MATCH Treatment Subprotocol S1: Phase II Study of Trametinib in Patients With Tumors With NF1 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-S1, Phase II Study of Trametinib in Patients with 
Tumors with NF1 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permitted to conduct the study utilizing outdated versions of any MATCH protocol documents 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’s February 22, 2019 Request for Rapid 
Amendment for Trametinib dimethyl sulfoxide. 
The following revisions to EAY131-S1 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-S1 Informed Consent Document have been made in this 
addendum: 
 
Section 
Change 
1. 
Page 1 
Updated Version Date. 

 
ii 
 
Section 
Change 
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. 
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-S1 so ECOG-ACRIN may 
activate it promptly.   
Thank you.  
Sincerely, 
Pamela Cogliano 
Senior Director, Protocol Development 
Enclosure 
CC: Jason Luke, MD, FACP  
Kari B. Wisinski, .MD 
Andrew Chi, 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-S1 
1 
Molecular Analysis for Therapy 
Choice (MATCH) 
MATCH Treatment Subprotocol S1: Phase II Study of 
Trametinib in Patients with Tumors with NF1 Mutations 
TRAMETINIB TREATMENT SUBPROTOCOL 
CHAIR: 
Jason Luke, MD, FACP 
TRAMETINIB TREATMENT SUBPROTOCOL 
CO-CHAIR: 
Kari B. Wisinski, MD 
TRAMETINIB TRANSLATIONAL CHAIR: 
Andrew Chi, MD, PhD 
Version Date:  March 11, 2019 
NOTE: This subprotocol (EAY131-S1) should 
be used in conjunction with the 
MATCH Master Protocol (EAY131) 
SUBPROTOCOL ACTIVATION DATE 
February 25, 2016 (Incorporated in Addendum #2) 
Addendum #3 – 5/16 
NOTE: As of 11/17, all protocol changes will 
be noted by addendum number. 
Addendum #5 – 12/16 
Addendum #6 – 1/17 
Addendum #7 – 3/17 
Addendum #13 
Addendum #19 
Agent 
IND# 
NSC# 
Supply 
Trametinib dimethyl sulfoxide 
NCI Supplied 
Rev. Add13 
Rev. Add19 

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Table of Contents 
Molecular Analysis for Therapy Choice (MATCH) ...................................................... i 
MATCH Treatment Subprotocol S1: Phase II Study of Trametinib in Patients with 
Tumors with NF1 Mutations ............................................................................... 1 
Table of Contents ...................................................................................................... 2 
Schema ...................................................................................................................... 4 
1. Introduction ........................................................................................................ 5 
1.1 Trametinib Dimethyl Sulfoxide (GSK1120212B, MEKINIST) ...................... 5 
1.2 Supporting Preliminary Data ..................................................................... 9 
2. Selection of Patients ......................................................................................... 13 
2.1 Eligibility Criteria: .................................................................................... 13 
3. Treatment Plan ................................................................................................. 15 
3.1 Administration Schedule ......................................................................... 15 
3.2 Adverse Event Reporting Requirements ................................................. 15 
3.3 Comprehensive Adverse Events and Potential Risks List (CAEPR) for 
Trametinib dimethyl sulfoxide (GSK1120212B, NSC 763093) ................. 19 
3.4 Dose Modifications ................................................................................. 24 
3.5 Dose Modifications for Trametinib and supportive care ........................ 31 
3.6 Supportive Care ....................................................................................... 36 
3.7 Duration of Agent-specific treatment ..................................................... 36 
3.8 Duration of Follow-Up ............................................................................. 36 
4. Study Parameters .............................................................................................. 37 
4.1 Therapeutic Parameters for Trametinib Treatment ............................... 37 
5. Drug Formulation and Procurement ................................................................. 39 
5.1 Trametinib (NSC 763093) ........................................................................ 40 
6. Translational Studies ......................................................................................... 42 
7. References ........................................................................................................ 42 
Appendix I   Patient Pill Calendar ............................................................................ 47 
Appendix II   Trametinib Ophthalmic Exam Form ................................................... 49 
Appendix III  Actionable Mutations for Sub-Protocol EAY131-S1 ........................... 50 
Appendix IV   Patient Drug Information Handout and Wallet Card ........................ 51 
 
 
 

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TREATMENT SUBPROTOCOL CHAIR 
Jason J. Luke, MD, FACP 
University of Chicago Comprehensive Cancer Center 
5841 S. Maryland Ave. MC2115 
Chicago, IL 60559 
Phone: (773) 834-3096 
Fax: (773) 702-0963 
jluke@medicine.bsd.uchicago.edu 
TREATMENT SUBPROTOCOL CO-CHAIR 
Kari B. Wisinski, MD 
University of Wisconsin Carbone Cancer Center 
1111 Highland Ave, WIMR 6033 
Madison, WI 53705-2275 
Phone: (608) 262-2876 
Fax: (608) 265-6905 
kbwisinski@medicine.wisc.edu 
 
TRANSLATIONAL CHAIR 
Andrew S. Chi, MD, PhD 
Laura and Isaac Perlmutter Cancer Center 
NYU Langone Medical Center 
240 E. 38th Street, 19th Floor 
New York, NY 10016 
Phone: (646) 501-4802 
Fax: (646) 754-9696 
chia01@nyumc.org 
 
 
 
 
 
 
 
 
 

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Schema 
 
 
 
Long-Term Follow-Up
Trametinib 2mg PO once daily
Until progression or 
unacceptable toxicity
Cycle = 28 days
Accrual Goal: 70
Rev. 3/17 

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1. 
Introduction 
1.1 
Trametinib Dimethyl Sulfoxide (GSK1120212B, MEKINIST) 
The RAF-MEK-ERK pathway plays a critical role in multiple cellular functions.  
Activation of the pathway can result from activation/mutations of the upstream 
receptor tyrosine kinases (RTKs) and RAS, or upregulation/mutations in RAF and 
MEK.  Upon activation, RAF acts as the MAPK kinase kinase and activates 
MAPKK (MEK1/2), which in turn catalyze activation of the effectors ERK1/ERK2.  
Once activated, ERK1/2 translocate into the nucleus and phosphorylate a 
number of effector proteins and transcriptional factors that regulate cell 
proliferation, motility, differentiation, and survival. 
Neurofibromatosis 1 (NF1) produces the protein product neurofibromin.  
Neurofibromatosis type 1 is an autosomal dominant familial cancer predisposition 
syndrome, which occurs as a result of inactivating mutations in NF1. (Patil et al, 
2012). Somatic NF1 mutations or deletions have also been identified in multiple 
cancer subtypes in a range from 1.8-14.3% of tumors (The Cancer Genome 
Atlas) Neurofibromin is a tumor suppressor that regulates the downstream 
RAS/RAF/MEK/ERK pathway. Preclinical data have demonstrated that tumors 
with NF1 inactivation are sensitive to MEK inhibitors (Denayer et al., 2008; See 
et al 2012; Gursel et al, 2011).  The antitumor activity of MEK inhibition in NF1 
mutant tumors will be tested in this subprotocol of the MATCH study. 
Trametinib Dimethyl Sulfoxide (hereafter, referred to as trametinib) is one of the 
several MEK inhibitors in clinical development.  On May 29, 2013, the U.S. Food 
and Drug Administration (FDA) approved trametinib for the treatment of patients 
with unresectable or metastatic melanoma with BRAFV600E or BRAFV600K 
mutations as detected by an FDA-approved test (U.S. Food and Drug 
Administration, 2013).  On January 10, 2014, the FDA granted accelerated 
approval to trametinib and dabrafenib for use in combination to treat patients with 
unresectable or metastatic melanoma with a BRAF V600E or V600K mutation as 
detected by an FDA-approved test (U.S. Food and Drug Administration, 2014). 
Experience to date indicates that MEK is a valid target.  In a phase 3 trial 
comparing single agent trametinib with dacarbazine or paclitaxel in patients with 
BRAF V600E or V600K mutant metastatic melanoma, trametinib demonstrated a 
significantly better response rate, progression-free survival, and overall survival 
(Flaherty et al., 2012).  Extensive research is underway to identify the patient 
selection markers and to develop rational combination strategies.  Preclinical 
studies have provided strong rationale and proof of principle for combination of 
MEK inhibitors with RTK inhibitors (EGFR or IGF-1R) (Gopal et al., 2010; Ebi et 
al., 2011), PI3K/AKT inhibitors (Engelman et al., 2008; Hoeflich et al., 2009), and 
mTOR inhibitors.  On the other hand, the optimal dose/schedule and patient 
selection criteria for combination regimens have not been defined.  Phase 1 
results for a number of combinations have been reported for other MEK 
inhibitors, including AZD6244 + MK2206 (Tolcher et al., 2011) and GDC-0973 + 
GDC-094 (MEK + PI3K inhibitor) (Bendell et al., 2011). Since trametinib is active 
as a single agent in a tumor with upstream BRAF activation, it is reasonable to 
test this drug as a single agent in tumors with NF1 inactivating mutations. 

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1.1.1 
Mechanisms of Action and Preclinical Data with Trametinib 
Trametinib is a dimethyl sulfoxide (DMSO) solvate compound (ratio 
1:1) with potent, allosteric and ATP non-competitive inhibition of 
MEK1/2 (IC50 of 0.7 and 0.9 nM against MEK1 and MEK2, 
respectively) (Gilmartin et al., 2011).  Trametinib inhibited MEK1/2 
kinase activity and prevented RAF-dependent MEK phosphorylation 
(S217 for MEK1), producing prolonged pERK1/2 inhibition.  
Trametinib showed better potency against unphosphorylated MEK1/2 
(u-MEK1/2) when compared with preactivated diphosphorylated MEK 
(pp-MEK), suggesting that u-MEK affords a higher affinity binding site 
for trametinib than does pp-MEK. 
The specificity of trametinib was confirmed against a panel of 183 
kinases, including MEK5 (the closet kinase homolog to MEK1/2), 
CRAF, BRAF, ERK1, and ERK2 (Yamaguchi et al., 2011).  Trametinib 
demonstrated equal potency against activated MEK1- and MEK2-
mediated phosphorylation of ERK (sequence identity of 85% across 
the whole protein and 100% in the active site for humans).  Trametinib 
demonstrated preferential inhibition of RAF-mediated MEK1 activation 
(IC50 = 0.60 nM) over pMEK1 kinase activity (IC50 = 13 nM) 
(Investigator’s Brochure, 2012a). 
BRAF-mutant Colo205, A375P F11s, and HT-29 human tumor 
xenograft mouse models showed the most significant mean tumor 
growth inhibition (TGI) (80% to 87%) at 3.0 mg/kg trametinib, with 
multiple complete and partial tumor regressions.  In the Colo205 
model, tumor regression was observed even at a dose of 0.3 mg/kg 
(Yamaguchi et al., 2011).  Two KRAS-mutant xenograft models, HCT-
116 and A549, also showed significant TGI (83% and 75%) but 
without significant tumor regressions (Gilmartin et al., 2011).  As 
predicted by cell proliferation assays, tumor xenograft lines with wild-
type (wt) RAF/RAS (PC3, BxPC3, and BT474) were much less 
sensitive, showing only modest TGI (44-46%) with no tumor 
regressions. 
Pharmacodynamic studies were performed in mice treated with 
trametinib for 14 days (Gilmartin et al., 2011).  In the A375P F11s 
xenograft model, the first dose of trametinib (3 mg/kg) significantly 
reduced pERK for more than 8 hours on Day 1.  pERK inhibition was 
more sustained (over 24 hours) after the Day 7 dose, probably due to 
an increase in the steady-state levels of trametinib after repeated 
doses.  The average Cmax in blood was 1,410 nM on Day 7, with an 
estimated half-life (t1/2) of 33 hours.  In addition, 
immunohistochemistry (IHC) also confirmed inhibition of cell 
proliferation (reduced Ki67) and G1 cell cycle arrest (elevated 
p27Kip1/CDKN1B) following 4 days of treatment. 
1.1.2 
Clinical Pharmacokinetics (PK) and Activity of Trametinib 
Phase 1 Trial of Trametinib Monotherapy (MEK111054) 
There were 3 parts in this industry sponsored study.  Part 1:  The 
dose-escalation portion involved administration of trametinib (repeat 
doses of 0.125 mg to 4.0 mg) to patients with solid tumors or 

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lymphoma in one of three schedules - (1) QD for 21 days followed by 
7 days without drug, (2) loading dose on Day 1 or Day 1-2, followed 
by QD with the designated dose, or (3) QD dosing without a drug 
holiday.  Part 2:  cohort expansion at the recommended phase 2 dose 
(RP2D) for pancreatic cancer, melanoma, non-small cell lung cancer 
(NSCLC), colorectal cancer (CRC), or any BRAF mutation-positive 
cancer.  Part 3:  expansion to characterize the biologically active 
range of trametinib via analysis of pharmacodynamic biomarkers 
(biopsies or FDG-PET).  The study has been completed and all parts, 
other than FDG-PET results, have been reported  
The MTD of trametinib was established as 3 mg QD, but the 
recommended phase 2 dose (RP2D) was chosen at 2 mg QD based 
on tolerability of repeated cycles (Infante et al., 2012).  
PK and metabolism of trametinib: 
PK measurements were conducted under fasting conditions.  After a 
single dose (Day 1), AUC0-24 and Cmax values were dose-proportional 
up to 6 mg, lower than dose proportional following 8 mg, and greater 
than dose proportional following the 10 mg dose.  Median Tmax was 
1.5 hours. 
After repeat doses (Day 15), trametinib accumulated with a mean 
accumulation ratio of 6.6 at the RP2D of 2 mg QD.  Between-subject 
variability in exposure ranged from 27-50% for Cmax and 20-41% for 
AUC0-24 across all dosing regimens.  The effective t1/2 was 
approximately 4.5 days, and steady state was reached by 
approximately Day 15.  Trametinib had a small peak:trough ratio of ~2 
(Infante et al., 2012).  At 2 mg QD on Day 15, mean AUC0-24 was 376 
ng•h/mL and Cmax 23 ng/mL, and the mean trough concentrations 
ranged from 10.0 to18.9 ng/mL.  The long half-life and small 
peak:trough ratio of trametinib allowed constant target inhibition within 
a narrow range of exposure. 
Drug-drug interactions: 
Trametinib is metabolized predominantly via deacetylation (non-
cytochrome P450 [CYP450]-mediated) with secondary oxidation or in 
combination with glucuronidation biotransformation pathways 
(Investigator’s Brochure, 2012a).  The deacetylation is likely mediated 
by hydrolytic esterases, such as carboxylesterases, or amidases.  
Based on in vitro studies, trametinib is not an inhibitor of CYP1A2, 
CYP2A6, CYP2B6, CYP2D6, and CYP3A4. Trametinib dimethyl 
sulfoxide is a weak CYP2C8 inhibitor and weak CYP3A4 inducer. 
Drug-drug interactions with sensitive substrates of 2C8 and 3A4 are 
not anticipated. Trametinib has an overall low potential for drug-drug 
interactions. 
Pharmacodynamic effect and biomarkers: 
The relationship between dose and tumor biomarkers such as pERK, 
Ki67, and p27, were evaluated in patients with BRAF or NRAS 
mutation-positive metastatic melanoma (Investigator's Brochure, 
2012a).  In general, increasing exposures and/or doses provided 
greater pharmacodynamic effects.  The median change observed at a 

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dose of 2 mg QD was 62% inhibition of pERK, 83% inhibition of Ki67, 
and a 175% increase in p27. 
Antitumor Activity in the phase 1 trial:  
In the phase 1 trial, 14 patients with BRAF-mutant melanoma received 
trametinib at 2 mg QD.  The overall objective response rate (ORR) 
was 43% (6/14), including 2 complete responses (CRs) (Investigator's 
Brochure, 2012a).  In 9 patients with BRAF wt melanoma, 2 patients 
achieved a partial response (PR), and 3 stable disease (SD) (Infante 
et al., 2010).  In 26 evaluable pancreatic cancer patients, there were 2 
PRs (1 PR was KRAS mutation-positive) and 11 SD (2 achieved  
≥ 20% tumor reduction) (Messersmith et al., 2011). Among the 27 
CRC patients (without selection of RAS or RAF mutations), 8 SD were 
observed. 
Antitumor Activity in Melanoma  
Phase 3 trial of trametinib vs. chemotherapy in advanced V600 
mutant melanoma: 
In a phase 3 trial, patients with unresectable stage IIIC or IV 
cutaneous melanoma with a BRAF V600E or V600K mutation were 
randomized (2:1) to trametinib (2 mg, PO, QD) or chemotherapy 
(dacarbazine or paclitaxel) (Flaherty et al., 2012; MEKINIST, 2013).  
There were 322 patients in the intention-to-treat (ITT) population, of 
whom 273 (85%) were in the primary efficacy population (patients with 
BRAFV600E-positive cancer who did not have brain metastases at 
baseline). Of the patients, 214 were randomized to receive trametinib, 
and 108 were randomized to receive chemotherapy. Investigator-
assessed efficacy data are summarized as follows: 
 
Trametinib 
(n=214) 
Chemotherapy (DTIC) 
(n=108) 
PFS 
Median, months (95% CI) 
4.8 (4.3, 4.9) 
1.5 (1.4, 2.7) 
HR (95% CI) 
P value (log-rank test) 
0.47 (0.34, 0.65) 
P< 0.0001 
Confirmed Tumor Responses 
Objective Response Rate (95% CI) 
CR, n (%) 
PR, n (%) 
22% (17, 28) 
4 (2%) 
43 (20%) 
8% (4, 15) 
0 
9 (8%) 
Duration of response 
Median, months (95% CI) 
5.5 (4.1, 5.9) 
NR (3.5, NR) 
CI = confidence interval; CR = complete response; HR = hazard ratio; NR = not reached; PFS = 
progression-free survival; PR = partial response 
The 6-month OS rate was 81% in the trametinib group and 67% in the 
chemotherapy group.  Mature data on OS are pending. 

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Experience with Trametinib in Metastatic Melanoma Following BRAF 
Inhibitor Therapy 
The clinical activity of single-agent trametinib was evaluated in a 
single-arm, multicenter, international trial in 40 patients with BRAF 
V600E or V600K mutation-positive, unresectable, or metastatic 
melanoma who had received prior treatment with a BRAF inhibitor.  
All patients received trametinib at a dose of 2 mg PO QD until disease 
progression or unacceptable toxicity.  None of the patients achieved a 
confirmed PR or CR. 
Antitumor Activity of Trametinib in Cancer Other Than Melanoma 
In a phase 1/2 monotherapy study, acute myeloid leukemia (AML) or 
myelodysplastic syndrome (MDS) patients were given trametinib at 
dose levels from 1-2 mg QD.  Drug-related AEs in 45 patients were 
similar to that observed in patients with solid tumors, and 2 mg PO 
QD was selected for further investigation in this patient population.  
Twelve patients (23%) withdrew due to an AE, including cardiac 
failure (2) and infection (2).  Efficacy results were reported for 39 
patients (Borthakur et al., 2010).  The best response in 13 patients 
with KRAS or NRAS mutations included 3 CRs (23%), 7 SD (54%), 
and 1 PD (progressive disease) (5%).  In 26 patients with wild-type 
RAS or an unknown mutation, there were 2 PRs (8%). 
In a multicenter phase 2 study, NSCLC patients with KRAS mutant 
tumors were randomized 2:1 to receive trametinib (2 mg QD) or 
docetaxel (75 mg/m2 IV every 3 weeks) (Blumenschein et al., 2013).  
A total of 134 pts were randomized to trametinib (89) or docetaxel 
(45); 129 patients had KRAS-mutant NSCLC.  The hazard ratio for 
PFS was 1.14 (95% CI, 0.75-1.75; P=0.5197) with a median PFS of 
11.7 versus 11.4 weeks for trametinib versus docetaxel.  The overall 
response rate (ORR) was 12% for trametinib and 12% for docetaxel. 
In a double-blind, phase 2 study evaluating the combination of 
gemcitabine with trametinib, untreated pancreatic cancer patients 
were randomized to receive gemcitabine (1000 mg/m2 weekly 7 for 8 
weeks, then weekly 3 every 4 weeks) plus either trametinib 2mg or 
placebo QD (Infante et al., 2013).  Median OS was 8.4 months with 
trametinib compared to 6.7 months with placebo.  Median PFS was 16 
weeks versus 15 weeks, and ORRs and median duration of 
responses were 22% and 23.9 weeks and 18% and 16.1 weeks on 
trametinib and placebo; the median OS and ORR in the subgroup of 
patients with KRAS mutations (143/160) was similar to OS and ORR 
for all randomized patients.   
1.2 
Supporting Preliminary Data  
NF1 Biology and Targeted Therapy Approaches 
Neurofibromatosis 1 (NF1) is a 350 kilobase, 60 exon gene located at the q11.2 
band of chromosome 17 (Jett et al., 2010). Neurofibromin, the protein product of 
NF1 gene translation functions in regulation of RAS proteins and results in 
modulation of multiple downstream effector pathways including mitogen-activated 
protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K) and protein kinase B 

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(PKB).  Titration of signaling through these pathways is essential in the 
modulation of proliferation and survival under standard physiologic conditions 
and is integral to multiple cancer phenotypes (Denayer et al., 2008).  
Neurofibromin activates GTPases, which promotes the hydrolysis of active RAS-
GTP to inactive RAS-GDP (Brems et al, 2009, Dilworth et al, 2006, Gottfried et 
al, 2006, Ismat et al, 2006).  Reduction in activity or complete loss of NF1 gene 
function leads to downstream hyperactivation of these pathways and in the 
context of other genetic abnormalities can contribute to malignant transformation. 
The NF1 gene was first described in the context of the familial cancer syndrome 
neurofibromatosis type I.  This is a relatively common autosomal dominant 
disorder characterized by multiple neurofibromas, hyperpigmented macules of 
the skin, known as café-au-lait macules, freckling, and iris hamartomas.  The 
incidence of neurofibromatosis has been reported as approximately 1 person per 
3,500 in the United States population.  The disease has a 100% penetrance 
though expression is variable and is likely influenced by the degree of NF1 loss 
(haploinsufficiency vs complete loss) and other genetic factors.  
Neurofibromatosis syndrome is associated with an increased risk for several 
cancer types.  Cancer is the leading cause of death among patients with NF1 
syndrome and a decreased life expectancy of up to 15-years relative to the 
general population (Patil et al, 2012).  Patients with NF1 syndrome have germline 
loss of one NF1 allele and subsequently develop loss of heterozygosity (LOH) at 
the other.  Cancers associated with neurofibromatosis (germline NF1 loss) can 
be observed in both pediatric and adult settings with pediatric tumors commonly 
including glioma and leukemia, while adult tumors often including sarcoma 
(malignant peripheral nerve sheath tumor [MPNST] and gastrointestinal stromal 
tumor), carcinoid, pheochromocytoma, breast cancer and glioma. 
As neurofibromin acts on Ras in the fashion of a tumor suppressor, multiple 
mechanisms of neurofibromin function loss have been described.  On a genetic 
level, more than 1000 different NF1 mutations have been identified (Cooper et al, 
2012, Ars et al, 2003).  These mutations are highly heterogeneous ranging from 
point mutations within the gene to large deletions of the entire NF1 gene and 
sometimes flanking genes. With these various mutational types, no correlation 
between specific mutation and cancer phenotype has to date been described.  A 
caveat to this is the three base pair deletion p.Met991del, which has been 
consistently associated with a higher risk for malignant nerve sheath tumors and 
overall larger tumor load (De Raedt et al, 2003).  Loss of neurofibromin function 
alone is not sufficient to drive human malignancy; rather NF1 loss in conjunction 
with other cellular environmental factors or genetic abnormalities are required 
(Zhu et al 2002). 
In somatic cancers, the significance of NF1 loss has been more and less clear in 
different tumor models.  Data from multiple sequencing projects have described 
NF1 mutations across tumor histologies as being present at rates of 1.8-14.3% 
(The Cancer Genome Atlas), 5-10% (Friedrich Miescher Institute; Frampton et al, 
2013) and 7.66% (cBIOPortal).  These mutations are commonly clustered at 
higher frequencies in certain histologies including breast adenocarcinoma (3%), 
glioblastoma (14%), melanoma (10%) and less commonly in other tumors such 
as lung, ovarian and colorectal adenocarcinomas.  Acute myelogenous leukemia 
is also commonly mutated in NF1 (however patients with this disease are not part 
of the MATCH clinical trial). 

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Mutations or deletions in the NF1 gene play an important role in the 
pathogenesis of glioblastoma (GBM). Loss of NF1 in conjunction with loss of 
another tumor suppressor is sufficient to form glioblastomas in mouse model 
systems, and the tumors generated in mice have activated Ras pathway (Zhu et 
al, 2005, Reilly et al, 2000, Kwon et al, 2008). Recent genome sequencing efforts 
in GBM have established that a significant subset of sporadic GBMs carry NF1 
inactivating mutations or deletions. Inactivating NF1 point mutations were 
reported in 14% – 15% of GBMs (Parsons et al, 2008, CGARN 2008) with an 
additional 9% having deletion of the NF1 gene (CGARN 2008). A subset of GBM 
cell lines with NF1 loss are dependent on the RAF/MEK/ERK pathway for growth, 
and are sensitive to MEK inhibitors in vitro and in vivo (See et al 2012). In 
addition, MEK inhibitors are effective at blocking anchorage-independent growth 
and migration of tumor cell lines generated from NF1 and TP53 deficient 
genetically engineered mice (Gursel et al, 2011). These preclinical data suggest 
glioblastomas with genetically inactivated NF1 may be sensitive to MEK 
inhibitors. 
Relative to melanoma, despite the obvious pigmentation abnormality seen in NF1 
syndrome, melanoma is not a cancer commonly associated with 
neurofibroamatosis (Jett et al., 2010, Ars et al, 2003). However, mutations in NF1 
have now been observed to be present in up to 10% of all cases of cutaneous 
melanoma and are observed in nearly half of melanomas demonstrating a 
desmoplastic phenotype (Hodis et al, 2012, Gutzmer et al, 2000 and personal 
communication from Boris Bastian, MD, PhD).  Mutation in NF1 can also arise as 
a mechanism of secondary resistance treatment with MAPK targeting via 
selective BRAF kinase inhibitors (Maertens et al, 2013, Whittaker et al 2013).   
Attempts to develop targeted therapy approaches toward dysregulated NF1 
signaling have had little success to date and have been complicated by 
heterogeneous cellular and molecular biology in tumors harboring these 
mutations (Thomas et al 2012).  Given the downstream actions of NF1 on RAS 
signaling, farnesyltransferase inhibitors were hypothesized as potential 
therapeutic agents and preclinical models appeared to support the utility of these 
agents in NF1 mutant cell lines (Van et al 1995).  As with other MAPK pathway 
mutant cancers however, the effects did not translate into improved clinical 
outcomes in a Phase II study of patients with NF1 mutations. c-KIT signaling 
upstream of NF1 has also been considered as a point of intervention and 
preclinical modeling in NF1 mutant Schwann cells has supported this (Yang et al, 
2008).  Beyond these studies, some signs of preliminary efficacy with the KIT 
inhibitor imatinib have been observed. A phase II study of imatinib did not reach 
the primary endpoint of response rate; however, there was a subset of patients 
who had tumor responses of less than 20% that were thought to possibly be 
clinically meaningful (Robertson et al, 2012). 
Another downstream effector of NF1 via RAS is the mammalian target of 
rapamycin (mTOR). This molecule is up-regulated in some gliomas (optic track) 
as well as in astrocytomas and MPNSTs in patients with NF1 mutations (Brems 
et al, 2009). Since mTOR inhibitors have shown activity in tuberous sclerosis, a 
disease with neuro-cutaneous manifestations, this molecule has been of interest 
in the treatment of NF1 mutant cancer. Though a Phase II study of sirolimus in 
NF1-associated plexiform neurofibromas is on-going, no objective tumor 
regressions have yet been observed (Rosenbaum et al, 2014). 

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More recent attempts to target NF1 mutations have focused on the MAPK 
pathway at downstream effectors such as MEK. Blockade of MEK  led to 
reduction of neurofibroma in mice harboring NF1 mutations and in longer survival 
of human to murine MPNST xenografts (Jessen et al, 2013). The use of MEK 
inhibition appeared to improve survival in a mouse model of NF1 mutant juvenile 
leukemia (Chang et al, 2013). No clinical trials of MEK inhibitors in NF1 mutant 
solid tumors have yet been completed. A case report of a patient with plexiform 
neurofibroma treated with the MEK inhibitor selumetinib in a pediatric phase I 
clinical trial suggests that tumor shrinkage is possible (Widemann et al, 2014) 
and an abstract presented at the ASCO 2015 annual meeting described 
shrinkage of progressive and non-progressive pediatric plexiform neurofibromas 
with partial responses observed in 11 of 18 patients (61%) (Marcus et al, 2015).  
Taken together, these data suggest that MEK inhibitors might be new 
therapeutics candidates to treat various disease manifestations of NF1. 
 

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2. 
Selection of Patients 
Each of the criteria in the checklist that follows must be met, along with the eligibility in 
the main screening study, in order for a patient to be considered eligible for this study. 
Use the checklist to confirm a patient’s eligibility. For each patient, this checklist must be 
photocopied, completed and maintained in the patient’s chart.  
In calculating days of tests and measurements, the day a test or measurement is 
done is considered Day 0. Therefore, if a test is done on a Monday, the Monday 
four weeks later would be considered Day 28.  
ECOG-ACRIN Patient No. ____________________________ 
Patient’s Initials (L, F, M) _______________________ 
Physician Signature and Date ___________________ 
NOTE: 
CTEP Policy does not allow for the issuance of waivers to any protocol 
specified criteria 
(http://ctep.cancer.gov/protocolDevelopment/policies_deviations.htm). 
Therefore, all eligibility criteria listed in Section 2 must be met, without 
exception. The registration of individuals who do not meet all criteria listed in 
Section 2 can result in the participant being censored from the analysis of the 
study, and the citation of a major protocol violation during an audit. All 
questions regarding clarification of eligibility criteria must be directed to the 
Group's Executive Officer (EA.Execofficer@jimmy.harvard.edu) or the 
Group's Regulatory Officer (EA.RegOfficer@jimmy.harvard.edu). 
NOTE: 
Institutions may use the eligibility checklist as source documentation if it has 
been reviewed, signed, and dated prior to registration by the treating 
physician. 
NOTE: 
All patients must have signed the relevant treatment consent form 
2.1 
Eligibility Criteria: 
2.1.1 
Patients must fulfill all eligibility criteria outlined in Section 3.1 of 
MATCH Master Protocol (excluding Section 3.1.6) at the time of 
registration to treatment step (Step 1, 3, 5, 7). 
2.1.2 
Patients must have deleterious inactivating mutations of NF-1, or 
another aberration, as determined via the MATCH Master Protocol 
and according to Appendix III. See Appendix III for information on the 
targeted mutations and corresponding Levels of Evidence. 
2.1.3 
Patients must have an electrocardiogram (ECG) within 8 weeks prior 
to treatment assignment and must have NONE of the following 
cardiac criteria: 
• 
Clinically important abnormalities in rhythm, conduction or 
morphology of resting ECG (e.g. complete left bundle branch 
block, third degree heart block). 
• 
Treatment-refractory hypertension defined as a blood pressure of 
systolic >140 mmHg and/or diastolic >90 mmHg which cannot be 
controlled by anti-hypertensive therapy. 
Date of ECG:  _______________ 
_____
_____ 
_____
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2.1.4 
Patients with a history of interstitial lung disease or pneumonitis are 
excluded. 
2.1.5 
Patients must have an ECHO or a nuclear study (MUGA or First 
Pass) within 4 weeks prior to registration to treatment and must not 
have a left ventricular ejection fraction (LVEF) < the institutional lower 
limit of normal (LLN). If the LLN is not defined at a site, the LVEF must 
be > 50% for the patient to be eligible. 
Date of ECHO/nuclear study:  _______________ 
2.1.6 
Patients must not have known hypersensitivity to trametinib or 
compounds of similar chemical or biologic composition or to dimethyl 
sulfoxide (DMSO). 
2.1.7 
Patients must not have a history or current evidence/risk of retinal 
vein occlusion (RVO). An eye exam is required at baseline. See 
Appendix II for the Trametinib Ophthalmic Exam Form. 
2.1.8 
Patients who previously received MEK inhibitors (including, but not 
limited to, trametinib, binimetinib, cobimetinib, selumetinib, 
RO4987655 (CH4987655), GDC-0623 and pimarsertib) will be 
excluded. 
2.1.9 
Patients who previously received monoclonal antibody therapy (eg. 
ipilimumab, nivolumab, pembrolizumab and others) must have 
stopped the prior therapy for 8 or more weeks before starting on 
trametinib. 
2.1.10 
Patients with glioblastoma must have histologically or radiographically 
confirmed recurrent or progressive WHO Grade 4 glioma 
(glioblastoma). 
NOTE: 
All baseline and post-baseline disease assessments must 
be performed using contrast-enhanced cranial MRI or 
contrast-enhanced CT for subjects who cannot have MRI 
performed. 
 
 
 
 
 
Physician Signature 
 
Date 
OPTIONAL: 
This signature line is provided for use by institutions wishing to 
use the eligibility checklist as source documentation. 
_____
_____
_____
_____ 
_____
_____
_____ 

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3. 
Treatment Plan 
3.1 
Administration Schedule 
All patients will receive trametinib 2mg daily continuously until intolerable toxicity, 
disease progression, or the end of the study.  
Trametinib should be administered once per day, continuously; and should be 
taken at about the same time each day. The study drug should be administered 
together with approximately eight ounces of water. Trametinib should be taken 
fasting, at least 1 hour before or 2 hours after a meal.  If a subject vomits after 
taking study medication, the subject should be instructed not to retake the dose 
and should take the next scheduled dose. 
If a dose of trametinib is missed, only take the dose if it is more than 12 hours 
until the next scheduled dose. 
Trametinib should be stored at 2-8°C (36-46°F). Refrigerate. Do not freeze. 
3.2 
Adverse Event Reporting Requirements 
The Adverse Event Reporting Requirements for all EAY131 subprotocols are 
outlined in the MATCH MASTER protocol.  Please refer to those guidelines when 
determining if an event qualifies as a Serious Adverse Event (SAE) and requires 
expedited reporting via CTEP’s Adverse Event Reporting System (CTEP-AERS).  
In addition, the following section outlines agent specific requirements and must 
be followed to ensure all reporting requirements are met. 
3.2.1 
Additional instructions, requirements and exceptions for EAY131- 
Subprotocol S1. 
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 S1 specific expedited reporting 
requirements: 
• 
LVEF Changes: If any of the following circumstances occur, 
the event(s) must be reported via CTEP-AERS according to 
the timeframes outlined in the AE table in section 5.3.6 of the 
MATCH Master protocol 
• 
Asymptomatic:  Absolute decrease of >10% in LVEF 
compared to baseline and ejection fraction below the 
institution’s LLN and LVEF does not recover within 4 
weeks 
• 
Symptomatic: Grade 3-4 LVEF 
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Please refer to the dose modification instructions for further 
information regarding Treatment Modification and Management 
Guidelines for LVEF Decrease 
 
• 
Visual Changes:  If RPED (retinal pigment epithelial 
detachments) or RVO (retinal vein occlusion) are diagnosed, 
the event(s) must be reported via CTEP-AERS according to 
the timeframes outlined in the AE table in Section 5.3.6 of the 
MATCH Master protocol. Please refer to the dose modification 
instructions for further information regarding Treatment 
Modification and Management Guidelines for Visual Changes. 
• 
Liver Chemistry Changes:  If any of the following 
circumstances occur, the event(s) must be reported via CTEP-
AERS according to the timeframes outlined in the AE table in 
section 5.3.6 of the MATCH Master protocol 
• 
ALT ≥ 3xULN and bilirubin ≥ 2x ULN or > 35% direct 
bilirubin 
• 
ALT  3xULN and INR ≥ 1.5, if INR measured  (INR 
threshold does not apply if subject is on anticoagulant) 
• 
Please refer to the dose modification instructions for further 
information regarding Treatment Modification and Management 
Guidelines for Liver Chemistry Changes 
• 
Pregnancies:  Pregnancies and suspected pregnancies 
(including a positive or inconclusive pregnancy test, regardless 
of age or disease state) occurring while the 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-S1 specific expedited reporting exceptions: 
For study Subprotocol S1, 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 tumortumor 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. 
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 
 
  
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
 Abdominal pain (Gr 2) 
 
 
Colitis 
  
 
 
Colonic perforation 
  
 
Constipation 
 
 Constipation (Gr 2) 
Diarrhea 
 
 
 Diarrhea (Gr 3) 
Rev. 1/17 
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Adverse Events with Possible 
Relationship to Trametinib (GSK1120212B) 
(CTCAE 5.0 Term) 
[n= 1111] 
 
 
Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER) 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
 
Dry mouth 
 
 Dry mouth (Gr 2) 
 
Dyspepsia 
 
 Dyspepsia (Gr 2) 
 
Mucositis oral 
 
 Mucositis oral (Gr 3) 
Nausea 
 
 
 Nausea (Gr 3) 
 
Vomiting 
 
 Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Chills 
 
 Chills (Gr 2) 
 
Edema face 
 
  
Fatigue 
 
 
 Fatigue (Gr 3) 
 
Fever 
 
 Fever (Gr 2) 
Generalized edema3  
 
 Generalized edema3 (Gr 2) 
IMMUNE SYSTEM DISORDERS 
  
 
Allergic reaction4 
 
  
INFECTIONS AND INFESTATIONS 
  
 
Folliculitis 
 
 Folliculitis (Gr 2) 
 
Lung infection 
 
  
 
Paronychia 
 
 Paronychia (Gr 2) 
 
Skin infection 
 
 Skin infection (Gr 2) 
INVESTIGATIONS 
  
 
Alanine 
aminotransferase 
increased 
 
 Alanine aminotransferase 
increased (Gr 3) 
 
Alkaline phosphatase 
increased 
 
 Alkaline phosphatase 
increased (Gr 2) 
 
Aspartate 
aminotransferase 
increased 
 
 
Aspartate 
aminotransferase 
increased (Gr 3) 
 
CPK increased 
 
  
 
Ejection fraction 
decreased 
 
  
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
 Anorexia (Gr 3) 
 
Dehydration 
 
 Dehydration (Gr 3) 
 
Hypoalbuminemia 
 
  
 
Hypomagnesemia 
 
 Hypomagnesemia (Gr 2) 
 
Hyponatremia 
 
 Hyponatremia (Gr 3) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
  
 
Back pain 
 
 Back pain (Gr 2) 
 
Pain in extremity 
 
 Pain in extremity (Gr 2) 
 
 
Rhabdomyolysis 
  
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
 Dizziness (Gr 2) 
 
Headache 
 
 Headache (Gr 2) 

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Adverse Events with Possible 
Relationship to Trametinib (GSK1120212B) 
(CTCAE 5.0 Term) 
[n= 1111] 
 
 
Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER) 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
 Cough (Gr 2) 
 
Dyspnea 
 
 Dyspnea (Gr 3) 
 
 
Pneumonitis 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Alopecia 
 
 Alopecia (Gr 2) 
 
Dry skin 
 
 Dry skin (Gr 2) 
 
Nail changes 
 
  
 
 
Palmar-plantar 
erythrodysesthesia syndrome   
 
Pruritus 
 
 Pruritus (Gr 2)  
Skin and 
subcutaneous 
tissue disorders - 
Other (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 
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 

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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 
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 

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SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Bullous dermatitis; Photosensitivity; 
Purpura; Skin and subcutaneous tissue disorders - Other (erythema nodosum); Skin ulceration; 
Urticaria 
VASCULAR DISORDERS - Hematoma; Hot flashes; Hypotension 
NOTE: 
Trametinib (GSK1120212B) in combination with other agents could cause an 
exacerbation of any adverse event currently known to be caused by the other agent, 
or the combination may result in events never previously associated with either 
agent. 
 

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3.4 
Dose Modifications  
NOTE: 
Patients who interrupt trametinib for > 2 weeks will be removed 
from this subprotocol, unless the interruption was for reduction 
in LVEF, visual changes or RPED with subsequent recovery as 
described in corresponding tables below. 
All toxicity grades below are described using the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0. 
All appropriate treatment areas should have access to a copy of the CTCAE 
version 4.0. A copy of the CTCAE version 4.0 can be downloaded from the 
CTEP website (http://ctep.cancer.gov). 
3.4.1 
Dose Modification Guidelines for Trametinib Adverse Events of 
Special Interest 
The dose levels for this study are provided in Table 1. 
Dose Levels 
Trametinib once daily 
Full dose 
2 mg 
1st Dose reduction 
1.5 mg 
2nd Dose reduction 
1.0 mg 
Table 1 
Dose Level Reduction Guidelines 
3.4.2 
If an AE resolves to grade 1 or lower (or baseline) and remains grade 
1 or lower at the reduced dose level and the subject does not 
experience any additional AEs requiring  dose hold or reductions, then 
after 4 weeks of the study treatment at reduced dose, the dose of 
trametinib may be increased one dose level. If a dose reduction below 
1 mg once daily for trametinib is required, then trametinib will be 
permanently discontinued. 
3.4.3 
Guidelines for Cardiovascular Adverse Events  
Cardiovascular adverse events have been seen in subjects receiving 
trametinib[4]).  Guidelines for LVEF decreases and hypertension are 
provided below. 
3.4.3.1 
Left Ventricular Ejection Fraction (LVEF) 
Decreases of the left-ventricular-ejection-fraction (LVEF) 
have been observed in subjects receiving trametinib. 
Therefore, ECHOs (preferred) or a MUGA must be 
performed for subjects experiencing symptoms concerning 
for decline in LVEF 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). 
Dose modification guidance and stopping criteria for LVEF 
decrease are provided (Table 2). 
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Table 2 
Dose Modification Guidelines and Stopping Criteria for LVEF Decrease 
Clinic 
LVEF-drop (%) or 
CTCAE grade 
Action and Dose Modification 
Asymptomatic 
Absolute decrease of >10% 
in LVEF compared to 
baseline and ejection 
fraction below the 
institution’s  LLN 
• Interrupt trametinib and repeat ECHO/MUGA 
within 2 weeksa   
• If the LVEF recovers within 4 weeks (defined as 
LVEF ≥ LLN and absolute decrease ≤ 10% 
compared to baseline): 
- Consult with the subprotocol Study Chair and 
request approval for restart  
- Restart treatment with trametinib at  reduced 
dose by one dose levelb 
- Repeat ECHO/MUGA 2, 4, 8 and 12 weeks  
after re-start; continue in intervals of 12 weeks 
thereafter 
• If LVEF does not recover within 4 weeks 
- Consult with cardiologist 
- Permanently discontinue trametinib 
- Report as SAE 
- Repeat ECHO/MUGA after 2, 4, 8, 12, and 16 
weeks or until resolution 
- Consult with the subprotocol Study Chair.c 
Symptomaticb 
Grade 3: resting LVEF 39-
20% or > 20% absolute 
reduction from baseline 
• Permanently discontinue trametinib.  
• Report as SAE 
• Consult with cardiologist 
• Repeat ECHO/MUGA after 2, 4, 8, 12, and 16 
weeks or until resolution 
Grade 4: resting LVEF < 
20% 
Abbreviations:  CTCAE = Common Terminology Criteria for Adverse Events; ECHO = 
echocardiogram; GSK = GlaxoSmithKline; LLN = lower limit of normal; LVEF = left ventricular ejection 
fraction; MUGA=Multi-gated acquisition 
a. If ECHO/MUGA does not show LVEF recovery after 2 weeks, repeat ECHO/MUGA 2 weeks later. 
b. Escalation of trametinib to previous dose level can be considered if LVEF remains stable for 4 
weeks after restarting of trametinib.  Approval from the subprotocol Study Chair is required. 
c. Symptoms may include: dyspnea, orthopnea, and other signs and symptoms of pulmonary 
congestion and edema. 
3.4.3.2 
Hypertension 
Increases in blood pressure (BP) have been observed in 
patients receiving trametinib. Recommendations for BP 
monitoring and management are provided below. 
Monitoring: All BP assessments should be performed 
under the following optimal conditions: 
• 
The subject has been seated with back support, 
ensuring that legs are uncrossed and flat on the floor 
• 
The subject is relaxed comfortably for at least 5 
minutes 
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• 
Restrictive clothing has been removed from  the cuff 
area and the right cuff size has been selected 
• 
The subjects arm is supported so that the middle of the 
cuff is at heart level 
• 
The subject remains quiet during the measurement.  
• 
In subjects with an initial blood pressure reading within 
the hypertensive range, a second reading should be 
taken at least 1 minute later, with the 2 readings 
averaged to obtain a final blood pressure 
measurement. The averaged value should be recorded 
in the eCRF. 
• 
Persistent hypertension is defined as an increase of 
systolic blood pressure (SBP) > 140 mm Hg and/or 
diastolic blood pressure (DBP) > 90 mm Hg in three 
consecutive visits with blood pressure assessments 
from two readings collected as described above. Visits 
to monitor increased blood pressure can be scheduled 
independently from the per-protocol visits outlined in 
the study calendar. Ideally, subsequent blood pressure 
assessments should be performed within one 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 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. 

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Table 4 
Management and Dose Modification Guidelines for Visual Changes and/or 
Ophthalmic Examination Findings 
CTCAE Gradea Adverse Event Management 
Action and Dose Modification 
Grade 1b 
• Consult ophthalmologist 
within 7 days of onset 
• If dilated fundus examination cannot be performed 
within 7 days of onset, interrupt trametinib until 
RPED and RVO can be excluded by retina 
specialist/ophthalmologist. 
• If RPED and RVO excluded, continue/or restart 
trametinib at same dose level 
• If RPED suspected or diagnosed: see RPED dose 
modification table 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 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 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 
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Event 
Treatment modifications and assessment/monitoring 
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. 
3.5.3 
Guidelines for Rash 
Rash is a frequent AE observed in subjects receiving trametinib (see 
the Investigator’s Brochures [4]] for more information). 
Recommendations for supportive care and guidelines for dose 
modifications for rash are based on experience with other MEK 
inhibitors and EGFR inhibitors [26, 27] and are provided (see Table 9 
and Table 10. 
The institutional standards for the management of skin-related AEs 
can differ from these guidelines. In this case, best clinical judgment 
should be applied and a consultation with the subprotocol Study Chair 
may be required. 
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Table 9 
Guidelines for Supportive Care of Rash 
Type of Care 
Action 
Prevention/Prophylaxisa 
• Avoid unnecessary exposure to sunlight 
• Apply broad-spectrum sunscreen (containing titanium dioxide or 
zinc oxide) with a skin protection factor (SPF) ≥15 at least twice 
daily. 
• Use thick, alcohol-free emollient cream (e.g., glycerine and 
cetomacrogol cream) on dry areas of the body at least twice daily. 
• Topical steroids and/or antibiotics should be applied at least twice 
daily starting on Day 1 of study treatment, to body areas such as 
face, chest, and upper back.   
Use mild-strength topical steroid  (hydrocortisone 1% cream)  
and/or 
topical antibiotic (e.g., clindamycin) or oral antibiotics (e.g., 
doxycycline 100 mg BID, minocycline 100 mg BID) 
Symptomatic Careb 
• Pruritic lesions: cool compresses and oral antihistamine therapies  
• Fissuring lesions: Monsel’s solution, silver nitrate, or zinc oxide 
cream  
• Desquamation: thick emollients and mild soap  
• Paronychia: antiseptic bath, local potent corticosteroids in addition 
to oral antibiotics; if no improvement, consult dermatologist or 
surgeon  
• Infected lesions: appropriate bacterial/fungal culture-driven 
systemic or topical antibiotics  
Abbreviations:  BID = twice daily; SPF = sun protection factor 
a. Rash prophylaxis is recommended for the first 6 weeks of study treatment  
b. Subjects who develop rash/skin toxicities should be seen by a qualified physician and should 
receive evaluation for symptomatic/supportive care management  
Guidelines for management and dose reduction for rash considered to 
be related to study treatment are provided (see Table 10). 

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Table 10 
Management and Dose Modification Guidelines for Rash  
CTCAE 
Grade 
Adverse Event Management 
Action and Dose Modification 
Grade 1 
• Initiate prophylactic and 
symptomatic treatment 
measuresa 
• Use moderate strength topical 
steroidb  
• Reassess after 2 weeks 
• Continue study treatment 
• If rash does not recover to baseline within 2 
weeks despite best supportive care, reduce 
trametinib by one dose levelc 
Grade 2 
• Initiate prophylactic and 
symptomatic treatment measures 
• Use moderate strength topical 
steroidb 
• Reassess after 2 weeks 
• Reduce trametinib by one dose level 
• If rash recovers to ≤ grade 1 within 2 weeks, 
increase dose to previous dose level 
• If no recovery to ≤ grade 1 within 2 weeks, 
interrupt study treatment until recovery to  
≤ grade 1 
• Restart trametinib at  reduced dose levelc 
Grade ≥ 3 • Use moderate strength topical 
steroidsb PLUS oral methyl-
prednisolone dose pack 
• Consult dermatologist  
• Interrupt trametinib until rash recovers to grade  
≤ 1 
• Restartc  trametinib reduced by one dose 
leveld  
• If no recovery to grade ≤ 2 within 2 weeks, 
permanently discontinue trametinib 
Abbreviations:  CTCAE = Common Terminology Criteria for Adverse Events 
a. Rash prophylaxis is recommended for the first 6 weeks of study treatment 
b. Moderate-strength topical steroids: hydrocortisone 2.5% cream or fluticasone prioprionate 0.5% 
cream 
c. Approval of subprotocol Study Chair is required to restart study treatment after > 2 weeks of 
interruption. 
d. Escalation of study treatment to previous dose level may be considered if no rash is evident 4 
weeks after restarting study treatment 
3.5.4 
Guidelines for Diarrhea  
Episodes of diarrhea have occurred in subjects receiving trametinib 
(see the Investigator Brochures [4] for more information). Other, 
frequent causes for diarrhea including concomitant medications (e.g., 
stool softeners, laxatives, antacids, etc.), infections by C. difficile or 
other pathogens, partial bowel obstruction, etc., should be clinically 
excluded. 
Guidelines regarding management and dose reduction for diarrhea 
considered to be related to trametinib by the investigator are provided 
(see Table 11). 
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Table 11 
Management and Dose Modification Guidelines for Diarrhea 
CTCAE Grade 
Adverse Event Management 
Action and Dose Modification 
Uncomplicated 
Diarrheaa 
 
Grade 1 or 2 
• Diet: stop all lactose containing products; eat 
small meals, BRAT-diet (banana, rice, 
apples, toast) recommended 
• Hydration: 8-10 large glasses of clear liquids 
per day (e.g., Gatorade or broth) 
• Loperamidec: initially 4 mg, followed by 2 mg 
every four hours or after every unformed 
stool; maximum 16 mg/day. Continue until 
diarrhea free for 12 hours 
• Diarrhea > 24h: loperamide 2 mg every two 
hours; maximum 16 mg/day.  Consider 
adding oral antibiotics 
• Diarrhea > 48h: loperamide 2 mg every two 
hours; maximum 16 mg/day. Add budesonide 
or other second-line therapies (otreotide, or 
tincture of opium) and oral antibiotics 
• Continue trametinib 
• If diarrhea is grade 2 for > 48h,  
interrupt trametinib until 
diarrhea resolves to grade ≤ 1 
• Restart trametinib at the same 
dose level  
• If treatment delay is > 14 days, 
discontinue trametinib. 
Uncomplicated 
Diarrheaa 
Grade 3 or 4 
 
Any 
Complicated 
Diarrheab 
• Clinical evaluation mandatory 
• Loperamidec: initially 4 mg, followed by 2 mg 
every four hours or after every unformed 
stool; maximum 16 mg/day. Continue until 
diarrhea free for 12 hours 
• Oral antibiotics and second-line therapies if 
clinically indicated 
• Hydration: intravenous fluids if clinically 
indicated 
• Antibiotics (oral or intravenous) if clinically 
indicated 
• Intervention should be continued until the 
subject is diarrhea free for ≥ 24 hours 
• Intervention may require hospitalization for 
subjects at risk of life-threatening 
complications 
• Interrupt trametinib until 
diarrhea resolves to grade ≤ 1 
• Restart with trametinib 
reduced by one dose leveld 
• If 3 dose reductions of study 
treatment are clinically 
indicated, permanently 
discontinue trametinib 
Abbreviation:  CTCAE = Common Terminology Criteria for Adverse Events 
a. Uncomplicated diarrhea defined by the absence of  symptoms such as, cramping, 
nausea/vomiting ≥ grade 2, decreased performance status, pyrexia, sepsis, neutropenia grade ≥ 3, 
frank bleeding, and/or dehydration requiring intravenous fluid substitution 
b. Complicated diarrhea defined by the presence of symptoms such as, cramping, nausea/vomiting  
≥ grade 2, decreased performance status, pyrexia, sepsis, neutropenia grade ≥ 3, frank bleeding, 
and/or dehydration requiring intravenous fluid substitution 
c. Loperamide should be made available prior to start of study treatment so loperamide administration 
can begin at the first signs of diarrhea 
d. Escalation of trametinib to previous dose level is allowed after consultation with the Subprotocol 
Study Chair and in the absence of another episode of complicated or severe diarrhea in the 4 
weeks subsequent to dose reduction. 

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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, 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 subprotocol Study Chair; if 
continuation of treatment agreed then restart trametinib at 
dose reduced by one dose level. 
If event does not resolve, permanently discontinue 
trametinib. 
Trametinib should be discontinued if treatment delay is ≥ 14 days due to toxicities.  If the investigator 
concludes that continued trametinib will benefit a patient, the subprotocol Study Chair may be consulted 
for the possibility of resuming trametinib, provided that toxicities have resolved to baseline or grade 1. 
3.6 
Supportive Care  
All supportive measures consistent with optimal patient care will be given 
throughout the study. 
3.7 
Duration of Agent-specific treatment  
In the absence of treatment delays due to adverse event(s), treatment may 
continue until one of the following criteria applies: 
• 
Extraordinary Medical Circumstances: If at any time the constraints of this 
protocol are detrimental to the patient's health, protocol treatment should be 
discontinued. In this event submit forms according to the instructions in the 
MATCH Forms Packet. 
• 
Patient withdraws consent. 
• 
Patient experiences unacceptable toxicity. 
• 
Non-protocol therapies are administered. 
• 
Disease 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 main screening protocol, the below parameters must also be 
performed for patients receiving Trametinib treatment.  
NOTE: 
All assessments required prior to registration to treatment should be done ≤ 4 weeks prior to registration to 
Steps 1, 3, 5, 7, excluding the radiologic evaluation and electrocardiogram (ECG). 
Test/Assessment 
Prior to Registration 
to Treatment 
Treatment 
End of 
Treatment 
Follow 
UpF 
Every Cycle, prior to 
treatment 
Every 2 Cycles 
H&P, Weight, Vital signsA 
X 
XJ 
 
 
X 
Performance status 
X 
XJ 
 
 
X 
CBC w/diff, pltsB 
X 
XJ 
 
 
X 
Serum chemistryB 
X 
XJ 
 
 
X 
Radiologic evaluationD 
X 
 
XD 
 
XF 
-HCGC 
X 
 
 
 
 
Toxicity AssessmentG 
X 
X 
 
X 
XF 
Pill Count/DiaryH 
 
X 
 
X 
 
ECGK,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 either ECHO or Nuclear Study (MUGA or First Pass) is needed at week 5, week 13, and every 12 weeks 
thereafter unless clinically indicated sooner. The same modality should be used at baseline and thereafter. 
 
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5. 
Drug Formulation and Procurement 
This information has been prepared by the ECOG-ACRIN Pharmacy and Nursing 
Committees. 
Availability 
NO STARTER SUPPLIES MAY BE ORDERED. Subjects must be enrolled and assigned 
to the treatment subprotocol prior to submitting the clinical drug request to PMB. 
Drug Ordering: NCI supplied agents may be requested by eligible participating 
Investigators (or their authorized designee) at each participating institution.  
Pharmaceutical Management Branch (PMB) policy requires that drug be shipped directly 
to the institution where the patient is to be treated. PMB does not permit the transfer of 
agents between institutions (unless prior approval from PMB is obtained – see general 
information) The CTEP-assigned protocol number must be used for ordering all CTEP-
supplied investigational agents.  The eligible participating investigators at each 
participating institution must be registered with CTEP, DCTD through an annual 
submission of FDA Form 1572 (Statement of Investigator), NCI Biosketch, Agent 
Shipment Form, and Financial Disclosure Form (FDF).  If there are several participating 
investigators at one institution, CTEP-supplied investigational agents for the study 
should be ordered under the name of one lead investigator at that institution. 
Submit agent requests through the PMB Online Agent Order Processing (OAOP) 
application (https://ctepcore.nci.nih.gov/OAOP).  Access to OAOP requires the 
establishment of a CTEP Identity and Access Management (IAM) account 
(https://ctepcore.nci.nih.gov/iam/) and the maintenance of an “active” account status, a 
“current” password, and an active person registration status. 
NCI Supplied Agent(s) – General Information 
Questions about drug orders, transfers, returns, or accountability should be 
addressed to the PMB by calling 240-276-6575 Monday through Friday between 
8:30 AM and 4:30 PM Eastern Time or email PMBAfterHours@mail.nih.gov 
anytime. 
Drug Returns: All undispensed drug supplies should be returned to the PMB. When it is 
necessary to return study drug (e.g., sealed bottles remaining when PMB sends a stock 
recovery letter), investigators should return the study drug to the PMB using the NCI 
Return Agent Form available on the NCI home page (http://ctep.cancer.gov). 
Drug Accountability: The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the receipt, disposition, and return of 
agent received from the PMB using the NCI Investigational Agent Accountability Record 
Form for Oral Agents available on the NCI home page (http://ctep.cancer.gov).  Maintain 
separate NCI Investigational Agent Accountability Records for each agent, strength, 
formulation and ordering investigator. 
Investigator Brochure Availability: The current versions of the IBs for PMB-supplied 
agents will be accessible to site investigators and research staff through the PMB Online 
Agent Order Processing (OAOP) application.  Access to OAOP requires the 
establishment of a CTEP Identity and Access Management (IAM) account and the 
maintenance of an “active” account status, a “current” password, and active person 
registration status.  Questions about IB access may be directed to the PMB IB 
coordinator at IBCoordinator@mail.nih.gov. 
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5.1 
Trametinib (NSC 763093) 
5.1.1 
Other Names  
GSK1120212, MEKINIST™, 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. 
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5.1.7 
Route of Administration  
Oral. Take by mouth on an empty stomach, either 1 hour before or 2 
hours after a meal. If a dose of trametinib is missed, the dose can be 
taken if it is more than 12 hours until the next scheduled dose. 
5.1.8 
Incompatibilities  
In vitro studies suggest that trametinib 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 
Women of childbearing potential and men must agree to use 
adequate contraception (hormonal or barrier method of birth control; 
abstinence) prior to study entry, for the duration of study participation, 
and for 4 months after completion of study. 
 
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6. 
Translational Studies 
Please refer to the MATCH Master Protocol for information on the Translational Studies.  
7. 
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306. 

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Molecular Analysis for Therapy Choice (MATCH) 
MATCH Treatment Subprotocol S1: Trametinib/NF1 
Appendix I  
 
Patient Pill Calendar 
 
Pill Calendar Directions 
1. Take your scheduled dose of each tablet at around the same time each day. 
2. Please bring the empty bottle or any leftover tablets and your pill calendar to your 
next clinic visit.  
3. Take trametinib (GSK1120212) once daily by mouth either 1 hour before or 2 hours 
after a meal. 
4. If a dose of trametinib is missed, only make up this missed dose if it is still more than 
12 hours until the next scheduled dose. 
5. Trametinib should be stored at 2-8°C (36-46°F). Refrigerate. Do not freeze. 
6. Trametinib should not be crushed, dissolved, or chewed. 
7. Do not take an additional dose as a replacement if vomiting were to occur after a 
dose of trametinib. 
 
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Patient Pill Calendar 
This is a calendar on which you are to record the time and number of tablets you take 
each day.  You should take your scheduled dose of each tablet. Note the times and the 
number of tablets that you take each day. If you develop any side effects, please 
record them and anything you would like to tell the doctor in the space provided.  Bring 
any unused tablets and your completed pill calendar to your doctor’s visits. 
Trametinib 
DAY  
Date 
Time 
tablets 
taken 
Number of 
tablets 
taken 
Use the space below to make notes 
about things you would like to tell the 
doctor (including unusual symptoms 
you experience, other medicine you 
have taken and anything else you 
think would be of interest.) 
Month 
Day 
Year 
 
1 
 
 
 
 
 
 
2 
 
 
 
 
 
 
3 
 
 
 
 
 
 
4 
 
 
 
 
 
 
5 
 
 
 
 
 
 
6 
 
 
 
 
 
 
7 
 
 
 
 
 
 
8 
 
 
 
 
 
 
9 
 
 
 
 
 
 
10 
 
 
 
 
 
 
11 
 
 
 
 
 
 
12 
 
 
 
 
 
 
13 
 
 
 
 
 
 
14 
 
 
 
 
 
 
15 
 
 
 
 
 
 
16 
 
 
 
 
 
 
17 
 
 
 
 
 
 
18 
 
 
 
 
 
 
19 
 
 
 
 
 
 
20 
 
 
 
 
 
 
21 
 
 
 
 
 
 
22 
 
 
 
 
 
 
23 
 
 
 
 
 
 
24 
 
 
 
 
 
 
25 
 
 
 
 
 
 
26 
 
 
 
 
 
 
27 
 
 
 
 
 
 
28 
 
 
 
 
 
 
Patient Signature: __________________________________ Date: _____________ 
 

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Molecular Analysis for Therapy Choice (MATCH) 
MATCH Treatment Subprotocol S1: Trametinib/NF1 
Appendix II  
 
Trametinib Ophthalmic Exam Form 
Please use the form on the following page for documenting ophthalmic examinations as 
appropriate to the clinical situation. 
Subject Name: ________________________________________________ 
Note to examiner: 
Please assess particularly for visible retinal pathology. 
*Optical coherence tomography is highly recommended For patients in whom retinal 
abnormalities are noted, color fundus photos, and fluorescein angiography if clinically 
indicated, are recommended.   
OPHTHALMIC EXAMINATION 
1. Date of Examination: 
_ _/_ _ _ /_ _ _ _ 
dd  /   mmm   /    yyyy 
VISUAL ACUITY 
Enter corrected visual acuity 
OD: 
OS: 
TONOMETRY 
Enter IOP (mmHg) 
OD: 
OS: 
INDIRECT FUNDOSCOPY 
Indirect Exam: Indicate normal or specify 
abnormalities 
OD: 
OS: 
CONFRONTATION VISUAL FIELD EXAM  OR AUTOMATED PERIMETRY (e.g., Humphrey 24-2 
or 30-2 or equivalent if using a non-Humphrey instrument) 
Indicate normal or specify any abnormalities 
OD: 
OS: 
OPTICAL COHERENCE TOMOGRAPHY (strongly recommended) 
Indicate normal or specify any abnormalities 
OD: 
OS: 
COLOR FUNDUS PHOTOS (recommended if retinal abnormalities are noted)* 
Indicate normal or specify any abnormalities 
OD: 
OS: 
FLORESCEIN ANGIOGRAPHY (suggested if retinal abnormalities are noted and test clinically 
indicated)* 
Indicate normal or specify any abnormalities 
OD: 
OS: 
Were any of the following noted on ocular history or exam? 
Yes 
No 
• 
History of CSR? 
 
 
• 
Evidence of new optic disc cupping? 
 
 
• 
Evidence of new visual field defects? 
 
 
EXCLUSION CRITERIA 
Yes 
No 
• 
History of RVO? 
o 
If yes, patient is not eligible for the study. 
 
 
Signature of Examiner: _____________________________   
Printed Name: _________________________      Date: ______________ 

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Molecular Analysis for Therapy Choice (MATCH) 
MATCH Treatment Subprotocol S1: Trametinib/NF1 
Appendix III 
 
Actionable Mutations for Sub-Protocol EAY131-S1 
A function has been implemented in MATCHBOX to identify any deleterious inactivation 
mutations in the NF1 gene at Level of Evidence code 3. This function also includes any 
deleterious mutations in the NF1 gene with Level of Evidence code 3 or higher. Please 
refer to Section 1.4.2 of the MATCH Master Protocol for more information. 
NF1 is a tumor suppressor gene. Inactivating deleterious mutations could occur 
anywhere in the coding regions. Instead of listing all possible deleterious mutations, we 
have implemented a function in MATCHBOX that can identify any point mutations 
creating stop codons that will lead to premature truncations or any insertions/deletions 
causing frameshifts, which are predicted to result in a non-functional or absent protein. 
Variants, including missense mutations, were not included for eligibility if there was a 
lack of adequate evidence that such variants resulted in loss of function in NF1 gene. 
 
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Molecular Analysis for Therapy Choice (MATCH) 
MATCH Treatment Subprotocol S1: Trametinib/NF1 
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. 
Your study doctor’s name is  
_____________________________________  
and he or she can be contacted at  
_____________________________________. 

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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 has a low risk of 
interacting with other medications.  It is a weak 
CYP2C8 Inhibitor and weak CYP3A4 inducer. 
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. 
 
➢ Before you start the study, your study doctor will work 
with your regular prescriber to switch any medicines 
that and herbal supplements that use the liver 
enzymes CYP2C8 and CYP3A4. 
➢ Before prescribing new medicines, your regular 
prescribers should go to frequently updated drug 
information reference for a list of drugs to avoid, or 
contact your study doctor.   
➢ Your study doctor’s name is 
_____________________________ and can be 
contacted at 
_________________________________.