-
Dahlberg design [Green, 1992] was evaluated and the sample size for the first stage will 
be used for the futility analysis.  To test the hypotheses (RR=30% vs RR=15%), using a 
Green-Dahlberg design, 20 subjects per arm would be needed for Stage 1 (assuming a 
type 1 error of 5% and power of 95%). The chance to effectively terminate the trial after 
20 subjects due to futility (true RR=15%) is 65%; the risk to incorrectly stop the trial 
after 20 subjects if the treatment is effective (true RR =40%) is less than 2% (Table 22).
Table 22
Futility Analysis Design Performance
True RR
Probability of Early Termination, after 20 pts 
15%
0.648
20%
0.411
30%
0.107
40%
0.016
A Bayesian posterior probability will also be calculated to further inform decision 
making.  Since neither BRAF in combination with panitumumab nor MEK in 
combination with BRAF and panitumumab has been tested previously in the clinic in 
CRC subjects, a Beta (0.003, 0.007) (0.005, 0.005) prior is assumed.  This prior is 
equivalent to the prior information from 0.01 subject.  The posterior probabilities of RR 
exceeding 20%, 30% and 40% based on 20 subjects are shown in Table 23.
Table 23 Bayesian Posterior Probabilities of Response Rate for Given 
Number of Observed Responses
# of Responses Observed out 
of 20 Subjects
Posterior Probability 
RR ≥20%
Posterior Probability 
RR ≥30%
Posterior Probability RR 
≥40%
4
0.45
0.14
0.024
5
0.69
0.29
0.075
6
0.83
0.48
0.17
7
0.93
0.66
0.31
8
0.97
0.81
0.49
Using this sample size, a Bayesian design that allows the trial to be monitored more 
frequently at multiple stages was evaluated. A Bayesian analysis expresses uncertainty 
about a parameter in terms of probability. A prior is defined to characterize the level of 
knowledge about a parameter before the data are collected. Once the data are collected, a 
posterior distribution is formed using the prior and the likelihood (i.e., the data). Since 
none of the treatment has been tested previously in the clinic in the target population, a 
weak prior Beta (0.003, 0.007) is assumed. Thus, the posterior distribution for the 
response rate will be primarily driven by the data and can be derived as follows: Let p 
denote the response rate for the treatment, the number of responses in the current n 
patients, x, follows a binomial distribution, Binomial (n, p). Taking the Bayesian method 
and combining the weak prior and the likelihood of the observed data x, the posterior 


Novartis
Confidential
Page 400
Clinical Study Protocol Version 05
Protocol No. MEK116833
distribution of the response rate follows a beta distribution, i.e., p Beta (0.003 + x, 
0.007 + n-x) with the posterior mean (0.003 + x)/(0.01 + n). 
Based on this posterior distribution of the response rate, the predictive probability that the 
response rate 15% or ≥30% after 19 subjects will be calculated for decision-making as 
described in the Section 5.1.2 (Hypotheses). The decision rule and a minimal required 
sample size of 10 patients for the first interim look is determined to generate the design 
that leads to a reasonable chance of early termination due to futility.
The design property, by utilizing the decision rule specified in Section 5.1.2, and sample 
size of 20 patients are shown (Table 24). The probability of early termination of the trial 
is calculated by simulations. The probability of early termination after the first 19 
evaluable subjects is 33% under the null hypothesized response rate, and the risk to 
incorrectly stop the trial early if the drug is effective is approximately 5%. Thus, the 
study will employ the Bayesian design that allows the trial to be monitored more 
frequently at multiple stages with the constraint of satisfactory stop for futility rate.
Table 24
Bayesian Design Performance by Response Rate
If True Response Rate to
The Treatment is: (%) 
Prob (early stop for futility) 
0.15
0.326
0.2
0.180
0.3
0.047
Rationale: Text was revised to incorporate a Bayesian design in Part 2.
Section 5.3.7.2 Part 2, paragraph 3
Previous text:
In the expansion cohorts in Part 2, if an increased incidence of DLTs (i.e., ≥4 subjects of 
the first 10 subjects enrolled) is observed, the dosing regimen may be adjusted for all 
future subjects in a specific cohort or for the whole study population.
Revised text:
In the expansion cohorts in Part 2, if an increased incidence of DLTs (clinically 
significant toxicity i.e., ≥4 subjects of the first 10 subjects enrolled) is observed, the 
dosing regimen may be adjusted for all future subjects in a specific cohort or for the 
whole study population.
Rationale: Correction; DLT evaluation is in Part 1/ dose escalation only.


Novartis
Confidential
Page 401
Clinical Study Protocol Version 05
Protocol No. MEK116833
Section 5.3.8.5 Other Safety Measures
Previous text:
The results of scheduled assessments of vital signs, ECOG performance status, 12-lead 
ECG, and ECHO will be summarized.  Summaries by visit will include data from 
scheduled assessments only.  All data will be reported according to the nominal visit date 
for which it was recorded (i.e., no visit windows will be applied).  Unscheduled data will 
be included in ‘worse case’ summaries which will capture a worst case across all 
scheduled and unscheduled visits after the first dose of study treatment.  All data will be 
listed.  Further details will be provided in the RAP.
Revised text:
The results of scheduled assessments of vital signs, ECOG performance status, 12-lead 
ECG, and ECHO/ MUGA will be summarized.  Summaries by visit will include data 
from scheduled assessments only.  All data will be reported according to the nominal 
visit date for which it was recorded (i.e., no visit windows will be applied).  Unscheduled 
data will be included in ‘worse case’ summaries which will capture a worst case across 
all scheduled and unscheduled visits after the first dose of study treatment.  All data will 
be listed.  Further details will be provided in the RAP.
Rationale: Revisions allow for use of MUGA at institutions that cannot perform ECHO.
Section 6.1 Demographic/ Medical History Assessments, paragraph 2
Previous text:
Medical/medication/alcohol history will be assessed as related to the eligibility criteria 
listed in Section 4.2.  Cardiovascular medical history/risk factors will also be assessed at 
baseline. 
Revised text: 
Medical/medication/alcohol history will be assessed, surgical, and treatment history 
including date (month and year) of first diagnosis and histology, as related to the 
eligibility criteria listed in Section 4.2. as well as cardiovascular medical history/ and risk 
factors will also, alcohol and tobacco history, plus family history will be taken as part of 
the medical history and disease status.  Additional information may be requested to 
evaluate eligibility per Section 4.2 assessed at baseline. 
Rationale: Text was revised to clarify that patients’ complete medical and medication 
history will be reviewed to determine eligibility and safety once enrolled in ongoing 
study.


Novartis
Confidential
Page 402
Clinical Study Protocol Version 05
Protocol No. MEK116833
Section 6.2 Safety, Electrocardiogram (ECG)
Previous text:
Twelve-lead ECGs will be obtained as indicated in the Time and Events table (Section 
3.8) using an ECG machine that automatically calculates the heart rate and measures PR, 
QRS, QT, and QTc intervals.  Results of the ECG will be transmitted to a central storage 
facility. At each assessment, a 12-lead ECG will be performed by qualified personnel at 
the site after the subject has rested at least 5 minutes in a semi-recumbent or supine 
position.  Those QTc values greater than 480msec as calculated by the machine must be 
confirmed manually using Fridericia’s formula given below:
QTcF=QT X (1/RR)1/3
Revised text:
Twelve-lead ECGs will be obtained as indicated in the Time and Events table (Section 
3.8) using an ECG machine that automatically calculates the heart rate and measures PR, 
QRS, QT, and QTc intervals.  Results of the ECG will be transmitted to a central storage 
facility. At each assessment, a 12-lead ECG will be performed by qualified personnel at 
the site after the subject has rested at least 5 minutes in a semi-recumbent or supine 
position.  Those QTc values greater than 480msec as calculated by the machine must be 
confirmed manually using Fridericia’sBazett’s formula [Bazett, 1920] given below:
QTcF=QT X (1/RR)1/3
RR
QT
QTcB 
Rationale: QT correction method was revised from Fridericia’s formula to Bazett’s to be 
consistent with other ongoing clinical studies of dabrafenib and/or trametinib.
Section 6.2 Safety, Echocardiogram (ECHO)
Previous text:
Echocardiogram (ECHO)
ECHO will be performed to assess cardiac ejection fraction and cardiac valve 
abnormalities as indicated in the Time and Events table (Section 3.8). Results will be 
transmitted to a central storage facility. Echocardiography should include an evaluation 
for left ventricular ejection fraction (LVEF) and both right- and left-sided valvular lesions. 
For each subject the same procedure should be performed at screening and any following 
visit to allow direct comparison. Additional ECHO assessments may be performed as 
clinically indicated.


Novartis
Confidential
Page 403
Clinical Study Protocol Version 05
Protocol No. MEK116833
Revised text:
Echocardiogram (ECHO) or Multiple Gated Acquisition (MUGA):
ECHO will be performed is the preferred method to assess cardiac ejection fraction and 
cardiac valve abnormalities; MUGA is acceptable only if ECHO is not available.  
Assessments should be performed as indicated in the Time and Events table (Section 3.8). 
Results will be transmitted to a central storage facility. Echocardiography should include 
an evaluation for left ventricular ejection fraction (LVEF) and both right- and left-sided 
valvular lesions. For each subject the same procedure should be performed at screening 
and any following visit to allow direct comparison. Additional ECHO/ MUGA
assessments may be performed as clinically indicated.
Rationale: Revisions allow for use of MUGA at institutions that cannot perform ECHO.
Section 6.2 Safety, Clinical Laboratory Assessments
Previous text:
Glucose, fasting 
Total carbon 
dioxide (CO2)
Alkaline phosphatase
Inorganic phosphorus
Other screening tests
FSH and estradiol (as needed in women of non-child bearing potential only)
Revised text:
Glucose
      fasting glucose 
at screening only
Total carbon 
dioxide (CO2)
Alkaline phosphatase
Inorganic phosphorus
Other screening tests
FSH and estradiol (as needed in women of non-child bearing potential only)
Coagulation (at screening, repeated only if clinically indicated)
Rationale: Fasting blood glucose is required at screening only; all other blood glucose 
assessments may be performed without regard to fasting status.  Text regarding 
coagulation at screening was added to ensure that the assessment was performed as 
indicated.
Section 6.3.1 Follow-up Assessements for Subjects Permanently 
Discontinued from Study Treatment
New section added:
Subjects will be followed for progression, survival and new anti-cancer therapy 
(including radiotherapy) every 8 weeks. If subjects are unable or unwilling to attend 
clinic visits during follow-up, contact to assess survival may be made via another 
form of communication (e.g., phone, email, etc.).


Novartis
Confidential
Page 404
Clinical Study Protocol Version 05
Protocol No. MEK116833
Subjects who permanently discontinue study treatment without disease progression will 
have radiographic disease assessments performed as indicated in the Time and Events 
Table (Section 3.8) until disease progression, new anti-cancer therapy start, or death is 
documented.
Subjects enrolled in Part 1 are to be followed until progression for collection of PFS data.  
Subjects enrolled in Part 2 and Part 3 are to be followed until progression for collection 
of PFS data and until death for collection of overall survival (OS) data.
Rationale: Collection of efficacy data.
Section 6.6.1 Fresh Pre- and Post-dose Tumor Tissues, paragraph 1
Previous text:
Tumor specimens that can be sampled easily will be requested in Part 1 and Part 2.  
These biopsies will be taken during the screening period, e.g., within 14 days before 
treatment, and within 2 to 4 hrs after dosing on Day 15 (+3 days) in those subjects who 
have signed the corresponding section of the informed consent.  A biopsy is also 
requested at tumor progression.  Details of the tumor biopsy collection including 
processing, storage and shipping procedures will be provided in the SPM.
Revised text:
Tumor specimens that are accessible and can be sampled easily will be requested in Part 
1 and Part 2.  These biopsies will be taken during the screening period, e.g., within 14 
days before treatment, and within 2 to 4 hrs after dosing on Day 15 (+3 days) in those 
subjects who have signed the corresponding section of the informed consent.  A biopsy is 
also requested at tumor progression.  Details of the tumor biopsy collection including 
processing, storage and shipping procedures will be provided in the SPM.
Rationale: Patients with inaccessible tumor lesions may be exposed to undue risk with 
mandatory biopsy.
Section 8.1 Permitted Medications, paragraph 1
Previous text:
The investigator must be informed as soon as possible about any medication taken from 
the time of screening until the end of the clinical phase of the study (final study visit).  
Revised text:
The investigator must be informed as soon as possible about any medication taken from 
the time of screening until 30 days after the end last dose of the clinical phase of the 
study (final study visit).treatment.  
Rationale: Patients will be followed for safety review for 30 days after the last dose of 
study treatment, including review of concomitant medications.


Novartis
Confidential
Page 405
Clinical Study Protocol Version 05
Protocol No. MEK116833
Section 8.2 Prohibited Medications, bullet 4
Previous text:

Dabrafenib is metabolized primarily by CYP2C8 and CYP3A4.  Drugs that are 
strong inhibitors or inducers of CYP3A or CYP2C8 are prohibited because 
they may alter dabrafenib concentrations.  The list may be modified based on 
emerging data.  These include but are not limited to those listed in Table 23, 
consider therapeutic substitutions for these medications.
Revised text:

Dabrafenib is metabolized primarily by CYP2C8  Cytochrome P450 (CYP) 
2C8 and CYP3A4.  Co-administration of dabrafenib with ketoconazole, a 
CYP3A4 inhibition, or with gemfibrozil, a CYP2C8 inhibitor, resulted in 
increases in dabrafenib AUC of 71% and 47%, respectively.  Drugs that are 
strong inhibitors or inducers of CYP3A or and CYP2C8 (see list in Table 26are 
prohibited because) may only be used under special circumstances (e.g. as a 
single use for a procedure) while treatment with study drug is interrupted as
they may alter dabrafenib concentrations.  The list may be modified based on 
emerging data.  These include but are not limited to those listed in, consider 
therapeutic substitutions for these medications.  Approval of the GSK medical 
monitor is required in these situations. The list may be modified based on 
emerging data.
Rationale: Emerging data from ongoing clinical studies shows that therapeutic warfarin 
may be used with approval of GSK Medical Monitor and with close monitoring of 
PT/INR.
Section 8.2, Table 26 Prohibited Medications
Additions:
Miscellaneous
bosentan, St John’s wort
Antiretroviral
ritonavir, saquinavir, atazanavir
Rationale: Emerging data from ongoing clinical studies.
Section 8.3, Cautionary Medications
Previous text:

Dabrafenib has been shown to induce CYP3A4 in vivo using midazolam.  
Dabrafenib is an in vitro inducer of CYP2B6 and and other enzymes such as 
CYP2C8, CYP2C9, and CYP2C19 may also be affected. Co-administration of 
dabrafenib and medications which are affected by the induction of these 
enzymes (including warfarin) may result in loss of efficacy. If co-


Novartis
Confidential
Page 406
Clinical Study Protocol Version 05
Protocol No. MEK116833
administration of these medications is necessary, investigators should monitor 
subjects for loss of efficacy or consider substitutions of these medications. 
Revised text:

Dabrafenib has been shown to induce CYP3A4 and CYP2C9 in vivo using 
midazolam. (CYP3A4 substrate) and S-warfarin (CYP2C9 substrate).  
Dabrafenib is an in vitro inducer of CYP2B6 and other enzymes such as 
CYP2C8, CYP2C9, and CYP2C19, UDP-glucuronyl transferases., and 
transporters may also be affected. Co-administration of dabrafenib and 
medications which are affected by the induction of these enzymes (including 
warfarin) may result in loss of efficacy. If co-administration of these 
medications is necessary, investigators should monitor subjects for loss of 
efficacy or consider substitutions of these medications. 

Therapeutic level dosing of warfarin can be used with approval by the GSK 
Medical Monitor and close monitoring of PT/INR by the site. Exposure 
decreased by 37% due to enzyme induction when on treatment, thus warfarin 
dosing may need to be adjusted based upon PT/INR. Consequently, when 
discontinuing dabrafenib, warfarin exposure may be increased and thus close 
monitoring via PT/INR and warfarin dose adjustments must be made as 
clinically appropriate. Prophylactic low dose warfarin may be given to maintain 
central catheter patency.

Dabrafenib solubility is pH-dependent with decreased solubility at higher pH. 
Drugs such as proton pump inhibitors that inhibit gastric acid secretion to 
elevate gastric pH may decrease the solubility of dabrafenib and reduce its 
bioavailability. No clinical study has been conducted to evaluate the effect of 
pH on dabrafenib pharmacokinetics. In an ad-hoc analysis, no differences in 
Cmax and AUC were noted between subjects who reported taking pH-elevating 
products relative to other subjects.  Due to the theoretical risk that pH-elevating 
agents may decrease oral bioavailability and exposure to dabrafenib, these 
medicinal products that increase gastric pH should be used with caution when 
administered with dabrafenib.
Rationale: Emerging data from ongoing clinical studies shows that therapeutic warfarin 
may be used with approval of GSK Medical Monitor and with close monitoring of 
PT/INR.
Section 8.2, Table 27 Cautionary Medications
Additions:
USE WITH CAUTION:  Moderate inhibitors of CYP3A and or
CYP2C8 since concentrations of dabrafenib may be increased
Class/Therapeutic Area 
Moderate CYP3A and CYP2C8 Inhibitors 


Novartis
Confidential
Page 407
Clinical Study Protocol Version 05
Protocol No. MEK116833
Class/Therapeutic Area 
CYP3A4, CYP2B6, CYP2C8, CYP2C9, CYP2C19 or 
Transporter Substrates that May be Affected by Induction  
HMG-CoA Reductase 
Inhibitors 
Atorvastatin, lovastatin, simvastatin, rosuvastatin, 
pravastatin
USE WITH CAUTION: Co-administration of drugs that increase gastric pH should be 
used with caution when administered with dabrafenib.
pH altering agents
dexlansoprazole. esomeprazole, famotidine, ilaprazole, 
lansoprazole, omeprazole, pantoprazole, rabeprazole, 
ranitidine
Rationale: Emerging data from ongoing clinical studies.
Section 9.2 Subject Completion Criteria, paragraphs 1 and 2
Previous text:
For Part 1 (dose-escalation phase), Part 2 (expansion cohorts) and Part 3 (randomized 
Phase 2), a completed subject is one who has discontinued study treatment for reasons 
listed in Section 3.7 and completed a post-treatment follow-up visit,  or has died while 
receiving study treatment, or was followed to progression or death.  
Revised text:
For Part 1 (dose-escalation phase), Part 2 (expansion cohorts) and Part 3 (randomized 
Phase 2),) subjects who are not treated with the RP2D, a completed subject is one who 
has discontinued study treatment for reasons listed in Section 3.7 and was followed to 
progression, or to death.  
For Part 1 subjects who are treated at RP2D, for Part 2 (expansion cohorts) subjects and 
for Part 3 (randomized Phase 2) subjects, a completed a post-subject is one who has 
discontinued study treatment for reasons listed in Section 3.7 follow-up visit,  and was 
followed to death or has died while receiving study treatment, or was followed to 
progression or death.  
Rationale: Clarification of which subjects will be followed for progression and overall 
survival after discontinuation of study treatment.


Novartis
Confidential
Page 408
Clinical Study Protocol Version 05
Protocol No. MEK116833
10.3.1 Preparation, bullet 2
Previous text:

Withdraw the necessary amount of panitumumab for a dose of 6 mg/kg.
Revised text:

Withdraw the necessary amount of panitumumab for a the study- prescribed dose 
of 6 mg/kg.
Rationale: Clarification of preparation of panitumumab for dosing in the event a dose 
less than 6mg/kg is required.
Section 11.2.1 Sentinel Events
Added section:
A Sentinel Event is a GSK-defined SAE that is not necessarily drug-related but has been 
associated historically with adverse reactions for other drugs and is therefore worthy of 
heightened pharmacovigilance.  The GSK Medical Monitor is accountable for reviewing 
all SAEs for possible Sentinel Events which is mandated at GSK.  The GSK medical 
monitor may request additional clinical information on an urgent basis if a possible 
Sentinel Event is identified on SAE review.  The current GSK-defined Sentinel Events 
are listed below:
Acquired Long QT Syndrome

Agranulocytosis/Severe Neutropenia 
Anaphylaxis & Anaphylactoid Reactions 

Hepatotoxicity

Acute Renal Failure

Seizure

Stevens Johnson syndrome/Toxic epidermal necrosis
Rationale: Section was added to address specific SAEs that may require additional 
reporting and review by site investigator and GSK Medical Monitor.
Section 11.3 Laboratory and Other Safety Assessment Abnormalities 
Reported as AEs and SAEs
Added section:
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis), or 
other safety assessments (e.g., electrocardiogram [ECGs], radiological scans, vital signs 
measurements) including those that worsen from baseline, and events felt to be clinically 
significant in the medical and scientific judgment of the investigator are to be recorded as 


Novartis
Confidential
Page 409
Clinical Study Protocol Version 05
Protocol No. MEK116833
an adverse event (AE) or serious adverse event (SAE), in accordance with the definitions 
provided.
In addition, an associated AE or SAE is to be recorded for any laboratory test result or 
other safety assessment that led to an intervention, including permanent discontinuation 
of study treatment, dose reduction, and/or dose interruption/delay.
Any new primary cancer must be reported as a SAE. 
However, any clinically significant safety assessments that are associated with the 
underlying disease, unless judged by the investigator to be more severe than expected for 
the subject's condition, are not to be reported as AEs or SAEs.
Rationale: Section was added to clarify reporting of SAEs.
Section 11.3.1 Cardiovascular Events
Added section:
Investigators will be required to fill out event specific data collection tools for the 
following AEs and SAEs:  

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularisation
This information should be recorded in the specific cardiovascular eCRF within one week 
of when the AE/SAE(s) are first reported.
Rationale: Section was added to address cardiovascular SAEs that have specific eCRF 
pages for completion and that may require additional reporting and review by site 
investigator and GSK Medical Monitor.


Novartis
Confidential
Page 410
Clinical Study Protocol Version 05
Protocol No. MEK116833
Section 11.6 Prompt Reporting of SAEs to GSK, addition to table
Type of Event
Time Frame
Documents
Time Frame
Documents
All SAEs
24 hours
SAE data collection 
tool
24 hours
Updated SAE data 
collection tool 
“CV events” and/or 
“death”
Initial and 
follow up 
reports to be 
completed 
within one 
week of when 
the 
cardiovascular 
event or death 
is reported
“CV events” 
and/or “death” 
data collection 
tool(s) if 
applicable
Initial and follow 
up reports to be 
completed within 
one week of when 
the cardiovascular 
event or death is 
reported
Updated “CV 
events” and/or 
“death” data 
collection tool(s) if 
applicable
Rationale: Text was added to address cardiovascular SAEs and requirements for 
reporting.
Section 13.9 Independent Data Monitoring Committee
Previous text:
An IDMC will be utilized during the conduct of this study to review all available data in 
Part 3.  An IDMC is generally assembled when there are significant safety or efficacy 
issues that warrant external objective medical and/or statistical review in order to protect 
the ethical and safety interests of subjects and to protect the scientific validity of the 
study.  The schedule of any planned interim analysis and the analysis plan for IDMC 
review is described in the charter.  A copy of the IDMC charter  available from GSK 
upon request.
Revised text:
An IDMC will be utilized during the conduct of this study to review all available data in 
Part 3.  An IDMC is generally assembled when there are significant safety or efficacy 
issues that warrant external objective medical and/or statistical review in order to protect 
the ethical and safety interests of subjects and to protect the scientific validity of the 
study.  The schedule of any planned interim analysis and the analysis plan for IDMC 
review is described in the charter.  A copy of the IDMC charter iswill be available from 
GSK, prior to start of Part 3, upon request.
Rationale: Clarification to the timing of the IDMC charter.


Novartis
Confidential
Page 411
Clinical Study Protocol Version 05
Protocol No. MEK116833
SECTION 14 REFERENCES
Added:
Bailey S, Neuenschwander B, Laird G, Branson M. A Bayesian case study in oncology 
phase I combination dose-finding using logisitic regression with covariates. J Biopharm 
Stats. 2009; 19 (3):469-484.
Bazett HC. An analysis of the time-relations of electrocardiograms. Heart 1920; 7:353-
370.
GlaxoSmithKline Document Number 2012N152310_00 Supplement to GSK1120212 + 
GSK2118436 Investigator’s Brochure. Version 01 Supplement 01. Report date 22-OCT-
2012.
GlaxoSmithKline Document Number 2012N152310_01 Supplement to GSK1120212 + 
GSK2118436 Investigator’s Brochure. Version 01 Supplement 02. Report date 13-FEB-
2013.
GlaxoSmithKline Document Number 2013N164649_00 Supplement to GSK1120212 
Investigator’s Brochure. Version 04 Supplement 01. Report date 05-MAR-2013.
Lee JJ, Liu DD. A predictive probability design for Phase II cancer clinical trials. Clin 
Trials. 2008. 5(2):93-106.
Deleted:
Gasparini, M, Bailey, S and Neuenschwander, B. 2009. A note on modeling drug-drug 
interactions in oncology combination trials. Under Submission to J. Royal Statist. Society. 
Series C (Applied Statistics).
APPENDIX 2 BLOOD REQUIREMENTS
Previous text:
Part 1: Dose Escalation Cohorts
Test
Sample Volume
Total Volume for Screening, One 4-wk treatment period 
and Follow-up 
Hematology/Clin Chem
5 mL
35
Coagulation
5 mL
5
PK & Metabolite Analysis 
4 mL
28
PK & Metabolite Analysis 
2 mL
8
Serum Pregnancy Test
1 mL
1
Total
129mL/subject


Novartis
Confidential
Page 412
Clinical Study Protocol Version 05
Protocol No. MEK116833
Part 2: Expansion Cohorts
Test
Sample Volume
Total Volume for Screening, One 4-wk treatment period 
and Follow-up 
Hematology/Clin Chem
5 mL
25
Coagulation
5 mL
5
PK & Metabolite Analysis 
4 mL
16
PK & Metabolite Analysis
2 mL
8
Serum Pregnancy Test
1 mL
1
Total
107mL/subject
Part 3: Randomized Phase II Study
Test
Sample Volume
Total Volume for Screening, One 4-wk treatment 
period and Follow-up 
Hematology/Clin Chem
5 mL
25
Coagulation
5 mL
5
Serum Pregnancy Test
1 mL
1
Total
83mL/subject
Revised text:
Part 1: Dose Escalation Cohorts
Test
Sample Volume
Total Volume for Screening, One 4-wk treatment period 
and Follow-up 
Hematology/Clin Chem
5 mL
3525
Coagulation
5 mL
5
PK & Metabolite Analysis 
(panitumumab)
4 mL
2820
PK & Metabolite Analysis 
(dabrafenib, trametinib)
24 mL
848
Serum Pregnancy Test
1 mL
1
Total
129mL155mL/subject
plus any wasteage associated with collection


Novartis
Confidential
Page 413
Clinical Study Protocol Version 05
Protocol No. MEK116833
Part 2: Expansion Cohorts
Test
Sample Volume
Total Volume for Screening, One 4-wk treatment period 
and Follow-up 
Hematology/Clin Chem
5 mL
2520
Coagulation
5 mL
5
PK & Metabolite Analysis 
(panitumumab)
4 mL
16
PK & Metabolite Analysis 
(dabrafenib, trametinib)
24 mL
848
Serum Pregnancy Test
1 mL
1
Total
107mL146mL/subject 
plus any wasteage associated with collection
Part 3: Randomized Phase II Study
Test
Sample Volume
Total Volume for Screening, One 4-wk treatment 
period and Follow-up 
Hematology/Clin Chem
5 mL
2520
Coagulation
5 mL
5
Serum Pregnancy Test
1 mL
1
Total
83mL82mL /subject 
plus any wasteage associated with collection
Rationale: Volumes were revised based on supply of collection tubes.
APPENDIX 5: ADDITIONAL WITHHOLDING AND STOPPING 
CRITERIA FOR SUBJECTS ENROLLED IN FRANCE
QTc-Prolongationa
Action and Dose Modification

QTcB ≥501 msec 

Interrupt study treatment until QTcB prolongation resolves to 
grade 1 or baseline

Restart at current dose levelb

If event recurs, permanently discontinue study treatment
Abbreviations:  msec = milliseconds; QTcB = QT interval on electrocardiogram corrected using the Bazett’s formula 
[Bazett, 1920]
f.
Based on average QTc value of triplicate ECGs.  For example, if an ECG demonstrates a prolonged QT interval, 
obtain two or more ECGs over a brief period, and then use the averaged QTc values of the three ECGs to 
determine if study treatments should be interrupted or discontinued.
g.
If the QTc prolongation resolves to grade 1 or baseline, the subject may resume study treatment if the 
investigator and GSK medical monitor agree that the subject will benefit from further treatment.
Guidelines for Valvular Toxicity for Subjects Enrolled in France

Subjects who have an asymptomatic, moderate regurgitation or stenosis by 
ECHO (Grade 2 mitral/tricuspid/aortic valvular toxicity per CTCAE v4.0) 
should temporarily discontinue dabrafenib and have a repeat evaluation by 


Novartis
Confidential
Page 414
Clinical Study Protocol Version 05
Protocol No. MEK116833
ECHO within 1 week.  ECHO should be repeated every 1-2 weeks for 4 weeks 
or until valve recovery to baseline. 
o
If the valve recovers to baseline any time during the next 4 weeks, after 
consultation and approval of the GSK medical monitor, the subject may be 
restarted on dabrafenib at a reduced dose(s). For such subjects, 
monitoring of the valve via ECHO will then be performed 2 and 4 weeks 
after rechallenge, and every 4 weeks thereafter for 12 weeks and then per 
protocol.
o
If repeat ECHO does not reveal valve recovery to baseline within 4 weeks, 
then the subject should permanently discontinue dabrafenib.  The valve 
should continue to be monitored via ECHO every 4 weeks for 16 weeks or 
until resolution. 

Subjects with a Grade 3 or 4 (symptomatic, severe regurgitation/stenosis by 
imaging, with symptoms controlled by medical intervention) valvular toxicity 
must discontinue dabrafenib.  Valvular toxicity should continue to be monitored 
every 4 weeks for 16 weeks or until resolution.  If recovery occurs (return to 
baseline via imaging AND symptom resolution) within 4 weeks, the subject may 
restart dabrafenib at a reduced dose after consultation and approval of the GSK 
medical monitor. For such subjects, monitoring of the valve via ECHO will then 
be performed 2 and 4 weeks after rechallenge, and every 4 weeks thereafter for 
12 weeks and then per protocol.
ECHO must be performed at baseline and at follow-up visit(s).  Copies of all ECHO(s) 
and cardiology consultations performed on subjects who experience a valvular toxicity 
will be required by GSK for review.
Rationale: Added section in response to review by Agence Nationale de Securite du 
Medicament et des Produits de Sante (ANSM), to address cardiovascular safety 
monitoring.
APPENDIX 6: BAZETT’S CORRECTION
Bazett's formula used to correct QT interval for heart rate is:
RR
QT
QTcB 
where QTcB is the QT interval corrected for heart rate, RR is the interval from the onset 
of one QRS complex to the onset of the next QRS complex, measured in seconds, often 
derived from the heart rate (HR) as 60/HR, and QT is the QT interval measured in 
milliseconds.  
Reference
Bazett HC.  An analysis of the time-relations of electrocardiograms.  Heart 1920; 7: 353-
370.
Rationale: Added formula for Bazett’s correction.

SAP_001.pdf: 
Clinical Development 
GSK1120212+GSK2118436/Mekinist®+Tafinlar® 
MEK116833 (CDRB436C2201) / NCT01750918 
An Open-Label, Four-Part, Phase I/II Study to Investigate 
the Safety, Pharmacokinetics, Pharmacodynamics, and 
Clinical Activity of the MEK Inhibitor GSK1120212, BRAF 
Inhibitor GSK2118436 and the anti-EGFR Antibody 
Panitumumab in Combination in Subjects with BRAF-           
mutation V600E Positive Colorectal Cancer and in 
Subjects with CRC With Secondary Resistance to Prior 
Anti-EGFR Therapy  
Statistical Analysis Plan (SAP) 
Author: 
 
Document type: 
SAP Documentation 
Document status: 
Final version 1.0 
Release date: 
22-Jul-2020
Number of pages: 
41 
Property of Novartis 
For business use only 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 


Novartis 
For business use only 
Page 2 
Final CSR SAP 
 
MEK116833 (CDRB436C2201) 
 
 
 
Table of contents 
Table of contents ................................................................................................................. 2 
List of abbreviations ............................................................................................................ 5 
1 
Introduction ......................................................................................................................... 6 
1.1 
Study design............................................................................................................. 6 
1.1.1 
Part 1 Dose Escalation Study Design/Schematic .................................... 6 
1.1.2 
Part 2A: Cohort Expansions Study Design/Schematic ........................... 7 
1.1.3 
Part 2B: Cohort Expansions Study Design/Schematic............................ 8 
1.1.4 
Part 3 Randomized Phase 2 Study .......................................................... 8 
1.1.5 
Part 4A Dose Escalation .......................................................................... 8 
1.1.6 
Part 4B Cohort Expansion ....................................................................... 9 
1.2 
Study objectives and endpoints ............................................................................... 9 
1.2.1 
Part 1: Phase 1 Dose Escalation ............................................................ 10 
1.2.2 
Part 2: Cohort Expansions ..................................................................... 11 
1.2.3 
Part 4A: Dose Escalation ...................................................................... 12 
1.2.4 
Part 4B: Cohort Expansion.................................................................... 12 
2 
Statistical methods ............................................................................................................. 13 
2.1 
Treatment group labels and ordering ..................................................................... 13 
2.2 
Data analysis general information ......................................................................... 14 
2.2.1 
Multicenter Studies ............................................................................... 14 
2.2.2 
Baseline Definition ................................................................................ 14 
2.2.3 
Change from baseline ............................................................................ 14 
2.2.4 
Withdrawal ............................................................................................ 15 
2.2.5 
Missing Data ......................................................................................... 15 
2.2.6 
Protocol Deviation ................................................................................ 15 
2.2.7 
Derived and Transformed Data ............................................................. 15 
2.2.8 
Assessment Windows............................................................................ 15 
2.2.9 
Study Day for Efficacy .......................................................................... 15 
2.2.10 
Reference Date ...................................................................................... 16 
2.2.11 
Durations and Elapsed Time ................................................................. 16 
2.2.12 
Imputation of Partial Dates ................................................................... 16 
2.2.13 
Data to be Included in the Analysis ...................................................... 16 
2.2.14 
Last Contact Date .................................................................................. 17 
2.2.15 
Other Issues ........................................................................................... 17 
2.3 
Analysis sets .......................................................................................................... 17 


Novartis 
For business use only 
Page 3 
Final CSR SAP 
 
MEK116833 (CDRB436C2201) 
 
 
 
2.3.1 
All Treated Population .......................................................................... 17 
2.3.2 
Pharmacokinetic Population.................................................................. 18 
2.3.3 
Biomarker Population ........................................................................... 18 
2.3.4 
Crossover Population ............................................................................ 18 
2.4 
Subgroup of interest ............................................................................................... 18 
2.5 
Patient disposition, demographics and other baseline characteristics ................... 18 
2.5.1 
Patient Disposition ................................................................................ 18 
2.5.2 
Demographic and Disease Characteristics Assessments ....................... 19 
2.6 
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance) ............................................................................................................ 19 
2.6.1 
Study treatment / compliance ................................................................ 19 
2.6.2 
Prohibited Medications ......................................................................... 21 
2.6.3 
Study time periods of Concomitant Medications .................................. 21 
2.7 
Study Time Periods in Relation to Treatment ....................................................... 22 
2.8 
Analysis of the primary objective .......................................................................... 22 
2.8.1 
Primary endpoint ................................................................................... 22 
2.8.2 
Statistical hypothesis, model, and method of analysis .......................... 22 
2.9 
Analysis of the key secondary objective ............................................................... 22 
2.10 
Analysis of secondary efficacy objective(s) .......................................................... 23 
2.10.1 
Secondary endpoints ............................................................................. 23 
2.11 
Safety analyses ....................................................................................................... 24 
2.11.1 
Dose-Limiting Toxicity ......................................................................... 25 
2.11.2 
Adverse events (AEs) ............................................................................ 25 
2.11.3 
Deaths and Serious Adverse Events ...................................................... 27 
2.11.4 
Adverse Events Leading to Discontinuation of Study Treatment 
and/or Withdrawal from the Study and Other ....................................... 27 
2.11.5 
Laboratory data ..................................................................................... 27 
2.11.6 
ECG and cardiac imaging data .............................................................. 28 
2.11.7 
ECHO .................................................................................................... 29 
2.11.8 
ECOG .................................................................................................... 30 
2.12 
Biomarkers ............................................................................................................. 30 
2.13 
Pharmacokinetic endpoints .................................................................................... 30 
2.13.1 
Statistical Analysis of PK Concentration Data ..................................... 31 
3 
Sample size calculation ..................................................................................................... 31 
3.1 
Part 1 and Part 4 Dose Escalation .......................................................................... 31 


Novartis 
For business use only 
Page 4 
Final CSR SAP 
 
MEK116833 (CDRB436C2201) 
 
 
 
3.2 
Part 2 and Part 4 Cohort Expansions ..................................................................... 32 
4 
Appendix ........................................................................................................................... 34 
4.1 
Imputation rules ..................................................................................................... 35 
4.1.1 
Imputation of Partial Dates ................................................................... 35 
4.1.2 
Imputation of Missing Exposure End Dates ......................................... 39 
4.2 
AEs coding/grading ............................................................................................... 39 
4.3 
Laboratory parameters derivations ........................................................................ 39 
4.4 
Statistical models ................................................................................................... 40 
4.4.1 
Primary analysis .................................................................................... 40 
4.4.2 
Secondary analysis ................................................................................ 40 
5 
Reference ........................................................................................................................... 40 


Novartis 
For business use only 
Page 5 
Final CSR SAP 
 
MEK116833 (CDRB436C2201) 
 
 
 
List of abbreviations 
AE 
Adverse Event 
CI 
Confidence Interval 
CR 
Complete Response 
CTCAE 
Common Terminology Criteria for Adverse Events 
DOR 
Duration of Response 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
ECOG 
Easter Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
GSK 
GlaxoSmithKline 
HR 
Hazard Ratio 
LDH 
Lactate Dehydrogenase 
LLN 
Lower Limit of Normal 
LVEF 
Left Ventricular Ejection Fraction 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI 
National Cancer Institutes 
ORR 
Overall Response Rate 
OS 
Overall Survival 
PD 
Progressive Disease 
PFS 
Progression-free Survival 
PK 
Pharmacokinetics 
PR 
Partial Response 
PT 
Preferred Term 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious Adverse Event 
SD 
Stable Disease 
SOC 
System Organ Class 
ULN 
Upper Limit of Normal 
 


Novartis 
For business use only 
Page 6 
Final CSR SAP 
 
MEK116833 (CDRB436C2201) 
 
 
 
1 
Introduction 
This Statistical Analysis Plan (SAP) describes the planned statistical analyses associated with 
the  final analysis of the CDRB436C2201/MEK116833 study. 
 
 
 
1.1 
Study design 
This four-part Phase 1/2 multi-center study allows for the phased evaluation of safety, 
tolerability, and activity of dabrafenib and/or trametinib in combination with panitumumab in 
subjects with BRAF-V600E mutation-positive CRC and in subjects with CRC with secondary 
resistance to prior anti-EGFR therapy. 
The study design was intended to allow investigation of two doublet combinations (Dabrafenib 
(D)/ Panitumumab (P) and Trametinib (T)/Panitumumab (P)), in addition to a triple regimen 
(D/T/P). 
There were multiple parts to this study as described in sections 1.1.1 to 1.1.6. 
 
 
1.1.1 
Part 1 Dose Escalation Study Design/Schematic 
 


Novartis 
For business use only 
Page 7 
Final CSR SAP 
 
MEK116833 (CDRB436C2201) 
 
 
 
In Part 1, it was the intention to define a combination dose for both the 
dabrafenib/panitumumab combination and the dabrafenib/trametinib/panitumumab 
combination. The combination dose was either be the recommended full monotheapy dose for 
all components of the combination or an MTD for the combination. Dosing for dabrafenib and 
trametinib was continuous daily dosing while panitumumab was dosed once every two weeks, 
and assessments will occur in 28-day intervals. Subjects were evaluated for dose-limiting 
toxicities during the first 28 days of treatment. 
1.1.2 
Part 2A: Cohort Expansions Study Design/Schematic 
 
In Part 2, the primary objective was to further assess the safety and preliminary clinical activity 
of given doses and regimen(s) in subjects with BRAF-V600E mutation positive CRC. 
In Part 2A, subjects were enrolled in the expansion cohorts at a selected dose of dabrafenib in 
combination with panitumumab and a selected dose of trametinib plus dabrafenib in 
combination with panitumumab.  
Subjects who participated in Part 1 of the study at the doses evaluated in Part 2A were included 
in Part 2A analysis, and contributed to the total count of the 20 subjects enrolled in Part 2A. 


Novartis 
For business use only 
Page 8 
Final CSR SAP 
 
MEK116833 (CDRB436C2201) 
 
 
 
1.1.3 
Part 2B: Cohort Expansions Study Design/Schematic 
 
After completion of Part 2A, additional subjects were enrolled into the triplet combination of 
dabrafenib and trametinib in combination with panitumumab. Based on the efficacy and long 
term tolerability observed in Part 2A, two doses were evaluated in Part 2B. 
10 subjects with no prior treatment and 22 subjects with at least one prior treatment were 
enrolled at the Cohort 3A dose (dabrafenib 150mg BID + trametinib 2mg QD + panitumumab 
4.8mg/kg IV Q2wks). 5 subjects with no prior treatment and 19 subjects with at least one prior 
treatment will be enrolled at the Cohort 4 dose (dabrafenib 150mg BID + trametinib 2mg QD 
+ panitumumab 6mg/kg IV Q2wks). 
1.1.4 
Part 3 Randomized Phase 2 Study 
The original intention of the study was to include a randomized phase 2 portion of the study 
(Part 3) but this will not be performed because the study failed to meet the “go criteria” with 
respect to response rate and progression free survival. 
1.1.5 
Part 4A Dose Escalation 
In Part 4A dose escalation, the intention was to determine the MTD for the trametinib/ 
panitumumab doublet. 
 


Novartis 
For business use only 
Page 9 
Final CSR SAP 
 
MEK116833 (CDRB436C2201) 
 
 
 
 
A combination dose was defined for combination of trametinib and panitumumab as shown in 
the above figure.  
1.1.6 
Part 4B Cohort Expansion 
 
In Part 4B cohort expansion, the primary objective was to further assess the safety 
and preliminary clinical activity of trametinib and panitumumab at the MTD determined 
in Part 4A. Clinical activity was determined in two patient populations of subjects 
with advanced/metastatic CRC:  
1. BRAF mutant population, subjects with BRAF-V600E mutation-positive CRC (described 
above) 
2. Anti-EGFR resistant population, subjects with CRC that developed secondary resistance to 
anti-EGFR therapy after initially deriving benefit. 
1.2 
Study objectives and endpoints 
The different parts of the study each had separate objectives with specific endpoints associated 
with each. These objectives and endpoints are described in the protocol and are repeated for 
primary and secondary obejectives in sections 1.2.1 to 1.2.4 for information. 
 


Novartis 
For business use only 
Page 10 
Final CSR SAP 
 
MEK116833 (CDRB436C2201) 
 
 
 
 
 
The main purpose of the final analysis is to assess the overall safety and efficacy of the different 
combinations by dose and to publish the clinical study report.  
1.2.1 
Part 1: Phase 1 Dose Escalation 
 
Objectives 
Endpoints 
Primary  
To determine the safety, tolerability 
and range of tolerated combination 
doses in subjects with BRAF-V600E 
mutation-positive CRC in two dosing 
groups: 
 dabrafenib dosed orally in 
combination with 
panitumumab 
 trametinib dosed orally in 
combination with dabrafenib 
and panitumumab 
Adverse events and changes in 
laboratory values, vital signs and 
dose interruptions, modifications and 
discontinuations 
 
Secondary 
To describe the pharmacokinetics of 
dabrafenib, trametinib and 
panitumumab after combination 
therapy 
 
To determine preliminary clinical 
activity of dabrafenib dosed orally in 
combination with panitumumab  
 
 
To determine clinical activity of 
trametinib dosed orally in 
combination with dabrafenib and 
panitumumab 
 
 
To evaluate the pharmacodynamic 
response in colorectal tumors 
following combination treatment 
 
Maximum observed concentration 
(Cmax), time of occurrence of Cmax 
(tmax), and area under the 
concentration-time curve from zero 
(pre-dose) 8 hours (AUC(0-8)), pre-
dose (trough) concentration at the 
end of the dosing interval (C) of 
trametinib and dabrafenib.  Predose 
(C) and Cmax concentrations of 
panitumumab. 
 
Response rate (complete response 
[CR] + partial response [PR]) 
Progression free survival 
Duration of response 
 
Change in levels of proteins/RNA 
implicated in MAPK/PI3K/EGFR 
pathways in pre- and post-dose 
tumor tissue.  
 


Novartis 
For business use only 
Page 11 
Final CSR SAP 
 
MEK116833 (CDRB436C2201) 
 
 
 
1.2.2 
Part 2: Cohort Expansions 
 
Objectives 
Endpoints 
Primary  
To confirm the safety and tolerability 
of combination doses in subjects with 
BRAF-V600E mutation-positive CRC 
in two dosing groups: 
 dabrafenib dosed orally in 
combination with 
panitumumab 
 trametinib dosed orally in 
combination with dabrafenib 
and panitumumab 
 
To determine clinical activity in 
subjects with BRAF-V600E mutation-
positive CRC in two dosing groups: 
 dabrafenib dosed orally in 
combination with 
panitumumab 
 trametinib dosed orally in 
combination with dabrafenib 
and panitumumab 
Adverse events and changes in 
laboratory values, vital signs and 
dose interruptions, modifications and 
discontinuations 
 
 
 
 
 
 
 
Response rate (CR +PR) 
 
 
Secondary 
To characterize the population PK 
parameters of dabrafenib and 
trametinib dosed orally in 
combination with anti-EGFR antibody 
(panitumumab)  
 
 
To characterize the durability of 
response with dabrafenib dosed 
orally in combination with 
panitumumab  
 
 
To characterize the durability of 
response with trametinib dosed orally 
in combination with dabrafenib and 
panitumumab  
 
Population PK parameters,  oral 
clearance (CL/F),  oral volume of 
distribution (V/F), and absorption rate 
constant (Ka)  
 
 
Duration of response 
Progression-free survival  
Overall survival 
 
 
 
 
Duration of response 
Progression-free survival 
Overall Survival 
 
 


Novartis 
For business use only 
Page 12 
Final CSR SAP 
 
MEK116833 (CDRB436C2201) 
 
 
 
To evaluate the pharmacodynamic 
response in colorectal tumors 
following combination treatment 
 
 
Change in levels of proteins/RNA 
implicated in MAPK/PI3K/EGFR 
pathways in pre- and post-dose 
tumor tissue 
 
1.2.3 
Part 4A: Dose Escalation 
 
 
Objectives 
Endpoints 
Primary  
To determine the safety, tolerability 
and range of tolerated doses in the 
combination of panitumumab and 
trametinib in subjects with 
advanced/metastatic CRC 
Adverse events and changes in 
laboratory values, vital signs and 
dose interruptions, modifications and 
discontinuations 
Secondary 
To describe the pharmacokinetics of 
trametinib and panitumumab after 
combination therapy 
 
 
To determine preliminary clinical 
activity of panitumumab/ trametinib 
combination therapy in two patient 
populations: 
 
 subjects with BRAF-V600E 
mutation-positive CRC 
 subjects with CRC that 
developed secondary resistance 
to anti-EGFR therapy after 
initially deriving benefit 
 
To evaluate the pharmacodynamic 
response in colorectal tumors 
following combination therapy 
Maximum observed concentration 
(Cmax), time of occurrence of Cmax 
(tmax), and area under the 
concentration-time curve from zero 
(pre-dose) the time of the last 
quantifiable concentration (AUC(0-t)), 
pre-dose (trough) concentration at the 
end of the dosing interval (C) of 
trametinib. Predose (C) and Cmax 
concentrations of panitumumab. 
 
Response rate (complete response 
[CR] + partial response [PR]) 
Progression free survival 
Duration of response 
 
Change in levels of proteins/RNA 
implicated in MAPK/PI3K/EGFR 
pathways in pre- and post-dose 
tumor tissue. 
 
1.2.4 
Part 4B: Cohort Expansion 
 
Objectives 
Endpoints 


Novartis 
For business use only 
Page 13 
Final CSR SAP 
 
MEK116833 (CDRB436C2201) 
 
 
 
Primary  
To confirm the safety and tolerability 
of  RP2R of the panitumumab/ 
trametinib combination in an 
expansion cohorts of 
 subjects with BRAF-V600E 
mutation-positive CRC 
 subjects with CRC that 
developed secondary resistance 
to anti-EGFR therapy after 
initially deriving benefit 
 
To determine clinical activity of 
combination therapy in this patient 
population 
 
Adverse events and changes in 
laboratory values, vital signs and 
dose interruptions, modifications and 
discontinuations 
 
 
 
 
 
 
 
Response rate (CR +PR) 
 
 
Secondary 
To characterize the population PK 
parameters of trametinib dosed orally 
in combination with anti-EGFR 
antibody (panitumumab) 
 
To characterize the durability of 
response with trametinib dosed in 
combination with panitumumab 
 
To evaluate the pharmacodynamic 
response in colorectal tumors 
following combination treatment 
 
Population PK parameters,  oral 
clearance (CL/F),  oral volume of 
distribution (V/F), and absorption rate 
constant (Ka) 
 
Duration of response, Progression-
free survival, Overall survival 
 
Change in levels of proteins/RNA 
implicated in MAPK/PI3K/EGFR 
pathways in pre- and post-dose 
tumor tissue 
2 
Statistical methods 
2.1 
Treatment group labels and ordering 
The final analysis will focus on evaluating the safety and the efficacy of each separate  treatment 
combination, from an overall perspective with all dose regimens combined, as well as assessing 
the individual dose regimens. To report the results, the following treatment labels and  
abbreviations will be used for all efficacy tables, listings and figures: 
 Dabrafenib (DAB), Trametinib (TRA), Panitumumab (PAN) 
 
 Triple Combination (T+D+P) 
 DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W 


Novartis 
For business use only 
Page 14 
Final CSR SAP 
 
MEK116833 (CDRB436C2201) 
 
 
 
 DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W 
 DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W 
 DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W 
 Double Combination (T+P) 
 TRA 2MG QD,  PAN 6MG/KG Q2W  
 TRA 1.5MG QD,  PAN 6MG/KG Q2W  
 TRA 2MG QD,  PAN 4.8MG/KG Q2W 
 Double Combination (D+P) 
 DAB 150MG BID, PAN 6MG/KG Q2W 
 
2.2 
Data analysis general information 
The following sections provide a general description of the derived and transformed variables 
used to describe and analyze the data. Separate analysis dataset specifications provide full 
details on all data derivations and transformations including standard Oncology algorithms. The 
analysis dataset specifications will clearly communicate the content and source of the datasets 
supporting the statistical analyses. Each treatment combination will be analyzed separately for 
safety as well as efficacy analyses. 
2.2.1 
Multicenter Studies 
Data from all participating centers will be pooled prior to analysis.  It is anticipated that subject 
accrual will be spread thinly across centers and summaries of data by center would be unlikely 
to be informative and therefore will not be provided. 
2.2.2 
Baseline Definition 
The most recent, non-missing value from a local laboratory prior to or on the first dose of study 
treatment will be defined as the baseline value. 
For subjects who did not receive study treatment during the study, baseline will be defined as 
the latest, non-missing collected value. 
2.2.3 
Change from baseline 
Change from baseline is calculated as: 
 For records occurring after baseline: (visit value) – baseline value.  
Percent change from baseline is calculated as: 
 For records occurring after baseline: ((change from baseline) / baseline value) * 100 
If either the baseline or visit value is missing, the change from baseline and/or percent change 
from baseline is set to missing as well. 


Novartis 
For business use only 
Page 15 
Final CSR SAP 
 
MEK116833 (CDRB436C2201) 
 
 
 
2.2.4 
Withdrawal 
Reason for subject withdrawal will be listed. 
2.2.5 
Missing Data 
Missing data will not be imputed.  Where appropriate, available data will be summarized over 
specified intervals (e.g., from start of treatment until withdrawal from study) using suitable 
summary statistics. 
2.2.6 
Protocol Deviation 
A summary and listing of important protocol deviations will be provided. 
2.2.7 
Derived and Transformed Data 
The PK parameters, AUC, Cmax, and terminal half-life will be log-transformed prior to analysis 
when needed. 
2.2.8 
Assessment Windows 
Safety assessments that occur prior to the administration of study drug will be considered 
screening assessments.  Safety assessments that occur after dosing has begun will be considered 
as having occurred while on treatment. 
Disease assessments will be distinguished as belonging to either screening, continued therapy 
or post-study phases of the study. 
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). See the definition of study periods in relation to treatment in section 
2.7.  Study Day for Safety 
If the date of interest occurs on or after the safety reference date then the safety study day will 
be calculated as (date of interest - safety reference date) + 1. If the date of interest occurs before 
the safety reference date then the safety study day will be calculated as (date of interest – safety 
reference date). There is no safety study day 0. 
2.2.9 
Study Day for Efficacy 
If the date of interest occurs on or after the efficacy reference date then efficacy study day will 
be calculated as (date of interest - efficacy reference date) + 1. If the date of interest occurs prior 
to the efficacy reference date then efficacy study day will be calculated as (date of interest – 
efficacy reference date). There is no efficacy study day 0. 


Novartis 
For business use only 
Page 16 
Final CSR SAP 
 
MEK116833 (CDRB436C2201) 
 
 
 
2.2.10 
Reference Date 
The reference date for age is the date of screening as age is an eligibility requirement. For other 
analyses the reference date is the treatment start date, and will be used to calculate study day 
for safety and efficacy measures. 
2.2.11 
Durations and Elapsed Time 
Durations (e.g. duration of adverse event, duration of response, etc) will be calculated as stop 
date minus start date plus one. For elapsed time (e.g. time since initial diagnosis): 
 if the reference date is on or after event date then elapsed time is the reference date 
minus the event date +1. 
 if the reference date is before the event date then ‘elapse time’ is the reference date 
minus the event date. 
When reporting time to event durations (e.g., PFS, DOR) in months, divide the number of days 
by 30.4375; to report in weeks divide the number of days by 7; to report in years divide the 
number of days by 365.25. These algorithms for time to event return decimal numbers, and 
ignore the actual numbers of days in the months or years between start date and stop date. The 
"year" used in these algorithms is 365.25 days long, and the "month" is one twelfth of that year. 
For converting all other durations (e.g. duration of adverse events, duration of exposure, age, 
etc.) to weeks, months or years the following algorithms are used: 
 To report the duration in weeks divide the number of days by 7. 
 To report the duration in months use: (YEAR (stopdate+1) – YEAR (startdate) ) * 12 + 
(MONTH (stopdate+1) – month (startdate) -1) + (DAY (stopdate+1) >= DAY 
(startdate) ) 
 To report the duration in years use: intck('year', startdate, stopdate+1) - 
( month(stopdate+1)<month(startdate) or (month(stopdate+1)=month(startdate) and 
day(stopdate+1)<day(startdate)) ) 
The algorithms above for age and duration return whole numbers for months and years, 
accurately accounting for the actual numbers of days in the months or years between the start 
date and the stop date. 
2.2.12 
Imputation of Partial Dates 
Missing data will not be imputed.  Imputed partial dates will not be used to derive study day, 
duration (e.g., duration of adverse events), or elapsed time variables. 
2.2.13 
Data to be Included in the Analysis 
The study will be considered completed for purposes of a final analysis when the last subject 
has been followed up for 8 weeks after the last treatment.  


Novartis 
For business use only 
Page 17 
Final CSR SAP 
 
MEK116833 (CDRB436C2201) 
 
 
 
For this planned analysis for the Final CSR, a unique cut-off date will be established 
approximately 8 weeks after the Last Patient Last Treatment. All statistical analyses will be 
performed using all data collected in the database up to the data cut-off date. All data with an 
assessment date or event start date (e.g. vital sign assessment date or start date of an adverse 
event) prior to or on the cut-off date will be included in the analysis. Any data collected beyond 
the cut-off date will not be included in the analysis and will not be used for any derivations. 
All events with start date before or on the cut-off date and end date after the cut-off date will be 
reported as ‘ongoing’. The same rule will be applied to events starting before or on the cut-off 
date and not having documented end date. This approach applies, in particular, to adverse event 
and concomitant medication reports. For these cases, the end date will not be imputed and 
therefore will not appear in the listings. 
2.2.14 
Last Contact Date 
Last contact date will be used for the censoring of patients in the analysis of overall 
survival. 
 
The last contact date will be derived for patients not known to have died at the analysis cut-
off using the last complete date among the following: 
 
    Last follow up visit  date collected on the ‘Survival information’ eCRF. 
 
    All  assessment  dates  (e.g.  tumor  assessment,  laboratory/PK  collection  dates,  
vital signs assessment, performance status, ECG assessment). Note, only a true on 
study assessment date or patient follow up visit date will be used.  
 
    No dates post cut-off will be used. 
 
    Medication dates including study medications, concomitant medications, and  
anti- cancer therapies administered after study treatment discontinuation. 
 
    Adverse event dates. 
 
 
Note: The cut-off date will not be used for last contact date, unless the patient was 
known to be alive on that date.  
 
2.2.15 
Other Issues 
Demographic and baseline characteristics will be summarized. 
2.3 
Analysis sets 
2.3.1 
All Treated Population 
All Treated will be defined as the population of all subjects that have been treated with at 
least one dose of the study drug at the time of the final analysis.  This will be the population 
for summaries of safety and efficacy data. 


Novartis 
For business use only 
Page 18 
Final CSR SAP 
 
MEK116833 (CDRB436C2201) 
 
 
 
We will also report efficacy for Anti-EGFR acquired resistance CRC population and BRAF-
mutant CRC population separately for the T+P drug combination. 
2.3.2 
Pharmacokinetic Population 
The PK Population is defined as those subjects in the All Treated Population and for whom a 
PK sample is obtained and analyzed prior to the data cut-off date. This population will be used 
for the secondary PK endpoints. 
2.3.3 
Biomarker Population  
The biomarker population is defined as subjects in the All Treated Population for whom a 
tumor biopsy/tissue was obtained and analysed.  
2.3.4 
Crossover Population 
The Crossover Population will comprise the subset of subjects in double combination who 
had intra-subject doublet to triplet crossover. It will be the primary population when 
summarizing data in Part 1, Part 2 and Part 4 crossover phase. 
The efficacy data collected after crossover for those subjects who crossed over from 
dabrafenib/panitumumab combination or trametinib/panitumumab to 
dabrafenib/trametinib/panitumumab combination will not be included in the main efficacy 
analysis for dabrafenib/trametinib/panitumumab combinations. The crossover efficacy data 
for these subjects will be only presenting in listings. All safety analysis including treatment 
emergent AE’s regardless of crossover will be reported. 
2.4 
Subgroup of interest 
There are no sub group analysis planned for the final CSR analysis. Efficacy and disease 
characteristics analysis for T+P cohort will be done separately for BRAF mutant patients and 
anti-EGFR patients. 
2.5 
Patient disposition, demographics and other baseline 
characteristics 
2.5.1 
Patient Disposition  
A summary of the number of subjects in each of the analysis populations will be provided. A 
listing of subjects included in each analysis population will also be provided.   
A summary of subject status and reason for study withdrawal will be provided. This display 
will show the number and percentage of subjects who withdrew from the study, including 
primary reason for study withdrawal. Reasons for study withdrawal will be presented in the 
order they are displayed in the eCRF.  
A summary of study treatment status will be provided. This display will show the number and 
percentage of subjects who are ongoing or discontinued study and the primary reason(s) for 
discontinuation of study treatment. Reasons for study treatment discontinuation will be 


Novartis 
For business use only 
Page 19 
Final CSR SAP 
 
MEK116833 (CDRB436C2201) 
 
 
 
presented in the order they are displayed in the eCRF. Separate table will be produced for each 
treatment combinations. 
2.5.2 
Demographic and Disease Characteristics Assessments 
The following demographic parameters will be captured: date of birth, gender, race, ECOG and 
ethnicity. 
Primary tumor type including date (month and year) of first diagnosis will be taken as part of 
the disease characteristics assessments.  Disease characteristics at screening will be reporting 
percentages of measurable disease, non-target lesions at baseline, primary tumor type, 
histology, BRAF V600E mutation, MSI status, Stages of disease, prior lines of therapy and 
prior anti-EGFR therapy. 
Disease characteristics assessments will be separated for the BRAF V600E mutant population 
and the anti_EGFR acquired resistance population. 
2.6 
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance) 
2.6.1 
Study treatment / compliance 
Duration of exposure, actual cumulative dose, dose intensity (DI) and relative dose intensity 
(RDI) will be summarized by each drug combination separately. Duration of exposure will be 
categorized into time intervals; frequency counts and percentages will be presented for the 
number(%) of subjects in each interval. The number (%) of subjects who have dose reductions 
or interruptions, and the reasons, will be summarized by treatment group.  
Subject level listings of all doses administered on treatment along with dose change reasons 
will be produced.   
The safety set will be used for all summaries and listings of study treatment.  
The subject’s average daily dose, defined as the cumulative dose divided by the duration of 
exposure for each subject, will be summarized. It will be calculated for each subject first and 
the summary statistics are calculated based on the subject average daily dose. In addition, 
summary of the population level daily dose will also be provided. In this analysis, a dose on 
each day for each subject will be treated as an observation and the summary will be based on 
the dose on each individual day for all subjects. 
Duration of exposure to study treatment 
Duration of exposure to study treatment is considered by taking into account the duration of 
exposure to the investigational drug or control, and any combination partner, if applicable: 
Duration of exposure to study treatment (days) = (last date of exposure to study treatment) – 
(date of first administration of study treatment) + 1.  


Novartis 
For business use only 
Page 20 
Final CSR SAP 
 
MEK116833 (CDRB436C2201) 
 
 
 
The last date of exposure to study treatment is the latest of the last dates of exposure to any drug 
combination. 
Summary of duration of exposure of study treatment in appropriate time units will include 
categorical summaries and continuous summaries (i.e. mean, standard deviation etc.) using 
appropriate units of time. 
Cumulative dose 
Cumulative dose of a study treatment is defined as the total dose given during the study 
treatment exposure and will be summarized for each of the study treatment components.  
The planned cumulative dose for a study treatment component refers to the total planned dose 
as per the protocol up to the last date of investigational drug administration.  
The actual cumulative dose  refers to the total actual dose administered, over the duration for 
which the subject is on the study treatment as documented in the Dose Administration eCRF.  
For patients who did not take any drug the cumulative dose is by definition equal to zero. 
For continuous dosing, the actual cumulative dose is the sum of the non-zero doses recorded 
over the dosing period and the planned cumulative dose is the planned starting dose summed 
over the same dosing period. 
For intermittent dosing, the actual cumulative dose should be defined based on the days when 
the subject is assumed to have taken a non-zerodose during dosing periods.  
Dose intensity and relative dose intensity 
Dose intensity (DI) for patients with non-zero duration of exposure is defined as follows:  
DI (dosing unit / unit of time) = Actual Cumulative dose (dosing unit) / Duration of exposure to 
study treatment (unit of time). 
For patients who did not take any drug the DI is by definition equal to zero.  
Planned dose intensity (PDI) is defined as follows: 
PDI (dosing unit / unit of time = Planned Cumulative dose (dosing unit) / Duration of exposure 
(unit of time). 
Relative dose intensity (RDI) is defined as follows: 
RDI = DI (dosing unit / unit of time)  / PDI (dosing unit / unit of time).   
DI and RDI will be summarized using the duration of exposure of each of the components.  
Dose reductions, interruptions or permanent discontinuations 
The number of subjects who have dose reductions, permanent discontinuations or interruptions, 
and the reasons, will be summarized separately for each of the study treatment components.  


Novartis 
For business use only 
Page 21 
Final CSR SAP 
 
MEK116833 (CDRB436C2201) 
 
 
 
‘Dose interrupted’, and ‘Dose permanently discontinued’ fields from the Dosage 
Administration CRF pages (DAR) will be used to determine the dose reductions, dose 
interruptions, and permanent discontinuations, respectively. 
The corresponding fields ‘Reason for dose change/dose interrupted’ and ‘Reason for permanent 
discontinuation’ will be used to summarize the reasons. 
A dose change is either ‘change in prescribed dose level’ or ‘dosing error’ where actual dose 
administered/total daily dose is different from the prescribed dose. 
For the purpose of summarizing interruptions and reasons, in case multiple entries for 
interruption that are entered on consecutive days with different reasons will be counted as 
separate interruptions. However, if the reason is the same in this mentioned multiple entries on 
consecutive days, then it will be counted as one interruption.  
Reduction: A dose change where the prescribed dose level is lower than the previous prescribed 
dose level or where the actual dose administered/total daily dose is lower than the calculated 
dose amount based on the prescribed dose. Therefore any dose change to correct a dosing error 
will not be considered a dose reduction.  Only dose change is collected in the CRF, number of 
reductions will be derived programmatically  based on the change and the  direction of the 
change. 
2.6.2 
Prohibited Medications 
The use of certain medications, and illicit drugs within 5 half-lives or 28 days, whichever is 
shorter prior to the first dose of study drug and for the duration of the trial will not be allowed.   
A list of protocol deviations regarding prohibited medications will be reported. There will be 
no separate analysis on prohibited and permitted medications in this reporting activity. 
2.6.3 
Study time periods of Concomitant Medications 
Concomitant Medication start and end dates will be assigned to study time periods in relation 
to first dose of study treatment as defined below. The start date references time flag variables 
and end date reference time flag variables will be added to the concomitant medications. 
Concomitant medication start relative to treatment and end relative to treatment flags are used 
to select data to include in the Concomitant Medication summaries as follows: 
 Summary of Prior Concomitant Medications: This summary will contain medications 
including those with start date prior to study treatment start date and continue (missing 
end date or end date after study treatment start date) on therapy. In addition, any 
medication that was started during post-therapy will be excluded. Include concomitant 
medication records where start relative to treatment in ('BEFORE','DURING') and end 
relative to treatment in ('DURING','AFTER'). 
Summary of Concomitant Medications with On-Therapy Onset: This summary will contain 
medications with start date after study treatment start date. In addition, any medication that was 
started during post-therapy (see above for definition of post-therapy) will be excluded. Include 


Novartis 
For business use only 
Page 22 
Final CSR SAP 
 
MEK116833 (CDRB436C2201) 
 
 
 
concomitant medication records where start relative to treatment in ('DURING') and end 
relative to treatment in ('DURING','AFTER'). 
2.7 
Study Time Periods in Relation to Treatment 
Adverse events, serious adverse events, death, laboratory data, vitals, ECG and ECHO, will be 
assigned to the study time periods defined below. Partial dates will be imputed into full dates, 
if applicable, for slotting data to the appropriate categories below (see Section 9.2.5). Flag 
variables (time in relation to study treatment) indicating the study time periods will be added to 
these datasets. 
Pre-therapy is defined as the time prior to the subject’s first dose of study treatment.  
On-therapy is defined as the time from first dose of study treatment to 30 days after the last 
dose date of study treatment.  
Post-therapy is defined as any time beyond the on-therapy period (i.e. starting at day 30+1 
after the last dose date of study treatment). 
Some datasets include the first dose day as On-therapy and some exclude the first dose date as 
On-Therapy. The first dose day (Day 1) is considered pre-therapy for ECOG, ECG, vital signs, 
liver events, lab tests, and cardiac scan. The first dose day (Day 1) is considered to be On-
therapy for adverse events and concomitant medications. 
2.8 
Analysis of the primary objective 
Please refer to Section 1.2 for objectives which relate to the individual study parts. 
2.8.1 
Primary endpoint 
The primary endpoint to assess efficacy for the Final Analysis will be the response rate. The 
results will be summarized by combination. 
For T+P drug combination, the efficacy will be reported for Anti-EGFR acquired resistance 
CRC population and BRAF-mutant CRC population separately. 
  
2.8.2 
Statistical hypothesis, model, and method of analysis 
The primary endpoint, overall response rate (ORR) is defined as the percentage of subjects with 
evidence of a confirmed complete response (CR) or partial response (PR) as per RECIST v1.1 
[Eisenhauer, 2009]. The estimated ORR along with corresponding 2-sided 95% exact CIs as 
derived by the Clopper-Pearson method will be presented by each treatment combination. 
 
2.9 
Analysis of the key secondary objective 
There are no key secondary objective. All secondary objectives are included in Section 2.10. 


Novartis 
For business use only 
Page 23 
Final CSR SAP 
 
MEK116833 (CDRB436C2201) 
 
 
 
2.10 
Analysis of secondary efficacy objective(s) 
Please refer to Section 1.2 for objectives relating to the individual study parts . 
2.10.1 
Secondary endpoints 
The secondary endpoints relevant for this Final Analysis will be DOR, PFS and OS. The 
results will be summarized by cohort and by dose. 
Duration of response (DOR) is defined as the time from the first documented occurrence of 
response (PR or CR) until the date of the first documented progression based on RECIST v1.1 
or death.  
2.10.2 
Statistical hypothesis, model, and method of analysis 
In each treatment combination, a KM curve will be constructed. The 25th, 50th (median), and 
75th percentiles of the DOR and the 2-sided 95% CIs will be reported for both treatments. For 
PFS, the HR for treatment effect will be estimated and its 2-sided 95% CIs will be reported. 
For OS, the HR will be estimated and its 2-sided 95% CIs will be reported.    
All analyses will be based on the All Treated Population. For T+P drug combination, the 
efficacy will be reported for Anti-EGFR acquired resistance CRC population and BRAF-
mutant CRC population separately.  
All efficacy analyses will be summaries on drug combination and by dose groups and not by 
part. No formal comparison will be conducted between cohorts. All efficacy data will be listed 
and summarized for the treatment period before the crossover.  
There are no separate analyses for the cross over population. Listings will include cross-over 
visits. 
The methods of analysis for PK endpoints are discussed in Section 2.13. 
Specifically, efficacy analyses in the each cohorts are illustrated in Table 2-1. 
The primary efficacy analysis ORR will be summarized using descriptive statistics (N,%) along 
with 2-sided exact 95% confidence interval (CI) [Clopper and Pearson 1934]. 
The secondary efficacy analysis for PFS, OS and DOR will be presented using a Kaplan-Meier 
curve. Median survival together with their 95% confidence intervals will be reported. 
Table 2-1 
Efficacy analysis by Drug Combination 
Endpoint Population  
Analysis 
 
ORR 
DOR 
PFS 
 
Triple combination D+T+P 
 
Double combination T+P [BRAF mutant]  
 
Double combination T+P [Anti-EGFR]  
 
Double combination (D+P)  
 
Primary analysis: 
based on 
investigator 
assessment  
 
Sensitivity analysis: 
based on 
independent 


Novartis 
For business use only 
Page 24 
Final CSR SAP 
 
MEK116833 (CDRB436C2201) 
 
 
 
reviewer assessment  
(except T+P) 
 
OS 
 
Triple combination D+T+P 
 
Double combination T+P [BRAF mutant]  
 
Double combination T+P [Anti-EGFR]  
 
Double combination (D+P) 
 
OS analysis 
 
2.10.3 
Handling of missing values/censoring/discontinuations 
The DOR will be analyzed based on data from responders only. Patients who did not 
experience progressive disease and are still alive will be censored at the last adequate 
response assessment. PFS is defined as the time from the date of randomization to the date of 
the first documented PD or relapse or death due to any cause.  
Subjects who progressed or died after an extended period without adequate assessment or who 
started a new anti-cancer therapy prior to a PFS event will be censored at their date of last 
adequate assessment prior to progression or death. An adequate assessment is defined as an 
assessment where the determined response is CR, PR or SD. As the assessment schedule 
changes through the course of the study, the following rules will be used for identifying 
extended loss to follow-up or extended time without an adequate assessment: 
 If death or PD is on or prior to Day 175 (Week 24 + 7 day window) then a patient will be 
identified as an extended loss to follow-up if the patient did not have an adequate 
assessment during the time period of 91 days (2*6 weeks + 7 day window) prior to death 
or PD; 
 If death or PD is after Day 175 then a patient will be identified as an extended loss to 
follow-up if the patient did not have an adequate assessment during the time period of 119 
days (2*8 weeks + 7 day window) prior to death or PD. 
OS is defined as the time from date of randomization 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 contact. 
2.10.4 
Supportive analyses 
A sensitivity analysis of ORR, DOR and PFS based on independent reviewer assessed response 
(RECIST 1.1) will also be provided. 
 
2.11 
Safety analyses 
To report the results, the following treatment labels and abbreviations will be used for all safty 
tables, listings and figures: Dabrafenib (DAB), Trametinib (TRA), Panitumumab (PAN) 
 Triple Combination (T+D+P) 
 DAB 150MG BID, TRA 1.5MG QD, PAN 4.8MG/KG Q2W 
 DAB 150MG BID, TRA 2MG QD, PAN 4.8MG/KG Q2W 


Novartis 
For business use only 
Page 25 
Final CSR SAP 
 
MEK116833 (CDRB436C2201) 
 
 
 
 DAB 150MG BID, TRA 1.5MG QD, PAN 6MG/KG Q2W 
 DAB 150MG BID, TRA 2MG QD, PAN 6MG/KG Q2W 
 Double Combination (T+P) 
 TRA 2MG QD,  PAN 6MG/KG Q2W  
 TRA 1.5MG QD,  PAN 6MG/KG Q2W  
 TRA 2MG QD,  PAN 4.8MG/KG Q2W 
 Double Combination (D+P) 
 DAB 150MG BID, PAN 6MG/KG Q2W 
2.11.1 
Dose-Limiting Toxicity  
There were no DLTs reported in the escalation phase of the study and as a result there are no 
analyses performed relating to dose-limiting toxicities. 
2.11.2 
Adverse events (AEs) 
Adverse events (AEs) were graded according to the CTCAE, Version 4.03. and coded to the 
preferred term (PT) level using the Medical Dictionary for Regulatory Affairs (MedDRA 
dictionary). 
A summary of number and percentage of subjects with any adverse events by maximum grade 
will be produced. AEs will be sorted by Preferred term (PT) in descending order of total 
incidence. The summary will use the following algorithms for counting the subject: 
 Preferred term row: Subjects experiencing the same AE preferred term several times with 
different grades will only be counted once with the maximum grade. 
 Any event row: Each subject with at least one adverse event will be counted only once at 
the maximum grade no matter how many events they have. 
2.11.2.1 Adverse events of special interest / grouping of AEs 
An adverse event of special interest (AESI) is a grouping of adverse events that are of scientific 
and medical concern specific to dabrafenib and trametinib. These groupings are defined using 
MedDRA terms, SMQs (standardized MedDRA queries), HGLTs (high level group terms), 
HLT (high level terms) and PTs (preferred terms). Customized SMQs (Novartis MedDRA 
queries, NMQ) may also be used. A NMQ is a customized group of search terms which defines 
a medical concept for which there is no official SMQ available or the available SMQ does not 
completely fit the need.  
 
AESI for the dabrafenib therapy are: 
 Hyperglycemia 
 Hypersensitivity 
 New Primary or Secondary Malignancy 
 Pancreatitis 


Novartis 
For business use only 
Page 26 
Final CSR SAP 
 
MEK116833 (CDRB436C2201) 
 
 
 
 Pre-renal and intrinsic renal failure 
 Pyrexia 
 Uveitis 
 
AESI for the trametinib therapy are: 
 Bleeding events 
 Cardiac related events 
 Hepatic disorders 
 Hypersensitivity 
 Hypertension 
 Ocular events 
 Pneumonitis and Interstitial Lung Disease 
 Skin toxicity 
 Venous Thromboembolism 
 
AESI for the dabrafenib + trametinib combination therapy are: 
 Bleeding events 
 Cardiac related events 
 Hepatic disorders 
 Hyperglycemia 
 Hypersensitivity 
 Hypertension 
 Neutropenia 
 New Primary or Secondary Malignancy 
 Ocular events 
 Pancreatitis 
 Pneumonitis and Interstitial Lung Disease 
 Pre-renal and intrinsic renal failure 
 Pyrexia 
 Skin toxicity 
 Uveitis 
 Venous Thromboembolism 
The summary of number and percentage of subjects with each type of adverse event of special 
interest by maximum grade will be produced for all cohort combined. AEs will be sorted by PT 
in descending order of total incidence. 
The events of special interest will be analysed using the most updated asset specific AESI 
(Adverse Event of Special Interest) at the time of analysis. 
 


Novartis 
For business use only 
Page 27 
Final CSR SAP 
 
MEK116833 (CDRB436C2201) 
 
 
 
2.11.3 
Deaths and Serious Adverse Events 
All deaths will be summarised based on the number and percentage of subjects. This summary 
will classify subjects by time of death (on-therapy and post-therapy) and the primary cause of 
death. A supportive listing will be generated to provide subject-specific details for subject who 
died.  
All SAEs will be tabulated based on the number and percentage of subjects who experienced 
the event. The summary tables will be displayed in descending order of total incidence by PT 
only. 
2.11.4 
Adverse Events Leading to Discontinuation of Study Treatment 
and/or Withdrawal from the Study and Other 
For each cohort, the following categories of AEs will be summarized separately in descending 
order of total incidence by PT only: 
 AEs Leading to Discontinuation of Study Treatment  
 AEs Leading to Dose Interruptions 
 AEs Leadings to Dose Reductions 
2.11.5 
Laboratory data 
The assessment of laboratory toxicities will examine the following laboratory tests:  
 Alanine aminotransferase (ALT) 
 Aspartate aminotransferase (AST)  
 Total bilirubin  
 Complete blood count and platelets 
 Serum creatinine 
 Glucose 
 Serum calcium  
 Lactate dehydrogenase (LDH)  
Laboratory grades will be reported using the Common Terminology Criteria for Adverse Events 
(CTCAE v4.03). 
Summaries of worst case grade increase from baseline grade will be provided for all the lab 
tests that are gradable by CTCAE v4.03. These summaries will display the number and 
percentage of subjects with a maximum on-therapy grade increasing from their baseline grade. 
Any increase in grade from baseline will be summarized along with any increase to a maximum 
grade of 3 and any increase to a maximum grade of 4. Missing baseline grade will be assumed 
as grade 0. In addition, the summary will include grade increase from baseline by scheduled 


Novartis 
For business use only 
Page 28 
Final CSR SAP 
 
MEK116833 (CDRB436C2201) 
 
 
 
visits. For laboratory tests that are graded for both low and high values, summaries will be done 
separately and labeled by direction, e.g., sodium will be summarized as hyponatremia and 
hypernatremia. 
For lab tests that are not gradable by CTCAE v4.03, summaries of worst case changes from 
baseline with respect to normal range will be generated. Decreases to low, changes to normal 
or no changes from baseline, and increases to high will be summarized at each scheduled visit 
as well as for the worst case on-therapy. If a subject has a decrease to low and an increase to 
high during the same time interval, then the subject is counted in both the “Decrease to Low” 
categories and the “Increase to High” categories. Detailed derivation of baseline assessment is 
specified in Section 9. 
Unless otherwise specified, the denominator in percentage calculation at each scheduled visit 
will be based on the number of subjects with non-missing value at each particular visit. 
2.11.5.1 Laboratory Parameters Ranges 
Reference ranges for all laboratory parameters collected throughout the study are provided by 
the laboratory. A laboratory value that is outside the reference range is considered either high 
abnormal (value above the upper limit of the reference range) or low abnormal (value below 
the lower limit of the reference range).  
Note: a high abnormal or low abnormal laboratory value is not necessarily of clinical concern. 
The laboratory reference ranges will be provided on the listings of laboratory data. Clinical 
laboratory test results outside of the reference range will be flagged in the listings. 
To identify laboratory values of potential clinical importance, National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI-CTCAE v4.03) will be used to assign 
grades to the relevant laboratory parameters.  
 For laboratory data which are not listed in the NCI CTCAE v4.03, a summary of values outside 
the normal range will be provided. 
2.11.6 
ECG and cardiac imaging data 
To identify QTc (Bazett’s) values of potential clinical importance, NCI-CTCAE v4.03 will be 
used to assign grades (see adverse event ‘Electrocardiogram QT corrected interval 
prolonged’).  The following tables will define interval values that will be use in ECG 
summary displays. 
 


Novartis 
For business use only 
Page 29 
Final CSR SAP 
 
MEK116833 (CDRB436C2201) 
 
 
 
ECG Parameter 
Potential Clinical Importance (PCI) Range 
Unit 
Absolute QTcB  interval 
450 to <481 (Grade 1) 
481 to <501 (Grade 2) 
501 (Grade 3) 
Msec 
Increase from baseline 
QTcB  
Increase of 31 to 60 
Increase of >60 
Msec 
 
The following criteria will be used to flag other ECG values that are values of potential 
clinical importance:  
ECG Parameter 
Potential Clinical Importance (PCI) Range 
Unit 
PR interval 
<110 (L) and >220 (H) 
Msec 
QRS interval 
<75 (L) and >110 (H) 
Msec 
2.11.7 
ECHO 
ECHO data including left ventricular ejection fraction (LVEF) values, the institution’s lower 
limit of normal (LLN), absolute change from baseline LVEF,  percentage change from baseline 
in LVEF, and ECHO scan results will be listed for each subject. Vital Signs 
Vital sign data (blood pressure, heart rate, respiration rate and temperature) and change from 
baseline will be listed for each subject. For the analysis of vital signs the clinically notable vital 
sign criteria are provided below.   
  
Vital sign 
(unit) 
Clinically notable criteria 
 
above normal value 
below normal value 
Weight (kg) 
increase > 10% from Baseline 
decrease  > 10% from Baseline 
Systolic blood 
pressure 
(mmHg) 
>=180 with increase from baseline 
of >=20 
<=90 with decrease from baseline 
of >=20 
 
Diastolic blood 
pressure 
(mmHg) 
>=105 with increase from baseline 
of >=15 
<=50 with decrease from baseline 
of >=15 
 
Pulse rate 
(bpm) 
>=100 with increase from baseline 
of >25% 
<=50 with decrease from baseline of  
> 25% 
 
Body 
temperature 
>= 39.1  
- 
 
The number and percentage of patients with notable vital sign values (high/low) will be 
presented by treatment group. 


Novartis 
For business use only 
Page 30 
Final CSR SAP 
 
MEK116833 (CDRB436C2201) 
 
 
 
2.11.8 
ECOG 
ECOG performance status at baseline will be summarized. ECOG shift from baseline will be 
produced for the worst case post-baseline.  A summary of change from baseline will be 
performed for the worst-case post-baseline and the best case post-baseline changes during the 
study (improved, no change, and deteriorated).  
A listing of ECOG performance status values for all subjects will be produced. Baseline value 
for each subject will be specified in the listing. 
2.12 
Biomarkers 
Measurements for levels of proteins/RNA implicated in MAPK/PI3K/EGFR pathways (pERK 
and pS6 H-score) will be summarized separately for pre- and post-dose and as changes from 
pre-dose for patients with both pre- and post-dose values. 
BRAF mutation central testing results will be listed and summarized. 
 
 
 
2.13 
Pharmacokinetic endpoints   
The PK results will be reported based on the drug combination and doseage. The tratment labels 
will follow the labels listed in safety section (2.11).  
PK parameters for dabrafenib, trametinib and panitumumab for subjects in whom the full blood 
sampling scheme was used will be calculated with standard non-compartmental methods 
according to current working practices and using WinNonlin Professional version 5.2 or higher. 
All calculations of non-compartmental parameters will be based on actual blood sampling 
times.  
The following parameters will be calculated for dabrafenib (and its metabolites) and trametinib 
as data permit: 
 The first occurrence of the maximum observed plasma concentration determined 
directly from the raw concentration-time data (Cmax) 
 The time at which Cmax is observed will be determined directly from the raw 
concentration-time data (tmax) 
 The area under the plasma concentration-time curve to the last quantifiable 
concentration (AUC(0-t)) determined using the linear trapezoidal rule for increasing 
concentrations and the logarithmic trapezoidal rule for decreasing concentrations. 
 The area under the plasma concentration-time curve to 8 hours (AUC(0-8)) determined 
using the linear trapezoidal rule for increasing concentrations and the logarithmic 
trapezoidal rule for decreasing concentrations. 
 The trough (pre-dose) plasma concentration determined directly from the raw 
concentration-time data (C) 


Novartis 
For business use only 
Page 31 
Final CSR SAP 
 
MEK116833 (CDRB436C2201) 
 
 
 
The following parameters will be calculated for panitumumab as data permit: 
 Cmax 
 C 
 
2.13.1 
Statistical Analysis of PK Concentration Data 
No formal comparison will be conducted between the cohorts within the treatment 
combinations. 
Concentrations of trametinib, dabrafenib and metabolites and panitumumab will be listed and 
summarized by nominal time/visit and each treatment cohort. Average pre-dose concentration 
for each subject will be calculated using pre-dose concentration at Day 1, Day 15, Week 8, 12, 
and 16 (where applicable), and will be included in the listing and summary table. Standard 
summary statistics will be calculated, including n, geometric mean and geo-mean CV%, mean, 
median, SD, minimum and maximum.  
PK parameters of trametinib, dabrafenib and metabolites and panitumumab will be listed and 
summarized by nominal visit and each treatment cohort. Descriptive statistics (e.g., n, geometric 
mean, geometric CV%, mean, median, SD, minimum, maximum) will be presented for all PK 
parameters, except for tmax, where only n, median, minimum and maximum will be presented. 
Coefficient of variation (CV) (%) is calculated as follows:  
100*(SD/arithmetic mean). 
Geometric CV (%) is calculated as follows: 
sqrt (exp (variance for log transformed data)-1)*100. 
Subjects may be excluded from the estimation of certain PK parameters on an individual basis 
depending on the number of available blood samples. Specific time points might be excluded 
from the analysis set if technical issues with the sample are reported (e.g. sampling issues, 
missing information) or if LLOQ sample is observed in between measurable concentrations. 
These patients and concentration data points will be identified at the time of analysis. 
3 
Sample size calculation 
3.1 
Part 1 and Part 4 Dose Escalation 
The total number of subjects in Part 1 and Part 4 dose escalation will depend on the number of 
dose escalations needed. However, the maximum anticipated number of subjects will be 
approximately 24 in Part 1 and approximately 22 in Part 4 dose escalation. 


Novartis 
For business use only 
Page 32 
Final CSR SAP 
 
MEK116833 (CDRB436C2201) 
 
 
 
Table 3-1 
Statistical Basis for Phase 1 Dose Escalation 
True incidence of dose-limiting toxicity 
10% 
20% 
30% 
40% 
50% 
60% 
Probability of escalating the dose 
0.91 
0.71 
0.49 
0.31 
0.17 
0.08 
3.2 
Part 2 and Part 4 Cohort Expansions 
Part 2 will enroll up to 90 subjects in total.  Part 4 cohort expansion will enroll 40-60 subjects 
in total (20 subjects in the anti-EGFR acquired resistance CRC population and 20-40 subjects 
in the BRAF mutant CRC population).  Subjects will be evaluated separately by dose cohort 
and population at the end of Part 2 and Part 4. 
To determine the sample size for dabrafenib in combination with panitumumab expansion 
cohort, and trametinib in combination with panitumumab expansion cohort, a traditional, 2-
stage Green-Dahlberg design [Green, 1992] was evaluated and the sample size for the first stage 
will be used for the futility analysis.  To test the hypotheses (RR=30% vs. RR=15%), using a 
Green-Dahlberg design, 20 subjects per drug combination would be needed for Stage 1 
(assuming a type 1 error of 10% and power of 80%).  The chance to effectively terminate the 
trial after 20 subjects due to futility (true RR=15%) is 33%; the risk to incorrectly stop the trial 
after 20 subjects if the treatment is effective (true RR=40%) is less than 2%.  To determine the 
maximum sample size for any cohort or patient population in trametinib plus dabrafenib in 
combination with panitumumab, Bayesian predictive adaptive design will be used for testing 
hypotheses: 
H0: RR≤15% 
HA:RR≥30% 
When maximum sample size is 54, the design will have a Type I error (α) of 0.089 and 88% 
power with the probability of termination is 0.911 when the treatment is futile and probability 
of early termination 0.116 when the treatment is effective (true RR=0.3). 
Table 3-2 
Futility Analysis Design Performance  
 
 True 
RR 
Probability of 
Termination, after 
20 pts 
Probability of 
Termination, after 
34 pts 
Probability of 
Termination, after 
40 pts 
Probability of 
Termination, after 
54 pts 
15% 
0.329 
0.548 
0.603 
0.911 
20% 
0.180 
0.288 
0.324 
0.641 
30% 
0.044 
0.054 
0.057 
0.116 
40% 
0.007 
0.011 
0.011 
0.013 
A Bayesian posterior probability will also be calculated to further inform decision making.   
Since neither dabrafenib in combination with panitumumab, trametinib in combination with 
panitumumab, nor trametinib in combination with dabrafenib and panitumumab has been tested 
previously in the clinic in CRC subjects, a Beta (0.003, 0.007) prior is assumed.  This prior is 
equivalent to the information from 0.01 subject. The posterior probabilities of ORR exceeding 


Novartis 
For business use only 
Page 33 
Final CSR SAP 
 
MEK116833 (CDRB436C2201) 
 
 
 
20%, 30% and 40% based on 20 subjects and the posterior probabilities of ORR exceeding 
20%, 30% and 40% based on 54 subjects are shown in Table 3-3. 
Table 3-3 
Bayesian Posterior Probabilities of Response Rate for Given Number 
of Observed Responses 
# of Responses Observed out 
of 20 Subjects 
Posterior Probability 
RR ≥20% 
Posterior Probability 
RR ≥30% 
Posterior Probability RR 
≥40% 
4 
0.45 
0.14 
0.024 
5 
0.69 
0.29 
0.075 
6 
0.83 
0.48 
0.17 
7 
0.93 
0.66 
0.31 
8 
0.97 
0.81 
0.49 
# of Responses Observed out 
of 34 Subjects 
Posterior Probability 
RR ≥20% 
Posterior Probability 
RR ≥30% 
Posterior Probability RR 
≥40% 
5 
0.18 
0.01 
0.000 
6 
0.33 
0.04 
0.002 
7 
0.50 
0.09 
0.007 
8 
0.67 
0.18 
0.019 
9 
0.80 
0.30 
0.044 
10 
0.89 
0.45 
0.092 
11 
0.95 
0.60 
0.169 
12 
0.98 
0.73 
0.276 
# of Responses Observed out 
of 40 Subjects 
Posterior Probability 
RR ≥20% 
Posterior Probability 
RR ≥30% 
Posterior Probability RR 
≥40% 
6 
0.18 
0.01 
0.000 
7 
0.31 
0.03 
0.001 
8 
0.47 
0.07 
0.003 
9 
0.62 
0.13 
0.008 
10 
0.76 
0.22 
0.020 
11 
0.86 
0.35 
0.045 
12 
0.93 
0.48 
0.088 
13 
0.96 
0.62 
0.155 
# of Responses Observed out 
of 54 Subjects 
Posterior Probability 
RR ≥20% 
Posterior Probability 
RR ≥30% 
Posterior Probability RR 
≥40% 
11 
0.50 
0.05 
0.001 
12 
0.63 
0.09 
0.002 
13 
0.75 
0.15 
0.006 
14 
0.84 
0.24 
0.014 


Novartis 
For business use only 
Page 34 
Final CSR SAP 
 
MEK116833 (CDRB436C2201) 
 
 
 
15 
0.91 
0.34 
0.028 
16 
0.95 
0.46 
0.053 
17 
0.97 
0.58 
0.092 
Using these sample sizes, a Bayesian design that allows the trial to be monitored more 
frequently at multiple stages was evaluated. A Bayesian analysis expresses uncertainty about a 
parameter in terms of probability. A prior is defined to characterize the level of knowledge 
about a parameter before the data are collected. Once the data are collected, a posterior 
distribution is formed using the prior and the likelihood (i.e., the data). Since none of the 
treatment has been tested previously in the clinic in the target population, a weak prior Beta 
(0.003, 0.007) is assumed. Thus, the posterior distribution for the response rate will be primarily 
driven by the data and can be derived as follows: Let p denote the response rate for the treatment, 
the number of responses in the current n patients, x, follows a binomial distribution, Binomial 
(n, p). Taking the Bayesian method and combining the weak prior and the likelihood of the 
observed data x, the posterior distribution of the response rate follows a beta distribution, i.e., 
p ~ Beta (0.003 + x, 0.007 + n-x) with the posterior mean (0.003 + x)/(0.01 + n). 
Based on this posterior distribution of the response rate, the predictive probability that the 
response rate >15% or ≥30% after 19 or 53 subjects will be calculated for decision- making. 
The decision rule and a minimal required sample size of 10 patients for the first interim look 
are determined to generate the design that leads to a reasonable chance of early termination due 
to futility. 
The design property, by utilizing the decision rule specified in [Section 5.1.2 of protocol], and 
sample size of 20 subjects or 54 subjects are shown (Table 3-4). The probability of early 
termination of the trial is calculated by simulations. The probability of early termination after 
the first 19 evaluable subjects is 33% under the null hypothesized response rate, and the risk to 
incorrectly stop the trial early if the drug is effective is approximately 5%. Thus, the study will 
employ the Bayesian design that allows the trial to be monitored more frequently at multiple 
stages with the constraint of satisfactory stop for futility rate. Bayesian model is designed for 
the futility analysis, and no Bayesian analysis will be performed in the final CSR. 
Table 3-4 
Bayesian Design Performance by Response Rate 
 
If True Response Rate to the 
Treatment is: (%) 
Probability (early stop for futility) 
after 19 subjects 
Probability (early stop for futility) 
after 53 subjects 
0.15 
0.326 
0.853 
0.2 
0.180 
0.483 
0.3 
0.043 
0.086 
4 
Appendix 
This section will be used for drafting CSR Appendix 16.1.9. 


Novartis 
For business use only 
Page 35 
Final CSR SAP 
 
MEK116833 (CDRB436C2201) 
 
 
 
4.1 
Imputation rules 
4.1.1 
Imputation of Partial Dates 
This section describes the rules to be used for imputation of partial dates.  
Imputed partial dates will not be used to derive study day, duration (e.g., duration of adverse 
events), or elapsed time variables. In addition, imputed dates are not used for deriving the last 
contact date in overall survival analysis dataset. 
With the exception of new anti-cancer start date on the Oncology time to event analysis dataset 
and exposure end date on the Exposure analysis dataset imputed dates will also not be stored 
on datasets.  
Imputed dates will not be displayed in listings. However, where necessary, display macros may 
impute dates as temporary variables for the purpose of sorting data in listings only. In addition 
partial dates may be imputed for ‘slotting’ data to study time periods or for specific analysis 
purposes as outlined below.  
The partial date imputation will follow ADaM conventions. The ADaM approach is to populate 
the numeric date variables with the imputed date and add a flag variable to the dataset that 
indicates the level of imputation.  
The flag variable can contain the values: blank, 'D', 'M', 'Y'. blank: indicates that no 
imputation was done 
D='Day': indicates that the day portion of the date is imputed 
M='Month': indicates that the month and day portions of the date are imputed 
Y='Year': indicates that the entire date (year, month, and day) is imputed 
Example of Date Variables:  
XYZD_ - character date variable 
XYZDT - numeric date variable 
XYZDTFL - flag variable 
Details on imputing partial dates for specific datasets are outlined below. 
4.1.1.1 
Adverse Events (AE): 
Imputations in the adverse events dataset are used for slotting events to the appropriate study 
time periods and for sorting in data listings. 
Dataset Date Missing 
Element 
Rule 
Adverse 
Events 
(AE) 
Start 
Date 
day, 
month, 
and year 
 No Imputation for completely missing dates 
 
 
day, 
month 
 If study treatment start date is missing (i.e. subject did not 
start study treatment), then set start date = January 1. 


Novartis 
For business use only 
Page 36 
Final CSR SAP 
 
MEK116833 (CDRB436C2201) 
 
 
 
Dataset Date Missing 
Element 
Rule 
 Else if study treatment start date is not missing:  
o If year of start date = year of study treatment start 
date then  
 
If stop date contains a full date and stop 
date is earlier than study treatment start 
date then set start date = January 1.  
 
Else set start date = study treatment start 
date.  
o Else set start date = January 1. 
 
 
day 
 If study treatment start date is missing (i.e. subject did not 
start study treatment), then set start date = 1st of month.  
 Else if study treatment start date is not missing:  
o If month and year of start date = month and year of 
study treatment start date then  
 
If stop date contains a full date and stop 
date is earlier than study treatment start 
date then set start date= 1st of month.  
 
Else set start date = study treatment start 
date. 
o Else set start date = 1st of month. 
 
End 
Date 
 
 No imputation for partial end dates will be performed 
 
4.1.1.2 
Anti-Cancer Therapy and Radiotherapy 
Start and end dates are generally not imputed. If start or end dates need to be imputed for an 
analysis (e.g., to calculate duration or elapsed time as covariates for efficacy analyses), the 
rules for imputation will be defined within the algorithm of the derived covariate. 
Additionally, post treatment anti-cancer therapy and radiotherapy start dates may be imputed 
to determine date of new anti-cancer therapy. In this case only, the date of new anti-cancer 
therapy (not all anti-cancer therapy and radiotherapy start dates) will be stored on appropriate 
efficacy datasets. Imputed partial dates will not be used to derive time since most recent prior 
therapy. In addition, the cancer therapy treatment status variable, and not any variables that 
use imputed partial dates, will be used to differentiate prior and follow-up anti-cancer therapy 
and radiotherapy.  
 
Dataset 
Date 
Missing 
Element 
Rule 
Anti-Cancer 
Therapy  
Start 
day, 
month, 
 
No Imputation for completely missing dates 


Novartis 
For business use only 
Page 37 
Final CSR SAP 
 
MEK116833 (CDRB436C2201) 
 
 
 
Dataset 
Date 
Missing 
Element 
Rule 
 
Radiotherapy  
Date 
and year 
 
 
day, 
month 
 
If partial date contains a year only set to January 
1st. 
 
 
day 
 
If partial date contains a month and year set to the 
1st of the month. 
 
End 
Date 
 
 
No imputation for partial end dates will be 
performed 
 
4.1.1.3 
Concomitant Medication and Blood and Blood Supportive Care 
Products 
Impute start and end dates for use in derivation of the reference variables concomitant 
medication start and end relative to treatment and blood and blood supportive care start and 
end relative to treatment, but do not permanently store the imputed start and end dates in the 
analysis datasets. The reference variables will be used to differentiate before, during and after 
for the concomitant medication or blood or blood supportive care start and end dates. The 
derived time in relation to treatment variables are not needed for reporting of these data. 


Novartis 
For business use only 
Page 38 
Final CSR SAP 
 
MEK116833 (CDRB436C2201) 
 
 
 
Dataset 
Date 
Missing 
Element 
Rule 
Concomitant 
Medication 
 
Start 
Date 
day, 
month, 
and year 
 
No Imputation for completely missing dates 
 
 
day, 
month 
 
If study treatment start date is missing (i.e. subject 
did not start study treatment), then set start date = 
January 1.  
 
Else if study treatment start date is not missing:  
o If year of start date = year of study 
treatment start date then  
 
If stop date contains a full date and 
stop date is earlier than study 
treatment start date then set start 
date = January 1.  
 
Else set start date = study treatment 
start date.  
o Else set start date = January 1. 
 
 
day 
 
If study treatment start date is missing (i.e. subject 
did not start study treatment), then set start date = 
1st of month.  
 
Else if study treatment start date is not missing:  
o If month and year of start date = month and 
year of study treatment start date then  
 
If stop date contains a full date and 
stop date is earlier than study 
treatment start date then set start 
date= 1st of month.  
 
Else set start date = study treatment 
start date. 
o Else set start date = 1st of month. 
 
End 
Date 
day, 
month, 
and year 
 
No Imputation for completely missing dates 
 
 
day, 
month 
 
If partial end date contains year only, set end date 
= earliest of December 31 or date of last contact.  
 
 
day 
 
If partial end date contains month and year, set end 
date = earliest of last day of the month or date of 
last contact (MSTONE.LCONTDT). 
 


Novartis 
For business use only 
Page 39 
Final CSR SAP 
 
MEK116833 (CDRB436C2201) 
 
 
 
4.1.2 
Imputation of Missing Exposure End Dates 
For subjects with missing exposure end dates at the time of data cutoff, the exposure end date 
will be imputed to the earliest of: the date of the data cutoff, the date of withdrawal from the 
study, or the death date. The imputed exposure end date will be used to calculate cumulative 
dose and exposure duration. The imputed exposure end date will be stored in the exposure 
analysis dataset and an exposure end date imputation flag variable will be derived indicating 
which exposure end date records are imputed. Imputed exposure end dates will also be stored 
on the study treatment end date variable. 
4.2 
AEs coding/grading 
Adverse events are coded using the Medical dictionary for regulatory activities (MedDRA) 
terminology. 
Note: The latest available MedDRA version at the time of the analyses should be used. The 
MedDRA version used will be specified in the footnote of relevant tables.   
AEs will be assessed according to the Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0.3. 
The CTCAE represents a comprehensive grading system for reporting the acute and late effects 
of cancer treatments. CTCAE grading is by definition a 5-point scale generally corresponding 
to mild, moderate, severe, life threatening, and death. This grading system inherently places a 
value on the importance of an event, although there is not necessarily proportionality among 
grades (a grade 2 is not necessarily twice as bad as a grade 1). The CTCAE grade of 5 (death) 
is used for death due to an AE; ‘fatal’ is collected as AE outcome and all death information is 
also collected on a separate (e) CRF page (DTH). 
4.3 
Laboratory parameters derivations 
Grade categorization of lab values will be assigned programmatically as per NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03. The calculation of CTCAE 
grades will be based on the observed laboratory values only, clinical assessments will not be 
taken into account.  
For laboratory tests where grades are not defined by CTCAE v4.03, results will be graded by 
the low/normal/high (or other project-specific ranges, if more suitable) classifications based on 
laboratory normal ranges. 
A severity grade of 0 will be assigned for all non-missing lab values not graded as 1 or higher. 
For laboratory tests that are graded for both low and high values, summaries will be done 
separately and labelled by direction, e.g., sodium will be summarized as hyponatremia and 
hypernatremia. 


Novartis 
For business use only 
Page 40 
Final CSR SAP 
 
MEK116833 (CDRB436C2201) 
 
 
 
4.4 
Statistical models 
4.4.1 
Primary analysis 
 
Overall response rate  
Responses will be summarized in terms of percentage rates with 95% CIs. An exact binomial 
confidence interval (implemented using SAS procedure FREQ with EXACT statement for one-
way tables) will be calculated [Clopper and Pearson 1934].  
SAS procedure FREQ will be used to estimate the proportion of responders (binary outcome = 
1 or “Yes”), along with the associated 95% (=100 × (1 – two-sided alpha level)) two-sided 
Pearson-Clopper CI. 
4.4.2 
Secondary analysis 
 
Kaplan-Meier estimates 
An estimate of the survival function in each drug combination will be constructed using 
Kaplan-Meier (product-limit) method as implemented in PROC LIFETEST with 
METHOD=KM option. The 
PROC 
LIFETEST 
statement 
will 
use 
the 
option 
CONFTYPE=LOGLOG. 
Median survival for each treatment drug combination will be obtained along with 95% 
confidence intervals calculated from PROC LIFETEST output using the method of 
[Brookmeyer and Crowley 1982]. Kaplan-Meier estimates of the survival function with 95% 
confidence intervals at specific time points will be summarized. The standard error of the 
Kaplan-Meier estimate will be calculated using Greenwood’s formula [Collett 1994]. 
5 
Reference 
Bailey S, Neuenschwander B, Laird G, Branson M. A Bayesian case study in oncology phase I 
combination dose-finding using logisitic regression with covariates. J Biopharm Stats. 2009; 19 
(3):469-484. 
Brookmeyer R and Crowley J (1982). A Confidence Interval for the Median Survival Time. 
Biometrics, 38, 29 - 41. 
Bokemeyer C, Bondarenko I, Makhson A, et al. Fluorouracil, leucovorin, and oxaliplatin with 
and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol 
2009; 27(5):663-671. 
Clopper CJ and Pearson PS, The Use of Confidence or Fiducial Limits Illustrated in the Case 
of the Binomial, Biometrika, 1934, Vol. 26 (4) pp. 404-413 


Novartis 
For business use only 
Page 41 
Final CSR SAP 
 
MEK116833 (CDRB436C2201) 
 
 
 
DeRoock W, Jonker DJ, Di Nicolantonio F, et al. Association of KRAS p.G13D mutation with 
outcome in patients with chemotherapy-refractory metastatic colorectal cancer treated with 
cetuximab. JAMA 2010; 304 (16):1812-1820.  
Green SJ, Dahlberg S. Planned versus attained design in phase II clinical trials. Stat Med; 1992. 
11(7):853-862.  
Hauschild A, Grob J-J, Demidov LV, et al. Dabrafenib in BRAF-mutated metastatic melanoma: 
a 
multicentre, 
open-label, 
phase 
3 
randomised 
controlled 
trial. 
Lancet 
2012. 
www.thelancet.com Published online June 25, 2012  
Lee JJ, Liu DD. A predictive probability design for Phase II cancer clinical trials. Clin Trials. 
2008. 5(2):93-106. 
Peeters M, Price TJ, Cervantes A, et al. Randomized phase III study of panitumumab with 
fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second 
line treatment in patients with metastatic colorectal cancer. J Clin Oncol 2010; 28(31): 4706-
4713.