A Randomized Two-Arm Phase II Study of Trametinib Alone and in Combination With GSK2141795 in Patients With Advanced Uveal Melanoma
Phase: PHASE2
Conditions: Recurrent Uveal Melanoma, Stage IV Uveal Melanoma AJCC v7
Sponsor: National Cancer Institute (NCI)

IRB: 13-144 A(15) 
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SUMMARY OF CHANGES 
 
For Protocol Amendment #15 to: A Randomized Two-Arm Phase II Study of Trametinib Alone and 
in Combination with GSK2141795 in Patients with Advanced Uveal Melanoma 
 
 
NCI Protocol #: 9445 
Local Protocol #: 13-144 
 
NCI Version Date: 12/01/2016 
Protocol Date: 12/01/2016 
 
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Formatting and grammatical changes have been made 
throughout the protocol.  
2. 
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NCI version date was updated to 12/01/2016 throughout the 
protocol document. 
3. 
N/A 
N/A 
Local IRB amendment number has been updated to A(15) 
throughout the protocol document. 
4. 
Protocol 
Type/Version 
Date 
4 
Amended/Version 1.13/Version date: 12/01/2016 was added to 
this section. 
5. 
Table of Contents 7-9 
The table of contents was updated to reflect the body of the 
protocol. 
6. 
5.3 
43 
Upon discussion with Helen Chen, MD, we have revised the 
protocol to state that under special circumstance, continued 
therapy may be considered on a case-by-case basis if the patient 
is considered benefiting from the treatment. 
7. 
7.1.1 
57-61 
In response to NCI RRA, dated November 18, 2016 from Helen 
Chen, MD, the Trametinib CAEPR was updated to Version 2.4, 
October 7, 2016.  
 
 

IRB: 13-144 A(15) 
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NCI Protocol #: 
9445 
 
Protocol Version Date:  12/01/2016 
 
Local Protocol #: 
13-144 
 
TITLE:  A Randomized Two-Arm Phase II Study of Trametinib Alone and in Combination with 
GSK2141795 in Patients with Advanced Uveal Melanoma  
 
Coordinating Center: 
 
 
Memorial Sloan Kettering Cancer Center 
 
 
 
 
 
 
 
 
 
1275 York Ave 
 
 
 
 
 
 
 
 
 
New York, NY 10065 
 
*Principal Investigator: 
Alexander Shoushtari, MD* 
Memorial Sloan Kettering Cancer Center 
300 East 66th Street 
New York, NY 10065 
Telephone: 646-888-4161 
Fax:  646-888-4253 
E-mail: shoushta@mskcc.org 
   
 
Co-Principal Investigator: 
Paul Chapman, MD* 
 
 
 
MSK Co-Investigators: 
Ping Chi, MD, PhD* 
(* = Consenting Professionals) 
Sandra D’Angelo, MD* 
Mark Dickson, MD* 
 
 
Mary Louise Keohan, MD* 
William Tap, MD* 
IRBPB7592 
 
 
Mrinal Gounder, MD* 
 
 
Michael Postow, MD* 
 
 
Margaret Callahan, MD, PhD* 
 
 
Jedd Wolchok, MD, PhD* 
Mark Bluth, MD 
Joseph P. Erinjeri, MD, PhD 
Mario E. Lacouture, MD 
Katherine Panageas, DrPH 
Mimma Errante, NP 
Yelena Shames, NP 
Nana Prempeh-Kete Ku, NP 
 
*Consenting professionals 
 
 
 
 

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Collaborating Site 
Principal Investigator 
Site’s Role 
M.D. Anderson Cancer 
Center 
 
*Sapna Patel, MD 
MD Anderson Cancer Center 
1515 Holcombe Blvd. 
Unit 430  Houston, TX 77030 
Telephone: 713-792-4955 
Email: SPPatel@mdanderson.org 
Data Collection 
and Specimen 
Analysis 
 
H. Lee Moffitt Cancer 
Center 
*Geoffrey Gibney, MD 
H. Lee Moffitt Cancer Center 
12902 Magnolia Drive, SRB-4 CUT-PROG 
Tampa, FL 33612 
Telephone: 813-745-3437 
Fax: 813-449-8584 
Email: Geoffrey.Gibney@moffitt.org  
Data Collection 
 
Vanderbilt University 
Medical Center 
 
*Kristin Kathleen Ancell, MD 
Vanderbilt University Medical Center 
2220 Pierce Avenue  
777 PRB 
Nashville, TN  37232 
Phone:  615-322-4967 
Email:  Kristin.k.ancell@vanderbilt.edu 
Data Collection 
 
Emory University 
*Ragini Kudchadkar, MD 
Emory University 
Winship Cancer Institute 
1365-C Clifton Road 
Atlanta, GA 30322 
Telephone: 404-778-1900 
Email: rkudcha@emory.edu 
Data Collection 
 
New York Presbyterian 
Hospital/Columbia 
University, College of 
Physicians and 
Surgeons 
 
*Richard D. Carvajal, MD 
New York Presbyterian Hospital/Columbia 
University, College of Physicians and Surgeons 
Milstein Hospital, Division of 
Hematology/Oncology 
161 Ft. Washington Avenue 
New York, NY 10032  
Telephone: 646-317-6041 
E-mail: rdc2150@cumc.columbia.edu  
Data Collection 
and Specimen 
Analysis Only 
 
 
 
 
 
 
 
 

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Institut Curie (EORTC) 
 
*Sophie Piperno-Neuamnn, MD, PhD 
Institut Curie 
26, rue d'Ulm 
75231 Paris, France 
Telephone: 33 (0)1 44 32 46 72 
Email: sophie.piperno-neumann@curie.net 
Data Collection 
and Specimen 
Analysis 
University of Liverpool 
 
Sarah Coupland, MBBS, PhD, FRCPath 
University of Liverpool 
Department of Molecular and Clinical Cancer 
Medicine 
Institute of Translational Medicine 
6th Floor Duncan Building 
Daulby Street 
Liverpool, L69 3GA 
Telephone: +44-151-706-5885 or 4494 
Email: S.E.Coupland@liverpool.ac.uk  
Specimen 
Analysis Only 
 
 
 
Statistician: 
 
 
Study Coordinator: 
Katherine Panageas, DrPH 
 
Leigh Gaffney 
Memorial Sloan Kettering Cancer Ctr 
 
Memorial Sloan Kettering Cancer Ctr 
307 E 63rd St., 3rd Floor (Box 44), NY, NY 10065 
300 E 66th St., 12th Floor NY, NY 10065 
Tel: 646-735-8119 
Tel: 646-888-4375 
panageak@mskcc.org  
Fax: 646-227-2426 
 
 
frigugll@mskcc.org 
 
Responsible Research Nurse: 
 
Responsible Data Manager: 
Mimma Errante, NP 
Roshani Shah 
Memorial Sloan Kettering Cancer Ctr 
 
Memorial Sloan Kettering Cancer Ctr 
160 E 53rd Street, NY, NY 10065 
300 E 66th St., 12th Floor NY, NY 10065 
Tel: 646-888-4377  
Tel: 646-888- 4375 
errantem@mskcc.org 
 
Fax: 646-227-2426 
 
 
shahr4@mskcc.org   
 
Research Project Coordinator (for participating sites): 
Talal Khawaja 
Memorial Sloan Kettering Cancer Center 
1114 First Avenue 7th Floor 
New York, NY 10065 
Tel: 646-888-1006 
Fax: 646-227-2482 
khawajat@mskcc.org 
 
 

IRB: 13-144 A(15) 
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NCI Supplied Agents:   
Trametinib dimethyl sulfoxide (GSK1120212B) (NSC 763093) 
 
GSK2141795 (NSC 767034) 
 
IND Sponsor:   
NCI  
 
 
 
IND  119432 
 
Protocol Type / Version # / Version Date: Original / Version 1.0 / Version Date: 03/27/2013 
Original / Version 1.1 / Version Date: 06/15/2013 
Original / Version 1.2 / Version Date: 07/11/2013 
Original / Version 1.3 / Version Date: 08/19/2013 
Amended / Version 1.4 / Version Date: 09/17/2013 
Amended / Version 1.5 / Version Date: 02/10/2014 
Amended / Version 1.6 / Version Date: 04/28/2014 
Amended / Version 1.7 / Version Date: 06/20/2014 
Amended / Version 1.8 / Version Date: 10/20/2014 
Amended / Version 1.9 / Version Date: 03/18/2015 
Amended / Version 1.10 / Version Date: 08/10/2015 
Amended/ Version 1.11/ Version Date: 11/06/2015 
Amended/ Version 1.12/ Version Date: 04/20/2016 
Amended/ Version 1.13/ Version Date: 12/01/2016 

IRB: 13-144 A(15) 
5 
 
SCHEMA 
 
This trial is a randomized phase II study of trametinib alone or in combination with GSK2141795 in 
patients with advanced uveal melanoma.  The primary endpoint (outcome measure) of this trial is 
progression-free survival (PFS).  Secondary endpoints include overall survival (OS), RECIST 
response, and safety/toxicity.  Exploratory endpoints include correlation of clinical outcome with 
Gnaq/11 mutational status.   
 
All treatment will be performed in the outpatient setting.  Eighty eligible and evaluable patients will 
be randomized on a 1:1 ratio, with randomization stratified by (i) the presence or absence of liver 
involvement and (ii) LDH (< 2 times ULN versus ≥ 2 times the upper limit of normal) to one of the 
two treatment arms: 
 
1. Arm A (Trametinib):  Experimental Arm A will explore the activity of MEK inhibition 
using trametinib in advanced UM.  Patients randomized to this arm will receive trametinib 2 
mg PO QD on a continual basis in 4 week cycles. 
 
2. Arm B (Trametinib and GSK2141795):  Experimental Arm B will explore the activity of 
combined MEK and AKT inhibition in advanced UM.  Patients randomized to this arm will 
receive trametinib 1.5 mg PO QD in combination with GSK2141795 50 mg PO QD on a 
continual basis in 4 week cycles.   
 
The study schema is as follows: 
 
 
 
Tumor response will be measured radiographically at baseline, week 8, and every 8 weeks 
subsequently using standard RECIST 1.1 criteria.  Although central radiology review will not be 
performed in real-time, all imaging studies will be collected to allow for the possibility of 
retrospective central review.  Patients will remain on their initially assigned treatment arm until the 
sooner of (i) disease progression (primary outcome measure) or (ii) the development of 
unacceptable toxicity that is not manageable with dose reduction.  
 
At that point, patients initially randomized to Arm A who develop disease progression and who 
remain eligible for trial therapy based upon the trial inclusion/exclusion criteria will be given the 

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option of receiving additional experimental therapy with trametinib and GSK2141795.  This option 
will not be available to patients who are taken off treatment due to the development of unacceptable 
toxicity that is not manageable with dose reduction.  This will provide, in an exploratory fashion, 
information about the ability of AKT inhibition with GSK2141795 to salvage progression to 
trametinib.  Tumor response assessments and progression-free survival will be recorded, but these 
patients will not be included in analysis of the primary analysis of PFS after first randomization; 
however, clinical outcome will be followed and reported in a descriptive fashion.   
 
Pre-treatment paraffin embedded tissue will be collected from all patients at baseline for Gnaq/11 
molecular analysis, with additional tissue stored for the future conduct of additional correlative 
studies.  All patients with safely accessible tumor will undergo pre- and post-treatment (day 14 +/- 3 
days) tumor biopsies for biomarker and correlative analysis.  The decision to not pursue these 
biopsies must be made in collaboration with the MSK Principal Investigator.  An additional tumor 
biopsy will be requested from patients at the time of disease progression; however, this biopsy is 
optional.  Blood samples will be collected from all patients at baseline and on a monthly basis for 
correlative analysis. 
 
As of 11/06/2015, Arm B met the specified stopping rule for futility. The remaining patients will be 
accrued to Arm A, no patients will be enrolled to Arm B or Crossover therapy. 
 

IRB: 13-144 A(15) 
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TABLE OF CONTENTS 
1 
OBJECTIVES ....................................................................................................................10 
1.1 
Primary Objectives.................................................................................................10 
1.2 
Secondary Objectives.............................................................................................10 
1.3 
Exploratory Objectives ..........................................................................................10 
2 
BACKGROUND ...............................................................................................................10 
2.1 
Uveal Melanoma ....................................................................................................10 
2.2 
CTEP IND Agents .................................................................................................11 
2.3 
Study Rationale ......................................................................................................22 
2.4 
Correlative Studies Background ............................................................................28 
3 
PATIENT SELECTION ....................................................................................................30 
3.1 
Inclusion Criteria ...................................................................................................30 
3.2 
Exclusion Criteria ..................................................................................................32 
3.3 
Eligibility Criteria for Crossover Registrations .....................................................34 
3.4 
Inclusion of Women and Minorities ......................................................................34 
4 
REGISTRATION PROCEDURES ...................................................................................35 
4.1 
Investigator Registration ........................................................................................35 
4.2 
MSK Research Participant Registration Procedures..............................................35 
4.3 
Participating Sites Research Participant Registration Process...............................35 
4.4 
Randomization .......................................................................................................36 
4.5 
Crossover ...............................................................................................................37 
5 
TREATMENT PLAN ........................................................................................................37 
5.1 
Agent Administration.............................................................................................37 
5.2 
General Concomitant Medication and Supportive Care Guidelines ......................43 
5.3 
Duration of Therapy ...............................................................................................43 
5.4 
Duration of Follow Up ...........................................................................................44 
5.5 
Criteria for Removal from Study ...........................................................................44 
6 
DOSING DELAYS/DOSE MODIFICATIONS ...............................................................44 
6.1 
Trametinib and GSK2141795 Dose Modifications ...............................................45 
6.2 
Dose Modifications for Toxicities Attributable to Both Trametinib and 
GSK2141795..........................................................................................................46 
6.3 
Dose Modifications for Toxicities Attributable to Trametinib ..............................51 
6.4 
Dose Modifications for Toxicities Attributable to GSK2141795 ..........................55 
7 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................56 
7.1 
Comprehensive Adverse Events and Potential Risks Lists (CAEPRs) .................56 
7.2 
Adverse Event Characteristics ...............................................................................63 
7.3 
Expedited Adverse Event Reporting ......................................................................63 
7.4 
Routine Adverse Event Reporting .........................................................................66 
7.5 
Secondary Malignancy...........................................................................................66 
7.6 
Second Malignancy ................................................................................................66 
7.7 
Serious Adverse Event (SAE) Reporting for MSK Patients Only .........................66 

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8 
PHARMACEUTICAL INFORMATION ..........................................................................67 
8.1 
CTEP IND Agent(s) ...............................................................................................67 
9 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................72 
9.1 
Biomarker Study Overview ...................................................................................72 
9.2 
Laboratory Correlative Studies ..............................................................................74 
9.3 
Specimen Shipment Procedures .............................................................................79 
9.4 
Laboratory Correlative Studies ..............................................................................81 
10 
STUDY CALENDAR .......................................................................................................83 
11 
MEASUREMENT OF EFFECT........................................................................................85 
11.1 
Antitumor Effect – Solid Tumors ..........................................................................85 
12 
DATA REPORTING / REGULATORY REQUIREMENTS ...........................................91 
12.1 
Data Reporting .......................................................................................................91 
12.2 
CTEP Multicenter Guidelines ................................................................................95 
12.3 
Collaborative Agreements Language .....................................................................95 
12.4 
Data and Safety Monitoring ...................................................................................96 
13 
STATISTICAL CONSIDERATIONS...............................................................................97 
13.1 
Study Design/Endpoints.........................................................................................97 
13.2 
Sample Size/Accrual Rate ......................................................................................98 
13.3 
Stratification Factors ..............................................................................................98 
13.4 
Analysis of Secondary Endpoints ..........................................................................98 
13.5 
Analysis of Exploratory Endpoints ........................................................................99 
13.6 
Reporting and Exclusions ......................................................................................99 
14 
Protection of Human Subjects .........................................................................................100 
14.1 
Privacy .................................................................................................................100 
15 
Informed Consent Procedures ..........................................................................................100 
15.1 
For Participating Centers .....................................................................................100 
REFERENCES ............................................................................................................................102 
APPENDIX A – PERFORMANCE STATUS CRITERIA .........................................................106 
APPENDIX B – POTENTIAL DRUG-DRUG INTERACTIONS .............................................107 
APPENDIX C – NEW YORK HEART ASSOCIATION CLASSIFICATIONS .......................111 
APPENDIX D – INFORMATION ON POSSIBLE DRUG INTERACTIONS .........................112 
APPENDIX E – CTEP MULTICENTER GUIDELINES ...........................................................114 
APPENDIX F – PATIENT’S MEDICATION DIARY ..............................................................116 
APPENDIX G – OPHTHALMOLOGY EXAMS .......................................................................119 
APPENDIX H– IMF/LCCI MSK RESEARCH LABORATORY REQUISITION ...................120 

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APPENDIX I – PARTICIPATING SITE SHIPPING REQUISITIONS ....................................122 
 
 
 

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1 
OBJECTIVES 
 
1.1 Primary Objectives 
 
• 
To compare progression-free survival between those treated with trametinib alone and those 
treated with the combination of trametinib and GSK2141795 
 
1.2 Secondary Objectives 
 
• 
To compare overall survival between those treated with trametinib alone and those treated 
with the combination of trametinib and GSK2141795 
• 
To compare the overall response rate between those treated with trametinib alone and those 
treated with the combination of trametinib and GSK2141795 
• 
To compare the safety and toxicity between those treated with trametinib alone and those 
treated with the combination of trametinib and GSK2141795 
 
1.3 Exploratory Objectives 
 
• 
To assess clinical outcomes (response rate, progression-free and overall survival) with 
trametinib and GSK2141795 after progression on trametinib 
• 
To assess toxicity with trametinib and GSK2141795 after progression on trametinib 
• 
To correlate clinical outcome with Gnaq/11 mutational status 
• 
To assess the pharmacodynamic effects of trametinib alone and with GSK2141795, and 
utilize whole-transcriptome and reverse phase protein array to identify markers of sensitivity 
and primary resistance to trametinib alone and with GSK2141795  
• 
To assess for changes in circulating tumor DNA with therapy  
 
 
2 
BACKGROUND 
 
2.1 Uveal Melanoma 
 
Uveal melanoma is the most common primary intraocular malignancy in adults, and arises from 
melanocytes within the choroid plexus of the eye.1  Melanomas of the ocular and adnexal 
structures comprise approximately 5% of all melanomas and are biologically and prognostically 
distinct from cutaneous melanoma.2  In the United States, an estimated 2000 patients are 
diagnosed with this disease each year.  Approximately 85% of ocular melanomas are uveal (iris, 
ciliary body, and choroid) in origin, with primary conjunctival and orbital melanomas being less 
common.2,3  Cases are nearly equally distributed between male and female subjects, with a 
median age at diagnosis of 62 years.4  The majority (97.8%) of cases of uveal melanoma occurs 
in the white population, with a white:black incidence ratio of 196:1.  
 
The development of metastasis in this disease is common and occurs in approximately 50% of 
patients with posterior uveal melanoma within 15 years after the initial diagnosis and treatment.5  
Uveal melanoma is thought to be particularly resistant to systemic treatment, and no systemic 
therapy has yet been demonstrated to improve survival.6  Drugs commonly used to treat 

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advanced cutaneous melanoma rarely achieve durable responses in patients with uveal 
melanoma.  Nathan et al compared the outcome between 139 patients with non-uveal melanoma 
and 16 patients with uveal melanoma who were treated with DTIC, BCNU, cisplatin, and 
tamoxifen (Dartmouth regimen).7  The response rates were 33% and 6% respectively.  In a 
review of the MD Anderson Cancer Center experience of 143 treated patients with metastatic 
ocular melanoma, there was only a single objective response observed.8  Retrospective reviews 
of the ECOG and SWOG experiences revealed similar findings.9  Because of the lack of 
effective systemic treatment options, outcomes are poor once metastatic disease occurs, and the 
median survival from the time of the development of distant metastatic disease is 6 to 12 
months.10-12  
 
Although it is clear that novel effective therapies are desperately needed for this disease, the 
development of such therapies has been hampered by the rarity of uveal melanoma.  Indeed, over 
the past decade, only 8 phase II trials in uveal melanoma have been published, with the largest of 
these trials accruing only 48 patients and none demonstrating significant efficacy in terms of 
response rate, overall survival or progression-free survival (see table below). 
 
Published phase II trials in uveal melanoma. 
 
Despite our inability to identify effective therapies for this disease thus far, our increasing 
understanding of the underlying biology of uveal melanoma has led to the identification of a 
number of novel and promising therapeutic strategies that warrant investigation.   
 
2.2 CTEP IND Agents 
 
2.2.1 
Trametinib Dimethyl Sulfoxide (GSK1120212B) 
 
The RAF-MEK-ERK pathway plays a critical role in multiple cellular functions.  Activation of 
the pathway can result from activation/mutations of the upstream receptor tyrosine kinases 
(RTKs) and RAS, or upregulation/mutations in RAF and MEK.  Upon activation, RAF acts as 
the MAPK kinase and activates MAPKK (MEK1/2), which in turn catalyze activation of the 
effectors ERK1/ERK2.  Once activated, ERK1/2 translocate into the nucleus and 
phosphorylate a number of effector proteins and transcriptional factors that regulate cell 
proliferation, motility, differentiation, and survival.   
 
Trametinib is one of the several MEK inhibitors in clinical development.  On May 29, 2013, 
Investigator 
Study Treatment 
n 
Response  
Rate 
Overall  
Survival 
Progression-
Free Survival 
Homsi et al, 201013 
Docosahexaenoic acid-Paclitaxel 
22 
4%  
9.8 mos 
NR 
Penel et al, 200814 
Imatinib 
10 
0% 
10.8 mos 
NR 
Schmittel et al, 200615 
Gemcitabine/Treosulfan vs Treosulfan 
48 
2%  
NR 
2-3 mos 
O’Neill et al, 200616 
DTIC/Treosulfan 
15 
0% 
NR 
3 mos 
Schmittel et al, 200517 
Gemcitabine/Cisplatin/ Treosulfan 
17 
0% 
NR 
3 mos 
Schmidt-Hieber et al, 
200418 
Bendamustine 
14 
0% 
NR 
NR 
Bedikian et al, 200419 
Temozolomide 
14 
0% 
6.7 mos 
1.8 mos 
Kivelä et al, 200320 
Bleomycin/Vincristine/Lomustine/ 
DTIC + Interferon 
22 
0% 
NR 
1.9 mos 

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the U.S. Food and Drug Administration (FDA) approved trametinib for the treatment of 
patients with unresectable or metastatic melanoma with BRAFV600E or BRAFV600K 
mutations as detected by an FDA-approved test (U.S. Food and Drug Administration, 2013).  
On January 10, 2014, the Food and Drug Administration granted accelerated approval to 
trametinib and dabrafenib for use in combination to treat patients with unresectable or 
metastatic melanoma with a BRAF V600E or V600K mutation as detected by an FDA-
approved test (U.S. Food and Drug Administration, 2014). 
 
Experience to date indicates that MEK is a valid target.  In a phase III trial comparing 
trametinib with dacarbazine or paclitaxel in patients with BRAF V600E or V600K mutant 
metastatic melanoma, trametinib demonstrated a significantly better response rate, progression-
free survival, and overall survival.21  However, single agent activities are limited.  Extensive 
research is underway to identify the patient selection markers and develop rational combination 
strategies.  Preclinical studies have provided strong rationale and proof of principle for 
combination of MEK inhibitors with RTK inhibitors (EGFR or IGF-1R),22,23 PI3K/AKT 
inhibitors,24,25 and mTOR inhibitors.  On the other hand, the optimal dose/schedule and patient 
selection criteria for combination regimens have not been defined.  Phase 1 results for a 
number of combinations have been reported:  Phase 1 selumetinib + MK2206,26 phase 1 GDC-
0973 + GDC-094 (MEK + PI3K inhibitor).27 
 
The most up-to-date preclinical and clinical study information for trametinib can be found in 
the GSK1120212 (trametinib) Investigator's Brochure (2013). 
 
2.2.1.1 Mechanisms of Action and Preclinical Data with Trametinib 
 
Trametinib is a dimethyl sulfoxide (DMSO) solvate compound (ratio 1:1) with potent, 
allosteric and ATP non-competitive inhibition of MEK1/2 (IC50 of 0.7 and 0.9 nM 
against MEK1 and MEK2, respectively).28  Trametinib inhibited MEK1/2 kinase activity 
and prevented RAF-dependent MEK phosphorylation (S217 for MEK1), producing 
prolonged pERK1/2 inhibition.  Trametinib showed better potency against 
unphosphorylated 
MEK1/2 
(u-MEK1/2) 
when 
compared 
with 
preactivated 
diphosphorylated MEK (pp-MEK), suggesting that u-MEK affords a higher affinity 
binding site for trametinib than does pp-MEK. 
 
The specificity of trametinib was confirmed against a panel of 183 kinases, including 
MEK5 (the closet kinase homolog to MEK1/2), CRAF, BRAF, ERK1, and ERK2.29  
Trametinib demonstrated equal potency against activated MEK1- and MEK2-mediated 
phosphorylation of ERK (sequence identity of 85% across the whole protein and 100% 
in the active site for humans).  Trametinib demonstrated preferential inhibition of RAF-
mediated MEK1 activation (IC50 = 0.60 nM) over pMEK1 kinase activity (IC50 = 13 
nM).30 
 
BRAF-mutant Colo205, A375P F11s, and HT-29 human tumor xenograft mouse models 
showed the most significant mean tumor growth inhibition (TGI) (80% to 87%) at 3.0 
mg/kg trametinib, with multiple complete and partial tumor regressions.  In the Colo205 
model, tumor regression was observed even at a dose of 0.3 mg/kg.29  Two KRAS-

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mutant xenograft models, HCT-116 and A549, also showed significant TGI (83% and 
75%) but without significant tumor regressions.28  As predicted by cell proliferation 
assays, tumor xenograft lines with wild-type (wt) RAF/RAS (PC3, BxPC3, and BT474) 
were much less sensitive, showing only modest TGI (44-46%) with no tumor 
regressions. 
 
Pharmacodynamic studies were performed in mice treated with trametinib for 14 days.28  
In the A375P F11s xenograft model, the first dose of trametinib (3 mg/kg) significantly 
reduced pERK for more than 8 hours on Day 1.  pERK inhibition was more sustained 
(over 24 hours) after the Day 7 dose, probably due to an increase in the steady-state 
levels of trametinib after repeated doses.  The average Cmax in blood was 1,410 nM on 
Day 7, with an estimated half-life (t1/2) of 33 hours.  In addition, immunohistochemistry 
(IHC) also confirmed inhibition of cell proliferation (reduced Ki67) and G1 cell cycle 
arrest (elevated p27Kip1/CDKN1B) following 4 days of treatment. 
 
2.2.1.2 Clinical Pharmacokinetics (PK) and Activity of Trametinib 
 
FTIH Phase 1 Trial of Trametinib Monotherapy (MEK111054):  There were 3 parts in 
this study.   
 
• Part 1:  The dose-escalation portion involves administration of trametinib (repeat doses 
of 0.125 mg to 4.0 mg) to patients with solid tumors or lymphoma in one of three 
schedules - (1) QD for 21 days followed by 7 days without drug, (2) loading dose on 
Day 1 or Day 1-2, followed by QD with the designated dose, or (3) QD dosing without a 
drug holiday.  
• Part 2:  Cohort expansion at the recommended phase 2 dose (RP2D) for pancreatic 
cancer, melanoma, NSCLC, CRC, or any BRAF mutation-positive cancer.   
• Part 3:  Expansion to characterize the biologically active range of trametinib via 
analysis of pharmacodynamic biomarkers (biopsies or FDG-PET). 
 
The MTD of trametinib was established as 3 mg QD, but the recommended phase 2 dose 
(RP2D) was chosen at 2 mg QD based on tolerability of repeated cycles.31 
 
PK and Metabolism of Trametinib:  PK measurements were conducted under fasting 
conditions.  After a single dose (Day 1), AUC0-24 and Cmax values were dose-
proportional up to 6 mg, lower than dose proportional following 8 mg, and greater than 
dose proportional following the 10 mg dose.  Median Tmax was 1.5 hours. 
 
After repeat doses (Day 15), trametinib accumulated with a mean accumulation ratio of 
6.6 at the RP2D of 2 mg QD.  Between-subject variability in exposure ranged from 27-
50% for Cmax and 20-41% for AUC0-24 across all dosing regimens.  The effective t1/2 was 
approximately 4.5 days, and steady state was reached by approximately Day 15.  
Trametinib had a small peak:trough ratio of ~2.31  At 2 mg QD on Day 15, mean AUC0-
24 was 376 ng•h/mL and Cmax 23 ng/mL, and the mean trough concentrations ranged 
from 10.0 to18.9 ng/mL.  The long half life and small peak:trough ratio of trametinib 
allowed constant target inhibition within a narrow range of exposure. 

IRB: 13-144 A(15) 
14 
 
 
Drug-Drug Interactions:  Trametinib is metabolized predominantly via deacetylation 
(non-cytochrome P450 [CYP450]-mediated) with secondary oxidation or in combination 
with glucuronidation biotransformation pathways.30  The deacetylation is likely 
mediated by hydrolytic esterases, such as carboxylesterases, or amidases.  Based on in 
vitro studies, trametinib is not an inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2D6, 
and CYP3A4.  Trametinib has an overall low potential for drug-drug interactions. 
 
Pharmacodynamic effect and biomarkers:  The relationship between dose and tumor 
biomarkers such as pERK, Ki67, and p27, were evaluated in patients with BRAF or 
NRAS mutation-positive metastatic melanoma (Investigator's Brochure, 2012a).  In 
general, increasing exposures and/or doses provided greater pharmacodynamic effects.  
The median change observed at a dose of 2 mg QD was 62% inhibition of pERK, 83% 
inhibition of Ki67, and a 175% increase in p27. 
 
Antitumor Activity of Trametinib Monotherapy:  In the FTIH phase 1 trial, 14 patients 
with BRAF-mutant melanoma received trametinib at 2 mg QD (2 mg/day continuously, 
or 2 mg for 21 days followed by a 1 week break).  The overall objective response rate 
(ORR) was 43% (6/14), including 2 complete responses (CRs).30  In 9 patients with 
BRAF wt melanoma, 2 patients achieved a partial response (PR), and 3 stable disease 
(SD).31  In 26 evaluable pancreatic cancer patients, there were 2 PRs (1 PR was KRAS 
mutation-positive) and 11 SD (2 achieved ≥20% tumor reduction).32  Among the 27 
CRC patients (without selection of RAS or RAF mutations), 8 SD were observed. 
 
In a phase 3 trial, patients with unresectable stage IIIC or IV cutaneous melanoma with a 
BRAF V600E or V600K mutation were randomized (2:1) to trametinib (2 mg, PO, QD) 
or chemotherapy (dacarbazine or paclitaxel).21  There were 322 patients in the intention-
to-treat (ITT) population, of whom 273 (85%) were in the primary efficacy population 
(patients with BRAFV600E-positive cancer who did not have brain metastases at 
baseline).  In the ITT analyses, the ORR was 22% in the trametinib group and 8% in the 
chemotherapy group; the median duration of PFS was 4.8 months in the trametinib 
group as compared with 1.5 months in the chemotherapy group; and the 6-month OS 
rate was 81% in the trametinib group and 67% in the chemotherapy group. 
 
Antitumor Activity of Trametinib in Cancer Other Than Melanoma:  In a phase 1/2 
monotherapy study, acute myeloid leukemia (AML) or myelodysplastic syndrome 
(MDS) patients were given trametinib at dose levels from 1-2 mg QD.  Drug-related 
AEs in 45 patients were similar to that observed in patients with solid tumors, and 2 mg 
PO QD was selected for further investigation in this patient population.  Twelve patients 
(23%) withdrew due to an AE, including cardiac failure (2) and infection (2).  Efficacy 
was reported in 39 patients.33  The best response in 13 patients with KRAS or NRAS 
mutations included 3 CRs (23%), 7 SD (54%), and 1 PD (progressive disease) (5%).  In 
26 patients with wild-type RAS or an unknown mutation, there were 2 PRs (8%). 
 
Antitumor Activity of Trametinib in Uveal Melanoma:  Although our initial trial of MEK 
inhibition in uveal melanoma utilized selumetinib, available clinical experience suggests 

IRB: 13-144 A(15) 
15 
 
that trametinib is a clinically more effective agent than selumetinib in cutaneous 
melanoma harboring BRAF mutations.  Indeed, while the RR of selumetinib in patients 
with BRAF mutant melanoma is 11.1%,34 the phase II study of trametinib demonstrated 
a 25% RR in previously treated patients with BRAF mutant cutaneous melanoma who 
have not received a prior RAF inhibitor.35  
 
Although no radiographic response was observed in 16 patients with advanced UM 
treated on the phase I study of trametinib,36 2 achieved 24% tumor reduction and 50% 
achieved stable disease, with 4 patients receiving treatment for 16 weeks or longer, and 
2 receiving treatment for at least 40 weeks.  Of these 16 patients, 7 had received 1-2 
prior lines of therapy and 8 received 3 or more prior lines of therapy. As preliminary 
data from our selumetinib trial suggests that patients previously treated respond less well 
to MEK inhibition,37 we do not believe that the published experience of trametinib in 
UM reflects the potential activity of this agent in an untreated patient population, and 
further evaluation of this agent is warranted.  
 
2.2.1.3 Trametinib Safety Profile 
 
A Comprehensive Adverse Events and Potential Risks (CAEPR) list using NCI 
Common Terminology Criteria for Adverse Events (CTCAE) terms is included in 
Section 7.1 of the protocol. 
 
Due to limited experience in human subjects, there is currently incomplete information 
available about the relationship of AEs and administration of trametinib.  Based on 
available AE data from clinical studies involving trametinib to date, the most common 
toxicities are rash and diarrhea.  Rash and diarrhea are common, class-effect toxicities 
for MEK inhibitors.  In addition, visual impairment and left ventricular ejection fraction 
(LVEF) reduction, although observed at lower frequencies, are also considered class-
effect toxicities as they have been observed with trametinib as well as other MEK 
inhibitors. 
 
AEs of special interest:  Rash, diarrhea, visual disorders, hepatic disorders, cardiac-
related AEs, and pneumonitis are considered AEs of special interest because they are 
either known class effects (i.e., have been observed with other MEK inhibitors) or are 
potentially life-threatening (Investigator’s Brochure, 2013).  The following sections 
provide integrated summaries for these AEs across different clinical trials, with 
emphasis on trials using trametinib as monotherapy, especially at the RP2D of 2 mg. 
 
Refer to dose modification guidelines for the toxicities for which they are addressed in 
Section 6. 
 
• Rash:  Rash was a common AE observed across different dose levels and in 
different combinations (Investigator’s Brochure, 2013).  At the 2 mg dose, rash 
was seen in 27% to 78% of patients in different trials.  Of the ~370 subjects with 
rash AEs at the 2 mg monotherapy dose (including crossover subjects) in five 
studies, the majority of rash AEs were grades 1 or 2 (24% to 73%); 0% to 9% of 

IRB: 13-144 A(15) 
16 
 
patients experienced grade 3 rash AEs, and four patients had a grade 4 rash AE. 
 
In a randomized phase 3 trial of trametinib vs. chemotherapy, the overall 
incidence of skin toxicity (including rash, dermatitis, acneiform rash, palmar-
plantar erythrodysesthesia syndrome, and erythema) was 87% in patients treated 
with trametinib and 13% in chemotherapy-treated patients.  Severe skin toxicity 
occurred in 12% of patients on the trametinib arm, most commonly for secondary 
infections of the skin  The median time to onset of skin toxicity was 15 days 
(range:  1 to 221 days), and median time to resolution was 48 days (range:  1 to 
282 days).  Dose reduction was required in 12% for skin toxicities, and 
permanent discontinuation of trametinib was required in 1% of patients.  
 
• Diarrhea:  At the 2 mg monotherapy dose, 33% to 58% of patients in five trials 
had diarrhea (Investigator’s Brochure, 2013).  Of ~320 subjects (including 
crossover subjects) with diarrhea at this dose, the majority of diarrhea AEs were 
grade 1 or 2 in severity (33% to 56% of all study patients); 17 patients had grade 
3 diarrhea, and none had grade 4 diarrhea. 
 
• Visual disorders:  At the 2 mg monotherapy dose, 4% to 21% of the patients in 
five trials experienced visual disorders (Investigator’s Brochure, 2013).  Of the 
85 total subjects (including crossover subjects) experiencing visual disorders at 
this dose level, the majority of visual disorders were grades 1 or 2 (4% to 20% of 
all study patients); six patients experienced grade 3 visual disorders, and one 
patient experienced a grade 4 visual disorder. 
 
o Retinal Pigment Epithelial Detachment (RPED):  Also known as 
chorioretinopathy, RPED is a visual impairment due to fluid 
accumulation under the retina and causes blurry vision.  There were five 
cases of RPED, previously termed central serous retinopathy, reported 
from the integrated trametinib safety population consisting of subjects 
treated with trametinib 2 mg once daily from five studies (Investigator’s 
Brochure, 2013).  As of 23 June 2013, 14 cases of RPED were reported 
across the entire trametinib program amongst subjects treated with 
trametinib either as monotherapy or in combination with other anti-cancer 
agents (including cases from a MEK/BRAF combination study). 
 
o Retinal vein occlusion (RVO):  As of 23 June 2013, a total of four cases 
of RVO were reported across the entire trametinib program (including 
one case from a MEK/BRAF combination study) (Investigator’s 
Brochure, 2013).  All cases of RVO occurred in one eye only.  Study 
drug was stopped at time of diagnosis in all cases.  There was a decrease 
of visual acuity in two subjects with central RVO (CRVO) while the 
other two subjects had no meaningful decrease of visual acuity.  In the 
two subjects with CRVO, local treatment with intravitreal injections of 
anti-VEGF antibodies was initiated within 2 weeks after RVO diagnosis, 
and visual acuity improved in one subject and restored to baseline 

IRB: 13-144 A(15) 
17 
 
conditions in another subject, at the time of the data cutoff.  Three of 
these four cases were considered related to study treatment by the 
investigators. 
 
• Hepatic disorders:  Abnormalities of liver enzymes and bilirubin have been 
observed with administration of trametinib (Investigator’s Brochure, 2013).  
However, assessment of these cases was often confounded by co-morbid 
conditions (such as biliary obstruction), concomitant use of other potentially 
hepatotoxic drugs, and liver metastases.  At the 2 mg monotherapy dose, 8% to 
34% of patients in five trials had LFT abnormalities.  Of the 96 total patients 
(including crossovers) with LFT changes, the majority were grade 1 or 2 in 
severity (4% to 20% of all study patients); 26 had grade 3 events, and 6 patients 
had grade 4 events. 
 
• Cardiac-related AEs:  At the 2 mg monotherapy dose, 3% to 21% of the subjects 
in six studies had cardiac-related AEs (Investigator’s Brochure, 2013).  Of the 65 
total subjects (including crossover subjects) experiencing cardiac-related AEs at 
the 2.0 mg monotherapy dose in five of the studies, the majority of cardiac-
related AEs were grades 1 or 2 in severity (0% to 16% of all study subjects); 18 
subjects had grade 3 cardiac-related AEs, and no subjects had Grade 4 cardiac-
related AEs in any study.  No subject in one study, which evaluated the effect of 
repeat oral dosing of trametinib 2 mg QD on cardiac repolarization in subjects 
with solid tumors, had cardiac-related AEs.  One study subject receiving 
trametinib 2 mg QD had grade 5 (fatal) acute cardiac failure, with evidence of 
massive tumor invasion of the heart; this AE was considered not drug-related by 
the investigator. 
 
In the phase 3 trial of trametinib vs. chemotherapy in patients with melanoma 
(MEK114267), cardiomyopathy (defined as cardiac failure, left ventricular 
dysfunction, or decreased LVEF) occurred in 7% (14/211) of patients treated 
with trametinib, and in no patients in the chemotherapy arm.  Cardiomyopathy 
was identified within the first month of treatment in five of these 14 patients; 
median onset of cardiomyopathy was 63 days (range: 16 to 156 days).  
Cardiomyopathy resolved in 10 of these 14 (71%) patients.  Cardiac monitoring 
should be included in trametinib protocols, to include LVEF assessment by 
echocardiogram or MUGA scan at baseline, one month after initiation of 
trametinib and then at 2- to 3-month intervals while on treatment.  Refer to dose 
modification guidelines for cardiac AEs in the event of LVEF decline or 
symptomatic cardiac AEs. 
 
• Pneumonitis:  At the 2 mg monotherapy dose, 0% to 4% of the subjects in five 
studies had pneumonitis (Investigator’s Brochure, 2013).  Of the nine total 
subjects (including crossovers) experiencing pneumonitis AEs at this dose, three 
subjects had grade 1 or 2 pneumonitis and six subjects had grade 3 pneumonitis. 
 
• Embryofetal toxicity:  Based on its mechanism of action, trametinib can cause 

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18 
 
fetal harm when administered to a pregnant woman.  Trametinib was 
embryotoxic and abortifacient in rabbits at doses greater than or equal to those 
resulting in exposures approximately 0.3 times the human exposure at the 
recommended clinical dose.  If this drug is used during pregnancy, or if the 
patient becomes pregnant while taking this drug, the patient should be apprised 
of the potential hazard to a fetus. 
 
Incidence of common AEs reported from a phase III trial of trametinib vs. chemotherapy 
in patients with advanced melanoma:  Patients with abnormal LVEF, history of acute 
coronary syndrome within 6 months, or current evidence of Class II or greater 
congestive heart failure (New York Heart Association) were excluded from this trial.  
Selected adverse reactions (AR) occurring in patients receiving trametinib as compared 
to patients in the chemotherapy arm are listed as below: 
 
Table:  Selected adverse reactions (ARs) occurring in ≥10% of patients receiving trametinib AND at a higher 
incidence than in the chemotherapy arm (high in the trametinib arm compared with chemotherapy by ≥5% in 
overall incidence or by ≥2% grade 3 or 4 AEs) 
 
Trametinib 
(n=211) 
Chemotherapy 
(n=99) 
Adverse Reactions 
All Grades 
Grades 
3 and 4 
All Grades 
Grades 
3 and 4 
Skin and subcutaneous tissue 
disorders 
 
 
 
 
Rash 
57 
8 
10 
0 
Dermatitis acneiform 
19 
<1 
1 
0 
Dry skin 
11 
0 
0 
0 
Pruritis 
10 
2 
1 
0 
Paronychia 
10 
0 
1 
0 
Gastrointestinal disorders 
 
 
 
 
Diarrhea 
43 
0 
16 
2 
Stomatitis 
15 
2 
2 
0 
Abdominal pain 
13 
1 
5 
1 
Vascular disorders 
 
 
 
 
Lymphedema 
32 
1 
4 
0 
Hypertension 
15 
12 
7 
3 
Hemorrhage 
13 
<1 
0 
0 
 
 
Table:  Percent-patient incidence of laboratory abnormalities occurring at a higher incidence in patients treated 
with trametinib versus chemotherapy (between-arm difference of ≥5% [all grades] or ≥2% [grades 3 or 4]) 
 
Trametinib 
(n=211) 
Chemotherapy 
(n=99) 
Preferred term 
All Grades 
Grades 
3 and 4 
All Grades 
Grades 
3 and 4 
Increased aspartate 
aminotransferase (AST) 
60 
2 
16 
1.1.1 
Increased alanine 
aminotransferase (ALT) 
39 
3 
20 
3 
Hypoalbuminemia 
42 
2 
23 
1 
Anemia 
38 
2 
26 
3 
Increased alkaline phosphatase 
24 
2 
18 
3 
 

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19 
 
Other clinically important adverse reactions observed in ≤10% of patients (n=329) treated with trametinib 
were: nervous system disorders (dizziness, dysgeusia), ocular disorders (blurred vision, dry eye), infections 
and infestations (folliculitis, rash pustular, cellulitis), cardiac disorders (bradycardia), gastrointestinal disorders 
(xerostomia), and musculoskeletal and connective tissue disorders (rhabdomyolysis).   
 
2.2.1.4 Clinical Experience with the Combination of Trametinib and Dabrafenib 
 
Preliminary data on 45 patients participating in the phase 1/2 study of dabrafenib and 
trametinib, BRF113220, have been reported.38 
 
PK:  The plasma levels of dabrafenib were higher in combination with trametinib as 
compared to that with monotherapy.  Geometric mean Day 15 AUC of dabrafenib in 
combination ranged from 3539 to 5187 ng•hr/mL, and the AUC observed in the 
monotherapy study was 2619 ng•hr/mL.  Further data are required to understand this 
difference. 
 
PK of trametinib did not appear to be affected by the addition of dabrafenib.  
Preliminary results showed that the geometric mean dose-normalized AUC0-τ (CV%) for 
trametinib (dose normalized for the 2.0 mg QD dose) in combination with dabrafenib at 
150 mg BID was 302 ng•hr/mL (n=17; 35%) on Day 15.  Historical PK data from the 
trametinib FTIH study (MEK111054) indicated a mean Day 15 AUC0-τ (CV%) of 360 
ng•hr/mL (31%). 
 
Safety and the RP2D for the combination of trametinib and dabrafenib:  One DLT of a 
recurrent grade 2 neutrophilic panniculitis occurred, and pyrexia was common (51%).  
The RP2D was 150 mg BID dabrafenib plus 2 mg QD trametinib (both agents at the 
RP2D for single agent).  Of the 137 patients enrolled, 32 patients were treated at the 
RP2D.  SAEs experienced by more than one patient include: pyrexia (5%), hypotension 
(4%), nausea (3%), and 2% of patients had a constellation of AEs including vomiting, 
dehydration, or renal failure.  The only grade 4 AE was a sepsis-like syndrome with 
fever/hypotension.  Grade 3 AEs included generalized rash (n=2, 4%) and neutropenia 
(n=2, 4%).  Skin toxicity (rash) occurred in 9 (20%) patients.  Of note, the rate of SCC 
was 2% in this study.  A single case of grade 5 hyponatremia was reported.  Other 
common AEs are listed in the table below. 
 
 Selected AEs experienced by ≥5% of patients regardless of causality in BRF113220 (treated at the RP2D) 
AE Term 
Dose Escalation Cohort 
(150mg BID/2 mg QD) 
(n=31) 
Any AE, n (%) 
24 (77) 
Pyrexia 
10 (32) 
Rash 
4 (13) 
Dermatitis acneiform 
1 (3) 
Hypotension 
4 (13) 
 
Activity:  Among 77 evaluable patients with melanoma who had not received prior 
BRAF inhibitors, there were 43 responses (56%), including 4 CRs (5%) and 39 PRs 
(51%).39  Twenty-nine patients experienced SD, and three patients experienced PD.  

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20 
 
Patients were treated on four escalating dose levels of dabrafenib/trametinib (mg 
BID/mg QD): 75/1, 150/1, 150/1.5, 150/2.  The confirmed RR for each dose level, 
respectively, was 67% (n=6), 64% (n=22), 48% (n=25), and 54% (n=24).  Median PFS 
(months) for each of the first three dose levels, respectively, was 8.7, 8.3, and 5.5; PFS 
data are not mature for the fourth (150/2) dose level.  Overall PFS was 7.4 months. 
 
Currently, the randomized phase 2 portion (Part C) of the study of dabrafenib with or 
without trametinib has enrolled 162 patients as of September 1, 2011.40 
 
 
2.2.1.5 Clinical Experience with the Combination of Trametinib + GSK2141795 (AKT 
inhibitor) (TAC113886) 
 
Twenty-three patients with advanced solid tumors received the combination using a 
zone-based escalation procedure enabling evaluation of multiple combination doses in 
parallel cohorts.41  While the RP2D for single agent for single agent trametinib and 
GSK2141795 are 2 mg/d and 75 mg/d, dose reductions were required for the 
combination.  DLTs include grade 2 AST and ALT elevation, and grade 3 chest pain 
with sustained ventricular tachycardia; all DLTs were reversible with drug interruption.  
The most common AEs (≥10%) included nausea (26%), AST elevation (22%; grade 3/4, 
9%), fatigue (22%) and rash (22%).   
 
Three MTDs were defined for variable dose ratios:  2 mg trametinib + 25 mg 
GSK2141795; 0.5 mg trametinib + 75 mg GSK2141795; and 1.5 mg trametinib + 50 mg 
GSK2141795.  Three of 13 evaluable patients (unselected) had tumor shrinkage of 8% 
(ovarian), 16% (endometrial), and 17% (ovarian) after 8 weeks on study.  The dose 
regime of 1.5 mg trametinib + 50 mg GSK2141795 will be considered for further 
development.  Additional trials to explore alternate schedules (e.g., intermittent) and 
pharmacodynamic markers are ongoing. 
 
Rationale for the Selection of a Continuous Dosing Schedule 
Combination studies were performed in vitro on colon (n=25), pancreas (n=6), and lung 
(n=15) cell lines.  A fixed ratio of GSK1120212 (0.25 µM) to GSK2141795 (10 µM) 
with 3-fold serial dilutions was used in a 3-day proliferation assay.  The combination 
effect was determined by excess over highest single agent (EOHSA), BLISS, and 
Combination Index (Cl) (<1).  Results indicated synergy in 14 colon, 7 lung, and 2 
pancreas cell lines; modest synergy in 7 each colon and lung, and 2 pancreas cell lines; 
additive in 3 colon, 1 lung, and 2 pancreas cell lines; and none in one colon cell line.  
Synergy was seen in one colon and one lung cell line at concentrations greater and equal 
to 0.003 µM (1.9 ng/mL) GSK1120212 and 0.124 µM (53 ng/mL) GSK2141795.  
Human steady-state plasma trough concentrations, not correcting for protein binding, 
similar to the in vitro values would be obtained at doses of 0.5 mg (GSK1120212) and 
20 mg (GSK2141795).  Different values were required for other tumor types. 
 
2.2.2 
GSK2141795 
 

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21 
 
2.2.2.1 Mechanisms of Action and Preclinical Data with GSK2141795 
 
GSK2141795 is a novel member of the N-alkyl pyrazole class of orally available kinase 
inhibitors and has been shown to be a potent, pan-AKT (a serine/threonine protein 
kinase with 3 isoforms, AKT1, AKT2 and AKT3) inhibitor, with potency (Ki*) values 
for human AKT1, 2, and 3 kinases being 0.066, 1.4, and 1.5 nM, respectively.  
GSK2141795 exhibited a time-dependent inhibition of AKT with a dissociation half-life 
of ≤20 minutes.   
 
In vitro, GSK2141795 caused a concentration- and time-dependent reduction in 
phosphorylation of multiple proteins downstream of AKT such as glycogen synthase 
kinase 3 (GSK-3)β, an insulin-regulated inhibitor of the mammalian target of rapamycin 
complex 1 (mTORC1) protein kinase (PRAS40), Forkhead gene product (FOXO), and 
caspase 9.  Treatment of tumor cells with GSK2141795 resulted in a concentration-
dependent increase in the nuclear translocation of the FOXO transcription factor as a 
functional consequence of reduced phosphorylation of FOXO.  GSK2141795 inhibited 
the proliferation of a range of tumor cell lines from multiple histologies including breast, 
hematological, colon, ovarian, and prostate (EC50 <1 μM).  AKT signaling was 
inhibited in cell lines both sensitive and less sensitive to GSK2141795, suggesting that 
resistance to GSK2141795 is not due to a lack of AKT kinase inhibition.  GSK2141795 
induced cell cycle arrest at G1 or apoptosis in a concentration-dependent manner 
depending on the cellular context. 
 
2.2.2.2 Clinical Pharmacokinetics (PK) and Activity of GSK2141795 
 
Single-dose (Day 1) PK parameters of GSK2141795 were evaluated in the first-time-in-
human (FTIH) study PCS112689 (GSK2141795 Investigator’s Brochure, 2012).  
Preliminary data indicated that plasma concentrations for GSK2141795 were measurable 
for all subjects over the 72 hours after a single dose over the dose range tested (10 mg to 
150 mg).  In addition, drug concentrations were measurable on Day 8, suggesting that 
GSK2141795 can still be found in the plasma at least 1 week after a single dose of study 
drug over the dose range tested (75 mg to 100 mg).  While the exposures for the 100 mg 
and 150 mg doses were similar following a single dose, drug exposure following 
multiple doses was approximately in proportion to dose.  GSK2141795 accumulated 2.5- 
to 8.4-fold with repeat daily dosing.  Mean area under the concentration-time curve 
(AUC0-24) and maximum plasma concentration (Cmax) values generally increased in a 
dose-proportional manner, although there was variability among subjects.  Median time 
to reach peak concentration (Tmax) across doses was 3 hours and ranged from 0 to 4 
hours.  The mean value for the effective half-life of elimination (t½, eff) across subjects 
was 3.0 days and ranged from approximately 1.3 to 5.5 days. 
 
The MTD of single-agent GSK2141795 is 75 mg once-daily as determined by the FTIH 
study (GSK2141795 Investigator’s Brochure, 2012).  The RP2D of single-agent 
GSK2141795 has not been determined. 
 

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22 
 
2.2.2.3 GSK2141795 Safety Profile 
 
Common Terminology Criteria for Adverse Events (CTCAE) terms is included in 
Section 7.1 of the protocol. 
 
Based on available adverse event (AE) data from 151 subjects dosed as of the data cut-
off date of May 6, 2012, the most common toxicities of GSK2141795 monotherapy or in 
combination with trametinib are gastrointestinal (GI)-related (diarrhea, nausea, and 
vomiting) and fatigue.40  Hyperglycemia, hypoglycemia, mucositis, and rash are also 
commonly observed.  In addition, three cases of hypothyroidism have been noted. 
 
2.3 Study Rationale 
 
2.3.1 
Uveal Melanoma is Characterized by Activation of the MAPK Pathway Via 
Functionally Activating Mutations in Gnaq/11.  
 
Whereas cutaneous melanoma is characterized by the presence of activating mutations in 
BRAF or NRAS in 50% and 20% of cases, respectively,42 leading to the constitutive activation 
of ERK1/2, such changes are rare in uveal melanoma (UM).43,44  Indeed, no BRAF mutations 
were identified in a total of 276 primary or secondary uveal melanoma screened samples 
(although such mutations have been identified in occasional uveal melanoma cell lines).45  
Despite the absence of these mutations, activation of the mitogen-activated protein kinase 
(MAPK) pathway in UM remains important in the development and progression of this 
disease.   
 
Work by William Harbour46 and Boris Bastian47 has demonstrated the presence of a 
functionally activating Q209L mutation in guanine nucleotide-binding protein Q polypeptide 
(Gnaq), a heterotrimeric protein that couples cell surface 7-transmembrane domain receptors to 
intracellular signaling pathways such as the MAP kinase pathway in 45% to 50% of primary 
UMs.46,47  Of the primary UMs without a Gnaq mutation, greater than 50% carry a gain-of-
function mutation in Gna11 that, like Gnaq, also encodes for a widely expressed G-protein 
alpha subunit.48  These mutations are responsible for MAPK activation in the majority of 
primary UMs.  
 
Harbour identified activating mutations of Gnaq in 33/67 (49%) primary UM samples.46  
Bastian sequenced the entire coding regions of Gnaq in a broad spectrum of melanocytic 
neoplasms and observed that 46% of UMs (n = 48) harbored mutations resulting in constitutive 
activation.49  The somatic Gnaq exon 5 Q209L and Q209P mutations most commonly 
identified lead to a glutamine to lysine and glutamine to proline substitution, respectively, at 
position 209, which lies in the Ras-like domain of Gnaq.  Mutations at this site cause loss of 
the intrinsic GTPase activity, similar to that seen in Ras family members, preventing hydrolysis 
of GTP and locking Gnaq in its active, GTP-bound state.  These mutations lead to melanocyte 
proliferation in mice and can cooperate with other oncogenes to transform 3T3 cells and 
melanocytes.47,50  Transfection of Q209L Gnaq into genetically modified melanocytes 
(transduced with telomerase and with inactivation of p53 and the p16/CDK4/RB pathways), as 
well as primary human melanocytes and 293T cells, results in increased levels of phospho-

IRB: 13-144 A(15) 
23 
 
ERK when compared with control cells transfected with wild-type Gnaq or an empty vector.  
Transduction of Q209L Gnaq results in anchorage-independent growth not observed when 
unmodified melanocytes were transfected.  Tumorgenicity studies in nude mice result in 
heavily pigmented tumors with injection of Q209L Gnaq transfected melanocytes, but not with 
injection of wild-type cells.47  Furthermore, siRNA-mediated knockdown of Gnaq in UM cell 
lines characterized by a Gnaq mut result in decreased phospho-ERK, decrease in cell number, 
loss of anchorage-independent growth, and an increase in the sub-G0/G1 subpopulation when 
compared with control. Similar findings are observed when the UM cell line OMM1.3, which 
harbors the Q209L Gnaq mut, is treated with the MEK inhibitor UO126.47  Gna11 mut most 
commonly results in a Q209L substitution and is analogous to the Q209L Gnaq mut.  Gna11 
has been validated as an oncogene that results in MAPK activation, comparable to that 
achieved with Gnaq.48 
 
2.3.2 
Gnaq/11 Mutant Uveal Melanoma Cell Lines Exhibit Dose Dependent Growth 
Inhibition and Inhibition of p-ERK by selumetinib 
 
As U0126, a non-specific inhibitor of MEK at micromolar concentrations, has been shown to 
inhibit the growth of Gnaq mut melanoma cell lines in prior studies, we evaluated if a similar 
effect could be achieved with selumetinib, a clinically available MEK inhibitor.51  We obtained 
and/or developed our own UM cell lines of differing genetic backgrounds.  We treated cells 
with increasing concentrations of selumetinib and analyzed cell viability after 3 days of 
continuous drug exposure in the Dojindo cell based assay.  Gnaq wild-type cells were resistant 
to increasing concentrations of selumetinib (see figure below)  BRAF mutant cell lines tended 
to be more sensitive to the drug (IC50s <50nM), but Gnaq/11 mutant cell lines still exhibited a 
high degree of sensitivity, with IC50s between 100-250nM. 
 
  
As shown by western blot (see figure below), this sensitivity correlated to the degree of p-ERK 
inhibition at 24 hours.  Thus, the decrease in cell viability of Gnaq mut cell lines to selumetinib 
is dose dependent, associated with sustained inhibition of pERK at 24 hours, and comparable 
to that observed in BRAF mutant UM cell lines at clinically achievable drug concentrations.   
 

IRB: 13-144 A(15) 
24 
 
  
2.3.3 
Clinical Efficacy of Selumetinib in Patients with Advanced Uveal Melanoma.   
 
Based upon this preclinical as well as preliminary clinical evidence of activity of selumetinib in 
advanced uveal melanoma,52 we developed and are conducting a CTEP sponsored trial entitled, 
“A Randomized Phase II Trial of Temozolomide versus selumetinib in Patients with Metastatic 
Uveal Melanoma (NCI#8443).”  As presented at the 2013 American Society of Clinical 
Oncology Annual Meeting (see figure below) , 7 of 46 patients initially randomized to 
selumetinib, achieved a RECIST partial response (15%), with half of the patients treated 
achieving radiographic shrinkage.53  The response rate of those randomized to 
temozolomide/DTIC is 0%. 
 
 
 
A total of 98 patients have been randomized to selumetinib (n=48) and temozolomide/DTIC 
(n=50).  Randomization was balanced by age, gender, performance status, stage and prior 
therapies.  Greater than 90% of patients on both arms had metastatic liver disease.  The primary 
endpoint of this study was progression-free survival, with secondary endpoints including 
overall survival and safety/toxicity.  As of April 22, 2013, 44 patients initially randomized to 
chemotherapy have experienced radiographic progression, with 3 patients having experienced 
clinical progression.  Thirty-four patients initially randomized to selumetinib experienced 
radiographic progression, with 2 having clinical progression.  The study met its primary 
endpoint of PFS, with a median PFS of 15.9 weeks (95% CI, 8.4 – 23.1) with selumetinib 

IRB: 13-144 A(15) 
25 
 
versus 7.0 weeks (95% CI, 4.3 – 8.4) with chemotherapy.  The hazard ratio was 0.46 (95% CI, 
.30 - .71) with a p value of 0.0005).  Despite the crossover design of the trial, with 80% of 
patients crossing over from chemotherapy to selumetinib, there was a trend towards improved 
survival with selumetinib (10.8 months versus 9.4 months; HR 0.79; p = 0.4). 
 
2.3.4 
Pharmacodynamic Activity of Selumetinib in Uveal Melanoma.   
 
As part of this trial, we are collecting fresh tumor biopsies at baseline and after 14 days of 
treatment in patients treated at MSK with selumetinib. We have thus far successfully collected 
paired samples from 28 patients.   
 
In our analysis of the first 18 patients treated with selumetinib from whom we have obtained 
paired tumor biopsies, we observed that the median pERK and cyclinD1 as measured by 
densitometry decreased by 48% (p=.03) and 76% (p=.03), respectively.54  Radiographic 
regression correlated with suppression of pERK (p=0.04), but not cyclinD1 (p=0.38) in this 
sample set.   Patients achieving clinical benefit as defined as having either a RECIST response 
or disease stability of 16 weeks or greater had a greater decline in median pERK (81.4%, 
interquartile range 58% to 96%) versus those not achieving clinical benefit (26.6%, 
interquartile range 11% to 60%), suggesting that more potent inhibition of the MAPK pathway 
may result in greater clinical benefit. 
 
As shown in the figure below, effective target inhibition was observed as characterized by 
decreased phospho-ERK and cyclinD1; however, these pharmacodynamic effects were greatest 
in patients who achieved a clinical benefit.  No suppression of phospho-ERK was observed in 
patients who experienced disease progression as their best response. 
 
 
 
 
Despite the promising results observed thus far, not all patients treated with selumetinib have 
achieved a response and the responses observed are not indefinite.  Using the matched tumor 
biopsies, we are working to assess mechanisms of primary and secondary resistance to MEK 
inhibition in uveal melanoma, and to identify potential methods to improve the efficacy of 
MEK inhibition in this disease.  We thus analyzed the transcriptional profile of cell lines 

IRB: 13-144 A(15) 
26 
 
treated with selumetinib to identify gene targets of activated Gnaq and to evaluate the biologic 
importance of these genes in uveal melanoma.55  We conducted microarray analysis of uveal 
melanoma cell lines with Gnaq mutations treated with selumetinib.  For comparison, we used 
cells carrying BRAF (V600E) and cells without either mutation.  Changes in the expression of 
selected genes were then confirmed by quantitative real-time PCR and immunoblotting.  We 
found that Gnaq mutant cells have a MEK-dependent transcriptional output and identified a 
unique set of genes that are downregulated by MEK inhibition, including the RNA helicase 
DDX21 and the cyclin-dependent kinase regulator CDK5R1, whereas the transcription factor 
c-Jun was induced.  These genes are involved in cell proliferation, tumor cell invasion, and 
drug resistance, respectively. We furthermore demonstrated that treatment with selumetinib 
regulates the expression of these genes in tumor tissues of patients with metastatic Gnaq/11 
mutant uveal melanoma. 
 
2.3.5 
Concurrent Inhibition of MEK and AKT Results in Greater Antitumor Effects than 
Inhibition of Either Alone 
 
To examine other signaling pathways downstream of Gnaq, we transfected uveal melanoma 
cells with control siRNA (Ctr) and specific Gnaq siRNA (Gnaq).  Forty-eight hours later, cell 
lysates were analyzed by Western blot.  As shown in the figure below, knock-down of Gnaq by 
siRNA inhibits both p-ERK and p-AKT in the 4 Gnaq mut cell lines, while Gnaq wt cell line 
(OCM290, lanes 1 and 2) shows no inhibition of p-ERK and only a minimal effect on p-AKT. 
  
 
This is consistent with the effect of Gnaq siRNA on cell proliferation (see figure below). Gnaq 
mutant siRNA transfected cells showed inhibition of cell proliferation by approximately 50%, 
whereas a B-RAF mutant (OCM1A) and Gnaq wt (Mel290) uveal melanoma cell lines were 
not affected. This data suggests that GnaqQ209L is required for activation of both the MAPK and 
PI3K/AKT pathways.   
 

IRB: 13-144 A(15) 
27 
 
  
We therefore hypothesized that combined inhibition of these pathways will more 
comprehensively phenocopy the biologic effect of downregulating Gnaq mutations and result 
in enhanced anti-tumor effects.  We thus treated UM cells with both MEK and AKT inhibition.  
We observed synergistic enhancement in the inhibition of cell proliferation in Gnaq mutant and 
BRAF mutant cells (see figure below) (combination Index <1 when analyzed with the Chou-
Talalay method, data not shown), but not in the Gnaq wt cell line (far left in the panel).   
Analysis of cell lysates confirmed inhibition of both p-ERK and p-AKT with the drug 
combination in the Gnaq mutant cell lines (see figure below).  Interestingly, MEK inhibition 
alone activated p-AKT, but this was inhibited with combination therapy.  Thus, it would appear 
that blocking both the MAPK and AKT pathways in Gnaq mutant UM cell lines will lead to an 
increased anti-tumor effect.  As indicated, this combination resulted in apoptosis with PARP 

IRB: 13-144 A(15) 
28 
 
cleavage in the BRAF mutant ocular melanoma, but induction of autophagy with increase in 
microtubule-associated protein 1 light chain 3 (LC3) a protein that localizes to 
autophagosomes as evidenced by western blot in the Gnaq mutant cells. 
 
 
 
2.3.6 
Concurrent Inhibition of MEK and AKT is a Strategy Worthy of Further 
Investigation in Uveal Melanoma.  
Given the preliminary evidence of clinical activity with MEK inhibition in uveal melanoma 
and this preclinical data demonstrating improved antitumor effects with concurrent MEK and 
AKT inhibition, we believe that testing this combination is of significant priority to the uveal 
melanoma community.  
2.4 Correlative Studies Background 
 
2.4.1 
Correlation of Treatment Response with Genetic Background 
 
Whereas cutaneous melanoma is characterized by the presence of activating mutations in 
BRAF or NRAS in 60% and 20% of cases, respectively, leading to the constitutive activation 
of ERK1/2, such changes are rare in UM.43,44  Despite the absence of BRAF or NRAS 
mutations,45 the MAPK pathway remains of importance in the pathophysiology of UM, and 
constitutive activation of MEK and ERK have been observed.45,56  Functionally activating 
mutations have been identified in codon 209 at Q209L of Gnaq in 45% to 50% of primary 
UMs which appears to account for MAPK activation in a significant proportion of tumors.46,47
Of the primary UMs without a Gnaq mutation (mut), greater than 50% carry a gain-of-function 
mutation in Gna11 that, like Gnaq, also encodes for a widely expressed G-protein alpha 
subunit and also results in MAPK activation.  Gna11 is a paralog of Gnaq that is 90% identical 
and shares overlapping functions in mouse melanocytes.57,58  Gnaq/11 are genes that encode for 
q class G-protein α-subunits. G proteins are a family of heterotrimeric proteins (Gαβγ) coupled 
to cell surface, seven-transmembrane spanning receptors.  Upon ligand binding to these 
receptors, the GDP bound to the Gα subunit of Gαβγ is exchanged for GTP, resulting in a 
conformational change and the subsequent dissociation of the Gα from the Gβγ subunits.  
These two subunits are then able to regulate various second messengers.  Gα activation is 
terminated by a GTPase intrinsic to the Gα subunit.  The q class Gα (Gqα) mediates its activity 

IRB: 13-144 A(15) 
29 
 
through stimulation of phospholipase Cβ, which cleaves phosphatidylinositol 4,5-bisphosphate 
(PIP2) to inosol triphosphate (IP3) and diacyl glycerol (DAG).  DAG goes on to activate 
protein kinase C, which ultimately activates downstream pathways including the MAPK 
signaling pathway.  These Gnaq/11 mutations are not associated with clinical, pathological, 
immunohistochemical, or genetic factors associated with advanced UM, and represent an early 
event in disease pathogenesis.46 
 
We hypothesize that tumors that harbor a mutation in Gnaq/11 are more dependent upon 
MAPK and PI3K pathway signaling and will be more susceptible to MEK inhibition alone and 
in combination with AKT inhibition.  To test this hypothesis, we will correlate clinical 
outcomes with mutation status.  Tumor genotyping for Gnaq/11 will be performed for patients 
enrolled on this study at MSK or elsewhere.  Genotyping can be performed retrospectively and 
will not delay patient enrollment.  Analysis for Gnaq/11 will be performed using previously 
collected paraffin embedded tumor tissue; however, should previously collected tumor tissue 
be unavailable or insufficient for testing, a repeat biopsy will be requested but will not be 
mandatory for study participation. 
 
2.4.2 
Pharmacodynamic Analysis of MEK Inhibition with or without AKT Inhibition 
 
We will continue the work we have initiated assessing the pharmacodynamic effects of MEK 
inhibition in uveal melanoma in this trial by performing pre- and post-treatment tumor 
biopsies.  All patients with safely accessible tumor will undergo pre- and post-treatment (day 
14 +/- 3 days) tumor biopsies for biomarker and correlative analysis.  The decision to not 
pursue these biopsies must be made in collaboration with the MSK Principal Investigator.  An 
additional tumor biopsy will be requested from patients at the time of disease progression; 
however, this biopsy is optional.  These patients will undergo several core biopsies (or one 
excisional biopsy) at each time point, with a portion of the sample flash frozen and a portion 
reserved for paraffin.  Analysis will include, but is not limited to, reverse phase protein array 
and gene expression analysis.  
 
2.4.3 
Assessment of Circulating Tumor DNA and Correlation with Treatment Response  
 
It is now well established that human tumor cells, through a variety of physiologic events such 
as apoptosis, necrosis and secretion, release single and double stranded fragments of DNA into 
the circulation.59,60  These oligonucleotides, which can range in size from 70 to 21,000 base 
pairs, have been detected in plasma samples as circulating, cell-free, tumor-derived DNA 
(ctdDNA) in a variety of human cancers.59 Interesting, ctdDNA share the specific genetic and 
epigenetic abnormalities as their tumor cell of origin, and thus, are readily distinguished from 
cell-free DNA derived from normal cells. Point mutations, methylation patterns, and 
microsatellite alterations have all been indentified in ctdDNA and have the potential to 
function as biomarkers for both tumor burden and even treatment response.     
 
As discussed above, 80% of uveal melanomas harbor mutations in GNAQ and GNA11.49 
These genetic alterations are found predominately at nucleotide position 626 on codon 209 and 
are the product of a missence mutation (i.e. GNAQ626A>T, GNAQ626A>C, and GNA11626A>T), 
which results ultimately in glutamine being replaced by leucine or proline (i.e. GNAQ 

IRB: 13-144 A(15) 
30 
 
Glu209Leu, GNA11 Glu209Leu, and GNAQ Glu209Pro).  Recently, Madic and colleagues 
developed 
and 
validated 
a 
method 
using 
real-time 
PCR 
using 
bi-directional 
pyrophosphorolysis-activated polymerization (PAP) that detects and quantifies tumor specific 
GNAQ/GNA11 mutations in  ctdDNA in patients with uveal melanoma.61 Activating 
mutations in GNAQ/GNA11 were detected in the plasma samples of 20 of 21 (95%) patients 
with metastatic uveal melanoma, while such ctdDNA was absent in 20 healthy donors.  
Interesting, the level of ctdDNA strongly and significantly correlated with tumor burden as 
assessed by cross sectional imaging.  This indicates that tumor volume is a major determinate 
of ctdDNA.    
 
In collaboration with investigators at the Institut Curie, Paris France, MSK, and/or Columbia, 
we propose to prospectively measure ctdDNA in patients with metastatic uveal melanoma.  
The primary objective is to describe the evolution of ctdDNA levels measured by PAP in 
plasma of patients under treatment for metastatic uveal melanoma. Additionally, we will 
evaluate the early changes of circulating tumor DNA levels as early indicator of efficiency or 
non-efficiency of treatment and correlate circulating DNA levels with tumor imaging of 
metastases.  Patients on this study at MSK will be required to submit peripheral blood samples 
prior to treatment, at various time points on treatment, and at progression.      
 
All patients will undergo blood collection on a monthly basis for analysis of circulating tumor 
DNA levels.  Using a real-time PCR developed based on bi-directional pyrophosphorolysis-
activated polymerization (bi-PAP) for the quantification of ctDNA using 3'blocked primer 
pairs specific for the 3 recurrent mutually exclusive mutations of Gα subunits Gnaq and Gna11, 
Madic et. al. have been able to detect and quantify circulating tumor DNA in metastatic UM 
patients.61  We will utilize this assay to measure circulating tumor DNA and correlate changes 
in DNA levels with response to treatment. 
 
 
3 PATIENT SELECTION 
 
The below eligbility sections contain eligbility requirements for Randomization and Crossover 
registrations. Additional Crossover-specific instructions and exceptions are listed in Section 3.3. 
 
3.1 Inclusion Criteria  
 
3.1.1 
Patients must have metastatic histologically or cytologically confirmed uveal 
melanoma.  If histologic or cytologic confirmation of the primary is not available, confirmation 
of the primary diagnosis of uveal melanoma by the treating investigator can be clinically 
obtained, as per standard practice for uveal melanoma.  Pathologic confirmation of metastatic 
disease will be performed at MSK or at a participating site. 
 
3.1.2 
Patients must have measurable disease, defined as at least one lesion that can be 
accurately measured in at least one dimension (longest diameter to be recorded) as > 20 mm 
with conventional techniques or as >10 mm with spiral CT scan.  See Section 11.0 for the 
evaluation of measurable disease.  
 

IRB: 13-144 A(15) 
31 
 
3.1.3 
Patients may not have received prior systemic or hepatic directed 
infusional/embolization therapies for advanced uveal melanoma.  Local therapies such as 
radiofrequency ablation or cryotherapy for metastatic disease are permitted but must have been 
performed at least 21 days prior to initiation of study therapy.  Lesions treated with local 
modalities such as radiofrequency ablation or cryotherapy may not be used as target lesions 
unless they demonstrate growth over a minimum of 3 months on subsequent imaging studies. 
 
3.1.4 
Age ≥18 years.  Because no dosing or adverse event data are currently available on 
the use of trametinib and GSK2141795 in patients <18 years of age, children are excluded 
from this study but will be eligible for future pediatric single-agent trials, if applicable. 
 
3.1.5 
ECOG performance status ≤ 1 (Karnofsky ≥ 70%, see Appendix A). 
 
3.1.6 
Life expectancy of greater than 3 months. 
 
3.1.7 
Able to swallow and retain orally-administered medication and does not have any 
clinically significant gastrointestinal abnormalities that may alter absorption such as 
malabsorption syndrome or major resection of the stomach or bowels. 
 
3.1.8 
All prior treatment-related toxicities must be CTCAE v4 grade ≤ 1 (except alopecia) 
at the time of randomization and crossover. 
 
3.1.9 
Patients must have normal organ and marrow function as defined below:   
 
 
 
 
Leukocytes 
 
 
≥ 3,000/mcL 
Absolute neutrophil count 
≥ 1,500/mcL 
Platelets 
 
 
 
≥ 100,000/mcL 
Hemoglobin  
 
 ≥ 9.0 g/dL (not requiring transfusions 
within the past 2 weeks) 
 
 Total bilirubin* 
 
 ≤ 1.5 X institutional upper limit of  normal 
AST (SGOT)/ALT(SGPT) 
≤ 1.5 X institutional upper limit of 
 
 
 
 
 
normal for patients with no concurrent  
 
 
 
 
 
liver metastases,  
 
 
 
 
 
OR 
 
 
 
 
 
 
 
 
 
 ≤ 2.5 X institutional upper limit of normal 
for patients with concurrent liver metastases 
 
 
 
 
Creatinine  
 
 
≤ 1.5 mg/dL  
 
 
 
 
 
 
 
 
 
 OR  
 
 
 
 
 
 
 
 
 
 Calculated creatinine clearance (Cockroft-
Gault formula) ≥50 mL/min OR  
 
 
 
 
 
 
 
 
 
 24-hour urine creatinine clearance ≥50 
mL/min 
 
Left ventricular ejection fraction ≥ institutional lower limit of normal (LLN) by ECHO 

IRB: 13-144 A(15) 
32 
 
or MUGA 
 
*Note:  Patients with hyperbilirubinemia clinically consistent with an inherited disorder of 
bilirubin metabolism (e.g., Gilbert syndrome) will be eligible at the discretion of the treating 
physician and/or the principal investigator. 
 
3.1.10 
The effects of trametinib and GSK2141795 on the developing human fetus are 
unknown.  For this reason, and because MEK inhibitors as well as other therapeutic agents 
used in this trial are known to be teratogenic, women of child-bearing potential and men must 
agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) 
prior to study entry and for the duration of study participation.  Women of child-bearing 
potential must have a negative blood pregnancy test within 14 days prior to start of protocol 
treatment.  Should a woman become pregnant or suspect she is pregnant while she or her 
partner is participating in this study, she should inform her treating physician immediately.  
Men treated or enrolled on this protocol must also agree to use adequate contraception prior to 
the study, for the duration of study participation, and 4 months after completion of trametinib 
administration. 
 
3.1.11 
Ability to understand and the willingness to sign a written informed consent 
document. 
 
3.1.12 
Patients must agree to provide all imaging studies for central radiology review.  This 
central radiology review may be performed retrospectively and will not be utilized for decision 
making for patients on study. 
 
3.2 Exclusion Criteria 
 
3.2.1 
History of another malignancy except for those who have been disease-free for 3 
years, or patients with a history of completely resected non-melanoma skin cancer and/or 
patients with indolent secondary malignancies not requiring active therapy, are eligible.  
Consult the study MSKPrincipal Investigator or the CTEP Medical Monitor if unsure whether 
second malignancies meet the requirements specified above. 
 
3.2.2 
History of interstitial lung disease or pneumonitis. 
 
3.2.3 
Any major surgery or extensive radiotherapy within 21 days prior to randomization 
and crossover. 
 
3.2.4 
Use of other investigational drugs within 28 days (or five half-lives, whichever is 
shorter; with a minimum of 14 days from the last dose) preceding the first dose of trametinib 
alone or with GSK2141795 and during the study. 
 
3.2.5 
Symptomatic or untreated leptomeningeal or brain metastases or spinal cord 
compression.  Treated brain metastases must have been stable for at least 1 month. 
 

IRB: 13-144 A(15) 
33 
 
3.2.6 
Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to 
drugs chemically related to trametinib, GSK2141795, or excipients or to dimethyl sulfoxide 
(DMSO). 
 
3.2.7 
Current use of a prohibited medication.  See Appendix B for a list of prohibited 
medications or non-drug therapies. 
 
3.2.8 
History or current evidence/risk of retinal vein occlusion (RVO) or retinal pigment 
epithelial detachment (RPED) in the eye unaffected by uveal melanoma.  
 
3.2.9 
Patients with abnormal fasting glucose values (values > ULN or < LLN) at screening 
will be excluded.  In addition, patients with Type 1 diabetes will also be excluded; however, 
patients with Type 2 diabetes will be allowed if diagnosed ≥6 months prior to enrollment, and 
if presenting with a normal fasting glucose value and a hemoglobin A1C (HbA1C) ≤8% at 
screening. 
 
3.2.10 
History or evidence of cardiovascular risk including any of the following: 
 
− 
LVEF < LLN 
− 
A QT interval corrected for heart rate using the Bazett’s formula QTcB ≥ 480 msec. 
− 
History or evidence of current clinically significant uncontrolled arrhythmias (exception: 
patients with controlled atrial fibrillation for >30 days prior to randomization are 
eligible). 
− 
History of acute coronary syndromes (including myocardial infarction and unstable 
angina), coronary angioplasty, or stenting within 6 months prior to randomization. 
− 
History or evidence of current ≥ Class II congestive heart failure as defined by the New 
York Heart Association (NYHA) functional classification system (see Appendix C). 
− 
Treatment-refractory hypertension defined as a blood pressure of systolic >140 mmHg 
and/or diastolic >90 mmHg which cannot be controlled by anti-hypertensive therapy. 
− 
Patients with intra-cardiac defibrillators. 
− 
Known cardiac metastases. 
 
3.2.11 
Known Hepatitis B Virus (HBV) or Hepatitis C Virus (HCV) infection (patients with 
chronic or cleared HBV and HCV infection are eligible).  Patients with Human 
Immunodeficiency Virus (HIV) are not eligible if on anti-retroviral medications.  
 
3.2.12 
Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, 
or psychiatric illness/social situations that would limit compliance with study requirements. 
 

IRB: 13-144 A(15) 
34 
 
3.2.13 
Animal reproductive studies have not been conducted with trametinib or 
GSK2141795.  Therefore, the study drug must not be administered to pregnant women or 
nursing mothers.  Women of childbearing potential should be advised to avoid pregnancy and 
use effective methods of contraception.  Men with a female partner of childbearing potential 
must have either had a prior vasectomy or agree to use effective contraception.  If a female 
patient or a female partner of a patient becomes pregnant while the patient receives trametinib, 
the potential hazard to the fetus should be explained to the patient and partner (as applicable).   
 
3.3 Eligibility Criteria for Crossover Registrations 
 
3.3.1 
Previously treated with Trametinib on Arm A and experienced objective disease 
progression by RECIST 1.1. 
 
3.3.2 
Not removed from trametinib treatment due to the development of unacceptable 
toxicity that is not manageable with dose reduction.  
 
3.3.3 
No other drug treatment for malignant melanoma administrered after completing 
study treatment with trametinib.  
 
3.3.4 
Meet all eligibility criteria as outlined in Sections 3.1 Inclusion Criteria and 3.2 
Exclusion Criteria with the exception of:  
o 3.1.3: Prior therapy with trametinib will be permitted. 
o 3.1.9: All laboratory parameters must be met as outlined in Section 3.1.9 except 
for ALT and total bilirubin, which must meet criteria for continued therapy as 
outlined in Section 6.2.4.  
o 3.2.4: Prior therapy with trametinib is permitted.  
o 3.2.8: Patients who are eligible for cross-over will not need to undergo another 
ophthalmologic examination. 
 
3.4 Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this trial.   
 
The accrual estimates for this trial are as follows: 
 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
 Males 
 Total 
Hispanic or Latino 
2 
+ 
2 
= 
4 
Not Hispanic or Latino 
38 
+ 
38 
= 
76 
Ethnic Category: Total of all subjects 
40 
+ 
40 
= 
80 
Racial Category 
 
American Indian or Alaskan Native 
1 
+ 
1 
= 
2 
Asian 
1 
+ 
1 
= 
2 
Black or African American 
1 
+ 
1 
= 
2 

IRB: 13-144 A(15) 
35 
 
Native Hawaiian or other Pacific 
Islander 
1 
+ 
1 
= 
2 
White 
36 
+ 
36 
= 
72 
Racial Category: Total of all subjects 
40 
+ 
40 
= 
80 
 
 
4 
REGISTRATION PROCEDURES 
 
4.1 Investigator Registration 
All investigators who participate on the clinical trial and will be responsible for patient care and 
patient enrollment to the trial must have an active investigator registration status with the NCI. 
The responsible investigator at each participating institution must be registered with CTEP, 
DCTD through an annual submission of FDA form 1572 (Statement of Investigator), Curriculum 
Vitae, Supplemental Investigator Date Form (IDF), and Financial Disclosure Form (FDF). 
Annual renewal is required. 
 
MSK, as the coordinator site, will be responsible for verifying the investigator registration status 
when registering patients from EU/UK sites. 
 
4.2 MSK Research Participant Registration Procedures 
 
 
Confirm eligibility as defined in the section entitled Patient Selection. 
 
Obtain informed consent by following procedures defined in section entitled Informed Consent 
Procedures. 
 
During the registration process, registering individuals will be required to complete a protocol 
specific Eligibility Checklist. 
 
All participants must be registered through the Protocol Participant Registration (PPR) Office at 
Memorial Sloan Kettering Cancer Center. PPR is available Monday through Friday from 8:30am 
– 5:30pm (ET) at 646-735-8000. Registrations must be submitted via the PPR Electronic 
Registration System (http://ppr/). The completed signature page of the written consent/RA, a 
completed Eligibility Checklist and other relevant documents must be uploaded via the PPR 
Electronic Registration System. 
 
 
4.3 Participating Sites Research Participant Registration Process 
 
 
To complete registration and enroll a participant from another institution within North America, 
the study staff at that site must contact the designated research staff at MSK to notify him/her of 
the participant registration. The site staff then needs to submit registration/eligibility documents 
to the Multi-Center Trial Core Representative at MSK (email to: medmctcore@mskcc.org).   
  

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36 
 
The following documents must be sent for each enrollment within 24 hours of the informed 
consent form being signed: 
 
• The completed or partially completed MSK eligibility checklist 
• The signed informed consent and signed HIPAA Authorization form (Research 
Authorization) 
• Supporting source documentation for eligibility questions (laboratory results, pathology 
report, radiology reports, MD notes, physical exam sheets, medical history, prior 
treatment records, EKG report, ECHO or MUGA report and ophthalmology report).   
 
Upon receipt, the research staff at MSK will conduct an interim review of all documents.   If the 
eligibility checklist is not complete, the patient will be registered PENDING and the site is 
responsible for sending a completed form within 30 days of the consent.  
  
If the eligibility checklist is complete, participant meets all criteria, all source documentation is 
received, the participating site IRB has granted approval for the protocol, and the site is in good 
standing with MSK, the MSK research staff will send the completed registration documents to 
the MSK Protocol Participant Registration (PPR) Office to be enrolled as stated in section 4.2.  
The participant will be registered. The Study Coordinator should be notified of cancellations as 
soon as possible. 
 
Once eligibility has been established and the participant is registered, the participant will be 
assigned an MSK Clinical Research Database (CRDB) number (protocol participant number).  
This number is unique to the participant and must be written on all data and correspondence for 
the participant.  This protocol participant number will be relayed back to study staff at the 
registering site via e-mail and will serve as the enrollment confirmation.   
 
Except in very unusual circumstances, each participating institution will order DCTD-supplied 
agents directly from CTEP.  Agents may be ordered by a participating site only after the initial 
IRB approval for the site has been forwarded by the Coordinating Center to the CTEP PIO 
(PIO@ctep.nci.nih.gov) except for Group studies. 
 
4.4 Randomization 
 
All patients will be randomized to trametinib alone or in combination with GSK2141795. After 
eligibility is established and immediately after consent is obtained, patients will be registered in 
the Protocol Participant Registration (PPR) system and randomized using the Clinical Research 
Database (CRDB), between the hours of 8:30am and 5:30pm (ET), Monday - Friday.  
Randomization will be accomplished by the method of random permuted block, and patients will 
be stratified by (i) the presence or absence of liver involvement and (ii) LDH (< 2 times ULN  
versus two times above (≥2 x) the upper limit of normal) (see section 5.1). 
 
As of 11/06/2015, Arm B met the specified stopping rule for futility. The remaining patients will 
be accrued to Arm A, no patients will be enrolled to Arm B or Crossover therapy. 
 

IRB: 13-144 A(15) 
37 
 
4.5 Crossover 
 
Patients initially randomized to Arm A and eligible for crossover will be registered using the 
crossover eligibility checklist.  
 
To complete a crossover registration from another institution within North America, the study 
staff at that site must contact the designated research staff at MSK to notify him/her of the 
participant registration. The site staff then needs to submit registration/eligibility documents to 
the Multi-Center Trial Core Representative at MSK (email to: medmctcore@mskcc.org).   
  
  
The following documents must be sent for each registration: 
• MSK Crossover eligibility checklist 
• Supporting source documentation for eligibility questions (radiology reports, MD notes, 
physical exam sheets).   
 
 
If the eligibility checklist is complete, participant meets all criteria, all source documentation is 
received, the participating site IRB has granted approval for the protocol, and the site is in good 
standing with MSK, the MSK research staff will send the completed registration documents to 
the MSK Protocol Participant Registration (PPR) Office to be enrolled to the crossover arm.  
Once the participant is registered to crossover, MSK research staff will send confirmation via e-
mail to the site study staff.  
 
Patients will be registered for crossover by MSK staff in the Protocol Participant Registration 
(PPR) system. PPR is available Monday through Friday from 8:30am – 5:30pm (ET) at 646-735-
8000. Registrations must be submitted via the PPR Electronic Registration System (http://ppr/). 
The completed Eligibility Checklist and other relevant documents must be uploaded via the PPR 
Electronic Registration System. 
 
As of 11/06/2015, Arm B met the specified stopping rule for futility. The remaining patients will 
be accrued to Arm A, no patients will be enrolled to Arm B or Crossover therapy. 
 
 
5 
TREATMENT PLAN 
 
5.1 Agent Administration 
 
Treatment will be administered on an outpatient basis.  Reported adverse events and potential 
risks are described in Section 7.  Appropriate dose modifications are described in Section 6.  No 
investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the patient's malignancy. 
 
Eligible patients will be randomized on a 1:1 ratio, with randomization stratified by presence or 
absence of liver involvement and LDH (<2 times ULN vs ≥2 times the upper limit of normal), to 
one of the two treatment arms: 
 
1. Arm A (Trametinib):  Experimental Arm A will explore the activity of MEK inhibition 

IRB: 13-144 A(15) 
38 
 
using trametinib in advanced UM.  Patients randomized to this arm will receive trametinib 2 
mg PO QD in 4 week cycles. 
 
2. Arm B (Trametinib + GSK2141795):  Experimental Arm B will explore the activity of 
combined MEK + AKT inhibition in advanced UM.  Patients randomized to this arm will 
receive trametinib 1.5 mg PO QD in combination with GSK2141795 50 mg PO QD in 4 
week cycles.   
 
Patients will remain on their initially assigned treatment arm until the sooner of (i) disease 
progression (primary outcome measure) or (ii) the development of unacceptable toxicity that is 
not manageable with dose reduction.  At that point, patients initially randomized to Arm A that 
experienced objective disease progression will be given the option of receiving additional 
experimental therapy with trametinib 1.5 mg QD and GSK2141795 50 mg QD.  
 
The option of crossover will not be available to patients who are taken off treatment due to the 
development of unacceptable toxicity that is not manageable with dose reduction. Tumor 
response assessments and progression-free survival following cross-over will be recorded, but, 
for the purposes of the primary endpoint of progression-free survival after first randomization, 
these patients will be counted as a progression-event.  Clinical outcome following cross-over will 
be followed and reported in a descriptive fashion.   
 
Patients randomized to Arm A will be eligible for crossover if they meet the eligibility criteria 
outlined in Section 3.0. 
 
Patients will be followed in an identical manner to those initially randomized as outlined in the 
Study Calendar below; however, no tumor biopsies will be performed on this cohort of patients.   
Results from these assessments will be collected in electronic CRFs up to the time of progression 
on trametinib in the same manner as during the randomized phase of the study (i.e., target and 
non-target lesions recorded in the same order). Patients may continue to receive trametinib and 
GSK2141795 until disease progression.  Patients may receive any subsequent therapy for their 
disease at the discretion of the investigator. 
 
All patients will be requested to maintain a medication diary of each dose of medication (see 
Appendix F).  The medication diary will be returned to the research staff at the end of each 
treatment cycle. Missed doses should be recorded on the Medication Diary but will not be 
considered violations of the protocol. 
 
Patients on the study may continue treatment, however, supply of GSK2141795 will end on 
March 31, 2017, and there will be no additional drug available for clinical use after that date. 
Therefore, all patients must be off treatment by March 31, 2017. 
 
As of 11/06/2015, Arm B met the specified stopping rule for futility. The remaining patients will 
be accrued to Arm A, no patients will be enrolled to Arm B or Crossover therapy. 
 
5.1.1 
Effect of Food 
 

IRB: 13-144 A(15) 
39 
 
The effect of food on trametinib and GSK2141795 absorption is unknown.   
 
The effect of a high-fat, high-calorie meal on the single-dose PK of trametinib was evaluated in 
a Phase I, open-label, randomized, 2-treatment, 2 period crossover study with an incomplete 7-
day wash-out in subjects with solid tumors.  Administration of a single dose of trametinib with 
a high-fat, high-calorie meal decreased AUC by 24%, Cmax by 70%, and delayed Tmax by 
approximately 4 hours as compared to fasted conditions    
 
A food effect study with GSK2141795 has not been completed; however its physiochemical 
properties suggest that a high fat meal may affect plasma concentrations.   
 
Therefore, both trametinib and GSK2141795 are recommended to be administered under 
fasting conditions, both 1 hour before or 2 hours after a meal.  These agents can be 
administered either (1) together at the same time of the day or (2) with one agent taken in the 
morning and the other taken in the evening, at the discretion at the treating investigator. 
 
5.1.2 
Management of Toxicities due to Trametinib 
 
Guidelines regarding the management of toxicities due to trametinib are below.  Please also 
refer to Section 6.1 regarding requirements for dose modification due to toxicity. 
 
Cutaneous AEs:  Rash is a frequent AE observed in patients receiving trametinib.30  
Recommendations for supportive care and guidelines for dose modifications for rash are based 
on experience with other MEK inhibitors and EGFR inhibitors.62,63  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 study chair or the CTEP 
Medical Monitor may be required. 
 
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). 

IRB: 13-144 A(15) 
40 
 
Guidelines for Supportive Care of Rash 
Type of Care 
Action 
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 
antibiotics; if no improvement, consult dermatologist or surgeon. 
• Infected lesions:  Appropriate bacterial/fungal culture-driven systemic or 
topical antibiotics. 
a Rash prophylaxis is recommended for the first 6 weeks of study treatment. 
b Patients who develop rash/skin toxicities should be seen by a qualified physician and should receive evaluation 
for symptomatic/supportive care management. 
 
Visual AEs:  Episodes of visual changes have been observed in subjects receiving trametinib, 
and ocular adverse events are known to be related to trametinib. An ophthalmologist or other 
qualified investigator (e.g., optometrist) should be consulted if changes in vision develop.  
However, if the visual changes are clearly unrelated to study treatment (e.g., allergic 
conjunctivitis), then close monitor closely as it may be reasonable to defer ophthalmic 
examination.  Special attention should be given to retinal findings (e.g., retinal pigment 
epithelial detachment (RPED) or retinovascular abnormalities (i.e., branch or central retinal 
vein occlusions (RVO)).   
 
Diarrhea:  Episodes of diarrhea have occurred in patients receiving trametinib or 
GSK2141795.30  Other frequent causes of diarrhea may include concomitant medications (e.g., 
stool softeners, laxatives, antacids, etc.), infections by C. difficile or other pathogens, or partial 
bowel obstruction.  Those conditions should be excluded. 
 
Cardiac AEs:   
 
• Decrease in LVEF - Decreases of the left ventricular ejection fraction (LVEF) have been 
observed in patients receiving trametinib.  Therefore, ECHOs must be performed in regular 
intervals as outlined in the Study Calendar.  The same procedure (either ECHO or MUGA, 
although ECHO is preferred) should be performed at baseline and at follow-up visit(s).   
 
• Hypertension - Increases in blood pressure (BP) have been observed in patients receiving 
trametinib.  All BP assessments should be performed under the following optimal 
conditions: 
 
• 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 correct cuff has 
been selected. 
• The subject’s arm is supported so that the middle of the cuff is at heart level. 

IRB: 13-144 A(15) 
41 
 
• The subject remains quiet during the measurement. 
• In subjects with an initial BP reading within the hypertensive range, a second 
reading should be taken at least 1 minute later. 
• Visits to monitor increased blood pressure can be scheduled independently from the 
per-protocol visits outlined in the Study calendar.  Ideally, subsequent blood pressure 
assessments should be performed within 1 week. 
 
5.1.3 
Management of Toxicities due to GSK2141795 
 
Based on available adverse event (AE) data from 151 patients dosed as of the data cut-off date 
of May 6, 2012, the most common toxicities of GSK2141795 monotherapy or in combination 
with trametinib are gastrointestinal (GI)-related (diarrhea, nausea, and vomiting) and fatigue 
(Investigator’s Brochure, 2012).  Hyperglycemia, hypoglycemia, mucositis, and rash are also 
commonly observed.  In addition, three cases of hypothyroidism have been noted. 
 
Interim medical history, continuous assessment of AEs, physical examination, and clinical 
laboratory assessments will be used to identify and assess toxicity in the GI tract.  Supportive 
therapy will be provided according to standard medical practice.  Treatment will be 
discontinued for clinically significant toxicity. 
 
Guidelines regarding the management of toxicities due to GSK2141795 are below.  Please also 
refer to Section 6.4 regarding requirements for dose modification due to toxicity. 
 
GI-related AEs:  Interim medical history, continuous assessment of AEs, physical examination, 
and clinical laboratory assessments will be used to identify and assess toxicity affecting the GI 
tract.  Supportive therapy will be provided according to standard medical practice.  Treatment 
will be discontinued for clinically significant toxicity. 
 
• Diarrhea - This is the most frequent drug-related AE in patients receiving GSK2141795.  
Most diarrhea events reported were Grade 1 and 2.  Based on current data, the majority of 
cases of diarrhea occur within the first 3 to 4 weeks of starting the drug.  In most cases, 
diarrhea resolves with interruption of GSK2141795 dosing and implementation of 
supportive treatment.  Based on preliminary data, re-challenge with a reduced dose of 
GSK2141795 is tolerated.  Early diarrhea management for subjects taking GSK2141795 is 
critical and must be initiated as soon as the first episode of diarrhea has occurred.  
Supportive care interventions should include dietary modifications, anti-diarrheal 
medications, and supplementary intravenous hydration as needed. 
 
• Mucosal inflammation - Mucositis has been observed as a dose-limiting toxicity (DLT).  
Early intervention for signs and symptoms of mucosal inflammation is recommended and 
encouraged.  Based on preliminary data, dose interruption followed by dose reduction on re-
challenge can ameliorate symptoms.  Supportive care interventions should include good oral 
hygiene, adequate pain control, prevention of superinfection, and maintenance of adequate 
of hydration with supplementary intravenous hydration as needed. 
 

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42 
 
Cutaneous AEs:  Two types of rashes may be seen with the trametinib + GSK2141795 
combination: 
 
1. Acneiform rash, typically associated with MEK inhibitor therapy (trametinib). 
2. Maculopapular rash, often associated with pruritus (GSK2141795). 
 
If the diagnosis is unclear, a biopsy and photographs should be obtained as well as a 
dermatology consult.  In addition, if the investigator feels the rash is not consistent with a 
MEK inhibitor-associated acneiform rash and is Grade 2 or greater, a skin punch biopsy should 
be performed.     
 
In general, topical and oral antibiotics (doxycycline or minocycline) play a larger role in 
management of the MEK inhibitor acneiform rash, while topical and oral steroids are more 
relevant to the management of the AKT inhibitor maculopapular rash. 
 
Rash may or may not be associated with pruritus.  Preliminary data suggest that drug 
interruption and dose reduction upon re-challenge ameliorate the symptoms.  Rash 
management should focus on symptom relief and maintenance of an intact integument. 
Dermatology consult is recommended when clinically appropriate.  Topical steroid creams 
have been found to provide some relief from symptoms.  Treatment will be dose reduced or 
discontinued for clinically significant toxicity not adequately controlled by supportive care 
measures. 
 
Glucose Abnormalities: 
 
• Hyperglycemia - Hyperglycemia occurred in patients receiving GSK2141795 ≥75 mg/day, 
with the majority of events occurring at doses exceeding the maximum tolerated dose 
(MTD) of 75 mg/day.  Treatment-related grade 3 or grade 4 events were observed at 75 mg, 
100 mg, and 150 mg daily doses.  The frequency and severity of hyperglycemia AEs is 
reduced at the 75mg/day dose as compared with higher doses.  It is not clear if oral anti-
hyperglycemic drugs are useful to ameliorate the hyperglycemia, although both intravenous 
and sliding scale insulin have been helpful. 
 
To reduce the risk of hyperglycemia, patients with abnormal fasting glucose values at 
screening will be excluded.  In addition, patients with Type 1 diabetes will also be excluded; 
however, patients with Type 2 diabetes will be allowed if diagnosed ≥6 months prior to 
enrollment, and if presenting with a normal fasting glucose value and a hemoglobin A1C 
(HbA1C) ≤8% at screening.  Patients will have glucose and insulin monitored during the 
study.  If hyperglycemia is observed, supportive therapy will be provided according to 
standard medical practice.  Treatment will be dose reduced or discontinued for clinically 
significant toxicity that cannot be adequately managed medically. 
 
• Hypoglycemia - Asymptomatic hypoglycemia occurred in patients receiving GSK2141795 
≥75 mg/day.  Treatment-related grade 3 or grade 4 events were observed at 75 mg and 100 
mg daily doses.  The mechanism of hypoglycemia is currently unknown.  Careful 
monitoring of glucose levels and encouragement of adequate oral intake are recommended. 

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43 
 
 
Thyroid Events:  Reversible minimal to mild hypertrophy of follicular cells was seen in the 
thyroid glands of dogs given 5 mg/kg/day for 4 weeks.  The relationship to GSK2141795 and 
clinical significance are unknown, although three cases of drug-related hypothyroidism have 
been reported.  Continued monitoring for thyroid function (thyroid-stimulating hormone 
laboratory testing) will be incorporated in all clinical protocols.  Supportive therapy will be 
provided according to standard medical practice, and treatment will be discontinued if 
necessary. 
 
Other Glandular Events:  In both rats and dogs, several glandular structures (salivary, nasal, 
mammary, and Brunner’s glands) had reversible reductions in secretory content and/or 
apoptosis of individual acinar cells.  The mechanism for this finding is not understood, 
although it may result in dry mouth, a toxicity that has been reported in some patients.  
Frequent monitoring with medical history, physical examination, and clinical laboratory 
assessments will be done.  If clinically significant toxicity is observed, supportive therapy will 
be provided according to standard medical practice, and treatment will be discontinued if 
necessary. 
 
5.2 General Concomitant Medication and Supportive Care Guidelines 
 
Because there is a potential for interaction of trametinib and GSK2141795 with other 
concomitantly administered drugs through the cytochrome P450 system, the electronic case 
report form must capture the concurrent use of all other drugs, over-the-counter medications, or 
alternative therapies.  The local Principal Investigator should be alerted if the patient is taking 
any agent known to affect or with the potential to affect selected CYP450 isoenzymes.  
Appendix D is a patient information sheet that can be used for this specific protocol and 
presented to the patient. 
 
5.3 Duration of Therapy 
 
In the absence of treatment delays due to adverse event(s), treatment may continue until one of 
the following criteria applies: 
 
• 
Disease progression, unless the patient is experiencing clinical benefit from therapy as 
determined by the study PI. Continued treatment in these situations will be approved 
once the study PI and CTEP medical monitor have reviewed the case, 
 
• 
Intercurrent illness that prevents further administration of treatment, 
 
• 
Unacceptable adverse event(s), 
 
• 
Patient decides to withdraw from the study, or 
 
• 
General or specific changes in the patient's condition render the patient unacceptable for 
further treatment in the judgment of the investigator. 
 

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44 
 
5.4 Duration of Follow Up 
 
Patients will be followed for 4 weeks after removal from study or until death, whichever occurs 
first.  Patients removed from study for unacceptable adverse event(s) will be followed until 
resolution or stabilization of the adverse event. 
 
Patients will be contacted or evaluated approximately every 12 weeks (+/- 1 week) until death 
for survival assessment.  Follow-up for overall survival will continue until all patients have 
completed study therapy and sufficient data is available to analyze the primary endpoint; 
however, survival follow-up may continue beyond this time point at the discretion of the MSK 
principal investigator and CTEP.   
 
5.5 Criteria for Removal from Study 
 
Patients will be removed from study when any of the criteria listed in Section 5.3 applies.  The 
reason for study removal and the date the patient was removed must be documented in the 
electronic Case Report Form. 
 
 
6 
DOSING DELAYS/DOSE MODIFICATIONS 
 
AEs occurring in patients treated with GSK2141795 and trametinib may be related to 1) 
overlapping toxicities between the two agents (e.g., rash and diarrhea); 2) toxicities typically 
associated with trametinib (e.g., visual disturbance) or GSK2141795 (e.g., hyperglycemia or 
hypoglycemia).  However, toxicities associated with individual agents may be potentiated in the 
combination, or unanticipated AEs may occur.   
 
The dose modifications may involve one or both agents, and should be based on the nature, 
severity and attributions of the AEs.  If a patient experiences several adverse events and there are 
conflicting recommendations, the investigator should use the recommended dose adjustment that 
reduces the dose to the lowest level.  General guidelines are provided below.  CTEP drug 
monitors should be consulted if there are questions about the attribution of AEs and how the 
doses should be modified. Although dose alterations and modifications are described below by 
specific CTCAE grade, in general any intolerable toxicity, regardless of severity, may necessitate 
transient breaks in drug therapy after discussion with the CTEP drug monitor.    
 
Hypertension, pneumonitis, and visual disturbances are AEs typically associated with trametinib.  
Please follow guidelines for trametinib outlined below.  In general, dosing for GSK2141795 may 
continue when trametinib is on hold if AEs are < grade 2; however: 
 
• If the above AEs are grade 3-4, GSK2141795 should be held when trametinib is held.  Once 
the AEs have resolved to grade 1 or baseline, GSK2141795 may resume at the same dose. 
• If GSK2141795795 has been held for >21 days, a discussion with the CTEP drug monitor is 
required before resuming treatment with the agent. 
 

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45 
 
6.1 Trametinib and GSK2141795 Dose Modifications 
 
6.1.1 
Trametinib Dose Modifications 
 
The table below outlines the dose levels to be used for any necessary trametinib dose 
modifications.  Please note that the trametinib starting doses are different depending upon 
treatment arm. 
  
Dose Level 
Trametinib Dose/Schedule 
0 
2 mg QD 
-1 
1.5 mg QD 
-2 
1 mg QD 
 
If trametinib 1 mg QD is not tolerated, then treatment will be permanently discontinued. 
 
6.1.2 
Trametinib Dose Modification for Toxicities Not Specified in Subsequent Sections 
 
Trametinib Treatment Modification for Clinically Significant Toxicities Deemed Related to Trametinib 
(This section is not for specific AEs such as hypertension, rash, ejection fraction changes, pneumonitis, diarrhea, 
liver chemistry, QTc prolongation, or visual changes.  Refer to other sections for these specific AEs). 
CTCAE v4 
Grade 
Management Guideline 
Dose Modification 
Grade 1 
Monitor as clinically indicated.  
Provide supportive care 
according to institutional 
standards 
Continue trametinib at current dose level. 
Grade 2 
• Interrupt treatment until resolution to grade 1 or baseline.   
• Upon resolution, restart treatment at current dose level. 
Grade 3 
• Interrupt treatment until resolution to grade 1 or baseline.   
• Upon resolution to baseline or grade 1, restart with one 
level of dose reduction 
• If the Grade 3 toxicity recurs, interrupt trametinib; When 
toxicity resolves to Grade 1 or baseline, restart trametinib 
reduced by another dose level 
Grade 4 
Permanently discontinue trametinib. 
Trametinib should be discontinued if treatment delay is >21 days due to toxicities.  If the investigator concludes 
that continued trametinib will benefit a patient, the study chair and CTEP Medical Monitor may be consulted for 
the possibility of resuming trametinib, provided that toxicities have resolved to baseline or grade 1. 
 
6.1.3 
GSK2141795 Dose Modification 
 
The table below outlines the dose levels to be used for any necessary GSK2141795 dose 
modifications: 
 
Dose Level 
GSK2141795 Dose/Schedule 
0 
50 mg QD 
-1 
25 mg QD 
 
A maximum of one GSK2141795 dose level reduction is allowed.  If a second dose level 
reduction is required, treatment will be permanently discontinued. 

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46 
 
 
6.1.4 
GSK2141795 Dose Modification for Toxicities Not Specified in Subsequent 
Sections 
 
Toxicity Gradea 
Dose Modification of GSK2141795 
Grade 1 
Continue at current dose level.  Consider supportive care recommendations. 
Grade 2 
Consider withholding dose until toxicity resolves to grade 1 or baseline.  Upon 
resolution, then restart at current dose level.  Consider supportive care 
recommendations. 
Grade 3 
Withhold dose until toxicity resolves to grade 1 or baseline.  Upon resolution, resume at 
the next lower dose level.  Consider supportive care recommendations. 
Grade 4 
Permanently discontinue GSK2141795. 
a:  The guidelines are for AEs thought to be related to GSK2141795.  However, temporary interruption of the 
agent should be considered if the patient is critically ill due to AEs of any attribution 
 
6.2 Dose Modifications for Toxicities Attributable to Both Trametinib and GSK2141795 
 
6.2.1 
Dose Modification for Rash 
 
Guidelines regarding event management and dose reduction for rash considered to be related  
to study treatment are provided in the table below.  Of note, the treating physician can at his or 
her discretion hold protocol therapy for rash sooner than listed below if they document that, in 
their opinion, it will mitigate the severity of a rash that would have otherwise compromised 
dose intensity. 
 
 
Dose Modification Guidelines and Management for Rash 
Rash Severity 
Management Guideline 
Dose Modification 
Grade 1 
 
• Initiate prophylactic and 
symptomatic treatment measures.1 
• Use moderate strength topical 
steroid.2 
• Reassess after 2 weeks. 
• Continue treatment. 
• If rash does not recover to baseline within 2 weeks 
despite best supportive care, reduce trametinib or 
both agents by one dose level.3 

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47 
 
Dose Modification Guidelines and Management for Rash 
Rash Severity 
Management Guideline 
Dose Modification 
Grade 2 
 
• Initiate prophylactic and 
symptomatic treatment measures.1 
• Use moderate strength topical 
steroid.2 
• Reassess after 2 weeks. 
 
• Continue treatment 
• Reduce trametinib or both agents by one dose 
level. 
• If rash recovers to ≤ grade 1 within 2 weeks, increase 
dose(s) to previous dose level. 
• If no recovery to ≤ grade 1 within 2 weeks, interrupt 
treatment until recovery to ≤ grade 1. 
• Restart trametinib or both agents at reduced dose 
level. 
Grade ≥3 
 
• Use moderate strength topical 
steroids PLUS oral methyl-
prednisolone dose pack.2 
• Consult dermatologist. 
• Interrupt trametinib or both agents until rash recovers 
to ≤ grade 1. 
• Restart with trametinib or both agents with one 
dose level reduction3, 
• If no recovery to ≤ grade 2 within 3 weeks, 
permanently discontinue both agents (resumption 
of trametinib or GSK2141795 alone may be 
considered based on toxicity-benefit consideration 
and after consultation with CTEP).  
1.  Rash prophylaxis is recommended for the first 6 weeks of study treatment (refer to guidelines for trametinib). 
2.  Moderate-strength topical steroids:  Hydrocortisone 2.5% cream or fluticasone propionate 0.5% cream. 
3.  Trametinib or GSK2141795 may be escalated to previous dose level if no rash is evident 4 weeks after 
restarting study treatment. 
 
 
 
 
6.2.2 
Dose Modification for Diarrhea 
 
Guidelines regarding event management and dose reduction for diarrhea considered to be 
related to study treatment are provided in the table below. 
 
 
 
Management and Dose Modification Guidelines for Diarrhea 
CTCAE Grade 
Adverse Event Management 
Action and Dose Modification 

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48 
 
Management and Dose Modification Guidelines for Diarrhea 
CTCAE Grade 
Adverse Event Management 
Action and Dose Modification 
Uncomplicated Diarrhea,1 
Grade 1 or 2 
• 
Diet:  Stop all lactose containing 
products; eat small meals, 
BRAT-diet (bananas, rice, 
apples, toast) recommended. 
• 
Hydration:  8-10 large glasses of 
clear liquids per day (e.g., 
Gatorade or broth). 
• 
Loperamide3:  Initially 4 mg, 
followed by 2 mg every 4 hours 
or after every unformed stool; 
maximum 16 mg/day.  Continue 
until diarrhea-free for 12 hours. 
• 
Diarrhea >24 hours:  
Loperamide 2 mg every 2 hours; 
maximum 16 mg/day.  Consider 
adding oral antibiotics. 
• 
Diarrhea >48 hours:  
Loperamide 2 mg every 2 hours; 
maximum 16 mg/day.  Add 
budesonide or other second-line 
therapies (octreotide, or tincture 
of opium) and oral antibiotics. 
• 
Continue treatment. 
• 
If diarrhea is grade 2 for >48 h, 
interrupt GSK2141795 and 
trametinib until diarrhea 
resolves to grade ≤1. 
• 
Restart treatment at the same 
dose level. 
• 
If treatment delay is > 21 days, 
discontinue both agents.  
(Resumption of trametinib or 
GSK2141795 alone may be 
considered based on toxicity-
benefit consideration and after 
consultation with CTEP). 
Uncomplicated Diarrhea,1 
Grade 3 or 4 
 
Any Complicated Diarrhea2 
 
• Clinical evaluation mandatory. 
• Loperamide3:  Initially 4 mg, 
followed by 2 mg every 4 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 protocol therapy until 
diarrhea resolves to ≤ grade 1. 
• Restart with trametinib or 
trametinib and GSK2141795 
reduced by one dose level (for the 
combination, reduce both agents by 
one level).4 
• If more than one dose reduction of 
study treatment is clinically 
indicated, permanently 
discontinue treatment. 
• If treatment delay is >21 days, 
discontinue treatment. (resumption 
of trametinib or GSK2141795 
alone may be considered based on 
toxicity-benefit consideration and 
after consultation with CTEP). 
1.  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. 
2.  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. 
3.  Loperamide should be made available prior to start of study treatment so loperamide administration can begin at 
the first signs of diarrhea. 
4.  Escalation of trametinib or trametinib and GSK2141795 to previous dose level(s) is allowed after consultation 
with the CTEP monitor and Study Chair and in the absence of another episode of complicated or severe diarrhea in 
the 4 weeks subsequent to dose reduction. 

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49 
 
 
6.2.3 
Dose Modification for Reduced Left Ventricular Ejection Fraction 
 
Decreases of the left ventricular ejection fraction (LVEF) have been observed in patients 
receiving trametinib.  GSK2141795 dose is to be modified the same as for trametinib.  ECHOs 
must be performed in regular intervals outlined in the Study Calendar.  The same procedure 
(either ECHO or MUGA, although ECHO is preferred) should be performed at baseline and at 
follow-up visit(s). 
 
Guidelines regarding event management and dose reduction for reduced left ventricular 
ejection fraction considered to be related to study treatment are provided in the table below. 
 
 
 
 
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), then: 
o 
Consult with the CTEP 
medical monitor and request 
approval to restart  
o 
Restart treatment with 
trametinib and GSK2141795 
reduced dose by one dose 
levelb 
o 
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 weeks: 
o 
Consult with cardiologist 
o 
Permanently discontinue 
trametinib and 
GSK2141795  
o 
Report as SAE 
o 
Repeat ECHO/MUGA after 
2, 4, 8, 12, and 16 weeks or 
until resolution 
Symptomaticc 
 
• Grade 3:  resting LVEF 39% or 
>20% absolute reduction from 
baseline 
• Grade 4:  Resting LVEF ≤20%. 
• Permanently discontinue 
trametinib and GSK2141795 
• Report as SAE. 
• Consult with cardiologist. 
• Repeat ECHO after 2, 4, 8, 12, and 
16 weeks or until resolution. 

IRB: 13-144 A(15) 
50 
 
Dose Modification Guidelines and Stopping Criteria for LVEF Decrease 
Clinic 
LVEF-drop (%) or 
CTCAE grade 
Action and Dose 
Modification 
       Abbreviations:  CTCAE = Common Terminology Criteria for Adverse Events; ECHO = echocardiogram; 
GSK = GlaxoSmithKline; LLN = lower limit of normal; LVEF = left ventricular ejection fraction;  
 
If ECHO/MUGA does not show LVEF recovery after 2 weeks, repeat ECHO/MUGA 2 weeks later. 
Escalation of trametinib to previous dose level can be considered if LVEF remains stable for 4 weeks after 
restarting of trametinib.  Approval from GSK Medical Monitor is required. 
Symptoms may include: dyspnea, orthopenea, and other signs and symptoms of pulmonary congestion and edema. 
 
6.2.4 
Dose Modification for Liver Chemistry Changes 
 
Guidelines regarding event management and dose reduction for liver chemistry changes 
considered to be related to study treatment are provided in the table below. 
 
Trametinib Dose Modification for Liver Function Test Abnormalities 
Event 
Treatment modifications and assessment/monitoring 
• 
ALT ≥ 3x ULN but < 5x ULN 
and TB < 2x ULN, without 
symptoms considered related to 
liver injury or hypersensitivity 
and who can be monitored 
weekly for 4 weeks 
 
• 
May continue study drug. 
• 
Report as SAE if CTEP-AERS reporting criteria is met. 
• 
If liver chemistry stopping criteria are met any at time, proceed as 
described below. 
 
MONITORING: 
Repeat LFTs (ALT, AST, ALK, bilirubin) until they return to 
normal/baseline or stabilize (LFTs may be repeated every 2 weeks after 4 
weeks if ALT < 3x ULN and TB < 2 ULN). 
Criteria for discontinuing study 
drug:  When any of the liver 
stopping  criteria below is met, 
discontinue trametinib  
 
1. ALT ≥ 3xULN and bilirubin ≥ 
2x ULN  or > 35% direct 
bilirubin1, 2 
2. ALT ≥ 3xULN and INR > 1.5, 
if INR measured2  (INR 
threshold does not apply if 
subject is on anticoagulant) 
3. ALT ≥ 5x ULN 
4. ALT ≥ 3x ULN persists for ≥ 4 
weeks 
5. ALT ≥ 3x ULN and cannot be 
monitored weekly for 4 weeks 
6. ALT  ≥ 3x ULN associated with 
symptoms3  (new or worsening) 
believed to be related to  liver 
injury or hypersensitivity 
 
 
• 
Immediately discontinue study treatment. 
• 
Do not restart/rechallenge unless approved by CTEP trametinib 
medical monitor.  
• 
Report as SAE if:  1) CTEP-AERS reporting criteria are met, or 2) 
patients meet criteria 1-2. 
• 
Perform liver event ASSESSMENT AND WORKUP (see below). 
• 
Monitor the subject until liver chemistries resolve, stabilize, or return to 
baseline (see MONITORING below). 
 
 
MONITORING: 
In patients stopping for criteria 1-2 (with abnormal TB and INR, indicating 
potentially more significant liver toxicities): 
• 
Repeat liver chemistries (ALT, AST, ALK, bilirubin) and perform liver 
event follow-up assessments within 24 hours. 
• 
Monitor subjects twice weekly until LFT return to normal/baseline or 
stabilize. 
• 
A specialist or hepatology consultation is recommended. 
 
In patients stopping for criteria 2-6: 
• 
Repeat LFT and perform liver event follow up assessments within  24-
72 hrs  
• 
Monitor subjects weekly until LFTs return to normal/baseline or 
stabilize. 

IRB: 13-144 A(15) 
51 
 
Trametinib Dose Modification for Liver Function Test Abnormalities 
Event 
Treatment modifications and assessment/monitoring 
 
ASSESSMENT and WORKUP: 
• Viral hepatitis.4 
• If possible, obtain blood sample for PK analysis.5 
• CPK and LDH. 
• Fractionate bilirubin, if total bilirubin ≥ 2x ULN. 
• CBC with differential to assess eosinophilia. 
• Record clinical symptoms of liver injury, or hypersensitivity on AE CRF. 
• Record concomitant medications (including acetaminophen, herbal 
remedies, other over the counter medications). 
• Record alcohol use. 
Additional work up for patient stopping for criteria 1-2 (with abnormal TB 
and INR, indicating potentially more significant liver toxicities): 
• Anti-nuclear antibody, anti-smooth muscle antibody, Type 1 anti-liver 
kidney microsomal antibodies, and quantitative total immunoglobulin G 
(IgG or gamma globulins). 
• Acetaminophen adduct HPLC assay (in subjects with likely preceeding 
acetaminophen use). 
• If there is underlying chronic hepatitis B (e.g. positive hepatitis B surface 
antigen):  quantitative hepatitis B DNA and hepatitis delta antibody.6 
• Liver imaging (ultrasound, MRI, CT) and /or liver biopsy. 
Footnotes: 
1.  Bilirubin fractionation should be performed if testing is available. If bilirubin fractionation testing is 
unavailable, record presence of detectable urinary bilirubin on dipstick, which indicates direct bilirubin 
elevations and suggesting liver injury. 
2.  All events of ALT ≥3xULN and bilirubin ≥2xULN (>35% direct bilirubin) or ALT ≥3x ULN and INR >1.5 (if 
INR measured) may indicate severe liver injury (possible “Hy’s Law”).  INR measurement is not required, and the 
threshold value stated will not apply to subjects receiving anticoagulants. 
3.  New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia) 
4.  Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); 
Hepatitis C RNA; Cytomegalovirus IgM antibody;  Epstein-Barr viral capsid antigen IgM antibody (or if 
unavailable, obtain heterophile antibody or monospot testing);  Hepatitis E IgM antibody  
5.  PK sample is desired if feasible.  Record the date/time of the PK blood sample draw and the date/time of the 
last dose of study treatment prior to blood sample draw on the CRF. If the date or time of the last dose is unclear, 
provide the subject’s best approximation. If the date/time of the last dose cannot be approximated OR a PK sample 
cannot be collected in the time period indicated above, do not obtain a PK sample.   
6.  If hepatitis delta antibody assay cannot be performed, it can be replaced with a PCR of hepatitis D RNA virus 
(where needed) (Le Gal et al., 2005). 
 
 
6.3 Dose Modifications for Toxicities Attributable to Trametinib 
 
6.3.1 
Trametinib Dose Modifications for Visual Changes 
 
Visual changes have been observed in patients receiving trametinib, and can be caused by 
retinal pigment epithelial detachments (RPED), or retinal vein abnormalities (e.g., branch or 
central Retinal Vein Occlusion [RVO]) or optic nerve swelling.  Patients are required to have a 

IRB: 13-144 A(15) 
52 
 
standard ophthalmic exam performed by an ophthalmologist or other qualified investigator 
(e.g., optometrist) at baseline and at any time patients report visual disturbance.   
 
The ophthalmology exam will include best corrected visual acuity, visual field examination, 
tonometry, slit lamp biomicroscopic examination, and indirect fundoscopy.  Optical coherence 
tomography is recommended at scheduled visits and if retinal abnormalities are suspected.  
Other types of ancillary testing including visual field examination, fundus photography, and 
fluorescein angiography are recommended if clinically indicated. 
 
Guidelines regarding event management and dose reduction for visual changes considered to 
be related to study treatment are provided in the table below: 
 
Management and Trametinib Dose Modification for Visual Changes 
Event 
CTCAE Grade 
Management Guideline 
Dose Modification 
Any grade of RPED, or RVO should be reported as SAEs to CTEP-AERS 
Grade 1 
Asymptomatic or symptomatic but 
not limiting ADL; intervention not 
indicated. 
 
• Consult ophthalmologist or 
other qualified investigator 
(e.g., optometrist) any time 
when patient reports visual 
disturbance.  This should be 
done within 7 days for grade 
1 events, and should be done 
immediately for grade 2-3 
events.   
• Workup to rule out, RPED or 
RVO.  Consult retinal 
specialist if available. 
• Continue follow up 
examination(s) for RPED, 
and RVO. 
• Report RVO or RPED as 
SAE regardless of grade 
 
 
 
• Continue therapy.  Obtain ophthalmologic 
exam* 
• If ophthalmologic examination cannot be 
performed within 7 days of onset, hold 
trametinib until RPED and RVO are 
excluded and symptoms resolve. 
• If RPED and RVO excluded, restart 
trametinib at same dose level. 
• If RPED (regardless of symptoms):  
Interrupt trametinib until symptoms 
resolve and ophthalmology exam shows 
resolution.  May restart trametinib with 
one dose level reduction*.  If no 
resolution within 3 weeks, permanently 
discontinue trametinib. 
• If RVO:  Permanently discontinue 
trametinib. 
Grade 2 and 3 
Grade 2defined as:  Symptomatic 
with moderate decrease in visual 
acuity (20/40 or better; limiting 
instrumental ADL; local or non-
invasive intervention indicated).   
 
Grade 3 defined as:  Symptomatic 
with marked decrease in visual 
acuity or marked visual field defect 
(worse than 20/40 but better than 
20/200); severe pain or medically 
significant; operative intervention 
indicated. 
• Interrupt trametinib until signs/ symptoms 
resolve to baseline*. 
• If not RPED/RVO but related to other 
trametinib-related ocular AE (e.g., optic 
neuropathy), restart trametinib with one 
dose level reduction AFTER symptoms 
resolved. 
• If not related to trametinib, resume 
trametinib at the same dose, AFTER 
symptoms resolved. 
• If RPED:  Hold trametinib until symptoms 
resolve and exam (by retinal specialist if 
available) shows resolution.  Restart 
trametinib with one dose level 
reduction.  
• If no resolution within 3 weeks, 
permanently discontinue trametinib. 
• If RVO:  Permanently discontinue 
trametinib. 

IRB: 13-144 A(15) 
53 
 
Grade 4 
Sight-threatening consequences; 
urgent intervention indicated; 
blindness (20/200 or worse). 
Permanently discontinue trametinib. 
Abbreviations: RPED = retinal pigment epithelial detachments; RVO = retinal vein occlusion; SAE = serious 
adverse event 
*If ocular toxicities do not resolve within 21 days, permanently discontinue trametinib. 
 
 
 
6.3.2 
Trametinib Dose Modification for Pneumonitis 
 
Pneumonitis has been observed in patients receiving trametinib.  To reduce the risk of 
pneumonitis, patients will be monitored closely for symptoms and evaluated with imaging and 
functional tests.  Dose modification and supportive care guidelines for pneumonitis are 
described in the tables below. 
 
Pneumonitis Guidelines for Trametinib Monotherapy 
CTCAE Grade 
Adverse Event Management 
Action and Dose Modification 
Grade 1 
• CT scan (high-resolution with lung windows) 
recommended. 
• 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). 
• 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. 
• If AE resolved to grade ≤1 and 
relationship to trametinib is 
equivocal, restarting trametinib 
with one dose reduction may be 
considered, after discussion with 
the medical monitor.   
• If treatment delay is > 4 weeks, 
permanently discontinue 
trametinib. 
Grade 3 
• CT scan (high-resolution with lung windows). 
• 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. 
• If AE resolved to grade ≤1 and 
relationship to trametinib is 
equivocal, restarting trametinib 
with one dose reduction may be 
considered, after discussion with 
the medical monitor.   
• If treatment delay is >4 weeks, 
permanently discontinue 
trametinib. 
Grade 4 
Same as grade 3. 
Permanently discontinue 
trametinib. 
Abbreviations:  BAL = bronchoalveolar lavage; CT = computed tomography. 

IRB: 13-144 A(15) 
54 
 
 
 
6.3.3 
Trametinib Dose Modification for QTc Prolongation 
 
Guidelines regarding event management and dose reduction for QTc prolongation considered 
to be related to study treatment are provided in the table below. 
 
 
 
6.3.4 
Trametinib Dose Modification for Hypertension 
 
Guidelines regarding event management and dose reduction for hypertension considered to be 
related to study treatment are provided in the table below. 
 
Management and Trametinib Dose Modification for Hypertension 
Event 
Management Guideline 
Dose Modification 
Definitions used in the table: 
- Persistent hypertension:  Hypertension detected in two separate readings during up to three subsequent visits. 
- Well-controlled hypertension:  Blood pressure of SBP ≤140 mmHg and DBP ≤90 mmHg in two separate 
readings during up to three subsequent visits. 
- Symptomatic hypertension:  Hypertension associated with symptoms (e.g., headache, light-headedness, 
vertigo, tinnitus, episodes of fainting or other symptoms indicative of hypertension) that resolve after the blood 
pressure is controlled within the normal range. 
- Asymptomatic hypertension: SBP >140 mmHg and/or DBP >90 mmHg in the absence of the above symptoms. 
QTc-Prolongationa 
Action and Dose Modification 
 
• 
QTcB ≥501 msec  or 
• 
 uncorrected QT>600 msec or 
• 
QTcB>530 msec for subjects with bundle 
branch block 
• 
Interrupt study treatment until QTcB prolongation resolves to 
Grade 1 or baseline 
• 
Test 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 
• 
If event recurs, permanently discontinue study treatment 
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 GSK medical monitor agree that the subject will benefit from further treatment. 

IRB: 13-144 A(15) 
55 
 
(Scenario A) 
• Asymptomatic and persistent SBP 
of ≥140 and <160 mmHg, or DBP 
≥90 and <100 mmHg,  
or 
Clinically significant increase in 
DBP of 20 mmHg (but still below 
100 mmHg). 
• Adjust current or initiate new 
antihypertensive medication(s). 
• Titrate antihypertensive 
medication(s) during the next 2 
weeks to achieve well-controlled 
BP.  If BP is not well-controlled 
within 2 weeks, consider referral to 
a specialist and go to scenario (B). 
Continue trametinib at the current 
dose. 
(Scenario B) 
• Asymptomatic SBP ≥160 mmHg, 
or DBP ≥100 mmHg,  
or 
Failure to achieve well-controlled BP 
within 2 weeks in Scenario A. 
• Adjust current or initiate new 
antihypertensive medication(s). 
• Titrate antihypertensive 
medication(s) during the next 2 
weeks to achieve well-controlled 
BP. 
• Interrupt trametinib if clinically 
indicated. 
• Once BP is well-controlled, restart 
trametinib reduced by one dose 
level.a 
(Scenario C) 
• Symptomatic hypertension  
or 
Persistent SBP ≥160 mmHg, or DBP 
≥100 mmHg, despite 
antihypertensive medication and 
dose reduction of trametinib 
• Adjust current or initiate new 
antihypertensive medication(s). 
• Titrate antihypertensive 
medication(s) during the next 2 
weeks to achieve well-controlled 
BP. 
• Referral to a specialist for further 
evaluation and follow-up is 
recommended. 
• Interrupt trametinib. 
• Once BP is well-controlled, restart 
trametinib reduced by one dose 
level.a 
(Scenario D) 
Refractory hypertension 
unresponsive to above interventions 
or hypertensive crisis. 
Continue follow-up per protocol. 
Permanently discontinue 
trametinib. 
a. Escalation of trametinib to previous dose level can be considered if BPs remain well controlled for 4 weeks 
after restarting of trametinib.  Approval from Medical Monitor is required. 
 
6.4 Dose Modifications for Toxicities Attributable to GSK2141795 
 
6.4.1 
GSK2141795 Dose Modification for Hypo- or Hyperglycemia 
 
Guidelines regarding event management and dose reduction for hypo- or hyperglycemia 
considered to be related to study treatment are provided in the table below. 
 
Management and Dose Modification Guidelines for Hypo- or Hyperglycemia 
Criteria 
Management Guidelines 
Study Drug Modification 
(For management purposes, refer to mild, moderate and severe intensity criteria; however for eCRF reporting use 
NCI-CTCAE version 4.0 Grades 1-5) 
Mild 
Fasting blood glucose > 150mg/dL 
Monitor fasting and preprandial 
glucose. 
Continue study drug 

IRB: 13-144 A(15) 
56 
 
Management and Dose Modification Guidelines for Hypo- or Hyperglycemia 
Criteria 
Management Guidelines 
Study Drug Modification 
Moderate to Severe 
Fasting blood glucose <70 mg/dL 
OR any blood glucose > 250mg/dL 
 
• If a blood glucose >250 mg/dL, 
monitor for ketoacidosis as 
clinically indicated. 
• When managing hyperglycemia 
associated with GSK2141795, be 
aware that the action of insulin or 
other antihyperglycemic agents 
(e.g., sulfonylureas, biguanides, 
etc.) may be substantially blocked 
by the study agent.  However the 
action of antihyperglycemic agents 
would be restored as GSK2141795 
is cleared.  The patient should be 
observed closely for rebound 
hypoglycaemia as GSK2141795 is 
held/or discontinued.   
• Intravenous insulin treatment is 
recommended. 
Hold drug(s) and notify investigator 
immediately.  The investigator 
should discuss intervention and 
possible resumption of study drug(s) 
with the CTEP monitor. 
 
6.4.2 
GSK2141795 Dose Modification for Nausea/Vomiting 
 
Guidelines regarding event management and dose reduction for nausea or vomiting considered 
to be related to study treatment are provided in the table below. 
 
Event Name 
Nausea 
Grade of Event 
Management/Next Dose for 
GSK2141795 
Management/Next Dose for 
GSK2141795 
≤ Grade 1 
No change in dose 
No change in dose 
Grade 2 
Hold until ≤ Grade 1.  Resume at same 
dose level. 
Hold until ≤ Grade 1.  Resume at same 
dose level. 
Grade 3 
Hold* until < Grade 2.  Resume at one 
dose level lower, if indicated.** 
Hold* until < Grade 2.  Resume at one 
dose level lower, if indicated.** 
Grade 4 
Off protocol therapy 
Off protocol therapy 
*Patients requiring a delay of >2 weeks should go off protocol therapy. 
**Patients requiring > two dose reductions should go off protocol therapy. 
Recommended management:  antiemetics. 
 
 
7 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The following 
list of AEs (Section 7.1) and the characteristics of an observed AE (Section 7.2) will determine 
whether the event requires expedited reporting (via CTEP-AERS) in addition to routine reporting.   
 
7.1 Comprehensive Adverse Events and Potential Risks Lists (CAEPRs) 
 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform presentation 

IRB: 13-144 A(15) 
57 
 
of events by body system.  In addition to the comprehensive list, a subset of AEs, the Specific 
Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column and is 
identified with bold and italicized text.  The SPEER is a list of events that are protocol-specific 
exceptions to expedited reporting to NCI via CTEP-AERS (except as noted below).  Refer to the 
'CTEP, 
NCI 
Guidelines: 
Adverse 
Event 
Reporting 
Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf 
for 
further clarification.  
 
NOTE:  The highest grade currently reported is noted in parentheses next to the AE in the SPEER.  
Report ONLY AEs higher than this grade expeditiously via CTEP-AERS.  If this CAEPR is part of 
a combination protocol using multiple investigational agents and has an AE listed on different 
SPEERs, use the lower of the grades to determine if expedited reporting is required. 
 
7.1.1 
CAEPRs for CTEP IND Agents 
 
7.1.1.1 CAEPR for Trametinib 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
Trametinib dimethyl sulfoxide (GSK1120212B, NSC 763093) 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform presentation 
of events by body system. In addition to the comprehensive list, a subset, the Specific Protocol 
Exceptions to Expedited Reporting (SPEER), appears in a separate column and is identified with 
bold and italicized text. This subset of AEs (SPEER) is a list of events that are protocol specific 
exceptions to expedited reporting to NCI (except as noted below). Refer to the 'CTEP, NCI 
Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for 
further clarification. Frequency is provided based on 1111 patients. Below is the CAEPR for 
Trametinib dimethyl sulfoxide (GSK1120212B). 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next 
to the AE in the SPEER. If this CAEPR is part of a combination protocol using multiple 
investigational agents and has an AE listed on different SPEERs, use the lower of the grades to 
determine if expedited reporting is required. 
 
Version 2.4, October 7, 20161 
 
 Adverse Events with Possible  
 Relationship to Trametinib dimethyl sulfoxide (GSK1120212B) 
 (CTCAE 4.0 Term) 
[n= 1111] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
Anemia 
 
 Anemia (Gr 2) 
CARDIAC DISORDERS 
  
 
 
Heart failure 
  

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58 
 
 
 Adverse Events with Possible  
 Relationship to Trametinib dimethyl sulfoxide (GSK1120212B) 
 (CTCAE 4.0 Term) 
[n= 1111] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
 
Left ventricular systolic 
dysfunction 
  
 
Sinus bradycardia 
 
  
EYE DISORDERS 
  
 
Blurred vision 
 
  
 
Dry eye 
 
  
 
 
Eye disorders - Other 
(chorioretinopathy also known 
as retinal pigment epithelial 
detachment) 
  
 
 
Eye disorders - Other (retinal 
vein occlusion) 
  
 
Eye disorders - Other (visual 
disorders)2  
 
  
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
 Abdominal pain (Gr 2) 
 
 
 Colitis 
  
 
 
 Colonic perforation 
  
 
Constipation 
 
 Constipation (Gr 2) 
Diarrhea 
 
 
 Diarrhea (Gr 3) 
 
Dry mouth 
 
 Dry mouth (Gr 2) 
 
Dyspepsia 
 
 Dyspepsia (Gr 2) 
 
Mucositis oral 
 
 Mucositis oral (Gr 2) 
Nausea 
 
 
 Nausea (Gr 3) 
 
Vomiting 
 
 Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Chills 
 
 Chills (Gr 2) 
 
Edema face 
 
  
Fatigue 
 
 
 Fatigue (Gr 3) 
 
Fever 
 
 Fever (Gr 2) 
IMMUNE SYSTEM DISORDERS 
  
 
Allergic reaction3 
 
  
INFECTIONS AND INFESTATIONS 
  
 
Lung infection 
 
  
 
Paronychia 
 
 Paronychia (Gr 2) 
 
Skin infection 
 
 Skin infection (Gr 2) 
INVESTIGATIONS 
  
 
Alanine aminotransferase 
increased 
 
 Alanine aminotransferase increased 
(Gr 2) 
 
Alkaline phosphatase increased  
 Alkaline phosphatase increased (Gr 2) 
 
Aspartate aminotransferase 
increased 
 
 Aspartate aminotransferase increased 
(Gr 2) 
 
CPK increased 
 
  
 
Ejection fraction decreased 
 
  
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
 Anorexia (Gr 2) 
 
Dehydration 
 
 Dehydration (Gr 3) 
 
Hypoalbuminemia 
 
  

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59 
 
 
 Adverse Events with Possible  
 Relationship to Trametinib dimethyl sulfoxide (GSK1120212B) 
 (CTCAE 4.0 Term) 
[n= 1111] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
Hypomagnesemia 
 
 Hypomagnesemia (Gr 2) 
 
Hyponatremia 
 
 Hyponatremia (Gr 3) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
  
 
Back pain 
 
 Back pain (Gr 2) 
 
 
Musculoskeletal and 
connective tissue disorder - 
Other (rhabdomyolysis) 
  
 
Pain in extremity 
 
 Pain in extremity (Gr 2) 
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
 Dizziness (Gr 2) 
 
Headache 
 
 Headache (Gr 2) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
 Cough (Gr 2) 
 
Dyspnea 
 
 Dyspnea (Gr 2) 
 
 
Pneumonitis 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Alopecia 
 
 Alopecia (Gr 2) 
 
Dry skin 
 
 Dry skin (Gr 2) 
 
 
Palmar-plantar 
erythrodysesthesia syndrome 
  
 
Periorbital edema 
 
  
 
Pruritus 
 
 Pruritus (Gr 2) 
 
Skin and subcutaneous tissue 
disorders - Other (folliculitis) 
 
 Skin and subcutaneous tissue 
disorders - Other (folliculitis) (Gr 2) 
Skin and subcutaneous tissue 
disorders - Other (rash)4 
 
 
 Skin and subcutaneous tissue 
disorders - Other (rash)4 (Gr 3) 
VASCULAR DISORDERS 
  
 
Hypertension 
 
 Hypertension (Gr 2) 
Vascular disorders - Other 
(edema)5 
 
 
 Vascular disorders - Other (edema)5 
(Gr 2) 
 
Vascular disorders - Other 
(hemorrhage)6 
 
  
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed 
to all Principal Investigators at the time of revision.  The current version can be obtained by 
contacting PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and 
the agent should be included in the e-mail. 
 
 
2Visual disorders include visual disturbance that can be associated with conjunctival hemorrhage, 
corneal graft rejection, cyclitis, eye nevus, halo vision, iritis, macular edema, retinal hemorrhage, 
visual acuity reduced, visual impairment, and vitreous detachment. 
 
3Hypersensitivity (allergic reactions) may present with symptoms such as fever, rash, increased 
liver function tests, and visual disturbances. 

IRB: 13-144 A(15) 
60 
 
 
4Skin and subcutaneous tissue disorders - Other (rash) may include rash, rash acneiform, rosacea, 
erythematous rash, genital rash, rash macular, exfoliative rash, rash generalized, erythema, rash 
papular, seborrhoeic dermatitis, dermatitis psoriasiform, rash follicular, and skin fissures. 
 
5Edema includes edema, lymphedema, and edema limbs. 
 
6The majority of hemorrhage events were mild.  Major events, defined as symptomatic bleeding in a 
critical area or organ (e.g., eye, GI hemorrhage, GU hemorrhage, respiratory hemorrhage), and fatal 
intracranial hemorrhages have been reported. 
 
 
Adverse events reported on Trametinib dimethyl sulfoxide (GSK1120212B) trials, but for 
which there is insufficient evidence to suggest that there was a reasonable possibility that 
Trametinib dimethyl sulfoxide (GSK1120212B) caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Disseminated intravascular coagulation; 
Febrile neutropenia; Leukocytosis 
CARDIAC DISORDERS - Atrial fibrillation; Cardiac arrest; Myocardial infarction; Restrictive 
cardiomyopathy; Sinus tachycardia 
EYE DISORDERS - Corneal ulcer; Eyelid function disorder; Flashing lights; Floaters; Glaucoma; 
Papilledema; Photophobia; Retinal detachment 
GASTROINTESTINAL DISORDERS - Anal hemorrhage; Ascites; Duodenal ulcer; 
Enterocolitis; Esophageal necrosis; Esophageal ulcer; Esophagitis; Gastric hemorrhage; Gastric 
ulcer; Gastritis; Gastrointestinal disorders - Other (intestinal obstruction); Gastrointestinal disorders 
- Other (oropharyngeal pain); Gastrointestinal disorders - Other (pneumatosis intestinalis); 
Gastrointestinal fistula; Gingival pain; Hemorrhoidal hemorrhage; Ileus; Lower gastrointestinal 
hemorrhage; Obstruction gastric; Pancreatitis; Rectal hemorrhage; Small intestinal obstruction; 
Upper gastrointestinal hemorrhage 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Flu like 
symptoms; General disorders and administration site conditions - Other (axillary pain); Localized 
edema; Malaise; Non-cardiac chest pain; Pain 
HEPATOBILIARY DISORDERS - Cholecystitis; Hepatic failure; Hepatic pain; Hepatobiliary 
disorders - Other (hepatic encephalopathy) 
INFECTIONS AND INFESTATIONS - Biliary tract infection; Catheter related infection; Device 
related infection; Endocarditis infective; Enterocolitis infectious; Hepatitis viral; Infections and 
infestations - Other (abscess limb); Infections and infestations - Other (necrotizing fasciitis); 
Infections and infestations - Other (oral infection); Pharyngitis; Rash pustular; Sepsis; Upper 
respiratory infection; Urinary tract infection 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Bruising 
INVESTIGATIONS - Blood bilirubin increased; Creatinine increased; Electrocardiogram QT 
corrected interval prolonged; GGT increased; Investigations - Other (blood lactate dehydrogenase 
increased); Lipase increased; Lymphocyte count decreased; Platelet count decreased; Serum 
amylase increased; White blood cell decreased 
METABOLISM AND NUTRITION DISORDERS - Hyperglycemia; Hyperkalemia; 
Hyperuricemia; Hypocalcemia; Hypoglycemia; Hypokalemia; Metabolism and nutrition disorders - 

IRB: 13-144 A(15) 
61 
 
Other (hyperphosphatemia) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Generalized muscle 
weakness; Musculoskeletal and connective tissue disorder - Other (compression fracture); 
Musculoskeletal and connective tissue disorder - Other (muscle spasm); Myalgia; Neck pain 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND 
POLYPS) - Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other (tumor 
hemorrhage); Tumor pain 
NERVOUS SYSTEM DISORDERS - Dysgeusia; Encephalopathy; Intracranial hemorrhage; 
Lethargy; Nervous system disorders - Other (diplopia); Seizure; Somnolence; Stroke; Syncope; 
Transient ischemic attacks 
PSYCHIATRIC DISORDERS - Anxiety; Confusion; Delirium; Depression; Hallucinations; 
Insomnia; Personality change 
RENAL AND URINARY DISORDERS - Acute kidney injury; Cystitis noninfective; Hematuria; 
Proteinuria; Renal and urinary disorders - Other (dysuria); Urinary incontinence 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Vaginal fistula; Vaginal 
hemorrhage 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Bronchopulmonary 
hemorrhage; Epistaxis; Hypoxia; Laryngeal edema; Pleural effusion; Pneumothorax; Productive 
cough; Pulmonary hypertension; Respiratory failure; Sinus disorder 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Bullous dermatitis; Photosensitivity; 
Purpura; Skin and subcutaneous tissue disorders - Other (erythema nodosum); Skin and 
subcutaneous tissue disorders - Other (nail disorder); Skin and subcutaneous tissue disorders - Other 
(skin fissures); Skin ulceration; Urticaria 
VASCULAR DISORDERS - Hematoma; Hot flashes; Hypotension; Thromboembolic event 
(venous) 
 
Note: Trametinib dimethyl sulfoxide (GSK1120212B) in combination with other agents could 
cause an exacerbation of any adverse event currently known to be caused by the other agent, or the 
combination may result in events never previously associated with either agent. 
 
 
7.1.1.2 CAEPR for GSK2141795  
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
GSK2141795 (NSC 767034) 
 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a single list of reported and/or potential 
adverse events (AE) associated with an agent using a uniform presentation of events by body system. In addition to the 
comprehensive list, a subset, the Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate 
column and is identified with bold and italicized text. This subset of AEs (SPEER) is a list of events that are protocol 
specific exceptions to expedited reporting to NCI via CTEP-AERS (except as noted below).  Refer to the 'CTEP, NCI 
Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for further clarification.  
Frequency is provided based on 150 patients. Below is the CAEPR for GSK2141795. 
 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to the AE in the 
SPEER.  If this CAEPR is part of a combination protocol using multiple investigational agents and has an AE 

IRB: 13-144 A(15) 
62 
 
listed on different SPEERs, use the lower of the grades to determine if expedited reporting is required. 
 
Version 2.1, July 26, 20131 
 
 Adverse Events with Possible  
 Relationship to GSK2141795 
 (CTCAE 4.0 Term) 
[n= 150]  
  
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
  
GASTROINTESTINAL DISORDERS 
  
Diarrhea 
 
 
 Diarrhea (Gr 2) 
 
Esophagitis 
 
  
 
 Gastrointestinal mucositis2 
 
  
Nausea 
 
 
 Nausea (Gr 2) 
 Vomiting 
 
 
 Vomiting (Gr 2) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
Fatigue 
 
 
 Fatigue (Gr 2) 
METABOLISM AND NUTRITION DISORDERS 
  
Anorexia 
 
 
 Anorexia (Gr 2) 
 
Hyperglycemia 
 
 Hyperglycemia (Gr 2) 
 
Hypoglycemia 
 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Respiratory mucositis3 
 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Rash maculo-papular 
 
  
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all Principal 
Investigators at the time of revision.  The current version can be obtained by contacting PIO@CTEP.NCI.NIH.GOV.  
Your name, the name of the investigator, the protocol and the agent should be included in the e-mail. 
 
2Gastrointestinal mucositis may include Anal mucositis, Mucositis oral, Rectal mucositis, or Small intestinal mucositis 
under the GASTROINTESTINAL DISORDERS SOC. 
 
3Respiratory mucositis may include Laryngeal mucositis, Pharyngeal mucositis, or Tracheal mucositis under the 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS SOC 
 
Also reported on GSK2141795 trials but with the relationship to GSK2141795 still 
undetermined: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Leukocytosis 
CARDIAC DISORDERS - Cardiac arrest, Left ventricular systolic dysfunction, Ventricular 
tachycardia 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Non-cardiac chest 
pain 
HEPATOBILIARY DISORDERS - Hepatic failure 
INFECTIONS AND INFESTATIONS - Wound infection  
INVESTIGATIONS - Alanine aminotransferase increased; Alkaline phosphatase increased; 
Aspartate aminotransferase increased; Ejection fraction decreased; GGT increased 
METABOLISM AND NUTRITION DISORDERS - Hypokalemia; Hyponatremia, 
Hypophosphatemia 
NERVOUS SYSTEM DISORDERS - Dysgeusia; Dysphasia 

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RENAL AND URINARY DISORDERS - Acute kidney injury 
VASCULAR DISORDERS - Thromboembolic event 
 
Note: GSK2141795 in combination with other agents could cause an exacerbation of any adverse 
event currently known to be caused by the other agent, or the combination may result in events 
never previously associated with either agent. 
 
7.2 Adverse Event Characteristics  
 
• CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 will be utilized for AE reporting.  All appropriate treatment areas should have access 
to a copy of the CTCAE version 4.0.  A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.   
 
• For expedited reporting purposes only:   
o AEs for the agent that are bold and italicized in the CAEPR (i.e., those listed in the 
SPEER column, Section 7.1.1) should be reported through CTEP-AERS only if the 
grade is above the grade provided in the SPEER. 
o Other AEs for the protocol that do not require expedited reporting are outlined in 
Section 7.3.4 . 
 
• Attribution of the AE: 
o Definite – The AE is clearly related to the study treatment. 
o Probable – The AE is likely related to the study treatment. 
o Possible – The AE may be related to the study treatment. 
o Unlikely – The AE is doubtfully related to the study treatment. 
o Unrelated – The AE is clearly NOT related to the study treatment. 
 
 
7.3 Expedited Adverse Event Reporting 
 
 
7.3.1 
Expedited AE reporting for this study must use CTEP-AERS (CTEP Adverse Event 
Reporting System), accessed via the CTEP Web site (http://ctep.cancer.gov).  The reporting 
procedures to be followed are presented in the “NCI Guidelines for Investigators: Adverse 
Event Reporting Requirements for DCTD (CTEP and CIP) and DCP INDs and IDEs” which 
can be downloaded from the CTEP Web site (http://ctep.cancer.gov).  These requirements are 
briefly outlined in the tables below (Section 7.3.3). 
 
In the rare occurrence when Internet connectivity is lost, a 24-hour notification is to be made 
to CTEP by telephone at 301-897-7497.  Once Internet connectivity is restored, the 24-hour 
notification phoned in must be entered electronically into CTEP-AERS by the original 
submitter at the site. 
 

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64 
 
7.3.2 
CTEP-AERS is programmed for automatic electronic distribution of reports to the 
following individuals:  Study Coordinator of the Lead Organization, Principal Investigator, and 
the local treating physician.  CTEP-AERS provides a copy feature for other e-mail recipients.  
 
In addition to reporting to CTEP-AERS: 
• Participating sites are responsible for submitting all reportable SAEs to their 
local IRB per institutional guidelines 
• 
Participating sites are responsible for reporting all reportable SAEs to the MSK 
PI via e-mail within 3 calendar days of learning of the event.  Participating sites 
should use the SAE Report Form found in MSK’s internet-based Clinical 
Research Database, CRDBi-Multicenter, to report SAEs to MSK. 
• Participating sites should notify the MSK PI of any grade 5 event immediately.   
 
 
SAE contact information for the Coordinating Center is listed below:  
 
 
Alexander Shoushtari, MD 
 
Memorial Sloan Kettering Cancer Center 
 
300 East 66th Street 
 
New York, NY 10065 
 
Telephone: 646-888-4161 
 
Fax: 646-888-4253 
 
Email: shoushta@mskcc.org  
 
 
Multicenter Research Team 
 
Memorial Sloan Kettering Cancer Center 
 
Email: medmctcore@mskcc.org  
 
The MSK Research Staff is responsible for submitting all SAEs to the MSK IRB/PB within 
5 days of learning of the event.  
 
Safety Reports: 
 
• MSK will distribute outside safety reports to the participating sites immediately upon 
receipt.  
• MSK must submit safety reports to the MSK IRB/PB according to institutional 
guidelines. 
• Participating sites must submit safety reports to their institution’s IRBs within 90 days of 
the date of the report, per CTEP guidelines.  
 
7.3.3 
Expedited Reporting Guidelines 
 
Use the NCI protocol number and the protocol-specific patient ID assigned during trial 
registration on all reports. 
 
Note:  A death on study requires both routine and expedited reporting regardless of 
causality, unless as noted below.  Attribution to treatment or other cause must be 

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provided. 
 
Death due to progressive disease should be reported as Grade 5 “Neoplasms benign, 
malignant and unspecified (incl cysts and polyps) - Other (Progressive Disease)” under 
the system organ class (SOC) of the same name.  Evidence that the death was a 
manifestation of underlying disease (e.g., radiological changes suggesting tumor growth or 
progression: clinical deterioration associated with a disease process) should be submitted.  
 
Late Phase 2 and Phase 3 Studies: Expedited Reporting Requirements for Adverse Events 
that Occur on Studies under an IND/IDE within 30 Days of the Last Administration of the 
Investigational Agent/Intervention1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not 
they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via CTEP-
AERS within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 
Calendar Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
10 Calendar Days 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific 
Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR 
Expedited AE reporting timelines are defined as: 
o 
“24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 hours of learning 
of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour report. 
o 
“10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 calendar days of 
learning of the AE. 

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66 
 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• 
All Grade 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• 
Grade 3 adverse events 
2For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 
applies after this reporting period. 
Effective Date:  May 5, 2011 
 
7.3.4 
Additional Protocol-Specific Expedited Adverse Event Reporting Exclusions 
 
Not applicable. 
 
7.4 Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions.  AEs reported through 
CTEP-AERS must also be reported in routine study data submissions. 
 
7.5 Secondary Malignancy 
 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., treatment 
with investigational agent/intervention, radiation or chemotherapy). A secondary malignancy is not 
considered a metastasis of the initial neoplasm.  
CTEP requires all secondary malignancies that occur following treatment with an agent under an 
NCI IND/IDE be reported via CTEP-AERS. Three options are available to describe the event:  
 
• Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia 
[AML])  
• Myelodysplastic syndrome (MDS)  
• Treatment-related secondary malignancy  
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the routine reporting mechanisms outlined in each protocol.  
 
7.6 Second Malignancy 
 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy).  Second malignancies require ONLY routine reporting via 
CDUS unless otherwise specified.  
 
7.7 Serious Adverse Event (SAE) Reporting for MSK Patients Only 
 
Any SAE must be reported to the IRB/PB as soon as possible but no later than 5 calendar days. The 
IRB/PB requires a Clinical Research Database (CRDB) SAE report be submitted electronically to 

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the SAE Office at sae@mskcc.org.  The report should contain the following information: 
 
Fields populated from CRDB: 
• Subject’s name (generate the report with only initials if it will be sent outside of     
MSK) 
• Medical record number 
• Disease/histology (if applicable) 
• Protocol number and title 
Data needing to be entered: 
• The date the adverse event occurred 
• The adverse event 
• Relationship of the adverse event to the treatment (drug, device, or intervention) 
• If the AE was expected 
• The severity of the AE 
• The intervention 
• Detailed text that includes the following 
o An explanation of how the AE was handled 
o A description of the subject’s condition 
o Indication if the subject remains on the study 
o If an amendment will need to be made to the protocol and/or consent form. 
The PI’s signature and the date it was signed are required on the completed report. 
 
 
8 
PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational agents 
administered in this study can be found in Section 7.1. 
 
8.1 CTEP IND Agent(s) 
 
8.1.1 
Trametinib dimethyl sulfoxide (GSK1120212B) (NSC 763093) Investigationally  
labeled 
 
Chemical Name (IUPAC): equimolecular combination of N-(3-{3-cyclopropyl-5-[(2-
fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-
d]pyrimidin-1(2H)-yl}phenyl)acetamide with (methylsulfinyl)methane 
 
Other Names: trametinib, GSK1120212, JTP-74057, JTP-78296, JTP-75303, Mekinist 
 
CAS Registry Number: 1187431-43-1 
 
Classification: MEK inhibitor 

IRB: 13-144 A(15) 
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Molecular Formula:  C26H23FIN5O4  •  C2H6OS 
M.W.: 693.54 (dimethyl sulfoxide         
solvate) 615.41 (anhydrous parent) 
 
Approximate Solubility: Trametinib dimethyl sulfoxide is almost insoluble in water (<0.0001 
mg/mL at 25° C) 
 
Mode of Action: Trametinib dimethyl sulfoxide is a reversible, highly selective, allosteric 
inhibitor of mitogen-activated extracellular signal regulated kinase 1 (MEK1) and MEK2. 
Tumor cells commonly have hyperactivated extracellular signal-related kinase (ERK) 
pathways in which MEK is a critical component. Trametinib dimethyl sulfoxide inhibits 
activation of MEK by RAF kinases and MEK kinases. 
 
Description:  Trametinib dimethyl sulfoxide is a white to almost white powder. 
 
How Supplied: GlaxoSmithKline supplies and CTEP, NCI, DCTD distributes 0.5 mg and 2 
mg (as free base) tablets. Tablets are packaged in high density polyethylene bottles with child-
resistant closures including an induction seal liner. Each bottle contains 32 tablets. 
 
The tablet core contains mannitol, microcrystalline cellulose, hypromellose, croscarmellose 
sodium, magnesium stearate (non-animal), colloidal silicon dioxide and sodium lauryl 
sulfate.  
 
• 0.5 mg tablets are yellow, modified oval, biconvex and film-coated. Aqueous film coating 
consists of Opadry Yellow 03B120006 (hypromellose, titanium dioxide, polyethylene 
glycol, iron oxide yellow). 
• 2 mg tablets are pink, round, biconvex and film-coated. Aqueous film coating consists of 
Opadry Pink YS-1-14762-A (hypromellose, titanium dioxide, polyethylene glycol, 
polysorbate 80, iron oxide red). 
 
Storage: Store tablets at 2°C -8°C in the original bottle. Do not repackage tablets or remove 
desiccant. Bottles should be protected from light and moisture. 
 
Stability: Shelf life studies of trametinib dimethyl sulfoxide are ongoing. 
 
Route of Administration: Oral. Take by mouth on an empty stomach, either 1 hour before or 
2 hours after a meal. 
 
Potential Drug Interactions: In vitro studies suggest that trametinib dimethyl sulfoxide is not 
a substrate of CYP enzymes or of human Pgp, BCRP, OATP1B1 or OATP1B3 transporters.  
 
Trametinib dimethyl sulfoxide is a weak CYP2C8 inhibitor and weak CYP3A4 inducer. 
Drug-drug interactions with sensitive substrates of 2C8 and 3A4 are not anticipated 
 
Availability:  Trametinib dimethyl sulfoxide (GSK1120212B) is an investigational agent 
supplied to investigators by the Division of Cancer Treatment and Diagnosis (DCTD), NCI. 

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Trametinib dimethyl sulfoxide (GSK1120212B) is provided to the NCI under a 
Collaborative Agreement between the Pharmaceutical Collaborator and the DCTD, NCI (see 
Section 12.3). 
 
8.1.2 
Trametinib dimethyl sulfoxide (GSK1120212B) (NSC 763093) Commercially 
labeled. 
 
Chemical Name (IUPAC): equimolecular combination of acetamide, N-[3-[3-cyclopropyl-5-[(2-
fluoro-4-iodophenyl)amino]-3,4,6,7-tetrahydro6,8-dimethyl- 2,4,7-trioxopyrido[4,3-
d]pyrimidin-1(2H)-yl]phenyl] with 1,1’-sulfinylbis[methane] 
 
Other Names: trametinib, GSK1120212, JTP-74057, JTP-78296, JTP-75303, Mekinist 
 
CAS Registry Number: 1187431-43-1 
 
Classification: MEK inhibitor 
 
Molecular Formula:  C26H23FIN5O4  •  C2H6OS 
M.W.: 693.53  
 
 
 
 
 
 
 
 
 
Approximate Solubility: Trametinib dimethyl sulfoxide is almost insoluble in water (<0.0001 
mg/mL at 25° C) 
 
Mode of Action: Trametinib dimethyl sulfoxide is a reversible, highly selective, allosteric inhibitor 
of mitogen-activated extracellular signal regulated kinase 1 (MEK1) and MEK2. Tumor 
cells commonly have hyperactivated extracellular signal-related kinase (ERK) pathways in 
which MEK is a critical component. Trametinib dimethyl sulfoxide inhibits activation of 
MEK by RAF kinases and MEK kinases. 
 
Description:  Trametinib dimethyl sulfoxide is a white to almost white powder. 
 
How Supplied: Novartis supplies and CTEP, NCI, DCTD distributes 0.5 mg and 2 mg (as free base) 
tablets. Each commercially-labeled bottle contains 30 tablets with a desiccant. 
 
The tablet core contains mannitol, microcrystalline cellulose, hypromellose, croscarmellose 
sodium, magnesium stearate (non-animal), colloidal silicon dioxide and sodium lauryl 
sulfate.  
 
• 0.5 mg tablets are yellow, modified oval, biconvex and film-coated with ‘GS’ debossed on 
one face and ‘TFC’ on the opposing face. Aqueous film coating consists of hypromellose, 
titanium dioxide, polyethylene glycol, iron oxide yellow. 
• 2 mg tablets are pink, round, biconvex and film-coated with ‘GS’ debossed on one face and 
‘HMJ’ on the opposing face. Aqueous film coating consists of hypromellose, titanium 
dioxide, polyethylene glycol, polysorbate 80, iron oxide red. 
 
Storage: Store tablets at 2°C -8°C in the original bottle. Do not repackage tablets or remove desiccant. 

IRB: 13-144 A(15) 
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Bottles should be protected from light and moisture. 
 
If a storage temperature excursion is identified, promptly return trametinib to 2°C -8°C and 
quarantine the supplies.  Provide a detailed report of the excursion (including documentation 
of temperature monitoring and duration of the excursion) to PMBAfterHours@mail.nih.gov 
for determination of suitability. 
 
Stability: Refer to the package label for expiration. 
 
Route of Administration: Oral. Take by mouth on an empty stomach, either 1 hour before or 2 hours 
after a meal. If a dose of trametinib is missed, the dose can be taken if it is more than 12 hours 
until the next scheduled dose. 
 
Potential Drug Interactions: In vitro studies suggest that trametinib dimethyl sulfoxide is not a 
substrate of CYP enzymes or of human BCRP, MRP2, OATP1B1, OATP1B3, OATP2B1, 
OCT1 or MATE1 transporters. Trametinib elimination by deacetylation to metabolite M5 is 
dependent on carboxylesterases (CES1b, CES1c and CES2). M5 is eliminated by CYP3A4 
and other pathways, presenting the clinically relevant, albeit low, potential for drug-drug 
interaction. Trametinib is a substrate for P-gp and BSEP, but this is not expected to be 
clinically relevant due to trametinib’s high permeability. 
 
Trametinib dimethyl sulfoxide is an in vitro inhibitor of CYP 2C8, and is anticipated to have 
overall low potential for drug interactions as a perpetrator. It is also a weak CYP3A4 
inducer and expected to have little clinical effect on sensitive substrates. Trametinib is not 
an inhibitor of CYP 1A2, 2A6, 2B6, 2C9, 2C19, 2D6 and 3A4 and not an inhibitor of P-gp, 
BCRP, OATP1B1, OATP1B3, OAT1, OAT3, OCT2 MRP2 and MATE1.  
 
Patient Care Implications: Advise women study participants of reproductive potential to use 
effective contraception while receiving study treatment and for 4 months after the last dose 
of trametinib. Refer to the protocol document for specific guidance. 
 
8.1.3 
GSK2141795 (NSC 767034) 
 
Chemical Name:  N-[(1S)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl]-5-chloro-4-(4-
chloro-1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide 
 
Other Names: GSK2141795C 
 
Classification: pan-AKT inhibitor 
 
CAS Registry Number: 1047634-65-0 
 
Molecular Formula:  C18H16Cl2F2N4O2       
M.W.: 429.25 g/mol 
 
Approximate Solubility: Very slightly soluble in water at room temperature (0.18 mg/mL). 
Solubility decreases as pH increases; for example solubility in gastric fluid at 37° C is >11 

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71 
 
mg/mL.  
 
Mode of Action: GSK2141795 is an ATP competitive pan-AKT inhibitor. AKT, a 
serine/threonine protein kinase with three isoforms, is active in several pathways that regulate 
survival, proliferation, tissue invasion and metabolism. Since AKT-mediated pathways are 
important in tumor proliferation and survival, AKT kinases are promising targets for 
therapeutic intervention. Hyperactivation of the AKT pathway can also correlate with 
chemotherapy resistance and poorer prognosis. 
 
Description: white to off-white powder 
 
How Supplied: GSK2141795 capsules are supplied by GlaxoSmithKline and distributed by 
the DCTD, NCI. The 25 mg capsule is a size 2 Swedish orange opaque body and Swedish 
orange opaque cap with no markings. The capsule contains active pharmaceutical 
ingredient, microcrystalline cellulose, and magnesium stearate. The capsules are packaged 
in white high density polyethylene (HDPE) bottles with white plastic, induction-seal, child-
resistant caps. Each bottle contains 35 capsules. 
 
GSK does not have stability data to support repackaging GSK2141795 capsules. Capsules 
must be dispensed in the original container. 
 
Storage: Store bottles at 2-8° C (36-46° F). 
 
Stability: Shelf life studies of GSK2141795 are on-going.  
 
Route of Administration: Oral administration. Capsules must be taken fasting 1 hour before 
or 2 hours after a meal. 
  
Potential Drug Interactions: In vitro data suggest GSK2141795 is a substrate of CYP450 
3A4. Potent inhibitors and inducers of 3A4 are prohibited. GSK2141795 appears to be a 
moderate inhibitor of CYP 2C8 and 3A4 by in vitro testing. Drugs that are substrates of these 
isoenzymes should be used with caution and ones with a narrow therapeutic index should be 
avoided. 
 
 
GSK2141795 is a substrate of p-glycoprotein (P-gp) and breast cancer resistant protein 
(BCRP). It is also an inhibitor of BCRP and OATP1B1. Administration of sensitive BCRP 
substrates should be prohibited, such as topotecan. 
 
Availability:  GSK2141795 is an investigational agent supplied to investigators by the 
Division of Cancer Treatment and Diagnosis (DCTD), NCI. 
 
GSK2141795 is provided to the NCI under a Collaborative Agreement between the 
Pharmaceutical Collaborator and the DCTD, NCI (see Section 12.3). 
 
8.1.4 
Agent Ordering and Agent Accountability 
Agent ordering and agent accountability will occur for other centers as outlined in this 

IRB: 13-144 A(15) 
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section. 
 
8.1.4.1 NCI-supplied agents may be requested by the Principal Investigator (or their 
authorized designee) at each participating institution.  Pharmaceutical Management Branch 
(PMB) policy requires that agent be shipped directly to the institution where the patient is to 
be treated.  PMB does not permit the transfer of agents between institutions (unless prior 
approval from PMB is obtained).  The CTEP-assigned protocol number must be used for 
ordering all CTEP-supplied investigational agents.  The responsible investigator at each 
participating institution must be registered with CTEP, DCTD through an annual submission 
of FDA Form 1572 (Statement of Investigator), Curriculum Vitae, Supplemental Investigator 
Data Form (IDF), and Financial Disclosure Form (FDF).  If there are several participating 
investigators at one institution, CTEP-supplied investigational agents for the study should be 
ordered under the name of one lead investigator at that institution. 
 
Agent may be requested electronically to PMB. Active CTEP-registered investigators 
and investigator-designated shipping designees and ordering designees can submit agent 
requests through the PMB Online Agent Order Processing (OAOP) application 
https://eapps-ctep.nci.nih.gov/OAOP/pages/login.jspx. Access to OAOP requires the 
establishment of a CTEP Identity and Access Management (IAM) account https://eapps-
ctep.nci.nih.gov/iam/ and the maintenance of an “active” account status and a “current” 
password. For questions about drug orders, transfers, returns, or accountability, call 
(240) 276-6575 Monday through Friday between 8:30 am and 4:30 pm (ET) or email 
PMBAfterHours@mail.nih.gov anytime. 
 
8.1.4.2 Agent Inventory Records – The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the inventory and disposition of all agents 
received from DCTD using the NCI Drug Accountability Record Form (DARF).  (See the 
NCI Investigator’s Handbook for Procedures for Drug Accountability and Storage.) 
 
 
9 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
9.1 Biomarker Study Overview 
 
Tumor GNAQ and GNA11 status will be determined for all patients treated on this study using 
archived or newly acquired tumor material.  All patients with safely accessible tumor will 
undergo pre- and post-treatment (day 14 +/- 3 days) tumor biopsies for biomarker and correlative 
analysis.  The decision to not pursue these biopsies must be made in collaboration with the MSK 
Principal Investigator.  An additional tumor biopsy will be requested from patients at the time of 
disease progression; however, this biopsy is optional.  Blood samples will be collected from all 
patients at baseline and on a monthly basis for correlative analysis. 
 
In addition to GNAQ and GNA11 analysis which will be performed in all cases, we will conduct 
next-generation DNA sequencing, whole-transcriptome sequencing (RNAseq), and reverse phase 
protein array (RPPA), among other assays, using the fresh tumor material acquired as part of this 
study.  Results from these analyses will be stored in the cBioPortal for Cancer Genomics 

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(http://www.cbioportal.org/public-portal/), an open access web-based database developed and 
maintained by the Computational Biology Center at Memorial Sloan Kettering Cancer Center 
that provides visualization, analysis and download of large-scale cancer genomics data sets.  The 
web-based database also provides access to analysis tools in the areas of signaling pathways, 
mutations, and copy number alterations.   
 
The analysis of specific correlative assays is planned as below; however, due to cost 
considerations or material scarcity, the tasks may be consolidated and performed in one or more 
of the centers below: 
 
 
• Whole-Transcriptome Sequencing 
 
 
Raya Kanin, PhD 
 
 
Memorial Sloan Kettering Cancer Center 
 
 
Bioinformatics Core  
 
 
Zuckerman Research Center 415-417 East 68th Street 
 
 
New York, NY 10065  
 
 
Telephone: 646-888-2603 
 
 
Email: khaninr@mskcc.org 
 
• Reverse Phase Protein Array 
Scott E. Woodman, MD, PhD 
M. D. Anderson Cancer Center 
South Campus Research Building 
SCR 2.3022 
7455 Fanning St. 
Houston, TX 77054 
Telephone: 713-792-2921 
Email: swoodman@mdanderson.org 
 
• Targeted Pharmacodynamic Analysis 
Gary K. Schwartz, MD 
 
 
New York Presbyterian/Columbia University 
 
 
Milstein Hospital  
 
 
Division of Hematology/Oncology 
 
 
177 Ft. Washington Avenue, Suite 6-435 
New York, NY 10032  
 
 
Telephone: 212-305-2055 
 
 
Email: schwartzg@columbia.edu 
 
• Circulating Tumor DNA Analysis 
Marc-Henri Stern, MD PhD 
Institut Curie 
Immunologie 4ème étage 
26 rue d’Ulm 
75005 Paris cedex 05 France 

IRB: 13-144 A(15) 
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Telephone: +33 (0)1 56 24 66 46 
Email: Marc-Henri.Stern@curie.fr 
 
• Exosomal/Proteomic Analyses of Plasma 
Professor Sarah Coupland 
Department of Molecular and Clinical Cancer Medicine 
Institute of Translational Medicine 
University of Liverpool 
6th Floor Duncan Building 
Daulby Street 
Liverpool 
L69 3GA 
Telephone: +44-151-706-5885 or 4494 
Email: S.E.Coupland@liverpool.ac.uk  
 
Utilization of the available tumor biopsy material will be prioritized as outlined below.  In the 
case of excisional biopsies (as opposed to core needle biopsies), material will be divided and 
utilized based upon prioritization.  Banked tumor material may be utilized for future correlative 
studies, as determined by a steering committee made up of the MSK Principal Investigator, and a 
representative from the UK. 
 
 
Prioritization for Baseline, Day 14 and Progression Tumor Biopsies 
 
1. Core 1 will be placed in buffered formalin and embedded in paraffin.  
2. Core 2 will be flash frozen. 
3. Core 3 will be flash frozen. 
4. Core 4 will be flash frozen. 
5. Core 5 will be placed in buffered formalin and embedded in paraffin. 
6. Core 6 will be flash frozen. 
7. Core 7 will be flash frozen. 
8. Any additional cores will be banked for future as-yet undefined correlative studies.  
 
 
9.2 Laboratory Correlative Studies 
 
9.2.1 
Tumor Biopsies 
 
Patients will undergo tumor biopsies at baseline and 14 days (+/- 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.  Issues that would cause 
treatment delays should be discussed with the MSK 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 14 ± 
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 

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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).  Up to eight core samples will be obtained with each 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 placed in buffered formalin and embedded in paraffin. From this, an H&E 
section will be cut for confirmation and diagnostic purposes. It will be designated for 
immunohistochemistry (IHC) and any remainder flash frozen in liquid nitrogen. 
 
Fresh tumor biopsy samples should be snap-frozen using liquid nitrogen or a dry ice slurry as 
outlined below.  The tissue must be frozen as soon as possible after biopsy to minimize any 
form of degradation and to avoid risking the viability of the tissue.   
 
Snap-Freezing in Liquid Nitrogen: 
 
1. Label cryogenic vial(s) with the subject’s study identification number (ie. Accession 
number for MSK patients), the date of collection, time point (baseline, day 14, 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. 
 
2. 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. 
 
3. Remove the crygenic vial from the liquid nitrogen. 
 
4. 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 
 
1. Materials required include: 5 lbs dry ice, alcohol (ethanol or comparable), basin, long 
forceps 
 
2. Place at least 5 lbs of dry ice into a basin and pour one liter of alcohol over the ice. 
 
3. Label cryogenic vial(s) with the subject’s study identification number (ie. Accession 
number for MSK patients), 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. 
 
4. 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.  

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Tumor cores should be frozen individually in separate cryovials as collected in order to 
minimize the time between removal and freezing. 
 
5. Pace the lower half of the sealed cryotube containing tissue into the solution for at least 
2 minutes until frozen solid. 
 
6. Store the sample in a -80°C freezer (-65°C to -80°C is acceptable) until ready for 
shipping. 
 
9.2.2 
Research Blood Collection 
 
Two 10 ml sodium heparin tubes will be collected from patients prior to treatment, at the 
beginning of each cycle, and at the off-study visit.  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.   
 
Processing instructions for the use of either green sodium heparin tubes or CPT tubes with 
sodium heparin are as follows:  
 
  
Green Sodium Heparin 
1. 
Collect two 10 mL Sodium heparin tubes 
 
2. 
Prepare Accuspin tubes by adding 15.5 ml of Ficoll (or Lymphoprep) to tube 
 
3. 
Spin 30 seconds at 1000 g at room temperature (RT)  
 
4. 
Use one Accuspin with Ficoll or LSM per 3 green top tubes of blood   
 
5. 
Pour blood from 3 green top tubes into Accuspin tubes making sure to wipe each cap 
with EtOH before opening  
 
6. 
Spin loaded tubes 20 min at 2000 RPM (Room Temperature) (brakes off) 
 
7. 
Collect plasma and place into 15 mL tubes.  The plasma may be discarded.   
 
8. 
Collect cells from Accuspin tubes and place into separate 15ml tubes 
 
9. 
Fill the 15 mL conical tubes with the cells (from Accuspin) with PBS.  Invert several 
times to mix.  
 
10. 
Cap tubes and centrifuge at 300 g for 10 minutes at room temperature.  Pour off 
PBS and repeat this step twice (wash).  
 

IRB: 13-144 A(15) 
77 
 
11. 
After the third wash, carefully pour off the PBS one last time and freeze the cell 
pellet at -80°C until shipment to the respective biorepository. No freezing media is 
necessary. 
 
12. 
Label tubes with the subject’s study identification number, initials, date of 
collection, time point and protocol NCI #9445. MSK patients will be identified by 
accession number. 
 
CPT with sodium heparin 
 
1. Collect two 8 mL CPT with sodium heparin tubes 
 
2. Mix the blood with the anticoagulant by gently inverting the tube 8 to 10 times 
 
3. Centrifuge sample within 2 hours of collection  at room temperature for 20 minutes at 
1500 to 1800 g with the brake off 
 
4. Transfer the plasma layer (leaving the mononuclear layer undisturbed at the interface) 
to 15 mL tubes.  The plasma may be discarded.   
 
5. Transfer the mononuclear cell layer to a 15 mL conical centrifuge tube    
 
6. Add phosphate buffered saline (PBS) to the centrifuge tube bringing the volume to 15 
mL 
 
7. Cap and mix the cells by gently inverting the tube  5 times 
 
8. Centrifuge for 15 minutes at 300 g at room temperature 
 
9. Discard the supernatant gently using the transfer pipettes provided, without disturbing 
the cell pellet 
 
10. Resuspend the cell pellet by gently vortexing or tapping the tube with your index finger. 
 
11. Add PBS to the tube bringing the volume to 10 mL 
 
12. Cap and invert 5 times to mix the cells 
 
13. Centrifuge for 10 minutes at 300 g at room temperature. Discard the supernatant   
Repeat the wash one more time. 
 
14. After the third wash, carefully pour off the PBS one last time and freeze the cell 
pellet at -80°C until shipment to the respective biorepository.  No freezing media is 
needed. 
 

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78 
 
15. Label tubes with the subject’s study identification number, initials, the date of 
collection, time point and protocol NCI #9445. MSK patients will be identified by 
accession number. 
 
9.2.3 
Circulating Tumor DNA Plasma Collection 
 
Two 10 cc lavender top tube (EDTA) will be collected prior to treatment, at the beginning of 
each cycle, and at the End of Treatment visit.  The samples drawn prior to treatment can be 
drawn on C1W1 prior to initiation of study drug.   
 
Plasma samples should be prepared as described by Diehl et. al. and as summarized below:65   
 
1. Within 1 hour of collection, blood is centrifuged at 820 g for 10 minutes.  
 
2. Supernatant is transferred to 1.5 mL sterile tubes in 1 mL aliquots and centrifuged at 
16,000g for 10 minutes at 4⁰C to pellet any remaining cellular debris. Discard the pellet. 
 
3. Label tubes with the subject’s study identification number, the date of collection, time 
point (baseline, cycle number, or end of study) and the study center.  MSK patients will 
be identified by accession number. 
 
4. The supernatant should subsequently be stored at -80°C.  
 
5. The overall process from blood collection to plasma storage should not exceed 3 hours.  
 
6. The supernatent will be shipped from each investigational site directly to the Institut 
Curie. 
 
DNA extraction will be performed at the Institut Curie as follows: 
 
1. DNA extraction from plasma of patients should be accomplished using the Qiagen 
QIAamp circulating nucleic acid kits or an acceptable alternative. Extraction should be 
performed according to the manufacturer instructions.  
 
2. Nucleic acids should be stored at -20°C. 
 
9.2.4 
Blood Collection and Processing for Exosomal/Proteomic Analyses  
 
Two 10ml EDTA tubes will be collected prior to treatment, at the beginning of each cycle, and 
at the end of treatment visit. Standardization of sample site, needle gauge (wider may be better) 
and other variables is recommended. The first few millimeters of drawn blood should be 
discarded.  
 
Collected blood should be handled gently and processed rapidly (within 30 minutes – 1 hour of 
drawing).  
 

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79 
 
Plasma samples should be prepared as follows: 
 
1. Centrifuge for 15 minutes at 2,000 g at 4⁰C.  
 
2. Immediately transfer the supernatant (plasma) into a clean polypropylene tube as 0.5ml 
aliquots and store at -80⁰C prior to shipping.  
 
3. Label tubes with the subject’s study identification number, the date of collection, time 
point (baseline, cycle number, or end of study) and the study center.  MSK patients will 
be identified by accession number. 
 
9.3 Specimen Shipment Procedures 
 
Two region-specific biospecimen repositories will be utilized for this trial, with one repository 
for the North American trial centers.The Institute Curie will collect circulating tumor DNA for 
all regions.  The University of Liverpool will collect plasma for exosomal/proteomic analysis for 
all regions. 
 
Trial Center Region 
Biospecimen 
Repository 
Shipping Address 
North America  
 
MSK 
(Tumor and Blood) 
Taha Merghoub, MD 
415 East 68th Street 
Room# Z-1525 
New York, NY 11065 
646-888-2580 
merghout@mskcc.org 
shoushta@mskcc.org 
 CTO_MSO_MCT@mskcc.org 
*Of note, MD Anderson Cancer Center can keep on site the core for reverse phase protein array 
(Core #3) as long as the collection of the sample is communicated to the MSK PI, Research 
Project Coordinator, and Research Study Assistant. 
All Regions 
Institut Curie 
(Circulating Tumor 
DNA) 
Marc-Henri Stern, MD PhD 
Institut Curie 
Immunologie 4ème étage 
26 rue d’Ulm 
75005 Paris cedex 05 France 
maud.milder@curie.net 
aurore.rampanou@curie.fr 
delphine.louis@curie.net 
isabelle.peguillet@curie.net 
All Regions 
University of Liverpool 
(Exosomal/Preoteomic 
Analysis) 
Professor Sarah Coupland 
Department of Molecular and Clinical 
Cancer Medicine 
Institute of Translational Medicine 
University of Liverpool 
6th Floor Duncan Building 

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80 
 
Daulby Street 
Liverpool 
L69 3GA 
S.E.Coupland@liverpool.ac.uk  
 
Shipments will be sent from participating centers to the appropriate biospecimen repository in 
batches whenever possible.  The biospecimen repository research team will be notified by email 
the day that the samples are sent.  This email will contain the following information: 
 
• Site Name 
• Subject ID 
• Subject initials 
• Shipment date 
• Contents of shipment 
 
All shipments should be directed to the address listed on the tissue sample shipment form.  
Samples should be shipped by courier so that the package can be tracked appropriately 
(specifically, Federal Express or UPS).  Study materials for sample collection, processing and 
shipping should be obtained by the site.   
 
Each repository will be responsible for coordinating with the MSK Principal Investigator the 
shipment of biospecimens from the repository to the analysis centers. 
 
9.3.1 
Paraffin-Embedded Tumor Specimens 
 
Up to 20 unstained slides from paraffin embedded tumor or the tumor block will be sent via 
messenger or shipped via overnight carrier, as applicable, to the appropriate repository.  All 
shipments should be directed to the address listed on the study tissue sample shipment form. 
 
Necessary slides will be cut from paraffin embedded pre-treatment tumor.  This material will 
be packaged in a way to ensure they do not break.  All slides (and/or blocks) must be shipped 
with appropriate identifiers including a pathology report from the collaborating institution and 
the tumor tissue shipment form.   
 
9.3.2 
Fresh-Frozen Tumor Specimens 
 
Specimens will be packaged with dry ice in a way to ensure they remain frozen during 
shipment and do not break.  All specimens must be shipped with appropriate identifiers 
including the study tumor tissue shipment form.   
 
9.3.3 
Research Blood Specimens 
 
Specimens will be packaged with dry ice in a way to ensure they remain frozen during 
shipment and do not break.  All specimens must be shipped with appropriate identifiers 
including the study tumor tissue shipment form.   
 

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81 
 
9.3.4 
Circulating Tumor DNA Plasma Specimens 
 
Samples will be shipped in bulk to the Institut Curie throughout the study.  
 
9.3.5 
Specimens will be packaged with dry ice in a way to ensure they remain frozen 
during shipment and do not break.  All specimens must be shipped with appropriate identifiers 
including the study tumor tissue shipment form. 
 
9.3.6 
Exosomal and Proteomic Plasma Specimens 
 
Samples will be shipped in bulk to the GCLP Facility at the University of Liverpool, UK 
throughout the study. 
9.3.7 
 
9.3.8 
Specimens will be packaged with dry ice in a way to ensure they remain frozen 
during shipment and do not break.  All specimens must be shipped with appropriate identifiers 
including the study tumor tissue shipment form. 
 
 
9.4  Laboratory Correlative Studies 
 
9.4.1 
Correlation of Clinical Outcome with Gnaq/11 Mutational Status 
 
Tumor Gnaq and Gna11 status will be determined for all patients treated on this study.  Five 
unstained slides obtained from paraffin-embedded tumor tissue will be required for this testing.  
DNA will be extracted from paraffin embedded tissue sections.  DNA will be extracted from 
the tumor area contained in at least 10x5µm-thick sections placed on uncharged glass slides. A 
hematoxylin-eosin stained slide will be used to distinguish tumor cells.  Genomic DNA will be 
prepared using the Wizard Genomic DNA purification kit (Promega).  Exon 5 of GNAQ will 
be sequenced by routine methods following polymerase chain reaction amplification of exon 5 
with primers: GNAQE5L: 5’-TTCCCTAAGTTTGTAAGTAGTGC and GNAQE5R:5’-
AGAAGTAAGTTCACTCCATTCC.  This will generate a product of 317 bp that includes 
codon 209.   Sequences will be analyzed with Sequencer 4.5 software (GeneCodes, Madison, 
WI, USA).  Tumor samples not harboring the more common exon 5 mutations may be tested 
for the presence of exon 4 Gnaq or Gna11 mutations should sufficient material be available. 
 
DNA from normal tissue, if available, will be analyzed to demonstrate the somatic nature of 
identified mutations and novel polymorphisms.   
 
9.4.2 
Assessment of Pharmacodynamic Effects of Therapy 
 
Patients with accessible tumor will undergo pre- and post-treatment (day 14 +/- 3 days) tumor 
biopsies for pharmacodynamic analysis. Studies which may include, but are not limited to, 
reverse phase protein array and Western blotting may be performed on serial tumor samples 
obtained from patients treated with trametinib alone and with the combination of trametinib 
and GSK2141795 for pERK, pAKT, cyclin D1, and others. Changes in protein levels will be 
semi-quantified by densitometry. We anticipate inhibition of pERK and cyclin D1 and 

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induction of pAKT with trametinib alone, and inhibition of pERK, cyclin D1, and pAKT with 
combination therapy.   
 
RNA-seq will be performed using pre- and post-treatment material obtained from 5 patients 
achieving clinical benefit and 5 patients not achieving clinical benefit on each treatment arm.  
Clinical benefit is defined as a RECIST response or progression-free survival greater than 16 
weeks. From our computations,64 in order to identify 90% of differentially expressed genes 
between two conditions (with fold-changes=2 and FDR=0.05), 4 replicates per condition would 
be required. However, taking in account the inherit variability of biological samples, our power 
calculations suggest that 5 biological replicates per condition will be sufficient to identify 85-
90% of differentially expressed (DE) genes.  Our interim analysis of patients treated with 
selumetinib on NCI Protocol #8443 demonstrated a 40% clinical benefit rate. Assuming a 
similar clinical benefit rate for patients treated with trametinib alone and a clinical benefit rate 
of 60% for patients treated with trametinib and GSK2141795, we would predict that for every 
13 patients, there will be at least 5 who achieve clinical benefit and 5 who do not. As the true 
clinical benefit rate for each arm is not known, we will perform paired biopsies on the first 15 
patients treated on each arm.  
 

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83 
 
10 
STUDY CALENDAR 
Baseline evaluations are to be conducted within 14 days prior to start of protocol therapy.  Imaging 
studies and cardiac evaluation (e.g., echocardiogram, MUGA, EKG) must be done <4 weeks prior 
to the start of therapy.  The pre-treatment biopsy for patients with safely accessible tumor will be 
obtained within 28 days of starting therapy (see Section 9.2.1 for more information). In the event 
that the patient’s condition is deteriorating, laboratory evaluations should be repeated within 48 
hours prior to initiation of therapy.  All blood work, examinations and procedures may be 
performed +/- 3 days from the scheduled date.  Imaging studies may be performed +/- 1 week from 
the scheduled date. 
 
 
Cycle 1 
Cycle 2 
Cycle 3m 
 
 
Pre- 
Study 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
6 
Wk 
7 
Wk 
8 
Wk 
9 
Wk 
10 
Wk 
11 
Wk 
12 
End of 
Treatmentn 
Trametinib (Arms A or 
B) 
 
X------------------------------------------------------------------------------X  
GSK2141795 (Arm B 
Only) 
 
X------------------------------------------------------------------------------X  
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concurrent meds 
X 
X------------------------------------------------------------------------------X  
Physical exam 
X 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
Ophthalmology Exama 
Xa 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signsb 
Xb 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
Performance status 
X 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
CBC w/diff, plts 
X 
X 
Xo 
X 
Xo 
X 
 
 
 
X 
 
 
 
X 
Chemistriesc 
X 
X 
Xo 
X 
Xo 
X 
 
 
 
X 
 
 
 
X 
PT/PTT 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fasting Lipid Paneld 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Fasting Glucose 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hemoglobin A1cd 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
TSHd 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
EKGe  
X 
 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
Echocardiogram or 
MUGAf 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Adverse event 
evaluation 
 
X------------------------------------------------------------------------------X X 

IRB: 13-144 A(15) 
84 
 
CAP CT or Chest CT 
and AP MRIg 
X 
Tumor measurements are repeated every 8 weeks.   
X 
B-HCGh 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Archived Tumor Tissuei X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor Biopsyj 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
(X) 
Research Blood 
Collectionk 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
ctDNA Blood 
Collectionl 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
a: 
Ophthalmic exam will include indirect fundoscopy, slit lamp exam, visual acuity, visual field examination, 
tonometry and color fundus photos.  Additional ophthalmic exams will be performed if symptomatically 
warranted.  Note that patients with the presence at baseline of a risk factor for RVO or REPD such as evidence 
of new optic disc cupping, evidence of new visual field defects, and intraocular pressure >21 mm Hg are 
excluded from this trial. 
b:     Patients with treatment-refractory hypertension defined as a blood pressure of systolic >140 mmHg and/or 
diastolic >90 mmHg which cannot be controlled by anti-hypertensive therapy are excluded from this trial. 
c:     Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, 
phosphorus, potassium, total protein, SGOT [AST], SGPT [ALT], sodium. 
d: Repeat test every 8 weeks. 
e: 
A single 12-lead ECG should be performed at Screening, Day 15, and prior to dosing at the start of every 4 
weeks. The baseline EKG may be conducted within 28 days of treatment start date. Additional EKGs will be 
performed as clinically indicated.  Patients with a baseline QT interval corrected for heart rate using the 
Bazett’s formula QTcB ≥ 480 msec are excluded from this trial. 
f:     Echocardiogram or MUGA should be performed at screening, Week 5 Day 1, then every 12 weeks, at final 
study visit, and as clinically indicated.  The same methodology should be used throughout the study. 
g:     CT of the chest, abdomen and pelvis with contrast OR CT of the chest (with or without contrast) and MRI of 
the abdomen and pelvis at baseline and again every subsequent 8 weeks (+/- 1 week). Other imaging modalities 
can be used in addition to these at the discretion of the treating physician.  If the patient is taken off treatment 
for any reason other than disease progression, End of Treatment imaging is not required at that visit; however, 
the patient should undergo restaging scans 8 weeks (+/- 1 week) from the time of the first dose and continue 
having scans every 8 weeks (+/- 1 week) until progression is documented, the start of new anticancer therapy, 
or death. 
h: Perform only in women of child-bearing potential.  A blood pregnancy test should be performed at Screening, 
and subsequent pregnancy tests may be either blood or urine. 
i:     Up to twenty unstained slides from archived or newly acquired paraffin embedded tumor or the tumor block 
will be collected from all patients enrolled on this study.    
j:     Tumor biopsies will be performed at baseline and after 14 +/- 3 days of therapy.  A third optional tumor biopsy 
may be performed on these patients at the time of disease progression. 
k:    Serum will be collected from patients as outlined in Section 9 prior to treatment, at the beginning of each 
cycle, and at the off-study visit and subsequently stored for future correlative studies. The samples drawn prior 
to treatment can be drawn on C1W1 prior to initiation of study drug. 
l:    Two 10 cc lavender top tube (EDTA) will be collected prior to treatment, at the beginning of each cycle, and at 
the End of Treatment visit.  The samples drawn prior to treatment can be drawn on C1W1 prior to initiation of 
study drug. 
m:   Cycle 4+ will be conducted as indicated for cycle 3. 
n:    End of Treatment Visit performed 4 weeks from last treatment. Patients will be contacted or evaluated every 12 
weeks (+/- 1 week) for survival assessment after End of Treatment visit or last date of follow up. In the event 
that the patient’s health deteriorates such that the follow-up visit is not feasible, a note will be placed in the 
subject’s medical record documenting the situation. This will not be considered a protocol violation. In 
addition, the last treatment visit can be considered the End of Treatment visit if the patient is unable to return, a 
note will be placed in the subject’s medical record documenting this situation. 
o:   Test can be performed locally. 

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11 
MEASUREMENT OF EFFECT 
 
11.1 Antitumor Effect – Solid Tumors 
 
For the purposes of this study, patients should be re-evaluated for response every 8 weeks.  As 
per RECIST 1.1, confirmatory scans obtained 4 weeks following initial documentation of 
objective response is not necessary in this study where the primary endpoint is PFS. Patients 
will be re-evaluated for response until progression is documented, the start of new anticancer 
therapy, or death. 
 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1).66  Changes in the largest diameter (unidimensional measurement) of the tumor 
lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST 
criteria. 
 
11.1.1 
Definitions 
 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of their first 
treatment with trametinib alone or with GSK2141795. 
 
Evaluable for objective response.  Only those patients who have measurable disease present 
at baseline, have received at least one cycle of therapy, and have had their disease re-
evaluated will be considered evaluable for response.  These patients will have their response 
classified according to the definitions stated below.  (Note:  Patients who exhibit objective 
disease progression prior to the end of cycle 1 will also be considered evaluable.) 
 
Evaluable Non-Target Disease Response.  Patients who have lesions present at baseline that 
are evaluable but do not meet the definitions of measurable disease, have received at least 
one cycle of therapy, and have had their disease re-evaluated will be considered evaluable 
for non-target disease.  The response assessment is based on the presence, absence, or 
unequivocal progression of the lesions.  
 
11.1.2 
Disease Parameters 
 
Measurable disease.  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as >20 mm by chest x-
ray or as ≥10 mm with CT scan, MRI, or calipers by clinical exam.  All tumor 
measurements must be recorded in millimeters (or decimal fractions of centimeters).   
 
Note:  Lesions that are previously irradiated must show clear evidence of 
progression over a minimum of 3 months to include as measurable.  This period of 
time is used to discount tumor edema in an irradiated field as a false sign of disease 
progression. 
 

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Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a lymph 
node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm).  At baseline and in follow-up, only the short axis 
will be measured and followed. 
 
Non-measurable disease.  All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), are 
considered non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, 
and abdominal masses (not followed by CT or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should 
not be considered as malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-cystic 
lesions are present in the same patient, these are preferred for selection as target lesions. 
 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target lesions 
and recorded and measured at baseline.  Target lesions should be selected on the basis of 
their size (lesions with the longest diameter), be representative of all involved organs, but in 
addition should be those that lend themselves to reproducible repeated measurements.  It 
may be the case that, on occasion, the largest lesion does not lend itself to reproducible 
measurement in which circumstance the next largest lesion which can be measured 
reproducibly should be selected.  A sum of the diameters (longest for non-nodal lesions, 
short axis for nodal lesions) for all target lesions will be calculated and reported as the 
baseline sum diameters.  If lymph nodes are to be included in the sum, then only the short 
axis is added into the sum.  The baseline sum diameters will be used as reference to further 
characterize any objective tumor regression in the measurable dimension of the disease. 
 
Non-target lesions.  All other lesions (or sites of disease) including any measurable lesions 
over and above the 5 target lesions should be identified as non-target lesions and should 
also be recorded at baseline.  Measurements of these lesions are not required, but the 
presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow-up.  
 
11.1.3 
Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  
All baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 4 weeks before the beginning of the treatment. 
 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 

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preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
 
Clinical lesions  Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm diameter as assessed 
using calipers (e.g., skin nodules).  In the case of skin lesions, documentation by color 
photography, including a ruler to estimate the size of the lesion, is recommended.  
 
Chest x-ray  Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung.  However, CT is preferable.  
 
Conventional CT and MRI  This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5 mm or less.  If CT scans have slice 
thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the 
slice thickness.  MRI is also acceptable in certain situations (e.g. for body scans).   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement.  Furthermore, the 
availability of MRI is variable globally.  As with CT, if an MRI is performed, the technical 
specifications of the scanning sequences used should be optimized for the evaluation of the 
type and site of disease.  Furthermore, as with CT, the modality used at follow-up should be 
the same as was used at baseline and the lesions should be measured/assessed on the same 
pulse sequence.  It is beyond the scope of the RECIST guidelines to prescribe specific MRI 
pulse sequence parameters for all scanners, body parts, and diseases.  Ideally, the same type 
of scanner should be used and the image acquisition protocol should be followed as closely 
as possible to prior scans.  Body scans should be performed with breath-hold scanning 
techniques, if possible. 
 
PET-CT  At present, the low dose or attenuation correction CT portion of a combined PET-
CT is not always of optimal diagnostic CT quality for use with RECIST measurements.  
However, if the site can document that the CT performed as part of a PET-CT is of identical 
diagnostic quality to a diagnostic CT (with IV and oral contrast), then the CT portion of the 
PET-CT can be used for RECIST measurements and can be used interchangeably with 
conventional CT in accurately measuring cancer lesions over time.  Note, however, that the 
PET portion of the CT introduces additional data which may bias an investigator if it is not 
routinely or serially performed.   
 
Ultrasound  Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement.  Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to 
the next.  If new lesions are identified by ultrasound in the course of the study, confirmation 
by CT or MRI is advised.  If there is concern about radiation exposure at CT, MRI may be 
used instead of CT in selected instances. 
 

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Endoscopy, Laparoscopy  The utilization of these techniques for objective tumor evaluation 
is not advised.  However, such techniques may be useful to confirm complete pathological 
response when biopsies are obtained or to determine relapse in trials where recurrence 
following complete response (CR) or surgical resection is an endpoint. 
 
Tumor markers  Tumor markers alone cannot be used to assess response.  If markers are 
initially above the upper normal limit, they must normalize for a patient to be considered in 
complete clinical response.  Specific guidelines for both CA-125 response (in recurrent 
ovarian cancer) and PSA response (in recurrent prostate cancer) have been published [JNCI 
96:487-488, 2004; J Clin Oncol 17, 3461-3467, 1999; J Clin Oncol 26:1148-1159, 2008].  
In addition, the Gynecologic Cancer Intergroup has developed CA-125 progression criteria 
which are to be integrated with objective tumor assessment for use in first-line trials in 
ovarian cancer [JNCI 92:1534-1535, 2000]. 
 
Cytology, Histology  These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor 
types, such as germ cell tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease 
is mandatory to differentiate between response or stable disease (an effusion may be a side 
effect of the treatment) and progressive disease. 
 
FDG-PET  While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis of 
FDG-PET imaging can be identified according to the following algorithm:  
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-
PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD.  If 
the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT  scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal FDG-
PET scan).  If the positive FDG-PET at follow-up corresponds to a pre-existing site of 
disease on CT that is not progressing on the basis of the anatomic images, this is not PD. 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in 
cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring.  The use of FDG-PET in this circumstance should be prospectively described 
in the protocol and supported by disease-specific medical literature for the indication.  
However, it must be acknowledged that both approaches may lead to false positive CR 
due to limitations of FDG-PET and biopsy resolution/sensitivity. 
 
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image. 
 

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11.1.4 
Response Criteria 
 
11.1.4.1 Evaluation of Target Lesions 
 
Complete Response (CR):  Disappearance of all target lesions.  Any pathological lymph 
nodes (whether target or non-target) must have reduction in short axis to <10 mm. 
 
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters. 
 
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum if 
that is the smallest on study).  In addition to the relative increase of 20%, the sum must 
also demonstrate an absolute increase of at least 5 mm.  (Note:  the appearance of one or 
more new lesions is also considered progressions). 
 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study. 
 
11.1.4.2 Evaluation of Non-Target Lesions 
 
Complete Response (CR):  Disappearance of all non-target lesions and normalization of 
tumor marker level.  All lymph nodes must be non-pathological in size (<10 mm short 
axis). 
 
Note:  If tumor markers are initially above the upper normal limit, they must normalize 
for a patient to be considered in complete clinical response. 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or maintenance 
of tumor marker level above the normal limits. 
 
Progressive Disease (PD):  Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.  Unequivocal progression should not 
normally trump target lesion status.  It must be representative of overall disease status 
change, not a single lesion increase.     
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of 
the treating physician should prevail in such circumstances, and the progression status 
should be confirmed at a later time by the review panel (or Principal Investigator). 
 
11.1.4.3 Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started).  The patient's best response 

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assignment will depend on the achievement of both measurement and confirmation 
criteria. 
 
For Patients with Measurable Disease (i.e., Target Disease) 
 
Target Lesions 
Non-Target 
Lesions 
New Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-CR/Non-PD 
No 
PR 
>4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not evaluated 
No 
SD 
Documented at least once >4 wks. 
from baseline** 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
∗ 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**        Only for non-randomized trials with response as primary endpoint. 
***      In exceptional circumstances, unequivocal progression in non-target lesions may be 
            accepted as disease progression. 
 
Note:  Patients with a global deterioration of health status requiring discontinuation of treatment without objective 
evidence of disease progression at that time should be reported as “symptomatic deterioration.”  Every 
effort should be made to document the objective progression even after discontinuation of treatment. 
 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
∗ 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is increasingly used 
as an endpoint for assessment of efficacy in some trials so to assign this category when no lesions can be 
measured is not advised 
 
 
11.1.5 
Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date 
that recurrent or progressive disease is objectively documented (taking as reference for 
progressive disease the smallest measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met for 
CR until the first date that progressive disease is objectively documented.  
 

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Duration of stable disease:  Stable disease is measured from the start of the treatment until 
the criteria for progression are met, taking as reference the smallest measurements recorded 
since the treatment started, including the baseline measurements.  
 
11.1.6 
Progression-Free Survival 
 
PFS is defined as the duration of time from start of treatment to time of progression or 
death, whichever occurs first. 
 
11.1.7 
Response Review 
 
All partial and complete responses will be reviewed by an independent radiologist at 
Memorial Sloan Kettering Cancer Center.  For patients treated at a site other than MSK, all 
appropriate radiological studies will be shipped to MSK either as hardcopy or by CD-ROM, 
as appropriate. 
 
 
12 
DATA REPORTING / REGULATORY REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements). 
 
12.1 Data Reporting 
 
12.1.1 
Method 
 
This study will be monitored by the Clinical Data Update System (CDUS) Version 3.0.  
Cumulative protocol- and patient-specific CDUS data will be submitted electronically to 
CTEP on a quarterly basis, either by FTP burst of data or via the CDS web application.  
Reports are due January 31, April 30, July 31, and October 31.  Instructions for submitting 
data using the CDUS can be found on the CTEP Web site 
(http://ctep.cancer.gov/reporting/cdus.html).  
 
MSK will assign a Research Study Assistant (RSA) and Research Project Coordinator 
(RPC) to manage data entry for this study. Data collected for this study will be entered into 
a secure database (CRDB) for MSK and outside patients. MSK is responsible for compiling 
and submitting CDUS data to CTEP for all participants and for providing the data to the 
Principal Investigator for review.   
 
Note:  If your study has been assigned to CDUS-Complete reporting, all adverse events 
(both routine and expedited) that have occurred on the study and meet the mandatory CDUS 
reporting guidelines must be reported via the monitoring method identified above.  If your 
study has been assigned to CDUS-Abbreviated reporting, no adverse event reporting 
(routine or expedited) is required to be reported via CDUS. 
 

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12.1.2 
Responsibility for Data Submission at Participating Sites 
 
The participating site(s) will enter data remotely into MSK’s internet-based Clinical 
Research Database, termed CRDBi-Multicenter. Standardized Case Report Forms (CRFs) 
and data entry guidelines have been generated for this study. The site staff will receive 
CRDB training prior to enrolling its first patient. The participating Site PI is responsible for 
ensuring these forms are completed accurately and in a timely manner. A schedule of 
required forms is shown in the table below. Participating sites will be responsible for 
completing the eCRFs and submitting them to MSK per the designated timelines. 
 
Data and Source Documentation Submission for Participating Sites  
Participating sites should enter data directly into CRDBi-Multicenter and study-specific 
paper CRFs (if applicable). Source documentation should be sent to MSK at 
CTO_MSO_MCT@mskcc.org. Submissions should include a cover page listing relevant 
records enclosed per participant.  
 
Data Submission Timelines for Participating Sites 
Data should be submitted to MSK according to the table below:  
 
 
Specific CRFs to be referenced are listed in the Data Management Handbook for CRDBi-MCT. 
 
Source Documentation 
Source documentation refers to original records of observations, clinical findings and 
evaluations that are subsequently recorded as data. Source documentation should be 
consistent with data entered into CRFs. The participating site is responsible for maintaining 
adequate and correct source documentation for all submitted data.  
 
Source documentation should include a minimum of two identifiers to allow for data 
verification. MSK will maintain the confidentiality of any subject-identifiable information it 
may encounter. 
 
Data Review and Queries for Participating Site Data 
Research staff at MSK will review data and source documentation as it is submitted. Data 
will be monitored against source documentation and discrepancies will be sent as queries to 
the participating sites. Participating sites should respond to data queries within 14 days of 
receipt. 
 
Data Submission Timelines for Therapeutic Studies 
Time point 
Submission requirement 
Baseline 
Eligibility checklist within 24 hours of ICF signature 
Cycle CRFs in EDC 
Within 14 days of study visit 
SAE 
Must be reported in EDC system within 3 days of learning of the 
event (see section 7.3.2); follow-up as needed 

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Regulatory Documentation 
Prior to implementing this protocol at MSK, the protocol, informed consent form, HIPAA 
authorization and any other information pertaining to participants must be approved by the 
MSK Institutional Review Board/Privacy Board (IRB/PB) and CTEP. Prior to implementing 
this protocol at the participating sites, approval for the MSK IRB/PB approved protocol 
must be obtained from the participating site’s IRB and submitted to the CTEP PIO. In 
addition, applicable contractual agreements must be finalized and executed before 
participating sites implement this protocol. 
 
The following documents must be provided to MSK before the participating site can be 
initiated and begin enrolling participants:  
• Participating Site IRB approval(s) for the protocol, appendices, informed consent form 
and HIPAA authorization 
• Participating Site IRB approved consent form 
 
Upon receipt of the required documents, MSK will formally contact the site and grant 
permission to proceed with enrollment.  
 
Participating sites that are consulting and/or conducting specimen or data analysis should 
submit this protocol to their IRB according to local guidelines. Copies of any site IRB 
correspondence should be forwarded to MSK. 
 
 
 
Amendments 
Each change to the protocol document must be organized and documented by MSK and first 
approved by the MSK IRB/PB. Upon receipt of MSK IRB/PB approval, MSK will 
immediately distribute all non expedited amendments to the participating sites, for 
submission to their local IRBs. 
 
Participating sites must obtain approval for all non expedited amendments from their IRB 
within 90 calendar days of MSK IRB/PB approval. If the amendment is the result of a safety 
issue or makes eligibility criteria more restrictive, sites will not be permitted to continuing 
enrolling new participants until the participating site IRB approval has been granted. 
 
The following documents must be provided to MSK for each amendment within the stated 
timelines:  
• Participating Site IRB approval  
• Participating Site IRB approved informed consent form and HIPAA  authorization 
 
Additional IRB Correspondence 
 
Continuing Review Approval 
The Continuing Review Approval letter from the participating site’s IRB and the most 
current approved version of the informed consent form should be submitted to MSK within 
7 days of expiration. Failure to submit the re-approval in the stated timeline will result in 
suspension of study activities. 
 

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Violations 
A protocol violation is any change or departure from the research protocol that occurred 
without prior approval from the MSK IRB/PB. For protocol violations that are identified 
after they occur, the participating site should report to MSK as soon as possible. The MSK 
PI will in turn report the violation to the MSK IRB/PB and CTEP.  
 
Participating sites should report violations to their institution’s IRBs as soon as possible per 
that site’s institutional guidelines. Approvals/acknowledgments from the participating site 
IRB for protocol violations should be submitted to MSK as received.  
 
Other correspondence 
Participating sites should submit other correspondence to their institution’s IRB according to 
local guidelines, and submit copies of that correspondence to MSK. 
 
Document maintenance 
The MSK PI and the Participating Site PI will maintain adequate and accurate records to 
enable the implementation of the protocol to be fully documented and the data to be 
subsequently verified. 
 
The participating sites will ensure that all participating site IRB correspondence (IRB 
approval letters referencing protocol version date and amendment number, IRB approved 
protocol, appendices, informed consent forms, deviations, violations, and approval of 
continuing reviews) is maintained in the regulatory binder on site and sent to MSK. 
 
A regulatory binder for each site will also be maintained at MSK; this binder may be paper 
or electronic. 
 
After study closure, the participating site will maintain all source documents, study related 
documents and CRFs for 7 years.  
 
Noncompliance  
If a participating site is noncompliant with the data and regulatory requirements set forth in 
the protocol document, accrual privileges may be suspended until the outstanding issues 
have been resolved.   
 
      Quality Assurance for Participating Sites  
Participating N01 contract holders and their affiliates may be audited by MSK. 
 
Response Review  
Since therapeutic efficacy is a stated primary objective, all sites participant’s responses are 
subject to review by MSK’s Therapeutic Response Review Committee (TRRC).  Radiology 
and possibly additional lab reports will need to be obtained from the participating sites for 
MSK TRRC review and confirmation of response assessment. These materials must be sent 
to MSK promptly upon request.   
 

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12.2 CTEP Multicenter Guidelines 
 
This protocol will adhere to the policies and requirements of the CTEP Multicenter Guidelines.  
The specific responsibilities of the Principal Investigator and the Coordinating Center (Study 
Coordinator) and the procedures for auditing are presented in Appendix E.  
• The Principal Investigator/Coordinating Center is responsible for distributing all IND 
Action Letters or Safety Reports received from CTEP to all participating institutions for 
submission to their individual IRBs for action as required. 
 
• Except in very unusual circumstances, each participating institution will order DCTD-
supplied agents directly from CTEP.  Agents may be ordered by a participating site only 
after the initial IRB approval for the site has been forwarded by the Coordinating Center to 
the CTEP PIO (PIO@ctep.nci.nih.gov) except for Group studies. 
 
12.3 Collaborative Agreements Language 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 
under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis.  Therefore, the following obligations/guidelines, in addition to the 
provisions in the “Intellectual Property Option to Collaborator”  
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the 
terms of award, apply to the use of the Agent(s) in this study: 
 
1. 
Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study.  
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and shall be 
maintained as such by the investigators.  The protocol documents for studies utilizing Agents 
contain confidential information and should not be shared or distributed without the permission 
of the NCI.  If a copy of this protocol is requested by a patient or patient’s family member 
participating on the study, the individual should sign a confidentiality agreement.  A suitable 
model agreement can be downloaded from: http://ctep.cancer.gov. 
 
2. 
For a clinical protocol where there is an investigational Agent used in combination with 
(an)other Agent(s), each the subject of different Collaborative Agreements, the access to and use 
of data by each Collaborator shall be as follows (data pertaining to such combination use shall 
hereinafter be referred to as "Multi-Party Data”): 
 
a. 
NCI will provide all Collaborators with prior written notice regarding the existence 
and nature of any agreements governing their collaboration with NCI, the design of the 
proposed combination protocol, and the existence of any obligations that would tend to 
restrict NCI's participation in the proposed combination protocol. 
 
b. 
Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical 
trial by any other Collaborator solely to the extent necessary to allow said other Collaborator 

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to develop, obtain regulatory approval or commercialize its own Agent. 
 
c. 
Any Collaborator having the right to use the Multi-Party Data from these trials must 
agree in writing prior to the commencement of the trials that it will use the Multi-Party Data 
solely for development, regulatory approval, and commercialization of its own Agent. 
 
3. 
Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement 
will be made available to Collaborator(s), the NCI, and the FDA, as appropriate and unless 
additional disclosure is required by law or court order as described in the IP Option to 
Collaborator 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm).  
Additionally, all Clinical Data and Results and Raw Data will be collected, used and disclosed 
consistent with all applicable federal statutes and regulations for the protection of human 
subjects, including, if applicable, the Standards for Privacy of Individually Identifiable Health 
Information set forth in 45 C.F.R. Part 164. 
 
4. 
When a Collaborator wishes to initiate a data request, the request should first be sent to the 
NCI, who will then notify the appropriate investigators (Group Chair for Cooperative Group 
studies, or PI for other studies) of Collaborator's wish to contact them. 
 
5. 
Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a DMC 
for this clinical trial. 
 
6. 
Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the 
Group office for Cooperative Group studies or by the principal investigator for non-Cooperative 
Group studies for immediate delivery to Collaborator(s) for advisory review and comment prior 
to submission for publication.  Collaborator(s) will have 30 days from the date of receipt for 
review.  Collaborator shall have the right to request that publication be delayed for up to an 
additional 30 days in order to ensure that Collaborator’s confidential and proprietary data, in 
addition to Collaborator(s)’s intellectual property rights, are protected.  Copies of abstracts must 
be provided to CTEP for forwarding to Collaborator(s) for courtesy review as soon as possible 
and preferably at least three (3) days prior to submission, but in any case, prior to presentation at 
the meeting or publication in the proceedings.  Press releases and other media presentations must 
also be forwarded to CTEP prior to release.  Copies of any manuscript, abstract and/or press 
release/ media presentation should be sent to: 
 
Email: ncicteppubs@mail.nih.gov  
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s confidential/ 
proprietary information. 
 
12.4 Data and Safety Monitoring 
 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan Kettering Cancer Center were 
approved by the National Cancer Institute in September 2001.  The plans address the new 

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policies set forth by the NCI in the document entitled “Policy of the National Cancer Institute for 
Data and Safety Monitoring of Clinical Trials” which can be found at:  
http://www.cancer.gov/clinicaltrials/conducting/dsm-guidelines/page1. The DSM Plans at MSK 
were established and are monitored by the Office of Clinical Research.  The MSK Data and 
Safety Monitoring Plans can be found on the MSK Intranet at: 
http://inside2/clinresearch/Documents/MSKCC%20Data%20and%20Safety%20Monitoring%20
Plans.pdf 
 
There are several different mechanisms by which clinical trials are monitored for data, safety and 
quality.  There are institutional processes in place for quality assurance (e.g., protocol 
monitoring, compliance and data verification audits, therapeutic response, and staff education on 
clinical research QA) and departmental procedures for quality control, plus there are two 
institutional committees that are responsible for monitoring the activities of our clinical trials 
programs.  The committees: Data and Safety Monitoring Committee (DSMC) for Phase I and II 
clinical trials, and the Data and Safety Monitoring Board (DSMB) for Phase III clinical trials, 
report to the Center’s Research Council and Institutional Review Board.   
During the protocol development and review process, each protocol will be assessed for its level 
of risk and degree of monitoring required.  Every type of protocol (e.g., NIH sponsored, in-house 
sponsored, industrial sponsored, NCI cooperative group, etc.) will be addressed and the 
monitoring procedures will be established at the time of protocol activation. 
 
13 
STATISTICAL CONSIDERATIONS 
 
13.1 Study Design/Endpoints 
 
The prognosis for patients with metastatic disease is poor, but this is an encouraging time and 
there are many agents which could be examined. Therefore, 2 investigational treatment strategies 
will be assessed in this trial.  
 
A total of 80 patients with advanced stage melanoma will be randomized to either trametinib plus 
GSK2141795 or trametinib alone (40 evaluable patients per arm).  The primary endpoint of this 
study is time to progression (PFS) defined from the date of randomization to the date of 
documented progression or death.  Patients will be assessed for progression every 8 weeks.  PFS 
will be calculated as time from randomization to the earlier date of objective disease progression 
per RECIST criteria or death due to any cause in the absence of progression; patients who have 
not progressed or died at the time of analysis will be censored at the time of their latest evaluable 
objective tumor assessment.  It is estimated that median PFS for the trametinib arm is 16 weeks 
based upon the results of CTEP8443 as presented at the 2013 ASCO Annual Meeting which 
demonstrated a median PFS of 15.9 weeks with selumetinib (n = 47, 95% CI, 8.4 – 23.1 weeks).  
With 80 patients and with 76 progression events, the probability is 80% that the study will detect 
a treatment difference at a one-sided 5% significance level, if the true hazard ratio is 0.56.   
 
Overall survival will be analyzed using the same methods as used for PSF.  Overall survival will 
be calculated as time from randomization to death due to any cause; patients who have not died 
at the time of analysis will be censored based on the last recorded date on which the subject was 
known to be alive.   

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This is based on the assumption that the accrual period will be approximately 26 months, the 
follow up period will be 12 months, and the median PFS for trametinib alone is 16 weeks.  It is 
anticipated that 3 patients per month will be accrued to this study and hence the study accrual 
will be completed in approximately two years and the trial will be completed in approximately 
three years. 
 
An early stopping rule for futility will be applied.  Clinical benefit rate will be examined in each 
arm after 40 evaluable patients have been accrued (20 patients per arm).  As noted above, early 
analysis of our on-going trial of selumetinib versus temozolomide in patients with advanced 
uveal melanoma, 40% of patients treated with selumetinib achieved disease control beyond 16 
weeks.  If at least two patients have achieved a radiographic response as defined as a RECIST 
partial or complete response in each arm, then the trial will continue as planned.  If zero or one 
patient achieves a RECIST response among the 20 patients of an arm, then that arm will be 
terminated. The upper bound of the 95% confidence interval for no clinical benefit out of 20 
patients with this early stopping rule is 25%.  PFS will also be reviewed at the end of the first 
stage, and adjustment to the futility rule may be considered if significant PFS prolongation is 
obtained in the absence of sufficient numbers of RECIST responses.  If we stop one arm of the 
trial due to futility, then we may revert to a single arm phase II study.  The alternate arm may 
continue to accrue 40 patients. The plan for the second stage will be finalized after discussion 
with the sponsor.  At the end of the study we will estimate the progression free survival 
distribution for that arm and provide the median PFS along with a 95% confidence interval. 
 
13.2 Sample Size/Accrual Rate 
 
This study design requires the accrual of up to 60 patients with advanced uveal melanoma.   
 
This study will be a multi-institution phase II study led by MSK.  The Melanoma Service at MSK 
sees between 2 and 4 patients with uveal melanoma monthly, with 75% or more presenting with 
metastatic disease.  We anticipate accrual of 2 patients monthly from MSK alone.  Once the 
study is open at all participating centers, we conservatively estimate an accrual of 3 patients per 
month.  
 
13.3 Stratification Factors 
 
Eligible patients will be randomized on a 1:1 ratio, with randomization stratified by presence or 
absence of liver involvement and LDH (< 2 times the ULN versus ≥ 2 times the upper limit of 
normal), to one of the two treatment arms. 
 
13.4 Analysis of Secondary Endpoints 
 
Analysis of secondary endpoints will be exploratory and hypothesis-generating.   
 
Progression-free survival and overall survival curves will be generated using Kaplan-Meier 
methodology.  Toxicity across both arms will be reported by type, frequency and severity according to 
the NCI Common Toxicity Criteria.  Response rate (CR+PR) by arm will be calculated along with a 

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95% confidence interval.   
 
13.5 Analysis of Exploratory Endpoints 
 
For patients who progress on trametinib and crossover to the combination arm clinical outcomes will 
be summarized.  Response rate (CR+PR) will be estimated along with progression-free and overall 
survival from the start of combination therapy.  Toxicity for the crossover patients will be reported by 
type, frequency and severity according to the NCI Common Toxicity Criteria.  
 
Clinical response will be associated with Gnaq/11 mutational status using Wilcoxon rank sum test.  An 
additional exploratory objective is to assess whether circulating tumor DNA can be detected.  If so, 
these numeric data will be summarized by clinical response.  
 
Using the 30 or more paired tumor biopsies collected on this study, associations between suppression 
specifically of p-ERK, AKT, Cyclin-D1, and response to treatment will be assessed using Fisher’s 
exact test.  Baseline and post-treatment status as well as changes will be reported.  Assessment of 
apoptosis in the paired samples will be performed by caspase3 cleavage; changes will be assessed by a 
Wilcoxon signed rank test.  These correlative studies will be considered exploratory in nature. 
 
13.6 Reporting and Exclusions 
 
13.6.1 
Evaluation of Toxicity 
 
All patients will be evaluable for toxicity from the time of their first treatment with trametinib 
and GSK2141795.  
 
13.6.2 
Evaluation of Response 
 
All patients included in the study must be assessed for response to treatment, even if there are 
major protocol treatment deviations or if they are ineligible.  Each patient will be assigned one 
of the following categories:  1) complete response, 2) partial response, 3) stable disease, 4) 
progressive disease, 5) early death from malignant disease, 6) early death from toxicity, 7) 
early death because of other cause, or 9) unknown (not assessable, insufficient data).  [Note:  
By arbitrary convention, category 9 usually designates the “unknown” status of any type of 
data in a clinical database.] 
 
Intent-to-treat analysis will be performed in all who were randomized and who received at least 
one dose of study treatment in the main analysis of PFS (evaluable population).  Patients in 
response categories 4-8 should be considered to have a treatment failure (disease progression).  
Thus, an incorrect treatment schedule or drug administration does not result in exclusion from 
the analysis of the response rate.   
 
All conclusions should be based on all eligible patients.  Subanalyses may then be performed 
on the basis of a subset of patients, excluding those for whom major protocol deviations have 
been identified (e.g., early death due to other reasons, early discontinuation of treatment, major 
protocol violations, etc.).  However, these subanalyses may not serve as the basis for drawing 

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conclusions concerning treatment efficacy, and the reasons for excluding patients from the 
analysis should be clearly reported.  The 95% confidence intervals will be provided.  
 
14 
PROTECTION OF HUMAN SUBJECTS 
 
14.1 Privacy 
 
MSK’s Privacy Office may allow the use and disclosure of protected health information 
pursuant to a completed and signed Research Authorization form. The use and disclosure of 
protected health information will be limited to the individuals described in the Research 
Authorization form. A Research Authorization form must be completed by the Principal 
Investigator and approved by the IRB and Privacy Board (IRB/PB).  
 
15 
INFORMED CONSENT PROCEDURES 
 
Before protocol-specified procedures are carried out, consenting professionals will explain full 
details of the protocol and study procedures as well as the risks involved to participants prior to 
their inclusion in the study. Participants will also be informed that they are free to withdraw from 
the study at any time. All participants must sign an IRB/PB-approved consent form indicating their 
consent to participate. This consent form meets the requirements of the Code of Federal Regulations 
and the Institutional Review Board/Privacy Board of this Center. The consent form will include the 
following:  
 
1. The nature and objectives, potential risks and benefits of the intended study.  
2. The length of study and the likely follow-up required. 
3. Alternatives to the proposed study. (This will include available standard and investigational 
therapies. In addition, patients will be offered an option of supportive care for therapeutic 
studies.) 
4. The name of the investigator(s) responsible for the protocol. 
5. The right of the participant to accept or refuse study interventions/interactions and to 
withdraw from participation at any time.  
 
Before any protocol-specific procedures can be carried out, the consenting professional will fully 
explain the aspects of patient privacy concerning research specific information.  In addition to 
signing the IRB Informed Consent, all patients must agree to the Research Authorization 
component of the informed consent form. 
 
Each participant and consenting professional will sign the consent form. The participant must 
receive a copy of the signed informed consent form. 
 
15.1 For Participating Centers  
 
The investigators listed on the protocol cover page and their qualified designees at each 
participating institution may obtain informed consent and care for the participants according 
to good clinical practice and protocol guidelines.  
 

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Signed copies of the informed consent should be distributed as follows: One copy will be 
given to the participant to be retained for their personal records. One copy will be 
maintained on file at the MSK. The third copy will be confidentially maintained by the 
participating institution.  
 
A note will be placed in the medical record documenting that informed consent was 
obtained for this study, and that the participant acknowledges the risk of participation.  

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APPENDIX A – PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
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). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active 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. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 
 
 
 
 
 
 

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APPENDIX B – POTENTIAL DRUG-DRUG INTERACTIONS 
 
B.1 
Potential CYP-Mediated Interactions 
 
In vitro data indicate that GSK2141795 is a CYP3A4 substrate (GSK2141795 Investigator’s 
Brochure, 2012).  Drugs that potently inhibit CYP3A4 could lead to increased GSK2141795 
exposure in subjects, and should either be prohibited or used with caution.  Drugs which are strong 
inducers of CYP3A and may result in lower exposures of GSK2141795 should also be prohibited.  
GSK2141795 also appears to be a moderate in vitro inhibitor of CYP2C8 (50% inhibitory 
concentration [IC50] 3 mcM) and CYP3A4 (IC50 11 mcM).  Drugs that are substrates of CYP3A4 
or CYP2C8 with a narrow therapeutic index may be prohibited.  Drugs that are sensitive substrates 
of CYP3A4 or CYP2C8 should be used with caution. 
 
Therefore, drugs that potently inhibit CYP3A4 could lead to increased GSK2141795 exposure in 
subjects, and drugs which are strong inducers of CYP3A are prohibited (see Tables below).  
Furthermore, drugs that are substrates of CYP3A4 or CYP2C8 with a narrow therapeutic index are 
prohibited (see Tables below).   
 
Whether or not GSK2141795 is a substrate of hepatic uptake transporter OATP is unknown, 
therefore co-administration of OATP potent inhibitors should be performed with caution.  
 
Because the lists of these agents are constantly changing, it is important to regularly consult a 
frequently-updated list such as http://medicine.iupui.edu/clinpharm/ddis/table.aspx; medical 
reference texts such as the Physicians’ Desk Reference may also provide this information.  As part 
of the enrollment/informed consent procedures, the patient will be counseled on the risk of 
interactions with other agents, and what to do if new medications need to be prescribed or if the 
patient is considering a new over-the-counter medicine or herbal product.   
 
B.2 
Oral Steroids 
 
Oral steroids should be used with caution and subjects monitored for steroid-induced 
hyperglycemia.  Short courses (up to a maximum of 14 days) of oral corticosteroids intended to 
treat study treatment related rash or diarrhea are allowed.  Budenoside is recommended for 
supportive care of diarrhea.  Subjects will be instructed to inform the investigator before taking any 
of these or any other medications.  Investigators (or their appropriate designee) will be expected to 
review concomitant medications with the subject at each clinical visit.   
 
B.3 
Herbal and Dietary Supplements 
 
Because the composition, PK, and metabolism of many herbal supplements are unknown, the 
concurrent use of all herbal supplements is prohibited during the study (including, but not limited 
to, St. John’s wort, kava, ephedra [ma huang], gingko biloba, dehydroepiandrosterone [DHEA], 
yohimbe, saw palmetto, or ginseng).  Subjects should abstain from taking any herbal and dietary 
supplements within 5 half lives (or 14 days if the drug is a potential enzyme inducer) prior to the 
first dose of either study drug until completion of the follow-up visit, unless in the opinion of the 
Investigator and sponsor there is little concern for a potential drug-drug interaction with the study 

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drug(s). For example, specific dietary supplements for evaluable deficiencies or imbalances (e.g. 
Vitamin D, zinc, omega 3) are not prohibited. The investigator should contact a CTEP Medical 
Monitor before initiating treatment with any herbal preparation. 
 
B.4 
Other Prohibited Medications 
 
Other anti-cancer therapy while on study treatment (note: megestrol [Megace] if used as an appetite 
stimulant is allowed). 
 
Concurrent treatment with bisphosphonates is permitted; however, treatment must be initiated prior 
to the first dose of study therapy.  Prophylactic use of bisphosphonates in patients without bone 
disease is not permitted, except for the treatment of osteoporosis. 
 
Use of repaglinide, rosiglitazone and/or pioglitazone is permitted only after consultation with the 
CTEP Medical Monitor. 
 
B.5 
Tables 
 
The following concurrent medications are prohibited while patients are receiving study drugs: 
Metabolism Class 
Therapeutic Area 
Agents 
CYP3A Substrate 
Hypnotics and Sedatives 
Cisapride 
 
Antidepressant, Antipsychotics, Antianxiety 
Agents 
Pimozide 
 
Antihistamine 
Astemizole 
 
 
 
Strong CYP3A 
Inhibitor/Inducer 
Antibiotics 
Clarithromycin 
Telithromycin 
Rifamycin class agents (e.g., 
rifampin, rifabutin, rifapentine) 
Troleandomycin 
 
Antifungals 
Itraconazole 
ketoconazole 
 
Antidepressants 
Nefazodone 
 
Antivirals 
Atazanzvir 
Delaviridine 
Indinavir 
Lopinavir 
Nelfinavir 
Ritonavir 
Saquinavir 
Nevirapine 
 
Anticonvulsants 
Carbamazepine 
Phenobarbital 
Phenytoin 
 
 
 
BCRP Substrates 
HMG-CoA Reductase Inhibitors, 
gastrointestinal agents 
Rosuvastatin 
Sulfasalazine 
 
The following concurrent medications (including, but not limited to) should be administered with 
caution while patients are receiving study drugs: 
 

IRB: 13-144 A(15) 
109 
 
Metabolism Class 
Therapeutic Area 
Agents 
CYP3A Inhibitors 
Antivirals 
Amprenavir 
Fosamprevanir 
 
Antibiotics 
Erythromycin 
 
Antifungals 
Fluconazole 
Voriconazole 
 
Calcium Channel Blockers 
Mibefradil 
Diltiazem 
Verapamil 
 
Miscellaneous 
Aprepitant 
 
Antibiotics 
Erythromycin 
 
Antifungals 
Fluconazole 
Voriconazole 
 
Calcium Channel Blockers 
Mibefradil 
Diltiazem 
Verapamil 
 
 
 
CYP3A Inducers 
Antivirals 
Efavirenz 
 
 
 
CYP2C8 Substrates 
HMG CoA-reductase inhibitors 
Cerivastatin 
 
Thiazolidinediones 
Rosiglitazone 
Pioglitazone 
 
Miscellaneous 
Chloroquine 
Zopiclone 
Repaglinide 
 
The following additional concurrent medications (including, but not limited to) should be 
administered with caution while patients are receiving study drugs: 
 
Drugs Potentially Affecting GSK2141795 concentrations 
Drug 
Therapeutic Area 
quinidine, diltiazem, verapamil 
Antiarrhythmics 
fluvoxamine, fluoxetine, paroxetine, nefazodone 
Antidepressants 
aprepitant, cimetidine 
Antiemetics 
fluconazole, terbinafine,  voriconazole 
Antifungals 
ciprofloxacin, erythromycin, isoniazid 
Anti-infectives 
mibefradil, diltiazem, verapamil 
Calcium Channel Blockers 
aprepitant, oxandrolone, tizanidine, gemfibrozil 
Miscellaneous 
Drugs that may inhibit P-gp and BCRP 
Drug 
Therapeutic Area 
valspoda 
Miscellaneous 
atorvastatin 
HMG-CoA Reductase Inhibitors 
carvedilol 
Congestive Heart Failure 

IRB: 13-144 A(15) 
110 
 
methadone 
Analgesic 
meperidine 
Narcotic 
omeprazole 
Proton Pump Inhibitor 
Drugs that may have their concentrations altered by trametinib or GSK2141795 
repaglinide, rosiglitazone, pioglitazone 
Antidiabetics 
alfentanil, fentanyl 
Analgesics 
quinidine 
Antiarrhythmics 
cilostazol 
Anticoagulants and Antiplatelets 
astemizole 
Antihistamines 
diergotamine, ergotamine, eletriptan 
Antimigraine agents 
pimozide 
Antipsychotics 
buspirone 
Anxiolytics 
felodipine 
Calcium Channel Blockers 
sildenafil, tadalafil, vardenafil 
Erectile Dysfunction agents 
cerivastatin, ovastatin, simvastatin, atorvastatin 
HMG-CoA Reductase Inhibitors 
alprazolam, diazepam, midazolam, triazolam 
Hypnotics and Sedatives 
cyclosporine, sirolimus, tacrolimus 
Immunosuppressive agents 
cisapride 
Prokinetic agents 
cyclosporine, torsemide, chloroquine, zopiclone 
Miscellaneous 
eplerenone 
Selective Aldosterone Blockers 
chloroquine, zopiclone 
Thiazolidinediones 
 
 
 
 
 
 
 

IRB: 13-144 A(15) 
111 
 
APPENDIX C – NEW YORK HEART ASSOCIATION CLASSIFICATIONS 
 
Clinical Evaluation of Functional Capacity of Patients 
with Heart Disease in Relation to Ordinary Physical Activity 
 
 
 
 
Class 
 
 
Cardiac Symptoms 
 
 
Limitations 
 
Need for 
Additional Rest* 
 
Physical Ability  
      to work**__ 
 
 
 
 
 
I 
None 
None 
None 
Full time 
 
 
 
 
 
II 
Only moderate 
Slight 
Usually only slight 
or occasional 
Usually full  
time 
 
 
 
 
 
III 
Defined, with  
less than  
ordinary activity 
Marked 
Usually moderate 
Usually part  
time 
 
 
 
 
 
IV 
May be present  
even at rest,  
and any activity 
increases discomfort 
Extreme 
Marked 
Unable to work 
 
 
* 
To control or relieve symptoms, as determined by the patient, rather than as advised by the 
physician. 
 
** At accustomed occupation or usual tasks. 
 
 
 
Reference: 
Bruce, R. A.: Mod. Concepts Cardiovasc. Dis. 25:321, 1956.  
 
 (Modified from New York Heart Association, 1953). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

IRB: 13-144 A(15) 
112 
 
APPENDIX D – INFORMATION ON POSSIBLE DRUG INTERACTIONS 
 
Information on Possible Interactions with Other Agents for Patients and Their Caregivers 
and Non-Study Healthcare Team 
 
The patient ____________________________ is enrolled on a clinical trial using the experimental 
agent GSK2141795 and Trametinib.  This clinical trial is sponsored by the National Cancer 
Institute.  This form is addressed to the patient, but includes important information for others who 
care for this patient.  
 
GSK2141795 interacts with many drugs that are processed by your liver.  Because of this, it is very 
important to tell your study doctors about all of your medicine before you start this study.  It is also 
very important to tell them if you stop taking any regular medicine, or if you start taking a new 
medicine while you take part in this study.  When you talk about your medicine with your study 
doctor, include medicine you buy without a prescription at the drug store (over-the-counter 
remedy), or herbal supplements such as St. John’s wort.  
 
Many health care prescribers can write prescriptions.  You must also tell your other prescribers 
(doctors, physicians’ assistants or nurse practitioners) that you are taking part in a clinical trial. 
Bring this paper with you and keep the attached information card in your wallet.  These are 
the things that you and they need to know:  
 
GSK2141795 interacts with certain specific enzymes in your liver.  The enzymes in question are 
CYP3A4 and 2C8.  CYP3A4 is responsible for breaking down GSK2141795 in your liver.  
GSK2141795 may prevent other drugs from being broken down in your liver by CYP2C8   
 
• GSK2141795 must be used very carefully with other medicines that need these liver enzymes 
to be effective or to be cleared from your system.   
• Other medicines may also affect the activity of the enzyme.   
o Substances that increase the activity of CYP 3A4 (“inducers”) could reduce the 
effectiveness of GSK2141795, while substances that decrease that enzyme’s activity 
(“inhibitors”) could result in high levels of the active drugs, increasing the chance of 
harmful side effects. 
• You and healthcare providers who prescribe drugs for you must be careful about adding or 
removing any drug in this category.  
• Before you start the study, your study doctor will work with your regular prescriber to switch 
any medicines that are considered “strong inducers/inhibitors” of CYP 3A4 or substrates of 
CYP 2C8. 
• Your 
prescribers 
should 
look 
at 
this 
web 
site 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx or consult a medical reference to see if 
any medicine they want to prescribe is on a list of drugs to avoid.   
• Please be very careful!  Over-the-counter drugs have a brand name on the label—it’s usually 
big and catches your eye.  They also have a generic name—it’s usually small and located 
above or below the brand name, and printed in the ingredient list.  Find the generic name 
and determine, with the pharmacist’s help, whether there could be an adverse interaction.   
• Be careful:  

IRB: 13-144 A(15) 
113 
 
o If you take acetaminophen regularly:  You should not take more than 4 grams a day 
if you are an adult or 2.4 grams a day if you are older than 65 years of age.  Read 
labels carefully!  Acetaminophen is an ingredient in many medicines for pain, flu, 
and cold. 
o If you drink grapefruit juice or eat grapefruit:  Avoid these until the study is over.  
o If you take herbal medicine regularly:  You should not take St. John’s wort while 
you are taking GSK2141795. 
 
Other medicines can be a problem with your study drugs.  
 
• You should check with your doctor or pharmacist whenever you need to use 
an over-the-counter medicine or herbal supplement.  
• Your regular prescriber should check a medical reference or call your study 
doctor before prescribing any new medicine for you.  Your study doctor’s 
name is _____________________________________ and he or she can be 
contacted at _____________________________________. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
INFORMATION ON POSSIBLE DRUG INTERACTIONS  
You are enrolled on a clinical trial using the experimental agents 
trametinib and GSK2141795. This clinical trial is sponsored by the 
NCI. Only GSK2141795 interacts with drugs that are processed by 
your liver.  Because of this, it is very important to: 
 Tell your doctors if you stop taking regular medicine or if you start 
taking a new medicine. 
 Tell all of your prescribers (doctor, physicians’ assistant, nurse 
practitioner, pharmacist) that you are taking part in a clinical trial. 
 Check with your doctor or pharmacist whenever you need to use 
an over-the-counter medicine or herbal supplement. 
GSK2141795 interacts with a specific liver enzyme called CYP 3A4 
and 2C8, and must be used very carefully with other medicines that 
interact with this enzyme.  
 Before you start the study, your study doctor will work with your 
regular prescriber to switch any medicines that are considered 
“strong inducers/inhibitors or substrates of CYP3A4 and 2C8.” 
 Before prescribing new medicines, your regular prescribers should 
go to http://medicine.iupui.edu/clinpharm/ddis//table.aspx for a 
list of drugs to avoid, or contact your study doctor.   
 Your study doctor’s name is _____________________________ 
and can be contacted at _______________________________.  

IRB: 13-144 A(15) 
114 
 
APPENDIX E – CTEP MULTICENTER GUIDELINES 
 
If an institution wishes to collaborate with other participating institutions in performing a CTEP 
sponsored research protocol, then the following guidelines must be followed. 
 
Responsibility of the Protocol Chair  
• The Protocol Chair will be the single liaison with the CTEP Protocol and Information Office 
(PIO).  The Protocol Chair is responsible for the coordination, development, submission, 
and approval of the protocol as well as its subsequent amendments.  The protocol must not 
be rewritten or modified by anyone other than the Protocol Chair.  There will be only one 
version of the protocol, and each participating institution will use that document.  The 
Protocol Chair is responsible for assuring that all participating institutions are using the 
correct version of the protocol. 
• The Protocol Chair is responsible for the overall conduct of the study at all participating 
institutions and for monitoring its progress.  All reporting requirements to CTEP are the 
responsibility of the Protocol Chair.  
• The Protocol Chair is responsible for the timely review of Adverse Events (AE) to assure 
safety of the patients. 
• The Protocol Chair will be responsible for the review of and timely submission of data for 
study analysis. 
 
Responsibilities of the Coordinating Center 
• Each participating institution will have an appropriate assurance on file with the Office for 
Human Research Protection (OHRP), NIH.  The Coordinating Center is responsible for 
assuring that each participating institution has an OHRP assurance and must maintain copies 
of IRB approvals from each participating site.  
• Prior to the activation of the protocol at each participating institution, an OHRP form 310 
(documentation of IRB approval) must be submitted to the CTEP PIO. 
• The Coordinating Center is responsible for central patient registration.  The Coordinating 
Center is responsible for assuring that IRB approval has been obtained at each participating 
site prior to the first patient registration from that site. 
• The Coordinating Center is responsible for the preparation of all submitted data for review 
by the Protocol Chair. 
• The Coordinating Center will maintain documentation of AE reports.  There are two options 
for AE reporting: (1) participating institutions may report directly to CTEP with a copy to 
the Coordinating Center, or (2) participating institutions report to the Coordinating Center 
who in turn report to CTEP.  The Coordinating Center will submit AE reports to the 
Protocol Chair for timely review. 
• Audits may be accomplished in one of two ways:  (1) source documents and research 
records for selected patients are brought from participating sites to the Coordinating Center 
for audit, or (2) selected patient records may be audited on-site at participating sites.  If the 
NCI chooses to have an audit at the Coordinating Center, then the Coordinating Center is 
responsible for having all source documents, research records, all IRB approval documents, 
NCI Drug Accountability Record forms, patient registration lists, response assessments 
scans, x-rays, etc. available for the audit. 
 

IRB: 13-144 A(15) 
115 
 
Inclusion of Multicenter Guidelines in the Protocol 
• The protocol must include the following minimum information:  
 The title page must include the name and address of each participating institution and 
the name, telephone number and e-mail address of the responsible investigator at each 
participating institution. 
 The Coordinating Center must be designated on the title page. 
 Central registration of patients is required.  The procedures for registration must be 
stated in the protocol. 
 Data collection forms should be of a common format.  Sample forms should be 
submitted with the protocol.  The frequency and timing of data submission forms to the 
Coordinating Center should be stated. 
 Describe how AEs will be reported from the participating institutions, either directly to 
CTEP or through the Coordinating Center. 
 Describe how Safety Reports and Action Letters from CTEP will be distributed to 
participating institutions. 
 
Agent Ordering 
• Except in very unusual circumstances, each participating institution will order DCTD-
supplied investigational agents directly from CTEP.  Investigational agents may be ordered 
by a participating site only after the initial IRB approval for the site has been forwarded by 
the Coordinating Center to the CTEP PIO.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

IRB: 13-144 A(15) 
116 
 
 APPENDIX F – PATIENT’S MEDICATION DIARY 
         Pill Diary for IRB #13-144: A Randomized Two-Arm Phase II Study of Trametinib 
Alone and in Combination with GSK2141795 in Patients with Advanced Uveal Melanoma 
 
Trametinib:  2 mg, by mouth once a day on an empty stomach one hour before a meal or two 
hours after a meal with water only 
 
Medication Instructions:  
 Your nurse or physician will review your prescribed dose with you.   
 Record all your doses in this pill diary.  
 Bring your study pills and this diary to every clinic visit.  You will take Trametinib with a 
nurse (not at home) on the days you come in for appointments. 
 Open only one bottle at a time when taking out your dose.  Do not transfer pills from one 
bottle to another. 
 Do not throw away any study pill bottles.  We will collect them. 
 If you think you are having a side effect, feel sick, or have any other questions about your 
pills please call your study doctor. 
 Trametinib should be taken by mouth on an empty stomach one hour before a meal or two 
hours after a meal with water only. 
 Trametinib tablets should be refrigerated in the original container. 
How to complete the diary: 
 Record the Date for each day of dosing in the Month – Day –Year (MM - DD - YY) format.  
 Trametinib may be provided in different strengths. You may be asked to take a combination 
of strengths in a single dose. Please write the number of pills taken for each mg strength in 
the space provided. 
 If you miss a dose, write “0” in the number of pills taken and add a comment for why the 
dose was missed. 
 Add a comment if you vomited after taking drug and if so, how long after taking drug you 
vomited.  
 Your doctor may change the amount of drug or how often you will be taking the drugs. 
Always record the actual amount of pills you took for each day.   
 If you forget to complete the diary, leave it blank. 
 
IF YOU HAVE QUESTIONS AT ANY TIME PLEASE CONTACT YOUR DOCTOR  
 
 
Participant Dosing Diary- Arm A 
This section to be completed by clinic staff 
Section completed by: ____________________________________________   
Participant ID #: ______________ 
Participant Initials:  ______-______-______ 
CYCLE: _______ 
Start on Day:   ______/______/_______ 
                            MM      DD        YY 
Circle the day participant starts medication: 
 
SUN     MON     TUES     WED     THURS     FRI      SAT 
Number of tablets returned: 
_______________ 
 

IRB: 13-144 A(15) 
117 
 
 
Protocol IRB#: 13-144 Cycle:       
Trametinib:  2 mg, by mouth, once a day 
Date:   
  Pill taken: 
Time taken: 
     Dose/Quantity: 
 
Comments: 
 
___/___/___ 
Day 1 
Yes 
No 
___:___AM/PM 
___0.5 mg  ___2 mg 
 
 
___/___/___ 
Day 2 
Yes 
No 
___:___AM/PM 
___0.5  mg  ___2 mg 
 
 
___/___/___ 
Day 3 
Yes 
No 
___:___AM/PM 
___0.5  mg  ___2 mg 
 
 
___/___/___ 
Day 4 
Yes 
No 
___:___AM/PM 
 
___0.5  mg  ___2 mg 
 
 
___/___/___ 
Day 5 
Yes 
No 
___:___AM/PM 
 
___0.5  mg  ___2 mg 
 
 
___/___/___ 
Day 6 
Yes 
No 
___:___AM/PM 
 
___0.5  mg  ___2 mg 
 
 
___/___/___ 
Day 7 
Yes 
No 
___:___AM/PM 
 
___0.5  mg  ___2 mg 
 
 
___/___/___ 
Day 8 
Yes 
No 
 
___:___AM/PM 
 
___0.5  mg  ___2 mg 
 
 
___/___/___ 
Day 9 
Yes 
No 
 
___:___AM/PM 
 
___0.5  mg  ___2 mg 
 
 
___/___/___ 
Day 10 
Yes 
No 
 
___:___AM/PM 
 
___0.5  mg  ___2 mg 
 
 
___/___/___ 
Day 11 
Yes 
No 
 
___:___AM/PM 
 
___0.5  mg  ___2 mg 
 
 
___/___/___ 
Day 12 
Yes 
No 
 
___:___AM/PM 
 
___0.5  mg  ___2 mg 
 
 
___/___/___ 
Day 13 
Yes 
No 
 
___:___AM/PM 
 
___0.5  mg  ___2 mg 
 
 
___/___/___ 
Day 14 
Yes 
No 
 
___:___AM/PM 
 
___0.5  mg  ___2 mg 
 
 
___/___/___ 
Day 15 
Yes 
No 
 
___:___AM/PM 
 
___0.5  mg  ___2 mg 
 
 
 

IRB: 13-144 A(15) 
118 
 
 
Protocol IRB#: 13-144 Cycle:       
Trametinib:  2 mg, by mouth, once a day 
Date:   
  Pill taken: 
Time taken: 
     Dose/Quantity: 
 
Comments: 
___/___/___ 
Day 16 
Yes 
No 
 
___:___AM/PM 
 
___0.5 mg  ___2 mg 
 
___/___/___ 
Day 17 
Yes 
No 
 
___:___AM/PM 
 
___0.5 mg  ___2 mg 
 
___/___/___ 
Day 18 
Yes 
No 
 
___:___AM/PM 
 
___0.5 mg  ___2 mg 
 
___/___/___ 
Day 19 
Yes 
No 
 
___:___AM/PM 
 
___0.5 mg  ___2 mg 
 
___/___/___ 
Day 20 
Yes 
No 
 
___:___AM/PM 
 
___0.5 mg  ___2 mg 
 
___/___/___ 
Day 21 
Yes 
No 
 
___:___AM/PM 
 
___0.5 mg  ___2 mg 
 
 
___/___/___ 
Day 22 
Yes 
No 
 
___:___AM/PM 
 
___0.5 mg  ___2 mg 
 
 
___/___/___ 
Day 23 
Yes 
No 
 
___:___AM/PM 
 
___0.5 mg  ___2 mg 
 
 
___/___/___ 
Day 24 
Yes 
No 
 
___:___AM/PM 
 
___0.5 mg  ___2 mg 
 
 
___/___/___ 
Day 25 
Yes 
No 
 
___:___AM/PM 
 
___0.5 mg  ___2 mg 
 
 
___/___/___ 
Day 26 
Yes 
No 
___:___AM/PM 
 
___0.5 mg  ___2 mg 
 
 
___/___/___ 
Day 27 
Yes 
No 
 
___:___AM/PM 
 
___0.5 mg  ___2 mg 
 
___/___/___ 
Day 28 
Yes 
No 
 
___:___AM/PM 
 
___0.5 mg  ___2 mg 
 
Final Review and Collection: 
Participant/LAR Signature: _____________________________ 
Date: _____/_____/_____ 
MD/RN Signature: ____________________________________ 
Date: _____/_____/_____ 
MD/RN Name (print): _________________________________ 
Additional Comments: 

IRB: 13-144 A(15) 
119 
 
APPENDIX G – OPHTHALMOLOGY EXAMS 
Instructions: This worksheet can be used to record the findings during the ophthalmology exam. 
 
Contact Information for Study Staff: 
PI: ___________________________ 
Coordinator (RSA): _____________ 
Participant: ____________________ 
Return form to: _________________ 
 
Date of Exam: __________________ 
 
 
Right Eye 
Left Eye 
Visual Acuity (Record Values)  
 
Tonometry (Record Values) 
 
 
Slit Lamp Exam 
 
 Normal 
 Abnormal – not clinically 
significant 
 Abnormal 
Explain:  
 
 Normal 
 Abnormal – not clinically 
significant 
 Abnormal 
Explain: 
Indirect Funduscopy  
 
 Normal 
 Abnormal – not clinically 
significant 
 Abnormal 
Explain: 
 
 Normal 
 Abnormal – not clinically 
significant 
 Abnormal 
Explain: 
Visual Field 
 
 Normal 
 Abnormal – not clinically 
significant 
 Abnormal 
Explain: 
 
 Normal 
 Abnormal – not clinically 
significant 
 Abnormal 
Explain: 
New Optic Disc Cupping? 
 
 Yes 
 No 
 Yes 
 No 
New Visual Field Defect? 
 Yes 
 No 
 Yes 
 No 
Intraocular Pressure 
>21mmHg? 
 Yes 
 No 
 Yes 
 No 
Other Risk Factors for 
RVO/RPED? 
 Yes 
 No 
 Yes 
 No 
 
Signature of Person Conducting Exam: _____________ 
Date: _____________ 
 

IRB: 13-144 A(15) 
120 
 
APPENDIX H– IMF/LCCI MSK RESEARCH LABORATORY REQUISITION 
 
Protocol 13-144: A Randomized Two-Arm Phase II Study of Trametinib Alone and in 
Combination with GSK2141795 in Patients with Advanced Uveal Melanoma (NCI #9445) 
 
 
 
 
 
 
 
 
 
Dr.                 ________  RSA Contact info: _________________ 
Arm:_______________  Timepoint: _______________________ 
 
 
Request (Please be Specific) 
 
DRAWN BY:__________________ ext.____ 
Please Print Name 
 
DATE:_________________TIME:_________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Research Sample Collection Instructions: 
 
1. Invert all tubes several times immediately after collection 
2. Write patient initials, date, and time of collection on each tube 
3. Fill in date and time of collection in requisition form 
4. Place all collected tubes in biohazard ziplock bag 
5. Please send all specimens via Stat Messengers to Immune Monitoring Core located at 
Zuckerman Research Building, Room 1513. (Place at blood bin on table.) 
Notify Teresa or Rosemarie above of sample delivery 
Please drop off samples by 4pm M-F; otherwise late processing fees will be applied. 
 
 
 
Send all samples to: 
Drs. Jedd Wolchok, Phillip Wong & Jianda Yuan 
Immune Monitoring Core Lab, room Z-1513 
ext. 125-3106  
Attention: Teresa Rasalan ext. 125-3106 (pager 
2877) 
Or Rosemarie Ramsawak 125-3106 
For Research Lab use only: 
Lab Number: 
Received by: 
Date/Time 
Sample Type  
 
Requisition visit type must be checked for samples to be processed 
 
 Day 1: 2 CPT tubes 
 Cycle ____ :  2 CPT tubes  
 Other time points 
              
 
Name:  
MRN: 
DOB:  
 

IRB: 13-144 A(15) 
121 
 
MEMORIAL SLOAN KETTERING CANCER CENTER 
RESEARCH LABORATORY REQUISITION 
 
DR.   ___________________________________ 
REFRIGERATE __________________________ 
C ______________________________________ 
H ______________________________________ 
K ______________________________________ 
M ______________________________________ 
S ______________________________________ 
OTHER  
REQUEST (BE SPECIFIC) 
 
 
 
 
 
 
 
 
 
 
AMOUNT c DRAWN 
BY: ________________ x_____  
 
 
 _______ 
(Please Print Name and extension) 
 
 
 
___________________ 
DATE: _________TIME:_____ 
Fold Here ⇓ 
13-144 
Research Samples Collection Instructions  
1. Write Patient Initials on each tube, date and time of collection 
 
 
 
 
2. Fill in date and time of collection in requisition form  
 
 
 
 
3. Place all collected tubes in biohazard ziplock bag 
 
 
 
 
 
4. Please send all specimen via Stat Messengers x 0732 to 
Zuckerman 1523 
ATTN: Dr Merghoub 
x 125-2580 
 
 
 
 
 
 
 
 
 
 
56-09250 
Please collect:  
 
 
2 Lavender Top Tube 10 ml 
 
 
 
Send all samples to  
Z-1523 
Attn: Dr Merghoub  x125-2581 
Protocol 13-144 
Name:
MRN:  
DOB:  
 
Timepoint: 
Arm:  
Treatment Medication:  

IRB: 13-144 A(15) 
122 
 
APPENDIX I – PARTICIPATING SITE SHIPPING REQUISITIONS 
 
Laboratory Requisition: Tumor/Blood (U.S. Respository) 
 
Laboratory Requisition: Circulating Tumor DNA 
 
Laboratory Requisition: Exosomal/Proteomic Analysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

IRB: 13-144 A(15) 
123 
 
 
MSK IRB Protocol 13-144 (NCI 9445): A Randomized Two-Arm Phase II 
Study of Trametinib Alone and in Combination with GSK2141795 in 
Patients with Advanced Uveal Melanoma 
 
US Repository Samples: Tumor and Blood 
LAB Project Name:  GSK Uveal Protocol 
Shipping Instructions:  
Complete the below requisition and include with sample. Label all samples with Protocol #9445, MSK-
Assigned Participant ID, Initials, Date of Collection, and Time Point. All samples are to be prepared and 
shipped as per protocol section 9.0. Notify laboratory of each shipment. 
Ship Samples to: 
Taha Merghoub, MD 
415 East 68th Street 
New York, NY 11065 
646-888-2580 
Notify via E-mail: 
merghout@mskcc.org 
shoushta@mskcc.org  
medmctcore@mskcc.org 
Participant Information 
Institution: ____________________________________ 
 
Participant Initials: ______________________________ 
 
MSK-Assigned  
Participant ID: _________________________________ 
Date of Birth (MM/DD/YYYY): ___________________ 
 
*MSK Laboratory/ID: ________________________ 
(Leave Laboratory ID blank for first shipment for each 
participant. Laboratory ID will be assigned once the 
first samples for each participant are received at the lab) 
Shipment Information 
Shipment Date:  ________________________ 
 
Shipping Method: ______________________ 
 
Tracking Number: ______________________ 
 
Sender’s Contact Information: 
 
Name:  ______________________________ 
Email:   ______________________________ 
Telephone Number:   ___________________ 
Address: _____________________________     
                 _____________________________     
Study Time Point (Check One) 
□Pretreatment/Screening Visit      □During Treatment, Day 1 of Cycle                □End of Treatment Visit 
                                                            List Cycle # _________________ 
Specimen Type and Information  
□Tumor 
List Organ/Site of Collection: ______________  
List Number of Cores Fixed in Formalin: ______ 
List Number of Cores Flash-Frozen:         ______ 
Block ID/Accession #:  ___________  
 
□Blood 
List Number of Aliquots: ______ 
 
 
For Laboratory Use: 
Date Received: 
MEL # Assigned: 
Date Entered into Database: 
 

IRB: 13-144 A(15) 
124 
 
 
 
MSK IRB Protocol 13-144 (NCI 9445): A Randomized Two-Arm Phase II 
Study of Trametinib Alone and in Combination with GSK2141795 in 
Patients with Advanced Uveal Melanoma 
 
Circulating Tumor DNA 
 
Shipping Instructions:  
Complete the below requisition and include with sample. Label all samples with Protocol #9445, MSK-
Assigned Participant ID, Initials, Date of Collection, and Time Point. All samples are to be prepared and 
shipped as per protocol section 9.0. Notify laboratory of each shipment. 
Ship Samples to: 
Marc-Henri Stern, MD PhD 
Institut Curie 
Immunologie 4ème étage 
26 rue d’Ulm 
75005 Paris cedex 05 France 
Shipment Information 
Shipment Date:  ________________________ 
 
Shipping Method: ______________________ 
 
Tracking Number: ______________________ 
Notify via E-mail: 
maud.milder@curie.net 
aurore.rampanou@curie.fr 
delphine.louis@curie.net 
isabelle.peguillet@curie.net 
medmctcore@mskcc.org 
Sender’s Contact Information: 
Institution: ___________________________ 
Name:  ______________________________ 
Email:   ______________________________ 
Telephone Number:   ___________________ 
Address: _____________________________     
                 _____________________________              
Contents 
Participant 
Initials 
MSK-Assigned 
Participant ID  
Date of 
Birth 
Study Time Point 
(ie. Pre-treatment, 
Cycle #___, or 
End of Treatment) 
Specimen Type 
 
# Tubes 
 
 
 
 
Plasma 
 
 
 
 
 
Plasma 
 
 
 
 
 
Plasma 
 
 
 
 
 
Plasma 
 
 
 
 
 
Plasma 
 
 
 
 
 
Plasma 
 
 
 
 
 
Plasma 
 
 
 
 
 
Plasma 
 
 
For Laboratory Use: 
Date Received: 

IRB: 13-144 A(15) 
125 
 
 
MSK IRB Protocol 13-144 (NCI 9445): A Randomized Two-Arm Phase II 
Study of Trametinib Alone and in Combination with GSK2141795 in 
Patients with Advanced Uveal Melanoma 
 
Exosomal/Proteomic Analysis 
 
Shipping Instructions:  
Complete the below requisition and include with sample. Label all samples with Protocol #9445, MSK-
Assigned Participant ID, Initials, Date of Collection, and Time Point. All samples are to be prepared and 
shipped as per protocol section 9.0. Notify laboratory of each shipment. 
Ship Samples to: 
Professor Sarah Coupland 
Department of Molecular and Clinical Cancer Medicine 
Institute of Translational Medicine 
University of Liverpool 
6th Floor Duncan Building, Daulby Street 
Liverpool L69 3GA 
Shipment Information 
Shipment Date:  ________________________ 
 
Shipping Method: ______________________ 
 
Tracking Number: ______________________ 
Notify via E-mail: 
S.E.Coupland@liverpool.ac.uk  
medmctcore@mskcc.org 
 
Sender’s Contact Information: 
Institution: ___________________________ 
Name:  ______________________________ 
Email:   ______________________________ 
Telephone Number:   ___________________ 
Address: _____________________________     
                 _____________________________    
Contents 
Participant 
Initials 
MSK-Assigned 
Participant ID  
Date of 
Birth 
Study Time Point 
(ie. Pre-treatment, 
Cycle #___, or End 
of Treatment) 
Specimen Type 
 
# Tubes 
 
 
 
 
Plasma 
 
 
 
 
 
Plasma 
 
 
 
 
 
Plasma 
 
 
 
 
 
Plasma 
 
 
 
 
 
Plasma 
 
 
 
 
 
Plasma 
 
 
 
 
 
Plasma 
 
 
 
 
 
Plasma 
 
 
For Laboratory Use: 
Date Received: