A Phase 2 Study of Trametinib in Combination With Radioiodine (RAI) for RAS Mutant or RAS/RAF Wild-Type, RAI-Refractory Recurrent and/or Metastatic Thyroid Cancers
Phase: PHASE2
Conditions: Metastatic Thyroid Gland Carcinoma, Poorly Differentiated Thyroid Gland Carcinoma, Recurrent Thyroid Gland Carcinoma, Refractory Thyroid Gland Carcinoma, Stage IV Thyroid Gland Follicular Carcinoma AJCC v7, Stage IV Thyroid Gland Papillary Carcinoma AJCC v7, Stage IVA Thyroid Gland Follicular Carcinoma AJCC v7, Stage IVA Thyroid Gland Papillary Carcinoma AJCC v7, Stage IVB Thyroid Gland Follicular Carcinoma AJCC v7, Stage IVB Thyroid Gland Papillary Carcinoma AJCC v7, Stage IVC Thyroid Gland Follicular Carcinoma AJCC v7, Stage IVC Thyroid Gland Papillary Carcinoma AJCC v7
Sponsor: National Cancer Institute (NCI)

i 
 
SUMMARY OF CHANGES - Protocol 
 
For Protocol Amendment to: A Phase 2 Study of Trametinib in Combination with 
Radioiodine (RAI) for RAS Mutant or RAS/RAF Wild-Type, RAI-Refractory Recurrent 
and/or Metastatic Thyroid Cancers 
 
NCI Protocol #: 9446 
Local Protocol #: 13-157 
 
NCI Version Date: 06/17/2020 
Protocol Date: 06/17/2020 
 
# 
Page(s) 
Change 
1. Throughout 
Editorial, formatting and grammatical changes were made throughout the 
protocol 
2. Throughout 
NCI Version Date has been updated to 06/17/2020 throughout the protocol 
3. 4 
Removed the following Co-Investigator: Korey Jaben, MD 
4. 29 
In Section 3.1.10, Changed “/” to “or” (Prothrombin time (PT) or 
International normalized ratio (INR)) for clarification  
 
In Section 3.1.11, Sentence was clarified to indicate that for both men and 
women, contraception should be used for the duration of the study and 4 
months after study completion 
5. 62-63 
 
In response to Dr. Johnson’s June 5, 2020 request for amendment, the 
following changes to the trametinib pharmaceutical section were made: 
 
• How Supplied: Novartis supplies and CTEP, NCI, DCTD distributes 
trametinib as 0.5 mg and 2 mg (as free base) tablets. Each 
investigationally-labeled bottle contains 32 tablets. 
 
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. 
 
 

ii 
 
# 
Page(s) 
Change 
• Storage: Store tablets at 2°C -8°C in the original bottle and dispense 
unopened bottles. Do not open bottles or repackage tablets or remove 
desiccant. Bottles should be protected from light and moisture. 
 
If a storage temperature excursion is identified, promptly return 
trametinib to 2°C -8°C and quarantine the supplies.  Provide a 
detailed report of the excursion (including documentation of 
temperature monitoring and duration of the excursion) to 
PMBAfterHours@mail.nih.gov for determination of suitability. 
 
 
• Stability: Stability studies are ongoing. Tablets are only stable for 32 
days once bottle has been opened. If multiple bottles are dispensed to 
a patient in the same visit, please advise the patient to open only one 
bottle at a time. 
 
6. 110-112 
Removed Appendix J for Drug Interactions 
7. 113 
Added Appendix J for Patient Clinical Trial Wallet Card 
 
 

1 
 
 
NCI Protocol #:         9446 
 
Local Protocol #: 
13-157 
 
ClinicalTrials.gov Identifier: NCT02152995 
 
TITLE:  A Phase 2 Study of Trametinib in Combination with Radioiodine (RAI) for RAS Mutant 
or RAS/RAF Wild-Type, RAI-Refractory Recurrent and/or Metastatic Thyroid Cancers. 
 
 
Coordinating Center: 
 
 
Memorial Sloan Kettering Cancer Center 
 
 
 
 
 
 
 
 
 
1275 York Avenue 
 
 
 
 
 
 
 
 
 
New York, NY 10065 
 
*Principal Investigator: 
Alan L. Ho MD, PhD 
 
Memorial Sloan Kettering Cancer Center 
 
1275 York Avenue 
 
New York, NY  10065 
 
Telephone: (646) 888-4235 
 
Fax: (646) 888-4271 
 
E-mail: hoa@mskcc.org 
 
Co – Principal Investigators:   David G. Pfister, MD 
 
Memorial Sloan Kettering Cancer Center 
 
1275 York Avenue 
 
 
New York, NY 10065 
 
Telephone: (646) 888-4237 
 
Fax: (646) 888-4269 
 
E-mail address: pfisterd@mskcc.org 
 
 
Ravinder K. Grewal, MD 
 
Memorial Sloan Kettering Cancer Center 
 
1275 York Avenue 
 
New York, NY 10065 
 
Telephone: (212) 639-2872 
 
Email: grewalr@mskcc.org 
 
Co-Investigators:            
Eric J. Sherman, MD 
 
Memorial Sloan Kettering Cancer Center 
 
1275 York Avenue 
 
New York, NY 10065 
 
Telephone: (646) 888-4234 
 
Fax: (646) 888-4269 
 
E-mail address: shermane@mskcc.org 
 

2 
 
 
Lara Dunn, MD 
 
Memorial Sloan Kettering Cancer Center 
 
1275 York Avenue 
 
New York, NY 10065 
 
Telephone: (646)-888-4233 
 
Fax: (646) 888-4269 
 
E-mail address:dunnl1@mskcc.org 
 
 
 
James V. Fetten, MD 
 
Memorial Sloan Kettering Cancer Center 
 
1275 York Avenue 
 
New York, NY 10065 
 
Telephone: (646) 888-4236 
 
Fax: (646) 888-4271 
 
E-mail address: fettenj@mskcc.org 
 
 
R. Michael Tuttle, MD 
 
Memorial Sloan Kettering Cancer Center  
 
1275 York Avenue 
 
 
New York, NY 10065 
 
Telephone: (646) 888-2716 
 
Fax: (646) 888-2700 
 
E-mail address: tuttlem@mskcc.org 
 
 
 
Laura Boucai, MD 
 
Memorial Sloan Kettering Cancer Center  
 
1275 York Avenue 
 
New York, NY 10065 
 
Telephone: (646) 888-3472 
 
E-mail address: boucail@mskcc.org  
 
 
Mona M. Sabra, MD 
 
Memorial Sloan Kettering Cancer Center  
 
1275 York Avenue 
 
New York, NY 10065 
 
Telephone: (646) 888-3275 
 
E-mail address: sabram@mskcc.org 
 
 
Stephanie A. Fish, MD 
 
Memorial Sloan Kettering Cancer Center  
 
1275 York Avenue 
 
New York, NY 10065 
 
Telephone: (646) 888-3274 
 
E-mail address: fishs@mskcc.org 
 
 
 
 
 

3 
 
 
Pat B. Zanzonico, PhD 
 
Memorial Sloan Kettering Cancer Center  
 
415 East 68th Street, Z 2002 
 
New York, NY 10065 
 
Telephone: (646) 888-2134 
 
E-mail address: zanzonip@mskcc.org 
 
Keith S. Pentlow, PhD 
 
Memorial Sloan Kettering Cancer Center  
 
1250 First Avenue, S 1119 
 
New York, NY 10065 
 
Telephone: (212) 639-7384 
 
E-mail address: pentlowk@mskcc.org 
 
 
Steve M. Larson, MD 
 
Memorial Sloan Kettering Cancer Center  
 
1275 York Avenue 
 
New York, NY 10065 
 
Telephone: (212) 639-7373 
 
E-mail address: larsons@mskcc.org 
 
 
Mario E. Lacouture, MD 
 
Memorial Sloan Kettering Cancer Center 
 
1275 York Avenue 
 
New York, NY 10065 
 
Telephone: (646) 888-6014 
 
Fax: (646) 277-7274 
 
E-mail address: lacoutum@mskcc.org 
 
 
Vaios Hatzoglou, MD     
 
Memorial Sloan Kettering Cancer Center 
 
1275 York Avenue 
 
New York, NY 10065 
 
Telephone: (212) 639-4891 
 
E-mail address: hatzoglv@mskcc.org 
 
                                                      Sofia S. Haque, MD 
 
Memorial Sloan Kettering Cancer Center 
 
1275 York Avenue 
 
New York, NY 10065 
 
Telephone: (212) 639-7170 
 
E-mail address: haques@mskcc.org 
 
 
 
 
 
 

4 
 
 
John K. Lyo, MD 
 
Memorial Sloan Kettering Cancer Center 
 
1275 York Avenue 
 
New York, NY 10065 
 
Telephone: (212) 639-8945 
 
E-mail address: lyoj@mskcc.org 
 
 
Ronald A. Ghossein, MD 
 
Memorial Sloan Kettering Cancer Center 
 
1275 York Avenue 
 
 
New York, NY 10065 
 
Telephone: (212) 639-2701 
 
E-mail address: ghosseir@mskcc.org 
 
 
Robert H. Siegelbaum, MD 
 
Memorial Sloan Kettering Cancer Center 
 
1275 York Avenue 
 
 
New York, NY 10065 
 
Telephone: (212) 639-4897 
 
E-mail address: siegelbr@mskcc.org 
 
 
 
Jasmine Francis, MD 
 
Memorial Sloan Kettering Cancer Center 
 
1275 York Avenue 
 
New York, NY 10065 
 
Telephone: (212) 639-7266 
 
E-mail address: francij1@mskcc.org 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

5 
 
Statistician: 
 
Study Coordinator: 
TBN 
Jamie Walters 
Memorial Sloan Kettering Cancer Center  
 Memorial Sloan Kettering Cancer Center 
307 East 63rd Street 
 300 East 66th Street 
New York, NY 10065 
 New York, NY 10065 
Telephone: (646) 735-8107 
 Telephone: (646) 888-4450 
E-mail address: simac@mskcc.org 
 Fax: (646) 227-2434 
 
 E-mail address: waltersj@mskcc.org 
Responsible Research Nurses: 
 
Lisa Cox, RN 
Memorial Sloan Kettering Cancer Center 
205 East 64th Street 
New York, NY 10065 
Telephone: (646) 888-4237 
Fax: (646) 227-2434 
E-mail address: coxl@mskcc.org 
 
Adriana Barison, PA 
205 East 64th Street 
New York, NY 10065 
Telephone: (646) 888-4232 
Fax: (646) 888-4269 
E-mail address: barisona@mskcc.org 
 
Colleen Hannon, NP 
Memorial Sloan Kettering Cancer Center 
205 East 64th Street  
New York, NY 10065 
Telephone: (212)-639-7337 
Fax: (646) 227-2434 
E-mail address: foleyc@mskcc.org 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Responsible Data Manager: 
Jamie Walters 
Memorial Sloan Kettering Cancer Center 
300 East 66th Street 
New York, NY 10065 
Telephone: (646) 888-4450 
Fax: (646) 227-2434 
E-mail address: waltersj@mskcc.org 

6 
 
NCI Supplied Agent:  Trametinib dimethyl sulfoxide (GSK1120212B) (NSC 763093) 
 
Commercially Available Agents: thyrotropin alpha (ThyrogenGenzyme); 131I (MDS Nordion, 
DraxImage, or International Isotopes) 
 
Imaging Agent: 124I tracer (Sofie Biosciences (fka IBA Molecular and Zevacor), 3 D Imaging 
LLC, cyclotron, or NCM) 
 
IND Sponsor:  NCI  
 
Protocol Type / Version # / Version Date:  Original/Version #1/Version Date: 01/09/2013 
 
 
 
      Original/Version #2/Version Date: 07/01/2013 
 
 
 
      Original/Version #3/Version Date: 08/23/2013 
 
 
 
Original/Version #4/Version Date: 09/12/2013 
 
 
 
Amended/Version #5/Version Date: 06/17/2014 
 
 
 
Amended/Version #6/Version Date: 07/10/2014 
 
 
 
Amended/Version #7/Version Date: 10/08/2014 
                                                                        Amended/Version #8/Version Date: 01/22/2015 
                                                                        Amended/Version #9/Version Date: 04/08/2015 
 
 
            Amended/Version #10/Version Date: 05/26/2015 
 
 
 
Amended/Version #11/Version Date: 11/09/2015 
 
 
 
Amended/Version #12/Version Date: 04/14/2016 
 
 
 
Amended/Version #13/Version Date:11/30/2016 
 
 
 
Amended/Version #14/Version Date: 08/10/2017 
 
 
 
Amended/Version #15/Version Date: 03/01/2018 
 
 
 
Amended/Version #16/Version Date: 08/20/2018 
 
 
 
Amended/Version #17/Version Date: 02/26/2019 
 
 
 
Amended/Version #18/Version Date: 12/05/2019 
 
 
 
Amended/Version #19/Version Date: 06/17/2020 
 
  

7
SCHEMA
NOTE: Research biopsies will be performed prior to Week 1 Day 1 and during Week 3.
Insufficient 124I 
PET response
Cohort C
Cohort B
Insufficient 124I 
PET response
Sufficient 124I PET 
response
Cohort A
Enroll patients with RAS MUT RAI-
refractory, progressive thyroid cancer 
Utilize 124I PET/CT lesional dosimetry to evaluate 
if trametinib enhances iodine incorporation 
sufficiently to warrant RAI therapy*
Discontinue 
trametinib 
Continue 
trametinib and 
treat with RAI
Tumor 
assessments
Continue 
trametinib on 
Cohort C
Sufficient 124I PET 
response
Enroll patients with BRAF/RAS WT 
RAI-refractory thyroid cancer 
Utilize 124I PET/CT lesional dosimetry to evaluate 
if trametinib enhances iodine incorporation 
sufficiently to warrant RAI therapy* 
* Schema for 124I PET/CT lesional dosimetry evaluation of 
trametinib impact upon iodine incorporation in thyroid tumors
Patients with insufficient 124I PET 
responses (from Cohort A or Cohort 
B) for whom the treating physician 
has determined that continuing 
trametinib alone for the treatment of 
thyroid cancer is clinically reasonable 
Continue with protocol 
assessments
Discontinue study when 
meeting criteria outlined in 
Section 5.5
Cohort C
Continue 
trametinib and 
treat with RAI
Tumor 
assessments
Discontinue 
trametinib 
Continue 
trametinib on 
Cohort C

8 
 
TABLE OF CONTENTS 
1. 
OBJECTIVES ....................................................................................................................10 
1.1 
Primary Objectives .................................................................................................10 
1.2 
Secondary Objectives .............................................................................................10 
2. 
BACKGROUND ...............................................................................................................11 
2.1 
Study Disease .........................................................................................................11 
2.2 
CTEP IND Agent ...................................................................................................11 
2.3 
Lesional dosimetry by 124I PET/CT .......................................................................21 
2.4 
Rationale for utilizing MAPK pathway inhibition to enhance iodine 
incorporation in RAI-refractory thyroid tumors ....................................................22 
2.5 
Correlative Studies Background ............................................................................26 
3. 
PATIENT SELECTION ....................................................................................................27 
3.1 
Inclusion Criteria ...................................................................................................27 
3.2 
Exclusion Criteria ..................................................................................................29 
3.3 
Inclusion of Women and Minorities ......................................................................31 
4. 
REGISTRATION PROCEDURES ...................................................................................32 
4.1 
Investigator and Research Associate Registration with CTEP ..............................32 
4.2 
General  Registration Procedures ...........................................................................33 
5. 
TREATMENT AND IMAGING PLAN ...........................................................................33 
5.1 
Agent Administration .............................................................................................33 
5.2 
General Concomitant Medication and Supportive Care Guidelines ......................38 
5.3 
Duration of Therapy ...............................................................................................39 
5.4 
Duration of Follow Up ...........................................................................................39 
5.5 
Criteria for Removal from Study ...........................................................................39 
6. 
DOSING DELAYS/DOSE MODIFICATIONS................................................................40 
6.1 
Trametinib Dose Modifications .............................................................................40 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................51 
7.1 
Comprehensive Adverse Events and Potential Risks List (CAEPR) .....................51 
7.2 
Adverse Event Characteristics ...............................................................................56 
7.3 
Expedited Adverse Event Reporting ......................................................................57 
7.4 
Routine Adverse Event Reporting .........................................................................59 
7.5 
Secondary Malignancy ...........................................................................................59 
7.6 
Second Malignancy ................................................................................................59 
7.7 
Serious Adverse Event (SAE) Reporting for MSK Patients Only .........................60 
8. 
PHARMACEUTICAL and/or IMAGING AGENT INFORMATION .............................60 
8.1 
CTEP IND Agent(s) ...............................................................................................60 
8.2 
Other Investigational Agent(s) ...............................................................................63 
8.3 
Commercial Agent(s) .............................................................................................64 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................65 

9 
 
9.1 
Biomarker Studies ..................................................................................................65 
9.2 
Laboratory Correlative Studies ..............................................................................66 
9.3 
Special Studies .......................................................................................................67 
10. 
STUDY CALENDAR .......................................................................................................68 
11. 
MEASUREMENT OF EFFECT........................................................................................72 
11.1 
Antitumor Effect – Solid Tumors ..........................................................................72 
11.2 
Antitumor Effect – Hematologic Tumors ..............................................................79 
11.3 
Other Response Parameters ...................................................................................79 
12. 
DATA REPORTING / REGULATORY REQUIREMENTS ...........................................79 
12.1 
Data Reporting .......................................................................................................79 
12.2 
Collaborative Agreements Language .....................................................................80 
13. 
STATISTICAL CONSIDERATIONS...............................................................................82 
13.1 
Study Design/Endpoints.........................................................................................82 
13.2 
Sample Size/Accrual Rate ......................................................................................84 
13.3 
Stratification Factors ..............................................................................................84 
13.4 
Analysis of Secondary Endpoints ..........................................................................84 
13.5 
For phase 2 protocols only: Reporting and Exclusions .........................................86 
14. 
Protection of Human Subjects ...........................................................................................86 
14.1 
Privacy ...................................................................................................................86 
15. 
Informed Consent Procedures ............................................................................................87 
REFERENCES ..............................................................................................................................89 
APPENDIX A: 
PERFORMANCE STATUS CRITERIA ..................................................93 
APPENDIX B:  
Low Iodine Diet .........................................................................................94 
APPENDIX C:  
PILL DIARY .............................................................................................99 
APPENDIX D: 
124I Normal Organ Radiation Dosimetry ..................................................101 
APPENDIX E: 
Dosimetric radioiodide scintigraphy (aka ‘Full Dosimetry’) ...................102 
Appendix F:  
 Research Lab Draw form ........................................................................103 
Appendix G:  
RESEARCH BIOPSY SAMPLE FORM ................................................104 
Appendix  H: 
  Research Slides form .............................................................................105 
APPENDIX I:  
 Patient calendar  handout ........................................................................106 
Appendix J:  Patient clinical trial wallet card ..............................................................................107 
 

10 
 
1. 
OBJECTIVES 
 
1.1 
Primary Objectives 
 
For Cohort A (RAS mutant (MUT) thyroid cancer patients):  
 
1) To evaluate the effect of trametinib on enhancing radioiodine (RAI) activity by determining 
the proportion of patients alive at 6 months without disease progression by RECIST v1.1 criteria 
following treatment with RAI in co-administration with trametinib. 
 
2) To evaluate the effect of trametinib on enhancing RAI activity by determining the objective 
response rate (ORR) at 6 months following treatment with radioiodine (RAI) in co-
administration with trametinib. 
 
For Cohort B (BRAF/RAS wild-type (WT) thyroid cancer): 
 
To determine the proportion of patients following trametinib therapy with increased tumoral 
iodine incorporation as quantified by 124I PET/CT lesional dosimetry. 
 
1.2 
Secondary Objectives 
 
For Cohort A (RAS MUT thyroid cancer patients):  
 
1) To determine the proportion of patients following trametinib therapy with increased tumoral 
iodine incorporation as quantified with 124I PET/CT lesional dosimetry. 
 
2) To evaluate the safety/tolerability of trametinib with or without RAI. 
 
3) To evaluate changes in thyroglobulin levels in patients treated with RAI.  
 
4) (Exploratory) To explore potential correlations between genomic alterations present in the 
tumor and/or tumoral pharmacodynamic changes induced by trametinib to clinical outcomes. 
 
For Cohort B (BRAF/RAS WT thyroid cancer): 
 
1) To evaluate the effect of trametinib on enhancing RAI activity by determining the ORR at 6 
months following treatment with RAI in co-administration with trametinib. 
 
2) To evaluate the effect of trametinib on enhancing RAI activity by determining the proportion 
of patients alive at 6 months without disease progression by RECIST v1.1 criteria following 
treatment with RAI in co-administration with trametinib. 
 
3) To evaluate the safety/tolerability of trametinib with or without RAI. 
 
4) To evaluate changes in thyroglobulin levels in patients treated with RAI.  
 
5) (Exploratory) To explore potential correlations between genomic alterations present in the 

11 
 
tumor and/or tumoral pharmacodynamic changes induced by trametinib to clinical outcomes. 
 
For Cohort C (select patients from Cohorts A and B with insufficient 124I PET changes): 
 
1) (Exploratory) Preliminary evaluation of best objective response (BOR) rate for patients 
treated with trametinib alone. 
 
2) (Exploratory) Preliminary evaluation of the proportion of patients following treatment with 
trametinib alive at 6 months without disease progression by RECIST v1.1 criteria. 
 
3) To evaluate the safety/tolerability of trametinib. 
 
4) To evaluate changes in thyroglobulin levels in patients treated with trametinib.  
 
5) (Exploratory) To explore potential correlations between genomic alterations present in the 
tumor and/or tumoral pharmacodynamic changes induced by trametinib to clinical outcomes. 
 
6) (Exploratory) To explore the impact of continued trametinib upon RAI avidity and efficacy. 
 
2. 
BACKGROUND 
 
2.1 
Study Disease 
 
The incidence of new thyroid cancers is the fastest growing among all cancers with more than 
40,000 new cases every year (Jemal et al., 2010).  The majority of thyroid cancers are 
differentiated thyroid carcinomas of follicular origin with papillary thyroid cancer (PTC) being 
the most common subtype followed by follicular thyroid cancer (FTC).  Metastatic disease 
represents the most frequent cause of thyroid cancer-related death (Mazzaferri and Kloos, 2001), 
and radioiodine (RAI or 131I) remains a mainstay of therapy for these patients. However, 
resistance to RAI is a significant clinical problem. In a study of 444 patients with metastatic 
PTCs or FTCs, 32% of patients had undetectable RAI uptake (Durante et al., 2006). RAI status 
holds substantial clinical significance: the 10-year survival rate of patients with RAI-avid 
metastases was 56% compared to 10% for those with non-RAI avid disease (Durante et al., 
2006).  Despite advances in identifying targeted therapies that can induce regressions in thyroid 
cancer, it remains unclear how these systemic therapies alter the natural history of RAI-
refractory disease.  Experimental approaches for restoring RAI avidity has historically yielded 
disappointing results, including studies evaluating lithium carbonate and retinoic acid (Coelho et 
al., 2004; Liu et al., 2006).  Furthermore, progress has also been stymied by the lack of 
techniques to precisely quantify iodine uptake.   
 
2.2 
CTEP IND Agent 
 
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 

12 
 
activation, RAF acts as the MAPK kinase kinase and activates MAPKK (MEK1/2), 
which in turn catalyze activation of the effectors ERK1/ERK2.  Once activated, ERK1/2 
translocate into the nucleus and phosphorylate a number of effector proteins and 
transcriptional factors that regulate cell proliferation, motility, differentiation, and 
survival. 
 
Trametinib is one of the several MEK inhibitors in clinical development.  On May 29, 
2013, the U.S. Food and Drug Administration (FDA) approved trametinib for the 
treatment of patients with unresectable or metastatic melanoma with BRAFV600E or 
BRAFV600K mutations as detected by an FDA-approved test (U.S. Food and Drug 
Administration, 2013).  On January 10, 2014, the 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 (2013). 
 
Mechanisms of Action and Preclinical Data with Trametinib 
 
Trametinib is a dimethyl sulfoxide (DMSO) solvate compound (ratio 1:1) with potent, 
allosteric and ATP non-competitive inhibition of MEK1/2 (IC50 of 0.7 and 0.9 nM 
against MEK1 and MEK2, respectively) (Gilmartin et al., 2011).  Trametinib inhibited 
MEK1/2 kinase activity and prevented RAF-dependent MEK phosphorylation (S217 for 
MEK1), producing prolonged pERK1/2 inhibition.  Trametinib showed better potency 
against unphosphorylated MEK1/2 (u-MEK1/2) when compared with preactivated 
diphosphorylated MEK (pp-MEK), suggesting that u-MEK affords a higher affinity 
binding site for trametinib than does pp-MEK. 
 
The specificity of trametinib was confirmed against a panel of 183 kinases, including 
MEK5 (the closet kinase homolog to MEK1/2), CRAF, BRAF, ERK1, and ERK2 
(Yamaguchi et al., 2011).  Trametinib demonstrated equal potency against activated 

13 
 
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. 
 
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). 
 
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). 
 
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 

14 
 
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. 
 
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 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-

15 
 
assessed efficacy data are summarized as follows: 
 
 
Trametinib 
(n=214) 
Chemotherapy (DTIC) 
(n=108) 
PFS 
Median, months (95% CI) 
 
4.8 (4.3, 4.9) 
 
1.5 (1.4, 2.7) 
HR (95% CI) 
P value (log-rank test) 
0.47 (0.34, 0.65) 
P<0.0001 
Confirmed Tumor Responses 
Objective Response Rate (95% CI) 
CR, n (%) 
PR, n (%) 
 
22% (17, 28) 
4 (2%) 
43 (20%) 
 
8% (4, 15) 
0 
9 (8%) 
Duration of response 
Median, months (95% CI) 
5.5 (4.1, 5.9) 
NR (3.5, NR) 
CI = confidence interval; CR = complete response; HR = hazard ratio; NR = not reached; PFS = progression-free 
survival; PR = partial response 
 
The 6-month OS rate was 81% in the trametinib group and 67% in the chemotherapy 
group.  Mature data on OS are pending. 
 
Experience with Trametinib in Metastatic Melanoma Following BRAF Inhibitor Therapy 
 
The clinical activity of single-agent trametinib was evaluated in a single-arm, 
multicenter, international trial in 40 patients with BRAF V600E or V600K mutation-
positive, unresectable, or metastatic melanoma who had received prior treatment with a 
BRAF inhibitor.  All patients received trametinib at a dose of 2 mg PO QD until disease 
progression or unacceptable toxicity.  None of the patients achieved a confirmed PR or 
CR. 
 
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 

16 
 
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 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. 
 
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 

17 
 
and 13% in chemotherapy-treated patients.  Severe skin toxicity occurred in 12% of 
patients on the trametinib arm, most commonly for secondary infections of the skin  The 
median time to onset of skin toxicity was 15 days (range:  1 to 221 days), and median 
time to resolution was 48 days (range:  1 to 282 days).  Dose reduction was required in 
12% for skin toxicities, and permanent discontinuation of trametinib was required in 1% 
of patients.  
 
Diarrhea:  At the 2 mg monotherapy dose, 33% to 58% of patients in five trials had 
diarrhea (Investigator’s Brochure, 2013).  Of ~320 subjects (including crossover subjects) 
with diarrhea at this dose, the majority of diarrhea AEs were grade 1 or 2 in severity 
(33% to 56% of all study patients); 17 patients had grade 3 diarrhea, and none had grade 
4 diarrhea. 
 
Visual disorders:  At the 2 mg monotherapy dose, 4% to 21% of the patients in five trials 
experienced visual disorders (Investigator’s Brochure, 2013).  Of the 85 total subjects 
(including crossover subjects) experiencing visual disorders at this dose level, the 
majority of visual disorders were grades 1 or 2 (4% to 20% of all study patients); six 
patients experienced grade 3 visual disorders, and one patient experienced a grade 4 
visual disorder. 
− 
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 

18 
 
total patients (including crossovers) with LFT changes, the majority were grade 1 or 2 in 
severity (4% to 20% of all study patients); 26 had grade 3 events, and 6 patients had 
grade 4 events. 
 
Cardiac-related AEs:  At the 2 mg monotherapy dose, 3% to 21% of the subjects in six 
studies had cardiac-related AEs (Investigator’s Brochure, 2013).  Of the 65 total subjects 
(including crossover subjects) experiencing cardiac-related AEs at the 2.0 mg 
monotherapy dose in five of the studies, the majority of cardiac-related AEs were grades 
1 or 2 in severity (0% to 16% of all study subjects); 18 subjects had grade 3 cardiac-
related AEs, and no subjects had Grade 4 cardiac-related AEs in any study.  No subject in 
one study, which evaluated the effect of repeat oral dosing of trametinib 2 mg QD on 
cardiac repolarization in subjects with solid tumors, had cardiac-related AEs.  One study 
subject receiving trametinib 2 mg QD had grade 5 (fatal) acute cardiac failure, with 
evidence of massive tumor invasion of the heart; this AE was considered not drug-related 
by the investigator. 
In the phase 3 trial of trametinib vs. chemotherapy in patients with melanoma 
(MEK114267), cardiomyopathy (defined as cardiac failure, left ventricular dysfunction, or 
decreased LVEF) occurred in 7% (14/211) of patients treated with trametinib, and in no 
patients in the chemotherapy arm.  Cardiomyopathy was identified within the first month of 
treatment in five of these 14 patients; median onset of cardiomyopathy was 63 days (range: 
16 to 156 days).  Cardiomyopathy resolved in 10 of these 14 (71%) patients.  Cardiac 
monitoring should be included in trametinib protocols, to include LVEF assessment by 
echocardiogram or MUGA scan at baseline, one month after initiation of trametinib and 
then at 2- to 3-month intervals while on treatment.  Refer to dose modification guidelines 
for cardiac AEs in the event of LVEF decline or symptomatic cardiac AEs. 
 
Pneumonitis:  At the 2 mg monotherapy dose, 0% to 4% of the subjects in five studies 
had pneumonitis (Investigator’s Brochure, 2013).  Of the nine total subjects (including 
crossovers) experiencing pneumonitis AEs at this dose, three subjects had grade 1 or 2 
pneumonitis and six subjects had grade 3 pneumonitis. 
Embryofetal toxicity:  Based on its mechanism of action, trametinib can cause 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: 
 

19 
 
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) 
3. 
 
Trametinib 
(n=211) 
Chemotherapy 
(n=99) 
Adverse Reactions 
All Grades 
Grades 
3 and 4 
All Grades 
Grades 
3 and 4 
Skin and subcutaneous tissue 
disorders 
 
 
 
 
Rash 
57 
8 
10 
0 
Dermatitis acneiform 
19 
<1 
1 
0 
Dry skin 
11 
0 
0 
0 
Pruritis 
10 
2 
1 
0 
Paronychia 
10 
0 
1 
0 
Gastrointestinal disorders 
 
 
 
 
Diarrhea 
43 
0 
16 
2 
Stomatitis 
15 
2 
2 
0 
Abdominal pain 
13 
1 
5 
1 
1.1.1 
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 
1.1.2 
1.1.3 
1.1.4 
1.1.5 
Increased alanine 
aminotransferase (ALT) 
1.1.6 
1.1.7 
1.1.8 
1.1.9 
1.1.10 Hypoalbuminemia 
1.1.11 
1.1.12 
1.1.13 
1.1.14 
1.1.15 Anemia 
1.1.16 
1.1.17 
1.1.18 
1.1.19 
1.1.20 Increased alkaline 
phosphatase 
1.1.21 
1.1.22 
1.1.23 
1.1.24 
 
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).   
 
Clinical Experience with the Combination of Trametinib + Dabrafenib 
Preliminary data on 45 patients participating in the phase 1/2 study of dabrafenib and 

20 
 
trametinib, BRF113220, have been reported (Infante et al., 2011). 
 
PK: 
The plasma levels of dabrafenib were higher in combination with trametinib as compared 
to that with monotherapy.  Geometric mean Day 15 AUC of dabrafenib in combination 
ranged from 3539 to 5187 ng•hr/mL, and the AUC observed in the monotherapy study 
was 2619 ng•hr/mL.  Further data are required to understand this difference. 
 
PK of trametinib did not appear to be affected by the addition of dabrafenib.  Preliminary 
results showed that the geometric mean dose-normalized AUC0-τ (CV%) for trametinib 
(dose normalized for the 2.0 mg QD dose) in combination with dabrafenib at 150 mg BID 
was 302 ng•hr/mL (n=17; 35%) on Day 15.  Historical PK data from the trametinib FTIH 
study (MEK111054) indicated a mean Day 15 AUC0-τ (CV%) of 360 ng•hr/mL (31%). 
 
Safety and the RP2D for the combination of trametinib and dabrafenib 
One DLT of a recurrent grade 2 neutrophilic panniculitis occurred, and pyrexia was 
common (51%).  The RP2D was 150 mg BID dabrafenib plus 2 mg QD trametinib (both 
agents at the RP2D for single agent).  Of the 137 patients enrolled, 32 patients were 
treated at the RP2D.  SAEs experienced by more than one patient include:  pyrexia (5%), 
hypotension (4%), nausea (3%), and 2% of patients had a constellation of AEs including 
vomiting, dehydration, or renal failure.  The only grade 4 AE was a sepsis-like syndrome 
with fever/hypotension.  Grade 3 AEs included generalized rash (n=2, 4%) and 
neutropenia (n=2, 4%).  Skin toxicity (rash) occurred in 9 (20%) patients.  Of note, the 
rate of SCC was 2% in this study.  A single case of grade 5 hyponatremia was reported.  
Other common AEs are listed in the table below. 
 
                             Summary of selected AEs experienced by ≥5% of patients regardless of causality 
in BRF113220 (treated at RP2D) 
AE Term 
Dose Escalation Cohort 
(150mg BID/2 mg QD) 
(n=31) 
Any AE, n (%) 
24 (77) 
Pyrexia 
10 (32) 
Rash 
4 (13) 
Dermatitis acneiform 
1 (3) 
Hypotension 
4 (13) 
 
Activity 
Among 77 evaluable patients with melanoma who had not received prior BRAF 
inhibitors, there were 43 responses (56%), including 4 CRs (5%) and 39 PRs (51%) 
(Weber et al., 2012).  Twenty-nine patients experienced SD, and three patients 
experienced PD.  Patients were treated on four escalating dose levels of 
dabrafenib/trametinib (mg BID/mg QD):  75/1, 150/1, 150/1.5, 150/2.  The confirmed RR 
for each dose level, respectively, was 67% (n=6), 64% (n=22), 48% (n=25), and 54% 
(n=24).  Median PFS (months) for each of the first three dose levels, respectively, was 
8.7, 8.3, and 5.5; PFS data are not mature for the fourth (150/2) dose level.  Overall PFS 
was 7.4 months. 
 

21 
 
Currently, the randomized phase 2 portion (Part C) of the study of dabrafenib with or 
without trametinib has enrolled 162 patients as of September 1, 2011 (Investigator’s 
Brochure, 2012b). 
 
Clinical Experience with the Combination of Trametinib + GSK2141795 (AKT inhibitor) 
(TAC113886) 
 
Twenty-three patients with advanced solid tumors received the combination using a zone-
based escalation procedure enabling evaluation of multiple combination doses in parallel 
cohorts (Kurzrock et al., 2011).  While the RP2D for single agent for single agent 
trametinib and GSK2141795 are 2 mg/d and 75 mg/d, dose reductions were required for 
the combination.  DLTs include grade 2 AST and ALT elevation, and grade 3 chest pain 
with sustained ventricular tachycardia; all DLTs were reversible with drug interruption.  
The most common AEs (≥10%) included nausea (26%), AST elevation (22%; grade 3/4, 
9%), fatigue (22%) and rash (22%).  Three MTDs were defined for variable dose ratios:  
2 mg trametinib + 25 mg GSK2141795; 0.5 mg trametinib + 75 mg GSK2141795; and 
1.5 mg trametinib + 50 mg GSK2141795.  Three of 13 evaluable patients (unselected) 
had tumor shrinkage of 8% (ovarian), 16% (endometrial), and 17% (ovarian) after 8 
weeks on study.  The dose regimen of 1.5 mg trametinib + 50 mg GSK2141795 will be 
considered for further development.  Additional trials to explore alternate schedules (e.g., 
intermittent) and pharmacodynamic markers are ongoing. 
 
2.3 
Lesional dosimetry by 124I PET/CT  
 
131I has been used since the late 1940s for the treatment of metastatic differentiated thyroid 
carcinoma (DTC).  This is based on the unique ability of normal and neoplastic thyroid cells to 
express a protein (the sodium-iodide symporter) which can pump iodide into the cells against an 
electrochemical gradient.  Many of the fundamental studies on the safety and efficacy of 131I for 
metastatic DTC were carried out at MSK in the early 1950s by Benua, Sonenberg, Rawson, J. 
Robbins, and Yeh (Benua and Leeper, 1986).  They discovered that exposure to large amounts of 
131I could result in toxicity to bone marrow and to the lung (Benua et al., 1962).  Benua 
developed a method to determine the radiation dose to the bone marrow and to the lung by 
frequent measurements of the blood, urine, and whole body radiation levels after a standard 
administration of small amounts of 131I.  This method, termed “dosimetry”, has been used for the 
past 50 years at MSK as a standard of care (Leeper, 1973).  The dosimetry methods produces a 
blood maximum tolerable activity (MTA) above which significant bone marrow toxicity is likely 
and a pulmonary MTA for patients with diffuse lung disease, above which pulmonary fibrosis is 
more likely.  This technique has provided important safety measures that enable us to give 
multiple radioiodine treatments with minimal side effects.  However, dosimetry does not predict 
tumor response.  This is due to technical limitations in precisely determining the concentration of 
131I in individual metastatic lesions. 
The recent widespread availability of positron emission tomography (PET) enables investigators 
to estimate biochemical events in patients.  Based on MSK studies from the 1950s, Dr. Ron Finn 
and colleagues have recently developed a method to generate a positron emitting isotope of 
iodine, 124I (Pentlow et al., 1996).  This enables, for the first time, to accurately determine the 
concentration of radioiodine in a specific lesion.  This information can be transformed into the 

22 
 
radiation dose that is delivered to the area of isotope retention, which can be determined due to 
the tomographic capability of the PET instrument.  In preliminary studies at MSK (Sgouros et 
al., 2004), we have shown that accurate whole body and lesional dosimetry can be accomplished 
by measuring the concentration of 124I at several time points over 96 hours following a single 
oral administration of 124I (Furhang et al., 1999).  In addition to providing the MTA safety limits, 
this new approach can estimate the radiation dose that each lesion will receive, depending on the 
isotope of iodine that is administered for therapy.  We have found that an extremely wide range 
of radiation dosages (over three log orders) exist in lesions that appear to be similar on visual 
inspection of a standard whole body radioiodine scintigraphic image.  This concept has been 
confirmed by investigators in Germany and Sweden (Eschmann et al., 2002; Lubberink et al., 
1999).  Our data here at MSKwith 124I PET in patients with metastatic thyroid cancer has 
established that clinical responses to RAI are observed when the lesional absorbed dose of RAI 
reaches ~ 2,000 cGy (rad).  This treatment threshold was utilized in our recently completed pilot 
study: among the 8 out of 20 total patients we selected for RAI therapy, all patients experienced 
tumor shrinkage (5 confirmed partial responses and 3 with stable disease).  At MSK, we hold the 
consensus view that the 2,000 cGy (rad) 124I PET lesional dosimetry threshold can effectively 
predict clinical efficacy with RAI utilizing the 2,000 cGy (rad) threshold and is hence clinically 
applicable.    
2.4 
Rationale for utilizing MAPK pathway inhibition to enhance iodine incorporation in RAI-refractory 
thyroid tumors 
 
Thyroid cancer mutations that activate the MAPK pathway de-differentiate thyroid cancer 
cells 
Mutually exclusive genetic alterations in the growth factor receptor RET, the three isoforms of 
RAS (N, H, K), and BRAF are present in ~70% of PTCs(Cohen et al., 2003; Kimura et al., 2003; 
Knauf and Fagin, 2009; Soares et al., 2003). These oncoproteins participate in MAPK signaling 
to activate downstream kinases MEK and ERK (RET->RAS->RAF->MEK->ERK).  The 
BRAFV600E mutation is the most common genetic alteration in PTC (involving about 45% of 
tumors)(Kimura et al., 2003; Ricarte-Filho et al., 2009). BRAF MUT tumors have a more 
aggressive clinical behavior and are prone to being RAI-refractory(Elisei et al., 2008; Lee et al., 
2007).  Beyond promoting cellular proliferation and survival, BRAF mutations in thyroid cancer 
have also been implicated in disrupting follicular cell differentiation, including the suppression 
of key genes involved in iodine metabolism (Durante et al., 2007; Liu et al., 2007; Riesco-
Eizaguirre et al., 2006).  The BRAFV600E mutation decreases expression of the sodium iodide 
symporter (NIS), a protein critical for mediating iodide uptake into thyroid cells(Riesco-
Eizaguirre et al., 2006).  In rat thyroid PCCL3 cells with inducible expression of BRAFV600E, 
treatment with the MEK inhibitor U0126 restored expression of NIS as well as thyroid 
stimulating hormone (TSH) receptor and thyroglobulin (Liu et al., 2007).   
Other MAPK activating alterations common to thyroid cancer can also cause de-differentiation.  
RAS mutations are found in approximately 10-20% of PTCs and 40-50% of FTCs (Nikiforov and 
Nikiforova, 2011).  Recombination events that lead to the fusion of the RET tyrosine kinase 
receptor with one of several partner genes (known as RET/PTC rearrangements) occur in 10-20% 
of PTCs (Nikiforov and Nikiforova, 2011; Soares et al., 2003; Zhu et al., 2006).  Overexpression 
of either the HRASV12 mutant or RET/PTC in thyroid cancer cells suppressed NIS expression, 
which was restored with MEK inhibitor treatment (De Vita et al., 2005; Knauf et al., 2003).  

23 
 
Hence, genetic alterations that account for MAPK activation in about 70% of thyroid cancers can 
promote MEK-dependent NIS suppression, diminished RAI avidity, and resistance to RAI 
therapy.   
MEK inhibition can restore iodine incorporation in an in vivo thyroid cancer model  
Dr. James Fagin’s group recently published studies conducted in a thyroid cancer mouse model 
with doxycycline (dox) inducible thyroid expression of BRAFV600E (Chakravarty et al., 2011).  In 
this model, dox treatment resulted in BRAFV600E overexpression, MAPK activation, development 
of PTC, and suppression of several thyroid specific genes, including NIS.  Withdrawal of dox to 
eliminate BRAFV600E expression resulted in suppression of MAPK activation and re-induction of 
thyroid gene expression, suggesting that oncogenic BRAF induced gene patterns can be reversed 
when BRAF activation of MAPK signaling is nullified (data not shown).  We went on to test 
whether or not this genetic proof of concept could be recapitulated with pharmacologic inhibition 
of BRAF activation (Figure 1).  BRAFV600E was induced with one week of dox treatment.  In the 
following week, dox was continued in order to maintain BRAFV600E expression while animals 
were treated with the MEK inhibitor PD0325901 (PD901) or the selective oncogenic BRAF 
inhibitor PLX4720 (Plexxikon/Roche). 124I microPET was performed to quantify iodine uptake. 
While expression of BRAFV600E suppressed thyroid RAI incorporation, inhibition of BRAF 
signaling with either drug increased RAI uptake over vehicle treatment (Figure 1).  These 
experiments validate that inhibiting MAPK signaling with small molecule inhibitors can restore 
RAI uptake in thyroid tumors driven by a MAPK activating genetic alteration. 
 
The MSK experience with MEK inhibition enhancing RAI incorporation and susceptibility 
We translated these preclinical findings into an IRB-approved pilot study evaluating the impact 
of the AstraZeneca MEK inhibitor selumetinib upon iodine uptake in patients with RAI-
Figure 1: Pharmacologic inhibition of oncogenic BRAF signaling increases RAI uptake in a doxycycline-inducible 
BRAFV600E thyroid cancer model. A) Schematic for the experiment. Tg-rtTA/tetO-BRAFV600E mice were treated for one 
week with doxycycline (“1 wk ON”) to induce thyroid specific BRAFV600E expression. Dox was either discontinued (“1 wk 
OFF”) to halt BRAFV600E expression or continued to maintain BRAFV600E expression while drug was administered (MEK 
inhibitor PD0325901 (PD901) or oncogenic BRAF inhibitor PLX4720 or vehicle) for approximately 1 week. B) Images 
from 124I microPET.   C) Quantification of 124I uptake measured by microPET.  Thyroid uptake was quantified as % 
injected dose per gram of tissue (%ID/gm) in Region of Interest (ROI). mpk, mg per kg; PDTC, poorly differentiated 
thyroid carcinoma. 

24 
 
Figure 2: Clinical MEK inhibition with selumetinib enhances iodine 
incorporation. A) Whole body MIP images from 124I  PET scan 
demonstrates new iodine incorporation in nearly all lung and neck 
metastases that were previously negative at baseline in a BRAF MUT 
patient following selumetinib treatment.   B) (from left to right) The 
PET, CT, and fused images from the 124I PET/CT scan performed on an 
NRAS MUT patient demonstrating significantly increased and new 
iodine incorporation after selumetinib treatment.  C) Fused and three-
dimensional rendering of a skull metastasis with significantly increased 
iodine incorporation with selumetinib therapy. 
refractory thyroid cancers.  A critical component of the study was the utilization of 124I positron 
emission tomography (PET)/CT scans to precisely quantify drug-induced changes in iodine 
incorporation within specific lesions (“lesional dosimetry”) (Pentlow et al., 1996; Sgouros et al., 
2004).  This provided a substantial advantage over traditional whole body radioactive iodine 
scintigraphy, which does not provide correlative anatomic localization for iodine uptake, is less 
sensitive for detecting iodine-avid metastases(Van Nostrand et al., 2010), and is only loosely 
quantitative (visually similar lesions can represent as much as a 3 log range of radiation 
dosages).  With 124I PET, we can also transform the 124I quantification into the predicted RAI 
radiation dosage delivered within every individual tumor within a patient’s body.     
Each of the 20 evaluable patients on the 
study had RAI-refractory disease as 
defined by one of the following 
criteria: 1) non-RAI-avid lesion/s on a 
diagnostic and/or post-therapy RAI 
scan, 2) RAI-avid lesion/s that 
remained stable or increased in size 
after RAI therapy, or 3) 
fluorodeoxyglucose (FDG)-avid 
lesion/s by PET scan.  In order to 
optimize iodine uptake, human 
recombinant TSH (rhTSH or Thyrogen 
from Genzyme) was administered prior 
to each 124I PET, which was performed 
before and after 4 weeks of treatment 
with selumetinib.  If the second 124I 
PET scan predicted that a lesional RAI 
dose of > 2,000  
cGy could be achieved, RAI was 
administered while patients continued 
on selumetinib.  Radiologic RECIST 
response and thyroglobulin levels (a 
thyroid tumor marker) were assessed 
after therapeutic RAI.   
 
Of the 20 evaluable patients, 12 (60%) 
had new or increased 124I incorporation 
after selumetinib (Figure 2 and Table 
1).  For 8 (40%) patients, the second 
124I PET scan predicted that the lesional 
absorbed radiation dose would equal or 
exceed 2,000 cGy; these patients were 
continued on selumetinib and went on 
to receive therapeutic RAI.  All 5 
patients with NRAS MUT tumors 
enrolled onto the study exceeded this 
dosimetry threshold and were treated 

25 
 
Table 1: Summary of the 124I PET/CT data by tumor genotype.  
Figure 3: Waterfall plot of best overall response amongst the 8 patients who received RAI. 
with RAI.  By contrast, 4 out of 9 BRAF MUT patients had selumetinib-induced increases in 124I 
incorporation, but only one achieved the dose threshold to warrant RAI treatment.  Two out of 3 
RET/PTC and 1 out of 3 WT patients also had greater iodine incorporation on the second 124I 
PET scan, and one of each of those genotypes went on to be treated with 131I.   
 
 
Reduction in tumor size by RECIST criteria was achieved in all patients, with 5 confirmed 
partial responses (cPRs) and 3 with stable disease (SD) (Figure 3).  Substantial decreases in 
thyroglobulin following RAI therapy were also achieved in all 8 patients.   
Rationale for evaluating trametinib in RAI-refractory thyroid cancer 
The selumetinib pilot study demonstrated that MEK inhibition can enhance iodine incorporation 
to induce clinical responses in a subset of patients with RAI-refractory thyroid cancer.  A 
particularly promising signal was observed in RAS MUT patients as all 5 enrolled in the pilot had 
a positive 124I response with selumetinib.  However, the limited number of RAS MUT patients 
treated on the study requires that further investigation be performed to better assess clinical 
efficacy.  Cohort A of this study will be dedicated to evaluating the clinically efficacy of MEK 
inhibition with trametinib in combination with RAI only in patients with RAS MUT, RAI-
refractory thyroid cancer.  Cohort B will explore if MEK inhibition with trametinib can be 
effective for enhancing iodine incorporation in BRAF/RAS WT tumors, a genotype subset that 

26 
 
was less susceptible to selumetinib in the pilot study.  In both cohorts, 124PET/CT lesional 
dosimetry will be used to quantify changes in tumoral iodine incorporation induced by 
trametinib.    
 
Trametinib was the agent selected for investigation based on emerging evidence that the clinical 
efficacy of MAPK pathway targeted therapies likely is related to the potency of signaling 
inhibition.  In the phase I study of the BRAF kinase inhibitor PLX4032 for BRAF MUT 
cutaneous melanoma, only patients with tumors demonstrating near complete inhibition of ERK 
phosphorylation (80% or greater) experienced tumor regressions; partial pathway inhibition 
resulted in little or no change in tumor dimensions (Bollag et al., 2010).  In a randomized phase 
II study of 99 melanoma patients treated with selumetinib, only 6 (5.8%) partial responses were 
observed, indicating that the vast majority of the estimated 46.2% of patients with BRAF MUT 
disease on the trial did not respond to selumetinib (Kirkwood et al., 2011).  In comparison, the 
phase III trial comparing trametinib to chemotherapy for patients with BRAF MUT cutaneous 
melanoma reported an overall response rate of 22% in the trametinib group (Flaherty et al., 
2012).  It is possible that the efficacy observed with trametinib reflects enhanced potency for 
inhibiting the MAPK pathway.  Therefore, we hypothesize that trametinib may be as effective as 
selumetinib for enhancing iodine incorporation in RAS MUT patients, and perhaps more 
effective for BRAF/RAS WT patients.    
For patients from Cohorts A and B who do not achieve sufficient increases in 124I PET tumor 
incorporation to warrant RAI therapy, if the treating physician determines that it is clinically 
reasonable to continue treatment with trametinib alone, these patients will have the option of 
joining Cohort C which will explore the potential clinical efficacy and safety of trametinib 
therapy for these patients.  The efficacy of MEK inhibition alone for RAI-refractory thyroid 
cancer has been evaluated with selumetinib in one phase II trial; that study reported only 1 partial 
response out of 32 evaluable patients.  Only one patient with a known NRAS Q61R MUT tumor 
and 11 patients with tumors wild-type for BRAF, NRAS, and HRAS were included in that 
analysis.  We hypothesize that more potent inhibition with trametinib will translate to greater 
clinical efficacy for patients with RAI-refractory thyroid cancers that are either RAS MUT or 
BRAF/RAS WT. 
 
2.5 
Correlative Studies Background 
The impact of trametinib upon MAPK signaling and thyroid-gene expression will be evaluated in 
serial biopsies.  The purpose of these studies will be to correlate potent MAPK pathway 
inhibition to changes in iodine incorporation and increase our understanding of the biologic 
underpinnings that may determine susceptibility/resistance to this strategy.  In order to explore 
the impact of trametinib in different tumor genotypes, the goal will be to have a minimum of 6 
patients from Cohort A and 3 patients from Cohort B undergo these two biopsies (for a total of 9 
patients total).  The first biopsy will be performed before Week 1 Day 1 of the study; the second 
biopsy will be obtained in Week 3 while the patient is on trametinib.  It is preferred, but not 
required, that the second biopsy be performed upon the same tumor that was sampled with the 
first research biopsy, if safe and feasible.   Both formalin fixed and flash frozen tissues will be 
prepared. 
The fresh frozen tissue will be analyzed with protein based assays to evaluate drug-induced 
changes in MAPK signaling and thyroid-specific gene expression.  Additionally, profiling of 

27 
 
cellular transcriptional output has been validated as a means of distinguishing tumor cell 
susceptibility to MEK inhibition (Dry et al., 2010) and the differential impact of MEK inhibition 
upon BRAF MUT versus WT tumors (Pratilas et al., 2009).  Hence, a separate aliquot of the 
fresh frozen tumor biopsies will be used for quantification of gene transcript levels as a readout 
of MAPK pathway activation (Pratilas et al., 2009).  In the thyroid, DUSP5 and PLAT are 
particularly useful markers of MAPK activity, and will be explored in the samples (Chakravarty 
et al., 2011).  Additionally, the re-expression of some key thyroid-specific genes such as NIS will 
be evaluated (Chakravarty et al., 2011). 
Archival and/or frozen tissues will also be analyzed for other genomic alterations that may 
potentially correlate to clinical benefit with this approach. 
  
3. PATIENT SELECTION 
 
3.1 
Inclusion Criteria  
 
For both Cohort A and B patients:  
 
3.1.1 Patients must have histologically or cytologically confirmed thyroid carcinoma of follicular origin 
(including papillary, follicular, or poorly differentiated subtypes and their respective variants).  
Confirmation of thyroid carcinoma will be done at MSK.  
 
3.1.2 Patients must have measurable disease, defined as at least one lesion that can be accurately measured 
in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for 
nodal lesions) as ≥ 20 mm with conventional techniques or as ≥10 mm with spiral CT scan, MRI, or 
calipers by clinical exam.  See Section 11 for the evaluation of measurable disease.  Tumors in 
previously irradiated fields may be considered measureable if there is evidence of tumor progression 
after radiation treatment. 
 
3.1.3 RAI-refractory disease on structural imaging, defined as any one of the following: 
 
a) A metastatic lesion that is not radioiodine-avid on a diagnostic radioiodine scan performed prior 
to enrollment in the current study, or 
 
b) A radioiodine-avid metastatic lesion which remained stable in size or progressed despite 
radioiodine treatment 6 months or more prior to entry in the study. There are no size limitations 
for the index lesion used to satisfy this entry criterion. 
 
c) The presence of at least one fluorodeoxyglucose (FDG) avid lesion.  
 
3.1.4 No recent treatment for thyroid cancer as defined as: 
 
a) No prior RAI therapy is allowed < 6 months prior to initiation of therapy on this 
protocol. A diagnostic study using < 10 mCi of RAI is not considered RAI 
therapy. 
 
b) No external beam radiation therapy < 4 weeks prior to initiation of therapy on 
this protocol.  (Previous treatment with radiation for any indication is allowed if 

28 
 
the investigator judges that the previous radiation does not significantly 
compromise patient safety on this protocol.) 
 
c) 
No chemotherapy or targeted therapy (e.g., tyrosine kinase inhibitor) is allowed 
< 4 weeks prior to the initiation of therapy on this protocol. 
 
3.1.5 Age ≥ 18 years.  Because no dosing or adverse event data are currently available on the use of 
trametinib alone or in combination with RAI in patients < 18 years of age, children are excluded 
from this study. 
 
3.1.6 ECOG performance status ≤ 2 (Karnofsky ≥60%, see Appendix A). 
 
3.1.7 Life expectancy of greater than 3 months. 
 
3.1.8 Able to swallow and retain orally-administered medication and does not have any clinically significant 
gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major 
resection of the stomach or bowels. 
 
3.1.9 All prior treatment-related toxicities must be CTCAE v4.0 grade ≤ 1 (except alopecia).  Grade 2 prior 
treatment related toxicities may be allowed after discussion with the Principal Investigator. 
 
3.1.10 Patients must have normal organ and marrow function as defined below:   
 
− 
Absolute neutrophil count (ANC) ≥1.5x109/L  
− 
Hemoglobin ≥ 9 g/dL 
− 
Platelets ≥ 100 x 109/L 
− 
Albumin ≥ 2.5 g/dL 
− 
Total bilirubin ≤ 1.5x institutional ULN 
− 
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤  
    2.5x institutional ULN 
− 
creatinine ≤ 1.5 mg/dL OR calculated creatinine clearance (Cockroft-Gault   
    formula) ≥ 50 mL/min OR 24-hour urine creatinine clearance ≥ 50 mL/min 
− 
Prothrombin time (PT) or International normalized ratio (INR) and partial  
    thromboplastin time (PTT) ≤ 1.5x institutional ULN 
− 
Left ventricular ejection fraction ≥ institutional lower limit of normal (LLN) 
    by ECHO or MUGA 
 
3.1.11 The effects of trametinib on the developing human fetus are unknown.  Since MEK inhibitors and 
RAI may be teratogenic, women of child-bearing potential and men must agree to use adequate 
contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the 
duration of study, and 4 months after study completion. Women of child-bearing potential must have 
a negative pregnancy test within 2 weeks prior study registration.  Should a woman become pregnant 
or suspect she is pregnant while she or her partner is participating in this study, she should inform 
the treating physician immediately.  Men treated or enrolled on this protocol must also agree to use 
adequate contraception prior to the study, for the duration of study participation, and 4 months after 
completion of trametinib administration. 
 
3.1.12 Ability to understand and the willingness to sign a written informed consent document. 
 

29 
 
3.1.13 Patients must agree to undergo two separate biopsies of a malignant lesion.  Biopsies do not need to 
be done if one of the following apply: 
 
a) If either the site investigator or person performing the biopsy judges that no tumor is accessible 
for biopsy or that biopsy poses too great of a risk to the patient. (If the only tumor accessible for 
biopsy is also the only lesion that can be used for RECIST v1.1 response evaluation, then the 
patient may be exempt from biopsy after discussion with the MSK Principal Investigator.) 
 
b) The goal will be to have a minimum of 6 patients from Cohort A and 3 patients from Cohort B 
attempt to have one or both of these research biopsies done (for a total of 9 patients total).  
Accrual may be limited only to subjects for whom tumor is accessible for biopsy and attempt at 
biopsy is considered safe if continued enrollment of those who are not candidates for biopsy 
make it impossible to reach the accrual goals for research biopsies described above.  (e.g., if 19 
(of 25) patients are accrued to Cohort A without any biopsies having been obtained within the 
cohort, then all further subjects who are registered to that cohort must qualify for attempted 
research biopsy in order to be enrolled into the study (i.e., subjects who would have been 
excluded from having biopsies done due to the above reasons would be excluded from 
participating in the study.  These conditions also apply to Cohort B.)). 
 
3.1.14 Availability of archival tumor tissue from the thyroid cancer primary or metastasis (A tissue block or 
a minimum of 30 unstained slides would be required.  Patients with less archival tissue available 
may still be eligible for the study after discussion with the MSKPrincipal Investigator.) 
 
For Cohort A patients only (RAS MUT patients):  
3.1.15 Confirmation in a CLIA certified laboratory that one of the patient’s thyroid tumors (primary tumor, 
recurrent tumor, or metastasis) has an NRAS or KRAS or HRAS mutation at G12, G13, or Q61.  This 
group of patients will also be referred to as “RAS MUT”. 
 
3.1.16 Patients must have progressive disease, defined as the presence of new or growing lesion(s) on 
radiologic imaging within 14 months of study enrollment and/or new/worsening disease related 
symptoms within 14 months of study enrollment.  (Progression according to RECIST v1.1 criteria is 
not required.) 
 
For Cohort B patients only (BRAF/RAS WT patients):  
 
3.1.17 Confirmation in a CLIA certified laboratory that one of the patient’s thyroid tumors (primary tumor, 
recurrent tumor, or metastasis) does not have any of the following mutations: 
 
a. 
Mutation at V600 of the BRAF gene  
 
b. Mutation in NRAS or KRAS or HRAS at G12, G13, or Q61 
 
These patients will be designated “BRAF/RAS WT”. 
 
3.2 
Exclusion Criteria 
 
3.2.1 History of another malignancy. 
 
Exception:  Patients who have been disease-free for 3 years, patients with a history 
of completely resected non-melanoma skin cancer, and/or patients with indolent 
secondary malignancies, are eligible.  MSK can consult the CTEP Medical Monitor 
if unsure whether second malignancies meet the requirements specified above. 

30 
 
 
3.2.2 History of interstitial lung disease or pneumonitis. 
 
3.2.3 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. 
 
3.2.4 Symptomatic or untreated leptomeningeal or brain metastases or spinal cord compression. 
 
3.2.5 Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically 
related to trametinib, or excipients or to dimethyl sulfoxide (DMSO) or to thyrotropin alpha 
(Thyrogen). 
 
3.2.6 Current use of a prohibited medication.  The following medications or non-drug therapies are 
prohibited: 
 
− 
Other anti-cancer therapy while on study.  (Note:  Megestrol [Megace] if used 
as an appetite stimulant is allowed.  TSH suppressive therapy is also allowed.  
Palliative radiation therapy to non-target lesions is also allowed.). 
− 
Concurrent treatment with bisphosphonates is permitted.  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], 
gingko biloba, dehydroepiandrosterone [DHEA], yohimbe, saw palmetto, or 
ginseng). 
 
3.2.7 Patients with the following ophthalmological findings/conditions: 
 
                     -     Intraocular pressure >21 mmHg, or uncontrolled glaucoma (irrespective of   
                           intraocular pressure) 
                     -     Current or past history of central serious retinopathy or retinal vein 
                           occlusion  
  
3.2.8 History or evidence of cardiovascular risk including any of the following: 
 
− LVEF<LLN. 
− A QT interval corrected for heart rate using the Bazett’s formula QTcB ≥480 
msec. 
− History or evidence of current clinically significant uncontrolled arrhythmias 
(Exception:  patients with controlled atrial fibrillation for >30 days prior to 
randomization are eligible). 
− History of acute coronary syndromes (including myocardial infarction and 
unstable angina), coronary angioplasty, or stenting within 6 months prior to 
randomization. 
− History or evidence of current ≥ Class II congestive heart failure as defined by the 
New York Heart Association (NYHA) functional classification system. 
− Treatment-refractory hypertension defined as a blood pressure of systolic >140 

31 
 
mmHg and/or diastolic >90 mmHg which cannot be controlled by anti-
hypertensive therapy. 
− Patients with intra-cardiac defibrillators. 
− Known cardiac metastases. 
 
3.2.9 Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) 
infection (with the exception of chronic or cleared HBV and HCV infection, which will be allowed). 
Patients with Human Immunodeficiency Virus (HIV) are not eligible if on anti-retroviral 
medications, 
 
3.2.10 Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric 
illness/social situations that would limit compliance with study requirements. 
 
3.2.11 Animal reproductive studies have not been conducted with trametinib.  Therefore, the study drug 
must not be administered to pregnant women or nursing mothers.  These potential risks may also 
apply to RAI and Thyrogen. 
 
3.2.12 HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for 
pharmacokinetic interactions with trametinib.  In addition, these patients are at increased risk of 
lethal infections when treated with marrow-suppressive therapy.   
 
3.2.13 Patients unable to follow a low iodine diet or requiring medication with high content in iodide 
(amiodarone). 
 
3.2.14 Patients who received iodinated intravenous contrast as part of a radiographic 
procedure within 3 months of study registration.  Those that have had iodinated 
intravenous contrast within this time frame may still be eligible if an urinary iodine 
analysis reveals that the excess iodine has been cleared after the last intravenous 
contrast administration.   
 
3.3 
Inclusion of Women and Minorities 
Both men and women of all races and ethnic groups are eligible for this trial. (NOTE: The letter 
designations below do not refer to study cohort designations.) 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
 
Males 
 
Total 
Hispanic or Latino 
4 
+ 
2 
= 
6 
Not Hispanic or Latino 
16 
+ 
13 
= 
29 
Ethnic Category: Total of all subjects 
20 
(A1) + 
15 
(B1) = 
35 
(C1) 
Racial Category 
 
American Indian or Alaskan Native 
0 
+ 
0 
= 
0 
Asian 
2 
+ 
1 
= 
3 
Black or African American 
3 
+ 
2 
= 
5 
Native Hawaiian or other Pacific 
Islander 
0 
+ 
0 
= 
0 
White 
15 
+ 
12 
= 
27 
Racial Category: Total of all subjects 
20 
(A2) + 
15 
(B2) = 
35 
(C2) 
 
(A1 = A2) 
 
(B1 = B2) 
 
(C1 = C2) 

32 
 
4. 
REGISTRATION PROCEDURES 
 
4.1 
Investigator and Research Associate Registration with CTEP 
 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy 
require all individuals contributing to NCI-sponsored trials to register and to renew their 
registration annually.  To register, all individuals must obtain a Cancer Therapy Evaluation 
Program (CTEP) Identity and Access Management (IAM) account 
(https://ctepcore.nci.nih.gov/iam).  In addition, persons with a registration type of Investigator 
(IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) (i.e., clinical site staff 
requiring write access to OPEN or RAVE or acting as a primary site contact) must complete 
their annual registration using CTEP’s web-based Registration and Credential Repository 
(RCR) (https://ctepcore.nci.nih.gov/rcr). Documentation requirements per registration type 
are outlined in the table below. 
 
Documentation Required 
IVR 
NPIV
R 
AP 
A 
FDA Form 1572 
 
 
Financial Disclosure Form 
 
 
 
NCI Biosketch (education, training, 
employment, license, and certification) 
 
 
 
HSP/GCP training 
 
 
 
Agent Shipment Form (if applicable) 
 
CV (optional) 
 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access all 
CTEP and CTSU (Cancer Trials Support Unit) websites and applications.  In addition, IVRs 
and NPIVRs must list all clinical practice sites and IRBs covering their practice sites on the 
FDA Form 1572 in RCR to allow the following: 
• Added to a site roster 
• Assigned the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN 
• Act as the site-protocol PI on the IRB approval 
• Assigned the Clinical Investigator (CI) role on the Delegation of Tasks Log (DTL).     
 
Additional information can be found on the CTEP website at 
https://ctep.cancer.gov/investigatorResources/default.htm. For questions, please contact the 
RCR Help Desk by email at  RCRHelpDesk@nih.gov 

33 
 
 
4.2 
General  Registration Procedures 
 
Confirm eligibility as defined in the section entitled Patient Selection. 
 
Obtain informed consent by following procedures defined in section entitled Informed Consent 
Procedures. 
 
During the registration process, registering individuals will be required to complete a protocol 
specific Eligibility Checklist. The individual signing the Eligibility Checklist is confirming that 
the participant is eligible to enroll in the study.  Study staff are responsible for ensuring that all 
institutional requirements necessary to enroll a participant to the study have been completed.  
See related Clinical Research Policy and Procedure #401 (Protocol Participant Registration). 
 
 
5.   TREATMENT AND IMAGING 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 (except for thyroid hormone TSH 
suppression, palliative radiation to a non-target lesion, or therapy to prevent pathologic fractures 
caused by bone metastases (e.g. zoledronic acid and denosumab)). 
 
 
5.1.1 Trametinib 
 
Regimen Description 
Agent 
Premedications; 
Precautions 
Dose 
Route 
Schedule 
Cycle Length 
Trametinib 
None 
 
2 mg 
Orally 
Daily 
28 days 
(4 weeks) 
(please see 
below for 
specifics 
regarding time 
on treatment) 
 
 
• 
After completion of the first 124I PET/CT lesional dosimetry process, all patients will 
start trametinib (Week 1, Day 6).  Patients will remain on trametinib for about 4 weeks 
through the completion of the second 124I PET/CT lesional dosimetry process.   
• 
Ideally, patients will remain on trametinib continuously for a minimum of 7 days prior 

34 
 
to the PET/CT scan for the second lesional dosimetry (this is not a requirement).  To 
achieve this, protocol assessments and treatments may be rescheduled  (including but 
not limited to the second 124I PET/CT lesional dosimetry, 131I dosimetry/therapy, 
and/or repeating Thyrogen injection administration) at the discretion of the treating 
physician. Extending time on trametinib in this manner will not be considered a 
protocol violation.  If the second 124I PET/CT lesional dosimetry is delayed more than 
4 weeks, the MSK Principal Investigator and the treating physician will determine if 
the patient should be continued or removed from the study.  Please note that missing 
less than 7 dose(s) of study drug in a cycle for reasons other than toxicity issues will 
not be considered a violation of the protocol. 
• 
Generally, missed doses do not need to be made up.  However, making up missed 
doses may be considered if necessary to ensure that the patient has remained on 
trametinib for a minimum of 7 consecutive days as discussed above.  If trametinib is 
missed for > 7 days total or interruptions in trametinib dosing have occurred prior to or 
during whole body and blood dosimetry and 131I (RAI) treatment, then having some or 
all of the doses made up and rescheduling the study assessments/treatments may be 
considered after discussion with the MSK Principal Investigator (this is not a 
requirement).  Please note that missing less than 7 dose(s) of study drug in a cycle for 
reasons other than toxicity issues will not be considered a violation of the protocol. 
• 
If lesional dosimetry with the second 124I PET/CT scan reveals that a dose of > 2,000 
cGy can be delivered to at least one tumor with < 300 mCi of RAI, then the treating 
physician(s) will make a clinical decision as to whether 131I therapy should proceed.  If 
131I is to be given, the patient will continue trametinib until 2 days after therapeutic 
RAI has been administered.  If therapeutic RAI will not be given, it will be concluded 
that the patient’s cancer is still refractory to RAI and he/she will not receive RAI.  
Such patients may be continued on trametinib alone if 1) the treating physician 
determines it to be clinically reasonable, and 2) the patient agrees to continue on 
trametinib.  If these conditions are not met, then trametinib will be discontinued and 
the patient will be removed from the study. 
• 
The impact of more than one month of trametinib therapy upon RAI uptake and/or 
efficiacy is unknown.  Patients who do not receive 131I therapy after the second 124I 
PET/CT scan and remain on trametinib may be evaluated with a third Thyrogen-
stimulated 124I PET/CT scan (with the procedure detailed in Section 10.0 for Week 5) 
4 weeks or more after completion of the prior 124I PET/CT scan process.  If the 
lesional dosimetry criteria for 131I therapy is met on the third 124I PET/CT, patients can 
go on to be prepared for/treated with 131I and followed as detailed in Section 10.0 (in 
the calendar under the heading “Study Calendar for PATIENTS WHO RECEIVE RAI 
(Week 5, Day 6 and beyond)” (treatment with 131I is not mandatory).  If the third 124I 
PET/CT scan results do not fulfill the 131I treatment criteria, patients may continue on 
trametinib alone with the evaluations/treatments required for Cohort C.    
• 
The effect of food on trametinib absorption is unknown.  The current recommendation 
is to administer trametinib on an empty stomach, either 1 hr before or 2 hr after a 
meal; the recommendation to administer trametinib fasting may change based on 
emerging data. 
• 
The patient will be requested to maintain a medication diary for each dose of 
medication (Appendix C).  The medication diary will be returned to clinic staff at the 

35 
 
end of each course. 
 
5.1.2 Diagnostic Agent thyrotropin alpha (Thyrogen;Genzyme) 
 
Patients will undergo 124I PET/CT scanning after thyrotropin alpha (Thyrogen;Genzyme Corp., Cambridge, 
MA) 0.9 mg IM daily injections (for two consecutive days) as previously described (Robbins et al., 2002). 
Thyrogen contains a highly purified recombinant form of human thyroid stimulating hormone (TSH), and is 
FDA approved for thyroid dosimetry.  
 
5.1.3 Diagnostic/Therapeutic Agent 131I (RAI) 
 
131I will be used for dosimetry studies and treatment of the patients whose second lesional dosimetry reveals 
iodine incorporation that satisfies the 131I treatment threshold (see Section 5.1.4).  131I has a half-life of 8 days 
and relatively high principal photon energy of 364 keV characterized by beta particle emissions.  It will be 
supplied by MDS Nordion , DraxImage, or International Isotopes. It is administered orally in the form of 
capsules or liquid.  Pregnancy is the only contraindication to radioiodine treatment.  A beta-HCG pregnancy 
test must be performed up to 2 days prior to the administration of 131I.   
 
131I therapeutic dosing will be guided by the whole body and blood dosimetry 
determination of the maximum tolerated activity (MTA): the 131I activity administered 
concomitantly with trametinib is not to exceed the MTA plus 3 mCi (i.e., [131I activity 
administered] < [MTA + 3 mCi]). 
 
5.1.4 Diagnostic Agent 124I PET tracer 
 
Clinical grade 124I was first produced at MSK in the 1950s. It has been produced in MSK 
cyclotrons by bombarding tellurium targets.  It is purified by novel radiochemical 
techniques.  It has been safely used for diagnostic studies in >40 thyroid cancer patients at 
MSK for over 5 years.  Clinical grade 124I will be provided by the MSK cyclotron staff or  
by an outside supplier (Sofie Biosciences (fka IBA Molecular and Zevacor), 3 D Imaging 
LLC, or NCM) who meets MSK’s minimum specifications as stated in our IND.  I-124 
preparation is detailed in MSK held IND # 71343.  Normal organ dosimetry of 124I is 
provided in Appendix D (Note, this is a general guideline for organ dosimetry). 
124I (dose, route, schedule, timing relative to imaging, special precautions or 
procedures, required pre-administration lab parameters): Approximately 6 mCi 
(range 4-7 mCi) of 124I will be administered orally on Day 3 of the lesional dosimetry 
protocol, 2 days prior to PET/CT image acquisition (see Section 10 for the Study 
Calendar).  A beta-HCG pregnancy test must be performed within 2 days prior to the 
administration of 124I. 
 
Image Acquisition/Analysis/Interpretation Details:  Since 124I PET/CT analysis will be 
performed at more than one participating site, before patients are imaged at any site a 
NEMA/IEC body phantom will be imaged and results analyzed under conditions similar 
to those to be used for patients.  The phantom approximates the size and shape of a 
typical adult cross-section and contains six fillable spheres of diameter ranging from 
10mm to 37mm surrounding a central cylindrical compartment containing non-
radioactive lung equivalent material.  The spheres and outer background compartment 
will be filled with 124I of precisely known activity concentration in the ratio of 5:1.  The 

36 
 
activity concentration will be determined from the supplier’s activity measurement 
(recommended activity approximately 150MBq (4mCi)) and a confirming measurement 
in a dose calibrator at the site using an approved calibration setting, followed by careful 
dilution and measurement of residual activities.  Following a scan of sufficient length to 
cover the whole phantom (two bed positions with ten minutes per bed for the phantom, 
patients will need more), data should be reconstructed with appropriate clinical 
parameters for the scanner used.  These should include CT attenuation correction, scatter 
correction, and parameters specific to I124 – 4.18 day half life, 0.23 positron abundance, 
and a cascade gamma correction.  SUV’s and activity concentrations within each sphere, 
the active background, the central lung compartment, and outside the phantom should be 
determined using an appropriate VOI as for a patient.  After applying partial volume 
recovery coefficients appropriate for the scanner used and for the individual sphere size, 
all measurements should match the activity concentrations derived from the dose 
calibrator measurements.  Any discrepancies should be addressed.  The resolution will 
depend on the cause and may involve modification of technique or possibly a correction 
factor.  Raw data, a record of all measurements, procedures and parameters used, and 
results for the phantom study should be forwarded to MSK for review before 
commencing patient imaging. 
 
The 124I PET-CT scan will be performed on a PET/CT scanner at 2 days post-
administration of approximately 6 mCi (range 4-7 mCi) of 124I, the time at which 
maximal uptake of iodide by thyroid tumors generally occurs.  The index lesion (i.e. 
metastatic thyroid tumor) will be identified by radiology co-investigators.  The index 
lesion volume (in milliliters, ml), Vlesion, will be estimated by the CT study performed for 
attenuation correction and anatomic registration as part of the 124I PET-CT scan on the 
PET/CT scanner.  Once reconstructed, and using the commercial image-processing 
software provided on the PET/CT scanner’s computer or a compatible, networked 
workstation, regions of interest (ROIs) circumscribing the index lesion on all contiguous 
CT slices on which the lesion appears will be drawn, yielding Vlesion.  Only lesions on 
the first 124I PET-CT scan that are > 5 mm in length in the minimum diameter will 
be used as the index lesion for this analysis. 
 
Using the PET acquisition and processing parameters routinely used for PET-CT scans at 
the participating sites, the reconstructed PET images will be parameterized, as usual, in 
terms of standard uptake value (SUV) ( Ci measured by PET/g of tissue / Ci 
administered/g of total-body mass).  Using the commercial image-processing software 
provided on the PET/CT scanner’s computer or a compatible workstation, ROIs 
circumscribing the index lesion on all contiguous PET slices on which the lesion appears 
will be drawn, yielding the index lesion mean SUV, 
____
SUVlesion; alternatively, the lesion 
ROIs drawn on the CT scan (see above) may be superimposed on the registered PET  
 
 
images to yield 
____
SUVlesion.  From the definition of the SUV (above), the mean PET-
derived 124I concentration (in  Ci/ml) in the index lesion not corrected for partial-

37 
 
volume-averaging, (
______
[124I A]lesion)RC-uncorrected, will be calculated from 
____
SUVlesion: 
 
 
(
______
[124I A]lesion)RC-uncorrected 
=    
____
SUVlesion AA
MTB  
(1) 
 
where AA is the 124I administered activity (in Ci) and MTB is the patient total-body mass 
(in Ci). 
 
Note that the SUVs provided by the PET scanner are not automatically corrected for 
partial-volume averaging.  Using the CT-derived lesion volume, Vlesion, and the volume 
(V)-dependent recovery coefficient (ie PET-derived activity concentration (in 
 Ci/ml)/actual activity concentration (in  Ci/ml)), RC(V), previously measured for the 
PET/CT scanner, the PET-derived mean 124I concentration (in  Ci/ml) in the index 
lesion not corrected for partial-volume-averaging, (
_____
[124I A]lesion)RC-uncorrected, will be 
corrected to yield the actual mean 124I concentration in the index lesion, (
_____
[124I A]lesion)RC-
corrected: 
 
(
______
[124I A]lesion)RC-corrected 
= 
(
______
[124I A]lesion)RC-uncorrected
 RC(Vlesion)
  
(2) 
 
The mean 124I activity concentration in the index lesion per 124I administered activity (in 
Ci/ml/mCi), (
__________
[124I Aper mCi]lesion)RC-corrected, will then be calculated: 
 
(
__________
[124I Aper mCi]lesion)RC-corrected = (
_____
[124I A]lesion)RC-corrected
AA/1000
  
(3) 
(
__________
[124I Aper mCi]lesion)RC-corrected can be converted to the mean 131I activity concentration in the 
index lesion per 131I administered activity (in Ci/ml/mCi), (
__________
[131I Aper mCi]lesion)RC-corrected, 
131I (and not 124I) being used for therapy: 
 
(
__________
[131I Aper mCi]lesion)RC-corrected = (
__________
[124I Aper mCi]lesion)RC-corrected  e(I124 - I131)timaging 
(4) 
 
where I124 and I131 are the physical decay constants of 124I (0.00693 /h) and 131I 
(0.00359 /h), respectively, and timaging is the time post-administration of PET-CT imaging 
(in h). 
 
 
 
 
Based on prior clinical experience, the biological half-life, Tb, of iodine in metastatic 
thyroid cancer lesions is typically 2 d (= 48 h).  For 131I, with a physical half-life Tp of 

38 
 
8.04 d = 193 h, the effective half-life, Te, of 131I in the index lesion is therefore: 
 
 
Te = 
Tb Tp
 Tb + Tp  
(5a) 
 
 = 
48 h • 193 h
 48 h + 193 h  
(5b) 
 
 = 38.4 h 
(5c) 
 
Assuming, as usual, that the uptake of radioiodine in the index lesion (ie the 24- to 48-h 
uptake value) will be instantaneous and that 131I lesion irradiation will be due exclusively 
to complete local absorption of 131I beta-rays, the mean lesion absorbed dose (in rad/mCi 
131I), 
__________
[131I Dper mCi]lesion, will be: 
 
 
__________
[131I Dper mCi]lesion = 1.44 Te (
__________
[131I Aper mCi]lesion)RC-corrected np 
(6a) 
 
 = 1.44 • 38.4 h (
__________
[131I Aper mCi]lesion)RC-corrected 
 
 
 
0.405 g-rad/Ci-h 
(6b) 
 
 = 22.4 (
__________
[131I Aper mCi]lesion)RC-corrected 
(6c) 
 
where np = 0.405 g-rad/Ci-h is the equilibrium dose constant for non-penetrating 
radiations (ie beta-rays) for 131I. 
 
Finally, the 131I administered activity (in mCi) required to deliver the stipulated mean 
absorbed dose of 2,000 rad to the index lesion, 131I AA2000 rad→lesion, will be: 
 
 
131I AA2000 rad→lesion = 2,000 rad/[131I Dper mci]lesion 
(7) 
 
If the projected 131I AA2000 rad→lesion is reasonable (< 300 mCi), the treating physican(s) 
will confer and make a clinical decision as to whether 131I therapy should proceed.  If the 
decision is made to proceed to therapy, the patient will undergo the standard-of-care (ie 
non-investigational) “whole body and blood dosimetry” to determine the maximum 
tolerated activity (MTA).  131I therapeutic dosing will be guided by the whole body and 
blood dosimetry determination of the maximum tolerated activity (MTA): the 131I activity 
administered concomitantly with trametinib is not to exceed the MTA plus 3 mCi (i.e., 
[131I activity administered] < [MTA + 3 mCi]). 
 
The foregoing analysis will have to be performed only for the second 124I administration. 
 
 
 
5.2 
General Concomitant Medication and Supportive Care Guidelines 
 
Patients will have to adhere to a low iodine diet 5 days prior to the initiation of the lesional 
dosimetry process and continued until the completion of that process.  For those patients who 

39 
 
will go on to receive therapeutic 131I, they will need to be continued on the low iodine diet 
through 1 day after 131I administration.  For details of the suggested low iodine diet, please see 
Appendix B.   
 
5.3 
Duration of Therapy 
 
In the absence of treatment delays due to adverse event(s), treatment may continue until one of 
the following criteria applies: 
 
1. Disease progression (however, Cohort A and B patients with evidence of clinical disease 
progression or RECIST v1.1 radiographic progression (such as on the 124I PET/CTs or 
other scans) prior to the 6-month evaluation of the primary/secondary endpoints may be 
continued on treatment and the study if the treating physician deems it clinically 
reasonable),  
 
2. Intercurrent illness that prevents further administration of treatment, 
 
3. Unacceptable adverse event(s), 
 
4. Patient decides to withdraw from the study,  
 
5. General or specific changes in the patient's condition render the patient unacceptable for 
further treatment in the judgment of the investigator, 
 
6. (For Cohort A and B patients) It is determined that a patient will not receive therapeutic 
131I and the treating physician determines that it is not clinically reasonable to continue 
with trametinib therapy alone or the patient does not want to continue with trametinib 
therapy alone,    
 
7. For patients who do receive therapeutic 131I, trametinib will be continued until 2 days 
after 131I is administered.  Patients will remain on study for tumor assessments that will 
be completed approximately 6 months after 131I therapy.  Safety monitoring for 
trametinib related toxicities will be continued until 30 days after last trametinib dose. 
 
8. All study therapy has been completed as planned. 
 
5.4 
Duration of Follow Up 
 
Adverse events will be followed for 30 days after the last dose of trametinib.  Patients removed 
from study for unacceptable adverse event(s) will be followed until resolution or stabilization of 
the adverse event. 
 
5.5 
Criteria for Removal from Study 
 
Patients will be removed from the study when criteria numbers 2-8 in Section 5.3 apply or if the 
following criteria apply:   
 

40 
 
• 
Progression of disease on Cohort C, 
 
• 
Progression of disease on Cohort A or B and the patient will not be continuing to 
Cohort C (exceptions to this for Cohorts A and B are detailed in the Section 5.3), 
 
• 
The patient is started on another therapy for his/her thyroid cancer besides what is 
detailed as allowed in this protocol 
 
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 QD 
-1 
1.5 mg QD 
-2 
1 mg QD 
 
A maximum of two trametinib dose level reductions are allowed.  If a third dose level reduction 
is required, treatment will be permanently discontinued.  In order to ensure that patients have 
taken trametinib for a minimum of 7 consecutive days, missed doses may be made up (as per 
Section 5.1.1) and study assessments/treatments appropriately rescheduled.  If trametinib is 
missed for > 7 days or interruptions in trametinib dosing have occurred prior to whole body and 
blood dosimetry and 131I (RAI) treatment, then having some or all of the doses made up and the 
study assessments/treatments appropriately rescheduled may be considered after discussion with 
the MSK Principal Investigator (this is not a requirement) (as per Section 5.1.1).  
  
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 v4 
Grade 
Management Guideline 
Dose Modification 
Grade 1 
Monitor as clinically indicated.  
Provide supportive care 
according to institutional 
standards 
Continue trametinib at current dose level. 
Grade 2 
Continue trametinib at current dose level.  If intolerable, 
interrupting treatment may be considered only after 
discussion with the Principal Investigator.  For patients who 
have trametinib held for grade 2 toxicities, trametinib may be 
restarted at the same dose or with one level of dose reduction. 

41 
 
Trametinib Treatment Modification for Clinically Significant Toxicities Deemed Related to Trametinib 
(This section is not for specific AEs such as hypertension, rash, ejection fraction changes, pneumonitis, diarrhea, 
liver chemistry, QTc prolongation, or visual changes.  Refer to other sections for these specific AEs). 
CTCAE v4 
Grade 
Management Guideline 
Dose Modification 
Grade 3 
• Interrupt treatment until resolution to grade 1 or baseline*. 
• Upon resolution to baseline or grade 1, restart with one 
level of dose reduction*. 
• If the Grade 3 toxicity recurs, interrupt trametinib. When 
toxicity resolves to Grade 1 or baseline, restart trametinib 
reduced by another dose level 
Grade 4 
Permanently discontinue trametinib.** 
Trametinib should be discontinued if treatment delay is > 21 days due to toxicities.  If the investigator concludes 
that continued trametinib will benefit a patient, the study chair (MSK PI) and CTEP Medical Monitor, may be 
consulted for the possibility of resuming trametinib, provided that toxicities have resolved to baseline or grade 1.  
*For non-life threatening Grade 3 laboratory abnormalities, trametinib may be continued at the same dose without 
interruption if deemed appropriate by the MSK Principal Investigator.  
**For Grade 4 lymphopenia, study treatment may be continued at the same dose level without interruption based 
upon investigator judgment. 
 
6.1.2 Trametinib Dose Modification for Rash 
 
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 
MSK Principal Investigator or the CTEP Medical Monitor, through MSK, 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 when 
exposed to sunlight. 
• Use thick, alcohol-free emollient cream (e.g., glycerine and cetomacrogol 
cream) on dry areas of the body at least twice daily. 
• Use mild-strength topical steroid (hydrocortisone 1% cream) or topical 
antibiotic (e.g., clindamycin) (should be applied at least twice daily 
starting on Day 1 of study treatment to areas such as face, chest, and upper 
back) or oral antibiotics (e.g., doxycycline 100 mg BID, minocycline 100 
mg BID). 

42 
 
Guidelines for Supportive Care of Rash 
Type of Care 
Action 
Symptomatic Careb 
 
• Pruritic lesions:  Cool compresses and oral antihistamine therapies. 
• Fissuring lesions:  Monsel’s solution, silver nitrate, or zinc oxide cream. 
• Desquamation:  Thick emollients and mild soap. 
• Paronychia:  Antiseptic bath, local potent corticosteroids in addition to 
antibiotics; if no improvement, consult dermatologist or surgeon. 
• Infected lesions:  Appropriate bacterial/fungal culture-driven systemic or 
topical antibiotics. 
a Rash prophylaxis is recommended for the first 6 weeks of study treatment. 
b Patients who develop rash/skin toxicities should be seen by a qualified physician and should receive evaluation 
for symptomatic/supportive care management. 
 
 
 
Trametinib Dose Modification Guidelines and Management for Rash Deemed Related to Trametinib 
Rash Severity 
Management Guideline 
Dose Modification 
Grade 1 
 
• Initiate prophylactic and 
symptomatic treatment measures.1 
• Use moderate strength topical 
steroid.2 
• Continue trametinib. 
Grade 2 
 
• Initiate prophylactic and 
symptomatic treatment measures.1 
• Use moderate strength topical 
steroid.2 
• Reassess after 2 weeks. 
 
• Continue trametinib. 
• If the rash is intolerable, trametinib may be 
interrupted until recovery to ≤ grade 1 or continued at 
a one dose level reduction after discussion with the 
MSK Principal Investigator.   
• If trametinib is interrupted, once rash recovers to ≤ 
grade 1, trametinib may be restarted at the original 
dose or at a one dose level reduction. 
• If trametinib was continued at a one dose level 
without treatment interruption and the rash recovers 
to ≤ grade 1 within 2 weeks, increasing the dose to 
previous dose level is permitted. 
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 at the original dose or 
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. 
* If grade 3 rash develops without optimal supportive care management and is considered tolerable, the treating 
physician may elect to continue trametinib while initiating optimal supportive care management.  
 
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 

43 
 
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]).  For events of visual changes regardless of severity but for which 
an ophthalmic examination is conducted, a blood sample for PK analysis is encouraged when 
feasible, and the blood sample should be drawn as close as possible to the time of the event. 
 
 
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. 
 
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. 
 

44 
 
 
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 
 
 
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 may include concomitant medications (e.g., stool 
softeners, laxatives, antacids, etc.), infections by C. difficile or other pathogens, or partial bowel 
obstruction.  Those conditions should be excluded. 
 
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 Deemed Related to Trametinib 
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 hours:  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 and 
intolerable, interrupt trametinib 
until diarrhea resolves to grade ≤1. 
• If there is an interruption in dosing, 
trametinib can be continued at the 
same dose level when treatment is 
restarted. 
 

45 
 
Management and Trametinib Dose Modification Guidelines for Diarrhea Deemed Related to Trametinib 
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 >21 
days, discontinue trametinib. 
1.  Uncomplicated diarrhea defined by the absence of symptoms such as vomiting ≥ grade 2, pyrexia, sepsis, 
neutropenia ≥ grade 3, frank bleeding, and/or dehydration requiring intravenous fluid substitution (the 
administration of fluids alone can still be considered ‘uncomplicated diarrhea’ if judged by the investigator as 
appropriate). 
2.  Complicated diarrhea defined by the presence of symptoms such as vomiting  ≥ grade 2, pyrexia, sepsis, 
neutropenia ≥ grade 3, frank bleeding, and/or dehydration requiring intravenous fluid substitution (the 
administration of fluids alone can still be considered ‘uncomplicated diarrhea’ if judged by the investigator as 
appropriate). 
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 Deemed Related to Trametinib 
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). 

46 
 
Trametinib Dose Modification for Liver Function Test Abnormalities Deemed Related to Trametinib 
Event 
Treatment modifications and assessment/monitoring 
Criteria for discontinuing study 
drug:  When any of the liver 
stopping  criteria below is met, 
discontinue trametinib  
 
1. ALT ≥3xULN and bilirubin ≥2x 
ULN  or >35% direct bilirubin 1, 2 
2. ALT  3xULN and INR >1.5, if 
INR measured2  (INR threshold 
does not apply if subject is on 
anticoagulant) 
3. ALT ≥5x ULN 
4. ALT ≥3x ULN persists for 4 
weeks 
5. ALT ≥3x ULN and cannot be 
monitored weekly for 4 weeks 
6. ALT  ≥3x ULN associated with 
symptoms3  (new or worsening) 
believed to be related to  liver 
injury or hypersensitivity 
 
 
• Immediately discontinue study treatment. 
• Do not restart/rechallenge unless approved by CTEP trametinib medical 
monitor.  [ 
• Report as SAE if:  1) CTEP-AERS reporting criteria are met, or 2) 
patients meet criteria 1-2. 
• Perform liver event ASSESSMENT AND WORKUP (see below). 
• Monitor the subject until liver chemistries resolve, stabilize, or return to 
baseline (see MONITORING below). 
[ 
 
MONITORING: 
In patients stopping for criteria 1-2 (with abnormal TB and INR, indicating 
potentially more significant liver toxicities): 
• Repeat liver chemistries (ALT, AST, ALK, bilirubin) and perform liver 
event follow-up assessments within 24 hours. 
• Monitor subjects twice weekly until LFT return to normal/baseline or 
stabilize. 
• A specialist or hepatology consultation is recommended. 
In patients stopping for criteria 2-6: 
• Repeat LFT and perform liver event follow up assessments within  24-72 
hrs  
• Monitor subjects weekly until LFTs return to normal/baseline or stabilize. 
 
ASSESSMENT and WORKUP: 
• Viral hepatitis serology.4 
• If possible, obtain blood sample for PK analysis.5 
• CPK and LDH. 
• Fractionate bilirubin, if total bilirubin ≥2x ULN. 
• CBC with differential to assess eosinophilia. 
• Record clinical symptoms of liver injury, or hypersensitivity on AE CRF. 
• Record concomitant medications (including acetaminophen, herbal 
remedies, other over the counter medications). 
• Record alcohol use. 
Additional work up for patient stopping for criteria 1-2 (with abnormal TB 
and INR, indicating potentially more significant liver toxicities): 
• Anti-nuclear antibody, anti-smooth muscle antibody, Type 1 anti-liver 
kidney microsomal antibodies, and quantitative total immunoglobulin G 
(IgG or gamma globulins). 
• acetaminophen adduct HPLC assay (in subjects with likely 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 bilirubin fractionation should be performed if testing is available. If bilirubin fractionation testing is unavailable, 
record presence of detectable urinary bilirubin on dipstick, which indicates direct bilirubin elevations and 
suggesting liver injury. 
2.  All events of ALT ≥3xULN and bilirubin ≥2xULN (>35% direct bilirubin) or ALT 3x ULN and INR >1.5 (if 
INR measured) may indicate severe liver injury (possible “Hy’s Law”).  INR measurement is not required, and the 
threshold value stated will not apply to subjects receiving anticoagulants. 

47 
 
Trametinib Dose Modification for Liver Function Test Abnormalities Deemed Related to Trametinib 
Event 
Treatment modifications and assessment/monitoring 
3.  New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia) 
4.  Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); 
Hepatitis C RNA; Cytomegalovirus IgM antibody;  Epstein-Barr viral capsid antigen IgM antibody (or if 
unavailable, obtain heterophile antibody or monospot testing);  Hepatitis E IgM antibody  
5.  PK sample is desired if feasible.  Record the date/time of the PK blood sample draw and the date/time of the 
last dose of study treatment prior to blood sample draw on the CRF. If the date or time of the last dose is unclear, 
provide the subject’s best approximation. If the date/time of the last dose cannot be approximated OR a PK sample 
cannot be collected in the time period indicated above, do not obtain a PK sample.   
6.  If hepatitis delta antibody assay cannot be performed, it can be replaced with a PCR of hepatitis D RNA virus 
(where needed) (Le Gal et al., 2005). 
 
 
6.1.6 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 table below. 
 
 
 
Guidelines for Trametinib Dose Modifications for Pneumonitis Deemed Related to Trametinib 
CTCAE Grade 
Adverse Event Management 
Action and Dose Modification 
Grade 1 
• CT scan (high-resolution with lung windows) 
recommended. 
• Work-up for infection. 
• Monitoring of oxygenation via pulse-oximetry 
recommended. 
•  Consultation with pulmonologist recommended. 
Continue trametinib at current dose. 
Grade 2 
• CT scan (high-resolution with lung windows). 
• Work-up for infection. 
• Consult pulmonologist. 
• Pulmonary function tests:  If < normal, repeat every 8 
weeks until ≥ normal. 
• Bronchoscopy with biopsy and/or BAL 
recommended. 
• Symptomatic therapy including corticosteroids if 
clinically indicated. 
• Interrupt trametinib until recovery 
to grade ≤1. 
• If AE resolved to grade ≤1 and 
relationship to trametinib is 
equivocal, restarting trametinib 
with one dose reduction may be 
considered, after discussion with 
the medical monitor.   
• If treatment delay is > 4 weeks, 
permanently discontinue 
trametinib. 

48 
 
Guidelines for Trametinib Dose Modifications for Pneumonitis Deemed Related to Trametinib 
CTCAE Grade 
Adverse Event Management 
Action and Dose Modification 
Grade 3 
• CT scan (high-resolution with lung windows). 
• Work-up for infection. 
• Consult pulmonologist. 
• Pulmonary function tests-if < normal, repeat every 8 
weeks until ≥ normal. 
• Bronchoscopy with biopsy and/or BAL if possible. 
• Symptomatic therapy including corticosteroids as 
clinically indicated. 
• Interrupt trametinib until recovery 
to grade ≤1. 
• If AE resolved to grade ≤1 and 
relationship to trametinib is 
equivocal, restarting trametinib 
with one dose reduction may be 
considered, after discussion with 
the medical monitor.   
• If treatment delay is >4 weeks, 
permanently discontinue 
trametinib. 
Grade 4 
Same as grade 3. 
Permanently discontinue 
trametinib. 
Abbreviations:  BAL = bronchoalveolar lavage; CT = computed tomography. 
 
6.1.7 Trametinib Dose Modification for Reduced Left Ventricular Ejection Fraction 
 
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 Deemed Related to 
Trametinib 
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 

49 
 
Trametinib Dose Modification Guidelines and Stopping Criteria for LVEF Decrease Deemed Related to 
Trametinib 
Clinic 
LVEF-drop (%) or 
CTCAE grade 
Action and Dose 
Modification 
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 
 
Trametinib Withholding and Stopping Criteria for QTc Prolongation Deemed Related to Trametinib 
QTc Prolongationa 
Action and Dose Modification 
• 
QTcB ≥501 msec, or 
• 
Uncorrected QT >600 msec, 
or 
• 
QTcB >530 msec for subjects 
with bundle branch block 
 
• Interrupt study treatment until QTcB prolongation resolves to grade 1 or 
baseline. 
• Test potassium, calcium, phosphorus, and magnesium.  If abnormal, 
correct per routine clinical practice to within normal limits. 
• Review concomitant medication usage for a prolonged QTc. 
• Restart at current dose 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. 

50 
 
• 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. 
 
Management and Trametinib Dose Modification for Hypertension Deemed Related to Trametinib 
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. 

51 
 
Management and Trametinib Dose Modification for Hypertension Deemed Related to Trametinib 
Event 
Management Guideline 
Dose Modification 
(Scenario B) 
• Asymptomatic SBP ≥160 mmHg, 
or DBP ≥100 mmHg,  
or 
Failure to achieve well-controlled BP 
within 2 weeks in Scenario A. 
• Adjust current or initiate new 
antihypertensive medication(s). 
• Titrate antihypertensive 
medication(s) during the next 2 
weeks to achieve well-controlled 
BP. 
• Interrupt trametinib if clinically 
indicated. 
• Once BP is well-controlled, restart 
trametinib reduced by one dose 
level.a 
(Scenario C) 
• Symptomatic hypertension  
or 
Persistent SBP ≥160 mmHg, or DBP 
≥100 mmHg, despite 
antihypertensive medication and 
dose reduction of trametinib 
• Adjust current or initiate new 
antihypertensive medication(s). 
• Titrate antihypertensive 
medication(s) during the next 2 
weeks to achieve well-controlled 
BP. 
• Referral to a specialist for further 
evaluation and follow-up is 
recommended. 
• Interrupt trametinib. 
• Once BP is well-controlled, restart 
trametinib reduced by one dose 
level.a 
(Scenario D) 
Refractory hypertension 
unresponsive to above interventions 
or hypertensive crisis. 
Continue follow-up per protocol. 
Permanently discontinue 
trametinib. 
a. Escalation of trametinib to previous dose level can be considered if BPs remain well controlled for 4 weeks 
after restarting of trametinib.  Approval from 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 and the characteristics of an observed AE (Section 7.2) will determine 
whether the event requires expedited reporting (via CTEP-AERS) in addition to routine 
reporting.   
 
7.1 
Comprehensive Adverse Events and Potential Risks List (CAEPR) 
 
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 of AEs, 
the Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column 
and is identified with bold and italicized text.  The SPEER is a list of events that are protocol-
specific exceptions to expedited reporting to NCI via CTEP-AERS (except as noted below).  
Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTEP-
AERS_Training_Guide.pdf for further clarification.  
 
NOTE:  The highest grade currently reported is noted in parentheses next to the AE in the 
SPEER.  Report ONLY AEs higher than this grade expeditiously via CTEP-AERS.  If this 
CAEPR is part of a combination protocol using multiple investigational agents and has an AE 

52 
 
listed on different SPEERs, use the lower of the grades to determine if expedited reporting is 
required. 
 
7.1.1 
CAEPRs for CTEP IND Agent 
 
7.1.1.1 
CAEPR for Trametinib 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
Trametinib (GSK1120212B, NSC 763093) 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system. In addition to the comprehensive list, a subset, the 
Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column and 
is identified with bold and italicized text. This subset of AEs (SPEER) is a list of events that are 
protocol specific exceptions to expedited reporting to NCI (except as noted below). Refer to the 
'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for 
further clarification. Frequency is provided based on 1111 patients. Below is the CAEPR for 
Trametinib (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) 
  

53 
 
 
 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%) 
 
 
Eye disorders - Other (visual 
disorders)2 
 
  
 
 
Papilledema 
  
 
Periorbital edema 
 
  
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
 Abdominal pain (Gr 2) 
 
 
Colitis 
  
 
 
Colonic perforation 
  
 
Constipation 
 
 Constipation (Gr 2) 
Diarrhea 
 
 
 Diarrhea (Gr 3) 
 
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 
  

54 
 
 
 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%) 
 
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
 Dizziness (Gr 2) 
 
Headache 
 
 Headache (Gr 2) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
 Cough (Gr 2) 
 
Dyspnea 
 
 Dyspnea (Gr 3) 
 
 
Pneumonitis 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Alopecia 
 
 Alopecia (Gr 2) 
 
Dry skin 
 
 Dry skin (Gr 2) 
 
Nail changes 
 
  
 
 
Palmar-plantar 
erythrodysesthesia syndrome 
  
 
Pruritus 
 
 Pruritus (Gr 2) 
 
 
Skin and subcutaneous tissue 
disorders - Other (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. 
 
6Stevens-Johnson syndrome has been observed in patients treated with trametinib and dabrafenib 

55 
 
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 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 

56 
 
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. 
 
 
 
7.1.2 Adverse Event List for thyrotropin alpha (Thyrogen) 
 
Potential side effects include nausea, vomiting, headache, fatigue, and flu-like symptoms.  
Thyrogen can also cause rapid enlargement of thyroid tumors and cause local tumor-
related symptoms.  For a comprehensive list of Thyrogen-related adverse events, please 
review the package insert. 
 
7.1.3 Adverse Event List for 131I 
 
Early side effects (may develop immediately or during the first days after RAI treatment): 
In 10-20% patients, painful swelling of the remnant thyroid tissue or metastases occur. 
Nausea or vomiting may occur due to radiation induced gastritis. In some patients 
salivary complications like salivary gland pain, swelling, altered taste, epiphora, change 
in the taste or smell occurs. In two-thirds of patients, transient and non-clinically 
significant decrease in thrombocytes and leukocytes may develop.  
 
Late side effects (may develop weeks, months or even years after radioiodine therapy): 
The most frequent late side effect is related to decreased salivary gland function. In 
approximately 5%, thrombocytopenia and leukopenia may develop. In approximately 1-
2% of patients, leukemia or bone marrow aplasia may occur especially with cumulative 
doses of 131I. Pulmonary fibrosis can develop in patients with iodine avid lung metastases 
in whom a delivered activity exceed the maximum tolerable activity determined by 
dosimetry. The females of childbearing age should avoid pregnancy for 6-12 months after 
RAI therapy. In males, transient elevation of follicle stimulated hormone (FSH) 
following 131I therapy may occur. In very rare case, persistent gonadal dysfunction i.e 
azoospermia may occur. 
 
7.1.4 
Adverse Event List for 124I 
 
There is no anticipated side effect of low-dose (approximately 6 mCi (range 4-7 mCi)) 
oral 124I based on data from MSK experience.  
 
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 (investigators may continue 

57 
 
to collect and locally store AE data in CTCAE v4.0).  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:   
o AEs for the agent that are bold and italicized in the CAEPR (i.e., those listed in the 
SPEER column, Section 7.1.1.1) should be reported through CTEP-AERS only if the 
grade is above the grade provided in the SPEER. 
o Other AEs for the protocol that do not require expedited reporting are outlined in 
section 7.3.4. 
 
• Attribution of the AE: 
o Definite – The AE is clearly related to the study treatment. 
o Probable – The AE is likely related to the study treatment. 
o Possible – The AE may be related to the study treatment. 
o Unlikely – The AE is doubtfully related to the study treatment. 
o Unrelated – The AE is clearly NOT related to the study treatment. 
 
7.3 
Expedited Adverse Event Reporting 
 
7.3.1    Expedited AE reporting for this study must use CTEP-AERS (Adverse Event Expedited  
            Reporting System), accessed via the CTEP Web site http://ctep.cancer.gov).  The  
            reporting procedures to be followed are presented in the “NCI Guidelines for 
            Investigators: Adverse Event Reporting Requirements for DCTD (CTEP and CIP) and  
            DCP INDs and IDEs” which can be downloaded from the CTEP Web site  
            (http://ctep.cancer.gov).  These requirements are briefly outlined in the tables below  
            (Section 7.3.3). 
 
In the rare occurrence when Internet connectivity is lost, a 24-hour notification is to be 
made to CTEP by telephone at (301) 897-7497.  Once Internet connectivity is restored, 
the 24-hour notification phoned in must be entered electronically into CTEP-AERS by 
the original submitter at the site. 
 
For protocols with CAEPRs not including a “SPEER” category, protocol-specific 
exceptions to the CTEP-AERs reporting table can be found in the CAEPR’s “ASAEL” 
category instead. This protocol-specific exception is limited to Grade 1 and Grade 2 
ASAEL events, i.e. Grade 3 through Grade 5 ASAEL-listed events are NOT exceptions 
to CTEP-AERS reporting 
 
7.3.2    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  

58 
 
            causality, unless as noted below.  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 
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 viaCTEP-
AERS within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 
Calendar Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
10 Calendar Days 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific 
Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR 
Expedited AE reporting timelines are defined as: 
o 
“24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 hours of learning 
of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour report. 
o 
“10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 calendar days of 
learning of the AE. 

59 
 
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 
 
7.3.3  Additional Protocol-Specific Expedited Adverse Event Reporting Exclusions 
 
          The reporting window for expedited adverse events begins on Week 1 Day 1.Any serious      
          adverse event occurring prior to Week 1 Day 1 is excluded from CTEP-AERs reporting. 
 
7.4 
Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions.  AEs reported through 
CTEP-AERS must also be reported in routine study data submissions. 
 
7.5 
Secondary Malignancy 
 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm.  
 
CTEP requires all secondary malignancies that occur following treatment with an agent under an 
NCI IND/IDE be reported via CTEP-AERS. Three options are available to describe the event:  
 
• Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia 
[AML])  
• Myelodysplastic syndrome (MDS)  
• Treatment-related secondary malignancy  
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the routine reporting mechanisms outlined in each protocol.  
 
 
7.6 
Second Malignancy 
 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy).  Second malignancies require ONLY routine reporting 
via CDUS unless otherwise specified.  
 

60 
 
7.7 
Serious Adverse Event (SAE) Reporting for MSK Patients Only 
 
Any SAE must be reported to the IRB/PB as soon as possible but no later than 5 calendar days. 
The IRB/PB requires a Clinical Research Database (CRDB) SAE report be submitted 
electronically to the SAE Office at sae@mskcc.org.  The report should contain the following 
information: 
 
Fields populated from CRDB: 
• 
Subject’s name (generate the report with only initials if it will be sent outside of     
        MSK) 
• 
Medical record number 
• 
Disease/histology (if applicable) 
• 
Protocol number and title 
Data needing to be entered: 
• 
The date the adverse event occurred 
• 
The adverse event 
• 
Relationship of the adverse event to the treatment (drug, device, or intervention) 
• 
If the AE was expected 
• 
The severity of the AE 
• 
The intervention 
• 
Detailed text that includes the following 
o An explanation of how the AE was handled 
o A description of the subject’s condition 
o Indication if the subject remains on the study 
o If an amendment will need to be made to the protocol and/or consent form. 
The PI’s signature and the date it was signed are required on the completed report. 
 
Hospitalization or prolonged hospitalization for scheduled therapy (eg. I-131 therapy) of the 
target disease of the study will not require adverse event reporting. 
 
8. 
PHARMACEUTICAL AND/OR IMAGING AGENT 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) 
 
8.1.1 Trametinib dimethyl sulfoxide (GSK1120212B) (NSC 763093) Commercially labeled. 
 
Chemical Name (IUPAC): equimolecular combination of acetamide, N-[3-[3-cyclopropyl-5-[(2-
fluoro-4-iodophenyl)amino]-3,4,6,7-tetrahydro6,8-dimethyl- 2,4,7-trioxopyrido[4,3-

61 
 
d]pyrimidin-1(2H)-yl]phenyl] with 1,1’-sulfinylbis[methane] 
 
Other Names: trametinib, GSK1120212, JTP-74057, JTP-78296, JTP-75303, Mekinist 
 
CAS Registry Number: 1187431-43-1 
 
Classification: MEK inhibitor 
 
Molecular Formula:  C26H23FIN5O4  •  C2H6OS 
M.W.: 693.53  
 
 
 
 
 
 
 
 
 
Approximate Solubility: Trametinib dimethyl sulfoxide is almost insoluble in water (<0.0001 
mg/mL at 25° C) 
 
Mode of Action: Trametinib dimethyl sulfoxide is a reversible, highly selective, allosteric 
inhibitor of mitogen-activated extracellular signal regulated kinase 1 (MEK1) and MEK2. 
Tumor cells commonly have hyperactivated extracellular signal-related kinase (ERK) 
pathways in which MEK is a critical component. Trametinib dimethyl sulfoxide inhibits 
activation of MEK by RAF kinases and MEK kinases. 
 
Description:  Trametinib dimethyl sulfoxide is a white to almost white powder. 
 
• How Supplied: Novartis supplies and CTEP, NCI, DCTD distributes trametinib as 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 or repackage tablets or remove desiccant. Bottles should be protected from 
light and moisture. 
 
If a storage temperature excursion is identified, promptly return trametinib to 2°C -
8°C and quarantine the supplies.  Provide a detailed report of the excursion (including 
documentation of temperature monitoring and duration of the excursion) to 
PMBAfterHours@mail.nih.gov for determination of suitability. 
 
 

62 
 
• 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). M5 is eliminated by 
CYP3A4 and other pathways, presenting the clinically relevant, albeit low, potential for 
drug-drug interaction. Trametinib is a substrate for P-gp and BSEP, but this is not 
expected to be clinically relevant due to trametinib’s high permeability. 
 
Trametinib dimethyl sulfoxide is an in vitro inhibitor of CYP 2C8, and is anticipated to 
have overall low potential for drug interactions as a perpetrator. It is also a weak 
CYP3A4 inducer and expected to have little clinical effect on sensitive substrates. 
Trametinib is not an inhibitor of CYP 1A2, 2A6, 2B6, 2C9, 2C19, 2D6 and 3A4 and not 
an inhibitor of P-gp, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, OCT2 MRP2 and 
MATE1.  
 
Patient Care Implications: Advise women study participants of reproductive potential to use 
effective contraception while receiving study treatment and for 4 months after the last 
dose of trametinib. Refer to the protocol document for specific guidance. 
 
8.1.2 
Agent Ordering and Agent Accountability 
 
8.1.2.1 
NCI-supplied agents may be requested by the responsible 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), NCI Biosketch, Agent Shipment 
From, and Financial Disclosure Form (FDF).  If there are several participating investigators at one 
institution, CTEP-supplied investigational agents for the study should be ordered under the name of 
one lead investigator at that institution. 
 
Agent may be requested electronically to PMB. Active CTEP-registered investigators 
and investigator-designated shipping designees and ordering designees can submit 
agent requests through the PMB Online Agent Order Processing (OAOP) application 
(https://eapps-ctep.nci.nih.gov/OAOP/pages/login.jspx).  Access to OAOP requires 
the establishment of a CTEP Identity and Access Management (IAM) account 
(https://ctepcore.nci.nih.gov/iam) and the maintenance of an “active” account status 
and a “current” password.  For questions about drug orders, transfers, returns, or 
accountability, call (240) 276-6575 Monday through Friday between 8:30 am and 

63 
 
4:30 pm (ET) or email PMBAfterHours@mail.nih.gov anytime. 
 
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 PMB using the appropriate Investigational Agent (Drug) (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 
Investigator Brochure Availability: The current versions of the IBs for PMB-supplied agents will be 
accessible to site investigators and research staff through the PMB Online Agent Order Processing 
(OAOP) application. Access to OAOP requires the establishment of a CTEP Identity and Access 
Management (IAM) account and the maintenance of an “active” account status and a “current” 
password. Questions about IB access may be directed to the PMB IB coordinator at 
IBCoordinator@mail.nih.gov.  
 
8.2 
Other Investigational Agent(s) 
 
8.2.1 Sodium iodide-124  
 
 
Molecular Formula: Na 124I  
 
 
Molecular Weight: 147 g/mol 
 
 
Half-Life: 4.18 days 
 
 
Formation Reaction: 124TE (p,n) 124I 
 
Supplier: Sofie Biosciences (fka IBA Molecular and Zevacor), 3 D Imaging LLC, 
MSK cyclotron staff, or NCM 
 
Solution preparation: The solution for oral administration is formulated by adding 
approximately 5 mCi of sodium iodide-124 suspended in a solution 0.1 N sodium 
phosphate buffer to 3-5 mL of 0.2% disodium EDTA in water for injection.  An 
aliquot of the sodium iodide-124 solution is added to an oral solution formulation 
consisting of 2 mg/mL disodium EDTA in purified water, USP.  A total of 3-5 mL of 
oral solution is prepared.  The sodium iodide-124 is diluted with not more than 5 mL 
of oral solution contained within a sterile glass vial fitted with a septum and 
aluminum crimp sealing ring.  The finished product is measured.  One unit should 
contain 6 mCi (range 4-7 mCi) per dose. 
 
Storage requirements/Stability: Sodium iodide-124 has a half-life of 4.2 days.  
Sodium iodide bulk material will be chemically processed for iodine-124 recovery 
within 72 hours of the end of bombardment.  The formulated sodium iodide solution 
will be used within 8 hours of formulation. 
 
Route of administration:  Administered orally. 
 
 

64 
 
 
8.3 
Commercial Agent(s) 
 
8.3.1 Thyrotropin alpha (Thyrogen)  
 
Product description:  Thyrogen
® 
(thyrotropin alfa for injection) (Genzyme)is a highly purified 
recombinant form of human thyroid stimulating hormone (TSH), a glycoprotein which is 
produced by recombinant DNA technology. Thyrotropin alfa is synthesized in a genetically 
modified Chinese hamster ovary cell line. 
 
Thyrotropin alfa is a heterodimeric glycoprotein comprised of two non-covalently linked 
subunits, an alpha subunit of 92 amino acid residues containing two N-linked glycosylation sites 
and a beta subunit of 118 residues containing one N-linked glycosylation site. The amino acid 
sequence of thyrotropin alfa is identical to that of human pituitary thyroid stimulating hormone.  
Both thyrotropin alfa and naturally occurring human pituitary thyroid stimulating hormone are 
synthesized as a mixture of glycosylation variants. Unlike pituitary TSH, which is secreted as a 
mixture of sialylated and sulfated forms, thyrotropin alfa is sialylated but not sulfated. The 
biological activity of thyrotropin alfa is determined by a cell-based bioassay. In this assay, cells 
expressing a functional TSH receptor and a cAMP-responsive element coupled to a heterologous 
reporter gene, luciferase, enable the measurement of rhTSH activity by measuring the luciferase 
response. The specific activity of thyrotropin alfa is determined relative to an internal Genzyme 
reference standard that was calibrated against the World Health Organization (WHO) human 
TSH reference standard.  
Thyrogen is supplied as a sterile, non-pyrogenic, white to off-white lyophilized product, intended 
for intramuscular (IM) administration after reconstitution with Sterile Water for Injection, USP. 
Each vial of Thyrogen contains 1.1 mg thyrotropin alfa, 36 mg Mannitol,5.1 mg Sodium 
Phosphate, and 2.4 mg Sodium Chloride.  
After reconstitution with 1.2 mL of Sterile Water for Injection, USP, the thyrotropin alfa 
concentration is 0.9 mg/mL. The pH of the reconstituted solution is approximately 7.0.  
 
Solution preparation:  Please refer to the package insert for standard preparation instructions. 
 
Route of administration:  Thyrogen is administered as an intramuscular injection after 
reconstitution with Sterile Water for Injection, USP. 
 
8.3.2 131I  
 
Product description:  131I will be used for dosimetry studies and treatment of the patients whose second lesional 
dosimetry reveals iodine incorporation that satisfies the 131I treatment threshold (see Section 5.1.3).  131I has a half-
life of 8 days and relatively high principal photon energy of 364 keV characterized by beta particle emissions.  It is 
supplied by MDS Nordion, DraxImage, or International Isotopes. It is administered orally in the form of capsules or 
liquid.  Pregnancy is the only contraindication to radioiodine treatment.  A beta-HCG pregnancy test must be 
performed up to 2 days prior to the administration of 131I.   
 
Route of administration:  Oral 

65 
 
 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
9.1 
Biomarker Studies  
 
9.1.1 Genomic studies for enrolled patients: (To be performed by Dr. James Fagin’s  MSK Human Oncology and 
Pathogenesis Program, HOPP laboratory) Beyond the RAS and BRAF mutation testing that will be done in a CLIA 
lab for eligibility assessment, further genetic characterization may be performed upon submitted tissues.  
Specifically, testing for RET and PAX8-PPARG rearrangements would be of interest for the BRAF/RAS WT patients.  
The genomic technology utilized to analyze these and other genetic alterations will be determined by platform and 
funding availability.  Potential approaches may include next generation sequencing platforms to analyze select 
genes/exons or whole exome/whole genome sequencing. Comparisons of DNA between tumor and normal tissue 
(from a 10 mL research blood draw) may be performed as appropriate, thus generating germline sequencing data.  
This will be limited to participants enrolled at MSK only.  There is no intention to analyze the germline data beyond 
utilizing it as a normal control for the tumor tissue analysis, and generally germline data will not be communicated 
to the patient.  
 
The following procedure will be followed by MSK investigators for the unique situation in 
which a potentially actionable incidental finding has been discovered in the course of research 
conducted on samples collected under this protocol:  
 
In the event an investigator's research identifies a finding that he or she believes should be 
communicated to the subject (and/or family designee), the investigator shall communicate this to 
the IRB. The finding will be reviewed by a group convened by the IRB (and appointed in 
consultation with the Physician-In-Chief) to determine whether the incidental finding should be 
discussed with the subject.  In the event that group convened by the IRB determines that the 
finding should be discussed with the subject, and the subject has consented to be re-contacted, 
then the treating/consenting physician shall be contacted by the -IRB representative and asked to 
refer the subject to the Clinical Genetics Service for further discussion of the research finding.  
 
After appropriate counseling and consent, the Clinical Genetics Service will request permission 
to confirm the result in a New York DOH-approved laboratory prior to communication of the 
specific result. If the patient is not available (e.g. deceased), then the surrogate designated on the 
consent will be contacted and the above will occur.  
 
Whole exome or genome sequencing data will be deidentified; samples will be labelled with 
patient study IDs to preserve links to clinical data.  The deidentified genomic data will be stored 
to a protected server that is specifically set aside for clinical trial data. 
 
The IRB and Clinical Genetics Service, as per above flow chart, will be notified when a 
participant’s samples uncover a potentially reportable incidental finding(s). The following 
information must be provided to IRB representative and Clinical Genetics: 
• Participant Name/MRN # 
• Type of Biospecimen (tissue, blood, etc) 
• Incidental Finding 
• Project # (HBUC/Waiver or Protocol #) that this analysis occurred under 
• Collection Protocol # 
Clinical Genetics Service Contact: rtmgapirb@mskcc.org 

66 
 
 
9.1.1.1 
Collection of Specimen(s) 
 
Archival tumor tissue (unstained slides or tissue blocks) will be collected for this analysis.       
(Tissues from research biopsies as described in Section 9.2.1.1 can also be used for this 
analysis.) 
 
For the research blood specimen, approximately 10 mL of blood will be collected in a tube with 
EDTA (usually lavender top) any time after the informed consent has been signed.  These blood 
samples can then be stored at 2-8oC for up to 3 days; for longer term storage, the tubes must be 
stored at -80oC. 
 
9.1.1.2 
Handling of Specimens(s) 
 
Genomic alterations will be assessed.  The approach(es) for detecting RET and PAX8-PPARG 
rearrangements and other genetic alterations will be determined by the availability of assays and 
funding at the time of analysis.   
  
9.1.1.3 
Shipping of Specimen(s) 
 
For each sample indicate the unique subject ID number, anatomic location of biopsy, and the 
date of the specimen.  
 
Archival paraffin blocks of formalin-fixed biopsy specimens should be placed in a padded 
envelope.  Paraffin blocks should be wrapped in a plastic bag before placement in the envelope 
and mailed to the address specified in 9.1.1.4.  The blood samples must be shipped by Overnight 
Delivery (specifically, Federal Express or UPS), packed in sufficient dry ice (at least 10 pounds) 
to ensure that they remain frozen for at least two days. Label the outside of the container with 
“Biohazard,” “Frozen Biopsy Samples, Freeze upon Arrival.” Shipment should ONLY be 
scheduled for early in the week (Mondays, Tuesdays or Wednesdays) to ensure that the samples 
do not wait over a weekend for delivery. Samples will be shipped in batches and must be in 
accordance with the guidelines set forth by the International Air Transport Association (IATA) 
for shipment of diagnostic specimen via air. Samples must be sorted by subject ID number so 
that all samples from a given subject are readily accessible. A notification regarding shipment 
must be sent via e-mail to Dr. Alan L. Ho (hoa@mskcc.org).  
  
 
9.2 
Laboratory Correlative Studies 
 
9.2.1 
Quantifying changes in MAPK and alternate signaling pathways in response to trametinib 
 
9.2.1.1 
Collection of Specimen(s) 
 
Pre-treatment biopsies will be performed prior to Week 1 Day 1 and on-treatment biopsies will be performed in 
Week 3.  It is preferred, but not required, that the second biopsy be performed upon the same tumor that was 
sampled with the first research biopsy, if safe and feasible. Patients may be exempt from biopsy if either the 
investigator or person performing the biopsy judges that no tumor is accessible for biopsy or that biopsy poses too 
great of a risk to the patient (if the only tumor accessible for biopsy is also the only lesion that can be used for 

67 
 
RECIST v1.1 response evaluation, then the patient may be exempt from biopsy after discussion with the MSK 
Principal Investigator).  Radiologic guidance (CT, MRI or ultrasound guided) approaches and obtaining multiple 
cores to ensure sufficient biopsy material (at least 3 cores preferred) are allowed as long as it is considered  
reasonably safe for the patient.     
 
Tissue will be divided for formalin fixation and flash freezing in liquid nitrogen as directed by 
the Principal Investigator.  Fixation will be done per institutional guidelines.  For flash frozen 
samples, the biopsy sample will be placed into a cryovial, which will be submerged in a liquid 
nitrogen bath until the tissue is frozen.  If tissue is limited, the local Principal Investigator may 
decide only to create flash frozen samples.     
  
9.2.1.2 
Handling of Specimens(s) 
 
The fresh frozen or fixed tissue will be analyzed with protein based assay(s) and/or gene 
transcriptional assay(s) to evaluate drug induced changes in MAPK signaling.  Abrogation of 
negative feedback pathways with small molecule targeted therapies leading to activation of 
alternate signaling pathways to mediate drug resistance have been well described.  Candidate 
signaling pathways that may be activated in response to trametinib-mediated MEK inhibition 
will also be interrogated.   
 
Profiling of cellular transcriptional output has been validated as a means of distinguishing tumor 
cell susceptibility to MEK inhibition (Dry et al., 2010) and the differential impact of MEK 
inhibition upon BRAF MUT versus WT tumors (Pratilas et al., 2009).  In the thyroid, DUSPs are 
particularly useful markers of MAPK activity, and may be explored in the samples (Chakravarty 
et al., 2011).  Additionally, the re-expression of some key thyroid-specific genes such as NIS will 
be evaluated (Chakravarty et al., 2011).    
 
The approach(es) utilized will be determined by the availability of assay(s) and funding at the 
time of analysis. This analysis could also be performed on the submitted archival tissue in 
addition to, or in lieu of, analysis of tissues obtained from research biopsies.  
 
9.2.1.3 
Shipping of Specimen(s) 
 
For each sample indicate the unique subject ID number, anatomic location of biopsy, and the date of the specimen.  
 
The frozen samples must be shipped by Overnight Delivery (specifically, Federal Express or UPS), packed in 
sufficient dry ice (at least 10 pounds) to ensure that they remain frozen for at least two days. Label the outside of the 
container with “Biohazard,” “Frozen Biopsy Samples, Freeze upon Arrival.” Shipment should ONLY be scheduled 
for early in the week (Mondays, Tuesdays or Wednesdays) to ensure that the samples do not wait over a weekend 
for delivery. Samples will be shipped in batches and must be in accordance with the guidelines set forth by the 
International Air Transport Association (IATA) for shipment of diagnostic specimen via air. Samples must be sorted 
by subject ID number so that all samples from a given subject are readily accessible. A notification regarding 
shipment must be sent via e-mail to Dr. Alan L. Ho (hoa@mskcc.org).  
 
 
9.3 
Special Studies 
 
Not Applicable 
 

68 
 
10. 
STUDY CALENDAR 
 
Pre-Study and Weeks 1-5 study calendar for all patients: 
 
 
NOTE FOR THE 124I PET/CT LESIONAL DOSIMETRY: Changes in the scheduling of the 
tests and/or assessments below, including the first or second 124I PET/CT lesional dosimetry 
process,  may be considered in the event of holidays, scheduling conflicts, unanticipated delays 
(e.g. delays in 124I shipment, weather, etc…) or interruptions in trametinib therapy after 
discussion with the Principal Investigator. (NOTE: Week and day number designations may 
change if there are interruptions in study treatments/assessments.) 
 
 
Pre- 
Studyf 
Wk 1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 5 
D1 
D2 
D3 
D4 
D5 
D6
& 
D7 
D1  
D2 
D3 
D4  
D5 
Trametiniba 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adherence to low iodine dietb 
Xb 
X 
X 
X 
X 
X 
 
 
 
Xb 
X 
X 
X 
X 
X 
Thyrogenc 
 
X 
X 
 
 
 
 
 
 
 
X 
X 
 
 
 
124I administration 
(approximately 6 mCi)d 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
124I PET/CT 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
beta-HCGg 
Xg 
Xj 
 
 
 
 
 
 
 
 
Xj 
 
 
 
 
Tumor Genotyping 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concurrent meds 
X 
X-------------------------------------------------------------------------------------------------------------------X 
Physical exam 
X 
 
 
 
 
Xk 
 
 
X 
 
 
 
 
 
Xk 
Vital signs 
X 
 
 
 
 
Xk 
 
 
X 
 
 
 
 
 
Xk 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
 
 
 
Xk 
 
 
X 
 
 
 
 
 
Xk 
Performance status 
X 
 
 
 
 
Xk 
 
 
X 
 
 
 
 
 
Xk 
CBC w/diff, plts 
X 
Xk 
 
 
 
 
 
 
X 
 
Xk 
 
 
 
 
chemistryh 
X 
Xk 
 
 
 
 
 
 
X 
 
Xk 
 
 
 
 
PT/aPTT (include INR) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EKG  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Echocardiogram or MUGAm 
X 
 
Ophthalmology examn 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse event evaluation 
 
X--------------------------------------------------------------------------------------------------------------------X 
Radiologic evaluation  
(CT(s) and/or MRI(s)) for 
tumor measurements 
NO IODINATED 
CONTRAST IS ALLOWED 
X 
 
TSH, free T4, thyroglobulin, 
thyroglobulin antibodyl 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
Research blood sampleo 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Research biopsyi 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
a: 
Trametinib is to be started on Week 1, Day 6 at 2 mg orally daily.  If the second lesional dosimetry with 124I PET/CT indicates that RAI 
should be given, trametinib will be continued until 2 days after RAI has been administered.  If the lesional dosimetry with 124I PET/CT 
indicates that RAI should not be given, trametinib may or may not be discontinued (see the appropriate table below).  Ideally, patients 
will remain on trametinib continuously for a minimum of 7 days prior to the performance of the PET/CT for the second lesional 
dosimetry (scheduled here in Week 5), (this is not a requirement).  To achieve this, the second lesional dosimetry may be rescheduled at 
the discretion of the treating physician. If the second lesional dosimetry is delayed more than 4 weeks, the MSK Principal Investigator 
and the treating physician will determine if the patient should be continued or removed from the study.  If trametinib is missed for > 7 
days total or interruptions in trametinib dosing have occurred prior to or during whole body and blood dosimetry and 131I (RAI) treatment, 
then having some or all of the doses made up and rescheduling the study assessments/treatments may be considered after discussion with 
the Principal Investigator (this is not a requirement).   
b: 
Patients should adhere to a low iodine diet for 5 days prior to the initiation of the lesional dosimetry process (considered in the first day of 
the 5 day process) until its completion (the fifth day when the PET/CT is performed).  Patients who go on to whole body and blood 
dosimetry and 131I treatment will be continued on the low iodine diet through 1 day after 131I is given.  Please see Appendix B for details 
of the low iodine diet. 

69 
 
c: 
0.9 mg Thyrogen will be administered intramuscularly on Days 1 and 2 of Weeks 1 and Week 5. 
d:      Approximately 6 mCi (range 4-7 mCi) of 124I administered orally. 
e:      Tumor genotyping can be conducted on the primary tumor, recurrent tumor, or a metastasis.  Results can be obtained any time before 
patient is registered to the study. 
f:      All Pre-Study evaluations must be done ≤28 days prior to Week 1 Day 1 unless otherwise specified. 
g:     pregnancy test (for women of childbearing potential).  Pre-study beta-HCG levels need to be drawn within 2 weeks prior study 
registration. 
h:      chemistry includes albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, phosphorus, 
potassium, total protein, SGOT [AST], SGPT [ALT], sodium. 
i:       The first research biopsy will be performed prior to initiation of Week 1 Day 1.  The second biopsy will be performed in Week 3 of the 
study.  It is preferred, but not required, that the second biopsy be performed upon the same tumor that was sampled with the first research 
biopsy, if safe and feasible.   Patients may be exempt from biopsy if either the investigator or person performing the biopsy judges that 
no tumor is accessible for biopsy or that biopsy poses too great of a risk to the patient (if the only tumor accessible for biopsy is also the 
only lesion that can be used for RECIST v1.1 response evaluation, then the patient may be exempt from biopsy after discussion with the 
MSK Principal Investigator).  Radiologic guidance (CT, MRI or ultrasound guided) approaches and obtaining multiple cores to ensure 
sufficient biopsy material (at least 3 cores preferred) are allowed as long as it is considered  reasonably safe for the patient.  
j:        beta-hcg (for women of childbearing potential) must be done within 2 days prior to administering 124I.    
k:       The days designated for these evaluations/tests are only suggestions.   These can be scheduled for any time during the week for which 
they are scheduled. 
l:       TSH, free T4, thyroglobulin, and thyroglobulin antibody will be drawn on Day 1 of weeks 1 and 5 (preferably prior to administration of 
Thyrogen on that day)  Only TSH will be drawn on Day 3 during Weeks 1 and 5. TSH and Thyroglobulin total and antibody will be 
drawn on Days 5 of  Weeks 1 and 5 (i.e., the weeks that the 124I PET/CT are to be performed).   TSH and Free T4 will be drawn for the 
Week 3 assessment (thyroglobulin and thyroglobulin antibodies are not required to be drawn during this week). 
m:     The same modality (echocardiogram or MUGA) should be used at baseline and at follow-up. 
n:      Ophthalmology exams should be obtained at baseline, and if clinically indicated, during study.  Ophthalmology exam should include 
Ocular Coherence Tomography, fundoscopy, tonometry, visual field examination, and corrected visual acuity assessments. 
o:      For the research blood specimen, approximately 10 mL of blood will be collected in a tube with EDTA (usually lavender top) any time 
after the informed consent has been signed.   
 

70 
 
Study Calendar for PATIENTS WHO RECEIVE RAI (Week 5, Day 6 and beyond) 
If the second lesional dosimetry with trametinib reveals sufficient tumoral iodine incorporation 
to deliver a dose of > 2,000 cGy with < 300 mCi of RAI, then the patient will continue on 
trametinib and a low iodine diet (as decided by the treating physician(s)).  The schedule of 
treatments and assessments for these patients are detailed below (NOTE: Week and day number 
designations may change if there are interruptions in study treatments/assessments): 
 
Wk 5 
Wks 6 & 7 
5 weeks (+/- 2 
weeks) after RAI 
therapy 
About 3 or 4 months  
after RAI 
About 6 months after RAI 
(+/- 1 week) 
D6 & D7 
Trametiniba 
X 
X 
 
 
 
Adherence to low iodine dieta 
X 
X 
 
 
 
Whole body and blood 
dosimetry and 131I (RAI) 
treatment with Thyrogen 
stimulation (per standard of 
care)a 
 
X 
 
 
 
Concurrent meds 
X-----------------------------------------------------X 
 
 
Physical exam 
 
 
X 
 
 
Vital signs 
 
 
X 
 
 
Weight 
 
 
X 
 
 
Performance status 
 
 
X 
 
 
CBC w/diff, plts 
 
 
X 
 
 
chemistryb 
 
 
X 
 
 
TSH, free T4, thyroglobulin, 
thyroglobulin antibody 
 
 
X 
X 
X 
beta-HCG 
 
Xc 
 
 
 
Echocardiogram or MUGAe 
 
 
Xe 
 
 
Adverse event evaluation 
X-------------------------------------------------X 
(Monitored for 30 days following the last dose 
of trametinib.)  
 
 
Radiologic evaluation (CT(s) 
and/or MRI(s)) for tumor 
measurements 
NO IODINATED 
CONTRAST IS ALLOWED 
Xd 
 
Xd 
Xd   
a:    Patients will be continued on trametinib and a low iodine diet.  Whole body and blood dosimetry and thyrogen-stimulated 131I (RAI) 
treatment is to be completed no later than in Week 7 (unless changes/interruptions of study drug administration and/or study assessments 
had to be enacted such that whole body and blood dosimetry and therapeutic RAI has to be completed after Week 7)(this dosimetry will 
be conducted as per institutional guidelines).  Trametinib will be continued through 2 days after therapeutic 131I administration.  The low 
iodine diet will be continued through 1 day after 131I treatment.  131I therapeutic dosing will be guided by the dosimetric determination of 
the maximum tolerated activity (MTA): the 131I activity administered concomitantly with trametinib is not to exceed the MTA plus 3 mCi 
(i.e., [131I activity administered] < [MTA + 3 mCi]).  Delays in performing the whole body and blood dosimetry and RAI treatment 
due to holidays, scheduling conflicts, or interruptions in trametinib therapy may be allowed after discussion with the MSK 
Principal Investigator.    
b:   chemistry includes albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, phosphorus, 
potassium, total protein, SGOT [AST], SGPT [ALT], sodium. 
c: beta-hcg (for women of childbearing potential).  To be completed within 2 days prior to administration of RAI. 
d:   CT(s) WITHOUT CONTRAST and/or MRI(s) to reassess disease is/are to be done after completion of the second 124I PET/CT scan and 
before the administration of RAI.  Scans will be repeated about 3 to 4 months after RAI and about 6 months (+/- 1 week) after RAI; it is 
requested that attempts be made to have scans performed as close to 6 months from the time RAI (131I)  was administered if possible to 
best assess the 6-month PFS endpoint.  If an additional scan is required to confirm a complete or partial response after the 6 month scan, 
an additional radiologic evaluation should be completed within 1 to 3 months after the last scan.    Schedule of the radiographic 
assessments may be altered if there are disruptions of the planned assessment/treatment schedule after discussion with the Principal 
Investigator.  Failure to complete the scans after RAI will not be considered protocol violations with the exception of those scheduled for 
6 months following RAI. 
e:  Followup echocardiogram or MUGA should be performed within 1 month after discontinuing trametinib.  The same modality used at 
baseline should be performed for this followup. 

71 
 
Study Calendar for PATIENTS WHO DO NOT RECEIVE RAI (Week 5, Day 6 and beyond) 
 
For both COHORT A (RAS MUT) and B (BRAF/RAS WT) patients: If analysis of the 
second lesional dosimetry suggests that therapeutic RAI will not be given, it will be concluded 
that the patient’s cancer is still refractory to RAI and RAI will not be administered.  Such 
patients may be continued on trametinib alone (in Cohort C) if 1) the treating physician 
determines it to be clinically reasonable, and 2) the patient agrees to continue on trametinib If 
these conditions are not met, then trametinib will be discontinued and the patient removed 
from the study; for these patients, the “Off Study” requirements detailed in the table below 
will be performed within 30 days of trametinib discontinuation.   
(NOTE: After completion of the designated evaluations/treatments through Week 5 detailed in 
the “Pre-Study and Weeks 1-5 study calendar for all patients” above, the subsequent week will 
be considered Cycle 2, Week 1 of treatment (what would have been considered Week 6 in the 
study calendars above). Week and day number designations may change if there are interruptions 
in study treatments/assessments: 
 
 
Cycle 2  
Wk 1 
Cycle 2  
Wk 2 
Cycle 2  
Wk 3 
Cycle 2  
Wk 4 
Cycle 3+  
Wk 1 
Off Studyc 
Trametinib 
X 
X 
X 
X 
X 
 
Concurrent meds 
X----------------------------------------------------------------------------X 
 
Physical exam 
 
 
X 
 
Xb 
X 
Vital signs 
 
 
X 
 
Xb 
X 
Weight 
 
 
X 
 
Xb 
X 
Performance status 
 
 
X 
 
Xb 
X 
CBC w/diff, plts 
 
 
X 
 
Xb 
X 
chemistrya 
 
 
X 
 
Xb 
X 
TSH, free T4, 
thyroglobulin, 
thyroglobulin antibody 
 
 
 
 
X (to be checked 
about every 2  
cycles)b 
 
Echocardiogram or 
MUGA 
Approximately every 3 cycles starting with Cycle 4.  Use the same methodology 
for baseline and follow up. 
Adverse event evaluation 
X----------------------------------------------------------------------------X 
X 
Tumor measurements 
CT and/or MRI will be performed every 8 weeks (+/- 1 week) (or 
approximately every 2 cycles) with the first scan assessment on 
trametinib treatment to be performed during Cycle 2, Week 4 or 
Cycle 3, Week 1.   After 10 months on treatment with trametinib, 
scans will be performed every 12 weeks (+/- 1 week)(or 
approximately every 3 cycles).  If early, unplanned CT and/or MRI 
scan(s) is/are performed which can serve as an assessment of 
response prior to the protocol-mandated radiologic scans, the next 
set of protocol-mandated scans may be rescheduled to occur in 8 
weeks (+/- 1 week) or 12 weeks (+/- 1 weeks) (according to the 
criteria described above) from the time of the last assessment (this is 
not mandatory).  Documentation (radiologic) must be provided for 
patients removed from study for progressive disease.  Objective 
responses should be confirmed with a second assessment performed 
at least 4 weeks later. 
 
a:  chemistry includes albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, phosphorus, 
potassium, total protein, SGOT [AST], SGPT [ALT], sodium. 
b: After the completion of Cycle 2, these tests and evaluations will be done once each cycle, preferably on week 1 of each cycle if possible.  
The exceptions are blood tests for TSH, free T4, thyroglobulin, and thyroglobulin antibody which are to be checked every 8 weeks +/- 1 
week (about every 2 cycles). 
c: These off study assessment will be performed within 30 days of discontinuing trametinib. 

72 
 
 
Trametinib toxicities will be monitored only for 30 days following the last dose of trametinib.   
 
The impact of more than one month of trametinib therapy upon RAI uptake and/or efficiacy is 
unknown.  Patients who do not receive 131I therapy after the second 124I PET/CT scan and remain 
on trametinib may be evaluated with a third Thyrogen-stimulated 124I PET/CT scan (with the 
procedure detailed in Section 10.0 for Week 5) 4 weeks or more after completion of the prior 124I 
PET/CT scan process.  If the lesional dosimetry criteria for 131I therapy is met on the third 124I 
PET/CT, patients can go on to be prepared for/treated with 131I and followed as detailed in 
Section 10.0 (in the calendar under the heading “Study Calendar for PATIENTS WHO 
RECEIVE RAI (Week 5, Day 6 and beyond)” (treatment with 131I is not mandatory).  If the third 
124I PET/CT scan results do not fulfill the 131I treatment criteria, patients may continue on 
trametinib alone with the evaluations/treatments required for Cohort C.    
 
11. 
MEASUREMENT OF EFFECT 
 
11.1 Antitumor Effect – Solid Tumors 
 
For the purposes of this study, patients should be re-evaluated for response as per the Study 
Calendars in Section 10.  In addition to a baseline scan if necessary, confirmatory scans should 
also be obtained not less than 4 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) 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 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.  Please see Section 13 for guidelines regarding 
evaluable for response. 
 
Evaluable Non-Target Disease Response.  Patients who have lesions present at baseline 
that are evaluable but do not meet the definitions of measurable disease, have received at 
least one cycle of therapy, and have had their disease re-evaluated will be considered 
evaluable for non-target disease.  The response assessment is based on the presence, 
absence, or unequivocal progression of the lesions.  
 
11.1.2 Disease Parameters 
 
Measurable disease.  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as >20 mm by chest 
x-ray or as ≥10 mm with CT scan, MRI, or calipers by clinical exam.  All tumor 

73 
 
measurements must be recorded in millimeters (or decimal fractions of centimeters). 
 
Note:  Tumor lesions that are situated in a previously irradiated area might or might not 
be considered measurable.  If the investigator thinks it appropriate to include them, the 
conditions under which such lesions should be considered must be defined in the 
protocol. 
 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a 
lymph node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm).  At baseline and in follow-up, only 
the short axis will be measured and followed. 
 
Non-measurable disease.  All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), 
are considered non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, 
and abdominal masses (not followed by CT or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions (neither measurable nor non-measurable) 
since they are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same patient, these are preferred for selection as target 
lesions. 
 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target 
lesions and recorded and measured at baseline.  Target lesions should be selected on the 
basis of their size (lesions with the longest diameter), be representative of all involved 
organs, but in addition should be those that lend themselves to reproducible repeated 
measurements.  It may be the case that, on occasion, the largest lesion does not lend itself 
to reproducible measurement in which circumstance the next largest lesion which can be 
measured reproducibly should be selected.  A sum of the diameters (longest for non-
nodal lesions, short axis for nodal lesions) for all target lesions will be calculated and 
reported as the baseline sum diameters.  If lymph nodes are to be included in the sum, 
then only the short axis is added into the sum.  The baseline sum diameters will be used 
as reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. 
 
Non-target lesions.  All other lesions (or sites of disease) including any measurable 
lesions over and above the 5 target lesions should be identified as non-target lesions and 
should also be recorded at baseline.  Measurements of these lesions are not required, but 
the presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow-up.  

74 
 
 
11.1.3 Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or 
calipers.  All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment. 
 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam. 
 
Clinical lesions  Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and 10 mm diameter as 
assessed using calipers (e.g., skin nodules).  In the case of skin lesions, documentation by 
color photography, including a ruler to estimate the size of the lesion, is recommended.  
 
Chest x-ray  Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung.  However, CT is preferable.  
 
 
Conventional CT and MRI  This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm or less.  If CT scans have 
slice thickness greater than 5 mm, the minimum size for a measurable lesion should be 
twice the slice thickness.  ALL CTs SHOULD BE PERFORMED WITHOUT 
IODINATED CONTRAST. 
 
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), 

75 
 
then the CT portion of the PET-CT can be used for RECIST measurements and can be 
used interchangeably with conventional CT in accurately measuring cancer lesions over 
time.  Note, however, that the PET portion of the CT introduces additional data which 
may bias an investigator if it is not routinely or serially performed.   
 
Ultrasound  Ultrasound is not useful in assessment of lesion size and should not be used 
as a method of measurement.  Ultrasound examinations cannot be reproduced in their 
entirety for independent review at a later date and, because they are operator dependent, it 
cannot be guaranteed that the same technique and measurements will be taken from one 
assessment to the next.  If new lesions are identified by ultrasound in the course of the 
study, confirmation by CT or MRI is advised.  If there is concern about radiation 
exposure at CT, MRI may be used instead of CT in selected instances. 
 
Endoscopy, Laparoscopy  The utilization of these techniques for objective tumor 
evaluation is not advised.  However, such techniques may be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in trials where 
recurrence following complete response (CR) or surgical resection is an endpoint. 
Tumor markers  Tumor markers alone cannot be used to assess response.  If markers are 
initially above the upper normal limit, they must normalize for a patient to be considered 
in complete clinical response.  Specific guidelines for both CA-125 response (in recurrent 
ovarian cancer) and PSA response (in recurrent prostate cancer) have been published 
[JNCI 96:487-488, 2004; J Clin Oncol 17, 3461-3467, 1999; J Clin Oncol 26:1148-1159, 
2008].  In addition, the Gynecologic Cancer Intergroup has developed CA-125 
progression criteria which are to be integrated with objective tumor assessment for use in 
first-line trials in ovarian cancer [JNCI 92:1534-1535, 2000]. 
 
Cytology, Histology  These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor 
types, such as germ cell tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or 
stable disease is mandatory to differentiate between response or stable disease (an 
effusion may be a side effect of the treatment) and progressive disease. 
 
FDG-PET  While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis 
of FDG-PET imaging can be identified according to the following algorithm:  
a. 
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based on a new 
lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-PET at follow-up 
corresponds to a new site of disease confirmed by CT, this is PD.  If the positive FDG-PET at follow-
up is not confirmed as a new site of disease on CT, additional follow-up CT  scans are needed to 
determine if there is truly progression occurring at that site (if so, the date of PD will be the date of the 
initial abnormal FDG-PET scan).  If the positive FDG-PET at follow-up corresponds to a pre-existing 
site of disease on CT that is not progressing on the basis of the anatomic images, this is not PD. 
c. 
FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in cases 

76 
 
where a residual radiographic abnormality is thought to represent fibrosis or scarring.  The use of 
FDG-PET in this circumstance should be prospectively described in the protocol and supported by 
disease-specific medical literature for the indication.  However, it must be acknowledged that both 
approaches may lead to false positive CR due to limitations of FDG-PET and biopsy 
resolution/sensitivity. 
 
 
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater than twice 
that of the surrounding tissue on the attenuation corrected image. 
 
11.1.4 Response Criteria 
 
11.1.4.1 
Evaluation of Target Lesions 
 
Complete Response (CR):  Disappearance of all target lesions.  Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to <10 
mm. 
 
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters. 
 
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study).  In addition to the relative increase of 
20%, the sum must also demonstrate an absolute increase of at least 5 mm.  (Note:  
the appearance of one or more new lesions is also considered progressions). 
 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study. 

77 
 
 
11.1.4.2 
Evaluation of Non-Target Lesions 
 
Complete Response (CR):  Disappearance of all non-target lesions and normalization 
of tumor marker level.  All lymph nodes must be non-pathological in size (<10 mm 
short axis). 
 
Note:  If tumor markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response. 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits. 
 
Progressive Disease (PD):  Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions.  Unequivocal progression 
should not normally trump target lesion status.  It must be representative of overall 
disease status change, not a single lesion increase.     
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion 
of the treating physician should prevail in such circumstances, and the progression 
status should be confirmed at a later time by the review panel (or Principal 
Investigator). 
 
11.1.4.3 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started).  The patient's best 
response 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 

78 
 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
• 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**        Only for non-randomized trials with response as primary endpoint. 
***      In exceptional circumstances, unequivocal progression in non-target lesions may be 
            accepted as disease progression. 
 
Note:  Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.”  Every effort should be made to document the 
objective progression even after discontinuation of treatment. 
 
 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
• 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign 
this category when no lesions can be measured is not advised 
 
NOTE: On this study, patients with clinical or radiographic evidence of progression of disease 
(as described above) on assessments prior to the 6-month disease evaluation (i.e. the scans and 
evaluations performed 6 months after therapeutic 131I is administered) will be allowed to 
continue on study treatment and/or evaluations given the potentially delayed therapeutic benefit 
of 131I, effects of Thyrogen, etc. For patients with clinical or radiographic evidence of 
progression of disease on assessments prior to the 6 month disease evaluation, the final objective 
response assessment at 6 months will be based upon a comparison between the 6 month 
radiologic scan(s)/evaluations and the baseline, pre-treatment radiologic scans.  If a new target or 
non-target lesion is identified on any radiologic study (including the 124I PET/CT scan) prior to 
the administration of therapeutic 131I,the first radiologic study prior to 131I that produces a 
RECIST measurement of the new lesion will be used as the baseline comparator for subsequent 
evaluations, including assessment of the 6-month response assessment.   
 
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). 
 

79 
 
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 (initiation of trametinib) to 
time of progression or death, whichever occurs first. 
 
11.2 Antitumor Effect – Hematologic Tumors 
 
Not applicable. 
 
11.3 Other Response Parameters 
 
Not applicable. 
 
12. 
DATA REPORTING / REGULATORY REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7 
(Adverse Events: List and Reporting Requirements). 
 
12.1 Data Reporting 
 
12.1.1 Method 
 
This study will be monitored by the Clinical Data Update System (CDUS) Version 3.0.  
Cumulative protocol- and patient-specific CDUS data will be submitted electronically to 
CTEP on a quarterly basis, either by FTP burst of data or via the CDS web application.  
Reports are due January 31, April 30, July 31, and October 31.  Instructions for 
submitting data using the CDUS can be found on the CTEP Web site 
(http://ctep.cancer.gov/reporting/cdus.html).  
 
 
Note:  If your study has been assigned to CDUS-Complete reporting, all adverse events 
(both routine and expedited) that have occurred on the study and meet the mandatory 
CDUS reporting guidelines must be reported via the monitoring method identified above.  
If your study has been assigned to CDUS-Abbreviated reporting, no adverse event 
reporting (routine or expedited) is required to be reported via CDUS. 
 
Weekly meetings will occur to monitor patient accrual.  Routine data quality reports will 
be generated to assess missing data and inconsistencies.  Accrual rates and extent and 
accuracy of evaluations and follow-up will be monitored periodically throughout the 

80 
 
study period and potential problems will be brought to the attention of the study team for 
discussion and action. 
 
Random-sample data quality and protocol compliance audits will be conducted by the 
study team, at a minimum of once per year, more frequently if indicated. 
 
Potential genotype/phenotype data may be sent to the NIH repository (or any other public 
database by participating investigators. If data is to be sent to the NIH, local investigators 
will follow the MSK IRB/PB GWAS SOP-503 to ensure compliance with the data 
submission. Investigators will not include identifying information such as the patient’s 
name, date of birth, etc with the submission to NIH and the data will be coded for 
transmission, as specificed by the applicable policies. The data will be maintained under 
the controlled access portion of the NIH database.  
 
12.1.2 Responsibility for Data Submission 
 
             
 
        N/A –Single  Institution  Study 
 
12.2 Collaborative Agreements Language 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 
under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis.  Therefore, the following obligations/guidelines, in addition to the 
provisions in the “Intellectual Property Option to Collaborator”  
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the 
terms of award, apply to the use of the Agent(s) in this study: 
 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study.  
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and shall 
be maintained as such by the investigators.  The protocol documents for studies utilizing 
Agents contain confidential information and should not be shared or distributed without the 
permission of the NCI.  If a copy of this protocol is requested by a patient or patient’s family 
member participating on the study, the individual should sign a confidentiality agreement.  A 
suitable model agreement can be downloaded from: http://ctep.cancer.gov. 
 
2. For a clinical protocol where there is an investigational Agent used in combination with 
(an)other Agent(s), each the subject of different Collaborative Agreements, the access to and 
use of data by each Collaborator shall be as follows (data pertaining to such combination use 
shall hereinafter be referred to as "Multi-Party Data”): 
 
a. NCI will provide all Collaborators with prior written notice regarding the existence and 
nature of any agreements governing their collaboration with NCI, the design of the 
proposed combination protocol, and the existence of any obligations that would tend to 
restrict NCI's participation in the proposed combination protocol. 
 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial 

81 
 
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 
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. 
 
 

82 
 
13. 
STATISTICAL CONSIDERATIONS 
 
13.1 Study Design/Endpoints 
 
Cohort A (RAS MUT): Two co-primary objectives are defined for this cohort: proportion of 
patients alive, progression-free at 6 months following treatment with trametinib and RAI; and 
objective response rate (ORR, complete response or partial response) at 6 months following 
treatment with trametinib and RAI. “6 months” (also described below as the “six-month time 
point”) refers to assessments performed approximately 6 months after the co-administration of 
RAI with trametinib.  (All radiologic assessments performed will be compared back to the 
baseline scans performed prior to trametinib and RAI therapy.)  If either one of these objectives 
is met, the treatment would be considered worthy of further testing in this disease.   
 
All patients enrolled in the trial who are treated with trametinib through the completion of the 
second 124I PET scan will be included in determination of these primary endpoints.  Patients who 
are taken off study prior to completion of the second 124I PET scan may be replaced.  Patients 
who are deemed to qualify for treatment with 131I based on the second 124I PET scan, but do not 
receive it, will be considered to have had a progression/death event and categorized as non-
responders.  After having received therapeutic 131I, patients who, for any reason, do not have the 
6-month evaluation, will be considered to have had a progression/death event and categorized as 
non-responders.  Patients for whom it is determined that the second 124I PET/CT demonstrates 
insufficient iodine incorporation to warrant treatment with RAI (131I) still have RAI-refractory 
disease; they will not receive RAI treatment and will be considered to have had a 
progression/death event and be categorized as non-responders.   
 
It is possible patients will have clinical or RECIST v1.1 radiologic evidence of disease 
progression prior to the 6-month time point evaluation.  These patients may still obtain clinical 
benefit on the study at the 6-month time point for several reasons: 1) trametinib alone prior to 
RAI may not have significant clinical efficacy, 2) Thyrogen stimulation can transiently increase 
tumor size which can be mistaken for disease progression; 3) the therapeutic effects of RAI can 
be delayed; and 4) evidence of progression may be evident prior to administration of RAI.  
Hence, patients with evidence of disease progression prior to the 6-month time point evaluation 
may remain on study at the discretion of the treating physician.  The final objective response and 
disease progression assessments at 6 months for these patients will be based upon a comparison 
between the 6-month radiologic scan(s) and the baseline, pre-study radiologic scans. The one 
exception is if a new target or non-target lesion is identified on any radiologic study (including 
the 124I PET/CT scan) prior to the administration of therapeutic 131I,the first radiologic study 
prior to 131I that produces a RECIST measurement of the new lesion will be used as the baseline 
comparator for subsequent evaluations, including assessment of the 6-month response 
assessment.  However, if in the opinion of the treating physician these patients are unlikely to 
demonstrate benefit at the 6-month time point, the patients will be classified as progression/death 
event /non-responders and taken off the study.  
 
Patients who receive additional treatment for their thyroid cancer outside of this protocol prior to 
the 6-month time point (except for thyroid hormone TSH suppression, palliative radiation to a 
non-target lesion, or therapy to prevent pathologic fractures caused by bone metastases (e.g. 
zoledronic acid and denosumab)) will be considered to have had a progression/death event and 

83 
 
be categorized as non-responders.   
 
(NOTE: For assessment of ORR, as long as one of the 2 scans required for confirmed PR or 
confirmed CR designations is performed for the 6 month evaluation, then that patient will be 
counted as having had a confirmed PR or CR.  The other scan required for confirmed PR or CR 
designation can be obtained on a scan prior to or following the 6 month time point assessment 
(as long as the two assessments are separated by 4 weeks)).   
An exact binomial stage design will be used to discriminate between true 6-month 
progression/death rates of 20% vs. 50%, and between true ORR rates at 6 months of 5% and 
25%. Twenty-five patients will be enrolled. If at least 9 patients are alive, free of progression and 
have not received additional non-protocol related therapy for thyroid cancer at the 6-month time 
point, or at least 4 RECIST responses (CR + PR) are observed among the 25 patients at the 6 
month time point, this regimen would be considered worthy of further testing in this disease.  
 
This design yields 94% power to detect a true 6-month time point progression/death rate of at 
least 50%, and 90% power to detect a ORR rate of at least 25%.  It yields a 0.05 probability of a 
positive progression/death result if the true 6-month time point progression/death rate is no more 
than 20%, and a 0.04 probability of a positive ORR at the 6-month time point result if the true 
ORR is no more than 5%. Therefore, assuming that progression/death and ORR are independent, 
the overall type 1 error is <0.1.  The type 1 error decreases very slightly if progression/death rate 
and ORR are positively correlated. 
 
The analysis of progression or death will capture the potential benefit of disease control without 
continuous treatment that the study strategy provides (as opposed to indefinite, continuous 
chemotherapy).  The pilot study evaluating selumetinib enhancement of RAI therapy had similar 
eligibility requirements to those in this study, except that the pilot did not require radiographic 
evidence of disease progression prior to enrollment as this study does.  Still, an unplanned, 
retrospective analysis of 16 patients on the pilot selumetinib study revealed that 15 had evidence 
of tumor progression on imaging up to one year prior to enrollment, suggesting that the disease 
for this patient population generally has a propensity to progress.   In a phase II study evaluating 
gefitinib for RAI-refractory thyroid cancer patients (disease progression prior to enrollment was 
not required) in which some minor reductions in tumor size but no RECIST responses were 
observed, the median progression-free survival was only 3.9 months (Pennell et al., 2008), 
corresponding to a 6-month PFS of 34% (under exponential distribution assumption).  Because 
our study requires progression of disease at enrollment, we expect a higher progression rate, 
therefore assumed a 20% 6-month PFS (null hypothesis).  Since all the RAI-refractory patients 
on the pilot selumetinib study with enhanced RAI incorporation had durable partial responses or 
stable disease up to 6 months following RAI, we are targeting 50% of patients to be progression-
free at the 6 month time point with treatment on this study.  For ORR, the assumption that only 
5% of these patients would have a RECIST response with RAI alone at the 6-month time point is 
based upon the premise that we are enrolling a population deemed refractory to RAI alone 
according to clinical criteria. 
 
Cohort B (BRAF/RAS WT): The primary objective for this arm will be to explore if treatment 
with trametinib can increase iodine incorporation in thyroid cancer metastases to a predicted 
lesional absorbed radiation dose equal to or exceeding 2,000 cGy with the administration of < 

84 
 
300 mCi RAI.  We will consider the treatment worthy of further investigation if at least 3 of the 
10 patients enrolled meet this criterion (what we call here “response”). If the true response rate in 
the population is less than 10%, the probability of seeing 3 or more responses in 10 patients is 
7% or less. Therefore, we can be reasonably certain that 3 or more responses are indicative of 
real drug activity.  All patients enrolled in the trial who receive at least one dose of trametinib 
will be included in determination of these endpoints.  Patients who are taken off study prior to 
receiving one dose of trametinib may be replaced.      
 
13.2 Sample Size/Accrual Rate 
 
The planned sample size for Cohort A is 25 patients and for Cohort B 10 patients.  We anticipate 
accruing 1-2 patients per month in both Cohorts A and B.   
 
13.3 Stratification Factors 
 
The study will consist of two cohorts: Cohort A (RAS MUT patients) and Cohort B (BRAF/RAS 
WT patients). 
 
13.4 Analysis of Secondary Endpoints 
 
Cohort A (RAS MUT patients):  One secondary endpoint will be to determine if treatment with 
trametinib can adequately increase iodine incorporation in thyroid cancer metastases to a 
threshold sufficient to warrant 131I treatment in patients with RAI-refractory thyroid cancer. 
“Adequate increase” is defined as increasing iodine incorporation in thyroid cancer metastases to 
a predicted lesional absorbed radiation dose equal to or exceeding 2,000 cGy with the 
administration of < 300 mCi RAI.  Proportion of patients with an adequate increase will be 
reported, along with the corresponding exact 95% confidence interval.   
 
In another secondary analysis, the goal will be to determine whether treatment with trametinib 
and RAI is accompanied by decrease in thyroglobulin. For that purpose, we will perform a 
Wilcoxon signed rank test for paired samples to compare the thyroglobulin level before and after 
RAI treatment in the subset of patients treated with RAI.  
 
Assessing the safety/tolerability of trametinib in combination with RAI will be investigated as a 
secondary endpoint. All patients will be evaluable for toxicity from the time of their first 
treatment with trametinib. Toxicities will be assessed through the NCI Common Terminology 
Criteria for Adverse Events version 4.0, individually reported and summarized.  CTCAE version 
5.0 will be utilized for AE reporting beginning April 1, 2018 but investigators may continue to 
collect and locally store AE data in CTCAE v4.0. Monitoring for trametinib-related toxicities 
will be continued until 30 days after the last dose of drug therapy. 
 
Cohort B (BRAF/RAS WT patients): Secondary objectives will be determining the ORR (per 
RECIST v1.1 criteria) at the 6-month time point and the proportion of patients following at the 
6-month time point alive without disease progression by RECIST v1.1 criteria (evaluation of 
these objectives will be conducted according to all the specific criteria described above in 
Section 13.1 for Cohort A, including the allowance for patients to remain on study even with 
evidence of clinical or RECIST v1.1 radiologic disease progression prior to the 6-month time 

85 
 
point assessments).   
 
In another secondary analysis, the goal will be to determine whether treatment with trametinib 
and RAI is accompanied by decrease in thyroglobulin. For that purpose, we will perform a 
Wilcoxon signed rank test for paired samples to compare the thyroglobulin level before and after 
RAI treatment in the subset of patients treated with RAI.  
 
Assessing the safety/tolerability of trametinib in combination with RAI will be investigated as a 
secondary endpoint. All patients will be evaluable for toxicity from the time of their first 
treatment with trametinib. Toxicities will be assessed through the NCI Common Terminology 
Criteria for Adverse Events version 4.0, individually reported and summarized.  CTCAE version 
5.0 will be utilized for AE reporting beginning April 1, 2018 but investigators may continue to 
collect and locally store AE data in CTCAE v4.0. Monitoring for trametinib-related toxicities 
will be continued until 30 days after the last dose of drug therapy. 
 
Cohort C (select patients from Cohorts A and B with insufficient 124I PET changes): If analysis 
of the second lesional dosimetry suggests that therapeutic RAI will not be given, it will be 
concluded that the patient’s cancer is still refractory to RAI and he/she will not receive RAI.  
Such patients may be continued on trametinib alone in Cohort C if 1) the treating physician 
determines it to be clinically reasonable, and 2) the patient agrees to continue on trametinib.  The 
efficacy of MEK inhibition alone for RAI-refractory thyroid cancer has been evaluated with 
selumetinib in one phase II trial; that study reported only 1 partial response out of 32 evaluable 
patients.  The study included only one patient with a NRAS Q61R MUT tumor and 11 patients 
with tumors wild-type for BRAF, NRAS, and HRAS.  We hypothesize that more potent inhibition 
with trametinib will translate to greater clinical efficacy for patients with RAI-refractory thyroid 
cancers that are either RAS MUT or BRAF/RAS WT.   
 
We estimate that approximately 10 patients in total from Cohorts A and B will be enrolled in 
Cohort C.  Amongst these patients, we will estimate the proportion of patients following at the 6-
month time point alive without disease progression by RECIST v1.1 criteria, the best objective 
response (BOR) along with the corresponding exact 95% confidence intervals, and the 
safety/tolerability of trametinib. 
 
Changes in thyroglobulin will also be assessed while on treatment with trametinib; a Wilcoxon 
signed rank test for paired samples to compare the thyroglobulin level before and after RAI 
treatment in the subset of patients treated with RAI.  
Exploratory Objectives: We will also be performing correlative studies on serial research 
biopsies in a minimum of 6 RAS MUT and 3 BRAF/RAS WT patients and archival tumor tissue 
in order to evaluate the impact of trametinib upon 1) expression and phosphorylation of MAPK 
signaling pathway proteins, 2) expression and phosphorylation of negative feedback loops 
connected to the MAPK pathway (such as her3), 3) quantitative levels of mRNA transcripts for 
MAPK regulated and thyroid-specific gene products, and 4) the presence of other genetic 
alterations (the studies and assays completed will be dependent upon the existing technology at 
the time of analysis as well as the funding that is available).  These analyses will be descriptive 
and exploratory given the limited number of samples examined. 
The impact of trametinib therapy upon RAI uptake and/or efficiacy beyond one month is 

86 
 
unknown.  Patients who do not receive 131I after the second 124I PET/CT and remain on 
trametinib (those on Cohort C) may be evaluated with a third 124I PET/CT scan.  These patients 
will have the same Cohort A and B primary/secondary endpoints evaluated in an exploratory 
manner.  For patients who go on to be treated with 131I, that data will not be included in the 
statistical analyses for Cohorts A and B, but kept separate for this exploratory analysis.  The 
BOR data collected with trametinib therapy alone (prior to 131I therapy) from these patients will 
still be used for Cohort C analysis. 
 
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 
assigned one of the following categories:  1) complete response, 2) partial response, 3) 
stable disease, 4) progressive disease, 5) early death from malignant disease, 6) early 
death from toxicity, 7) early death because of other cause, or 9) unknown (not assessable, 
insufficient data).  [Note:  By arbitrary convention, category 9 usually designates the 
“unknown” status of any type of data in a clinical database.] 
 
All of the patients who met the eligibility criteria (with the possible exception of those 
who received no study medication) and received one dose of trametinib should be 
included in the main analysis of the response rate.  Patients in response categories 4-9 
should be considered to have a treatment failure (disease progression).  Thus, an incorrect 
treatment schedule or drug administration does not result in exclusion from the analysis 
of the response rate.  Precise definitions for categories 4-9 will be protocol specific.  
 
 
All conclusions should be based on all eligible patients.  Subanalyses may then be 
performed on the basis of a subset of patients, excluding those for whom major protocol 
deviations have been identified (e.g., early death due to other reasons, early 
discontinuation of treatment, major protocol violations, etc.).  However, these 
subanalyses may not serve as the basis for drawing conclusions concerning treatment 
efficacy, and the reasons for excluding patients from the analysis should be clearly 
reported.  The 95% confidence intervals should also be provided.  
 
14. 
PROTECTION OF HUMAN SUBJECTS 
 
14.1 Privacy 
 
MSK’s Privacy Office may allow the use and disclosure of protected health information 
pursuant to a completed and signed Research Authorization form. The use and disclosure 

87 
 
of protected health information will be limited to the individuals described in the Research 
Authorization form. A Research Authorization form must be completed by the Principal 
Investigator and approved by the IRB and Privacy Board (IRB/PB).  
 
The consent indicates that individualized de identified information collected for the 
purposes of this study may be shared with other qualified researchers. Only researchers 
who have received approval from MSK will be allowed to access this information which 
will not include protected health information, such as the participant’s name, except for 
dates. It is also stated in the Research Authorization that their research data may be shared 
with other qualified researchers. 
 
It is also stated in the consent formthat research data (e.g. genomic sequence) may be 
placed into databases monitored by the National Institutes of Health, and may be made 
accessible to investigators approved by the U.S. government. The requirements for 
submission of the genotype/phenotype data into the NIH GWAS Repository (or any other 
public database) will be followed as per MSK IRB GWAS SOP-503. 
 
15. 
INFORMED CONSENT PROCEDURES 
 
Before protocol-specified procedures are carried out, consenting professionals will explain full 
details of the protocol and study procedures as well as the risks involved to participants prior to 
their inclusion in the study. Participants will also be informed that they are free to withdraw from 
the study at any time. All participants must sign an IRB/PB-approved consent form indicating 
their consent to participate. This consent form meets the requirements of the Code of Federal 
Regulations and the Institutional Review Board/Privacy Board of this Center. The consent form 
will include the following:  
 
1. The nature and objectives, potential risks and benefits of the intended study.  
2. The length of study and the likely follow-up required. 
3. Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of supportive care 
for therapeutic studies.) 
4. The name of the investigator(s) responsible for the protocol. 
5. The right of the participant to accept or refuse study interventions/interactions and to 
withdraw from participation at any time.  
 
Before any protocol-specific procedures can be carried out, the consenting professional will fully 
explain the aspects of patient privacy concerning research specific information.  In addition to 
signing the IRB Informed Consent, all patients must agree to the Research Authorization 
component of the informed consent form. 
 
Each participant and consenting professional will sign the consent form. The participant must 
receive a copy of the signed informed consent form. 
 
Future Contact: Participants will be provided with results of the clinical assay tests, but will not 
be told the results from the research assays. With their permission, the participant and/or family 

88 
 
members may be contacted in the future to ask if they are interested in learning about the 
potential findings of inherited risks for cancer (and other types of diseases) that may have been 
an outcome of the research assay testing of their samples. Requirements for reporting incidental 
findings are located in Section 9.1.  
 

89 
 
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McCormack, R., Byrne, N., Cockerill, M., et al. (2010). Transcriptional pathway signatures 
predict MEK addiction and response to selumetinib (AZD6244). Cancer research 70, 2264-2273. 
 
Durante, C., Haddy, N., Baudin, E., Leboulleux, S., Hartl, D., Travagli, J.P., Caillou, B., Ricard, 
M., Lumbroso, J.D., De Vathaire, F., et al. (2006). Long-term outcome of 444 patients with 

90 
 
distant metastases from papillary and follicular thyroid carcinoma: benefits and limits of 
radioiodine therapy. The Journal of clinical endocrinology and metabolism 91, 2892-2899. 
 
Durante, C., Puxeddu, E., Ferretti, E., Morisi, R., Moretti, S., Bruno, R., Barbi, F., Avenia, N., 
Scipioni, A., Verrienti, A., et al. (2007). BRAF mutations in papillary thyroid carcinomas inhibit 
genes involved in iodine metabolism. The Journal of clinical endocrinology and metabolism 92, 
2840-2843. 
 
Elisei, R., Ugolini, C., Viola, D., Lupi, C., Biagini, A., Giannini, R., Romei, C., Miccoli, P., 
Pinchera, A., and Basolo, F. (2008). BRAF(V600E) mutation and outcome of patients with 
papillary thyroid carcinoma: a 15-year median follow-up study. The Journal of clinical 
endocrinology and metabolism 93, 3943-3949. 
 
Eschmann, S.M., Reischl, G., Bilger, K., Kupferschlager, J., Thelen, M.H., Dohmen, B.M., 
Besenfelder, H., and Bares, R. (2002). Evaluation of dosimetry of radioiodine therapy in benign 
and malignant thyroid disorders by means of iodine-124 and PET. Eur J Nucl Med Mol Imaging 
29, 760-767. 
 
Furhang, E.E., Larson, S.M., Buranapong, P., and Humm, J.L. (1999). Thyroid cancer dosimetry 
using clearance fitting. J Nucl Med 40, 131-136. 
 
Infante, J.R., Falchook, G.S., Lawrence, D.P., Weber, J.S., Kefford, R.F., Bendell, J.C., 
Kurzrock, R., Shapiro, G., Kudchadkar, R.R., Long, G.V., et al. (2011). Phase I/II study to assess 
safety, pharmacokinetics, and efficacy of the oral MEK 1/2 inhibitor GSK1120212 (GSK212) 
dosed in combination with the oral BRAF inhibitor GSK2118436 (GSK436). ASCO Meeting 
Abstracts 29, Abstract CRA8503. 
 
Jemal, A., Siegel, R., Xu, J., and Ward, E. (2010). Cancer statistics, 2010. CA Cancer J Clin 60, 
277-300. 
 
Kimura, E.T., Nikiforova, M.N., Zhu, Z., Knauf, J.A., Nikiforov, Y.E., and Fagin, J.A. (2003). 
High prevalence of BRAF mutations in thyroid cancer: genetic evidence for constitutive 
activation of the RET/PTC-RAS-BRAF signaling pathway in papillary thyroid carcinoma. 
Cancer research 63, 1454-1457. 
 
Kirkwood, J.M., Bastholt, L., Robert, C., Sosman, J.A., Larkin, J., Hersey, P., Middleton, M.R., 
Cantarini, M.V., Zazulina, V., Kemsley, K., et al. (2011). Phase II, Open-Label, Randomized 
Trial of the MEK 1/2 Inhibitor Selumetinib as Monotherapy versus Temozolomide in Patients 
with Advanced Melanoma. Clinical cancer research : an official journal of the American 
Association for Cancer Research. 
 
Knauf, J.A., and Fagin, J.A. (2009). Role of MAPK pathway oncoproteins in thyroid cancer 
pathogenesis and as drug targets. Curr Opin Cell Biol 21, 296-303. 
 
Knauf, J.A., Kuroda, H., Basu, S., and Fagin, J.A. (2003). RET/PTC-induced dedifferentiation of 
thyroid cells is mediated through Y1062 signaling through SHC-RAS-MAP kinase. Oncogene 

91 
 
22, 4406-4412. 
 
Lee, J.H., Lee, E.S., and Kim, Y.S. (2007). Clinicopathologic significance of BRAF V600E 
mutation in papillary carcinomas of the thyroid: a meta-analysis. Cancer 110, 38-46. 
Leeper, R.D. (1973). The effect of 131 I therapy on survival of patients with metastatic papillary 
or follicular thyroid carcinoma. J Clin Endocrinol Metab 36, 1143-1152. 
 
Liu, D., Hu, S., Hou, P., Jiang, D., Condouris, S., and Xing, M. (2007). Suppression of 
BRAF/MEK/MAP kinase pathway restores expression of iodide-metabolizing genes in thyroid 
cells expressing the V600E BRAF mutant. Clinical cancer research : an official journal of the 
American Association for Cancer Research 13, 1341-1349. 
 
Liu, Y.Y., van der Pluijm, G., Karperien, M., Stokkel, M.P., Pereira, A.M., Morreau, J., Kievit, 
J., Romijn, J.A., and Smit, J.W. (2006). Lithium as adjuvant to radioiodine therapy in 
differentiated thyroid carcinoma: clinical and in vitro studies. Clin Endocrinol (Oxf) 64, 617-
624. 
 
Lubberink, M., Lundqvist, H., Westlin, J.E., Tolmachev, V., Schneider, H., Lovqvist, A., Sundin, 
A., and Carlsson, J. (1999). Positron emission tomography and radioimmunotargeting--aspects of 
quantification and dosimetry. Acta Oncol 38, 343-349. 
 
Mazzaferri, E.L., and Kloos, R.T. (2001). Clinical review 128: Current approaches to primary 
therapy for papillary and follicular thyroid cancer. The Journal of clinical endocrinology and 
metabolism 86, 1447-1463. 
 
Nikiforov, Y.E., and Nikiforova, M.N. (2011). Molecular genetics and diagnosis of thyroid 
cancer. Nat Rev Endocrinol 7, 569-580. 
 
Pennell, N.A., Daniels, G.H., Haddad, R.I., Ross, D.S., Evans, T., Wirth, L.J., Fidias, P.H., 
Temel, J.S., Gurubhagavatula, S., Heist, R.S., et al. (2008). A phase II study of gefitinib in 
patients with advanced thyroid cancer. Thyroid : official journal of the American Thyroid 
Association 18, 317-323. 
 
Pentlow, K.S., Graham, M.C., Lambrecht, R.M., Daghighian, F., Bacharach, S.L., Bendriem, B., 
Finn, R.D., Jordan, K., Kalaigian, H., Karp, J.S., et al. (1996). Quantitative imaging of iodine-
124 with PET. Journal of nuclear medicine : official publication, Society of Nuclear Medicine 
37, 1557-1562. 
 
Pratilas, C.A., Taylor, B.S., Ye, Q., Viale, A., Sander, C., Solit, D.B., and Rosen, N. (2009). 
(V600E)BRAF is associated with disabled feedback inhibition of RAF-MEK signaling and 
elevated transcriptional output of the pathway. Proceedings of the National Academy of Sciences 
of the United States of America 106, 4519-4524. 
 
Ricarte-Filho, J.C., Ryder, M., Chitale, D.A., Rivera, M., Heguy, A., Ladanyi, M., Janakiraman, 
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92 
 
BRAF, PIK3CA, and AKT1. Cancer research 69, 4885-4893. 
 
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Santisteban, P. (2006). The oncogene BRAF V600E is associated with a high risk of recurrence 
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alternative events in the etiopathogenesis of PTC. Oncogene 22, 4578-4580. 
 
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and Wartofsky, L. (2010). (124)I positron emission tomography versus (131)I planar imaging in 
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RET/PTC rearrangements in thyroid papillary carcinomas: effects of the detection methods and 
genetic heterogeneity. The Journal of clinical endocrinology and metabolism 91, 3603-3610. 

93 
 
 
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. 
 
 
 
 
 
 
 
 
 

94 
 
 
APPENDIX B:  
LOW IODINE DIET 
 
The Low Iodine Diet 
 
What is Iodine? 
Iodine is a mineral. It plays an important role in several processes that take place in the body. One is the 
production of a hormone called thyroxine, which occurs in the thyroid gland. 
 
Where is Iodine Found? 
The amount of iodine found in food varies. Much of the iodine we get comes from iodized salt and 
breads. Adults need 150 micrograms of iodine a day. This booklet describes a low iodine diet. This is a 
diet with less than 50 micrograms of iodine per day. 
 
Why is a Low Iodine Diet Necessary? 
The iodine in your diet can block the uptake of radioactive iodine by the thyroid gland. Your doctor could 
put you on a low iodine diet one or two weeks before you get the radioactive iodine. Stay on this diet until 
your test or treatment is complete. Your doctor will tell you when to begin and when to stop this diet. If 
you have any questions, speak with your doctor. You may also see a dietitian if necessary. If you have 
any questions about your diet, call (212) 639-7312 to speak to a dietitian. 
 
What Should You Avoid? 
 
Read all food labels to check for iodine content. Do NOT eat or use: 
• Iodized salt. 
• Sea salt in any form. 
• Onion salt. 
• Celery salt. 
• Garlic salt. 
• Seasoned salt. 
• Kelp (seaweed). 
• Any food that has: 
o Iodates 
o Iodides 
o Algin 
o Alginates 
o Carrageen 
o Agar 
• Commercial breads and bakery products because they often contain iodate. 
• Milk (except for 1 ounce a day), eggs, and seafood. 
• Vitamins and food supplements if they have iodine. If you have any doubt, do not take them. 
• Food, pills, or capsules with food dyes or that are orange, red, or brown in color. Examples include red 
or pink cereals or candies. 
• Antiseptics, such as tincture of iodine (Betadine®) applied on a cut. 
• Cough medicines (especially those with red coloring). 
• Supplements such as: 
o Ensure® 
o Boost® 
o Commercial shakes 

95 
 
o Nutrament® 
• Restaurant and processed foods, because they are often high in iodine content. 
• Soy products such as edamame, tofu, soy burgers (e.g., Boca®), etc. 
• All canned foods, because the lining of the can contains iodine. 
 
Do not stop taking any of your medicines unless your doctor tells you. If you are receiving tube feeding 
formula, ask your dietitian or doctor what to do. This low iodine diet does not meet the suggested daily 
allowance for all nutrients. You will be on it for a short time only. 
 
Drink Plenty of Fluids 
Note: Unless your doctor tells you differently, you must drink at least 8 to 10, 8-ounce cups of fluid a day. 
This includes the drinks in the diet guidelines and as much water as you want. 
 
Low Iodine Diet Guidelines: 
 
Breads and Cereals 
 
Total number of servings per day: 6-8 
(1 serving equals 1 slice of bread or 1/2 cup of cooked pasta) 
 
Include 
Plain cooked barley, oats, millet, buckwheat, bulgur wheat, quinoa; unsalted, unprocessed preservative-
free boxed cereals such as puffed rice and shredded wheat; rice, plain macaroni, spaghetti, noodles; cream 
of rice or cream of wheat hot cereals; unsalted rice cakes, unsalted plain matzah, English muffins, plain 
unsalted popcorn, homemade breads prepared without commercial dough. 
 
Avoid 
All commercial breads and rolls, processed boxed cereals, salted crackers, potato chips, pretzels, bagels, 
bialys, Melba toast, all other crackers, egg noodles, packaged rice and pasta mixes. 
 
Meat and Meat Substitutes 
 
Total number of servings per day: Two–three 
(1 serving equals 3 ounces of meat, fish, poultry, or 2 Tablespoons of unsalted peanut or almond butter) 
 
Include 
Fresh beef, veal, pork, lamb, chicken and turkey; unsalted peanut or almond butter; fresh-water fish such 
as carp, riverbass, lake trout, and river perch; fresh egg white. 
 
Avoid 
Egg yolks and whole eggs, foods made with eggs; all fast foods; all canned fish such as salmon and tuna; 
seafood, shellfish (clams, crabs, oysters, lobsters), or any food made with fish stock; all processed meats; 
liver and all organ meats; all canned, dried, salted, or cured meats such as bacon, sausage, ham, 
frankfurters, chipped beef, luncheon meats (salami, bologna, pastrami); spicy meats such as chili, beef 
jerky, liverwurst; all canned or processed poultry such as turkey or chicken roll; tofu and soy products, 
such as soy burgers (e.g., Boca); salted peanut butter. 
Milk and Milk Products 
 
Total number of servings per day: Zero 
 

96 
 
Include 
None allowed 
Exception: Only 1 ounce of milk a day in your coffee 
or tea. 
 
Avoid 
All milk (except for one ounce daily) and milk products such as condensed or evaporated milk, cheese, 
yogurt, puddings, ice cream, custard; any cream such as heavy or light cream, whipped cream, sour 
cream; any foods made with cream or milk or cheese such as cream soup, pizza, macaroni and cheese. 
 
Fruits 
 
Total number of servings per day: Five 
(1 serving equals 1 small piece of fruit or 3/4 cup of juice) 
 
Include 
All fresh fruit, exception: limit bananas to 1 serving per day; fresh apple sauce; all natural frozen fruits; 
fresh fruit juices (including bottles or cartons of fruit juice without artificial coloring or preservatives); 
white grape juice. 
 
Avoid 
Cranberries, all dried fruits, all canned fruits and canned fruit juices; jarred applesauce; cranberry and 
grape juice, canned or bottled cherries; rhubarb. 
 
Vegetables 
Total number of servings per day: Four 
(1 serving equals 1/2 cup of cooked or 1 cup raw vegetable) 
 
Include 
All fresh vegetables except spinach, fresh potatoes without skin, all plain frozen vegetables without added 
salt, fresh or dried legumes such as lentils and peas. 
 
Avoid 
All canned vegetables and all canned vegetable juices, fresh or dried beans such as red kidney beans, lima 
beans, navy beans,pinto beans and cowpeas; canned legumes (such as beans, peas, and lentils); canned 
soups; sauerkraut, celery; commercially prepared potatoes (e.g. instant mashed potatoes); frozen 
vegetables with added salt; spinach. 
 
Fat 
Total number of servings per day: 
Suggest four to six servings a day 
(1 serving equals 1 teaspoon of butter or oil) 
 
Include 
Unsalted margarine or sweet butter (not more than 1 teaspoon of each per day), oils, vegetable shortening, 
plain oil and white vinegar dressing. 
 
Avoid 
Salted nuts and seeds, mayonnaise, commercial salad dressings, and lard. 
 

97 
 
Beverages 
Total number of servings per day: No restrictions 
One serving equals 12 ounces of a carbonated beverage or 1 cup 
(8 ounces) of any of the other beverages listed 
 
Include 
Water; bottled carbonated beverages without added coloring (such as Sprite®, 7-Up®, sodium-free 
seltzer); brewed coffee, tea steeped from tea leaves; white tea bags; fresh lemonade or fresh orangeade. 
 
Avoid 
Mineral water containing sodium; all bottled, canned, or powdered: iced tea, lemonade, instant coffee, 
instant tea, instant iced-tea, fruit punch, and other powdered or commercial drinks, such as Hi-C® and 
Kool-Aid®; tea steeped from tea bags; soy milk and rice milk ( which contain sea salt); ginger ale, 
Coke®, Pepsi® or any other carbonated beverages with added coloring. 
 
Desserts and sweets 
Total number of servings per day: Two 
(See below for serving equivalents) 
 
Include 
Each of the following equals 
1 serving: 
• 1 cup Knox® clear gelatin 
• 2 tablespoons (T) sugar 
• 2T Honey 
• 2T Maple syrup 
• 2 regular size Marshmallows 
• 1/2 cup Natural sorbets with no coloring or added salt 
 
Avoid 
All bakery products such as pies, cakes, pastries, 
danishes, muffins, donuts and cookies; graham crackers; 
Jell-O®, colored gelatins; chocolate and chocolate 
desserts; candy. 
 
Miscellaneous 
Total number of servings per day: Unlimited 
 
Include 
Pepper, spices such as cinnamon; herbs such as oregano; white vinegar, and non-iodized salt 
(contains trace amounts of iodine, use sparingly). 
 
Avoid 
All salted foods such as salted nuts, Chinese food, soy sauce, catsup, Worcestershire sauce, chili sauce, all 
commercial sauces, tomato sauce, all gravies, olives, pickles, relish, bouillon cubes, soup bases, iodized 
salt, sea salt, onion salt, garlic salt, celery salt, seasoned salt, kelp (seaweed); molasses; any food 
containing food coloring, iodates, iodides, iodate dough conditioners or stabilizers, algin, alginate, 
carrageens, agar, or nori (seaweed); all sushi; red wine vinegar, balsamic vinegar (with caramel coloring); 
all additives, preservatives, or artificial colorings. 
 

98 
 
Sample Menu for a Low Iodine Diet 
 
BREAKFAST 
1 Fruit 1⁄2 cup orange juice 
3 Breads 1⁄2 cup oatmeal (no milk) 
1 plain unsalted matzah 
1 Meat 1 egg white omelet 
Misc. 2 teaspoons sugar 
1 Beverage 1 cup brewed coffee 
 
MID MORNING SNACK 
1 Fruit 2 Rice cakes 
1 teaspoon unsalted butter 
1 cup water 
 
LUNCH 
1 Meat 3 oz fresh turkey breast 
2 Fats 2 tsp oil 
2 Breads 2 slices homemade white bread 
1 Vegetable 1 cup Romaine lettuce 
1 Beverage 1 cup fresh lemonade 
 
MID AFTERNOON SNACK 
1 Fruit 1 fresh apple 
1 Meat 2 tablespoons unsalted peanut butter 
DINNER 
1 Meat 3 oz roast beef 
2 Breads 1 baked potato (no skin) 
2 Vegetables 1 cup fresh broccoli 
2 Fats 2 tsp oil (used in cooking) 
1 Fruit 1 orange 
1 Beverage 1 cup white tea 
 
BEDTIME SNACK 
1 Fruit 1 small pear 
1 Beverage 1 cup tea made from fresh tea leaves 
©1997 Memorial Sloan Kettering Cancer Center 
1275 York Avenue, New York, New York 10065 
Revised 2002, 2004, 2006, 2008 

99 
 
APPENDIX C:  
PILL DIARY 
 
 
MSK IRB 13-157: A Phase 2 Study of Trametinib in Combination with Radioiodine (RAI) for 
RAS Mutant or RAS/RAF Wild-Type, RAI-Refractory Recurrent and/or Metastatic Thyroid 
Cancers 
 
Patient Name:  ____________________ MRN:_________________ 
Cycle Number: ____(cycle length = 28 days) 
 
To be completed by MD/RN:  
Total Daily Dose of Trametinib: _____________________________ 
 
Study Medication Instructions:  
• Take trametinib once daily, either 1 hour before or 2 hours after a meal 
• Please fill out each dose on this diary 
• Bring your study medication and diary to your next visit   
  
Date 
Was Dose Taken? 
 
At What Time? 
Total Number of Pills 
Taken 
EXAMPLE: 
11/3/2016 
Day 1 
Yes  
No 
08:52  AM/PM 
1 pill 2 mg 
___/___/___ 
Day 1 
Yes  
No 
___:___ AM/PM 
___        mg 
___/___/___ 
Day 2 
Yes  
No 
___:___ AM/PM 
___        mg 
___/___/___ 
Day 3 
Yes  
No 
___:___ AM/PM 
___        mg 
___/___/___ 
Day 4 
Yes  
No 
___:___ AM/PM 
___        mg 
___/___/___ 
Day 5 
Yes  
No 
___:___ AM/PM 
___        mg 
___/___/___ 
Day 6 
Yes  
No 
___:___ AM/PM 
___        mg 
___/___/___ 
Day 7 
Yes  
No 
___:___ AM/PM 
___        mg 
___/___/___ 
Day 8 
Yes  
No 
___:___ AM/PM 
___        mg 
___/___/___ 
Day 9 
Yes  
No 
___:___ AM/PM 
___        mg 
___/___/___ 
Day 10 
Yes  
No 
___:___ AM/PM 
___        mg 
___/___/___ 
Day 11 
Yes  
No 
___:___ AM/PM 
___        mg 
___/___/___ 
Day 12 
Yes  
No 
___:___ AM/PM 
___        mg 
___/___/___ 
Day 13 
Yes  
No 
___:___ AM/PM 
___        mg 
___/___/___ 
Day 14 
Yes  
No 
___:___ AM/PM 
___        mg 
___/___/___ 
Yes  
No 
___:___ AM/PM 
___        mg 

100 
 
Day 15 
___/___/___ 
Day 16 
Yes  
No 
___:___ AM/PM 
___        mg 
___/___/___ 
Day 17 
Yes  
No 
___:___ AM/PM 
___        mg 
___/___/___ 
Day 18 
Yes  
No 
___:___ AM/PM 
___        mg 
___/___/___ 
Day 19 
Yes  
No 
___:___ AM/PM 
___        mg 
___/___/___ 
Day 20 
Yes  
No 
___:___ AM/PM 
___        mg 
___/___/___ 
Day 21 
Yes  
No 
___:___ AM/PM 
___        mg 
___/___/___ 
Day 22 
Yes  
No 
___:___ AM/PM 
___        mg 
___/___/___ 
Day 23 
Yes  
No 
___:___ AM/PM 
___        mg 
___/___/___ 
Day 24 
Yes  
No 
___:___ AM/PM 
___        mg 
___/___/___ 
Day 25 
Yes  
No 
___:___ AM/PM 
___        mg 
___/___/___ 
Day 26 
Yes  
No 
___:___ AM/PM 
___        mg 
___/___/___ 
Day 27 
Yes  
No 
___:___ AM/PM 
___        mg 
___/___/___ 
Day 28 
Yes  
No 
___:___ AM/PM 
___        mg 
 
 
 
Patient Signature:  ___________________________________  Date: ___/___/___ 
 
MD/RN Signature:___________________________________  Date: ___/___/___ 
 
Comments:  

101 
 
APPENDIX D: 
124I NORMAL ORGAN RADIATION DOSIMETRY  
       (Note: this is a general guideline) 
 
 
 

102 
 
APPENDIX E: 
DOSIMETRIC RADIOIODIDE SCINTIGRAPHY (AKA ‘FULL DOSIMETRY’) 
(I-131 as Sodium Iodide) 
 
Equipment Required 
 
A 
Whole body scanning gamma camera with dual detectors and High Energy General Purpose (I-
131) collimators; calibrated for use with I-131using a 20% window centered at 364 keV. 
 
B. 
SPECT/CT as needed post therapy. 
 
C. 
Well scintillation counter capable of counting I-131 blood samples. 
 
D. 
I-131 standard for well counter, activity approximately 0.5 microcuries, accurately known. 
 
E. 
I-131 standard for gamma camera, activity approximately 300 microcuries, accurately known. 
 
Radiopharmaceutical, Dose, & Technique of Administration 
 
• 
Radiopharmaceutical: I-131 as sodium iodide 
 
• 
Dose: I-131 for full dosimetry:  ≤5.0 mCi  
 
• 
Technique of administration: Oral 
 
Patient Preparation 
 
A. 
Pregnancy:  I-131 is contraindicated in pregnant women.  In women who are of childbearing age, 
pregnancy testing must be performed before the use of I-131 as dictated by the protocol. 
 
 
B. 
Breast feeding:   
 
1. Elective studies using I-131 in lactating women should be postponed for at least 2 weeks, to 
decrease the radiation dose to the breast.   
 
2. Breast feeding should be discontinued, following the administration of I-131. 
 
C. 
Patients are instructed to continue their Levoxyl/Synthroid. They do not have to be fasting and can 
have a light breakfast before the scheduled appointment for dosimetry. 
 
 

103 
 
APPENDIX F:  
 
RESEARCH LAB DRAW FORM 
 
NCI Protocol #: 9446 
Local Protocol #: 13-157  
 
Protocol Title:  A Phase 2 Study of Trametinib in Combination with Radioiodine (RAI) for RAS 
Mutant or RAS/RAF Wild-Type, RAI-Refractory Recurrent and/or Metastatic Thyroid Cancers 
 
 
 
 
 
Sample drawn by:_________________________ 
 
 
 
 
10 milliliters of blood will be collected in one Purple Top EDTA tube. 
 
Please contact the Research Study Assistant below immediately once the blood is drawn.  
 
 
Research Study Assistant:   
  
Phone:  
   
 
 
Pager: 
 
Principal Investigator: Alan Ho, MD, PhD 
Solid Tumor 
Head and 
Neck 
 
Research blood for Protocol 13-157.  
 
Please place in -80 freezer 
 
Time(s) Samples Brought To Storage: ______________ 
Dr. James Fagin’s lab, Z519   
                                                                    
 
Date of Informed Consent:  
Date Drawn:   
Time Drawn:  

104 
 
APPENDIX G:  
RESEARCH BIOPSY SAMPLE FORM 
 
NCI Protocol #: 9446 
Local Protocol #: 13-157  
 
Protocol Title:  A Phase 2 Study of Trametinib in Combination with Radioiodine (RAI) for RAS 
Mutant or RAS/RAF Wild-Type, RAI-Refractory Recurrent and/or Metastatic Thyroid Cancers 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Research Study Assistant:   
  
Phone:  
   
 
 
Pager: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Principal Investigator: Alan Ho, MD, PhD 
Solid Tumor 
Head and 
Neck 
Sample Type:  
 
 
 
 
Time(s) Samples Brought To Storage:  
 
______________ 
Dr. James Fagin’s lab, Z519   
                                                                    
 
Date of Informed Consent:  
Type of Biopsy:  
Date of Biopsy:   

105 
 
APPENDIX  H: 
 
 RESEARCH SLIDES FORM 
 
NCI Protocol #: 9446 
Local Protocol #: 13-157  
 
Protocol Title:  A Phase 2 Study of Trametinib in Combination with Radioiodine (RAI) for RAS 
Mutant or RAS/RAF Wild-Type, RAI-Refractory Recurrent and/or Metastatic Thyroid Cancers 
 
 
 
 
 
 
 
 
Research Study Assistant:   
  
Phone:  
   
 
 
Pager: 
                                     
 
Principal Investigator: Alan Ho, MD, PhD 
Solid Tumor 
Head and 
Neck 
 
Sample Type:  
 
 
Date dropped off: 
 
 
Time(s) Samples Brought To Storage:  
______________ 
Dr. James Fagin’s lab, Z519   
                                                                    

106 
 
APPENDIX I:  
 
PATIENT CALENDAR  HANDOUT 
 
Protocol Title:  A Phase 2 Study of Trametinib in Combination with Radioiodine (RAI) for RAS 
Mutant or RAS/RAF Wild-Type, RAI-Refractory Recurrent and/or Metastatic Thyroid Cancers 
 
 
NOTE: ALL lab appointments must be done first during Week 1 and Week 5 
 
 
Please contact your MD’s office with any scheduling questions or concerns. 
 
Monday 
Tuesday 
Wednesday 
Thursday 
Friday 
Saturday 
Week  1: Day 1 
 
Lab 
  
Nuclear Medicine 
Follow-up with Primary 
MD on regular clinic 
day(s) 
Day 2 
 
 
Nuclear Medicine 
Day 3 
 
Lab 
 
 
Nuclear Medicine 
      Day 4 
 
 
Off-Day 
Day 5 
 
Lab 
 
 
Nuclear  Medicine 
Day 6 
 
Begin study drug  
Off week, drug only 
 
 
 
 
 
Week 3: 
 
Lab* 
 
Follow-up with Primary 
MD on regular clinic 
day(s) 
 
* anytime this week 
 
 
 
 
 
Off week, drug only 
 
 
 
 
 
Week 5: Day 1 
 
Lab  
 
Nuclear Medicine 
 
    Day 2 
 
Nuclear Medicine 
         Day 3 
 
Lab 
 
 
Nuclear Medicine 
 
    Day 4 
Off-Day 
    Day 5 
Lab 
Nuclear Medicine 
Week 5 Day 5 MD 
visit 
 

107
Appendix J: 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