Conditions: Breast Adenocarcinoma Metastatic Triple-Negative Breast Carcinoma Stage III Breast Cancer AJCC v7 Stage IIIA Breast Cancer AJCC v7 Stage IIIB Breast Cancer AJCC v7 Stage IIIC Breast Cancer AJCC v7 Stage IV Breast Cancer AJCC v6 and v7
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 23
Healthy volunteers: no

Brief summary:
This phase I/II trial studies the best dose of pembrolizumab and binimetinib and how well it works when given together with pembrolizumab in treating patients with triple negative breast cancer that has spread to other parts of the body (metastatic). Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Binimetinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving pembrolizumab and binimetinib may work better in treating patients with triple negative breast cancer.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) of binimetinib in combination with pembrolizumab. (Phase I) II. To evaluate the objective response rate (ORR) of binimetinib in combination with pembrolizumab in patients with unresectable locally advanced or metastatic triple negative breast cancer by Response Evaluation Criteria in Solid Tumors (RECIST). (Phase II)

SECONDARY OBJECTIVES:

I. To evaluate the safety and tolerability of binimetinib in combination with pembrolizumab.

II. To evaluate the ORR by immune-related RECIST criteria (irRECIST). III. To evaluate the progression free survival (PFS), duration of response (DoR), and disease control rate (DCR) by RECIST and irRECIST.

IV. To assess overall survival (OS).

CORRELATIVE RESEARCH OBJECTIVES:

I. To assess the correlation between ORR, PFS, or OS and baseline and/or change in tumor infiltrating lymphocytes (TILs).

II. To assess the correlation between ORR, PFS, or OS and baseline and/or change in immune related gene signature and PDJ amplification.

III. To assess the change in immunoregulatory cells (IRC). IV. To assess the change in the cytokine profile. V. To assess the change in circulating tumor cells (CTC).

OUTLINE: This is phase I, dose-escalation study of binimetinib followed by a phase II study.

Patients receive binimetinib orally (PO) twice daily (BID) on days 1-14 of cycle 1 and on days 1-21 of cycle 2 and subsequent cycles. Beginning cycle 2, patients also receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Cycle 1 equals 14 days. Cycles 2 and beyond repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and then every 3 months until progressive disease, then every 6 months for up to 3 years.

Arms:
arm 1: Patients receive binimetinib PO BID on days 1-14 of cycle 1 and on days 1-21 of cycle 2 and subsequent cycles. Beginning cycle 2, patients also receive pembrolizumab IV over 30 minutes on day 1. Cycle 1 equals 14 days. Cycles 2 and beyond repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Interventions: intervention 1: Binimetinib intervention 2: Laboratory Biomarker Analysis intervention 3: Pembrolizumab
Intervention descriptions: intervention 1: Given PO intervention 2: Correlative studies intervention 3: Given IV

Protocol document:
Prot_SAP_000.pdf: 
 
 
MC1632 
Protocol Version Date: 23Jun2021 
 
Mayo Clinic Cancer Center 
 
Phase I/II Trial of Pembrolizumab in Combination with Binimetinib in 
Unresectable Locally Advanced or Metastatic Triple Negative Breast Cancer 
 
 
Study Chairs: 
 
  
 
 
Study Cochairs: 
 
 
 
Statistician: 
  
 
√Study contributor(s) not responsible for patient care 
 
 
Drug Availability 
Drug Company Supplied: 
Pfizer Inc. (formerly Array Biopharma LLC and Array Biopharma Inc.): Binimetinib (IND# 132,753)  
Merck: Pembrolizumab (IND# 132,753) 
 
 
Document History 
(Effective Date) 
Activation 
Amendment #1 
09/26/2017 
03/07/2018 
Amendment #2 
10/03/2018 
Amendment #3 
Amendment #4 
Amendment #5 
Amendment #6 
Amendment #7 
Amendment #8 
Amendment #9 
12/27/2018 
06/25/2019 
10/22/2019 
06/11/2020 
07/06/2020 
05/07/2021 
07/19/2021 


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Protocol Resources 
 
Questions: 
Contact Name: 
Patient eligibility*, test schedule, 
treatment delays/interruptions/adjustments, 
dose modifications, adverse events, 
forms completion and submission 
 
 
 
Forms completion and submission 
 
 
Protocol document, consent form, 
regulatory issues 
 
 
Laboratory Contact 
 
 
 
Serious Adverse Event Reporting 
 
 
*No waivers of eligibility allowed 


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Table of Contents 
Phase I/II Trial of Pembrolizumab in Combination with Binimetinib in Unresectable Locally Advanced or 
Metastatic Triple Negative Breast Cancer .................................................................................................... 1 
Protocol Resources ........................................................................................................................................ 2 
Table of Contents .......................................................................................................................................... 3 
Schema .......................................................................................................................................................... 4 
1.0 
Background ................................................................................................................................... 5 
2.0 
Goals ........................................................................................................................................... 10 
3.0 
Patient Eligibility ........................................................................................................................ 11 
4.0 
Study Calendar ............................................................................................................................ 17 
5.0 
Grouping Factor .......................................................................................................................... 20 
6.0 
Registration Procedures .............................................................................................................. 20 
7.0 
Protocol Treatment ...................................................................................................................... 23 
8.0 
Dosage Modification Based on Adverse Events ......................................................................... 27 
9.0 
Ancillary Treatment/Supportive Care ......................................................................................... 38 
10.0 
Adverse Event (AE) Reporting and Monitoring ......................................................................... 47 
11.0 
Treatment Evaluation .................................................................................................................. 59 
12.0 
Descriptive Factors ..................................................................................................................... 65 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient ............................................................ 65 
14.0 
Body Fluid Biospecimens ........................................................................................................... 67 
15.0 
Drug Information ........................................................................................................................ 71 
16.0 
Statistical Considerations and Methodology ............................................................................... 78 
17.0 
Pathology Considerations/Tissue Biospecimens ......................................................................... 83 
18.0 
Records and Data Collection Procedures .................................................................................... 86 
19.0 
Budget ......................................................................................................................................... 87 
20.0 
References ................................................................................................................................... 88 
Appendix I 
ECOG Performance Status ............................................................................................... 90 
Appendix II 
Patient Medication Diary .................................................................................................. 91 
Appendix III 
List of medications to be used with caution with binimetinib .......................................... 93 
Appendix IV 
Biospecimen Accessioning Processing Requisition Form .............................................. 104 
. 


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Schema 
Phase I Only: Prior to discussing protocol entry with the patient, call the MCCC Registration 
Office (507-284-2753) for dose level and to insure that a place on the protocol is open to the patient. 
 
 
 
*Unless adequate tissue is available from biopsy obtained ≤90 days prior to registration (see Section 17.0) 
**Retreatment (Second Course Phase): Patients who stop pembrolizumab and binimetinib with SD or 
better may be eligible for up to one year of additional pembrolizumab and binimetinib therapy if they 
progress after stopping study treatment. This retreatment is termed the Second Course Phase of this study 
and is only available if the study remains open and the patient meets the requirements as outlined in 
section 7.5. 
Cycle 1 = 14 days 
Cycle length for Cycle 2 onward = 21 days 
 
Generic name: pembrolizumab, MK-3475 
Brand name(s): Keytruda™ 
Mayo Abbreviation: MK3475 
Availability: Mayo Clinic Pharmacy 
Generic name: binimetinib, MEK162 
Brand name(s): 
Mayo Abbreviation: MEK162 
Availability: Mayo Clinic Pharmacy 
Registration 
↓ 
Mandatory Biopsy* 
↓ 
Cycle 1 
Binimetinib alone 
2 weeks 
↓ 
Optional biopsy 
and research blood 
↓ 
Cycle 2 onward** 
Binimetinib and 
SD 
Pembrolizumab 
3 weeks 
↓ 
Disease Progression by irRECIST 
Intolerable adverse effects 
Patient refusal 
↓ 
Event Monitoring 
Retreatment (Second 
Course Phase): 
Up to 1 year of 
pembrolizumab 


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1.0 
Background 
Emerging studies suggest that breast cancer, particularly triple negative breast cancer (TNBC), is 
also sensitive to immunotherapy. While the initial early phase clinical trials showed promising 
results with prolonged durable response with immune checkpoint blockade agents in TNBC, the 
number of patients who responded to immunotherapy is fairly small. TNBC is an aggressive form 
of breast cancer that lacks drug targets, namely estrogen receptor (ER), progesterone receptor 
(PR), and human epidermal growth factor receptor 2 (HER2). Despite advancements in targeted 
therapies, this group of patients continues to have poor outcome with a median overall survival 
(OS) of 13 months {Anders 2008}. Due to the lack of a validated drug target, TNBC represents 
not only a significant clinical challenge but also a critical unmet medical need. 
1.1 
Triple Negative Breast Cancer 
Approximately 15-20% of all breast cancers do not express functional cell surface 
receptors like ER, PR, and HER2. Triple-negative tumors are typically associated with a 
higher histologic grade, increased mitotic count, pushing margins of invasion, and a 
stromal lymphocytic response. Patients with TNBC often have poorer prognosis 
compared to other breast cancer subtypes. It is commonly misconceived that TNBC is 
more sensitive to chemotherapy. Although higher pathologic complete response rate 
(pCR) was observed in TNBC (25–45%) compared to luminal breast cancers (6–7%), 
patients with TNBC had worse four-year distant disease free and overall survival {Irvin 
& Carey 2008}. 
1.2 
Immunotherapy and Pembrolizumab 
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. 
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 


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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. Keytruda™ (pembrolizumab) has recently been approved in 
the United Stated for the treatment of patients with unresectable or metastatic melanoma 
and disease progression following ipilumumab and, if BRAF V600 mutation positive, a 
BRAF inhibitor. 
1.3 
Immunotherapy in TNBC 
Over recent years, several studies demonstrated that the genetic and epigenetic alterations 
in TNBC may provide a set of tumor-associated antigens that the immune system can 
recognize and use to distinguish tumor cells from normal cells {Shah 2012; Stephens 
2012}. More recently, the presence of tumor-infiltrating lymphocytes (TILs) at the time 
of the diagnosis has been shown to correlate with a significant increase in complete 
pathological response (pCR) to neoadjuvant chemotherapy (NAC) {Denkert 2010}. 
Subsequently, TILs also has been shown to correlate with both disease free survival 
(DFS) and OS among TNBC patients in a large adjuvant BIG 02-98 trial (Loi 2013). This 
observation was confirmed in a subsequent retrospective analysis of the Eastern 
Cooperative Oncology Group (ECOG) 2197 and 1199 trials {Adams 2014}. Although 
preclinical evidence suggests that antitumor immunity can control TNBC progression, 
tumors progress despite having tumor-specific CD8+ T cells infiltration. This paradox is 
mainly due to the exhausted nature of tumor-infiltrating T cells and the presence of 
immunosuppressive factors in the tumor microenvironment. T-cell exhaustion is a result 
of the upregulation of inhibitory receptors and serves as immune checkpoints in order to 
prevent uncontrolled immune reactions. In the past few years, there are several immune 
checkpoint blockade agents that have shown promising activities across several cancer 
types, including breast cancer. In a phase Ib trial of Pembrolizumab (Keynote-012) 
{Nanda 2014}, a humanized anti-PD1 monoclonal antibody, in TNBC, the overall 
response rate (ORR) was 18.5% and an additional 25.9% of patients had stable disease. 
Furthermore, among patients who responded, their responses appeared to be durable and 
lasted 15-40+ weeks. Another clinical trial with anti-PD-L1, MPDL3280A9, also showed 
promising activity of immune checkpoint blockade agent with ORR of 33%. From a total 
of 9 evaluable patients, one patient had complete response (CR) and 2 patients had partial 
response (PR). 


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1.4 
MAPK Pathway and Binimetinib 
Growth factor-mediated proliferative signals are transmitted from the extracellular 
environment to the nucleus through several pathways, including the 
RAS/RAF/MEK/ERK pathway {Roberts 2007}. This pathway comprises an 
evolutionarily conserved signaling cascade initiated by the RAS family of small 
GTPases, which activate the RAF kinases. Activated RAF kinases, phosphorylate and 
thereby activate the MEK1 and MEK2 kinases, which in turn phosphorylate and activate 
the ERK1 and ERK2 kinases. Subsequent phosphorylation of a variety of downstream 
effector proteins, including transcription factors, by activated ERK serve to regulate key 
cellular activities including proliferation, differentiation, migration, survival and 
angiogenesis. Aberrant signaling through this pathway has been shown to lead to 
unconstrained cell growth and cell transformation {Yoon 2006} and is a characteristic 
feature of many cancers. Inappropriate activation of the RAS/RAF/MEK/ERK pathway 
can occur through a variety of mechanisms, including activating mutations in RAS and 
BRAF {Lea 2007}, activated growth factor signaling {Nakazawa 2005} and stress 
response signals {McCubrey 2000}. Preclinical studies indicate that the presence of 
mutations that activate RAS/RAF/MEK/ERK pathway signaling, typically those 
occurring in the BRAF, NRAS and KRAS genes, are predictive for response to MEK 
inhibitors {Barretina 2012}. Collectively, these data suggest that targeting MEK may 
inhibit cancer signaling mediated by a wide variety of signals, making MEK an attractive 
target for the treatment of cancer and its associated symptoms. The identification of an 
allosteric regulatory site on the MEK enzyme allows the design of highly specific 
inhibitor molecules {Ohren 2004}. Other than binimetinib, there are a number of 
approved and investigational small-molecule MEK inhibitors of significance that are 
undergoing clinical evaluation for different tumor types (solid and hematologic 
malignancies). These compounds include: trametinib, selumetinib, cobimetinib, 
rafametinib and pimasertib. Trametinib (www.fda.gov) was the first MEK inhibitor 
approved by the US FDA and is indicated as a single-agent treatment and in combination 
with the BRAF inhibitor dabrafenib for the treatment of patients with unresectable or 
metastatic melanoma with BRAFV600E or BRAFV600K mutations. 
Binimetinib (also known as binimetinib or ARRY-438162) is a potent, selective, 
allosteric small-molecule inhibitor of mitogen-activated protein (MAP) kinase kinase 
(MEK) that is uncompetitive with adenosine triphosphate (ATP). Binimetinib is currently 
being evaluated clinically in healthy subjects, in Noonan syndrome patients and in cancer 
patients. Previously, binimetinib has also been evaluated in the treatment of rheumatoid 
arthritis. 
1.5 
Rationale 
Optimizing immune checkpoint blockade will be possible with the conduct of trials 
utilizing combination-targeted therapies. One such target is MEK. Balko and colleagues 
{Balko 2014} evaluated genomic alterations in tumors that may be associated TILs in 
residual tumor after NAC in TNBC. In parallel to previous studies, increased TILs are 
associated with favorable outcomes, including DFS (p = 0.0008) and OS (p = 0.007). 
There appeared to be a trend toward reduction in TIL level among patients who did not 
achieve pCR (p = 0.07). Using next-generation sequencing, lower TIL level in residual 
disease after NAC was associated with genetic alteration in the Ras/MAPK pathways, 
including KRAS, BRAF and RAF1 amplifications and NF1 truncations (p = 0.005). 
There was also an inverse correlation between the MEK activation signature and TILs in 
residual disease samples (p = 0.00028). These findings suggested that the association 
between TIL levels and dysregulation of Ras/MAPK pathway may be pathway specific. 


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The investigators further evaluate the effects of MEK inhibition in several TNBC cell 
lines and found that MEK inhibition, using AZD6244, up-regulates major 
histocompatibility complex (MHC) class I and II molecules in both in vitro and in vivo 
models. The investigators also went back and evaluated the expression of HLA-A and 
HLA-DR in their patient samples and found the inverse correlation between the 
expression level of these MHC class I and II molecules and the MEK activation 
signature. However, there was also a significant increase in the PD-L1 expression after 
MEK inhibition treatment, which has opposing inhibitory effects on tumor immune 
surveillance. The investigators further investigated the combination of MEK inhibitor and 
anti-PD-L1 antibody in in vivo mouse model and found that the combination can 
completely eradicate the tumors, while each single agent only had modest effects on 
tumor growth. 
Currently, there is no clinical trial evaluating the combination of pembrolizumab and 
binimetinib in breast cancer. Based on the intriguing preclinical data above, it is logical to 
develop and conduct a phase I/II trial of pembrolizumab in combination with binimetinib 
in patients with unresectable locally advanced or metastatic triple negative breast cancer. 
1.6 
Correlative studies 
Currently, there are several correlative studies that are being investigated as biomarkers 
for immunotherapy in cancer. Immune checkpoint blockade agents, like pembrolizumab, 
exerts its activity by blocking the distinct immunosuppressive checkpoints PD-1 or its 
major ligand PD-L1. Previous studies demonstrated that PD-L1 expression in the tumors 
appears to correlate with improved outcome in patients treated with immune checkpoint 
blockade agents {Topalian, 2012}. Furthermore, studies also showed that immune 
checkpoint blockade agent can also increase tumor infiltrating lymphocytes and improve 
response to adoptive cell therapy (1). 
As described in the previous rationale section, MEK inhibition has been shown to 
upregulate cell surface MHC expression as well as PD-L1 in both in vivo and in vitro 
triple negative breast cancer models. Moreover, the combination of MEK and immune 
checkpoint blockade agent were synergistic and enhanced antitumor immune responses 
were observed in vivo breast cancer syngeneic mouse models {Balko 2014}. 
Nevertheless, the effects of MEK inhibitors to immune response in human remain largely 
unknown. 
To evaluate immunologic response to single agent binimetinib and the combination of 
binimetinib and pembrolizumab, several correlative studies will be carried out as 
followed: 
 
1.61 
Correlative studies for tumor tissue 
We will perform the following correlative studies using tumor tissue. 
1. Tumor infiltrating lymphocytes: Tumor infiltrating lymphocytes will be 
quantified based on the H&E as described (2). Furthermore, the composition 
of different subsets of lymphocytes will also be quantify using 
immunohistochemistry staining for CD4 for T helper cells, CD8 for cytotoxic 
T cells as well as CD25 and FOXP3 for regulatory T cells as we previously 
published (3). 
2. PD-L1 expression: PD-L1 expression in the tumor will be assessed by 
immunohistochemistry as previously described {Topalian, 2012} 


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3. Gene expression analysis: Global assessment of immune-related gene 
expression in pre- and post-treatment tumors will be assessed using the 
NanoString PanCancer Immune Profiling Panel which includes 770 genes for 
24 different immune cell types and populations, 30 common cancer antigens 
and genes that represent all categories of immune response including key 
checkpoint blockade genes. 
4. PDJ amplification: We have recently reported that approximately 30% of 
patients with TNBC harbor PDJ amplification (4). Locating at chromosome 
9p24.1, this amplicon encompasses JAK2, PD-L1, and PD-L2 genes. TNBC 
patients with PDJ amplification had worse disease free (25.0% vs. 66.0%, p 
= 0.005) and overall survival (25.0% vs. 69.0%, p = 0.004). This amplicon 
has been previously described in the majority of Hodgkin’s lymphoma, 
which has been reported to have remarkable response to Nivolumab (86% 
clinical benefit rate in heavily pretreated patients)(5). Based on these 
intriguing results, we plan to correlate PDJ amplification measured by 
fluorescent in situ hybridization and clinical outcome of patients in this trial. 
 
1.62 
Correlative studies for blood 
We will perform the following correlative studies using blood specimens. 
1. Immunoregulatory cell quantification: To evaluate the systemic immune 
response to binimetinib and binimetinib in combination with pembrolizumab, 
peripheral blood mononuclear cells will be collected and quantified for CD4 
helper T cells, cytotoxic CD8 T cells, FOXP3 positive regulatory T cells, 
myeloid derived suppressor cells, and NK cells. 
2. Cytokine profiling: Systemic cytokine response before and after treatment 
will also be evaluated using Luminex Multianalyte assay which allows 
simultaneous quantification of multiple cytokines in a single sample. A panel 
of 17 cytokines and chemokines will be analyzed using a multiplexed 
approach with commercially available human 17-plex kits. The following 
cytokines will be assessed: IL-1β, IL-2, IL-4, IL-5, IL-6, IL-7, CXCL8 (IL- 
8), IL-10, IL-12, IL-13, IL-17A, IFN-IFN-γ, TNF-α, CCL2 (MCP-1), CCL4 
(MIP-1β), G-CSF, and GM-CSF. A panel of 17 cytokines and chemokines 
will be analyzed using a multiplexed approach with commercially available 
human 17-plex kits. The following cytokines will be analyzed using the 
manufacturer-supplied reagents. 
3. Circulating tumor cells: Circulating tumor cell (CTC) quantification will be 
performed by Creatv MicroTech, Inc. using CellSieve microfiltration 
technique. Furthermore, the expression of other targets, including PD-L1 and 
phosphorylated ERK (p-ERK), will also be assessed before and after 
treatment. Previously, we demonstrated another unique form of CTCs that 
are associated with macrophage in the circulation of patients with metastatic 
breast, pancreatic, and prostate cancer, termed circulating cancer-associated 
macrophage-like cells or CAMLs. CAMLs are large multinucleated cells in 
peripheral blood that express epithelial, monocytic, and endothelial surface 
makers. The role of CAMLs, particularly in the context of immune therapy, 
is largely unknown. 


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2.0 
Goals 
2.1 
Primary Goal 
2.11 
Phase I 
To determine the maximum tolerated dose (MTD) of binimetinib in combination 
with pembrolizumab. 
2.12 
Phase II 
To evaluate the objective response rate (ORR) of binimetinib in combination 
with pembrolizumab in patients with unresectable locally advanced or metastatic 
triple negative breast cancer by RECIST. 
2.2 
Secondary Goals 
2.21 
To evaluate the safety and tolerability of binimetinib in combination with 
pembrolizumab. 
2.22 
To evaluate the ORR by immune-related RECIST criteria (irRECIST) 
2.23 
To evaluate the progression free survival (PFS), duration of response (DoR), and 
disease control rate (DCR) by RECIST and irRECIST. 
2.24 
To assess overall survival (OS). 
2.3 
Correlative Research 
2.31 
To assess the correlation between ORR, PFS, or OS and baseline and/or change 
in TILs. 
2.32 
To assess the correlation between ORR, PFS, or OS and baseline and/or change 
in immune related gene signature and PDJ amplification. 
2.33 
To assess the change in immunoregulatory cells (IRC). 
2.34 
To assess the change in the cytokine profile. 
2.35 
To assess the change in circulating tumor cells (CTC). 


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3.0 
Patient Eligibility 
Phase I Only: Prior to discussing protocol entry with the patient, call the MCCC 
Registration Office 
for dose level and to insure that a place on the protocol is 
open to the patient. 
3.1 
Registration – Inclusion Criteria 
3.11 
Age ≥18 years. 
3.12 
Histological confirmation of adenocarcinoma of the breast. 
3.13 
Estrogen receptor (ER) and progesterone receptor (PR) negative; defined as 
ER≤10% and PR≤10% staining by immunohistochemistry (IHC). 
3.14 
HER2 negative in the primary or metastatic tumor tissue defined as: 
• 
Immunohistochemistry (IHC) Grade 0 as defined by no staining observed or 
membrane staining that is incomplete and is faint/barely perceptible and 
within ≤10% of the invasive tumor cell; OR 
• 
IHC 1+ as defined by incomplete membrane staining that is faint/barely 
perceptible and within >10% of the invasive tumor cell; OR 
• 
IHC Grade 2+ staining intensity by means of IHC analysis with no gene 
amplification below; OR 
• 
No gene amplification on ISH based on: 
o Single-probe average HER2 copy number <4.0 signals/cell 
OR 
o Dual-probe HER2/CEP17 ratio <2.0 with an average HER2 copy number 
<4.0 signals/cell 
3.15 
For phase II part of the trial: ≤3 prior lines of treatment in the metastatic setting 
for the current breast cancer. However, there is no limit on number of prior line 
of therapy in phase I part of the trial. 
3.16 
Measurable disease as defined in Section 11.0. 
3.17 
ECOG Performance Status (PS) 0 or 1 (Appendix I). 
3.18 
The following laboratory values obtained ≤14 days prior to registration. 
• 
Hemoglobin ≥9.0 g/dL (Must be ≥7 days after most recent transfusion) 
• 
Absolute neutrophil count (ANC) ≥1500/mm3 or ≥1.5 X 109/L 
• 
Platelet count ≥100,000/mm3 or ≥100 X 109/L (Must be ≥7 days after most 
recent transfusion) 
• 
Total bilirubin ≤1.5 x upper limit of normal (ULN) 
• 
Aspartate transaminase (AST) and alanine transaminase (ALT) ≤2.5 x ULN 
or ≤5 x ULN for patients with liver metastases 
• 
Creatinine ≤1.5 x ULN 
OR 
• 
Calculated creatinine clearance must be ≥50 ml/min using the Cockcroft- 
Gault formula below: 


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• 
International Normalized Ratio (INR) or Prothrombin Time (PT) and 
activated Partial Thromboplastin Time (aPTT) ≤1.5 x ULN unless patient is 
receiving anticoagulant therapy as long as PT or PTT is within therapeutic 
range of intended use of anticoagulants 
3.19 a 
Adequate cardiac function: 
• 
Left ventricular ejection fraction (LVEF) ≥50% as determined by multigated 
acquisition (MUGA) scan or echocardiogram (echo) 
• 
QTc interval ≤480 ms 
3.19b Negative serum pregnancy test done ≤7 days prior to registration, for women of 
childbearing potential only. 
3.19c 
Able to swallow oral medication. 
3.19d Both female and male patients of reproductive potential must agree to avoid 
pregnancy or impregnating a partner (respectively) while receiving drug and for 
120 days after last dose of study drug. (See Section 9.0 for specific 
requirements). 
3.19e 
Provide written informed consent. 
3.19f 
Willing to return to enrolling institution for follow-up (during the Active 
Monitoring Phase of the study). 
3.19g Willing to provide mandatory tissue and blood for correlative research purposes 
(see Sections 6, 14 and 17). 
3.2 
Registration – Exclusion Criteria 
3.21 
Any of the following because this study involves an investigational agent whose 
genotoxic, mutagenic and teratogenic effects on the developing fetus and 
newborn are unknown: 
• 
Pregnant women 
• 
Nursing women 
• 
Men or women of childbearing potential who are unwilling to employ 
adequate contraception as defined in Section 9.0. 
3.22 
Receiving any other investigational agent which would be considered as a 
treatment for the primary neoplasm 
OR 
Participated in a study of an investigational agent, received study therapy or used 
an investigational device ≤4 weeks prior to registration 
 
 
3.24 
Immunocompromised patients and patients with known immunodeficiency; or 
receiving systemic steroid therapy or any other immunosuppressive therapy 
≤7 days prior to registration. 
NOTE: Inhaled steroids and low-dose corticosteroids are allowed (see 
Section 9.0). 
Cockcroft-Gault Equation: 
Creatinine clearance for males = 
(140 - age)(weight in kg) 
(72)(serum creatinine in mg/dL) 
Creatinine clearance for females = 
(140 - age)(weight in kg)(0.85) 
(72)(serum creatinine in mg/dL) 


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3.25 
History of active tuberculosis (TB), human immunodeficiency virus (HIV), 
active hepatitis B (e.g., HBsAg reactive) and/or active hepatitis C infection (e.g. 
HCV RNA qualitative is detected). 
3.26 
Received a live vaccine ≤30 days prior to registration. 
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. 
3.27 
Hypersensitivity to pembrolizumab, binimetinib, or any excipients of either drug. 
3.28 
Prior anti-cancer therapy with a monoclonal antibody (mAb) ≤4 weeks prior to 
registration 
OR Failure to recover (to ≤Grade1) from adverse events (AE) attributable to 
agents received >4 weeks prior to registration. 
3.29 a 
Prior therapy including chemotherapy, targeted small molecule therapy or 
radiation therapy ≤2 weeks prior to registration 
OR Failure to recover (to ≤Grade1 or to baseline) from adverse events (AE) 
attributable to agents received >4 weeks prior to registration. 
NOTE: Exception for neuropathy ≤Grade 2, which is allowed. 
3.29b Any active central nervous system (CNS) lesion (i.e., those with radiographically 
unstable, symptomatic lesions) and/or leptomeningeal metastases. 
NOTE: Patients treated with stereotactic radiotherapy or surgery are eligible if no 
evidence of CNS disease progression ≥4 weeks and patients must be off 
corticosteroid therapy for ≥3 weeks. 
NOTE: Carcinomatous meningitis is excluded regardless of clinical stability. 
3.29c 
Active autoimmune disease requiring systemic treatment in the past 2 years (i.e. 
use of disease modifying agents, corticosteroids or immunosuppressive drugs). 
NOTE: Replacement therapy (e.g., thyroxine, insulin, or physiologic 
corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is 
not considered a form of systemic treatment. 
3.29d Known history of, or any evidence of active, non-infectious pneumonitis. 
3.29e 
Active infection requiring systemic therapy. 
3.29f 
Known history of acute or chronic pancreatitis. 
3.29g History of or current evidence of retinal vein occlusion (RVO) or predisposing 
factors to RVO (e.g. uncontrolled glaucoma or ocular hypertension, history of 
hyperviscosity or hypercoagulability syndromes). 
3.29h History of retinal degenerative disease. 
3.29i 
History of Gilbert’s syndrome. 
3.29j 
Other active malignancy ≤3 years prior to registration. 
EXCEPTIONS: Adequately treated non-melanotic skin cancer (adequate wound 
healing is required prior to study entry) or carcinoma-in-situ of the cervix. 
NOTE: If there is a history of prior solid tumor malignancy, it must have been 
treated curatively with no evidence of recurrence ≤3 years prior to registration. 


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3.29k Impaired cardiovascular function or clinically specific cardiovascular disease 
including any of the following: 
• 
History of acute coronary syndromes (including myocardial infarction 
unstable angina, coronary artery bypass grafting, coronary angioplasty, 
or stenting) ≤6 months; OR 
• 
Symptomatic chronic heart failure history or current evidence of 
clinically significant cardiac arrhythmia and/or conduction abnormality 
<6 months prior to screening; except atrial fibrillation and paroxysmal 
supraventricular tachycardia. 
3.29l 
 Uncontrolled arterial hypertension defined as persistent elevation of systolic 
blood pressure ≥150 mmHg or diastolic blood pressure ≥100mmHg despite 
medical treatment. 
3.29m History of neuromuscular disorders that are associated with elevated CK (e.g., 
inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, 
spinal muscular atrophy). 
3.29n Planning to embark on a new strenuous exercise regimen after first dose of study 
treatment. 
Note: Muscular activities, such as strenuous exercise, that can result in 
significant increases in plasma CK levels should be avoided while on binimetinib 
treatment. 
3.29o Impairment of gastrointestinal function or gastrointestinal disease (e.g., 
ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption 
syndrome, small bowel resection). 
NOTE: Gastric bypass is allowed. 
3.29p Any other condition that would, in the Investigator’s judgment, contraindicate the 
patient’s participation in the clinical study due to safety concerns or compliance 
with clinical study procedures, e.g., infection/inflammation, intestinal 
obstruction, unable to swallow medication, social/ psychological issues, etc. 
3.29q Major surgery ≤3 weeks prior to registration or failure to adequately recover 
from surgery. 
3.29r 
Medical, psychiatric, cognitive or other conditions that may compromise the 
patient's ability to understand the patient information, give informed consent, 
comply with the study protocol or complete the study 


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3.3 
Retreatment Registration – Inclusion Criteria 
3.31 
Treatment cannot begin prior to registering to the retreatment phase and will 
ideally begin ≤7 days after registration for the retreatmentphase. 
3.32 
Stopped initial treatment with pembrolizumab and binimetinib after attaining an 
investigator-determined confirmed CR according to RECIST 1.1, and: 
• 
Was treated for at least 24 weeks with pembrolizumab and binimetinib 
before discontinuing therapy 
• 
Received at least 2 cycles with pembrolizumab and binimetinib beyond 
the date when the initial CR was declared 
OR 
• 
Had SD, PR, or CR and stopped pembrolizumab and binimetinib 
treatment after 24 months of study therapy for reasons other than disease 
progression or intolerability 
3.33 
ECOG Performance Status (PS) 0 or 1 (Appendix I). 
3.34 
Demonstrates adequate organ fuction. The following laboratory values obtained 
≤14 days prior to re-registration: 
• 
Hemoglobin ≥9.0 g/dL (Must be ≥7 days after most recent transfusion) 
• 
Absolute neutrophil count (ANC) ≥1500/mm3 or ≥1.5 X 109/L 
• 
Platelet count ≥100,000/mm3 or ≥100 X 109/L (Must be ≥7 days after most 
recent transfusion) 
• 
Total bilirubin ≤1.5 x upper limit of normal (ULN) 
• 
Aspartate transaminase (AST) and alanine transaminase (ALT) ≤2.5 x ULN 
or ≤5 x ULN for patients with liver metastases 
• 
Creatinine ≤1.5 x ULN 
OR 
• 
Calculated creatinine clearance must be ≥50 ml/min using the Cockcroft- 
Gault formula below: 
 
International Normalized Ratio (INR) or Prothrombin Time (PT) and activated 
Partial Thromboplastin Time (aPTT) ≤1.5 x ULN unless patient is receiving 
anticoagulant therapy as long as PT or PTT is within therapeutic range of 
intended use of anticoagulants 
3.35 
Females of childbearing potential should have a negative serum or urine 
pregnancy test ≤72 hours prior to re-registration. 
3.36 
Females or males of childbearing potential must be willing to use adequate 
methods of contraception as outline in section 9.9b or abstain from heterosexual 
activity for the course of th study through 120 days after last dose of study 
medication. 
3.37 
Experienced an investigator-determined confirmed radiographic disease 
progression after stopping their initial treatment with pembrolizumab and 
binimetinib. 
3.4 
Retreatment Registration – Exclusion Criteria 
Cockcroft-Gault Equation: 
Creatinine clearance for males = 
(140 - age)(weight in kg) 
(72)(serum creatinine in mg/dL) 
Creatinine clearance for females = 
(140 - age)(weight in kg)(0.85) 
(72)(serum creatinine in mg/dL) 


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3.41 
Received any type anti-cancer treatment since the last dose of pembrolizumab 
3.42 
History or current evidence of any condition, therapy, or laboratory abnormality 
that might interfere with 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. 


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4.0 
Study Calendar 
4.1 
Test Schedule for Breast Cancer1 
 
 
 
 
Active Treatment 
End of 
Treatment 
Post- 
Treatment 
 
 
 
Tests and procedures 
 
≤28 days 
 
≤14 days 
 
 
Pre-Tx 
biopsy 
Cycle 1 
binimeti 
nib 
alone 
Cycles 2-3 
with pembro 
Cycles 
4-8 
 
Cycle 9 
Cycle 
10 
 
At time of 
Safety follow 
up: 
prior to 
registration 
prior to 
registration 
Prior to 
C2 D1 
Prior to 
C3 D1 
Prior to 
Day 1 
Prior to 
Day 1 
and 
beyond 
 
disease 
progression 
 
30 days post- 
discontinuation 
Window 
 
 
 
±3 days 
±3 days 
±3 days 
±3 days 
±3 days 
±7 days 
±7 days 
Clinical Procedures 
 
 
 
 
 
 
 
 
 
 
 
History and exam12, vital signs (temp, 
BP, heart rate), weight, ECOG PS 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
Concomitant medications 
X 
 
 
 
X 
X 
X 
X 
X 
 
X 
Pregnancy test2 
 
X2 
 
 
 
 
 
 
 
 
 
Hematology: CBC/diff with PLT 
 
X 
 
 
X 
X 
X 
X 
X 
 
X 
Chemistry Panel3 
 
X 
 
 
X 
X 
X 
X 
X 
 
X 
CA15-3 
 
X 
 
 
X 
X 
X 
X 
X 
 
X 
Creatine Kinase (CK/CPK), troponin 
T4,R 
 
X 
 
 
X 
X 
X 
X 
X 
 
X 
Urinalysis 
 
X 
 
 
X 
X 
X 
X 
X 
 
X 
Coagulation INR (PT), PTT 
 
X 
 
 
 
 
 
 
 
 
 
Total T3, Free T4, TSHR 
 
X 
 
 
X 
X 
X 
X 
X 
 
X 
Tumor measurement by CT or MRI5 
X 
 
 
 
 
 
X 
 
 
 
 
Bone scan (only if clinically indicated) 
X 
 
 
 
 
 
 
 
 
 
 
 
*Retreatment Phase-Patients entering the study for retreatment will follow the test and procedures as indicated in the study calendar for Cycle 2 and beyond. 
Labs and blood forms are not required to be entered into RAVE during the Retreatment Phase. 
1 All tests and procedures are clinically indicated, unless noted with an R to indicate funding by research 
2 For women of childbearing potential only: Serum βHCG must be done ≤7 days prior to registration, and if necessary, again ≤72 hours prior to Cycle 1, Day 1 
3 AST (SGOT), ALT (SGPT), alkaline phosphatase, total bilirubin (direct if TBili is elevated), BUN, creatinine with calculated creatinine clearance, albumin, 
total protein, uric acid, bicarbonate, calcium, chloride, glucose, LDH, magnesium, phosphorus, potassium, sodium 
4 Follow up for total creatine kinase (CK/CPK) ≥3 X ULN will include weekly assessment of isoenzymes and myoglobin in blood/or urine, and troponin T 
as applicable 
5 Every 12-16 weeks after Cycle 4 during active treatment (per the treating physician’s discretion). Same method should be used throughout the study. Note: 
PET/CT is not allowed as CT portion of PET/CT is not adequate for RECIST. 


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Active Treatment 
End of 
Treatment 
Post- 
Treatment 
 
 
 
Tests and procedures 
 
≤28 days 
 
≤14 days 
 
 
Pre-Tx 
biopsy 
Cycle 1 
binimeti 
nib 
alone 
Cycles 2-3 
with pembro 
Cycles 
4-8 
 
Cycle 9 
Cycle 
10 
 
At time of 
Safety follow 
up: 
prior to 
registration 
prior to 
registration 
Prior to 
C2 D1 
Prior to 
C3 D1 
Prior to 
Day 1 
Prior to 
Day 1 
and 
beyond 
 
disease 
progression 
 
30 days post- 
discontinuation 
Window 
 
 
 
±3 days 
±3 days 
±3 days 
±3 days 
±3 days 
±7 days 
±7 days 
ECG, 12 lead, triplicateR 
X 
 
 
 
 
X 
 
 
 
 
 
Echocardiogram (ECHO)6 – limited, 
LVEF only 
X 
 
 
 
X6 
 
X6 
 
X6 
 
X 
Full ophthalmic evaluation 7 
X 
 
 
 
 
X7 
X7 
 
X7 
 
X 
Adverse event assessment 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Research Blood and Tissue- Analysis  
 
 
 
 
 
 
 
 
 
 
Blood for correlative research 8,R 
(See Section 14.0) 
 
 
X 
 
X 
X 
 
X 
 
 
X 
Mandatory tissue sample (see Section 
17.0) 9,10,R 
 
 
X 
 
 
 
 
 
 
 
 
Optional follow up tissue sample(see 
Section 17.0)11,R 
 
 
 
 
X 
 
 
 
 
X 
 
 
6 Echocardiogram will be performed at baseline, on Cycle 2 Day 1, and Cycle 5 Day 1, then every 12 weeks to determine cardiac ejection fraction in patients who 
continue on binimetinib.  Follow-up echocardiogram is not required in patients who discontinue binimetinib. 
7 Full ophthalmic examination will be performed at baseline, at Cycle 3 Day 1 ± 7 days, and then every 12 weeks ± 7 days in patients who continue on 
binimetinib.  Follow-up ophthalmic examination is not required in patients who discontinue binimetinib. Full ophthalmic examination includes best corrected 
visual acuity, slit lamp examination, intraocular pressure, dilated fundoscopy and Ocular Coherence Tomography (OCT). Examination of the retina is 
required, especially to identify findings associated with serous retinopathy and RVO. For patients with clinical suspicion of retinal abnormalities of any grade 
(e.g., serous retinopathy, RVO, photopsia, metamorphopsia, impairment of visual acuity), these additional assessments should be mandatory: 
• 
For non-vasclular abnormalities: spectral domain OCT recommended 
• 
For Vascular abnormalities: fluorescein angiography of central 30 degrees. 
8 Whole blood samples for correlative research will be collected at the following timepoints: Baseline, 2nd week of binimetinib prior to starting pembrolizumab, 
After 1 cycle of bini and pembro at Cycle 3, Cycle 9, Day 1 (only if >6 months of stable disease/CR/PR), and at the end of therapy (i.e., ≤4 weeks after final 
administered dose of therapy), or at the time of tumor recurrence. 
9 Submission of tissue from the primary or metastatic tumor is mandatory 
10 Mandatory tumor biopsy except in patients who have adequate tumor tissue samples collected ≤90 days prior to registration. Adequate sample is defined as 
core needle, punch, or incisional biopsy samples that can provide ≥10 unstained sections of 5 υM thickness. Fine needle aspiration (FNA) sample alone is not 
sufficient. 
11 An optional newly-obtained core or excisional biopsy (FNA not adequate) is requested after 10 days of binimetinib prior to starting pembrolizumab and at the 
end of treatment for any reason. 
12 Physical exam includes gross perimeter test. After baseline, patients receiving binimetinib should be assessed at every physical examination for decreased 


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Active Treatment 
End of 
Treatment 
Post- 
Treatment 
 
 
 
Tests and procedures 
 
≤28 days 
 
≤14 days 
 
 
Pre-Tx 
biopsy 
Cycle 1 
binimeti 
nib 
alone 
Cycles 2-3 
with pembro 
Cycles 
4-8 
 
Cycle 9 
Cycle 
10 
 
At time of 
Safety follow 
up: 
prior to 
registration 
prior to 
registration 
Prior to 
C2 D1 
Prior to 
C3 D1 
Prior to 
Day 1 
Prior to 
Day 1 
and 
beyond 
 
disease 
progression 
 
30 days post- 
discontinuation 
Window 
 
 
 
±3 days 
±3 days 
±3 days 
±3 days 
±3 days 
±7 days 
±7 days 
Patient Medication Diary (See 
Appendix II) 
 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
visual acuity using a gross perimetry test (as opposed to automated visual field testing). Symptomatic patients should be referred for a full ophthalmic 
consultation. 


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4.2 
Event Monitoring/Survival Follow-up 
 
 
Event Monitoring Phase1 
q. 3 months 
until PD 
 
At PD 
After PD 
q. 6 months 
 
Death 
 
New Primary 
Event Monitoring 
X 
X 
X 
X 
At each occurrence 
1. If a patient is still alive 3 years after registration, no further follow-up is required. 
 
5.0 Grouping Factor 
Phase I vs. Phase II 
 
6.0 
Registration Procedures 
6.1 
Phase I Registration 
Prior to discussing protocol entry with the patient, call the MCCC Registration 
Office 
for dose level and to insure that a place on the protocol is 
open to the patient. 
6.11 
Registration 
To register a patient, fax
 a completed eligibility checklist to the 
Mayo Clinic Cancer Center (MCCC) Registration Office between 8 a.m. and 
4:30 p.m. central time Monday through Friday. 
6.12 
Prior to accepting the registration, the registration/randomization application will 
verify the following: 
• 
IRB approval at the registering institution 
 
• 
Patient pre registration eligibility 
 
• 
Existence of a signed consent form 
 
• 
Existence of a signed authorization for use and disclosure of protected health 
information 
6.13 
Registration tests/procedures (see Section 4.0) must be completed within the 
guidelines specified on the test schedule. 
6.2 
Phase II Registration 
6.21 
Registration 
To register a patient, access the Mayo Clinic Cancer Center (MCCC) 
web page and enter the remote registration/randomization application. 
The registration/randomization application is available 24 hours a day, 7 
days a week. Back up and/or system support contact information is 
available on the Web site. If unable to access the Web site, call the 
MCCC Registration Office at 
 between the hours of 8 
a.m. and 5:00 p.m. Central Time (Monday through Friday). 
The instructions for the registration/randomization application are available on 
the MCCC web page 
and detail the 
process for completing and confirming patient registration. Prior to initiation of 
protocol treatment, this process must be completed in its entirety and a MCCC 


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subject ID number must be available as noted in the instructions. It is the 
responsibility of the individual and institution registering the patient to confirm 
the process has been successfully completed prior to release of the study agent. 
Patient registration via the registration/randomization application can be 
confirmed in any of the following ways: 
• 
Contact the MCCC Registration Office 
 If the patient was 
fully registered, the MCCC Registration Office staff can access the 
information from the centralized database and confirm the registration. 
• 
Refer to “Instructions for Remote Registration” in section 
“Finding/Displaying Information about A Registered Subject.” 
6.22 
Verification 
Prior to accepting the registration, registration/randomization application will 
verify the following: 
• 
IRB approval at the registering institution 
• 
Patient eligibility 
• 
Existence of a signed consent form 
• 
Existence of a signed authorization for use and disclosure of protected health 
information 
• 
Grouping factor 
6.3 
Both Phase I and Phase II 
6.31 
Documentation of IRB approval 
Documentation of IRB approval must be on file in the Registration Office before 
an investigator may register any patients. 
In addition to submitting initial IRB approval documents, ongoing IRB approval 
documentation must be on file (no less than annually) at the Registration Office 
 If the necessary documentation is not submitted in advance 
of attempting patient registration, the registration will not be accepted and the 
patient may not be enrolled in the protocol until the situation is resolved. 
When the study has been permanently closed to patient enrollment, submission of 
annual IRB approvals to the Registration Office is no longer necessary. 
6.32 
Correlative studies 
6.321 Mandatory correlative studies 
A mandatory correlative component is part of this study. The patient will 
be automatically registered onto this component (see Section 3.1 and 
17.0). 
6.322 Optional correlative studies 
An optional correlative component is part of this study. At the time of 
registration, the following will be recorded: 
• 
Patient has/has not given permission to store and use his/her 
sample(s) for future research of breast cancer at Mayo. 
• 
Patient has/has not given permission to store and use his/her 
sample(s) for future research to learn, prevent, or treat other health 
problems. 
• 
Patient has/has not given permission for MCCC to give his/her 
sample(s) to researchers at other institutions. 


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6.33 
Treatment on protocol 
Treatment on this protocol must commence at Mayo Clinic under the supervision 
of a medical oncologist. 
6.34 
Treatment start 
Treatment cannot begin prior to registration and must begin ≤14 days after 
registration. 
6.35 
Pretreatment 
Pretreatment tests/procedures (see Section 4.0) must be completed within the 
guidelines specified on the test schedule. 
6.36 
Baseline symptoms 
All required baseline symptoms (see Section 10.6) must be documented and 
graded. 
6.37 
Study drug availability 
Study drug is available on site for this patient. 
6.38 
Retreatment Registration 
6.38a 
To register a patient, fax 
a completed retreatment 
eligibility checklist to the Mayo Clinic Cancer Center (MCCC) 
Registration Office between 8 a.m. and 4:30 p.m. central time Monday 
through Friday. 
6.38b Treatment cannot begin prior to registration to the retreatment phase and 
will begin ≤7 days after registration for the retreatment phase. 


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7.0 
Protocol Treatment 
7.1 
Treatment Schedule 
7.11 
Phase I treatment medication tables 
Cycle 1: 
 
 
 
 
Cycle 2 and all subsequent cycles: 
Agent 
Dose Level 
Route 
Day 
ReRx 
 
Binimetinib 
As assigned by 
Registration 
Office 
 
PO BID 
 
1-21 
 
q3w 
Pembrolizumab 
200 mg 
IV 
1 
q3w 
7.12 
Phase II treatment medication tables 
Cycle 1: 
 
 
 
Cycle 2 and all subsequent cycles: 
Agent 
Dose Level 
Route 
Day 
ReRx 
Binimetinib 
As determined 
by Phase I 
PO BID 
1-21 
q3w 
Pembrolizumab 
200 mg 
IV 
1 
q3w 
7.13 
Treatment Plan 
All trial treatments will be administered on an outpatient basis. 
In Cycle 1, patients will receive binimetinib for 2 weeks followed by blood draw 
and optional tumor biopsy to evaluate the effects of binimetinib single agent on 
immune system and tumors prior to starting pembrolizumab in Cycle 2 and every 
subsequent cycle. 
7.14 
Pembrolizumab 
Trial treatment should be administered on Day 1 of each cycle after all 
procedures/assessments have been completed. Trial treatment may be 
administered up to 3 days before or after the scheduled Day 1 of each cycle due 
to administrative reasons. 
Pembrolizumab at the fixed dose of 200 mg will be administered as a 30 minute 
IV infusion once every 3 weeks. Every effort should be made 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). 
Agent 
Dose Level 
Route 
Day 
 
Binimetinib 
As assigned by 
Registration 
Office 
 
PO BID 
 
1-14 
Agent 
Dose Level 
Route 
Day 
Binimetinib 
As determined 
by Phase I 
PO BID 
1-14 


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7.15 
Binimetinib 
Binimetinib is an oral medication. Binimetinib will be administered by patients 
twice daily on a continuous basis. 
Given that food-effect clinical studies have shown influence of food on PK of 
binimetinib is mild and not clinically relevant (see binimetinib Investigator 
Brochure), binimetinib can be taken with food. 
7.2 
Return to consenting institution 
For this protocol, the patient must return to the consenting institution for evaluation at 
least every 21 days during treatment (Active Monitoring Phase). 
7.3 
Treatment by local medical doctor (LMD) 
Treatment by a local medical doctor (LMD) is not allowed. 
7.4 
Phase I – determination of Maximum Tolerated Dose (MTD) 
7.41 
Dose De-Escalation 
 
Dose level 
Pembrolizumab** 
Binimetinib 
-2 
200 mg IV q3w 
15 mg PO twice daily 
-1 
200 mg IV q3w 
30 mg PO twice daily 
0* 
200 mg IV q3w 
45 mg PO twice daily 
*starting dose level 
**NOTE: There are no dose modifications for pembrolizumab 
If dose level -1 does not meet MTD determination, the study will be stopped and 
evaluated by the principal investigator and the industry partners to determine an 
appropriate dose level. 
7.411 Treatment by a local medical doctor is not allowed. 
7.412 Three patients will be treated at each dose level and observed for a 
minimum of 21 days after start of pembrolizumab, to assess toxicities, 
before new patients are treated. Doses will not be escalated in any 
individual patient. Decisions on when and how to enroll patients at each 
dose level are described in Section 16.42. 
7.413 Investigators are to contact the Study Chair as soon as any dose-limiting 
toxicity (DLT) occurs. 
7.42 
Definitions of DLT 
7.421 For this protocol, DLT will be defined as follows for Cycle 2 only: 
 
CTCAE SOC/AE* 
Definition (CTCAE Grade) 
Blood and lymphatic system 
disorders 
• 
Febrile neutropenia 
Grade 4 
Eye disorders 
• 
Blurred vision 
• 
Flashing lights 
• 
Floaters 
≥Grade 3 
Eye disorders 
• 
Retinopathy 
Grade 2 lasting >14 consecutive days confirmed 
by ophthalmic examination 
Or Grade 3 
Eye disorders 
• 
Retinal vascular disorder 
Any grade confirmed by ophthalmic 
examination 


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CTCAE SOC/AE* 
Definition (CTCAE Grade) 
Eye disorders 
• 
Eye disorders, Other specify 
Any visual event ≥Grade 3 confirmed by 
ophthalmic examination 
Investigations 
• 
Alanine aminotransferase 
increased 
OR 
• 
Aspartate aminotransferase 
increased 
≥Grade 3 
Investigations 
• 
Blood bilirubin increased 
≥Grade 3 
Investigations 
• 
CPK increased 
≥Grade 3 associated with an increase in 
creatinine ≥1.5 times patient’s baseline 
(screening) creatinine level 
Investigations 
• 
Creatinine increased 
≥Grade 3 
Investigations 
• 
Ejection fraction decreased 
≥Grade 3 
Or Absolute decrease of LVEF >10% compared 
to Baseline and is below the institution’s LLN 
Investigations 
• 
Electrocardiogram QT 
corrected interval prolonged 
≥Grade 3 on at least two separate ECGs 
Investigations 
• 
Neutrophil count decreased 
Grade 4 lasting >7 consecutive days 
Investigations 
• 
Platelet count decreased 
Grade 3 with signs of clinically significant 
bleeding 
Or Grade 4 
Gastrointestinal disorders 
• 
Diarrhea 
≥Grade 3 for ≥48 hours despite optimal anti- 
diarrheal therapy 
Or Grade 4 
Gastrointestinal disorders 
• 
Nausea 
• 
Vomiting 
Grade 3 for ≥48 hours despite optimal anti- 
emetic therapy 
Or Grade 4 
General disorders and 
administration site conditions 
• 
Fatigue 
Grade 3 lasting >14 consecutive days 
Skin and subcutaneous tissue 
disorders 
• 
Rash maculo-papular 
• 
Palmar-plantar 
erythrodysesthesia 
syndrome 
• 
Photosensitivity 
Grade 3 lasting >14 consecutive days despite 
maximal skin toxicity treatment per local 
practice 
Or Grade 4 
Vascular disorders 
• 
Hypertension 
Grade 3 lasting >14 consecutive days 
Or Grade 4 
Other events** 
Any ≥Grade 3 
*Adverse event at least possibly related to the study medication. 
** Lymphocyte count decreased ≥Grade 3 (unless clinically significant) and 
Grade 3 alopecia will not be considered a DLT 
7.5 
Retreatment (Second Course Phase) 
Patients who stop pembrolizumab and binimetinib with SD or better may be eligible for 
up to one year of additional pembrolizumab and binimetinib therapy if they progress after 


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stopping study treatment. This retreatment is termed the Second Course Phase of this 
study and is only available if the study remains open and the patient meets the following 
conditions: 
EITHER 
• 
Stopped initial treatment with pembrolizumab and binimetinib after attaining an 
investigator-determined confirmed CR according to RECIST 1.1, and 
o Was treated for at least 24 weeks with pembrolizumab and binimetinib 
before discontinuing therapy 
o Received at least two cycles with pembrolizumab and binimetinib 
beyond the date when the initial CR was declared 
OR 
• 
Had SD, PR or CR and stopped pembrolizumab and binimetinib treatment after 
24 months of study therapy for reasons other than disease progression or 
intolerability 
AND 
• 
Experienced an investigator-determined confirmed radiographic disease 
progression after stopping their initial treatment with pembrolizumab and 
binimetinib 
• 
Did not receive any anti-cancer treatment since the last dose of pembrolizumab 
and binimetinib 
• 
Has a performance status of 0 or 1 on the ECOG Performance Scale 
• 
Demonstrates adequate organ function (as required for initial eligibility in 
Section 3.0) 
• 
Females of childbearing potential should have a negative serum or urine 
pregnancy test within 72 hours prior to receiving retreatment with study 
medication 
• 
Females or males of childbearing potential must be willing to use adequate 
methods of contraception as outlined in Section 9.9b or abstain from heterosexual 
activity for the course of the study through 120 days after the last dose of study 
medication. 
• 
Does not have a history or current evidence of any condition, therapy, or 
laboratory abnormality that might 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. 
Baseline procedures as outlined in the pretrial screening should be repeated ≤28 days 
prior to retreatment. 
Patients who restart treatment will be retreated at the same dose and dose interval as 
when they last received pembrolizumab and binimetinib. Patients may continue 
treatment for up to one additional year and will follow the original treatment schedule 
starting at cycle 2. 


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8.0 
Dosage Modification Based on Adverse Events 
Strictly follow the modifications in this table for the first two cycles, until individual treatment 
tolerance can be ascertained. Thereafter, these modifications should be regarded as guidelines to 
produce mild-to-moderate, but not debilitating, side effects. If multiple adverse events are seen, 
administer dose based on greatest reduction required for any single adverse event observed. 
Reductions or increases apply to treatment given in the preceding cycle and are based on adverse 
events observed since the prior dose. 
→ALERT: 
ADR reporting may be required for some adverse events (See Section 10.0)← 
** Use the following to describe actions in the Action column: 
 Omit = Treatment is not given for this cycle 
 Hold/Delay = Treatment can be made up as part of this cycle 
 Discontinue = Treatment is totally stopped 
NOTE: If the patient experiences a significant adverse event requiring a dose reduction at the 
start of the next cycle, then the dose will remain lowered. 
8.1 
Dose Levels (Based on Adverse Events in Table 8.2) 
 
Dose 
Level 
 
Binimetinib 
0* 
45 mg BID 
-1 
30 mg BID 
-2 
15 mg BID 
-3 
Discontinue 
*Dose level 0 refers to the starting dose. 
NOTE: If binimetinib is discontinued, the patient can continue treatment on single- 
agent pembrolizumab. The patient will continue to follow the test schedule (Section 
4.1) 
For binimetinib, if dose reduction goes below -2 dose level, then binimetinib must be 
discontinued. If binimetinib is started at -2 dose level, then there are no further dose 
reductions. 
NOTE: There are no dose changes for pembrolizumab, only dose schedule modifications. 
For patients who do not tolerate the 45 mg BID dosing schedule, dose adjustment to 30 
mg BID is permitted in order to allow the patient to continue on study drug. The 
following guidelines need to be applied and these changes must be recorded on the on the 
specific section of the patient record. 
A dose reduction below 15 mg BID is not allowed. Dose interruptions of more than 21 
days are not allowed. 
Missed/skipped doses will not be made up (i.e. the patient should not double their dose if 
the previous dose was missed). When the adverse event that resulted in a dose reduction 
improves to and remains stable at Grade 1 or less for a minimum of 21 days, the dose can 
be re-escalated at the investigators discretion provided there are no other concomitant 
adverse events. 
No dose re-escalation is allowed after dose reduction due to left ventricular dysfunction 
or prolonged QTcF >500 msec. 


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Dose reduction/interruption/discontinuation decisions should be based on the CTCAE 
grade of the adverse event (AE) and the guidelines provided below. In general, doses 
should not be reduced or interrupted for Grade 1 events, but treatment to control 
symptoms should be provided as appropriate. All AEs should be followed weekly or as 
clinically appropriate until stabilization or resolution. 
A patient with a Grade 4 AE may resume treatment at the lower dose level if the AE 
recovers to grade ≤1 within 21 days of interrupting drug and, if in the opinion of the 
Investigator and Medical Monitor, the event is not life-threatening, and the patient can be 
managed and monitored for recurrence of AE. Dose interruptions of more than 21 days 
are not allowed unless approved by the Investigator, and the Pfizer Inc. (formerly Array 
Biopharma LLC and Array Biopharma Inc.) Medical Monitor or designee. 
Please refer to the table below for dose adjustment recommendations for binimetinib- 
induced adverse events. 
For adverse events that can be attributed to either pembrolizumab or binimetinib, dose 
adjustment for both agents will be applied. These toxicities include but are not limited to 
diarrhea and liver function abnormalities. 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) current version 4.0* 
unless otherwise specified  
* 
Located at http:/ctep.cancer.gov/protocolDevelopment/electronic_applications.ctc.htm 


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8.2 
Dose Modifications for Binimetinib 
 
CTCAE 
System/Organ/Class 
(SOC) 
 
 
ADVERSE EVENT 
 
Grade 
 
ACTION FOR BINIMETINIBC 
Cardiac disorders 
Left ventricular systolic 
dysfunction 
Grade 1-2 
Asymptomatic absolute 
decrease of >10% compared 
to baseline and below 
institutional LLN 
Hold binimetinib and repeat evaluation of LVEF within 2 weeks: 
o If the LVEF recovers (defined as LVEF ≥50% or ≥LLN and 
absolute decrease ≤10% compared to Baseline) in ≤21 days, reduce 
1 dose level after approval of the Principal Investigator. Monitor 
LVEF 2 weeks after resuming binimetinib, every 4 weeks for 12 
weeks and subsequently as per protocol 
o If the LVEF does not recover in ≤21 days, permanently discontinue 
binimetinib. Closely monitor LVEF until resolution or for up to 
16 weeks 
No dose re-escalation allowed after dose reduction for LVEF 
Eye disordersa,b 
Retinal detachment 
Grade 1 
Maintain dose level of binimetinib and increase frequency of ophthalmic 
monitoring to at least every 14 days until stabilization or resolution 
Grade 2 
Maintain dose level of binimetinib and refer the patient to ophthalmologist 
within 1 week: 
o If resolved to Grade ≤1 in ≤21 days, maintain dose of binimetinib 
o If not resolved to Grade ≤1 in ≤21 days, reduce 1 dose level of 
binimetinib or maintain dose of binimetinib based upon the 
Investigator’s discretion after consultation with the ophthalmologist 
Grade 3 
Hold binimetinib and refer the patient to ophthalmologist within 1 week: 
o If resolved to Grade ≤1 in ≤21 days, reduce 1 dose level of 
binimetinib 
o If not resolved to Grade ≤1 in ≤21 days, permanently discontinue 
binimetinib and close follow-up with ophthalmic monitoring until 
stabilization or resolution 
Grade 4 
Permanently discontinue binimetinib and immediate follow-up with 
ophthalmic monitoring until stabilization or resolution 
Retinal vascular 
disorder (RVO) 
Any 
Permanently discontinue binimetinib and immediate follow-up with 
ophthalmic monitoring until stabilization or resolution 
Eye disorders – Other 
specify – any non-retinal 
events 
Grade 1-2 
Maintain dose level of binimetinib and increase frequency of ophthalmic 
monitoring to at least every 14 days until stabilization or resolution 


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CTCAE 
System/Organ/Class 
(SOC) 
 
 
ADVERSE EVENT 
 
Grade 
 
ACTION FOR BINIMETINIBC 
Eye disordersa,b 
Eye disorders – Other 
specify – any non-retinal 
events 
Grade 3 
Hold binimetinib and refer patient to ophthalmologist within 1 week: 
o 
If resolved to Grade ≤1 in ≤21 days, reduce 1 dose level of 
binimetinib 
o 
If not resolved to Grade ≤1 in ≤21 days, permanently discontinue 
binimetinib and close follow-up with ophthalmic monitoring until 
stabilization or resolution 
Grade 4 
Permanently discontinue binimetinib and immediate follow-up with 
ophthalmic monitoring until stabilization or resolution 
Gastrointestinal 
disorders 
Diarrhea 
Grade 1-2 Uncomplicated 
Consider temporary hold of binimetinib until resolved to Grade ≤1 
Resume binimetinib at current dose level 
Grade 1-2 Complicated 
Temporarily hold binimetinib until resolved to Grade ≤1 
Resume binimetinib at 1 reduced dose level 
Grade 3 
Temporarily hold binimetinib until resolved to Grade ≤1 
Resume binimetinib at 1 reduced dose level 
Grade 4 
Temporarily hold binimetinib until resolved to Grade ≤1 
Resume binimetinib at 1 reduced dose level 
Investigations 
Alanine 
aminotransferase 
increased (ALT) 
OR 
Aspartate 
aminotransferase 
increased (AST) 
Grade 1 
Maintain dose level of binimetinib 
Alanine 
aminotransferase 
increased (ALT) 
OR 
Aspartate 
aminotransferase 
increased (AST) 
AND 
Blood bilirubin 
increased 
Grade 2 
For patients with Baseline 
ALT/AST values ≤ULN: 
ALT or AST >3.0 to 5.0 × 
ULN and blood bilirubin 
(total) ≤2.0 × ULN 
Hold binimetinib until resolved to Grade ≤1, then: 
o If resolved in ≤14 days, maintain dose level of binimetinib 
o If not resolved in ≤14 days, reduce 1 dose level of binimetinib 


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CTCAE 
System/Organ/Class 
(SOC) 
 
 
ADVERSE EVENT 
 
Grade 
 
ACTION FOR BINIMETINIBC 
Investigations 
Alanine 
aminotransferase 
increased (ALT) 
OR 
Aspartate 
aminotransferase 
increased (AST) 
AND 
Blood bilirubin 
increased 
Grade 2 
For patients with liver 
metastases or ALT/AST 
Baseline values >ULN: 
ALT or AST 3 × Baseline 
value to 5.0 × ULN and 
blood bilirubin (total) ≤2.0 × 
ULN 
Hold binimetinib until resolved to Grade ≤2, then: 
o If resolved in ≤14 days, maintain dose level of binimetinib 
o If not resolved in ≤14 days, reduce 1 dose level of binimetinib 
Grade 2 
For all patients: 
ALT or AST >3.0 to 5.0 × 
ULN 
and 
blood bilirubin (total) >2.0 × 
ULN 
Hold binimetinib until resolved to Grade ≤1, then: 
o If resolved in ≤7 days, reduce 1 dose level of binimetinib 
o If not resolved in ≤7 days, permanently discontinue binimetinib 
Alanine 
aminotransferase 
increased (ALT) 
OR 
Aspartate 
aminotransferase 
increased (AST) 
AND 
Blood bilirubin 
increased 
Grade 3 
ALT or AST >5.0 to 8.0 × 
ULN 
and 
blood bilirubin (total) ≤2.0 × 
ULN 
Hold binimetinib until resolved to Grade ≤1 (Grade ≤2 in case of liver 
metastases) then: 
o If resolved in ≤14 days, maintain dose level of binimetinib 
o If not resolved in ≤14 days, reduce 1 dose level of binimetinib 
Grade 3 
ALT or AST >8.0 ×ULN 
and 
blood bilirubin (total) ≤2.0 × 
ULN 
Permanently discontinue binimetinib 


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CTCAE 
System/Organ/Class 
(SOC) 
 
 
ADVERSE EVENT 
 
Grade 
 
ACTION FOR BINIMETINIBC 
Investigations 
Alanine 
aminotransferase 
increased (ALT) 
OR 
Aspartate 
aminotransferase 
increased (AST) 
AND 
Blood bilirubin 
increased 
Grade 3 
ALT or AST >5.0 ×ULN 
and 
blood bilirubin (total) >2.0 × 
ULN 
Permanently discontinue binimetinib 
Alanine 
aminotransferase 
increased (ALT) 
OR 
Aspartate 
aminotransferase 
increased (AST) 
Grade 4 
>20.0 × ULN 
Permanently discontinue binimetinib 
CPK increased 
Grade 1-2 
Maintain dose level of binimetinib 
o If total CK ≥3 × ULN, measure CK, CK isoenzymes and myoglobin 
in blood or urine weekly for 3 weeks and if total CK remains 
≤Grade 2, continue to assess CK, CK isoenzymes and myoglobin 
along with regularly scheduled clinical chemistry assessments 
Grade 3 
>5.0 to 10.0 × ULN 
If asymptomatic, maintain dose of binimetinib and monitor closely 
o Measure CK, CK isoenzymes and myoglobin in blood or urine 
weekly for 3 weeks and if total CK remains ≤Grade 3, continue to 
assess CK, CK isoenzymes and myoglobin along with regularly 
scheduled clinical chemistry assessments 
If symptomatic (muscle pain/spasms), interrupt binimetinib until resolved 
to Grade ≤1 and monitor closely, then: 
o If resolved in ≤21 days, reduce 1 dose level of binimetinib 
o If not resolved in ≤21 days, permanently discontinue binimetinib 


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CTCAE 
System/Organ/Class 
(SOC) 
 
 
ADVERSE EVENT 
 
Grade 
 
ACTION FOR BINIMETINIBC 
Investigations 
CPK increased 
Grade 4 
If asymptomatic, interrupt binimetinib until resolved to Grade ≤1 and 
monitor closely, then: 
o If resolved in ≤21 days, reduce 1 dose level of binimetinib 
o If not resolved in ≤21 days, permanently discontinue binimetinib 
If symptomatic, permanently discontinue binimetinib 
Electrocardiogram QT 
corrected interval 
prolonged 
Grade 3 
mean triplicate 
QTcF≥501 msec 
(confirmed by a separate 
mean triplicate ECG) 
First Occurrence: 
o Interrupt binimetinib. Electrolyte abnormalities (if applicable) should 
be corrected and any concomitant medication that could potentially 
prolong QT should be discontinued 
o Monitor patient until resolution of the AE. Include a consultation with 
a cardiologist, if indicated 
o Once resolved to Grade ≤1, resume binimetinib at 1 reduced dose 
level 
Second Occurrence: 
o If second occurrence is attributed to binimetinib, permanently 
discontinue binimetinib 
No dose re-escalation after dose reduction due to QTcF>500msec 
Skin and 
subcutaneous tissue 
disorders 
Rash acneiform or 
Rash maculo-papular 
Grade 1 
Maintain dose level of binimetinib 
Initiate Initial Rash Treatment Regimen (Section 9.9f) if it was not already 
started and rash should be closely monitored 
Grade 2 
First Occurrence: 
o Maintain dose level of binimetinib and rash should be closely 
monitored 
o Initiate Initial Rash Treatment if it was not already started 
o Reassess within ≤14 days. If rash worsens or does not improve, 
interrupt binimetinib until resolved to Grade ≤1. Resume binimetinib 
at current dose level 
Second Occurrence: 
o Reassess within ≤14 days. If rash worsens or does not improve, 
interrupt binimetinib until resolved to Grade ≤1. Resume binimetinib 
at 1 reduced dose level 


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CTCAE 
System/Organ/Class 
(SOC) 
 
 
ADVERSE EVENT 
 
Grade 
 
ACTION FOR BINIMETINIBC 
Skin and 
subcutaneous tissue 
disorders 
Rash acneiform or 
Rash maculo-papular 
Grade 3 
First Occurrence: 
o Interrupt binimetinib until resolved to Grade ≤1 
Reassess weekly; Resume binimetinib at current dose level 
o Consider referral to dermatologist and manage rash per 
dermatologist’s recommendation 
Second Occurrence: 
o Interrupt binimetinib until resolved to Grade ≤1 
Reassess weekly; Resume binimetinib at 1 reduced dose level 
o Consider referral to dermatologist and manage rash per 
dermatologist’s recommendation 
Grade 4 
Permanently discontinue binimetinib 
Vascular disorders 
Thromboembolic event Grade 3 
Withhold binimetinib for up to 3 weeks. 
• 
If improved to Grade 0 or 1, resume at reduced dose. 
• 
If not improved, permanently discontinue 
Grade 4 
Permanently discontinue binimetinib 
All other events 
Related to binimetinib 
treatment 
Grade 1-2 
• If the event is Grade 1 or non-persistent Grade 2, maintain dose level of 
binimetinib and monitor until stabilization or resolution 
• If the event is a persistent Grade 2 AE not responsive to a specific 
therapy, consider binimetinib dose interruption or reduction 
Grade 3 
Interrupt binimetinib until resolved to ≤Grade 1 or to pretreatment/Baseline 
level 
If the event resolves ≤21 days, then binimetinib may be resumed at 
1 reduced dose level based upon the Investigator’s discretion 
Grade 4 
Permanently discontinue binimetinib 
a 
Further evaluation with specialized retinal imaging (e.g., OCT [spectral domain OCT recommended] of the macula for non-vascular abnormalities; and color fundus 
photography of the central 30 degrees and/or fluorescein angiography for vascular abnormalities) is recommended. 
b 
Images/results of the ophthalmic examinations (at a minimum, OCT, color fundus photography and/or fluorescein angiography) must be made available upon Sponsor 
request. 
c 
If binimetinib is discontinued, patient can continue on single-agent pembrolizumab. 


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8.3 
Dose Modifications for Pembrolizumab 
Adverse events (both non-serious and serious) associated with pembrolizumab exposure 
may represent an immunologic etiology. These AEs 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 the Table below. See 
Section 9.0 for supportive care guidelines, including use of corticosteroids. 
Table 8.31 
Dose Modification Guidelines for Drug-Related Adverse Events for 
Pembrolizumab 
CTCAE 
System/Organ/Class 
(SOC) 
 
 
Adverse Event 
Hold 
Treatment 
for Grade 
 
Timing for Restarting 
Treatment 
 
 
Treatment Discontinuation 
 
 
Gastrointestinal 
disorders 
 
 
Diarrhea or 
Colitis 
 
 
2-3 
 
 
AE resolves to 
Grade 0-1 
AE does not resolve within 
12 weeks of last dose or 
inability to reduce 
corticosteroid to 10mg or less 
of prednisone or equivalent per 
day within 12 weeks 
4 
Permanently discontinue 
Permanently discontinue 
Investigations 
AST, or ALT, or 
Blood bilirubin 
increased 
2 
AE resolves to 
Grade 0-1 
AE does not resolve within 
12 weeks of last dose. 
3-4 
Permanently discontinue 
(see exception below)a 
Permanently discontinue 
 
 
Metabolism and 
nutrition disorders 
Glucose 
intolerance (Type 
1 diabetes 
mellitus [if new 
onset]) or 
Hyperglycemia 
 
 
T1DM or 
3-4 
Hold pembrolizumab for 
new onset Type 1 
diabetes mellitus or 
Grade 3-4 
hyperglycemia 
associated with evidence 
of beta cell failure 
 
 
Resume pembrolizumab when 
patients are clinically and 
metabolically stable. 
 
 
Endocrine disorders 
 
Endocrine 
disorders – Other, 
specify: 
Hypophysitis 
 
 
2-4 
AE resolves to 
Grade 0-1. Therapy with 
pembrolizumab can be 
continued while 
endocrine replacement 
therapy is instituted 
AE does not resolve within 
12 weeks of last dose or 
inability to reduce cortico- 
steroid to 10 mg or less of 
prednisone or equivalent per 
day within 12 weeks 
 
 
Endocrine disorders 
 
 
Hyperthyroidism 
 
 
3 
 
 
AE resolves to 
Grade 0-1 
AE does not resolve within 
12 weeks of last dose or 
inability to reduce cortico- 
steroid to 10 mg or less of 
prednisone or equivalent per 
day within 12 weeks 
4 
Permanently discontinue 
Permanently discontinue 
 
 
Endocrine disorders 
 
 
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 


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CTCAE 
System/Organ/Class 
(SOC) 
 
 
Adverse Event 
Hold 
Treatment 
for Grade 
 
Timing for Restarting 
Treatment 
 
 
Treatment Discontinuation 
General disorders and 
administration site 
conditions 
 
Infusion related 
reaction 
2b 
AE resolves to 
Grade 0-1 
Permanently discontinue if AE 
develops despite adequate 
premedication 
3-4 
Permanently discontinue 
Permanently discontinue 
 
Respiratory, thoracic 
and mediastinal 
disorders 
 
 
Pneumonitis 
 
 
2 
 
 
AE resolves to 
Grade 0-1 
AE does not resolve within 
12 weeks of last dose or 
inability to reduce cortico- 
steroid to 10 mg or less of 
prednisone or equivalent per 
day within 12 weeks 
3-4 
Permanently discontinue 
Permanently discontinue 
 
 
Renal and urinary 
disorders 
Acute kidney 
injury or Chronic 
kidney disease 
(e g Renal failure 
or Nephritis) 
 
 
2 
 
 
AE resolves to 
Grade 0-1 
AE does not resolve within 
12 weeks of last dose or 
inability to reduce cortico- 
steroid to 10 mg or less of 
prednisone or equivalent per 
day within 12 weeks 
3-4 
Permanently discontinue 
Permanently discontinue 
 
 
All Other Drug- 
Related Adverse 
Eventsc 
 
 
3 or severe 
 
 
AE resolves to 
Grade 0-1 
AE does not resolve within 
12 weeks of last dose or 
inability to reduce cortico- 
steroid 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. 
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. 
8.32 
Other instructions for pembrolizumab 
If pembrolizumab-related toxicity does not resolve to Grade 0-1 within 12 weeks 
after last administration of study drug, study therapy discontinuation is 
recommended. With Investigator agreement, patients with a laboratory adverse 
event still at Grade 2 may continue in the study only if asymptomatic and 
controlled. 
In patients who continue on study therapy after experiencing an Adverse Event 
warranting potential dose modification, if considered drug-related by the 
investigator, once the patient has recovered to Grade 0-1 the dosing interval in 


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subsequent cycles will be increased by 1 week (e.g., to 3 weeks in patients who 
were on an every 2-week schedule). Following each such dose delay due to 
toxicity, the dosing interval should increase by an additional week. For example, 
patients who began the study on a 3-week dosing schedule, and have stopped 
drug twice for due to a drug-related toxicity that meets the above criteria, should 
now be dosing every 5 weeks. 
For patients who experience a recurrence of the same severe AEs listed above 
with rechallenge of pembrolizumab, a consultation with the Investigator will 
occur to determine whether the patient should continue in the study. A patient 
who experiences the same SAE of the same NCI CTCAE grade or higher with 
rechallenge of pembrolizumab must discontinue pembrolizumab immediately. 
Reduced dose of pembrolizumab dose (ie, below 200 mg) will not be 
administered. 


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9.0 
Ancillary Treatment/Supportive Care 
9.1 
Full supportive care 
Patients should receive full supportive care while on this study. This includes blood 
product support, antibiotic treatment, and treatment of other newly diagnosed or 
concurrent medical conditions. All blood products and concomitant medications such as 
antidiarrheals, analgesics, and/or antiemetics received from the first day of study 
treatment administration until 30 days after the final dose will be recorded in the medical 
records. 
Suggested supportive care measures for the management of adverse events 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 8.2 
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. 
9.2 
Blood products and growth factors 
Blood products and growth factors should be utilized as clinically warranted and 
following institutional policies and recommendations. The use of growth factors should 
follow published guidelines of the American Society of Clinical Oncology (ASCO) 
Update of Recommendations for the Use of White Blood Cell Growth Factors: An 
Evidence-Based Clinical Practice Guideline. J Clin Oncol 2006; 24:3187-3205, 2006. 
9.21 
Neutropenia 
Prophylactic use of colony-stimulating factors including Granulocyte Colony- 
Stimulating Factor (G-CSF), pegylated G-CSF or Granulocyte Macrophage 
Colony-Stimulating Factor GM-CSF is not allowed in this study. Therapeutic use 
of G-CSF is allowed in patients with Grade 3-4 febrile neutropenia. 
9.22 
Anemia 
Transfusions and/or erythropoietin may be utilized as clinically indicated for the 
treatment of anemia, but should be clearly noted as concurrent medications. 
9.23 
Thrombocytopenia 
Transfusion of platelets may be used if clinically indicated. ITP should be ruled 
out before initiation of platelet transfusion. 
9.3 
Antiemetics 
Antiemetics may be used at the discretion of the attending physician. Nausea and 
vomiting should be treated aggressively, and consideration should be given to the 
administration of prophylactic antiemetic therapy according to standard institutional 
practice. Patients should be strongly encouraged to maintain liberal oral fluid intake. 
Volume depletion should be corrected before initiation of study drug. 


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9.4 
Anti-Diarrheals 
Patients should be 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). In symptomatic patients, infectious etiologies should 
be ruled out, and if symptoms are persistent and/or severe, endoscopic evaluation should 
be considered. (See Section 9.5 and 9.9a for management of treatment-related 
enterocolitis) 
All patients who experience diarrhea 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. 
NOTE: Loperamide/diphenoxylate/atropines should NOT be used for diarrhea symptoms 
unless: (1) it is believed that pembrolizumab-related enterocolitis is unlikely to be present 
after detailed evaluation by gastroenterology, including endoscopy; PLUS (2) approval is 
documented by a gastroenterology specialist. 
9.5 
Management of treatment related enterocolitis 
In patients with severe enterocolitis, pembrolizumab will be held and treatment with 
systemic corticosteroids should be initiated at a dose of 1 to 2 mg/kg/day of prednisone or 
equivalent. When symptoms improve to Grade 1 or less, corticosteroid taper should be 
started and continued over at least 1 month. 
In patients with moderate enterocolitis, pembrolizumab should be withheld and 
antidiarrheal treatment should be started. If symptoms are persistent for more than one 
week, systemic corticosteroids should be initiated (e.g., 0.5 mg/kg/day of prednisone or 
equivalent). When symptoms improve to Grade 1 or less, corticosteroid taper should be 
started and continued over at least 1 month. 
9.6 
Anti-infectives 
Patients with a documented infectious complication should receive oral or IV antibiotics 
or other anti-infective agents as considered appropriate by the treating Investigator for a 
given infectious condition, according to standard institutional practice. 
9.7 
Corticosteroids 
Patients requiring chronic steroid administration (excluding inhaled steroids).are 
excluded from the trial. Patients may continue on inhalation therapy. Corticosteroids are 
known immunosuppressive agents that can mitigate the effects of pembrolizumab. 
Steroids should be generally reserved to treat side effects of pembrolizumab. Steroids can 
be used as primary prevention of nausea per institutional guidelines, but steroid doses 
should be reduced in subsequent cycles if nausea/vomiting is absent or very mild (see 
Section 9.3). 
9.8 
Concomitant medications 
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 final decision on any supportive therapy 
or vaccination rests with the investigator and/or the subject's primary physician. 
9.81 
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 on the baseline case report form (CRF) including all prescription, over- 
the-counter (OTC), herbal supplements, and IV medications and fluids. If 


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changes occur during the trial period, documentation of drug dosage, frequency, 
route, and date may also be included on the CRF. 
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 in 
the patient medical record. Concomitant medications administered after 30 days 
after the last dose of trial treatment should be recorded for SAEs. 
9.82 
Permitted concomitant medications requiring caution for binimetinib 
Binimetinib potently inhibits CYP2B6 (Ki of 1.67 µM). Based on these in vitro 
findings, binimetinib may inhibit the metabolic clearance of co-medications 
metabolized by CYP2B6, if sufficiently high concentrations are achieved in vivo. 
At 45 mg BID, the maximum concentrations achieved in plasma are normally 
<1.5 µM so the risk of drug interaction is limited. Caution should be used in 
patients receiving concomitant treatment with other drugs that are substrates of 
this enzyme. 
In vitro data showed that both binimetinib is a substrate of P-gp. Binimetinib is 
also a substrate of BCRP. Thus, the use of drugs that are known to inhibit or 
induce P-gp and BCRP should be used with caution. 
Binimetinib has been identified to be primarily metabolized by UGT1A1 in vitro. 
It is advised that inhibitors and inducers of UGT1A1 should be taken with 
caution when co-administered with binimetinib. Patients should be closely 
monitored for the occurrence of adverse events. Please refer to the table below 
for a list of these known drugs but this list may not be exhaustive. 
 
Inhibitors of UGT1A1 
Inducers of UGT1A1 
Atazanavir, erlotinib, flunitrazepam, 
gemfibrozil, indinavir, ketoconazole, 
nilotinib, pazopanib, propofol, regorafenib, 
sorafenib 
 
Carbamazepine, nicotine, rifampicin, 
testosterone propionate 
The solubility of binimetinib is pH dependent and a 10-fold decrease in solubility 
is observed between pH 1 and 2. Patients receiving concomitant treatments that 
could potentially modify the gastric pH (i.e. PPI) should be instructed to take 
them at least two hours after the administration of binimetinib. 
Drugs with a conditional, possible, or known risk to induce Torsade de Pointes 
(TdP) should be used with caution. Patients receiving such medications must be 
carefully monitored for potentiating of toxicity due to any individual concomitant 
medication, and may require dose titration of the drug substance. Investigators 
should use caution when prescribing co-medications, as clinical experience with 
these compounds in patients with cancer is often limited. 
See Appendix III for list of medications to be used with caution with used with 
binimetinib. 
9.83 
Prohibited concomitant medications 
Subjects are prohibited from receiving the following therapies during the 
Screening and Treatment Phase (including retreatment for post-complete 
response relapse) 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 


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• 
Radiation therapy 
o 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 (e.g. equivalent 
to or less than oral prednisone 10 mg daily) is allowed and do not require 
Sponsor approval. 
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 describe other medications, which are prohibited in this 
trial. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
9.9 a 
Immunotherapy-related toxicities 
Patients should be monitored for signs and symptoms of immunotherapy-related 
toxicities, which include but are not limited to the following: 
• 
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 
Patients 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 patients 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 diarrhea/colitis, administer oral corticosteroids. 
o For Grade 3 or 4 diarrhea/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. 
• 
Type 1 Diabetes Mellitus (if new onset, including diabetic ketoacidosis [DKA]) 
or ≥Grade 3 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic 
acidosis (DKA) 
For T1DM or Grade 3-4 Hyperglycemia: 


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o Insulin replacement therapy is recommended for Type I diabetes mellitus and for 
Grade 3-4 hyperglycemia associated with metabolic acidosis or ketonuria. 
o Evaluate patients with serum glucose and a metabolic panel, urine ketones, 
glycosylated hemoglobin, and C-peptide. 
• 
Hypophysitis (Autoimmune disorder affecting pituitary gland) 
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. 
• 
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. 
 
9.9b 
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 patients 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 patients 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 patients 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. 
‡If a contraceptive method listed above is restricted by local regulations/guidelines, then 
it does not qualify as an acceptable method of contraception for patients participating at 
sites in this country/region. 


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Patients 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 patients 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 
patient of childbearing potential will not reliably comply with the requirements for 
contraception, that patient should not be entered into the study. 
9.9c 
Use in Pregnancy 
If a patient inadvertently becomes pregnant while on treatment with pembrolizumab, the 
patient will immediately be removed from the study. The site will contact the patient at 
least monthly and document the patient’s status until the pregnancy has been completed 
or terminated. The outcome of the pregnancy will be reported to Mayo Clinic and to 
Merck without delay and within 24 hours to Mayo Clinic and within 2 working days to 
Merck 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. If a male subject 
impregnates his female partner the study personnel at the site must be informed 
immediately and the pregnancy reported to Mayo Clinic and to Merck and followed as 
described above. 
9.9d 
Use in Nursing Women 
Since many drugs are excreted in human milk, and because of the potential for serious 
adverse reactions in the nursing infant, patients who are breast-feeding are not eligible for 
enrollment. Specific additional information follows for individual agents used in this 
trial. 
9.9d1 Pembrolizumab 
It is unknown whether pembrolizumab is excreted in human milk. 
9.9d2 Binimetinib 
It is unknown whether binimetinib is excreted in human milk. 
9.9e 
Hypertension Management 
Patients that will receive binimetinib must monitor their blood pressure at home on Days 
10 and 30 after treatment initiation if they meet the following criteria: 
• 
Patients with history of hypertension and/or 
• 
Patient receiving antihypertensive drugs before onset of study treatment and/or 
• 
Patients with a screening systolic blood pressure ≥140 mmHg and/or 
• 
Patients with a screening diastolic blood pressure of ≥90 mmHg 
The investigator is to educate the patient on the signs and symptoms of hypertension and 
use of the home blood pressure monitor (if not already in place). More frequent 
assessments during the study drug treatment period may also be performed at the 
discretion of the investigator and if medically indicated. 
Measurements are to be taken at the same time on Study Days 10 and 30 after taking any 
hypertensive medications and after being at rest for 5 minutes in a sitting position. If SBP 
≥160 mmHg, or DBP ≥100 mmHg, the patient should contact their investigator to have 
an unscheduled visit. At this unscheduled visit, the patient’s blood pressure should be 
assessed and these measurements must be documented in the patient record. Early 


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initiation of treatment and aggressive management of emergent hypertension must be 
implemented after its diagnosis. 
For patients monitoring their blood pressure at home, it is suggested to develop a patient 
diary to record their self-assessed blood pressure measurements and present the collected 
data to the investigator for evaluation and appropriate management. This diary must be 
maintained in the patient’s source documentation 
9.9f 
Skin disorders/care 
Initial Rash Treatment Regimen 
Clinical judgment and experience of the treating physician should guide the management 
plan of each patient. In general, the following interventions are in addition to the rash 
dosing guidelines in Table 8.2: 
o Prophylaxis of skin events to be initiated 24 hours prior to the first treatment with 
study drug or later as needed 
o Application of topical agents to the most commonly affected skin areas such as face, 
scalp, neck, upper chest and upper back 
Topical agents include non-oily sunscreen (PABA free, SPF ≥30, UVA/UVB protection), 
topical steroids (preferably mometasone cream i.e. Elocon®) and topical erythromycin 
evening (i.e. Eryaknen® or topical pimocrolimus) 
Note: Topical agents should be applied on a daily basis starting on Day 1 of study 
treatment or 24 hours prior to the first dose, and more often as needed. 
o Possibly oral doxycycline (100 mg daily) for the first 2-3 weeks of study drug 
administration. 
Other effective medications are antihistamines, other topical corticosteroids, other topical 
antibiotics and low-dose systemic corticosteroids. 
The treatment algorithm based on CTCAE grade is as follows: 
Mild rash (CTCAE Grade 1) 
o Consider prophylactic rash treatment if not already started 
o Topical or other topical corticosteroid (i.e. mometasone cream) and/or topical 
antibiotic (i.e. erythromycin 2%) are recommended. 
o The patient should be reassessed within a maximum of 2 weeks or as per investigator 
opinion. 
Moderate rash (CTCAE Grade 2) 
o Use of topical erythromycin or clindamycin (1%) plus topical mometasone or 
pimecrolimus cream (1%) plus oral antibiotics such as: lymecycline (408 mg QD), 
doxycycline (100 mg BID) or minocycline (50 to 100 mg QD). 
o Although there has been no evidence of phototoxicity or photosensitivity in patients 
being treated with MEK162, doxycycline (or minocycline as second-line) should be 
used with thorough UV protection (i.e., avoidance of direct exposure to sunlight, use 
of sunscreen and sunglasses, etc.). 
o Use of acitretin is not recommended 
 
Severe rash (CTCAE Grade 3-4) 
CTCAE Grade 3 
o In addition to the interventions recommended for moderate rash, consider oral 
prednisolone at a dose of 0.5 mg/kg. Upon improvement, taper the dose in a stepwise 
manner (25 mg for 7 days, subsequently decreasing the dose by 5 mg/day every day). 


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o Alternatively, in addition to the interventions recommended for moderate rash, 
consider oral isotretinoin (low doses, i.e. 0.3 to 0.5 mg/kg) (Lacouture et al 2011) 
o Use of acitretin is not recommended 
CTCAE Grade 4 
o Immediately discontinue the patient from study drug and treat the patient with oral 
and topical medications (see recommendation CTCAE Grade 3). 
Symptomatic treatment: 
o It is strongly recommended that patients who develop rash/skin toxicities receive 
symptomatic treatment: 
o For pruritic lesions, use cool compresses and oral antihistaminic agents 
o For fissuring, use Monsel’s solution, silver nitrate, or zinc oxide cream. If not 
sufficient use mild steroid ointments or combinations of steroids and antibiotics such 
as Fucicort® 
o For desquamation, use emollients with mild pH 5/neutral (best containing urea 10%) 
o For paronychia, antiseptic bath and local potent corticosteroids, use oral antibiotics 
and if no improvement is seen, refer to a dermatologist or surgeon 
o For infected lesions, obtain bacterial and fungal cultures and treat with topical or 
systemic antibiotics based on sensitivity of culture 


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10.0 
Adverse Event (AE) Reporting and Monitoring 
The site principal investigator is responsible for reporting any/all serious adverse events to the 
sponsor as described within the protocol, regardless of attribution to study agent or treatment 
procedure. 
The sponsor/sponsor-investigator is responsible for notifying FDA and all participating 
investigators in a written safety report of any of the following: 
• 
Any suspected adverse reaction that is both serious and unexpected. 
• 
Any findings from laboratory animal or in vitro testing that suggest a significant risk for 
human subjects, including reports of mutagenicity, teratogenicity, or carcinogenicity. 
• 
Any findings from epidemiological studies, pooled analysis of multiple studies, or 
clinical studies, whether or not conducted under an IND and whether or not conducted by 
the sponsor, that suggest a significant risk in humans exposed to the drug 
• 
Any clinically important increase in the rate of a serious suspected adverse reaction over 
the rate stated in the protocol or Investigator’s Brochure (IB). 
Summary of SAE Reporting for this study 
(please read entire section for specific instructions): 
WHO: 
WHAT form: 
WHERE to send: 
 
 
All sites 
 
Pregnancy Reporting 
http://ctep.cancer.gov/protocolDevelopment/electronic_a 
pplications/docs/PregnancyReportFormUpdated.pdf 
Mayo Sites – attach to MCCC 
Electronic SAE Reporting Form 
Non Mayo sites – complete and 
forward to  
 
 
 
Mayo Clinic 
Sites 
Mayo Clinic Cancer Center SAE Reporting Form: 
 
 
ND attach 
MedWatch 3500A: 
http://www.fda.gov/downloads/AboutFDA/ReportsMa 
nualsForms/Forms/UCM048334.pdf 
 
 
Will automatically be sent to 
 
 
 
Definitions 
Adverse Event 
Any untoward medical occurrence associated with the use of a drug in humans, whether or 
not considered drug related. 
Suspected Adverse Reaction 
Any adverse event for which there is a reasonable possibility that the drug caused the adverse 
event. 
Expedited Reporting 
Events reported to sponsor within 24 hours, 5 days or 10 days of study team becoming aware 
of the event. 
Routine Reporting 
Events reported to sponsor via case report forms 
Events of Interest 


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Events that would not typically be considered to meet the criteria for expedited reporting, but 
that for a specific protocol are being reported via expedited means in order to facilitate the 
review of safety data (may be requested by the FDA or the sponsor). 
Unanticipated Adverse Device Event (UADE) 
Any serious adverse effect on health or safety or any life-threatening problem or death caused 
by, or associated with, a device, if that effect, problem, or death was not previously identified 
in nature, severity, or degree of incidence in the investigational plan or application (including 
a supplementary plan or application), or any other unanticipated serious problem associated 
with a device that relates to the rights, safety, or welfare of subjects 
10.1 
Adverse Event Characteristics 
CTCAE term (AE description) and grade: The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 will be utilized for AE reporting. All appropriate treatment areas should have access 
to a copy of the CTCAE version 4.0. A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP web site: 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm) 
a. Identify the grade and severity of the event using the CTCAE version 4.0. 
b. Determine whether the event is expected or unexpected (see Section 10.2). 
c. Determine if the adverse event is related to the study intervention (agent, treatment or 
procedure) (see Section 10.3). 
d. Determine whether the event must be reported as an expedited report. If yes, 
determine the timeframe/mechanism (see Section 10.4). 
e. Determine if other reporting is required (see Section 10.5). 
f. Note: All AEs reported via expedited mechanisms must also be reported via the 
routine data reporting mechanisms defined by the protocol (see Sections 10.6 and 
18.0). 
NOTE: A severe AE is NOT the same as a serious AE, which is defined in Section 10.4. 
10.2 
Expected vs. Unexpected Events 
Expected events - are those described within the Section 15.0 of the protocol, the study 
specific consent form, package insert (if applicable), and/or the investigator brochure, (if 
an investigator brochure is not required, otherwise described in the general 
investigational plan). 
Unexpected adverse events or suspected adverse reactions are those not listed in Section 
15.0 of the protocol, the study specific consent form, package insert (if applicable), or in 
the investigator brochure (or are not listed at the specificity or severity that has been 
observed); if an investigator brochure is not required or available, is not consistent with 
the risk information described in the general investigational plan. 
Unexpected also refers to adverse events or suspected adverse reactions that are 
mentioned in the investigator brochure as occurring with a class of drugs but have not 
been observed with the drug under investigation. 
An investigational agent/intervention might exacerbate the expected AEs associated with a 
commercial agent. Therefore, if an expected AE (for the commercial agent) occurs with a 
higher degree of severity or specificity, expedited reporting is required. 


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NOTE: *The consent form may contain study specific information at the discretion of the 
Principal Investigator; it is possible that this information may NOT be included in the 
protocol or the investigator brochure. Refer to protocol or IB for reporting needs. 
10.3 
Attribution to agent(s) or procedure 
When assessing whether an adverse event (AE) is related to a medical agent(s) medical or 
procedure, the following attribution categories are utilized: 
Definite - The AE is clearly related to the agent(s)/procedure. 
Probable - The AE is likely related to the agent(s)/procedure. 
Possible - The AE may be related to the agent(s)/procedure. 
Unlikely - The AE is doubtfully related to the agent(s)/procedure. 
Unrelated - The AE is clearly NOT related to the agent(s)/procedure. 
10.31 EXPECTED Serious Adverse Events: Protocol Specific Exceptions to 
Expedited Reporting 
For this protocol only, the following Adverse Events/Grades are expected to occur 
within this population and do not require Expedited Reporting. These events must still 
be reported via Routine Reporting (see Section 10.6).* 
*Report any clinically important increase in the rate of a serious suspected 
adverse reaction (at your study site) over that which is listed in the protocol or 
investigator brochure as an expedited event. 
*Report an expected event that is greater in severity or specificity than expected 
as an expedited event. 
 
 
System Organ Class 
(SOC) 
 
 
Adverse event/ Symptoms 
CTCAE Grade at which the event 
will not be reported in an expedited 
manner1 
Blood and lymphatic 
system disorders 
Anemia 
≤Grade 4 
Gastrointestinal disorders Vomiting 
≤Grade 3 
Nausea 
≤Grade 3 
Diarrhea 
≤Grade 3 
General disorders and 
administrations site 
conditions 
Fatigue 
≤Grade 3 
Malaise 
≤Grade 3 
Investigations 
Neutrophil count decreased 
≤Grade 4 
White blood cell count 
decreased 
≤Grade 4 
Lymphocyte count decreased 
≤Grade 4 
Platelet count decreased 
≤Grade 4 
Skin and subcutaneous 
tissue disorders 
Alopecia 
≤Grade 4 
Rash (acneiform or maculo- 
papular) 
≤Grade 4 
1 These exceptions only apply if the adverse event does not result in hospitalization. If the adverse 
event results in hospitalization, then the standard expedited adverse events reporting 
requirements must be followed. 
Specific protocol exceptions to expedited reporting should be reported expeditiously by 
investigators ONLY if they exceed the expected grade of the event. 


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The following hospitalizations are not considered to be SAEs because there is no “adverse event” 
(i.e., there is no untoward medical occurrence) associated with the hospitalization: 
● Hospitalizations for respite care 
● Planned hospitalizations required by the protocol 
● Hospitalization planned before informed consent (where the condition requiring the hospitalization 
has not changed post study drug administration) 
● Hospitalization for elective procedures unrelated to the current disease and/or treatment on this trial 
● Hospitalization for administration of study drug or insertion of access for administration of study 
drug 
● Hospitalization for routine maintenance of a device (e.g., battery replacement) that was in place 
before study entry 
● Hospitalization, or other serious outcomes for signs and symptoms of progression of the cancer. 
 
10.4 
Expedited Reporting Requirements for IND/IDE Agents 
10.41 Phase 1 and Early Phase 2 Studies: Expedited Reporting Requirements for 
Adverse Events that Occur on Studies under an IND/IDE within 30 Days of 
the Last Administration of the Investigational Agent/Intervention 1, 2 
 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE: Investigators MUST immediately report to the sponsor ANY Serious Adverse Events, whether or not they 
are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes: 
1) 
Death 
2) 
A life-threatening adverse event 
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours 
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions 
5) 
A congenital anomaly/birth defect. 
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or subject 
and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. (FDA, 
21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the sponsor within 
the timeframes detailed in the table below. 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in 
Hospitalization 
≥24 hrs 
 
7 Calendar Days 
 
 
24-Hour 3 Calendar 
Days 
Not resulting in 
Hospitalization 
≥24 hrs 
 
Not required 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 3 Calendar Days” - The AE must initially be reported within 24 hours of learning of the AE, 
followed by a complete expedited report within 3 calendar days of the initial 24-hour report. 
o “7 Calendar Days” - A complete expedited report on the AE must be submitted within 7 calendar days 
of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows: 
Expedited 24-hour notification followed by complete report within 3 calendar days for: 
• All Grade 3, 4, and Grade 5 AEs 
Expedited 7 calendar day reports for: 
• Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 


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NOTE: Refer to Section 10.31 for exceptions to Expedited Reporting 
10.42 General reporting instructions 
The Mayo IND Coordinator will assist the sponsor-investigator in the processing 
of expedited adverse events and forwarding of suspected unexpected serious 
adverse reactions (SUSARs) to the FDA and IRB. 
Binimetinib expedited reports must be submitted to the FDA using MedWatch 
3500A. 
Commercial agent (eg pembrolizumab) expedited reports must be submitted to the 
FDA via MedWatch 3500A for Health Professionals (complete all three pages of 
the form). 
http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM0 
48334.pdf 
or 
http://www.fda.gov/AboutFDA/ReportsManualsForms/Forms/ListFormsAlphabe 
tically/default.htm 
Instructions for completing the MedWatch 3500A: 
http://www.fda.gov/downloads/Safety/MedWatch/HowToReport/DownloadFor 
ms/UCM387002.pdf 
Submit SAEs to Industry Partner Contacts: 
 
 
 
 
 
for investigational agents or 
commercial/investigational agents on the same arm and attach MedWatch 
3500A. 
10.43 Reporting of re-occurring SAEs 
ALL SERIOUS adverse events that meet the criteria outlined in Table 10.41 
MUST be immediately reported to the sponsor within the timeframes detailed in 
the corresponding table. This reporting includes, but is not limited to SAEs that 
re-occur again after resolution. 
10.5 
Other Required Reporting 
10.51 Unanticipated Problems Involving Risks to Subjects or Others (UPIRTSOS) 
Unanticipated Problems Involving Risks to Subjects or Others (UPIRTSOS) in 
general, include any incident, experience, or outcome that meets all of the 
following criteria: 
1. Unexpected (in terms of nature, severity, or frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the 
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered. Footnote “1” above 
applies after this reporting period. 
Effective Date: May 5, 2011 


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IRB-approved research protocol and informed consent document; and (b) the 
characteristics of the subject population being studied; 
2. Related or possibly related to participation in the research (in this guidance 
document, possibly related means there is a reasonable possibility that the 
incident, experience, or outcome may have been caused by the procedures 
involved in the research); and 
3. Suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was 
previously known or recognized. 
Some unanticipated problems involve social or economic harm instead of the 
physical or psychological harm associated with adverse events. In other cases, 
unanticipated problems place subjects or others at increased risk of harm, but no 
harm occurs. 
Note: If there is no language in the protocol indicating that pregnancy is not 
considered an adverse experience for this trial, and if the consent form does not 
indicate that subjects should not get pregnant/impregnate others, then any 
pregnancy in a subject/patient or a male patient’s partner (spontaneously 
reported) which occurs during the study or within 120 days of completing the 
study should be reported as a UPIRTSO. 
Mayo Clinic Cancer Center (MCCC) Institutions: 
If the event meets the criteria for IRB submission as a Reportable 
Event/UPIRTSO, provide appropriate documentation using Mayo Expedited 
Event Report form 
 
 
he Mayo Regulatory Affairs Office 
will review and process the submission to the Mayo Clinic IRB. 
10.52 Death 
Note: A death on study requires both routine and expedited reporting 
regardless of causality, unless as noted below. Attribution to treatment or 
other cause must be provided. 
Any death occurring within 30 days of the last dose, regardless of attribution to 
an agent/intervention under an IND/IDE requires expedited reporting within 24-
hours. 
Any death occurring greater than 30 days with an attribution of possible, 
probable, or definite to an agent/intervention under an IND/IDE requires 
expedited reporting within 24-hours. 
Reportable categories of Death 
• 
Death attributable to a CTCAE term. 
• 
Death Neonatal: A disorder characterized by cessation of life during the 
first 28 days of life. 
• 
Death NOS: A cessation of life that cannot be attributed to a CTCAE term 
associated with Grade 5. 
• 
Sudden death NOS: A sudden (defined as instant or within one hour of the 
onset of symptoms) or an unobserved cessation of life that cannot be 
attributed to a CTCAE term associated with Grade 5. 


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• 
Death due to progressive disease should be reported as Grade 5 
“Neoplasms benign, malignant and unspecified (including cysts and 
polyps) – Other (Progressive Disease)” under the system organ class 
(SOC) of the same name. Evidence that the death was a manifestation of 
underlying disease (e.g., radiological changes suggesting tumor growth or 
progression: clinical deterioration associated with a disease process)  
should be submitted. 
10.53 Secondary Malignancy 
• 
A secondary malignancy is a cancer caused by treatment for a previous 
malignancy (e.g., treatment with investigational agent/intervention, radiation 
or chemotherapy). A secondary malignancy is not considered a metastasis of 
the initial neoplasm. 
• 
All secondary malignancies that occur following treatment with an agent under 
an IND/IDE will be reported. Three options are available to describe the event: 
o Leukemia secondary to oncology chemotherapy (e.g., Acute Myeloctyic 
Leukemia [AML]) 
o Myelodysplastic syndrome (MDS) 
o Treatment-related secondary malignancy 
• 
Any malignancy possibly related to cancer treatment (including AML/MDS) 
should also be reported via the routine reporting mechanisms outlined in each 
protocol. 
10.54 Second Malignancy 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is 
NOT a metastasis from the initial malignancy). Second malignancies require ONLY 
routine reporting unless otherwise specified. 
10.55 Pregnancy, Fetal Death, and Death Neonatal 
If a female subject (or female partner of a male subject) taking investigational 
product becomes pregnant, the subject taking should notify the Investigator, and 
the pregnant female should be advised to call her healthcare provider 
immediately. The patient should have appropriate follow-up as deemed necessary 
by her physician. If the baby is born with a birth defect or anomaly, a second 
expedited report is required. 
Prior to obtaining private information about a pregnant woman and her infant, the 
investigator must obtain consent from the pregnant woman and the newborn 
infant’s parent or legal guardian before any data collection can occur. A consent 
form will need to be submitted to the IRB for these subjects if a pregnancy 
occurs. If informed consent is not obtained, no information may be collected. 
In cases of fetal death, miscarriage or abortion, the mother is the patient. In cases 
where the child/fetus experiences a serious adverse event other than fetal death, 
the child/fetus is the patient. 
NOTE: When submitting Mayo Expedited Adverse Event Report reports for 
“Pregnancy”, “Pregnancy loss”, or “Neonatal loss”, the potential risk of exposure 
of the fetus to the investigational agent(s) or chemotherapy agent(s) should be 
documented in the “Description of Event” section. Include any available medical 
documentation. Include this form: 


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http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/Pregna 
ncyReportFormUpdated.pdf 
Attach copy to automated Mayo Clinic Cancer Center Adverse Event Reporting 
Form
 
10.551 
Pregnancy 
Pregnancy should be reported in an expedited manner as Grade 3 
“Pregnancy, puerperium and perinatal conditions - Other 
(pregnancy)” under the Pregnancy, puerperium and perinatal 
conditions SOC. Pregnancy should be followed until the outcome is 
known. 
10.552 
Fetal Death 
Fetal death is defined in CTCAE as “A disorder characterized by death 
in utero; failure of the product of conception to show evidence of 
respiration, heartbeat, or definite movement of a voluntary muscle after 
expulsion from the uterus, without possibility of resuscitation.” 
Any fetal death should be reported expeditiously, as Grade 4 
“Pregnancy, puerperium and perinatal conditions - Other 
(pregnancy loss)” under the Pregnancy, puerperium and perinatal 
conditions SOC. 
10.553 
Death Neonatal 
Neonatal death, defined in CTCAE as “A disorder characterized by 
cessation of life occurring during the first 28 days of life” that is felt by 
the investigator to be at least possibly due to the investigational 
agent/intervention, should be reported expeditiously. 
A neonatal death should be reported expeditiously as Grade 4 
“General disorders and administration - Other (neonatal loss)” 
under the General disorders and administration SOC. 
10.6 
Required Routine Reporting 
10.61 Baseline and Adverse Events Evaluations 
Pretreatment symptoms/conditions to be graded at baseline and adverse events to 
be graded at each evaluation. (Grading is per CTCAE v4.0 unless alternate 
grading is indicated in the table below): 
 
CTCAE SYSTEM 
ORGAN CLASS 
 
Adverse event/Symptoms 
 
Baseline 
Each 
evaluation 
Blood and lymphatic 
system disorders 
Febrile neutropenia 
X 
X 
 
Eye disorders 
Retinal detachment 
X 
X 
Retinal vascular disorder (RVO) 
X 
X 
General disorders and 
administration site 
conditions 
 
Fatigue 
 
X 
 
X 
Gastrointestinal 
Nausea 
X 
X 
disorders 
Vomiting 
X 
X 


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CTCAE SYSTEM 
ORGAN CLASS 
 
Adverse event/Symptoms 
 
Baseline 
Each 
evaluation 
 
# of Stools 
X 
 
Diarrhea 
 
X 
Constipation 
X 
X 
Infections and 
infestations 
Sepsis 
X 
X 
Investigations 
CPK (CK) increased 
X 
X 
Creatinine increased 
X 
X 
Neutrophil count decreased 
X 
X 
Platelet count decreased 
X 
X 
Nervous system 
Peripheral sensory neuropathy 
X 
X 
disorders 
Peripheral motor neuropathy 
X 
X 
Skin and 
subcutaneous tissue 
disorders 
Rash, acneiform 
X 
X 
Rash, maculo-papular 
X 
X 
Vascular disorders 
Hypertension 
X 
X 
10.62 All other AEs 
Submit via appropriate MCCC Case Report Forms (i.e., paper electronic, as 
applicable) the following AEs experienced by a patient and not specified in 
Section 10.6: 
10.621 Grade 2 AEs deemed possibly, probably, or definitely related to the study 
treatment or procedure. 
10.622 Grade 3 and 4 AEs regardless of attribution to the study treatment or 
procedure. 
10.623 Grade 5 AEs (Deaths) 
10.6231 
Any death within 30 days of the patient’s last study 
treatment or procedure regardless of attribution to the study 
treatment or procedure. 
10.6232 
Any death more than 30 days after the patient’s last study 
treatment or procedure that is felt to be at least possibly 
treatment related must also be submitted as a Grade 5 AE, 
with a CTCAE type and attribution assigned. 
10.7 
Late Occurring Adverse Events 
Refer to the instructions in the Forms Packet (or electronic data entry screens, as 
applicable) regarding the submission of late occurring AEs following completion of the 
Active Monitoring Phase (i.e., compliance with Test Schedule in Section 4.0). 
10.8 
Additional Event Reporting Instructions 
10.81 Additional Instructions for AE Reporting to Merck 
A serious adverse event is any adverse event occurring at any dose or during any 
use of Merck’s product that: 
• 
Results in death; 


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• 
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 an other 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. 
• 
Is a new cancer (that is not a condition of the study); 
• 
Is associated with an overdose. 
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 (Mayo Clinic) 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 whether or not 
related to the Merck product, must be reported within 24 hours to the Sponsor 
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 and to Merck Global Safety. 
All patients 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: 
 
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. 
 
at the time of submission to 
FDA. 
10.82 Additional Instructions for AE Reporting to Pfizer 
To ensure patient safety, every SAE, regardless of suspected causality, occurring 
after the patient has provided main informed consent and until at least 30 days 


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after the patient has stopped study treatment must be reported to Pfizer within 24 
hours of learning of its occurrence. 
Any SAEs experienced after this 30 days period should only be reported to Pfizer 
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 Form in English, and 
send the completed, signed form by fax within 24 hours to the Pfizer Drug Safety 
department. 
Pfizer Drug Safety 
 
 
The original copy of the SAE Report Form and the fax confirmation sheet must 
be kept with the case report form documentation at the 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, and whether the patient continued or 
withdrew from study participation. 
If the SAE is not previously documented in the Investigator’s Brochure and is 
thought to be related to the Pfizer study treatment, an Pfizer Drug Safety 
associate may urgently require further information from the investigator for 
Health Authority reporting. Pfizer 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. 
10.821 
Pregnancies 
To ensure patient safety, each pregnancy occurring while the patient is 
on study treatment must be reported to Pfizer 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. 


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Pregnancy should be recorded on a Clinical Trial Pregnancy Form and 
reported by the investigator to Pfizer Drug Safety. 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. 
Pregnancy outcomes must be collected for the female partners of any 
males who took study treatment in this study. Consent to report 
information regarding these pregnancy outcomes should be obtained 
from the mother. 
Women of childbearing potential should be advised to use highly 
effective contraception methods while they are receiving study 
treatment and up to 8 weeks after treatment has been stopped. 
If a pregnancy occurs while on study treatment, the newborn will be 
followed for at least 3 months following the expected delivery date 
10.822 
Warnings and precautions 
No evidence available at the time of the approval of this study protocol 
indicated that special warnings or precautions were appropriate, other 
than those noted in the provided Investigator Brochure. 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. 


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11.0 
Treatment Evaluation 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guidelines 
(version 1.1) and by the ESMO 2014 Adaptation of the Immune-Related Response Criteria: 
irRECIST {Bohnsack 2014}. RECIST version 1.1 will be used for assessment of tumor response 
for the primary endpoint. irRECIST will be used to make patient management decisions 
during the trial. 
Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the short 
axis measurements in the case of lymph nodes are used in the RECIST 1.1 and irRECIST 
guidelines. In RECIST 1.1, the appearance of new lesions automatically signifies progressive 
disease (PD), while in irRECIST new measurable lesions are factored into the total tumor 
burden. The specifics are presented below. 
NOTE: This study uses protocol RECIST v1.1 template dated 2/16/2011. See the footnote for the 
table regarding measureable disease in Section 11.44, as it pertains to data collection and 
analysis. 
11.1 
Schedule of Evaluations 
For the purposes of this study, patients should be reevaluated every 6 weeks. In addition 
to a baseline scan, confirmatory scans should also be obtained 4 weeks following initial 
documentation of objective response. 
11.2 
Definitions of Measurable and Non-Measurable Disease (same definitions for RECIST 
1.1 and irRECIST) 
11.21 Measurable Disease 
11.211 A non-nodal lesion is considered measurable if its longest diameter can 
be accurately measured as ≥2.0 cm with chest x-ray, or as ≥1.0 cm with 
CT scan, , or MRI. 
11.212 A superficial non-nodal lesion is measurable if its longest diameter is 
≥1.0 cm in diameter as assessed using calipers (e.g. skin nodules) or 
imaging. In the case of skin lesions, documentation by color 
photography, including a ruler to estimate the size of the lesion, is 
recommended. 
11.213 A malignant lymph node is considered measurable if its short axis is 
>1.5 cm when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm). 
NOTE: Tumor lesions in a previously irradiated area are not considered 
measurable disease. 
11.22 Non-Measurable Disease 
11.221 All other lesions (or sites of disease) are considered non-measurable 
disease, including pathological nodes (those with a short axis ≥1.0 to 
<1.5 cm). Bone lesions, leptomeningeal disease, ascites, pleural/ 
pericardial effusions, lymphangitis cutis/pulmonis, inflammatory breast 
disease, and abdominal masses (not followed by CT or MRI), are 
considered as non-measurable as well. 
Note: ‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. 
However, if non-cystic lesions are present in the same patient, these are preferred 


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for selection as target lesions. In addition, lymph nodes that have a short axis 
<1.0 cm are considered non- pathological (i.e., normal) and should not be 
recorded or followed. 
11.3 
Guidelines for Evaluation of Measurable Disease 
11.31 Measurement Methods: 
• 
All measurements should be recorded in metric notation (i.e., decimal 
fractions of centimeters) using a ruler or calipers. 
• 
The same method of assessment and the same technique must be used to 
characterize each identified and reported lesion at baseline and during 
follow-up. For patients having only lesions measuring at least 1 cm to less 
than 2 cm must use CT imaging for both pre- and post-treatment tumor 
assessments. 
• 
Imaging-based evaluation is preferred to evaluation by clinical examination 
when both methods have been used at the same evaluation to assess the 
antitumor effect of a treatment. 
11.32 Acceptable Modalities for Measurable Disease: 
Conventional CT and MRI: This guideline has defined measurability of lesions 
on CT scan based on the assumption that CT slice thickness is 5 mm or less. If 
CT scans have slice thickness greater than 5 mm, the minimum size for a 
measurable lesion should be twice the slice thickness. 
• 
As with CT, if an MRI is performed, the technical specifications of the 
scanning sequences used should be optimized for the evaluation of the type 
and site of disease. The lesions should be measured on the same pulse 
sequence. Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior scans. 
Body scans should be performed with breath-hold scanning techniques, if 
possible. 
• 
PET-CT: If the site can document that the CT performed as part of a PET-CT 
is of identical diagnostic quality to a diagnostic CT (with IV and oral 
contrast), then the CT portion of the PET-CT can be used for RECIST and 
irRECIST measurements and can be used interchangeably with conventional 
CT in accurately measuring cancer lesions over time. 
• 
Chest X-ray: Lesions on chest x-ray are acceptable as measurable lesions 
when they are clearly defined and surrounded by aerated lung. However, CT 
scans are preferable. 
• 
Physical Examination: For superficial non-nodal lesions, physical 
examination is acceptable, but imaging is preferable, if both can be done. In 
the case of skin lesions, documentation by color photography, including a 
ruler to estimate the size of the lesion, is recommended. 
11.33 Measurement at Follow-up Evaluation: 
A subsequent scan must be obtained a minimum of 4 weeks following initial 
documentation of an objective status of either complete response (irCR) or partial 
response (irPR). 
In the case of stable disease (SD), follow-up measurements must have met the 
SD criteria at least once after study entry at a minimum interval of 6 weeks (see 
Section 11.44). 


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NOTE: Once patient has had SD for ≥6 months, scanning can be reduced to 
every 3 months. 
The cytological confirmation of the neoplastic origin of any effusion that appears 
or worsens during treatment when the measurable tumor has met criteria for 
response or stable disease is mandatory to differentiate between response or 
stable disease (an effusion may be a side effect of the treatment) and progressive 
disease. 
• 
Cytologic and histologic techniques can be used to differentiate between PR 
and CR in rare cases (e.g., residual lesions in tumor types such as germ cell 
tumors, where known residual benign tumors can remain.) 
11.4 
Measurement of Effect 
11.41 Target Lesions & Target Lymph Nodes 
• 
Measurable lesions (as defined in Section 11.21) up to a maximum of 5 
lesions, representative of all involved organs, should be identified as “Target 
Lesions” and recorded and measured at baseline. These lesions can be non- 
nodal or nodal (as defined in 11.21), where no more than 2 lesions are from 
the same organ and no more than 2 malignant nodal lesions are selected. 
Note: If fewer than 5 target lesions and target lymph nodes are identified (as 
there often will be), there is no reason to perform additional studies beyond 
those specified in the protocol to discover new lesions. 
• 
Target lesions and target lymph nodes should be selected on the basis of their 
size, be representative of all involved sites of disease, but in addition should 
be those that lend themselves to reproducible repeated measurements. It may 
be the case that, on occasion, the largest lesion (or malignant lymph node) 
does not lend itself to reproducible measurements in which circumstance the 
next largest lesion (or malignant lymph node) which can be measured 
reproducibly should be selected. 
• 
Baseline Sum of Dimensions (BSD): A sum of the longest diameter for all 
target lesions plus the sum of the short axis of all the target lymph nodes will 
be calculated and reported as the baseline sum of dimensions (BSD). The 
BSD will be used as reference to further characterize any objective tumor 
response in the measurable dimension of the disease. 
• 
Post-Baseline Sum of the Dimensions (PBSD, or irPBSD for irRECIST): A 
sum of the longest diameter for all target lesions plus the sum of the short 
axis of all the target lymph nodes (and for irRECIST, plus the sum of new 
measurable lesions) will be calculated and reported as the post-baseline sum 
of dimensions (PBSD, or irPBSD for irRECIST). If the radiologist is able to 
provide an actual measure for the target lesion (or target lymph node), that 
should be recorded, even if it is below 0.5 cm. If the target lesion (or target 
lymph node) is believed to be present and is faintly seen but too small to 
measure, a default value of 0.5 cm should be assigned. If it is the opinion of 
the radiologist that the target lesion or target lymph node has likely 
disappeared, the measurement should be recorded as 0 cm. 
• 
The minimum sum of the dimensions (MSD, or irMSD for irRECIST) is the 
minimum of the BSD and the PBSD (or the irPBSD for irRECIST) 


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11.42 Non-Target Lesions & Non-Target Lymph Nodes 
Non-measurable sites of disease (Section 11.22) are classified as non-target 
lesions or non-target lymph nodes and should also be recorded at 
baseline. These lesions and lymph nodes should be followed in accord with 
Section 11.443. 
11.43 irRECIST Response Criteria 
11.431 
All target lesions and target lymph nodes followed by CT/MRI/PET- 
CT/Chest X-ray/physical examination must be measured on re- 
evaluation at evaluation times specified in Section 11.1. Specifically, a 
change in objective status to either irPR or irCR cannot be done 
without re-measuring target lesions and target lymph nodes. 
Note: Non-target lesions and non-target lymph nodes should be 
evaluated at each assessment, especially in the case of first response or 
confirmation of response. In selected circumstances, certain non-target 
organs may be evaluated less frequently. For example, bone scans may 
need to be repeated only when complete response is identified in target 
disease or when progression in bone is suspected. 
11.432 
irRECIST Overall Tumor Assessments 
11.4321 irRECIST Complete Response (irCR): 
a. Complete disappearance of all measurable and non- 
measurable lesions, and 
b. Each target lymph node must have reduction in short 
axis to <1.0 cm. 
11.4322 irRECIST Partial Response (irPR): 
a. At least a 30% decrease in irPBSD (sum of the longest 
diameter for all target lesions plus the sum of the short 
axis of all the target lymph nodes at current evaluation, 
plus the measurements of new measurable lesions) 
taking as reference the BSD (see Section 11.41), and 
b. Non-target lesions are irNN (no target disease was 
identified at baseline and at follow-up the patient fails to 
meet criteria for irCR and irPD), and 
c. No unequivocal progression of new non-measurable 
lesions. 
11.4323 irRECIST Stable Disease (irSD): 
a. Failure to meet criteria for irCR or irPR in the absence 
of irPD. 
11.4324 irRECIST Progression (irPD): 
a. At least a 20% increase in irPBSD taking as reference 
the irMSD (see Section 11.41) with an absolute increase 
of at least 0.5 cm from the irMSD, or 
b. Unequivocal irPD for non-target or new non-measurable 
lesions. 
11.44 RECIST 1.1 Response Criteria 
11.441 
All target lesions and target lymph nodes followed by CT/MRI/PET- 
CT/Chest X-ray/physical examination must be measured on re- 


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evaluation at evaluation times specified in Section 11.1. Specifically, a 
change in objective status to either a PR or CR cannot be done without 
re-measuring target lesions and target lymph nodes. 
Note: Non-target lesions and non-target lymph nodes should be 
evaluated at each assessment, especially in the case of first response or 
confirmation of response. In selected circumstances, certain non-target 
organs may be evaluated less frequently. For example, bone scans may 
need to be repeated only when complete response is identified in target 
disease or when progression in bone is suspected. 
11.442 
Evaluation of Target Lesions 
Complete Response (CR): All of the following must be true: 
a. Disappearance of all target lesions. 
b. Each target lymph node must have reduction in short axis to <1.0 
cm. 
Partial Response (PR): At least a 30% decrease in PBSD (sum of the 
longest diameter for all target lesions plus the sum of the short axis of 
all the target lymph nodes at current evaluation) taking as reference the 
BSD (see Section 11.41). 
Progression (PD): At least one of the following must be true: 
c. At least one new malignant lesion, which also includes any lymph 
node that was normal at baseline (<1.0 cm short axis) and 
increased to ≥1.0 cm short axis during follow-up. 
d. At least a 20% increase in PBSD (sum of the longest diameter for 
all target lesions plus the sum of the short axis of all the target 
lymph nodes at current evaluation) taking as reference the MSD 
(Section 11.41). In addition, the PBSD must also demonstrate an 
absolute increase of at least 0.5 cm from the MSD. 
e. See Section 11.32 for details in regards to the requirements for PD 
via FDG-PET imaging. 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR, nor 
sufficient increase to qualify for PD taking as reference the MSD. 
11.443 
Evaluation of Non-Target Lesions & Non-target Lymph Nodes 
Complete Response (CR): 
All of the following must be true: 
a. Disappearance of all non-target 
lesions. 
b. Each non-target lymph node must 
have a reduction in short axis to 
<1.0 cm. 
Non-CR/Non-PD: 
Persistence of one or more non-target 
lesions or non-target lymph nodes. 
Progression (PD): 
At least one of the following must be 
true: 
a. At least one new malignant lesion, 
which also includes any lymph node 
that was normal at baseline (<1.0 cm 
short axis) and increased to ≥1.0 cm 
short axis during follow-up. 


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b. Unequivocal progression of existing 
non-target lesions and non-target 
lymph nodes. (NOTE: Unequivocal 
progression should not normally 
trump target lesion and target lymph 
node status. It must be representative 
of overall disease status change.) 
c. See Section 11.32 for details in 
regards to the requirements for PD 
via FDG-PET imaging. 
11.45 RECIST 1.1 Overall Objective Status 
The overall objective status for an evaluation is determined by combining the 
patient’s status on target lesions, target lymph nodes, non-target lesions, non- 
target lymph nodes, and new disease as defined in the following tables: 
11.451 For Patients with Measurable Disease 
 
Target Lesions & 
Target Lymph Nodes 
Non-Target Lesions & 
Non-Target Lymph 
Nodes 
 
New 
Sites of Disease 
RECIST 1.1 
Overall Objective 
Status 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
PR 
CR 
Non-CR/Non-PD 
No 
PR 
CR/PR 
Not All Evaluated* 
No 
PR** 
 
SD 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
 
No 
 
SD 
 
Not all Evaluated 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
 
No 
 
Not Evaluated (NE) 
 
PD 
Unequivocal PD 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
 
Yes or No 
 
PD 
CR/PR/SD/PD/Not all 
Evaluated 
Unequivocal PD 
Yes or No 
PD 
CR/PR/SD/PD/Not all 
Evaluated 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
 
Yes 
 
PD 
*See Section 11.441 
** NOTE: This study uses the protocol RECIST v1.1 template dated 2/16/2011. For data collection 
and analysis purposes the objective status changed from SD to PR in the MCCC protocol RECIST 
v1.1 template as of 2/16/2011 and to match RECIST v1.1 requirements. 
11.46 Symptomatic Deterioration 
Patients with global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time, and not 
either related to study treatment or other medical conditions, should be reported 
as PD and irPD due to “symptomatic deterioration.” Every effort should be made 
to document the objective progression even after discontinuation of treatment due 
to symptomatic deterioration. A patient is classified as having PD and irPD due 


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to “symptomatic deterioration” if any of the following occur that are not either 
related to study treatment or other medical conditions: 
• 
Unintentional weight loss >10% of body weight 
• 
Decline in performance status of >1 level on ECOG scale 
 
12.0 
Descriptive Factors 
12.1 
Prior treatment: 1 vs 2 vs 3+ 
12.2 
Phase I dose level: 0 vs -1 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient 
13.1 
Continuation of treatment 
Patients who are irCR, irPR, or irSD will continue treatment per protocol. 
13.2 
Progressive disease (PD/irPD) 
Patients who develop irPD while receiving therapy will go to the event-monitoring phase. 
13.3 
Off protocol treatment 
Patients who go off protocol treatment for reasons other than irPD will go to the event- 
monitoring phase per Section 18.0. 
13.4 
Duration of therapy for irCR 
Patients who achieve irCR will receive treatment for a maximum of 2 years, then they 
will go to event monitoring 
13.5 
Duration of therapy for irPR or irSD 
Patients who are in irPR or irSD will continue on therapy for a total of 2 years. After 2 
years, then they will go to event monitoring (see 13.4 above). Subsequent treatment is at 
the discretion of their attending physician 
13.6 
Retreatment 
Patients who achieve SD, PR, CR may be eligible for retreatment for up to 1 year if their 
disease progresses after stopping treatment. (See Section 7.5 for criteria.) 
13.7 
Inevaluable patients 
Phase I only: If a patient fails to complete the first two cycles (Cycles 1 and 2) of 
treatment for reasons other than toxicity, the patient will be regarded as inevaluable and 
will be replaced. 
13.8 
Ineligible 
A patient is deemed ineligible if after registration, it is determined that at the time of 
registration, the patient did not satisfy each and every eligibility criteria for study entry. 
The patient may continue treatment off-protocol at the discretion of the physician as long 
as there are no safety concerns, and the patient was properly registered. The patient will 
go directly to the event-monitoring phase of the study (or off study, if applicable). 
• 
If the patient received treatment, all data up until the point of confirmation of 
ineligibility must be submitted. Event monitoring will be required per Section 18.0 of 
the protocol. 
• 
If the patient never received treatment, on-study material must be submitted. Event 
monitoring will be required per Section 18.0 of the protocol. 


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13.9 a 
Major violation 
A patient is deemed a major violation, if protocol requirements regarding treatment in the 
first two cycles (Cycles 1-2) of the initial therapy are severely violated that evaluability 
for primary end point is questionable. All data up until the point of confirmation of a 
major violation must be submitted. The patient will go directly to the event-monitoring 
phase of the study. The patient may continue treatment off-protocol at the discretion of 
the physician as long as there are no safety concerns, and the patient was properly 
registered. Event monitoring will be required per Section 18.0 of the protocol. 
13.9b Cancel 
A patient is deemed a cancel if he/she is removed from the study for any reason before 
any study treatment is given. On-study material and the End of Active Treatment/Cancel 
Notification Form must be submitted. No further data submission is necessary. 


 
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14.0 
Body Fluid Biospecimens 
14.1 
Summary Table of Research Blood and Body Fluid Specimens to be Collected for this Protocol 
 
 
 
 
Correlative Study 
(Section for more 
information) 
 
 
 
 
Mandatory1 
or Optional 
 
 
Blood or 
Body Fluid 
being 
Collected 
 
 
Type of 
Collection 
Tube (color 
of tube top) 
 
 
Volume to 
collect per 
tube (# of 
tubes to be 
collected) 
 
 
 
 
Baseline 
B0 
 
 
End of 
Cycle 1 
Prior to 
pembro 
B1 
 
C3, D1 
After 1 
cycle of 
bini and 
pembro 
B2 
C9, D1 
Only after 
objective 
response 
or SD 
>6mos 
B3 
 
 
End of Tx 
for any 
reason 
B4 
 
 
Process 
at site? 
(Yes or 
No) 
 
 
Temperature 
Conditions for 
Storage 
/Shipping 
 
Immunoregulatory cell 
quantification 
(Section 14.21) 
 
 
Mandatory 
 
PBMCs 
and plasma 
Mononuclear 
(CPT) 
sodium 
citrate (lt 
blue/black) 
 
8 mL 
(1) 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
No 
 
 
Ambient 
 
Cytokine profiling 
(Section 14.21) 
 
 
Mandatory 
 
PBMCs 
and plasma 
Mononuclear 
(CPT) 
sodium 
citrate (lt 
blue/black) 
 
8 mL 
(1) 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
No 
 
 
Ambient 
Circulating Tumor Cells 
(CTC) 
(Section 14.22) 
 
Mandatory 
Whole 
Blood 
 
CellSave 
10 mL 
(2) 
 
X 
 
X 
 
X 
 
X 
 
X 
 
No 
 
Ambient 
1. Samples are required at baseline and requested at all other timepoints. 


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14.2 
Collection and Processing 
All samples should be labeled with the study number
 the patient’s study ID, 
treatment phase (I or II), dose level (-1 or 0), and the designated specimen timepoint in 
Section 14.1 (i.e. B0/B1/B2/B3/B4). The samples should not contain patients’ identifying 
information. 
14.21 Immunoregulatory cell quantification and cytokine profiling 
Collect two 8 ml, BD Vacutainer® Mononuclear Cell Preparation Tubes (CPT) 
with sodium citrate and ship overnight within 24 hours of collection. 
14.22 Circulating tumor cells 
Collect two 10 mL CellSave Preservative vacutainers and ship overnight within 
24 hours of collection per Section 14.32. 
14.3 
Shipping and Handling 
14.31 Kits will be provided for Minnesota only. 
14.311 
Kits will be supplied by the Mayo Florida Biospecimen Acessioning 
and Processing Shared Resource (BAP). 
14.312 
The kit contains supplies and instructions for collecting, processing, 
and shipping specimens. 
14.313 
Participating institutions may obtain kits by submitting the supply 
order form to 
 Because we are charged for all 
outgoing kits, a small, but sufficient, supply of the specimen collection 
kits should be ordered prior to patient entry. Supply Order Forms must 
be filled in completely and legibly for quick processing. 
14.314 
Kits will be sent via Fed Ex® Ground at no additional cost to the 
participating institutions. Allow at least two weeks to receive the kits. 
14.315 
Kits will not be sent via rush delivery service unless the participating 
institution provides their own Fed Ex® account number or alternate 
billing number for express mail. Cost for rush delivery of kits will 
not be covered by the study. 
14.316 
For Jacksonville: 
Immunoregulatory cell quantification and cytokine profiling should be 
hand carried to 
 
14.317 
For Rochester samples: 
Immunoregulatory cell quantification and cytokine profiling must be 
shipped overnight within 24 hours of draw to 
 
laboratory. 
14.318 
For all sites: CTCs must be shipped overnight within 24 hours of 
draw (see Section 14.323) 
14.319 
All specimens must be collected and shipped Monday – Thursday 
ONLY. 
14.32 Shipping Specimens 
14.321 
Immunoregulatory cell quantification and cytokine profiling must be 
shipped OVERNIGHT within 24 hours to: 


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PRIOR to 
shipping. 
14.323 Circulating Tumor Cells 
Two 10 mL blood collection CellSave Preservative vacutainers will be 
collected for this purpose. After collection, samples should be labeled 
as previously described and shipped OVERNIGHT within 24 hours 
to: 
 
 
 
 PRIOR to shipping. 
14.4 
Background and Methodology 
14.41 Immunoregulatory cell quanitification 
Several subtypes of circulating immunoregulatory cells (IRC) (CD8, CD4, Treg, 
MDSC, NK cells) will be evaluated in the peripheral blood of patients treated 
with pembrolizumab and binimetinib as previously described {Thomas 2014}. 
These subsets of IRC include CD4, CD8, regulatory T cells, myeloid derived 
suppressor cells, and NK cells. 
14.42 Cytokine profiling 
Luminex Multianalyte assay is a multiplex assay that allows simultaneous 
quantification of multiple cytokines in a single sample. A panel of 17 cytokines 
and chemokines will be analyzed using a multiplexed approach with 
commercially available human 17-plex kits. The following cytokines will be 
assessed: IL-1β, IL-2, IL-4, IL-5, IL-6, IL-7, CXCL8 (IL-8), IL-10, IL-12, IL-13, 
IL-17A, IFN-γ, TNF-α, CCL2 (MCP-1), CCL4 (MIP-1β), G-CSF, and GM-CSF. 
Cytokine concentrations will be determined based on a standard curve generated 
on each plate using the manufacturer-supplied reagents. 
14.43 Circulating Tumor Cells 
Circulating tumor cells (CTC) will be isolated by Creatv MicroTech, Inc. using 
CellSeive microfiltration technique as previously described {Adams 2014}. 
Using a standard CTC fluorescent stain, we identify, quantify and score these 
cells according to their Cytokeratin, CD14 and CD45 positivity. The filtered 
samples are then processed by the QUAS-R technique, whereby the fluorescent 
CTC stain is “Quenched-Underivatized- Amine Striped” removing all 
fluorescence while leaving the cells intact and unaltered. The samples are 
“Restained” for subtyping of additional biomarker panels against biological 
targets (i.e. p-ERK, PD-L1, etc.) as well as circulating cancer-associated 
macrophage-like cells (CAMLs). The same previously identified CTC and CStC 
are reimaged with the new immuno-targets, the markers are quantified and 


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scored. The process is repeated with up to 12 biomarkers identified, quantified 
and scored using the initially identified CStC and CTC. 


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15.0 
Drug Information 
15.1 
Binimetinib (MEK162, ARRY-438162, ONO-7703) 
15.11 Background: Binimetinib is an orally bioavailable, selective and potent MEK1 
and MEK 2 inhibitor. As a MEK inhibitor, this compound has the potential to 
benefit patients with advanced cancers by inhibiting the MAPK (mitogen- 
activated protein kinases) pathway. 
15.12 Formulation: Binimetinib drug product is supplied as film-coated tablets in a 
dose strength of 15 mg. The film coated-tablets consist of binimetinib, lactose 
monohydrate, microcrystalline cellulose, colloidal silicon dioxide, 
croscarmellose sodium, magnesium stearate and a commercial film coating. The 
tablets are yellow to dark yellow and capsule shaped. 
Binimetinib tablets can be constituted in 3:1 (v/v) Ora Sweet®/water at 1 mg/mL 
binimetinib concentration to provide an easy to swallow oral suspension. 
15.13 Preparation and storage: Binimetinib film-coated tablets should not be stored 
above 25°C and should be protected from light. Tablets are packaged in plastic 
bottles acceptable for pharmaceutical use. 
Binimetinib oral suspension prepared from 15 mg binimetinib tablets should not 
be stored above 25°C and should not be refrigerated. The suspension should be 
used within 30 days after preparation. 
 
15.14 Administration: Binimetinib is administered twice daily with water, 
approximately 12 hours apart with or without meals. Tablets should be 
swallowed whole and should not be chewed. 
Binimetinib oral suspension is intended for oral administration as prepared. 
15.15 Pharmacokinetic information: 
Absorption: The pharmacokinetics of binimetinib are characterized by moderate 
to high variability, accumulation of approximately 1.5-fold, and steady state 
concentrations reached within 15 days. The human ADME study indicated that 
approximately 50% of binimetinib dose was absorbed. 
Distribution: Binimetinib is more distributed in plasma than blood. The blood- 
to-plasma concentration ratio of binimetinib in humans is 0.718. It is highly 
bound to plasma proteins (humans: 97.2%) 
Metabolism: The primary metabolic pathways include glucuronidation (up to 
61.2% via UGT1A1), N-dealkylation (up to 17.8% via CYP1A2 and CYP2C19) 
and amide hydrolysis. 
Excretion: The excretion route was 31.7% of unchanged binimetinib in feces 
and 18.4% in urine. Estimated renal clearance of unchanged binimetinib was 
6.3% of total dose. 
 
15.16 Potential Drug Interactions: 
Overall, the risk for binimetinib to be a cause of or be affected by significant 
drug-drug interactions is predicted to be low. However, given the predominant 
role of UGT1A1 in the metabolism of binimetinib, special consideration should 


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be taken for co-administration of drugs that are UGT1A1 inhibitors or inducers, 
and administration of binimetinib to patients with low UGT1A1 activity. 
 
 
Binimetinib has been shown to be a substrate for P-gp and BCRP in vitro. The impact of 
P-gp/BCRP inhibitors on the PK of binimetinib in vivo is unknown; therefore, it 
is recommended that P-gp and BCRP inhibitors are dosed with caution. 
15.17 Known potential toxicities: 
Very Common (≥10%) - Anemia, abdominal pain, constipation, diarrhea, 
nausea, vomiting, fatigue, peripheral edema, increased AST, increased ALT, 
increased blood creatine phosphokinase (CPK), dyspnea, dermatitis acneiform, 
pruritus, rash, hypertension 
Common (≥1% - <10%) – Left ventricular dysfunction, tachycardia, 
chorioretinopathy, eye edema, macular edema, retinal detachment, retinopathy, 
blurred vision, visual impairment, dry mouth, gastritis, gastrointestinal 
obstruction, stomatitis, asthenia, facial edema, general physical health 
deterioration, generalized edema, malaise, mucosal inflammation, pyrexia, 
cellulitis, pneumonia, infection, decreased ejection fraction, increased GGT, 
increased INR, increased troponin T, dehydration, hyponatremia, arthralgia, 
muscular weakness, myalgia, cough, epistaxis, hypoxia, pulmonary embolism, 
alopecia, maculo-papular rash, skin fissures, hypotension 
Uncommon (≥0.1 - <1%) - Left ventricular failure, retinal vein occlusion, retinal 
vein thrombosis, reduced visual acuity, enteritis, gastroenteritis, gastrointestinal 
hemorrhage, acute hepatic failure, irregular heart rate, increased troponin I, 
increased troponin T, hypoglycemia, myositis, dropped head syndrome, renal 
failure, atelectasis, lung infiltration, pneumonitis, pneumothorax, wheezing, 
angioedema, erythema nodosum/panniculitis, palmar-plantar dysesthesia 
syndrome, macular rash, deep vein thrombosis, hematoma 
 
15.18 Drug procurement: 
Binimetinib is supplied by Pfizer Inc. (formerly Array Biopharma LLC and Array 
Biopharma Inc.), Inc 
 
15.19 Nursing guidelines 
15.191 
Instruct patient to take binimetinib twice daily approximately 12 hours 
apart. Agent may be taking with or without food. 
15.192 
MEK inhibitors can have significant cardiac side effects; including 
cardiac failure, tachycardia, myocarditis, and decreased ejection 
fraction. Instruct patients to report any side effects concerning for heart 
failure (SOB, peripheral edema, chest, pain, etc) to the study team 
immediately. 
15.193 
Warn patient of eye disorders, which can be severe and lead to 
permanent loss of eyesight. Instruct patient to report any eye pain, 
dryness, itching, etc. to study team. Refer patient to ophthalmologist 
for treatment. 
15.194 
Binimetinib may cause gastrointestinal side effects (diarrhea, nausea, 
vomiting, GI bleeding, etc). Treat symptomatically and/or premedicate 
as necessary and monitor for effectiveness. 


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15.195 
Monitor LFTs. Patients have experienced acute hepatic failure. Instruct 
patients to report any acute and or worsening RUQ pain and/or any 
jaundice to study team immediately. 
15.196 
Patients may experience pruritus and/or rash. Manage symptomatically 
and monitor for effectiveness. 
15.197 
Patients may experience generalized edema, including the face and the 
limbs. Instruct patient to report any edema and rule out any allergic 
and/or cardiac component. 
15.198 
Monitor creatinine levels. 
15.199 a Patients may experience myositis or rarely rhabdomyolysis. Patients 
should be instructed to report generalized muscle pain to the study 
team. 
15.199b Agent may cause pneumonitis. Instruct patients to report any cough, 
SOB, or chest pain to study team. 
15.199c Monitor any new skin lesions. Patients may develop secondary skin 
cancer or cysts. Refer to dermatology as necessary. 
15.199d Patients may experience palma-plantar erythrodysesthesia (hand-foot 
syndrome). Instruct patients to report any redness, pain or skin changes 
of the hands or feet to the study team immediately. Encourage good 
hand and foot care and use of moisturizers. 


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15.2 
Pembrolizumab (MK-3475, SCH 900475, Keytruda™) 
15.21 Background: Pembrolizumab is a potent humanized IgG4 monoclonal antibody 
with high specificity of binding to the PD-1 receptor, thus inhibiting its 
interaction with PD-L1 and PD-L2. Based on preclinical in vitro data, 
pembrolizumab has high affinity and potent receptor blocking activity for PD-1. 
 
15.22 Formulation: 
Pembrolizumab is available as a liquid 25 mg/mL, 100 mg/vial. 
 
15.23 Preparation and storage: 
Vials should be stored in the refrigerator at temperatures between 2-8°C. 
 
Drug concentrate is further diluted with normal saline (or 5% dextrose) in the 
concentration range of 1 to 10 mg/mL. The infusion solution in the IV bag should 
be immediately administered. Diluted pembrolizumab solutions may be stored at 
room temperature for a cumulative period of up to 6 hours. This includes room 
temperature storage of admixture solutions in the IV bags and the duration of 
infusion. In addition, IV bags can be stored at 2-8 °C for up to a cumulative time 
of 2 hours. This 24-hour total hold time from dilution may include up to 6 hours 
at room temperature. IV bags must be allowed to come to room temperature 
before use. 
 
15.24 Administration: Pembrolizumab is administered by intravenous infusion over 
30 minutes via a 0.22 micron in-line filter. The final infusion volume must be 
between 1 and 10 mg/mL. Maximum rate of infusion should not exceed 6.7 
mL/minute through a peripheral or indwelling catheter. Flush the line with 0.9% 
NaCL following the completion of the infusion. 
 
15.25 Pharmacokinetic information: 
a) Absorption – Because pembrolizumab is administered intravenously, it is 
immediately and completely bioavailable. Steady-state concentrations 
of pembrolizumab are reached by 16 weeks of repeated dosing with a 
Q3W regimen and the systemic accumulation is 2.1-fold. The peak 
concentration, trough concentration, and area under the plasma 
concentration versus time curve at steady state of pembrolizumab 
increased dose proportionally in the dose range of 2 to 10 mg/kg Q3W. 
b) Distribution – Pembrolizumab has a limited volume of distribution. 
c) Excretion – CL is approximately 23% lower after achieving maximal change 
at steady state compared with the first dose. The terminal elimination 
half-life(t½) is estimated to be 22 days at steady state. 
d) Metabolism – Pembrolizumab is catabolized through non-specific pathways; 
metabolism does not contribute to its CL. 
 
15.26 Potential Drug Interactions: There are no known significant drug interactions. 
 
15.27 Known potential toxicities: 
Very common known potential toxicities, ≥ 10%: 
Gastrointestinal disorders: diarrhea, nausea, abdominal pain 
Skin and subcutaneous tissue disorders: rash, pruritis 
General disorders and administration site conditions: fatigue 


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Common known potential toxicities, ≥1% to <10%: 
Blood and lymphatic system disorders: anemia 
Immune system disorders: infusion related reaction 
Endocrine disorders: hyperthyroidism, hypothyroidism 
Metabolism and nutrition disorders: decreased appetite 
Nervous system disorders: headache, dizziness, dysgeusia 
Respiratory, thoracic, and mediastinal disorders: pneumonitis, dyspnea, 
cough 
Gastrointestinal disorders: colitis, vomiting, constipation, dry mouth 
Skin and subcutaneous tissue disorders: severe skin reactions, 
vitiligo, dry skin, erythema 
Musculoskeletal and connective tissue disorders: arthralgia, 
myositis, musculoskeletal pain, arthritis, pain in extremity 
 
General disorders and administration site conditions: asthenia, 
edema, pyrexia, influenza like illness, chills 
Investigations: alanine aminotransferase increased, aspartate 
aminotransferase increased, blood alkaline phosphatase increased, blood 
creatinine increased 
 
 
Uncommon known potential toxicities, ≥0.1% to <1%: 
Infusion related reactions 
Blood and lymphatic system disorders: neutropenia, thrombocytopenia, 
leukopenia, lymphopenia, eosinophilia 
 
Endocrine disorders: hypophysitis, adrenal insufficiency, 
Thyroiditis, hypopituitarism 
Metabolism and nutrition disorders: type I diabetes mellitus, 
hyponatremia, hypokalemia, hypocalcemia 
Psychiatric disorders: insomnia, confusional state 
Nervous system disorders: epilepsy, lethargy, peripheral neuropathy 
Eye disorders: uveitis, dry eye 
Cardiac disorders: myocarditis, atrial fibrillation 
Vascular disorders: hypertension 
Gastrointestinal disorders: pancreatitis 
Hepatobiliary disorders: hepatitis 
Skin and subcutaneous tissue disorders: lichenoid keratosis, psoriasis, 
alopecia, dermatitis, dermatitis acneiform, eczema, hair color changes, 
papule 
Musculoskeletal and connective tissue disorders: tenosynovitis 
Renal and urinary disorders: nephritis, acute kidney injury 
Investigations: blood bilirubin increased, amylase increased, 
hypercalcemia 
 
 
Rare known potential toxicities, <0.1% (Limited to important or life- 
threatening): 
Blood and lymphatic system disorders: immune thrombocytopenic 


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purpura, hemolytic anemia 
 
Immune system disorders: sarcoidosis 
Nervous system disorders: Guillain-Barre syndrome, myasthenic syndrome 
Gastrointestinal disorders: small intestinal perforation 
Skin and subcutaneous tissue disorders: toxic epidermal necrolysis, Stevens- 
Johnson syndrome, erythema nodosum 
The risk profile for pembrolizumab also includes two important potential risks: a) 
myasthenic syndrome, and b) an increased risk of severe complications (such as 
early severe graft versus host disease and veno-occlusive disease) of allogeneic 
transplant in patients with hematologic malignancies who have previously been 
treated with PD-1 inhibitors. 
 
Patients with multiple myeloma who were treated with pembrolizumab in 
combination with either pomalidomide or lenalidomide and dexamethasone, had 
an increased number of serious side effects and deaths as compared to patients 
who received only dexamethasone and either pomalidomide or lenalidomide. The 
benefit-risk profile is unfavorable for the combination of pembrolizumab, 
pomalidomide, and dexamethasone in relapsed refractory multiple myeloma, and 
the combination of pembrolizumab, lenalidomide, and dexamethasone in newly 
diagnosed treatment-naive multiple myeloma. 
 
Post marketing reports identified Vogt-Koyanagi-Harada syndrome and 
hemophagocytic lymphohistiocytosis. 
 
 
15.28 Drug procurement: Pembrolizumab will be provided free of charge to study 
participants by Merck. 
 
15.29 Nursing Guidelines 
15.291 
Pembrolizumab side effects vary greatly from those of traditional 
chemotherapy and can vary in severity from mild to life threatening. 
Instruct patients to report any side effects to the study team 
immediately. Side effects may be immediate or delayed up to months 
after discontinuation of therapy. Most side effects are reversible with 
prompt intervention of corticosteroids. 
15.292 
Diarrhea can be seen however it is less common than that seen with 
anti-CTLA-4 agents. However it can be severe, leading to colonic 
perforation. Instruct patients to report ANY increase in the number of 
stools and/or change in baseline, blood in the stool, abdominal pain to 
the study team immediately. 
15.293 
Rash/pruritis/dermatitis is seen. Patients should report any rash to the 
study team. Treat per section 9.0 and monitor for effectiveness. 
15.294 
Monitor LFTs closely as elevations in these levels could indicate early 
onset autoimmune hepatitis. Patients should also be instructed to report 
any jaundice, or right upper quadrant pain to the study team 
immediately. 


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15.295 
Pneumonitis can be seen and may be mild (only seen on imaging) to 
severe. Patients should be instructed to report any SOB, dyspnea, 
cough, chest pain, etc. to the study team immediately. Patients 
reporting these symptoms should have a pulse ox checked and consider 
immediate imaging per the treating MD. 
15.296 
Endocrinopathies (including hypopituitarism, hypothyroidism, 
hypophysitis, and adrenal insufficiency) are seen with this agent. 
Patients may present only with the vague sense of fatigue and “not 
feeling well.” Additional symptoms may be that of nausea, sweating 
and decreased activity tolerance. Instruct patients to report these signs 
or symptoms immediately and obtain appropriate labs as ordered by 
MD. 
15.297 
Patients who are started on steroid therapy for any side effects of 
pembrolizumab toxicity should be instructed to take the steroids as 
ordered, and not to discontinue abruptly as symptoms may return and 
be severe. Patients may be on steroid therapy for weeks. Instruct 
patients to report any increase or change in side effects with any 
dosage decrease as patients may need a slower taper. 
15.298 
Fatigue is common and may or may not be associated with immune 
related side effects. Assess patient’s fatigue level prior to each cycle of 
therapy and report any changes to the study team. 
15.299 
Patients should avoid receiving live vaccines within 30 days of study 
drug administration or per other study guidelines. 
15.299a Patients who have undergone an allogenic bone marrow transplant, 
have an increased risk of severe complications including early GVHD, 
and venoocclusive disease, if they have previously been treated with 
pembrolizumab 
15.299b Myocarditis has been reported and associated with pembrolizumab. 
Instruct patients to report chest pain, SOB, or dyspnea to study team 
immediately and/or seek emergency medical attention. 
15.299c Autoimmune hematologic disorders including ITP and hemolytic 
anemia have been reported. Monitor blood counts closely and report 
any abnormalities to the study team. 
15.299d Rare neurologic disorders including Guillian-Barre syndrome and 
myasthenia gravis have been reported. Instruct patients to report any 
neurologic symptoms including weakness, parasthesias or numbness, 
tingling to the study team immediately. 


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16.0 
Statistical Considerations and Methodology 
16.1 
Overview 
This is a Phase I/II, single-arm, open-labeled, multi-center study of pembrolizumab in 
combination with binimetinib in women with unresectable locally advanced or metastatic 
triple negative breast cancer. The main objective of this study is to assess the safety and 
efficacy of the combination of pembrolizumab and binimetinib. 
The phase I part will be a dose-finding study, utilizing the classic 3+3 study design. The 
primary objectives are to determine the DLTs, to evaluate the safety of this combination, 
and to establish the recommended dose for the phase II part. There are a total of 2 dose 
levels as defined in the treatment section. The number of participants enrolled in the 
phase I of this study will range from 6-12 participants. 
16.11 Primary Endpoint 
16.111 
Phase I 
The primary endpoint in the phase I portion is to determine the 
maximum tolerated dose of this combination. 
16.112 
Phase II 
The primary endpoint in the phase II portion is confirmed objective 
response rate (ORR) by RECIST criteria with pembrolizumab and 
binimetinib. 
We will utilize Simon’s Two-Stage Optimal Design to test the null 
hypothesis that this two-drug combination has an ORR of at most 15% 
versus the alternative hypothesis that it has an ORR of at least 35%. 
Patients in the phase I part who are treated with the recommended dose 
of phase II and are evaluable for response will be included in the phase 
II analysis. The first stage will require 9 evaluable patients. With this 
design, if ≤1 of the first 9 patients has objective response (i.e. CR or 
PR), the study will be closed since there is sufficient evidence that the 
therapy is not promising. Otherwise, an additional 14 patients will be 
enrolled. In total, if >5 patients of 23 patients have objective response, 
this combination will be considered promising. This design has 80% 
power while controlling the type I error at 10%. Under the null 
hypothesis (when the true objective response rate is 15%), this design 
has a 60% chance of stopping the trial early. A minimum of 9 and a 
maximum of 23 evaluable patients are required to evaluate the primary 
endpoint. To account for cases that are ineligible or non-evaluable, we 
will accrue an additional 3 patients for a maximum accrual of 26 
patients in this phase. The secondary endpoints in part II include 
objective response rate by irRECIST, progression free survival, and 
overall survival. 
16.2 
Sample size and accrual rate 
For phase I, the study will require 6-12 patients to complete, allowing for 6 patients per 
dose level and 2 predefined dose levels. In phase II, the study will require 9-26 patients to 
complete. Therefore, the total sample size for this study is 15-38 patients. At an 
anticipated accrual rate of 10-12 patients/year, we expect that this trial will need to accrue 
patients for anywhere from 15 to 32 months. 


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16.3 
Statistical Analysis Plan 
The objective of the phase I portion of the study is to estimate the maximum tolerated 
dose (MTD) using the standard 3+3 design. Safety/adverse events data will be tabulated, 
including adverse events of all grades. 
For the phase II portion of the study, the overall response rate by RECIST will be 
estimated using the approach of Jung and Kim [On the estimation of the binomial 
probability in multistage clinical trials. Stat Med 23:881-96, 2004]. The 90% lower 
confidence bound will be calculated using the approach of Koyama and Chen [Proper 
inference from Simon's two-stage designs. Stat Med 27:3145-54, 2008]. Secondary 
efficacy endpoints include objective response rate by immune-related response criteria 
(irRECIST), progression-free survival (PFS) and overall survival (OS). Objective 
response rate by irRECIST will be estimated as a binomial proportion with a 2-sided 95% 
CI. PFS will be defined as the time from study enrollment to date of progression. Patients 
who have not progressed (including those lost to follow-up) at the time of data analysis 
will be censored at the date last known to be free of progression. OS will be defined as 
the time from study enrollment to death attributable to any cause (i.e. death from breast 
cancer, non-breast cancer cause, or from unknown cause). Patients who are alive 
(including those lost to follow-up) at the time of data analysis will be censored at the last 
known alive date. A Kaplan-Meier curve will be used to summarize the PFS and OS 
experience of this patient cohort. 
Baseline TILs and percent change in TILs from baseline will be summarized. Logistic 
regression models will be used to assess the correlation between these biomarkers and 
ORR in order to assess their prognostic significance. Cox Proportional Hazard models 
will be used to assess their correlation with time-to-event endpoints such as PFS and OS. 
Similar analyses will be performed for other exploratory biomarkers such as immune 
related gene signature, PDJ amplification, etc. These analyses will be exploratory in 
nature. As such, no adjustment for multiple comparisons will be made; all hypothesis 
tests will be based on 2-sided alpha = 0.05 level. 
 
16.4 
Phase I 
This portion of the study is designed to determine the MTD and toxicity profile of 
binimetinib in combination pembrolizumab. 
16.41 MTD Definition: MTD is defined as the dose level below the lowest dose that 
induces dose-limiting toxicity (DLT) in at least one-third of patients (at least 2 of 
a maximum of 6 new patients). A total of 6 patients treated at the MTD will be 
sufficient to identify common toxicities at the MTD. 
Refer to Section 7.52 for definition of dose-limiting toxicity (DLT). The focus of 
this study is to establish the DLT of the combination of binimetinib and 
pembrolizumab. Therefore, only adverse events that occur during the first cycle 
of treatment with the combination (Cycle 2) will be considered when evaluating 
for dose-limiting toxicity. 
 
16.42 
MTD Determination 
The phase I portion of this study will utilize a standard cohort of three design. 
The dose levels to which patients will be assigned in sequential cohorts are 
described in Section 7.51. The first cohort of three patients will be treated at dose 
level 0. Decisions on when and how to dose escalate are described below. 


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16.421 Three patients will be treated at a given dose level combination and 
observed for one cycle of the combination (Cycle 2) from start of 
treatment to assess toxicity. 
16.422 If DLT is not seen in any of the 3 patients, 3 new patients will be 
accrued and treated at the next higher dose level. If DLT is seen in 2 or 
3 of 3 patients treated at a given dose level, then the next 3 patients will 
be treated at the next lower dose level, if only 3 patients were enrolled 
and treated at this lower dose level. 
16.423 If DLT is seen in 1 of 3 patients treated at a given dose level, up to 3 
additional patients will be enrolled and treated at the same dose level. If 
DLT is seen in at least one of these additional three patients (≥2 of 6), 
the MTD will have been exceeded and further accrual will cease to this 
cohort. If dose-limiting toxicity (DLT) is not seen in any of the three 
additional patients, 3 new patients will be accrued and treated at the next 
higher dose level. 
16.424 After enrolling 6 patients on a specific dose level, if DLT is observed in 
at least 2 of 6 patients, then the MTD will have been exceeded and 
defined as the previous dose unless only 3 patients were treated at the 
lower dose level. In that case, 3 additional patients will be treated at this 
lower dose level such that a total of 6 patients are treated at the MTD to 
more fully assess the toxicities associated with the MTD. 
16.426 If a patient fails to complete the first combined cycle (Cycle 2) of 
therapy for reasons other than dose-limiting toxicity defined adverse 
events, the patient will be regarded as uninformative in regard to the 
primary study goal (i.e. MTD determination) and will be replaced. 
16.427 Operating Characteristics for standard cohort of 3 design: The following 
table gives the probability of dose escalation at a single dose level as a 
function of the true probability of DLT at that level using the cohorts of 
3 design described above. 
True Rate 
of DLT (%) 
 
Probability of Dose Escalation 
10 
0.91 
20 
0.71 
30 
0.49 
40 
0.31 
50 
0.17 
 
16.5 
Data & Safety Monitoring 
16.51 
The principal investigator(s) and the study statistician will review the study at 
least twice a year to identify accrual, adverse event, and any endpoint problems 
that might be developing. The Mayo Clinic Cancer Center (MCCC) Data Safety 
Monitoring Board (DSMB) is responsible for reviewing accrual and safety data 
for this trial at least twice a year, based on reports provided by the MCCC 
Statistical Office. 
16.52 Adverse Event Stopping Rules: 


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The stopping rules specified below are based on the knowledge available at study 
development. We note that the rules may be adjusted in the event of either (1) the 
study re-opening to accrual or (2) at any time during the conduct of the trial and 
in consideration of newly acquired information regarding the adverse event 
profile of the treatments under investigation. The study team may choose to 
suspend accrual because of unexpected adverse event profiles that have not 
crossed the specified rules below. 
Phase I (Includes all dose levels in phase I): 
By the nature of the “cohorts of three” phase I study design, toxicity (i.e., adverse 
events that are possibly, probably or definitely related to study treatment) 
stopping rules are in place for each dose level. Specifically, if 2 or more dose- 
limiting toxicities (DLTs) are observed during Cycle 2 at any given dose level, 
accrual to that dose level will be stopped, and patients will be accrued to the next 
lower dose level until a maximum of 6 patients are treated at the lower level. 
Note that a DLT that affects dose escalation is only that which is observed in the 
second cycle of treatment. However, all cycles will be reviewed and the study 
team will determine whether the dose level needs to be adjusted for future 
patients if ≥1 in the first 3 patients OR ≥2 in the first 6 patients experience a 
Grade 4 or higher adverse event at least possibly related to treatment over all 
cycles at any given dose level. 
Phase II (includes all phase II patients including phase I patients treated at 
the MTD: 
Accrual will be temporarily suspended to this study if at any time we observe 
events considered at least possibly related to study treatment (i.e. an adverse 
event with attribute specified as “possible,” “probable,” or “definite”) that satisfy 
either of the following: 
• 
If 3 or more patients in the first 9 treated patients experience a Grade 4 or 
higher adverse event at least possibly related to treatment. 
• 
If after the first 9 patients have been treated, 25% of all patients experience a 
Grade 4 or higher adverse event at least possibly related to treatment. 
We note that we will review Grade 4 and 5 adverse events deemed “unrelated” or 
“unlikely to be related”, to verify their attribution and to monitor the emergence 
of a previously unrecognized treatment-related adverse events. 
 
16.6 
Inclusion of Women and Minorities 
16.61 This study will be available to all eligible patients, regardless of race, gender, or 
ethnic origin. 
16.62 There is no information currently available regarding differential effects of this 
regimen in subsets defined by race, gender, or ethnicity, and there is no reason to 
expect such differences to exist. Therefore, although the planned analysis will, as 
always, look for differences in treatment effect based on racial and gender 
groupings, the sample size is not increased in order to provide additional power 
for subset analyses. 
16.63 The geographical region served by MCCC has a population which includes 
approximately 3% minorities. Based on prior MCCC studies involving similar 
disease sites, we expect about 3-5% of patients will be classified as minorities by 


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race and about 100% of patients will be women. Expected sizes of racial by 
gender subsets are shown in the following table: 
 
16.64 Table of Accrual by Ethnicity/Race/Gender 
 
Accrual Targets 
 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
1 
0 
1 
Not Hispanic or Latino 
37 
0 
37 
Ethnic Category: Total of all subjects 
38 
0 
38 
Racial Category 
American Indian or Alaskan Native 
0 
0 
0 
Asian 
1 
0 
1 
Black or African American 
1 
0 
1 
Native Hawaiian or other Pacific Islander 
0 
0 
0 
White 
36 
0 
36 
Racial Category: Total of all subjects 
38 
0 
38 
 
Ethnic 
Categories: 
Hispanic or Latino – a person of Cuban, Mexican, Puerto Rican, South or Central 
American, or other Spanish culture or origin, regardless of race. The term “Spanish 
origin” can also be used in addition to “Hispanic or Latino.” 
Not Hispanic or Latino 
Racial 
Categories: 
American Indian or Alaskan Native – a person having origins in any of the original 
peoples of North, Central, or South America, and who maintains tribal affiliations or 
community attachment. 
Asian – a person having origins in any of the original peoples of the Far East, 
Southeast Asia, or the Indian subcontinent including, for example, Cambodia, China, 
India, Japan, Korea, Malaysia, Pakistan, the Philippine Islands, Thailand, and 
Vietnam. (Note: Individuals from the Philippine Islands have been recorded as Pacific 
Islanders in previous data collection strategies.) 
Black or African American – a person having origins in any of the black racial 
groups of Africa. Terms such as “Haitian” or “Negro” can be used in addition to 
“Black or African American.” 
Native Hawaiian or other Pacific Islander – a person having origins in any of the 
original peoples of Hawaii, Guam, Samoa, or other Pacific Islands. 
White – a person having origins in any of the original peoples of Europe, the Middle 
East, or North Africa. 


 
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17.0 
Pathology Considerations/Tissue Biospecimens 
17.1 
Summary Table of Research Tissue Specimens to be Collected for this Protocol 
 
 
 
Correlative Study 
(Section for more 
information) 
 
 
Type of 
Tissue to 
Collect 
Block, 
Slides, Core, 
etc. (# of 
each to 
submit) 
 
 
 
Baseline 
 
End of 
Cycle 1 
(prior to 
pembro) 
 
End of 
Tx for 
any 
reason 
 
Process 
at site? 
(Yes or 
No) 
 
Temperature 
Conditions 
for Storage 
/Shipping 
 
Tumor infiltrating 
lymphocytes 
(Section 17.41 
 
 
FFPE 
H&E slide 
and 5 
unstained 
slides of 5 
microns. 
 
 
Mandatory 
 
 
Optional 
 
 
Optional 
 
 
Yes 
 
 
Ambient 
Immunohistochemistry 
for PD-L1 
(Section 17.42) 
 
FFPE 
2 unstained 
slides of 5 
microns 
 
Mandatory 
 
Optional 
 
Optional 
 
Yes 
 
Ambient 
Gene expression 
analysis 
(Section 17.43) 
 
FFPE 
10 unstained 
slides of 5 
microns 
 
Mandatory 
 
Optional 
 
Optional 
 
Yes 
 
Ambient 
PDJ amplification 
(Section 17.44) 
 
FFPE 
2 unstained 
slides of 5 
microns 
 
Mandatory 
 
Optional 
 
Optional 
 
Yes 
 
Ambient 
NOTE: First biopsy* is mandatory, second and third are optional. (*Unless adequate tissue is available from biopsy obtained ≤90 days prior to 
registration) 
NOTE: Tests are listed in order of priority. If insufficient material to do all items, start with top and work down. 


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17.2 
Diagnostic Slides from Original and /or Recurrent Tissue 
Please see the number of required unstained slides for each test in the table. Slides should 
be sent to BAP lab in Jacksonville 
 
 
 
 
 
 
 
Along with original diagnostic slides, include pathology reporting form, surgical 
pathology report and operative report. 
17.3 
Correlative Tissue Collection 
17.31 Tissue Kits will not be provided for this protocol. Kits will be supplied by the 
Mayo Florida Biospecimen Acessioning and Processing Shared Resource (BAP). 
See section 14.31 on how to order kits. 
17.32 Paraffin Embedded Tissue 
17.321 
Submit H&E as well as uncharged, unstained slides – see table. Do not 
use coverslips, do not bake. 5 micron thick sections on uncharged 
slides at ambient temperature. 
17.322 
 
 
 
 
 
 
 
 
17.33 Correlative Tissue will be sent to: 
 
 
17.4 
Background and Methodology 
17.41 Tumor infiltrating lymphocytes 
Given that tumor infiltrating lymphocytes (TILs) have been shown to correlate 
with patients’ outcome in several tumor types, we plan to evaluate both stromal 
and intraepithelial TILs in patient samples from this trial. Besides H&E, more 
comprehensive evaluation of TILs will be performed using 
immunohistochemistry (IHC) staining for CD4, CD8, CD25, and FOXP3 as we 
previously published {Knutson 2015}. 
17.42 Immunohistochemistry for PD-L1 


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Since PD-L1 expression had been shown to correlate with response to anti-PD1 
therapy in the past20, we also plan to evaluate PD-L1 expression by 
immunohistochemistry {Topalian 2012} 
17.43 Gene expression analysis 
Global assessment of immune-related gene expression in pre- and post-treatment 
tumors will be assessed to potentially identify baseline gene expression signature 
and/or changes in gene expression that may predict response to this combination. 
Gene expression analysis will be performed using NanoString platform with the 
nCounter GX Human ImmunologyV2 panel comprised of 594 immune-related 
and 15 reference genes. 
17.44 PDJ amplification 
We have recently reported that approximately 30% of patients with TNBC harbor 
PDJ amplification {Barrett 2015}. Locating at chromosome 9p24.1, this 
amplicon encompasses JAK2, PD-L1, and PD-L2 genes. TNBC patients with 
PDJ amplification had worse disease free (25.0% vs. 66.0%, p = 0.005) and 
overall survival (25.0% vs. 69.0%, p = 0.004). This amplicon has been previously 
described in the majority of Hodgkin’s lymphoma, which has been reported to 
have remarkable response to nivolumab (86% clinical benefit rate in heavily 
pretreated patients) {Ansell 2015}. Based on these intriguing results, we plan to 
correlate PDJ amplification and clinical outcome of patients in this trial. 
 
. 


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18.0 
Records and Data Collection Procedures 
18.1 
Submission Timetable 
Data submission instructions for this study can be found in the Case Report Form packet. 
18.2 
Event monitoring 
See Section 4.2 and data submission table in the case report form packet for the event 
monitoring schedule. 
18.3 
CRF completion 
This study will use Medidata Rave for remote data capture (rdc) of all study data. 
18.4 
Site responsibilities 
Each site will be responsible for insuring that all materials contain the patient’s initials, 
MCCC registration number, and MCCC protocol number. Patient’s name must be 
removed. 
18.5 
Supporting documentation 
This study requires supporting documentation for evidence of response to study therapy 
and progression after study therapy. 
For Phase II patients only, attach a copy of documentation of response or progression in 
RAVE on the Supporting Documentation Form 
18.6 
Labelling of materials 
Each site will be responsible for insuring that all materials contain the patient’s initials, 
MCCC registration number, and MCCC protocol number. Patient’s name must be 
removed. 
18.7 
Incomplete materials 
Any materials deemed incomplete by the MCCC Operations Office will be considered 
“not received” and will not be edited or otherwise processed until the missing 
information is received. A list of the missing documents will be made available to the 
appropriate co-sponsor/participant. 
18.8 
Overdue lists 
A list of overdue materials and forms for study patients will be generated monthly. The 
listings will be sorted by location and will include the patient study registration number. 
The appropriate co-sponsor/participant will be responsible to obtain the overdue material. 
18.9 
Corrections forms 
If a correction is necessary the QAS will query the site. The query will be sent to the 
appropriate site to make the correction and return the query and documentation of 
correction back to the QAS. 


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19.0 
Budget 
19.1 
Costs charged to patient: routine clinical care 
19.2 
Tests to be research funded: biopsies and research testing on blood and tissue specimens 
19.3 
Other budget concerns: 
19.31 Binimetinib will be supplied by Pfizer Inc. (formerly Array Biopharma LLC and Array 
Biopharma Inc.) 
19.32 Pembrolizumab will be supplied by Merck. 
19.33 Merck, Inc. will provide funding to support this study. 


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20.0 
References 
Adams S, Gray RJ, Demaria S, et al: Prognostic value of tumor-infiltrating lymphocytes in triple-negative 
breast cancers from two phase III randomized adjuvant breast cancer trials: ECOG 2197 and 
ECOG 1199. Journal of clinical oncology : official journal of the American Society of Clinical 
Oncology 32:2959-66, 2014 
Anders C, Carey LA: Understanding and treating triple-negative breast cancer. Oncology 22:1233-9; 
discussion 1239-40, 1243, 2008 
Ansell SM, Lesokhin AM, Borrello I, et al: PD-1 blockade with nivolumab in relapsed or refractory 
Hodgkin's lymphoma. The New England journal of medicine 372:311-9, 2015 
Balko J, Denkert C, Salgado R, et al: Reduced tumor lymphocytic infiltration in the residual disease (RD) 
of post-neoadjuvant chemotherapy (NAC) triple-negative breast cancers (TNBC) is associated 
with Ras/MAPK activation and poorer survival, San Antonio Breast Cancer Symposium, 2014 
Barretina J, Caponigro G, Stransky N, et al: The Cancer Cell Line Encyclopedia enables predictive 
modelling of anticancer drug sensitivity. Nature 483:603-7, 2012 
Barrett MT, Anderson KS, Lenkiewicz E, et al: Genomic amplification of 9p24.1 targeting JAK2, PD-L1, 
and PD-L2 is enriched in high-risk triple negative breast cancer. Oncotarget 6:26483-93, 2015 
Bohnsack O, Ludajic K, Hoos A: Adaptation of the Immune-Related Response Criteria: irRECIST. 
ESMO 2014 abstract 4958, 2014. 
Denkert C, Loibl S, Noske A, et al: Tumor-associated lymphocytes as an independent predictor of 
response to neoadjuvant chemotherapy in breast cancer. Journal of clinical oncology : official 
journal of the American Society of Clinical Oncology 28:105-13, 2010 
Eisenhauer EA, Therasse P, Bogaert J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, 
Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. New response 
evaluation criteria in solid tumors: revised RECIST guideline (version 1.1). Eur J Cancer 45(2): 
228-247, 2009. 
Emens L, Braiteh F, Cassier P, et al: Inhibition of PD-L1 by MPDL3280A leads to clinical activity in 
patients with metastatic triple-negative breast cancer, San Antonio Breast Cancer Symposium, 
2014 
Hammond ME, Hayes DF, Dowsett M, et al: American Society of Clinical Oncology/College Of 
American Pathologists guideline recommendations for immunohistochemical testing of estrogen 
and progesterone receptors in breast cancer. J Clin Oncol 28:2784-95, 2010 
Irvin WJ, Carey LA: What is triple-negative breast cancer? Eur J Cancer:doi:10.1016/j.ejca.2008.09.034, 
2008 
Knutson KL, Maurer MJ, Preston CC, et al: Regulatory T cells, inherited variation, and clinical outcome 
in epithelial ovarian cancer. Cancer immunology, immunotherapy : CII 64:1495-504, 2015 
Lea IA, Jackson MA, Li X, et al: Genetic pathways and mutation profiles of human cancers: site- and 
exposure-specific patterns. Carcinogenesis 28:1851-8, 2007 
Loi S, Sirtaine N, Piette F, et al: Prognostic and predictive value of tumor-infiltrating lymphocytes in a 
phase III randomized adjuvant breast cancer trial in node-positive breast cancer comparing the 
addition of docetaxel to doxorubicin with doxorubicin-based chemotherapy: BIG 02-98. Journal 
of clinical oncology : official journal of the American Society of Clinical Oncology 31:860-7, 
2013 
McCubrey JA, May WS, Duronio V, et al: Serine/threonine phosphorylation in cytokine signal 
transduction. Leukemia 14:9-21, 2000 


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Nakazawa K, Dobashi Y, Suzuki S, et al: Amplification and overexpression of c-erbB-2, epidermal 
growth factor receptor, and c-met in biliary tract cancers. J Pathol 206:356-65, 2005 
Nanda R, Chow L, Dees E, et al: A phase Ib study of pembrolizumab (MK-3475) in patients with 
advanced triple-negative breast cancer, San Antonio Breast Cancer Symposium, 2014 
Ohren JF, Chen H, Pavlovsky A, et al: Structures of human MAP kinase kinase 1 (MEK1) and MEK2 
describe novel noncompetitive kinase inhibition. Nat Struct Mol Biol 11:1192-7, 2004 
Roberts PJ, Der CJ: Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the 
treatment of cancer. Oncogene 26:3291-310, 2007 
Shah SP, Roth A, Goya R, et al: The clonal and mutational evolution spectrum of primary triple-negative 
breast cancers. Nature 486:395-9, 2012 
Stephens PJ, Tarpey PS, Davies H, et al: The landscape of cancer genes and mutational processes in 
breast cancer. Nature 486:400-4, 2012 
Thomas A, Rajan A, Szabo E, et al: A phase I/II trial of belinostat in combination with cisplatin, 
doxorubicin, and cyclophosphamide in thymic epithelial tumors: a clinical and translational 
study. Clinical cancer research : an official journal of the American Association for Cancer 
Research 20:5392-402, 2014 
Topalian SL, Hodi FS, Brahmer JR, et al: Safety, activity, and immune correlates of anti-PD-1 antibody 
in cancer. The New England journal of medicine 366:2443-54, 2012 
Tusher VG, Tibshirani R, Chu G: Significance analysis of microarrays applied to the ionizing radiation 
response. Proc Natl Acad Sci U S A 98:5116-21, 2001 
Wardley AM, Stein R, McCaffrey J, et al: Phase II data for entinostat, a class 1 selective histone 
deacetylase inhibitor, in patients whose breast cancer is progressing on aromatase inhibitor 
therapy, J Clin Oncol 28:15s, 2010 (suppl; abstr 1052), 2010 
Wu Z, Irizarry RA: Stochastic Models Inspired by Hybridization Theory for Short Oligonucleotide 
Arrays. Proceedings of RECOMB In Press, 2004 
Yoon S, Seger R: The extracellular signal-regulated kinase: multiple substrates regulate diverse cellular 
functions. Growth Factors 24:21-44, 2006 


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Appendix I 
ECOG Performance Status 
 
 
ECOG PERFORMANCE STATUS* 
Grade ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work 
activities. Up and about more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours. 
4 
Completely disabled. Cannot carry on any selfcare. 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 ECOG Performance Status is in the public domain therefore available for public use. To duplicate the 
scale, please cite the reference above and credit the Eastern Cooperative Oncology Group, Robert Comis 
M.D., Group Chair. 
 
From http://www.ecog.org/general/perf_stat.html 


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Appendix II 
Patient Medication Diary 
 
Name _ 
 
Study ID Number 
 
 
Please complete this diary on a daily basis. Write in the amount of the dose of binimetinib that you took 
in the appropriate “Day” box. Binimetinib can be taken with or without food and should be taken twice a 
day approximately 12 hours apart. 
On the days that you do not take any study drug, please write in “0”. If you forget to take your dose, 
please write in “0”, but remember to take your prescribed dose at the next regularly scheduled time. 
Please drink at least 6 to 8 cups of liquid per day to help drug absorption. Swallow pills whole, with 
water, and do not to break, chew, crush or open the pills. 
If you experience any health/medical complaints or take any NEW medication other than your regular 
medications and binimetinib, please record this information. 
 
Week of: 
Binimetinib 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Morning dose 
 
 
 
 
 
 
 
Evening dose 
 
 
 
 
 
 
 
 
Week of: 
Binimetinib 
Day 8 
Day 9 
Day 10 
Day 11 
Day 12 
Day 13 
Day 14 
Morning dose 
 
 
 
 
 
 
 
Evening dose 
 
 
 
 
 
 
 
 
Week of: 
Binimetinib 
Day 15 
Day 16 
Day 17 
Day 18 
Day 19 
Day 20 
Day 21 
Morning dose 
 
 
 
 
 
 
 
Evening dose 
 
 
 
 
 
 
 
 
Patient signature:  
Date:   
 
 
 
Health or medical complaints during this time: 
 
 
 
 
 
 
 
 


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Other NEW medications or supplements (not previously reported) taken during this time: 
 
Name of NEW medication or 
supplement 
 
How much did you take? 
(example: Two 500mg pills) 
When did you take it 
(examples: Every day 
Or Day 19 and Day 20) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Use a separate sheet of paper if more space is needed. 
 
If you’ve been instructed by the study team to monitor your Blood Pressure please record your blood 
pressure readings in the space below. You should take your blood pressure at the same time after taking 
any hypertensive medications and after being at rest for 5 minutes in a sitting position 10 days & 30 days 
after starting binimetinib 
 
DAY 10 ( 
):   
 
 
DAY 30 ( 
):   
 
If the systolic reading (top number) is ≥160 mmHg, or diastolic reading (bottom number) is ≥100 mmHg, 
contact your study team. 
 
 
 
 
 
Study Coordinator Use Only 
 
Number of pills returned   
 
Number of bottles returned:   
  
Discrepancy Yes  
/No  
 
Verified by   
 
Date  
 
My next scheduled visit is:   
 
If you have any questions, please call:   
 
Bring all bottles and any unused study medication along with this diary when you return for your next 
appointment. 


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Appendix III List of medications to be used with caution with binimetinib 
List of CYP2B6, CYP2C9 and CYP3A substrates to be used with caution 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  List of strong CYP3A inhibitors to be used with caution 
 
Strong Inhibitors – AUC substrate increased by ≥ 5 fold 
Boceprevir, clarithromycin, cobicistat, conivaptan, elivegravir, indinavir, itraconazole, ketoconazole, 
lopinavir, mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, 
tipranavir, troleandomycin, voriconazole 
CYP Enzymes 
Substrates 
CYP2B6 
Alkylating Agents (anticancer): cyclophosphamide, ifosfamide, thiotepa 
Others: bupropion1, efavirenz1, methadone 
CYP2C9 
Angiotensin II Blockers: losartan, irbesartan 
NSAIDs: diclofenac, ibuprofen, piroxicam 
Oral Hypoglycemics: tolbutamide, glipizide 
Others: acenocoumarol, celecoxib1, phenytoin2, sulfamethoxazole, tolbutamide, 
torsemide, warfarin2 
CYP3A4,5,7 
Antiarrhythmics: quinidine→3-OH (not CYP3A5)2, dronedarone1 
Antihistamines: astemizole2, ebastine1, [ terfenadine]1,2 
Benzodiazepines (CNS agents): alprazolam, brotizolam1, diazepam→3OH, 
midazolam1, triazolam1 
Calcium Channel Blockers: amlodipine, diltiazem, felodipine1, nifedipine, 
nisoldipine1, nitrendipine, verapamil 
Protease Inhibitors: boceprevir, brecanavir1, capravirine1, darunavir1, indinavir1, 
lopinavir1, ritonavir, saquinavir1, telaprevir, tipranavir1 
HMG CoA Reductase Inhibitors: atorvastatin1, lovastatin1, simvastatin1 
Immune Modulators: cyclosporine2, everolimus1, sirolimus1,2, tacrolimus1,2 
Antibiotics: clarithromycin, erythromycin (not CYP3A5), telithromycin 
Antipsychotics: aripiprazole, haloperidol, lurasidone1, perospirone1, pimozide2, 
quetiapine1 
Tyrosine Kinase Inhibitors (anticancer): dasatinib1, imatinib, neratinib1, nilotinib 
Opioids: alfentanil1,2, fentanyl2, methadone, levomethadyl1 
Ergot derivatives (for migraines): diergotamine (dihydroergotamine)2, ergotamine2 
Corticosteroids: budesonide1, fluticasone1 
Erectile Dysfunction Agents: sildenafil1, vardenafil1 
Antiemetics: aprepitant1, casopitant1 
Others: alpha-dihydroergocryptine1, aplaviroc1, buspirone1, cisapride2, conivaptan1, 
darifenacin1, eletriptan1, eplerenone1, lumefantrine1, maraviroc1, quinine, 
ridaforolimus1, tamoxifen, ticagrelor1, tolvaptan1, trazodone, vicriviroc1, vincristine 
This database of CYP substrates was compiled from the Indiana University School of Medicine’s 
“Clinically Relevant” Table; from the FDA’s “Guidance for Industry, Drug Interaction Studies” and from 
the University of Washington’s Drug Interaction Database. 
1 Sensitive substrates: Drugs that exhibit an AUC ratio (AUCi/AUC) of 5-fold or more when co- 
administered with a known potent inhibitor. 
2 Substrates with narrow therapeutic index (NTI): Drugs whose exposure-response indicates that 
increases in their exposure levels by the concomitant use of potent inhibitors may lead to serious safety 
concerns (e.g., Torsades de Pointes). 


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List of P-gp inhibitors and dual P-gp/CYP3A inhibitors to be used with caution 
 
Inhibitor* 
(P-gp probe substrate is digoxin unless otherwise specified; CYP3A 
probe substrate is midazolam unless otherwise specified) 
P-gp 
CYP3A4,5,7 
Maximum 
AUC Ratio 
(AUCi/AUC)** 
Inhibition 
Coding 
Calcium Channel Blockers: 
 
 
felodipine 
1.5 
 
verapamil 
1.5 
2 
diltiazem 
1.4 
2 
mibefradil 
1.3 
3 
nifedipine 
1.2 
 
nitrendipine 
1.2 
 
Protease Inhibitors: 
 
 
indinavir/ritonavir 
4.8a 
3d 
indinavir 
3.3a 
3 
lopinavir/ritonavir 
1.8 
3e 
telaprevir 
1.8 
3 
saquinavir/ritonavir 
1.7 
3 
tipranavir/ritonavir 
1.6 
3 
nelfinavir 
1.3 
3 
ritonavir 
1.2 
3 
Antibiotics: 
 
 
fexofenadine 
1.7a 
 
clarithromycin 
1.7 
3 
azithromycin 
1.7a 
1 
erythromycin 
1.5b 
2 
rifampin 
1.5 
 
Antiarrhythmics: 
 
 
quinidine 
2.7 
 
dronedarone 
2.3 
 
amiodarone 
1.7 
 
α/β Adrenergic Antagonists: 
 
 
carvedilol 
1.6 
 
talinolol 
1.2 
 
Herbal Medications: 
 
 
Schisandra chinensis 
1.5b 
 
St John’s wort (hypericum perforatum) 
1.3a 
 
milk thistle (silybum marianum) 
1.3b 
 
ginkgo (ginkgo biloba) 
1.2b 
 


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Inhibitor* 
(P-gp probe substrate is digoxin unless otherwise specified; CYP3A 
probe substrate is midazolam unless otherwise specified) 
P-gp 
CYP3A4,5,7 
Maximum 
AUC Ratio 
(AUCi/AUC)** 
Inhibition 
Coding 
Others: 
 
 
valspodar (PSC 833) 
3 
 
elacridar (GF120918) 
2.4c 
 
ranolazine 
1.9 
 
fluvoxamine 
1.8a 
1 
amiodarone 
1.7 
 
itraconazole 
1.7 
 
quercetin 
1.6a 
 
captopril 
1.4 
 
conivaptan 
1.4 
 
paroxetine 
1.4a 
 
ticagrelor 
1.3 
 
telmisartan 
1.2 
 
tolvaptan 
1.2 
1 
*This database of P-gp and CYP3A inhibitors was compiled from the FDA’s “Guidance for Industry, Drug 
Interaction Studies;” and from the University of Washington (UW)’s Drug Interaction Database. 
**Maximum AUC ratios are provided from UW Database. 
X = 3 for strong inhibitors, which result in substrate AUC ratio (AUCi/AUC) of ≥ 5-fold. 
X = 2 for moderate inhibitors, which result in substrate AUC ratio (AUCi/AUC) of ≥ 2-fold and < 5-fold. 
X = 1 for weak inhibitors, which result in substrate AUC ratio (AUCi/AUC) of ≥ 1.25-fold and < 2-fold. 
X = BLANK for inhibitors whose level of inhibition is unknown or results in an AUC ratio (AUCi/AUC) of < 
1.25-fold. 
a P-gp probe substrate is fexofenadine. b P-gp probe substrate is talinolol. c P-gp probe substrate is 
topotecan. d CYP3A probe substrate is alfentanil. e CYP3A probe substrate is aplaviroc. 
 
 
List of substrates and inhibitors/inducers of human transporters to be used with caution 
Transporter 
Substrates 
Inhibitors 
Inducers 
P-gp* 
 
See previous table 
rifampin (rifampicin), St- 
John’s worth (hypericum 
perforatum) 
BCRP 
daunorubicin, 
doxorubicin, 
topotecan, rosuvastatin, 
sulfasalazine 
elacridar (GF120918)  


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Transporter 
Substrates 
Inhibitors 
Inducers 
OATP1B1* 
atrasentan, atorvastatin, 
bosentan, ezetimibe, 
fluvastatin, glyburide, 
SN-38, rosuvastatin, 
simvastatin acid, 
pitavastatin, pravastatin, 
repaglinide, rifampin, 
valsartan, olmesartan 
 
OATP1B3* 
atorvastatin, 
rosuvastatin, 
pitavastatin, telmisartan, 
valsartan, olmesartan 
 
* This database was compiled from the FDA’s “Guidance for Industry, Drug Interaction Studies-study 
design, data analysis, implications for dosing, and labeling recommendations” published in February 
2012 
 
 
List of drugs with known risk for causing Torsades de Pointes to be used with caution 
Substantial evidence supports the conclusion that these drugs, when used as directed in labeling, can 
prolong the QT interval and can have a risk of Torsades de pointes (TdP) in some patients. 
 
Generic Name 
Brand Name 
Class/Clinical Use 
Comments 
Amiodarone 
Cordarone® 
Anti-arrhythmic / 
abnormal heart rhythm 
Females>Males,TdP 
risk regarded as low 
Amiodarone 
Pacerone® 
Anti-arrhythmic / 
abnormal heart rhythm 
Females>Males,TdP 
risk regarded as low 
Arsenic trioxide 
Trisenox® 
Anti-cancer / Leukemia  
Astemizole 
Hismanal® 
Antihistamine / Allergic 
rhinitis 
No Longer available in 
U.S. 
Azithromycin 
Zithromax® 
Antibiotic / bacterial 
infection 
 
Bepridil 
Vascor® 
Anti-anginal / heart pain 
Females>Males 
Chloroquine 
Aralen® 
Anti-malarial / malaria 
infection 
 
 
Chlorpromazine 
 
Thorazine® 
Anti-psychotic/ Anti- 
emetic / schizophrenia/ 
nausea 
 
Cisapride 
Propulsid® 
GI stimulant / heartburn 
No longer available in 
U.S. 
Citalopram 
Celexa® 
Anti-depressant / 
depression 
 
Clarithromycin 
Biaxin® 
Antibiotic / bacterial 
infection 
 


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Generic Name 
Brand Name 
Class/Clinical Use 
Comments 
Disopyramide 
Norpace® 
Anti-arrhythmic / 
abnormal heart rhythm 
Females>Males 
Dofetilide 
Tikosyn® 
Anti-arrhythmic / 
abnormal heart rhythm 
Females > Males 
Domperidone 
Motilium® 
Anti-nausea / nausea 
Not available in U.S. 
 
Droperidol 
 
Inapsine® 
Sedative;Anti-nausea / 
anesthesia adjunct, 
nausea 
 
 
Erythromycin 
 
E.E.S.® 
Antibiotic;GI stimulant / 
bacterial infection; 
increase GI motility 
 
Females>Males 
 
Erythromycin 
 
Erythrocin® 
Antibiotic;GI stimulant / 
bacterial infection; 
increase GI motility 
 
Females>Males 
 
Escitalopram 
 
Cipralex® 
Anti-depressant / Major 
depression/ Anxiety 
disorders 
 
 
Escitalopram 
 
Lexapro® 
Anti-depressant / Major 
depression/ Anxiety 
disorders 
 
Flecainide 
Tambocor® 
Anti-arrhythmic / 
abnormal heart rhythm 
 
Halofantrine 
Halfan® 
Anti-malarial / malaria 
infection 
Females>Males 
Haloperidol 
Haldol® 
Anti-psychotic / 
schizophrenia, agitation 
TdP risk with I.V. or 
excess dosage 
Ibutilide 
Corvert® 
Anti-arrhythmic / 
abnormal heart rhythm 
Females>Males 
 
Levomethadyl 
 
Orlaam® 
Opiate agonist / pain 
control, narcotic 
dependence 
 
Not available in U.S. 
Mesoridazine 
Serentil® 
Anti-psychotic / 
schizophrenia 
Removed from US 
market in 2004 
 
Methadone 
 
Dolophine® 
Opiate agonist / pain 
control, narcotic 
dependence 
 
Females>Males 
 
Methadone 
 
Methadose® 
Opiate agonist / pain 
control, narcotic 
dependence 
 
Females>Males 
Moxifloxacin 
Avelox® 
Antibiotic / bacterial 
infection 
 
Pentamidine 
NebuPent® 
Anti-infective / 
pneumocystis 
Females>Males 


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Generic Name 
Brand Name 
Class/Clinical Use 
Comments 
 
 
pneumonia 
 
 
Pentamidine 
 
Pentam® 
Anti-infective / 
pneumocystis 
pneumonia 
 
Females>Males 
Pimozide 
Orap® 
Anti-psychotic / 
Tourette's tics 
Females>Males 
Probucol 
Lorelco® 
Antilipemic / 
Hypercholesterolemia 
No longer available in 
U.S. 
Procainamide 
Pronestyl® 
Anti-arrhythmic / 
abnormal heart rhythm 
 
Procainamide 
Procan® 
Anti-arrhythmic / 
abnormal heart rhythm 
 
Quinidine 
Quinaglute® 
Anti-arrhythmic / 
abnormal heart rhythm 
Females>Males 
Quinidine 
Cardioquin® 
Anti-arrhythmic / 
abnormal heart rhythm 
Females>Males 
 
 
Sevoflurane 
 
 
Ulane® 
 
Anesthetic, general / 
anesthesia 
Label warning for 
patients with congenital 
long QT or patients 
taking QT prolonging 
drugs 
 
 
Sevoflurane 
 
 
Sojourn® 
 
Anesthetic, general / 
anesthesia 
Label warning for 
patients with congenital 
long QT or patients 
taking QT prolonging 
drugs 
Sotalol 
Betapace® 
Anti-arrhythmic / 
abnormal heart rhythm 
Females>Males 
Sparfloxacin 
Zagam® 
Antibiotic / bacterial 
infection 
No longer available in 
U.S. 
Terfenadine 
Seldane® 
Antihistamine / Allergic 
rhinitis 
No longer available in 
U.S. 
Thioridazine 
Mellaril® 
Anti-psychotic / 
schizophrenia 
 
Vandetanib 
Caprelsa® 
Anti-cancer / Thyroid 
cancer 
 


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List of drugs with possible risk for causing Torsades de Pointes to be used with caution 
Substantial evidence supports the conclusion that these drugs, when used as directed in labeling, can 
cause QT prolongation but there is insufficient evidence at this time that they have a risk of causing TdP. 
 
Generic Name 
Brand Name 
Class/Clinical Use 
Comments 
Alfuzosin 
Uroxatral® 
Alpha1-blocker / Benign 
prostatic hyperplasia 
 
 
Amantadine 
 
Symmetrel® 
Dopaminergic/Anti-viral 
/ Anti-infective/ 
Parkinson's Disease 
 
Artenimol+piperaquine 
Eurartesim® 
Anti-malarial / 
Not available in U.S. 
Atazanavir 
Reyataz® 
Protease inhibitor / HIV  
Bedaquiline 
Sirturo® 
Anti-infective / Drug- 
resistant Tuberculosis 
Black Box for QT 
Chloral hydrate 
Noctec® 
Sedative / sedation/ 
insomnia 
 
Clozapine 
Clozaril® 
Anti-psychotic / 
schizophrenia 
 
Dolasetron 
Anzemet® 
Anti-nausea / nausea, 
vomiting 
 
Dronedarone 
Multaq® 
Anti-arrhythmic / Atrial 
Fibrillation 
 
Eribulin 
Halaven® 
Anti-cancer / metastatic 
breast neoplasias 
 
Famotidine 
Pepcid® 
H2-receptor antagonist / 
Peptic ulcer/ GERD 
 
Felbamate 
Felbatol® 
Anti-convulsant / 
seizure 
 
Fingolimod 
Gilenya® 
Immunosuppressant / 
Multiple Sclerosis 
 
Foscarnet 
Foscavir® 
Anti-viral / HIV infection  
Fosphenytoin 
Cerebyx® 
Anti-convulsant / 
seizure 
 
 
Gatifloxacin 
 
Tequin® 
 
Antibiotic / bacterial 
infection 
Oral/I.V. forms no 
longer available in U.S. 
and Canada, only 
ophthalmic 
Gemifloxacin 
Factive® 
Antibiotic / bacterial 
infection 
 
Granisetron 
Kytril® 
Anti-nausea / nausea 
and vomiting 
 
Iloperidone 
Fanapt® 
Antipsychotic, atypical / 
Schizophrenia 
 


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Generic Name 
Brand Name 
Class/Clinical Use 
Comments 
Indapamide 
Lozol® 
Diuretic / stimulate urine 
& salt loss 
 
Isradipine 
Dynacirc® 
Anti-hypertensive / high 
blood pressure 
 
Lapatinib 
Tykerb® 
Anti-cancer / breast 
cancer, metastatic 
 
Lapatinib 
Tyverb® 
Anti-cancer / breast 
cancer, metastatic 
 
Levofloxacin 
Levaquin® 
Antibiotic / bacterial 
infection 
 
Lithium 
Eskalith® 
Anti-mania / bipolar 
disorder 
 
Lithium 
Lithobid® 
Anti-mania / bipolar 
disorder 
 
Mirtazapine 
Remeron 
Anti-depressant / 
 
Moexipril/HCTZ 
Uniretic® 
Anti-hypertensive / high 
blood pressure 
 
Nicardipine 
Cardene® 
Anti-hypertensive / high 
blood pressure 
 
Nilotinib 
Tasigna® 
Anti-cancer / Leukemia  
Octreotide 
Sandostatin® 
Endocrine / acromegaly, 
carcinoid diarrhea 
 
Ofloxacin 
Floxin® 
Antibiotic / bacterial 
infection 
 
Olanzapine 
Zyprexa® 
Antipsychotic, atypical / 
Schizophrenia, bipolar 
Combo c fluoxetine: 
Symbyax 
Ondansetron 
Zofran® 
Anti-emetic / nausea 
and vomiting 
 
Oxytocin 
Pitocin® 
Oxytocic / Labor 
stimulation 
 
Paliperidone 
Invega® 
Antipsychotic, atypical / 
Schizophrenia 
 
Perflutren lipid 
microspheres 
Definity® 
Imaging contrast agent / 
Echocardiography 
 
Quetiapine 
Seroquel® 
Anti-psychotic / 
schizophrenia 
 
Ranolazine 
Ranexa® 
Anti-anginal / chronic 
angina 
 
Risperidone 
Risperdal® 
Anti-psychotic / 
schizophrenia 
 


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Generic Name 
Brand Name 
Class/Clinical Use 
Comments 
Roxithromycin* 
Rulide® 
Antibiotic / bacterial 
infection 
*Not available in U.S. 
Sertindole 
Serdolect® 
Antipsychotic, atypical / 
Anxiety, Schizophrenia 
Not available in U.S. 
Sertindole 
Serlect® 
Antipsychotic, atypical / 
Anxiety, Schizophrenia 
Not available in U.S. 
Sunitinib 
Sutent® 
Anti-cancer / RCC, 
GIST 
 
Tacrolimus 
Prograf® 
Immunosuppressant / 
Immune suppression 
 
Tamoxifen 
Nolvadex® 
Anti-cancer / breast 
cancer 
 
Telithromycin 
Ketek® 
Antibiotic / bacterial 
infection 
 
Tizanidine 
Zanaflex® 
Muscle relaxant / 
 
Vardenafil 
Levitra® 
phosphodiesterase 
inhibitor / vasodilator 
 
Venlafaxine 
Effexor® 
Anti-depressant / 
depression 
 
Voriconazole 
VFend® 
Anti-fungal / anti-fungal  
Ziprasidone 
Geodon® 
Anti-psychotic / 
schizophrenia 
 
 
 
List of drugs with conditional risk for causing Torsades de Pointes to be used with caution 
Substantial evidence supports the conclusion that these drugs can prolong QT and therefore have a risk of 
TdP but only under certain known conditions (e.g. excessive dose, drug interaction, etc.). 
 
Generic Name 
Brand Name 
Class/Clinical Use 
Comments 
 
Amisulpride 
 
Solian® and others 
 
Antipsychotic, atypical / 
Risk of TdP with 
overdose - not available 
in US 
Amitriptyline 
Elavil® 
Tricyclic Antidepressant 
/ depression 
Risk of TdP with 
overdosage 
Ciprofloxacin 
Cipro® 
Antibiotic / bacterial 
infection 
Drug interaction risk - 
metabolic inhibitor 
Clomipramine 
Anafranil® 
Tricyclic Antidepressant 
/ depression 
 
Desipramine 
Pertofrane® 
Tricyclic Antidepressant 
/ depression 
Risk of TdP with 
overdosage 
 
Diphenhydramine 
 
Benadryl® 
Antihistamine / Allergic 
rhinitis, insomnia 
Risk of QT 
increase/TdP in 
overdosages 


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Generic Name 
Brand Name 
Class/Clinical Use 
Comments 
 
Diphenhydramine 
 
Nytol® 
Antihistamine / Allergic 
rhinitis, insomnia 
Risk of QT 
increase/TdP in 
overdosages 
Doxepin 
Sinequan® 
Tricyclic Antidepressant 
/ depression 
 
 
Fluconazole 
 
Diflucan® 
 
Anti-fungal / fungal 
infection 
Drug interaction risk- 
metabolic inhibitor. Can 
also increase QT at high 
doses - 800 mg/day 
Fluoxetine 
Sarafem® 
Anti-depressant / 
depression 
 
Fluoxetine 
Prozac® 
Anti-depressant / 
depression 
 
Galantamine 
Reminyl® 
Cholinesterase inhibitor 
/ Dementia, Alzheimer's 
 
Imipramine 
Norfranil® 
Tricyclic Antidepressant 
/ depression 
TdP risk with excess 
dosage 
Itraconazole 
Sporanox® 
Anti-fungal / fungal 
infection 
Drug interaction risk - 
metabolic inhibitor 
 
Ketoconazole 
 
Nizoral® 
Anti-fungal / fungal 
infection 
Prolongs QT & Drug 
interaction risk - 
metabolic inhibitor. 
Nortriptyline 
Pamelor® 
Tricyclic Antidepressant 
/ depression 
 
Paroxetine 
Paxil® 
Anti-depressant / 
depression 
 
Protriptyline 
Vivactil® 
Tricyclic Antidepressant 
/ depression 
 
 
Quinine sulfate 
 
Qualaquin® 
Anti-malarial / Malaria or 
leg cramps 
TdP with overdose or 
drug-drug or drug food 
interaction 
Ritonavir 
Norvir® 
Protease inhibitor / HIV 
 
Sertraline 
Zoloft® 
Anti-depressant / 
depression 
 
 
Solifenacin 
 
VESIcare® 
muscarinic receptor 
anatagonist / treatment 
of overactive bladder 
 
Trazodone 
Desyrel® 
Anti-depressant / 
Depression, insomnia 
 
Trimethoprim-Sulfa 
Septra® or Bactrim® 
Antibiotic / bacterial 
infection 
Also available in DS 
(double strength) 


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Generic Name 
Brand Name 
Class/Clinical Use 
Comments 
Trimipramine 
Surmontil® 
Tricyclic Antidepressant 
/ depression 


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Appendix IV Biospecimen Accessioning Processing Requisition Form 
 
 
 
 
 
 
 
 
 
 
Patient Initials: 
 
F 
M 
L 
 
Other Subject ID #: 
 
Date of Birth: 
 
- 
- 
Day Month Year 
Gender: 
Male 
Female 
Study Name: MC1632 
Visit Description: Please check box and include label time 
point 
 
  
Visit: Blood Draw Label   
 
Study Contact: 
Visit: Tissue Label   
 
 
 
Collection Site Contact: (Please 
write/print legibly) 
 
Specimen collection 
 
Date: 
- 
- 
(M-D-Y) 
 
Name: 
  
_  
_ 
 
Time: 
: 
(24-hour clock) 
Phone: 
  
_  
_ 
 
 
 
Email: 
  
_  
_ 
FedEx Tracking Number: Please fill in prior to shipping 
Place Patient Label below: 
Notes: Send package – Priority Overnightt 
 
 
 
 


MC1632 
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1. 
Kodumudi KN, Siegel J, Weber AM, Scott E, Sarnaik AA, Pilon-Thomas S. Immune Checkpoint 
Blockade to Improve Tumor Infiltrating Lymphocytes for Adoptive Cell Therapy. PLoS One. 
2016;11:e0153053. 
2. 
Salgado R, Denkert C, Demaria S, Sirtaine N, Klauschen F, Pruneri G, et al. The evaluation of 
tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs 
Working Group 2014. Ann Oncol. 2015;26:259-71. 
3. 
Knutson KL, Maurer MJ, Preston CC, Moysich KB, Goergen K, Hawthorne KM, et al. 
Regulatory T cells, inherited variation, and clinical outcome in epithelial ovarian cancer. Cancer Immunol 
Immunother. 2015;64:1495-504. 
4. 
Barrett MT, Anderson KS, Lenkiewicz E, Andreozzi M, Cunliffe HE, Klassen CL, et al. Genomic 
amplification of 9p24.1 targeting JAK2, PD-L1, and PD-L2 is enriched in high-risk triple negative breast 
cancer. Oncotarget. 2015;6:26483-93. 
5. 
Ansell SM, Lesokhin AM, Borrello I, Halwani A, Scott EC, Gutierrez M, et al. PD-1 blockade 
with nivolumab in relapsed or refractory Hodgkin's lymphoma. N Engl J Med. 2015;372:311-9.