Clinical trial NCT03148275
Conditions: Locally Advanced Epithelioid Hemangioendothelioma Metastatic Epithelioid Hemangioendothelioma Unresectable Epithelioid Hemangioendothelioma
Sponsor: National Cancer Institute (NCI)
Start date: 2017-06-20; Completion date: 2023-06-23
Enrollment: 44 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies how well trametinib works in treating patients with epithelioid hemangioendothelioma that has spread to other places in the body (metastatic), nearby tissue or lymph nodes (locally advanced), or cannot be removed by surgery (unresectable). Trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed description:
PRIMARY OBJECTIVE:

I. Estimate the objective response rate (ORR) using Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1).

SECONDARY OBJECTIVES:

I. Estimate the 6-month and median progression free survival (PFS) rates. II. Estimate the 2-year and median overall survival (OS) rates. III. Evaluate the safety of trametinib in patients with epithelioid hemangioendothelioma.

IV. Evaluate patient-reported symptoms using National Institutes of Health Patient Reported Outcomes Measurement Information System (NIH PROMIS) global health; pain intensity, interference and behavior short form inventories prior to, after 4 weeks and after 6 months (if stable or better disease) of treatment, and on evidence of disease progression.

EXPLORATORY OBJECTIVES:

I. Compare the rates of epithelioid hemangioendothelioma progression prior to starting trametinib to rates on treatment by central review of radiology images.

II. Evaluate the effect of trametinib on change in tumor volume and compare to RECIST 1.1 response through central imaging review.

III. Evaluate the effect of trametinib on markers of inflammation including c-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and plasma connective tissue growth factor (CTGF).

OUTLINE:

Patients receive trametinib orally (PO) once daily (QD) on days 1-28. Treatment repeats every 28 days for up to 52 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 6 months.

Arms: arm 1: Patients receive trametinib PO QD on days 1-28. Treatment repeats every 28 days for up to 52 cycles in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Questionnaire Administration intervention 2: Trametinib
Intervention descriptions: intervention 1: Ancillary studies intervention 2: Given PO

Protocol documents:
Prot_SAP_000.pdf: 
NCI Protocol #: 10015 
Version Date: June 23, 2020 
 
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SUMMARY OF CHANGES – Protocol 
 
For Protocol Amendment # to: 
 
NCI Protocol #: 10015 
Local Protocol #: SARC033 
 
Protocol Version Date: June 23, 2020 
 
Summary of changes Memo 
 
 
 
Revisions June 23, 2020 
 
 
1. Updated Section 8.1.1. 
2. Updated Patient Clinical Trial Wallet Card 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


NCI Protocol #: 10015 
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NCI Protocol #: 
10015 
 
Local Protocol #: 
SARC033 
 
ClinicalTrials.gov Identifier: NCT03148275 
 
TITLE:  A Non-Randomized, Open-Label, Phase 2 Study of Trametinib in Patients with 
Unresectable or Metastatic Epithelioid Hemangioendothelioma 
 
Corresponding Organization: University of Michigan Comprehensive Cancer Center 
EDDOP (EDDO-MI014) 
 
Coordinating Center: 
SARC (Sarcoma Alliance for Research through Collaboration) 
24 Frank Lloyd Wright Dr., Lobby A, Suite 3100 
 
Ann Arbor MI 48105 
 
Principal Investigator: 
Scott Schuetze, MD, PhD 
 
Division of Hematology/Oncology 
Department of Internal Medicine 
University of Michigan 
1500 E Medical Center Drive 
C342 Med Inn, SPC 5848 
Ann Arbor, MI 48109 
Phone: 734-647-8925 
Fax: 734-647-7279 
scotschu@med.umich.edu 
 
Participating Organizations (Only the participating LAOs should be listed.) 
LAO-11030 / University Health Network Princess Margaret Cancer Center LAO 
LAO-CA043 / City of Hope Comprehensive Cancer Center LAO 
LAO-CT018 / Yale University Cancer Center LAO 
LAO-MA036 / Dana-Farber - Harvard Cancer Center LAO 
LAO-MD017 / JHU Sidney Kimmel Comprehensive Cancer Center LAO 
LAO-MN026 / Mayo Clinic Cancer Center LAO 
LAO-NC010 / Duke University - Duke Cancer Institute LAO 
LAO-NJ066 / Rutgers University - Cancer Institute of New Jersey LAO 
LAO-OH007 / Ohio State University Comprehensive Cancer Center LAO 
LAO-PA015 / University of Pittsburgh Cancer Institute LAO 
LAO-TX035 / University of Texas MD Anderson Cancer Center LAO 
LAO-NCI / National Cancer Institute LAO 


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EDDOP/ Early Drug Development Opportunity Program 
Statistician: 
 
SARC Research Project Manager:  
Karla Ballman, PhD 
Rachel Luchs 
402 East 67th Street 
24 Frank Lloyd Wright DR 
New York, NY 10065 
Lobby A, Suite 3100 
Phone: 646-962-8023 
Ann Arbor MI 48105 
kab2053@med.cornell.edu 
Phone: 734-930-7600 
 
 
Fax: 734-930-7557 
 
 
SARC033@sarctrials.org 
 
SARC Medical Monitor: 
 
Scott Okuno 
 
Mayo Clinic 
 
200 1st St SW 
Rochester, MN 55905 
 
Phone: 507-266-9161 
 
 
okuno.scott@mayo.edu 
 
 
 
NCI-Supplied Agent(s):  Trametinib dimethyl sulfoxide (GSK1120212B) (NSC 763093) 
 
Other Agent(s): 
Not applicable 
 
 
Protocol Type / Version # / Version Date: 
Original /Version 6/ June 23, 2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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SCHEMA 
 
 
 
 
 
 
Patients with metastatic or unresectable epithelioid 
hemangioendothelioma 
Screening 
Administer trametinib PO daily. Assess disease 
every 2 cycles (± 7 days) with 28 day cycle length 
for the 1st 6 cycles then every 3 cycles (± 7 days). 
Treatment will continue for up to 4 
years or until disease progression or 
dose-limiting toxicity 
Patients will be followed for survival for 2 years or for 
6 months after discontinuation, whichever is longer 
Off Study 


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TABLE OF CONTENTS 
SCHEMA .........................................................................................................................................4 
1. 
OBJECTIVES ......................................................................................................................7 
1.1 
Primary Objectives ...................................................................................................7 
1.2 
Secondary Objectives ...............................................................................................7 
1.3 
Exploratory Objectives ............................................................................................7 
2. 
BACKGROUND .................................................................................................................7 
2.1 
Epithelioid Hemangioendothelioma ........................................................................7 
2.2 
CTEP IND Agent .....................................................................................................9 
2.3 
Rationale ................................................................................................................17 
2.4 
Correlative Studies Background ............................................................................17 
3. 
PATIENT SELECTION ....................................................................................................20 
3.1 
Eligibility Criteria ..................................................................................................20 
3.2 
Exclusion Criteria ..................................................................................................22 
3.3 
Inclusion of Women and Minorities ......................................................................24 
4. 
REGISTRATION PROCEDURES ...................................................................................24 
4.1 
Investigator and Research Associate Registration with CTEP ..............................24 
4.2 
Site Registration .....................................................................................................25 
4.3 
Patient Registration ................................................................................................27 
4.4 
General Guidelines .................................................................................................28 
5. 
TREATMENT PLAN ........................................................................................................28 
5.1 
Agent Administration .............................................................................................28 
5.2 
Definition of Dose-Limiting Toxicity ....................................................................29 
5.3 
Dose Expansion Cohorts ........................................................................................29 
5.4 
General Concomitant Medication and Supportive Care Guidelines ......................29 
5.5 
Duration of Therapy ...............................................................................................29 
5.6 
Duration of Follow Up ...........................................................................................30 
5.7 
Criteria for Removal from Study ...........................................................................30 
6. 
DOSING DELAYS/DOSE MODIFICATIONS................................................................30 
6.1 
Trametinib Dose Modifications .............................................................................30 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................41 
7.1 
Comprehensive Adverse Events and Potential Risks List(s) (CAEPRs) ...............42 
7.2 
Adverse Event Characteristics ...............................................................................46 
7.3 
Expedited Adverse Event Reporting ......................................................................47 
7.4 
Routine Adverse Event Reporting .........................................................................48 
7.5 
Secondary Malignancy ...........................................................................................49 
7.6 
Second Malignancy ................................................................................................49 


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8. 
PHARMACEUTICAL INFORMATION ..........................................................................49 
8.1 
CTEP IND Agent(s) ...............................................................................................49 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................53 
9.1 
Integral Laboratory or Imaging Studies .................................................................53 
9.2 
Integrated Studies...................................................................................................53 
9.3 
Exploratory/Ancillary Correlative Studies ............................................................54 
9.4 
Special Studies .......................................................................................................57 
10. 
STUDY CALENDAR .......................................................................................................59 
11. 
MEASUREMENT OF EFFECT........................................................................................61 
11.1 
Antitumor Effect – Solid Tumors ..........................................................................61 
11.2 
Antitumor Effect – Hematologic Tumors N/A ......................................................67 
11.3 
Other Response Parameters – N/A ........................................................................67 
12. 
STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS .............................................................................................................67 
12.1 
Study Oversight .....................................................................................................67 
12.2 
Data Reporting .......................................................................................................67 
12.3 
CTEP Multicenter Guidelines - N/A ......................................................................69 
12.4 
Collaborative Agreements Language .....................................................................69 
12.5 
Genomic Data Sharing Plan ...................................................................................71 
13. 
STATISTICAL CONSIDERATIONS...............................................................................71 
13.1 
Study Design/Endpoints.........................................................................................71 
13.2 
Sample Size/Accrual Rate ......................................................................................72 
13.3 
Stratification Factors ..............................................................................................73 
13.4 
Analysis of Exploratory Endpoints ........................................................................73 
13.5 
For phase 2 protocols only: Reporting and Exclusions.........................................74 
REFERENCES ..............................................................................................................................76 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ..................................................80 
APPENDIX B 
PATIENT CLINICAL TRIAL WALLET CARD .....................................81 
APPENDIX C 
BIOASSAY TEMPLATES .......................................................................82 
APPENDIX D            SARC033 STUDY DRUG DIARY ...........................................................83 
APPENDIX E            PROMIS Questionnaires ............................................................................83 
 
 
 


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1. OBJECTIVES 
 
1.1 
Primary Objectives 
• Estimate the objective response rate (ORR) using RECIST 1.1 
 
1.2 
Secondary Objectives 
• Estimate the 6-month and median progression free survival (PFS) rates 
• Estimate the 2-year and median overall survival (OS) rates 
• Evaluate the safety of trametinib in patients with epithelioid hemangioendothelioma 
• Evaluate patient-reported symptoms using NIH PROMIS global health; pain intensity, 
interference and behavior short form inventories prior to, after 4 weeks and after 6 
months (if stable or better disease) of treatment, and on evidence of disease progression 
 
1.3 
Exploratory Objectives 
• Compare the rates of epithelioid hemangioendothelioma progression prior to starting 
trametinib to rates on treatment by central review of radiology images 
• Evaluate the effect of trametinib on change in tumor volume and compare to RECIST1.1 
response through central imaging review 
• Evaluate the effect of trametinib on markers of inflammation including c-reactive protein 
(CRP), erythrocyte sedimentation rate (ESR) and plasma connective tissue growth factor 
(CTGF). 
 
2. BACKGROUND 
 
2.1 
Epithelioid Hemangioendothelioma 
 
Epithelioid hemangioendothelioma (EHE) is a rare sarcoma that shows vascular (endothelial) 
differentiation. It usually presents with widespread metastases. Although metastatic disease can 
be stable for years, it inevitably progresses rapidly and without warning, is highly lethal and has 
no effective treatment. EHE can occur at any age, but peaks in adulthood (Weiss & Enzinger, 
1982). Five-year disease-specific mortality is 40% and 65% for EHE that arises in the lung and 
liver, respectively (Weiss & Goldblum, 2008). Although localized EHE can often be treated with 
surgery and radiation, systemic therapy options are limited for patients with metastatic disease in 
which the median survival is less than 4 years.  
 
Due to the rarity of this disease, there is no consensus on standard systemic therapy and data is 
limited to single-institution case reports or retrospective case series. Cioffi et al. (Cioffi et al., 
2011) reported a retrospective study of 42 patients with metastatic EHE. Thirty-four patients 
received systemic chemotherapy including conventional doxorubicin-containing regimens 
(n=16), other chemotherapy regimens (n=6), and anti-angiogenesis agents or tyrosine kinase 
inhibitors (TKI, n=12). There were no objective responses although 14 patients had stable 
disease for at least 6 months. Of those with stable disease, 4 patients received doxorubicin-
containing chemotherapy, 4 received other chemotherapy and 6 received angiogenesis targeting 
agents or TKIs. Median PFS was 4.8 months and median OS was 41 months.  
 


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Mehrabi et al. published a comprehensive review of patients with malignant hepatic EHE 
comprised of 434 patients (Mehrabi et al., 2006). The most common treatment was liver 
transplantation (44.8%), followed by observation (24.8%) and chemotherapy or radiotherapy 
(21%). One-year and five-year patient survival rates were 73.3% and 30%, respectively, for 
patients who received treatment with chemotherapy or radiotherapy. Chemotherapeutic regimens 
were diverse and included thalidomide, doxorubicin, 5-fluorouricil, epirubicin plus dacarbazine 
and interferon-alpha. Based on the data presented as a retrospective observational analysis, the 
effectiveness of the different chemotherapy treatments used cannot be inferred.  
 
There have been few clinical trials that have prospectively investigated drug therapies for 
patients with EHE. For example, a phase II study evaluated bevacizumab in seven patients with 
locally advanced or metastatic EHE (Agulnik et al., 2013). Two patients had a partial response 
and four patients demonstrated stable disease with one patient experiencing progressive disease 
at first evaluation. The mean number of cycles received was 17.3 (52 weeks). Median PFS was 
39.1 weeks and median OS was 142.6 weeks. Given the small number of patients in this study, 
further conclusions cannot be made.  
 
A phase II study by the French Sarcoma Group evaluated the efficacy of sorafenib (800 mg 
daily) in 15 patients with progressive EHE with a primary endpoint of 9-month PFS (Chevreau et 
al., 2013). Twelve patients had metastatic disease at the time of enrollment. The 2-month, 4-
month, 6-month and 9-month progression free rates were 84.6%, 46.4%, 38.4% and 30.7%, 
respectively. Median follow-up was 12 months, with a median PFS of 6 months. Median overall 
survival was not reached at the time of analysis. Two partial responses were noted and lasted 2 
months and 9 months. The median treatment duration was 124 days with seven patients requiring 
dose reductions or transient treatment discontinuation due to toxicity including hand-foot 
syndrome, diarrhea and mucositis with anorexia. Previously reported treatment and trials have 
used chemotherapy, immunotherapy, multi-kinase inhibitors or anti-vascular endothelial growth 
factor inhibitors with marginal benefit; therefore, standard drug therapy for patients with locally 
advanced or metastatic unresectable EHE has not been established. 
 
Recently, a disease-defining TAZ-CAMTA1 gene fusion has been identified in EHE. This is a 
balanced, reciprocal translocation that results in the fusion of TAZ (also known as WWTR1), to 
CAMTA1, dysregulating the Hippo pathway (Tanas et al., 2016; Tanas et al., 2011). Importantly, 
this fusion is found in more than 90% of EHE tumors, and EHE tumors have no other consistent 
genetic alterations, suggesting that the fusion is an early and important genetic event and that 
EHE cells are highly dependent on TAZ-CAMTA1 (Tanas et al., 2011). TAZ-CAMTA1 drives 
oncogenic transformation through a TAZ-like transcriptional program and the Hippo pathway is 
unable to regulate TAZ-CAMTA1 (Tanas et al., 2016). Thus, this fusion unleashes an otherwise 
tightly controlled transcriptional program resulting in EHE oncogenesis. Rubin et al. have 
studied signal transduction downstream of TAZ-CAMTA1, identifying connective tissue growth 
factor (CTGF) and MAP kinase signaling as key pathways and potential therapeutic targets 
(unpublished data). Most of the clinical studies discussed above predate the discovery of this 
gene fusion. The limited success of systemic therapies as demonstrated in these reports 
underscores the need for further research to identify more effective treatments.  
 


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2.2 
CTEP IND Agent 
 
2.2.1 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 and activates MAPKK (MEK1/2), which in 
turn catalyzes activation of the effectors ERK1/ERK2.  Once activated, ERK1/2 
translocate into the nucleus and phosphorylate a number of effector proteins and 
transcriptional factors that regulate cell proliferation, motility, differentiation, and 
survival. 
 
Trametinib is one of 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 Food and Drug Administration granted accelerated 
approval to trametinib and dabrafenib for use in combination to treat patients with 
unresectable or metastatic melanoma with a BRAF V600E or V600K mutation as 
detected by an FDA-approved test (U.S. Food and Drug Administration, 2014). 
 
Experience to date indicates that MEK is a valid target.  In a phase 3 trial comparing 
trametinib with dacarbazine or paclitaxel in patients with BRAF V600E or V600K 
mutant metastatic melanoma, trametinib demonstrated a significantly better response rate, 
progression-free survival, and overall survival (Flaherty et al., 2012).  However, single 
agent activities are limited.  Extensive research is underway to identify the patient 
selection markers and develop rational combination strategies.  Preclinical studies have 
provided strong rationale and proof of principle for combination of MEK inhibitors with 
RTK inhibitors (EGFR or IGF-1R) (Gopal et al., 2010; Ebi et al., 2011), PI3K/AKT 
inhibitors (Engelman et al., 2008; Hoeflich et al., 2009), and mTOR inhibitors.  On the 
other hand, the optimal dose/schedule and patient selection criteria for combination 
regimens have not been defined.  Phase 1 results for a number of combinations have been 
reported, including AZD6244 + MK2206 (Tolcher et al., 2011) and GDC-0973 + GDC-
094 (MEK + PI3K inhibitor) (Bendell et al., 2011). 
 
The most up-to-date preclinical and clinical study information for trametinib can be 
found in the GSK1120212 (trametinib) Investigator's Brochure (August 10, 2018). 
 
2.2.1.1 
Mechanisms of Action and Preclinical Data with Trametinib 
 
Trametinib is a dimethyl sulfoxide (DMSO) solvate compound (ratio 1:1) with potent, 
allosteric and ATP non-competitive inhibition of MEK1/2 (IC50 of 0.7 and 0.9 nM 
against MEK1 and MEK2, respectively) (Gilmartin et al., 2011).  Trametinib inhibited 
MEK1/2 kinase activity and prevented RAF-dependent MEK phosphorylation (S217 for 


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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. 
 
2.2.1.2 
Clinical Pharmacokinetics (PK) and Activity of Trametinib 
 
FTIH Phase 1 Trial of Trametinib Monotherapy (MEK111054) 
There are 3 parts in this study.  Part 1:  The dose-escalation portion involves 
administration of trametinib (repeat doses of 0.125 mg to 4.0 mg) to patients with solid 
tumors or lymphoma in one of three schedules - (1) QD for 21 days followed by 7 days 
without drug, (2) loading dose on Day 1 or Day 1-2, followed by QD with the designated 
dose, or (3) QD dosing without a drug holiday.  Part 2:  cohort expansion at the 
recommended phase 2 dose (RP2D) for pancreatic cancer, melanoma, 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). 


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The MTD of trametinib was established as 3 mg QD, but the recommended phase 2 dose 
(RP2D) was chosen at 2 mg QD based on tolerability of repeated cycles (Infante et al., 
2010). 
 
Trametinib treatment in children 
A 3 part phase 1/2, open-label, multicenter study of trametinib in pediatric subjects with 
recurrent or refractory tumors (NCT02124772) is underway. Unpublished results from 
the part A, dose escalation portion of the study which included 38 subjects is complete. 
The recommended phase 2 dose in children 6 years of age or older is 0.025 mg/kg per 
day with the total dose not to exceed 2 mg per day. A dose of 0.04 mg/kg per day 
(corresponding to a dose of 2 mg per day in a subject weighing 50 kg) was associated 
with skin related dose-limiting toxicities. Pharmacokinetic steady state drug 
concentration target was met in children 6 years of age or older using a dose of 0.025 
mg/kg per day. (confidential information from Novartis) 
 
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., 2010).  At 2 mg QD on 
Day 15, mean AUC0-24 was 376 ng•h/mL and Cmax 23 ng/mL, and the mean trough 
concentrations ranged from 10.0 to18.9 ng/mL.  The long half-life and small peak:trough 
ratio of trametinib allowed constant target inhibition within a narrow range of exposure. 
 
Drug-drug interactions: 
Trametinib is metabolized predominantly via deacetylation (non-cytochrome P450 
[CYP450]-mediated) with secondary oxidation or in combination with glucuronidation 
biotransformation pathways (Investigator’s Brochure, 2012a).  The deacetylation is likely 
mediated by hydrolytic esterases, such as carboxylesterases, or amidases.  Based on in 
vitro studies, trametinib is not an inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2D6, 
and CYP3A4.  Trametinib has an overall low potential for drug-drug interactions. 
 
Pharmacodynamic effect and biomarkers: 
The relationship between dose and tumor biomarkers such as pERK, Ki67, and p27, were 
evaluated in patients with BRAF or NRAS mutation-positive metastatic melanoma 
(Investigator's Brochure, 2012a).  In general, increasing exposures and/or doses provided 
greater pharmacodynamic effects.  The median change observed at a dose of 2 mg QD 
was 62% inhibition of pERK, 83% inhibition of Ki67, and a 175% increase in p27. 


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Antitumor Activity in the FTIH phase 1 trial:  
In the FTIH 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 patients with 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. 
 
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-


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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 was reported in 39 patients (Borthakur et al., 2010).  The best response in 13 
patients with KRAS or NRAS mutations included 3 CRs (23%), 7 SD (54%), and 1 PD 
(progressive disease) (5%).  In 26 patients with wild-type RAS or an unknown mutation, 
there were 2 PRs (8%). 
 
In a multicenter phase 2 study, NSCLC patients with KRAS mutant tumors were 
randomized 2:1 to receive trametinib (2 mg QD) or docetaxel (75 mg/m2 IV every 3 
weeks) (Blumenschein et al., 2013).  A total of 134 pts were randomized to trametinib 
(89) or docetaxel (45); 129 patients had KRAS-mutant NSCLC.  The hazard ratio for PFS 
was 1.14 (95% CI, 0.75-1.75; P=0.5197) with a median PFS of 11.7 versus 11.4 weeks 
for trametinib versus docetaxel.  The overall response rate (ORR) was 12% for trametinib 
and 12% for docetaxel. 
 
In a double-blind, phase 2 study evaluating the combination of gemcitabine with 
trametinib, untreated pancreatic cancer patients were randomized to receive gemcitabine 
(1000 mg/m2 weekly 7 for 8 weeks, then weekly 3 every 4 weeks) plus either 
trametinib 2mg or placebo QD (Infante et al., 2013).  Median OS was 8.4 months with 
trametinib compared to 6.7 months with placebo.  Median PFS was 16 weeks versus 15 
weeks, and ORRs and median duration of responses were 22% and 23.9 weeks and 18% 
and 16.1 weeks on trametinib and placebo; the median OS and ORR in the subgroup of 
patients with KRAS mutations (143/160) was similar to OS and ORR for all randomized 
patients.   
 
Trametinib has not been formally evaluated in patients with EHE or soft tissue sarcoma. 
We do not expect drug pharmacokinetics or adverse events rates to differ significantly 
from the experience of trametinib in treatment of metastatic melanoma or non-small cell 
lung cancer. 
 
2.2.1.3 
Trametinib Safety Profile 
 
A Comprehensive Adverse Events and Potential Risks (CAEPR) list using NCI 
Common Terminology Criteria for Adverse Events (CTCAE) terms is included in 
Section 7.1 of the protocol. 


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Based on available AE data from clinical studies involving trametinib to date, the most 
common toxicities are rash and diarrhea.  Rash and diarrhea are common, class-effect 
toxicities for MEK inhibitors.  In addition, visual impairment and left ventricular ejection 
fraction (LVEF) reduction, although observed at lower frequencies, are also considered 
class-effect toxicities as they have been observed with trametinib as well as other MEK 
inhibitors. 
 
AEs of special interest: 
Rash, diarrhea, visual disorders, hepatic disorders, cardiac-related AEs, and pneumonitis 
are considered AEs of special interest because they are either known class effects (i.e., 
have been observed with other MEK inhibitors) or are potentially life-threatening 
(Investigator’s Brochure, 2013).  The following sections provide integrated summaries 
for these AEs across different clinical trials, with emphasis on trials using trametinib as 
monotherapy, especially at the RP2D of 2 mg. 
 
Refer to dose modification guidelines for the toxicities for which they are addressed in 
Section 6. 
 
Rash:  Rash was a common AE observed across different dose levels and in different 
combinations (Investigator’s Brochure, 2013).  At the 2 mg dose, rash was seen in 27% to 
78% of patients in different trials.  Of the ~370 subjects with rash AEs at the 2 mg 
monotherapy dose (including crossover subjects) in five studies, the majority of rash AEs 
were grades 1 or 2 (24% to 73%); 0% to 9% of patients experienced grade 3 rash AEs, 
and four patients had a grade 4 rash AE. 
 
In a randomized phase 3 trial of trametinib vs. chemotherapy, the overall incidence of 
skin toxicity (including rash, dermatitis, acneiform rash, palmar-plantar 
erythrodysesthesia syndrome, and erythema) was 87% in patients treated with trametinib 
and 13% in chemotherapy-treated patients.  Severe skin toxicity occurred in 12% of 
patients on the trametinib arm, most commonly for secondary infections of the skin  The 
median time to onset of skin toxicity was 15 days (range:  1 to 221 days), and median 
time to resolution was 48 days (range:  1 to 282 days).  Dose reduction was required in 
12% for skin toxicities, and permanent discontinuation of trametinib was required in 1% 
of patients.  
 
Diarrhea:  At the 2 mg monotherapy dose, 33% to 58% of patients in five trials had 
diarrhea (Investigator’s Brochure, 2013).  Of ~320 subjects (including crossover subjects) 
with diarrhea at this dose, the majority of diarrhea AEs were grade 1 or 2 in severity 
(33% to 56% of all study patients); 17 patients had grade 3 diarrhea, and none had grade 
4 diarrhea. 
 
Visual disorders:  At the 2 mg monotherapy dose, 4% to 21% of the patients in five trials 
experienced visual disorders (Investigator’s Brochure, 2013).  Of the 85 total subjects 
(including crossover subjects) experiencing visual disorders at this dose level, the 


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majority of visual disorders were grades 1 or 2 (4% to 20% of all study patients); six 
patients experienced grade 3 visual disorders, and one patient experienced a grade 4 
visual disorder. 
− 
Retinal Pigment Epithelial Detachment (RPED):  Also known as chorioretinopathy, 
RPED is a visual impairment due to fluid accumulation under the retina and causes 
blurry vision.  There were five cases of RPED, previously termed central serous 
retinopathy, reported from the integrated trametinib safety population consisting of 
subjects treated with trametinib 2 mg once daily from five studies (Investigator’s 
Brochure, 2013).  As of 23 June 2013, 14 cases of RPED were reported across the 
entire trametinib program amongst subjects treated with trametinib either as 
monotherapy or in combination with other anti-cancer agents (including cases from a 
MEK/BRAF combination study). 
 
− 
Retinal vein occlusion (RVO):  As of 23 June 2013, a total of four cases of RVO were 
reported across the entire trametinib program (including one case from a MEK/BRAF 
combination study) (Investigator’s Brochure, 2013).  All cases of RVO occurred in 
one eye only.  Study drug was stopped at time of diagnosis in all cases.  There was a 
decrease of visual acuity in two subjects with central RVO (CRVO) while the other 
two subjects had no meaningful decrease of visual acuity.  In the two subjects with 
CRVO, local treatment with intravitreal injections of anti-VEGF antibodies was 
initiated within 2 weeks after RVO diagnosis, and visual acuity improved in one 
subject and restored to baseline conditions in another subject, at the time of the data 
cutoff.  Three of these four cases were considered related to study treatment by the 
investigators. 
 
Hepatic disorders:  Abnormalities of liver enzymes and bilirubin have been observed with 
administration of trametinib (Investigator’s Brochure, 2013).  However, assessment of 
these cases was often confounded by co-morbid conditions (such as biliary obstruction), 
concomitant use of other potentially hepatotoxic drugs, and liver metastases.  At the 2 mg 
monotherapy dose, 8% to 34% of patients in five trials had LFT abnormalities.  Of the 96 
total patients (including crossovers) with LFT changes, the majority were grade 1 or 2 in 
severity (4% to 20% of all study patients); 26 had grade 3 events, and 6 patients had 
grade 4 events. 
 
Cardiac-related AEs:  At the 2 mg monotherapy dose, 3% to 21% of the subjects in six 
studies had cardiac-related AEs (Investigator’s Brochure, 2013).  Of the 65 total subjects 
(including crossover subjects) experiencing cardiac-related AEs at the 2.0 mg 
monotherapy dose in five of the studies, the majority of cardiac-related AEs were grades 
1 or 2 in severity (0% to 16% of all study subjects); 18 subjects had grade 3 cardiac-
related AEs, and no subjects had Grade 4 cardiac-related AEs in any study.  No subject in 
one study, which evaluated the effect of repeat oral dosing of trametinib 2 mg QD on 
cardiac repolarization in subjects with solid tumors, had cardiac-related AEs.  One study 
subject receiving trametinib 2 mg QD had grade 5 (fatal) acute cardiac failure, with 
evidence of massive tumor invasion of the heart; this AE was considered not drug-related 
by the investigator. 


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In the phase 3 trial of trametinib vs. chemotherapy in patients with melanoma 
(MEK114267), cardiomyopathy (defined as cardiac failure, left ventricular dysfunction, or 
decreased LVEF) occurred in 7% (14/211) of patients treated with trametinib, and in no 
patients in the chemotherapy arm.  Cardiomyopathy was identified within the first month of 
treatment in five of these 14 patients; median onset of cardiomyopathy was 63 days (range: 
16 to 156 days).  Cardiomyopathy resolved in 10 of these 14 (71%) patients.  Cardiac 
monitoring should be included in trametinib protocols, to include LVEF assessment by 
echocardiogram or MUGA scan at baseline, one month after initiation of trametinib and 
then at 2- to 3-month intervals while on treatment.  Refer to dose modification guidelines 
for cardiac AEs in the event of LVEF decline or symptomatic cardiac AEs. 
 
Pneumonitis:  At the 2 mg monotherapy dose, 0% to 4% of the subjects in five studies 
had pneumonitis (Investigator’s Brochure, 2013).  Of the nine total subjects (including 
crossovers) experiencing pneumonitis AEs at this dose, three subjects had grade 1 or 2 
pneumonitis and six subjects had grade 3 pneumonitis. 
 
Embryofetal toxicity:  Based on its mechanism of action, trametinib can cause fetal harm 
when administered to a pregnant woman.  Trametinib was embryotoxic and abortifacient 
in rabbits at doses greater than or equal to those resulting in exposures approximately 0.3 
times the human exposure at the recommended clinical dose.  If this drug is used during 
pregnancy, or if the patient becomes pregnant while taking this drug, the patient should 
be apprised of the potential hazard to a fetus. 
 
Incidence of common AEs reported from a phase III trial of trametinib vs. chemotherapy 
in patients with advanced melanoma: 
 
Patients with abnormal LVEF, history of acute coronary syndrome within 6 months, or 
current evidence of Class II or greater congestive heart failure (New York Heart 
Association) were excluded from this trial.  Selected adverse reactions (AR) occurring in 
patients receiving trametinib as compared to patients in the chemotherapy arm are listed 
as below: 
 
Table:  Selected adverse reactions (ARs) occurring in ≥10% of patients receiving trametinib 
AND at a higher incidence than in the chemotherapy arm (high in the trametinib arm compared 
with chemotherapy by ≥5% in overall incidence or by ≥2% grade 3 or 4 AEs) 
 
Trametinib 
(n=211) 
Chemotherapy 
(n=99) 
Adverse Reactions 
All Grades 
Grades 
3 and 4 
All Grades 
Grades 
3 and 4 
Skin and subcutaneous tissue 
disorders 
 
 
 
 
Rash 
57 
8 
10 
0 
Dermatitis acneiform 
19 
<1 
1 
0 
Dry skin 
11 
0 
0 
0 
Pruritis 
10 
2 
1 
0 
Paronychia 
10 
0 
1 
0 
Gastrointestinal disorders 
 
 
 
 


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Diarrhea 
43 
0 
16 
2 
Stomatitis 
15 
2 
2 
0 
Abdominal pain 
13 
1 
5 
1 
Vascular disorders 
 
 
 
 
Lymphedema 
32 
1 
4 
0 
Hypertension 
15 
12 
7 
3 
Hemorrhage 
13 
<1 
0 
0 
 
 
Table:  Percent-patient incidence of laboratory abnormalities occurring at a higher incidence in 
patients treated with trametinib versus chemotherapy (between-arm difference of ≥5% [all 
grades] or ≥2% [grades 3 or 4]) 
 
Trametinib 
(n=211) 
Chemotherapy 
(n=99) 
Preferred term 
All Grades 
Grades 
3 and 4 
All Grades 
Grades 
3 and 4 
Increased aspartate aminotransferase 
(AST) 
60 
2 
16 
1 
Increased alanine aminotransferase (ALT) 
39 
3 
20 
3 
Hypoalbuminemia 
42 
2 
23 
1 
Anemia 
38 
2 
26 
3 
Increased alkaline phosphatase 
24 
2 
18 
3 
 
Other clinically important adverse reactions observed in ≤10% of patients (n=329) treated 
with trametinib were: nervous system disorders (dizziness, dysgeusia), ocular disorders 
(blurred vision, dry eye), infections and infestations (folliculitis, rash pustular, cellulitis), 
cardiac disorders (bradycardia), gastrointestinal disorders (xerostomia), and 
musculoskeletal and connective tissue disorders (rhabdomyolysis).   
 
2.3 
Rationale 
 
The MAPK pathway is activated downstream of the TAZ-CAMTA1 gene fusion seen in over 90% 
of EHE tumors and pre-clinical studies demonstrated that MEK activation correlates with the 
ability of TAZ-CAMTA1-expressing cells to grow as colonies in soft agar or in suspension. 
Exposure of these cells to either the selective MEK inhibitor PD325901 or trametinib inhibited 
colony formation in agar and in suspension establishing a role of MAP kinase pathway in growth 
and survival of cells dependent on TAZ-CAMTA1 mediated oncogenesis and MEK as a 
potential tumor-dependent target for therapy. The IC50 for trametinib inhibition of tumor growth 
in vitro was less than 10 nM, which is a therapeutically achievable dose. 
 
2.4 
Correlative Studies Background 
 
2.4.1 Fluorescence In-situ Hybridization (FISH) for TAZ-CAMTA1 gene fusion 
We believe EHE most likely to respond to MEK inhibition are tumors that harbor the 
TAZ-CAMTA1 translocation because MEK activation requires TAZ-CAMTA1 expression 
(see section 2.4.2). In pathology review of tumors that morphologically resembled EHE, 
over 90% of the tumors contained TAZ-CAMTA1 gene fusion detected by FISH (Tanas et 


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al. 2011). Therefore, we believe most, if not all, patients enrolled in this trial will have 
tumor that contains TAZ-CAMTA1 gene fusion. A fusion FISH test has been developed at 
Cleveland Clinic and will be used to evaluate the presence of  the TAZ-CAMTA1 gene 
fusion in tumor from patients enrolled in the trial. Archival formalin-fixed, paraffin-
embedded tumor samples will be collected and processed by the SARC SPORE 
pathology core. Representative H&E stained sections will be reviewed by the pathology 
core as a central review of the diagnosis. Fusion FISH for TAZ-CAMTA1 will be 
performed on unstained sections from diagnostic tissue using the CLIA-certified FISH 
laboratory at Cleveland Clinic after enrollment (See section 9.1). Tumors with at least 
10% fused gene signals will be considered positive for TAZ-CAMTA1 gene fusion and 
will be scored as TAZ-CAMTA1 fusion detected. Tumors with less than 10% fused gene 
signals will be scores as TAZ-CAMTA1 fusion not detected. Tumor in which the fusion 
FISH test is not informative for technical reasons including lack of sufficient tumor tissue 
in the sample/slide will be scored as test failed.  
 
2.4.2 Ability of trametinib to inhibit MAP kinase signaling in EHE 
EHE tumor samples prior to treatment with trametinib demonstrate activation of the MAP 
kinase pathway and administration of trametinib to patients with EHE in standard clinical 
doses will result in inactivation of the MAP kinase pathway resulting in a decrease in the 
level of phosphorylation of ERK. In pre-clinical studies, NIH/3T3 cells stably expressing 
TAZ-CAMTA1 were grown in suspension and the MAPK and PI3K pathways were 
examined. NIH/3T3 cells containing empty vector, which do not proliferate in 
suspension, were used as a control. Phospho-ERK, which is emblematic of MAPK 
pathway activation, was sustained in TAZ-CAMTA1-expressing cells (7 day-13 day 
lanes) while cells expressing vector alone lost ERK phosphorylation over time (Fig. 1A). 
This suggests that TAZ-CAMTA1 maintained MAPK activation in these cells. In 
contrast, phospho-AKT, a surrogate of PI3K pathway activation was activated both in 
cells with empty vector and cells expressing TAZ-CAMTA1, suggesting that it was 
MAPK pathway activation and not PI3K activation that was driving proliferation of 
NIH/3T3-expressing cells in suspension (Fig. 1A). Phospho-ERK has been detected in 
protein lysates of snap-frozen EHE tumor samples (Fig 1B) and in EHE tumor cells by 
immunohistochemistry using a phospho-specific anti-ERK antibody (Fig 1 C-D). Based 
on these observations, we hypothesize that tumor response to clinically administered 
doses of trametinib will be accompanied by suppression of the MAPK pathway signaling 
detected by loss of phosphorylated ERK. Fresh tumor tissue will be obtained by core 
needle biopsy in patients who consent to the optional biopsies prior to treatment and 
approximately 4 weeks after start of treatment with trametinib for the analysis of MAP 
kinase pathway activation. The analysis will be performed by a research laboratory at 
Cleveland Clinic. 


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2.4.3 Biomarkers of EHE activity in patients treated with trametinib 
Plasma CTGF levels may be a useful biomarker of EHE survival as CTGF is a secreted 
protein whose gene is an immediate downstream target of TAZ-CAMTA1 (Tanas et al., 
2016). CTGF is secreted and binds to αIIbβ3 integrin on the cell surface, leading in an 
autocrine fashion to downstream activation of RAS and MAP kinase pathways. This 
signal transduction pathway drives TAZ-CAMTA1-mediated NIH/3T3 cell 
transformation. Inhibition of any portion of this pathway inhibits transformation. This 
pathway is summarized in Figure 2. Preliminary studies have shown that CTGF is 
produced at high levels and secreted into culture media by cells that express TAZ-
CAMTA1. 
 
 
 
CTGF is secreted by EHE and can be quantified in plasma from EHE patients using 
enzyme-link immunosorbent assay (ELISA). If trametinib results in EHE cell death and 
objective tumor response, we hypothesize that CTGF plasma levels will decline. 
Alternatively, if trametinib blocks growth of EHE by inhibiting MEK but does not result 
 
Fig. 1. MAPK/ERK is activated in EHE. A. NIH/3T3 cells stably transfected with either TAZ-CAMTA1 (TC) or empty vector 
(EV) were cultured on HEMA-coated plates, which prevent attachment and so force the cells to grow in suspension. Cell 
lysates were prepared at various time points, fractionated on PAGE and western blotted with antibodies to total ERK, pERK 
(T202/204), total AKT, pAKT (S473), total S6, and phospho-S6 (S235/236), and actin. Note that at later time points pERK is 
elevated in TC cells while it is lost in EV cells, suggesting that pERK/MAPK activation is driving proliferation in suspension. B. 
Protein lysates from three different frozen EHE tumor samples from three separate patients were fractionated on PAGE and 
western blotted with antibodies to pERK (T202/204), total ERK, and actin demonstrating abundant phospho-ERK in all tumor 
samples. EHE histological section (C) with pERK (T202/204) immunohistochemistry (D) revealing abundant cytoplasmic 
positivity in tumor cells but not admixed inflammatory cells. 


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in cell death, we expect CTGF plasma levels will remain unchanged because the 
production and secretion of CTGF is upstream of the RAS and MAP kinase pathways. 
Additionally, patients with advanced EHE have elevated c-reactive protein levels and 
erythrocyte sedimentation rate in the blood (unpublished observation) which may be 
related to tumor production of CTGF. Blood from patients will be obtained prior to 
starting trametinib, approximately 4 weeks and 6 months after start of treatment with 
trametinib, and at the time objective tumor response or progression is identified to 
explore the relationship between trametinib treatment, plasma levels of circulating CTGF, 
c-reactive protein levels and erythrocyte sedimentation rate. ELISA for CTGF 
quantification will be performed by a central reference laboratory and CRP and ESR will 
be determined by local CLIA-certified laboratories using standard methods. 
 
2.4.4 Tumor volume 
We hypothesize that a change in volume of EHE will correlate with EHE response to 
treatment. Analysis of change in tumor volume identified more patients than RECIST 1.1 
with response and correlated with survival in a retrospective analysis of Ewing sarcoma 
treated with anti-insulin-like growth factor therapy (Koshkin et al., 2016). Dr. Lawrence 
Schwartz has experience in determining tumor volume using Columbia University’s 
semi-automated solid tumor segmentation software (Koshkin et al., 2016). Digital 
radiology files will be obtained from treating centers and sent to Dr. Schwartz for 
analysis. Tumor volume will be determined for up to 3 dominant lesions per patient and 
change in volume over time will be calculated. Tumor response by volume will be 
compared to response by RECIST 1.1 and correlated with survival. Based on prior 
studies, increase in tumor volume of 100% or more will be scored as progression and 
decrease in volume of 45% or more will be scored as response (Koshkin et al., 2016).  
 
3. PATIENT SELECTION 
 
3.1 
Eligibility Criteria  
 
3.1.1 Patients must have measurable disease, defined as at least one lesion that can be 
accurately measured in at least one dimension (longest diameter to be recorded for non-
nodal lesions and short axis for nodal lesions) as ≥20 mm (≥2 cm) with conventional 
techniques or as ≥10 mm (≥1 cm) with spiral CT scan, MRI, or calipers by clinical exam. 
Baseline imaging must be obtained within 30 days of Day 1 of study.  See Section 11 for 
the evaluation of measurable disease. 
 
3.1.2 Patients must have histologically confirmed epithelioid hemangioendothelioma which is 
metastatic or locally advanced (unresectable), and tumor tissue (paraffin-embedded tissue 
block or tumor tissue on unstained glass slides) available for fusion FISH analysis at 
Cleveland Clinic. Patient tumor tissue stored in pathology archives may be used for 
fusion FISH; a new biopsy is not mandatory. 
 
 


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3.1.3 Patients must have evidence of disease progression per RECIST1.1 prior to enrollment or 
have evidence of cancer-related pain requiring symptom management with narcotic 
analgesics. 
 
3.1.4 Because there is no established standard or approved drug therapy for treatment of EHE, 
patients previously untreated or treated with drug therapy for EHE are eligible. There is 
no limit on the number of prior regimens used to be eligible. 
 
3.1.5 Age ≥15 years.  EHE is very unlikely to arise before the age of 15 years. 
 
3.1.6 ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A). 
 
3.1.7 Life expectancy of greater than 6 months. 
 
3.1.8 Able to swallow orally-administered medication and does not have any clinically 
significant gastrointestinal abnormalities that may alter absorption such as malabsorption 
syndrome or major resection of the stomach or small bowel. 
 
3.1.9 All prior treatment-related toxicities must be CTCAE v5 grade ≤1 (except alopecia) at 
the time of enrollment. 
 
3.1.10 Patients must have normal organ and marrow function as defined below within 2 weeks 
of patient registration (for blood results) and 30 days of registration for LVEF 
assessment:   
− 
Absolute neutrophil count (ANC) ≥1x109/L  
− 
Hemoglobin ≥9 g/dL, patients may receive transfusion to meet criterion 
− 
Platelets ≥75x109/L  
− 
Albumin ≥2.5 g/dL 
− 
Total bilirubin ≤1.5x institutional upper limit of normal (ULN). NOTE: patients with 
elevated bilirubin secondary to Gilbert’s disease are eligible to participate in the study 
− 
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5x 
institutional ULN 
− 
Serum creatinine ≤1.5 mg/dL OR calculated creatinine clearance (Cockroft-Gault 
formula) ≥50 mL/min OR 24-hour urine creatinine clearance ≥50 mL/min 
− 
Left ventricular ejection fraction (LVEF) ≥ institutional lower limit of normal (LLN) 
by ECHO or MUGA 
 
3.1.11 Criteria related to reproductive issues. 
Trametinib can cause fetal harm when administered to a pregnant woman.  Women of 
child-bearing potential and men must agree to use adequate contraception (hormonal or 
barrier method of birth control; abstinence) prior to study entry, during the study 
participation, and for four months after the last dose of the drug.  Women of child-
bearing potential must have a negative serum pregnancy test within 14 days prior to 
enrollment and agree to use effective contraception throughout the treatment period and 
for 4 months after the last dose of study treatment.  Should a woman become pregnant or 


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suspect she is pregnant while she or her partner is participating in this study, she should 
inform her treating physician immediately. 
 
3.1.12 HIV-Patients positive for human immunodeficiency virus (HIV) are NOT excluded from 
this study, however HIV-positive patients must meet the following criteria:  
 
• A stable regimen of highly active anti-retroviral therapy (HAART)  
• No requirement for concurrent antibiotics or antifungal agents for the prevention 
of opportunistic infections  
• A CD4 count above 250 cells/mcL and an undetectable HIV viral load on 
standard PCR-based test  
 
3.2 
Exclusion Criteria 
 
3.2.1 Prior systemic therapy with a MEK inhibitor 
 
3.2.2 History of another malignancy. 
Exception:  Patients who have been disease-free for 3 years or patients with a history of 
completely resected non-melanoma skin cancer and/or patients with indolent secondary 
malignancies, are eligible.  Consult the CTEP Medical Monitor if unsure whether second 
malignancies meet the requirements specified above. 
 
3.2.3 History of interstitial lung disease or pneumonitis requiring supplemental oxygen or 
treatment with oral or intravenously administered corticosteroids. 
 
3.2.4 Any major surgery, extensive radiotherapy, chemotherapy with delayed toxicity (e.g. 
doxorubicin), biologic therapy, or immunotherapy within 21 days prior to enrollment 
and/or daily or weekly chemotherapy (e.g. sunitinib, sorafenib and pazopanib) without 
the potential for delayed toxicity within 14 days prior to enrollment. 
 
3.2.5 Use of other investigational drugs within 28 days (or five half-lives, whichever is shorter; 
with a minimum of 14 days from the last dose) preceding the first dose of trametinib and 
during the study. 
 
3.2.6 Symptomatic or untreated leptomeningeal or brain metastases or spinal cord 
compression. 
 
3.2.7 Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs 
chemically related to trametinib, or excipients or to dimethyl sulfoxide (DMSO). 
 
3.2.8 Current use of a prohibited medication.  The following medications or non-drug therapies 
are prohibited: 
− 
Other anti-cancer therapy while on study treatment.  (note:  megestrol [Megace] if 
used as an appetite stimulant is allowed). 
− 
Concurrent treatment with bisphosphonates is permitted; however, treatment must be 


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initiated prior to the first dose of study therapy.  Prophylactic use of bisphosphonates 
in patients without bone disease is not permitted, except for the treatment of 
osteoporosis. 
− 
Because the composition, PK, and metabolism of many herbal supplements are 
unknown, the concurrent use of all herbal supplements is prohibited during the study 
(including, but not limited to, St. John’s wort, kava, ephedra [ma huang], ginkgo 
biloba, dehydroepiandrosterone [DHEA], yohimbe, saw palmetto, or ginseng). 
 
3.2.9 History or current evidence/risk of retinal vein occlusion (RVO). 
 
3.2.10 History or evidence of cardiovascular risk including any of the following: 
− 
A QT interval corrected for heart rate using the Bazett’s formula QTcB ≥480 msec. 
− 
History or evidence of current clinically significant uncontrolled arrhythmias 
(Exception:  patients with controlled atrial fibrillation for >30 days prior to 
randomization are eligible). 
− 
History of acute coronary syndromes (including myocardial infarction and unstable 
angina), coronary angioplasty, or stenting within 6 months prior to randomization. 
− 
History or evidence of current ≥ Class II congestive heart failure as defined by the 
New York Heart Association (NYHA) functional classification system. 
− 
Treatment-refractory hypertension defined as a blood pressure of systolic >140 
mmHg and/or diastolic >90 mmHg which cannot be controlled by anti-hypertensive 
therapy. 
− 
Patients with intra-cardiac defibrillators. 
− 
Known cardiac metastases. 
 
3.2.11 Known Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection (patients with 
chronic or cleared HBV and HCV infection are eligible). 
 
3.2.12 Any serious and/or unstable pre-existing medical disorder (aside from malignancy 
exception above), psychiatric disorder, or other conditions that could interfere with 
subject’s safety, obtaining informed consent or compliance to the study procedures. 
 
3.2.13 Trametinib was embryotoxic and abortifacient in rabbits at doses greater than or equal to 
those resulting in exposures approximately 0.3 times the human exposure at the 
recommended clinical dose. Therefore, the study drug must not be administered to 
pregnant women or nursing mothers.  Women of childbearing potential should be advised 
to avoid pregnancy and use effective methods of contraception.  Men with a female 
partner of childbearing potential must have either had a prior vasectomy or agree to use 
effective contraception.  If a female patient or a female partner of a patient becomes 
pregnant while the patient receives trametinib, the potential hazard to the fetus should be 
explained to the patient and partner (as applicable). 
 
 
3.2.14 Inability to comply with protocol-required procedures. 
  


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24 
 
3.3 
Inclusion of Women and Minorities 
 
NIH policy requires that women and members of minority groups and their subpopulations be 
included in all NIH-supported biomedical and behavioral research projects involving NIH-
defined clinical research unless a clear and compelling rationale and justification establishes to 
the satisfaction of the funding Institute & Center (IC) Director that inclusion is inappropriate 
with respect to the health of the subjects or the purpose of the research.  Exclusion under other 
circumstances must be designated by the Director, NIH, upon the recommendation of an IC 
Director based on a compelling rationale and justification.  Cost is not an acceptable reason for 
exclusion except when the study would duplicate data from other sources.  Women of 
childbearing potential should not be routinely excluded from participation in clinical research.  
Please see http://grants.nih.gov/grants/funding/phs398/phs398.pdf. 
 
Epithelioid hemangioendothelioma is slightly more prevalent in females than males. There is no 
known predilection of the disease for a particular race or ethnic background. The study is open to 
eligible males and females of all races and ethnicity and enrollment will not discriminate on the 
basis of race or ethnicity. Because of the rarity of locally advanced or metastatic EHE and the 
need to complete accrual to the trial in a timely manner, patients will be enrolled as they consent 
and are determined to be eligible to participate. The study will not target enrollment to meet a 
predefined goal for accrual for any particular gender, race or ethnicity. 
 
4. REGISTRATION PROCEDURES 
 
4.1 
Investigator and Research Associate Registration with CTEP 
 
4.1.1 CTEP Registration Procedures 
 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) 
policy require all investigators participating in any NCI-sponsored clinical trial to register 
and to renew their registration annually. 
 
Registration requires the submission of: 
 
• a completed Statement of Investigator Form (FDA Form 1572) with an original 
signature 
• a current Curriculum Vitae (CV) 
• a completed and signed Supplemental Investigator Data Form (IDF) 
• a completed Financial Disclosure Form (FDF) with an original signature 
 
Fillable PDF forms and additional information can be found on the CTEP website at 
http://ctep.cancer.gov/investigatorResources/investigator_registration.htm. 
 
For questions about Investigator Registration, please contact the CTEP Investigator 
Registration Help Desk by email at pmbregpend@ctep.nci.nih.gov. 
 


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4.1.2 CTEP Associate Registration Procedures / CTEP-IAM Account 
 
The Cancer Therapy Evaluation Program (CTEP) Identity and Access Management 
(IAM) application is a web-based application intended for use by both Investigators (i.e., 
all physicians involved in the conduct of NCI-sponsored clinical trials) and Associates 
(i.e., all staff involved in the conduct of NCI-sponsored clinical trials). 
 
Associates will use the CTEP-IAM application to register (both initial registration and 
annual re-registration) with CTEP and to obtain a user account. 
 
Investigators will use the CTEP-IAM application to obtain a user account only.  (See 
CTEP Investigator Registration Procedures above for information on registering with 
CTEP as an Investigator, which must be completed before a CTEP-IAM account can be 
requested.) 
 
An active CTEP-IAM user account is required to access all CTEP applications and, if 
applicable (e.g., all Network trials), all Cancer Trials Support Unit (CTSU) applications 
and websites. 
 
Additional information can be found on the CTEP website at 
http://ctep.cancer.gov/branches/pmb/associate_registration.htm. 
 
For questions about Associate Registration or CTEP-IAM Account Creation, please 
contact the CTEP Associate Registration Help Desk by email at 
ctepreghelp@ctep.nci.nih.gov. 
 
4.2 
Site Registration 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
Each investigator or group of investigators at a clinical site must obtain Institutional Review 
Board (IRB) approval for this protocol and submit IRB approval and supporting documentation 
to the CTSU Regulatory Office before they can be approved to enroll patients. Assignment of 
site registration status in the CTSU Regulatory Support System (RS) uses extensive data to make 
a determination of whether a site has fulfilled all regulatory criteria including but not limited to: 
an active Federal Wide Assurance (FWA) number, an active roster affiliation with the Lead 
Network or a participating organization, a valid IRB approval, and compliance with all protocol 
specific requirements.  
 
Sites participating on the NCI CIRB initiative that are approved by the CIRB for this study are 
not required to submit IRB approval documentation to the CTSU Regulatory Office. For sites 
using the CIRB, IRB approval information is received from the CIRB and applied to the RSS in 
an automated process. Signatory Institutions must submit a Study Specific Worksheet for Local 
Context (SSW) to the CIRB via IRBManager to indicate their intent to open the study locally. 
The CIRB’s approval of the SSW is then communicated to the CTSU Regulatory Office. In order 


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26 
 
for the SSW approval to the processed, the Signatory Institution must inform the CTSU which 
CIRB-approved institutions aligned with the Signatory Institution are participating in the study. 
 
 
4.2.1 Downloading Regulatory Documents 
 
Site registration forms may be downloaded from the NCI protocol #10015 protocol page 
located on the CTSU Web site.  Permission to view and download this protocol is 
restricted and is based on person and site roster data housed in the CTSU RSS.  To 
participate, Investigators and Associates must be associated with the Corresponding or 
Participating protocol organization in the RSS.  
 
• Go to https://www.ctsu.org and log in using your CTEP-IAM username and 
password. 
• Click on the Protocols tab in the upper left of your screen.  
o Either enter the protocol # in the search field at the top of the protocol tree, or 
click on the By Lead Organization folder to expand, then select EDDO-MI014, 
and protocol #10015. 
• Click on LPO Documents, select the Site Registration documents link, and 
download and complete the forms provided.  (Note: For sites under the CIRB 
initiative, IRB data will load to RSS as described above.) 
 
4.2.2 Requirements For #10015 Site Registration: 
 
• CTSU Transmittal Sheet (optional) 
• IRB approval (For sites not participating via the NCI CIRB; local IRB 
documentation, and IRB-signed CTSU IRB Certification Form, Protocol of 
Human Subjects Assurance Identification/IRB Certification/Declaration of 
Exemption Form, or combination is accepted) 
 
4.2.3 Submitting Regulatory Documents 
 
Submit required forms and documents to the CTSU Regulatory Office, where they will 
be entered and tracked in the CTSU RSS.   
 
ONLINE: www.ctsu.org (members’ section) → Regulatory Submission Portal(Note: The 
use of the Regulatory Submission Portal will become mandatory in early 2017) 
EMAIL: CTSURegulatory@ctsu.coccg.org (for regulatory document submission only) 
FAX: 215-569-0206 
MAIL: CTSU Regulatory Office 
            1818 Market Street, Suite 1100 
            Philadelphia, PA 19103 
 
4.2.4 Checking Site Registration Status 
 


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You can verify your site registration status on the members’ section of the CTSU 
website.  
• Go to https://www.ctsu.org and log in to the members’ area using your CTEP-
IAM username and password. 
• Click on the Regulatory tab at the top of your screen. 
• Click on the Site Registration tab. 
• Enter your 5-character CTEP Institution Code and click on Go. 
Note: The status given only reflects compliance with RIB documentation and institutional 
compliance with protocol-specific requirements as outlined by the Lead Network. It does 
not reflect compliance with protocol requirements for individuals participating on the 
protocol or the enrolling investigator’s status with the NCI or their affiliated networks.  
4.3 
Patient Registration 
 
4.3.1 OPEN / IWRS 
 
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network 
(OPEN).  OPEN is a web-based registration system available to users on a 24/7 basis.  It 
is integrated with the CTSU Enterprise System for regulatory and roster data interchange 
and with the Theradex Interactive Web Response System (IWRS) for retrieval of patient 
registration/randomization assignment.  Patient enrollment data entered by Registrars in 
OPEN / IWRS will automatically transfer to the NCI’s clinical data management system, 
Medidata Rave. 
 
The OPEN system will provide the site with a printable confirmation of registration and 
treatment information.  Please print this confirmation for your records.  
 
4.3.2 OPEN/IWRS User Requirements 
 
OPEN/IWRS users must meet the following requirements: 
• Have a valid CTEP-IAM account (i.e., CTEP username and password). 
• To enroll patients:  Be on an ETCTN Corresponding or Participating Organization 
roster with the role of Registrar. 
• Have regulatory approval for the conduct of the study at their site. 
 
Prior to accessing OPEN/IWRS, site staff should verify the following: 
• All eligibility criteria have been met within the protocol stated timeframes.   
• If applicable, all patients have signed an appropriate consent form and HIPAA 
authorization form. 
 


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4.3.3 Patient Enrollment Instructions   
 
The SARC Research Project Manager (RPM) must be notified before patients are 
consented and begin eligibility screening for enrollment in the study. The RPM may be 
notified by phone: 734-930-7600, fax: 734-930-7557, or email: 
SARC033@sarctrials.org. The SARC RPM will inform the site if an enrollment slot is 
available based on the total number of patients with TAZ-CAMTA1 gene fusion positive 
EHE enrolled in the trial. Patients must not be consented until the site has been informed 
that an enrollment slot is available. An enrollment slot will only be opened (made 
available) if a patient enrolled in the trial and started on trametinib does not have TAZ-
CAMTA1 gene fusion positive EHE confirmed after testing by FISH at the 
central/reference laboratory. After obtaining patient consent, the site should provide the 
SARC RPM the date informed consent was obtained, patient initials, patient age, and 
whether the patient has agreed to participate in the optional tumor biopsies for research. 
This information will be used by the SARC office to track enrollment and assist sites 
with shipment of the biologic samples for the correlative research studies. 
 
4.3.4 OPEN/IWRS Questions? 
 
Further instructional information on OPEN is provided on the OPEN tab of the CTSU 
website at https://www.ctsu.org or at https://open.ctsu.org.  For any additional questions 
contact the CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com.  
 
4.4 
General Guidelines 
 
Following registration, patients should begin protocol treatment within 7 days.  Issues that would 
cause treatment delays should be discussed with the Principal Investigator.  If a patient does not 
receive protocol therapy following registration, the patient’s registration on the study may be 
canceled.  The Study Coordinator should be notified of cancellations as soon as possible. 
 
5. TREATMENT PLAN 
 
5.1 
Agent Administration 
 
Treatment will be administered on an outpatient basis.  Reported adverse events and potential 
risks are described in Section 7.  Appropriate dose modifications are described in Section 6.  No 
investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the patient's malignancy. 
 
5.1.1 Trametinib 
 
Trametinib 2 mg will be taken orally once daily with a cycle length of 28 days. The effect 
of food on trametinib absorption is unknown.  The current recommendation is to 
administer trametinib on an empty stomach, 1 hour before or 2 hours after a meal; the 
recommendation to administer trametinib on an empty stomach may change based on 


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emerging data. Patients will be instructed to take the medication at approximately the 
same time each day with a full glass of water. If a dose is missed, the patient will be 
instructed to take it as soon as they remember. If the next scheduled dose is within 12 
hours, they will skip the missed dose. The patient will be requested to maintain a 
medication diary of each dose of medication. The medication diary should be returned to 
and/or reviewed by clinic staff at each scheduled clinic visit during the course of 
treatment. 
 
Regimen Description 
Agent 
Premedications; 
Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
Trametinib 
Take 1 or more 
hours before or 
2 or more hours 
after food. Take 
with at least 8 
ounces of water 
 
2 mg 
PO 
once daily 
28 days 
(4 weeks) 
 
5.2 
Definition of Dose-Limiting Toxicity 
Not Applicable 
 
5.3 
Dose Expansion Cohorts 
Not Applicable 
 
5.4 
General Concomitant Medication and Supportive Care Guidelines 
 
Routine supportive care for management of nausea, anorexia, diarrhea, rash and hypertension are 
allowed. Additional supportive care recommendations are provided below in section 6. 
Trametinib is highly bound to plasma proteins (97.3%) and has the potential to interfere with 
other highly protein-bound drugs. Use caution in patients taking concomitant drugs that are 
highly protein-bound and have narrow therapeutic ranges. Trametinib is an in vitro inhibitor of 
CYP 2C8, 2C9, 2C19 and is anticipated to have overall low potential for drug interactions. It is 
also a weak CYP 2B6 and 3A4 inducer and expected to have little clinical effect on sensitive 
substrates. 
 
5.5 
Duration of Therapy 
 
In the absence of treatment delays due to adverse event(s), treatment may continue for 52 cycles 
or until one of the following criteria applies: 
 
• 
Disease progression per RECIST, 
• 
Clinical progression, 
• 
Intercurrent illness that prevents further administration of treatment, 


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• 
Unacceptable adverse event(s), 
• 
Patient decides to withdraw from the study 
• 
Pregnancy 
o All women of child bearing potential should be instructed to contact the 
investigator immediately if they suspect they might be pregnant (e.g., missed 
or late menstrual period) at any time during study participation. 
o The investigator must immediately notify CTEP in the event of a confirmed 
pregnancy in a patient participating in the study. 
• 
General or specific changes in the patient's condition render the patient unacceptable 
for further treatment in the judgment of the investigator. 
 
Patients with clinical progression or disease progression per RECIST who are benefitting 
from trametinib in reduction of tumor-related symptoms may continue on treatment 
with trametinib after discussion with the Study PI and CTEP Medical Monitor and 
approval. 
 
5.6 
Duration of Follow Up 
 
Patients will be followed for 24 months after initiation of trametinib unless the patient remains 
on active treatment beyond 24 months. In that case, follow-up will be continued until 6 months 
after discontinuation of treatment or until death, whichever occurs first.  If the patient 
discontinues therapy prior to 24 months, follow-up will continue for 6 months after 
discontinuation or 24 months after initiation of trametinib, whichever is longer. Patients removed 
from study for unacceptable adverse event(s) will be followed until resolution or stabilization of 
the adverse event. 
 
5.7 
Criteria for Removal from Study 
 
Patients will be removed from study if they decide to withdraw from the study or die. Patient 
participation in the study will conclude when they complete study follow-up described in section 
5.6. The reason for study removal and the date the patient was removed must be documented in 
the Case Report Form. 
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
6.1 
Trametinib Dose Modifications 
 
The table below outlines the dose levels to be used for any necessary trametinib dose 
modifications: 
 
Dose Level 
Trametinib Dose/Schedule 
0 
2 mg once daily 
-1 
1.5 mg once daily 
-2 
1 mg once daily 
 


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A maximum of two trametinib dose level reductions are allowed.  If a third dose level reduction 
is required, treatment will be permanently discontinued. 
 
If a dose reduction of trametinib is required, but the toxicity resolves and no additional toxicities 
are seen after two cycles of treatment, the dose of trametinib may be re-escalated but should not 
exceed 2 mg once a day. 
 
Dose modification and AE guidelines are outlined in the sections below for AEs that are deemed 
possibly related to trametinib: 
 
• AEs not otherwise specified 
• Rash 
• Visual changes 
• Diarrhea  
• Liver chemistry elevation 
• Ejection fraction changes 
• Hypertension 
• Prolonged QTc 
• Pneumonitis 
 
6.1.1 Trametinib Dose Modification for Toxicities Not Specified in Subsequent Sections 
 
Trametinib Treatment Modification for Clinically Significant Toxicities Deemed Related to Trametinib 
(This section is not for specific AEs such as hypertension, rash, ejection fraction changes, pneumonitis, diarrhea, 
liver chemistry, QTc prolongation, or visual changes.  Refer to other sections for these specific AEs). 
CTCAE v5 
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 Medical Monitor; 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 >21 days due to toxicities.  If the investigator concludes 
that continued trametinib will benefit a patient, the study chair and CTEP Medical Monitor may be consulted for 
the possibility of resuming trametinib, provided that toxicities have resolved to baseline or grade 1. 
 
6.1.2 Trametinib Dose Modification for Rash 
 


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Rash is a frequent AE observed in patients receiving trametinib (Investigator’s Brochure, 
2012a).  Recommendations for supportive care and guidelines for dose modifications for 
rash are based on experience with other MEK inhibitors and EGFR inhibitors (Balagula 
et al., 2010; Lacouture et al., 2011). 
 
The institutional standards for the management of skin-related AEs can differ from these 
guidelines.  In this case, best clinical judgment should be applied and a consultation with 
the study chair or the CTEP Medical Monitor may be required. 
 
Guidelines for Supportive Care of Rash 
Type of Care 
Action 
Prevention/Prophylaxisa 
 
• Avoid unnecessary exposure to sunlight. 
• Apply broad-spectrum sunscreen (containing titanium dioxide or zinc 
oxide) with a skin protection factor (SPF) ≥15 at least twice daily. 
• Use thick, alcohol-free emollient cream (e.g., glycerine and cetomacrogol 
cream) on dry areas of the body at least twice daily. 
• Topical steroids and antibiotics should be applied at least twice daily, 
starting on Day 1 of study treatment, to body areas such as face, chest, and 
upper back.   
• Use mild-strength topical steroid (hydrocortisone 1% cream) or topical 
antibiotic (e.g., clindamycin) or oral antibiotics (e.g., doxycycline 100 mg 
BID, minocycline 100 mg BID). 
Symptomatic Careb 
 
• Pruritic lesions:  Cool compresses and oral antihistamine therapies. 
• Fissuring lesions:  Monsel’s solution, silver nitrate, or zinc oxide cream. 
• Desquamation:  Thick emollients and mild soap. 
• Paronychia:  Antiseptic bath, local potent corticosteroids in addition to 
antibiotics; if no improvement, consult dermatologist or surgeon. 
• Infected lesions:  Appropriate bacterial/fungal culture-driven systemic or 
topical antibiotics. 
a Rash prophylaxis is recommended for the first 6 weeks of study treatment. 
b Patients who develop rash/skin toxicities should be seen by a qualified physician and should receive evaluation 
for symptomatic/supportive care management. 
 
 
Trametinib Dose Modification Guidelines and Management for Rash 
Rash Severity 
Management Guideline 
Dose Modification 
Grade 1 
 
• Initiate prophylactic and 
symptomatic treatment measures.1 
• Use moderate strength topical 
steroid.2 
• Reassess after 2 weeks. 
• Continue trametinib. 
• If rash does not recover to baseline within 2 weeks 
despite best supportive care, reduce trametinib by 
one dose level.3 


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Trametinib Dose Modification Guidelines and Management for Rash 
Rash Severity 
Management Guideline 
Dose Modification 
Grade 2 
 
• Initiate prophylactic and 
symptomatic treatment measures.1 
• Use moderate strength topical 
steroid.2 
• Reassess after 2 weeks. 
 
• 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 
trametinib until recovery to ≤ grade 1. 
• Restart trametinib at reduced dose level.3 
Grade ≥3 
 
• Use moderate strength topical 
steroids PLUS oral methyl-
prednisolone dose pack.2 
• Consult dermatologist. 
• Interrupt trametinib until rash recovers to ≤ grade 1. 
• Restart with trametinib reduced by one dose 
level.3,4 
• If no recovery to ≤ grade 2 within 4 weeks, 
permanently discontinue trametinib. 
1.  Rash prophylaxis is recommended for the first 6 weeks of study treatment. 
2.  Moderate-strength topical steroids:  Hydrocortisone 2.5% cream or fluticasone propionate 0.5% cream. 
3.  Approval of CTEP Medical Monitor is required to restart study treatment after >4 weeks of interruption. 
4.  Trametinib may be escalated to previous dose level if no rash is evident 4 weeks after restarting study treatment. 
 
6.1.3 Trametinib Dose Modifications 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 the table below. 
 


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34 
 
Management and Trametinib Dose Modification for Visual Changes 
and/or Ophthalmic Examination Findings 
Event 
CTCAE Grade 
Management Guideline 
Dose Modification 
Grade 1* 
 
 
• Consult ophthalmologist 
within 7 days of onset. 
 
• If dilated fundus examination cannot be performed 
within 7 days of onset, hold 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/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 or RVO excluded, restart trametinib at same 
dose level after visual AE is < grade 1.  If no recovery 
within 3 weeks, discontinue trametinib 
• If RPED diagnosed:  See RPED dose modification table 
below; report as SAE. 
• If RVO:  Permanently discontinue trametinib and 
report as SAE. 
Grade 4 
 
• Consult ophthalmologist 
immediately. 
• Report as SAE. 
• Hold Trametinib 
• If RPED/RVO excluded, may restart trametinib at same 
or reduced dose after discussion with the CTEP Medical 
Monitor. 
• If RVO or RPED, permanently discontinue 
trametinib. 
Abbreviations: RPED = retinal pigment epithelial detachments; RVO = retinal vein occlusion; SAE = serious 
adverse event 
*If visual changes are clearly unrelated to study treatment (e.g., allergic conjunctivitis), monitor closely but 
ophthalmic examination is not required. 
 
 
Trametinib Dose Modification for RPED 
Event 
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 with one dose level reduction 
(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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6.1.4 Trametinib Dose Modification for Diarrhea 
 
Episodes of diarrhea have occurred in patients receiving trametinib (Investigator’s 
Brochure, 2012a).  Other frequent causes of diarrhea including concomitant medications 
(e.g., stool softeners, laxatives, antacids, etc.), infections by C. difficile or other 
pathogens, or partial bowel obstruction should be clinically excluded. 
 
Guidelines regarding management and dose modification for diarrhea considered related 
to trametinib are provided in the table below. 
 
Management and Trametinib Dose Modification Guidelines for Diarrhea 
CTCAE Grade 
Adverse Event Management 
Action and Dose Modification 
Uncomplicated 
Diarrhea,1 
Grade 1 or 2 
• Diet:  Stop all lactose containing products; 
eat small meals, BRAT-diet (banana, rice, 
apples, toast) recommended. 
• Hydration:  8-10 large glasses of clear 
liquids per day (e.g., Gatorade or broth). 
• Loperamide3:  Initially 4 mg, followed by 
2 mg every 4 hours or after every 
unformed stool; maximum 16 mg/day.  
Continue until diarrhea-free for 12 hours. 
• Diarrhea >24 hours:  Loperamide 2 mg 
every 2 hours; maximum 16 mg/day.  
Consider adding oral antibiotics. 
• Diarrhea >48 hous:  Loperamide 2 mg 
every 2 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 > 48 h,  
interrupt trametinib until diarrhea 
resolves to grade ≤1. 
• Restart trametinib at the same dose 
level 
• If treatment delay is >4 weeks, 
discontinue trametinib. 


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Management and Trametinib Dose Modification Guidelines for Diarrhea 
CTCAE Grade 
Adverse Event Management 
Action and Dose Modification 
Uncomplicated 
Diarrhea,1 
Grade 3 or 4 
 
Any Complicated 
Diarrhea2 
 
• Clinical evaluation mandatory. 
• Loperamide3:  Initially 4 mg, followed by 
2 mg every 4 hours or after every 
unformed stool; maximum 16 mg/day.  
Continue until diarrhea-free for 12 hours. 
• Oral antibiotics and second-line therapies 
if clinically indicated. 
• Hydration:  Intravenous fluids if clinically 
indicated. 
• Antibiotics (oral or intravenous) if 
clinically indicated. 
• Intervention should be continued until the 
subject is diarrhea-free for ≥24 hours. 
• Intervention may require hospitalization 
for subjects at risk of life-threatening 
complications. 
• Interrupt trametinib until diarrhea 
resolves to ≤ grade 1. 
• Restart with trametinib reduced by 
one dose level.4 
• If 3 dose reductions of study 
treatment are clinically indicated, 
permanently discontinue 
trametinib. 
• If treatment delay is >4 weeks, 
discontinue trametinib. 
1.  Uncomplicated diarrhea defined by the absence of symptoms such as cramping, nausea/vomiting, ≥ grade 
2, decreased performance status, pyrexia, sepsis, neutropenia ≥ grade 3, frank bleeding, and/or dehydration 
requiring intravenous fluid substitution. 
2.  Complicated diarrhea defined by the presence of symptoms such as cramping, nausea/vomiting, ≥ grade 2, 
decreased performance status, pyrexia, sepsis, neutropenia ≥ grade 3, frank bleeding, and/or dehydration 
requiring intravenous fluid substitution. 
3.  Loperamide should be made available prior to start of study treatment so loperamide administration can 
begin at the first signs of diarrhea. 
4.  Escalation of trametinib to previous dose level is allowed after consultation with the medical monitor and in 
the absence of another episode of complicated or severe diarrhea in the 4 weeks subsequent to dose reduction. 
 
6.1.5 Trametinib Dose Modification for Liver Chemistry Changes 
 
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). 
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 
• Immediately discontinue study treatment. 
• Do not restart/rechallenge unless approved by CTEP trametinib medical 
monitor.   
• Report as SAE if:  1) CTEP-AERS reporting criteria are met, or 2) 
patients meet criteria 1-2. 
• Perform liver event ASSESSMENT AND WORKUP (see below). 
• Monitor the subject until liver chemistries  resolve, stabilize, or return to 


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Trametinib Dose Modification for Liver Function Test Abnormalities 
Event 
Treatment modifications and assessment/monitoring 
2. ALT  3xULN and INR >1.5, if 
INR measured2  (INR threshold 
does not apply if subject is on 
anticoagulant) 
3. ALT ≥5x ULN 
4. ALT ≥3x ULN persists for 4 
weeks 
5. ALT ≥3x ULN and cannot be 
monitored weekly for 4 weeks 
6. ALT  ≥3x ULN associated with 
symptoms3  (new or worsening) 
believed to be related to  liver 
injury or hypersensitivity 
 
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 
• If possible, obtain blood sample for PK analysis.5 
• 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.6 
• Liver imaging (ultrasound, MRI, CT) and /or liver biopsy. 
Footnotes: 
1.  Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation testing 
is unavailable, record presence of detectable urinary bilirubin on dipstick, which indicates direct bilirubin 
elevations and suggesting liver injury. 
2.  All events of ALT ≥3xULN and bilirubin ≥2xULN (>35% direct bilirubin) or ALT 3x ULN and INR >1.5 (if 
INR measured) may indicate severe liver injury (possible “Hy’s Law”).  INR measurement is not required, and the 
threshold value stated will not apply to subjects receiving anticoagulants. 
3.  New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia) 
4.  Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); 
Hepatitis C RNA; Cytomegalovirus IgM antibody;  Epstein-Barr viral capsid antigen IgM antibody (or if 


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Trametinib Dose Modification for Liver Function Test Abnormalities 
Event 
Treatment modifications and assessment/monitoring 
unavailable, obtain heterophile antibody or monospot testing);  Hepatitis E IgM antibody  
5.  PK sample is desired if feasible.  Record the date/time of the PK blood sample draw and the date/time of the 
last dose of study treatment prior to blood sample draw on the CRF. If the date or time of the last dose is unclear, 
provide the subject’s best approximation. If the date/time of the last dose cannot be approximated OR a PK sample 
cannot be collected in the time period indicated above, do not obtain a PK sample.   
6.  If hepatitis delta antibody assay cannot be performed, it can be replaced with a PCR of hepatitis D RNA virus 
(where needed) (Le Gal et al., 2005). 
 
6.1.6 Trametinib Dose Modification for Pneumonitis 
 
Pneumonitis has been observed in patients receiving trametinib.  To reduce the risk of 
pneumonitis, patients will be monitored closely for symptoms and evaluated with 
imaging and functional tests.  Dose modification and supportive care guidelines for 
pneumonitis are described in the tables below. 
 
Pneumonitis Guidelines for Trametinib Monotherapy 
CTCAE 
Grade 
Adverse Event Management 
Action and Dose Modification 
Grade 1 
• CT scan (high-resolution with lung windows) 
recommended. 
• Work-up for infection  
• Monitoring of oxygenation via pulse-oximetry 
recommended 
• Consultation with pulmonologist recommended 
• 
Continue trametinib at current dose 
Grade 2 
• CT scan (high-resolution with lung windows) 
recommended. 
• 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 
• 
Permanently discontinue trametinib 
if pneumonitis is related to 
treatment. 
Grade 3 
• Same as grade 2 
• 
Permanently discontinue trametinib 
Grade 4 
• Same as grade 2 
• 
Permanently discontinue trametinib 
 
 
 
6.1.7 Trametinib Dose Modification for Reduced Left Ventricular Ejection Fraction 
 


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Decreases of the left ventricular ejection fraction (LVEF) have been observed in patients 
receiving trametinib.  Therefore, ECHO/MUGAs must be performed in regular intervals 
outlined in the Study Calendar.  The same procedure (either ECHO or MUGA, although 
ECHO is preferred) should be performed at baseline and at follow-up visit(s). 
 
Trametinib Dose Modification Guidelines and Stopping Criteria for LVEF Decrease 
Clinic 
LVEF-drop (%) or 
CTCAE grade 
Action and Dose 
Modification 
Asymptomatic 
 
Absolute decrease of 
>10% in LVEF compared 
to baseline and ejection 
fraction below the 
institution’s LLN. 
• Interrupt trametinib and repeat ECHO/MUGA 
within 2 weeks.a 
• If the LVEF recovers within 4 weeks 
(defined as LVEF ≥LLN and absolute 
decrease ≤10% compared to baseline): 
− Consult with the CTEP trametinib medical 
monitor and request approval for restart. 
− Restart treatment with trametinib at 
reduced dose by one dose level.b 
− Repeat ECHO/MUGA 2, 4, 8, and 12 
weeks after re-start; continue in intervals 
of 12 weeks thereafter. 
• If LVEF does not recover within 4 weeks: 
− Consult with cardiologist. 
− Permanently discontinue trametinib. 
− Report as SAE 
− Repeat ECHO/MUGA after 2, 4, 8, 12, and 
16 weeks or until resolution. 
− Consult with the CTEP trametinib medical 
monitor.c 
Symptomaticb 
 
• Grade 3:  resting LVEF 
39-20% or >20% 
absolute reduction from 
baseline 
• Grade 4:  Resting LVEF 
≤20%. 
• Permanently discontinue trametinib. 
• Report as SAE. 
• Consult with cardiologist. 
• Repeat ECHO/MUGA after 2, 4, 8, 12, and 
16 weeks or until resolution. 
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 CTEP trametinib medical monitor is required. 
c Symptoms may include:  dyspnea, orthopnea, and other signs and symptoms of pulmonary congestion and edema. 
 
6.1.8 Trametinib Dose Modification for QTc Prolongation 
 


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Trametinib 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 study treatment 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 level.b 
• If the event does not resolve or recurs after restarting, permanently 
discontinue study treatment. 
Abbreviations:  msec = milliseconds; QTcB = QT interval on electrocardiogram corrected using 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 CTEP trametinib medical monitor agree that the subject will benefit from further treatment. 
 
6.1.9 Trametinib Dose Modification for Hypertension 
 
Increases in blood pressure (BP) have been observed in patients receiving trametinib.  
Recommendations for BP monitoring and management are provided below. 
 
Monitoring:  All BP assessments should be performed under the following optimal 
conditions: 
 
The subject has been seated with back support, ensuring that legs are uncrossed and flat 
on the floor. 
The subject is relaxed comfortably for at least 5 minutes. 
Restrictive clothing has been removed from the cuff area, and the right cuff size has been 
selected. 
The subject’s arm is supported so that the middle of the cuff is at heart level. 
The subject remains quiet during the measurement. 
In subjects with an initial BP reading within the hypertensive range, a second reading 
should be taken at least 1 minute later, with the two readings averaged to obtain a final 
BP measurement.  The averaged value should be recorded in the eCRF. 
Persistent hypertension is defined as an increase of systolic blood pressure (SBP) >140 
mmHg and/or diastolic blood pressure (DBP) >90 mmHg in three consecutive visits with 
blood pressure assessments from two readings as described above.  Visits to monitor 
increased blood pressure can be scheduled independently from the per-protocol visits 
outlined in the study calendar.  Ideally, subsequent blood pressure assessments should be 
performed within 1 week. 
 


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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 Medical Monitor is required. 
 
 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of AEs (Section 7.1) and the characteristics of an observed AE (Section 7.2 and 
7.3) will determine whether the event requires expedited reporting via the CTEP Adverse Event 
Reporting System (CTEP-AERS) in addition to routine reporting. 
 


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7.1 
Comprehensive Adverse Events and Potential Risks List(s) (CAEPRs) 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
Trametinib dimethyl sulfoxide (GSK1120212B, NSC 763093) 
 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system. In addition to the comprehensive list, a subset, the 
Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column and 
is identified with bold and italicized text. This subset of AEs (SPEER) is a list of events that are 
protocol specific exceptions to expedited reporting to NCI via CTEP-AERS (except as noted 
below).  Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for 
further clarification.  Frequency is provided based on 1111 patients. Below is the CAEPR for 
Trametinib (GSK1120212B). 
 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to 
the AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple 
investigational agents and has an AE listed on different SPEERs, use the lower of the grades to 
determine if expedited reporting is required. 
Version 2.6, October 10, 20191 
 
 Adverse Events with Possible  
 Relationship to Trametinib (GSK1120212B) 
 (CTCAE 5.0 Term) 
[n= 1111] 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
Anemia 
 
 Anemia (Gr 3) 
CARDIAC DISORDERS 
  
 
 
Heart failure 
  
 
 
Left ventricular systolic 
dysfunction 
  
 
Sinus bradycardia 
 
  
EYE DISORDERS 
  
 
Blurred vision 
 
  
 
Dry eye 
 
  
 
 
Eye disorders - Other 
(chorioretinopathy also known as 
retinal pigment epithelial 
detachment) 
  
 
 
Eye disorders - Other (retinal vein 
occlusion) 
  
 
Eye disorders - Other (visual 
disorders)2 
 
  
 
 
Papilledema 
  
 
Periorbital edema 
 
  
GASTROINTESTINAL DISORDERS 
  


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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%) 
 
 
Abdominal pain 
 
 Abdominal pain (Gr 2) 
 
 
Colitis 
  
 
 
Colonic perforation 
  
 
Constipation 
 
 Constipation (Gr 2) 
Diarrhea 
 
 
 Diarrhea (Gr 3) 
 
Dry mouth 
 
 Dry mouth (Gr 2) 
 
Dyspepsia 
 
 Dyspepsia (Gr 2) 
 
Mucositis oral 
 
 Mucositis oral (Gr 3) 
Nausea 
 
 
 Nausea (Gr 3) 
 
Vomiting 
 
 Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Chills 
 
 Chills (Gr 2) 
 
Edema face 
 
  
Fatigue 
 
 
 Fatigue (Gr 3) 
 
Fever 
 
 Fever (Gr 2) 
Generalized edema3 
 
 
 Generalized edema3 (Gr 2) 
IMMUNE SYSTEM DISORDERS 
  
 
Allergic reaction4 
 
  
INFECTIONS AND INFESTATIONS 
  
 
Folliculitis 
 
 Folliculitis (Gr 2) 
 
Lung infection 
 
  
 
Paronychia 
 
 Paronychia (Gr 2) 
 
Skin infection 
 
 Skin infection (Gr 2) 
INVESTIGATIONS 
  
 
Alanine aminotransferase increased  
 Alanine aminotransferase 
increased (Gr 3) 
 
Alkaline phosphatase increased 
 
 Alkaline phosphatase increased 
(Gr 2) 
 
Aspartate aminotransferase 
increased 
 
 Aspartate aminotransferase 
increased (Gr 3) 
 
CPK increased 
 
  
 
Ejection fraction decreased 
 
  
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
 Anorexia (Gr 3) 
 
Dehydration 
 
 Dehydration (Gr 3) 
 
Hypoalbuminemia 
 
  
 
Hypomagnesemia 
 
 Hypomagnesemia (Gr 2) 
 
Hyponatremia 
 
 Hyponatremia (Gr 3) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
  
 
Back pain 
 
 Back pain (Gr 2) 
 
Pain in extremity 
 
 Pain in extremity (Gr 2) 
 
 
Rhabdomyolysis 
  
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
 Dizziness (Gr 2) 
 
Headache 
 
 Headache (Gr 2) 


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 Adverse Events with Possible  
 Relationship to Trametinib (GSK1120212B) 
 (CTCAE 5.0 Term) 
[n= 1111] 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
 Cough (Gr 2) 
 
Dyspnea 
 
 Dyspnea (Gr 3) 
 
 
Pneumonitis 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Alopecia 
 
 Alopecia (Gr 2) 
 
Dry skin 
 
 Dry skin (Gr 2) 
 
Nail changes 
 
  
 
 
Palmar-plantar erythrodysesthesia 
syndrome 
  
 
Pruritus 
 
 Pruritus (Gr 2) 
 
 
Skin and subcutaneous tissue 
disorders - Other (drug reaction 
with eosinophilia and systemic 
symptoms [DRESS]) 
  
Skin and subcutaneous tissue 
disorders - Other (rash)5 
  
 
 Skin and subcutaneous tissue 
disorders - Other (rash)5 (Gr 3) 
 
 
Stevens-Johnson syndrome6 
  
VASCULAR DISORDERS 
  
 
Hypertension 
 
 Hypertension (Gr 3) 
 
 
Thromboembolic event (venous) 
  
 
Vascular disorders - Other 
(hemorrhage)7 
 
  
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be 
distributed to all Principal Investigators at the time of revision.  The current version can be 
obtained by contacting PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, 
the protocol and the agent should be included in the e-mail. 
 
2Visual disorders include visual disturbance that can be associated with conjunctival hemorrhage, 
corneal graft rejection, cyclitis, eye nevus, halo vision, iritis, macular edema, retinal hemorrhage, 
visual acuity reduced, visual impairment, and vitreous detachment. 
 
3Generalized edema includes edema, lymphedema, and edema limbs. 
 
4Hypersensitivity (allergic reactions) may present with symptoms such as fever, rash, increased 
liver function tests, and visual disturbances. 
 
5Skin and subcutaneous tissue disorders - Other (rash) may include rash, rosacea, rash acneiform,  
erythematous rash, genital rash, rash macular, exfoliative rash, rash generalized, erythema, rash 
papular, seborrhoeic dermatitis, dermatitis psoriasiform, rash follicular, skin fissures, and skin 
chapped. 
 


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6Stevens-Johnson syndrome has been observed in patients treated with trametinib and dabrafenib 
combination. 
 
 
7The majority of hemorrhage events were mild.  Major events, defined as symptomatic bleeding 
in a critical area or organ (e.g., eye, GI hemorrhage, GU hemorrhage, respiratory hemorrhage), 
and fatal intracranial hemorrhages have been reported. 
 
 
 Adverse events reported on trametinib dimethyl sulfoxide (GSK1120212B) trials, but for 
which there is insufficient evidence to suggest that there was a reasonable possibility that 
trametinib dimethyl sulfoxide (GSK1120212B) caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Disseminated intravascular 
coagulation; Febrile neutropenia; Leukocytosis 
CARDIAC DISORDERS - Atrial fibrillation; Cardiac arrest; Myocardial infarction; Restrictive 
cardiomyopathy; Sinus tachycardia 
EYE DISORDERS - Corneal ulcer; Eyelid function disorder; Flashing lights; Floaters; 
Glaucoma; Photophobia 
GASTROINTESTINAL DISORDERS - Ascites; Duodenal ulcer; Esophageal necrosis; 
Esophageal ulcer; Esophagitis; Gastric hemorrhage7; Gastric ulcer; Gastritis; Gastrointestinal 
disorders - Other (intestinal obstruction); Gastrointestinal disorders - Other (pneumatosis 
intestinalis); Gastrointestinal fistula; Gingival pain; Hemorrhoidal hemorrhage7; Ileus; 
Obstruction gastric; Pancreatitis; Small intestinal obstruction 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Flu like 
symptoms; General disorders and administration site conditions - Other (axillary pain); 
Localized edema; Malaise; Non-cardiac chest pain; Pain 
HEPATOBILIARY DISORDERS - Cholecystitis; Hepatic failure; Hepatic pain; Hepatobiliary 
disorders - Other (hepatic encephalopathy) 
INFECTIONS AND INFESTATIONS - Biliary tract infection; Catheter related infection; 
Device related infection; Endocarditis infective; Enterocolitis infectious; Hepatitis viral; 
Infections and infestations - Other (abscess limb); Infections and infestations - Other (necrotizing 
fasciitis); Infections and infestations - Other (oral infection); Pharyngitis; Sepsis; Upper 
respiratory infection; Urinary tract infection 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Bruising 
INVESTIGATIONS - Blood bilirubin increased; Blood lactate dehydrogenase increased; 
Creatinine increased; Electrocardiogram QT corrected interval prolonged; GGT increased; 
Lipase increased; Lymphocyte count decreased; Platelet count decreased; Serum amylase 
increased; White blood cell decreased 
METABOLISM AND NUTRITION DISORDERS - Hyperglycemia; Hyperkalemia; 
Hyperphosphatemia; Hyperuricemia; Hypocalcemia; Hypoglycemia; Hypokalemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Generalized muscle 
weakness; Muscle cramp; Musculoskeletal and connective tissue disorder - Other (compression 
fracture); Myalgia; Neck pain 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND 


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POLYPS) - Tumor hemorrhage7; Tumor pain 
NERVOUS SYSTEM DISORDERS - Dysgeusia; Encephalopathy; Intracranial hemorrhage7; 
Lethargy; Nervous system disorders - Other (diplopia); Seizure; Somnolence; Stroke; Syncope; 
Transient ischemic attacks 
PSYCHIATRIC DISORDERS - Anxiety; Confusion; Delirium; Depression; Hallucinations; 
Insomnia; Personality change 
RENAL AND URINARY DISORDERS - Acute kidney injury; Cystitis noninfective; Dysuria; 
Hematuria; Proteinuria; Urinary incontinence 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Vaginal fistula; Vaginal 
hemorrhage7 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Bronchopulmonary 
hemorrhage7; Hypoxia; Laryngeal edema; Oropharyngeal pain; Pleural effusion; Pneumothorax; 
Productive cough; Pulmonary hypertension; Respiratory failure; Sinus disorder 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Bullous dermatitis; Photosensitivity; 
Purpura; Skin and subcutaneous tissue disorders - Other (erythema nodosum); Skin ulceration; 
Urticaria 
VASCULAR DISORDERS - Hematoma; Hot flashes; Hypotension 
 
 
Note: Trametinib (GSK1120212B) in combination with other agents could cause an exacerbation 
of any adverse event currently known to be caused by the other agent, or the combination may 
result in events never previously associated with either agent. 
 
 
 
7.2 
Adverse Event Characteristics  
 
• CTCAE term (AE description) and grade: The descriptions and grading scales found in 
the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 
will be utilized for AE reporting beginning April 1, 2018. All appropriate treatment areas 
should have access to a copy of the CTCAE version 5.0. A copy of the CTCAE version 
5.0 can be downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm .  
 
• For expedited reporting purposes only:   
- 
AEs for the agent that are bold and italicized in the CAEPR (i.e., those listed in the 
SPEER column, Section 7.1.1) should be reported through CTEP-AERS only if the 
grade is above the grade provided in the SPEER. 
- 
Other AEs for the protocol that do not require expedited reporting are outlined in 
section 7.3.4. 
 
• Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 


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- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
7.3 
Expedited Adverse Event Reporting 
 
7.3.1 Expedited AE reporting for this study must use CTEP-AERS (CTEP Adverse Event 
Reporting System), accessed via the CTEP Web site (https://eapps-
ctep.nci.nih.gov/ctepaers).  The reporting procedures to be followed are presented in the 
“NCI Guidelines for Investigators: Adverse Event Reporting Requirements for DCTD 
(CTEP and CIP) and DCP INDs and IDEs” which can be downloaded from the CTEP 
Web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm.  
These requirements are briefly outlined in the tables below (Section 7.3.3). 
 
In the rare occurrence when Internet connectivity is lost, a 24-hour notification is to be 
made to CTEP by telephone at 301-897-7497.  Once Internet connectivity is restored, the 
24-hour notification phoned in must be entered electronically into CTEP-AERS by the 
original submitter at the site. 
 
7.3.2 Distribution of Adverse Event Reports 
 
CTEP-AERS is programmed for automatic electronic distribution of reports to the 
following individuals:  Principal Investigator and Adverse Event Coordinator(s) (if 
applicable) of the Corresponding Organization or Lead Organization, the local treating 
physician, and the Reporter and Submitter.  CTEP-AERS provides a copy feature for 
other e-mail recipients.  
 
7.3.3 Expedited Reporting Guidelines 
 
Use the NCI protocol number and the protocol-specific patient ID assigned during trial 
registration on all reports. 
 
Note:  A death on study requires both routine and expedited reporting, regardless of 
causality.  Attribution to treatment or other cause must be provided. 
 
Death due to progressive disease should be reported as Grade 5 “Disease progression” in the 
system organ class (SOC) “General disorders and administration site conditions.” Evidence that 
the death was a manifestation of underlying disease (e.g., radiological changes suggesting tumor 
growth or progression: clinical deterioration associated with a disease process) should be 
submitted. 
Late Phase 2 and Phase 3 Studies: Expedited Reporting Requirements for Adverse Events 
that Occur on Studies under an IND/IDE within 30 Days of the Last Administration of the 
Investigational Agent/Intervention1, 2 


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FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not 
they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via electronic 
submission within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 
Calendar Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
10 Calendar Days 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific 
Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR 
Expedited AE reporting timelines are defined as: 
o 
“24-Hour; 5 Calendar Days” - The AE must initially be submitted electronically within 24 hours of 
learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-
hour report. 
o 
“10 Calendar Days” - A complete expedited report on the AE must be submitted electronically within 
10 calendar days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• 
All Grade 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• 
Grade 3 adverse events 
2For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 
applies after this reporting period. 
Effective Date:  May 5, 2011 
 
7.3.4 Additional Protocol-Specific Expedited Adverse Event Reporting Exclusions 
 
Not Applicable 
 
7.4 
Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions.  AEs reported 


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expeditiously through CTEP-AERS must also be reported in routine study data 
submissions. 
 
Adverse event data collection and reporting, which are required as part of every clinical trial, are 
done to ensure the safety of patients enrolled in the studies as well as those who will enroll in 
future studies using similar agents.  AEs are reported in a routine manner at scheduled times 
during the trial using Medidata Rave.  For this trial the Adverse Event CRF is used for routine 
AE reporting in Rave. 
 
7.5 
Secondary Malignancy 
 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm. 
 
CTEP requires all secondary malignancies that occur following treatment with an agent under an 
NCI IND/IDE be reported expeditiously via CTEP-AERS.  Three options are available to 
describe the event:  
 
• Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia 
[AML])  
• Myelodysplastic syndrome (MDS)  
• Treatment-related secondary malignancy  
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported to SARC033@sarctrials.org.  
 
Indicate form for reporting in Rave, timeframes, and if loading of the pathology report is 
required – to be determined by SARC. 
 
7.6 
Second Malignancy 
 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy).  Second malignancies require ONLY routine AE 
reporting unless otherwise specified. 
 
8. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational or commercial 
agents administered in this study can be found in Section 7.1. 
 
 
8.1 
CTEP IND Agent(s) 
 


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50 
 
8.1.1 Trametinib dimethyl sulfoxide (GSK1120212B) (NSC 763093) 
 
Chemical Name (IUPAC): equimolecular combination of N-(3-{3-cyclopropyl-5-[(2-
fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-
d]pyrimidin-1(2H)-yl}phenyl)acetamide with (methylsulfinyl)methane 
 
Other Names:  trametinib, GSK1120212, MEKINIST™, JTP-74057, JTP-78296, JTP-
75303 
 
CAS Registry Number:  1187431-43-1 
 
Classification:  MEK inhibitor 
 
Molecular Formula:  C26H23FIN5O4 • C2H6OS 
 
M.W.:  693.54 (dimethyl sulfoxide solvate), 615.41 (anhydrous parent) 
 
Approximate Solubility:  Trametinib dimethyl sulfoxide is almost insoluble in water 
(<0.0001 mg/mL at 25° C) 
 
Mode of Action:  Trametinib dimethyl sulfoxide is a reversible, highly selective, 
allosteric inhibitor of mitogen-activated extracellular signal regulated kinase 1 (MEK1) 
and MEK2.  Tumor cells commonly have hyperactivated extracellular signal-related 
kinase (ERK) pathways in which MEK is a critical component.  Trametinib dimethyl 
sulfoxide inhibits activation of MEK by RAF kinases and MEK kinases. 
 
Description:  Trametinib dimethyl sulfoxide is a white to almost white powder. 
 
How Supplied:  Novartis supplies and CTEP, NCI, DCTD distributes 0.5 mg and 2 mg 
(as free base) tablets.  Each investigationally-labeled bottle contains 32 tablets. 
The tablet core contains mannitol, microcrystalline cellulose, hypromellose, 
croscarmellose sodium, magnesium stearate (non-animal), colloidal silicon dioxide, and 
sodium lauryl sulfate. 
 
• 0.5 mg tablets are yellow, modified oval, biconvex and film-coated. Aqueous film 
coating consists of hypromellose, titanium dioxide, polyethylene glycol, iron oxide 
yellow. 
• 
2 mg tablets are pink, round, biconvex and film-coated. Aqueous film coating 
consists of hypromellose, titanium dioxide, polyethylene glycol, polysorbate 80, iron 
oxide red. 
Storage:  Store tablets at 2°C - 8°C in the original bottle and dispense unopened bottles. 
Do not open bottles, repackage tablets or remove desiccant. Bottles should be protected 
from light and moisture.  
 
If a storage temperature excursion is identified, promptly return trametinib to 2oC -8oC 


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51 
 
and quarantine the supplies. Provide a detailed report of the excursion (including 
documentation of temperature monitoring and duration of the excursion) to 
PMBAfterHours@mail.nih.gov for determination of suitability.  
 
Stability:  Stability studies are ongoing. Tablets are only stable for 32 days once bottle 
has been opened. If multiple bottles are dispensed to a patient in the same visit, please 
advise the patient to open only one bottle at a time. 
 
Route of Administration:  Oral. Take by mouth on an empty stomach, either 1 hour 
before or 2 hours after a meal. If a dose of trametinib is missed, the dose can be taken if it 
is more than 12 hours until the next scheduled dose. 
 
Potential Drug Interactions 
 
In vitro studies suggest that trametinib dimethyl sulfoxide is not a substrate of CYP 
enzymes or of human  BCRP, MRP2, OATP1B1, OATP1B3, OATP2B1, OCT1 or 
MATE1 transporters. Trametinib elimination by deacetylation to metabolite M5 is 
dependent on carboxylesterases (CES1b, CES1c and CES2). 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, 2C9, 2C19 and is 
anticipated to have overall low potential for drug interactions as a perpetrator. It is also a 
weak CYP 2B6 and 3A4 inducer and expected to have little clinical effect on sensitive 
substrates. Trametinib is not an inhibitor of CYP 1A2, 2A6, 2B62D6 and 3A4 and not an 
inhibitor of MRP2 or BSEP, but an in vitro inhibitor of P-gp, BCRP, OATP1B1, 
OATP1B3, OAT1, OAT3, OCT2 and MATE1. No clinically relevant inhibition by 
trametinib is predicted in the liver or kidney and a low risk of intestinal drug-drug 
interaction is possible with BCRP.  
Trametinib is highly bound to plasma proteins (97.3%) and has the potential to interfere 
with other highly protein-bound drugs. Use caution in patients taking concomitant drugs 
that are highly protein-bound and have narrow therapeutic ranges.  
 
Patient Care Implications 
 
Advise women study participants of reproductive potential to use effective contraception 
while receiving study treatment and for 4 months after the last dose of trametinib. Refer 
to the protocol document for specific guidance. 
 
Availability 
 
Trametinib dimethyl sulfoxide (GSK1120212B) is an investigational agent supplied to 
investigators by the Division of Cancer Treatment and Diagnosis (DCTD), NCI. 
 


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52 
 
Trametinib dimethyl sulfoxide (GSK1120212B) is provided to the NCI under a 
Collaborative Agreement between the Pharmaceutical Collaborator and the DCTD, NCI 
(see Section 12.3). 
 
8.1.2 Agent Ordering and Agent Accountability 
 
8.1.2.1 
NCI-supplied agents may be requested by the Principal Investigator (or their 
authorized designee) at each participating institution.  Pharmaceutical Management 
Branch (PMB) policy requires that agent be shipped directly to the institution where 
the patient is to be treated.  PMB does not permit the transfer of agents between 
institutions (unless prior approval from PMB is obtained).  The CTEP-assigned 
protocol number must be used for ordering all CTEP-supplied investigational agents.  
The responsible investigator at each participating institution must be registered with 
CTEP, DCTD through an annual submission of FDA Form 1572 (Statement of 
Investigator), Curriculum Vitae, Supplemental Investigator Data Form (IDF), and 
Financial Disclosure Form (FDF).  If there are several participating investigators at 
one institution, CTEP-supplied investigational agents for the study should be ordered 
under the name of one lead investigator at that institution. 
 
Starter supplies are not being provided. Subjects must be enrolled prior to submitting 
the clinical drug request in OAOP. 
 
Active CTEP-registered investigators and investigator-designated shipping designees 
and ordering designees can submit agent requests through the PMB Online Agent 
Order Processing (OAOP) application.  Access to OAOP requires the establishment 
of a CTEP Identity and Access Management (IAM) account and the maintenance of 
an “active” account status and a “current” password.  For questions about drug orders, 
transfers, returns, or accountability, call or email PMB any time.  Refer to the PMB’s 
website for specific policies and guidelines related to agent management.   
 
8.1.2.2 
Agent Inventory Records – The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the receipt, dispensing and final 
disposition of all agents received from the PMB using the appropriate NCI 
Investigational Agent (Drug) Accountability Record (DARF) available on the CTEP 
forms page.  Store and maintain separate NCI Investigational Agent Accountability 
Records for each agent, strength, formulation and ordering investigator on this 
protocol. 
 
8.1.2.3 
Useful Links and Contacts 
• CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/ 
• NCI CTEP Investigator Registration:  PMBRegPend@ctep.nci.nih.gov 
• PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm  
• PMB Online Agent Order Processing (OAOP) application: https://eapps-
ctep.nci.nih.gov/OAOP/pages/login.jspx  


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53 
 
• CTEP Identity and Access Management (IAM) account: https://eapps-
ctep.nci.nih.gov/iam/ 
• CTEP Associate Registration and IAM account help:  
ctepreghelp@ctep.nci.nih.gov  
• PMB email:  PMBAfterHours@mail.nih.gov 
• PMB phone and hours of service: (240) 276-6575 Monday through Friday 
between 8:30 am and 4:30 pm (ET) 
• IB Coordinator: IBCoordinator@mail.nih.gov 
 
8.1.2.4 
Investigator Brochure Availability 
The current versions of the IBs for the 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 and a “current” password.  Questions about IB access may be directed to the 
PMB IB coordinator via email. 
 
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
9.1 
Integral Laboratory or Imaging Studies 
None. 
 
9.2 
Integrated Studies 
9.2.1 Evaluate tumor for presence of TAZ-CAMTA1 gene fusion by fluorescence in-situ 
hybridization. 
 
9.2.1.1 
FISH for TAZ-CAMTA1 gene fusion 
The presence of TAZ-CAMTA1 gene fusion may be detected by fluorescence in situ 
hybridization (FISH) or polymerase chain reaction. FISH probes have been developed 
using a red fluorophore to the 5’ end of TAZ (WWTR1 gene) and a green fluorophore to 
the 3’ end of CAMTA1 gene. Cells containing translocation of TAZ (WWTR1) on 
chromosome 3 with CAMTA1 on chromosome 1 can be detected by fusion of the red and 
green fluorescent signals in nuclei. After processing tissue for FISH, at least 50 nuclei 
will be examined. Tumor with at least 10% of the nuclei containing a fused signal will be 
scored as containing the TAZ-CAMTA1 translocation. 
9.2.1.2 
Collection of Specimen(s) 
The registering site should submit the required specimen for FISH within 2 weeks of 
patient registration/enrollment. Formalin-fixed, paraffin-embedded archival tumor tissue 
may be submitted for FISH analysis. Tissue may be from core needle biopsy or excision 
of an EHE lesion. An adequate amount of tissue should be available to produce 12 slides 
containing 4 micron thick sections of tumor tissue for FISH and at least 1 slide for 
hematoxylin and eosin staining. Sites may submit 1 H&E stained slide of representative 
tumor tissue and either 12 slides containing four micron-thick unstained tumor sections or 
a paraffin block containing tumor tissue. Unstained sections should be placed on charged 


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54 
 
slides and NOT baked. 
9.2.1.3 
Handling of Specimens(s) 
Routine handling of patient tissue at ambient room temperature. 
Tumor block and/or slides will be shipped to: 
 
Cleveland Clinic 
Department of Pathology 
ATTN: Dr. Brian Rubin 
2119 East 93rd Street, L15 
Cleveland OH 44106 
Contact: Barbara Bailey or Brian Rubin (216)445-5551 
 
Notification of shipment should be sent to SARC RPM at SARC033@sarctrials.org 
 
9.2.1.4  
Site performing integrated study 
 
Cleveland Clinic CLIA-certified FISH laboratory 
 
9.3 
Exploratory/Ancillary Correlative Studies 
 
9.3.1 Plasma Connective Tissue Growth Factor (CTGF) Level 
Plasma CTGF levels may be a useful biomarker of EHE survival as CTGF is a secreted 
protein whose gene is an immediate downstream target of TAZ-CAMTA1 (Tanas et al., 
2016). CTGF is secreted and binds to αIIbβ3 integrin on the cell surface, leading in an 
autocrine fashion to downstream activation of RAS and MAP kinase pathways. This 
signal transduction pathway drives TAZ-CAMTA1-mediated NIH/3T3 cell 
transformation. Inhibition of any portion of this pathway inhibits transformation. 
Preliminary studies have shown that CTGF is produced at high levels and secreted into 
culture media by cells that express TAZ-CAMTA1. CTGF is expressed in human EHE as 
demonstrated by anti-CTGF western blot of patient tumor lysates. CTGF is secreted by 
EHE and can be quantified in plasma from EHE patients using standard ELISA. Fibrogen 
(San Francisco) has supplied a CTGF-specific monoclonal antibody to CTGF that 
performs well in ELISA. If trametinib results in EHE cell death and objective tumor 
response, we hypothesize that CTGF plasma levels will decline. Alternatively, if 
trametinib blocks growth of EHE by inhibiting MEK but does not result in cell death, we 
expect CTGF plasma levels will remain unchanged. 
9.3.1.1 
Collection of Specimen(s) 
Samples (3-5 mL blood) will be obtained prior to treatment, after 4 weeks and 6 months 
(in patients with stable or better disease) of treatment, at the time of objective tumor 
response and upon determination of EHE radiologic or clinical progression. 
 
9.3.1.2 
Handling of Specimens(s) 
Blood will be drawn in sodium or potassium-EDTA collection tubes and processed 


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55 
 
within 60 minutes of collection. After collection of blood into collection tubes, the tubes 
should be gently inverted 4-6 times to ensure proper mixing of blood with EDTA. The 
tubes should be centrifuged at 1,000 – 2,000 x gravity at 4 degrees centigrade for 15-20 
minutes to separate plasma. After centrifugation, 1-2 mL of plasma should be removed 
using a clean pipet and placed into two 1.5 mL Eppendorf (or similar) collection vials, 
labeled with the date of collection, patient ID and study ID or similar specimen tracking 
information and immediately frozen at -80oC. Specimens should be stored frozen at -
80oC or colder until shipped on dry ice. 
9.3.1.3 
Shipping of Specimen(s) 
Samples should be batched for shipping. The site may batch all aliquots from each time 
point from each study participant in one shipment to avoid unnecessary shipping expense. 
Samples must be kept frozen and shipped on dry ice via overnight delivery service for 
arrival to the laboratory on Monday through Friday. Samples should not arrive on 
Saturday, Sunday or recognized Federal holiday. Samples should be sent to: 
 
Lisa Denero 
Biopathology Center 
Nationwide Children’s Hospital 
700 Children’s Drive, WA 1340 
Columbus OH 43205 
 
Phone: 614-355-2799 
 
Notification of shipment should be sent to SARC RPM at SARC033@sarctrials.org 
9.3.1.4 
Site(s) Performing Correlative Study 
Dr. Brian Rubin’s research laboratory at Cleveland Clinic. 
Department of Pathology 
2119 East 93rd Street, L15 
Cleveland OH 44106 
 
9.3.2 Assessment of MAP kinase pathway signaling 
In pre-clinical studies, NIH/3T3 cells stably expressing the TAZ-CAMTA1 gene fusion 
were grown in suspension and the MAPK pathway was examined. NIH/3T3 cells 
containing empty vector were used as control. Phospho-ERK, which is emblematic of 
MAPK pathway activation was sustained in TAZ-CAMTA1 expressing cells while cells 
expressing vector alone lost ERK phosphorylation over time. This suggests that TAZ-
CAMTA1 maintained MAPK activation. Furthermore, phospho-ERK has been detected 
in protein lysates of snap-frozen EHE tumor samples and localized phospho-ERK in EHE 
tumor cells by immunohistochemistry with a phospho-specific anti-ERK antibody which 
demonstrated strong activation specifically in tumor cells. We hypothesize that tumor 
responses to clinically administered doses of trametinib will be accompanied by 
suppression of the MAPK pathway signaling. 
Formalin-fixed paraffin-embedded samples will undergo quality review by the SARC 
SPORE Pathology core and tumor tissue will be analyzed for ERK phosphorylation by 


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56 
 
semi-quantitative immunohistochemistry using phospho-ERK (Thr202/Tyr204)-specific 
antibody (Cell Signaling #4370) and quantitative immunochemistry by AQUA. If ERK is 
no longer suppressed in tumor progression, MEK 1/2 will be sequenced to identify 
genetic mechanisms of resistance. Frozen tumor tissue will be reserved for primarily for 
protein studies of intracellular protein kinase signaling studies, if needed. For example, if 
IHC suggests that ERK is inhibited, then the snap frozen tissue will be used to make 
protein lysates for phospho-proteomic arrays (R&D systems) which will provide a panel 
of anti-phospho-protein antibodies targeting proteins involved in a variety of intracellular 
signaling pathways to identify activation of alternative signaling pathways that 
mechanistically could drive progression. 
9.3.2.1 
Collection of Specimens 
Optional tumor biopsy will be performed prior to starting trametinib and after 
approximately 4 weeks of trametinib treatment (+/- 7 days), and upon progression in 
patients who previously had objective tumor response. It is encouraged that biopsies be 
performed to collect tumor tissue for correlative research studies to evaluate the effect of 
trametinib on MEK signaling. Patients will be provided the option of participating in 
biopsy of tumor prior to treatment an on treatment with trametinib. If treatment is 
interrupted in a patient, the biopsy should be delayed until drug is restarted and taken 
daily for at least 7 days. At a minimum, biopsy should consist of 4 core biopsies using 14 
to 16 gauge needles at least 8-10 mm in length. Two core biopsies should be immediately 
placed in formalin and processed using standard methods in paraffin for standard 
immunohistochemistry. The remaining cores should be immediately flash frozen in liquid 
nitrogen or embedded in OCT (optimal cutting temperature) compound and frozen at -80 
degrees Celsius. 
9.3.2.2 
Handling of Specimens 
Paraffin-embedded samples should be labeled with date of biopsy, subject ID and Study 
ID and kept at ambient temperature. Tissue frozen in liquid nitrogen should be kept 
frozen in an Eppendorf (or similar) clean collection vial labeled with the date of biopsy, 
subject ID and study ID and stored at -80 degrees Celsius until shipped to Cleveland 
Clinic on dry ice. 
9.3.2.3 
Shipping of Specimens 
Paraffin-embedded samples should be shipped at ambient temperature. Frozen samples 
may be batched for shipping. The site may batch all frozen tissue biopsies from each time 
point from each study participant in one shipment to avoid unnecessary shipping expense. 
Samples must be kept frozen and shipped on dry ice via overnight delivery service for 
arrival to the laboratory on Monday through Friday. Samples should not arrive on 
Saturday, Sunday or recognized Federal holiday. Samples should be sent to: 
 
Lisa Denero 
Biopathology Center 
Nationwide Children’s Hospital 
700 Children’s Drive, WA 1340 


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57 
 
Columbus OH 43205 
 
Notification of shipment should be sent to SARC RPM at SARC033@sarctrials.org 
 
9.3.2.4 
Sites Performing Correlative Study 
Dr. Brian Rubin’s research laboratory, Cleveland Clinic 
Department of Pathology 
ATTN: Dr. Brian Rubin 
2119 East 93rd Street, L15 
Cleveland OH 44106 
 
9.4 
Special Studies 
 
9.4.1 Tumor Volume 
9.4.1.1 
Measure: Change in volume of EHE on treatment with trametinib. In a retrospective 
analysis, a change in tumor volume identified more patients than RECIST 1.1 with 
response and correlated with survival in a prospective trial of Ewing sarcoma treated 
with anti-insulin-like growth factor. We will assess changes in tumor volume over 
time, compare this to response by RECIST 1.1 criteria and correlate with survival. An 
increase in tumor volume of 100% or more will be scored as progression and decrease 
in volume of 45% or more will be scored as response. 
9.4.1.2 
Assessment 
9.4.1.2.1. Sites of tumor will be imaged by CT or MRI using standard protocols. 
9.4.1.2.2. Imaging tumor will occur within 30 days prior to starting drug, after 
cycles 2, 4 and 6 and thereafter approximately every 12 weeks. For 
patients will evidence of disease progression prior to enrollment, CT or 
MRI scans documenting progression will also be reviewed. 
9.4.1.3 
Data Recording 
 
9.4.1.3.1. The TRIAD software anonymizes, encrypts and validates the images as 
they are transferred. Site staff who submit images through TRIAD will 
need to be registered with the Cancer Therapy Evaluation Program 
(CTEP) and have a valid and active CTEP Identity and Access 
Management (IAM) account. Please refer to CTEP Registration 
Procedures of the protocol for instructions on how to request a CTEP-
IAM account. To submit images, the site TRIAD user must be on the 
site’s affiliate rosters and be assigned the TRIAD site user role on the 
CTSU roster. Users should contact the site’s CTSU Administrator of Data 
Administrator to request assignment of the TRIAD site user role. After 
the user receives a CTEP-IAM account with proper user role, he/she will 
need to have the TRIAD application installed on his/her workstation to be 


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58 
 
able to submit the image files. TRIAD installation documentation can be 
found at the link https://triadinstall.acr.org/triadclient/. This process can 
be done in parallel to obtaining the CTEP-IAM account username and 
password. If you have questions regarding this information, please send 
an email to the TRIAD Support mailbox at TRIAD-Support@acr.org. For 
support with the TRIAD application, please send an email to TRIAD-
Support@ACR.org. Participating sites that are unable to use or access 
TRIAD may submit digital images through QARC’s secure FTP site or in 
DICOM files on CD/DVD. For questions regarding diagnostic imaging 
submission, please contact SARC@QARC.org or 401-753-7600. 
9.4.1.3.2. Timing of Recording. Sites will submit images of CT or MRI obtained 
prior to starting trametinib within 4 weeks after enrollment. Sites will 
submit images of CT or MRI performed during the treatment period 
within 4 weeks of completion of the radiology scan. 
 


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59 
 
10. STUDY CALENDAR 
 
Baseline evaluations are to be conducted within 2 weeks prior to patient registration.  Tumor 
imaging, cardiac evaluation and ophthalmology evaluations must be done within 30 days prior to 
patient registration.  In the event that the patient’s condition is deteriorating, laboratory 
evaluations should be repeated within 48 hours prior to initiation of the next cycle of therapy. 
The window for cycle visits is +/- 7 days. 
 
 
Pre- 
Study 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
6 
Wk 
7 
Wk 
8 
Wk 
9 
Wk 
10 
Wk 
11 
Wki 
12 
Off 
Treatment 
Trametinib Daily 
 
A 
A 
A 
A 
A 
A 
A 
A 
A 
A 
A 
A 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Archival tumor tissue sent for 
TAZ-CAMTA1 FISH 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concurrent meds 
X 
X---------------------------------------------------------------------------------------------X 
 
Physical exam 
X 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
Vital signs 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Performance status 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
CBC w/diff, plts 
X 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
Serum chemistrya 
X 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
ESR, CRPb 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Plasma collection for CTGFb 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
EKG  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Echocardiogram or MUGAc 
X 
Every 12 weeks (+/- 14 days) (use same methodology for baseline and follow up). 
Ophthalmology examd 
X 
 
 
Adverse event evaluation 
 
X---------------------------------------------------------------------------------------------X 
X 
Tumor measuremente 
X 
Tumor measurements are repeated every 8 weeks (± 7 days) for first 24 weeks, then 
every 12 weeks (± 7 days). Digital files of radiology images sent to QARC. 
X 
Radiologic evaluationf 
X 
Radiologic measurements should be performed every 8 weeks (± 7 days) for first 24 
weeks, then every 12 weeks (± 7 days). 
X 
Pregnancy testg 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Optional fresh biopsy of 
tumor 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
NIH PROMIS Questionnaireh 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
A: 
Trametinib: Dose as assigned; to be taken daily 
a: 
Comprehensive metabolic panel. The panel should include albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, 
chloride, creatinine, glucose, potassium, total protein, SGOT [AST], SGPT [ALT], sodium. 
b: 
Biomarker assessment: ESR-westergren method preferred and CRP, to be performed by local lab prior to therapy, after 4 weeks and 6 
months of treatment (for patients with stable for better disease), at time of objective response and at progression. Plasma for 


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60 
 
determination of CTGF level to be obtained at the same time points and sent to central lab for analysis. 
c:      The same modality (ECHO or MUGA) should be used at baseline and at follow-up 
d:      Ophthalmology exams should be obtained at baseline, and if clinically indicated, during study.  Opthalmology exam should include 
Ocular Coherence Tomography, fundoscopy, tonometry, visual field examination, and corrected visual acuity assessments. 
e: 
Tumor digital files to be sent to QARC for tumor volume assessment. 
f:      Tumor measurements do not need to be repeated if patient ends treatment because of documented tumor progression by imaging. 
g:       Blood or urine  pregnancy test (women of childbearing potential). 
h:      NIH PROMIS global health, pain intensity, interference and behavior short form inventories to be obtained prior to trametinib treatment, 
after 1 month and 6 months of treatment, and on evidence of disease progression or response. 
i:     For patients remaining on treatment after week 12, evaluations will include physical exam, weight, performance status, complete blood 
count with differential and platelet count, and serum chemistry at least once per cycle.   
 
 
 
 


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11. MEASUREMENT OF EFFECT 
 
11.1 
Antitumor Effect – Solid Tumors 
 
For the purposes of this study, patients should be re-evaluated for response every 8 weeks (± 7 
days) for the first 24 weeks, then every 12 weeks (± 7 days).  In addition to a baseline scan, 
confirmatory scans should also be obtained 4 to 8 weeks following initial documentation of 
objective response. 
 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST 1.1) guideline 
(version 1.1) [Eur J Ca 45:228-247, 2009].  Changes in the largest diameter (unidimensional 
measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph 
nodes are used in the RECIST 1.1 criteria. 
 
11.1.1 Definitions 
 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of their 
first treatment with trametinib. 
 
Evaluable for objective response.  Only those patients who have measurable disease 
present at baseline, have received at least one cycle of therapy, and have had their disease 
re-evaluated will be considered evaluable for response.  These patients will have their 
response classified according to the definitions stated below.  (Note:  Patients who exhibit 
objective disease progression prior to the end of cycle 1 will also be considered 
evaluable.) 
 
Evaluable Non-Target Disease Response.  Patients who have lesions present at baseline 
that are evaluable but do not meet the definitions of measurable disease, have received at 
least one cycle of therapy, and have had their disease re-evaluated will be considered 
evaluable for non-target disease.  The response assessment is based on the presence, 
absence, or unequivocal progression of the lesions.  
 
11.1.2 Disease Parameters 
 
Measurable disease.  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as ≥20 mm (≥2 cm) 
by chest x-ray or as ≥10 mm (≥1 cm) with CT scan, MRI, or calipers by clinical exam.  
All tumor measurements must be recorded in millimeters (or decimal fractions of 
centimeters). 
 
Note:  Tumor lesions that are situated in a previously irradiated area will be considered 
measurable only if demonstration of progression of the lesion has occurred following 
radiation. 
 


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Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a 
lymph node must be ≥15 mm (≥1.5 cm) in short axis when assessed by CT scan (CT scan 
slice thickness recommended to be no greater than 5 mm [0.5 cm]) or MRI.  At baseline 
and in follow-up, only the short axis will be measured and followed. 
 
Non-measurable disease.  All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm [<1 cm] or pathological lymph nodes with ≥10 to <15 mm [≥1 
to <1.5 cm] short axis), are considered non-measurable disease.  Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed by 
CT or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions (neither measurable nor non-measurable) 
since they are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same patient, these are preferred for selection as target 
lesions. 
 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target 
lesions and recorded and measured at baseline.  Target lesions should be selected on the 
basis of their size (lesions with the longest diameter), be representative of all involved 
organs, but in addition should be those that lend themselves to reproducible repeated 
measurements.  It may be the case that, on occasion, the largest lesion does not lend itself 
to reproducible measurement in which circumstance the next largest lesion which can be 
measured reproducibly should be selected.  A sum of the diameters (longest for non-
nodal lesions, short axis for nodal lesions) for all target lesions will be calculated and 
reported as the baseline sum diameters.  If lymph nodes are to be included in the sum, 
then only the short axis is added into the sum.  The baseline sum diameters will be used 
as reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. 
 
Non-target lesions.  All other lesions (or sites of disease) including any measurable 
lesions over and above the 5 target lesions should be identified as non-target lesions and 
should also be recorded at baseline.  Measurements of these lesions are not required, but 
the presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow-up.  
 
11.1.3 Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or 
calipers.  All baseline evaluations should be performed as closely as possible to the 


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beginning of treatment and never more than 30 days before the beginning of the 
treatment. 
 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam. 
 
Clinical lesions.  Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm (≥1 cm) diameter 
as assessed using calipers (e.g., skin nodules).  In the case of skin lesions, documentation 
by color photography, including a ruler to estimate the size of the lesion, is 
recommended.  
 
Chest x-ray.  Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung.  However, CT is preferable.  
 
Conventional CT and MRI.  This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm (0.5 cm) or less.  If CT 
scans have slice thickness greater than 5 mm (0.5 cm), the minimum size for a 
measurable lesion should be twice the slice thickness.  MRI is also acceptable in certain 
situations (e.g. for body scans).   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement.  Furthermore, the 
availability of MRI is variable globally.  As with CT, if an MRI is performed, the 
technical specifications of the scanning sequences used should be optimized for the 
evaluation of the type and site of disease.  Furthermore, as with CT, the modality used at 
follow-up should be the same as was used at baseline and the lesions should be 
measured/assessed on the same pulse sequence.  It is beyond the scope of the RECIST 
guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases.  Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior scans.  Body scans 
should be performed with breath-hold scanning techniques, if possible. 
 
PET-CT.  At present, the low dose or attenuation correction CT portion of a combined 
PET-CT is not always of optimal diagnostic CT quality for use with RECIST 
measurements.  However, if the site can document that the CT performed as part of a 
PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), 
then the CT portion of the PET-CT can be used for RECIST measurements and can be 
used interchangeably with conventional CT in accurately measuring cancer lesions over 
time.  Note, however, that the PET portion of the CT introduces additional data which 
may bias an investigator if it is not routinely or serially performed.   
 


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Ultrasound.  Ultrasound is not useful in assessment of lesion size and should not be used 
as a method of measurement.  Ultrasound examinations cannot be reproduced in their 
entirety for independent review at a later date and, because they are operator dependent, it 
cannot be guaranteed that the same technique and measurements will be taken from one 
assessment to the next.  If new lesions are identified by ultrasound in the course of the 
study, confirmation by CT or MRI is advised.  If there is concern about radiation 
exposure at CT, MRI may be used instead of CT in selected instances. 
 
Endoscopy, Laparoscopy.  The utilization of these techniques for objective tumor 
evaluation is not advised.  However, such techniques may be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in trials where 
recurrence following complete response (CR) or surgical resection is an endpoint. 
 
Tumor markers.  Tumor markers are not available for EHE and cannot be used to assess 
response. 
 
11.1.4 Response Criteria 
 
11.1.4.1 
Evaluation of Target Lesions 
 
Complete Response (CR):  Disappearance of all target lesions.  Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to <10 
mm (<1 cm). 
 
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters. 
 
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study).  In addition to the relative increase of 
20%, the sum must also demonstrate an absolute increase of at least 5 mm (0.5 cm).  
(Note:  the appearance of one or more new lesions is also considered progressions). 
 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study. 
 
11.1.4.2 
Evaluation of Non-Target Lesions 
 
Complete Response (CR):  Disappearance of all non-target lesions and normalization 
of tumor marker level.  All lymph nodes must be non-pathological in size (<10 mm 
[<1 cm] short axis). 
 
Note:  If tumor markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response. 


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Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits. 
 
Progressive Disease (PD):  Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions.  Unequivocal progression 
should not normally trump target lesion status.  It must be representative of overall 
disease status change, not a single lesion increase. 
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion 
of the treating physician should prevail in such circumstances, and the progression 
status should be confirmed at a later time by the review panel (or Principal 
Investigator). 
 
11.1.4.3 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started).  The patient's best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria. 
 
For Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
≥4 wks. Confirmation** 
CR 
Non-CR/Non-
PD 
No 
PR 
≥4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once ≥4 
wks. from baseline** 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**    Confirmation is required in this protocol. 
***  In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
 
Note:  Patients with a global deterioration of health status requiring discontinuation of 


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treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.”  Every effort should be made to document the 
objective progression even after discontinuation of treatment. 
 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised 
 
11.1.5 Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first 
date that recurrent or progressive disease is objectively documented (taking as reference 
for progressive disease the smallest measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met 
for CR until the first date that progressive disease is objectively documented. 
 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started, including the baseline measurements.  
 
11.1.6 Progression-Free Survival 
 
PFS is defined as the duration of time from start of treatment to time of progression or 
death, whichever occurs first. 
 
11.1.7 Response Review 
 
CT and MRI scans performed to document patient tumor progression prior to study 
enrollment and response to treatment with trametinib will be electronically sent via 
TRIAD to IROC Rhode Island (QARC). Digital images will be transferred to Dr. 
Lawrence Schwartz at Columbia University for review and independent assessment of 
tumor response. The decision to continue a patient on treatment with trametinib will be 
based on the treating investigator or site assessment of tumor response.  
 


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11.2 
Antitumor Effect – Hematologic Tumors N/A 
 
11.3 
Other Response Parameters – N/A 
 
12. STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements). 
 
 
12.1 
Study Oversight 
 
This protocol is monitored at several levels, as described in this section.  The Protocol Principal 
Investigator is responsible for monitoring the conduct and progress of the clinical trial, including 
the ongoing review of accrual, patient-specific clinical and laboratory data, and routine and 
serious adverse events; reporting of expedited adverse events; and accumulation of reported 
adverse events from other trials testing the same drug(s).  The Protocol Principal Investigator and 
statistician have access to the data at all times through the CTMS web-based reporting portal.   
 
During the study, the SARC office will help monitor patient enrollment, treatment and adverse 
events including reasons for discontinuation of treatment. A running list of patient accrual, 
duration of therapy, reason for drug discontinuation and SAEs will be maintained and reviewed 
during the conference calls. Any unexpected AEs that are felt to be clinically significant will also 
be reviewed. SARC Clinical Trials review calls occur monthly with the study PI, SARC medical 
officer, study statistician and SARC staff. This process is standard for all SARC clinical trials. 
The Protocol Principal Investigator will have, at a minimum, quarterly conference calls with the 
Site Investigators and the CTEP Medical Officer(s) to review accrual, progress, and 
pharmacovigilance.  Decisions to proceed to the second stage of the Phase 2 trial will require 
sign-off by the Protocol Principal Investigator and the Protocol Statistician. 
 
All Study Investigators at participating sites who register/enroll patients on a given protocol are 
responsible for timely submission of data via Medidata Rave and timely reporting of adverse 
events for that particular study.  This includes timely review of data collected on the electronic 
CRFs submitted via Medidata Rave. 
 
All studies are also reviewed in accordance with the enrolling institution’s data safety monitoring 
plan. 
 
12.2 
Data Reporting 
 
Data collection for this study will be done exclusively through Medidata Rave.  Access to the 
trial in Rave is granted through the iMedidata application to all persons with the appropriate 
roles assigned in the Regulatory Support System (RSS).  To access Rave via iMedidata, the site 
user must have an active CTEP IAM account (https://eapps-ctep.nci.nih.gov/iam) and the 


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appropriate Rave role (Rave CRA, Read-Only, or Site Investigator) on either the Corresponding 
Organization or Participating Organization roster at the enrolling site.   
 
Upon initial site registration approval for the study in RSS, all persons with Rave roles assigned 
on the appropriate roster will be sent a study invitation e-mail from iMedidata.  To accept the 
invitation, site users must log into the Select Login (https://login.imedidata.com/selectlogin) 
using their CTEP-IAM user name and password, and click on the “accept” link in the upper 
right-corner of the iMedidata page.  Please note, site users will not be able to access the study in 
Rave until all required Medidata and study specific trainings are completed.  Trainings will be in 
the form of electronic learnings (eLearnings), and can be accessed by clicking on the link in the 
upper right pane of the iMedidata screen.   
 
Users that have not previously activated their iMedidata/Rave account at the time of initial site 
registration approval for the study in RSS will also receive a separate invitation from iMedidata 
to activate their account. Account activation instructions are located on the CTSU website, Rave 
tab under the Rave resource materials (Medidata Account Activation and Study Invitation 
Acceptance).  Additional information on iMedidata/Rave is available on the CTSU members’ 
website under the Rave tab or by contacting the CTSU Help Desk at 1-888-823-5923 or by e-
mail at ctsucontact@westat.com. 
 
12.2.1 Method 
 
For studies assigned for CTMS Routine Monitoring: 
This study will be monitored by the Clinical Trials Monitoring Service (CTMS).  Data 
will be submitted to CTMS at least once every two weeks via Medidata Rave (or other 
modality if approved by CTEP).  Information on CTMS reporting is available at:  
http://www.theradex.com/CTMS.  On-site audits will be conducted on an 18-36 month 
basis as part of routine cancer center site visits. More frequent audits may be conducted if 
warranted by accrual or due to concerns regarding data quality or timely submission.  For 
CTMS monitored studies, after users have activated their accounts, please contact the 
Theradex Help Desk at (609) 799-7580 or by email at ctms@theradex.com for additional 
support with Rave and completion of CRFs. 
 
12.2.2 Responsibility for Data Submission 
 
For ETCTN trials, it is the responsibility of the PI(s) at the site to ensure that all 
investigators at the ETCTN Sites understand the procedures for data submission for each 
ETCTN protocol and that protocol specified data are submitted accurately and in a timely 
manner to the CTMS via the electronic data capture system, Medidata Rave.   
 
Data are to be submitted via Medidata Rave to CTMS on a real-time basis, but no less 
than once every 2 weeks.  The timeliness of data submissions and timeliness in resolving 
data queries will be tracked by CTMS.  Metrics for timeliness will be followed and 
assessed on a quarterly basis.  For the purpose of Institutional Performance Monitoring, 
data will be considered delinquent if it is greater than 4 weeks past due. 


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Data from Medidata Rave and CTEP-AERS is reviewed by the CTMS on an ongoing 
basis as data is received.  Queries will be issued by CTMS directly within Rave.  The 
queries will appear on the Task Summary Tab within Rave for the CRA at the ETCTN to 
resolve.  Monthly web-based reports are posted for review by the Drug Monitors in the 
IDB, CTEP.  Onsite audits will be conducted by the CTMS to ensure compliance with 
regulatory requirements, GCP, and NCI policies and procedures with the overarching 
goal of ensuring the integrity of data generated from NCI-sponsored clinical trials, as 
described in the ETCTN Program Guidelines, which may be found on the CTEP 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm
)  and CTSU websites. 
 
An End of Study CRF is to be completed by the PI, and is to include a description of any 
dose-limiting toxicities (DLTs).  CTMS will utilize a core set of eCRFs that are Cancer 
Data Standards Registry and Repository (caDSR) compliant 
(http://cbiit.nci.nih.gov/ncip/biomedical-informatics-resources/interoperability-and-
semantics/metadata-and-models).  Customized eCRFs will be included when appropriate 
to meet unique study requirements.  The PI is encouraged to review the eCRFs, working 
closely with CTMS to ensure prospectively that all required items are appropriately 
captured in the eCRFs prior to study activation.  CTMS will prepare the eCRFs with 
built-in edit checks to the extent possible to promote data integrity. 
 
CDUS data submissions for ETCTN trials activated after March 1, 2014, will be carried 
out by the CTMS contractor, Theradex.  CDUS submissions are performed by Theradex 
on a monthly basis.  The trial’s lead institution is responsible for timely submission to 
CTMS via Rave, as above. 
 
Further information on data submission procedures can be found in the ETCTN Program 
Guidelines 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm
). 
12.3 
CTEP Multicenter Guidelines - N/A 
 
12.4 
Collaborative Agreements Language 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 
under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis.  Therefore, the following obligations/guidelines, in addition to the 
provisions in the “Intellectual Property Option to Collaborator”  
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the 
terms of award, apply to the use of the Agent(s) in this study: 
 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 


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70 
 
Agent(s) be transferred or licensed to any party not participating in the clinical study.  
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and shall 
be maintained as such by the investigators.  The protocol documents for studies utilizing 
Agents contain confidential information and should not be shared or distributed without the 
permission of the NCI.  If a copy of this protocol is requested by a patient or patient’s family 
member participating on the study, the individual should sign a confidentiality agreement.  A 
suitable model agreement can be downloaded from: http://ctep.cancer.gov. 
 
2. For a clinical protocol where there is an investigational Agent used in combination with 
(an)other Agent(s), each the subject of different Collaborative Agreements, the access to and 
use of data by each Collaborator shall be as follows (data pertaining to such combination use 
shall hereinafter be referred to as "Multi-Party Data”): 
 
a. NCI will provide all Collaborators with prior written notice regarding the existence and 
nature of any agreements governing their collaboration with NCI, the design of the 
proposed combination protocol, and the existence of any obligations that would tend to 
restrict NCI's participation in the proposed combination protocol. 
 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial 
by any other Collaborator solely to the extent necessary to allow said other Collaborator 
to develop, obtain regulatory approval or commercialize its own Agent. 
 
c. Any Collaborator having the right to use the Multi-Party Data from these trials must 
agree in writing prior to the commencement of the trials that it will use the Multi-Party 
Data solely for development, regulatory approval, and commercialization of its own 
Agent. 
 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement 
will be made available to Collaborator(s), the NCI, and the FDA, as appropriate and unless 
additional disclosure is required by law or court order as described in the IP Option to 
Collaborator (http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm).  
Additionally, all Clinical Data and Results and Raw Data will be collected, used and 
disclosed consistent with all applicable federal statutes and regulations for the protection of 
human subjects, including, if applicable, the Standards for Privacy of Individually 
Identifiable Health Information set forth in 45 C.F.R. Part 164. 
 
4. When a Collaborator wishes to initiate a data request, the request should first be sent to the 
NCI, who will then notify the appropriate investigators (Group Chair for Cooperative Group 
studies, or PI for other studies) of Collaborator's wish to contact them. 
 
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a 
DMC for this clinical trial. 
 
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the 


NCI Protocol #: 10015 
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71 
 
Group office for Cooperative Group studies or by the principal investigator for non-
Cooperative Group studies for immediate delivery to Collaborator(s) for advisory review and 
comment prior to submission for publication.  Collaborator(s) will have 30 days from the 
date of receipt for review.  Collaborator shall have the right to request that publication be 
delayed for up to an additional 30 days in order to ensure that Collaborator’s confidential and 
proprietary data, in addition to Collaborator(s)’s intellectual property rights, are protected.  
Copies of abstracts must be provided to CTEP for forwarding to Collaborator(s) for courtesy 
review as soon as possible and preferably at least three (3) days prior to submission, but in 
any case, prior to presentation at the meeting or publication in the proceedings.  Press 
releases and other media presentations must also be forwarded to CTEP prior to release.  
Copies of any manuscript, abstract and/or press release/ media presentation should be sent to: 
 
Email:  ncicteppubs@mail.nih.gov 
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s confidential/ 
proprietary information. 
 
12.5 
Genomic Data Sharing Plan 
 
Not applicable. 
 
13. STATISTICAL CONSIDERATIONS 
 
13.1 
Study Design/Endpoints 
 
The primary endpoint is the objective response rate using RECIST 1.1. Tumor response assessed 
by the local site investigator or delegate will be used to assess the objective response rate. Tumor 
response will be centrally reviewed by Dr. Lawrence Schwartz but the local site assessment will 
be used to determine patient treatment and tumor response outcome. 
 
A Simon minimax sampling two-stage design will be used to estimate the objective response rate 
with a goal of at least 20% of patients to be considered as having preliminary evidence of 
activity and less than 5% indicating that trametinib is ineffective as a potential EHE treatment. 
Thirteen patients with EHE will be enrolled in stage I, and if there is at least one objective 
response as defined by RECIST 1.1, additional patients with EHE will be enrolled until 27 
patients with EHE in which TAZ-CAMTA1 translocation is detected by fusion FISH in archival 
tumor tissue have been registered and started treatment. The diagnosis of EHE will be 
determined by the local site, but the presence of TAZ-CAMTA1 translocation will be determined 
by the Cleveland Clinic FISH laboratory. If four or more objective tumor responses are 
documented among 27 patients with TAZ-CAMTA1 translocation positive EHE, trametinib will 
be considered to have activity in EHE. With a type 1 error of 5%, this design will have a power 
of approximately 80% and will have a 51% probability of terminating after the first step if the 
response rate is 5%. The ORR, 6-month PFS and 2-year OS rates will be calculated along with 
their 95% confidence intervals. PFS and OS will be estimated by the Kaplan-Meier method.  


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72 
 
In stage I enrollment, the presence of TAZ-CAMTA1 translocation was not detected in 3 tumor 
samples and in one case there was insufficient tumor tissue available for the analysis. The rate of 
TAZ-CAMTA1 translocation negative EHE is higher than the expected rate of less than 10%, and 
because we anticipate activation of the MAP kinase pathway to occur in tumor with expression 
of TAZ-CAMTA1 but not in tumor without the translocation, the protocol is amended to enroll 
at least 27 patients with EHE containing TAZ-CAMTA1 translocation. 
 
Secondary objectives of the 6-month PFS rate, median PFS, and 2-year OS rate will be 
determined from analyses of patients with TAZ-CAMTA1 translocation positive EHE. Evaluation 
of the safety of trametinib, and patient reported symptoms using NIH-PROMIS questionnaires 
will be determined from analyses of all patients who started treatment with trametinib. 
 
Progression-free survival will be calculated from time of first dose of study medication to 
occurrence of radiologic tumor progression per RECIST1.1, clinical progression based on 
treating physician’s assessment or death from any cause. Overall survival will be calculated from 
the time of first dose of study drug to occurrence of death from any cause. Patients who are 
registered and are determined to be eligible for study treatment but do not start study drug will be 
replaced. All patients who receive study drug for any period of time will be evaluable for 
toxicity. The rates of adverse events occurring in at least 5% of subjects and rates of grade 3-5 
adverse events will be tabulated by system and term using Common Terminology Criteria of 
Adverse Events (CTCAE). For dose adjustment schedule see Section 6.1. PROMIS 
questionnaires will be scored according to recommended standardized system and t-scores 
generated. A mixed model will be used to analyze change in t-scores over time. Whether or not 
having evidence of disease progression will be used as a time-dependent variable in the mixed 
model with adjustment of other potential confounding variables. 
 
13.2 
Sample Size/Accrual Rate 
 
This study will be conducted in a two-stage process. In stage I, 13 patients with EHE will be 
enrolled. If there is at least 1 objective response, additional patients will be enrolled in stage II 
until there is evidence that a total of 27 patients with EHE with TAZ-CAMTA1 translocation 
detected by fusion FISH have been registered and started treatment. After 27 patients have been 
enrolled and started treatment, enrollment of additional patients will be held until FISH testing is 
performed on available tissue from the enrolled patients. One enrollment slot will be opened for 
each case of FISH result of TAZ-CAMTA1 translocation “not detected”, “test failed”, or “test not 
performed” (no tumor tissue in sample) until a total of 27 patients have enrolled and started 
treatment with FISH result of TAZ-CAMTA1 translocation “detected”. Enrollment in the second 
stage will be held until at least 1 objective response has occurred. Enrollment for stage I is 
anticipated to be complete within the first 12 months of study activation. Enrollment for stage II 
is anticipated to be complete within 18 months of proceeding to stage II. We anticipate that on 
average, 1 patient per month will be accrued to the study. The study is open to all eligible 
persons at least 15 years of age. Because of the very rare nature of the disease under study, we 
will not restrict enrollment based on sex, race or ethnicity in order to complete accrual within 2-3 
years. 
 
 


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73 
 
PLANNED ENROLLMENT REPORT 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
 
Female 
Male 
Female 
Male 
 
American Indian/ Alaska 
Native 
0 
0 
0 
0 
0 
Asian 
1 
1 
0 
0 
2 
Native Hawaiian or 
Other Pacific Islander 
0 
0 
0 
0 
0 
Black or African 
American 
3 
2 
0 
0 
5 
White 
9 
6 
2 
1 
18 
More Than One Race 
1 
1 
0 
0 
2 
Total 
14 
10 
2 
1 
27 
PHS 398 / PHS 2590 (Rev. 08/12 Approved Through 8/31/2015)  
OMB No. 0925-0001/0002 
 
 
13.3 
Stratification Factors 
None. 
 
13.4 
Analysis of Exploratory Endpoints 
 
Exploratory correlative studies will evaluate rates of EHE growth prior to starting trametinib to 
growth rates on treatment, the change in c-reactive protein (CRP), erythrocyte sedimentation rate 
(ESR), plasma connective tissue growth factor (CTGF) and tumor volume as potential 
biomarkers of EHE activity, and the effect of trametinib on MAP kinase activation. 
 
Digital files of cross-sectional radiology images (CT and MRI) will be provided to Lawrence 
Schwartz (Columbia University, NY) to evaluate the change in rate of EHE growth pre-
trametinib therapy and on trametinib. Evidence of tumor progression per RECIST will be 
required for enrollment of patients (except in setting of severe tumor-related pain); therefore, 
longitudinal pre-treatment radiology images will be available in the majority of cases for 
comparison. A 50% or more reduction in the change in tumor size/unit of time following start of 
treatment with trametinib will be considered clinically significant. McNemar test will be used to 
compare the number of patients with EHE progression prior to starting trametinib to the number 


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74 
 
of patients with EHE progression during treatment. 
 
Patient CTGF samples collected at indicated time points will be run in triplicate and average 
values used for the comparison. The CTGF, CRP and ESR levels over time will be used as time-
dependent variables in a Cox model to determine the association with EHE survival. 
 
The agreement of change in tumor volume and in tumor size assessed by RECIST will be 
summarized with a scatterplot. The Pearson correlation coefficient (or Spearman, if more 
appropriate) will be assessed to determine the strength of the agreement. Agreement of the tumor 
classifications (response versus no response) will be summarized as the raw agreement and with 
a Kappa Statistic. The association of the change in tumor volume with survival will be evaluated 
in two ways. The first will be to use the change in tumor volume as a time dependent variable in 
a Cox model. The second will be a landmark analysis (done at either the first radiographic 
assessment or at the second radiographic assessment) to compare the survival of patients 
classified as a responder (based on tumor volume) to those who have not responded by the 
selected landmark time. Patients who died prior to the landmark time point will be omitted from 
analysis. 
 
Evaluation of MAP kinase activation is an exploratory analysis on relatively few samples. In 
another multicenter SARC phase II clinical trial (SARC028) that required paired pre-treatment 
and on-treatment tumor biopsy, matched samples were obtained in 75% of the cases and tumor 
biopsy was performed in about 50% of patients at the time of progression. We estimate a similar 
success rate in obtaining matched tumor tissue. Descriptive statistics will be generated, and 
estimates for the proportion of samples with demonstrated inhibition of MAPK signaling post-
treatment compared to pre-treatment will be generated along with 95% confidence intervals. 
Likewise, the proportion of patients with demonstrated MAPK signaling inhibition at time of 
disease progression will be determined with the corresponding 95% confidence interval. These 
are exploratory analyses and all available data will be used. 
 
Evaluation of presence of TAZ-CAMTA1 gene fusion will be performed by FISH. Tumor in 
which at least 10% of nuclei are scored as having a fused signal will be counted as EHE with 
presence of TAZ-CAMTA1 translocation. The number and percent of TAZ-CAMTA1 gene fusion 
positive EHE will be reported. 
 
13.5 
For phase 2 protocols only: Reporting and Exclusions 
 
13.5.1 Evaluation of Toxicity 
 
All patients will be evaluable for toxicity from the time of their first treatment with 
Trametinib. 
 
13.5.2 Evaluation of Response 
 
All patients included in the study must be assessed for response to treatment, even if there 
are major protocol treatment deviations or if they are ineligible.  Each patient will be 


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75 
 
assigned one of the following categories:  1) complete response, 2) partial response, 3) 
stable disease, 4) progressive disease, 5) early death from malignant disease, 6) early 
death from toxicity, 7) early death because of other cause, or 9) unknown (not assessable, 
insufficient data). 
 
All of the patients who met the eligibility criteria and took at least 1 dose of trametinib 
will be included in the main analysis of the response rate.  Patients in response categories 
4-9 will be considered to have a treatment failure (disease progression).  Thus, an 
incorrect treatment schedule or drug administration does not result in exclusion from the 
analysis of the response rate.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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76 
 
REFERENCES 
 
Agulnik, M., JL Yarker, SH Okuno, et al. (2013).  An open-label, multicenter, phase II study of 
bevacizumab for the treatment of angiosarcoma and epithelioid hemangioendotheliomas. Ann 
Oncol. 24:257-2563 
 
Balagula, Y., K. Barth Huston, K.J. Busam, et al.  (2010).  Dermatologic side effects associated 
with the MEK 1/2 inhibitor selumetinib (AZD6244, ARRY-142886).  Invest New Drugs.  
29:1114-1121. 
 
Bekaii-Saab, T., M.A. Phelps, X. Li, et al.  (2011).  Multi-institutional phase II study of 
selumetinib in patients with metastatic biliary cancers.  J Clin Oncol.  29:2357-2363. 
 
Bendell, J., P. LoRusso, E. Kwak, et al.  (2011).  Clinical combination of the MEK inhibitor 
GDC-0973 and the PI3K inhibitor GDC-0941: A first-in-human phase Ib study in patients with 
advanced solid tumors.  AACR Meeting Abstracts.  Abstract LB-89. 
 
Blumenschein, G.R., E.F. Smit, D. Planchard, et al.  (2013).  MEK114653:  A randomized, 
multicenter, phase II study to assess efficacy and safety of trametinib (T) compared with 
docetaxel (D) in KRAS-mutant advanced non-small cell lung cancer (NSCLC).  J Clin Oncol.  
31:Abstract 8029. 
 
Borthakur, G., J.M. Foran, T. Kadia, et al.  (2010).  GSK1120212, a MEK1/MEK2 inhibitor, 
demonstrates acceptable tolerability and preliminary activity in a dose rising trial In subjects 
with AML and other hematologic malignancies.  Blood (ASH Annual Meeting Abstracts).  
116:Abstract 3281. 
 
Chevreau, C., A LeCesne, I Ray-Coquard, et al. (2013).  Sorafenib in patients with epithelioid 
hemangioendothelioma: a phase 2 study by the French Sarcoma Group (GSF/GETO). Cancer. 
119:2639-2644 
 
Coiffi, A., Italiano, A., N. Penel, et al. (2011). Metastatic epithelioid hemangioendothelioma 
(EHE): role of systemic therapy and survival. J Clin Oncol. 29, no. 15_suppl:10079. 
 
Ebi, H., R.B. Corcoran, A. Singh, et al.  (2011).  Receptor tyrosine kinases exert dominant 
control over PI3K signaling in human KRAS mutant colorectal cancers.  J Clin Invest.  
121:4311-4321. 
 
Engelman, J.A., L. Chen, X. Tan, et al.  (2008).  Effective use of PI3K and MEK inhibitors to 
treat mutant Kras G12D and PIK3CA H1047R murine lung cancers.  Nat Med.  14:1351-1356. 
 
Flaherty, K.T., C. Robert, P. Hersey, et al.  (2012).  Improved survival with MEK inhibition in 
BRAF-mutated melanoma.  N Engl J Med.  367:107-114. 
 
Gilmartin, A.G., M.R. Bleam, A. Groy, et al.  (2011).  GSK1120212 (JTP-74057) is an inhibitor 


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of MEK activity and activation with favorable pharmacokinetic properties for sustained in vivo 
pathway inhibition.  Clin Cancer Res.  17:989-1000. 
 
Gopal, Y.N., W. Deng, S.E. Woodman, et al.  (2010).  Basal and treatment-induced activation of 
AKT mediates resistance to cell death by AZD6244 (ARRY-142886) in Braf-mutant human 
cutaneous melanoma cells.  Cancer Res.  70:8736-8747. 
 
Hoeflich, K.P., C. O'Brien C, Z. Boyd, et al.  (2009).  In vivo antitumor activity of MEK and 
phosphatidylinositol 3-kinase inhibitors in basal-like breast cancer models.  Clin Cancer Res.  
15:4649-4664. 
 
Infante, J.R., B.G. Somer, J.O. Park, et al.  (2013).  A randomized, double-blind, placebo-
controlled trial of trametinib, a MEK inhibitor, in combination with gemcitabine for patients with 
untreated metastatic adenocarcinoma of the pancreas.  J Clin Oncol.  30:Abstract 291. 
 
Infante, J.R., L.A. Fecher, S. Nallapareddy, et al.  (2010).  Safety and efficacy results from the 
first-in-human study of the oral MEK 1/2 inhibitor GSK1120212.  J Clin Oncol.  28:Abstract 
2503. 
 
Investigator's Brochure.  (2012a).  GSK1120212.  GlaxoSmithKline.  Version 04.  September 5, 
2012. 
 
Investigator’s Brochure.  (2012b).  GSK2118436.  GlaxoSmithKline.  Version 04.  May 15, 
2012. 
 
Investigator’s Brochure.  (2013).  GSK1120212 (trametinib).  GlaxoSmithKline.  Version 05.  
September 25, 2013. 
 
Kirkwood, J.M., L. Bastholt, C. Robert, et al.  (2012).  Phase II, open-label, randomized trial of 
the MEK1/2 inhibitor selumetinib as monotherapy versus temozolomide in patients with 
advanced melanoma.  Clin Cancer Res.  18:555-567. 
 
Koshkin, V., V Bolejack, LH Schwartz, et al. (2016). Assessment of imaging modalities and 
response metrics in Ewing Sarcoma: Correlation with survival. J Clin Oncol 
 
Kurzrock, R., A. Patnaik, L. Rosenstein, et al.  (2011).  Phase I dose-escalation of the oral 
MEK1/2 inhibitor GSK1120212 (GSK212) dosed in combination with the oral AKT inhibitor 
GSK2141795 (GSK795).  J Clin Oncol.  29:Abstract 3085. 
 
Lacouture, M.E., M.J. Anadkat, R.J. Bensadoun, et al.  (2011).  Clinical practice guidelines for 
the prevention and treatment of EGFR inhibitor-associated dermatologic toxicities.  Support 
Care Cancer.  19:1079-1095. 
 
Le Gal, F., E. Gordien, D. Affolabi, et al.  2005.  Quantification of hepatitis delta virus RNA in 
serum by consensus real-time PCR indicates different patterns of virological response to 


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interferon therapy in chronically infected patients.  J Clin Microbiol.  43:2363-2369. 
 
Mehrabi, A., A Kashfi, H Fonouni, et al. (2006). Primary malignant hepatic epithelioid 
hemangioendothelioma: a comprehensive review of the literature with emphasis on the surgical 
therapy. Cancer. 107:2108-2121 
 
MEKINIST [Package insert].  (2013).  GlaxoSmithKline.  May 2013. 
 
Messersmith, W.A., G.S. Falchook, L.A. Fecher, et al.  (2011).  Clinical activity of the oral 
MEK1/MEK2 inhibitor GSK1120212 in pancreatic and colorectal cancer.  J Clin Oncol.  
29:Abstract 246. 
 
Tanas, M., S Ma, FO Jadaan, et al. (2016). Mechanism of action of a WWTR1(TAZ)-CAMTA1 
fusion oncoprotein. Oncogene. 35:929-938 
 
Tanas, M, A Sboner, AM Oliveira, et al. (2011). Identification of a disease-defining gene fusion 
in epithelioid hemangioendothelioma. Sci Transl Med. 3:82-98 
 
Tolcher, A.W., J.C. Bendell, A. Patnaik, et al.  (2011).  A phase Ib study of the MEK inhibitor 
GSK1120212 combined with gemcitabine in patients with solid tumors: Interim results.  J Clin 
Oncol.  29:Abstract 278. 
 
U.S. Food and Drug Administration.  (2013).  FDA approves two drugs, companion diagnostic 
test for advanced skin cancer [Press release].  Retrieved from 
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm354199.htm. 
 
U.S. Food and Drug Administration.  (2014).  FDA approves Mekinist in combination with 
Tafinlar for advanced melanoma [Press release].  Retrieved from 
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm381159.htm. 
 
Weber, J.S., K.T. Flaherty, J.R. Infante, et al.  (2012).  Updated safety and efficacy results from 
a phase I/II study of the oral BRAF inhibitor dabrafenib (GSK2118436) combined with the oral 
MEK 1/2 inhibitor trametinib (GSK1120212) in patients with BRAFi-naïve metastatic 
melanoma.  J Clin Oncol.  30:Abstract 8510. 
 
Weiss, SW. and FM Enzinger. (1982). Epithelioid hemangioendothelioma: a vascular tumor 
often mistaken for a carcinoma. Cancer. 50:970-981 
 
Weiss, SW and JR Goldblum. (2008). Epithelioid hemangioendothelioma. Enzinger and Weiss’ 
Soft Tissue Tumors. (pp. 681-687). Philadelphia: Mosby. 
 
Yamaguchi, T., R. Kakefuda, N. Tajima, et al.  (2011).  Antitumor activities of JTP-74057 
(GSK1120212), a novel MEK1/2 inhibitor, on colorectal cancer cell lines in vitro and in vivo.  
Int J Oncol.  39:23-31. 
 


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Zingone, A., N. Korde, J. Chen, et al.  (2011).  Molecular characterization and clinical 
correlations of MEK1/2 inhibition (AZD6244) in relapse or refractory multiple myeloma:  
analysis from a phase II study.  Blood (ASH Annual Meeting Abstracts).  118:Abstract 306. 


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80 
 
APPENDIX A 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 


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81 
 
APPENDIX B 
PATIENT CLINICAL TRIAL WALLET CARD 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CLINICAL TRIAL WALLET CARD 
Show this card to all of your 
healthcare providers and keep 
it with you in case you go to 
the emergency room. 
Patient Name:        
Diagnosis:        
Study Doctor:       
Study Doctor Phone #:       
NCI Trial #:        
Study Drug(S):        
 
 
 
 
For more information: 1-800-4-CANCER 
cancer.gov | clinicaltrials.gov 
 
 


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82 
 
APPENDIX C 
BIOASSAY TEMPLATES 
 
If the protocol includes any integral biomarker studies using in situ hybridization (ISH),  
immunohistochemistry (IHC), and/or DNA-based mutation assays, you may fill out the 
appropriate template (found at 
http://www.cancerdiagnosis.nci.nih.gov/diagnostics/templates.htm) and attach to this protocol 
submission as separate Appendices. 
 
If the laboratory or laboratories performing the studies has an alternatively-formatted document 
that supplies the same level of information regarding validation, materials and methods, etc., it 
may be used instead of the templates. 
 
Not applicable 
 
 


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83 
 
 
APPENDIX D        SARC033 STUDY DRUG DIARY    PATIENT INITIALS: __________  SUBJECT STUDY ID# ______________ 
• 
Please complete this chart each time you take study drug. 
• 
Trametinib should be taken at approximately the same time each day.  
• 
Each dose should be taken on an empty stomach everyday approximately1 hour before or 2 hours after a meal with a full glass of water. 
• 
If you forget to take your dose at the scheduled time, please take as soon as you remember. If the next scheduled dose is within 12 hours, please skip the missed 
dose. 
• 
If you vomit your dose of trametinib, do not take that dose again. Mark the vomited dose in this diary. Take the next day’s dose as 
• 
schedule. 
• 
Bring any unused trametinib, all containers (empty and full), and this diary to each clinic visit.  
• 
The study staff will make sure you have an adequate supply of drug to take home at the end of each clinic visit. 
• 
You must inform the study doctor of any medication you take (prescription, or over-the-counter). 
• 
You must not take any new medicines unless you/your child talk to your study doctor first. 
• 
You must not take any other medicines to treat you cancer, unless specifically allowed by your/your child’s study doctor. 
Please select study drug dose (once daily): 
 
2 mg 
 
1.5 mg 
 
1 mg 
Day 
Date 
Time 
Dose 
Comment / Symptom*  
Day 
Date 
Time 
Dose 
Comment / Symptom*  
Day 1 
 
 
 
 
Day 15 
 
 
 
 
Day 2 
 
 
 
 
Day 16 
 
 
 
 
Day 3 
 
 
 
 
Day 17 
 
 
 
 
Day 4 
 
 
 
 
Day 18 
 
 
 
 
Day 5 
 
 
 
 
Day 19 
 
 
 
 
Day 6 
 
 
 
 
Day 20 
 
 
 
 
Day 7 
 
 
 
 
Day 21 
 
 
 
 
Day 8 
 
 
 
 
Day 22 
 
 
 
 
Day 9 
 
 
 
 
Day 23 
 
 
 
 
Day 10 
 
 
 
 
Day 24 
 
 
 
 
Day 11 
 
 
 
 
Day 25 
 
 
 
 
Day 12 
 
 
 
 
Day 26 
 
 
 
 
Day 13 
 
 
 
 
Day 27 
 
 
 
 
Day 14 
 
 
 
 
Day 28 
 
 
 
 
*what to describe at the next office visit.  Note: You/your child can ask the study doctor questions about symptoms or side effects at any time. 
FOR OFFICE USE 
 
 
Date Dispensed: _______________ 
# of pills/tabs dispensed: _____ 
 
Patient’s Signature: _____________________________________________ 
Date Returned:_______________ 
# of pills/tabs returned:  _____ 
 
 
Total # pills/tabs that should have been taken: _____ 
 
Date: _________________________________________________________ 
Discrepancy Notes: 
Staff Initials: 
 
 


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APPENDIX E           PROMIS QUESTIONNAIRES 
 
PROMIS Item Bank v.1.0 – Pain Intensity – Short Form 3a 
 
 
Pain Intensity – Short Form 3a 
 
Please respond to each item by marking one box per row. 
 
 
 
In the past 7 days… 
Had no 
pain 
Mild 
Moderate 
Severe 
Very 
severe 
PAINQU6 
How intense was your pain at its worst?.... 
 
1 
 
2 
 
3 
 
4 
 
5 
 
PAINQU8 
How intense was your average pain?......... 
 
1 
 
2 
 
3 
 
4 
 
5 
 
No pain 
Mild 
Moderate 
Severe 
Very 
severe 
PAINQU21 
What is your level of pain right now?........ 
 
1 
 
2 
 
3 
 
4 
 
5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
23 June 2016 
© 2008-2016 PROMIS Health Organization and PROMIS Cooperative Group                               Page 1 of 1 
 
 
 
 


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PROMIS Item Bank v1.0 – Pain Interference – Short Form 4a 
 
 
Pain Interference – Short Form 4a 
 
Please respond to each question or statement by marking one box per row. 
 
  
In the past 7 days… 
Not at all 
A little bit 
Somewhat Quite a bit 
Very much 
1 
How much did pain interfere with your 
day to day activities?................................. 
 
 
 
 
 
2 
How much did pain interfere with work 
around the home? ...................................... 
 
 
 
 
 
3 
How much did pain interfere with your 
ability to participate in social activities? 
 
 
 
 
 
4 
How much did pain interfere with your 
household chores? ................................... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Participant Format © 2008-2015 PROMIS Health Organization and PROMIS Cooperative Group 
Page 1 of 1 
 


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Global Health 
 
Please respond to each item by marking one box per row. 
 
Excellent 
Very 
good 
Good 
Fair 
Poor 
 
Global01 
In general, would you say your health is: ........... 
 
5 
 
4 
 
3 
 
2 
 
1 
 
 
Global02 
In general, would you say your quality of 
life is: ................................................................... 
 
5 
 
4 
 
3 
 
2 
 
1 
 
 
Global03 
In general, how would you rate your physical 
health? .................................................................. 
 
5 
 
4 
 
3 
 
2 
 
1 
 
 
 
Global04 
In general, how would you rate your mental 
health, including your mood and your ability to 
think?.................................................................. 
 
5 
 
4 
 
3 
 
2 
 
1 
 
 
Global05 
In general, how would you rate your satisfaction 
with your social activities and relationships? ...... 
 
5 
 
4 
 
3 
 
2 
 
1 
 
 
 
 
 
Global09 
In general, please rate how well you carry out 
your usual social activities and roles. (This 
includes activities at home, at work and in your 
community, and responsibilities as a parent, 
child, spouse, employee, friend, etc.)................... 
 
5 
 
4 
 
3 
 
2 
 
1 
 
Completely 
Mostly 
Moderately 
A little 
Not at all 
 
 
 
Global06 
To what extent are you able to carry out your 
everyday physical activities such as walking, 
climbing stairs, carrying groceries, or moving a 
chair?..................................................................... 
 
5 
 
4 
 
3 
 
2 
 
1 
 
© 2008-2012 PROMIS Health Organization and PROMIS Cooperative Group                                       Page 1 of 2 


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86 
 
 
 
 
In the past 7 days… 
Never 
Rarely 
Sometimes 
Often 
Always 
 
 
Global10 
How often have you been bothered by emotional 
problems such as feeling anxious, depressed or 
irritable? ................................................................ 
 
1 
 
2 
 
3 
 
4 
 
5 
 
None 
Mild 
Moderate 
Severe 
Very 
severe 
 
Global08 
How would you rate your fatigue on average? .... 
 
1 
 
2 
 
3 
 
4 
 
5 
 
 
Global07 
How would you rate your 
pain on average?................... 
 
0 
 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
7 
 
8 
 
9 
 
10 
 
No 
pain 
i
Worst 
imaginable 
pain 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
© 2008-2012 PROMIS Health Organization and PROMIS Cooperative Group                                       Page 86 of 2 
 
 
 
 


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PROMIS v1.1 Item Bank – Pain Behavior – 
Short Form 7a 
 
Pain Behavior – Short Form 7a 
 
Please respond to each item by marking one box per row 
 
 
In the past 7 days.... 
Had no 
pain 
 
Never
Rarely
Sometimes
Often
Always
 
PAINBE2 
When I was in pain I became 
irritable............................................... 
 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
 
PAINBE3 
When I was in pain I grimaced ........ 
 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
 
PAINBE8 
When I was in pain I moved extremely 
slowly…………..…….…. 
 
1 
 
2 
 
3 
 
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PAINBE24 
When I was in pain I moved stiffly ...  
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PAINBE25 
When I was in pain I called out for 
someone to help me ......................... 
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PAINBE37 
When I was in pain I isolated myself 
from others......................................... 
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PAINBE45 
When I was in pain I thrashed ...........  
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2 May 2016© 2008-2016 PROMIS Health Organization and PROMIS Cooperative Group 
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