MATCH Treatment Subprotocol R: Phase II Study of Trametinib in Patients With BRAF Fusions, or With NonV600E, Non-V600K BRAF 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 
 
 
 
March 11, 2019 
 
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 #19 to EAY131-R, Phase II Study of Trametinib in Patients with BRAF 
Fusions, or with Non-V600E, Non-V600K BRAF Mutations. 
 
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permitted to conduct the study utilizing outdated versions of any MATCH protocol documents 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. 
This addendum is in response to Dr. Helen Chen February 22, 2019 Request for Rapid 
Amendment for Trametinib dimethyl sulfoxide.   
The following revisions to EAY131-R protocol have been made in this addendum: 
 
Section 
Change 
1. 
Cover Page 
Updated Version Date. 
2. 
Cover Page  
In second note, removed second sentence, ”Please reference activation 
memo for the addendum activation date.” 
3. 
3.3 
Updated the Trametinib CAEPR list with version 2.5, February 1, 2019. 
The following revisions to EAY131-R 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 the possible risks language and the Trametinib risk list with 
version 2.5 February 1, 2019. 

ii 
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-R so ECOG-ACRIN may activate 
it promptly.   
Thank you.  
Sincerely, 
Pamela Cogliano 
Senior Director, Protocol Development 
Enclosure 
CC: Douglas B. Johnson, MD  
Marcus S.Noel.MD  
Gregory J. Riely, M.D.  Ph.D  
Alice Chen, MD 
Keith Thomas Flaherty, MD 
Lyndsay N. Harris. MD 
Peter O’Dwyer, MD 
Mickey Williams, PhD 
James V. Tricoli, PhD 
Stanley Hamilton, MD 
Lisa McShane, PhD  
Larry Rubinstein, PhD 
Robert Gray, PhD 
Shuli Li, PhD 
Lalitha Shankar, MD 
Susanna Lee, MD, PhD 
Constantine Gastonis, PhD 
Paolo Caimi, MD 
Shaji Kumar, MD 
Carlos Arteaga, MD 
Edith Mitchell, MD 
John J. Wright, MD, PhD 
Bruce Giantonio, MD 
Donna Marinucci 
Kerry Higgins 
Gayle Ipock 
Jean MacDonald 
Carol Chami, R.N. 
Juanita Andrews 
Melinda Flood 
Julianne Human 
Kelly Redmond 
Becky Fillingham 
Jeffrey Zhang 
Amy Li 
Kevin Pollard 
Abuchi Agu 
Michael T. Balco 
Lauren Lambert 
Cayden Maican 
Margaret Cavenagh 
Ben Kim 
Alexandra Sachs 
Russell McDaniel  
 
 

EAY131-R 
1 
Molecular Analysis for Therapy 
Choice (MATCH) 
MATCH Treatment Subprotocol R: Phase II Study of 
Trametinib in Patients with BRAF Fusions, or with Non-
V600E, Non-V600K BRAF Mutations 
TRAMETINIB TREATMENT SUBPROTOCOL CHAIR: 
Douglas B. Johnson, MD, MSCI 
TRAMETINIB TREATMENT SUBPROTOCOL CO-CHAIR: 
Marcus Noel, MD 
TRAMETINIB TRANSLATIONAL CHAIR: 
Gregory Riely, MD, PhD 
Version Date:  March 11, 2019 
NCI Update Date: August 12, 2015 
NOTE: 
This subprotocol (EAY131-R) 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. 
ACTIVATION DATE 
August 12, 2015 
PRE-ACTIVATION DATE 
May 29, 2015 
Update #1 – Incorporated Prior to Activation 
Addendum #1 – 8/15 
Update #2 – 8/15 
Addendum #2 – 2/16 
Addendum #3 – 5/16 
Addendum #5 – 12/16 
Addendum #6 – 1/17 
Addendum #7 – 3/17 
Addendum #13 
Addendum #19 
Agent 
IND# 
NSC# 
Supply 
Trametinib 
NCI Supplied 
Rev. Add13 
Rev. Add19 

ECOG-ACRIN 
EAY131-R 
Cancer Research Group 
Version Date: March 11, 2019 
 
NCI Update Date: August 12, 2015 
2 
Table of Contents 
Molecular Analysis for Therapy Choice (MATCH) ...................................................... i 
MATCH Treatment Subprotocol R: Phase II Study of Trametinib in Patients with 
BRAF Fusions, or with Non-V600E, Non-V600K BRAF Mutations ....................... 1 
Table of Contents ...................................................................................................... 2 
Schema ...................................................................................................................... 4 
1. Introduction ........................................................................................................ 5 
1.1 Trametinib ................................................................................................. 5 
1.2 Supporting Preliminary Data ..................................................................... 7 
2. Selection of Patients ........................................................................................... 9 
2.1 Eligibility Criteria ....................................................................................... 9 
3 
Trametinib Treatment Plan ............................................................................... 11 
3.1 Administration Schedule ......................................................................... 11 
3.2 Adverse Event Reporting Requirements ................................................. 11 
3.3 Comprehensive Adverse Events and Potential Risks List (CAEPR) for 
Trametinib dimethyl sulfoxide (GSK1120212B, NSC 763093) ................. 15 
3.4 Dose Modifications ................................................................................. 20 
3.5 Dose Modifications for Trametinib and supportive care ........................ 27 
3.6 Supportive Care ....................................................................................... 32 
3.7 Duration of Agent-specific treatment ..................................................... 32 
3.8 Duration of Follow-Up ............................................................................. 32 
4. Study Parameters .............................................................................................. 33 
4.1 Therapeutic Parameters for Trametinib Treatment ............................... 33 
5. Drug Formulation and Procurement ................................................................. 35 
5.1 Trametinib (NSC 763093) ........................................................................ 36 
6. Translational Studies-TBD ................................................................................. 38 
7. References ........................................................................................................ 38 
Appendix I  Patient Pill Calendar ............................................................................. 40 
Appendix II  BRAF non-V600 Mutations Eligible for Inclusion................................. 42 
Appendix III  Trametinib Ophthalmic Exam Form ................................................... 47 
Appendix IV  Patient Drug Information Handout and Wallet Card ......................... 48 
 
 
 
Rev. 12/16 

ECOG-ACRIN 
EAY131-R 
Cancer Research Group 
Version Date: March 11, 2019 
 
NCI Update Date: August 12, 2015 
3 
TREATMENT SUBPROTOCOL CHAIR 
Douglas B. Johnson, MD, MSCI 
Division of Hematology/Oncology 
Department of Medicine 
Vanderbilt University Medical Center 
777 PRB 
2220 Pierce Ave 
Nashville, TN 37232 
Phone: (615) 875-2139 
E-mail: douglas.b.johnson@vanderbilt.edu 
 
TREATMENT SUBPROTOCOL CO-CHAIR 
Marcus S. Noel, MD 
Division of Hematology/Oncology 
Department of Medicine 
Wilmot Cancer Institute 
601 Elmwood Avenue 
Box 704 
Rochester, NY 14642 
Phone: (585) 275-4583 
Email: marcus_noel@urmc.rochester.edu 
 
TRANSLATIONAL CHAIR 
Gregory J. Riely, MD, PhD 
Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, NY 10065 
Phone: (646) 888-4199 
E-mail: rielyg@mskcc.org 
 
 
 
 
 
 
 
 

ECOG-ACRIN 
EAY131-R 
Cancer Research Group 
Version Date: March 11, 2019 
 
NCI Update Date: August 12, 2015 
4 
Schema 
 
 
 
*  
Long-Term Follow-Up
Trametinib 2 mg oral daily, 
continuous dosing
Until progression or 
unacceptable toxicity
Cycle = 28 days
Accrual Goal: 35

ECOG-ACRIN 
EAY131-R 
Cancer Research Group 
Version Date: March 11, 2019 
 
NCI Update Date: August 12, 2015 
5 
1. Introduction 
1.1 
Trametinib 
1.1.1 
Background 
Trametinib is a potent, highly selective, allosteric inhibitor of MEK1 
and MEK2, is non-competitive towards ATP, and inhibits both MEK 
activation and kinase activity. Trametinib interferes with cellular signal 
transduction and induces apoptosis in human tumor cell lines both in 
vitro and in xenograft mouse models. Activity was most extensive in 
cell lines and models that contained activating BRAF mutations [1, 2]. 
Trametinib was first dosed in humans in 2008 in MEK111054 
(NCT00687622) [3]. This first-in-human study identified the 
recommended monotherapy dose for trametinib (2 mg once daily 
continuous dosing); established the safety, PK, and PD profiles; and 
demonstrated clinical activity in several tumor types including BRAF 
wild type melanoma [3]. Trametinib has been administered to > 1700 
subjects in 13 studies, which are complete and 9 additional studies 
which are ongoing. Trametinib has been administered as 
monotherapy in 12 studies and in combination in the other 10, two 
additional trials are ongoing as part of the compassionate use 
program [4].  Trametinib was approved by the United States Food and 
Drug administration on May 29, 2013, under the brand name Mekinist, 
as a monotherapy in the setting of BRAFV600 mutant melanoma. 
1.1.2 
Pharmacokinetics of Trametinib in Humans 
Peak plasma trametinib concentrations were observed 1.5 hours 
following single-dose administration of trametinib tablets under fasted 
conditions. The absolute oral bioavailability of  the trametinib 2.0 mg 
tablet is moderate to high (72%) relative to a coadministered IV 
microdose [4]. Trametinib is highly bound to plasma proteins (97.4%), 
has a high volume of distribution (Vd; 1060 L), a long terminal half-life 
(5.3 days), and accumulates with repeat once daily dosing. 
The metabolism of trametinib has been investigated using a series of 
in vitro and in vivo studies.  Trametinib is metabolized via 
deacetylation to form M5 (deacetylation alone) and deacetylation in 
combination with mono-oxygenation to form M7 (mono oxygenation 
and deacetylation).  M5 can be N-glucuronidated to form M6 (N 
glucuronidation of M5) while M7 undergoes O-glucuronidation to form 
M9 (O glucuronidation of M7), a minor pathway in humans. Trametinib 
is metabolized predominantly via deacetylation (non-CYP450 
mediated) alone or with mono-oxygenation or in combination with 
glucuronidation biotransformation pathways.  Although the specific 
enzyme responsible has not been identified, deacetylation is likely 
mediated by hydrolytic esterases, such as carboxyl-esterases or 
amidases [4]. 

ECOG-ACRIN 
EAY131-R 
Cancer Research Group 
Version Date: March 11, 2019 
 
NCI Update Date: August 12, 2015 
6 
1.1.3 
Safety 
The adverse events (AEs) observed in the pivotal, Phase III 
registration study of trametinib in BRAFV600 mutant melanoma [5] were 
consistent with that seen across trametinib monotherapy studies and 
is summarized here. The Phase III study demonstrated that the 2 mg, 
continuous, once daily dose of trametinib has an acceptable safety 
profile. Adverse events occurring in ≥15% of subjects that received at 
least one dose of trametinib (N=211) were rash (57%), diarrhea 
(43%), peripheral edema (26%), fatigue (26%), dermatitis acneiform 
(19%), nausea (18%), alopecia (17%), and hypertension (15%). Less 
than 8% of the subjects had grade 3 or 4 rash (including only one 
patient with grade 4), and no grade 3 or 4 diahrrea was observed.  
Decreased ejection fraction or ventricular dysfunction occurred in 7% 
of the subjects, and <1% (n=2) had grade 3 cardiac-related events 
that were considered trametinib related and led to permanent 
discontinuation of the study treatment. Ocular events, most of which 
were grade 1 or 2, occurred in 9% of the subjects.  Blurred vision was 
the most frequent ocular event (4%), and there was one case of 
reversible chorioretinopathy. Retinal vein occlusion, an AE that has 
been associated with MEK inhibitors, was observed only extremely 
rarely.  Rash, diarrhea, visual disorders, hepatic disorders, cardiac-
related AEs, and pneumonitis are considered AEs of special interest 
for trametinib because they are either known class effects (i.e.,were 
observed with other MEK inhibitors) or are potentially life-threatening. 
1.1.4 
Clinical Efficacy 
Trametinib has demonstrated significant clinical activity with an 
acceptable safety profile in Phase I-III studies [3, 5-7]. In BRAFV600 
mutant melanoma, the Phase III study of trametinib demonstrated 
improved rates of progression-free survival and overall survival versus 
cytotoxic chemotherapy [5].  In this study, trametinib demonstrated an 
overall response rate of 22% and a median PFS of 4.8 months.  The 
duration of response was 5.5 months. 
BRAFV600 wild type (WT) melanoma and other malignancies were 
evaluated in the trametinib first-in-human study [3]. This study 
enrolled 39 subjects with BRAFV600 WT cutaneous melanoma, of 
which 4 (10%) had confirmed objective responses [6]. The median 
PFS for these 39 subjects was 2.0 months (95% CI 1.7-3.7 months). 
Subjects who were both BRAFV600 WT and NRAS WT (n=20) had a 
higher response rate (20%) than those who were wild type only at 
BRAF (n=11; response rate= 0%). Moreover, a higher proportion of 
patients that were wild type for both genes, compared to those that 
were wild type for only BRAF, were on study treatment at week 24 
(40% versus 18%; p=0.26) and at 1 year (30% versus 0%; p=0.07).  
Importantly, 2 patients with BRAF mutations at non-V600 codons 
(L597V and G469A) were treated in this study with one achieving a 
partial response and the other with temporary stabilization of 
melanoma growth (see Section 1.2.2). Among other malignancies, 
several patients experienced partial responses (see Section 1.2.3). 

ECOG-ACRIN 
EAY131-R 
Cancer Research Group 
Version Date: March 11, 2019 
 
NCI Update Date: August 12, 2015 
7 
These results demonstrate that trametinib has clinical activity in 
subgroups other than BRAFV600 mutant melanoma. 
1.2 
Supporting Preliminary Data  
1.2.1 
Frequency of non-V600 BRAF mutations 
Mutatations in BRAF at codons other than V600 (non-V600) have 
been identified in 2.79% of all tissue samples in the cBIO repository, a 
biorepository that includes 69 next generation sequencing studies 
across 23 histologic subtypes of cancer [8, 9].  These widely vary 
across cancer types, for example, in melanoma, approximately 5% of 
tumors harbor these mutations. These alterations are present in 1-3% 
of lung adenocarcinomas, and 1% or less of ovarian carcinomas, 
gastric carcinomas, prostate cancer, lung squamous cell carcinomas, 
glioblastomas, 
1.2.2 
Frequency of BRAF fusions 
The frequency and tumor type distribution of BRAF fusions has not 
been well described to this point. Several distinct BRAF fusions have 
been described in the majority of pediatric astrocytomas and low 
grade gliomas over the past several years [10-12]. In addition, these 
alterations have been identified in 7-30% of adult pilocytic 
astrocytomas, and nearly 10% of adult diffuse gliomas [13, 14]. BRAF 
fusions have also been recently appreciated in melanoma, with up to 
10% of the non-BRAF, non-NRAS mutated melanomas (3-4% of all 
melanomas), and other melanocytic tumors [15-17]. BRAF fusions 
have also been described in prostate adenocarcinoma [18].  
1.2.3 
Rationale for trametinib in the BRAF non-V600 and BRAF fusion 
populations 
Recurrent mutations in exon 11 and 15 of BRAF were initially 
identified by Davies et al in 2002 [19]. These mutations (notably 
V600E, L597V, G469A, G464V) were demonstrated to constitutively 
activate MAPK signaling and ERK phosphorylation many fold greater 
than wild type BRAF. Wan and colleagues then delineated high 
activity mutants, which directly activate ERK signaling through MEK 
activation, and low-activity, which activate ERK signaling through 
CRAF and protein-protein interactions [20]. Direct inhibition of mutant 
BRAF with vemurafenib or dabrafenib appears ineffective in the non-
V600 population, although modest in vitro activity and a brief partial 
response have been reported for vemurafenib [21, 22]. By contrast, in 
the preclinical setting and in occasional patients treated in clinical 
trials, MEK inhibition appears to be a more active therapeutic 
approach.  
Clinical corroboration has been demonstrated by several patients with 
melanoma who have achieved a response to MEK inhibitors. For 
example, a patient with BRAFL597S mutant melanoma had a dramatic 
response to an experimental MEK inhibitor (TAK-733) [21]. 
Furthermore, in the phase I trial of trametinib, a patient with BRAFL597V 
mutant melanoma experienced a prolonged partial response and 

ECOG-ACRIN 
EAY131-R 
Cancer Research Group 
Version Date: March 11, 2019 
 
NCI Update Date: August 12, 2015 
8 
remained on study for more than 2 years [6]. An additional patient with 
a BRAFG469A mutation had a best response of stable disease. Finally, 
in a trametinib phase II study, a patient with BRAFK601E mutant 
melanoma experienced a prolonged partial response [7]. Patients with 
other cancers have also had tumor regression and/or partial 
responses with trametinib although the presence of a non-V600 BRAF 
mutation or BRAF fusion has not been determined in these patients 
[3].  MEK inhibition in this population has not been studied in a 
systematic fashion and has never been evaluated prospectively.  
BRAF rearrangements fuse the BRAF kinase domain with a partner 
gene which leads to constitutive activation of the MAPK pathway [15, 
16]. BRAF fusion melanoma appears to confer resistance to 
vemurafenib. By contrast, trametinib strongly inhibited MAPK 
signalling in vitro and is predicted to have clinical activity in BRAF 
fusions [15]. At this time, no patients with BRAF fusions have been 
treated with trametinib.  
MEK inhibitors have been associated with occasional responses in 
other cancers. In these studies, it is unclear whether BRAF non-V600 
mutations or fusions were present. MEK inhibitors have been studied 
in advanced biliary tract cancer, notably a second line phase II trial 
with selumetinib. No BRAFV600E mutations were found, however 12% 
of patients had a confirmed response and another 68% stable disease 
[23]. Selumetinib has also been investigated in non-small cell lung 
cancer (NSCLC). 87 patients were randomized to either selumetinib 
plus docetaxel or placebo plus docetaxel. There was a significant 
increase in progression free survival 5.3 months versus 2.1 months 
(HR 0.58 80% CI 0.42-0.79; p=0.014) and trend towards increased 
overall survival (9.4 months versus 5.2 months, HR 0.8-, 80% CI 0.56-
1.14;p=0.21) in the selumetinib-containing arm [24]. A randomized 
phase II trial evaluated the MEK inhibitor AZD6244 versus 
pemetrexed in NSCLC.  Among, 84 patients randomized, 2 patients in 
the AZD6244 arm had a partial response. Additional mutational 
analysis of the tumors was not available in this trial. Trametinib was 
evaluated in a phase 1 trial of advanced refractory solid tumors. 
Several patients experienced objective responses including two 
patients with pancreatic cancer (one with a KRAS mutation) and two 
with non-small cell lung cancer (NSCLC; both with KRAS mutations; 
one concurrently had a BRAF mutation) [3]. In addition, patients with 
colon, ovarian, and thyroid cancer also had some regression of their 
disease that did not reach a partial response. Of note, several patients 
harbored BRAF mutations although it was not reported whether these 
were V600 mutations.  Another MEK inhibitor, BAY 86-9766, was 
evaluated as a single agent in a phase 1 trial, of 53 evaluable 
patients. One (colorectal) patient had a partial response, and 11 had 
stable disease [25]. 
 

ECOG-ACRIN 
EAY131-R 
Cancer Research Group 
Version Date: March 11, 2019 
 
NCI Update Date: August 12, 2015 
9 
2. 
Selection of Patients 
Each of the criteria in the checklist that follows must be met, along with the eligibility in 
the MATCH Master Protocol, 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: 
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 
Patient 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 a BRAF non-V600 mutation or BRAF fusion, or 
another aberration, as identified via the MATCH Master Protocol and 
described in Appendix II. See Appendix II for information on the 
targeted mutations/fusions and the corresponding Levels of Evidence 
(LOE). 
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. 
_____ 
_____
Rev. 8/15 
Rev. 8/15 
Rev. 8/15 
Rev.2/16 
Rev. Add13 

ECOG-ACRIN 
EAY131-R 
Cancer Research Group 
Version Date: March 11, 2019 
 
NCI Update Date: August 12, 2015 
10 
Date of ECG:  _______________ 
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 III for the Trametinib Ophthalmic Exam Form. 
2.1.8 
Patients who previously received MEK inhibitors (including, but not 
limited to, trametinib, binimetinib, cobimetinib, selumetinib, 
RO4987655 (CH4987655), GDC-0623 and pimasertib) 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. 
 
 
 
 
 
Physician Signature 
 
Date 
OPTIONAL: 
This signature line is provided for use by institutions wishing to 
use the eligibility checklist as source documentation. 
 
 
Rev. 8/15, 2/16 
Rev. 8/15 
Rev. 8/15 
Rev. 8/15 

ECOG-ACRIN 
EAY131-R 
Cancer Research Group 
Version Date: March 11, 2019 
 
NCI Update Date: August 12, 2015 
11 
3 
Trametinib Treatment Plan 
3.1 
Administration Schedule 
Trametinib will be taken orally at a dose of 2mg once daily, continuously for each 
28 day cycle. Patients will continue therapy 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 treatments 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.  
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 EAY131 - 
Subprotocol R 
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 R 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 
Rev.2/16 

ECOG-ACRIN 
EAY131-R 
Cancer Research Group 
Version Date: March 11, 2019 
 
NCI Update Date: August 12, 2015 
12 
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 subject is on 
Trametinib, or within 28 days of the 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 – Subprotocol R specific expedited reporting 
exceptions: 
For Subprotocol R, 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 

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for this subprotocol. Please adhere to the guidelines 
outlined below for the reporting of second primaries 
on this subprotocol. 
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. 

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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 
provided with a copy of the form and the associated 
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 
Form. 
 

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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 in the SPEER. 
Version 2.5, February 1, 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 
 
  
Rev. 2/16, 1/17 
Rev. Add19 

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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%)  
 
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
 Abdominal pain (Gr 2) 
 
 
Colitis 
  
 
 
Colonic perforation 
  
 
Constipation 
 
 Constipation (Gr 2) 
Diarrhea 
 
 
 Diarrhea (Gr 3) 
 
Dry mouth 
 
 Dry mouth (Gr 2) 
 
Dyspepsia 
 
 Dyspepsia (Gr 2) 
 
Mucositis oral 
 
 Mucositis oral (Gr 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 
 
  

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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%)  
 
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) 
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 (rash)5 
 
 
 
Skin and subcutaneous 
tissue disorders - Other 
(rash)5 (Gr 3) 
VASCULAR DISORDERS 
  
 
Hypertension 
 
 Hypertension (Gr 3) 
 
 
Thromboembolic event 
(venous) 
  
 
Vascular disorders - 
Other (hemorrhage)6 
 
  
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 

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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, 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 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 hemorrhage; Gastric ulcer; Gastritis; Gastrointestinal 
disorders - Other (intestinal obstruction); Gastrointestinal disorders - Other (pneumatosis 
intestinalis); Gastrointestinal fistula; Gingival pain; Hemorrhoidal hemorrhage; 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 

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NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - 
Tumor hemorrhage; Tumor pain 
NERVOUS SYSTEM DISORDERS - Dysgeusia; Encephalopathy; Intracranial hemorrhage; 
Lethargy; Nervous system disorders - Other (diplopia); Seizure; Somnolence; Stroke; Syncope; 
Transient ischemic attacks 
PSYCHIATRIC DISORDERS - Anxiety; Confusion; Delirium; Depression; Hallucinations; 
Insomnia; Personality change 
RENAL AND URINARY DISORDERS - Acute kidney injury; Cystitis noninfective; Dysuria; 
Hematuria; Proteinuria; Urinary incontinence 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Vaginal fistula; Vaginal hemorrhage 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Bronchopulmonary 
hemorrhage; 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 baseline at the reduced dose level, 
and no additional toxicities are seen after four weeks of study 
treatment at the reduced dose, the dose of trametinib may be 
increased to the previous dose level. If a dose reduction below 1 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 
subsequent visits as outlined in the Time and Events Table 
(See Section 4.1). Electronic copies of all ECHO/MUGA 
scans will be collected by GSK for review.  Instructions for 
submission of ECHO/MUGA scans are provided in the 
Study Procedures Manual (SPM). 
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 weeks.a 
• 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 level.b 
 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 
Symptomatica 
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. 
• 
Restrictive clothing has been removed from the cuff 
Rev. 8/15 
Rev. Add13 

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area, and the right cuff 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 mmHg and/or 
diastolic blood pressure (DBP) >90 mmHg 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 1 week. 

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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 
dose. 
(Scenario B) 
Asymptomatic SBP ≥ 160 mmHg, 
or DBP ≥ 100 mmHg,  
or 
Failure to achieve well-controlled 
BP within 2 weeks in Scenario A. 
• Adjust current or initiate new 
antihypertensive medication(s). 
• Titrate antihypertensive 
medication(s) during the next 2 
weeks to achieve well-
controlled BP. 
• Interrupt trametinib if clinically 
indicated. 
• Once BP is well-controlled, 
restart trametinib reduced by 
one dose level.a 
(Scenario C) 
Symptomatic hypertension  
or 
Persistent SBP ≥ 160 mmHg, or 
DBP ≥ 100 mmHg, despite 
antihypertensive medication and 
dose reduction of trametinib 
• Adjust current or initiate new 
antihypertensive medication(s). 
• Titrate antihypertensive 
medication(s) during the next 2 
weeks to achieve well-
controlled BP. 
• Referral to a specialist for 
further evaluation and follow-up 
is recommended. 
• Interrupt trametinib. 
• Once BP is well-controlled, 
restart trametinib reduced by 
one dose level.a 
(Scenario D) 
Refractory hypertension 
unresponsive to above 
interventions or hypertensive 
crisis. 
Continue follow-up per protocol. 
Permanently discontinue 
trametinib. 
a. Escalation of trametinib to previous dose level can be considered if BPs remain well controlled for 4 
weeks after restarting of trametinib.  Approval from the subprotocol Study Chair is required. 
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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 
provided in Tables 4 and 5. 
Rev. 8/15 

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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 
discontinue trametinib 
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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 
Terminology Criteria for Adverse Events 
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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). 
• [ 
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 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 
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Event 
Treatment modifications and assessment/monitoring 
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). 
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. 
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NCI Update Date: August 12, 2015 
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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 the subprotocol Study 
Chair may be required. 
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 antibiotics should be applied at least twice 
daily starting on Day 1 of study treatment, to body areas such as 
face, chest, and upper back.   
Use mild-strength topical steroid  (hydrocortisone 1% cream)  
or 
topical antibiotic (e.g., clindamycin) or oral antibiotics (e.g., 
doxycycline 100 mg BID, minocycline 100 mg BID) 
Symptomatic Careb 
• Pruritic lesions: cool compresses and oral antihistamine therapies  
• Fissuring lesions: Monsel’s solution, silver nitrate, or zinc oxide 
cream  
• Desquamation: thick emollients and mild soap  
• Paronychia: antiseptic bath, local potent corticosteroids in addition 
to oral antibiotics; if no improvement, consult dermatologist or 
surgeon  
• Infected lesions: appropriate bacterial/fungal culture-driven 
systemic or topical antibiotics  
Abbreviations:  BID = twice daily; SPF = sun protection factor 
a. Rash prophylaxis is recommended for the first 6 weeks of study treatment  
b. Subjects who develop rash/skin toxicities should be seen by a qualified physician and should 
receive evaluation for symptomatic/supportive care management  
Guidelines for management and dose reduction for rash considered to 
be related to study treatment are provided (see Table 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 propionate 
concentration 0.05% cream 
c. Approval of the 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. 
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3.5.5 
Trametinib Dose Modification for Toxicities Not Specified in 
Subsequent Sections 
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, QTc prolongation, or visual changes. Refer to other sections for these specific 
AEs). 
CTCAE v4 Grade Management Guideline 
Dose Modification 
Grade 1 
Monitor as clinically 
indicated. Provide 
supportive care 
according to institutional 
standards. 
Continue trametinib at current dose level. 
Grade 2 
(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. See adverse reaction sections, tables 9-12. 
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 progression 
3.8 
Duration of Follow-Up 
Refer to the MATCH Master Protocol for specifics on the 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 MATCH Master Protocol at Step 0, the below parameters 
must also be performed for patients on 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 
 XF 
Pill Count/DiaryH 
 
X 
 
X 
 
ECGK,L 
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 ECHO/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 (NSC 763093) 
5.1.1 
Other Names  
MEKINIST™, GSK1120212, JTP-74057, JTP-78296, JTP-75303 
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 in the original bottle. Do not 
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: 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 0.5 mg and 2 mg 
(as free base) tablets. 
Each commercially-labeled bottle contains 30 tablets with a desiccant. 
The tablet core contains mannitol, microcrystalline cellulose, 
hypromellose, croscarmellose sodium, magnesium stearate (non-
animal), colloidal silicon dioxide and sodium lauryl sulfate.  
• 
0.5 mg tablets are yellow, modified oval, biconvex and film-coated 
with ‘GS’ debossed on one face and ‘TFC’ on the opposing face. 
Aqueous film coating consists of hypromellose, titanium dioxide, 
polyethylene glycol, iron oxide yellow. 
• 
2 mg tablets are pink, round, biconvex and film-coated with ‘GS’ 
debossed on one face and ‘HMJ’ on the opposing face. Aqueous 
film coating consists of hypromellose, titanium dioxide, 
polyethylene glycol, polysorbate 80, iron oxide red. 
Rev. 8/15, 12/16 
Rev. 8/15 
Rev. 5/16 
Rev. 12/16 
Rev. 12/16 

ECOG-ACRIN 
EAY131-R 
Cancer Research Group 
Version Date: March 11, 2019 
 
NCI Update Date: August 12, 2015 
37 
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 dimethyl sulfoxide is not a 
substrate of CYP enzymes or of human BCRP, MRP2, OATP1B1, 
OATP1B3, OATP2B1, OCT1 or MATE1 transporters. Trametinib 
elimination by deacetylation to metabolite M5 is dependent on 
carboxylesterases (CES1b, CES1c and CES2). M5 is eliminated by 
CYP3A4 and other pathways, presenting the clinically relevant, albeit 
low, potential for drug-drug interaction. Trametinib is a substrate for P-
gp and BSEP, but this is not expected to be clinically relevant due to 
trametinib’s high permeability.  
Trametinib dimethyl sulfoxide is an in vitro inhibitor of CYP 2C8, and 
is anticipated to have overall low potential for drug interactions as a 
perpetrator. It is also a weak CYP3A4 inducer and expected to have 
little clinical effect on sensitive substrates. Trametinib is not an 
inhibitor of CYP 1A2, 2A6, 2B6, 2C9, 2C19, 2D6 and 3A4 and not an 
inhibitor of P-gp, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, OCT2 
MRP2 and MATE1. 
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. 
 
Rev. 12/16 
Rev. 12/16 
Rev. 12/16 

ECOG-ACRIN 
EAY131-R 
Cancer Research Group 
Version Date: March 11, 2019 
 
NCI Update Date: August 12, 2015 
38 
6. 
Translational Studies-TBD 
Please refer to the MATCH Master Protocol for information on the Translational Studies. 
7. 
References 
1. 
Gilmartin AG, Bleam MR, Groy A, et al.: GSK1120212 (JTP-74057) is an 
inhibitor of MEK activity and activation with favorable pharmacokinetic 
properties for sustained in vivo pathway inhibition. Clin Cancer Res, 2011, 
17:989-1000. 
2. 
Jing J, Greshock J, Holbrook JD, et al.: Comprehensive predictive biomarker 
analysis for MEK inhibitor GSK1120212. Mol Cancer Ther, 2012, 11:720-9. 
3. 
Infante JR, Fecher LA, Falchook GS, et al.: Safety, pharmacokinetic, 
pharmacodynamic, and efficacy data for the oral MEK inhibitor trametinib: a 
phase 1 dose-escalation trial. Lancet Oncol, 2012, 13:773-81. 
4. 
GSK1120212 (trametinib) Investigator's Brochure Version 5. 
5. 
Flaherty KT, Robert C, Hersey P, et al.: Improved survival with MEK inhibition 
in BRAF-mutated melanoma. N Engl J Med, 2012, 367:107-14. 
6. 
Falchook GS, Lewis KD, Infante JR, et al.: Activity of the oral MEK inhibitor 
trametinib in patients with advanced melanoma: a phase 1 dose-escalation 
trial. Lancet Oncol, 2012, 13:782-9. 
7. 
Kim KB, Kefford R, Pavlick AC, et al.: Phase II study of the MEK1/MEK2 
inhibitor Trametinib in patients with metastatic BRAF-mutant cutaneous 
melanoma previously treated with or without a BRAF inhibitor. J Clin Oncol, 
2013, 31:482-9. 
8. 
Cerami E, Gao J, Dogrusoz U, et al.: The cBio cancer genomics portal: an 
open platform for exploring multidimensional cancer genomics data. Cancer 
Discov, 2012, 2:401-4. 
9. 
Gao J, Aksoy BA, Dogrusoz U, et al.: Integrative analysis of complex cancer 
genomics and clinical profiles using the cBioPortal. Sci Signal, 2013, 6:pl1. 
10. 
Jones DT, Kocialkowski S, Liu L, et al.: Tandem duplication producing a novel 
oncogenic BRAF fusion gene defines the majority of pilocytic astrocytomas. 
Cancer Res, 2008, 68:8673-7. 
11. 
Roth JJ, Santi M, Pollock AN, et al.: Chromosome Band 7q34 Deletions 
Resulting in KIAA1549-BRAF and FAM131B-BRAF Fusions in Pediatric Low-
Grade Gliomas. Brain Pathol, 2014. 
12. 
Cruz GR, Dias Oliveira I, Moraes L, et al.: Analysis of KIAA1549-BRAF fusion 
gene expression and IDH1/IDH2 mutations in low grade pediatric 
astrocytomas. J Neurooncol, 2014, 117:235-42. 
13. 
Theeler BJ, Ellezam B, Sadighi ZS, et al.: Adult pilocytic astrocytomas: clinical 
features and molecular analysis. Neuro Oncol, 2014, 16:841-7. 
14. 
Badiali M, Gleize V, Paris S, et al.: KIAA1549-BRAF fusions and IDH mutations 
can coexist in diffuse gliomas of adults. Brain Pathol, 2012, 22:841-7. 
Rev.2/16 

ECOG-ACRIN 
EAY131-R 
Cancer Research Group 
Version Date: March 11, 2019 
 
NCI Update Date: August 12, 2015 
39 
15. 
Hutchinson KE, Lipson D, Stephens PJ, et al.: BRAF Fusions Define a Distinct 
Molecular Subset of Melanomas with Potential Sensitivity to MEK Inhibition. 
Clin Cancer Res, 2013, 19:6696-702. 
16. 
Botton T, Yeh I, Nelson T, et al.: Recurrent BRAF kinase fusions in 
melanocytic tumors offer an opportunity for targeted therapy. Pigment Cell 
Melanoma Res, 2013. 
17. 
Wiesner T, He J, Yelensky R, et al.: Kinase fusions are frequent in Spitz 
tumours and spitzoid melanomas. Nat Commun, 2014, 5:3116. 
18. 
Beltran H, Yelensky R, Frampton GM, et al.: Targeted next-generation 
sequencing of advanced prostate cancer identifies potential therapeutic 
targets and disease heterogeneity. Eur Urol, 2013, 63:920-6. 
19. 
Davies H, Bignell GR, Cox C, et al.: Mutations of the BRAF gene in human 
cancer. Nature, 2002, 417:949-54. 
20. 
Wan PT, Garnett MJ, Roe SM, et al.: Mechanism of activation of the RAF-ERK 
signaling pathway by oncogenic mutations of B-RAF. Cell, 2004, 116:855-67. 
21. 
Dahlman KB, Xia J, Hutchinson K, et al.: BRAF L597 mutations in melanoma 
are associated with sensitivity to MEK inhibitors. Cancer Discov, 2012. 
22. 
Bahadoran P, Allegra M, Le Duff F, et al.: Major Clinical Response to a BRAF 
Inhibitor in a Patient With a BRAF L597R-Mutated Melanoma. J Clin Oncol, 
2013. 
23. 
Bekaii-Saab T, Phelps MA, Li X, et al.: Multi-institutional phase II study of 
selumetinib in patients with metastatic biliary cancers. J Clin Oncol, 2011, 
29:2357-63. 
24. 
Janne PA, Shaw AT, Pereira JR, et al.: Selumetinib plus docetaxel for KRAS-
mutant advanced non-small-cell lung cancer: a randomised, multicentre, 
placebo-controlled, phase 2 study. Lancet Oncol, 2013, 14:38-47. 
25. 
Weekes CD, Von Hoff DD, Adjei AA, et al.: Multicenter phase I trial of the 
mitogen-activated protein kinase 1/2 inhibitor BAY 86-9766 in patients with 
advanced cancer. Clin Cancer Res, 2013, 19:1232-43. 
26. 
Balagula Y, Barth Huston K, Busam KJ, et al.: Dermatologic side effects 
associated with the MEK 1/2 inhibitor selumetinib (AZD6244, ARRY-142886). 
Invest New Drugs, 2011, 29:1114-21. 
27. 
Lacouture ME, Anadkat MJ, Bensadoun RJ, et al.: Clinical practice guidelines 
for the prevention and treatment of EGFR inhibitor-associated dermatologic 
toxicities. Support Care Cancer, 2011, 19:1079-95. 
28. 
Weber J, Atkins M, Hwu P, et al.: White paper on adoptive cell therapy for 
cancer with tumor-infiltrating lymphocytes: a report of the CTEP 
subcommittee on adoptive cell therapy. Clin Cancer Res, 2011, 17:1664-73. 
29. 
Zheng, Gang, Tseng LH, Chen G, et al.: Clinical detection and categorization 
of uncommon and concomitant mutations involving BRAF. BMC Cancer 
2015, 15:779. 
 

ECOG-ACRIN 
EAY131-R 
Cancer Research Group 
Version Date: March 11, 2019 
 
NCI Update Date: August 12, 2015 
40 
Molecular Analysis for Therapy Choice (MATCH) 
MATCH Treatment Subprotocol R: Trametinib 
Appendix I 
 
Patient Pill Calendar 
Pill Calendar Directions 
1. Take your scheduled dose of each tablet. 
2. If a dose of trametinib is missed, only take the dose if it is more than 12 hours until 
the next scheduled dose. 
3. Please bring the empty bottle or any leftover tablets and your pill calendar to your 
next clinic visit.  
4. Take trametinib (GSK1120212) once daily by mouth either 1 hour before or 2 hours 
after a meal. 
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. 
Rev. 12/16, 3/17 

ECOG-ACRIN 
EAY131-R 
Cancer Research Group 
Version Date: March 11, 2019 
 
NCI Update Date: August 12, 2015 
41 
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 
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: _____________ 

ECOG-ACRIN 
EAY131-R 
Cancer Research Group 
Version Date: March 11, 2019 
 
NCI Update Date: August 12, 2015 
42 
Molecular Analysis for Therapy Choice (MATCH) 
MATCH Treatment Subprotocol R: Trametinib 
Appendix II 
 
BRAF non-V600 Mutations Eligible for Inclusion 
Gene 
Name 
Variant ID 
Variant Type 
Variant Description 
Level of 
Evidence Code 
BRAF 
COSM1739329 
SNV 
p.L485W 
2 
BRAF 
COSM478 
SNV 
p.K601E 
3 
BRAF 
COSM6265 
SNV 
p.K601N 
3 
BRAF 
COSM472 
SNV 
p.T599I 
3 
BRAF 
COSM21549  
SNV 
p.A598V 
3 
BRAF 
COSM1126 
SNV 
p.L597S 
3 
BRAF 
COSM1125 
SNV 
p.L597Q 
3 
BRAF 
COSM471 
SNV 
p.L597R 
3 
BRAF 
COSM470  
SNV 
p.L597V 
3 
BRAF 
COSM469  
SNV 
p.G596R 
3 
BRAF 
COSM53198 
SNV 
p.F595L 
3 
BRAF 
COSM468 
SNV 
p.F595L 
3 
BRAF 
COSM21612 
SNV 
p.F595L 
3 
BRAF 
COSM466 
SNV 
p.D594V 
3 
BRAF 
COSM253330 
SNV 
p.D594E 
3 
BRAF 
COSM144576 
SNV 
p.D594H 
3 
BRAF 
COSM467 
SNV 
p.D594G 
3 
BRAF 
COSM211600 
SNV 
p.D594N 
3 
BRAF 
COSM1583010 
SNV 
p.D594A 
3 
BRAF 
COSM27639 
SNV 
p.D594N 
3 
BRAF 
COSM463 
SNV 
p.E586K 
3 
BRAF 
COSM462 
SNV 
p.N581S 
3 
BRAF 
COSM1133046  
SNV 
p.Y472C 
3 
BRAF 
COSM459 
SNV 
p.G469V 
3 
BRAF 
COSM460 
SNV 
p.G469A 
3 
BRAF 
COSM461 
SNV 
p.G469E 
3 
BRAF 
COSM451 
SNV 
p.G466V 
3 
BRAF 
 COSM453 
SNV 
p.G466E 
3 
BRAF 
COSM452 
SNV 
p.G466A 
3 
BRAF 
COSM253328  
SNV 
p.G466R 
3 
BRAF 
COSM449 
SNV 
p.G464E 
3 
BRAF 
COSM450 
SNV 
p.G464V 
3 
BRAF 
COSM1448615 
SNV 
p.G464R 
3 
Rev.2/16 
Rev. 5/16, 
Add13 

ECOG-ACRIN 
EAY131-R 
Cancer Research Group 
Version Date: March 11, 2019 
 
NCI Update Date: August 12, 2015 
43 
Gene 
Name 
Variant ID 
Variant Type 
Variant Description 
Level of 
Evidence Code 
BRAF 
COSM1111  
SNV 
p.G464R 
3 
BRAF 
COSM448 
SNV 
p.I463S 
3 
BRAF 
COSM447  
SNV 
p.R462I 
3 
BRAF 
AGAP3-BRAF.A9B9 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
AGAP3-BRAF.A10B11 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
AGK-BRAF.A2B8 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
AGTRAP-
BRAF.A5B8.COSF828.1 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
AKAP9-BRAF.A7B11 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
AKAP9-BRAF.A21B10 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
AKAP9-BRAF.A22B9 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
AKAP9-BRAF.A28B9 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
AKAP9-BRAF.A8B9.COSF1013.1 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
AP3B1-BRAF.A22B9 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
ARMC10-BRAF.A4B11 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
ATG7-BRAF.A18B9 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
BAIAP2L1-BRAF.B12B9 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
BBS9-BRAF.B19B4 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
BCL2L11-BRAF.B3B10 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
BRAF-AP3B1.B8A23 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
BRAF-CIITA.B9C6 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
BRAF-MACF1.B8M15 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
BRAF-MRPS33.B1M2 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
BRAF-SLC26A4.B3S7 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
BRAF-SUGCT.B1S13 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
BTF3L4-BRAF.B3B11 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
C7orf73-BRAF.C2B9 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
CCDC6-BRAF.C1B9 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
CCDC91-BRAF.C11B9 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
CCNY-BRAF.C1B10 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
CDC27-BRAF.C16B9.1 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
CEP89-BRAF.C16B9 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
CLCN6-BRAF.C2B11.COSF1440 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
CLIP2-BRAF.C6B11 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
CUL1-BRAF.C7B9 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
CUX1-BRAF.C10B9 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
DYNC1I2-BRAF.D7B10 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
EML4-BRAF.E6B10 
Gene Fusion 
BRAF Translocation 
3 

ECOG-ACRIN 
EAY131-R 
Cancer Research Group 
Version Date: March 11, 2019 
 
NCI Update Date: August 12, 2015 
44 
Gene 
Name 
Variant ID 
Variant Type 
Variant Description 
Level of 
Evidence Code 
BRAF 
EPS15-BRAF.E22B10 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
ERC1-BRAF.E12B10 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
ERC1-BRAF.E17B8 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
FAM114A2-BRAF.F9B11 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
FAM131B-
BRAF.F1B10.COSF1191 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
FAM131B-
BRAF.F3B9.COSF1193 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
FAM131B-
BRAF.F2B9.COSF1189.1 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
FCHSD1-BRAF.F13B9.COSF403 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
FXR1-BRAF.F13B10 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
GATM-BRAF.G2B11 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
GHR-BRAF.G1B10 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
GNAI1-BRAF.G1B10.COSF1442 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
GTF2I-BRAF.G4B10 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
HERPUD1-BRAF.H4B7 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
KCTD7-BRAF.K3B8 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
KCTD7-BRAF.K4B8 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
KDM7A-BRAF.K11B11 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
KIAA1549-BRAF.K9B9 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
KIAA1549-
BRAF.K12B9.COSF1474 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
KIAA1549-BRAF.K12B11 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
KIAA1549-BRAF.K13B9 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
KIAA1549-
BRAF.K14B9.COSF483 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
KIAA1549-
BRAF.K14B11.COSF1226 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
KIAA1549-BRAF.K16B10 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
KIAA1549-
BRAF.K17B10.COSF509 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
KIAA1549-
BRAF.K18B9.COSF511 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
KIAA1549-
BRAF.K15B9.COSF481.1 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
KIAA1549-
BRAF.K15B10.COSF1283.1 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
KIAA1549-
BRAF.K15B11.COSF485.1 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
KLHL7-BRAF.K5B9 
Gene Fusion 
BRAF Translocation 
3 

ECOG-ACRIN 
EAY131-R 
Cancer Research Group 
Version Date: March 11, 2019 
 
NCI Update Date: August 12, 2015 
45 
Gene 
Name 
Variant ID 
Variant Type 
Variant Description 
Level of 
Evidence Code 
BRAF 
LSM12-BRAF.L3B9 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
LSM14A-BRAF.L9B9 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
MACF1-BRAF.M60B9 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
MAD1L1-BRAF.M16B9 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
MAD1L1-BRAF.M17B10 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
MKRN1-BRAF.M4B9 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
MKRN1-
BRAF.M4B11.COSF1444 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
MYRIP-BRAF.M16B9 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
MZT1-BRAF.M2B11 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
NUB1-BRAF.N3B9 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
NUDCD3-BRAF.N4B9 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
NUP214-BRAF.N21B10 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
PAPSS1-BRAF.P5B9.1 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
PLIN3-BRAF.P1B9 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
RAD18-BRAF.R7B10 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
RBMS3-BRAF.R11B11 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
RNF11-BRAF.R1B11 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
RNF130-BRAF.R3B9.COSF1483 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
RP2-BRAF.R3B10 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
SLC12A7-BRAF.S17B11 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
SLC45A3-BRAF.S1B8.COSF871 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
SND1-BRAF.S9B2 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
SND1-BRAF.S9B9 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
SND1-BRAF.S10B9 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
SND1-BRAF.S10B11 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
SND1-BRAF.S11B11 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
SND1-BRAF.S14B9 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
SND1-BRAF.S14B11 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
SND1-BRAF.S18B10 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
SND1-BRAF.S16B9.1 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
SOX6-BRAF.S5B9 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
SOX6-BRAF.S6B9 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
STRN3-BRAF.S3B10 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
TANK-BRAF.T4B9 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
TAX1BP1-BRAF.T8B11.1 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
TMEM178B-BRAF.T2B9 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
TMPRSS2-BRAF.T3B11 
Gene Fusion 
BRAF Translocation 
3 

ECOG-ACRIN 
EAY131-R 
Cancer Research Group 
Version Date: March 11, 2019 
 
NCI Update Date: August 12, 2015 
46 
Gene 
Name 
Variant ID 
Variant Type 
Variant Description 
Level of 
Evidence Code 
BRAF 
TRIM4-BRAF.T6B10 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
TRIM24-BRAF.T3B10 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
TRIM24-BRAF.T3B11 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
TRIM24-BRAF.T5B8 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
TRIM24-BRAF.T10B9 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
TRIM24-BRAF.T11B2 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
TRIM24-BRAF.T9B9.1 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
UBN2-BRAF.U3B11 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
ZC3HAV1-BRAF.Z3B10 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
ZC3HAV1-BRAF.Z7B11 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
ZKSCAN5-BRAF.Z2B9 
Gene Fusion 
BRAF Translocation 
3 
BRAF 
ZSCAN30-BRAF.Z3B10 
Gene Fusion 
BRAF Translocation 
3 
Other BRAF Fusion events or novel BRAF 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 R: Trametinib  
Appendix III 
 
Trametinib Ophthalmic Exam Form 
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: _____________________________   
Printed Name: _________________________      Date: ______________ 
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Version Date: March 11, 2019 
 
NCI Update Date: August 12, 2015 
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Molecular Analysis for Therapy Choice (MATCH) 
MATCH Treatment Subprotocol R: Trametinib  
Appendix IV 
 
Patient Drug Information Handout and Wallet Card 
Information for Patients, Their Caregivers and Non-Study Healthcare Team on Possible 
Interactions with Other Drugs and Herbal Supplements  
The patient ____________________________ is enrolled on a clinical trial using the 
experimental study drug, Trametinib.  This clinical trial is sponsored by the National Cancer 
Institute.  This form is addressed to the patient, but includes important information for others who 
care for this patient.  
These are the things that you as a healthcare provider need to know: 
Trametinib is a weak CYP2C8 inhibitor and weak CYP3A4 inducer.  
Drug-drug interactions with any substrates of  CYP2C8 and CYP3A4 are not anticipated. 
To the patient: Take this paper with you to your medical appointments and keep the 
attached information card in your wallet.   
There is a very low risk that Trametinib may interact with other drugs which can cause side 
effects. For this reason, it is very important to tell your study doctors of any medicines you are 
taking before you enroll onto this clinical trial.  It is also very important to tell your doctors if you 
stop taking any regular medicines, or if you start taking a new medicine while you take part in this 
study.  When you talk about your current medications with your doctors, include medicine you 
buy without a prescription (over-the-counter remedy), or any herbal supplements such as St. 
John’s Wort.  It is helpful to bring your medication bottles or an updated medication list with you. 
Many health care providers can write prescriptions.  You must tell all of your health care 
providers (doctors, physician assistants, nurse practitioners, pharmacists) you are taking part in 
a clinical trial.  
These are the things that you and they need to know:  
There is a very low risk of drug interaction when Trametinib is combined with other medicines 
that use certain liver enzymes to be effective or to be removed from your body. Before you enroll 
onto the clinical trial, your study doctor will work with your regular health care providers to review 
any medicines and herbal supplements  that use the liver enzymes  CYP2C8 and CYP 3A4. 
• 
Please be very careful!  Over-the-counter drugs (including herbal supplements) may contain 
ingredients that could interact with your study drug.  Speak to your doctors or pharmacist to 
determine if there could be any side effects.  
• 
Your regular health care provider should check a frequently updated medical reference or call 
your study doctor before prescribing any new medicine or discontinuing any medicine. 
Rev. 8/15 
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Your study doctor’s name is  
_____________________________________  
and he or she can be contacted at  
_____________________________________. 
 
INFORMATION ON POSSIBLE DRUG 
INTERACTIONS  
You are enrolled on a clinical trial using the 
experimental agent Trametinib.  This clinical trial is 
sponsored by the NCI.  Trametinib could interact with 
drugs that affect the QT interval, a measurement of 
heart conductivity. Because of this, it is very important 
to: 
➢ Tell your doctors if you stop taking regular medicine 
or if you start taking a new medicine. 
➢ Tell all of your prescribers (doctor, physicians’ 
assistant, nurse practitioner, pharmacist) that you 
are taking part in a clinical trial. 
➢ Check with your doctor or pharmacist whenever you 
need to use an over-the-counter medicine or herbal 
supplement. 
Trametinib could lengthen the QT interval rarely and 
must be used very carefully with other medicines that 
affect the QT interval.  
➢ Before you start the study, your study doctor will work 
with your regular prescriber to switch any medicines 
that are considered QT prolonging agents. 
➢ Before prescribing new medicines, your regular 
prescribers should go to 
http://medicine.iupui.edu/clinpharm/ddis/ for a list of 
drugs to avoid, or contact your study doctor.   
➢ Your study doctor’s name is 
_____________________________ and can be 
contacted at 
_________________________________.