Clinical trial NCT02296112
Conditions: Recurrent Melanoma Stage IIIB Melanoma Stage IIIC Melanoma Stage IV Melanoma
Sponsor: Vanderbilt-Ingram Cancer Center
Start date: 2015-01-01; Completion date: 2021-04-16
Enrollment: 9 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies trametinib in treating patients with melanoma with v-Raf murine sarcoma viral oncogene homolog B (BRAF) non-V600 mutations that has spread to other places in the body. Trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine the clinical efficacy of trametinib in advanced BRAF nonV600mutation (MUT) melanoma ("high activity" group).

SECONDARY OBJECTIVES:

I. To characterize the safety of trametinib. II. To evaluate the progression-free survival (PFS) and overall survival (OS) of trametinib in advanced BRAF nonV600MUT melanoma.

TERTIARY OBJECTIVES:

I. To determine the clinical efficacy of trametinib in advanced BRAF nonV600MUT melanoma ("low activity/unknown" group).

II. Identify mechanisms of resistance to trametinib in this patient population.

OUTLINE:

Patients receive trametinib orally (PO) once daily (QD) on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 28 days.

Arms: arm 1: Patients receive trametinib PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: trametinib intervention 2: laboratory biomarker analysis intervention 3: pharmacological study
Intervention descriptions: intervention 1: Given PO intervention 2: Correlative studies intervention 3: Correlative studies

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
TITLE PAGE 
 
Division:  Worldwide Development 
Information Type: Clinical Protocol 
CONFIDENTIAL 
 
 
 
 
 
Title: 
[A Phase II Open-Label, Two-Arm Study of the MEK Inhibitor, 
Trametinib, To Investigate the Safety and Anti-Cancer Activity 
in Subjects with Melanoma with BRAF non-V600 Mutations] 
 
 
Compound 
Number(s): 
GSK1120212 
 
Vanderbilt-Ingram  
 
Cancer Center (VICC) 
 
 
Coordinating Center 
Protocol Number: 
 
VICC MEL 1457 
 
Development Phase: 
II 
 
 
Description: This study is a Phase II, open-label, multi-site two-arm study designed to 
determine the activity and safety of orally administered MEK inhibitor trametinib 
(GSK1120212), in subjects with melanoma harboring mutations in BRAF at locations 
other than codon 600 (BRAFnonV600MUT) or BRAF fusions.  The study will also 
evaluate the effect of therapy on tumor biomarkers.  All patients will receive trametinib 
2mg orally administered once daily. Cohort A will consist of subjects with melanoma 
harbouring mutations which have high or intermediate intrinsic catalytic activity and/or 
which previously been described sensitive to MEK inhibitors in pre-clinical and/or 
clinical studies (L597, K601E, G469A, E586K, F595L) as well as BRAF fusions. Cohort 
B will consist of subjects with melanoma harbouring mutations that have previously been 
shown to have low affinity for MEK phosphorylation and low intrinsic catalytic activity 
and/or low sensitivity to MEK inhibitors from previous studies (D594V, G466V, G496R 
etc), or for which the catalytic activity and effects on sensitization to MEK inhibitors is 
unknown. The primary endpoint is objective response rate to trametinib for patients in 
Cohort A; secondary endpoints include objective response rates in Cohort B, safety, 
progression free survival and overall survival in both treatment arms. 
 
Subject: MEK inhibitor, trametinib, GSK1120212, BRAFV600 wild type, BRAF non- 
V600 mutant, NRAS wild type, cutaneous melanoma 
 
Author(s):  Johnson, Douglas B; Flaherty Keith T; Sosman Jeffrey A; Davies, Michael 
A. 
 Copyright Novartis, 2015. All rights reserved. Unauthorized copying or use of this information is prohibited. 
 
 
 
 
 
 
Version Date: February 12, 2016 
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2 
 
 
 
 
 
 
COORDINATING CENTER / MEDICAL MONITOR INFORMATION PAGE 
 
Medical Monitor and Sponsor Contact Information: 
 
Role 
Name 
Day Time 
Phone 
Number 
After-hours 
Phone/Cell
/ Pager 
Number 
Fax Number Address 
Primary 
Medical 
Monitor 
Douglas B 
Johnson, 
MD  
 
Vanderbilt-Ingram Cancer 
Center 
2220 Pierce Ave. 777 PRB 
Nashville, TN 37232 
Secondary 
Medical 
Monitor 
 
Novartis 
One Health Plaza,  
East Hanover, NJ 07936 
 
 
Supporter   
 
 
National Comprehensive Cancer Network (NCCN) 
275 Commerce Drive, Suite 300 
 
 
 
 
 
Fort Washington, PA  19034 
 
 
 
 
 
 
 
 
Novartis 
 
 
 
One Health Plaza,  
 
 
 
East Hanover, NJ 07936 
 
Coordinating Center 
 
Vanderbilt-Ingram Cancer Center (VICC)  
 
 
 
 
Multi-Institutional Coordinating Office 
Phone: (615) 936-5770 
Facsimile:  (615) 875-0040 
 
Protocol Chair 
 
 
Douglas B Johnson, MD 
 
 
 
 
 
Vanderbilt-Ingram Cancer Center 
2220 Pierce Ave. 777 PRB 
Nashville, TN 37232 
 


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Regulatory Agency Identifying Number(s): 
 
Compound Number 
IND Number 
EudraCT Number 
GSK1120212 
Exempt 


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INVESTIGATOR PROTOCOL AGREEMENT PAGE 
 
Title: 
[A Phase II Open-Label, Two-Arm Study of the MEK Inhibitor, 
Trametinib, To Investigate the Safety and Anti-Cancer Activity in 
Subjects with Melanoma with BRAF non-V600 Mutations] 
Vanderbilt-Ingram  
 
Cancer Center (VICC) 
 
 
Coordinating Center 
Protocol Number: 
 
VICC MEL 1457 
 
 
• 
I confirm agreement to conduct the study in compliance with the protocol. 
 
• 
I acknowledge that I am responsible for overall study conduct. I agree to 
personally conduct or supervise the described clinical study. 
 
• 
I agree to ensure that all associates, colleagues and employees assisting in the 
conduct of the study are informed about their obligations. Mechanisms are in 
place to ensure that site staff receives the appropriate information throughout the 
study. 
 
Investigator Name: 
Investigator Address: 
Investigator Phone Number: 
 
Investigator Signature 
Date 


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TABLE OF CONTENTS 
 
PAGE 
 
LIST OF ABBREVIATIONS ........................................................................................... 9 
 
1. INTRODUCTION.................................................................................................... 12 
1.1. 
Background ................................................................................................ 12 
1.2. 
Trametinib................................................................................................... 13 
1.2.1. 
Trametinib Background................................................................ 13 
1.2.2. 
Pharmacokinetics of Trametinib in Humans ................................. 14 
1.2.3. 
Clinical Safety of Trametinib ........................................................ 14 
1.2.4. 
Clinical Activity of Trametinib ....................................................... 14 
1.3. 
Ration 
1.3.1. 
ale in population ............................................................................... 15 
Rationale for targeted therapy in BRAF nonV600EMUT 
melanoma.................................................................................... 15 
1.3.2. 
Rationale for study cohorts .......................................................... 15 
 
2. OBJECTIVES AND ENDPOINTS ........................................................................... 16 
 
3. INVESTIGATIONAL PLAN ..................................................................................... 17 
3.1. 
Discussion of Study Design and Study Schematic ...................................... 17 
3.2. 
Treatment Schedule ................................................................................... 19 
3.3. 
Genetic Analysis ......................................................................................... 19 
3.4. 
Product Dosing/Administration.................................................................... 19 
3.5. 
Rationale .................................................................................................... 20 
3.5.1. 
Rationale for Study ...................................................................... 20 
3.5.2. 
Rationale for Population............................................................... 20 
3.5.3. 
Rationale for Dose ....................................................................... 20 
3.5.4. 
Rationale for Endpoints................................................................ 20 
3.6. 
Study Treatment ......................................................................................... 21 
3.7. 
Dosage and Administration of Study Treatment .......................................... 21 
3.7.1. 
Meals and Dietary Restrictions .................................................... 21 
3.7.2. 
Blinding........................................................................................ 21 
3.8. 
Safety Management Guidelines .................................................................. 21 
3.8.1. 
Dose Levels of trametinib ............................................................ 22 
3.8.2. 
General Guidelines for Clinically Significant Toxicities ................. 22 
3.9. 
Dose Modification Guidelines for Trametinib Adverse Events of 
Special Interest ........................................................................................... 23 
3.9.1. 
Guidelines for Cardiovascular Adverse Events ............................ 23 
3.9.1.1. 
Left Ventricular Ejection Fraction (LVEF) .................... 23 
3.9.1.2. 
Hypertension .............................................................. 24 
3.9.2. 
Guidelines for Visual Changes ..................................................... 27 
3.9.3. 
Pneumonitis Management Guidelines.......................................... 29 
3.10. Dose Modifications for Trametinib and supportive care............................... 31 
3.10.1. 
Liver Chemistry Stopping Criteria ................................................ 31 
3.9.1.1. 
Liver Chemistry Follow-up Procedures ....................... 31 
3.10.2. 
Guidelines for Prolonged QTc...................................................... 33 
3.10.3. 
Guidelines for Rash ..................................................................... 34 
3.10.4. 
Guidelines for Diarrhea ................................................................ 35 


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4. INVESTIGATIONAL PRODUCT(S) ........................................................................ 37 
4.1. 
Description of Investigational Product and/or Comparators/Placebo ........... 37 
4.1.1. 
Trametinib.................................................................................... 37 
4.2. 
Preparation/Handling/Storage of Trametinib ............................................... 37 
4.3. 
Product Accountability ................................................................................ 37 
4.4. 
Treatment Compliance................................................................................ 38 
4.5. 
Treatment of Investigational Product Overdose .......................................... 38 
 
5. STUDY POPULATION ........................................................................................... 38 
5.1. 
Number of Subjects .................................................................................... 38 
5.2. 
Subject Selection Criteria............................................................................ 39 
5.2.1. 
Inclusion Criteria .......................................................................... 39 
5.2.2. 
Exclusion Criteria ......................................................................... 40 
 
6. 
CO MPLETION OR WITHDRAWAL OF SUBJECTS ............................................... 42 
6.1. 
Screen and Baseline Failures ..................................................................... 42 
6.2. 
Subject Completion Criteria ........................................................................ 42 
6.3. 
Permanent Discontinuation from Study Treatment ...................................... 42 
6.4. 
Study Completion ....................................................................................... 43 
6.5. 
Treatment after the End of the Study .......................................................... 43 
 
7. STUDY ASSESSMENTS AND PROCEDURES................................................... 44 
7.1. 
Time and Events Table ............................................................................... 44 
7.2. 
Demographic/Medical History and Baseline Assessments .......................... 48 
7.3. 
Safety Evaluations ...................................................................................... 49 
7.3.1. 
Physical Examinations ................................................................. 49 
7.3.2. 
ECOG Performance Status.......................................................... 49 
7.3.3. 
Vital Signs.................................................................................... 49 
7.3.4. 
Electrocardiogram (ECG)............................................................. 49 
7.3.5. 
Echocardiogram (ECHO) and/or Multi-gated Acquisition 
(MUGA) Scans............................................................................. 49 
7.3.6. 
Brain MRI and/or CT Scan ........................................................... 50 
7.3.7. 
Laboratory Assessments ............................................................. 50 
7.3.8. 
Ophthalmic Examination .............................................................. 51 
7.3.9 
Pregnancy Testing and Reporting ................................................ 52 
7.4. 
Baseline documentation of target and non-target lesions ............................ 52 
7.5. 
Efficacy ....................................................................................................... 53 
7.5.1. 
Assessment Guidelines ............................................................... 54 
7.5.2. 
Measurable and Non-measurable Definitions......................................55 
7.5.3. 
Response Criteria ........................................................................ 56 
7.5.3.1. 
Target Lesions............................................................ 56 
7.5.3.2. 
Non-Target Lesions .................................................... 57 
7.5.3.3. 
New Lesions............................................................... 57 
7.5.3.4. 
Evaluation of overall response.................................... 58 
7.5.3.5. 
Evaluation of best overall response ............................ 58 


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7.6. 
Translational Research ............................................................................... 59 
7.6.1. 
Tumor Tissue for Genetic and Protein Biomarker Analysis .......... 60 
7.6.2. 
Blood Biomarkers ........................................................................ 61 
 
8. ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS..................................... 61 
8.1. 
Definition of an AE ...................................................................................... 61 
8.2. 
Definition of an SAE.................................................................................... 62 
8.2.1. 
Sentinel Events............................................................................ 63 
8.3. 
Laboratory and Other Safety Assessment Abnormalities Reported 
as AEs and SAEs ....................................................................................... 64 
8.3.1. 
Cardiovascular Events ................................................................. 64 
8.4. 
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as SAEs ..................................................................................... 64 
8.5. 
Time Period and Frequency of Detecting AEs and SAEs ............................ 65 
8.5.1. 
Prompt Reporting of SAEs and Other Events to Vanderbilt 
.................. 65 
8.5.2. 
Regulatory reporting requirements for SAEs ................................ 67 
 
9. LIVER CHEMISTRY FOLLOW-UP PROCEDURES ............................................... 67 
9.1. 
Liver Chemistry Testing Procedures ........................................................... 67 
9.2. 
Liver Chemistry Monitoring Criteria ............................................................. 69 
9.3. 
Drug Restart/Rechallenge Following Liver Events that are Possibly 
Related to Study Drug(s) ............................................................................ 69 
9.4. 
Drug Restart Following Transient, Resolving Liver Events Not 
Related to Study Drug(s) ............................................................................ 70 
 
10.  CONCOMITANT MEDICATIONS AND NON-DRUG THERAPIES ......................... 71 
10.1. Permitted Medication(s) .............................................................................. 71 
10.2. Prohibited Medications and Non-Drug Therapies........................................ 71 
 
11.  LIFESTYLE AND/OR DIETARY RESTRICTIONS .................................................. 72 
11.1. Contraception ............................................................................................. 72 
11.1.1. 
Female Subjects .......................................................................... 72 
11.1.2. 
Male Subjects .............................................................................. 73 
11.2. Lactation Restrictions.................................................................................. 73 
 
12.  DATA MANAGEMENT ........................................................................................... 73 
 
13.  DATA ANALYSIS AND STATISTICAL CONSIDERATIONS................................... 74 
13.1. Hypotheses................................................................................................. 74 
13.2. Sample Size Assumptions .......................................................................... 74 
13.3. Data Analysis Considerations ..................................................................... 75 
13.3.1. 
Interim Analysis ........................................................................... 75 
13.3.2. 
Final Analysis .............................................................................. 75 
13.3.2.1. Primary Analysis......................................................... 75 
13.3.2.2. Secondary Analyses ................................................... 75 
13.3.2.2.1.Cohort B ........................................................... 75 
13.3.2.2.2.Survival............................................................. 76 
13.3.2.2.3. Safety .............................................................. 76 


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13.4.1. 
Pharma odynamic Analyses........................................................ 78 
13.4.1. 
Translational Research Analyses ............................... 78 
13.4.2. 
Novel Biomarker Assays ............................................ 78 
 
 
13.3.2.2.2. Biomarkers and Pharmacodynamic 
Analysis...............................................................................76 
13.3.3. 
Accrual Considerations ................................................................ 77 
13.3.4. 
Missing Data ................................................................................ 77 
13.3.5. 
Protocol Violations ....................................................................... 77 
13.3.6. 
Derived and Transformed Data .................................................... 77 
13.3.7. 
Assessment Windows.................................................................. 77 
13.3.8. 
Other Issues ................................................................................ 77 
13.4. Other Elements of Analysis Plan................................................................. 77 
c 
 
 
 
 
14.  STUDY CONDUCT CONSIDERATIONS ............................................................... 78 
14.1. Posting of Information on Clinicaltrials.gov.................................................. 78 
14.2. Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................78 
14.3. Urgent Safety Measures ............................................................................. 79 
14.4. Quality Control (Study Monitoring) .............................................................. 80 
14.5. Quality Assurance....................................................................................... 80 
14.6. Study and Site Closure ............................................................................... 81 
14.7. Records Retention ...................................................................................... 81 
14.8. Provision of Study Results to Investigators, Posting of Information 
on Publicly Available Clinical Trials Registers and Publication .................... 82 
 
15.  REFERENCES....................................................................................................... 83 
 
APPENDICES ............................................................................................................... 85 
Appendix 1:   BRAF Mutations by Cohort ............................................................... 85 
Appendix 2 :  NYHA Functional Classification System............................................ 86 
Appendix 3 :  COCKCROFT-GAULT FORMULA.................................................... 87 
Appendix 4:  ECOG Performance Status................................................................ 88 
Appendix 5 :  Liver Safety Drug Restart Guidelines ................................................ 89 
Appendix 6 :  QT interval on electrocardiogram corrected using the Bazett’s 
formula (QTcB) ........................................................................................... 92 
Appendix 7 :  Medication Diary................. 93 


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LIST OF ABBREVIATIONS 
 
AE(s) 
Adverse Event(s) 
AJCC 
American Joint Committee on Cancer 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
ANOVA 
Analysis of Variance 
AST 
Aspartate aminotransferase 
AUC(0-∞) 
Area under the concentration-time curve from time zero (pre-dose) 
extrapolated to infinite time 
AUC(0-x) 
Area under the concentration-time curve from zero (pre-dose) to some 
fixed nominal time x 
AUC(0-t) 
Area under the concentration-time curve from time zero (pre-dose) to 
last time of quantifiable concentration within a subject across all 
treatments 
AUC(0-τ) 
Area under the concentration-time curve over the dosing interval 
β-HCG 
Beta-Human Chorionic Gonadotropin 
BP 
Blood pressure 
BPM 
Beats per minute 
BUN 
Blood urea nitrogen 
CBC 
Complete blood count 
CfDNA 
Circulating cell free DNA 
CI 
Confidence Interval 
CL 
Systemic clearance of parent drug 
CL/F 
Apparent clearance following oral dosing 
Cmax 
Maximum observed concentration 
Cmin 
Minimum observed concentration 
Cτ 
Pre-dose (trough) concentration at the end of the dosing interval 
CO2 
Carbon dioxide 
CPK 
Creatine phosphokinase 
CPMS 
Clinical Pharmacokinetic Modeling and Simulation 
CPSR 
Clinical Pharmacology Study Report 
CR 
Complete response 
CRO 
Contract Research Organization 
CRU 
Clinical Research Unit 
CSR 
Clinical Study Report 
CTA 
Clinical Trial Authorization 
CTR 
Clinical Trial Registry 
CV 
Coefficient of variance 
DBP 
Diastolic blood pressure 
DILI 
Drug Induced Liver Injury 
DLT 
Dose-limiting toxicity 
DMPK 
Drug Metabolism and Pharmacokinetics 
DNA 
Deoxyribonucleic acid 
ECG(s) 
Electrocardiogram(s) 
ECHO 
Echocardiogram 


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ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
FDA 
Food and Drug Administration 
FTIH 
First time in humans 
GCP 
Good Clinical Practice 
GCSP 
Global Clinical Safety and Pharmacovigilance 
GGT 
Gamma glutamyltransferase 
HBsAg 
Hepatitis B surface antigen 
HIV 
Human Immunodeficiency Virus 
h/hr 
Hour(s) 
HR 
Heart rate 
HRT 
Hormone replacement therapy 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonization 
IDMC 
Independent Data Monitoring Committee 
IDSL 
International Data Standards Library 
IgM 
Immunoglobulin M 
IHC 
Immunohistochemistry 
IMP 
Investigational Medicinal Product 
IND 
Investigational New Drug 
INR 
International normalization ratio 
IP 
Investigational Product 
IRB 
Institutional Review Board 
IRC 
Independent Review Committee 
IU 
International Unit 
IV 
Intravenous 
IVRS 
Interactive voice response system 
Kg 
Kilogram 
L 
Liter 
LFTs 
Liver function tests 
LLN 
Lower limit of normal 
Ln 
Naperian (natural) logarithm 
LOQ 
Limit of quantification 
LLQ 
Lower limit of quantification 
LSLV 
Last subject’s last visit 
LVEF 
Left Ventricular Ejection Fraction 
µg 
Microgram 
µL 
Microliter 
MedDRA 
Medical Dictionary for Regulatory Activities 
Mg 
Milligrams 
mL 
Milliliter 
MRS 
Magnetic resonance spectroscopy 
MRT 
Mean residence time 
MSDS 
Material Safety Data Sheet 


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Msec 
Milliseconds 
MTD 
Maximum tolerated dose 
MUGA 
Multigated  (radionuclide) angiogram 
NCI-CTCAE 
National Cancer Institute - Common Terminology Criteria for Adverse 
Events 
NYHA 
New York Heart Association 
PD 
Progressive disease or pharmacodynamic 
PFS 
Progression-free survival 
PGx 
Pharmacogenetics 
PK 
Pharmacokinetic 
PR 
Partial response 
QC 
Quality control 
QTc 
Corrected QT interval duration 
QTcB 
QT interval corrected for heart rate by Bazett’s formula 
QTcF 
QT interval corrected for heart rate by Fridericia’s formula 
RAMOS 
Registration and Medication Ordering System 
RAP 
Reporting and Analysis Plan 
RBC 
Red blood cells 
RCR 
Recommended Combination Regimen 
RNA 
Ribonucleic acid 
RPED 
Retinal Pigment Epithelial Detachment 
RVO 
Retinal Vein Occlusion 
SAE 
Serious adverse event(s) 
SAS 
Statistical Analysis Software 
SD 
Standard deviation or stable disease 
SOP 
Standard Operating Procedure 
T 
Time of last observed quantifiable concentration 
t1/2 
Terminal phase half-life 
Τ 
Dosing interval 
Tlag 
Lag time before observation of drug concentrations in sampled matrix 
Tmax 
Time of occurrence of Cmax 
ULN 
Upper limit of normal 
UK 
United Kingdom 
UPC 
Urine protein creatinine 
US/USA 
United States/United States of America 
Vd/F 
Apparent volume of distribution after extravascular (e.g., oral) 
administration 
VICC 
Vanderbilt-Ingram Cancer Center 
WBC 
White blood cells 
 
Trademark Information 
 
 
Trademarks of the Novartis group of 
companies 
 
Mekinist 


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Version Date: February 12, 2016 
12 
 
 
 
 
1. 
INTRODUCTION 
 
1.1. 
Background 
 
Cutaneous melanoma is the most aggressive form of all skin cancers.  Worldwide, it is 
currently expected that approximately 132,000 people will be diagnosed with melanoma 
each year and some 37,000 people are expected to die of the disease annually.  Untreated, 
the median survival time for patients with Stage IV melanoma is approximately 6 months 
with 26% of subjects alive at 1-year (Korn 2008); the estimated 5-year survival rate is < 
10% (Huncharek 2001).  Median progression-free survival (PFS) is also short at 1.7 
months and only 14.5% of subjects are progression-free at 6 months (Korn 2008). 
 
Much has changed in the treatment landscape of cutaneous melanoma recently, but with 
the exception of ipilimumab, significant advancements have been made exclusively for 
patients with mutations in a specific locus of the BRAF protein (BRAFV600) that causes 
constitutive activation of the RAS/RAF/MEK/ERK (MAPK) pathway. BRAF is part of 
the RAS/RAF/MEK/ERK (MAPK) pathway, which is a critical proliferation pathway in 
melanoma.  Normally, the MAPK pathway is activated by the binding of extracellular 
growth factors to membrane-bound growth factor receptors which then recruit 
intracellular proteins to the cell membrane, leading to the activation of the small 
guanosine triphosphate (GTP)-binding protein RAS.  As a result, RAS adopts an 
activated conformation which in turn activates RAF, which phosphorylates MEK on two 
regulatory serine residues.  Activated MEK then phosphorylates threonine and tyrosine 
residues on its only known substrates, the MAP kinases ERK1 and ERK2. 
Phosphorylated ERK dimerizes and translocates to the nucleus, where it plays a critical 
role in cellular proliferation, nuclear transport, deoxyribonucleic acid (DNA) repair, 
messenger ribonucleic acid processing, and translation. 
 
Approximately 40% of cutaneous melanomas harbor a BRAFV600 mutation (BRAF 
V600MUT). These mutations increase the intrinsic serine-threonine kinase activity of the 
BRAF protein (Davies 2002). The presence of a BRAF V600MUT in a melanoma 
correlates with increased activity of, and functional dependence upon, the MAPK 
pathway. Most importantly, the presence of BRAF V600MUT also correlates with clinical 
benefit in patients to treatment with small molecule inhibitors of the V600-mutant BRAF 
protein and MEK inhibitors. Vemurafenib (BRAFi, Genentech), dabrafenib (BRAFi, 
GlaxoSmithKline), and trametinib (MEKi, GlaxoSmithKline) have all gained regulatory 
approval for the treatment of stage IV or unresectable stage III melanoma patients with 
BRAF V600MUT melanoma. However, these agents are not approved for use in patients 
without a mutation. As these patients represent > 50% of cutaneous melanoma patients, 
and a much higher proportion of patients with non-cutaneous melanomas, there is a 
critical need to identify additional effective therapeutic approaches. 
 
Approximately 5% of all melanomas harbour mutations in BRAF in loci other than V600 
(BRAF nonV600 MUT).  These mutations are often not detected by many testing platforms 
which are commonly used in clinical practice that assess only codon 600.  However, they 
are detected by testing platforms that assess for other regions of the BRAF gene that are 
known to be affected by somatic mutations, as well as platforms that sequence the entire 
BRAF gene.  Many of these BRAF nonV600 MUT result in increased kinase activity of the 


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13 
 
 
 
 
BRAF protein in vitro (“high activity group” including L597V, K601E, G469A) (Wan 
2004). In addition, other mutations that do not increase the catalytic activity of BRAF 
(“low activity/unknown” group, including G466E, D594V, G596R) (Wan 2004) appear 
to be able to increase MAPK pathway activity through protein-protein interactions with 
other components of this pathway. Furthermore, BRAF fusions have been recently 
identified in a small percentage of melanomas which activate MAPK signaling (Botton 
2013; Hutchinson 2013). MEK inhibitors have demonstrated activity in vitro in 
melanomas with high activity non-V600 BRAF mutations and individual patients with 
these mutations have demonstrated significant clinical responses to treatment with MEK 
inhibitors. Thus, MEK inhibitors may have value as a targeted therapy in this population. 
Although there is evidence that low-activity BRAF mutations activate MEK and ERK 
signaling, the clinical benefit of MEK inhibition in melanomas with such mutations is 
poorly defined. In addition, multiple somatic mutations in BRAF have been identified 
that have yet to be functionally characterized (Wan 2004). 
 
1.2. 
Trametinib 
 
1.2.1. 
Trametinib Background 
 
Trametinib is a potent, highly selective, allosteric inhibitor of MEK1 and MEK2, is non- 
competitive towards ATP, and inhibits both MEK activation and kinase activity. 
Trametinib interferes with cellular signal transduction and induces apoptosis in human 
tumor cell lines both in vitro and in xenograft mouse models. Activity was most 
extensive in cell lines and models that contained activating BRAF mutations (Gilmartin 
2011; Jing 2012). 
 
Trametinib was first dosed in humans in 2008 in MEK111054 (Infante 2012). This first- 
in-human study identified the recommended monotherapy dose for trametinib (2 mg once 
daily continuous dosing); established the safety, PK, and PD profiles; and demonstrated 
clinical activity in several tumor types including BRAFWT melanoma (Falchook 2012). 
As of 23 June 2012, trametinib has been administered to more than 1700 subjects in 20 
studies, including 10 monotherapy studies [Novartis, 2016. Trametinib was approved by 
the United States Food and Drug administration on 29 May 2013, under the brand name 
Mekinist, as a monotherapy in the setting of BRAFV600MUT melanoma. 
 
Trametinib has also been evaluated in combination with dabrafenib in BRAFV600MUT 
melanoma. In BRF113220, this combination appeared more efficacious than dabrafenib 
alone, prolonging progression-free survival and increasing objective response rates 
(Flaherty 2012) Although trametinib has been most extensively tested in BRAFV600MUT 
melanoma, studies combining trametinib with other antineoplastic molecules are opening 
in other melanoma subtypes. The study described here is the first study in which 
trametinib or any molecularly targeted therapy will be evaluated specifically in 
BRAFnonV600MUT melanoma. 


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1.2.2. 
Pharmacokinetics of Trametinib in Humans 
 
Peak plasma trametinib concentrations were observed 1.50 hours following single-dose 
administration of trametinib tablets under fasted conditions. The absolute oral 
bioavailability of the trametinib 2.0 mg tablet is moderate to high (72%) relative to a 
coadministered IV microdose [Novartis,  2016]. Trametinib is highly bound to plasma 
proteins (97.4%), has a high volume of distribution (Vd; 1060 L) and a long terminal 
half-life (5.3 days), and accumulates with repeat once daily dosing. 
 
The metabolism of trametinib has been investigated using a series of in vitro and in vivo 
studies.  Trametinib is metabolized via deacetylation to form M5 (deacetylation alone) 
and deacetylation in combination with mono-oxygenation to form M7 
(mono-oxygenation and deacetylation). M5 can be N-glucuronidated to form M6 
(N-glucuronidation of M5) while M7 undergoes O-glucuronidation to form M9 
(O-glucuronidation of M7), a minor pathway in humans. Trametinib is metabolized 
predominantly via deacetylation (non-CYP450 mediated) alone or with mono- 
oxygenation or in combination with glucuronidation biotransformation pathways. 
Although the specific enzyme responsible has not been identified, deacetylation is likely 
mediated by hydrolytic esterases, such as carboxyl-esterases or amidases. 
 
1.2.3. 
Clinical Safety of Trametinib 
 
The adverse events (AEs) observed in the pivotal, Phase III registration study (Flaherty 
2012) was consistent with that seen across trametinib monotherapy studies and is 
summarized here.  The Phase III study demonstrated that the 2 mg, continuous, once 
daily dose of trametinib has an acceptable safety profile. Adverse events occurring in 
≥15% of subjects that received at least one dose of trametinib (N=211) were rash (57%), 
diarrhea (43%), peripheral edema (26%), fatigue (26%), dermatitis acneiform (19%), 
nausea (18%), alopecia (17%), and hypertension (15%). Less than 8% of the subjects had 
grade 3 or 4 rash (including only one patient with grade 4), and no grade 3 or 4 diarrhea 
was observed.  Decreased ejection fraction or ventricular dysfunction occurred in 7% of 
the subjects, and <1% (n=2) had grade 3 cardiac-related events that were considered 
trametinib related and led to permanent discontinuation of the study treatment. Ocular 
events, most of which were grade 1 or 2, occurred in 9% of the subjects.  Blurred vision 
was the most frequent ocular event (4%), and there was one case of reversible 
chorioretinopathy. Retinal vein occlusion, an AE that has been associated with MEK 
inhibitors, was observed only extremely rarely.  Rash, diarrhea, visual disorders, hepatic 
disorders, cardiac-related AEs, and pneumonitis are considered AEs of special interest for 
trametinib because they are either known class effects (i.e. were observed with other 
MEK inhibitors) or are potentially life-threatening. 
 
 
1.2.4. 
Clinical Activity of Trametinib 
 
Trametinib has demonstrated significant clinical activity with an acceptable safety profile 
in Phase I-III studies (Falchook 2012; Flaherty 2012; Infante 2012; Kim 2013). In 
BRAFV600MUT melanoma, the Phase III study of trametinib demonstrated improved 
rates of progression-free survival and overall survival (Flaherty 2012).  In this study, 


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trametinib demonstrated an overall response rate of 22% and a median PFS of 4.8 
months.  The duration of response was 5.5 months. 
 
BRAFV600WT melanoma has been evaluated in the trametinib first-in-human study 
(Infante 2012). This study enrolled 39 subjects with BRAFV600WT cutaneous melanoma, 
of which 4 (10%) had confirmed objective responses (Falchook 2012). The median PFS 
for these 39 subjects was 2.0 months (95% CI 1.7-3.7 months; (Falchook 2012)). 
Subjects who were both BRAFV600WT and NRASWT (n=20) had a higher response rate 
(20%) than those who were wild type only at BRAF (n=11; response rate= 0%). 
Moreover, a higher proportion of patients that were wild type for both genes, compared to 
those that were wild type for only BRAF, were on study treatment at week 24 (40% 
versus 18%; p=0.26) and at 1 year (30% versus 0%; p=0.07).  Importantly, 2 patients 
with BRAFnonV600MUT melanoma (L597V and G469A) were treated in this study with 
one achieving a partial response and the other with temporary stabilization of melanoma 
growth (see section 1.3.1). These results demonstrate that trametinib has clinical activity 
in subgroups other than BRAFV600MUT melanoma. 
 
1.3 Rationale in study population 
 
1.3.1  Rationale for targeted therapy in BRAF nonV600MUT melanoma 
 
BRAF alterations in loci other than codon V600 occur in 4-6% of advanced melanomas 
in several published reports (Berger 2012; Dahlman 2012; Krauthammer 2012; Botton 
2013). Some of these recurrent alterations constitutively activate MAPK signaling and 
may be exploited therapeutically. Direct inhibition of mutant BRAF with vemurafenib or 
dabrafenib appears ineffective in this population, although modest in vitro activity and a 
brief partial response have been reported for vemurafenib (Dahlman 2012; Bahadoran 
2013). By contrast, in the preclinical setting and in occasional patients treated in clinical 
trials, MEK inhibition appears to be a more active therapeutic approach. For example, 
BRAF L597MUT and K601E MUT melanoma demonstrated in vitro sensitivity to trametinib 
(Dahlman 2012). 
 
Clinical corroboration has been demonstrated by several patients who have achieved a 
response to MEK inhibitors. For example, a patient with BRAF L597SMUT melanoma had 
a dramatic response to an experimental MEK inhibitor (TAK-733) (Dahlman 2012). 
Furthermore, in the phase I trial of trametinib, a patient with BRAF L597V MUT 
melanoma experienced a prolonged partial response and remained on study for more than 
2 years (Falchook 2012). An additional patient with a BRAF G469A mutation had a best 
response of stable disease. Finally, in a trametinib phase II study, a patient with BRAF 
K601E MUT melanoma experienced a prolonged partial response (Kim 2013). MEK 
inhibition in this population has not been studied in a systematic fashion and has never 
been evaluated prospectively. There is strong rationale to systematically evaluate MEK 
inhibition in the BRAF nonV600EMUT melanoma population as this is a significant 
subgroup without current approved targeted therapy options. 
 
1.3.2  Rationale for study cohorts 
 
Subjects with BRAF nonV600EMUT melanoma may be further classified by the functional 
effects of each particular mutation on BRAF kinase activation and subsequent MEK 


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phosphorylation. All well-characterized BRAF mutations in the kinase domain activate 
MAPK signaling, although the mechanisms vary. Many of the more common mutations, 
including V600, L597, K601 (see appendix 1 for full mutation list), robustly activate 
MAPK signaling through MEK phosphorylation and are predicted to be sensitive to MEK 
inhibition (Cohort A, “high activity”) (Wan 2004). However, other observed mutations 
including G469E and D594G may signal through other effectors which may confer 
resistance to MEK inhibition, although the clinical experience with these melanomas is 
extremely limited (Smalley 2009). Together with additional mutations of unclear 
significance, (including S467L and P731S), we have labelled this group as cohort B, the 
“low activity/unknown” group. Additionally, BRAF nonV600 mutations may occur 
coincidentally with activating NRAS or BRAF V600E mutations. The functional 
significance of these mutations is not clear. It is hypothesized that these play a secondary 
role in these tumors; therefore these patients will not be included in our study. 
 
Insight into the relative frequencies of these groups can be obtained from a large group of 
melanomas which were subjected to whole exon sequencing as part of the melanoma 
TCGA effort. Among the first 266 tumors, all of which were primaries or metastases of 
non-acral cutaneous melanomas, 17 (6.3%) harbored somatic BRAF nonV600 
mutations and were NRASWT and BRAF V600WT. Of these, 10 (3.8%) could be classified 
as “high activity,” with the additional 7 melanomas (2.6%) in the “low activity/unknown” 
group (3 with low activity, 4 with unknown activity). Our primary study group of 
interest is cohort A: the “high activity” group, as there is known pre-clinical and clinical 
rationale to study this population. However, there may be additional patients who will 
benefit from trametinib in the “low activity/unknown” group (cohort B); therefore this 
group will also be eligible to receive therapy in an exploratory fashion. 
 
Approximately 1% of melanomas harbor fusions in the BRAF gene. (Botton 2013; 
Hutchinson 2013). These rearrangements fuse the BRAF kinase domain with a partner 
gene which leads to constitutive activation of the MAPK pathway. BRAF fusions are a 
frequent recurrent event in pilocytic astrocytomas and other cancers and were recently 
identified in melanoma and melanocytic tumors (Ciampi 2005; Jones 2008; Palanisamy 
2010).  BRAF fusion melanoma appears to confer resistance to vemurafenib. By contrast, 
trametinib strongly inhibited MAPK signaling in vitro and is predicted to have clinical 
activity in BRAF fusions (Hutchinson 2013). Therefore, patients with identified BRAF 
fusions will be included in cohort A. 
 
2. 
OBJECTIVES AND ENDPOINTS 
Table 1 lists the objectives and corresponding endpoints. 
Table 1 
 
Objectives and Endpoints 
 
Objectives 
Endpoints 
Primary 
1. To determine the clinical efficacy of 
trametinib in advanced BRAF 
nonV600MUT melanoma (“high 
activity” group) 
1. Overall response rate (primary statistical 
endpoint), duration of 
response, clinical benefit (CR+PR+SD) 
per RECIST v. 1.1. 
Secondary 
1. To characterize the safety of 
trametinib 
2. To evaluate the  
1. Safety and tolerability as measured by 
clinical assessments including vital signs 
and physical examinations, 12-lead 


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time to progression (TTP) and overall 
survival 
(OS) of trametinib in advanced 
BRAF nonV600MUT melanoma 
electrocardiograms (ECG), 
echocardiogram (ECHO) or Multi Gated 
Acquisition (MUGA) scans, chemistry 
and hematology laboratory values, and 
adverse events (AEs). 
2. TTP and overall survival. 
Exploratory 
1. To determine the clinical efficacy of 
trametinib in advanced BRAF 
nonV600MUT melanoma (“low 
activity/unknown” group) 
2. Identify mechanisms of resistance to 
trametinib in this patient population 
1. Overall response rate, duration of 
response, clinical benefit (CR+PR+SD) 
per RECIST v. 1.1. 
2. Assess molecular characteristics of 
patient samples, including archival 
samples, pre-treatment, early while on 
treatment, and/or at the time of 
progression 
 
 
 
 
3. 
INVESTIGATIONAL PLAN 
 
3.1. 
Discussion of Study Design and Study Schematic 
 
This is a Phase II, open-label, multi-center study in subjects with advanced 
BRAFnonV600MUT melanoma stratified by activity of genetic alterations. Cohort A will 
be patients with “high activity” BRAF mutations or BRAF fusion events (see appendix 
A); cohort B is an exploratory group with BRAF mutations of “low activity/unknown” 
significance. The study is designed to evaluate the response rate to trametinib at the dose 
approved by the Food and Drug Administration (FDA) for BRAF V600 MUT melanoma in 
the BRAFnonV600MUT population. Safety will also be assessed. 
 
Figure 1: Study Schematic 
 
 
Subjects with advanced melanoma 
with no BRAF V600 mutations, 
and no mutations in NRAS codons 
12, 13, and 61 
 
 
 
 
 
Screen for BRAF nonV600 mutation 
 
 
 
 
 
 
 
If mutation positive, screen for 
enrollment 


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18 
 
 
 
 
 
 
 
 
 
Register with the Vanderbilt-Ingram Cancer Center (VICC) 
Multi-Institutional Coordinating Office 
 
 
 
 
 
 
 
Enroll in trial with trametinib 2mg once daily in either Cohort 
A (“high activity”) or Cohort B (“low activity/unknown”) 
 
 
 
Protocol waivers or exemptions are not allowed.  Therefore, adherence to the study 
design requirements, including those specified in the Time and Events Table (see Section 
7.1), are essential. 
 
 
 
Enrollment Procedures 
All patients MUST be registered with the Vanderbilt-Ingram Cancer Center (VICC) Multi-
Institutional Coordinating Office prior to the start of protocol treatment. Each participating 
site must also be registered with their own institution according to their institutional 
guidelines prior to start of protocol treatment.  Prior to the first patient registration, a copy 
of IRB approval at the respective sites will be requested and on file at the VICC 
Coordinating Center.  
 
Patients will be centrally registered by sending the completed enrollment packet to the 
VICC Multi-Institutional Coordinating Office as outlined in the instructions provided on the 
enrollment form. The enrollment packet must include the following documents:   
 
• Copy of the patient’s signed and dated Informed Consent  
• Eligibility Checklist 
• Coordinating Center enrollment form 
  
 
 
 
3.2. 
Treatment Schedule 
 
The dose and schedule of trametinib is 2.0 mg administered orally once daily. Alterations 
to the dose and schedule of trametinib may be incorporated based on toxicity for 
individual patients. However, the dose level and schedule will not exceed 2.0 mg once 
daily. Dosing with start with Treatment period 1, Day 1 and the subject may continue 
treatment with trametinib until the Treatment Discontinuation Criteria are met (Section 


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19 
 
 
6.3). 
 
3.3. 
Genetic Analysis 
 
Prior to enrolment, subjects will be required to provide archived tumor tissue or undergo 
tumor biopsy if archived tumor tissue is not available. Evaluation of BRAF mutational 
status may be performed at any laboratory with Clinical Laboratory Certification 
Amendment (CLIA) certification status. Most commonly performed diagnostics of BRAF 
mutations assess only mutations found at codon 600. Therefore, BRAF nonV600 
mutations will likely be identified by either next generation sequencing methods (for 
example, FoundationOneTM assay which assesses the entire coding region of BRAF as 
well as functional rearrangements in BRAF). Targeted polymerase chain reaction assays 
may also be performed (for example, MD Anderson Cancer Center performs PCR-based 
mutational analysis in codons 444, 464, 466, 469, 471, 581, 586, 587, 592, 594, 595, 596, 
597, 599, 600, 601, and 605).  Patients with detected alterations in BRAF at known or 
previously unknown loci will be included. Prior testing results from a CLIA-certified 
laboratory that meet molecular entry criteria (presence of a non-V600 BRAF mutation or 
BRAF gene fusion; no mutation in codon 600 of BRAF; no mutation in codons 12, 13, 
and 61 of NRAS) will be sufficient for patient enrolment in the study without further 
testing. 
 
3.4. 
Product dosing/administration 
 
Product name 
Trametinib 
Formulation 
description: 
The drug substance is blended with inert ingredients (mannitol, sodium 
lauryl sulfate, colloidal silicon dioxide, microcrystalline cellulose, 
hypromellose, croscarmellose sodium, and magnesium stearate), and 
compressed into tablets. 
The tablets are then coated with either a white or pink opaque film* 
(*Opadry White or Pink, a titanium dioxide-based formulation with iron 
oxide as colorant as applicable) 
Dosage form : 
 
Tablet 
Unit dose 
strength(s)/ 
Dosage levels 
 
0.5mg 
2mg 
Physical 
Description: 
White, oval , 
biconvex film coated 
tablet, 4.8mm x 8.7 mm 
Pink, round 
biconvex film 
coated-tablets 
8.0 mm in diameter. 
Route/Duration 
Oral/ Until treatment discontinuation criteria are met 
Dosing 
Instructions: 
Trametinib should be taken fasting, at least 1 hour before or 2 hours after a 
meal. Trametinib will be administered with approximately eight ounces of 
water. If a subject vomits after taking study medication, the subject should 
be instructed not to retake the dose and should take the next scheduled dose. 


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3.5. 
Rationale 
 
3.5.1. 
Rationale for Study 
 
Trametinib has demonstrated clinical activity in subjects with BRAFV600WT cutaneous 
melanoma (Falchook 2012). In patients with BRAFnonV600MUT melanoma, several 
clinical responses have been described to MEK inhibition, including one lasting over two 
years from trametinib (Dahlman 2012; Falchook 2012). Finally, in vitro evidence 
supports that inhibition of MAPK signaling through MEK inhibition in 
BRAFnonV600MUT melanoma, including those with BRAF fusions, is an effective 
treatment strategy. 
 
3.5.2. 
Rationale for Population 
 
Subjects with BRAFnonV600MUT melanoma may respond to targeted therapy although as 
yet there have been no trial specifically enrolling this group. This patient population has 
an unmet medical need and trametinib monotherapy has achieved objective responses in 
such subjects. We are subdividing subjects based on the predicted activity of BRAF 
alterations into Cohort A (“high activity” BRAF mutations and BRAF fusion events) and 
Cohort B (“low activity/unknown” BRAF mutations) as defined by Wan et al published 
in Cell 2004; complete list is in appendix 1. This predetermined stratification will allow 
for improved definition of which subjects are likely to benefit from trametinib. 
 
3.5.3. 
Rationale for Dose 
 
The starting regimen of trametinib will be 2 mg continuous, once daily.  This dose has 
demonstrated an acceptable safety profile (see Section 1.2.3), clinical activity, and a 
pharmacodynamic effect in subjects with BRAFV600MUTmelanoma (Falchook 2012; 
Infante 2012). This dose is also the FDA approved dose for subjects with 
BRAFV600MUT melanoma. 
 
 
3.5.4. 
Rationale for Endpoints 
 
The primary endpoint is to determine the clinical efficacy of trametinib in 
BRAFnonV600MUT melanoma for Cohort A (“high activity” mutations and BRAF 
fusions). Response criteria based on RECIST 1.1 will be used to assess complete or partial 
responses, stable disease, or progressive disease. Safety for both cohorts is a secondary 
endpoint and as such clinical assessments including vital signs and physical examinations, 
12-lead ECG, ECHO, chemistry and hematology laboratory values, retinal 
exams as needed, and AEs will be monitored and evaluated. Progression free survival and 
overall survival will be additional secondary endpoints. 
 
The exploratory endpoint is to determine the clinical efficacy of trametinib in Cohort B 
(“low activity/unknown” group). Response criteria based on RECIST 1.1 will be used to 
assess complete or partial responses, stable disease, or progressive disease (Eisenhauer 
2009). PFS and OS for this cohort will be additional exploratory endpoints. 
 


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3.6. 
Study Treatment 
 
All patients will receive trametinib 2 mg orally once daily 
 
3.7. 
Dosage and Administration of Study Treatment 
 
Trametinib should be administered once per day, continuously; and should be taken at 
about the same time each day. The study treatment should be administered together with 
approximately eight ounces of water. Trametinib should be taken fasting, at least 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 scheduled 
dose. A subject may take a dose within 12 hours of the scheduled time. If a dose is 
missed, a subject should not take a dose within 12 hours of their next scheduled dose of 
trametinib. Trametinib may not be crushed, chewed, or dissolved in water.  
 
3.7.1. 
Meals and Dietary Restrictions 
Study treatment(s) will be administered under fasting conditions (see Section 3.7). 
Fasting will consist of avoiding the oral ingestion of calorie-containing products; 
ingestion of water is permitted.  Any ongoing, usual concomitant medications may be 
administered while fasting. 
 
3.7.2. 
Blinding 
 
This is an open-label study. 
 
3.8. 
Safety Management Guidelines 
 
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.  The 
severity of AEs will be graded using the CTCAE, version 4.0.  The section includes: 
 
• general guidelines for clinically significant toxicities related to study 
treatments and 
 
• specific guidelines for adverse events of special interest, which include but are 
not limited to events that have been observed with higher frequency or severity 
in subjects receiving trametinib. 
 
Subjects should be carefully evaluated for evidence of drug-related toxicity.  The 
investigator should use clinical judgment to determine which drug may be contributing 
to the treatment emergent toxicity and make the appropriate dosing adjustments.  This 
may include interruption and/or reducing the dose of one or both treatments.  
Guidelines for toxicity and dose modifications are provided.  Investigators should also 
refer to the trametinib Investigator Brochure [Novartis, 2016]. 
 


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3.8.1. 
Dose Levels of trametinib 
 
The dose levels for this study are provided in Table 2. 
 
Table 2 
Dose Level Reduction Guidelines 
 
Dose Levels 
Trametinib once daily 
Full dose 
2 mg 
1st Dose reduction 
1.5 mg 
2nd Dose reduction 
1.0 mg 
 
If an AE resolves to grade 1 or baseline at the reduced dose level, and no additional 
toxicities are seen after four weeks of study treatment at the reduced dose, the dose of 
trametinib may be increased to the previous dose level. If a dose reduction below 1.0 mg 
once daily for trametinib is required, then trametinib will be permanently discontinued. 
 
3.8.2. 
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 (see Table 2) are provided in Table 3. 
 
Table 3 
Dose Modification Guidelines for Events Considered Related to 
Study Treatment 
 
CTCAE Grade 
Action and Dose Modification 
Grade 1 
• 
Continue study treatment at current dose level 
• 
Monitor closely 
• 
Provide supportive care according to institutional standards 
Grade 2 
• 
Interrupt study treatment if clinically indicated 
• 
Monitor closely 
• 
Provide supportive care according to institutional standards 
• 
When toxicity resolves to grade 1 or baseline, restart study treatment 
at current dose level 


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CTCAE Grade 
Action and Dose Modification 
Grade 3 
• 
Interrupt study treatment 
• 
Monitor closely 
• 
Provide supportive care according to institutional standards 
• 
When toxicity resolves to grade 1 or baseline, restart study treatment 
reduced by one dose level 
• 
If the grade 3 toxicity recurs, interrupt study treatment 
• 
When toxicity resolves to grade 1 or baseline, restart study treatment 
reduced by another dose level 
Grade 4 
• 
Interrupt study treatment 
• 
Monitor closely 
• 
Provide supportive care according to institutional standards 
• 
Discontinue trametinib OR if the subject is clinically benefiting, 
discuss continuation of the study treatment with the  medical 
monitor once toxicity resolves to grade 1 or baseline. If continued, 
reduce by one dose level. 
• 
If the grade 4 toxicity recurs, permanently discontinue study 
treatment 
Treatment with trametinib may be delayed for up to 21 days to allow resolution of 
toxicity, scheduling difficulties, or investigator discretion. Approval to restart a 
subject after >21 day delay will require consultation with the medical monitor. 
Laboratory abnormalities that are not clinically significant (i.e. creatinine phosphokinase 
levels) but are grade 3 or 4 do not automatically require dose reduction or 
discontinuation of study drug. They should be discussed in detail with the medical 
monitor. 
 
3.9. 
Dose Modification Guidelines for Trametinib Adverse Events 
of Special Interest 
 
3.9.1. 
Guidelines for Cardiovascular Adverse Events 
 
Cardiovascular adverse events have been seen in subjects receiving trametinib; (see the 
trametinib IB [GlaxoSmithKline, 2012] for additional information). Guidelines for 
LVEF decreases and hypertension are provided in Sections 3.9.1.1 and 3.9.1.2, 
respectively. 
 
3.9.1.1. 
Left Ventricular Ejection Fraction (LVEF) 
 
Decreases of the left-ventricular-ejection-fraction (LVEF) have been observed in subjects 
receiving trametinib. Therefore, ECHOs (preferred) or MUGA’s must be performed to 
assess cardiac ejection fraction.  The procedure performed at baseline must be performed 
at all subsequent visits as outlined in the Time and Events Table (see Section 7.1). 
Electronic copies of all ECHO/MUGA scans will be collected by Vanderbilt for review.  


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Dose modification guidance and stopping criteria for LVEF decrease are provided (Table 
4). 
 
Table 4 
Dose Modification Guidelines and Stopping Criteria for LVEF 
Decrease 
 
Clinic 
LVEF-drop (%) or 
CTCAE grade 
Action and Dose Modification 
Asymptomatic 
Absolute decrease of >10% in 
LVEF compared to baseline and 
ejection fraction below the 
institution’s  LLN 
• 
Interrupt trametinib and repeat ECHO/MUGA 
within 2 weeksa 
• 
If the LVEF recovers within 4 weeks (defined 
as LVEF ≥LLN and absolute decrease ≤10% 
compared to baseline) 
• Consult with the  medical monitor and 
request approval for restart 
• Restart treatment with trametinib at 
reduced dose by one dose level 
• 
Repeat ECHO/MUGA 2 , 4 , 8 and 12 
weeks  after re-start; continue in intervals 
of 12  weeks thereafter 
• 
If LVEF does not recover within 4 weeksc 
• Consult with cardiologist 
• Permanently discontinue trametinib 
• Repeat ECHO after 2, 4, 8, 12, and 16 
weeks or until resolution 
Symptomaticb 
Grade 3: resting LVEF 39-20% 
or >20% absolute reduction from 
baseline 
• 
Permanently discontinue 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% 
Abbreviations: CTCAE = Common Terminology Criteria for Adverse Events; ECHO = echocardiogram; ; LLN = lower limit 
of normal; LVEF = left ventricular ejection fraction; MUGA=Multi-gated acquisition 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.  If dose is delayed more than 21 days, discussion with the medical monitor is required to resume therapy.  
 
3.9.1.2. 
Hypertension 
 
Increases in blood pressure have been observed in subjects receiving trametinib. 
Recommendations for blood pressure monitoring and management are provided. 
 
Monitoring of Hypertension 
All blood pressure assessments should be performed under the following optimal 
conditions: 


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• 
the subject has been seated with back support, ensuring that legs are uncrossed 
and flat on the floor 
 
• 
the subject is relaxed comfortably for at least 5 minutes 
 
• 
restrictive clothing has been removed from  the cuff area and the appropriate 
cuff size has been selected 
 
• 
the subjects arm is supported so that the middle of the cuff is at heart level 
 
• 
the subject remains quiet 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 later, with the 2 readings averaged to obtain a 
final blood pressure measurement. The averaged value should be recorded in the eCRF. 
 
Persistent hypertension is defined as an increase of systolic blood pressure (SBP) > 140 
mm Hg and/or diastolic blood pressure (DBP) > 90 mm Hg in three consecutive visits 
with blood pressure assessments from two readings collected as described above. Visits 
to monitor increased blood pressure can be scheduled independently from the per- 
protocol visits outlined in the Time and Events Table (see Section 7.1). Ideally, 
subsequent blood pressure assessments should be performed within one week. 
 
Asymptomatic hypertension is defined as an increase of SBP >140 mm Hg and/or DBP 
>90 mm Hg in the absence of headache, light-headedness, vertigo, tinnitus, episodes of 
fainting or other symptoms indicative of hypertension. 
 
Management of Hypertension 
For subjects experiencing an increase in systolic and/or diastolic blood pressure that is 
persistent and may be associated with the study treatment, recommendations for the 
clinical management of hypertension are described in Table 5. 


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Table 5 
Management and Dose Modification Guidelines for Hypertension 
 
Hypertension 
Action and Dose Modification 
(Scenario A) 
• 
Asymptomatic and persistenta SBP of ≥140 and 
<160 mmHg, or DBP ≥90 and <100 mmHg, 
or 
• 
Clinically significant increase in DBP of 20 
mmHg (but still below 100 mmHg). 
• 
Continue trametinib at the current dose 
 
• 
Adjust current or initiate new antihypertensive 
medication 
 
• 
Titrate antihypertensive medication(s) during 
the next 2 weeks as indicated to achieve well- 
controlledb BP 
 
• 
If BP is not well controlled within 2 weeks, 
consider referral to a specialist and go to 
scenario (B). 
(Scenario B) 
• 
Asymptomatic SBP ≥160 mmHg, or DBP 
≥100 mmHg, 
or 
• 
Failure to achieve well-controlled BP within 2 
weeks in Scenario A 
• 
Interrupt trametinib if clinically indicated 
 
• 
Adjust current or initiate new antihypertensive 
medication(s) 
 
• 
Titrate antihypertensive medication(s) during 
the next 2 weeks as indicated to achieve well- 
controlled BP 
 
• 
Once BP is well controlledb, restart study 
treatment reduced by one dose level 
(Scenario C) 
• 
Symptomaticc hypertension 
or 
• 
Persistent SBP ≥160 mmHg, or DBP 
≥100 mmHg, despite antihypertensive 
medication and dose reduction of study 
treatment 
• 
Interrupt trametinib 
 
• 
Adjust current or initiate new antihypertensive 
medication(s) 
 
• 
Titrate antihypertensive medication during the 
next 2 weeks as indicated to achieve well- 
controlled BP 
 
• 
Referral to a specialist for further evaluation 
and follow-up is recommended 
 
• 
Once BP is well controlled, restart trametinib 
reduced by one dose level 
(Scenario D) 
• 
Refractory hypertension unresponsive to above 
interventions or hypertensive crisis. 
• 
Permanently discontinue trametinib 
 
• 
Continue follow-up per protocol. 
 
• 
If hypertension resolves to ≤Grade 1, 
trametinib may be restarted with 
permission from the medical monitor 
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 consecutive visits 
b. 
Well-controlled blood pressure defined as SBP ≤140 mm Hg and DBP ≤90 mm Hg in two separate readings 
during up to three consecutive visits. 
c. 
Symptomatic hypertension defined as hypertension aggravated by symptoms (e.g., headache, light-headedness, 
vertigo, tinnitus, episodes of fainting) that resolve after the blood pressure is controlled within the normal range. 


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3.9.2. 
Guidelines for Visual Changes 
 
Episodes of visual changes have been observed in subjects receiving trametinib. 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., RPED) or retinal vein abnormalities (e.g., RVO). 
 
Guidelines regarding management and dose reduction for visual changes considered to be 
related to study treatment are provided (see Table 6 and 7). 


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Table 6 
Management and Dose Modification Guidelines for Visual Changes 
and/or Ophthalmic Examination Findings 
 
CTCAE 
Gradea 
Adverse Event Management 
Action and Dose Modification 
 
Grade 1b 
• Consult ophthalmologist within 
7 days of onset 
• 
• If dilated fundus examination cannot 
be performed within 7 days of onset, 
interrupt trametinib until RPED and 
RVO can be excluded by retina 
specialist/ophthalmologist. 
• If RPED and RVO excluded, 
continue (or restart) trametinib at 
same dose level 
• If RPED suspected or diagnosed: 
see RPED dose modification table 7 
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 RPED and RVO excluded, restart 
trametinib at same dose level 
• If RPED diagnosed, see RPED dose 
modification table below; report as 
SAE. 
• If RVO diagnosed: Permanently 
discontinue trametinib and report 
as SAE 
• 
 
Grade 4 
• Consult ophthalmologist 
immediately 
• Interrupt trametinib 
• Report as SAE 
• 
• 
• 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 
trametinib 
Abbreviations: RPED = retinal pigment epithelial detachment; CTCAE = Common Terminology Criteria for Adverse 
Events; 
RVO= retinal vein occlusion; SAE = serious adverse event 


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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. 
 
Table 7 
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 
c. 
Refers to CTCAE Version 4.0 ‘Retinopathy’ 
 
 
3.9.3. 
Pneumonitis Management Guidelines 
 
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. Dose modification and supportive care guidelines for pneumonitis 
are described (see Table 8). 


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Table 8 
Pneumonitis Guidelines for Trametinib 
 
CTCAE 
Grade 
Adverse Event Management 
Action and Dose Modification 
Grade 1 
• 
CT scan (high-resolution with lung 
windows) recommended 
• 
Clinical evaluation and laboratory work-up 
for infection 
• 
Monitoring of oxygenation via pulse- 
oximetry recommended 
• 
Consultation with pulmonologist 
recommended 
• 
Continue trametinib at current dose 
Grade 2 
• 
CT scan (high-resolution with lung 
windows) 
• 
Clinical evaluation and laboratory work-up 
for infection 
• 
Consult pulmonologist 
• 
Pulmonary function tests -if < normal, 
repeat every 8 weeks until ≥ normal 
• 
Bronchoscopy with biopsy and/or BAL 
recommended 
• 
Symptomatic therapy including 
corticosteroids if clinically indicated 
• 
Interrupt trametinib until recovery 
to grade ≤1 
• 
Restart treatment with trametinib 
reduced by one dose level 
• 
Escalation to previous dose level 
after 4 weeks and consultation with 
medical monitor possible 
• 
If no recovery to grade ≤1 within 4 
weeks, permanently discontinue 
trametinib 
Grade 3 
• 
CT scan (high-resolution with lung 
windows) 
• 
Clinical evaluation and laboratory work-up 
for infection 
• 
Consult pulmonologist 
• 
Pulmonary function tests-if < normal, repeat 
every 8 weeks until ≥ normal 
• 
Bronchoscopy with biopsy and/or BAL if 
possible 
• 
Symptomatic therapy including 
corticosteroids as clinically indicated 
• 
Interrupt trametinib until recovery 
to grade ≤1 
• 
After consultation with medical 
monitor, treatment with trametinib 
may be restarted reduced by one 
dose level 
• 
If no recovery to grade ≤1 within 21 
days, permanently discontinue 
trametinib 
Grade 4 
• 
Same as grade 3 
• 
Permanently discontinue 
trametinib 
Abbreviations: BAL= bronchioalveolar lavage; CT = computed tomography; CTCAE = Common Terminology Criteria 
for Adverse Events 


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3.10. 
Dose Modifications for Trametinib and supportive care 
 
3.10.1. 
Liver Chemistry Stopping Criteria 
 
Liver chemistry threshold stopping criteria have been designed to assure subject safety 
and to evaluate liver event etiology during administration of study treatment(s) and the 
follow-up period.  Study treatment(s) will be stopped if any of the following liver 
chemistry stopping criteria is/are met: 
 
1. Alanine aminotransferase (ALT) ≥3 X (times) upper limit of normal (ULN) and 
bilirubin ≥2 Xs ULN (or ALT ≥3 X ULN and international normalization ratio 
[INR] >1.5) 
 
NOTE: Serum bilirubin fractionation should be performed if testing is available.  If 
fractionation is unavailable, urinary bilirubin is to be measured via dipstick (a 
measurement of direct bilirubin, which would suggest liver injury). 
 
2. ALT ≥5 X ULN. 
 
3. ALT ≥3 X ULN if associated with the appearance or worsening of rash or hepatitis 
symptoms (fatigue, nausea, vomiting, right upper quadrant pain or tenderness, or 
jaundice) or hypersensitivity ( such as fever, rash or eosinophilia). 
 
4. ALT ≥3 X ULN persists for ≥4 weeks. 
 
5. ALT ≥3 X ULN and cannot be monitored weekly for 4 weeks. 
 
Subjects with ALT ≥3 X ULN and <5 Xs ULN and bilirubin <2 X ULN, who do not 
exhibit hepatitis symptoms or rash, can continue study treatment(s) as long as they can be 
monitored weekly for 4 weeks. As with other causes of dose holding, discussion with the 
medical monitor is required if trametinib is held for >21 days.  See following section for 
details on weekly follow-up procedures for these subjects. 
 
3.10.1.1. 
Liver Chemistry Follow-up Procedures 
 
Refer to the diagram in Appendix 5 for a visual presentation of the procedures listed 
below. 
 
The procedures listed below are to be followed if a subject meets the liver chemistry 
stopping criteria defined in Section 3.10.1: 
 
• 
Immediately and permanently withdraw the subject from study treatment. 
 
• 
Notify the Medical Monitor within 24 hours of learning of the abnormality to 
confirm the subject’s study treatment(s) cessation and follow-up. 
 
• 
Complete the “Safety Follow-Up Procedures” listed below. 
 
• 
Complete the liver event electronic case report forms (eCRFs).  If the event also 
meets the criteria of a serious adverse event (SAE) (see Section 8.2), the SAE data 
collection tool will be completed separately with the relevant details. 
 
• 
Upon completion of the safety follow-up permanently withdraw the subject from the 
study and do not rechallenge with study treatment(s). 


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Safety Follow-Up Procedures for subjects with ALT ≥3 times ULN: 
 
• 
Monitor subjects weekly until liver chemistries (ALT, aspartate aminotransferase 
[AST], alkaline phosphatase [ALP], and bilirubin) resolve, stabilize or return to 
within baseline values. 
 
Safety Follow-Up Procedures for subjects with ALT ≥3 times ULN and bilirubin ≥2 
times ULN (or ALT ≥3 times ULN and INR >1.5): 
 
• 
This event is considered an SAE (see Section 8.2).  Serum bilirubin fractionation 
should be performed if testing is available.  If fractionation is unavailable, urinary 
bilirubin is to be measured via dipstick (a measurement of direct bilirubin, which 
would suggest liver injury). 
 
• 
Make every reasonable attempt to have subjects return to the clinic within 24 hours 
for repeat liver chemistries, additional testing, and close monitoring (with specialist 
or hepatology consultation recommended). 
 
• 
Monitor subjects twice weekly until liver chemistries (ALT, AST, alkaline 
phosphatase, bilirubin) resolve, stabilize or return to within baseline values. 
 
In addition, for all subjects with ALT ≥3 times ULN, every attempt must be made to 
also obtain the following: 
 
• Viral hepatitis serology including: 
 
• 
Hepatitis A Immunoglobulin M (IgM) antibody. 
 
• 
Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM). 
 
• 
Hepatitis C ribonucleic acid (RNA). 
 
• 
Cytomegalovirus IgM antibody. 
 
• 
Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing). 
 
• 
Hepatitis E IgM antibody (if subject resides outside the United States (US) or 
Canada, or has traveled outside US or Canada in past 3 months). 
 
• Serum creatine phosphokinase and lactate dehydrogenase. 
 
• Fractionate bilirubin, if total bilirubin ≥2 times ULN. 
 
• Obtain complete blood count with differential to assess eosinophilia 
 
• Record the appearance or worsening of clinical symptoms of hepatitis or 
hypersensitivity, such as fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever, rash or eosinophilia, on the AE eCRF. 
 
• Record use of concomitant medication(s), acetaminophen, herbal remedies, other 
over-the-counter medication(s), or putative hepatotoxins on the Concomitant 
Medications eCRF. 
 
• Record alcohol use on the Liver Events eCRF. 


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The following are required for subjects with ALT ≥3 times ULN and bilirubin ≥2 times 
ULN 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] scan) to evaluate liver disease. 
 
• Liver Imaging and/or Liver Biopsy eCRFs are also to be completed if these tests are 
performed. 
 
• 
Serum acetaminophen adduct HPLC assay (quantifies potential acetaminophen 
contribution to liver injury in subjects with definite or likely acetaminophen use in 
the preceding week [CTCAE, 2009]). 
 
• Only in those with underlying chronic hepatitis B at study entry (identified by 
positive hepatitis B surface antigen):  quantitative hepatitis B DNA and hepatitis delta 
antibody. NOTE:  If hepatitis delta antibody assay cannot be performed, it can be 
replaced with a PCR of hepatitis D RNA virus (where needed) – as outlined in: 
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1153793. 
 
3.10.2. 
Guidelines for Prolonged QTc 
 
Investigators should review concomitant medication usage for those that cause a 
prolonged QTc. Guidelines for dose modification and stopping criteria due to QTc-
prolongation are provided (see Table 9). 
 
Table 9 
Withholding and Stopping Criteria for QTc-Prolongation 
 
QTc-Prolongationa 
Action and Dose Modification 
• 
QTcB ≥501 msec 
• 
Interrupt all study treatments 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 usage for a prolonged 
QTc. 
 
• 
Restart at current dose levelb,c 
 
• 
If event recurs, permanently discontinue study 
treatments 
Abbreviations: msec = milliseconds; QTcB = QT interval on electrocardiogram corrected using the Bazett’s formula 
a. 
Based on average QTc value of triplicate ECGs. For example, if an ECG demonstrates a prolonged QT interval, 
obtain two or more ECGs over a brief period, and then use the averaged QTc values of the three ECGs 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  medical monitor agree that the subject will benefit from further treatment. 
c.  If dose is delayed more than 21 days, discussion with the medical monitor is required to resume therapy.  
 


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3.10.3. 
Guidelines for Rash 
 
Rash is a frequent AE observed in subjects receiving trametinib (see the Investigator’s 
Brochures [GlaxoSmithKline, 2012] for more information). Recommendations for 
supportive care and guidelines for dose modifications for rash are based on experience 
with other MEK inhibitors and EGFR inhibitors (Balagula 2011; Lacouture 2011) and 
are provided (see Table  10 and Table 11). 
 
The institutional standards for the management of skin-related AEs can differ from these 
guidelines. In this case, best clinical judgment should be applied and a consultation with 
the Medical Monitor may be required. 
 
Table 10 
Guidelines for Supportive Care of Rash 
 
Type of Care 
Action 
Prevention/Prophylaxisa 
• 
Avoid unnecessary exposure to sunlight 
• 
Apply broad-spectrum sunscreen (containing titanium dioxide or zinc 
oxide) with a skin protection factor (SPF) ≥15 at least twice daily. 
• 
Use thick, alcohol-free emollient cream (e.g., glycerine and 
cetomacrogol cream) on dry areas of the body at least twice daily. 
• 
Topical steroids and antibiotics should be applied at least twice daily 
starting on Day 1 of study treatment, to body areas such as face, chest, 
and upper back. 
• 
Use mild-strength topical steroid  (hydrocortisone 1% cream) 
or 
• 
topical antibiotic (e.g., clindamycin) or oral antibiotics (e.g., 
doxycycline 100 mg BID, minocycline 100 mg BID) 
Symptomatic Careb 
• 
Pruritic lesions: cool compresses and oral antihistamine therapies 
• 
Fissuring lesions: Monsel’s solution, silver nitrate, or zinc oxide cream 
• 
Desquamation: thick emollients and mild soap 
• 
Paronychia: antiseptic bath, local potent corticosteroids in addition to 
oral antibiotics; if no improvement, consult dermatologist or surgeon 
• 
Infected lesions: appropriate bacterial/fungal culture-driven systemic or 
topical antibiotics 
Abbreviations: BID = twice daily; SPF = sun protection factor 
a. 
Rash prophylaxis is recommended for the first 6 weeks of study treatment 
b. 
Subjects who develop rash/skin toxicities should be seen by a qualified physician and should receive 
evaluation for symptomatic/supportive care management 
 
 
Guidelines for management and dose reduction for rash considered to be related to study 
treatment are provided (see Table 11). 
Commented [d1]: Change to Novartis 2016? 


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Table 11 
Management and Dose Modification Guidelines for Rash 
 
CTCAE Grade 
Adverse Event Management 
Action and Dose Modification 
Grade 1 
• 
Initiate prophylactic and 
symptomatic treatment measuresa 
 
• 
Use moderate strength topical 
steroidb 
 
• 
Reassess after 2 weeks 
• 
Continue study treatment 
 
• 
If rash does not recover to 
baseline within 2 weeks despite 
best supportive care, reduce 
trametinib by one dose levelc 
Grade 2 
• 
Initiate prophylactic and 
symptomatic treatment measures 
 
• 
Use moderate strength topical 
steroidb 
 
• 
Reassess after 2 weeks 
• 
Reduce trametinib by one dose 
level 
 
•   If rash recovers to ≤grade 1 
within 2 weeks, increase dose 
to previous dose level 
 
•   If no recovery to ≤grade 1 
within 2 weeks, interrupt study 
treatment until recovery to 
≤grade 1 
 
• 
Restart trametinib at reduced 
dose levelc 
Grade ≥3 
• 
Use moderate strength topical 
steroidsb PLUS oral methyl- 
prednisolone dose pack 
 
• 
Consult dermatologist 
• 
Interrupt trametinib until rash 
recovers to grade ≤1 
 
• 
Restartc  trametinib reduced by 
one dose leveld 
 
• 
If no recovery to grade ≤2 within 4 
weeks, permanently discontinue 
trametinib 
Abbreviations: CTCAE = Common Terminology Criteria for Adverse Events 
a. 
Rash prophylaxis is recommended for the first 6 weeks of study treatment 
b. 
Moderate-strength topical steroids: hydrocortisone 2.5% cream or fluticasone prioprionate 0.5% cream 
c. 
Approval of medical monitor is required to restart study treatment after >21 days of interruption. 
d. 
Escalation of study treatment to previous dose level may be considered if no rash is evident 4 weeks after 
restarting study treatment 
 
3.10.4. 
Guidelines for Diarrhea 
 
Episodes of diarrhea have occurred in subjects receiving trametinib (see the Investigator 
Brochures [Novartis, 2016] for more information). 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 trametinib by the investigator are provided (see Table 12). 


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Table 12 
Management and Dose Modification Guidelines for Diarrhea 
 
CTCAE Grade 
Adverse Event Management 
Action and Dose Modification 
Uncomplicated 
Diarrheaa 
Grade 1 or 2 
• 
Diet: stop all lactose containing products; eat 
small meals, BRAT-diet (banana, rice, apples, 
toast) recommended 
• 
Hydration: 8-10 large glasses of clear liquids per 
day (e.g., Gatorade or broth) 
• 
Loperamidec: initially 4 mg, followed by 2 mg 
every four hours or after every unformed stool; 
maximum 16 mg/day. Continue until diarrhea 
free for 12 hours 
• 
Diarrhea > 24h: loperamide 2 mg every two 
hours; maximum 16 mg/day. Consider adding 
oral antibiotics 
• 
Diarrhea > 48h:  loperamide 2 mg every two 
hours; maximum 16 mg/day. Add budesonide or 
other second-line therapies (otreotide, or 
tincture of opium) and oral antibiotics 
• 
Continue trametinib 
 
• 
If diarrhea is grade 2 for >  
48h,  interrupt trametinib 
until diarrhea resolves to 
grade ≤1 
 
• 
Restart trametinib at the 
same dose leveld 
Uncomplicated 
Diarrheaa 
Grade 3 or 4 
Any Complicated 
Diarrheab 
• 
Clinical evaluation mandatory 
• 
Loperamidec: initially 4 mg, followed by 2 mg 
every four hours or after every unformed stool; 
maximum 16 mg/day. Continue until diarrhea 
free for 12 hours 
• 
Oral antibiotics and second-line therapies if 
clinically indicated 
• 
Hydration: intravenous fluids if clinically 
indicated 
• 
Antibiotics  (oral or intravenous) if clinically 
indicated 
• 
Intervention 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 trametinib until 
diarrhea resolves to grade 
≤1 
 
• 
Restart with trametinib 
reduced by one dose 
leveld,e 
 
 
• 
If 3 dose reductions of 
study treatment are 
clinically indicated, 
permanently discontinue 
trametinib 
Abbreviation: CTCAE = Common Terminology Criteria for Adverse Events 
a. 
Uncomplicated diarrhea 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 intravenous fluid substitution 
b. 
Complicated diarrhea 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 intravenous fluid substitution 
c. 
Loperamide should be made available prior to start of study treatment so loperamide administration can begin at 
the first signs of diarrhea 
d.  If dose is delayed more than 21 days, discussion with the medical monitor is required to resume therapy. 
e. 
Escalation of trametinib to previous dose level is allowed after consultation with the medical monitor and in the 
absence of another episode of complicated or severe diarrhea in the 4 weeks subsequent to dose reduction. 


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4. 
INVESTIGATIONAL PRODUCT(S) 
 
The term ‘study treatment’ is used throughout the protocol to describe any combination 
of investigational product(s) (IP) received by the subject as per the protocol design. 
Study treatment may therefore refer to the individual study treatment or the combination 
of those study treatments. 
 
4.1. 
Description of Investigational Product(s) and/or 
Comparators/Placebo 
 
4.1.1. 
Trametinib 
 
Trametinib will be provided as 0.5 mg and 2.0 mg tablets.  Each tablet will contain 0.5 
mg or 2.0 mg of trametinib parent (present as the DMSO solvate). 
 
Trametinib commercial available supply with auxiliary label will also be provided by 
Novartis. The study drug should be administered and stored according to the instructions 
specified on the drug labels (refer to label, PI, and IB for detailed information). 
 
Trametinib will be shipped to sites by the Clinical Research Management Group. The 
contents of the label will be in accordance with all applicable regulatory requirements. 
 
4.2. 
Preparation/Handling/Storage of Trametinib 
 
Handling 
 
Under normal conditions of handling and administration, investigational products (IPs) 
are not expected to pose significant safety risks to site staff.  A Material Safety Data 
Sheet (MSDS) describing the occupational hazards and recommended handling 
precautions will be provided to site staff if required by local laws or will otherwise be 
available from Novartis upon request. 
 
In the case of unintentional occupational exposure notify the study monitor, the 
Medical Monitor and/or the study manager. 
 
 
Storage 
 
Study treatments must be stored in a secure area under the appropriate physical conditions 
for the product.  Access to and administration of the study treatments will be limited to the 
investigator and authorized site staff. Study treatments must be dispensed or administered 
only to subjects enrolled in the study and in accordance with the protocol.  Study 
medication is to be refrigerated and stored at the temperature specified on the label. 
Maintenance of a temperature log (manual or automated) is required. 
4.3. 
Product Accountability 
 
In accordance with local regulatory requirements, the investigator, designated site staff, 
or head of the medical institution (where applicable) must document the amount of study 
treatments dispensed and/or administered to study subjects, the amount returned by study 


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subjects, and the amount received from and returned to Novartis, when applicable.  
Product accountability records must be maintained throughout the course of the study.  
See Appendix 8 for medication diary.  
 
4.4. 
Treatment Compliance 
 
Treatment compliance will be assessed through querying the subject during the site visits 
and documented in the source documents, electronic case report form (eCRF), and the 
medication diary.  A record of the number of trametinib tablets capsules 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.  Investigators must make every 
effort to bring non-compliant subjects into compliance. 
 
4.5. 
Treatment of Investigational Product Overdose 
 
In the event of an overdose defined as administration of more than 3.0 mg once daily for 
trametinib (the maximum tolerated dose defined in the MEK111054 Study),  the 
investigator should: 
 
• 
contact the Medical Monitor immediately 
 
• 
closely monitor the subject for adverse events (AEs)/serious adverse events 
(SAEs) and laboratory abnormalities 
 
• 
obtain a plasma sample for pharmacokinetic (PK) analysis if requested by the 
Medical Monitor (determined on a case-by-case basis) 
 
• 
document the quantity of the excess dose as well as the duration of the 
overdosing in the electronic case report form (eCRF). 
 
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the Medical Monitor based on the clinical evaluation of the subject. 
 
5. 
STUDY POPULATION 
 
5.1. 
Number of Subjects 
 
The number of subjects enrolled will be dependent on the early response rate. In stage I, 
15 subjects will be enrolled in cohort A and if less than one response is confirmed, the 
trial will be terminated. If one or more responses are observed, an additional 10 subjects 
will be enrolled. For cohort B, we will enroll patients concurrently.  In stage I we will 
enroll up to 15 patients. If no responses are seen, this arm will be terminated. If one or 
more responses occur, we will accrue up to 10 additional patients. However, this 
exploratory study arm will close at the completion of cohort A accrual.  


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5.2. 
Subject Selection Criteria 
 
5.2.1. 
Inclusion Criteria 
 
Specific information regarding warnings, precautions, contraindications, adverse events 
(AEs), and other pertinent information on the study treatments that may impact subject 
eligibility is provided in the Investigator Brochures and Supplements [Novartis, 2016]. 
 
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 the study must meet all of the following criteria: 
 
1. ≥18 years old. 
 
2. Signed written informed consent. 
 
3. Histologically or cytologically confirmed diagnosis of melanoma. 
 
4.   BRAF mutation in loci other than V600 (BRAF nonV600 MUT) or BRAF fusion 
detected by genetic testing of the primary tumor or regional/distant metastasis. 
 
5. Subjects must provide either a fresh or archived tumor sample for correlative study 
analyses. 
 
6.   For subjects with melanoma, archived or freshly biopsied tumor tissue (preferred) 
must be obtained prior to enrollment. Tissue shipment tracking information should be 
provided before administration of study treatment is initiated. However, if shipping 
will be delayed and tissue shipment tracking information is unavailable, study drug 
may be administered prior to tissue receipt pending discussion with principal 
investigator. 
 
7.   Measurable disease (i.e., present with at least one measurable lesion per RECIST, 
version 1.1 (Eisenhauer 2009). 
 
8.   All prior anti-cancer treatment-related toxicities (except alopecia and laboratory 
values as listed on Table 12) must be ≤ grade 1 according to the Common 
Terminology Criteria for Adverse Events version 4 (CTCAE version 4.0; 
CTCAE, 2009) at the time of randomization. Subjects with endocrinopathies 
(e.g. hypopituitarism, hypothyroidism, hypoadrenalism) caused by immune 
therapies currently on adequate hormone replacement WILL be permitted. 
 
9.   Able to swallow and retain oral medication and must not have any clinically 
significant gastrointestinal abnormalities that may alter absorption such as 
malabsorption syndrome or major resection of the stomach or bowels. 
 
10.  Women of childbearing potential must have a negative serum pregnancy test within 
14 days prior to randomization and agree to use effective contraception as defined 
(see Section 7.3.9). 
 
11.  Men with a female partner of childbearing potential must have either had a prior 
vasectomy or agree to use effective contraception as described in Section 11.1.2. 
 
12. An Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 
Refer to Appendix for details. 


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13.  Adequate baseline organ function as defined in Table 13.


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Table 13 
Definitions for Adequate Baseline Organ Function 
 
System 
Laboratory Values 
Hematologic 
ANC 
≥ 1.0 × 109/L 
Hemoglobin 
≥ 9 g/dL 
Platelet count 
≥ 75 x 109/L 
PT/INRa and PTT 
≤ 1.3 x ULN 
Hepatic 
Albumin 
≥ 2.5 g/dL 
Total bilirubin 
≤ 1.5 x ULN 
ALT 
≤ 2.5 x ULN 
Renal 
Creatinine or 
≤ 1.5 ULN 
Calculated creatinine clearanceb 
≥50 mL/min 
Cardiac 
Left Ventricular Ejection fraction (LVEF) 
≥ LLN by ECHO, >50% if not specified 
Abbreviations: ALT = alanine transaminase; ANC = absolute neutrophil count; INR = international normalized ratio; 
LLN = lower limit of normal; PT = prothrombin time; PTT = partial thromboplastin time; ULN = upper limit of normal. 
a. 
Subjects receiving anticoagulation treatment may be allowed to participate with INR established within the 
therapeutic range prior to randomization. PT and PTT > 1.3 x ULN are permitted in these subjects. 
b. 
Calculate creatinine clearance using standard Cockcroft-Gault formula (Appendix ). Creatinine clearance must be 
≥50 mL/min to be eligible. 
 
 
5.2.2. 
Exclusion Criteria 
 
Deviations from exclusion criteria are not allowed because they can potentially 
jeopardize the scientific integrity of the study, regulatory acceptability or subject safety. 
Therefore, adherence to the criteria as specified in the protocol is essential. 
 
Subjects meeting any of the following criteria must not be enrolled in the study: 
 
1. No prior therapy with inhibitors affecting the MAPK pathways at any level (BRAF, 
MEK, NRAS, ERK inhibitors) for unresectable stage IIIC of Stage IV (metastatic) 
melanoma. No limit to other therapies (immunotherapy or chemotherapy). Prior 
systemic treatment in the adjuvant setting is allowed. (Note: Ipilimumab treatment 
must end at least 8 weeks prior to Study Day 1). 
 
2. BRAFV600 mutation positive. 
 
3. NRAS codon 12, 13, or 61 mutation. 
 
4. Any major surgery, extensive radiotherapy, chemotherapy with delayed toxicity, 
biologic therapy, or immunotherapy within 21 days prior to Study Day 1, or daily or 
weekly chemotherapy without the potential for delayed toxicity within 14 days prior 
to Study Day 1. 
 
5. Taken an investigational drug within 28 days or 5 half-lives (minimum 14 days), 
whichever is shorter, prior to Study Day 1. 
 
6. Current use of a prohibited medication as described (see Section 10). 


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7. History of another malignancy 
 
Exception: Subjects who have been disease-free for 3 years, or subjects with a 
history of completely resected, non-melanoma skin cancer, or subjects with indolent 
second malignancies are eligible. T1a melanoma and melanoma in situ are permitted. 
Consult Medical Monitor if unsure whether second malignancies meet requirements 
specified above. 
 
8. Any serious or unstable pre-existing medical conditions (aside from malignancy 
exceptions specified above), psychiatric disorders, or other conditions that could 
interfere with the subject’s safety, obtaining informed consent, or compliance with 
study procedures. 
 
9. Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or 
Hepatitis C Virus (HCV) infection (subjects with laboratory evidence of cleared 
HBV and HCV infection will be permitted). 
 
10.  History of leptomeningeal disease or spinal cord compression secondary to 
metastasis. 
 
11.  Brain metastasis, unless previously treated with surgery or stereotactic radiosurgery 
and the disease has been confirmed stable (i.e., no increase in lesion size) for at least 
6 weeks with two consecutive MRI scans using contrast prior to Study Day 1 
(the first MRI may be prior to surgical resection or radiation).  
 
12.  A history or evidence of cardiovascular risk including any of the following: 
 
a.   A QT interval corrected for heart rate using the Bazett’s formula (QTc; Appendix 
6 ) ≥480 msec; 
b.   A history or evidence of current clinically significant uncontrolled arrhythmias; 
Exception:  Subjects with atrial fibrillation controlled for > 30 days prior to Study 
Day 1; 
 
c.   History of acute coronary syndromes (including myocardial infarction and unstable 
angina), coronary angioplasty, or stenting within 6 months prior to Study Day 1; 


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d.   A history or evidence of current Class I congestive heart failure as defined by the 
New York Heart Association (NYHA) guidelines (Appendix 2 ); 
 
e.   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; 
 
f. Patients with intra-cardiac defibrillators or permanent pacemakers; 
 
g.   Known cardiac metastases; 
 
13.  A history or current evidence of RVO including: 
 
a.   History of RVO or 
 
b.   Visible retinal pathology as assessed by ophthalmic examination that is 
considered a risk factor for RVO such as: 
 
• Evidence of new optic disc cupping; 
 
• Evidence of new visual field defects; 
 
• Intraocular pressure >21 mmHg as measured by tonography. 
 
14.  Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs 
chemically related to the study treatments, their excipients, and/or dimethyl sulfoxide 
(DMSO). 
 
15.  History of interstitial lung disease or pneumonitis. 
 
16.  Females who are pregnant or nursing (see Section 11.2). 
 
 
 
6. 
COMPLETION OR WITHDRAWAL OF SUBJECTS 
 
6.1. 
Screen and Baseline Failures 
 
Data for screen and baseline failures will be collected in source documentation at the site 
but will not be transmitted to the Coordinating Center. 
 
6.2. 
Subject Completion Criteria 
 
A completed subject is one who has discontinued study treatment for reasons listed in 
Section 6.3 and completed a post-treatment follow-up visit or has died while receiving 
study treatment. 
 
6.3. 
Permanent Discontinuation from Study Treatment 
 
Subjects will receive study treatment until disease progression, death or unacceptable 
toxicity, including meeting stopping criteria for liver chemistry defined in Section 3.10.1. 
In addition, study treatment may be permanently discontinued for any of the following 
reasons: 
 
• deviation(s) from the protocol 


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• 
request of the subject or proxy (withdrawal of consent by subject or proxy) 
 
• 
investigator’s discretion 
 
• 
a dose delay of > 21 days unless the investigator or Medical Monitor agree that 
further treatment may benefit the subject 
 
• 
intercurrent illness that prevents further administration of study treatment(s) 
 
• 
subject is lost to follow-up or study is closed or terminated. 
 
The primary reason study treatment was permanently discontinued must be documented 
in the subject’s medical records and electronic case report form (eCRF). 
 
If the subject voluntarily discontinues from treatment due to toxicity, ‘adverse event 
(AE)’ will be recorded as the primary reason for permanently discontinuation on the 
electronic case report form (eCRF). 
 
Once a subject has permanently discontinued from trametinib, the subject will not be re- 
administered with the discontinued study treatment. 
 
All subjects who discontinue from both study treatments will have safety assessments at 
the time of discontinuation and during post-study treatment follow-up as specified in 
Time and Events Table (see Section 7.1). 
 
6.4. 
Study Completion 
 
Study will be completed having met the study objectives, approximately 24 month s after 
last subject first visit, or when all subjects have withdrawn from the study, whichever 
occurs first. 
 
6.5. 
Treatment after the End of the Study 
 
The investigator is responsible for ensuring that consideration has been given for the 
post-study care of the subject’s medical condition whether or not the Coordinating 
Center is providing specific post-study treatment. 
 
After study participation is completed or terminated, subjects may either: 
 
• 
Transition to a future rollover study if eligible and continue receiving their 
current treatment with trametinib 
 
OR 
 
• 
Complete a follow-up visit within approximately 28 days of the last dose of study 
treatments if the subject: 
 
• 
chooses not to enter the roll-over study, or 
 
• 
is withdrawn due to an adverse event (AE) considered related to study treatment, 
or 
 
• 
is considered ineligible to enter the rollover study. 


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7. 
STUDY ASSESSMENTS AND PROCEDURES 
 
A signed, written informed consent form must be obtained from the subject prior to any 
study-specific procedures or assessments being performed. 
 
The timing of each assessment is listed in the Time and Events Table (Section 7.1).  The 
timing and number of the planned study assessments may be altered during the course of 
the study based on newly available data (e.g. to obtain data closer to the time of peak 
plasma concentrations) to ensure appropriate monitoring for the following assessments: 
safety, pharmacokinetic (PK), pharmacodynamics (PD)/biomarker or other assessments. 
The change in timing or addition of time points for any of the planned study assessments 
listed above must be approved and documented by the Coordinating Center, but this will 
not constitute a protocol amendment.  The institutional review board (IRB) or ethics 
committee (EC) will be informed of any safety issues that require alteration of the safety 
monitoring scheme. No more than 100 ml of blood will be collected over the duration of 
the study, including any extra assessments that may be required. 
 
 
7.1. 
Time and Events Table 
 
This section consists of the Time and Events Table (Table 14) and supplemental 
footnotes to describe assessment windows and sequencing of study-specific assessments 
and procedures.


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Table 14         Time and Events 
 
STUDY PHASES1 
SCR2 
TREATMENT-One Cycle=28 days 
Follow up3 
D1 
D1521 
Continuation 
EOT 
Post EOT FU 
Visit Window (Days)                           
-28 
N/A 
±3 
±3 
± 3 
±7 
CLINICAL ASSESSMENTS 
Informed Consent4                                    
X 
 
 
 
 
 
Baseline demographics                      
X 
 
 
 
 
 
Medical History                                   
X 
 
 
 
 
 
Interim Medical History                       
 
 
 
Day 1 of each cycle 
 
 
Disease Characteristics 
X 
 
 
 
 
 
Prior Anti-Cancer Therapy 
X 
 
 
 
 
 
ECOG Performance Status                
X 
X5 
 
Day 1 of each cycle 
X 
 
SAFETY ASSESSMENTS 
Physical Exam, Weight, Height17 
X 
X5 
 
Day 1 of each cycle 
X 
 
Ophthalmologic Exam6 
X 
(≤35 days) 
 
 
 
As clinically warranted 
As clinically warranted 
 
Vital Signs7 
X 
X 
X 
Day 1 of each cycle 
X 
X 
12-lead ECG8 
X 
 
 
Cycle 2 day 1, cycle 4 day 1, then every 12 
weeks thereafter; more frequently if clinically 
warranted 
 
X 
ECHO or MUGA9 
X 
(≤35 days) 
 
 
Cycle 2 day 1, cycle 4 day 1, then every 12 
weeks thereafter; more frequently if clinically 
warranted 
 
X18 
Adverse Events10     
X 
Continuous 
X 
Concomitant Medications                   
X 
Continuous 
X 
LABORATORY ASSESSMENTS 
Hematology/Chemistry22 
X 
(≤14days) 
X5 
X 
Day 1 of each cycle or more often as 
clinically warranted 
X 
X 
Coagulation/Urinalysis 
X 
 
 
As clinically warranted 
 
X 
Serum Pregnancy Test11 
X 
(≤14 days) 
 
 
Cycle 3, day 1, then every 8 weeks 
 
X 
Hepatitis B and Hepatitis C16 
X 
 
 
 
 
 
EFFICACY ASSESSMENTS 
Disease assessment/imaging 
studies 
X14 
 
 
Every 8 weeks through week 56 then 
every 12 weeks thereafter (+/- 7 days) 
 
X15 


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STUDY PHASES1 
SCR2 
TREATMENT-One Cycle=28 days 
Follow up3 
D1 
D15 
Continuation 
EOT 
Post EOT FU 
Visit Window (Days) 
-28 
N/A 
±3 
±3 
± 3 
±7 
EXPLORATORY ASSESSMENTS 
Archival tumor tissue 19 
X 
Optional Pre-Dose/Post-Dose 
Biopsies12 
X 
(≤28 days) 
X20 
 
Blood Biomarkers 
X 
X 
 
Optional Post-Progression Tumor 
Biopsy13 
X 
SCR=Screening, D=Day 
1. All assessments mandated throughout the study should be performed on the visit day prior to administration of study treatments unless otherwise indicated. Dose modifications of 
any nature for either study treatment must not alter the pre-planned schedule of visits starting with the first dose of study treatment on Cycle 1, day 1. The start of a Cycle is 
defined as the day when trametinib administration begins. If a cycle is delayed by one week or less, assessments need not be repeated if results were not clinically significant. 
2. Assessments within 28 days prior to the first dose of study treatment unless otherwise noted. 
3. For subjects meeting permanent study treatment withdrawal criteria (Section 6.3), perform follow-up visit approximately 28 days after withdrawal from study treatment. For 
subjects eligible to continue study treatments in a rollover protocol at study end (Section 6.5), perform follow-up visit just prior to the start of dosing in the rollover trial. 
Assessments completed at this end of study follow-up visit may be used as baseline values for the rollover trial, provided that these assessments are collected within 
14 days of the first dose of study treatment. 
4. Informed consent may be obtained at any time prior to commencement of screening procedures and does not expire. 
5. If completed within 72 hrs prior to the first dose of study treatment, this assessment need not be repeated unless clinically indicated. If labs are obtained, inclusion criteria remain the 
same and subjects may not begin therapy if laboratory parameters have changed outside study limits.  
6. An ophthalmic examination will be performed as described (see Section 7.3.8). 
7. Vital signs include temperature, respiratory rate, blood pressure, and pulse rate (see Section 7.3.3). 
8. For ECG collection, the subject should rest in a semi-recumbent or supine position for at least 5 minutes prior to digital ECG acquisition (see Section 7.3.4). 
9. LVEF is measured with either ECHO (preferred) or MUGA. The method used to initially document the subject’s baseline status must be used consistently throughout the study 
(see Section 7.3.5). 
10.  From the time of consent until first dose of study treatment: only collect SAEs related to study participation or a Novartis concomitant medication. From Day 1 of study treatment to 
28 days after the last dose: collect all AEs and SAEs regardless of causality. From 29 days post treatment and onward, if available: only collect SAEs related to study participation, 
study treatment, or a Novartis concomitant medication. 
11.  Perform only in women of childbearing potential. Serum testing is required at screening; serum or urine pregnancy test may be used at subsequent time points (see Section 
7.3.9). 
12.  If available and with their consent, subjects may choose to provide fresh tumor tissue samples at the times indicated (see Section 0). Samples collected on Day 15 should be 
collected prior to dosing. Tissue may be obtained through excisional, incisional, core needle, or punch biopsies (or by other methods after discussion with medical monitor.) 
13.  Post-progression tumor tissue collection is optional and should be performed on all consenting subjects within 28 days of disease progression. 


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14.  Baseline CT with contrast (or MRI if CT is contraindicated) should be performed within 28 days of the first dose of study treatment. The method (CT or MRI) used to document the 
subject’s baseline status must be used consistently throughout the study. Subjects with melanoma must also have head MRI to fulfil eligibility criteria. (See Section 7.3.6 details.) 
15.  Required only if previous assessment was more than 8 weeks prior to follow-up visit. 
16.  Subjects must be negative for Hepatitis B surface antigen and Hepatitis C antibody at the screening visit. False positive patients may be cleared for enrollment based on RNA- 
based assays (see Section 7.3.7). 
17.  Height will be collected at screening only. 
18.  ECHO/MUGA not required at Follow-up visit if all other on-study LVEF assessments were normal and treating physician feels it is not indicated. 
19.  Archival tumor tissue (10 unstained slides, 5 micron thickness) will be collected if available for further research if a baseline biopsy is not performed. Efforts should be made to obtain 
the archival tissue prior to receiving drug; if a plan to receive the tumor tissue is in place, however, day 1 should not be delayed. 
20.  Optional early on-treatment biopsy may occur on day 15 +/- 3 days. 
21. Day 15 visit only for cycle 1; thereafter patients will be seen every 28 days (+/- 3 days).  
22. See Table 15 for required laboratory tests.


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7.2. 
Demographic/Medical History and Baseline Assessments 
 
The following demographic parameters will be captured during Screening: date of birth, 
gender, race and ethnicity. 
 
Medical/medication history assessed as related to the eligibility criteria listed in Section 
5.2. 
 
Baseline (Screening) assessments obtained will include: 
 
• 
Complete physical examination, including height (in cm) and weight (in kg). 
 
• 
Vital signs:  blood pressure, temperature, respiratory rate, pulse rate 
 
• 
Eastern Cooperative Oncology Group (ECOG) performance status 
 
• 
Clinical laboratory tests:  hematology, clinical chemistry and urinalysis 
 
• 
Serum beta-human chorionic gonadotropin (β-HCG) pregnancy test for female 
subjects of childbearing potential only 
 
• 
12-lead electrocardiogram (ECG) 
 
• 
Echocardiogram (ECHO) or multi-gated acquisition (MUGA) scan 
 
• 
Brain magnetic resonance imaging (MRI) with contrast or a computed tomography 
(CT) scan (with/without contrast) if MRI is contraindicated for all subjects with 
cutaneous melanoma 
 
• 
Ophthalmic exam by an ophthalmologist 
 
• 
Review of concomitant medications 
 
Procedures conducted as part of the subject’s routine clinical management (e.g., blood 
count, imaging study) and obtained prior to signing of informed consent may be utilized 
for Screening or baseline purposes provided the procedure meets the protocol-defined 
criteria and has been performed in the timeframe of the study. 
 
 
 
7.2.1. 
Critical Baseline Assessments 
 
Critical baseline assessments include height, weight, blood pressure, smoking history, 
medical conditions and family history of cardiovascular disease and risk factors, and 
stage of disease at screening. 
 


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7.3. 
Safety Evaluations 
 
Planned time points for all safety assessments are provided in the Time and Events Table 
(Section 7.1). 
 
7.3.1. 
Physical Examinations 
 
A complete physical examination will include assessments of the head, eyes, ears, nose, 
throat, skin, thyroid, neurological, lungs, cardiovascular, abdomen (liver and spleen), 
lymph nodes and extremities.  Height and weight will also be measured and recorded. 
 
A brief physical examination will include assessments of the skin, lungs, cardiovascular 
system, and abdomen (liver and spleen). 
 
7.3.2. 
ECOG Performance Status 
 
The performance status will be assessed using the Eastern Cooperative Oncology Group 
(ECOG) scale (Appendix 4) as specified in the Time and Events Table (see Section 7.1). 
 
7.3.3. 
Vital Signs 
 
Vital sign measurements will include (i.e., systolic and diastolic blood pressure, 
temperature, respiration rate and pulse rate).  Vital signs should be measured after resting 
for at least 5 minutes in a semi-supine position.  Vital signs will be measured more 
frequently if warranted by clinical condition of the subject.  On days where vital signs are 
measured multiple times, temperature does not need to be repeated unless clinically 
indicated.   
 
7.3.4. 
Electrocardiogram (ECG) 
 
A single 12-lead ECG will be obtained at designated time points during the study using 
an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, 
and corrected QT (QTc) intervals.  At each assessment a 12-lead ECG will be performed 
by qualified personnel at the site after the subject has at least a 5 minute rest and is in a 
semi-recumbent or supine position. 
 
The QT interval should be corrected for heart rate by Bazette’s formula (QTcB; see 
Appendix 6). Refer to Section 3.10.2 for QTc stopping criteria and additional 
information. 
 
7.3.5. 
Echocardiogram (ECHO) and/or Multi-gated Acquisition (MUGA) 
Scans 
 
An ECHO (preferred) or a MUGA scan will be performed at baseline to assess cardiac 
ejection fraction and cardiac valve morphology for the purpose of study eligibility, as 
specified in the Time and Events Table (see Section 7.1). Additional ECHO or MUGA 
assessments may be performed if clinically warranted.  The procedure used to document 
the subject’s baseline LVEF status should be used consistently throughout the study.  If 
possible, the interpretation of LVEF status should be performed consistently by the same 
reviewer throughout the study.  The evaluation of the echocardiographer should include 


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an evaluation for left ventricular ejection fraction (LVEF) and both right and left-sided 
valvular lesions. 
 
Copies of all ECHO or MUGA scans performed on subjects who experience an absolute 
decrease >10% in LVEF compared to baseline concurrent with LVEF < institutional 
lower limit of normal (LLN) may be required by the Coordinating Center for review. 
 
7.3.6. 
Brain MRI and/or CT Scan 
 
A magnetic resonance imaging (MRI) with contrast will be performed at Screening (see 
Time and Events Table, Section 7.1) to rule out any new untreated brain metastases and 
to verify stability of brain metastases if present for all subjects with cutaneous melanoma. 
A computed tomography (CT) scan with and without contrast may be performed if a MRI 
is contraindicated. 
 
7.3.7. 
Laboratory Assessments 
 
All protocol required laboratory assessments should be performed according to the 
Time and Events Table (see Section 
7.1).   
 
Prior to administration of the first dose of study treatment, results of laboratory 
assessments should be reviewed.  Any laboratory test with a value outside the normal 
range may be repeated (prior to the first dose) at the discretion of the investigator. 
 
If laboratory assessments for screening are completed within 72 hours of the first 
dose, they do not have to be repeated on cycle 1, day 1. If labs are obtained on the 
first day, values are still required to meet inclusion criteria (Table 13).  
 
If additional non-protocol specified laboratory assessments are performed at the 
institution’s local laboratory and result in a change in patient management or are 
considered clinical significant by the Investigator (for example SAE or AE or dose 
modification) the results must be recorded in the subject’s CRF. 
 
All laboratory tests with abnormal values that are considered clinically significant during 
participation in the study or within 30 days after the last dose of study treatment should 
be repeated until the values return to normal or baseline.  If such values do not return to 
normal within a period judged reasonable by the investigator, the possible etiology 
should be identified and the Coordinating Center notified. 
 
Hematology, clinical chemistry, urinalysis and additional parameters to be tested are 
listed in Table 15: 


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Table 15 
List of Clinical Laboratory Tests 
 
Hematology 
Platelet Count 
RBC Indices: 
Automated WBC Differential: 
Red blood cell (RBC) Count 
MCV 
Neutrophils 
White blood cell (WBC) Count 
(absolute) 
MCH 
Lymphocytes 
 
MCHC 
Monocytes 
Hemoglobin 
Eosinophils 
Hematocrit 
Basophils 
International Normalized Ratio (INR; at screening only)a 
Prothrombin time (PT; at screening only)a 
Partial thromboplastin time (PTT; at screening only)a 
Clinical Chemistry 
Blood urea nitrogen 
(BUN) 
Potassium 
Aspartate aminotransferase 
(AST) 
Total and direct bilirubin 
Creatinineb 
Chloride 
Alanine aminotransferase 
(ALT) 
 
Glucose, (random) 
Total carbon 
dioxide (CO2) 
 
Albumin 
Sodium 
Calcium 
Alkaline phosphatase 
 
Lactate 
Dehydrogenase 
(LDH) 
 
Potassium 
 
Routine Urinalysis 
Specific gravity 
pH, glucose, protein, blood and ketones by dipstick 
Microscopic examination (if blood or protein is abnormal) 
Other screening tests 
Human Immunodeficiency virus (HIV) c 
Hepatitis B (HBsAg) 
Hepatitis C (Hep C antibody -- if second generation Hepatitis C antibody positive, a hepatitis C antibody 
Chiron RIBA®  immunoblot assay should be reflexively performed  on the same sample to confirm the 
result) 
Follicle stimulating hormone (FSH) and estradiol (as needed in women of non-child bearing potential only) 
a. 
Coagulation panel to be done at Screening only 
b. 
If serum creatinine is > 1.5 mg/dL, creatinine clearance should be calculated using the standard Cockroft-Gault 
formula (Appendix ) 
c. 
HIV testing is optional 
 
 
7.3.8. 
Ophthalmic Examination 
 
Subjects are required to have a standard ophthalmic examination performed by an 
ophthalmologist at the times described (Section 7.1). At certain time points in the trial 
and if visual changes develop, an eye exam is indicated. (Refer to Table 6 for visual 
changes stopping criteria).  The exam will include best corrected visual acuity, 
tonometry, slit lamp biomicroscopic examination, visual field examination, and dilated 
indirect fundoscopy with special attention to retinal abnormalities.  Optical coherence 
tomography is strongly recommended at scheduled visits, and if retinal abnormalities are 
suspected. Other types of ancillary testing including color fundus photography and 


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fluorescein angiography are also recommended if clinically indicated. 


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7.3.9. 
Pregnancy Testing and Reporting 
 
The need for a screening pregnancy test depends on whether a female subject is of 
childbearing potential or non-childbearing potential. 
 
If a female subject is of childbearing potential, she must have a serum β-HCG pregnancy 
test performed within 14 days prior to the first dose of study treatment(s).  Subjects with 
positive pregnancy test result must be excluded from the study.  Subjects with negative 
pregnancy test result must agree to use an effective contraception method as described 
(Section 11.1.1) during the study until four months following the last dose of study 
treatment(s). 
 
Any pregnancy that occurs during study participation must be reported using a clinical 
trial pregnancy form.  To ensure subject safety, each pregnancy must be reported to the 
Coordinating Center within two weeks of learning of its occurrence.  The pregnancy must 
be followed up to determine outcome (including premature termination) and status of 
mother and child. Pregnancy complications and elective terminations for medical reasons 
must be reported as an adverse event (AE) or serious adverse event (SAE).  Spontaneous 
abortions must be reported as an SAE. 
 
Any SAE occurring in association with a pregnancy brought to the investigator’s 
attention after the subject has completed the study and considered by the investigator as 
possibly related to the study treatment(s), must be promptly reported to the 
Coordinating Center. 
 
In addition, the investigator must attempt to collect pregnancy information on any female 
partners of male study subjects who become pregnant while the subject is enrolled in the 
study.  Pregnancy information must be reported to the Coordinating Center as described 
above. 
 
7.4. 
Baseline Assessment of Target and non-target lesions 
 
All baseline lesion assessments must be performed within 28 days of enrollment. 
• Lymph nodes that have a short axis of <10mm are considered non- 
pathological and should not be recorded or followed. 
• Pathological lymph nodes with <15mm and but ≥10mm short axis are 
considered non measurable. 
• Pathological lymph nodes with ≥15mm short axis are considered measurable and 
can be selected as target lesions; however lymph nodes 
should not be selected as target lesions when other suitable target lesions 
are available. 
• Measurable lesions up to a maximum of two lesions per organ and five lesions in 
total, representative of all involved organs, should be identified as target lesions, 
and recorded and measured at baseline. These lesions should be selected on the 
basis of their size (lesions with the longest diameter) and their suitability for 
accurate repeated measurements (either by imaging techniques or clinically). 
 
Note: Cystic lesions thought to represent cystic metastases should not be selected 
as target lesions when other suitable target lesions are available. 


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Note: Measurable lesions that have been previously irradiated and have not been shown to 
be progressing following irradiation should not be considered as target lesions. 
 
 
• Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by CT or MRI can be considered measurable. 
Bone scans, FDG-PET scans or X-rays are not considered adequate imaging 
techniques to measure bone lesions. 
• All other lesions (or sites of disease) should be identified as non-target and should 
also be recorded at baseline. Non-target lesions will be group by organ. 
Measurements of these lesions are not required, but the presence or absence of 
each should be noted throughout follow-up. 
 
7.5. 
Efficacy Assessments 
 
Disease progression and response evaluations will be determined according to the 
definitions established in the Response Evaluation Criteria in Solid Tumors (RECIST 
version 1.1) [Eisenhauer, 2009]. 
 
See the Time and Events Table (Section 7.1) for the schedule of efficacy 
assessments. Assessments must be performed on a calendar schedule and should not 
be affected by dose interruptions/delays. 
 
The following are required at baseline: 
• Computed tomography (CT) scan with contrast (e.g., chest, abdomen, and/or 
pelvis as appropriate for a given subject) for assessment of baseline disease 
burden within four weeks of enrollment. All post- treatment assessments require 
CT imaging of disease sites identified by these baseline scans. 
NOTE: Although CT is preferred, MRI may be used as an alternative method of 
baseline disease assessment, especially for those subjects where CT is 
contraindicated (i.e., allergy), provided that the method used to document 
baseline status is used consistently throughout study treatment to facilitate direct 
comparison. 
• A baseline brain scan is required for all subjects for assessment of CNS disease 
within four weeks of enrollment. Head CT with contrast or magnetic resonance 
imaging (MRI) are both acceptable methods of CNS disease assessment, but 
contrast enhanced MRI is preferred. For subjects without CNS disease at baseline, 
subsequent brain scans should only be performed as clinically indicated (i.e., 
symptoms suggestive of CNS progression). Subjects demonstrating brain 
metastasis at baseline must have the baseline scan compared to an earlier scan 
performed (preferably 6 weeks earlier) to demonstrate that the metastasis is stable. 
Stable is defined as no increase in lesions between the two scans. The radiologist 
reports and the primary investigator’s analysis for these scans must be sent to the 
medical monitor for approval. Timing between the baseline scan and original scan 
is described above. 


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NOTE: For subjects with CNS disease at baseline, a brain scan  is 
required every eight weeks or as clinically indicated. 
 
NOTE: The method used to document baseline status should be used 
consistently throughout study treatment to facilitate direct comparison 
 
For subjects with palpable/superficial lesions, clinical disease assessments by 
physical examination should be performed at baseline and throughout study 
treatment as clinically indicated. 
 
Confirmation of CR and PR are required per protocol. Confirmation assessments must be 
performed no less than four weeks after the criteria for response have initially been met 
and may be performed at the next protocol scheduled assessment. If a confirmation 
assessment is performed prior to the next protocol schedule assessment, the next protocol 
scheduled evaluation is still required (e.g., evaluations must occur at each protocol 
scheduled time point regardless of unscheduled assessments). 
 
7.5.1 
Assessment Guidelines 
 
Please note the following: 
 
• 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. 
• 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 scan 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.  
• 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 electronic 
CRF. 
 
Clinical Examination: Clinically detected lesions will only be considered measurable 
when they are superficial (e.g., skin nodules). In the case of skin 


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lesions, documentation by color photography, including a ruler or calipers to 
measure the size of the lesion, is required. 
 
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 
optimized 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. 
 
Brain Scan: If brain scans are required, then contrast enhanced MRI is preferable to 
contrast enhanced CT. 
 
 
7.5.2 
Measurable and Non-measurable Definitions 
 
A measurable lesion is 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 caliper/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: 
• ≥15 mm in the short axis when assessed by CT or MRI (slice thickness 
recommended to be no more than 5 mm). At baseline and follow-up, only the 
short axis will be measured (Eisenhauer 2009). 
 
A non-measurable lesion is: 
• 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: 
ascites, pleural or pericardial effusions, inflammatory breast disease, 
lymphangitic involvement of the skin or lung, abdominal 


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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. Note: 
non-measurable only disease is not allowed per protocol. 
 
 
7.5.3 
Response Criteria 
 
7.5.3.1 
Target Lesions 
 
Definitions for assessment of response for target lesion(s) are as follows: 
• Complete Response (CR): Disappearance of all target lesions. Any 
pathological lymph nodes must be <10 mm in the short axis. 
• Partial Response (PR): At least a 30% decrease in the sum of the diameters of 
target lesions, taking as a reference, the baseline sum of the 
diameters (e.g. percent change from baseline). 
• Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for progressive disease. 
• Progressive Disease (PD): At least a 20% increase in the sum of the diameters of 
target lesions, taking as a reference, the smallest sum of diameters recorded since 
the treatment started (e.g. percent change from nadir, where nadir is defined as the 
smallest sum of diameters recorded 
since treatment start). In addition, the sum must have an absolute 
increase from nadir of 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. 


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• 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. 
 
 
 
7.5.3.2 
Non-target lesions 
 
Definitions for assessment of response for non-target lesions are as follows: 
• Complete Response (CR): The disappearance of all non-target lesions. All 
lymph nodes identified as a site of disease at baseline must be non- pathological 
(e.g. <10 mm short axis). 
• Non-CR/Non-PD: The persistence of 1 or more non-target lesion(s) or lymph 
nodes identified as a site of disease at baseline ≥ 10 mm short axis. 
• Progressive Disease (PD): Unequivocal progression of existing non-target 
lesions. 
• Not Applicable (NA): No non-target lesions at baseline. 
• Not Evaluable (NE): Cannot be classified by one of the four preceding 
definitions. 
 
NOTE: 
• In the presence of measurable disease, progression on the basis of solely non-
target disease requires substantial worsening such that even in the presence of SD 
or PR in target disease, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy. 
• Sites of non-target lesions, which are not assessed at a particular time point 
based on the assessment schedule, should be excluded from the 
response determination (e.g. non-target response does not have to be 
"Not Evaluable"). 
 
 
 
7.5.3.3 
New Lesions 
 
New malignancies denoting disease progression must be unequivocal. Lesions 
identified in follow-up in an anatomical location not scanned at baseline are considered 
new lesions. 
 
Any equivocal new lesions should continue to be followed. Treatment can continue at the 
discretion of the investigator until the next scheduled assessment. 


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If at the next assessment the new lesion is considered to be unequivocal, 
progression should be documented. 
 
 
7.5.3.4          Evaluation of overall response 
 
Table 16 presents the overall response at an individual time point for all possible 
combinations of tumor responses in target and non-target lesions with or without the 
appearance of new lesions for subjects with measurable disease at baseline. 
 
Table 16 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 
CR=complete response, PR = partial response, SD=stable disease, PD=progressive disease, 
NA= Not applicable, and NE=Not Evaluable 
 
NOTE: 
• Subjects with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
classified as having "symptomatic deterioration." Objective response status is 
determined by evaluations of disease burden. Every effort should be made to 
document the objective progression even after discontinuation of treatment. 
• In some circumstances, it may be difficult to distinguish residual disease from 
normal tissue. When the evaluation of CR depends on this determination, it is 
recommended that the residual lesion be investigated (fine needle aspirate/biopsy) 
to confirm the CR. 
 
 
7.5.3.5 
Evaluation of best overall response 
 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence and will be determined programmatically by the 
study investigator. 
• To be assigned a status of SD, the post-baseline disease assessment must have 
met the SD criteria at least once after study Day 1. 


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• If the minimum time for SD is not met, best response will depend on the subsequent 
assessments. For example if an assessment of PD follows the assessment of SD and 
SD does not meet the minimum time requirement the best response will be PD. 
Alternative subjects lost to follow-up after an SD assessment not meeting the 
minimum time criteria will be considered not evaluable. 
 
Confirmation Criteria: 
To be assigned a status of PR or CR, a confirmatory disease assessment should be 
performed no less than 28 days after the criteria for response are first met. Electronic 
scans will be required for independent review. 
 
 
7.6. 
Translational Research 
 
Performance of these investigations may be conditional on the results of the clinical trial, 
and samples may be selected for analysis on the basis of the clinical outcome.  A table of 
samples to be collected for translational research, whether the samples are mandatory or 
optional, and the primary purpose for collection is provided (see Table 17). 
 
Comparative examination of pre-dosing profiles of subjects may uncover known or novel 
candidate biomarkers/profiles which could be used to predict response to treatment with 
trametinib or provide new insights into cancer and medically related conditions. 
Comparative examination of post-dosing profiles in conjunction with pre-dosing profiles 
may yield known and novel candidate biomarkers/profiles and new insights which relate 
to the action of trametinib in this patient population. 
 
All samples may be retained for a maximum of 15 years after the last subject’s last visit 
of the follow-up period. Future research may be performed on available sample with an 
IRB-approved protocol.  
 
Novel candidate biomarkers and subsequently discovered biomarkers of the biological 
response associated with cancer or medically related conditions and/or the action of 
trametinib may be identified by application of: 
 
• DNA/gene, RNA, and protein analysis of tumor tissue and blood/plasma. 
 
Table 17 
Table of Samples for PD and Translational Research 
 
Samples 
Mandatory/Optional Archived/Fresh 
tumor tissue 
Primary Purpose 
Tumor 
tissue for 
genetic 
analysis 
Mandatory1 
Either 
For genetic analysis 
Pre-dose 
and post- 
Optional 
Fresh 
For PD analysis of protein 
biomarkers via IHC 


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dose tumor 
tissue 
biopsies 
or other analyses. 
Post- 
progression 
tumor 
biopsy 
Optional 
Fresh 
For evaluation of DNA, RNA 
and proteins related to drug 
response and resistance 
1Patients without available tumor tissue with genetic analysis may be included if previous next 
generation sequencing panels that have already assessed genetic biomarkers of 
interest have been performed. Discussion with the principle investigator is required. 
 
7.6.1. 
Tumor Tissue for Genetic and Protein Biomarker Analysis 
 
Molecular inclusion for the trial include: (1) The presence of a mutation in BRAF at a 
codon other than V600, or a BRAF gene fusion event; (2) The documented absence of a 
mutation at BRAFV600 (i.e., BRAFV600WT) in tumor tissue; and (3) The documented 
absence of a mutation in codons 12, 13, and 61 of NRAS. These molecular criteria for 
inclusion may be met by previously performed molecular testing performed in a CLIA- 
certified laboratory. Alternatively, archival or fresh tissue must be provided for testing of 
BRAF and NRAS. In addition to these required molecular tests, archival specimens are 
required to allow for testing of additional molecular alterations that may correlate with 
sensitivity or resistance to treatment with trametinib. Such alterations include, but are not 
limited to, gene mutations (MEK1, MEK2, KRAS, HRAS, NF1, PTEN, PIK3CA, AKT, 
TP53, CDKN2A, CDK4), gene deletions (PTEN, CDKN2A), gene amplifications (BRAF, 
CDK2, CCND1, MITF), and/or changes in gene or protein expression (growth factor 
receptors, p-ERK, p-AKT, PTEN, CDKN2A). 
 
During the screening period prior to enrollment, all subjects with melanoma will be 
required to provide archived tumor tissue or to undergo tumor biopsy if archived tumor 
tissue is not available.  New biopsy samples must be taken from lesions not required 
for disease assessment. 
 
Optional tumor biopsies may also be performed to allow for assessment of the 
pharmacodynamics effects of trametinib treatment. Such biopsies may be performed 
within 28 days of the start of treatment, and on Cycle 1 Day 15 (+/- 3 days to allow for 
scheduling conflicts). Assessment of these samples will include, but are not limited to, 
changes in the activation status of components of the MAPK pathway and other 
compensatory signaling pathways implicated in melanoma (i.e. PI3K-AKT pathway). 
 
Optional tumor biopsies may also be collected after documented disease progression 
from subjects that have provided appropriate consent. Samples will be used to investigate 
the molecular mechanisms of treatment resistance. Exact methodologies and markers 
examined will be determined by the Principal Investigators at the time the samples are 
available for analysis, based on existing knowledge about resistance and melanoma; the 
nature and amount of the biopsy material, and the molecular analysis platforms available 
at that time. Analyses may include, but are not limited to, changes in DNA, RNA, and/or 
protein, and the establishment of cell lines and/or xenografts. 


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Investigators are highly encouraged to collect tumor biopsies at baseline (in the 
absence of sufficient archival tissue) and day 15 (+/- 3 days) following initiation of 
therapy, with an optional tumor biopsy conducted at the time of disease progression.  
The pre-treatment biopsy will be obtained within 28 days of starting therapy. As noted, 
archival tissue within one year of starting therapy of sufficient quantity will preclude 
the need for an initial biopsy.  Issues that would cause treatment delays should be 
discussed with the PI who may grant permission on a case-by-case basis to analyze 
tissue from a protocol pre-treatment biopsy that has occurred greater than 28 days prior 
to study treatment.  The post-treatment biopsy will be performed at day 15 ± 3 days 
prior to the morning dose of the study medications.  An optional third tumor biopsy 
will be requested of these patients at the time of tumor progression, with particular 
efforts made at obtaining such biopsies in patients who have developed progression 
after achieving a radiographic response to treatment or after prolonged disease control 
(i.e., greater than 4 months). All biopsies may be obtained through excisional, 
incisional, core-needle, or punch biopsy methods. Up to eight core samples will be 
obtained with each biopsy (in the case of a core biopsy), providing sufficient tissue for 
the correlative studies.   
 
Tissue will be divided such that a portion (one core in the case of core needle biopsy 
procedures) is formalin fixed and designated for immunohistochemistry (IHC) and the 
remainder flash frozen in liquid nitrogen or embedded in optimal cutting temperature 
(OCT) compound. When limited tissue is available, flash frozen/OCT tissue will 
generally be prioritized.  
 
Fresh tumor biopsy samples should be snap-frozen using liquid nitrogen or a dry ice 
slurry, or embedded in OCT. The tissue must be processed as soon as possible after 
biopsy to minimize any form of degradation and to avoid risking the viability of the 
tissue.  The following procedures may be used or standard operating procedures (SOPs) 
for each institution may be used after discussion with the principal investigator.  
 
Snap-Freezing in Liquid Nitrogen: 
• 
Label cryogenic vial(s) with the subject’s study identification number, 
the date of collection, time point (baseline, day 15, or progression) and the study 
center performing the biopsy.  Ensure that the label adheres to the vial and does 
not come off when placed in liquid nitrogen.  Labels cannot be adequately 
affixed to the vials after freezing. 
• 
Immediately place the freshly obtained tissue into the labelled cryogenic 
vial.  Place the vial with tissue in liquid nitrogen for 2 minutes or longer to snap-
freeze the tissue.  Tumor cores should be frozen individually in separate 
cryovials as collected in order to minimize the time between removal and 
freezing. 
• 
Remove the cryogenic vial from the liquid nitrogen. 
• 
Store the sample in a -80°C freezer (-65°C to -80°C is acceptable) until 
ready for shipping. 
 
Freezing Procedure with Dry Ice Slurry 
• 
Materials required include: 5 lbs dry ice, alcohol (ethanol or comparable), 
basin, long forceps 


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• 
Place at least 5 lbs of dry ice into a basin and pour one liter of alcohol 
over the ice. 
• 
Label cryogenic vial(s) with the subject’s study identification number, 
the date of collection, and the study center performing the biopsy.  Ensure that 
the label adheres to the vial and does not come off when placed in liquid 
nitrogen.  Labels cannot be adequately affixed to the vials after freezing. 
• 
Immediately place the freshly obtained tissue into the labelled cryogenic 
vial.  Place the vial with tissue in liquid nitrogen for 2 minutes or longer to snap-
freeze the tissue.  Tumor cores should be frozen individually in separate 
cryovials as collected in order to minimize the time between removal and 
freezing. 
• 
Pace the lower half of the sealed cryotube containing tissue into the 
solution for at least 2 minutes until frozen solid. 
• 
Store the sample in a -80°C freezer (-65°C to -80°C is acceptable) until 
ready for shipping. 
 
Archival tumor tissue should be obtained as 10 unstained slides with 5 micron thickness. 
 
7.6.2. 
Blood Biomarkers 
 
Blood samples (3X 10 ml) will be collected as indicted in the Time and Events Table (see 
Section 7.1). Blood will be processed to isolate both PBMCs and serum for future 
biomarker analyses at the conclusion of the study, as to be determined by the 
investigators based on the state of knowledge at that time, and available molecular 
analysis platforms. Possible analyses include, but are not limited to, immune cell 
populations, circulating free DNA (cfDNA), circulating miRNA, and proteins/cytokines. 
 
Three 10 ml sodium heparin tubes will be collected from patients prior to treatment, and 
at day 15.  Samples will be subsequently stored for future correlative studies. The 
samples drawn prior to treatment can be drawn on C1W1 prior to initiation of study 
drug.   
Process samples in the following manner. If institutional standards differ for PBMC or 
plasma processing, other processing methods may be acceptable pending discussion with 
the principal investigator.  
 
• 
Processing – Plasma  
1. Centrifuge the tubes at 609 x g or equivalent speed for 10-15 minutes with low brake. 
Centrifuge at 4 °C.  
2. Use a transfer pipette to transfer the plasma into cryovials in 1mL aliquots. Store 
cryovials in -80 °C freezer until shipped. 
3. Save remaining sample for PBMC processing. 
  
Processing - Peripheral Blood Mononuclear Cells 
1. Remove the Ficoll from the refrigerator and aliquot 12mls of Ficoll into two separate 
50mL centrifuge tubes (or prepare Ficoll for underlay using pre-measured transfer 
packs). 
2. Dilute remaining sample from plasma processing above (white and red blood cells) 
with 1:1 1XPBS. Wash the original green-top blood tubes with the diluent prior to 
mixing in the empty 50mL tube. Mix the PBS and blood well.  


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3. Slant the 50mL tube containing Ficoll being careful not to spill. Carefully pour the 
diluted blood on top of the Ficoll so as to not disturb the Ficoll layer. Discard the 
now empty 50mL tubes as well as the original blood tubes.  
4. Spin at 609 x g or equivalent speed for 20 minutes, no brake. Centrifuge at 4ºC.  
5. Aspirate the PBMC layer at the interface above the density gradient (white layer/buffy 
coat) including a small amount of plasma but as little Ficoll as possible.  
6. Transfer to a sterile, 50mL centrifuge tube. Add sufficient 1X PBS to bring the fluid 
volume to 50mls in each tube. Spin at 343 x g or equivalent speed for 15 minutes.  
7. Pour off supernatant, flick tube to re-suspend cells (repeat steps 7-8 two more times to 
give a total of three washes.)  
8. After third wash, add 10mL 1X PBS and count cells. Record cell count and cell 
viability. 
9. Spin at 343 x g or equivalent speed for 15 minutes. Pour off supernatant. 
10. Prepare a 10% DMSO in 100% FBS (1:10 dilution) for freezing solution. Ensure the 
FBS is chilled before adding the DMSO.  
11.  Suspend cell pellet in enough freezing media to ensure 1 mL aliquots of 5.0x106 
cells. 
12.  Make 1mL aliquots into cryovials, and store at -80 °C until shipment. 
 
8. 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
The investigator or site staff will be responsible for detecting, documenting and reporting 
events that meet the definition of an adverse event (AE) or serious adverse event (SAE) 
as outlined in Section 8.1 and Section 8.2, respectively. 
 
8.1. 
Definition of an AE 
 
Any untoward medical occurrence in a subject or clinical investigation subject, 
temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product. 
 
Note: An adverse event (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]). 
 
“Lack of efficacy” or “failure of expected pharmacological action” per se is not to be 
reported as an AE or SAE.  However, any signs and symptoms and/or clinical sequelae 
resulting from “lack of efficacy” will be reported as an AE or SAE, if they fulfill the 
definition of an AE or SAE. 


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Events that do not meet the definition of an AE include: 
 
• 
Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition that 
leads to the procedure is an AE. 
 
• 
Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen. 
 
• 
The disease/disorder being studied, or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the subject’s 
condition. 
 
8.2. 
Definition of an SAE 
 
A serious adverse event (SAE) is any untoward medical occurrence that, at any dose: 
 
a. 
Results in death 
 
b. Is life-threatening 
 
NOTE:  The term 'life-threatening' in the definition of 'serious' refers to an event in 
which the subject was at risk of death at the time of the event.  It does not refer to an 
event, which hypothetically might have caused death, if it were more severe. 
 
c. 
Requires hospitalization or prolongation of existing hospitalization 
 
NOTE:  In general, hospitalization signifies that the subject has been detained 
(usually involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or out-subject setting. Complications that occur during hospitalization are 
adverse events (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. 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 


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surgical intervention to prevent one of the other outcomes listed in the above 
definition.  These should also be considered serious.  Examples of such events are 
invasive or malignant cancers, intensive treatment in an emergency room or at home 
for allergic bronchospasm, blood dyscrasias or convulsions that do not result in 
hospitalization, or development of drug dependency or drug abuse. 
 
g. Protocol-Specific SAEs: 
 
• 
All events of possible study treatment-induced liver injury with 
hyperbilirubinemia defined as alanine aminotransferase (ALT) ≥3 times upper 
limit of normal (ULN) and bilirubin ≥2 times ULN (>35% direct) (or 
ALT ≥3 times ULN and international normalization ratio (INR) >1.5, if INR is 
measured) or termed ‘Hy’s Law’ events (INR measurement is not required and 
the threshold value stated will not apply to patients receiving anticoagulants). 
 
NOTE:  Bilirubin fractionation is performed if testing is available.  If testing is 
not available, record presence of detectable urinary bilirubin on dipstick 
indicating direct bilirubin elevations and suggesting liver injury.  If testing is 
unavailable and a subject meets the criterion of total bilirubin ≥2 times ULN, 
then the event is still reported as a serious adverse event (SAE).  If INR is 
obtained, include values on the SAE form.  INR elevations >1.5 suggest severe 
liver injury. 
 
• 
Any new primary cancers 
 
• 
LVEF that meets stopping criteria (see Section 3.9.1.1) 
 
• 
Retinal pigment epithelial detachment (RPED) or retinal vein occlusion 
 
8.2.1. 
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 Medical Monitor is accountable for 
reviewing all SAEs for possible Sentinel Events which is mandated by the Supporter.  
The medical monitor 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: 
 
• 
Acquired Long QT Syndrome 
 
• 
Agranulocytosis/Severe Neutropenia 
 
• 
Anaphylaxis & Anaphylactoid Reactions 
 
• 
Hepatotoxicity 
 
• 
Acute Renal Failure 
 
• 
Seizure 
 
• 
Stevens Johnson syndrome/Toxic epidermal necrosis 


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8.3. 
Laboratory and Other Safety Assessment Abnormalities 
Reported as AEs and SAEs 
 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis), or 
other safety assessments (e.g., 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. 
 
8.3.1. 
Cardiovascular Events 
 
Investigators will be required to fill out event specific data collection tools for the 
following AEs and SAEs: 
 
• 
Myocardial infarction/unstable angina 
 
• 
Congestive heart failure 
 
• 
Arrhythmias 
 
• 
Valvulopathy 
 
• 
Pulmonary hypertension 
 
• 
Cerebrovascular events/stroke and transient ischemic attack 
 
• 
Peripheral arterial thromboembolism 
 
• 
Deep venous thrombosis/pulmonary embolism 
 
• 
Revascularization 
 
This information should be recorded in the specific cardiovascular eCRF within one week 
of when the AE/SAE(s) are first reported. 
 
8.4. 
Disease-Related Events and/or Disease-Related Outcomes 
Not Qualifying as SAEs 
 
An event which is part of the natural course of the disease under study (i.e., disease 
progression or hospitalization due to disease progression) does not need to be reported as 
a serious adverse event (SAE).  Death due to disease under study is to be recorded on the 
Death electronic case report form (eCRF).  However, if the underlying disease (i.e., 


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progression) is greater than that which would normally be expected for the subject, or if 
the investigator considers that there was a causal relationship between treatment with 
study treatment(s) or protocol design or procedures and the disease progression, then this 
must be reported as a SAE. 
 
8.5. 
Time Period and Frequency of Detecting AEs and SAEs 
 
The investigator or site staff is responsible for detecting, documenting and reporting 
events that meet the definition of an adverse event (AE) or serious adverse event (SAE). 
 
AEs will be collected from the time the first dose of study treatment is administered until 
30 days following discontinuation of study treatment regardless of initiation of a new 
cancer therapy or transfer to hospice. 
 
SAEs will be collected over the same time period as stated above for AEs.  In addition, 
any SAE assessed as related to study participation (e.g., protocol-mandated procedures, 
invasive tests, or change in existing therapy), study treatment or Novartis concomitant 
medication must be recorded from the time a subject consents to participate in the study 
up to and including any follow-up contact.  All SAEs will be reported to Coordinating 
Center within 24 hours, as indicated in Section 8.5.1. 
 
After discontinuation of study treatment, the investigator will monitor all AEs/SAEs that 
are ongoing until resolution or stabilization of the event or until the subject is lost to 
follow-up.  At any time after 30 days the investigator may report any AE that they 
believe possibly related to study treatment. 
 
8.5.1. 
Prompt Reporting of SAEs and Other Events 
 
Serious adverse events (SAEs), pregnancies, and liver function abnormalities and any 
other events meeting pre-defined criteria will be reported promptly by the investigator on 
a Vanderbilt Serious Adverse Event Form and the centralized electronic case report form 
called ON-line Clinical Oncology Research Environment = Oncore 
 as described (Table 18) in the following 
table once the investigator determines the event meets the protocol definition for that 
event. SAEs should also be sent to Novartis and the NCCN as listed below: 
 
All Events must be reported to Novartis within 24 hours of learning of its occurrence. 
Information about all SAEs is collected and recorded on a Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess and record the relationship of each SAE to 
each specific study treatment (if there is more than one study treatment), complete the SAE 
Report Form in English, and send the completed, signed form by fax to (
within 24 hours to the oncology Novartis DS&E department with the provided FAX 
cover sheets and to NCCN via email to 


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Table 18 
Rules for Reporting SAE, Cardiovascular, Pregnancy and Liver 
Function Abnormalities 
 
 
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 
2 Weeks 
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. 
Coordinating Center is 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. 
 


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8.5.2. 
Regulatory reporting requirements for SAEs 
 
Prompt notification of serious adverse events (SAEs) by the investigator to the 
Coordinating Center is essential so that legal obligations and ethical 
responsibilities towards the safety of subjects are met. All serious adverse events 
must be reported to the Coordinating Center within 1 business day after the treating 
institution becomes aware of the event. Events should be reported using the 
Vanderbilt Serious Adverse Event Form. 
 
Follow-up information must also be reported within 1 business day of receipt of 
the information by the investigator. 
 
The Coordinating Center has a legal responsibility to notify the local regulatory 
authority, the FDA and other regulatory agencies about the safety of a product under 
clinical investigation.  The Coordinating Center will comply with country specific 
regulatory requirements relating to safety reporting to the regulatory authority, 
institutional review board (IRB)/ethics committee (EC) and investigators. 
 
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and Novartis policy and are 
forwarded to investigators as necessary. 
 
An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from Novartis will file it 
with the IB and will notify the IRB/EC, if appropriate according to local requirements. 
 
Food and Drug Administration (FDA) 
 
In this trial, unexpected adverse events believed to be definitely, probably, or possibly 
related to the medications will be reported to the Food and Drug Administration via 
MedWatch Form 3500A Mandatory Reporting Form (using the online form available at:  
http://www.fda.gov/downloads/Safety/MedWatch/HowToReport/DownloadForms/UCM
082728.pdf by telephone 1-800-FDA-1088; or by fax 1-800-FDA-0178 using form 
available at: 
 http://www.fda.gov/Safety/MedWatch/HowToReport/ucm085692.htm.  
The Coordinating Center will be responsible for correspondence regarding adverse 
events with the FDA for all participating sites. 
 
 
9. 
LIVER CHEMISTRY FOLLOW-UP PROCEDURES 
 
9.1. 
Liver Chemistry Testing Procedures 
 
For subjects meeting any of the liver chemistry stopping criteria in Section 3.10.1, 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) 


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• 
Hepatitis C RNA 
 
• 
Cytomegalovirus IgM antibody 
 
• 
Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, then obtain 
heterophile antibody or monospot testing) 
 
• 
 
• 
Serum creatinine phosphokinase (CPK) and lactate dehydrogenase (LDH). 
 
• 
Fractionate bilirubin, if total bilirubin ≥2 X upper limit of normal (ULN). 


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• 
Obtain a complete blood count (CBC) with differential to assess eosinophilia. 
 
• 
Record the appearance or worsening of clinical symptoms indicative of hepatitis 
or hypersensitivity, such as fatigue, nausea, vomiting, right upper quadrant pain 
or tenderness, fever, rash or eosinophilia as relevant on the AE eCRF. 
 
• 
Record the use of concomitant medications, including acetaminophen, herbal 
remedies or any other over the counter (OTC) medications, or any putative 
hepatotoxins, on the concomitant medication eCRF. 
 
• 
Record alcohol use on the liver event alcohol intake eCRF. 
 
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. 
 
 
 
9.2. 
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 Medical Monitor 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 3.10.1), then proceed as described in Section 9). 
 
• 
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. 
 
9.3. 
Drug Restart/Rechallenge Following Liver Events that are 
Possibly Related to Study Drug(s) 
 
Approval by the Medical Monitor 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. 


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• 
If the restart/rechallenge is approved by Coordinating Center 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 Medical 
Monitor. 
 
• 
Subjects approved by the Coordinating Center 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. 
 
9.4. 
Drug Restart Following Transient, Resolving Liver Events 
Not Related to Study Drug(s) 
 
Approval by the Medical Monitor 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 Coordinating Center 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 Medical 
Monitor. 
 
• 
Subjects approved by the Coordinating Center 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. 


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10. 
CONCOMITANT MEDICATIONS AND NON-DRUG 
THERAPIES 
 
Subjects will be instructed to inform the investigator prior to starting any new 
medications from the time of first dose of study treatment until the end of the study (Final 
Study Visit). Any concomitant medication(s), including non-prescription medication(s) 
and herbal product(s), taken during the study will be recorded in the electronic case 
report form (eCRF).  Additionally, a complete list of all prior anti-cancer therapies will 
be recorded in the eCRF. 
 
If future changes are made to the list of permitted/prohibited medications, formal 
documentation will be provided by the Coordinating Center and stored in the study file.  
Any such changes will be communicated to the investigative sites in the form of a letter. 
 
As trametinib is metabolized predominantly via deacetylation likely mediated by 
hydrolytic esterases, its PK is unlikely to be affected by other agents through metabolic 
interactions. Trametinib repeat-dose exposure was not affected by co-administration with 
a CYP3A4 inducer. 
 
Based on in vitro and in vivo data, trametinib is unlikely to significantly affect the PK of 
other medicinal products via interactions with CYP enzymes or transporters. 
 
Any questions regarding concomitant medications should be directed to the Medical 
Monitor for clarification. 
 
10.1. 
Permitted Medication(s) 
 
Subjects should receive full supportive care during the study, including transfusion of 
blood and blood products, and treatment with antibiotics, antiemetics, antidiarrheals, and 
analgesics, and hematopoietic growth factors as appropriate. 
 
10.2. 
Prohibited Medications and Non-Drug Therapies 
 
The use of certain medications prior to the first dose of study treatment (refer to inclusion 
and exclusion criteria, Section 5.2) and for the duration of the study will not be allowed. 
If a prohibited medication is required for single use (such as for a procedure) while 
treatment with study treatment is interrupted, the Medical Monitor can approve such 
use. 
 
The following medications or non-drug therapies are prohibited: 
 
• Anticancer agents: Additional investigational or commercial anticancer agents 
such as chemotherapy, immunotherapy, targeted therapy, biological response 
modifiers, or endocrine therapy will be prohibited. 
 
• Herbal therapies: Subjects will abstain from using herbal 
preparations/medications within 14 days prior to the first dose of Trametinib and 
throughout the study until the end of treatment visit. These herbal medications 
include, but are not limited to, St. John’s wort, kava, ephedra (ma huang), gingko 
biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and ginseng. 


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The investigator should contact the Medical Monitor before initiating 
treatment with any herbal preparation. 
 
11. 
LIFESTYLE AND/OR DIETARY RESTRICTIONS 
 
11.1. 
Contraception 
 
11.1.1. 
Female Subjects 
 
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 during the study and 
so must be sexually inactive by abstinence or use contraceptive methods with a 
failure rate of <1%. 
 
Abstinence 
 
Sexual inactivity by abstinence must be consistent with the preferred and usual lifestyle 
of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of contraception. 
 
Complete abstinence from sexual intercourse for 14 days prior to first dose of study 
treatment, through the dosing period, and for at least four months after the last dose of 
study treatment. 
 
Contraceptive Methods with a Failure Rate of <1% 
 
• 
Oral contraceptives (either combined or progesterone only) if not contraindicated for 
this subject population or per local practice. 
 
• 
Estrogenic vaginal ring if not contraindicated for this subject population or per local 
practice. 
 
• 
Percutaneous contraceptive patches if not contraindicated for this subject population 
or per local practice. 
 
• 
Implants of levonorgestrel if not contraindicated for this subject population or per 
local practice. 
 
• 
Injectable progesterone if not contraindicated for this subject population or per local 
practice. 


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• Intrauterine device or intrauterine system 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. 
 
11.1.2. Male Subjects 
 
To prevent pregnancy in a female partner, male subjects must use one of the following 
contraceptive methods from the beginning of the study until 90 days after the last dose of 
study treatment: 
 
 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. 
 
 Condom (during non-vaginal intercourse with any partner - male or female) OR 
 
 Double-barrier method: condom and occlusive cap (diaphragm or cervical/vault 
caps) plus spermicidal agent (foam/gel/film/cream/suppository) (during sexual 
intercourse with a female) 
 
11.2. 
Lactation Restrictions 
 
Female subjects who are lactating must discontinue nursing prior to the first dose of study 
treatment and must refrain from nursing throughout the treatment period and for four 
months following the last dose of study treatment. 
 
 
 
12. 
DATA MANAGEMENT 
 
Each participating institution will be collaborating with Vanderbilt on patient accrual. 
Data will be collected using a centralized electronic case report form called ON-line 
Clinical Oncology Research Environment = Oncore 
Oncore is a highly secure, web based, 
cancer specific, and customizable system that provides fully integrative clinical data 
management and study administration capabilities developed in an ongoing collaborative 
effort with NCI designated Comprehensive Cancer Centers. It fully integrates study 
administration functionality including protocol tracking, patient registration, NCI 
reporting, review committee tracking, and SAE tracking, with clinical data management 


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functionality including electronic case report forms (eCRF) design, clinical data capture, 
protocol and regulatory compliance monitoring. Also the system is capable in storing 
basic protocol information (e.g., IRB approval dates, dates for annual renewals, etc.) and 
clinical trials research data. Oncore allows the investigator to define specific protocol 
requirements and generate data collection forms. Creation of the data collection form is 
done with a single button click after the parameters of an individual protocol have been 
specified. Oncore permits specification of study protocols, management of patient 
enrollment, clinical data entry and viewing, and the generation of patient or study-specific 
reports based on time stamping. OnCore is embedded with a comprehensive domain 
repository of standard reference codes and forms to promote standardization. The sources 
for the repository include CDUS, CTC, CDEs from NCI, ICD, MedDRA and various best 
practices from contributing NCI-designated Comprehensive Cancer Centers. OnCore 
provides several reporting features specifically addressing NCI Summary 3 and Summary 
4 and other reporting requirements. Data may also be exported in a format suitable for 
import into other database, spreadsheets or analysis systems (such as SPSS). This system 
will be used to manage all VICC clinical trials data. OnCore is maintained and supported 
in the VICC Clinical and Research Informatics Resource. 
 
Specified members at each participating site will submit all pertinent regulatory 
documents to the Coordinating Center team member, who will upload it on Oncore. 
 
The Principal Investigator or designee will inform the sponsor within 24 hrs of any serious 
adverse event, and will inform the IRB in accordance with each institution’s IRB policy. 
The investigator is responsible for the detection and documentation of events meeting the 
criteria and definition of an AE or SAE, as provided in this protocol. During the study 
when there is a safety evaluation, the investigator or site staff will be responsible for 
detecting, documenting, and report AEs and SAEs, as detailed in the protocol. 
Furthermore, the investigator will be required to provide periodic (monthly) safety updates 
on the conduct of the study at his/her site and notification of study closure to the SRC/IRB. 
If any problem is identified related to the conduct of this research, the VICC Data Safety 
and Monitoring Committee (DSMC) will be formally asked to review the study and the 
situation that required DSMC intervention.  
 
13. 
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS 
 
13.1. 
Hypothesis 
 
The primary objective is to determine wither trametinib is an effective targeted therapy in 
BRAF nonV600MUT melanoma. The hypothesis described below will apply to cohort A 
(“high activity” mutations and fusion events). The null hypothesis is that the objective 
response rate (ORR; percentage of patients achieving a confirmed CR or PR is not 
attractive (defined as ≤5%). The alternative hypothesis is that the response rate is of 
interest for further development (defined as ≥25%). 
 
The final analysis of the overall response rate will be performed using one sided test with 
α=0.05. It is calculated that at least 4 responses are needed out of a total of 25 patients to 
reject the null hypothesis. 
 
To allow early termination of the trial due to lack of efficacy, the trial will be conducted 
in two stages per Simon’s Minimax Design. If no responses are demonstrated in the first 
15 patients, then the trial will be terminated early for futility. If ≥1 responses are observed, 


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enrollment will continue to 25 patients. 
 
For the experimental arm (cohort B), the trial will also be conducted in two stages. If no 
responses are demonstrated in the first 15 patients, then the cohort will be terminated 
early for futility. If ≥1 responses are observed, enrollment will continue to a maximum of 
25 patients. Additionally, when cohort A accrual has completed, cohort B will close and 
not accrue further patients. 
 
Given the rapid changes in melanoma therapies, we will also have the option of closing 
either cohort if the clinical activity is low. If one or two responses occur in cohort A from 
the first 15 patients, the principal investigators and Coordinating Center will have the 
option of closing the trial at the interim analysis. The principal investigators must be in 
universal agreement for this to occur. 
 
13.2. 
Sample Size Assumptions 
 
To determine the overall sample size and the interim sample size, a two stage Simon’s 
Minimax design was evaluated. To test the hypotheses (ORR=5% vs. 25%), 1 
response from the first 15 subjects would be required to progress to stage 2 and a total 
of 25 subjects will be needed to achieve the desired type I (<5%) and type II error rate 
(Power>90%). The risk of incorrectly stopping the trial after stage I if the drug is 
effective is <1.5%. 


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Table 20: Sample size calculations 
 
If the True Response Rate to 
trametinib is: (%) 
Probability of Early Termination 
after Stage I 
Probability of Rejecting the Null 
Hypothesis 
5% 
0.463 
0.034 (type 1 error) 
10% 
0.206 
0.234 
15% 
0.087 
0.525 
20% 
0.035 
0.762 
25% 
0.013 
0.901 
30% 
0.005 
0.965 
 
 
13.3. 
Data Analysis Considerations 
 
Data will be listed and summarized according to Novartis integrated data standards 
library (IDSL) reporting standards where applicable. Complete details will be provided 
in the Reporting and Analysis Plan (RAP). Analyses will be performed for each cohort. 
 
13.3.1. 
Interim Analysis 
 
An interim analysis will be performed for each cohort after 15 subjects have completed 
their first post-dose disease assessment at 8 weeks. The primary analysis of this includes 
a boundary for early decision on futility. 
 
By the Simon Optimal design, it is calculated that at least 1 response of 15 subjects are 
needed to further progress enrolment. There is no early stopping boundary for efficacy, 
however if ≥4 patients experience CR or PR, then further planning of additional 
development may occur. 
 
Core members of the Novartis clinical team will be notified of the results of the 
interim analysis. Investigators will be informed as to whether or not the study will be 
stopped prematurely. 
 
13.3.2. 
Final Analysis 
 
13.3.2.1. 
Primary Analysis 
 
The primary comparison of interest (and primary endpoint) is to determine whether the 
objective response rate to trametinib in cohort A (“high affinity” group) is less than or 
equal to a null hypothesized response rate of 5% versus an alternative response rate of 
25%. No comparisons between treatments will be performed as there is a single arm in 
each cohort. The primary analysis of ORR will be performed following treatment of all 
patients for at least 8 weeks or have discontinued therapy. 
 
13.3.2.2. 
Secondary Analyses 
 
13.3.2.2.1. Cohort B 
 
Overall response rate will be assessed in cohort B as defined by RECIST 1.1 criteria and 
will be reported in a descriptive fashion. No statistical comparisons will be performed. 


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13.3.2.2.2. Overall Survival and Progression-Free Survival for both cohort A and B 
 
Overall survival, defined as the time from Day 1 of the trametinib therapy to death from 
any cause. Progression free survival, defined as the time from Day 1 of trametinib 
therapy to progression of disease as defined by RECIST 1.1 criteria or death, will be 
reported for each arm. We will also perform subset analysis for PFS stratified by 
baseline characteristics including LDH level, metastatic stage, and previous therapy 
(particularly whether a subject has received immune-based therapy). 
 
13.3.2.2.3. Safety 
 
Adverse events (AEs) will be coded using the standard MedDRA and grouped by system 
organ class.  Adverse events (AEs) will be graded by the investigator according to the 
National Cancer Institute- Common Toxicity Criteria for Adverse Events (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, treatment- 
related AEs, serious adverse events (SAEs) and AEs leading to discontinuation of study 
treatment.  Adverse events (AEs), if listed in the NCI-CTCAE (version 4.0) will be 
summarized by the maximum grade.  Otherwise, the AEs will be summarized by 
maximum intensity. 
 
Characteristics (e.g. number of occurrences, action taken, grade, etc.) of the following 
AEs of special interest will be summarized separately. 
 
The incidence of deaths and the primary cause of death will be summarized. 
 
13.3.2.2.4. Biomarkers and Pharmacodynamic Analyses 
 
The study will analyze tumor tissue and/or blood to understand genetic mechanism of 
MEK inhibitor response and resistance. As data warrant, correlation analysis will be 
performed to explore the relationship between patient’s biomarker and PD data (e.g. 
change from baseline) to patient’s tumor response. As data warrant, additional analysis 
will be conducted on cfDNA data. Full details will be provided in RAP prior to study 
initiation. 
 
Molecular characterization of tumor tissue will be performed to identify markers that 
correlate with clinical responsiveness to treatment with trametinib.  Analysis will 
incorporate detection of DNA-based alterations in other genes known to be altered in 
melanoma, including (but not limited to) genes in the MAPK pathway (i.e. MEK1/2, 
NF1), PI3K-AKT pathway (i.e. PIK3CA, AKT, PTEN), cell cycle regulators (i.e. 
CDKN2A, CDK4, CCND1), and/or broader molecular testing.  Analysis of RNA and 
protein may also be performed for tumors with sufficient material available to assess 
functional networks and pathways.  The exact methodologies used will be selected based 
on the DNA/RNA/protein amounts, technologies, and information available at the time 
the analyses will be performed.  Analyses will be performed on pre-treatment and/or 
archival samples to identify predictors of treatment outcomes. Optional on-treatment 
biopsies will be used to evaluate pharmacodynamic and other molecular effects of 


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treatment, which will be compared to clinical outcomes.  Optional post-progression 
samples will be analyzed to identify mechanisms of resistance. 
 
13.3.3. 
Withdrawal 
 
Reason for subject withdrawal will be listed. 
 
13.3.4. 
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. 
 
13.3.5. 
Protocol Violations 
 
A summary and listing of protocol violations will be provided. 
 
13.3.6. 
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. 
 
13.3.7. 
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. 
 
13.4. 
Key Elements of Analysis Plan 
 
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).  Any deviations from, or additions to, the original analysis plan described in this 
protocol will be documented in the RAP and final study report. 
 
As it is anticipated that accrual will be spread thinly across centers and summaries of data 
by center would be unlikely to be information, data from all participating centers will be 
pooled prior to analysis. 
 
All data up to the time of study completion/withdrawal from study will be included in the 
analysis, regardless of duration of treatment. 


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13.4.1. 
Pharmacodynamic Analyses 
 
13.4.1.1. 
Translational Research Analyses 
 
The results of translational research investigations may be reported separately from the 
main clinical study report (CSR).  All endpoints of interest from all comparisons will be 
descriptively and/or graphically summarized as appropriate to the data. 
 
Further details on the translational research analyses will be addressed in the Reporting 
and Analysis Plan (RAP). 
 
13.4.1.2. 
Novel Biomarker(s) Analyses 
 
The results of these biomarker investigations may be reported separately from the main 
clinical study report.  All endpoints of interest from all comparisons will be descriptively 
and/or graphically summarized as appropriate to the data. 
 
Additional exploratory analyses may be performed to further characterize the novel 
biomarker. 
 
14. 
STUDY CONDUCT CONSIDERATIONS 
 
14.1. 
Posting of Information on Clinicaltrials.gov 
 
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrolment of subjects begins. 
 
14.2. 
Regulatory and Ethical Considerations, Including the 
Informed Consent Process 
 
Prior to initiation of a study site, the Coordinating Center will obtain approval from the 
appropriate regulatory agency to conduct the study in accordance with International 
Conference on Harmonization Good Clinical Practice (ICH GCP) and applicable 
country-specific regulatory requirements. 
The study will be conducted in accordance with all applicable regulatory requirements. 
The study will be conducted in accordance with ICH GCP, all applicable subject privacy 
requirements, and the ethical principles that are outlined in the Declaration of Helsinki 
2008, including, but not limited to: 
 
• 
Institutional review board (IRB)/ethics committee (EC) review and approval of study 
protocol and any subsequent amendments 
 
• 
Subject informed consent 
 
• 
Investigator reporting requirements 
 
The Coordinating Center will provide full details of the above procedures, either verbally, 
in writing, or both. 


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Written informed consent must be obtained from each subject prior to participation in the 
study. 
 
Protocol Review and Amendments 
Information regarding study conduct and progress will be reported to the Institutional 
Review Board (IRB) per the current institutional standards of each participating center. 
 
Any changes to the protocol will be made in the form of an amendment and must be 
approved by the IRB of each institution prior to implementation.   
 
The Protocol Chair (or his designee) is responsible for the coordination and development 
of all protocol amendments, and will disseminate this information to the participating 
sites. 
Before implementing this study, the protocol, the proposed informed consent form and 
other information to subjects, must be reviewed by a properly constituted Institutional 
Review Board/Independent Ethics Committee (IRB/IEC/REB). A signed and dated 
statement that the protocol and informed consent have been approved by the 
IRB/IEC/REB must be given to the Coordinating Center before study initiation. Any 
amendments to the protocol, other than administrative ones, must be approved by this 
committee. 
Amendments significantly affecting the safety of subjects, the scope of the investigation 
or the scientific quality of the study, require additional approval by the IRB/IEC/REB. A 
copy of the written approval of the IRB/IEC/REB, must be sent to the Coordinating 
Center. 
Amendments affecting only administrative aspects of the study do not require formal 
protocol amendments or IRB/IEC/REB approval but the IRB/IEC/REB of each site must 
be kept informed of such administrative changes.  
 
Protocol Deviations 
 
The Coordinating Center is responsible for implementing and maintaining quality 
assurance and quality control to ensure that studies are conducted according to the 
protocol, GCP, and all applicable regulatory requirements. A protocol deviation is any 
noncompliance with the protocol. Noncompliance can be on the part of the study 
participant, the Investigator, or the study site staff. Deviations to the protocol are not 
permitted except when necessary to eliminate an immediate hazard to study subjects. 
 
 
14.3. 
Urgent Safety Measures 
 
If an event occurs that is related to the conduct of the study or the development of the IP, 
and this new event is likely to affect the study of subjects, the Coordinating Center, and 
the investigator will take appropriate urgent safety measures to protect subjects against 
any immediate hazard. 
 
The Coordinating Center will work with the investigator to ensure the Institutional review 
board (IRB)/ethics committee (EC) is notified. 
 


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14.4. 
Quality Control (Study Monitoring) 
 
In accordance with applicable regulations, Good Clinical Practice (GCP) and the 
Coordinating Center procedures, the site will be contacted prior to the start of the study 
to review with the site staff the protocol, study requirements, and their responsibilities to 
satisfy regulatory, ethical, and the Coordinating Center requirements.  When reviewing 
data collection procedures, the discussion will include identification, agreement and 
documentation of data items for which the electronic case report form (eCRF) will serve 
as the source document. 
 
During the course of the study, the Coordinating Center will routinely monitor sites for 
protocol compliance, compare CRFs with individual subjects’ original source documents, 
assess drug accountability, and ensure that the study is being conducted according to the 
pertinent regulatory requirements. The review of subjects’ medical records will be 
performed in a manner to ensure that subjects’ confidentiality is maintained. Investigators 
must agree to cooperate with the Coordinating Center to ensure that any problems detected 
are resolved.  
 
Quarterly safety and monitoring reports are available to the Data and Safety Monitoring 
Committee (DSMC). The DSMC reviews all serious adverse events reported during the 
previous quarter for all clinical trials active at the VICC and makes recommendations to 
address concerns of patient safety.  
 
A Quality Assurance auditor under the direction of the DSMC will audit this clinical trial 
quarterly for compliance with adverse event reporting, regulatory and studies 
requirements, and data accuracy and completion. Audit reports detailing the findings are 
provided to the DSMC. 
 
14.5. 
Quality Assurance 
 
To ensure compliance with International Conference on Harmonization Good Clinical 
Practice (ICH GCP) and all applicable regulatory requirements, the Coordinating Center 
may conduct quality assurance audits of the site.  Regulatory agencies may conduct a 
regulatory inspection at any time during or after completion of the study.  In the event of 
an audit or inspection, the investigator (and institution) must agree to grant the auditor(s) 
and inspector(s) direct access to all relevant documents and to allocate their time and the 
time of their staff to discuss any findings/relevant issues. 
 
Study Documentation  
 
Each participating site is responsible for submitting copies of all relevant regulatory 
documentation to the Coordinating Center. The required documents include, but are not 
limited to the following: local IRB approvals (i.e., protocol, consent form, amendments, 
patient brochures, recruitment material, etc.), each participant’s informed consent, 
enrollment form, eligibility checklist, summary of unanticipated problems or protocol 
deviations, and documentation of expertise of the investigators. The Coordinating Center 
will provide each participating site with a comprehensive list of the necessary 
documents. It is the responsibility of the participating sites to maintain copies of all 
documentation submitted to the Coordinating Center. 
 
 
 


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14.6. 
Study and Site Closure 
 
The end of the study will be defined as the date of the last visit of the last subject 
enrolled. 
 
Upon completion or termination of the study, the monitor will conduct site closure 
activities with the investigator or site staff (as appropriate), in accordance with applicable 
regulations, International Conference on Harmonization Good Clinical Practice (ICH 
GCP), and the Coordinating Center Standard Operating Procedures. 
 
The Coordinating Center reserves the right to temporarily suspend or terminate the 
study at any time for reasons including (but not limited to) unsatisfactory enrollment, 
GCP noncompliance, inaccurate or incomplete data collection, falsification of records, 
safety issues, ethical issues, or noncompliance.  If the Coordinating Center determines 
that such action is required, the Coordinating Center will discuss the reasons for taking 
such action with the investigator or head of the medical institution (where applicable).  
When feasible, the Coordinating Center will provide advance notice to the investigator 
or head of the medical institution of the impending action. 
 
If a study is suspended or terminated for safety reasons, the Coordinating Center will 
promptly inform all investigators, heads of the medical institutions (where 
applicable),and/or institutions conducting the study.  The Coordinating Center will also 
promptly inform the relevant regulatory authorities of the suspension/termination along 
with the reasons for such action.  Where required by applicable regulations, the 
investigator or head of the medical institution must inform the IRB/EC promptly and 
provide the reason(s) for the suspension/termination. 
 
The Coordinating Center may also close study sites which fail to recruit subjects 
within a predefined timeframe. 
 
 
14.7. 
Records Retention 
 
U.S. FDA regulations (21 CFR §312.62[c]) require that records and documents pertaining 
to the conduct of this study and the distribution of investigational drug, including CRFs, 
consent forms, laboratory test results, and medication inventory records, must be retained 
by each Principal Investigator for 2 years after marketing application approval. If no 
application is filed, these records must be kept 2 years after the study is discontinued and 
the U.S. FDA and the applicable national and local health authorities are notified. 
Following closure of the study, each participating center will maintain a copy of all site 
study records in a safe and secure location. The Coordinating Center will inform the 
Investigator at each site at such time that the records may be destroyed. 
 
The investigator must notify the Coordinating Center of any changes in the archival 
arrangements, including, but not limited to archival of records at an off-site facility or 
transfer of ownership of the records in the event that the investigator is no longer 
associated with the site. 


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14.8. 
Provision of Study Results to Investigators, Posting of 
Information on Publicly Available Clinical Trials Registers 
and Publication 
 
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report.  The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a Novartis site or other mutually- 
agreeable location. 
 
Novartis will also provide the investigator with the full summary of the study results.  
The investigator is encouraged to share the summary results with the study subjects, as 
appropriate. 
 
The results summary will be posted to the Novartis Clinical Study Register no later than 
eight months after the final primary completion date, the date that the final subject was 
examined or received an intervention for the purposes of final collection of data for the 
primary outcome.  In addition, a manuscript will be submitted to a peer reviewed journal 
for publication no later than 18 months after the last subject’s last visit (LSLV).  When 
manuscript publication in a peer reviewed journal is not feasible, a statement will be 
added to the register to explain the reason for not publishing. 


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15. 
REFERENCES 
 
Bahadoran, P., M. Allegra, et al. (2013). "Major Clinical Response to a BRAF Inhibitor 
in a Patient With a BRAF L597R-Mutated Melanoma." J Clin Oncol. 
Balagula, Y., K. Barth Huston, et al. (2011). "Dermatologic side effects associated with 
the MEK 1/2 inhibitor selumetinib (AZD6244, ARRY-142886)." Invest New  
Drugs 29(5): 1114-1121. 
Berger, M. F., E. Hodis, et al. (2012). "Melanoma genome sequencing reveals frequent 
PREX2 mutations." Nature 485(7399): 502-506. 
Botton, T., I. Yeh, et al. (2013). "Recurrent BRAF kinase fusions in melanocytic tumors 
offer an opportunity for targeted therapy." Pigment Cell Melanoma Res. 
Ciampi, R., J. A. Knauf, et al. (2005). "Oncogenic AKAP9-BRAF fusion is a novel 
mechanism of MAPK pathway activation in thyroid cancer." J Clin Invest 115(1): 
94-101. 
Dahlman, K. B., J. Xia, et al. (2012). "BRAF L597 mutations in melanoma are associated 
with sensitivity to MEK inhibitors." Cancer Discov. 
Davies, H., G. R. Bignell, et al. (2002). "Mutations of the BRAF gene in human cancer." 
Nature 417(6892): 949-954. 
Eisenhauer, E. A., P. Therasse, et al. (2009). "New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1)." Eur J Cancer 45(2): 228-247. 
Falchook, G. S., K. D. Lewis, et al. (2012). "Activity of the oral MEK inhibitor 
trametinib in patients with advanced melanoma: a phase 1 dose-escalation trial." 
Lancet Oncol 13(8): 782-789. 
Flaherty, K. T., J. R. Infante, et al. (2012). "Combined BRAF and MEK Inhibition in 
Melanoma with BRAF V600 Mutations." N Engl J Med. 
Flaherty, K. T., C. Robert, et al. (2012). "Improved survival with MEK inhibition in 
BRAF-mutated melanoma." N Engl J Med 367(2): 107-114. 
Gilmartin, A. G., M. R. Bleam, et al. (2011). "GSK1120212 (JTP-74057) is an inhibitor 
of MEK activity and activation with favorable pharmacokinetic properties for 
sustained in vivo pathway inhibition." Clin Cancer Res 17(5): 989-1000. 
Huncharek, M., J. F. Caubet, et al. (2001). "Single-agent DTIC versus combination 
chemotherapy with or without immunotherapy in metastatic melanoma: a meta- 
analysis of 3273 patients from 20 randomized trials." Melanoma Res 11(1): 75- 
81. 
Hutchinson, K. E., Lipson D, Stephens PJ, et al. (2013). "BRAF Fusions Define a 
Distinct Molecular Subset of Melanomas with Potential Sensitivity to MEK 
Inhibition." Clinical Cancer Research 19(24): 6696-6702. 
Infante, J. R., L. A. Fecher, et al. (2012). "Safety, pharmacokinetic, pharmacodynamic, 
and efficacy data for the oral MEK inhibitor trametinib: a phase 1 dose-escalation 
trial." Lancet Oncol 13(8): 773-781. 
Jing, J., J. Greshock, et al. (2012). "Comprehensive predictive biomarker analysis for 
MEK inhibitor GSK1120212." Mol Cancer Ther 11(3): 720-729. 
Jones, D. T., S. Kocialkowski, et al. (2008). "Tandem duplication producing a novel 
oncogenic BRAF fusion gene defines the majority of pilocytic astrocytomas." 
Cancer Res 68(21): 8673-8677. 
Kim, K. B., R. Kefford, et al. (2013). "Phase II study of the MEK1/MEK2 inhibitor 
Trametinib in patients with metastatic BRAF-mutant cutaneous melanoma 


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88 
 
 
 
 
previously treated with or without a BRAF inhibitor." J Clin Oncol 31(4): 482- 
489. 
Korn, E. L., P. Y. Liu, et al. (2008). "Meta-analysis of phase II cooperative group trials in 
metastatic stage IV melanoma to determine progression-free and overall survival 
benchmarks for future phase II trials." J Clin Oncol 26(4): 527-534. 
Krauthammer, M., Y. Kong, et al. (2012). "Exome sequencing identifies recurrent 
somatic RAC1 mutations in melanoma." Nat Genet 44(9): 1006-1014. 
Lacouture, M. E., M. J. Anadkat, et al. (2011). "Clinical practice guidelines for the 
prevention and treatment of EGFR inhibitor-associated dermatologic toxicities." 
Support Care Cancer 19(8): 1079-1095. 
Palanisamy, N., B. Ateeq, et al. (2010). "Rearrangements of the RAF kinase pathway in 
prostate cancer, gastric cancer and melanoma." Nat Med 16(7): 793-798. 
Smalley, K. S., M. Xiao, et al. (2009). "CRAF inhibition induces apoptosis in melanoma 
cells with non-V600E BRAF mutations." Oncogene 28(1): 85-94. 
Wan, P. T., M. J. Garnett, et al. (2004). "Mechanism of activation of the RAF-ERK 
signaling pathway by oncogenic mutations of B-RAF." Cell 116(6): 855-867. 


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APPENDICES 
 
Appendix 1 BRAF mutations by Cohort 
 
Cohort A – “High 
Activity”* 
Cohort B – “Low 
Activity/Unknown” 
Excluded 
R462I 
G466E 
Concurrent BRAF V600E 
mutation 
I463S 
G466V 
Concurrent NRAS codon 
12, 13, or 61 mutation 
G464V 
D594V 
G464E 
G596R 
G466A 
All other BRAF mutations 
G469A 
G469E 
N581S 
E486K 
F595L 
L597V 
L597S 
L597R 
L597Q 
T599I 
K601E 
A728V 
BRAF fusions/truncations 
*Defined by affinity for MEK phosphorylation in Wan et al, Cell 2004. Mutations with 
documented responses to MEK inhibitors are also included 


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Appendix 2 :  NYHA Functional Classification System 
 
The New York Heart Association (NYHA) Functional Classification: Class I, II, III 
or IV Heart Failure [NYHA, 1994] provides a simple way of classifying the extent of 
heart failure.  It places subjects in one of 4 categories based on the level of limitation 
experienced during physical activity: 
 
Class 
Symptoms 
Class I 
(Mild) 
No limitation of physical activity.  Ordinary physical activity 
does not cause undue fatigue, palpitation or dyspnea (shortness 
of breath). 
Class II 
(Mild) 
Slight limitation of physical activity.  Comfortable at rest, but 
ordinary physical activity results in fatigue, palpitation or 
dyspnea. 
Class III 
(Moderate) 
Marked limitation of physical activity.  Comfortable at rest, but 
less than ordinary physical activity results in fatigue, palpitation 
or dyspnea. 
Class IV 
(Severe) 
Unable to carry out any physical activity without discomfort. 
Symptoms of cardiac insufficiency at rest.  If any physical 
activity is undertaken, discomfort is increased. 
 
Reference: 
 
The Criteria Committee of the New York Heart Association (NYHA).  Nomenclature and 
Criteria for Diagnosis of Diseases of the Heart and Great Vessels. 9th Ed. Boston, Mass: 
Little, Brown & Co.;  1994:253-256. 


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Appendix 3 :  COCKCROFT-GAULT FORMULA 
 
ClCr (mL/min) = 
Q x (140 - age[yr]) x ideal body weight [kg]* 
72 x serum creatinine [mg/dL] 
Q = 0.85 for females 
Q = 1.0 for males 
 
OR 
 
ClCr (mL/min) = 
K x (140 - age[yr]) x ideal body weight [kg]* 
Serum creatinine [umol/L] 
K = 1.0 for females 
K = 1.23 for males 
 
 
 
*Calculation of Ideal Body Weight Using the Devine Formula [Devine, 1974] 
Ideal body weight: 
Males = 
50.0 kg + (2.3 kg x each inch over 5 feet) or 50.0 kg + (0.906 kg x each cm over 
152.4 cm) 
Females = 
45.5 kg + (2.3 kg x each inch over 5 feet) or 45.5 kg + (0.906 kg x each cm over 
152.4 cm) 
Example: 
Male, actual body weight = 90.0 kg, height = 68 inches 
Ideal body weight = 50.0 + (2.3) (68-60) = 68.4 kg. 
This subject’s actual body weight is >30% over ideal body weight. Therefore, in this case, the 
subject’s ideal body weight of 68.4 kg should be used in calculating estimated CrCl. 
 
Reference 
 
Devine, BJ.  Case Number 25 Gentamicin Therapy: Clinical Pharmacology Case Studies. 
Drug Intelligence and Clinical Pharmacy. 1974; 8:650-655 


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Appendix 4:  ECOG Performance Status 
 
Grade 
Descriptions 
 
0 
Normal activity.  Fully active, able to carry on all pre-disease 
performance without restriction. 
 
 
 
1 
Symptoms, but ambulatory.  Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
 
2 
In bed <50% of the time.  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 
In bed >50% of the time.  Capable of only limited self-care, 
confined to bed or chair more than 50% of waking hours. 
 
4 
100% bedridden.  Completely disabled.  Cannot carry on any 
self-care.  Totally confined to bed or chair. 
5 
Dead. 
 
 
Reference: 
 
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., 
Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology 
Group. Am J Clin Oncol 5:649-655, 1982. 


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Appendix 5:  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. Medical Monitor & Clinical Safety Physician.to review the subject’s 
restart/rechallenge risk factors & complete checklist (Table 1). 
 
Table 1. 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: 
 


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• 
IP associated with known preclinical hepatic liability/ injury 
 
 
 
 
3. If the Coordinating Center 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 approved dose(s). 
 
• Subjects approved by the Coordinating Center 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. 
 
• The Coordinating Center is to be notified of any adverse events, as per Section 
8.5.1. 


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Novartis process for drug restart after possible drug-induced liver injury 
 
 
 
Subject exhibits liver injury on 
drug, while disease condition 
stable or improving 
 
Principal Investigator requests the 
Coordinating Center approve drug readmin. 
with investigational product (IP) 
 
Medical Monitor & Clinical Safety Physician(s) to discuss benefit: risk and: 
1 
Any fever, rash or eosinophilia/hypersens. with initial liver injury 
subject? 
in this 
Bilirubin >2xULN or INR>1.5 in this subject, suggesting failing liver? 
3 
Any prior severe/fatal outcomes reported on drug restart with this drug? 
Any evidence of preclinical hepatic liability/injury with this drug? 
Agree to allow IP reinitiation with 
endorsement of  senior Safety and 
Medicines Development Physicians; 
Hepatotoxicity Panel available for 
input 
 
Principal Investigator promptly informed in writing of 
the Coordinating Center decision to restart 
IP & dosing regimen 
PI to request drug restart approval with Ethics Comm. 
or Institutional Review Board, as required 
PI to discuss with subject the benefits/risks of drug 
restart; subject consent must be recorded in chart 
Liver chemistries obtained twice weekly until 
normal/stable 
PI to provide restart outcome to Ethics Comm./IRB 
 
 The Coordinating 
Center does not allow 
drug reinitiation 
 
 
 
Principal 
Investigator 
promptly informed 
of decision to not 
restart 
investigational 
product 
 
 
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. 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. 
3. 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 


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Appendix 6 : QT interval on electrocardiogram corrected using the Bazett’s 
formula (QTcB) 
 
Bazett's formula used to correct QT interval for heart rate is: 
 
QTcB =  QT 
RR 
 
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. 


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Appendix 7 – Medication Diary 
 
 
Patient Name: _________________  Study ID: __________________  MRN:__________ 
Number of Trametinib Tablets Given: __  _     Pill Bottle(s) returned: Circle Yes or No 
Total Daily Dose of Trametinib: ______    Number of Trametinib tablets returned ______ 
 
PLEASE FILL OUT AND BRING THIS SHEET AT YOUR NEXT VISIT 
 
SPECIAL INSTRUCTIONS 
1. Trametinib should be taken by mouth on an empty stomach one hour before a 
meal or two hours after a meal with water only. 
2. Trametinib tablets should be refrigerated. 
3. If a dose of Trametinib is missed for more than 12 hours after a scheduled dose, 
wait until the next scheduled dose. Doses can be “made up” prior to the 12 hour 
limit.  
 
 
Cycle #: _________  # of Weeks _________ 
Day 
Medication Date 
Time 
# of 2mg 
tablets 
taken 
# of 0.5mg 
tablets 
taken 
Comments 
Example 
Trametinib 01/01/2014 9:00 AM 
1 
0 
 
1 
 
 
 
 
 
 
2 
 
 
 
 
 
 
3 
 
 
 
 
 
 
4 
 
 
 
 
 
 
5 
 
 
 
 
 
 
6 
 
 
 
 
 
 
7 
 
 
 
 
 
 
8 
 
 
 
 
 
 
9 
 
 
 
 
 
 
10 
 
 
 
 
 
 
11 
 
 
 
 
 
 
12 
 
 
 
 
 
 
13 
 
 
 
 
 
 
14 
 
 
 
 
 
 
15 
 
 
 
 
 
 
16 
 
 
 
 
 
 
17 
 
 
 
 
 
 
18 
 
 
 
 
 
 
19 
 
 
 
 
 
 
20 
 
 
 
 
 
 
21 
 
 
 
 
 
 
22 
 
 
 
 
 
 
23 
 
 
 
 
 
 
24 
 
 
 
 
 
 
25 
 
 
 
 
 
 
26 
 
 
 
 
 
 
27 
 
 
 
 
 
 
28 
 
 
 
 
 
 
 
Patient Signature: _________________________________________    Date: __________ 


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Consenting Professional/Research RN Signature _________________   Date: ___________ 
 
Consenting Professional/Research RN Comments: 
__________________________________________________________________________ 
__________________________________________________________________________ 
__________________________________________________________________________ 
__________________________________________________________________________