Clinical trial NCT03299088
Conditions: KRAS Gene Mutation Metastatic Non-Squamous Non-Small Cell Lung Carcinoma Recurrent Non-Squamous Non-Small Cell Lung Carcinoma Stage IV Non-Small Cell Lung Cancer AJCC v7
Sponsor: Jonathan Riess
Start date: 2018-06-26; Completion date: 2024-06-25
Enrollment: 15 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This phase Ib trial studies the side effects of pembrolizumab and trametinib in treating patients with non-small cell lung cancer and KRAS gene mutations that has spread to other places in the body. Monoclonal antibodies, such as pembrolizumab, may interfere with the ability of tumor cells to grow and spread. Trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving pembrolizumab and trametinib may work better in treating patients with non-small cell lung cancer.

Detailed description:
PRIMARY OBJECTIVES:

I. To evaluate the safety and tolerability of pembrolizumab (MK-3475) when given in combination with trametinib in the proposed sequencing schemes in patients with advanced or metastatic non-small cell lung cancer with KRAS mutations.

SECONDARY OBJECTIVES:

To assess in a preliminary manner the clinical efficacy of these combinations with the proposed sequencing schemes including overall response rate and progression free survival.

TERTIARY OBJECTIVES:

To determine in an exploratory manner changes in PD-L1 expression as well as other immune correlates induced by mitogen-activated extracellular signal-regulated kinase (MEK) inhibition.

Arms: arm 1: Patients receive trametinib PO daily. Beginning on day 1 of course 2, patients also receive pembrolizumab IV over 30 minutes. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity. arm 2: Patients receive pembrolizumab IV over 30 minutes on day 1. Beginning on day 1 of course 2, patients also receive trametinib PO daily. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Pembrolizumab intervention 2: Trametinib
Intervention descriptions: intervention 1: Given IV intervention 2: Given PO

Protocol documents:
Prot_SAP_000.pdf: 
 
 
A PHASE IB TRIAL OF PEMBROLIZUMAB (MK-3475) AND TRAMETINIB 
FOCUSED ON ADVANCED KRAS MUTANT NON-SMALL CELL LUNG CANCER 
 
Funding Sources: 
Merck & Co., Inc. [study ID TBD] 
 
Novartis [study ID TBD] 
 
Protocol Number(s):  
UCDCC#259; (Merck); (Novartis) 
 
Phase: 
1 
 
Principal Investigator:  
Jonathan Riess, MD, MS 
UC Davis Comprehensive Cancer Center 
4501 X Street 
Sacramento, CA 95817 
Telephone: (916) 734-3771 
Fax: (916) 734-7946  
jwriess@ucdavis.edu 
 
Co-Investigators: 
David Gandara, MD  
UC Davis Comprehensive Cancer Center 
4501 X Street 
Sacramento, CA 95817 
Telephone: (916) 734-3771 
Fax: (916) 734-7946  
drgandara@ucdavis.edu 
 
Karen Kelly, MD 
UC Davis Comprehensive Cancer Center 
4501 X Street, Sacramento, CA 95817 
Telephone: (916) 734-3771 
Fax: (916) 734-7946 
karkelly@ucdavis.edu 
 
Primo N. Lara, Jr. MD 
UC Davis Comprehensive Cancer Center 
4501 X Street, Sacramento, CA 95817 
Telephone: (916) 734-3771 
Fax: (916) 734-7946 
pnlara@ucdavis.edu 
 
Statistician:  
Laurel Beckett, PhD 
Division of Biostatistics, MS1C 
University of California Davis 
One Shields Avenue 
Davis, CA 95616  
labeckett@ucdavis.edu 
 
 


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IND NUMBER: 
TBD 
 
IND Sponsor: 
UC Davis Comprehensive Cancer Center 
 
Version No./Date: 
Original / May 9, 2017  
 
Participating Site(s):  
Select SU2C Sites 
 
 
 
 
 


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INVESTIGATOR SIGNATURE PAGE 
 
Protocol Number:  UCDCC#259 
Protocol Title: A Phase Ib Trial of Pembrolizumab (MK-3475) and Trametinib Focused on 
Advanced KRAS Mutant Non-Small Cell Lung Cancer 
I have read this protocol and agree that it contains all necessary details for carrying out this 
study. I will conduct the study as outlined herein and will complete the study within the time 
designated, in accordance with all stipulations of the protocol and in accordance with Good 
Clinical Practices, local regulatory requirements, and the Declaration of Helsinki.  
I will provide copies of the protocol and all pertinent information to all individuals responsible to 
me who assist in the conduct of this study. I will discuss this material with them to ensure that 
they are fully informed regarding the study agent(s) and the conduct of the study.  
 
__________________________________ 
Investigator Name (print) 
__________________________________ 
Investigator Signature  
_____________________ 
Date 
 
 
 


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TABLE OF CONTENTS 
INVESTIGATOR Signature Page ................................................................................................................ 3 
TABLE OF CONTENTS .............................................................................................................................. 4 
List of Tables ................................................................................................................................................ 5 
List of Figures ............................................................................................................................................... 5 
List of Abbreviations .................................................................................................................................... 6 
1.0 
TRIAL SUMMARY ........................................................................................................................ 8 
2.0 
TRIAL DESIGN .............................................................................................................................. 9 
2.1 
Trial Design ................................................................................................................................. 9 
2.2 
Trial Diagram .............................................................................................................................. 9 
3.0 
OBJECTIVES & HYPOTHESES ................................................................................................. 10 
3.1 
Primary Objective & Hypotheses .............................................................................................. 10 
3.2 
Secondary Objective & Hypotheses .......................................................................................... 10 
3.3 
Exploratory Objective ............................................................................................................... 10 
4.0 
BACKGROUND & RATIONALE ............................................................................................... 10 
4.1 
Pembrolizumab (MK-3475) ...................................................................................................... 10 
4.2 
Trametinib ................................................................................................................................. 12 
4.3 
Rationale .................................................................................................................................... 12 
5.0 
METHODOLOGY ........................................................................................................................ 18 
5.1 
Entry Criteria ............................................................................................................................. 18 
5.2 
Trial Treatments ........................................................................................................................ 22 
5.3 
Treatment ................................................................................................................................... 33 
5.4 
Definition of Dose Limiting Toxicities ..................................................................................... 33 
5.5 
Concomitant Medications/Vaccinations (allowed & prohibited) .............................................. 35 
5.6 
Rescue Medications & Supportive Care .................................................................................... 36 
5.7 
Diet/Activity/Other Considerations ........................................................................................... 41 
5.8 
Subject Withdrawal/Discontinuation Criteria ........................................................................... 43 
5.9 
Subject Replacement Strategy ................................................................................................... 45 
5.10 
Clinical Criteria for Early Trial Termination ............................................................................ 45 
6.0 
Study Calendar ............................................................................................................................... 46 
7.0 
TRIAL PROCEDURES ................................................................................................................. 48 
7.1 
Trial Procedures......................................................................................................................... 48 
7.2 
Assessing and Recording Adverse Events................................................................................. 62 
8.0 
STATISTICAL ANALYSIS PLAN .............................................................................................. 70 
9.0 
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES .............. 73 
9.1 
Pembrolizumab .......................................................................................................................... 73 
9.2 
Trametinib ................................................................................................................................. 73 
9.3 
Packaging and Labeling Information ........................................................................................ 74 
9.4 
Clinical Supplies Disclosure ...................................................................................................... 74 
9.5 
Storage and Handling Requirements ......................................................................................... 74 
9.6 
Returns and Reconciliation ........................................................................................................ 75 
10.0 
ADMINISTRATIVE AND REGULATORY DETAILS .............................................................. 75 
10.1 
Confidentiality ........................................................................................................................... 75 
10.2 
Good Clinical Practice ............................................................................................................... 75 
10.3 
Patient Information and Informed Consent ............................................................................... 75 
10.4 
Records and Retention ............................................................................................................... 76 


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10.5 
Data and Safety Monitoring ...................................................................................................... 76 
10.6 
Compliance with Law and Regulations ..................................................................................... 77 
10.7 
Compliance with Trial Registration and Results Posting Requirements ................................... 77 
10.8 
Quality Management System .................................................................................................... 77 
11.0 
Appendices ..................................................................................................................................... 78 
11.1 
Multisite Patient Registration .................................................................................................... 78 
11.2 
Data Management ...................................................................................................................... 79 
11.3 
ECOG Performance Status ........................................................................................................ 80 
11.4 
FRIDERICIA’S CRITERIA FOR QTC CALCULATION ....................................................... 81 
11.5 
New York Heart Association Classification of Heart Failure ................................................... 82 
11.6 
Common Terminology Criteria for Adverse Events V4.0 (CTCAE) ........................................ 83 
11.7 
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for Evaluating Response 
in Solid Tumors ......................................................................................................................... 84 
11.8 
Drug Diary ................................................................................................................................. 85 
11.9 
References ................................................................................................................................. 87 
 
LIST OF TABLES 
Table 1.  Adequate Organ Function Laboratory Values .......................................................................... 19 
Table 2.  Trial Treatments ....................................................................................................................... 22 
Table 3. Dose Escalation Schema for Trametinib ................................................................................... 23 
Table 4. Dose Modification for Trametinib. Lowest permitted Trametinib dose will be 1.5 mg daily. .. 24 
Table 5. Dose Modification Guidelines for Pembrolizumab (MK-3475) for Drug-Related Adverse 
Events ...................................................................................................................................... 24 
Table 6 Dose Modification Guidelines for Trametinib for Drug-Related Adverse Events (Unless 
Otherwise Specified) ............................................................................................................... 26 
Table 7. Trametinib Dose Modification Guidelines and Stopping Criteria for LVEF Decrease ............. 27 
Table 8. Trametinib Withholding and Stopping Criteria for QTc Prolongation ...................................... 28 
Table 9. Trametinib Dose Modification Guidelines for Hypertension .................................................... 28 
Table 10. Management and Trametinib Dose Modification for Visual Changes and/or Ophthalmic 
Examination Findings .............................................................................................................. 29 
Table 11. Trametinib Dose Modification for RPED ................................................................................ 29 
Table 12. Management and Dose Modification Guidelines for Diarrhea ................................................ 30 
Table 13. Dose Modification Guidelines and Management for Rash ...................................................... 31 
Table 14. Pneumonitis Guidelines ........................................................................................................... 32 
Table 15: Dose Escalation Decision Rule Summary ............................................................................... 35 
Table 16. Infusion Reaction Treatment Guidelines ................................................................................. 40 
Table 17. Guidelines for Supportive Care of Rash from Trametinib ...................................................... 41 
Table 18.Tissue Summary ....................................................................................................................... 52 
Table 19. Laboratory Tests ...................................................................................................................... 60 
Table 20. Evaluating Adverse Events ...................................................................................................... 68 
Table 21. Product Descriptions ................................................................................................................ 73 
 
LIST OF FIGURES 
Figure 1. Response rates to pembrolizumab according to mutation status ............................................ 14 
Figure 2. In vivo antitumor activity in CT26 Mouse Model dependent on sequencing of MEK 
inhibition with trametinib and PD-1 blockade (Liu et al, Clinical Cancer Research 2015) ...... 14 


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LIST OF ABBREVIATIONS 
AE 
adverse event 
 
AST 
aspartate aminotransferase  
ALT 
alanine aminotransferase  
BAL  
bronchoalveolar lavage 
β-HCG3 
β-human chorionic gonadotropin 
BID  
twice daily 
CBC 
complete blood count 
CLIA 
Clinical Laboratory Improvement Amendments  
CNS 
central nervous system 
CR 
complete response 
CRF 
case report form (paper or electronic as appropriate for this study) 
CSR 
central serous retinopathy  
CT 
computed tomography 
DKA 
diabetic ketoacidosis  
DLT 
dose limiting toxicity 
DMSO 
dimethyl sulfoxide  
DNA 
deoxyribonucleic acid 
DSMB 
UCDCC Data and Safety Monitoring Board 
ECI 
events of clinical interest 
ECOG 
Eastern Cooperative Oncology Group  
EGFR  
Epidermal growth factor receptor 
ERK 
extracellular signal-regulated kinase  
EU 
European Union 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Amendments Act  
FDAMA 
Food and Drug Administration Modernization Act 
FFPE 
formalin-fixed, paraffin-embedded  
GCP 
Good Clinical Practice  
HBsAg 
hepatitis B surface antigen 
HCV 
Hepatitis C 
H&E 
hematoxylin & eosin  
HIV 
Human Immunodeficiency Virus  
IB 
investigator's brochure 
ICH 
International Conference on Harmonisation  
IHC 
immunohistochemistry 
INR 
international normalized ratio  
IRB 
institutional review board 
ITIM 
immunoreceptor tyrosine-based inhibition motif  
ITSM 
immunoreceptor tyrosine-based switch motif 
IV 
intraveinous 
LDH 
lactate dehydrogenase  
LLN 
lower limit of normal 
mAb 
monoclonal antibody  
MEK 
mitogen-activated extracellular signal-regulated kinase 
MK-3475 
pembrolizumab 
MTD 
maximum tolerated dose 
NCI CTCAE  
National Cancer Institute Common Terminology for Adverse Events  
NSAIDS 
nonsteroidal anti-inflammatory drugs  
NSCLC 
non-small cell lung cancer  


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NYHA 
New York Heart Association  
OCR 
Office of Clinical Research 
ORR 
overall response rate 
OTC 
over-the-counter  
PI 
principal investigator 
PD 
progressive disease 
PD-1 
Programmed cell Death protein 1 
PD-L1 
Programmed Death-Ligand 1 
PFS 
progression-free survival 
PK 
pharmacokinetic 
PBMC  
peripheral blood mononuclear cell 
Pt 
platinum 
PT 
prothrombin time  
PTT 
partial thromboplastin time  
QTc 
QT interval on electrocardiogram 
RNA 
ribonucleic acid 
RECIST 
Response Evaluation Criteria In Solid Tumors 
RP2D 
recommended phase II dose  
RPED 
retinal pigment epithelial detachment  
RPPA 
Reverse Phase Protein Assays 
RVO 
retinal vein occlusion  
SAE 
serious advese event 
SPF  
sun protection factor 
SRC 
Scientific Review Committee 
SU2C 
Stand Up to Cancer 
T3 
total thriiodothyronine  
T4 
free thyroxine  
T1DM 
Type 1 diabetes mellitus  
TB 
Bacillus tuberculosis 
TIL 
tumor-infiltrating lymphocytes  
TKI 
tyrosine kinase inhibitors  
TSH 
thyroid stimulating hormone  
UCD 
University of California, Davis; UC Davis 
UCDCC 
UC Davis Comprehensive Cancer Center 
ULN 
upper limit of normal 
 
 
 


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1.0 TRIAL SUMMARY 
Abbreviated Title 
A Phase Ib Trial of Pembrolizumab and Trametinib Focused on 
Advanced KRAS mutant Non-Small Cell Lung Cancer 
Trial Phase 
Ib 
Clinical Indication 
Advanced Non-Small Cell Lung Cancer Harboring a KRAS mutation  
Trial Type 
Phase Ib with Expansion Cohorts 
Route of administration 
Pembrolizumab (MK-3475) (Intravenous) 
Trametinib (Oral) 
Trial Blinding 
Unblinded Open-label 
Treatment Groups  
Phase I dose escalation of combination Pembrolizumab and Trametinib 
with lead in trametinib (cohort A) or lead in pembrolizumab (cohort B) 
in advanced NSCLC patients to determine the MTD and expansion 
phase dose.  
At the MTD, there are two Expansion Cohorts in KRAS Mutant NSCLC 
as follows: 
Cohort A: Lead in intermittent Trametinib for 1 cycle (3 weeks) 
followed by intermittent Trametinib and Pembrolizumab 
Cohort B: Lead in Pembrolizumab for 1 cycle (3 weeks) followed by 
intermittent Trametinib and Pembrolizumab 
Number of trial subjects 
We estimate 42 evaluable patients total (9 in each dose escalation cohort 
and 24 patients total for the dose expansion cohorts. A minimum of 12 
patients (i.e., only 6 in each dose escalation arm if trial is terminated 
early due to unacceptable toxicity) and a maximum of 62 patients (18 
patients in each dose escalation cohort and 24 patients total for the dose 
expansion cohorts.)  
Estimated enrollment period 
2 years 
Estimated duration of trial 
3 years 
Duration of Participation 
3 years 
 
 
 
 


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2.0 TRIAL DESIGN 
2.1 
Trial Design 
This is a trial for patients with advanced or metastatic non-small cell lung cancer patients with 
KRAS mutations who have progressed on prior platinum-based frontline therapy. After the 
initial dose escalation with two different sequencing schemes (lead in trametinib and lead in 
pembrolizumab), in the expansion cohorts patients will be allocated to one of these two different 
arms: a) lead in trametinib followed by the intermittent trametinib/pembrolizumab and b) lead in 
pembrolizumab followed by intermittent pembrolizumab and trametinib to further define 
toxicities at the MTD, to determine the RP2D, to assess initial estimates of efficacy and to 
examine in the tumor and immune microenvironment changes in PD-L1 expression and T-cell 
subsets) across these two different sequencing schemes. Safety findings and preliminary efficacy 
will be employed as primary criteria for whether one or both treatment sequences may warrant 
further study. Exploratory immune correlates will be examined as secondary criteria to inform 
further development of this approach in future studies. The treatment arm that provides the better 
RR, PFS, safety profile and enhanced tumor immune microenvironment at rebiopsy will be 
recommended for further development. It is anticipated that ORR ≥ 50% or a median PFS ≥ 8 
months would be sufficient to recommend further development, provided safety and tolerability 
are acceptable. Patients will be treated until progression per RECIST 1.1 guidelines or 
intolerable toxicity. 
2.2 
Trial Diagram 
 
 
Intercalated Trametinib and Pembrolizumab in Advanced KRAS Mutant NSCLC 
Advanced NSCLC PD 
after Pt-based chemo  
(KRAS mutant for 
expansion). 
 
3+3 dose escalation to 
MTD in Arm A and 
Arm B. 
 
Starting dose level: 
trametinib 1.5 mg 
daily. 
Arm B:  
Lead in Pembrolizumab 
(N=12) 
• Add trametinib  
(Cycle 2)Intercalated 
trametinib and 
pembrolizumab after 
C1* 
• Disease assessment 
every 9 weeks. 
• Add pembrolizumab  
(Cycle 2) 
• Intercalated trametinib 
and pembrolizumab 
after C1* 
• Disease assessment  
every 9 weeks 
* Dose escalation in Arm A and Arm B followed by dose expansion (see 8.0 Statistical Analysis Plan). 
  Trametinib starting 10 days on and 11 days off.  Starting dose level 1.5 mg daily. 
  Paired biopsy baseline, D11, and at progression (optional). 
  Pt=platinum, PD=progressive disease, MTD=maximum tolerated dose, NSCLC=non-small cell lung cancer 
Arm A:  
Lead in Trametinib  
(N=12) 


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3.0 OBJECTIVES & HYPOTHESES 
3.1 
Primary Objective & Hypotheses 
Objective: To evaluate the safety and tolerability of pembrolizumab (MK-3475) when given in 
combination with trametinib in the proposed sequencing schemes in patients with advanced or 
metastatic non-small cell lung cancer with KRAS mutations. 
Hypothesis:  We hypothesize that pembrolizumab in combination with trametinib given with our 
lead in and intermittent sequencing schemes will be safe and tolerable. 
3.2 
Secondary Objective & Hypotheses 
Objective:  To assess in a preliminary manner the clinical efficacy of these combinations with 
the proposed sequencing schemes outlined above including overall response rate and progression 
free survival. 
Hypothesis for Secondary Objective:  We hypothesize that the combination of trametinib and 
pembrolizumab will be efficacious. 
3.3 
Exploratory Objective 
Objective: To determine in an exploratory manner changes in PD-L1 expression as well as other 
immune correlates induced by MEK inhibition. 
Hypothesis for Exploratory Objective:  We hypothesize that lead in trametinib will 
demonstrate the most promise for preliminary efficacy based on clinical outcome and changes in 
immune micro-environment. 
 
4.0 BACKGROUND & RATIONALE 
4.1 
Pembrolizumab (MK-3475) 
4.1.1 Background 
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background information 
on pembrolizumab. 
4.1.2 Pharmaceutical and Therapeutic Background 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades.  Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies.  In particular, the presence of CD8+ T-cells and the ratio of CD8+ effector 
T-cells / FoxP3+ regulatory T-cells seems to correlate with improved prognosis and long-term 
survival in many solid tumors. 


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The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune 
control.  The normal function of PD-1, expressed on the cell surface of activated T-cells under 
healthy conditions, is to down-modulate unwanted or excessive immune responses, including 
autoimmune reactions.  PD-1 (encoded by the gene Pdcd1) is an Ig superfamily member related 
to CD28 and CTLA-4 which has been shown to negatively regulate antigen receptor signaling 
upon engagement of its ligands (PD-L1 and/or PD-L2).  The structure of murine PD-1 has been 
resolved.  PD-1 and family members are type I transmembrane glycoproteins containing an Ig 
Variable-type (V-type) domain responsible for ligand binding and a cytoplasmic tail which is 
responsible for the binding of signaling molecules.  The cytoplasmic tail of PD-1 contains 2 
tyrosine-based signaling motifs, an immunoreceptor tyrosine-based inhibition motif (ITIM) and 
an immunoreceptor tyrosine-based switch motif (ITSM).  Following T-cell stimulation, PD-1 
recruits the tyrosine phosphatases SHP-1 and SHP-2 to the ITSM motif within its cytoplasmic 
tail, leading to the dephosphorylation of effector molecules such as CD3ζ, PKCθ and ZAP70 
which are involved in the CD3 T-cell signaling cascade.  The mechanism by which PD-1 down 
modulates T-cell responses is similar to, but distinct from that of CTLA-4 as both molecules 
regulate an overlapping set of signaling proteins.  PD-1 was shown to be expressed on activated 
lymphocytes including peripheral CD4+ and CD8+ T-cells, B-cells, T regs and Natural Killer 
cells.  Expression has also been shown during thymic development on CD4-CD8- (double 
negative) T-cells as well as subsets of macrophages and dendritic cells.  The ligands for PD-1 
(PD-L1 and PD-L2) are constitutively expressed or can be induced in a variety of cell types, 
including non-hematopoietic tissues as well as in various tumors.  Both ligands are type I 
transmembrane receptors containing both IgV- and IgC-like domains in the extracellular region 
and contain short cytoplasmic regions with no known signaling motifs.  Binding of either PD-1 
ligand to PD-1 inhibits T-cell activation triggered through the T-cell receptor.  PD-L1 is 
expressed at low levels on various non-hematopoietic tissues, most notably on vascular 
endothelium, whereas PD-L2 protein is only detectably expressed on antigen-presenting cells 
found in lymphoid tissue or chronic inflammatory environments.  PD-L2 is thought to control 
immune T-cell activation in lymphoid organs, whereas PD-L1 serves to dampen unwarranted T-
cell function in peripheral tissues.  Although healthy organs express little (if any) PD-L1, a 
variety of cancers were demonstrated to express abundant levels of this T-cell inhibitor.  PD-1 
has been suggested to regulate tumor-specific T-cell expansion in subjects with melanoma 
(MEL).  This suggests that the PD-1/PD-L1 pathway plays a critical role in tumor immune 
evasion and should be considered as an attractive target for therapeutic intervention. 
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of the 
IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-
L1 and PD-L2.  KeytrudaTM (pembrolizumab) has recently been approved in the United States 
for the treatment of patients with unresectable or metastatic melanoma and disease progression 
following ipilumumab and, if BRAF V600 mutation positive, a BRAF inhibitor. 
4.1.3 Preclinical and Clinical Trial Data 
Refer to the Investigator’s Brochure for Preclinical and Clinical data. 


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4.2 
Trametinib 
4.2.1 Background 
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background information 
on trametinib. 
4.2.2 Pharmaceutical and Therapeutic Background 
Trametinib is a reversible and highly selective allosteric inhibitor of mitogen-activated 
extracellular signal-regulated kinase (MEK1 and MEK2 activation and kinase activity). MEK 
proteins are critical components of the extracellular signal-regulated kinase (ERK) pathway 
which is commonly hyperactivated in tumor cells. Oncogenic mutations in both BRAF (a 
member of the RAF kinases) and RAS signal through MEK1 or MEK2.  
Trametinib is administered with doses up to 2 mg once daily. Subjects should take trametinib 
under fasting conditions, at least 1 hour prior to or 2 hours after a meal. 
Trametinib is being developed for the treatment of a variety of cancers and is currently approved 
in the United States, Canada, Australia, and the EU as a monotherapy treatment for the treatment 
of subjects with unresectable or metastatic melanoma with BRAF V600 E/K mutation (approval 
was also granted in Chile on 22 September 2014). It is also approved in combination with 
dabrafenib for the same indication in the US and Australia. 
4.2.3 Preclinical and Clinical Trial Data 
Refer to the Investigator’s Brochure for Preclinical and Clinical data. 
4.3 
Rationale 
4.3.1 Rationale for the Trial and Selected Subject Population 
Recent advances such as targeted therapy with EGFR and ALK tyrosine kinase inhibitors (TKIs) 
for patients harboring EGFR mutations and ALK translocations have dramatically improved 
patient outcomes and quality of life. However, no therapies targeting KRAS, the most common 
oncogenic driver mutation in NSCLC (~25%) are FDA approved. 
Discovery of new therapeutic combinations that can alter the natural history of KRAS mutant 
lung cancer addresses a major unmet medical need. 
KRAS was the first oncogenic driver mutation identified in NSCLC patients over a quarter of a 
century ago. Ras is a GTP-binding membrane-associated protein that typically modulates cell 
cycling and survival in response to external stimuli. Oncogenic KRAS mutations lock KRAS in a 
persistently activated state that triggers three main downstream signaling pathways to varying 
degrees (Ral, MEK/ERK and PI3K/AKT/MTOR)[1]. 


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Though no approved clinical therapies exist specifically for KRAS mutant lung cancer, there are 
several promising clinical trials targeting MEK in KRAS mutated lung cancer. MEK inhibition 
alone appears insufficient to have meaningful clinical activity in KRAS positive NSCLC, but 
preclinical and early clinical trial data suggest that combination therapy with MEK inhibitors can 
be a highly effective treatment option in advanced NSCLC. In particular, preclinical data 
suggests that taxanes such as docetaxel are synergistic with MEK inhibitors [2]  and in a 
randomized phase II clinical trial of 97 patients with KRAS mutated lung cancer, patients who 
received the MEK inhibitor selumetinib with docetaxel versus patients who received docetaxel 
alone had a significant improvement in progression free survival (PFS) and a trend towards 
increased overall survival (OS). In a recently presented single-arm phase I clinical trial from UC 
Davis and others at ASCO, a 28% response rate to docetaxel combined with the MEK inhibitor 
trametinib was observed in KRAS mutant patients (single agent docetaxel response rates ~7%)9. 
A signal towards preferential activity in KRAS G12C mutant patients was observed (40% vs. 
20%), though sample size was small [3]. 
In several tumor types, in preclinical and translational studies the MEK-ERK pathway modulates 
PD-L1 expression, though different studies come to different conclusions regarding the degree 
and direction of this immunomodulation. In one preclinical study, PD-L1 expression is 
upregulated in melanoma cells resistant to BRAF inhibition and reversed by MEK inhibition 
with downregulation of PD-L1 and induction of apoptosis [4]. 
In a recently published clinical study, patient samples with metastatic melanoma BRAF 
inhibition increased PD-L1 expression while also enhancing markers of T-cell toxicity and 
providing a more favorable tumor immune microenvironment [5]. In other tumor types, studies 
suggest PD-L1 is also dependent on MEK/ERK and suppressed by MEK/ERK inhibition 
including Hodgkin’s and Non-Hodgkin’s Lymphoma and restores anti-immune activity [6]. 
Though there are somewhat discrepant conclusions regarding pre-clinical and 
clinical/translational data with MEKi and PD1/PDL1 inhibition in several tumor types, the 
weight of the evidence suggests that MEKi can potentiate the immune response and modulate 
PD-L1 expression. In KRAS mutant NSCLC treatment with selumetinib led to upregulation of 
PD-1 on CD8 T-cells and depletion of Treg with increase in PD-1 and CTLA-4 providing some 
rationale for integrating PD-1 blockade with MEK inhibition and highlighting the need to biopsy 
tissue on treatment to examine the tumor immune microenvironment[7]. Examination of immune 
correlates in tissue and blood in this early phase trial (including modulation of PD-L1 expression 
and T-cell subsets) are required to determine optimal sequencing of MEKi and PD1 antibody for 
maximum clinical impact. 
This proposal builds a foundation for the study of pembrolizumab (MK-3475) with targeted 
therapeutic combinations incorporating MEK inhibitors in KRAS mutant NSCLC (a major 
unmet clinical need) and data regarding safety and tolerability from this proposal can be 
extended to other tumor types where MEK inhibition and PD1/PD-L1 blockade may be utilized. 
Higher response rates with PD-1 blockade in tumors known to be highly mutated such as 
melanoma and NSCLC have been noted and we have observed higher responses in NSCLC 


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tumors with KRAS mutations (28% vs. 19%) suggesting potential roles for both KRAS and 
overall mutation burden in driving an adaptive immune escape phenotype (Figure 1). 
Figure 1. Response rates to pembrolizumab according to mutation status 
 
 
 
 
 
 
 
 
 
 
Figure 2. In vivo antitumor activity in CT26 Mouse Model dependent on sequencing of MEK 
inhibition with trametinib and PD-1 blockade (Liu et al, Clinical Cancer Research 2015) 
 
 
 


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Rationale for sequencing of combined therapy with MEK inhibitors and PD-1/PD-L1 
blockade[8].  The combination of trametinib (a MEKi) and anti-PD1 antibodies (RMP1-14 clone, 
rat IgG2a, Bioxcell) was studied in the CT26 murine syngeneic tumor model, which is 
homozygous for the KRAS (G12D) mutation, and contains amplification of MAPK1 and MET 
genes, in immune competent mice. Three combination regimens were evaluated: (1) trametinib 
and anti-PD1 antibody given concurrently starting week; (2) trametinib in week 1 as a single 
agent with anti-PD-1 added in week 2; and (3) anti-PD-1 in week 1 with addition of trametinib in 
week 2 (Figure 2). All three combinations were found to inhibit tumor growth more effectively 
than the single agents during the initial 2-3 weeks of treatment (Figure 2). However, schedule 
mattered as the combination in which anti-PD-1 was administered first did not lead to a profound 
effect on tumor growth (Figure 2, C). These findings reinforce the view that a detailed 
understanding of dose and schedule will likely have a profound impact on efficacy. Furthermore, 
the combination of trametinib and anti-PD-1 antibody increased tumor infiltrating CD8+ T cells 
in vivo compared to anti-PD-1 alone (data not shown), demonstrating the importance of 
concurrent immune monitoring for optimization of targeted therapy combinations.  Similar in 
vivo anti-tumor activity was observed in the CT26 model using a different mouse anti-PD1 
antibody (mDX400), supporting the validity of the observations.  
4.3.2 Rationale for Dose Selection/Regimen/Modification  
An open-label Phase I trial (Protocol 001) is being conducted to evaluate the safety and clinical 
activity of single agent pembrolizumab.  The dose escalation portion of this trial evaluated three 
dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 weeks (Q2W) in subjects 
with advanced solid tumors.  All three dose levels were well tolerated and no dose-limiting 
toxicities were observed.  This first in human study of pembrolizumab showed evidence of target 
engagement and objective evidence of tumor size reduction at all dose levels (1 mg/kg, 3 mg/kg 
and 10 mg/kg Q2W).  No MTD has been identified to date.  10.0 mg/kg Q2W, the highest dose 
tested in PN001, will be the dose and schedule utilized in Cohorts A, B, C and D of this protocol 
to test for initial tumor activity.  Recent data from other clinical studies within the 
pembrolizumab program has shown that a lower dose of pembrolizumab and a less frequent 
schedule may be sufficient for target engagement and clinical activity. 
PK data analysis of pembrolizumab administered Q2W and Q3W showed slow systemic 
clearance, limited volume of distribution, and a long half-life (refer to IB).  Pharmacodynamic 
data (IL-2 release assay) suggested that peripheral target engagement is durable (>21 days).  This 
early PK and pharmacodynamic data provides scientific rationale for testing a Q2W and Q3W 
dosing schedule.   
A population pharmacokinetic analysis has been performed using serum concentration time data 
from 476 patients. Within the resulting population PK model, clearance and volume parameters 
of pembrolizumab were found to be dependent on body weight. The relationship between 
clearance and body weight, with an allometric exponent of 0.59, is within the range observed for 
other antibodies and would support both body weight normalized dosing or a fixed dose across 
all body weights.  Pembrolizumab has been found to have a wide therapeutic range based on the 
melanoma indication.  The differences in exposure for a 200 mg fixed dose regimen relative to a 
2 mg/kg Q3W body weight based regimen are anticipated to remain well within the established 


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exposure margins of 0.5 – 5.0 for pembrolizumab in the melanoma indication. The exposure 
margins are based on the notion of similar efficacy and safety in melanoma at 10 mg/kg Q3W vs. 
the proposed dose regimen of 2 mg/kg Q3W (i.e. 5-fold higher dose and exposure). The 
population PK evaluation revealed that there was no significant impact of tumor burden on 
exposure. In addition, exposure was similar between the NSCLC and melanoma indications. 
Therefore, there are no anticipated changes in exposure between different indication settings. 
The rationale for further exploration of 2 mg/kg and comparable doses of pembrolizumab in 
solid tumors is based on: 1) similar efficacy and safety of pembrolizumab when dosed at either 2 
mg/kg or 10 mg/kg Q3W in melanoma patients, 2) the flat exposure-response relationships of 
pembrolizumab for both efficacy and safety in the dose ranges of 2 mg/kg Q3W to 10 mg/kg 
Q3W, 3) the lack of effect of tumor burden or indication on distribution behavior of 
pembrolizumab (as assessed by the population PK model) and 4) the assumption that the 
dynamics of pembrolizumab target engagement will not vary meaningfully with tumor type. 
The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed dosing is based on 
simulations performed using the population PK model of pembrolizumab showing that the fixed 
dose of 200 mg every 3 weeks will provide exposures that 1) are optimally consistent with those 
obtained with the 2 mg/kg dose every 3 weeks, 2) will maintain individual patient exposures in 
the exposure range established in melanoma as associated with maximal efficacy response and 3) 
will maintain individual patients exposure in the exposure range established in melanoma that 
are well tolerated and safe.  
A fixed dose regimen will simplify the dosing regimen to be more convenient for physicians and 
to reduce potential for dosing errors.  A fixed dosing scheme will also reduce complexity in the 
logistical chain at treatment facilities and reduce wastage. 
The FDA approved starting dose of trametinib is 2 mg administered orally daily. This fixed dose 
of pembrolizumab is combined with trametinib starting a dose reduction of 1.5 mg daily and then 
escalated to trametinib 2 mg daily if the combination is well tolerated. Pembrolizumab is 
approved for the treatment of advanced NSCLC with positive PD-L1 expression. Intermittent 
and dose reduced schedule is designed to manage potential toxicities seen in KEYNOTE-022 
trial in phase 1 dose escalation of continuous 2 mg of trametinib with pembrolizumab. 
Intermittent dosing also may be more favorable for reducing depletion of T-cells in response to 
prolonged MEK inhibition. 
4.3.3 Rationale for Endpoints 
This is a phase I 3+3 dose escalation study followed by expansion cohorts for safety and 
correlative studies. Therefore, the endpoints include determination of MTD, and recommended 
phase II dose (RP2D) correlative endpoints and secondary efficacy endpoints. MTD and RP2D 
are standard endpoints for phase I dose escalation studies. 
• The recommended dose expansion and recommended phase II dose (RP2D) will be 
determined by the overall assessment of the MTD and toxicities observed in the dose 
escalation portion of this study. 


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4.3.3.1 Efficacy Endpoints 
• Overall response rate (ORR). ORR is an acceptable measure of clinical benefit in 
early phase clinical trials to provide a preliminary signal of activity to consider later 
phase trials. 
• Progression-free survival (PFS). PFS is an acceptable measure of assessing benefit in 
NSCLC clinical trials. 
As this is a phase I study, our goal is a preliminary assessment of a signal of efficacy as defined 
in the statistical plan. 
4.3.3.2 Biomarker Research 
4.3.3.2.1 Immunology Correlates 
Immunology correlates will be performed by collaborators at the Translational Immuno-
Oncology Laboratory Yale University and/or by the Human Immune Monitoring Core at 
UC Davis as defined in the protocol. The Human Immune Monitoring Core at UC Davis is under 
the supervision of Emanual Maverakis, MD. Dr.  Maverakis’  laboratory  is  a  world  renowned  
immunology  laboratory  and  has  the equipment and expertise to conduct the proposed studies. 
The Translational Immuno-Oncology Laboratory at Yale University is under the direction of 
David Rimm MD, Ph.D and Kurt Schalper, MD, Ph.D and has been a leader in the translational 
immuno-oncology of immune checkpoint inhibitors. 
a. Biopsy (Biopsy at Baseline, C1D11-13 and at progression (optional) 
• PD-L1 expression by immunohistochemistry at baseline and in repeat biopsy specimens 
to assess for changes in PD-L1 expression in response to treatment will be conducted by 
Yale Immuno-Oncology under the direction of Kurt Schalper using the approved DAKO 
22C3 antibody and in addition quantitative IHC assays for PD-L1 if tissue permits. UC 
Davis may also perform IHC for PD-L1 using the standard DAKO 22C3 antibody. 
• Enumeration and changes in immune cell subsets by immunohistochemistry in repeat 
biopsy specimens in response to treatment will be conducted by Yale Translational 
Immuno-Oncology. 
• Whole exome DNA/RNA next generation sequencing and assessment of mutational load 
will be performed by the Broad Institute in Boston. The Broad Institute is a world leader 
in genomic sequencing and analysis. 
• Tissue banked for RPPA (Reverse Phase Protein Assays) for on-target EGFR pathway 
inhibition will be performed by Theranostics in collaboration with the Mack lab at UC 
Davis. 
 


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b. Plasma PD-L1 DNA/RNA levels will be assayed by Liquid Genomics in a CLIA certified 
laboratory. 
Additional peripheral blood will be collected and banked at relevant time points for enumeration 
of immune cell subsets and changes in cytokine expression in response to treatment with 
methods including Flow Cytometry and Luminex Cytokine Assays by the Human Immune 
Monitoring Core at UC Davis.  
4.3.3.2.2 Molecular Correlates  
a. Biopsy 
Whole exome DNA/RNA next generation sequencing including KRAS aminio acid substitution, 
p53 and LKB1 mutations, and assessment of mutational load will be performed by the Broad 
Institute in Boston. The Broad Institute is a world leader in genomic sequencing and analysis. 
b. Plasma KRAS-mutant DNA/RNA Levels 
Changes in plasma KRAS-mutant DNA/RNA in patients with KRAS-mutant NSCLC may be 
prognostic for recurrence, the development of resistance to existing therapies and may track 
response or lack of benefit to existing treatment. Determination of plasma KRAS-mutant 
DNA/RNA levels will be conducted at Liquid Genomics in a CLIA certified laboratory. 
c. If tissue permits, analysis for pharmacodynamic markers of on-target MEK-ERK inhibition 
with RPPA will be performed by Theranostics and the Mack lab at UC Davis. 
 
5.0 METHODOLOGY 
5.1 
Entry Criteria 
5.1.1 Diagnosis/Condition for Entry into the Trial 
Stage IV or Metastatic/Recurrent Non-Small Cell Lung Cancer. For expansion cohorts, patient’s 
tumor must also harbor a KRAS mutation detected in a CLIA certified laboratory. 
5.1.2 Subject Inclusion Criteria 
In order to be eligible for participation in this trial, the subject must: 
1. Have histologically or cytologically confirmed non-small cell lung cancer. 
2. Have stage IV, metastatic or recurrent non-squamous NSCLC with progressive disease 
after platinum containing chemotherapy (EGFR mutant, ALK, or ROS-1 rearranged 
NSCLC must have progressed on prior approved TKI’s). 


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3. For phase I dose expansion cohorts the patient’s tumor must harbor a KRAS mutation 
detected by a CLIA certified laboratory. 
4. Be willing and able to provide written informed consent/assent for the trial. 
5. Be ≥ 18 years of age on day of signing informed consent. 
6. Have measurable disease based on RECIST 1.1.   
7. Be willing to provide tissue from a newly obtained core or excisional biopsy of a tumor 
lesion.  In the opinion of the investigator, the patient must have tumor accessible by CT 
or ultrasound guided core biopsy.   Subjects for whom newly-obtained samples cannot be 
provided may submit an archived specimen provided it was obtained after last systemic 
treatment, within 6 months of signing consent and that tissue is available for either 2 cell 
blocks or 20 uncut slides (core or excisional biopsy required, fine needle aspirate is not 
acceptable). 
8. Have a performance status of 0 or 1 on the ECOG Performance Scale. 
9. 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. 
10. Demonstrate adequate organ function as defined in Table 1, all screening labs should be 
performed within 10 days of treatment initiation.   
 
Table 1.  Adequate Organ Function Laboratory Values 
System 
Laboratory Values 
Absolute neutrophil count 
≥1.5 × 109/L 
Hemoglobin 
≥9 g/dL  
Platelets 
≥100 × 109/L   
PT/INR and PTT 
≤1.5 x ULN 
Hepatic 
Albumin 
≥2.5 g/dL 
Total bilirubin 
≤1.5 x ULN 
AST and ALT 
≤ 2.5× ULN  
Renal 
Creatinine or 
≤ 1.5 ULN 
Calculated creatinine clearancea  
≥ 50 mL/min  
Cardiac 
Left Ventricular Ejection fraction (LVEF) 
≥ LLN by ECHO or MUGAb 
ALT=alanine aminotransferase; AST=aspartate aminotransferase; INR=international normalized ratio;  
PT=prothrombin time; PTT=partial thromboplastin time; ULN=upper limit of normal; LLN=lower limit of 
normal 
a  Calculated by the Cockcroft-Gault formula.  
b  Same method as used at baseline must be use throughout the study, ECHO is the preferred method 
 


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11. Female subject of childbearing potential should have a negative urine or serum pregnancy 
test within 72 hours prior to receiving the first dose of study medication.  If the urine test 
is positive or cannot be confirmed as negative, a serum pregnancy test will be required.   
 
12. Female subjects of childbearing potential (Section 5.8.2) must be willing to use an 
adequate method of contraception as outlined in Section 5.8.2 – Contraception, for the 
course of the study through 120 days after the last dose of study medication. 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for 
the subject. 
 
13. Male subjects of childbearing potential (Section 5.8.1) must agree to use an adequate 
method of contraception as outlined in Section 5.8.1- Contraception, starting with the 
first dose of study therapy through 120 days after the last dose of study therapy. 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for 
the subject. 
 
5.1.3 Subject Exclusion Criteria 
The subject must be excluded from participating in the trial if the subject: 
1. Is currently participating and receiving study therapy or has participated in a study of an 
investigational agent and received study therapy or used an investigational device within 
3 weeks of the first dose of treatment. 
2. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any 
other form of immunosuppressive therapy within 7 days prior to the first dose of trial 
treatment.  Inhaled or topical steroids are allowed.  
3. Has a known history of active TB   (Bacillus Tuberculosis). 
4. Hypersensitivity to pembrolizumab or any of its excipients. 
5. Has had a prior anti-cancer monoclonal antibody (mAb) within 3 weeks prior to study 
Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due 
to agents administered more than 3 weeks earlier. 
6. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 
2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) 
from adverse events due to a previously administered agent. 
- 
Note:  Subjects with ≤ Grade 2 neuropathy or alopecia are an exception to this 
criterion and may qualify for the study. 
- 
Note:  If subject received major surgery, they must have recovered adequately 
from the toxicity and/or complications from the intervention prior to starting 
therapy.   


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7. Has a known additional malignancy that is progressing or requires active treatment.  
Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the 
skin that has undergone potentially curative therapy or in situ cervical cancer. 
8. Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis.  Subjects with previously treated brain metastases may participate provided 
they are stable (without evidence of progression by imaging for at least four weeks prior 
to the first dose of trial treatment and any neurologic symptoms have returned to 
baseline), have no evidence of new or enlarging brain metastases, and are not using 
steroids for at least 7 days prior to trial treatment.  This exception does not include 
carcinomatous meningitis which is excluded regardless of clinical stability.   
9. Has active autoimmune disease that has required systemic treatment in the past 2 years 
(i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). 
Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic 
treatment.  
10. Has known history of, or any evidence of active, non-infectious pneumonitis. History of 
radiation pneumonitis is allowed provided that it is not active and no corticosteroids were 
required for pneumonitis management. 
11. Evidence of interstitial lung disease. 
12. Has an active infection requiring systemic therapy. 
13. Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs 
chemically related to trametinib, or excipients or to dimethyl sulfoxide (DMSO). 
14. History of retinal vein occlusion (RVO). 
15. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the trial, interfere with the subject’s participation for 
the full duration of the trial, or is not in the best interest of the subject to participate, in 
the opinion of the treating investigator.   
16. Has known psychiatric or substance abuse disorders that would interfere with cooperation 
with the requirements of the trial. 
17. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting with the pre-screening or screening visit through 
120 days after the last dose of trial treatment. 
18. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent for dose 
expansion. (Patients in dose escalation may have received an anti-PD-1, anti-PD-L1, or 
anti-PD-L2 agent). 
19. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
20. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected). 
21. History or evidence of cardiovascular risk including any of the following: 


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•  LVEF<LLN on screening exam. 
• A QT interval corrected for heart rate using the Fridericia’s formula (QTcF; 
Appendix X) ≥470 msec (Appendix 11.2) on screening exam. 
• History or evidence of current clinically significant uncontrolled arrhythmias. 
• Clarification: Subjects with atrial fibrillation controlled for >30 days prior to 
dosing are eligible. 
• History of acute coronary syndromes (including myocardial infarction and 
unstable angina), coronary angioplasty, or stenting within 6 months prior to 
enrollment. 
• History or evidence of current ≥ Class II congestive heart failure as defined by 
New York Heart Association (NYHA; Appendix 11.5). 
• Treatment refractory hypertension defined as a blood pressure of systolic> 140 
mmHg and/or diastolic > 90 mm Hg which cannot be controlled by anti-
hypertensive therapy; 
• Patients with intra-cardiac defibrillators. 
22. Has received a live vaccine within 30 days of planned start of study therapy. 
 
Note:  Seasonal influenza vaccines for injection are generally inactivated flu vaccines and 
are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated 
vaccines, and are not allowed. 
 
5.2 
Trial Treatments 
The treatment to be used in this trial is outlined below in Table 2.  
Table 2.  Trial Treatments 
Drug 
Dose/Potency 
Dose 
Frequency 
Route of 
Administration 
Regimen/Treatment 
Period 
Use 
Pembrolizumab 
(MK-3475) 
200 mg 
Q3W 
IV infusion 
Day 1  
of each 3 week cycle 
Experimental 
Trametinib 
x mg† 
Daily† 
PO 
Daily starting D1 
Experimental 
† See dose escalation schema. RP2D for expansion cohorts. 
 
Dose Escalation Cohort (Arm A): Trametinib will be adminstered starting C1D1 and continued 
as per Table 3, until determination of the MTD.  Pembrolizumab will be added to trametinib 
starting C2D1.  


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Dose Escalation Cohort (Arm B): Pembrolizumab will be administered starting C1D1 and 
trametinib will be added to pembrolizumab starting C2D1.  
Expansion Cohort (Arm) A: Trametinib will be administered starting C1D1 and pembrolizumab 
will be added to trametinib starting C2D1 at the MTD of the combination as determined from the 
dose escalation portion of the study.   
Expansion Cohort (Arm) B: Pembrolizumab will be administered starting C1D1 and trametinib 
will be added to pembrolizumab starting C2D1 at the MTD of the combination as determined 
from the dose escalation portion of the study.  
 
5.2.1 Dose Selection/Modification 
5.2.1.1 Dose Selection 
The rationale for selection of doses to be used in this trial is provided in Section 4.0 – 
Background and Rationale.   
The dose of pembrolizumab is fixed at 200 mg IV Q3W. 
The dose escalation schema of trametinib is as follows. Each cycle is Q3W (21 days). 
Table 3. Dose Escalation Schema for Trametinib 
Dose Level 
Trametinib dose  
(PO Daily) Q3W 
Pembrolizumab (MK-3475) dose IV Q3W 
-1 
1.5 mg (D1-D7) 
200 mg 
*1 
1.5 mg (D1-D10) 
200 mg 
2 
2.0 mg (D1-D10) 
200 mg 
* Dose level 1 is the starting dose. For each cohort, trametinib dose will be the same for lead in and for concurrent 
trametinib + pembrolizumab administration. 
 
For Cohort A: Lead in trametinib will precede combination trametinib and pembrolizumab, 
which will commence for C2. 
For Cohort B: Lead in pembrolizumab will precede combination trametinib and pembrolizumab, 
which will commence for C2. 
The recommended dose expansion and recommended phase II dose (RP2D) will be determined 
by the overall assessment of the MTD (the maximum dose level where 6 patients have been 
treated in the dose escalation portion of the study) and toxicities observed in the dose escalation 
portion of this study. 


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5.2.1.2 Dose Modification (Escalation/Titration/Other) 
Adverse events (both non-serious and serious) associated with pembrolizumab exposure may 
represent an immunologic etiology.  These adverse events may occur shortly after the first dose 
or several months after the last dose of treatment. Pembrolizumab must be withheld for drug-
related toxicities and severe or life-threatening AEs as per Table 5 below. See dose modification 
and supportive care guideline sections, including use of corticosteroids. There are no dose 
reductions for pembrolizumab. 
Dosing interruptions are permitted in the case of medical/surgical events or logistical reasons not 
related to study therapy (e.g., elective surgery, unrelated medical events, patient vacation, and/or 
holidays). Subjects should be placed back on study therapy within 3 weeks of the scheduled 
interruption. The reason for interruption should be documented in the patient's medical record. 
Table 4. Dose Modification for Trametinib. Lowest permitted Trametinib dose will be 1.5 mg 
daily. 
 
Table 5. Dose Modification Guidelines for Pembrolizumab (MK-3475) for Drug-Related 
Adverse Events 
Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting 
Treatment 
Treatment Discontinuation 
Diarrhea/Colitis 
2-3 
 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose 
or inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks 
4 
Permanently discontinue 
Permanently discontinue 
AST, ALT, or 
Increased 
Bilirubin 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose 
3-4 
Permanently discontinue 
(see exception below)a 
Permanently discontinue 
Type 1 diabetes 
mellitus (if new 
onset) or 
T1DM or 
3-4 
Hold pembrolizumab for new 
onset Type 1 diabetes mellitus or 
Grade 3-4 hyperglycemia 
Resume pembrolizumab when patients are clinically 
and metabolically stable 
Dose Level 
Trametinib Dose (QD)  
(D1-D10 administration unless otherwise specified) 
For Starting Dose 
2 mg 
1.5 mg 
1.5 mg (dosed 
from D1-D7) 
1st Does Reduction 
1.5 mg 
1.5 mg (dosed from D1-D7) 
Discontinue 
Trametinib 
2nd Dose Reduction 
1.5 mg  
(dosed from D1-D7) 
Discontinue trametinib 
- 


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Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting 
Treatment 
Treatment Discontinuation 
Hyperglycemia 
associated with evidence of beta 
cell failure 
Hypophysitis 
2-4 
Toxicity resolves to Grade 0-1. 
Therapy with pembrolizumab can 
be continued while endocrine 
replacement therapy is instituted 
Toxicity does not resolve within 12 weeks of last dose 
or inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks 
Hyperthyroidism  
3 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose 
or inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks 
4 
Permanently discontinue 
Permanently discontinue 
Hypothyroidism 
 
Therapy with pembrolizumab can 
be continued while thyroid 
replacement therapy is instituted 
Therapy with pembrolizumab can be continued while 
thyroid replacement therapy is instituted 
 
Infusion 
Reaction 
2b 
Toxicity resolves to Grade 0-1  
Permanently discontinue if toxicity develops despite 
adequate premedication  
3-4 
Permanently discontinue 
Permanently discontinue 
Pneumonitis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose 
or inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks 
3-4 
Permanently discontinue 
Permanently discontinue 
Renal Failure or 
Nephritis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose 
or inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks 
3-4 
Permanently discontinue 
Permanently discontinue 
All Other Drug-
Related 
Toxicityc 
3 or Severe 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose 
or inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks 
4 
Permanently discontinue 
Permanently discontinue 
Note: Permanently discontinue for any severe or Grade 3 drug-related AE that recurs or any life-threatening event. 
a  For patients with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT increases by greater than 
or equal to 50% relative to baseline and lasts for at least 1 week then patients should be discontinued. 
b  If symptoms resolve within one hour of stopping drug infusion, the infusion may be restarted at 50% of the original infusion 
rate   (e.g., from 100 mL/hr to 50 mL/hr).  Otherwise dosing will be held until symptoms resolve and the subject should be 
premedicated for the next scheduled dose; Refer to Table 3 – Infusion Treatment Guidelines for further management 
details. 
c  Patients with intolerable or persistent Grade 2 drug-related AE may hold study medication at physician discretion.  
Permanently discontinue study drug for persistent Grade 2 adverse reactions for which treatment with study drug has been 
held, that do not recover to Grade 0-1 within 12 weeks of the last dose. 
 
In case toxicity does not resolve to Grade 0-1 within 12 weeks after last infusion, trial treatment 
should be discontinued after consultation with the Sponsor Investigator. Subjects who require 
corticosteroids to manage drug-related adverse events must be at an equivalent dose of ≤10mg 
per day of prednisone to resume dosing with pembrolizumab. Furthermore, an inability to reduce 


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the corticosteroid dose for managing a drug-related adverse event to the equivalent of ≤10 mg 
prednisone per day within 12 weeks of last pembrolizumab dose should result in permanent 
discontinuation from pembrolizumab. With investigator and Sponsor Investigator agreement, 
subjects with a laboratory adverse event still at Grade 2 after 12 weeks may continue treatment in 
the trial only if asymptomatic and controlled. For information on the management of adverse 
events, see Section 5.7.2. 
In subjects who continue on pembrolizumab having experienced a Grade 3, Grade 4, or 
persistent (> 4 weeks) Grade 2 drug-related AE, once the subject has recovered from the AE to 
Grade 0-1, the dosing interval in subsequent cycles may be increased by 1 week (e.g., to every 4 
week dosing in subjects who were on an every 3 week schedule). However, in subjects who 
experience Grade 3 or 4 pneumonitis, or recurrent persistent (>4 weeks) Grade 2 drug - related 
pneumonitis after rechallenge from a prior episode of persistent (> 4 weeks)Grade 2 drug-related 
pneumonitis, pembrolizumab must be permanently discontinued. 
For subjects who experience a recurrence of the same AE(s) at the same grade or greater with 
rechallenge of pembrolizumab, a consultation between the Sponsor Investigator and investigator 
should occur to determine whether the subject should continue in the trial. However, for a 
subject who experiences a recurrence of the same serious adverse event at the same grade or 
greater with rechallenge of pembrolizumab, the subject must discontinue pembrolizumab. 
Table 6 Dose Modification Guidelines for Trametinib for Drug-Related Adverse Events (Unless 
Otherwise Specified) 
Grade (CTC-AE)* 
Dose Modifications 
Grade 1 or Grade 2 (Tolerable) 
Continue treatment and monitor as clinically indicated. 
Grade 2 (Intolerable) or Grade 3 
Interrupt therapy until toxicity is grade 0-1 and reduce by one dose 
level when resuming therapy. 
Grade 4 
Discontinue permanently, or interrupt therapy until Grade 0 to 1 and 
reduce by one dose level when resuming therapy. 
 
Please follow Table 5 and Table 6 for dose modifications unless specified below. 
For Grade ≥ 3 drug related adverse events attributed to trametinib both pembrolizumab and 
trametinib should be simultaneously interrupted with the exceptions shown  below. 
Except for Grade ≥ 3 lymphopenia 
Exceptions where dose modifications are necessary for only trametinib: 
• LVEF reduction 
• Retinal Vein Occlusion (RVO) and Retinal Pigment Epithelial Detachment (RPED) 


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Table 7. Trametinib Dose Modification Guidelines and Stopping Criteria for LVEF Decrease 
Clinical 
Evaluation 
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 Novartis trametinib medical monitor and 
request approval for restart. 
– Restart treatment with trametinib at reduced dose by one 
dose level. 
– 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 after 2, 4, 8, 12, and 16 weeks or until 
resolution. 
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 Symptoms may include: dyspnea, orthopenea, and other signs and symptoms of pulmonary congestion and edema. 
 
 
 
 


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Table 8. Trametinib Withholding and Stopping Criteria for QTc Prolongation  
Prolongation* 
Action and Dose Modification 
• QTc ≥501 msec, or 
• Uncorrected QT >600 msec, or 
• QTc >530 msec for subjects with bundle branch 
block 
• Interrupt study treatment until QTc prolongation resolves to 
grade 1 or baseline. 
• Test serum potassium, calcium, phosphorus, and 
magnesium. If abnormal, correct per routine clinical 
practice to within normal limits. 
• If the QTc prolongation resolves to grade 1 or baseline, 
trametinib may be resumed if the investigator and study 
chair agree that the subject will benefit from further 
treatment. 
• If the event does not resolve, permanently discontinue 
study treatment. 
• If the event recurs, permanently discontinue study 
treatment. 
Abbreviations:  msec = milliseconds; QTc = QT interval on electrocardiogram 
*  Based on average QTcF 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 QTcF values of the three ECGs to determine if study treatments 
should be interrupted or discontinued. (See Appendix 11.4 for QTcF calculation). 
 
Table 9. Trametinib Dose Modification Guidelines for Hypertension 
Toxicity Grade 
Dose Modification 
2: Asymptomatic 
Maintain dose level 
3: Asymptomatic 
Hold until blood pressure is well controlled. Restart at reduced dose level. 
3: Symptomatic 
Hold until blood pressure is well controlled. Restart at reduced dose level. 
4 
Permanent discontinuation of treatment. 
 
Eye Disorders 
Visual changes have been observed in patients receiving trametinib, and can be caused by central 
serous retinopathy (CSR) with retinal pigment epithelial detachments (RPED), or Retinal Vein 
Occlusion (RVO). Patients are required to have a standard ophthalmic exam performed by an 
ophthalmologist at baseline and any time patients report visual disturbance. The exam will 
include indirect fundoscopic examination, visual acuity (corrected), visual field examination, 
tonometry, and direct fundoscopy. Special attention should be given to retinal (e.g., CSR, RPED) 
or retinal vein abnormalities (e.g., RVO). 
 
 


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Table 10. 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 Principal Investigator 
• 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. 
 
Table 11. Trametinib Dose Modification for RPED 
Event CTCAE Grade 
Action and Dose Modification 
Grade 1 RPED (Asymptomatic; 
clinical or diagnostic observations only) 
• Continue treatment with retinal evaluation monthly until resolution. 
If RPED worsens, follow instructions below. 
Grade 2-3 RPED (Symptomatic with 
mild to moderate decrease in visual 
acuity; limiting instrumental ADL) 
• Interrupt trametinib. 
• Retinal evaluation monthly. 
• If improved to ≤ Grade 1, restart trametinib with one dose level 
reduction (reduced by 
• 0.5 mg) or discontinue in patients taking trametinib 1 mg daily. 
• If no recovery within 4 weeks permanently discontinue trametinib 
 


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Table 12. Management and Dose Modification Guidelines for Diarrhea 
 
 
 
CTCAE Grade 
Adverse Event Management 
Action and Dose Modification 
Uncomplicated 
Diarrhea,1 
Grade 1 or 2 
• Diet: Stop all lactose containing products; eat small 
meals, BRAT-diet (banana, rice, apples, toast) 
recommended. 
• Hydration: 8-10 large glasses of clear liquids per day 
(e.g., Gatorade or broth). 
• Loperamide3: Initially 4 mg, followed by 2 mg every 4 
hours or after every unformed stool; maximum 16 
mg/day. Continue until diarrhea- free for 12 hours. 
• Diarrhea >24 hours: Loperamide 2 mg every 2 hours; 
maximum 16 mg/day. Consider adding oral antibiotics. 
• Diarrhea >48 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 for > 48h, 
interrupt trametinib until 
diarrhea resolves to grade ≤1. 
• Restart trametinib at the same 
dose level 
• If treatment delay is > 28 days, 
discontinue trametinib. 
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 and 
pembrolizumab until diarrhea 
resolves to ≤ grade 1. Then  
restart pembrolizumab and 
trametinib reduced by one dose 
level.4 
• If 3 dose reductions of study 
treatment are clinically 
indicated, permanently 
discontinue trametinib. 
• If treatment delay is >28 days, 
discontinue trametinib and 
pembrolizumab. 
1 Uncomplicated diarrhea defined by the absence of symptoms such as cramping, nausea/vomiting, ≥ grade 2, decreased 
performance status, pyrexia, sepsis, neutropenia ≥ grade 3, frank bleeding, and/or dehydration requiring intravenous fluid 
substitution. 
2 Complicated diarrhea defined by the presence of symptoms such as cramping, nausea/vomiting, ≥ grade 2, decreased 
performance status, pyrexia, sepsis, neutropenia ≥ grade 3, frank bleeding, and/or dehydration requiring intravenous fluid 
substitution. Patients with complicated diarrhea should be evaluated for pembrolizumab mediated autoimmune colitis with 
additional management as specified for pembrolizumab.  
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 study chair and in the absence of another 
episode of complicated or severe diarrhea in the 4 weeks subsequent to dose reduction. 


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Table 13. Dose Modification Guidelines and Management for Rash 
Rash 
Severity 
Management Guideline 
Dose Modification 
Grade 1 
• Initiate prophylactic and 
symptomatic treatment measures.1 
• Use moderate strength topical 
steroid.2 
• Reassess after 2 weeks. 
• Continue trametinib. 
• If rash does not recover to baseline within 2 weeks 
despite best supportive care, reduce trametinib by 
one dose level.3 
Grade 2 
• Initiate prophylactic and 
symptomatic treatment measures.1 
• Use moderate strength topical 
steroid.2 
• Reassess after 2 weeks. 
• Reduce trametinib by one dose level. 
• If rash recovers to ≤ grade 1 within 2 weeks, increase 
dose to previous dose level. 
• If no recovery to ≤ grade 1 within 2 weeks, interrupt 
trametinib until recovery to ≤ grade 1. 
• Restart trametinib at reduced dose level. 
Grade ≥3 • Use moderate strength topical 
steroids. Consider oral methyl-
prednisolone dose pack.2 
• Consider consulting dermatologist. 
• Interrupt trametinib until rash recovers to ≤ grade 1. 
Then restart pembrolizumab and trametinib (reduced 
by one dose level).3 
• If no recovery to ≤ grade 2 within 4 weeks, 
permanently discontinue trametinib and 
pembrolizumab. 
1 Rash prophylaxis is recommended for the first 6 weeks of study treatment. 
2 Moderate-strength topical steroids: Hydrocortisone 2.5% cream or fluticasone priopionate 0.5% cream. 
3 Trametinib may be escalated to previous dose level if no rash is evident 4 weeks after restarting study treatment. 
 
 
 
 
 
 
 
 
 


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Table 14. Pneumonitis Guidelines 
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 and pembrolizumab 
until recovery to grade ≤1. 
• If AE resolved to Grade ≤1 and 
relationship to trametinib and or 
pembrolizumab is equivocal, restarting 
pembrolizumab and trametinib (with 
dose reduction at investigators 
discretion) may be considered, after 
discussion with the study chair. 
• If treatment delay is > 4 weeks, 
permanently discontinue trametinib and 
pembrolizumab. 
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. 
• Permanently discontinue trametinib and 
pembrolizumab. 
Grade 4 
• Same as grade 3. 
• Permanently discontinue trametinib and 
pembrolizumab. 
Abbreviations:  BAL = bronchoalveolar lavage; CT = computed tomography. 
 
Dose Reduction Scheme for Trametinib 
 
No dose reductions for trametinib are permitted below 1.5 mg PO daily. 
 
 


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5.2.2 Timing of Dose Administration 
Trial treatment should be administered on Day 1 of each cycle after all procedures/assessments 
have been completed as detailed on the Study Calendar (Section 6.0).  Trial treatment may be 
administered up to 3 days before or after the scheduled Day 1 of each cycle due to administrative 
reasons. 
All trial treatments will be administered on an outpatient basis. 
Pembrolizumab 200 mg will be administered as a 30 minute IV infusion every 3 weeks.  Sites 
should make every effort to target infusion timing to be as close to 30 minutes as possible.  
However, given the variability of infusion pumps from site to site, a window of -5 minutes and 
+10 minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min). 
5.3 
Treatment  
The dose escalation portion of the trial will determine the MTD. Once the dose escalation portion 
is complete, patients will enroll sequentially (see Statistical Analysis Plan section for further 
details) into one of two expansion cohorts as noted below.   Enrollment into Expansion Cohorts 
A and B are pre-planned in regards to sequence and timing. Arm A (lead in trametinib) will open 
first to dose escalation and will accrue 3 patients. Once 3 patients are accrued for Arm A, Arm B 
will open and accrue 3 patients. 
 
5.4 
Definition of Dose Limiting Toxicities 
All toxicities will be graded using National Cancer Institute (NCI) CTCAE Version 4.0. The 
occurrence of any of the following toxicities during the first two cycles (i.e. after completion of 
the lead in cycle and the first cycle where both pembrolizumab and trametinib are administered) 
will be considered a DLT, if judged by the Investigator to be possibly, probably or definitely 
related to study drug administration. The goal of the dose escalation portion of the study is to 
assess the safety of the combination after pembrolizumab or trametinib lead in, therefore, 
patients must have completed the lead in phase and also have received both trametinib and 
pembrolizumab concurrently to be evaluable for a DLT. 
A DLT evaluable subject is defined as a subject who receives treatment for the 6 week dose-
limiting toxicity (DLT) observation period and who receives at least 80% of all planned 
treatments. A subject who does not receive at least 80% of planned treatment due to AEs that are 
unrelated to study treatment will not be considered evaluable for DLTs and may be replaced as 
Expansion 
Cohort (Arm) 
Regimen 
Number of patients 
A 
Lead in trametinib for 1 cycle (Q3W) followed by 
intercalated Trametinib and Pembrolizumab. 
12 
B 
Lead in pembrolizumab for 1 cycle (Q3W) followed by 
intercalated Trametinib and Pembrolizumab. 
12 


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needed during dose escalation or dose confirmation. More than 3 or 6 subjects may be enrolled 
to a given dose level if needed to replace subjects who are not evaluable for DLT or to ensure a 
thorough evaluation of a given dose level during the dose escalation part of the study. An event 
will be considered a dose-limiting toxicity (DLT) if it occurs during the first two cycles of 
treatment (first 6 weeks after initiating treatment) and meets at least one of the following criteria: 
• Clinically significant hematologic toxicity (e.g. grade 4 neutropenia lasting more than 
7 days or accompanied by neutropenic fever, or Grade 4 thrombocytopenia of any 
duration)   
• Clinically significant Grade ≥3 non-hematologic toxicity that has not been previously 
identified for either pembrolizumab or dabrafenib/trametinib and cannot be controlled 
with routine supportive measures (e.g. anti-emetics) 
• Clinically significant Grade ≥3 non-hematologic toxicities that are known to occur with 
either pembrolizumab or trametinib but that cannot be controlled using the recommended 
product-specific supportive measures (e.g. steroids for pembrolizumab -related immune 
toxicities) 
• Drug-related toxicity, regardless of CTCAE grade, that results in an interruption of any 
component of study therapy during Cycle 1 for more than 21 consecutive days and cannot 
be controlled within 2 weeks from its onset 
• Any other Grade 2 or greater non-hematological toxicity that in the judgment of the 
investigator and Sponsor Investigator is dose limiting, with the exception of mild or 
moderate immune -mediated adverse reactions or symptomatic endocrinopathy 
attributable to pembrolizumab 
• For Liver Function Tests 
- 
ALT or AST  ≥8x ULN 
- 
ALT or AST ≥5x ULN but <8x ULN persists for ≥2 weeks 
- 
ALT or AST  ≥3x ULN if associated with the appearance or worsening of 
symptoms of hepatitis or hypersensitivity such as fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, pyrexia, rash or eosinophilia. 
The following will NOT be considered a DLT for the purposes of this protocol: 
• Clinically insignificant laboratory values of any grade (i.e. asymptomatic amylase, lipase 
elevations). 
 
Dose escalation will proceed within each cohort according to the following scheme.  Dose-
limiting toxicity (DLT) is defined above.   
The MTD is the highest dose tested in which ≤ 1 out of 6 patients has experienced a DLT. 


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Table 15: Dose Escalation Decision Rule Summary 
Number of Patients with DLT  
at a Given Dose Level 
Escalation Decision Rule 
0 out of 3 
Enter 3 patients at the next dose level. 
≥2 
Dose escalation will be stopped.  This dose level will be 
declared the maximum administered dose (highest dose 
administered).  Three (3) additional patients will be 
entered at the next lowest dose level if only 3 patients were 
treated previously at that dose. 
1 out of 3 
Enter at least 3 more patients at this dose level. 
• If 0 of these 3 patients experience DLT, proceed to the 
next dose level. 
• If 1 or more of this group suffer DLT, then dose 
escalation is stopped, and this dose is declared the 
maximally administered dose.  Three (3) additional 
patients will be entered at the next lowest dose level if 
only 3 patients were treated previously at that dose. 
≤1 out of 6 at highest dose level below the 
maximum administered dose (unless ≤1 out of 
6 patients have DLT’s at Dose Level 2 – in 
which case this is also the MTD). 
This is the maximum tolerated dose (MTD), and generally 
the recommended phase 2 dose (RP2D). At least 6 patients 
must be entered at the RP2D. 
 
If ≤1 out of 6 patients treated at Dose Level 2 have DLT, this will be declared the maximum 
administered dose and the presumptive RP2D.  The RP2D may be less than the MTD or the 
maximum administered dose, depending on toxicities in later cycles and the extent of toxicities 
not qualifying as DLT. 
5.5 
Concomitant Medications/Vaccinations (allowed & prohibited) 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for one of these or other medications or 
vaccinations specifically prohibited during the trial, discontinuation from trial therapy or 
vaccination may be required.  The investigator should discuss any questions regarding this with 
the Merck Clinical team.  The final decision on any supportive therapy or vaccination rests with 
the investigator and/or the subject's primary physician.  
5.5.1 Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care.  All concomitant medication will be recorded in the subject’s medical record 
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications and 
fluids.  If changes occur during the trial period, documentation of drug dosage, frequency, route, 
and date may also be included in the subject’s medical record. 


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All concomitant medications received within 28 days before the first dose of trial treatment and 
30 days after the last dose of trial treatment should be recorded.  Concomitant medications 
administered after 30 days after the last dose of trial treatment should be recorded for SAEs and 
ECIs as defined in Section 7.2. 
5.5.2 Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase of this trial: 
• Antineoplastic systemic chemotherapy or biological therapy  
• Immunotherapy not specified in this protocol 
• Chemotherapy not specified in this protocol 
• Investigational agents other than pembrolizumab 
• Radiation therapy  
Note:  Radiation therapy to a symptomatic solitary lesion or to the brain may be allowed 
at the investigator’s discretion.   
• Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial.  Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and 
typhoid vaccine.  
• Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
event of clinical interest of suspected immunologic etiology.  The use of physiologic 
doses of corticosteroids may be approved after consultation with the Investigator. 
Subjects who, in the assessment by the investigator, require the use of any of the aforementioned 
treatments for clinical management should be removed from the trial.  Subjects may receive 
other medications that the investigator deems to be medically necessary. 
The Exclusion Criteria describes other medications which are prohibited in this trial. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
5.6 
Rescue Medications & Supportive Care 
5.6.1 Supportive Care Guidelines 
5.6.2 Pembrolizumab 
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of adverse events 


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with potential immunologic etiology are outlined below. Where appropriate, these guidelines 
include the use of oral or intravenous treatment with corticosteroids as well as additional anti-
inflammatory agents if symptoms do not improve with administration of corticosteroids.   Note 
that several courses of steroid tapering may be necessary as symptoms may worsen when the 
steroid dose is decreased. For each disorder, attempts should be made to rule out other causes 
such as metastatic disease or bacterial or viral infection, which might require additional 
supportive care. The treatment guidelines are intended to be applied when the investigator 
determines the events to be related to pembrolizumab.  
Note: if after the evaluation the event is determined not to be related, the investigator does not 
need to follow the treatment guidance (as outlined below). Refer to Section 5.2.1 for dose 
modification.  
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or skin 
photography as part of evaluation of the event.  
• Pneumonitis:  
o For Grade 2 events, treat with systemic corticosteroids. When symptoms 
improve to Grade 1 or less, steroid taper should be started and continued over no 
less than 4 weeks. 
o For Grade 3-4 events, immediately treat with intravenous steroids.  Administer 
additional anti-inflammatory measures, as needed. 
o Add prophylactic antibiotics for opportunistic infections in the case of prolonged 
steroid administration. 
• Diarrhea/Colitis:  
 
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such as 
diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of bowel 
perforation (such as peritoneal signs and ileus).   
o All subjects who experience diarrhea/colitis should be advised to drink liberal 
quantities of clear fluids.  If sufficient oral fluid intake is not feasible, fluid and 
electrolytes should be substituted via IV infusion.  For Grade 2 or higher diarrhea, 
consider GI consultation and endoscopy to confirm or rule out colitis. 
o For Grade 2 colitis, administer oral corticosteroids.  
o For Grade 3 or 4 colitis, treat with intravenous steroids followed by high dose 
oral steroids.   
o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 


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• Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) 
or Grade ≥3 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic 
acidosis (DKA) 
o For T1DM or Grade 3-4 Hyperglycemia 
 Insulin replacement therapy is recommended for Type I diabetes mellitus 
and for Grade 3-4 hyperglycemia associated with metabolic acidosis or 
ketonuria.  
 Evaluate patients with serum glucose and a metabolic panel, urine ketones, 
glycosylated hemoglobin, and C-peptide.  
• Hypophysitis: 
o For Grade 2 events, treat with corticosteroids. When symptoms improve to Grade 
1 or less, steroid taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the steroid dose is 
tapered. 
o For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed by 
oral corticosteroids. When symptoms improve to Grade 1 or less, steroid taper 
should be started and continued over no less than 4 weeks. Replacement of 
appropriate hormones may be required as the steroid dose is tapered. 
• Hyperthyroidism or Hypothyroidism:  
 
Thyroid disorders can occur at any time during treatment. Monitor patients for changes in 
thyroid function (at the start of treatment, periodically during treatment, and as indicated 
based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. 
o Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism): 
 In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are 
suggested as initial therapy. 
 In hypothyroidism, thyroid hormone replacement therapy, with 
levothyroxine or liothyroinine, is indicated per standard of care. 
o Grade 3-4 hyperthyroidism  
 Treat with an initial dose of IV corticosteroid followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid taper 
should be started and continued over no less than 4 weeks. Replacement of 
appropriate hormones may be required as the steroid dose is tapered. 
 


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• Hepatic: 
o For Grade 2 events, monitor liver function tests more frequently until returned to 
baseline values (consider weekly). 
 Treat with IV or oral corticosteroids 
o For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 hours.  
o When symptoms improve to Grade 1 or less, a steroid taper should be started and 
continued over no less than 4 weeks. 
• Renal Failure or Nephritis: 
o For Grade 2 events, treat with corticosteroids. 
o For Grade 3-4 events, treat with systemic corticosteroids. 
o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks.  
• Management of Infusion Reactions: Signs and symptoms usually develop during or 
shortly after drug infusion and generally resolve completely within 24 hours of 
completion of infusion.  
Table 16 below shows treatment guidelines for subjects who experience an infusion reaction 
associated with administration of pembrolizumab (MK-3475).  May follow institutional 
guidelines.  
 


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Table 16. Infusion Reaction Treatment Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
Grade 1 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
Increase monitoring of vital signs as medically indicated until the 
subject is deemed medically stable in the opinion of the investigator, 
or per institutional policies. 
None 
Grade 2 
Requires infusion 
interruption but responds 
promptly to symptomatic 
treatment (e.g., 
antihistamines, NSAIDS, 
narcotics, IV fluids); 
prophylactic medications 
indicated for < =24 hrs 
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy may include but is not 
limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as medically indicated until the 
subject is deemed medically stable in the opinion of the investigator. 
If symptoms resolve within one hour of stopping drug infusion, the 
infusion may be restarted at 50% of the original infusion rate (e.g., 
from 100 mL/hr to 50 mL/hr).  Otherwise dosing will be held until 
symptoms resolve and the subject should be premedicated for the 
next scheduled dose. 
Subjects who develop Grade 2 toxicity despite adequate 
premedication should be permanently discontinued from further 
trial treatment administration. 
Subject may be 
premedicated 1.5h 
(±30 minutes) prior 
to infusion of 
pembrolizumab 
(MK-3475) with: 
Diphenhydramine 50 
mg po (or equivalent 
dose of 
antihistamine). 
Acetaminophen 500-
1000 mg po (or 
equivalent dose of 
antipyretic). 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not 
rapidly responsive to 
symptomatic medication 
and/or brief interruption of 
infusion); recurrence of 
symptoms following 
initial improvement; 
hospitalization indicated 
for other clinical sequelae 
(e.g., renal impairment, 
pulmonary infiltrates) 
Grade 4: 
Life-threatening; pressor 
or ventilatory support 
indicated 
Stop Infusion. 
Additional appropriate medical therapy may include but is not 
limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
Increase monitoring of vital signs as medically indicated until the 
subject is deemed medically stable in the opinion of the investigator. 
Hospitalization may be indicated. 
Subject is permanently discontinued from further trial 
treatment administration. 
No subsequent 
dosing 
 
Appropriate resuscitation equipment should be available in the room and a physician readily available during the period 
of drug administration. 
 
 
 


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5.6.3 Supportive Care for Trametinib 
Rash is a frequent AE observed in subjects receiving trametinib (see the Investigator Brochures 
for more information). Recommendations for supportive care and guidelines for dose 
modifications for rash are based on experience with other MEK inhibitors[9] and EGFR 
inhibitors[10] and are provided in the table below and in the dose modification section for rash. 
Additional supportive care guidelines for trametinib and pembrolizumab are included in the dose 
modification guidelines in section 5.2. 
Table 17. Guidelines for Supportive Care of Rash from Trametinib 
Type of Care 
Action 
 
Prevention 
/Prophylaxisa 
 
• Avoid unnecessary exposure to sunlight 
• Apply broad-spectrum sunscreen (containing titanium dioxide or zinc oxide) with a 
skin protection factor (SPF) ≥15 at least twice daily. 
• Use thick, alcohol-free emollient cream (e.g., glycerine and cetomacrogol cream) 
on dry areas of the body at least twice daily. 
• Topical steroids and antibiotics should be applied at least twice daily starting on 
Day 1 of study treatment, to body areas such as face, chest, and upper back.   
Use mild-strength topical steroid  (hydrocortisone 1% cream) or topical antibiotic 
(e.g., clindamycin) or oral antibiotics (e.g., doxycycline 100 mg BID, minocycline 
100 mg BID) 
 
Symptomatic 
Careb  
• Pruritic lesions: cool compresses and oral antihistamine therapies  
• Fissuring lesions: Monsel’s solution, silver nitrate, or zinc oxide cream  
• Desquamation: thick emollients and mild soap  
• Paronychia: antiseptic bath, local potent corticosteroids in addition to oral 
antibiotics; if no improvement, consult dermatologist or surgeon  
• Infected lesions: appropriate bacterial/fungal culture-driven systemic or topical 
antibiotics  
Abbreviations:  BID = twice daily; SPF = sun protection factor 
a  Rash prophylaxis is recommended for the first 6 weeks of study treatment  
b  Subjects who develop rash/skin toxicities should be seen by a qualified physician and should receive evaluation for 
symptomatic/supportive care management  
 
5.7 
Diet/Activity/Other Considerations 
5.7.1 Diet 
Subjects should maintain a normal diet unless modifications are required to manage an AE such 
as diarrhea, nausea or vomiting. 
5.7.2 Contraception 
Pembrolizumab may have adverse effects on a fetus in utero.  Furthermore, it is not known if 
pembrolizumab has transient adverse effects on the composition of sperm.   


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For this trial, male subjects will be considered to be of non-reproductive potential if they have 
azoospermia (whether due to having had a vasectomy or due to an underlying medical 
condition).   
Female subjects will be considered of non-reproductive potential if they are either:  
(1) postmenopausal (defined as at least 12 months with no menses without an alternative medical 
cause; in women < 45 years of age a high follicle stimulating hormone (FSH) level in the 
postmenopausal range may be used to confirm a post-menopausal state in women not using 
hormonal contraception or hormonal replacement therapy. In the absence of 12 months of 
amenorrhea, a single FSH measurement is insufficient.);  
OR  
(2) have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or bilateral 
tubal ligation/occlusion, at least 6 weeks prior to screening;  
OR  
(3) has a congenital or acquired condition that prevents childbearing. 
Female and male subjects of reproductive potential must agree to avoid becoming pregnant or 
impregnating a partner, respectively, while receiving study drug and for 120 days after the last 
dose of study drug by complying with one of the following:   
(1) practice abstinence† from heterosexual activity;  
OR  
(2) use (or have their partner use) acceptable contraception during heterosexual activity.   
Acceptable methods of contraception are‡: 
Single method (one of the following is acceptable): 
• intrauterine device (IUD) 
• vasectomy of a female subject’s male partner  
• contraceptive rod implanted into the skin 
 Combination method (requires use of two of the following): 
• diaphragm with spermicide (cannot be used in conjunction with cervical cap/spermicide) 
• cervical cap with spermicide (nulliparous women only)   
• contraceptive sponge (nulliparous women only)  
• male condom or female condom (cannot be used together) 
• hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or progestin-only 
pill), contraceptive skin patch, vaginal contraceptive ring, or subcutaneous contraceptive 
injection 
 †Abstinence (relative to heterosexual activity) can be used as the sole method of contraception if 
it is consistently employed as the subject’s preferred and usual lifestyle and if considered 
acceptable by local regulatory agencies and ERCs/IRBs.  Periodic abstinence (e.g., calendar, 
ovulation, sympto-thermal, post-ovulation methods, etc.) and withdrawal are not acceptable 
methods of contraception.  


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‡If a contraceptive method listed above is restricted by local regulations/guidelines, then it does 
not qualify as an acceptable method of contraception for subjects participating at sites in this 
country/region. 
Subjects should be informed that taking the study medication may involve unknown risks to the 
fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate in the 
study subjects of childbearing potential must adhere to the contraception requirement (described 
above) from the day of study medication initiation (or 14 days prior to the initiation of study 
medication for oral contraception) throughout the study period up to 120 days after the last dose 
of trial therapy.  If there is any question that a subject of childbearing potential will not reliably 
comply with the requirements for contraception, that subject should not be entered into the study. 
5.7.3 Use in Pregnancy 
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab and/or 
trametinib, the subject will immediately be removed from the study.  The site will contact the 
subject at least monthly and document the subject’s status until the pregnancy has been 
completed or terminated.  The outcome of the pregnancy will be reported to the Sponsor 
Investigator and to Merck and to Novartis without delay and within 24 hours to the Sponsor 
Investigator and within 2 working days to Merck and Novartis if the outcome is a serious adverse 
experience (e.g., death, abortion, congenital anomaly, or other disabling or life-threatening 
complication to the mother or newborn).   
The study investigator will make every effort to obtain permission to follow the outcome of the 
pregnancy and report the condition of the fetus or newborn to the Sponsor Investigator, Merck 
and Novartis.   If a male subject impregnates his female partner the study personnel at the site 
must be informed immediately and the pregnancy reported to the Sponsor Investigator and to 
Merck and to Novartis and followed as described above and in Section 7.2.2. 
5.7.4 Use in Nursing Women 
It is unknown whether pembrolizumab is excreted in human milk.  Since many drugs are 
excreted in human milk, and because of the potential for serious adverse reactions in the nursing 
infant, subjects who are breast-feeding are not eligible for enrollment. 
5.8 
Subject Withdrawal/Discontinuation Criteria 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur.  In addition, a subject may be 
withdrawn by the investigator or the Sponsor Investigator if enrollment into the trial is 
inappropriate, the trial plan is violated, or for administrative and/or other safety reasons.  
Specific details regarding discontinuation or withdrawal are provided in Section 7.1.3 – Other 
Procedures. 
 
 


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A subject must be discontinued from the trial for any of the following reasons: 
• The subject or legal representative (such as a parent or legal guardian) withdraws 
consent. 
• Confirmed radiographic disease progression 
 
Note: For unconfirmed radiographic disease progression, please see Section 5.2.2 
 
Note: A subject may be granted an exception to continue on treatment with confirmed 
radiographic progression if clinically stable or clinically improved. 
• Unacceptable adverse experiences as described in Section 5.2.1.2 
• Intercurrent illness that prevents further administration of treatment 
• Investigator’s decision to withdraw the subject 
• The subject has a confirmed positive serum pregnancy test 
• Noncompliance with trial treatment or procedure requirements 
• The subject is lost to follow-up 
• Completed 24 months of uninterrupted treatment with pembrolizumab. Trametinib may 
be continued longer. 
 
Note: 24 months of pembrolizumab is calculated from the date of first dose.  
• Administrative reasons 
The End of Treatment and Follow-up visit procedures are listed in Section 6 (Study Calendar) 
and Section 7.1.4 (Visit Requirements).  After the end of treatment, each subject will be followed 
for 30 days for adverse event monitoring (serious adverse events will be collected for 90 days 
after the end of treatment as described in Section 7.2.3.1).  Subjects who discontinue for reasons 
other than progressive disease will have post-treatment follow-up for disease status until disease 
progression, initiating a non-study cancer treatment, withdrawing consent or becoming lost to 
follow-up.  After documented disease progression each subject will be followed by telephone for 
overall survival until death, withdrawal of consent, or the end of the study, whichever occurs 
first. 
 


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5.8.1 Discontinuation of Study Therapy after CR  
Discontinuation of treatment may be considered for subjects who have attained a confirmed CR 
that have been treated for at least 24 weeks with pembrolizumab and had at least two treatments 
with pembrolizumab beyond the date when the initial CR was declared.   
5.9 
Subject Replacement Strategy 
N/A 
5.10 
Clinical Criteria for Early Trial Termination 
Early trial termination will be the result of the criteria specified below: 
1. Quality or quantity of data recording is inaccurate or incomplete 
2. Poor adherence to protocol and regulatory requirements 
3. Incidence or severity of adverse drug reaction in this or other studies indicates a potential 
health hazard to subjects 
4. Plans to modify or discontinue the development of the study drug 
In the event of Merck’s or Novartis’ decision to no longer supply study drugs, ample notification 
will be provided so that appropriate adjustments to subject treatment can be made. 
 


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6.0 STUDY CALENDAR 
Time Period: 
Screening Phase 
Treatment Cycle1 
End of Treatment 
Post-Treatment 
Treatment Cycle/Title: 
Main Study 
Screening (Visit 1) 
1 
2 
3 
4 
To be repeated 
beyond 8 cycles 
Discontinuation 
Visit 
Safety Follow-up  
30 days Post 
Discontinuation14 
Follow-
up15 
Survival 
Follow-
up16 
5 
6 
7 
8 
Scheduling Window (Days): 
-28 to -1 
 
± 3 ± 3 ± 3 ± 3 ± 3 ± 3 
± 3 
At time of 
Discontinuation 
Administrative Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Prior and Concomitant Medication Review 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Trial Treatment Administration8 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Survival Status 
 
X 
------------------Ongoing---------------- 
X 
X 
X 
X 
Clinical Procedures/Assessments1,2 
 
 
 
 
 
 
 
Review Adverse Events 
 
X 
-----------------Ongoing----------------- 
X 
X 
 
 
Full Physical Examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Directed Physical Examination 
 
X1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Vital Signs, Weight and Height  
(height only at screening). 
X 
X1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
ECOG Performance Status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Ophthalmology Exam11 
X 
As clinically indicated 
 
 
 
ECG13 
X 
X 
X 
X 
 
 
 
 
X 
 
 
 
 
ECHO/MUGA12 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
Laboratory Procedures/Assessments5,6 
-10 to -1 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test – Urine or Serum β-HCG3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
PT/INR and aPTT4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with Differential 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Comprehensive Serum Chemistry Panel 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
T3, FT4 and TSH 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
 
Efficacy Measurements 
 
 
 
 
 
 
Tumor Imaging7 
X 
Every 9 weeks while on treatment 
X 
X 
X 
 
Tumor Biopsies/Archival Tissue Collection/Correlative Studies Blood 
 
 
 
 
Archival or Newly Obtained Tissue Collection9 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
Correlative Studies Blood Collection10 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 


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1.  In general, assessments/procedures are to be performed on Day 1 and prior to the first dose of trial treatment for each cycle unless otherwise specified. Treatment cycles are 3 weeks 
(21-days); however the pembrolizumab (MK-3475) treatment cycle interval may be increased due to toxicity according to the dose modification guidelines provided. If treatment 
cycles are increased all procedures except imaging will be completed according to the Cycle number and not weeks on treatment, imaging will be performed every 9 weeks (± 3 days) 
from the first dose of trial treatment regardless of any treatment delays. Weekly visits will also occur for the first cycle when starting trametinib (when trametinib is added (Cohort A 
C1D1, Cohort B C2D1).  The first cycle where both drugs are given requires weekly clinic visits for review of adverse events, vital signs, ECOG performance status, directed physical 
exam and CBC and CMP. 
2. In general, the window for each visit is ± 3 days unless otherwise specified. 
3. For women of reproductive potential, a urine or serum pregnancy test will be performed within 72 hours prior to first dose of trial treatment. If urine pregnancy results cannot be 
confirmed as negative, a serum pregnancy test, performed by the local study site laboratory, will be required. Pregnancy tests (serum and/or urine tests) should be repeated if required 
by local guidelines. 
4. Coagulation factors (PT/INR and aPTT) should be monitored closely throughout the trial for any subject receiving anticoagulant therapy. 
5. Laboratory tests for screening are to be performed within 10 days prior to the first dose of trial treatment. See Table 19 for a list of specific laboratory procedures/assessments to be 
performed in this study. 
6. After Cycle 1, lab samples can be collected up to 72 hours prior to the scheduled time point. Laboratory results must be known and acceptable prior to dosing. 
7. The initial tumor imaging will be performed within 30 days prior to the first dose of trial treatment. Scans performed as part of routine clinical management are acceptable for use as 
the screening scan if they are of diagnostic quality and performed within 30 days prior to the first dose of trial treatment. On-study imaging will be performed every 9 weeks (63 ±7 
days) after the first dose of trial treatment or more frequently if clinically indicated. The timing for imaging studies should follow calendar days and should not be adjusted for delays 
in cycle starts or extension of pembrolizumab /trametinib cycle frequencies. The same imaging technique should be used in a subject throughout the trial. CT including the chest, 
abdomen and pelvis or PET-CT is required for the baseline assessment.  Patients who discontinue for reasons other than progression will be followed by imaging every 9 weeks. 
8. Pembrolizumab (MK-3475) can be administered for up to 2 years. For the dose escalation and expansion Cohort (Arm) A (concurrent trametinib and pembrolizumab (MK-3475) both 
drugs will be administered as outlined in this protocol starting with cycle #1. For cohort B. trametinib will be initiated with cycle #1 and pembrolizumab (MK-3475) will commence in 
combination with trametinib starting with cycle #2, for Cohort C pembrolizumab (MK-3475) will be given for cycle 1 with concurrent trametinib added on C2D1. 
9. Tumor biopsy for immune and molecular biomarker analysis will be performed prior to Cycle 1 of treatment either on archival tissue or fresh biopsy (within 6 months– no intervening 
treatment). Repeat biopsy will be performed on cycle 1 D11-13 or within 2 days after the last dose of trametinib for Arm A) and an optional end of study biopsy (within 28 days after 
progression). 
10.Correlative blood draws for immune correlates will be performed prior to cycle 1 (- 3 days), prior to cycle 4 (-3 days), prior to cycle 7 (-3 days) and at discontinuation visit (± 5 days). 
Correlative blood draws for plasma DNA/RNA will be performed at baseline (cycle 1, day 1 prior to dosing or prior during screening), prior to each cycle of treatment (prior to 
concurrent administration of trametinib and pembrolizumab), and at progression (± 5 days). 
11. Ophthalmology Exam: Indirect fundoscopic examination, visual acuity (corrected), visual field examination, tonometry, and direct fundoscopy within 6 weeks prior to registration. 
12. ECHO/MUGA will be performed every 12-16 weeks unless clinically indicated. The same study should be used for follows that was done for the baseline exam. 
13. EKG at baseline, C1D1, C2D1, C3D1. Then every 12-16 weeks unless clinically indicated. 
14.  Safety Follow-Up Visit should be conducted approximately 30 days after the last dose of trial treatment or before the initiation of a new anti-cancer treatment, whichever 
comes first.15. Subjects who discontinue trial treatment for a reason other than disease progression will move into the Follow-Up phase and should be assessed every 9 
weeks (63 ±7 days) by radiologic imaging to monitor disease status.  
16. Once a patient has progression, they will be followed every 12 weeks until death or withdraw from follow-up. 
 


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7.0 TRIAL PROCEDURES 
7.1 
Trial Procedures 
The Study Calendar - Section 6.0 summarizes the trial procedures to be performed at each visit.  
Individual trial procedures are described in detail below.  It may be necessary to perform these 
procedures at unscheduled time points if deemed clinically necessary by the investigator. 
Furthermore, additional evaluations/testing may be deemed necessary by the Sponsor 
Investigator and/or Merck/Novartis for reasons related to subject safety. In some cases, such 
evaluation/testing may be potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus 
local regulations may require that additional informed consent be obtained from the subject.  In 
these cases, such evaluations/testing will be performed in accordance with those regulations. 
7.1.1 Administrative Procedures 
7.1.1.1 Informed Consent 
The Investigator must obtain documented consent from each potential subject prior to 
participating in a clinical trial. 
7.1.1.1.1 General Informed Consent 
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature of 
the person conducting the consent discussion.  
A copy of the signed and dated consent form should be given to the subject before participation 
in the trial. 
The initial informed consent form, any subsequent revised written informed consent form and 
any written information provided to the subject must receive the IRB/ERC’s approval/favorable 
opinion in advance of use.  The subject or his/her legally acceptable representative should be 
informed in a timely manner if new information becomes available that may be relevant to the 
subject’s willingness to continue participation in the trial.  The communication of this 
information will be provided and documented via a revised consent form or addendum to the 
original consent form that captures the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature. 
Specifics about a trial and the trial population will be added to the consent form template at the 
protocol level.   
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations and 
Sponsor Investigator requirements. 


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7.1.1.2 Inclusion/Exclusion Criteria 
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee to 
ensure that the subject qualifies for the trial.  
7.1.1.3 Medical History 
A medical history will be obtained by the investigator or qualified designee.  Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that are 
considered to be clinically significant by the Investigator.  Details regarding the disease for 
which the subject has enrolled in this study will be recorded separately and not listed as medical 
history.   
7.1.1.4 Prior and Concomitant Medications Review 
7.1.1.4.1 Prior Medications 
The investigator or qualified designee will review prior medication use, including any protocol-
specified washout requirement, and record prior medication taken by the subject within 28 days 
before starting the trial.  Treatment for the disease for which the subject has enrolled in this study 
will be recorded separately and not listed as a prior medication.  
7.1.1.4.2 Concomitant Medications 
The investigator or qualified designee will record medication, if any, taken by the subject during 
the trial.  All medications related to reportable SAEs and ECIs should be recorded as defined in 
Section 7.2. 
7.1.1.5 Disease Details and Treatments 
7.1.1.5.1 Disease Details 
The investigator or qualified designee will obtain prior and current details regarding disease 
status.  
7.1.1.5.2 Prior Treatment Details 
The investigator or qualified designee will review all prior cancer treatments including systemic 
treatments, radiation and surgeries. 
7.1.1.5.3 Subsequent Anti-Cancer Therapy Status 
The investigator or qualified designee will review all new anti-neoplastic therapy initiated after 
the last dose of trial treatment.  If a subject initiates a new anti-cancer therapy within 30 days 
after the last dose of trial treatment, the 30 day Safety Follow-up visit must occur before the first 
dose of the new therapy.  Once new anti-cancer therapy has been initiated the subject will move 
into survival follow-up.  


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7.1.2 Clinical Procedures/Assessments 
7.1.2.1 Adverse Event (AE) Monitoring 
The investigator or qualified designee will assess each subject to evaluate for potential new or 
worsening AEs as specified in the Study Calendar and more frequently if clinically indicated.  
Adverse experiences will be graded and recorded throughout the study and during the follow-up 
period according to NCI CTCAE Version 4.0 (see Section 11.6).  Toxicities will be characterized 
in terms regarding seriousness, causality, toxicity grading, and action taken with regard to trial 
treatment.  
Please refer to section 7.2 for detailed information regarding the assessment and recording of 
AEs.   
7.1.2.2 Full Physical Exam 
The investigator or qualified designee will perform a complete physical exam during the 
screening period.  Clinically significant abnormal findings should be recorded as medical history.  
A full physical exam should be performed during screening,  
7.1.2.3 Directed Physical Exam 
For cycles that do not require a full physical exam per the Study Calendar, the investigator or 
qualified designee will perform a directed physical exam as clinically indicated prior to trial 
treatment administration.   
7.1.2.4 Vital Signs 
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of pembrolizumab treatment and at treatment discontinuation as 
specified in the Study Calendar (Section 6.0).  Vital signs should include temperature, pulse, 
respiratory rate, weight and blood pressure.  Height will be measured at screening only. 
7.1.2.5 Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The investigator or qualified designee will assess ECOG status (see Section 11.5) at screening, 
prior to the administration of each dose of trial treatment and discontinuation of trial treatment as 
specified in the Study Calendar.   
7.1.2.6 Tumor Imaging and Assessment of Disease  
This will be performed using RECIST 1.1 Criteria. 
 
 


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7.1.2.7 Tumor Tissue Collection and Correlative Studies Blood Sampling 
Molecular Studies Blood 
• Plasma DNA/RNA detection of KRAS and PD-L1 
• Prior to each cycle of treatment two tubes of blood (1 for RNA and 1 for DNA) will be 
collected for KRAS and PD-L1 DNA and RNA quantification. Tubes will be provided in 
a collection kit from Liquid Genomics. The assay will be performed by Liquid Genomics, 
which has validated DNA and RNA assays for KRAS and PD-L1. Please see appendix 
for tube collection and shipping instructions.Immune studies blood - Peripheral blood 
will be collected prior to cycle 1 (-3 days), prior to cycle 4 (-3 days), prior to cycle 7 (-3 
days), and at progression (± 5 days) for flow cytometry for immune cell subsets, DNA 
sequencing for T-cell repertoire, Luminex Assay for measurement of cytokines (25 plea) 
in plasma and supernatant after activation with CD3+ CD28 or PMA+Ionomycine will 
also be performed in the HIMC at UC Davis at select time points. These studies will be 
performed by the Human Immune Monitoring Core at UC Davis.  
From each patient, at the relevant time points indicated in the study calendar, for the immune 
studies blood will be withdrawn directly into two 10 mL lavender-topped (EDTA coated) 
tubes. Samples will be banked and stored and assays run at the Human Immune Monitoring 
Core (Director: Emanual Maverakis laboratory at UC Davis). 
Contact information: 
Human Immune Monitoring Core (Maverakis Laboratory) 
UC Davis School of Medicine 
IRC Bldg., Room 1630 
2921 Stockton Blvd. Sacramento CA 95817 
LAB: 916-734-2156 
The HIMC laboratory (Director: Emanual Maverakis, MD) is a research laboratory at UC 
Davis with both immunology expertise and the appropriate equipment to carry out the proposed 
studies. These studies may include: Luminex Cytokine Assays to determine changes in 
cytokine profiles in response to treatment and Flow Cytometry to detect changes in immune 
cell subsets. 
The tubes should be centrifuged as soon as possible at approximately 800 x g for 10 minutes. 
Plasma should be transferred to a 15 mL conical tube and centrifuged a second time at 1000 – 
1500 x g for 10 minutes.  After the second centrifugation, aliquot plasma in 500 ul aliquots 
into labeled cryovials. For peripheral blood mononuclear cell (PBMC) preparation, replace the 
plasma removed with an equal amount of PBS (Ca and Mg free) in the original lavender-top 
tubes, and then slowly layer it on top of the 15ml of Ficoll in a 50ml conical tube, followed 
by centrifugation at 800 x g for 20 minutes with the break off. The buffy coat, a whitish layer 
of cells between the PBS and Ficoll layers above the red blood cell layer, should be collected 
and transferred into a new 50ml tube, washed once with 50ml of PBS, re-suspended in an 
appropriate volume of freezing medium and then transferred into labeled cryovials 
(107/ml/vial).  All cryovials are then to be frozen as rapidly as possible, and stored in a -70 
degree freezer until batch analysis is feasible by the HIMC. 


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Molecular correlates tissue – whole exome sequencing, determination of mutational load and 
RNA sequencing will be performed by the Broad Institute as part of the SU2C Team. A tube of 
blood will be collected for germline DNA comparison. Kits will be provided by the Broad 
Institute. 
Immune Studies Tissue 
Tumor biopsy at three time points with a biopsy prior to treatment, cycle 1, day 11 (+/- 2 days) 
and within 28 days post-treatment  upon progression for immune correlates (optional), anti-
apoptotic proteins, p-ERK by multiplexed immunofluorescence. Next generation sequencing 
on baseline and post-progression biopsies will also be conducted by the Broad Institute, 
conducted by the Stand Up to Cancer Core Facility, the Broad institution (NGS), the Mack lab 
and Theranostics.  Studies performed at SU2C Core (Yale and Broad) are part of the the SU2C 
Lung Cancer Dream Team. 
Table 18.Tissue Summary 
 
 
Order 
Prioritya 
Tissue Correlative 
Study 
Baseline 
C1D11-13 
Progression 
Slidesc 
Cell 
Blocksb 
Institution 
1 
IHC and QIF of PD-L1 
and other Immune 
Proteins and Tumor 
Infiltrating Immune 
Cells 
X 
X 
X 
5 
minimum 
(10 ideal) 
1 
SU2C 
Immune Core 
2 
Next Generation 
Sequencing (tissue + 
blood for germline 
DNA comparison) 
X 
 
X 
20 
1 
Broad 
Institute 
(SU2C Core) 
3 
RPPA and Multiplex 
Immunofluorescence 
for MEK-ERK pathway 
X 
X 
X 
4 
minimum 
(10 ideal) 
1 
Mack Lab UC 
Davis, 
Theranostics 
5 
YAP1/TAZ IHC 
X 
- 
X 
2 
1 
Bivona Lab, 
UCSF 
6 
PDX 
X 
- 
X 
Fresh 
Tissue 
N/A 
Jackson 
Laboratory 
West 
a. Prioritization of tissue use and correlates in order from #1 to #5 for baseline biopsy. Biopsy on or around  C1D11-D13  will 
be sent for Multiplex Immunofluorescence for p-MEK, DUSP6 and Immune IHC/QIF. 
b. Paraffin embedded cell block(s) may be substituted for slides.  
c. Unstained slides total cut from FFPE blocks at 5 microns thickness. The sample must contain a minimum of 20% tumor 
tissue.  Slides must be positively charged. 1 H&E slide should also be made for IHC and NGS. 
Please see the relevant correlative study sections below for further details regarding proper collection, shipping and handling 
of specimens. 


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Tissue Collection 
Tumor  tissue  obtained  at  each  biopsy  time  point  will  be  collected  by  a representative 
of the study team. At the first biopsy, one of the cores will be submitted directly to Pathology 
for  clinical  interpretation  and  report  as  well  as  standard  of  care  molecular  studies.  The 
remaining cores will be delivered to UC Davis Research Pathology, Pavilion Room 2P524 (or 
corresponding local research lab at other trial sites) and divided into 2 components.  
At least two core biopsies not less than 22 gauge in diameter and 1cm in length or tissue the 
equivalent of core biopsies sufficient to generate at least 20 cut slides should be paraffin 
embedded and stored in research pathology until ready for processing and shipping. Ideally, 6 
cores per biopsy timepoint should be obtained. At the first timepoint 2 cores should be used for 
histologic confirmation and standard molecular testing.  2 cores should be paraffin embedded for 
IHC of PD-L1 and other markers of the tumor immune microenvironment. At UC Davis, this 
FFPE specimen may also be stored in the laboratory of Dr. Philip Mack or the UC Davis 
HIMC for storage until sent for further testing. 
If available, two additional cores should be immediately stored in 2ml of RNAlater 
solution (Life Technologies) (the tissue portion should be processed into pieces, each less 
than 0.5cm3) for comprehensive DNA/RNA sequencing at the Broad Institute. The Samples in 
RNAlater solution should be kept refrigerated until processed at HIMC.  This should be 
delivered to the Human Immune Monitoring Core with the contact information listed below. If 
not enough cores are obtained DNA/RNA sequencing can be sent of the initial FFPE 
tissue 
Specimens in RNA Later should be shipped on cool packs (Monday – Thursday only) to: 
Human Immune Monitoring Core (Maverakis Laboratory) 
Department of Dermatology 
UC Davis School of Medicine 
IRC Bldg., Room 1630 
2921 Stockton Blvd.  
Sacramento CA 95817 
LAB: 916-734-2156 
Tissue from the second biopsy time point will be divided into the 2 research components with the 
procedures outlined above.  Component 1: at least 2 cores or enough tissue for 20 cut slides as 
specified for initial biopsy for FFPE for PD-L1 and additional IHC quantification by UC Davis 
or Yale and 2: remaining cores in RNA later solution then FFPE for DNA/RNA sequencing. (If 
no cores were available for processing with RNA later in the initial biopsy, the repeat 
biopsy should all go through FFPE and not through an RNA later step).  A research H&E 
slide will also be generated and reviewed by a research pathologist to confirm presence of tumor.  


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If there is limited tissue for all biopsy timepoints priority should be given to immunofluorescence 
panel and PD-L1 testing by SU2C Core Facility at Yale or UC Davis HIMC.  
Molecular Studies Tissue 
For the baseline biopsy, archival tissue is acceptable if a core or surgical was performed after last 
systemic treatment and within 6 months of consent for this study and if at least 20 unstained 
slides or 2 cell block is available for analyses (Fine needle specimens or cell blocks from 
cytology specimens are not acceptable). 
Next Generation Sequencing (DNA and RNA (if enough tissue available) of a Customized SU2C 
Gene Panel will be performed at the Broad Institute as part of the SU2C Collaboration. This will 
be performed at baseline biopsy and post-progression biopsy. When requested the Broad Institute 
Samples lab will ship sample collection kits to research site.  A companion blood collection tube 
will also be provided and should be collected at baseline. 
Kits are specific for Material Type collected 
i. Labels – FFPE or Frozen Tumors 
ii. Labels – Blood or Buffy Coat Samples 
iii. Matrix Kits – DNA or RNA analytes 
1. Researcher fill kit & provides Sample Kit Metadata spreadsheet (example provided). 
2. Kits are shipped back to the Broad Institute Samples lab per instructions provided in the 
kits.  (See Attached Documents). Specimens should be coded with a unique identifier (ie. 
patient number and biopsy number in sequence (ie. for patient 1, 001-01 (baseline 
biopsy), 001-02 (on-treatment biopsy), 001-03 (post progression biopsy). 
3. Sample Processing & Data Generation will proceed.   
(Turnaround Time is expected to be 5-6 weeks for Exome runs). RNA sequencing will be 
batched into runs of 96 samples across the project so timeline will be more variable. 
 
 


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Quantitative Immunofluorescence  
To demonstrate on target knockdown of MEK inhibition with trametinib, the Mack lab at UC 
Davis and Theranostics Health (Gaithersburg, MD) will bank tissue to perform multiplexed 
immunofluorescence and RPPA for phospho-MEK, DUSP6 and associated pathway proteins on 
FFPE. 
The Mack laboratory at UC Davis has extensive experience in the multiplexed 
immunofluorescence assay including incorporation into NCI sponsored studies such as SWOG 
0931 Everest study of the mTOR inhibitor everolimus as adjuvant therapy in Renal Cell 
Carcinoma and FGF/FGFR. 
Up to 10 unstained slides (minimum 4) or 1 FFPE block will be sent to the Mack lab. 
Dr. Philip Mack 
UC Davis Comprehensive Cancer Center 
4501 X Street, Suite 1009 
Sacramento, CA 95817 
Phone: 916-734-6447 
Email: pcmack@ucdavis.edu 
 
Patient-Derived Xenotransplants 
Collection of Specimen(s) 
Tissue for PDX should only be obtained at procedures performed on a Monday, Tuesday, 
Wednesday, or Thursday. The fresh specimen will be submitted directly and immediately to The 
Jackson Laboratory using the following procedures.  
a. 
The physician should obtain the maximum amount of tumor that is prudent at the time of 
biopsy or resection. Minimum sample size is a core measuring 8mm x 3mm. Please approximate 
these dimensions. 
b. 
The specimen should be collected following Institution Universal precautions SOPs for 
maintaining tissue integrity. Please remind all personnel that are involved in processing the 
sample that it will be implanted in profoundly immune deficient mice, which is why it is 
imperative that extra care be taken in sample collection to minimize the risk of transferring 
human bacteria to the mice. 
Handling of Specimens(s) 
The tumor sample should be placed in a 50 ml screw cap conical tube containing 40 ml RPMI 
buffer (without fetal calf serum); preferably within 30 minutes of tumor removal. Seal cap tightly 
with Parafilm. Sample should be refrigerated at 4°C until packed for shipping on the same day as 
procurement. 
 


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Shipping of Specimen(s) 
The sealed conical tube containing RPMI & the tumor specimen must be wrapped in absorbent 
material (i.e. paper towels) and placed in an airtight plastic bag (i.e. a ziplock bag). Pack the 
specimen into an insulated Styrofoam shipper with a refrigerated (4° C) cool pack (not frozen) to 
protect specimen from temperature fluctuations. All paperwork pertaining to the patient should 
be placed in a plastic bag, sealed tightly, and packed with the tissue shipment. Include the 
Jackson Laboratory Sample Submission Form. 
Ship by Fed Ex for overnight delivery to:  
The Jackson Laboratory 
In Vivo Services 
c/o Margaret Bundy or James Keck  
1650 Santa Ana Ave. 
Sacramento, CA 95838 
Prior to shipping, contact for sample coordination:  Margaret Bundy 916-469-2609. 
Creation of PDX is funded under a UC Davis – Jackson Laboratory Collaboration. 
 
Immune Studies Tissue 
   Immunohistochemistry and Quantitative Immunofluorescence 
      PD-L1 and Evaluation of TILS 
The PD-L1 immunohistochemistry will be performed in 3-5 µm-thick histology preparations 
obtained from conventional biopsy formalin-fixed, paraffin-embedded (FFPE) tissue samples.  
The tumor PD-L1 protein will be tested using the FDA-approved Dako 22C3 assay using 
chromogenic immunohistochemistry in the Yale Pathology Labs or UC Davis under CLIA 
laboratory conditions. The scoring procedure will include the determination of the percentage of 
positive cells in the tumor by a surgical pathologist using bright field microscopy. The score will 
be semi-quantitative and determined based on the percentage of positive cells. 
The level of major TIL subtypes, TIL activation/proliferation and expression of major immune 
inhibitory receptors will be evaluated using multiplexed quantitative immunofluorescence (QIF) 
performed in 3-5 µm-thick histology preparations obtained from formalin-fixed, paraffin-
embedded (FFPE) tissue samples, as previously reported [11]. We will perform three 
multiplexed QIF panels containing the following markers: Panel #1: DAPI/CD4/CD8/CD20; 
Panel #2: DAPI/CD3/Granzyme-B/Ki-67; and Panel #3: DAPI/CD3/PD-1/TIM-3/LAG-3.  The 
Yale group has already performed validation of the antibodies and combined these markers into 
multiplexed QIF panels. Simultaneous measurements of the targets will be performed using 
multispectral imaging and the AQUA® method providing continuous fluorescence marker 
scores. Eventually, quantification of positive cells for each marker will also be performed using 
the Vectra multispectral imaging platform with the cell phenotyping tool of the InForm® 


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software; and reported as cell density (number of cells/area unit).See section 7.2.4 for processing 
and shipping information for the PD-L1 and QIF samples. 
Immune correlates will be performed by Yale University Translational Immuno-Oncology or 
the Human Immune Monitoring Core (HIMC) at UC Davis as outlined below. 
 
PD-L1 expression will be assayed using Merck’s proprietary 22C3 antibody that is FDA 
approved as a companion diagnostic for pembrolizumab for quantifying PD-L1 expression for 
MK-3475 trials in NSCLC and melanoma including [12]. 
Biopsied tumor for PD-L1 Quantification 
PD-L1 expression by immunohistochemistry at baseline and in repeat biopsy specimens to 
assess for changes in PD-L1 expression in response to treatment will be conducted  by UC 
Davis or Yale Translational Immuno-Oncology using the FDA approved DAKO 22C3 
antibody and  by quantitative IHC. 
If there is not enough tissue for entire DNA/RNA sequencing panel at the Broad Institute 
biopsied tumor for Tumor Infiltrating Lymphocytes and Subsets and RT-PCR for Immune 
Markers Real time-PCR for immune markers (if tissue size permits) including CD3, PD-1, 
GranzB, Perforin, IL-2, IFNg, Tim3, LAG3, CTLA-4, Foxp3 will be performed if adequate tissue 
is available. 
Processing Instructions for Immunohistochemistry and Quantitative Immunofluorescence 
Immunohistochemistry and Quantitative Immunofluorescence: Staining for PD-L1, relevant 
immunoproteins and tumor infiltrating immune cells will be performed by the SU2C Immune 
Core at Yale University as outlined below. Tissue samples will be collected from participants 
who have been properly consented and who have agreed to participate in the research study. 
Tumor tissues are optimally suitable for IHC/QIF studies if fixed in 10% neutral buffered 
formalin (NBF) for 16-24 hours and processed into paraffin blocks using clinical-grade 
pathology laboratory conditions. 
1. Select the tumor block and obtain one Hematoxylin & Eosin (H&E) stained slide for 
review by site pathologist to confirm diagnosis and ensure presence of tumor cells.  For 
in situ analyses, there is no lower limit in the amount of tumor cell content.   
 
a. Samples with few tumor cells (<100-200 cells) may be insufficient for PD-L1 
immunostaining but should still be submitted for the QIF studies of TILs and other 
stromal markers. 
 
2. If pathologist review is not possible or available at the site, the H&E slides or a digital 
version may be sent directly to Yale Pathology for initial assessment. 
 
3. Obtain 5 additional serial 4-5µm thick sections from the reviewed paraffin block and 
place each section in a positively-charged glass histology slide.  Tissues should be cut 


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and processed using conventional, clinical-grade in-house histology protocols.  Paraffin 
dipping of slides after sectioning is not recommended.  
 
4. Collect 5 freshly cut (<5 days) unstained serial section slides from each case, label each 
preparation using the SU2C coding system and place them in a conventional plastic 
histology slidebox.  Make sure slides are in a firm position to avoid damage during 
transportation and cover with paper towel prior to packing to prevent movement within 
the box.  If possible, also include the sectioning order on the label for each slide. 
 
a.  Whenever feasible, blocks should be processed in batches, and shipped together within 
a 5-day period after sectioning. 
 
5. Include H&E stained preparation together with the 5 unstained sections in the slidebox.  
This slide will be digitalized and become available for review within the SU2C group.  
Specimens should be coded with a unique identifier (ie. institution, trial number, patient 
number and biopsy number in sequence (ie. for UC Davis patient 1, UCD250-001-01 
(baseline biopsy), UCD250-001-02 (on-treatment biopsy), UCD250-001-03 (post 
progression biopsy). 
 
6. Seal the slidebox using Parafilm and/or a plastic envelope and wrap with bubble wrap 
prior to shipping.  Include detailed sender information (with email) and ship using 
overnight service to: 
 
Attention to: Nikita Mani (nikita.mani@yale.edu).   
Backup contact should Nikita be out is Ila Datar (ila.datar@yale.edu) 
Address: BML112/BML113 
   
Department of Pathology 
    
Yale School of Medicine 
    
310 Cedar Street 
    
New Haven, CT  06510 
Phone 1:  203-737-4205 
Phone 2:  203-785-3588 
 
A confirmation of sample reception will be sent via email to the sender within 72 hours.  
 
7.  Slides will be stained for IHC and the QIF panels within 5 working days from reception 
in the lab or stored in appropriately until use and batched to accommodate projects in 
single experimental runs (whenever possible). 
 
8. Results of the analyzed markers will be provided as continuous scores using fluorescence 
intensity scores and/or phenotype cell counts.  The turnaround time will depend on the 
amount of slides and project volume.   
 
 
 


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YAP1/TAZ Immunohistochemistry 
We will collect pre- and post- treatment tissues as available. Formalin-fixed, paraffin-embedded 
(FFPE) slides will be applied for immunohistochemistry (IHC) staining with YAP and TAZ 
antibody separately. YAP1 antibody will be purchased from Santa Cruz Biotechnology (sc-
15407). And TAZ antibody will be purchased from Sigma (HPA007415). The nuclear and 
cytosol YAP/TAZ expression will be quantified and scored by board-certificated pathologists. 
The scores of YAP/TAZ expression in pre- and post- treatment will be compared to explore up 
regulation of YAP/TAZ as a biomarker of resistance to trametinib + pembrolizumab treatment. 
These studies will be funded by the Addario Lung Cancer Foundation and Van Auken 
Foundation Young Innovators Team Award. 
Collection of Specimen(s) 
Completion of both assays requires a total of 2 unstained slides cut from FFPE blocks at 5 
microns thickness on positively charged (+) slides.  
Shipping of Specimen(s): 
Bivona Laboratory 
Room N216R, Genentech Hall 
600 16th Street, San Francisco, CA 94158 
Laboratory Procedures/Assessments 
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below. Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) 
Laboratory tests for hematology, chemistry, urinalysis, and others are specified below.  
 


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Table 19. Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Other 
Hematocrit 
Albumin 
Blood 
Serum β-human chorionic gonadotropin† 
Hemoglobin 
Alkaline phosphatase 
Glucose 
  (β-hCG)† 
Platelet count 
Alanine aminotransferase (ALT) 
Protein 
PT (INR) 
WBC (total and differential) 
Aspartate aminotransferase (AST) 
Specific gravity  
aPTT 
Red Blood Cell Count 
Lactate dehydrogenase (LDH) 
Microscopic exam (If abnormal)  Total thriiodothyronine (T3) 
Absolute Neutrophil Count 
Carbon Dioxide ‡ 
results are noted 
Free thyroxine (T4) 
Absolute Lymphocyte Count 
(CO2 or biocarbonate) 
Urine pregnancy test † 
Thyroid stimulating hormone (TSH) 
 
Uric Acid 
 
 
 
Calcium 
 
 
 
Chloride 
 
Blood for correlative studies 
 
Glucose 
 
  
 
Phosphorus 
 
  
 
Potassium   
 
  
 
Sodium 
 
  
 
Magnesium 
 
  
 
Total Bilirubin 
 
  
 
Direct Bilirubin (If total bilirubin is elevated 
above the upper limit of normal) 
 
 
 
Total protein 
 
 
 
Blood Urea Nitrogen 
 
 
† Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed as negative, a serum pregnancy test will be required.   
‡ If considered standard of care in your region. 
 


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Laboratory tests for screening should be performed within 10 days prior to the first dose of 
treatment.  After Cycle 1, pre-dose laboratory procedures can be conducted up to 3 days prior to 
dosing.  Results must be reviewed by the investigator or qualified designee and found to be 
acceptable prior to each dose of trial treatment.  
7.1.3 Other Procedures 
7.1.3.1 Withdrawal/Discontinuation 
When a subject discontinues/withdraws prior to trial completion, all applicable activities 
scheduled for the discontinuation visit should be performed at the time of discontinuation.  Any 
adverse events which are present at the time of discontinuation/withdrawal should be followed in 
accordance with the safety requirements outlined in Section 7.2 - Assessing and Recording 
Adverse Events.  Subjects who a) attain a CR or b) complete 24 months of treatment with 
pembrolizumab may discontinue treatment.  Trametinib may be continued after 24 months. After 
discontinuing treatment following assessment of CR, these subjects should return to the site for a 
Safety Follow-up Visit (described in Section 7.1.4.4) and then proceed to the Follow-Up Period 
of the study (described in Section 7.1.4.5). 
7.1.4 Visit Requirements 
Visit requirements are outlined in Section 6.0 - Study Calendar.   Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures. 
7.1.4.1 Screening 
Screening should be completed within 28 days of the patient signing consent. 
7.1.4.2 Treatment Period 
Please see study calendar for treatment period details. 
7.1.4.3 Post-Treatment Visits 
Only safety follow up period required. 
7.1.4.4  Safety Follow-Up Visit 
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the last 
dose of trial treatment or before the initiation of a new anti-cancer treatment, whichever comes 
first.  All AEs that occur prior to the Safety Follow-Up Visit should be recorded.  Subjects with 
an AE of Grade > 1 will be followed until the resolution of the AE to Grade 0-1 or until the 
beginning of a new anti-neoplastic therapy, whichever occurs first.  SAEs that occur within 90 
days of the end of treatment or before initiation of a new anti-cancer treatment should also be 
followed and recorded.   


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7.1.4.5 Follow-up Visits 
Subjects who discontinue trial treatment for a reason other than disease progression will move 
into the Follow-Up Phase and should be assessed every 9 weeks (63 ± 7 days) by radiologic 
imaging to monitor disease status.  After 1 year, the imaging time point will occur every 9 weeks 
(± 7 days). Every effort should be made to collect information regarding disease status until the 
start of new anti-neoplastic therapy, disease progression, death, or end of the study.  Information 
regarding post-study anti-neoplastic treatment will be collected if new treatment is initiated. 
7.1.4.5.1 Survival Follow-up 
Once a subject experiences confirmed disease progression or starts a new anti-cancer therapy, the 
subject moves into the survival follow-up phase and should be contacted by telephone every 12 
weeks to assess for survival status until death, withdrawal of consent, or the end of the study, 
whichever occurs first.  
7.2 
Assessing and Recording Adverse Events 
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily have 
to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in frequency 
and/or intensity) of a preexisting condition that is temporally associated with the use of the 
Merck’s product, is also an adverse event. 
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  Examples of 
this may include, but are not limited to, teething, typical crying in infants and children and onset 
of menses or menopause occurring at a physiologically appropriate time. 
Merck product includes any pharmaceutical product, biological product, device, diagnostic agent 
or protocol-specified procedure, whether investigational (including placebo or active comparator 
medication) or marketed, manufactured by, licensed by, provided by or distributed by Merck for 
human use. 
Adverse events may occur during the course of the use of Merck product in clinical trials, or as 
prescribed in clinical practice, from overdose (whether accidental or intentional), from abuse and 
from withdrawal. 
Progression of the cancer under study is not considered an adverse event.  
All adverse events that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 


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excluded from the trial, or are the result of a protocol-specified intervention, including but not 
limited to washout or discontinuation of usual therapy, diet, placebo treatment or a procedure. 
From the time of treatment allocation/randomization through 30 days following cessation of 
treatment, all adverse events must be reported by the investigator. Such events will be recorded 
at each examination on the Adverse Event case report forms/worksheets.  The reporting 
timeframe for adverse events meeting any serious criteria is described in section 7.2.3.1. The 
investigator will make every attempt to follow all subjects with non-serious adverse events for 
outcome. 
7.2.1 Definition of an Overdose for this Protocol and Reporting of Overdose to the 
Sponsor Investigator and to Merck 
For purposes of this trial, an overdose of pembrolizumab will be defined as any dose of 1,000 mg 
or greater (≥5 times the indicated dose).  No specific information is available on the treatment of 
overdose of pembrolizumab. Appropriate supportive treatment should be provided if clinically 
indicated. In the event of overdose, the subject should be observed closely for signs of toxicity.  
Appropriate supportive treatment should be provided if clinically indicated. 
If an adverse event(s) is associated with (“results from”) the overdose of a Merck product, the 
adverse event(s) is reported as a serious adverse event, even if no other seriousness criteria are 
met. 
If a dose of Merck’s product meeting the protocol definition of overdose is taken without any 
associated clinical symptoms or abnormal laboratory results, the overdose is reported as a non-
serious Event of Clinical Interest (ECI), using the terminology “accidental or intentional 
overdose without adverse effect.” 
All reports of overdose with and without an adverse event must be reported within 24 hours to 
the Sponsor Investigator and within 2 working days hours to Merck Global Safety. (Attn: 
Worldwide Product Safety; FAX 215 993-1220) 
7.2.2 Reporting of Pregnancy and Lactation to the Sponsor Investigator and to Merck 
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject (spontaneously 
reported to them) that occurs during the trial. 
Pregnancies and lactations that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but not 
limited to washout or discontinuation of usual therapy, diet, placebo treatment or a procedure.   
Pregnancies and lactations that occur from the time of treatment allocation/randomization 
through 120 days following cessation of Merck product, or 30 days following cessation of 
treatment if the subject initiates new anticancer therapy, whichever is earlier, must be reported by 
the investigator. All reported pregnancies must be followed to the completion/termination of the 


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pregnancy. Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform 
mole, blighted ovum, fetal death, intrauterine death, miscarriage and stillbirth must be reported 
as serious events (Important Medical Events). If the pregnancy continues to term, the outcome 
(health of infant) must also be reported. 
Such events must be reported within 24 hours to the Sponsor Investigator and within 2 working 
days to Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220) 
7.2.3 Immediate Reporting of Adverse Events to the Sponsor Investigator and to Merck 
7.2.3.1 Serious Adverse Events 
A serious adverse event is any adverse event occurring at any dose or during any use of Merck’s 
product that: 
• Results in death; 
• Is life threatening; 
• Results in persistent or significant disability/incapacity; 
• Results in or prolongs an existing inpatient hospitalization; 
• Is a congenital anomaly/birth defect; 
• Is another important medical event  
• Note: In addition to the above criteria, adverse events meeting either of the below criteria, 
although not serious per ICH definition, are reportable to the Merck in the same 
timeframe as SAEs to meet certain local requirements. Therefore, these events are 
considered serious by Merck for collection purposes. 
o Is a new cancer (that is not a condition of the study); 
o Is associated with an overdose. 
Refer to Table 20 for additional details regarding each of the above criteria. 
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any serious adverse event, or follow up to a serious adverse event, 
including death due to any cause other than progression of the cancer under study that occurs to 
any subject must be reported within 24 hours to the Sponsor Investigator and within 2 working 
days to Merck Global Safety if it causes the subject to be excluded from the trial, or is the result 
of a protocol-specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, placebo treatment or a procedure. 
For the time period beginning at treatment allocation/randomization through 90 days following 
cessation of treatment, or 30 days following cessation of treatment if the subject initiates new 
anticancer therapy, whichever is earlier, any serious adverse event, or follow up to a serious 
adverse event, including death due to any cause other than progression of the cancer under study 


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whether or not related to the Merck product, must be reported within 24 hours to the Sponsor 
Investigator and within 2 working days to Merck Global Safety. 
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to Merck product that is brought to the attention of the investigator at any 
time following consent through the end of the specified safety follow-up period specified in the 
paragraph above, or at any time outside of the time period specified in the previous paragraph 
also must be reported immediately to the Sponsor Investigator and to Merck Global Safety. 
• All subjects with serious adverse events must be followed up for outcome. 
• SAE reports and any other relevant safety information are to be forwarded to the 
Merck Global Safety facsimile number:  +1-215-993-1220 
• A copy of all 15 Day Reports and Annual Progress Reports is submitted as required by 
FDA, European Union (EU), Pharmaceutical and Medical Devices agency (PMDA) or 
other local regulators. Investigators will cross reference this submission according to 
local regulations to the Merck Investigational Compound Number (IND, CSA, etc.) at the 
time of submission.  Additionally investigators will submit a copy of these reports to 
Merck & Co., Inc. (Attn: Worldwide Product Safety; FAX 215 993-1220) at the time of 
submission to FDA. 
7.2.3.2 Events of Clinical Interest 
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported within 24 hours to the Sponsor Investigator and within 2 working 
days to Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220). 
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any subject must be 
reported within 24 hours to the Sponsor Investigator and within 2 working days to Merck Global 
Safety if it causes the subject to be excluded from the trial, or is the result of a protocol-specified 
intervention, including but not limited to washout or discontinuation of usual therapy, diet, 
placebo treatment or a procedure. 
For the time period beginning at treatment allocation/randomization through 90 days following 
cessation of treatment, or 30 days following cessation of treatment if the subject initiates new 
anticancer therapy, whichever is earlier, any ECI, or follow up to an ECI, whether or not related 
to Merck product, must be reported within 24 hours to the Sponsor Investigator and within 24 
hours to Merck Global Safety. 
Events of clinical interest for this trial include: 
1.  an overdose of Merck product, as defined in Section 7.2.1 - Definition of an Overdose for 
This Protocol and Reporting of Overdose to the Sponsor Investigator, that is not associated with 
clinical symptoms or abnormal laboratory results.  


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2.  an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the upper limit 
of normal and, at the same time, an alkaline phosphatase lab value that is less than 2X the upper 
limit of normal, as determined by way of protocol-specified laboratory testing or unscheduled 
laboratory testing.* 
*Note:  These criteria are based upon available regulatory guidance documents. The purpose of 
the criteria is to specify a threshold of abnormal hepatic tests that may require an additional 
evaluation for an underlying etiology.  
7.2.3.3 Protocol-Specific Exceptions to Serious Adverse Event Reporting  
Efficacy endpoints as outlined in this section will not be reported to Merck as described in 
Section 7.2.3.- Immediate Reporting of Adverse Events to the Sponsor Investigator and to 
Merck, unless there is evidence suggesting a causal relationship between the drug and the event. 
Any such event will be submitted to the Sponsor Investigator within 24 hours and to Merck 
Global Safety within 2 working days either by electronic or paper media. 
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study. 
The Sponsor Investigator will monitor unblinded aggregated efficacy endpoint events and safety 
data to ensure the safety of the subjects in the trial. Any suspected endpoint which upon review is 
not progression of the cancer under study will be forwarded to Merck Global Safety as a SAE 
within 2 working days of determination that the event is not progression of the cancer under 
study. 
Hospitalization related to convenience (e.g., transportation issues, etc.) will not be considered a 
SAE. 
Reporting Adverse Events to Novartis 
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the patient 
has provided the main informed consent and until at least 30 days after the patient has stopped 
study treatment must be reported to Novartis within 24 hours of learning of its occurrence. 
Any SAEs experienced after this 30 days period should only be reported to Novartis if the 
investigator suspects a causal relationship to the study treatment. Recurrent episodes, 
complications, or progression of the initial SAE must be reported as follow-up to the original 
episode within 24 hours of the investigator receiving the follow-up information. An SAE 
occurring at a different time interval or otherwise considered completely unrelated to a 
previously reported one should be reported separately as a new event. 
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess and record the relationship of each SAE to each 
specific study treatment (if there is more than one study treatment), complete the SAE Report 


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Form in English, and send the completed, signed form by fax within 24 hours to the oncology 
Novartis Drug Safety and Epidemiology (DS&E) department - Fax: (877-778-9739). The 
original copy of the SAE Report Form and the fax confirmation sheet must be kept with the case 
report form documentation at the study site. 
Follow-up information is sent to the same contact(s) to whom the original SAE Report Form was 
sent, using a new SAE Report Form stating that this is a follow-up to the previously reported 
SAE and giving the date of the original report. Each re-occurrence, complication, or progression 
of the original event should be reported as a follow-up to that event regardless of when it occurs. 
The follow-up information should describe whether the event has resolved or continues, if and 
how it was treated, whether the blind was broken or not, and whether the patient continued or 
withdrew from study participation. 
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the Novartis study treatment, an oncology Novartis 
Drug Safety and Epidemiology (DS&E) department associate may urgently require further 
information from the investigator for Health Authority reporting. Novartis may need to issue an 
Investigator Notification (IN), to inform all investigators involved in any study with the same 
drug that this SAE has been reported. Suspected Unexpected Serious Adverse Reactions 
(SUSARs) will be collected and reported to the competent authorities and relevant ethics 
committees in accordance with Directive 2001/20/EC or as per national regulatory requirements 
in participating countries. 
Pregnancies 
To ensure patient safety, each pregnancy occurring while the patient is on study treatment must 
be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of the 
birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications. 
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the oncology Novartis Drug Safety and Epidemiology Department (DS&E). 
Pregnancy follow-up should be recorded on the same form and should include an assessment of 
the possible relationship to the study treatment any pregnancy outcome. Any SAE experienced 
during pregnancy must be reported on the SAE Report Form. 
Warnings and Precautions 
Additional safety information collected between IB updates will be communicated in the form of 
Investigator Notifications. This information will be included in the patient informed consent and 
should be discussed with the patient during the study as needed 
7.2.4 Evaluating Adverse Events 
An investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), version 4.0. Any adverse event which 


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changes CTCAE grade over the course of a given episode will have each change of grade 
recorded on the adverse event case report forms/worksheets. 
All adverse events regardless of CTCAE grade must also be evaluated for seriousness. 
Table 20. Evaluating Adverse Events 
An investigator, who is a qualified physician, will evaluate all adverse events as to: 
V4.0 CTCAE 
Grading 
Grade 1 
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental ADL. 
 
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation or hospitalization indicated; disabling; limiting self-care ADL. 
 
Grade 4 
Life threatening consequences; urgent intervention indicated. 
 
Grade 5 
Death related to AE 
Seriousness 
A serious adverse event is any adverse event occurring at any dose or during any use of Merck product that: 
 
†Results in death; or 
 
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the 
event as it occurred (Note: This does not include an adverse event that, had it occurred in a more severe form, 
might have caused death.); or 
 
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to 
conduct normal life functions); or 
 
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient 
admission, regardless of length of stay, even if the hospitalization is a precautionary measure for continued 
observation. (Note: Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not a serious adverse event.  A pre-existing condition is a clinical condition that is diagnosed 
prior to the use of a Merck product and is documented in the patient’s medical history.); or 
 
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to 
diagnosis);or 
 
Is a new cancer (that is not a condition of the study) (although not serious per ICH definition, is reportable to 
the Sponsor Investigator within 24 hours and to Merck within 2 working days to meet certain local 
requirements); or 
 
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is 
considered a serious adverse event for collection purposes. An overdose that is not associated with an adverse 
event is considered a non-serious event of clinical interest and must be reported within 24 hours to the 
Sponsor Investigator and to Merck within 2 working days. 
 
Other important medical events that may not result in death, not be life threatening, or not require 
hospitalization may be considered a serious adverse event when, based upon appropriate medical judgment, 
the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the 
outcomes listed previously (designated above by a †). 
Duration 
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time 
and units 
Action taken  
Did the adverse event cause Merck product to be discontinued? 
 
 


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Relationship 
to Merck 
Product  
Did Merck product cause the adverse event? The determination of the likelihood that Merck  product caused 
the adverse event will be provided by an investigator who is a qualified physician. The investigator’s 
signed/dated initials on the source document or worksheet that supports the causality noted on the AE form, 
ensures that a medically qualified assessment of causality was done. This initialed document must be 
retained for the required regulatory time frame. The criteria below are intended as reference guidelines to 
assist the investigator in assessing the likelihood of a relationship between the test drug and the adverse event 
based upon the available information. 
The following components are to be used to assess the relationship between Merck product and the 
AE; the greater the correlation with the components and their respective elements (in number and/or 
intensity), the more likely Merck product caused the adverse event (AE): 
Exposure 
Is there evidence that the subject was actually exposed to Merck product such as: reliable 
history, acceptable compliance assessment (pill count, diary, etc.), expected pharmacologic 
effect, or measurement of drug/metabolite in bodily specimen? 
Time Course 
Did the AE follow in a reasonable temporal sequence from administration of Merck 
product?  
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with 
investigational medicinal product)? 
Likely Cause 
Is the AE not reasonably explained by another etiology such as underlying disease, other 
drug(s)/vaccine(s), or other host or environmental factors 
Dechallenge 
Was Merck product discontinued or dose/exposure/frequency reduced? 
If yes, did the AE resolve or improve? 
If yes, this is a positive dechallenge. If no, this is a negative dechallenge. 
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent 
disability; (2) the AE resolved/improved despite continuation of the Merck product; or (3) 
the trial is a single-dose drug trial); or (4) Merck product(s) is/are only used one time.) 
 
Rechallenge 
Was the subject re-exposed to Merck product in this study? 
If yes, did the AE recur or worsen? 
If yes, this is a positive rechallenge. If no, this is a negative rechallenge. 
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent 
disability, or (2) the trial is a single-dose drug trial); or (3) Merck product(s) is/are used 
only one time). 
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH 
WAS SERIOUS AND WHICH MAY HAVE BEEN CAUSED BY MERCK PRODUCT, 
OR IF REEXPOSURE TO MERCK PRODUCT POSES ADDITIONAL POTENTIAL 
SIGNIFICANT RISK TO THE SUBJECT, THEN THE RECHALLENGE MUST BE 
APPROVED IN ADVANCE BY THE SPONSOR INVESTIGATOR AS PER DOSE 
MODIFICATION GUIDELINES IN THE PROTOCOL. 
 
Consistency 
with Trial 
Treatment 
Profile 
Is the clinical/pathological presentation of the AE consistent with previous knowledge 
regarding Merck product or drug class pharmacology or toxicology? 
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified 
physician according to his/her best clinical judgment, including consideration of the above elements. 
Record one of the following 
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of Merck product relationship). 
Yes, there is a reasonable 
possibility of Merck product 
relationship. 
There is evidence of exposure to Merck product.  The temporal sequence of the AE onset 
relative to the administration of Merck product is reasonable.  The AE is more likely 
explained by Merck product than by another cause. 
No, there is not a reasonable 
possibility of Merck product 
relationship 
Subject did not receive the Merck product OR temporal sequence of the AE onset relative 
to administration of Merck product is not reasonable OR the AE is more likely explained 
by another cause than the Merck product.  (Also entered for a subject with overdose 
without an associated AE.) 


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7.2.5 Sponsor Investigator Responsibility for Reporting Adverse Events 
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations.  
 
8.0 STATISTICAL ANALYSIS PLAN 
The initial dose escalation will follow a standard 3+3 design, starting at dose level 1. The 
decision to escalate to the next dose level will be determined by the rate of dose-limiting toxicity 
(DLT) observed during Cycle 2, with a cycle length defined as 3 weeks. Up to 3 patients will be 
initially enrolled in a dose cohort, starting at dose level 1. If 1 of 3 patients were to experience 
DLT, 3 additional patients will be enrolled at same dose level. If 0 of 3 patients or 1 of 6 patients 
enrolled at a dose level were to experience DLT, enrollment to next dose level will be opened. If 
>1 of 3 patients or >1 of 6 patients enrolled at a dose level were to experience DLT, the 
maximum tolerated dose (MTD) will have been exceeded. Adverse events will be collected and 
described for the expansion cohorts. Enrollment to dose level 1 will be expanded to 6 patients if 
applicable, or enrollment to dose level -1 will be opened if dose level 1 were to exceed the MTD. 
The highest dose level at which 0 of 3 patients or 1 of 6 patients experience DLT will be 
declared the MTD. A minimum of 6 patients and maximum of 18 patients will be enrolled for 
each cohort (Arm A: Lead in Trametinib and Arm B: Lead in Pembrolizumab) in this dose 
escalation portion of the study. 
Enrollment into Cohorts A and B are pre-planned in regards to sequence and timing. Arm A 
(lead in trametinib) will open 1st to dose escalation and will accrue 3 patients. Once 3 patients are 
accrued for Arm A, Arm B will open and accrue 3 patients. This is to ensure cohorts remain open 
for accrual given the 6-week DLT period; these cohorts will alternate in opening in this fashion 
until the MTD is achieved for both Arm A and Arm B. Once the MTD is achieved for both Arms 
A and B, Arm A will open to dose expansion at the MTD and complete accrual, followed by 
Arm B. If one Arm is delayed in opening additional dose levels due to toxicity, the alternate 
cohort may open at additional dose levels if approved by the Primary Investigator in consultation 
with Novartis and Merck.  
The recommended dose expansion and recommended phase II dose (RP2D) will be 
determined by the overall assessment of the MTD and toxicities observed in the study. 
All patients who receive a dose of pembrolizumab and trametinib will be analyzed for safety and 
efficacy. Subjects who discontinue from study participation prior to receiving the combination of 
trametinib and pembrolizumab will be replaced. Subjects in dose escalation who discontinue 
from study and are not evaluable for dose limiting toxicities will be replaced. Patients removed 
from study for unacceptable treatment related adverse event(s) will be followed until resolution 
or stabilization of all treatment related AEs to grade 2 or lower. However, they will not be 
replaced. 


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A group of 12 patients will be enrolled in each of the 2 expansion cohorts at the MTD. Patients 
will enroll into the next subsequent cohort upon completion of the previous cohort (Arm A then 
Arm B). A sequencing scheme will be considered as promising if at least 5 of 12 patients were to 
achieve a complete or partial response per RECIST 1.1. The decision rule is associated with 80% 
exact power with an exact alpha of 0.16 if the underlying response rate associated with a 
sequencing scheme were truly at least 50% compared to current expectation of 25% ORR with 
single agent pembrolizumab. A median PFS of 8 months in 12 patients per cohort will provide 
81 power to detect a difference compared to historical PFS of about 4 months with single agent 
pembrolizumab with an alpha of 0.1 based on accrual time of 24 months and follow up of 12 
months. A sequencing scheme will be recommended for further development based on a 
combination of promising efficacy (response rate, PFS) and favorable changes in the tumor 
immune microenvironment at rebiopsy, provided the safety and tolerability profiles are 
acceptable.  
Assays will be performed at the SU2C Lung Cancer Dream Team Immune Monitoring Core, 
Yale University, The Broad Institute, UCSF and at UC Davis Comprehensive Cancer Center as 
part of the SU2C Dream Team Lung Cancer Collaboration. Next generation sequencing by the 
Broad Institute will perform whole exome DNA/RNA sequencing to confirm KRAS amino acid 
substitution and examine mutational load and other co-mutations of interest and well as changes 
in RNA expression of relevant gene in the tumor immune microenvironment. A subset analysis 
will explore clinical outcome by KRAS amino acid substitution (G12C vs. non-G12C). The 
immune correlative studies performed in baseline and repeat biopsy specimens include: (in order 
of priority) 1) IHC and IF to determine PD-L1 expression, MEK target inhibition 2) additional 
immunophenotyping, and functional assessment of tumor infiltrating immune cells 3) Luminex 
evaluation of local tumor cytokine / chemokine signatures. In blood, FACS for quantification, 
immunophenotyping, and functional assessment of PBMCs will also be performed. 
Adverse events will be summarized descriptively by type and by severity, with number and 
relative frequency calculated for all non-zero occurrences. With 16 patients treated at the MTD 
for either regimen, we will have an at least an 81% chance of seeing one or more cases of any 
adverse event that occurs in 10% or more patients.  
All molecular and immune correlates will be assessed in exploratory analyses. Due to the limited 
sample size and exploratory framework, any such analysis will be stated carefully as hypothesis-
generating with the reported p-values not adjusted for multiple comparisons. Standard 
descriptive and graphical methods will be used to summarize the baseline levels and post-
treatment changes for comparison of the three MEKi and pembrolizumab sequencing schemes, 
which will allow us to examine whether observed patterns are consistent with hypothesized 
mechanisms. The quantitative immune studies will be compared using a t-test to further inform 
the decision. Multiplicity of testing will not be considered since this considered an exploratory 
analysis. Association with response rate will be summarized descriptively by presenting the 
mean, SD, and other characteristics of molecular and immune measures, stratified by response 
status. Associations of molecular and immune measures with PFS will be summarized 
descriptively by stratified Kaplan-Meier curves and, if numbers permit, by proportional hazards 
models with molecular and immune responses as predictors. If the MEKi and pembrolizumab 
combination were not found to have sufficient activity, the molecular and immune patterns may 


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help explain the lack of activity. If sufficient activity were observed, then the correlates will be 
compared between patients who experience an objective response and those who did not. Results 
of these correlative studies including biopsies at pre-treatment and week 1 on treatment will be 
analyzed in conjunction with the Battle-Immunotherapy trial (with its later biopsy correlative 
timepoints) to inform the optimal dosing and sequencing of pembrolizumab with trametinib. 
Decisions for whether to pursue one of these strategies in a larger trial will incorporate ORR, 
toxicity and immune correlative endpoints in collaboration with the company sponsors and 
SU2C Dream Team. The primary considerations will be ORR and toxicity, with immune and 
genomic correlative studies used as supplementary criteria.  
If only one arm meets safety criteria and preliminary efficacy criteria (ORR ≥ 50% or a median 
PFS ≥ 8 months), then that treatment will be considered for future study. Immune and genomic 
correlative studies will be examined for the potential to inform future study design for that arm. 
If both arms A and B meet the safety criteria and preliminary efficacy criteria and give 
comparable response rates and toxicities, we will carry out two additional sets of analyses to 
inform the decision process of which treatment to pursue for further study. First, we will use 
regression models to assess whether one arm might have superior performance after accounting 
for key patient differences (PD-L1 status, KRAS amino acid substitution (G12C vs. non-G12C), 
smoking status). We will assess whether one arm has superior ORR, using logistic regression 
analysis to control for clinical covariates, and whether one arm has superior PFS, using 
proportional hazards models to control for clinical covariates. Second we Second, we will 
examine biomarkers that might shed light on the impact of the treatments. We will compare 
exploratory immune correlates (enhanced tumor immune microenvironment). The final decision 
will be based on best clinical judgment of all investigators. 
We expect that the distribution of PD-L1 expression in Arm A and Arm B to be comparable. 
Based on the current indication for first line pembrolizumab in PD-L1 high (>50%) NSCLC, the 
majority of patients accrued into this second line trial will likely contain tumors with lower PD-
L1 expression. At completion of Arm A we will review baseline characteristics and current 
clinical practice at that time to assess whether it is anticipated there would be a shift in biomarker 
distribution in Arm B. 
 
 
 


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9.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES 
9.1 
Pembrolizumab 
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and regulations. 
Clinical Supplies will be provided by Merck as summarized in Table 21. 
Table 21. Product Descriptions 
Product Name & Potency 
Dosage Form 
Pembrolizumab 50 mg 
Lyophilized Powder for Injection 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
 
9.2 
Trametinib 
Trametinib tablets are provided as immediate release tablets for oral administration containing 
trametinib dimethyl sulfoxide (GSK1120212B) equivalent to 0.125 mg, 0.5 mg or 2 mg of 
trametinib. All formulation excipients are compendial and are commonly used in oral 
formulations. Refer to the trametinib Investigator's Brochure for a list of excipients.  
The trametinib tablets are packaged in high-density polyethylene bottles with labels bearing the 
appropriate label text as required by governing regulatory agencies. All study drug will be 
dispensed in child-resistant packaging.  
Refer to the Pharmacy Manual/site investigational product manual for additional guidance on 
study drug storage, preparation and handling. 
Study drug labels will contain information to meet the applicable regulatory requirements. 
Classification 
Cytotoxic drug: molecular targeted cytotoxic drug 
Mechanism of Action 
Trametinib is a reversible inhibitor of mitogen-activated extracellular signal regulated kinase 1 
256 (MEK1) and MEK2 activation and of MEK1 and MEK2 kinase activity. MEK proteins are 
257 upstream regulators of the extracellular signal-related kinase (ERK) pathway, which 
promotes 258 cellular proliferation. BRAF V600E mutations result in constitutive activation of 
the BRAF 259 pathway which includes MEK1 and MEK2. Trametinib inhibits BRAF V600 
mutation-positive 260 melanoma cell growth in vitro and in vivo. 


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Metabolism 
Trametinib is metabolized predominantly via deacetylation alone or with mono282 oxygenation 
or in combination with glucuronidation biotransformation pathways in vitro. 283 Deacetylation 
is likely mediated by hydrolytic enzymes, such as carboxyl-esterases or amidases. 284 Following 
a single dose of [14C]-trametinib, approximately 50% of circulating radioactivity is 285 
represented as the parent compound. However, based on metabolite profiling after repeat dosing 
286 of trametinib, > 75% of drug-related material in plasma is the parent compound. 
 
Contraindications 
None.  
Availability 
Trametinib will be supplied by Novartis. 
Storage and Handling 
Trametinib tablets should be stored refrigerated at 2° to 8°C (36° to 46°F). Do not freeze. 
Dispense in original bottle. Do not remove desiccant. Protect from moisture and light. Do not 
place medication in pill boxes. 
Side Effects 
Complete and updated adverse event information is available in the Investigational Drug 
Brochure and/or product package insert. 
9.3 
Packaging and Labeling Information 
Clinical supplies will be affixed with a clinical label in accordance with regulatory requirements. 
9.4 
Clinical Supplies Disclosure 
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor Investigator 
and/or designee are not blinded to treatment. Drug identity (name, strength) is included in the 
label text; random code/disclosure envelopes or lists are not provided. 
9.5 
Storage and Handling Requirements 
Clinical supplies must be stored in a secure, limited-access location under the storage conditions 
specified on the label.   
Receipt and dispensing of trial medication must be recorded by an authorized person at the trial 
site. 
Clinical supplies may not be used for any purpose other than that stated in the protocol. 


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9.6 
Returns and Reconciliation 
The investigator is responsible for keeping accurate records of the clinical supplies received from 
Merck/Novartis or designee, the amount dispensed to and returned by the subjects and the 
amount remaining at the conclusion of the trial.  
Upon completion or termination of the study, all unused and/or partially used investigational 
product will be destroyed at the site per institutional policy. It is the Investigator’s responsibility 
to arrange for disposal of all empty containers, provided that procedures for proper disposal 
have been established according to applicable federal, state, local and institutional guidelines and 
procedures, and provided that appropriate records of disposal are kept. 
 
10.0  ADMINISTRATIVE AND REGULATORY DETAILS 
10.1 
Confidentiality 
In order to maintain patient privacy, all study reports and communications will identify the 
patient by initials and the assigned patient number.  Data capture records and drug accountability 
records will be stored in secure cabinets in the UCD Office of Clinical Research.  Medical 
records of patients will be maintained in strict confidence according to legal requirements.  The 
investigator will grant monitor(s) and auditor(s) from Merck or its designees and regulatory 
authority(ies) access to the patient’s original medical records for verification of data gathered on 
the data capture records and to audit the data collection process.  The patient’s confidentiality 
will be maintained and will not be made publicly available to the extent permitted by the 
applicable laws and regulations. 
10.2 
Good Clinical Practice 
The study will be conducted in accordance with the International Conference on Harmonisation 
(ICH) for Good Clinical Practice (GCP) and the appropriate regulatory requirement(s).  The 
investigator will be thoroughly familiar with the appropriate use of the drug as described in the 
protocol and Investigator’s Brochure.  Essential clinical documents will be maintained to 
demonstrate the validity of the study and the integrity of the data collected.  Master files should 
be established at the beginning of the study, maintained for the duration of the study and retained 
according to the appropriate regulations. 
10.3 
Patient Information and Informed Consent 
After the study has been fully explained, written informed consent will be obtained from either 
the patient or his guardian or legal representative prior to study participation.  The method of 
obtaining and documenting the informed consent and the contents of the consent will comply 
with ICH-GCP and all applicable regulatory requirement(s).  In accordance with UCD OCR 
policy an original signed and dated participant Informed Consent document will reside in a 
secured location within the UCD OCR.  Copies of the signed and dated Informed Consent 
document will be provided to the study participant and UCD Health System Information 


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Management for inclusion in the participant’s UCD Health System Medical Record or per 
participating site’s policies. 
10.4 
Records and Retention 
The investigator will maintain all study records according to ICH-GCP and applicable regulatory 
requirement(s).   
10.5 
Data and Safety Monitoring 
In addition to the requirements for adverse event reporting this protocol is also subject to the UC 
Davis Cancer Center’s (UCDCC) Data and Safety Monitoring Plan. The UCDCC is committed 
to pursuing high-quality patient-oriented clinical research and has established mechanisms to 
ensure both scientific rigor and patient safety in the conduct of clinical research studies. The 
UCDCC relies on a multi-tiered committee system that reviews and monitors all cancer clinical 
trials and ensures the safety of its participants, in compliance with institutional and federal 
requirements on adverse event (AE) reporting, verification of data accuracy, and adherence to 
protocol eligibility requirements, treatment guidelines, and related matters. The Scientific 
Review Committee (SRC) assumes overall oversight of cancer studies, with assistance and input 
from two independent, but interacting, committees: the Quality Assurance Committee and the 
Data Safety Monitoring Committee. A multi-level review system strengthens the ability of the 
UCDCC to fulfill its mission in conducting high quality clinical cancer research. 
As per University of California Davis Cancer Center (UCDCC) Office of Clinical Research 
(OCR) SOP AM 506: Protocol Specific Meetings, the principal investigator (PI) and clinical 
research coordinator (CRC) meet at least monthly for ongoing study information, to discuss 
patient data and adverse events and to determine if dose escalation is warranted, when 
applicable.  Because this is a phase I study, a meeting and/or conference call will take place 
when the last subject on each cohort completes DLT (dose-limiting toxicity) assessment.  The 
meeting and/or call will update the attendees of the current status of the study and will include 
investigators from all participating centers, and, if necessary, representatives from the drug 
provider or financial supporter.  All serious adverse events experienced by study subjects will be 
discussed and appropriate action taken.  If serious adverse events occur between these meetings 
and/or calls, all investigators will be informed by email. 
According to the UCDCC Data and Safety Monitoring Plan (DSMP), any new serious adverse 
events related to the drugs being used on this trial are reviewed monthly by the UCDCC Data 
and Safety Monitoring Committee (DSMC) and any applicable changes to the study are 
recommended to the PI, if necessary. 
The UCDCC Scientific Review Committee (SRC) determines if a UCDCC Data and Safety 
Monitoring Board (DSMB) is required.  If required, the DSMC will appoint a DSMB. The 
DSMB is responsible for reviewing study accrual logs, adverse event information and dose 
escalation meeting minutes (where applicable) to ensure subject safety and compliance with 
protocol defined guidelines. 


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10.6 
Compliance with Law and Regulations 
This study will be conducted in accordance with current US Food and Drug Administration 
(FDA) Good Clinical Practices (GCPs), International Conference on Harmonization (ICH) 
guidelines and local ethical and legal requirements. Specifically, the study will be conducted 
under a protocol reviewed by an IRB; the study will be conducted by scientifically and medically 
qualified persons; the benefits of the study are in proportion to the risks; the rights and welfare of 
the subjects will be respected; the physicians conducting the study do not find the hazards to 
outweigh the potential benefits; and each subject will give his or her written, informed consent 
before any protocol-driven tests or evaluations are performed. All patients will have signed an 
informed consent for participation in research activities in accord with all institutional, NCI and 
Federal regulations, and will have been given a copy of the Experimental Subject's Bill of 
Rights. 
10.7 
Compliance with Trial Registration and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the Sponsor Investigator of the trial 
is solely responsible for determining whether the trial and its results are subject to the 
requirements for submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov.  
Information posted will allow subjects to identify potentially appropriate trials for their disease 
conditions and pursue participation by calling a central contact number for further information 
on appropriate trial locations and trial site contact information.     
10.8 
Quality Management System 
Quality assurance audits of select patients and source documents may be conducted by the UC 
Davis Comprehensive Cancer Center Quality Assurance Committee as outlined in the UC Davis 
Cancer Center Data and Safety Monitoring plan. 
Quality control will be maintained by the OCR Quality Assurance team according to OCR 
policy. 
 
 


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11.0  APPENDICES 
11.1 
Multisite Patient Registration 
A. Before registration, the site study coordinator should check to make sure that the 
corresponding Investigational Drug Service or equivalent has investigational product(s) in 
stock.  
B. Registrations must be made through the Office of Clinical Research (OCR) of the University 
of California, Davis Comprehensive Cancer Center between the hours of 9am and 3pm 
(Pacific Time), Monday through Friday (except holidays).  Documentation of current IRB 
approval of this protocol must be on file prior to registration of patients. 
C. Slot reservation. Prior to consenting, email the UCD team the following information: patient 
initials and anticipated start date. Confirmation of slot reservation will be emailed back to 
the site within 3 hours. Enrollment is competitive. Confirmed slots are only valid for 2 
weeks. Should enrollment take longer than 2 weeks you must contact UC Davis to request 
additional time, otherwise you will be notified that the slot will be released. 
D. Pre-study laboratory tests, scans, and x-rays, must be completed prior to registration, within 
the time frame specified in the protocol.  The eligibility checklist must be completed.  
Patients must sign an informed consent prior to registration.  
E. Patients may be registered up to 72 hours prior to treatment initiation. The signed consent, 
completed checklist and reports from all pre-study laboratory tests, scans and x-rays (where 
applicable) must be faxed to UC Davis Study Coordinator in order to register the patient. 
These documents are to be redacted and the “patient initials” or “a participating site subject 
identifier” will be written on the documents until the Study Subject ID is issued. The UC 
Davis Study Coordinator will review these documents and fax and/or email a registration 
confirmation (which includes a subject ID number). 
F. Reminder: Confirm eligibility of ancillary studies and willingness to participate at the same 
time as eligibility for the treatment study. 
G. If the patient is to be registered the same day as the proposed treatment start date, the UC 
Davis Study Coordinator must be notified by fax 24 hours prior to proposed treatment start 
date that the site has a patient to register.   
I. 
A patient failing to meet all protocol requirements may not be registered.  If you have any 
questions regarding eligibility, contact the coordinating site PI or Study Coordinator.   
NOTE: Administration of study medication may not be initiated until the registration 
confirmation has been received.  
 


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11.2 
    Data Management 
All data will be collected using UC Davis data collection forms. Any and all source 
documentation should be maintained. 
 SUBMIT WITHIN 24 HOURS OF REGISTRATION:  
Patient Registration Form  
 SUBMIT WITHIN 14 DAYS OF REGISTRATION:  
In‐House Pre‐Study Evaluation Form (IH‐102)  
 SUBMIT WITHIN 7 DAYS OF SCREENING FAILURE:  
Patient Screen Failure Form  
 SUBMIT WITH 14 DAYS OF CYCLE COMPLETION:  
Adverse Event-Drug Relationship Form  
 SUBMIT WITHIN 14 DAYS OF END OF EACH TREATMENT CYCLE:  
In‐House Treatment Cycle Form (IH‐201)  
 SUBMIT WITHIN 14 DAYS OF OFF TREATMENT:  
Off Treatment/In Follow-up/Off Study/Expiration Form (IH‐301)  
 SUBMIT WITHIN 14 DAYS OF KNOWLEDGE OF DEATH IF PATIENT IS STILL 
ON STUDY OR 30–DAYS IF OFF STUDY:  
Off Treatment/In Follow-up/Off Study/Expiration Form (IH‐301)  
 SUBMIT WITHIN 2 DAYS OF KNOWLEDGE OF PROTOCOL DEVIATION:  
Clinical Trials Support Unit: Notice of Protocol Deviation  
 SUBMIT WITHIN 14 DAYS OF EACH REQUIRED FOLLOW‐UP ENCOUNTER: 
Follow‐Up Form (IH‐302)  
 ALL SERIOUS ADVERSE EVENTS MUST BE REPORTED AS OUTLINED IN THE 
PROTOCOL  
 
 
 


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11.3 
ECOG Performance Status 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction. 
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). 
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. 
3 
In bed >50% of the time. Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-
care. Totally confined to bed or chair. 
5 
Dead. 
* As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. 
Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, Robert Comis M.D., Group Chair. 
 
 
 
 
 


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11.4 
FRIDERICIA’S CRITERIA FOR QTC CALCULATION  
Fridericia’s formula QTcF = (QT/RR^0.33). RR is the time from the interval of 1 QRS complex 
to the next measured in seconds and is commonly calculated as (60/HR) (Hosmane et al, Journal 
of Applied Research 2006). 
 
 
 


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11.5 
New York Heart Association Classification of Heart Failure 
 
Class 
Patient Symptoms 
Class I (Mild) 
No limitation of physical activity.  
Ordinary physical activity does not cause undue fatigue, 
palpitation, or dyspnea (shortness of breath) 
Class II (Mild) 
Slight limitation of physical activity.  
Comfortable at rest, but ordinary physical activity results in 
fatigue, palpitation, or dyspnea. 
Class III (Moderate) 
Marked limitation of physical activity.  
Comfortable at rest, but less than ordinary activity causes 
fatigue, palpitation, or dyspnea. 
Class IV (Severe) 
Unable to carry out any physical activity without discomfort. 
Symptoms of cardiac insufficiency at rest.  
If any physical activity is undertaken, discomfort is increased. 
 
 
 
 
 
 
 


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11.6 
Common Terminology Criteria for Adverse Events V4.0 (CTCAE) 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0 will be utilized for adverse event reporting. 
(http://ctep.cancer.gov/reporting/ctc.html) 
 
 


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11.7 
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for 
Evaluating Response in Solid Tumors 
RECIST version 1.1* will be used in this study for assessment of tumor response. While either 
CT or MRI may be utilized, as per RECIST 1.1, CT is the preferred imaging technique in this 
study. 
* As published in the European Journal of Cancer: 
E.A. Eisenhauer, P. Therasse, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J. Dancey, S. 
Arbuck, S. Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. Kaplan, D. Lacombe, 
J. Verweij. New response evaluation criteria in solid tumors: Revised RECIST guideline (version 
1.1). Eur J Cancer. 2009 Jan;45(2):228-47. 
In addition, volumetric analysis will be explored by central review for response assessment. 
 
 
 
 


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11.8 
Drug Diary 
D1-10 DOSING 
Protocol Number: UCDCC#259 
Patient Name: _________________________________ 
Medical Record #: _____________ 
Cycle #: ____________ 
Start Date: ________________ 
Dose: __________________ 
Instructions: Please record the time that you take your study medications. Return this diary, the 
medication bottles (even if empty or unopened), and any unused tablets at your next clinic visit 
and make sure you are given another diary. 
Store your study medication in the original bottle in the refrigerator (2°C to 8°C). Temperature 
excursions should be limited to the time it takes for you to transport your study medication from 
the clinic/hospital to your home refrigerator. 
Trametinib comes in a tablet form and should be taken by mouth every day for the first 10 days 
of each 21 day cycle. You should take trametinib at least 1 hour before or 2 hours after a meal. 
D1-10 Dosing 
Day 
Date 
(mm/dd/yy) 
Dose 
(mg) 
Time Taken 
Notes 
1 
 
 
 
 
2 
 
 
 
 
3 
 
 
 
 
4 
 
 
 
 
5 
 
 
 
 
6 
 
 
 
 
7 
 
 
 
 
8 
 
 
 
 
9 
 
 
 
 
10 
 
 
 
 
 
 
Signature of Participant:  ________________________________ 
Date: __________ 


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D1-7 DOSING 
Protocol Number: UCDCC#259 
Patient Name: _________________________________ 
Medical Record #: _____________ 
Cycle #: ____________ 
Start Date: ________________ 
Dose: __________________ 
Insructions: Please record the time that you take your study medications. Return this diary, the 
medication bottles (even if empty or unopened), and any unused tablets at your next clinic visit 
and make sure you are given another diary. 
Store your study medication in the original bottle in the refrigerator (2°C to 8°C). Temperature 
excursions should be limited to the time it takes for you to transport your study medication from 
the clinic/hospital to your home refrigerator. 
Trametinib comes in a tablet form and should be taken by mouth every day for the first 7 days of 
each 21 day cycle. You should take trametinib at least 1 hour before or 2 hours after a meal. 
D1-7 Dosing 
Day 
Date 
(mm/dd/yy) 
Dose 
(mg) 
Time Taken 
Notes 
1 
 
 
 
 
2 
 
 
 
 
3 
 
 
 
 
4 
 
 
 
 
5 
 
 
 
 
6 
 
 
 
 
7 
 
 
 
 
 
 
Signature of Participant:  ________________________________ 
Date: __________ 
 
 


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11.9 
References 
1. 
Cully, M. and J. Downward, SnapShot: Ras Signaling. Cell, 2008. 133(7): p. 1292-1292 
e1. 
2. 
Janne, P.A., et al., Selumetinib plus docetaxel for KRAS-mutant advanced non-small-cell 
lung cancer: a randomised, multicentre, placebo-controlled, phase 2 study. The lancet 
oncology, 2013. 14(1): p. 38-47. 
3. 
David R. Gandara, S.H., George R. Blumenschein, Fabrice Barlesi, Jean-Pierre Delord, 
Jeannick Madelaine, Jeffrey R. Infante, Karen L. Reckamp, Primo Lara, Christine 
Audebert, Byoung Chul Cho, Keunchil Park, Fadi S. Braiteh, Robert M. Jotte, Yuehui 
Wu, Daniel J. Schramek, Alexandra M. Piepszak, Olivia S. Gardner, Vijay Gopal Reddy 
Peddareddigari, Natasha B. Leighl, Oral MEK1/MEK2 inhibitor trametinib 
(GSK1120212) in combination with docetaxel in KRAS-mutant and wild-type (WT) 
advanced non-small cell lung cancer (NSCLC): A phase I/Ib trial. Journal of clinical 
oncology : official journal of the American Society of Clinical Oncology, 2013. 31: p. 
suppl; abstr 8028. 
4. 
Jiang, X., et al., The activation of MAPK in melanoma cells resistant to BRAF inhibition 
promotes PD-L1 expression that is reversible by MEK and PI3K inhibition. Clinical 
cancer research : an official journal of the American Association for Cancer Research, 
2013. 19(3): p. 598-609. 
5. 
Frederick, D.T., et al., BRAF inhibition is associated with enhanced melanoma antigen 
expression and a more favorable tumor microenvironment in patients with metastatic 
melanoma. Clinical cancer research : an official journal of the American Association for 
Cancer Research, 2013. 19(5): p. 1225-31. 
6. 
Yamamoto, R., et al., B7-H1 expression is regulated by MEK/ERK signaling pathway in 
anaplastic large cell lymphoma and Hodgkin lymphoma. Cancer science, 2009. 100(11): 
p. 2093-100. 
7. 
Carter, C.A., et al., Selumetinib with and without erlotinib in KRAS mutant and KRAS 
wild-type advanced non-small cell lung cancer. Ann Oncol, 2016. 
8. 
Liu, L., et al., The BRAF and MEK Inhibitors Dabrafenib and Trametinib: Effects on 
Immune Function and in Combination with Immunomodulatory Antibodies Targeting 
PD-1, PD-L1, and CTLA-4. Clin Cancer Res, 2015. 21(7): p. 1639-51. 
9. 
Balagula, Y., et al., Dermatologic side effects associated with the MEK 1/2 inhibitor 
selumetinib (AZD6244, ARRY-142886). Invest New Drugs, 2011. 29(5): p. 1114-21. 
10. 
Lacouture, M.E., et al., Clinical practice guidelines for the prevention and treatment of 
EGFR inhibitor-associated dermatologic toxicities. Support Care Cancer, 2011. 19(8): p. 
1079-95. 
11. 
Schalper, K.A., et al., Objective measurement and clinical significance of TILs in non-
small cell lung cancer. J Natl Cancer Inst, 2015. 107(3). 
12. 
Garon, E.B., et al., Pembrolizumab for the treatment of non-small-cell lung cancer. N 
Engl J Med, 2015. 372(21): p. 2018-28.