MATCH Treatment Subprotocol S2: Phase II Study of Trametinib in Patients With Tumors With GNAQ or GNA11 Mutations
Phase: PHASE2
Conditions: Advanced Lymphoma, Advanced Malignant Solid Neoplasm, Hematopoietic and Lymphoid Cell Neoplasm, Refractory Lymphoma, Refractory Malignant Solid Neoplasm, Refractory Multiple Myeloma
Sponsor: National Cancer Institute (NCI)

i 
28 State Street, Suite 1100, Boston, MA 02109 
p: 857.504.2900 
f: 617. 589.0914 
ecog-acrin.org 
 
 
August 19, 2020 
 
Martha Kruhm, MS RAC 
Head, Protocol and Information Office
Quality Assurance Section
CTEP, DCT, NCI 
6130 Executive Blvd, EPN Room 7000 
Bethesda, MD   20892 
Dear Ms. Kruhm: 
Enclosed is Addendum #25 to EAY131-S2, Phase II Study of Trametinib in Patients with 
Tumors with GNAQ or GNA11 Mutations 
This addendum is in response to Dr. Helen Chen’s Request for Rapid Amendment for 
Trametinib dimethyl sulfoxide dated November 19, 2019, and also, Dr. Tali Johnson’s 
Amendment Request for updates to specific protocol language for Trametinib dimethyl sulfoxide 
dated June 5, 2020 
Please replace your current copy of the protocol and Informed Consent document with these 
updated versions. We recommend that each institution maintain a file containing the original 
protocol, Informed Consent, and all subsequent revisions/versions.
IRB Review Requirements: 
This addendum has been reviewed and approved by the Central IRB, which is the sole 
IRB of record for this study. Local IRB review and approval is unnecessary. 
Implementation of this addendum must occur on the activation date. Sites are not 
permitted to conduct the study utilizing outdated versions of any MATCH protocol documents 
after the activation date of this addendum. 
Re: Review of Amendment #36 of Protocol #EAY131-S2: “MATCH Treatment Subprotocol S2: 
Phase II Study of Trametinib in Patients with Tumors with GNAQ or GNA11 Mutations.” The 
following are ECOG-ACRIN’s responses to the CTEP review comments dated 5/26/2020. 
Please note that the Principal Investigator’s comments appear in bold below. 
I. 
Comments Requiring a Response– Administrative & Editorial Issues:
# 
Section 
Comments 
1. 
Title page 
This protocol amendment has not completely updated the subprotocol chair’s 
contact information according to CTEP’s records. 
Our records indicate: 
• 
Jason Luke, MD (IVR – 47003) has relocated to University of Pittsburgh 
Cancer Institute. Please update his practice site including address. 
PI Response:  Dr. Luke’s contact information, including the practice site 
address, has been updated.

 
ii 
II. 
Additional Protocol Changes by Principal Investigator: 
The following revisions to EAY131-S2 protocol have been made in this addendum: 
 
Section 
Change 
1. 
Cover Page 
Updated version date and addendum number. 
2. 
3.2.1 
In second box, under “Pregnancies” revised language referencing 
“subject” to “female patient”.  
3. 
3.3 
Updated CAEPR list for Trametinib dimethyl sulfoxide with Version 2.6 
October 10, 2019  
4. 
5 
Updated Trametinib dimethyl sulfoxide supply language.  
5. 
Appendix IV 
Updated patient drug information template format. 
The following revisions to EAY131-S2 Informed Consent Document have been made in this 
addendum: 
 
Section 
Change 
1. 
Page 1 
Updated version date. 
2. 
What possible risks 
can I expect from 
taking part in this 
study? 
Updated condensed risk list for Trametinib dimethyl sulfoxide with Version 
2.6 October 10, 2019.  
If you have any questions regarding this addendum, please contact aagu@ecog-acrin.org or 
857-504-2900. 
We request review and approval of this addendum to EAY131-S2 so ECOG-ACRIN may 
activate it promptly.   
Thank you.  
Sincerely, 
Pamela Cogliano 
Senior Director of Protocol Development 
 
 

EAY131-S2 
1 
Molecular Analysis for Therapy Choice (MATCH)
MATCH Treatment Subprotocol S2: Phase II Study of 
Trametinib in Patients with Tumors with GNAQ or GNA11 
Mutations 
TRAMETINIB TREATMENT  
SUBPROTOCOL CHAIR:
Jason Luke, MD, FACP 
TRAMETINIB TREATMENT  
SUBPROTOCOL CO-CHAIR:
Hussein Tawbi, MD, PhD 
TRAMETINIB TRANSLATIONAL CHAIR:
Andrew Chi, MD, PhD 
Version Date: August 19, 2020 
NOTE: This subprotocol (EAY131-S2) 
should be used in conjunction with 
the MATCH Master Protocol 
(EAY131) 
NOTE: As of 11/17, all protocol changes will 
be noted by addendum number. 
SUBPROTOCOL ACTIVATION DATE 
February 25, 2016 (Incorporated in Addendum 
#2) 
Addendum #3 – 5/16 
Addendum #5 – 12/16 
Addendum #6 – 1/17 
Addendum #7 – 3/17 
Addendum #13 
Addendum #19 
Addendum #25 
Agent 
IND# 
NSC# 
Supply 
Trametinib dimethyl sulfoxide 
IND Sponsor:  DCTD, NCI IND#:  
763093
NCI Supplied 
Rev.5/16 
Rev. Add13 
Rev. Add19 

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Version Date: August 19, 2020 
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Table of Contents 
Molecular Analysis for Therapy Choice (MATCH) ...............................................i 
MATCH Treatment Subprotocol S2: Phase II Study of Trametinib in Patients with 
Tumors with GNAQ or GNA11 Mutations ...................................................1 
Table of Contents ........................................................................................2 
Schema ......................................................................................................4 
1. Introduction ..........................................................................................5 
1.1 Trametinib Dimethyl Sulfoxide (GSK1120212B, MEKINIST) ...................5 
1.2 Supporting Preliminary Data.......................................................... 10 
2. Selection of Patients ............................................................................. 13 
2.1 Eligibility Criteria:......................................................................... 13 
3. Treatment Plan .................................................................................... 15 
3.1 Administration Schedule ............................................................... 15 
3.2 Adverse Event Reporting Requirements .......................................... 15 
3.3 Comprehensive Adverse Events and Potential Risks List (CAEPR) for 
Trametinib dimethyl sulfoxide (GSK1120212B, NSC 763093) .............. 19 
3.4 Dose Modifications ...................................................................... 24 
3.5 Dose Modifications for Trametinib and supportive care..................... 30 
3.6 Supportive Care........................................................................... 36 
3.7 Duration of Agent-specific treatment.............................................. 36 
3.8 Duration of Follow-Up .................................................................. 36 
4. Study Parameters ................................................................................. 37 
4.1 Therapeutic Parameters for Trametinib Treatment ........................... 37 
5. Drug Formulation and Procurement ........................................................ 39 
5.1 Trametinib dimethyl sulfoxide (NSC 763093).................................... 40 
6. Translational Studies............................................................................. 42 
7. References .......................................................................................... 42 
Appendix I   Patient Pill Calendar .................................................................. 47 
Appendix II   Trametinib Ophthalmic Exam Form ............................................ 49 
Appendix III  Actionable Mutations for Sub-Protocol EAY131-S2 ....................... 51 
Appendix IV:  Patient Clinical Trial Wallet Card ............................................... 52 
 
 
 

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TREATMENT SUBPROTOCOL CHAIR 
Jason J. Luke, MD, FACP 
University of Pittsburgh Medical Center and 
Hillman Cancer Center 
5150 Centre Ave. Room 563 
Pittsburgh PA 15232 
Phone: 412-623-4511 
Fax: (412) 623-7948 
E-mail: lukejj@upmc.edu 
 
TREATMENT SUBPROTOCOL CO-CHAIR  
Hussein Abdul-Hassan Tawbi, MD, PhD 
MD Anderson Cancer Center 
Department of Melanoma Medical Oncology 
1515 Holcombe Boulevard. Unit 0430 
Houston, TX 77030 
Phone: (713) 792- 6111 
Fax: (713) 745-1046 
htawbi@mdanderson.org 
 
TRANSLATIONAL CHAIR 
Andrew S. Chi, MD, PhD 
Laura and Isaac Perlmutter Cancer Center 
NYU Langone Medical Center 
240 E. 38th Street, 19th Floor 
New York, NY 10016 
Phone: (646) 501-4802 
Fax: (646) 754-9696 
chia01@nyumc.org 
 
 
 
 
 
 
 
 
 
Rev.5/16 
Rev. Add25 

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Schema 
 
 
Long-Term Follow-Up
Trametinib 2mg PO once daily
Until progression or 
unacceptable toxicity
Cycle = 28 days
Accrual Goal: 35
 

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1. 
Introduction 
1.1 
Trametinib Dimethyl Sulfoxide (GSK1120212B, MEKINIST) 
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 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 Dimethyl Sulfoxide (hereafter, referred to as trametinib) is one of the 
several MEK inhibitors in clinical development.  On May 29, 2013, 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 
Amdinistration, 2013).  On January 10, 2014, the FDA 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 3 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 (Flaherty et 
al., 2012).  Extensive research is underway to identify the patient selection 
markers and to 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) (Gopal et al., 2010; Ebi et al., 2011), 
PI3K/AKT inhibitors (Engelman et al., 2008; Hoeflich et al., 2009), 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, including AZD6244 + MK2206 
(Tolcher et al., 2011) and GDC-0973 + GDC-094 (MEK + PI3K inhibitor) (Bendell 
et al., 2011). In addition, efforts have focused on identifying other upstream 
mutations in cancers like GNAQ and GNA11, which may benefit from selective 
MEK inhibition. 
1.1.1 
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) (Gilmartin et al., 2011).  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. 

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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 (Yamaguchi et al., 2011).  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) 
(Investigator’s Brochure, 2012a). 
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 
(Yamaguchi et al., 2011).  Two KRAS-mutant xenograft models, HCT-
116 and A549, also showed significant TGI (83% and 75%) but 
without significant tumor regressions (Gilmartin et al., 2011).  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 (Gilmartin et al., 2011).  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. 
1.1.2 
Clinical Pharmacokinetics (PK) and Activity of Trametinib 
Phase 1 Trial of Trametinib Monotherapy (MEK111054) 
There were 3 parts in this industry sponsored study.  Part 1:  The 
dose-escalation portion involved 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, non-small cell lung cancer 
(NSCLC), colorectal cancer (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 study has been completed and all parts, other 
than FDG-PET results, have been reported  

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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 (Infante et al., 2012). 
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 T max 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 
(Infante et al., 2010).  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. 
Drug-drug interactions: 
Trametinib is metabolized predominantly via deacetylation (non-
cytochrome P450 [CYP450]-mediated) with secondary oxidation or in 
combination with glucuronidation biotransformation pathways 
(Investigator’s Brochure, 2012a).  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 dimethyl 
sulfoxide is a weak CYP2C8 inhibitor and weak CYP3A4 inducer. 
Drug-drug interactions with sensitive substrates of 2C8 and 3A4 are 
not anticipated. 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 in the phase 1 trial:  
In the phase 1 trial, 14 patients with BRAF-mutant melanoma received 
trametinib at 2 mg QD.  The overall objective response rate (ORR) 
was 43% (6/14), including 2 complete responses (CRs) (Investigator's 
Brochure, 2012a).  In 9 patients with BRAF wt melanoma, 2 patients 
achieved a partial response (PR), and 3 stable disease (SD) (Infante 
et al., 2010).  In 26 evaluable pancreatic cancer patients, there were 2 
PRs (1 PR was KRAS mutation-positive) and 11 SD (2 achieved  

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≥ 20% tumor reduction) (Messersmith et al., 2011).  Among the 27 
CRC patients (without selection of RAS or RAF mutations), 8 SD were 
observed. 
Antitumor Activity in Melanoma  
Phase 3 trial of trametinib vs. chemotherapy in advanced V600 
mutant melanoma: 
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) (Flaherty et al., 2012; MEKINIST, 2013).  
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). Of the patients, 214 were randomized to receive trametinib, 
and 108 were randomized to receive chemotherapy. Investigator-
assessed efficacy data are summarized as follows: 
 
Trametinib 
(n=214) 
Chemotherapy (DTIC) 
(n=108) 
PFS 
Median, months (95% CI) 
4.8 (4.3, 4.9) 
1.5 (1.4, 2.7) 
HR (95% CI) 
P value (log-rank test) 
0.47 (0.34, 0.65) 
P < 0.0001 
Confirmed Tumor Responses 
Objective Response Rate (95% CI) 
CR, n (%) 
PR, n (%) 
22% (17, 28) 
4 (2%) 
43 (20%) 
8% (4, 15) 
0 
9 (8%) 
Duration of response 
Median, months (95% CI) 
5.5 (4.1, 5.9) 
NR (3.5, NR) 
CI = confidence interval; CR = complete response; HR = hazard ratio; NR = not reached; PFS 
= progression-free survival; PR = partial response 
The 6-month OS rate was 81% in the trametinib group and 67% in the 
chemotherapy group.  Mature data on OS are pending. 
Experience with Trametinib in Metastatic Melanoma Following BRAF 
Inhibitor Therapy 
The clinical activity of single-agent trametinib was evaluated in a 
single-arm, multicenter, international trial in 40 patients with BRAF 
V600E or V600K mutation-positive, unresectable, or metastatic 
melanoma who had received prior treatment with a BRAF inhibitor.  
All patients received trametinib at a dose of 2 mg PO QD until disease 
progression or unacceptable toxicity.  None of the patients achieved a 
confirmed PR or CR. 

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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 
(Borthakur et al., 2010).  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%). 
In a multicenter phase 2 study, NSCLC patients with KRAS mutant 
tumors were randomized 2:1 to receive trametinib (2 mg QD) or 
docetaxel (75 mg/m2 IV every 3 weeks) (Blumenschein et al., 2013).  
A total of 134 pts were randomized to trametinib (89) or docetaxel 
(45); 129 patients had KRAS-mutant NSCLC.  The hazard ratio for 
PFS was 1.14 (95% CI, 0.75-1.75; P=0.5197) with a median PFS of 
11.7 versus 11.4 weeks for trametinib versus docetaxel.  The overall 
response rate (ORR) was 12% for trametinib and 12% for docetaxel. 
In a double-blind, phase 2 study evaluating the combination of 
gemcitabine with trametinib, untreated pancreatic cancer patients 
were randomized to receive gemcitabine (1000 mg/m2 weekly 7 for 8 
weeks, then weekly 3 every 4 weeks) plus either trametinib 2mg or 
placebo QD (Infante et al., 2013).  Median OS was 8.4 months with 
trametinib compared to 6.7 months with placebo.  Median PFS was 16 
weeks versus 15 weeks, and ORRs and median duration of 
responses were 22% and 23.9 weeks and 18% and 16.1 weeks on 
trametinib and placebo; the median OS and ORR in the subgroup of 
patients with KRAS mutations (143/160) was similar to OS and ORR 
for all randomized patients.   
The guanine nucleotide-binding protein G(q) subunit alpha (GNAQ) 
and guanine nucleotide-binding protein subunit alpha-11 (GNA11) are 
large GTPases of the Gαq family (Van Raamsdonk et al., 2009; Van 
Raamsdonk et al., 2010).  Recurrent activating mutations in GNAQ 
(3.3% of 8778 cancer samples in COSMIC v63) or GNA11 (2.3% OF 
6237 cancers in COSMIC v62) have been identified in cancers. Most 
of these mutations result in defective GTPase activity and render the 
proteins constitutively active (O'Hayre et al., 2013). Activating 
mutations ultimately lead to downstream activation of MAPK signaling 
(Hubbard and Hepler, 2006; Griner and Kazanietz, 2007).  The 
highest prevalence of GNAQ and GNA11 mutations are found in uveal 
melanoma (33% AND 39% respectively), blue nevi (32% and 3-5%, 
respectively) and cutaneous melanoma (1.4% and 1.3%, 
respectively), but are also found in colon adenocarcinoma at about 
2%.(Shoushtari AN et al GNAQ and GNA11 mutations in uveal 
melanoma.  Melanoma Res 2014; 24: 525-534).  MEK inhibitors can 
be active in melanomas with GNAQ or GNA11 mutations.  Preclinical 
activity of the MEK 1 and 2 inhibitor selumetinib has been published 

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(Ambrosini et al. Identification of unique MEK dependent genes in 
GNAQ mutant uveal melanoma involved in cell growth, tumor cell 
invasion and MEK resistance. Clin Cancer Res 2012; 18: 3552-3561).  
A subsequent randomized phase II trial of investigator’s choice 
chemotherapy with or without selumetinib in metastatic uveal 
melanoma showed, in an unplanned analysis, a significant 
improvement in PFS for the selumetinib group (Carvajal RD, Sosman 
JA, Quevedo JF, Milhem MM, Joshua AM, 
Kudchadkar RR, et al. Effect of selumetinib vs chemotherapy on 
progressionfree survival in uveal melanoma: a randomized clinical 
trial. JAMA 2014; 311:2397–2405). In a phase I study of trametinib in 
patients with melanoma, combined exploratory and clinical genotyping 
of patients who entered the trial with uveal melanoma revealed 6 
patients with GNAQ or GNA11 mutations. 50% had response of stable 
disease and one patient with a GNA11 mutation remained on 
trametinib for more than 40 weeks (Falchook GS et al. Activity of the 
oral MEK inhibitor trametinib in patients with advanced melanoma: a 
phase 1 dose escalation trial.  Lancet Oncol 2012; 13: 782-89). 
1.2 
Supporting Preliminary Data  
GNAQ / GNA11 Biology and Targeted Therapy 
The guanine nucleotide-binding protein G(q) subunit alpha (GNAQ) and guanine 
nucleotide-binding protein subunit alpha-11 (GNA11) are two closely related 
large GTPases of the Gαq family (Van Raamsdonk et al., 2009; Van Raamsdonk 
et al., 2010).  Mutations in GNAQ or GNA11 are likely to be present in 1.6 - 2% of 
the population of cancer patients based on the cBIO Portal database. Mutations 
in GNAQ or GNA11 eliminate the activity of the heterotrimeric G protein α 
subunits Gαq and Gα11 GTPase, leading to hyperactivation of signaling 
downstream of the GNAQ and GNA11 (O'Hayre et al., 2013). The oncogenic 
activity of GNAQ was initially revealed as part of a systematic analysis of the 
transforming potential of G proteins and their coupled receptors (Kalinec et al., 
1992). The best-described signaling event downstream of Gαq involves 
activation of phospholipase C (PLC) with subsequent increase in inositol 1,4,5-
trisphosphate (IP3), and diacylglycerol (DAG) (Hubbard and Hepler, 2006). IP3 
increases cytoplasmic Ca2+ levels leading to modulation of multiple calcium-
regulated pathways.  Together with DAG, this stimulates classical protein kinase 
C (PKC) isoforms (Griner and Kazanietz, 2007). GNAQ thus utilizes PLC to 
stimulate MAPK. 
Based upon the finding that uveal melanoma (UM) is characterized by 
functionally active mutations in GNAQ or GNA11 (Ivey et al., 2003; Onken et al., 
2008; Raamsdonk et al., 2008), as well as preclinical findings demonstrating 
antitumor effects of MEK inhibition in GNAQ/GNA11 mutant UM (Ambrosini et al., 
2012), a randomized trial of the MEK inhibitor selumetinib versus temozolomide 
was performed in patients with UM. The primary endpoint of the study, 
progression-free survival, was doubled as compared with chemotherapy.  A 
hazard ratio for progression of 0.46 in favor of selumetinib was observed 
(Carvajal et al., 2013).  The overall response for patients whose tumors harbored 
GNAQ/GNA11 mutations was 15%. The overall response rate was zero in 
patients who crossed over to selumatinib after failure of temozolomide. Patients 
experiencing RECIST responses and tumor shrinkage form baseline were found 

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to harbor mutations in the Q209L; Q209P; Q209H; and Q209R of exon 5 as well 
as R183 of exon 4 of GNAQ (personal communication from Richard Carvajal, 
MD) 
The preliminary success of the MEK inhibitor selumetinib in targeting 
GNAQ/GNA11 suggests that MAPK inhibition is a reasonable therapeutic target 
in UM and other GNAQ/11 mutant cancers.  Two approaches may be considered 
in improving the clinical outcome of patients then including adding a second 
signaling inhibitor to a MEK inhibitor or alternatively, more completely 
suppressing MAPK signaling with a more potent MEK inhibitor. In considering 
combination approaches, it is important to make note that signaling downstream 
of GNAQ/GNA11 is mediated through PKC isoforms, this molecule has been of 
interest for targeted therapy development in this molecular model.  Inhibitors of 
PKC such as sotrastaurin and related compounds, selectively block the 
proliferation of melanoma cell lines with mutations in GNAQ or GNA11 (Wu et al., 
2012a; Wu et al., 2012c).  Similar results are observed with human melanoma 
cell lines with GNAQ or GNA11 mutations.  While MEK inhibitors suppress the 
growth of UM cell lines, they show no selectivity compared to melanoma cell 
lines with mutations in other oncogenes such as RAS or BRAF. By contrast, in 
UM with GNAQ or GNA11 mutations, a combination of PKC inhibition and MEK 
inhibitors leads to a highly synergistic effect.  These results suggest that 
combined inhibition of PKC and MEK may represent a rational combination to be 
evaluated in GNAQ and GNA11 mutant cancers. 
Combination approaches of MEK inhibition with other pathway inhibitors have 
also been examined in GNAQ or GNA11 mutant uveal melanoma. Based upon 
preclinical data demonstrating enhancement of MEK inhibitor-induced antitumor 
effects by concurrent inhibition of AKT or PI3K (Ambrosini et al., 2013; Khalili et 
al., 2012), a phase II trial of trametinib in combination with GSK2141795, an oral 
AKT inhibitor, was launched (NCI 9445). Furthermore, building upon preclinical 
data demonstrating the enhanced susceptibility of tumor cells to chemotherapy 
with concurrent MEK inhibition (Holt et al., 2012), as well as the greater PFS 
observed with the combination in a study of cutaneous melanoma (Holt et al., 
2012; Robert et al., 2013), a phase II trial of DTIC with or without selumetinib has 
also begun accrual (NCT01974752). 
To date, combination approaches of molecular inhibitors have proved to be toxic 
relative to expectations for targeted therapies (Bendell et al., 2014).  Therefore, 
consideration of MAPK suppression by a higher potency MEK inhibitor would be 
reasonable.  As above, selumetinib demonstrated a clinically significant response 
rate of 15% in UM.  Selumetinib in a MEK1/2 inhibitor with MEK1 IC50 of 10 ɳM.  
Other MEK inhibitors are available including the MEK1/2 inhibitor trametinib, 
which demonstrates a MEK1 IC50 of 0.7 ɳM (Luke et al. 2014).  Trametinib has 
not been evaluated in UM or GNAQ/11 mutant tumors in a robust manner.  In the 
single agent phase I study of trametinib (Infante et al., 2012), 16 patients with UM 
were treated without identification of any partial response. However, the 
GNAQ/11 mutational status of these patients was not disclosed.  Whereas in the 
selumetinib phase II trial, patients were untreated, in the trametinib phase I study 
the median number of prior therapies was 3.  This likely impacted on the result.  
Of the 16 patients treated, best response included 8 patients with stable disease 
with 4 patients on treatment greater than 16 weeks.  This decrease in efficacy of 
MEK inhibition after further lines of therapy is consistent with what was seen in 
the selumetinib trial.  In that study, no patients who received chemotherapy first 

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had a response to selumetinib after crossing over on the study.  The molecular 
mechanism underpinning this change in biology is unknown though it has been 
postulated that perhaps the essential signaling pathways in UM can change after 
chemotherapy. An on-going study is evaluating trametinib with and without an 
AKT inhibitor in untreated advanced UM. This prior experience with MEK 
inhibitors suggests that treatment with trametinib for UM and GNAQ/11 mutant 
tumors may be efficacious and is an important clinical question to explore. 
Trametinib is chosen for this study in place of selumatinib because of its better 
efficacy based on cross trial comparison for similar patient population 
(BRAFV600E melanoma). 
 

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2. 
Selection of Patients 
Each of the criteria in the checklist that follows must be met, along with the eligibility in 
the main screening study, in order for a patient to be considered eligible for this study. 
Use the checklist to confirm a patient’s eligibility. For each patient, this checklist must be 
photocopied, completed and maintained in the patient’s chart.  
In calculating days of tests and measurements, the day a test or measurement is 
done is considered Day 0. Therefore, if a test is done on a Monday, the Monday 
four weeks later would be considered Day 28.  
ECOG-ACRIN Patient No. ____________________________ 
Patient’s Initials (L, F, M) _______________________ 
Physician Signature and Date ___________________ 
NOTE: 
All CTEP Policy does not allow for the issuance of waivers to any protocol 
specified criteria 
(http://ctep.cancer.gov/protocolDevelopment/policies_deviations.htm). 
Therefore, all eligibility criteria listed in Section 2 must be met, without 
exception. The registration of individuals who do not meet all criteria listed in 
Section 2 can result in the participant being censored from the analysis of the 
study, and the citation of a major protocol violation during an audit.  All 
questions regarding clarification of eligibility criteria must be directed to the 
Group's Executive Officer (EA.Execofficer@jimmy.harvard.edu) or the 
Group's Regulatory Officer (EA.RegOfficer@jimmy.harvard.edu). 
NOTE: 
Institutions may use the eligibility checklist as source documentation if it has 
been reviewed, signed, and dated prior to registration/randomization by the 
treating physician. 
NOTE: 
All patients must have signed the relevant treatment consent form 
2.1 
Eligibility Criteria:  
2.1.1 
Patients must fulfill all eligibility criteria outlined in Section 3.1 of 
MATCH Master Protocol (excluding Section 3.1.6) at the time of 
registration to treatment step (Step 1, 3, 5, 7). 
2.1.2 
Patients must have GNAQ or GNA11 mutations, or another 
aberration, as determined via the MATCH Master Protocol and 
according to Appendix III. See Appendix III for information on the 
targeted mutations and corresponding Levels of Evidence. 
2.1.3 
Patients must have an electrocardiogram (ECG) within 8 weeks prior 
to treatment assignment and must have NONE of the following 
cardiac criteria: 
• 
Clinically important abnormalities in rhythm, conduction or 
morphology of resting ECG (e.g. complete left bundle branch 
block, third degree heart block). 
• 
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. 
Date of ECG:  _______________ 
_____
_____
_____
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2.1.4 
Patients with a history of interstitial lung disease or pneumonitis are 
excluded. 
2.1.5 
Patients must have an ECHO or a nuclear study (MUGA or First 
Pass) within 4 weeks prior to registration to treatment and must not 
have a left ventricular ejection fraction (LVEF) < the institutional lower 
limit of normal (LLN). If the LLN is not defined at a site, the LVEF must 
be > 50% for the patient to be eligible. 
Date of ECHO/nuclear study:  _______________ 
2.1.6 
Patients must not have known hypersensitivity to trametinib or 
compounds of similar chemical or biologic composition or to dimethyl 
sulfoxide (DMSO). 
2.1.7 
Patients must not have a history or current evidence/risk of retinal 
vein occlusion (RVO). An eye exam is required at baseline. See 
Appendix II for the Trametinib Ophthalmic Exam Form. 
2.1.8 
Patients who previously received prior treatment with other MEK 
inhibitors (including, but not limited to, trametinib, binimetinib, 
cobimetinib, selumetinib, RO4987655 (CH4987655), GDC-0623 and 
pimarsertib) will be excluded. 
2.1.9 
Patients who previously received monoclonal antibody therapy (eg. 
ipilimumab, nivolumab, pembrolizumab and others) must have 
stopped the prior therapy for 8 or more weeks before starting on 
trametinib. 
2.1.10 
Patients with glioblastoma must have histologically or radiographically 
confirmed recurrent or progressive WHO Grade 4 glioma 
(glioblastoma). 
NOTE: 
All baseline and post-baseline disease assessments must 
be performed using contrast-enhanced cranial MRI or 
contrast-enhanced CT for subjects who cannot have MRI 
performed. 
2.1.11 
Patients with uveal melanoma are excluded. 
 
 
 
 
 
Physician Signature 
 
Date 
OPTIONAL: 
This signature line is provided for use by institutions wishing to 
use the eligibility checklist as source documentation. 
 
_____
_____
_____
_____
_____
_____
_____
_____

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3. 
Treatment Plan 
3.1 
Administration Schedule 
All patients will receive trametinib 2mg daily continuously until intolerable toxicity, 
disease progression, or the end of the study.  
Trametinib should be administered once per day, continuously; and should be 
taken at about the same time each day. The study drug should be administered 
together with approximately eight ounces of water. Trametinib should be taken 
fasting, at least 1 hour before or 2 hours after a meal.  If a subject vomits after 
taking study medication, the subject should be instructed not to retake the dose 
and should take the next scheduled dose. 
If a dose of trametinib is missed, only take the dose if it is more than 12 hours 
until the next scheduled dose.   
Trametinib should be stored at 2-8°C (36-46°F). Refrigerate. Do not freeze. 
3.2 
Adverse Event Reporting Requirements 
The Adverse Event Reporting Requirements for all EAY131 subprotocols are 
outlined in the MATCH MASTER protocol.  Please refer to those guidelines when 
determining if an event qualifies as a Serious Adverse Event (SAE) and requires 
expedited reporting via CTEP’s Adverse Event Reporting System (CTEP-AERS).  
In addition, the following section outlines agent specific requirements and must 
be followed to ensure all reporting requirements are met. 
3.2.1 
Additional instructions, requirements and exceptions for protocol 
EAY131-Subprotocol S2. 
Additional Instructions 
For instructions on how to specifically report events that result in 
persistent or significant disability/incapacity, congenital anomaly, 
or birth defect events via CTEP-AERS, please contact the AEMD 
Help Desk at aemd@tech-res.com or 301-897-7497. This will 
need to be discussed on a case-by-case basis. 
 
EAY131- Subprotocol S2 specific expedited reporting 
requirements: 
• LVEF Changes: If any of the following circumstances occur, 
the event(s) must be reported via CTEP-AERS according to 
the timeframes outlined in the AE table in section 5.3.6 of the 
MATCH Master protocol 
• 
Asymptomatic:  Absolute decrease of >10% in LVEF 
compared to baseline and ejection fraction below the 
institution’s LLN and LVEF does not recover within 4 
weeks 
• 
Symptomatic: Grade 3-4 LVEF 
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Please refer to the dose modification instructions for further 
information regarding Treatment Modification and Management 
Guidelines for LVEF Decrease 
• 
Visual Changes:  If RPED (retinal pigment epithelial 
detachments) or RVO (retinal vein occlusion) are diagnosed, 
the event(s) must be reported via CTEP-AERS according to 
the timeframes outlined in the AE table in section 5.3.6 of the 
MATCH Master protocol.  Please refer to the dose modification 
instructions for further information regarding Treatment 
Modification and Management Guidelines for Visual Changes. 
• Liver Chemistry Changes:  If any of the following 
circumstances occur, the event(s) must be reported via CTEP-
AERS according to the timeframes outlined in the AE table in 
section 5.3.6 of the MATCH Master protocol 
• 
ALT ≥ 3xULN and bilirubin ≥ 2x ULN or > 35% direct 
bilirubin 
• 
ALT  3xULN and INR ≥ 1.5, if INR measured  (INR 
threshold does not apply if subject is on anticoagulant) 
• Please refer to the dose modification instructions for further 
information regarding Treatment Modification and Management 
Guidelines for Liver Chemistry Changes 
• 
Pregnancies: Pregnancies and suspected pregnancies 
(including a positive or inconclusive pregnancy test, regardless 
of age or disease state) occurring while the female patient is on 
Trametinib, or within 28 days of the patient subject’s last dose 
of Trametinib, are considered immediately reportable events. 
The pregnancy, suspected pregnancy, or positive/ inconclusive 
pregnancy test must be reported via CTEP-AERS within 24 
hours of the Investigator’s knowledge.  Please refer to 
Appendix VIII in MATCH Master protocol for detailed 
instructions on how to report the occurrence of a pregnancy as 
well as the outcome of all pregnancies. 
 
EAY131-S2 specific expedited reporting exceptions: 
For study Subprotocol S2, the adverse events listed below do not 
require expedited reporting via CTEP-AERS: 
• 
If an AE meets the reporting requirements of the protocol, and 
it is listed on the SPEER, it should ONLY be reported via 
CTEP-AERS if the grade being reported exceeds the grade 
listed in the parentheses next to the event 
3.2.2 
Second Primary Cancer Reporting Requirements 
NOTE: 
The MATCH Master Protocol outlines the standard 
requirements for the reporting of second primaries. 
Please be aware that there are additional requirements 
for this subprotocol. Please adhere to the guidelines 
outlined below for the reporting of second primaries 
on this subprotocol. 
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All cases of second (second malignancy is a cancer that is unrelated 
to any prior anti-cancer treatment, including the treatment on this 
protocol) and secondary malignancies (secondary malignancy is a 
cancer caused by any prior anti-cancer treatment, including the 
treatment on this protocol),   including acute myeloid leukemia (AML) 
and myelodysplastic syndrome (MDS)], regardless of attribution, that 
occur following treatment on NCI-sponsored trials must be reported as 
follows: 
1. Complete a Second Primary Form in Medidata Rave within 14 
days. 
2. Report the diagnosis via CTEP-AERS, regardless of attribution, at 
http://ctep.cancer.gov 
Report under a.) leukemia secondary to oncology chemotherapy, 
b.) myelodysplastic syndrome, or c.) treatment related secondary 
malignancy 
3. Upload a copy of the pathology report to ECOG-ACRIN via 
Medidata Rave and submit a copy to NCI/CTEP confirming the 
diagnosis. 
4. If the patient has been diagnosed with AML/MDS, upload a copy 
of the cytogenetics report (if available) to ECOG-ACRIN via 
Medidata Rave and submit a copy to NCI/CTEP. 
NOTE: 
All new malignant tumors must be reported through 
CTEP-AERS whether or not they are thought to be 
related to either previous or current treatment.  All new 
malignancies should be reported including solid tumors 
(including non-melanoma skin malignancies), hematologic 
malignancies, Myelodysplastic Syndrome (MDS)/Acute 
Myelogenous Leukemia (AML), and in situ tumors.   
Whenever possible, the CTEP-AERS report should include the 
following:   
• 
tumor pathology 
• 
history of prior tumors 
• 
prior treatment/current treatment including duration 
• 
any associated risk factors or evidence regarding how long the 
tumor may have been present 
• 
when and how the tumor was detected 
• 
molecular characterization or cytogenetics or the original tumor (if 
available) and of any new tumor  
• 
tumor treatment and outcome (if available) 
NOTE: 
The Second Primary Form and the CTEP-AERS report 
should not be used to report recurrence or development of 
metastatic disease. 
NOTE: 
If a patient has been enrolled in more than one NCI-
sponsored study, the Second Primary Form must be 
submitted for the most recent trial. ECOG-ACRIN must be 
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pathology report and cytogenetics report (if available) even 
if ECOG-ACRIN was not the patient's most recent trial. 
NOTE: 
Once data regarding survival and remission status are no 
longer required by the protocol, no follow-up data should 
be submitted via CTEP-AERS or by the Second Primary 
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3.3 
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/aeguide
lines.pdf for further clarification. Frequency is provided based on 1111 patients. 
Below is the CAEPR for Trametinib dimethyl sulfoxide (GSK1120212B). 
NOTE: 
If an AE meets the reporting requirements of the protocol, and it is 
listed on the SPEER, it should ONLY be reported via CTEP-AERS if 
the grade being reported exceeds the grade listed in the parentheses 
next to the event. 
Version 2.6, October 10, 20191 
 
Adverse Events with Possible 
Relationship to Trametinib (GSK1120212B) 
(CTCAE 5.0 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 3) 
CARDIAC DISORDERS 
 
Heart failure 
 
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 
 
 
Papilledema 
Periorbital edema 
GASTROINTESTINAL DISORDERS 
Abdominal pain 
Abdominal pain (Gr 2) 
 
Colitis 
 
Colonic perforation 
Constipation 
Constipation (Gr 2) 
Rev. 1/17 
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Adverse Events with Possible 
Relationship to Trametinib (GSK1120212B) 
(CTCAE 5.0 Term) 
[n= 1111] 
Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
Diarrhea 
 
Diarrhea (Gr 3) 
Dry mouth 
Dry mouth (Gr 2) 
Dyspepsia 
Dyspepsia (Gr 2) 
Mucositis oral 
Mucositis oral (Gr 3) 
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) 
Generalized edema3 
Generalized edema3 (Gr 2) 
IMMUNE SYSTEM DISORDERS 
Allergic reaction4 
INFECTIONS AND INFESTATIONS 
Folliculitis 
Folliculitis (Gr 2) 
Lung infection 
Paronychia 
Paronychia (Gr 2) 
Skin infection 
Skin infection (Gr 2) 
INVESTIGATIONS 
Alanine 
aminotransferase 
increased 
Alanine aminotransferase 
increased (Gr 3) 
Alkaline phosphatase 
increased 
Alkaline phosphatase 
increased (Gr 2) 
Aspartate 
aminotransferase 
increased 
Aspartate 
aminotransferase 
increased (Gr 3) 
CPK increased 
Ejection fraction 
decreased 
METABOLISM AND NUTRITION DISORDERS 
Anorexia 
Anorexia (Gr 3) 
Dehydration 
Dehydration (Gr 3) 
Hypoalbuminemia 
Hypomagnesemia 
Hypomagnesemia (Gr 2) 
Hyponatremia 
Hyponatremia (Gr 3) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
Arthralgia 
Back pain 
Back pain (Gr 2) 
Pain in extremity 
Pain in extremity (Gr 2) 
 
Rhabdomyolysis 
NERVOUS SYSTEM DISORDERS 
Dizziness 
Dizziness (Gr 2) 
Headache 
Headache (Gr 2) 

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Adverse Events with Possible 
Relationship to Trametinib (GSK1120212B) 
(CTCAE 5.0 Term) 
[n= 1111] 
Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
Cough 
Cough (Gr 2) 
Dyspnea 
Dyspnea (Gr 3) 
 
Pneumonitis 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
Alopecia 
Alopecia (Gr 2) 
Dry skin 
Dry skin (Gr 2) 
Nail changes 
 
Palmar-plantar 
erythrodysesthesia 
syndrome 
Pruritus 
Pruritus (Gr 2) 
 
Skin and subcutaneous 
tissue disorders - Other 
(drug reaction with 
eosinophilia and systemic 
symptoms [DRESS]) 
Skin and 
subcutaneous 
tissue disorders - 
Other (rash)5 
  
 
Skin and subcutaneous 
tissue disorders - Other 
(rash)5 (Gr 3) 
 
 
Stevens-Johnson 
syndrome6 
VASCULAR DISORDERS 
Hypertension 
Hypertension (Gr 3) 
 
Thromboembolic event 
(venous) 
Vascular disorders - 
Other (hemorrhage)7 
1 This 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. 
2 Visual 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. 
3 Generalized edema includes edema, lymphedema, and edema limbs. 
4 Hypersensitivity (allergic reactions) may present with symptoms such as fever, rash, increased liver 
function tests, and visual disturbances. 
5 Skin and subcutaneous tissue disorders - Other (rash) may include rash, rosacea, rash acneiform, 
erythematous rash, genital rash, rash macular, exfoliative rash, rash generalized, erythema, rash 
papular, seborrhoeic dermatitis, dermatitis psoriasiform, rash follicular, skin fissures, and skin chapped. 
6 Stevens-Johnson syndrome has been observed in patients treated with trametinib and dabrafenib 
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7 The 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; Photophobia 
GASTROINTESTINAL DISORDERS - Ascites; Duodenal ulcer; Esophageal necrosis; 
Esophageal ulcer; Esophagitis; Gastric hemorrhage7; Gastric ulcer; Gastritis; 
Gastrointestinal disorders - Other (intestinal obstruction); Gastrointestinal disorders - 
Other (pneumatosis intestinalis); Gastrointestinal fistula; Gingival pain; Hemorrhoidal 
hemorrhage7; Ileus; Obstruction gastric; Pancreatitis; Small intestinal obstruction 
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; 
Sepsis; Upper respiratory infection; Urinary tract infection 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Bruising 
INVESTIGATIONS - Blood bilirubin increased; Blood lactate dehydrogenase increased; 
Creatinine increased; Electrocardiogram QT corrected interval prolonged; GGT increased; 
Lipase increased; Lymphocyte count decreased; Platelet count decreased; Serum 
amylase increased; White blood cell decreased 
METABOLISM AND NUTRITION DISORDERS - Hyperglycemia; Hyperkalemia; 
Hyperphosphatemia; Hyperuricemia; Hypocalcemia; Hypoglycemia; Hypokalemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Generalized muscle 
weakness; Muscle cramp; Musculoskeletal and connective tissue disorder - Other 
(compression fracture); Myalgia; Neck pain 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND 
POLYPS) - Tumor hemorrhage7; Tumor pain 
NERVOUS SYSTEM DISORDERS - Dysgeusia; Encephalopathy; Intracranial 
hemorrhage7; 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; Dysuria; 
Hematuria; Proteinuria; Urinary incontinence 

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REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Vaginal fistula; Vaginal 
hemorrhage7 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Bronchopulmonary 
hemorrhage7; Hypoxia; Laryngeal edema; Oropharyngeal pain; 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 ulceration; Urticaria 
VASCULAR DISORDERS - Hematoma; Hot flashes; Hypotension 
NOTE: 
Trametinib (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. 
 

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3.4 
Dose Modifications  
NOTE: Patients who interrupt trametinib for > 2 weeks will be removed from 
this subprotocol, unless the interruption was for reduction in LVEF, 
visual changes or RPED with subsequent recovery as described in 
corresponding tables below. 
All toxicity grades below are described using the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0. 
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 website (http://ctep.cancer.gov). 
3.4.1 
Dose Modification Guidelines for Trametinib Adverse Events of 
Special Interest 
The dose levels for this study are provided in Table 1. 
Dose Levels 
Trametinib once daily 
Full dose 
2 mg 
1st Dose reduction 
1.5 mg 
2nd Dose reduction 
1.0 mg 
Table 1 
Dose Level Reduction Guidelines 
3.4.2 
If an AE resolves to grade 1 or lower (or baseline) and remains grade 
1 or lower at the reduced dose level and the subject does not 
experience any additional AEs requiring dose hold or reductions, then 
after 4 weeks of the study treatment at reduced dose, the dose of 
trametinib may be increased one dose level.  If a dose reduction 
below 1 mg once daily for trametinib is required, then trametinib will 
be permanently discontinued. 
3.4.3 
Guidelines for Cardiovascular Adverse Events  
Cardiovascular adverse events have been seen in subjects receiving 
trametinib[4]).  Guidelines for LVEF decreases and hypertension are 
provided below. 
3.4.3.1 
Left Ventricular Ejection Fraction (LVEF) 
Decreases of the left-ventricular-ejection-fraction (LVEF) 
have been observed in subjects receiving trametinib. 
Therefore, ECHOs (preferred) or MUGA’s must be 
performed to assess cardiac ejection fraction.  The 
procedure performed at baseline must be performed at all 
designated visits as outlined in the Time and Events Table 
(See Section 4.1). 
Dose modification guidance and stopping criteria for LVEF 
decrease are provided (Table 2). 
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Table 2 
Dose Modification Guidelines and Stopping Criteria for LVEF Decrease 
Clinic 
LVEF-drop (%) or 
CTCAE grade 
Action and Dose Modification 
Asymptomatic Absolute decrease of 
>10% in LVEF compared 
to baseline and ejection 
fraction below the 
institution’s  LLN 
• Interrupt trametinib and repeat ECHO/MUGA within 
2 weeksa 
• If the LVEF recovers within 4 weeks (defined as 
LVEF ≥ LLN and absolute decrease ≤ 10% compared 
to baseline):  
- Consult with the subprotocol Study Chair and 
request approval for restart 
- Restart treatment with trametinib at  reduced dose 
by one dose levelb 
- 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 
- Consult with cardiologist 
- Permanently discontinue trametinib 
- Report as SAE 
- Repeat ECHO/MUGA after 2, 4, 8, 12, and 16 
weeks or until resolution  
- Consult with the subprotocol Study Chair.c 
Symptomaticb Grade 3: resting LVEF 
39-20% or > 20% 
absolute reduction from 
baseline 
• Permanently discontinue trametinib.  
• Report as SAE 
• Consult with cardiologist 
• Repeat ECHO/MUGA after 2, 4, 8, 12, and 16 weeks 
or until resolution 
Grade 4: resting LVEF  
< 20% 
Abbreviations:  CTCAE = Common Terminology Criteria for Adverse Events; ECHO = 
echocardiogram; GSK = GlaxoSmithKline; LLN = lower limit of normal; LVEF = left ventricular ejection 
fraction; MUGA=Multi-gated acquisition 
a. If ECHO/MUGA does not show LVEF recovery after 2 weeks, repeat ECHO/MUGA 2 weeks later. 
b. Escalation of trametinib to previous dose level can be considered if LVEF remains stable for 4 
weeks after restarting of trametinib. Approval from the subprotocol Study Chair is required. 
c. Symptoms may include: dyspnea, orthopnea, and other signs and symptoms of pulmonary 
congestion and edema. 
3.4.3.2 
Hypertension 
Increases in blood pressure (BP) have been observed in 
patients receiving trametinib. Recommendations for BP 
monitoring and management are provided below. 
Monitoring: 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 
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• 
Restrictive clothing has been removed from  the cuff 
area and the appropriate right size has been selected 
• 
The subject's arm is supported so that the middle of the 
cuff is at heart level 
• 
The subject remains quiet during the measurement.  
• 
In subjects with an initial BP reading within the 
hypertensive range, a second reading should be taken 
at least 1 minute later, with the two readings averaged 
to obtain a final BP measurement. The averaged value 
should be recorded in the eCRF. 
• 
Persistent hypertension is defined as an increase of 
systolic blood pressure (SBP) > 140 mm Hg and/or 
diastolic blood pressure (DBP) > 90 mm Hg in three 
consecutive visits with blood pressure assessments 
from two readings as described above. 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 one week. 
Table 3 
Management and Dose Modification Guidelines for Hypertension 
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. 
(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 
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Management and Trametinib Dose Modification for Hypertension 
Event 
Management Guideline 
Dose Modification 
(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 the subprotocol Study Chair is required. 
3.4.4 
Guidelines for Visual Changes 
Trametinib is known to be associated with visual adverse events.  An 
ophthalmologist should be consulted if changes in vision develop.  
However, if the visual changes are clearly unrelated to study 
treatment (e.g., allergic conjunctivitis), then monitor closely as it may 
be reasonable to defer ophthalmic examination.  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]).   
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 may 
also be indicated as determined by clinical exam. 
Guidelines regarding event management and dose reduction for 
visual changes considered to be related to study treatment are 
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Table 4 
Management and Dose Modification Guidelines for Visual Changes and/or 
Ophthalmic Examination Findings 
CTCAE 
Gradea,c 
Adverse Event 
Management 
Action and Dose Modification 
Grade 1b 
• Consult 
ophthalmologist 
within 7 days of 
onset 
• If dilated fundus examination cannot be performed within 7 days 
of onset, interrupt trametinib until RPED and RVO can be 
excluded by retina specialist/ophthalmologist. 
• If RPED and RVO excluded, continue/or restart trametinib at 
same dose level 
• If RPED suspected or diagnosed: see RPED dose modification 
table below (following this table); report as SAE. 
• If RVO diagnosed:  Permanently discontinue trametinib and 
report as SAE. 
Grade 2 and 
Grade 3 
• Consult 
ophthalmologist 
immediately 
• Hold trametinib 
• If RPED and RVO excluded, restart trametinib at same dose 
level after visual AE is ≤ grade 1.  If no recovery within 4 weeks, 
discontinue trametinib. 
• If RPED diagnosed, see RPED dose modification table below; 
report as SAE. 
• If RVO diagnosed: Permanently discontinue trametinib and 
report as SAE. 
Grade 4 
• Consult 
ophthalmologist 
immediately  
 
• Report as SAE 
• Hold trametinib 
• If RPED and RVO excluded, may restart trametinib at same or 
reduced dose after discussion with the subprotocol Study Chair 
• If RVO or RPED diagnosed, permanently discontinue 
trametinib  
Abbreviations:  RPED = retinal pigment epithelial detachment; CTCAE = Common Terminology Criteria 
for Adverse Events;  
RVO= retinal vein occlusion; SAE = serious adverse event 
a. Refers to CTCAE Version 4.0 ‘Eye disorders – Other, specify’ 
b. If visual changes are clearly unrelated to study treatment (e.g., allergic conjunctivitis), monitor closely 
but ophthalmic examination is not required. 
c. Refers to CTCAE Version 4.0 ‘Retinopathy’ 
Table 5  
Recommended dose modifications for trametinib for retinal pigment epithelial 
detachments (RPED)a 
CTCAE Grade 
Action and Dose Modification 
Grade 1 RPED (Asymptomatic; clinical or 
diagnostic observations only) 
• Continue treatment with retinal evaluation monthly until 
resolution. If RPED worsens follow instructions below  
Grade 2-3 RPED (Symptomatic with 
mild to moderate decrease in visual 
acuity; limiting instrumental ADL) 
• Interrupt trametinib  
• Retinal evaluation monthly  
• If improved to ≤ Grade 1, restart trametinib at lower 
dose (reduced by 0.5 mg) or discontinue in patients 
taking trametinib 1 mg daily 
• If no recovery within 4 weeks, permanently 
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3.4.5 
Pneumonitis Management Guidelines 
Pneumonitis has been observed in subjects receiving trametinib. To 
reduce the risk of pneumonitis, subjects will be monitored closely for 
symptoms, evaluated with imaging and functional tests. Dose 
modification and supportive care guidelines for pneumonitis are 
described (see Table 6). 
Table 6 
Pneumonitis Guidelines for Trametinib  
CTCAE 
Grade 
Adverse Event Management 
Action and Dose Modification 
Grade 1 
• CT scan (high-resolution with lung 
windows) recommended 
• Clinical evaluation and laboratory 
work-up for infection 
• Monitoring of oxygenation via pulse-
oximetry recommended  
• Consultation with pulmonologist 
recommended 
• Continue trametinib at current dose 
Grade 2 
• CT scan (high-resolution with lung 
windows) recommended 
• Clinical evaluation and laboratory 
work-up for infection 
• Consult pulmonologist 
• Pulmonary function tests -if < normal, 
repeat every 8 weeks until ≥ normal 
• Bronchoscopy with biopsy and/or BAL 
recommended 
• Symptomatic therapy including 
corticosteroids if clinically indicated 
• Interrupt trametinib until recovery to 
grade ≤ 1 
• Restart treatment with trametinib reduced 
by one dose level 
• Escalation to previous dose level after 4 
weeks and consultation with the 
subprotocol Study Chair possible 
• If no recovery to grade ≤ 1 within 2 
weeks, permanently discontinue 
trametinib 
Grade 3 
•  Same as Grade 2 
• Interrupt trametinib until recovery to 
grade ≤1 
• After consultation with the subprotocol 
Study Chair, treatment with trametinib  
may be restarted reduced by one dose 
level 
• If no recovery to grade ≤ 1 within 2 
weeks, permanently discontinue 
trametinib 
Grade 4 
• Same as Grade 2 
• Permanently discontinue trametinib 
Abbreviations: BAL= bronchioalveolar lavage; CT = computed tomography; CTCAE = Common 
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3.5 
Dose Modifications for Trametinib and supportive care 
3.5.1 
Trametinib Dose Modification for Liver Chemistry Changes 
Table 7: 
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 time, proceed as 
described below. 
MONITORING: 
Repeat LFT (ALT, AST, ALK, bilirubin) until they return to 
normal/baseline or stabilise (LFT may be every 2 weeks after 4 
weeks if ALT < 3x ULN and TB < 2 ULN). If baseline ALT and Tbili 
already meet these criteria, then monitoring is required only if ALT or 
TB rises after initiation of study therapy. 
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 
bilirubin 1, 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. However, if ALT was 
elevated 3-5x at baseline due 
to liver mets, then this criteria 
should not be used for 
treatment discontinuation 
UNLESS the ALT improves to 
< 3x ULN and then 
subsequently rises. 
5. ALT ≥ 3x ULN and cannot be 
monitored weekly for 4 weeks. 
However, if ALT was elevated 
3-5x at baseline due to liver 
mets, then this criteria should 
not be used for treatment 
discontinuation UNLESS the 
ALT improves to < 3x ULN 
and then subsequently rises. 
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 the subprotocol 
Study Chair.  [ 
• 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). 
• If applicable, provide details on required follow up assessments 
(e.g., follow up for overall survival or disease recurrence or 
progression).  [Do not include for single-dose studies] 
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. 
ASSESSMENT and WORKUP: 
• Viral hepatitis serology.4 
• Serum 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 
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Event 
Treatment modifications and assessment/monitoring 
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). 
• Serum acetaminophen adduct HPLC assay (in subjects with likely 
acetaminophen use in the preceding). 
• If there is underlying chronic hepatitis B (e.g. positive hepatitis B 
surface antigen):  quantitative hepatitis B DNA and hepatitis delta 
antibody.5 
• Liver imaging (ultrasound, MRI, CT) and /or liver biopsy. 
Footnotes: 
1. Serum bilirubin fractionation should be performed if testing is available. If serum 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. 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). 
3.5.2 
Guidelines for Prolonged QTc 
Guidelines for dose modification and stopping criteria due to QTc-
prolongation are provided (see Table 8). 
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Table 8 
Withholding and Stopping Criteria for QTc-Prolongation 
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 all study treatments until QTcB prolongation resolves to grade 1 
or baseline 
• Test serum potassium, calcium, phosphorus and magnesium. If 
abnormal correct per routine clinical practice to within normal limits. 
• Review concomitant medication usage for a prolonged QTc. 
• Restart at current dose levelb 
• If event does not resolve or recurs after restarting, permanently 
discontinue study treatments. 
Abbreviations:  msec = milliseconds; QTcB = QT interval on electrocardiogram corrected using the 
Bazett’s formula 
A: Based on average QTc value of triplicate ECGs.  For example, if an ECG demonstrates a 
prolonged QT interval, obtain two or more ECGs over a brief period, and then use the averaged 
QTc values of the three ECGs to determine if study treatments should be interrupted or 
discontinued. 
B: If the QTc prolongation resolves to grade 1 or baseline, the subject may resume study treatment if 
the investigator and the subprotocol Study Chair agree that the subject will benefit from further 
treatment. 
3.5.3 
Guidelines for Rash 
Rash is a frequent AE observed in subjects receiving trametinib (see 
the Investigator’s Brochures [4]] for more information). 
Recommendations for supportive care and guidelines for dose 
modifications for rash are based on experience with other MEK 
inhibitors and EGFR inhibitors [26, 27] and are provided (see Table 9 
and Table 10. 
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 subprotocol Study Chair 
may be required. 
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Table 9 
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/or 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)  
and/or 
topical antibiotic (e.g., clindamycin) or oral antibiotics (e.g., 
doxycycline 100 mg BID, minocycline 100 mg BID) 
Symptomatic Careb 
• Pruritic lesions: cool compresses and oral antihistamine therapies  
• Fissuring lesions: Monsel’s solution, silver nitrate, or zinc oxide 
cream  
• Desquamation: thick emollients and mild soap  
• Paronychia: antiseptic bath, local potent corticosteroids in addition 
to oral antibiotics; if no improvement, consult dermatologist or 
surgeon  
• Infected lesions: appropriate bacterial/fungal culture-driven 
systemic or topical antibiotics  
Abbreviations:  BID = twice daily; SPF = sun protection factor 
a. Rash prophylaxis is recommended for the first 6 weeks of study treatment  
b. Subjects who develop rash/skin toxicities should be seen by a qualified physician and should 
receive evaluation for symptomatic/supportive care management  
Guidelines for management and dose reduction for rash considered to 
be related to study treatment are provided (see Table 10). 

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Table 10 
Management and Dose Modification Guidelines for Rash  
CTCAE 
Grade 
Adverse Event Management 
Action and Dose Modification 
Grade 1 
• Initiate prophylactic and 
symptomatic treatment 
measuresa 
• Use moderate strength topical 
steroidb  
• Reassess after 2 weeks 
• Continue study treatment 
• If rash does not recover to baseline within 2 
weeks despite best supportive care, reduce 
trametinib by one dose levelc 
Grade 2 
• Initiate prophylactic and 
symptomatic treatment 
measures 
• Use moderate strength topical 
steroidb 
• Reassess after 2 weeks 
• Reduce trametinib by one dose level 
• If rash recovers to ≤ grade 1 within 2 weeks, 
increase dose to previous dose level 
• If no recovery to ≤ grade 1 within 2 weeks, 
interrupt study treatment until recovery to ≤ 
grade 1 
• Restart trametinib at  reduced dose levelc 
Grade ≥ 3 
• Use moderate strength topical 
steroidsb PLUS oral methyl-
prednisolone dose pack 
• Consult dermatologist  
• Interrupt trametinib until rash recovers to grade  
≤ 1 
• Restartc  trametinib reduced by one dose 
leveld  
• If no recovery to grade ≤ 2 within 2 weeks, 
permanently discontinue trametinib 
Abbreviations:  CTCAE = Common Terminology Criteria for Adverse Events 
a. Rash prophylaxis is recommended for the first 6 weeks of study treatment 
b. Moderate-strength topical steroids: hydrocortisone 2.5% cream or fluticasone prioprionate 0.5% 
cream 
c. Approval of subprotocol Study Chair is required to restart study treatment after > 2 weeks of 
interruption. 
d. Escalation of study treatment to previous dose level may be considered if no rash is evident 4 
weeks after restarting study treatment 
3.5.4 
Guidelines for Diarrhea  
Episodes of diarrhea have occurred in subjects receiving trametinib 
(see the Investigator Brochures [4] for more information). Other, 
frequent causes for diarrhea including concomitant medications (e.g., 
stool softeners, laxatives, antacids, etc.), infections by C. difficile or 
other pathogens, partial bowel obstruction, etc., should be clinically 
excluded. 
Guidelines regarding management and dose reduction for diarrhea 
considered to be related to trametinib by the investigator are provided 
(see Table 11). 
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Table 11 
Management and Dose Modification Guidelines for Diarrhea 
CTCAE Grade Adverse Event Management 
Action and Dose Modification 
Uncomplicated 
Diarrheaa 
 
Grade 1 or 2 
• Diet: stop all lactose containing products; eat 
small meals, BRAT-diet (banana, rice, 
apples, toast) recommended 
• Hydration: 8-10 large glasses of clear liquids 
per day (e.g., Gatorade or broth) 
• Loperamidec: initially 4 mg, followed by 2 mg 
every four hours or after every unformed 
stool; maximum 16 mg/day. Continue until 
diarrhea free for 12 hours 
• Diarrhea > 24h: loperamide 2 mg every two 
hours; maximum 16 mg/day.  Consider 
adding oral antibiotics 
• Diarrhea > 48h: loperamide 2 mg every two 
hours; maximum 16 mg/day. Add budesonide 
or other second-line therapies (otreotide, or 
tincture of opium) and oral antibiotics 
• Continue trametinib 
• If diarrhea is grade 2 for > 48h,  
interrupt trametinib until 
diarrhea resolves to grade ≤1 
• Restart trametinib at the same 
dose level 
• If treatment delay is > 14 days, 
discontinue trametinib. 
Uncomplicated 
Diarrheaa 
Grade 3 or 4 
 
Any 
Complicated 
Diarrheab 
• Clinical evaluation mandatory 
• Loperamidec: initially 4 mg, followed by 2 mg 
every four hours or after every unformed 
stool; maximum 16 mg/day. Continue until 
diarrhea free for 12 hours 
• Oral antibiotics and second-line therapies if 
clinically indicated 
• Hydration: intravenous fluids if clinically 
indicated 
• Antibiotics (oral or intravenous) if clinically 
indicated 
• Intervention should be continued until the 
subject is diarrhea free for ≥ 24 hours 
• Intervention may require hospitalization for 
subjects at risk of life-threatening 
complications 
• Interrupt trametinib until 
diarrhea resolves to grade  ≤1 
• Restart with trametinib 
reduced by one dose leveld 
• If 3 dose reductions of study 
treatment are clinically 
indicated, permanently 
discontinue trametinib 
Abbreviation:  CTCAE = Common Terminology Criteria for Adverse Events 
a. Uncomplicated diarrhea defined by the absence of  symptoms such as, cramping, 
nausea/vomiting ≥ grade 2, decreased performance status, pyrexia, sepsis, neutropenia grade ≥ 3, 
frank bleeding, and/or dehydration requiring intravenous fluid substitution 
b. Complicated diarrhea defined by the presence of symptoms such as, cramping, nausea/vomiting  
≥ grade 2, decreased performance status, pyrexia, sepsis, neutropenia grade ≥ 3, frank bleeding, 
and/or dehydration requiring intravenous fluid substitution 
c. Loperamide should be made available prior to start of study treatment so loperamide administration 
can begin at the first signs of diarrhea 
d. Escalation of trametinib to previous dose level is allowed after consultation with the Subprotocol 
Study Chair and in the absence of another episode of complicated or severe diarrhea in the 4 
weeks subsequent to dose reduction. 
3.5.5 
Trametinib Dose Modification for Toxicities Not Specified in 
Subsequent Sections 
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Table 12 
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, 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 (tolerable) 
• Interrupt treatment until resolution to grade 1 or 
baseline.   
• Upon resolution, restart treatment at current dose level. 
Grade 2 
(intolerable) and 
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 
If event resolves to grade 1 or baseline discuss potential 
continuation of trametinib with the subprotocol Study 
Chair; if continuation of treatment agreed then restart 
trametinib at dose reduced by one dose level. 
If event does not resolve, permanently discontinue 
trametinib. 
Trametinib should be discontinued if treatment delay is ≥14 days due to toxicities.  If the investigator 
concludes that continued trametinib will benefit a patient, the subprotocol Study Chair may be consulted 
for the possibility of resuming trametinib, provided that toxicities have resolved to baseline or grade 1. 
3.6 
Supportive Care  
All supportive measures consistent with optimal patient care will be given 
throughout the study. 
3.7 
Duration of Agent-specific treatment  
In the absence of treatment delays due to adverse event(s), treatment may 
continue until one of the following criteria applies: 
• 
Extraordinary Medical Circumstances: If at any time the constraints of this 
protocol are detrimental to the patient's health, protocol treatment should be 
discontinued. In this event submit forms according to the instructions in the 
MATCH Forms Packet. 
• 
Patient withdraws consent. 
• 
Patient experiences unacceptable toxicity. 
• 
Non-protocol therapies are administered.  
• 
Disease Progession 
3.8 
Duration of Follow-Up 
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4. 
Study Parameters 
4.1 
Therapeutic Parameters for Trametinib Treatment  
NOTE: 
In addition to the study parameters listed in the main screening protocol, the below parameters must also be 
performed for patients receiving Trametinib treatment.  
NOTE:  
All assessments required prior to registration to treatment should be done ≤ 4 weeks prior to registration to 
Steps 1, 3, 5, 7, excluding the radiologic evaluation and electrocardiogram (ECG). 
Test/Assessment 
Prior to 
Registration to 
Treatment 
Treatment 
End of 
Treatment 
Follow 
UpF 
Every Cycle, prior to 
treatment 
Every 2 
Cycles 
H&P, Weight, Vital signsA 
X 
 XJ 
 
 
X 
Performance status 
X 
 XJ 
 
 
X 
CBC w/diff, pltsB 
X 
 XJ 
 
 
X 
Serum chemistryB 
X 
 XJ 
 
 
X 
Radiologic evaluationD 
X 
 
 XD 
 
 XF 
-HCGC 
X 
 
 
 
 
Toxicity AssessmentG 
X 
X 
 
X 
 XF 
Pill Count/DiaryH 
 
X 
 
X 
 
ECGK 
X 
 XL 
 
 
 
Echocardiogram or Nuclear StudyL 
 X 
XL 
 
 
 
Eye exam 
 X 
 XI 
 
 
 
Tumor biopsy and blood sample for MATCH Master ProtocolE 
 
 
X 
X 
 
A. History and physical, including vital signs and weight at the start of each cycle (up to 3 days before start of new cycle). 
B. Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, creatinine, glucose, phosphorus, potassium,  SGOT[AST], 
SGPT[ALT], sodium, magnesium, and serum tumor markers (including LDH, PSA if appropriate).  For eligibility purposes, participants with 
creatinine levels above institutional normal, Cockcroft-Gault will be used to calculate creatinine clearance.  CBC w/diff, platelets and serum 
chemistries should be performed on cycle 1, day 1 (or up to 7 days prior), and at the start of each subsequent cycle (up to 3 days before start of 
new cycle).  CBC with differential will be performed more frequently in patients with grade 4 neutropenia or thrombocytopenia until resolution to ≤ 
grade 3. CBC and serum chemistries are only required in follow-up until values return to pre-treatment levels or until progressive disease. 
C. Blood pregnancy test (women of childbearing potential) required prior to beginning treatment. 
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D. Disease measurements are repeated every 2 cycles for the first 26 cycles, and every 3 cycles thereafter until PD or start of another MATCH 
treatment step. The baseline evaluation should be performed as closely as possible to the beginning of treatment and never more than 6 weeks 
before registration to treatment step. For multiple myeloma patients, please refer to Section 6.4 of the MATCH Master Protocol for additional 
information on myeloma response criteria and the required disease assessments. Documentation (radiologic) must be provided for patients 
removed from study for progressive disease. 
E. Additional blood specimens and/or biopsies are to be submitted from consenting patients per Section 9.3.2 of the MATCH Master Protocol. 
Submit at the following time points, as applicable: 
• Blood specimens are to be submitted at the end of Cycle 2 (prior to start of Cycle 3 treatment). If patient progresses or treatment is 
discontinued prior to Cycle 3, collect the blood at that time instead. On-treatment kits for blood sample collections will be automatically 
shipped to sites upon registration to the treatment step. 
• Screening biopsies for additional aMOI assessments after registration to appropriate screening step, if applicable (Step 2 or Step 4). 
• At end of all MATCH study treatments, blood specimens and/or research biopsy after consent and registration to Step 8 
Please refer to Section 4 of the MATCH Master Protocol to determine whether the patient proceeds to the next screening step or to follow-up 
(with a potential end of treatment biopsy for research purposes on Step 8). Samples are to be submitted as outlined in Section 9 of the MATCH 
Master Protocol. To order Step 2/4 Screening or Step 8 kits, complete the EAY131 Collection and Shipping Kit Order Form (See Appendix XII of 
the MATCH Master Protocol) and fax to 713-563-6506. 
F. Every 3 months if patient is < 2 years from study entry, and every 6 months for year 3. Toxicity assessments and radiologic evaluations are not 
required to be done during Follow Up if progression has been previously reported; however if an adverse event occurs post treatment that meets 
the SAE reporting requirements, it still must be reported via CTEP-AERS, even if progression has occurred. 
G. Site personnel should evaluate for toxicity and discuss treatment compliance with the patient in order to ensure the medication is taken correctly; 
this evaluation may be conducted by telephone or in person. The Toxicity Assessment is not required prior to Cycle 1, but is required every 
subsequent cycle. 
H. The pill calendar will be collected at the end of every cycle. The Pill Count/Diary is not required prior to Cycle 1, but is required every subsequent 
cycle. 
I. 
As clinically indicated. 
J. For Cycle 1, if the following tests/assessments occurred within 7 days of Day 1, they do not need to be repeated at this timepoint: H&P, Weight, 
Vital signs; Performance Status; CBC w/diff, plts; Serum chemistry; Concomitant Medications.   
K. Within 8 weeks of treatment assignment.  
L. Cardiac monitoring with ECG and either ECHO or Nuclear Study (MUGA or First Pass) is needed at week 5, week 13, and every 12 weeks 
thereafter unless clinically indicated sooner. The same modality should be used at baseline and thereafter. 
 
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5. 
Drug Formulation and Procurement 
This information has been prepared by the ECOG-ACRIN Pharmacy and Nursing 
Committees. 
Availability 
NO STARTER SUPPLIES MAY BE ORDERED. Subjects must be enrolled and assigned 
to the treatment subprotocol prior to submitting the clinical drug request to PMB. 
Drug Ordering: NCI supplied agents may be requested by eligible participating 
Investigators (or their authorized designee) at each participating institution.  
Pharmaceutical Management Branch (PMB) policy requires that drug 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 – see general 
information) The CTEP-assigned protocol number must be used for ordering all CTEP-
supplied investigational agents.  The eligible participating investigators at each 
participating institution must be registered with CTEP, DCTD through an annual 
submission of FDA Form 1572 (Statement of Investigator), NCI Biosketch, Agent 
Shipment Form, 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. 
Submit agent requests through the PMB Online Agent Order Processing (OAOP) 
application (https://ctepcore.nci.nih.gov/OAOP).  Access to OAOP requires the 
establishment of a CTEP Identity and Access Management (IAM) account 
(https://ctepcore.nci.nih.gov/iam/) and the maintenance of an “active” account status, a 
“current” password, and an active person registration status. 
NCI Supplied Agent(s) – General Information 
Questions about drug orders, transfers, returns, or accountability should be 
addressed to the PMB by calling 240-276-6575 Monday through Friday between 
8:30 AM and 4:30 PM Eastern Time or email PMBAfterHours@mail.nih.gov 
anytime. 
Drug Returns: All undispensed drug supplies should be returned to the PMB. When it is 
necessary to return study drug (e.g., sealed bottles remaining when PMB sends a stock 
recovery letter), investigators should return the study drug to the PMB using the NCI 
Return Agent Form available on the NCI home page (http://ctep.cancer.gov).  
Drug Accountability: The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the receipt, disposition, and return of 
agent received from the PMB using the NCI Investigational Agent Accountability Record 
Form for Oral Agents available on the NCI home page (http://ctep.cancer.gov). Maintain 
separate NCI Investigational Agent Accountability Records for each agent, strength, 
formulation and ordering investigator. 
Investigator Brochure Availability: The current versions of the IBs for PMB-supplied 
agents will be accessible to site investigators and research staff through the PMB Online 
Agent Order Processing (OAOP) application. Access to OAOP requires the 
establishment of a CTEP Identity and Access Management (IAM) account and the 
maintenance of an “active” account status, a “current” password, and active person 
registration status.  Questions about IB access may be directed to the PMB IB 
coordinator at IBCoordinator@mail.nih.gov. 
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5.1 
Trametinib dimethyl sulfoxide (NSC 763093) 
5.1.1 
Other Names  
Trametinib, GSK1120212B, TMT212-NXA, JTP-74057, JTP-78296, 
JTP-75303, Mekinist® 
5.1.2 
Classification  
MEK inhibitor 
5.1.3 
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. 
5.1.4 
Storage and Stability  
Storage: Store tablets at 2°C -8°C (36° F to 46° F) in the original 
bottle and dispense unopened bottles. Do not open bottles or 
repackage tablets or remove desiccant. 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: Stability studies are ongoing. Tablets are only stable for 32 
days once bottle has been opened. If multiple bottles are dispensed to 
a patient in the same visit, please advise the patient to open only one 
bottle at a time. 
Storage: Refer to the package label for expiration. 
5.1.5 
Dose Specifics  
Trametinib will be given continuous dosing 2mg daily. 
5.1.6 
Preparation  
Novartis supplies and CTEP, NCI, DCTD distributes trametinib as 0.5 
mg and 2 mg (as free base) tablets. Each investigationally-labeled 
bottle contains 32 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. 
Aqueous film coating consists of hypromellose, titanium dioxide, 
polyethylene glycol, iron oxide yellow. 
• 
2 mg tablets are pink, round, biconvex and film-coated. Aqueous 
film coating consists of hypromellose, titanium dioxide, 
polyethylene glycol, polysorbate 80, iron oxide red. 
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5.1.7 
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. 
5.1.8 
Incompatibilities  
In vitro studies suggest that trametinib 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). 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 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 CYP 2B6 and 3A4 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 
MRP2 or BSEP, but an in vitro inhibitor of P-gp, BCRP, OATP1B1, 
OATP1B3, OAT1, OAT3, OCT2 and MATE1 at systemic 
concentrations that are not clinically relevant. No clinically relevant 
inhibition by trametinib is predicted in the liver or kidney and a low risk 
of intestinal drug-drug interaction is possible with BCRP.  
Trametinib is highly bound to plasma proteins (97.3%) and has the 
potential to interfere with other highly protein-bound drugs. Use 
caution in patients taking concomitant drugs that are highly protein-
bound and have narrow therapeutic ranges. 
5.1.9 
Side Effects  
See Section 3.3 for side effects. 
5.1.10 
Nursing/Patient 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. Advise women not to 
breastfeed while receiving study treatment and for 4 months after the 
last dose of trametinib. Advise men study participants to use barrier 
contraception and not to father a child while taking study treatment 
and for 4 months after the last dose of trametinib. 
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6. 
Translational Studies 
Please refer to the MATCH Master Protocol for information on the Translational Studies.  
7. 
References 
Ambrosini, G., Musi, E., Ho, A. L., De Stanchina, E., and Schwartz, G. K. (2013). 
Inhibition of mutant GNAQ signaling in uveal melanoma induces AMPK-dependent 
autophagic cell death. Molecular cancer therapeutics 12, 768-76. 
Ambrosini, G., Pratilas, C. A., Qin, L. X., Tadi, M., Surriga, O., Carvajal, R. D., and 
Schwartz, G. K. (2012). Identification of unique MEK-dependent genes in GNAQ mutant 
uveal melanoma involved in cell growth, tumor cell invasion, and MEK-resistance. Clin 
Cancer Res 18 1-10. 
Ars E, Kruyer H, Morell M, et al. Recurrent mutations in the NF1 gene are common 
among neurofibromatosis type 1 patients. J Med Genet 2003;40:e82. 
Balagula, Y., K. Barth Huston, K.J. Busam, et al.  (2010).  Dermatologic side effects 
associated with the MEK 1/2 inhibitor selumetinib (AZD6244, ARRY-142886).  Invest 
New Drugs.  29:1114-1121. 
Bekaii-Saab, T., M.A. Phelps, X. Li, et al.  (2011).  Multi-institutional phase II study of 
selumetinib in patients with metastatic biliary cancers.  J Clin Oncol.  29:2357-2363. 
Bendell, J., P. LoRusso, E. Kwak, et al.  (2011).  Clinical combination of the MEK 
inhibitor GDC-0973 and the PI3K inhibitor GDC-0941: A first-in-human phase Ib study in 
patients with advanced solid tumors.  AACR Meeting Abstracts.  Abstract LB-89. 
Blumenschein, G.R., E.F. Smit, D. Planchard, et al.  (2013).  MEK114653:  A 
randomized, multicenter, phase II study to assess efficacy and safety of trametinib (T) 
compared with docetaxel (D) in KRAS-mutant advanced non-small cell lung cancer 
(NSCLC).  J Clin Oncol.  31:Abstract 8029. 
Borthakur, G., J.M. Foran, T. Kadia, et al.  (2010).  GSK1120212, a MEK1/MEK2 
inhibitor, demonstrates acceptable tolerability and preliminary activity in a dose rising 
trial In subjects with AML and other hematologic malignancies.  Blood (ASH Annual 
Meeting Abstracts).  116:Abstract 3281. 
Brems H, Beert E, de Ravel T, Legius E. Mechanisms in the pathogenesis of malignant 
tumours in neurofibromatosis type 1. Lancet Oncol 2009;10:508-15. 
Cancer Genome Atlas Research Network. Comprehensive genomic characterization 
defines human glioblastoma genes and core pathways. Nature. 2008;455:1061-8. 
Carvajal, R. D., Sosman, J. A., Quevedo, F., Milhem, M. M., Joshua, A. M., Kudchadkar, 
R. R., Linette, G. P., Gajewski, T., Lutzky, J., Lawson, D. H., et al. (2013). Phase II study 
of selumetinib (sel) versus temozolomide (TMZ) in gnaq/Gna11 (Gq/11) mutant (mut) 
uveal melanoma (UM). J Clin Oncol 31, 2013 (suppl; abstr CRA9003). 
Chang T, Krisman K, Theobald EH, et al. Sustained MEK inhibition abrogates 
myeloproliferative disease in Nf1 mutant mice. J Clin Invest 2013;123:335-9. 
Cooper D, Upadhyaya M. The Germline Mutational Spectrum in Neurofibromatosis Type 
1 and Genotype–Phenotype Correlations. In: Upadhyaya M, Cooper DN, eds. 
Neurofibromatosis Type 1: Springer Berlin Heidelberg; 2012:115-34. 

ECOG-ACRIN 
EAY131-S2 
Cancer Research Group 
Version Date: August 19, 2020 
43 
Denayer E, de Ravel T, Legius E. Clinical and molecular aspects of RAS related 
disorders. J Med Genet 2008;45:695-703. 
De Raedt T, Brems H, Wolkenstein P, et al. Elevated risk for MPNST in NF1 
microdeletion patients. Am J Hum Genet 2003;72:1288-92. 
Dilworth JT, Kraniak JM, Wojtkowiak JW, et al. Molecular targets for emerging anti-tumor 
therapies for neurofibromatosis type 1. Biochem Pharmacol 2006;72:1485-92. 
Ebi, H., R.B. Corcoran, A. Singh, et al.  (2011).  Receptor tyrosine kinases exert 
dominant control over PI3K signaling in human KRAS mutant colorectal cancers.  J Clin 
Invest.  121:4311-4321. 
Engelman, J.A., L. Chen, X. Tan, et al.  (2008).  Effective use of PI3K and MEK 
inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers.  Nat 
Med.  14:1351-1356. 
Flaherty, K.T., C. Robert, P. Hersey, et al.  (2012).  Improved survival with MEK 
inhibition in BRAF-mutated melanoma.  N Engl J Med.  367:107-114. 
Frampton GM, Fichtenholtz A, Otto GA, et al. Development and validation of a clinical 
cancer genomic profiling test based on massively parallel DNA sequencing. Nat 
Biotechnol 2013;31:1023-31. 
Gilmartin, A.G., M.R. Bleam, A. Groy, et al.  (2011).  GSK1120212 (JTP-74057) is an 
inhibitor of MEK activity and activation with favorable pharmacokinetic properties for 
sustained in vivo pathway inhibition.  Clin Cancer Res.  17:989-1000. 
Gopal, Y.N., W. Deng, S.E. Woodman, et al.  (2010).  Basal and treatment-induced 
activation of AKT mediates resistance to cell death by AZD6244 (ARRY-142886) in Braf-
mutant human cutaneous melanoma cells.  Cancer Res.  70:8736-8747. 
Gottfried ON, Viskochil DH, Fults DW, Couldwell WT. Molecular, genetic, and cellular 
pathogenesis of neurofibromas and surgical implications. Neurosurgery 2006;58:1-16; 
discussion 1-. 
Griner, E. M., and Kazanietz, M. G. (2007). Protein kinase C and other diacylglycerol 
effectors in cancer. Nat Rev Cancer 7, 281-94. 
Gursel DB, Connell-Albert YS, Tuskan RG, Anastassiadis T, Walrath JC, Hawes JJ, et 
al. Control of proliferation in astrocytoma cells by the receptor tyrosine kinase/PI3K/AKT 
signaling axis and the use of PI-103 and TCN as potential anti-astrocytoma therapies. 
Neuro Oncol. 2011;13:610-21. 
Gutzmer R, Herbst RA, Mommert S, et al. Allelic loss at the neurofibromatosis type 1 
(NF1) gene locus is frequent in desmoplastic neurotropic melanoma. Human genetics 
2000;107:357-61. 
Hodis E, Watson IR, Kryukov GV, et al. A landscape of driver mutations in melanoma. 
Cell 2012;150:251-63. 
Hoeflich, K.P., C. O'Brien C, Z. Boyd, et al.  (2009).  In vivo antitumor activity of MEK 
and phosphatidylinositol 3-kinase inhibitors in basal-like breast cancer models.  Clin 
Cancer Res.  15:4649-4664. 
Holt, S. V., Logie, A., Odedra, R., Heier, A., Heaton, S. P., Alferez, D., Davies, B. R., 
Wilkinson, R. W., and Smith, P. D. (2012). The MEK1/2 inhibitor, selumetinib (AZD6244; 
ARRY-142886), enhances anti-tumour efficacy when combined with conventional 
chemotherapeutic agents in human tumour xenograft models. Br J Cancer 106, 858-66. 

ECOG-ACRIN 
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Version Date: August 19, 2020 
44 
Hubbard, K. B., and Hepler, J. R. (2006). Cell signalling diversity of the Gqalpha family 
of heterotrimeric G proteins. Cell Signal 18, 135-50. 
Infante, J.R., B.G. Somer, J.O. Park, et al.  (2013).  A randomized, double-blind, 
placebo-controlled trial of trametinib, a MEK inhibitor, in combination with gemcitabine 
for patients with untreated metastatic adenocarcinoma of the pancreas.  J Clin Oncol.  
30:Abstract 291. 
Infante J.R., Fecher L.A., Falchook G.S., Nallapareddy S., et al.  Safety, 
pharmacokinetic,, pharmacodynamics, and efficacy data for the oral MEK inhibitor 
trametinib; a phase I dose-escalation trial.  Lancet Oncol 2012; 13(8): 773-81 
Investigator's Brochure.  (2012a).  GSK1120212.  GlaxoSmithKline.  Version 04.  
September 5, 2012. 
Investigator’s Brochure.  (2013).  GSK1120212 (trametinib).  GlaxoSmithKline.  Version 
05.  September 25, 2013. 
Ismat FA, Xu J, Lu MM, Epstein JA. The neurofibromin GAP-related domain rescues 
endothelial but not neural crest development in Nf1 mice. J Clin Invest 2006;116:2378-
84. 
Ivey, K., Tyson, B., Ukidwe, P., Mcfadden, D. G., Levi, G., Olson, E. N., Srivastava, D., 
and Wilkie, T. M. (2003). Galphaq and Galpha11 proteins mediate endothelin-1 signaling 
in neural crest-derived pharyngeal arch mesenchyme. Dev Biol 255, 230-7. 
Jessen WJ, Miller SJ, Jousma E, et al. MEK inhibition exhibits efficacy in human and 
mouse neurofibromatosis tumors. J Clin Invest 2013;123:340-7. 
Jett K, Friedman JM. Clinical and genetic aspects of neurofibromatosis 1. Genetics in 
medicine : official journal of the American College of Medical Genetics 2010;12:1-11. 
Kalinec, G., Nazarali, A. J., Hermouet, S., Xu, N., and Gutkind, J. S. (1992). Mutated 
alpha subunit of the Gq protein induces malignant transformation in NIH 3T3 cells. Mol 
Cell Biol 12, 4687-93. 
Kirkwood, J.M., L. Bastholt, C. Robert, et al.  (2012).  Phase II, open-label, randomized 
trial of the MEK1/2 inhibitor selumetinib as monotherapy versus temozolomide in 
patients with advanced melanoma.  Clin Cancer Res.  18:555-567. 
Kwon CH, Zhao D, Chen J, Alcantara S, Li Y, Burns DK, et al. Pten haploinsufficiency 
accelerates formation of high-grade astrocytomas. Cancer Res. 2008;68:3286-94. 
Lacouture, M.E., M.J. Anadkat, R.J. Bensadoun, et al.  (2011).  Clinical practice 
guidelines for the prevention and treatment of EGFR inhibitor-associated dermatologic 
toxicities.  Support Care Cancer.  19:1079-1095. 
Le Gal, F., E. Gordien, D. Affolabi, et al.  2005.  Quantification of hepatitis delta virus 
RNA in serum by consensus real-time PCR indicates different patterns of virological 
response to interferon therapy in chronically infected patients.  J Clin Microbiol.  
43:2363-2369. 
Luke JL, Ott PA, Shapiro GI. (2014) The biology and clinical development of MEK 
inhibitors for cancer. Drugs. 74(18):2111-28. 
MEKINIST [Package insert].  (2013).  GlaxoSmithKline.  May 2013. 
Maertens O, Johnson B, Hollstein P, et al. Elucidating distinct roles for NF1 in 
melanomagenesis. Cancer Discov 2013;3:338-49. 

ECOG-ACRIN 
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Version Date: August 19, 2020 
45 
Messersmith, W.A., G.S. Falchook, L.A. Fecher, et al.  (2011).  Clinical activity of the 
oral MEK1/MEK2 inhibitor GSK1120212 in pancreatic and colorectal cancer.  J Clin 
Oncol.  29:Abstract 246. 
O'hayre, M., Vazquez-Prado, J., Kufareva, I., Stawiski, E. W., Handel, T. M., Seshagiri, 
S., and Gutkind, J. S. (2013). The emerging mutational landscape of G proteins and G-
protein-coupled receptors in cancer. Nat Rev Cancer 13, 412-24. 
Onken, M. D., Worley, L. A., Ehlers, J. P., and Harbour, J. W. (2004). Gene expression 
profiling in uveal melanoma reveals two molecular classes and predicts metastatic 
death. Cancer research 64, 7205-9. 
Onken, M. D., Worley, L. A., Long, M. D., Duan, S., Council, M. L., Bowcock, A. M., and 
Harbour, J. W. (2008). Oncogenic mutations in GNAQ occur early in uveal melanoma. 
Invest Ophthalmol Vis Sci 49, 5230-4. 
Parsons D, Jones S, Zhang X, Lin J, Leary R, Angenendt P, et al. An integrated genomic 
analysis of human glioblastoma multiforme. Science. 2008;321:1807-12. 
Patil S, Chamberlain RS. Neoplasms associated with germline and somatic NF1 gene 
mutations. Oncologist 2012;17:101-16. 
Reilly KM, Loisel DA, Bronson RT, McLaughlin ME, Jacks T. Nf1;Trp53 mutant mice 
develop glioblastoma with evidence of strain-specific effects. Nat Genet. 2000;26:109-
13. 
Robert, C., Dummer, R., Gutzmer, R., Lorigan, P., Kim, K. B., Nyakas, M., Arance, A., 
Liszkay, G., Schadendorf, D., Cantarini, M., et al. (2013). Selumetinib plus dacarbazine 
versus placebo plus dacarbazine as first-line treatment for BRAF-mutant metastatic 
melanoma: a phase 2 double-blind randomised study. Lancet Oncol 14, 733-40. 
Robertson KA, Nalepa G, Yang FC, et al. Imatinib mesylate for plexiform neurofibromas 
in patients with neurofibromatosis type 1: a phase 2 trial. Lancet Oncol 2012;13:1218-24. 
Rosenbaum T, Wimmer K. Neurofibromatosis type 1 (NF1) and Associated Tumors. 
Klinische Padiatrie 2014. 
See WL, Tan IL, Mukherjee J, Nicolaides T, Pieper RO. Sensitivity of glioblastomas to 
clinically available MEK inhibitors is defined by neurofibromin 1 deficiency. Cancer Res. 
2012;72:3350-9. 
Thomas L, Mautner VF, Cooper DN, Upadhyaya M. Molecular heterogeneity in 
malignant peripheral nerve sheath tumors associated with neurofibromatosis type 1. 
Human genomics 2012;6:18. 
Tolcher, A.W., J.C. Bendell, A. Patnaik, et al.  (2011).  A phase Ib study of the MEK 
inhibitor GSK1120212 combined with gemcitabine in patients with solid tumors: Interim 
results.  J Clin Oncol.  29:Abstract 278. 
U.S. Food and Drug Administration.  (2013).  FDA approves two drugs, companion 
diagnostic test for advanced skin cancer [Press release].  Retrieved from 
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm354199.htm. 
U.S. Food and Drug Administration.  (2014).  FDA approves Mekinist in combination with 
Tafinlar for advanced melanoma [Press release].  Retrieved from 
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm381159.htm. 

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Van Raamsdonk, C. D., Bezrookove, V., Green, G., Bauer, J., Gaugler, L., O'brien, J. 
M., Simpson, E. M., Barsh, G. S., and Bastian, B. C. (2009). Frequent somatic mutations 
of GNAQ in uveal melanoma and blue naevi. Nature 457, 599-602. 
Van Raamsdonk, C. D., Griewank, K. G., Crosby, M. B., Garrido, M. C., Vemula, S., 
Wiesner, T., Obenauf, A. C., Wackernagel, W., Green, G., Bouvier, N., et al. (2010). 
Mutations in GNA11 in uveal melanoma. N Engl J Med 363, 2191-9. 
Weber, J.S., K.T. Flaherty, J.R. Infante, et al.  (2012).  Updated safety and efficacy 
results from a phase I/II study of the oral BRAF inhibitor dabrafenib (GSK2118436) 
combined with the oral MEK 1/2 inhibitor trametinib (GSK1120212) in patients with 
BRAFi-naïve metastatic melanoma.  J Clin Oncol.  30:Abstract 8510. 
Whittaker SR, Theurillat JP, Van Allen E, et al. A genome-scale RNA interference screen 
implicates NF1 loss in resistance to RAF inhibition. Cancer Discov 2013;3:350-62. 
Widemann B, Marcus L, Fisher M, et al. Phase I study of the MEK1/2 inhibitor 
selumetinib (AZD6244) hydrogen sulfate in children and young adults with 
neurofibromatosis type 1 (NF1) and inoperable plexiform neurofibromas (PNs). J Clin 
Oncol 32:5s, 2014 (suppl; abstr 10018). 
Wu, X., Li, J., Zhu, M., Fletcher, J. A., and Hodi, F. S. (2012a). Protein kinase C inhibitor 
AEB071 targets ocular melanoma harboring GNAQ mutations via effects on the 
PKC/Erk1/2 and PKC/NF-kappaB pathways. Molecular cancer therapeutics 11, 1905-14. 
Wu, X., Zhou, J., Rogers, A. M., Janne, P. A., Benedettini, E., Loda, M., and Hodi, F. S. 
(2012b). c-Met, epidermal growth factor receptor, and insulin-like growth factor-1 
receptor are important for growth in uveal melanoma and independently contribute to 
migration and metastatic potential. Melanoma Res. 
Wu, X., Zhu, M., Fletcher, J. A., Giobbie-Hurder, A., and Hodi, F. S. (2012c). The protein 
kinase C inhibitor enzastaurin exhibits antitumor activity against uveal melanoma. PloS 
one 7, e29622. 
Yamaguchi, T., R. Kakefuda, N. Tajima, et al.  (2011).  Antitumor activities of JTP-74057 
(GSK1120212), a novel MEK1/2 inhibitor, on colorectal cancer cell lines in vitro and in 
vivo.  Int J Oncol.  39:23-31. 
Yan N, Ricca C, Fletcher J, Glover T, Seizinger BR, Manne V. Farnesyltransferase 
inhibitors block the neurofibromatosis type I (NF1) malignant phenotype. Cancer Res 
1995;55:3569-75. 
Yang FC, Ingram DA, Chen S, et al. Nf1-dependent tumors require a microenvironment 
containing Nf1+/-- and c-kit-dependent bone marrow. Cell 2008;135:437-48. 
Zhu Y, Ghosh P, Charnay P, Burns DK, Parada LF. Neurofibromas in NF1: Schwann cell 
origin and role of tumor environment. Science 2002;296:920-2. 
Zhu Y, Guignard F, Zhao D, Liu L, Burns D, Mason R, et al. Early inactivation of p53 
tumor suppressor gene cooperating with NF1 loss induces malignant astrocytoma. 
Cancer Cell. 2005;8:119-30. 
Zingone, A., N. Korde, J. Chen, et al.  (2011).  Molecular characterization and clinical 
correlations of MEK1/2 inhibition (AZD6244) in relapse or refractory multiple myeloma:  
analysis from a phase II study.  Blood (ASH Annual Meeting Abstracts).  118:Abstract 
306. 

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Molecular Analysis for Therapy Choice (MATCH) 
MATCH Treatment Subprotocol S2: Trametinib/GNAQ/GNA11 
Appendix I  
 
Patient Pill Calendar 
Pill Calendar Directions 
1. Take your scheduled dose of each tablet at around the same time each day. 
2. Please bring the empty bottle or any leftover tablets and your pill calendar to your 
next clinic visit. 
3. Take trametinib (GSK1120212) once daily by mouth either 1 hour before or 2 hours 
after a meal.  
4. If a dose of trametinib is missed, only make up this missed dose if it is still more than 
12 hours until the next scheduled dose. 
5. Trametinib should be stored at 2-8°C (36-46°F). Refrigerate. Do not freeze. 
6. Trametinib should not be crushed, dissolved, or chewed.  
7. Do not take an additional dose as a replacement if vomiting were to occur after a 
dose of trametinib. 
 
 
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Patient Pill Calendar 
This is a calendar on which you are to record the time and number of tablets you take 
each day.  You should take your scheduled dose of each tablet. Note the times and the 
number of tablets that you take each day. If you develop any side effects, please 
record them and anything you would like to tell the doctor in the space provided.  Bring 
any unused tablets and your completed pill calendar to your doctor’s visits. 
Trametinib 
DAY  
Date 
Time 
tablets 
taken 
Number of 
tablets 
taken 
Use the space below to make notes about things you 
would like to tell the doctor (including unusual 
symptoms you experience, other medicine you have 
taken and anything else you think would be of interest.) 
Month 
Day 
Year 
 
 
1 
 
 
 
 
 
 
2 
 
 
 
 
 
 
3 
 
 
 
 
 
 
4 
 
 
 
 
 
 
5 
 
 
 
 
 
 
6 
 
 
 
 
 
 
7 
 
 
 
 
 
 
8 
 
 
 
 
 
 
9 
 
 
 
 
 
 
10 
 
 
 
 
 
 
11 
 
 
 
 
 
 
12 
 
 
 
 
 
 
13 
 
 
 
 
 
 
14 
 
 
 
 
 
 
15 
 
 
 
 
 
 
16 
 
 
 
 
 
 
17 
 
 
 
 
 
 
18 
 
 
 
 
 
 
19 
 
 
 
 
 
 
20 
 
 
 
 
 
 
21 
 
 
 
 
 
 
22 
 
 
 
 
 
 
23 
 
 
 
 
 
 
24 
 
 
 
 
 
 
25 
 
 
 
 
 
 
26 
 
 
 
 
 
 
27 
 
 
 
 
 
 
28 
 
 
 
 
 
 
Patient Signature: __________________________________ Date: _____________ 
 

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Molecular Analysis for Therapy Choice (MATCH) 
MATCH Treatment Subprotocol S2: Trametinib/GNAQ/GNA11  
Appendix II  
Trametinib Ophthalmic Exam Form 
Please use the form on the following page for documenting ophthalmic examinations as 
appropriate to the clinical situation. 
Subject Name: ________________________________________________ 
Note to examiner: 
Please assess particularly for visible retinal pathology. 
*Optical coherence tomography is highly recommended For patients in whom retinal 
abnormalities are noted, color fundus photos, and fluorescein angiography if clinically 
indicated, are recommended.   
OPHTHALMIC EXAMINATION 
1. Date of Examination: 
_ _/_ _ _ /_ _ _ _ 
dd  /   mmm   /    yyyy 
VISUAL ACUITY 
Enter corrected visual acuity 
OD: 
OS: 
TONOMETRY 
Enter IOP (mmHg) 
OD: 
OS: 
INDIRECT FUNDOSCOPY 
Indirect Exam: Indicate normal or specify 
abnormalities
OD: 
OS: 
CONFRONTATION VISUAL FIELD EXAM  OR AUTOMATED PERIMETRY (e.g., Humphrey 24-2 
or 30-2 or equivalent if using a non-Humphrey instrument) 
Indicate normal or specify any abnormalities 
OD: 
OS: 
OPTICAL COHERENCE TOMOGRAPHY (strongly recommended) 
Indicate normal or specify any abnormalities 
OD: 
OS: 
COLOR FUNDUS PHOTOS (recommended if retinal abnormalities are noted)* 
Indicate normal or specify any abnormalities 
OD: 
OS: 
FLORESCEIN ANGIOGRAPHY (suggested if retinal abnormalities are noted and test clinically 
indicated)* 
Indicate normal or specify any abnormalities 
OD: 
OS: 
Were any of the following noted on ocular history or exam? 
Yes 
No 
• 
History of CSR? 
• 
Evidence of new optic disc cupping? 
 
 
• 
Evidence of new visual field defects? 
 
 
EXCLUSION CRITERIA 
Yes 
No 
• 
History of RVO? 
o 
If yes, patient is not eligible for the study.
 
 
Signature of Examiner: _______________________________________ 

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Printed Name: _________________________      Date: ______________ 

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Molecular Analysis for Therapy Choice (MATCH) 
MATCH Treatment Subprotocol S2: Trametinib/GNAQ/GNA11 
Appendix III 
 
Actionable Mutations for Sub-Protocol EAY131-S2 
 
Gene Name 
Variant ID 
Variant Type 
Level of Evidence 
Code 
Variant 
Description 
GNA11 
COSM52969 
SNV 
2 
p.Q209L 
GNA11 
COSM52970 
SNV 
2 
p.Q209P 
GNAQ 
COSM28757 
SNV 
2 
p.Q209L 
GNAQ 
COSM28758 
SNV 
2 
p.Q209P 
GNAQ 
COSM28760 
SNV 
2 
p.Q209R 
GNAQ 
COSM52975 
SNV 
3 
p.R183Q 
Other novel GNAQ or GNA11 activating mutations not listed in the above table but identified by 
one of the designated outside laboratories as described in the MATCH Master Protocol will also 
be considered actionable mutations (aMOIs) at Level of Evidence Code 3.  Please refer to 
Section 1.4.2 of the MATCH Master Protocol for more information. 
 
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Molecular Analysis for Therapy Choice (MATCH) 
MATCH Treatment Subprotocol S2: Trametinib/GNAQ/GNA11 
Appendix IV: 
 
Patient Clinical Trial Wallet Card 
 
 
CLINICAL TRIAL WALLET CARD 
Show this card to all of your 
healthcare providers and keep 
it with you in case you go to 
the emergency room. 
Patient Name:        
Diagnosis:        
Study Doctor:       
Study Doctor Phone #:       
NCI Trial #:        
Study Drug(S):        
 
 
 
 
For more information: 1-800-4-CANCER 
cancer.gov | clinicaltrials.gov