Conditions: Multiple Myeloma
Keywords: Relapsed/Refractory MK-3475 & Pomalidomide Immunotherapy
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 48
Healthy volunteers: no

Brief summary:
This is an open label trial of Anti PD1/MD-3475, Pomalidomide and dexamethasone. The study will use standard (FDA approved) doses for both pomalidomide and dexamethasone. The experimental drug Anti PD-1 (MK 3475) given on days 1 and 14.

Detailed description:
This phase I/II study is focused on patients with relapsed or refractory multiple myeloma. MK-3475 will be given as an intravenous infusion at every 2 weeks. Treatment will be administered on an outpatient basis.

Arms:
arm 1: Pomalidomide is given at standard dose of 4 mg daily orally for 21 days and dexamethasone is given at 40 mg orally weekly. MK3475 will be given as an intravenous infusion at 200 mg every 2 weeks (days 1 and 14).

Interventions: intervention 1: MK-3475 intervention 2: Pomalidomide intervention 3: Dexamethasone
Intervention descriptions: intervention 1: Anti PD-1 (MD 3475) will be given as an intravenous infusion at 200 mg every 2 weeks. intervention 2: Pomalidomide is given at standard dose of 4 mg daily orally for 21 days intervention 3: Dexamethasone is given at 40 mg orally weekly

Protocol document:
Prot_SAP_000.pdf: 
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SPONSOR: Ashraf Badros, M.B., ChB.  
 
STUDY SITE: 
University of Maryland Greenebaum Cancer Center (UMGCC)  
 
TITLE: A Phase I/II Study of Anti PD-1 (MK 3475), Pomalidomide and 
Dexamethasone in Patients with Relapsed or Refractory Multiple Myeloma 
 
IND NUMBER: 124276 
Protocol numbers: GCC1454 / HP-00061522 
Protocol version and date: Amendment 3.1 July 7, 2016  
Inclusive of Letter of Clarification Changes dated: August 24, 2015 
Sponsor and Principal Investigator  
Ashraf Badros, M.B., ChB. 
22 South Greene Street 
Baltimore, MD 21201 
Telephone: (410) 328-1230 
Fax: (410) 328-1975 
Email: abadros@umm.edu 
 
Co-Investigators 
Aaron Rapoport, MD 
Jean Yared, MD 
Nancy Hardy, MD 
Mehmet Hakan Kocoglu 
 
Laboratories 
University of Maryland Medical Center Laboratories of Pathology 
22 South Greene Street 
Baltimore, MD 21201 
 
Merck Research Laboratories 
QEDI 
Quintiles Laboratories Europe 
Alba Campus, Roseband 
Livingston, West Lothian 
Scotland, EH54 7EG UK 
 
Statistical analysis 
Olga Goloubeva, Ph.D. 
 
 


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Monitor 
University of Maryland Greenebaum Cancer Center Monitor 
 
Trial Financial Support 
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. 
 


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TRIAL SUMMARY 
Abbreviated Title 
Anti-PD-1 (MK-3475) and IMiD (Pomalidomide) and 
Dexamethasone 
Combination 
Immunotherapy 
in 
Relapsed/Refractory Multiple Myeloma 
Trial Phase 
Phase I/II 
Clinical Indication 
Relapsed and/or Refractory multiple myeloma 
Trial Type 
Open label dose escalation  
Type of control 
None 
Route of administration 
Anti PD1/ MK-3475 - Intravenous 
Pomalidomide and dexamethasone - Oral 
Trial Blinding 
N/A 
Treatment Groups  
Run up dose escalation for safety  
Phase 2 …expansion cohort for efficacy and safety  
Number of trial subjects 
Maximum 48 patients 
Estimated duration of trial 24 months 
Duration of Participation 
12 months with an option to continue for responding/stable 
patients. 
 
 
 
 


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Table of Contents 
 
1.0 Trial Design 
 
 
 
 
 
 
 
 
5 
2.0 Objectives & Hypothesis  
 
 
 
 
 
 
6 
3.0 Background 
 
 
 
 
 
 
 
 
6 
4.0 Rationale  
 
 
 
 
 
 
 
 
11 
5.0 Patient Selection  
 
 
 
 
 
 
 
14 
6.0 Treatment  
 
 
 
 
 
 
 
 
17 
7.0 Trial Flow Chart  
 
 
 
 
 
 
 
32 
8.0 Trial Procedures  
 
 
 
 
 
 
 
37 
9.0 Statistical Analysis Plan  
 
 
 
 
 
 
49 
10.0 Labeling, Packaging, Storage and Return of Clinical Supplies  
 
50 
11.0 Compliance with Laws and Regulations 
 
 
 
 
54 
12.0 List of References 
 
 
 
 
 
 
 
56 
Appendices 
 
 
 
 
 
 
 
 
 
57 
 
 
 
 
 
 


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1.0 TRIAL DESIGN 
1.1 
Trial Design 
This phase I/II study is focused on patients with relapsed or refractory multiple myeloma. 
(MM); 48 patients will be enrolled at University of Maryland. Patients must sign informed 
consent, complete pretreatment evaluations and fulfill all eligibility criteria before 
enrollment. Pomalidomide is given at standard dose of 4 mg daily orally for 21 days and 
dexamethasone is given at 40 mg orally on days 1, 8, 15, & 22.  MK-3475 will be given as an 
intravenous infusion at 200 mg every 2 weeks (days 1 and 15). The drug is infused over 30 
minutes. Treatment will be administered on an outpatient basis. A run off stage (6 patients) 
will be treated with MK-3475 at 200 mg every 4 weeks, to establish safety of the 
combination. If dose limiting toxicity (DLT, defined in Appendix B) is seen in 2 of 6 patients 
we will review the dosing schedule and consider amending the protocol before the expansion 
cohorts are started, though this is very unlikely considering the side effect profile of each 
drug. Additional 6 patients will be treated with MK-3475 at 200 mg on days 1 and 15; DLT 
will be assessed after cycle-1. If no toxicity is seen will continue the expansion cohort. If 
DLT is seen in 2/6 patients will consider MK-3475 at 200 mg every 4 weeks the appropriate 
dose for the expansion cohort. 
1.2 
Trial Schema 
Day 
1 
8 
15 
22 
28 
Pomalidomide 4 mg Daily 
Orally Days 1-21 
4 mg 
 
 
MK-3475 
Intravenously Days 1 and 15  
200 mg * 
 
200 mg*  
 
 
Dexamethasone 
Orally weekly**  
40 mg PO  
40 mg PO 
40 mg PO 
40 mg PO 
 
• * In a run off phase, 6 patients will receive MK-3475 intravenously 200 mg on day 1.  
• The study will enroll up to 48 patients with possible additional 2 patients allowing for 
5% non-evaluable patients.  
• Cycles are repeated every 28 days up to 24 months for responding/stable patients, at 
the assigned dose of pomalidomide and MK-3475 (given on day 1 and day 15 of each 
28 day cycle).  
• 
**Elderly patients (over age 70 years) will receive 20 mg of dexamethasone with 2 dose 
reductions at 12 mg weekly (dose level -1) and 12 mg on days 1 & 15 (dose level -2).  
Maintenance 
After 24 months of study drugs, stable and responding patients can continue on the study in 
the maintenance phase until progression, adverse side effects, principal investigator’s 
decision to remove or patient’s wish or inability to comply with the study procedure. While 
on the maintenance phase patients will receive the following:  
 
• Pomalidomide 4 mg daily x 21 days (patients on lower doses due to toxicity will 
continue on the designated dose).  


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• Pembrolizumab 200 mg once monthly (patients on lower doses due to toxicity will 
continue on the designated dose). .  
• Dexamethasone 20-40 mg PO will be given weekly (patients on lower does due to 
toxicity will continue on the designated dose).   
Patient follow-up will be monthly to include CBC, chemistry profile, 24 hour urine, and MM 
staging.  A standard of care bone marrow aspirate will be done once yearly. TSH, T3, T4 will 
be checked every 3 months during the maintenance period.  
2.0 OBJECTIVES & HYPOTHESIS 
The broad expression of PD-1 and its ligands on malignant plasma cells and bone marrow 
microenvironment in Relapsed/Refractory Multiple Myeloma (RRMM) patients establishes 
the importance of the PD-1 pathway in the immune evasion by MM cells.  Immune-mediated 
inflammatory diseases (IMiDs) can down regulate PD-1 and its ligand on T cells and plasma 
cells 
respectively. 
Further 
inhibition 
of 
PD-1/PDL-1 
pathway 
would 
provide 
immunotherapeutic benefit as supported by preclinical data. Currently no data is available 
concerning interaction between Anti-PD-1 and IMiDs. In this study we will evaluate this 
combination in RRMM patients. Besides establishing the safety and efficacy of the regimen 
we will focus on correlative studies to identify markers/profiles that can help select patients 
for future anti-PD-1 therapy. 
2.1 
Primary Objectives 
2.1.1 Establish the safety and tolerability of Pomalidomide and Dexamethasone in 
combination with MK-3475. 
2.1.2 To determine the objective response rate  
2.2 
Secondary Objectives 
2.2.1 Establish time to disease progression in responding RRMM patients. 
2.2.2 Exploratory Correlative Studies  
a. Identify a biomarker for response by evaluating PD-1/PDL-1 expression in 
patients’ samples. 
b. Pharmacogenomics correlation between peripheral blood and bone 
marrow gene expression profiling and response to therapy. 
3.0 BACKGROUND  
3.1 
Disease 
Multiple myeloma (MM) is a clonal plasma cell malignancy characterized by the 
accumulation of plasma cells in the bone marrow and secretion of immunoglobulin leading to 
end organ damage that commonly results in anemia, bone destruction, hypercalcemia, and 
renal failure.[1] MM accounts for 1% of all cancers and 10-15% of hematologic 
malignancies. In the United States (US), approximately 23,000 cases of MM are diagnosed 
each year, and 10,650 die yearly.[2] MM survival has dramatically improved over the last 
decade.  This is due to the widespread use of stem cell transplantation, and the introduction 
of 2 classes of drugs immune modulator (IMiDs) such as thalidomide, lenalidomide and 


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pomalidomide and the proteasome inhibitors (PI) bortezomib and carfilzomib. Most patients 
receive multiple lines of therapy over the course of their disease; however, responses remain 
transient. Patients who relapse and are refractory to these IMiDS and PI do fairly poorly with 
overall survival of less than 9 months.[3] There are few effective salvage therapies available, 
so it is crucial to consider innovative targets to improve outcome in the advanced setting. 
3.2 
Pharmaceutical and Therapeutic Background 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades.[4]  Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies[5].  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.[6] 
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) [7; 
8].  The structure of murine PD-1 has been resolved [9].  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. [7] 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. [8] 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. [9] Expression has also been shown during thymic development on CD4-
CD8- (double negative) T-cells as well as subsets of macrophages and dendritic cells. [10] 
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. [11] 
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 


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expansion in subjects with melanoma. [12] 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. 
3.3 
Agents 
MK-3475  
Summarized from the Investigator’s Brochure (IB). MK-3475 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. MK-3475 
strongly enhances T-lymphocyte immune responses in cultured blood cells from healthy 
human donors, cancer patients, and primates. In T-cell activation assays using human donor 
blood cells, the EC50 (concentration where 50% of the maximum effect is achieved) has 
been ~0.1 to 0.3 nM. In addition to interleukin-2 (IL-2), tumor necrosis factor alpha (TNFα), 
interferon gamma (IFN), and levels of other cytokines were found to be modulated by MK-
3475. The antibody potentiates existing immune responses only in the presence of antigen 
and does not nonspecifically activate T-cells.  
Using an anti-murine PD-1 analog antibody, PD-1 blockade has been shown to significantly 
inhibit tumor growth in a variety of syngeneic murine tumor models. In these experiments in 
mice, anti-PD-1 therapy is synergistic with chemotherapeutic agents such as gemcitabine and 
5-fluorouracil (5-FU) and combination therapy results in increased complete tumor 
regression rates in vivo. After intravenous (IV) administration of MK-3475 to cynomolgus 
monkeys, systemic exposure to MK-3475 independent of sex, increased with increasing dose. 
Systemic exposure for the 7-day dosing interval increased after repeated dosing from 40 to 
200 mg/kg. Area under the concentration-time curve (AUC) for the 7-day dosing interval 
(AUC[0-7 days]) after one dose appeared to be dose-proportional from 0.3 to 200 mg/kg, 
suggesting dose-independent pharmacokinetics (PK). Terminal half-life (t½) values from 
individual animals after repeated IV dosing ranged from 11.8 to 23.7 days (mean values 
ranged from 15.7 to 22.3 days) across the doses tested. There was no test article-related 
mortality, and test article-related changes were limited to an increased incidence of inguinal 
swelling, and increased splenic weights in males receiving 200 mg/kg. The presence of anti-
drug antibodies (ADA) in monkeys did not impact the pharmacodynamic response. The 
presence of ADA was observed in five out of ten animals at 6 mg/kg/dose during the dosing 
phase, which correlated with an apparent increased rate of elimination of MK-3475 in these 
animals. No anti-MK-3475 antibodies were detected at 40 or 200 mg/kg/dose. The potential 
for systemic toxicity was assessed in cynomolgus monkeys administered an IV dose of 6, 40, 
or 200 mg/kg once every other week for approximately 6 months (a total of 12 doses) 
followed by a 4-month treatment free period. MK-3475 was well tolerated at all dose levels. 
There were no test article-related antemortem findings.  
Six clinical trials are currently evaluating MK-3475: PN001, PN002, PN006, PN010, PN011, 
and PN012. 
- 
PN001 is the Phase I first in human (FIH) study of MK-3475, a dose-escalation study 
in patients with progressive locally advanced or metastatic carcinomas, along with 
subject expansion cohorts in MEL and NSCLC. Part A examined 3 dose levels (1, 3, 


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and 10 mg/kg) in patients with solid tumors. With no DLTs observed and no MTD 
reached, additional PK cohorts were examined at various doses (Parts A-1 and A-2).  
- 
PN002 is a Phase II study designed to evaluate 2 doses of MK-3475 versus a 
chemotherapy control arm in patients with IPI-refractory metastatic melanoma. 
Patients are randomized in a 1:1:1 ratio to receive blinded MK-3475 2 mg/kg Q3W or 
MK-3475 10 mg/kg Q3W, or chemotherapy (according to current clinical practice). 
- 
PN006 is a randomized, controlled, open-label, three-arm pivotal study of two dosing 
regimens of MK-3475 versus IPI in patients with unresectable or metastatic MEL 
who have not received IPI treatment. Patients are randomized in a 1:1:1 ratio to 
receive 10 mg/kg Q2W, 10 mg/kg Q3W, or ipilimumab. 
- 
PN010 is multi-center, worldwide, randomized, adaptively designed Phase II/III trial 
of MK-3475 at two dosing schedules versus docetaxel in patients with NSCLC with 
PD-L1 positive tumors who have experienced disease progression after platinum-
containing systemic therapy. Patients are randomized to receive 10 mg/kg Q3W, 2 
mg/kg Q3W, or docetaxel 75 mg/m2 Q3W. 
- 
PN011 is an open-label, non-randomized, multi-center Phase I study of MK-3475 
alone in Japanese patients with advanced solid tumors, and in combination with 
cisplatin/pemetrexed and carboplatin/paclitaxel in patients with advanced NSCLC.  
- 
PN012 is a multicenter, nonrandomized, multi-cohort trial of MK-3475 in patients 
with PD-L1 positive advanced solid tumors. All patients will receive MK-3475 10 
mg/kg Q2W.  
Clinical data from 789 patients treated in PN001 with MK-3475 as a 30-minute IV infusion. 
MK-3475 has been generally well-tolerated at doses up to 10 mg/kg every other week 
without DLTs. One (0.002%) patient assayed to date had samples confirmed positive for 
ADA, but no impact on safety has been observed. Five other clinical studies (PN002, PN006, 
PN010, PN011, and PN012) are ongoing however preliminary data analyses are not yet 
available. The observed pharmacokinetic profile of MK-3475 was typical of other IgG mAbs 
with a half-life (t½) of approximately 2 to 3 weeks. There was no indication of dose 
dependency of half-life in the 3 dose groups and a dose related increase in exposure was 
observed from 1 to 10 mg/kg. The long half-life supports a dosing interval of every 2 or 3 
weeks. Durable objective responses have been reported in patients with melanoma and 
NSCLC. Adverse events have generally been manageable and infrequently require 
discontinuation of MK-3475 treatment.  
Of importance, and based on the literature review, and consideration of mechanism of action 
of MK-3475, potential immune-related adverse events (irAEs) are the primary events of 
clinical interest (ECI). Given that immune-related events can involve different organ 
systems, Merck is providing a guidance document based on the major potential target organs 
that could be affected by MK-3475 and other molecules that function via an immune 
mechanism. It is possible that irAEs other than those listed in this document may be observed 
in patients receiving MK-3475; therefore, all adverse events (AEs) of unknown etiology 
associated with drug exposure should be evaluated to determine if they are possibly immune-
related. See Appendix D for document of ie AEs and ECI. 
Pomalidomide: 


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Pomalidomide, which is an analog of thalidomide, is an immunomodulatory agent with 
antineoplastic activity. The agent enhances T cell and natural killer cell–mediated immunity 
and inhibits monocyte production of pro-inflammatory cytokines (e.g., tumor necrosis factor 
alpha and interleukin-6). It has shown anti-angiogenic activity in animal tumor models and in 
vitro in the umbilical cord model. In cellular assays, pomalidomide inhibits proliferation and 
induces apoptosis of hematopoietic tumor cells. It has been found to inhibit proliferation of 
lenalidomide-resistant multiple myeloma cell lines and to exhibit synergistic activity in 
inducing apoptosis when combined with dexamethasone in both lenalidomide-sensitive and 
lenalidomide resistant cell lines. [13-15] 
Phase 1 Studies Using Pomalidomide: 
An open-label dose-escalation (1, 2, 5, and 10 mg) phase 1 trial established pomalidomide as 
being well tolerated in doses ranging from 1 to 5 mg/d continuously or on alternate days with 
response. The maximum tolerated dose (MTD) of pomalidomide given for 21 of 28 days per 
cycle in patients with RRMM was grade 4 neutropenia at 5 mg/d; the MTD was 4 mg/d. This 
study determined the dose of 4 mg daily for 21 of 28 days as the recommended dose. A series 
of phase 2 studies used doses of 2 mg and 4 mg continuously for 28 days with 
dexamethasone 40 mg once a week. In the first Mayo Clinic trial, responses of PR or better 
were seen in 63% of patients treated with 2 mg daily. The median duration of response was 
21 months, and median progression-free survival was 13 months. Follow-up trials in 
lenalidomide-refractory patients using pomalidomide 2 mg and 4 mg daily showed responses 
of PR or better in 32% and 38% of patients, respectively. Among patients refractory to both 
lenalidomide and bortezomib, responses of PR or better were seen in 26% of the patients 
treated with 2 mg daily and in 29% of those treated with 4 mg daily. Similar results were 
reported by the French Intergroup. An analysis of 345 patients enrolled in the Mayo Clinic 
studies suggested the strongest predictors of response and survival were the number and type 
of prior regimens. A large multicenter randomized phase 3 trial that compares pomalidomide 
and low-dose dexamethasone with high-dose (HD) dexamethasone in 455 patients with MM 
refractory to lenalidomide and bortezomib confirmed the above benefits which is also seen in 
patients with high-risk cytogenetic. The major toxicity described in pomalidomide myeloma 
trials is neutropenia. Grade 3-4 neutropenia is reported in 26%-66% of patients and is 
affected by dose (2 mg or 4 mg) as well as the number of prior treatment regimens. 
Thrombocytopenia and anemia are also common side effects of therapy. However, grade 3 
toxicity is seen in only 13% of patients, and grade 4 is seen in 17% of patients. Non-
hematologic toxicities are uncommon. Fatigue is the most commonly reported adverse effect, 
with 62% of patients experiencing any fatigue and 8% experiencing fatigue of grade 3 or 
higher. The incidence of thromboembolic events in patients treated with pomalidomide is 
similar to that in patients treated with the other IMiDs. Venous thromboembolism occurred at 
a rate of 2-3%. Prophylactic treatment with aspirin is a reasonable strategy for preventing 
thromboembolic complications. The risk of neuropathy has varied from zero to 33%, but 
these data are confounded by preexisting neuropathy in these heavily pretreated populations. 
Infections were seen in 12% of patients, primarily pneumonia, which was seen in 10% of 
patients. Acute noninfectious pulmonary toxicity has been described in 2 patients. This injury 
seems to respond to corticosteroids, and reintroduction of pomalidomide has been successful. 
Finally, skin rash is commonly seen with lenalidomide and thalidomide but rarely seen with 


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pomalidomide. Pomalidomide induces less constipation, asthenia, and neuropathy than 
thalidomide. [17, 18, 20-22] 
Dexamethasone: 
The addition of dexamethasone to all MM therapies (melphalan and prednisone vincristine, 
doxorubicin, and dexamethasone-VAD) and more recently to IMiDs and PI improves 
responses rates and in few studies the duration of response. Findings from an ECOG trial 
which was mostly toxicity profile of high dose dexamethasone led to widespread use of 
weekly dexamethasone regimens in the recent years. Side effects of dexamethasone are 
predictable and very manageable.  
4.0 RATIONALE 
MM patients have an impaired cellular immune response that may contribute to the 
development and aggressiveness of the malignant clone.  The PD1/PDL1 pathway is a 
critical component of immune suppression in MM. B7-H1 (PDL-1) is differential expressed 
on malignant plasma cells, especially in the relapsed and refractory setting and is 
significantly associated with more aggressive features such as high lactate dehydrogenase 
(LDH).  Moreover, increased PD-1 expression was observed on T cells and NK cells isolated 
from MM patients compared to controls, thus increasing apoptosis of antigen-specific T cells 
and inhibiting tumor immune surveillance. [23-26]  
It is interesting to note that after autologous transplantation, T-cell expression of PD-1 
returned to levels seen in normal controls.  Similar results were noted in lenalidomide treated 
patients, resulting in T cell polarization to T-helper-1 phenotype and enhancement of T-cell 
proliferation and suppression of T-regs. Moreover, lenalidomide treatment led to decrease in 
PDL-1 expression on plasma cells in MM patients. These emerging data suggest that PD-
1/PDL-1 pathway is critical for the immune-modulatory activities of IMiDs.  Pre-clinical 
data suggest that PDL-1 inhibition improves survival of mice after failure of cell-based 
vaccine in syngeneic transplants.[27-29]  
We hypothesize that immunotherapeutic combination with an IMiD (pomalidomide) and 
anti-PD-1 (MK-3475) can improve overall response in RRMM by combining direct tumor 
kill and improving T cell immune functions: proliferation and activation.[29]  
This is based on  
- 
The broad expression of PD-1 and its ligands on malignant plasma cells and bone 
marrow microenvironment in RRMM patients.  
- 
The importance of the PD-1 pathway in the immune evasion by MM cells.  
- 
Preclinical data suggesting immunotherapeutic benefit from DP-1/DPL-1.  
4.1 
Rationale for the Trial and Selected Subject Population 
The broad expression of PD-1 and its ligands on malignant plasma cells and bone marrow 
microenvironment in RRMM patients establishes the importance of the PD-1 pathway in the 
immune evasion by MM cells.  IMiDs can down regulate PD-1 and its ligand on T cells and 
plasma cells respectively. Further inhibition of PD-1/PDL-1 pathway would provide 
immunotherapeutic benefit as supported by preclinical data.  


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4.2 
Rationale  
4.2.1 Efficacy Endpoints 
Currently no data is available concerning interaction between Anti-PD-1 and 
IMiDs. In this study we will evaluate this combination in RRMM patient with 
safety and efficacy as the primary endpoints. Considering none overlapping 
side effects of the 3 drug combination in this trial we do not expect cumulative 
increase in toxicity. 
As far as overall response and its durability, we expect an incremental 
increase of approximately 15% with the addition of MK-3475 to 
pomalidomide and dexamethasone. The median duration of response to 
pomalidomide and weekly dexamethasone was 21 months, and median 
progression-free survival was 13 months. In RRMM patients, especially 
lenalidomide-refractory patients, pomalidomide showed responses of PR or 
better in approximately 30% of patients (range: 29-39%), and lower 25% 
among patients refractory to both lenalidomide and bortezomib (26%)  
4.2.2 Biomarker Research 
Besides establishing the safety and efficacy of the regimen, we will focus on 
correlative studies to identify markers/profiles that can help select patients for 
future anti-PD-1 therapy. Baseline bone marrow and blood samples will be 
evaluated for PD-L1 and correlate positive expression with overall responses. 
Staining for PD1, CD3 and T cell markers CD4, CD8, CD45RO, and FoxP3 
 
 
Evaluating PDL-1 Expression in Patients’ Bone Marrow 
In collaboration with University of Chicago we have shown that PD-L1 
expression can be detected using anti PD1 antibody used in the study , which 
was Mab from abcam , clone NAT105, cat # ab 62687. PD-L1 expression on 
BM bxs was very hard to detect and we are not sure whether the level of 
expression detected is not affected by BM fixation and decalcification. We 
have presented preliminary data at ASH 2015. With the significant impact of 
such finding on patients (correlation with response and later decision to treat) 
we are refining the methodology for evaluation of PD-L1 expression including 
comparative study of PDL1 expression by flow cytometry versus paraffin 
tissue sections. FC is more sensitive than IHC and there is available published 
literature in this matter. Furthermore, FC measures directly levels of Ag 
expression whereas IHC uses different amplification systems to increase 
sensitivity and is difficult to quantify. In addition, fixation and decalcification 
of BM bxs greatly destroys the antigenicity of some antigens/epitopes, 
especially  PDL-1. Therefore, the results of IHC for PD-L1 on BM bxs may 
be biased. Since PD-L1 is class II antibody (e.g. interpreted for therapeutically 
purposes), the PD-L1 stain on BM biopies (fixed and decalcified) has to be 
calibrated in reference to standard, which has to be defined. It may be the 
level of PD-L1 expression on PCs by FC and/or IHC on formalin fixed (but 
not decalcified) plasma cells from the patient's BM aspirate samples. To get 


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Amendment No. 3.1   page46 
 
 
 
 
hands on the methodology, we will first to calibrate PD-L1 IHC on Myeloma 
cell lines, which express PD-L1 and are readily available, and then on 
patient's samples. The purpose of this calibration is to compare PD-L1 
expression by FC vs clots of plasma cell from cell culture, pelleted and  
resuspended in fibrinogen and clotted with thrombin, vs myeloma cells 
processed in the same way as patient's BM biopies  (fixed and decalcified). 
Once this is done and we get an idea how they relate (how much PD-L1 Ag is 
destroyed by fixation and decalcification) we could move to patient's samples. 
 
Evaluate the Expression of PD-1 in Bone Marrow Samples on T Cell 
Subjects. 
To determine whether T-cell expression of PD-1 correlate with clinical 
features and prognosis among MM patients receiving pembrolizumab, 
pomalidomide and dexamethasone.  This work will be done with Myeloma 
Service and Immunotherapeutics, Core Memorial Sloan-Kettering Cancer 
Center. Previous studies suggest that PD-1 expressing CD3+ T cells in newly 
diagnosed MM had poor overall survival, suggesting the possibility that T cell 
exhaustion represents a high risk disease characteristic. The University of 
Maryland laboratory will perform immunohistochemistry (IHC) on 
formalin-fixed paraffin-embedded specimens using an anti-human CD3 
monoclonal antibody (mAb) (Dako, Clone F7.2.38) and an anti-human PD-1 
mAb (Cell Marque, catalog #315M-95). CD3 and PD1 IHC staining were 
graded as negative (<5% for CD3,  < 1% for PD1), or positive (≥5% for CD3, 
≥1% for PD1).  
 
 
4.2.3 Rationale for Dose Selection/Regimen/Modification 
An open-label Phase I trial (Protocol 001) is being conducted to evaluate the 
safety and clinical activity of single agent MK-3475.  The dose escalation 
portion of this trial evaluated three dose levels, 1 mg/kg, 3 mg/kg, and 10 
mg/kg, administered every 2 weeks (Q2W) in subjects with advanced solid 
tumors.  All three dose levels were well tolerated, and no dose-limiting 
toxicities were observed.  This first in human study of MK-3475 showed 
evidence of target engagement and objective evidence of tumor size reduction 
at all dose levels (1 mg/kg, 3 mg/kg and 10 mg/kg Q2W).  No MTD has been 
identified to date.  10mg Q2W, the highest dose tested in PN001, will be the 
dose and schedule utilized in Cohorts A, B, C and D of this protocol to test for 
initial tumor activity.  Recent data from other clinical studies within the MK-
3475 program has shown that a lower dose of MK-3475 and a less frequent 
schedule may be sufficient for target engagement and clinical activity.  PK 
data analysis of MK-3475 administered Q2W and Q3W showed slow 
systemic clearance, limited volume of distribution, and a long half-life (refer 
to IB).  Pharmacodynamic data (IL-2 release assay) suggested that peripheral 
target 
engagement 
is 
durable 
(>21 
days).  
This 
early 
PK 
and 
pharmacodynamic data provides scientific rationale for testing a Q2W and 


Product:  MK-3475 & Pomalidomide in R/R Myeloma 
Amendment No. 3.1   page46 
 
 
 
 
Q3W dosing schedule.  A population pharmacokinetic analysis has been 
performed using serum concentration time data from 476 patients. Within the 
resulting population PK model, clearance and volume parameters of MK-3475 
were found to be dependent on body weight. The relationship between 
clearance and body weight, with an allometric exponent of 0.59, is within the 
range observed for other antibodies and would support both body weight 
normalized dosing or a fixed dose across all body weights.  MK-3475 has 
been found to have a wide therapeutic range based on the melanoma 
indication.  The differences in exposure for a 200 mg fixed dose regimen 
relative to a 2 mg/kg Q3W body weight based regimen are anticipated to 
remain well within the established exposure margins of 0.5 – 5.0 for MK-3475 
in the melanoma indication. The exposure margins are based on the notion of 
similar efficacy and safety in melanoma at 10 mg/kg Q3W vs. the proposed 
dose regimen of 2 mg/kg Q3W (i.e. 5-fold higher dose and exposure). The 
population PK evaluation revealed that there was no significant impact of 
tumor burden on exposure. In addition, exposure was similar between the 
NSCLC and melanoma indications. Therefore, there are no anticipated 
changes in exposure between different indication settings. 
 
Pomalidomide has been effective in therapy of MM at doses ranging from 2-5 
mg daily for 21 days; the approved dose is 4 mg with dexamethasone 40 mg 
weekly.  
 
This study will evaluate the combination of Pomalidomide given at standard 
dose of 4 mg daily orally for 21 days, dexamethasone is given at 40 mg orally 
on days 1, 8, 15, & 22  and MK3475 given as an intravenous infusion at 200 
mg every 2 weeks (days 1 and 15). A run off stage (6 patients) will be treated 
with MK3475 at 200 mg every 4 weeks (day 1), to establish safety of the 
combination. Once safety is established however, these 6 patients will always 
receive D1 dosing only.  
 
5.0 PATIENT SELECTION  
 
 
5.1 
Inclusion Criteria:  
 
1. Confirmed diagnosis of relapsed and/or refractory MM according to International 
Myeloma Working Group guidelines (2003); refractory disease is defined as 
documented disease progression during or within 60 days after their most recent 
line of anti-myeloma therapy. 


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Amendment No. 3.1   page46 
 
 
 
 
2. Received two lines of prior therapy that includes an IMiD (lenalidomide or 
thalidomide) and a proteosome inhibitor (bortezomib and/or carfilzomib) (used 
either separately or in combination). 
a. Prior pomalidomide therapy is permitted, provided the patient achieved at 
least a partial remission and had not progressed for 3 months after 
stopping therapy.  
3. Measurable disease as defined by one or more of the following criteria (assessed 
within 28 days prior to registration): 
a. Serum paraprotein ≥ 5 g/L (for IgA patients whose disease can only be 
reliably measured by serum quantitative immunoglobulin (IgA): ≥ 7.5 g/L) 
b. Urine Bence Jones Protein: ≥ 200 mg/24 h 
c. Serum light chain assay: Involved free light chain (FLC) level ≥ 100 
mg/L, provided serum FLC ratio is abnormal 
4. Be willing and able to provide written informed consent/assent for the trial. 
5. Be  18 years of age on day of signing informed consent. 
6. Have a performance status of < 2 on the ECOG Performance Scale. 
7. Demonstrate adequate organ function as defined in Table 1 below, all screening 
labs should be performed within 28 days of treatment initiation.   
Table 1 
System 
Laboratory Value 
Hematological 
 
Absolute neutrophil count (ANC) 
≥1,000 /mcL 
Platelets 
≥75,000 / mcL 
Hemoglobin 
≥9 g/dL 
Serum creatinine OR 
creatinine clearance (if Cr > 2 mg/dL) 
≤2 mg/dl 
≥60 mL/min  
Serum total bilirubin 
≤ 1.5 X ULN  
AST (SGOT) and ALT (SGPT) 
≤ 2.5 X ULN  
International Normalized Ratio (INR)  
Activated Partial Thromboplastin Time (aPTT) 
 
 
 
≤1.5 X ULN  
≤1.5 X ULN  
If on anticoagulant therapy (PT or PTT should 
be therapeutic) 
aCreatinine clearance should be calculated per institutional standard. 


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Amendment No. 3.1   page46 
 
 
 
 
8. Female subject of childbearing potential should have a negative serum pregnancy 
within 72 hours prior to receiving the first dose of study medication.  If the urine 
test is positive or cannot be confirmed as negative, a serum pregnancy test will be 
required.   
9. Male subjects should agree to use an adequate method of contraception starting 
with the first dose of study therapy through 120 days after the last dose of study 
therapy. 
5.2 
Exclusion Criteria 
 
1. Is currently participating in or has participated in a study of an investigational agent 
or using an investigational device within 4 weeks of the first dose of treatment. 
2. Has a diagnosis of immunodeficiency (HIV) or is receiving systemic steroid therapy 
(in excess of 20 mg of prednisone daily) or any other form of immunosuppressive 
therapy within 7 days prior to the first dose of trial treatment. 
 
3. Has had a prior monoclonal antibody within 4 weeks prior to study Day 1 or who has 
not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents 
administered more than 4 weeks earlier.  
4. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy 
within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at 
baseline) from adverse events due to a previously administered agent. Subjects with < 
Grade 2 neuropathy are an exception to this criterion and may qualify for the study.  
5. Has a known additional malignancy that is progressing or requires active treatment.  
Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the 
skin, or in situ cervical cancer that has undergone potentially curative therapy.   
6. Has known active central nervous system disease and/or carcinomatous meningitis. 
7. Has an active autoimmune disease requiring systemic treatment within the past 3 
months or a documented history of clinically severe autoimmune disease, or a 
syndrome that requires systemic steroids or immunosuppressive agents.  Subjects 
with vitiligo or resolved childhood asthma/atopy would be an exception to this rule.  
Subjects that require intermittent use of bronchodilators or local steroid injections 
would not be excluded from the study.  Subjects with hypothyroidism stable on 
hormone replacement or Sjorgen’s syndrome will not be excluded from the study. 
8. Has evidence of interstitial lung disease or active, non-infectious pneumonitis. 
9. Has an active infection requiring systemic therapy. 
10. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the trial, interfere with the subject’s participation 
for the full duration of the trial, or is not in the best interest of the subject to 
participate, in the opinion of the treating investigator.   
11. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 


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Amendment No. 3.1   page46 
 
 
 
 
12. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting with the pre-screening or screening visit 
through 120 days after the last dose of trial treatment. 
13. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, 
or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including 
ipilimumab or other antibody or drug specifically targeting T-cell co-stimulation). 
14. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
15. Has known active Hepatitis B (HBsAg reactive) or Hepatitis C (HCV RNA 
[qualitative] is detected). 
16. Has received a live vaccine within 30 days prior to the first dose of trial treatment.   
6.0 TREATMENT  
6.1 
Study schedule  
The treatment to be used in this trial is outlined below  
Table 2 
Drug 
Dose Level 
Dose Frequency 
Route of 
Administration 
Treatment Period 
MK-3475 
200 mg 
Every 2 weeks* 
IV infusion 
Days 1 and 15 
Pomalidomide 
4 mg  
Daily  
PO 
Days 1-21 
Dexamethasone 
40 mg 
Weekly 
PO 
Days 1, 8, 15, & 22 
* In a run off phase, 6 patients will receive MK-3475 200 mg intravenously day 1. 
• 
Dose adjustment due to toxicity as described in Section 6.2. 
• 
Trial treatment should begin on the day of registration or as close as possible to the date on which treatment 
is allocated/assigned. 
6.2 
Dose Modification 
Following the DLT evaluation Cycle-1 for the first 6 patients on the monthly schedule and 6 
in the twice monthly schedule, the dose of MK-3475, pomalidomide and dexamethasone 
could be modified as outlined in Tables below. Subjects, who discontinue pomalidomide or 
dexamethasone due to toxicity, may continue receiving MK-3475 until unacceptable toxicity 
or progression. Subjects who discontinue MK-3475 due to untoward toxicities may not 
continue on the study receiving only pomalidomide and dexamethasone.  
After any study medication has been held for any reason it may be restarted when clinically 
indicated according to any applicable dose modification guidelines and the dosing schedule 
conforms to the schedule of the normal dosing Cycle (e.g. MK-3475 must always be given 
on Day 1 or Day 15 and cannot be given on Day 21).   
If dose modifications are necessary during the DLT observation period due to drug-related 
AEs that do not meet DLT criteria, then this would be considered a DLT in the run-off phase.  


Product:  MK-3475 & Pomalidomide in R/R Myeloma 
Amendment No. 3.1   page46 
 
 
 
 
6.2.1 Dexamethasone 
Dexamethasone doses will be modified due to toxicity as follows: 
Table 3: Dose modification guidelines for Dexamethasone-related adverse events  
Toxicity 
Grade 
Hold 
Treatment 
(Y/N) 
Timing for 
Restarting 
Treatment 
Dose/Schedule 
for Restarting 
Treatment 
Discontinue 
Subject (after 
consultation 
with sponsor) 
Non-
hematological 
toxicity 
 
 
 
1 
No 
N/A 
N/A 
N/A 
2 
Consider 
withholding 
for persistent 
symptoms 
Toxicity 
resolves to 
Grade 0-1 or 
baseline 
Clinical AE 
resolves within1  
week:  Same dose 
and schedule  
N/A 
3, 4 
 
Yes 
 
Toxicity 
resolves to 
Grade 0-1 or 
baseline 
May decrease the 
dosing one level 
for each 
occurrence 
Toxicity does 
not resolve 
within 4 weeks 
• 
Dexamethasone doses will be modified due to toxicity as follows: 
o Original dose Level: Dexamethasone 40 mg by mouth on days 1, 8, 15, & 22of a 28-
day cycle. 
o Dose level -1: Dexamethasone 20 mg by mouth on days 1, 8, 15, & 22 of a 28-day 
cycle. 
o Dose level -2: Dexamethasone 20 mg by mouth on days 1&15) of a 28-day cycle. 
 
• 
Elderly patients (over age 70 years) will receive 20 mg of dexamethasone with 2 dose 
reductions at 12 mg weekly (dose level -1) and 12 mg on days 1, & 15 (dose level -2). 
 
6.2.2 MK-3475  
MK-3475 will be withheld for drug-related Grade 4 hematologic toxicities, non-hematologic 
toxicity ≥ Grade 3 including laboratory abnormalities, and severe or life-threatening AEs as 
per Tables below. 
Table 4: Dose Modification Guidelines for Hematological Drug-Related Adverse Events 
Toxicity 
Grade 
Hold 
Treatment 
(Y/N) 
Timing for 
Restarting 
Treatment 
Dose/Schedule 
for Restarting 
Treatment 1 
Discontinue 
Subject (after 
consultation 
with sponsor) 
Hematological 
1, 2, 3 
No 
N/A 
N/A 
N/A 


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Amendment No. 3.1   page46 
 
 
 
 
Toxicity 
Grade 
Hold 
Treatment 
(Y/N) 
Timing for 
Restarting 
Treatment 
Dose/Schedule 
for Restarting 
Treatment 1 
Discontinue 
Subject (after 
consultation 
with sponsor) 
Toxicity 
 
4  
Yes 
Toxicity 
resolves to 
Grade 0-1 or 
baseline 
May decrease 
dose to next 
dose level below 
Toxicity does 
not resolve 
within 4 weeks 
of last infusion 
Permanent 
discontinuation 
should be 
considered for 
any severe or 
life-threatening 
event 
1 See below for dose levels of MK-3475 
 
 
Table 5 Dose Modification Guidelines for Non-Hematological Drug-Related Adverse Events 
Toxicity 
Grade 
Hold 
Treatment 
(Y/N) 
Timing for 
Restarting 
Treatment 
Dose/Schedule 
for Restarting 
Treatment 1 
Discontinue 
Subject 
(after 
consultation 
with 
Sponsor) 
Non-hematological 
toxicity 
 
Note:  Exceptions to 
be treated similar to 
Grade 1 toxicity  
• Grade 2 alopecia 
• Grade 2 fatigue 
 
For additional 
information regarding 
Adverse Events with a 
potential Immune-
Etiology reference 
Section 6.5 with tables 
8 and table 9. 
1 
No 
N/A 
N/A 
N/A 
2 
Consider 
withholding 
for 
persistent 
symptoms 2, 
3 
Toxicity 
resolves to 
Grade 0-1 or 
baseline 
Clinical AE 
resolves within 4 
weeks:  Same 
dose and schedule 
(reference Section 
6.5.1.f  for 
recommendations 
regarding 
pneumonitis) 
Clinical AE does 
resolve within 4 
weeks:  May 
decrease dose to 
next lower dose 
level for each 
occurrence 
Toxicity does 
not resolve 
within 4 
weeks of last 
infusion 
3 
Yes 4 
Toxicity 
resolves to 
Grade 0-1 or 
baseline 
May decrease 
dose to next lower 
dose level for 
each occurrence 
Toxicity does 
not resolve 
within 4 
weeks of last 
infusion 
4 
NA 
NA 
NA 
MK-3475 
will be 
Permanently 
discontinued  
1 
See below for dose levels of MK-3475. 
2 
During DLT evaluation period, depending on the nature of AE, for subjects who develop Grade 2 non-
heme drug-related AE, MK-3475 will not be held, if symptoms improve with appropriate supportive care 


Product:  MK-3475 & Pomalidomide in R/R Myeloma 
Amendment No. 3.1   page46 
 
 
 
 
Toxicity 
Grade 
Hold 
Treatment 
(Y/N) 
Timing for 
Restarting 
Treatment 
Dose/Schedule 
for Restarting 
Treatment 1 
Discontinue 
Subject 
(after 
consultation 
with 
Sponsor) 
and symptomatic treatment within 3 days.   
3 
During DLT evaluation period, depending on the nature of AE, for subjects who develop Grade 2 non-
heme drug-related AE, MK-3475 will be held, if symptoms do not improve with appropriate supportive 
care and symptomatic treatment within 3 days and it will be considered DLT. 
4 
During DLT evaluation period, for subjects who develop Grade 3 non-heme drug-related AE, MK-3475 
will be held (except for inadequately treated nausea, hypersensitivity reactions, or fatigue lasting less than 
3 days) and it will be considered DLT. 
MK-3475 doses will be modified due to toxicity as follows: 
o Original dose level: MK-3475 200 mg IV on days 1and 15 of a 28-day cycle. 
o Dose level -1: MK-3475 200 mg IV every 4 weeks of a 28-day cycle. 
o Dose level -2: MK-3475 100 mg IV on days 1 and 15 of a 28-day cycle  
o Dose level -3: MK-3475 100 mg IV every 4 weeks of a 28-day cycle. 
For toxicity related to MK-3475 that does not resolve to Grade 0-1 within 4 weeks after last 
infusion, trial treatment (i.e., MK-3475+Pom+Dex) should be discontinued after consultation 
with the Principal Investigator.  For information on the management of adverse events, see 
Section 6.2.2. 
• For subjects who experience a recurrence of the same AE(s) at the same grade or 
greater with rechallenge of MK3475, the subject must discontinue trial treatment. 
• In subjects who continue on trial treatment after experiencing an adverse event 
warranting potential dose modification, if considered drug-related by the investigator, 
once the subject has recovered to ≤ Grade 1 the dose of MK-3475 in subsequent 
cycles will be decreased to next lower dose level (e.g., if the subject is receiving 200 
mg, it will be reduced to 100 mg every 4-weeks).  Following such dose reduction due 
to toxicity, an additional dose reduction may be allowed.  For example, subjects who 
began the study receiving 200 mg on a 2 week dosing schedule, and have stopped 
drug twice due to a drug-related toxicity that meets the above criteria, should now be 
dosed 100 mg every 4 weeks.  Subjects who experience a DLT in Cycle 1 should be 
discontinued from the study. However, if it has been determined that the subject is 
deriving clinical benefit from the study therapy, the subject may be allowed to 
continue at a lower dose as indicated in table 5.  It should be noted that if the dose of 
MK-3475 is reduced due to toxicity, the pomalidomide and dexamethasone should 
continue to be administered per study guidelines.   
• In an individual subject, following a reduction in the dose of MK-3475, 
pomalidomide and dexamethasone, a subsequent increase in the dose will not be 
permitted. 
6.2.3 Pomalidomide  


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Amendment No. 3.1   page46 
 
 
 
 
Pomalidomide will be withheld for drug-related Grade 4 hematologic toxicities, non-
hematological toxicity ≥ Grade 3 including laboratory abnormalities, and severe or life-
threatening AEs as per Table 6 below.  
Table 6: Dose Modification Guidelines for Pomalidomide-Related Adverse Events  
 
Toxicity 
Grade 
Hold 
Treatment 
(Y/N) 
Timing for 
restarting 
treatment 
Dose/Schedule 
for restarting 
treatment 
Discontinue 
Subject (after 
consultation with 
Sponsor) 
Neutropenia 
or 
Febrile neutropenia 
(fever ≥ 38.5°C and 
ANC < 
1,000/μL) 
1, 2, 3 
 
 
4 
No 
 
 
Yes, for the 
reminder of the 
cycle 
N/A  
 
 
Toxicity resolves 
to Grade 1 or 
baseline. Can use 
granulocyte 
colony-stimulating 
factor (GCFS) 
N/A 
N/A 
 
 
If ANC  > 
1000/μLcontinue 
same dose 
otherwise 
decrease 1 dose 
level 
N/A 
 
 
Toxicity does not 
resolve within 4 
weeks 
Thrombocytopenia 
 
1, 2, 3 
 
4 
No 
 
Yes, for the 
reminder of the 
cycle 
N/A 
 
Toxicity resolves 
to Grade 1 or 
baseline. 
N/A 
 
Decrease one dose 
level 
N/A 
 
Toxicity does not 
resolve within 4 
weeks 
Rash 
3 
 
 
 
4 
Yes, for the 
reminder of the 
cycle  
 
Discontinue 
Toxicity resolves 
to Grade 1 
 
 
Discontinue 
Decrease one dose 
level 
 
 
Discontinue 
Rash does not 
resolve within 4 
weeks 
 
Discontinue 
Deep Vein 
Thrombosis (DVT) 
1, 2, 3 
4 
No 
Yes, for the 
reminder of the 
cycle 
N/A 
Initiate 
anticoagulation 
treatment. 
Maintain dose 
level when dosing 
restarted at next 
cycle at discretion 
of treating 
physician. 
N/A 
Initiate 
anticoagulation 
treatment. 
Maintain dose 
level when dosing 
restarted at next 
cycle at discretion 
of treating 
physician. 
N/A 
Initiate 
anticoagulation 
treatment. 
Maintain dose 
level when dosing 
restarted at next 
cycle at discretion 
of treating 
physician. 
Peripheral 
neuropathy 
2, 3, 4 
Yes, for the 
reminder of the 
cycle 
neuropathy 
must resolve to ≤ 
Grade 1 
Decrease one dose 
level 
If painful 
neuropathy  
persist for > 4 
weeks 


Product:  MK-3475 & Pomalidomide in R/R Myeloma 
Amendment No. 3.1   page46 
 
 
 
 
Other Non-
hematological 
toxicity 
 
Note:  Exceptions to 
be treated similar to 
grade 1 toxicity  
• Grade 2 
alopecia 
• Grade 2 fatigue 
 
 
1 
 
2 
 
 
 
 
 
3,4 
No 
 
Consider 
withholding for 
persistent 
symptoms 
 
 
Yes 
N/A 
 
Toxicity resolves 
to Grade 0-1 or 
baseline 
 
 
 
Toxicity resolves 
to Grade 0-1 or 
baseline 
N/A 
 
Clinical AE 
resolves within 1 
week: Same dose 
and schedule 
 
 
May decrease the 
dosing one level 
for each 
occurrence 
N/A 
 
N/A 
 
 
 
 
 
Toxicity does not 
resolve within 4 
weeks.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pomalidomide doses will be modified due to toxicity as follows: 
o Original dose level: Pomalidomide 4 mg /day PO on days 1-21 of a 28-day 
cycle 
o Dose level -1: Pomalidomide 3 mg/day PO on days 1-21 of a 28-day cycle 
o Dose level -2: Pomalidomide 2 mg/day PO on days 1-21 of a 28-day cycle 
o Dose level -3: Pomalidomide 1 mg/day PO on days 1-21 of a 28-day cycle 
6.3 
Timing of Dose Administration 
All trial treatments will be administered on an outpatient basis.  
Cycles are repeated every 28 days.  


Product:  MK-3475 & Pomalidomide in R/R Myeloma 
Amendment No. 3.1   page46 
 
 
 
 
MK-3475 should be administered on Day 1 and 15 of each cycle after all 
procedures/assessments have been completed as detailed on the Trial Flow Chart (Section 
6.0).  In a run off phase, 6 patients will receive MK-3475 intravenously on day 1.  Trial 
treatment may be administered up to 3 days before or after the scheduled Day 1 of each cycle 
due to administrative reasons. No delays are allowed for day 15. On day 15 if the MK-3475 
is not given the dose is cancelled. MK-3475 will be administered as a 30 minute IV infusion 
(treatment cycle intervals may be increased due to toxicity as described in Section 6.2.2).  
Sites should make every effort to target infusion timing to be as close to 30 minutes as 
possible.  However, given the variability of infusion pumps from site to site, a window of -5 
minutes and +10 minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min). 
Pomalidomide will be given orally days 1-21. Pomalidomide capsules should be swallowed 
whole, and should not be broken, chewed or opened.  Pomalidomide should be taken without 
food, at least 2 hours before or 2 hours after a meal. If a dose of pomalidomide is missed, it 
should be taken as soon as possible on the same day.  If it is missed for the entire day, it 
should not be made up, rather it should be taken at the next scheduled time point. Patients 
who take more than the prescribed dose of pomalidomide should be instructed to seek 
emergency medical care if needed and contact study staff immediately.   
Dexamethasone will be given orally on days 1, 8, 15, & 22. 
6.4 
Concomitant Medications 
6.4.1 Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care.  All concomitant medication will be recorded on the case report form (CRF) 
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications 
and fluids.  If changes occur during the trial period, documentation of drug dosage, 
frequency, route, and date will 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.  Concomitant 
medications administered after 30 days after the last dose of trial treatment should be 
recorded for SAEs and events of clinical interest (ECIs) as defined in Section 7.2. 
6.4.2 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: 
• Anti-cancer systemic chemotherapy or biological therapy  
• Immunotherapy not specified in this protocol 
• Chemotherapy not specified in this protocol 
• Investigational agents other than MK-3475 
• Radiation therapy  
o Note:  Radiation therapy to a symptomatic solitary lesion is allowed.   


Product:  MK-3475 & Pomalidomide in R/R Myeloma 
Amendment No. 3.1   page46 
 
 
 
 
• 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, chicken pox, yellow fever, rabies, Bacillus 
Calmette-Guerin (BCG), and typhoid (oral) vaccine. Seasonal influenza vaccines for 
injection are generally killed virus vaccines and are allowed; however intranasal 
influenza vaccines (e.g. Flu-Mist®) are live attenuated vaccines, and are not allowed.  
• Glucocorticoids for any purpose other than to modulate symptoms from an event of 
clinical interest of suspected immunologic etiology.  The use of physiologic doses of 
corticosteroids may be approved after consultation with the Sponsor.  
Subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial.  
Subjects may receive other medications that the investigator deems to be medically 
necessary. 
The Exclusion Criteria describes other medications which are prohibited in this trial. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
6.5 
Supportive Care Guidelines 
6.5.1 For MK-3475 
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator including but not limited to the items outlined below: 
a. Diarrhea: Subjects should be carefully monitored for signs and symptoms of 
enterocolitis (such as diarrhea, abdominal pain, blood or mucus in stool, with or without 
fever) and of bowel perforation (such as peritoneal signs and ileus).  In symptomatic 
subjects, infectious etiologies should be ruled out, and if symptoms are persistent and/or 
severe, endoscopic evaluation should be considered. 
o In subjects with severe enterocolitis (Grade 3), MK-3475 will be permanently 
discontinued 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. 
o In subjects with moderate enterocolitis (Grade 2), MK-3475 should be withheld 
and anti-diarrheal 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.  
Regarding guidelines for continuing treatment with MK-3475, see Section 6.2. 
o All subjects 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 given via IV infusion. 
b. Nausea/vomiting: Nausea and vomiting should be treated aggressively, and 
consideration should be given in subsequent cycles to the administration of prophylactic 


Product:  MK-3475 & Pomalidomide in R/R Myeloma 
Amendment No. 3.1   page46 
 
 
 
 
antiemetic therapy according to standard institutional practice.  Subjects should be 
strongly encouraged to maintain liberal oral fluid intake. 
c. Anti-infectives: Subjects 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. 
d. Infusion Reactions:  Acute infusion reactions (which can include cytokine release 
syndrome, angioedema, or anaphylaxis) are different from allergic/hypersensitive 
reactions, although some of the manifestations are common to both AEs.  Signs and 
symptoms usually develop during or shortly after drug infusion and generally resolve 
completely within 24 hours of completion of infusion. Signs/symptoms may include: 
allergic reaction/hypersensitivity (including drug fever); arthralgia (joint pain); 
bronchospasm; cough; dizziness; dyspnea (shortness of breath); fatigue (asthenia, 
lethargy, malaise); headache; hypertension; hypotension; myalgia (muscle pain); nausea; 
pruritis/itching; rash/desquamation; rigors/chills; sweating (diaphoresis); tachycardia; 
tumor pain (onset or exacerbation of tumor pain due to treatment); urticaria (hives, welts, 
wheals); vomiting. 
Table 7 below shows treatment guidelines for subjects who experience an infusion reaction 
associated with administration of MK-3475. 
Table 7 : Infusion Reaction Treatment Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
Grade 1 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion 
of the investigator. 
 
None 
Grade 2 
Requires infusion interruption 
but responds promptly to 
symptomatic treatment (e.g., 
antihistamines, NSAIDS, 
narcotics, IV fluids); 
prophylactic medications 
indicated for < =24 hrs 
Stop 
infusion 
and 
monitor 
symptoms. 
Additional appropriate medical therapy 
may include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion 
of the investigator. 
If symptoms resolve within one hour of 
stopping drug infusion, the infusion 
may be restarted at 50% of the original 
infusion rate (e.g. from 100 mL/hr to 
50 mL/hr).  Otherwise dosing will be 
held until symptoms resolve and the 
subject should be premedicated for the 
next scheduled dose. 
Subjects who develop Grade 2 
toxicity despite adequate 
Subject may be 
premedicated 1.5h (± 30 
minutes) prior to infusion of 
MK-3475 with: 
 
Diphenhydramine 50 mg po 
(or equivalent dose of 
antihistamine). 
 
Acetaminophen 500-1000 
mg po (or equivalent dose 
of antipyretic). 


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Amendment No. 3.1   page46 
 
 
 
 
NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
premedication should be 
permanently discontinued from 
further trial treatment 
administration. 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial improvement; 
hospitalization indicated for 
other clinical sequelae (e.g., 
renal impairment, pulmonary 
infiltrates) 
 
Grade 4: 
Life-threatening; pressor or 
ventilatory support indicated 
 
Stop Infusion. 
Additional appropriate medical therapy 
may include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion 
of the investigator. 
Hospitalization may be indicated. 
Subject is permanently discontinued 
from further trial treatment 
administration. 
 
No subsequent dosing 
Appropriate resuscitation equipment should be available in the room and a physician readily available 
during the period of drug administration. 
For Further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 
(CTCAE) at http://ctep.cancer.gov 
 
e. Immune-related Adverse Events (irAEs) 
Events of clinical interest of a potential immunologic etiology (irECIs) may be defined as an 
adverse event of unknown etiology, associated with drug exposure and is consistent with an 
immune phenomenon. irAEs may be predicted based on the nature of the MK-3475 
compound, its mechanism of action, and reported experience with immunotherapies that have 
a similar mechanism of action.  Special attention should be paid to AEs that may be 
suggestive of potential irAEs.  An irAE can occur shortly after the first dose or several 
months after the last dose of treatment.   
If an irAE is suspected, efforts should be made to rule out neoplastic, infectious, metabolic, 
toxin or other etiologic causes prior to labeling an adverse event as an irAE.  Information on 
how to identify and evaluate irAEs has been developed and is included in the Event of 
Clinical Interest and Immune-Related Adverse Event Guidance Document located at the end 
of this protocol document.   Subjects who develop a Grade 2 or higher irAE should be 
discussed immediately with the Sponsor.   
Recommendations to managing irAEs not detailed elsewhere in the protocol are detailed in 
Table 8. 


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Amendment No. 3.1   page46 
 
 
 
 
 
Table 8 General Approach to Handling irAEs 
irAE 
Withhold/Discontinue 
MK-3475? 
Supportive Care 
Grade 1 
No action 
Provide symptomatic treatment 
Grade 2 
May withhold MK-3475 
Consider systemic corticosteroids in addition 
to appropriate symptomatic treatment 
Grade 3  
Withhold MK-3475 
Discontinue if unable to 
reduce corticosteroid dose 
to < 10 mg per day 
prednisone 
equivalent 
within 12 weeks of toxicity 
Systemic corticosteroids are indicated in 
addition to appropriate symptomatic treatment.  
May utilize 1 to 2 mg/kg prednisone or 
equivalent per day. 
Steroid taper should be considered once 
symptoms improve to Grade 1 or less and 
tapered over at least 4 weeks. 
 
f. Supportive Care Guidelines for Pneumonitis 
Subjects with symptomatic pneumonitis should immediately stop receiving MK-3475 and 
have an evaluation.  The evaluation may include bronchoscopy and pulmonary function tests 
to rule out other causes such as infection.  If the subject is determined to have study drug 
associated pneumonitis, the suggested treatment plan is detailed in Table 9. 
Table 9 Recommended Approaches to Handling Pneumonitis 
Study drug associated 
pneumonitis 
Withhold/Discontinue 
MK-3475? 
Supportive Care 
Grade 1 (asymptomatic) 
No action 
Intervention not indicated 
Grade 2 
Withhold MK-3475, may 
return to treatment if 
improves to Grade 1 or 
resolves within 12 weeks 
Systemic corticosteroids are indicated.  Taper 
if necessary. 
Grade 3 and Grade 4 
Discontinue MK-3475 
Systemic corticosteroids are indicated. The use 
of infliximab may be indicated as appropriate.  
Refer to the Event of Clinical Interest and 
Immune-related Adverse Event Guidance 
Document for additional recommendations. 
 
For Grade 2 pneumonitis that improves to ≤ Grade 1 within 12 weeks, the following rules 
should apply: 
• First episode of pneumonitis 
o May increase dosing interval by one week in subsequent cycles 
• Second episode of pneumonitis – permanently discontinue MK-3475 if upon 
rechallenge subject develops pneumonitis  Grade 2 
6.5.2 For Pomalidomide  
Pomalidomide increases the risk of thrombotic events in patients who are at high risk 
or with a history a thrombosis, in particular when combined with other drugs known 
to cause thrombosis. Consideration should be given to the use of aspirin (81 or 325 


Product:  MK-3475 & Pomalidomide in R/R Myeloma 
Amendment No. 3.1   page46 
 
 
 
 
mg) or some other form of prophylaxis as deemed appropriate. Low molecular weight 
heparin may be utilized in patients that are intolerant to aspirin (ASA). Coumadin 
should be used with caution and close monitoring of INR. 
6.5.3 Supportive Care Guidelines Specific to Dexamethasone 
Body System 
Symptom 
Recommended Action 
Gastrointestinal 
Dyspepsia, gastric or duodenal 
ulcer, gastritis Grade 1–2 (requiring 
medical management) 
Treat with H2 blockers, sucralfate, or omeprazole. 
If symptoms persist despite above measures, 
decrease dexamethasone dose by one dose level. 
Gastrointestinal 
> 
Grade 
3 
(requiring 
hospitalization or surgery) 
Hold dexamethasone until symptoms adequately 
controlled.  Restart and decrease one dose level of 
current dose along with concurrent therapy with H2 
blockers, sucralfate, or omeprazole.  If symptoms 
persist 
despite 
above 
measures, 
discontinue 
dexamethasone and do not resume. 
Gastrointestinal 
Acute pancreatitis 
Discontinue dexamethasone and do not resume. 
Cardiovascular 
Edema 
>Grade 3 (limiting function and 
unresponsive to therapy or anasarca) 
Diuretics as needed, and decrease dexamethasone 
dose by one dose level; if edema persists despite 
above measures, decrease dose another dose level. 
Discontinue dexamethasone and do not resume if 
symptoms persist despite second reduction. 
Neurology 
Confusion 
or 
mood 
alteration 
> Grade 2 (interfering with function 
+/- interfering with activities of 
daily living) 
Hold dexamethasone until symptoms resolve. 
Restart with one dose level reduction.  If symptoms 
persist 
despite 
above 
measures, 
discontinue 
dexamethasone do not resume. 
Musculoskeletal Muscle 
weakness 
> 
Grade 
2 
(symptomatic and interfering with 
function 
+/- 
interfering 
with 
activities of daily living) 
Decrease dexamethasone dose by one dose level.  If 
weakness persists despite above measures, decrease 
dose by one dose level.  Discontinue dexamethasone 
and do not resume if symptoms persist. 
Metabolic 
Hyperglycemia > Grade 3 or higher Treatment with insulin or oral hypoglycemics as 
needed.  If uncontrolled despite above measures, 
decrease dose by one dose level until levels are 
satisfactory. 
 
6.6 
Diet/Activity/Other Considerations 
6.6.1 Diet 
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea or vomiting. 
6.6.2 Contraception 
Subjects should be informed that taking pomalidomide may involve unknown risks to the 
fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate in 
the study they must adhere to the contraception requirement (described above) for the 
duration of the study and during the follow-up period defined. Although pregnancy and 
lactation are not considered adverse events, it is the responsibility of investigators or their 
designees to report any pregnancy or lactation in a subject (spontaneously reported to them), 
including the pregnancy of a male subject's female partner that occurs during the trial or 
within 120 days of completing the trial. If there is any question that a subject will not reliably 


Product:  MK-3475 & Pomalidomide in R/R Myeloma 
Amendment No. 3.1   page46 
 
 
 
 
comply with the requirements for contraception, that subject should not be entered into the 
study. 
MK-3475 may have adverse effects on a fetus in utero.  Furthermore, it is not known if 
MK-3475 has transient adverse effects on the composition of sperm.  Non-pregnant, non-
breast-feeding women may be enrolled if they are willing to use 2 methods of birth control or 
are considered highly unlikely to conceive.  Highly unlikely to conceive is defined as 1) 
surgically sterilized, or 2) postmenopausal (a woman who is ≥45 years of age and has not had 
menses for greater than 1 year will be considered postmenopausal), or 3) not heterosexually 
active for the duration of the study.  The two birth control methods can be either two barrier 
methods or a barrier method plus a hormonal method to prevent pregnancy. Subjects should 
start using birth control from study Visit 1 throughout the study period up to 120 days after 
the last dose of study therapy.  
The following are considered adequate barrier methods of contraception: diaphragm, condom 
(by the partner), copper intrauterine device, sponge, or spermicide.  Appropriate hormonal 
contraceptives will include any registered and marketed contraceptive agent that contains an 
estrogen and/or a progestational agent (including oral, subcutaneous, intrauterine, or 
intramuscular agents). 
6.6.3 Use in Pregnancy 
Pregnancies and suspected pregnancies (including a positive pregnancy test regardless of age 
or disease state) of a female subject occurring while the subject is on pomalidomide and MK-
4375 , or within 28 days of the subject’s last dose are considered immediately reportable 
events. Both pomalidomide and MK-4375 are to be discontinued immediately. The 
pregnancy, suspected pregnancy, or positive pregnancy test must be reported to Merck Drug 
Safety immediately by facsimile, or other appropriate method, using the Pregnancy Initial 
Report Form, or approved equivalent form. 
The female subject should be referred to an obstetrician-gynecologist, preferably one 
experienced in reproductive toxicity for further evaluation and counseling. 
The Investigator will follow the female subject until completion of the pregnancy, and must 
notify Merck immediately about the outcome of the pregnancy (either normal or abnormal 
outcome) using the Pregnancy Follow-up Report Form, or approved equivalent form. 
If the outcome of the pregnancy was abnormal (e.g., spontaneous or therapeutic abortion), 
the Investigator should report the abnormal outcome as an AE. If the abnormal outcome 
meets any of the serious criteria, it must be reported as an SAE to Merck Drug Safety 
immediately by facsimile, or other appropriate method, within 24 hours of the Investigator’s 
knowledge of the event using the SAE Report Form, or approved equivalent form. 
All neonatal deaths that occur within 28 days of birth should be reported, without regard to 
causality, as SAEs. In addition, any infant death after 28 days that the Investigator suspect is 
related to the in utero exposure to the pomalidomide and MK-3475 should also be reported. 
Male Subjects: If a female partner of a male subject taking investigational product becomes 
pregnant, the male subject taking pomalidomide and MK-4375should notify the Investigator 
immediately, and the pregnant female partner should be advised to call their healthcare 
provider immediately. 


Product:  MK-3475 & Pomalidomide in R/R Myeloma 
Amendment No. 3.1   page46 
 
 
 
 
Drug Safety Contact Information: 
Merck Global Safety. (Attn: Worldwide Product Safety; FAX (215) 993-1220) 
 
6.6.4 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, subjects who are breast-feeding are not eligible for 
enrollment. 
6.7 
Subject Withdrawal/Discontinuation Criteria 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur.  In addition, a subject may be 
withdrawn by the investigator or the Sponsor if enrollment into the trial is inappropriate, the 
trial plan is violated, or for administrative and/or other safety reasons.  Specific details 
regarding discontinuation or withdrawal are provided in Section 8.4.  
A subject must be discontinued from the trial for any of the following reasons: 
• The subject or legal representative (such as a parent or legal guardian) withdraws 
consent. 
• Confirmed disease progression 
Note: A subject may be granted an exception to continue on treatment with 
confirmed radiographic progression if clinically stable or clinically improved, 
please see Section 8.4 
• Unacceptable adverse experiences as described in Section 6.2 
• Intercurrent illness that prevents further administration of treatment 
• Investigator’s decision to withdraw the subject 
• The subject has a confirmed positive serum pregnancy test 
• Noncompliance with trial treatment or procedure requirements 
• The subject is lost to follow-up 
• Completed 24 months of treatment with MK-3475 
• Administrative reasons 
The End of Treatment (EOT) and Follow-up visit procedures are listed in Trial Flow Chart 
and Section 8.6 (Visit Requirements).  After the end of treatment, each subject will be 
followed for 30 days for adverse event monitoring (serious adverse events will be collected 
for 90 days after the end of treatment as described in Section 8.6.  Subjects who discontinue 
for reasons other than progressive disease will have post-treatment follow-up for disease 
status until disease progression, initiating a non-study cancer treatment, withdrawing consent 
or becoming lost to follow-up.  After documented disease progression each subject will be 
followed by telephone for overall survival until death, withdrawal of consent, or the end of 
the study, whichever occurs first. 


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Amendment No. 3.1   page46 
 
 
 
 
6.8 
Subject Replacement Strategy 
If the patient did not finish at least one cycle of therapy he/she will be considered un-
evaluable and will be replaced; unless the patient stopped therapy for an SAE related to drug.  
6.9   Clinical Criteria for Early Trial Termination 
Early trial termination will be the result of the criteria specified below: 
1. Quality or quantity of data recording is inaccurate or incomplete 
2. Poor adherence to protocol and regulatory requirements 
3. Incidence or severity of adverse drug reaction in this or other studies indicates a potential 
health hazard to subjects 
4. Plans to modify or discontinue the development of the study drug 
In the event of Merck’s decision to no longer supply study drug, ample notification will be 
provided so that appropriate adjustments to subject treatment can be made. 
 
7.0 TREATMENT PHASE TRIAL FLOW CHART  


Product:  MK-3475 & Pomalidomide in R/R Myeloma 
Amendment No. 3.1   page46 
 
 
 
 
Trial Period: 
Screening 
Phase 
Treatment Period (28 
Day Cycles)  
 
EOT 
Post-Treatment 
Treatment Cycle/Title: 
Main Study 
Screening  
Cycles 1 through 1217 
 
 
Cycles 13-24 
Discontinuation 
Safety Follow-up 
Follow Up Visits 
Survival 
Follow-Up 
Scheduling Window (Days): 
-28 to -1 
D 112,16 
D 1516 
D 112,16 
D 1516 
At time of 
discontinuation 
30 days post 
discontinuation 
Every 8 weeks post 
discontinuation 
Every 12-
16 weeks  
 Administrative Procedures 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
Prior and Concomitant Medication 
Review 
X 
X 
X 
X 
X 
X 
X 
 
 
IV MK-3475 administration 
 
X 
X 
X 
X 
 
 
 
 
Oral POM dosing 
 
Days 1-21 
 
 
 
 
Oral Dex dosing 
 
Days 1, 8, 15 and 22 
 
 
 
 
Dispense/Collect / Review drug 
diary 
 
X 
X 
X 
X 
X 
 
 
 
Post-study anticancer therapy status 
 
 
 
 
 
 
 
X 
 
Survival Status 
 
 
 
 
 
 
 
 
X 
 Clinical Procedures/Assessments 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
 
 
Full Physical Examination 
X 
 X 
 
X 
 
X 
X 
 
 
Directed Physical Examination6 
 
  
X 
 
X 
 
 
 
 
Vital Signs, Height5  and Weight 
X 
X 
X 
X 
X 
X 
X 
 
 
ECOG Performance Status 
X 
X 
 
X 
 
X 
X 
 
 
12 Lead EKG 
X 
 
 
 
 
 
 
 
 
 Laboratory Procedures 
Pregnancy Test:1 
Urine or Serum -HCG-1 
X 
X 
 
X 
 
X 
X 
 
 
PT/INR and aPTT,15 
X 
X 
 
 
 
X 
X 
 
 
CBC with Differential 
X 
X 
X 
X 
X 
X 
X 
 
 
Comprehensive Serum Chemistry 
Panel2,  
X 
X 
X 
X 
X 
X 
X 
 
 
Urinalysis 15 
X 
X 
 
 
 
X 
X 
 
 
T3, FT4 and TSH,15 
X 
X 
 
 
 
X 
X 
 
 
 Efficacy Measurements 
SPEP, IF, quant immunoglobulin3,10  
X 
X 
 
X 
 
X 
 
X 
 


Product:  MK-3475 & Pomalidomide in R/R Myeloma 
Amendment No. 3.1   page46 
 
 
 
 
 
1. Pregnancy tests for females of childbearing potential. A female of childbearing potential (FCBP) is a sexually mature female who: 1) has not undergone a hysterectomy or 
bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months). 
Pregnancy tests must occur 10 – 14 days before the first dose of POMALIDOMIDE and again within 24 hours prior to the first dose of POMALIDOMIDE. Once on study the 
following applies – Pregnancy test every week during the first 4 weeks of treatment. After the first 4 weeks are complete females with regular menstrual cycles will have a 
pregnancy test done every 4 weeks (including breaks in therapy). Females with irregular cycles will have a pregnancy test done every 2 weeks. Pregnancy testing will also be done 
at discontinuation of study and at Day 28 post the last dose of pomalidomide. 
2. Includes sodium, potassium, chloride, CO2, calcium, blood urea nitrogen (BUN), creatinine, glucose, albumin, total protein, alkaline phosphatase, total bilirubin, SGOT/AST, 
SGPT/ALT, LDH, uric acid, magnesium, phosphorous 
3. SPEP = serum protein electrophoresis; IF = serum immunofixation; UTP = urine total protein; UPEP = urine protein electrophoresis; UIF = urine immunofixation; B2M = beta-
2 microglobulin; CRP = C-reactive protein 
4. Bone marrow will be repeated to confirm complete remission or as clinically indicated.  
5. Required at screening only 
6. Day 15 if clinically indicated  
7. PET/CT OR MRI of neck/chest/abdomen/pelvis as clinically indicated.   
8. At initial screening, Day 1 and 15 of cycle 1, 2 and 3 and at time of relapse 
9. Correlative Studies Blood Collection to be drawn at time of relapse also. 
10. Required from Cycle 2 onwards on day 1. Also on C1D1 if screening is > 14 days from C1D1. 
11. ECOG will be done every other cycle after Cycle 8 
12. After Cycle 1, pre-dose lab procedures can be conducted up to 72 hours prior to dosing. Results must be reviewed by the investigator or qualified designee and found to be 
acceptable prior to each dose of trial treatment. 
13. Standard of care Bone marrow will be repeated on Cycle 3 Day 1 (+/- 3 days) to confirm complete remission or as clinically indicated. 
Trial Period: 
Screening 
Phase 
Treatment Period 
(28 Day Cycles)  
 
EOT 
Post-Treatment 
Treatment Cycle/Title: 
Main Study 
Screening  
Cycles 1 through 
1217 
 
 
Cycles 13-24 
Discontinuation 
Safety Follow-
up 
Follow Up Visits 
Survival 
Follow-Up 
Scheduling Window (Days): 
-28 to -1 
D 1,12,16 
D 1516 
D 
1,12,16 
D 1516 
At time of 
discontinuation 
30 days post 
discontinuation 
(+/- 7 days) 
Every 8 weeks post 
discontinuation (+/- 
7 days) 
Every 12-
16 weeks  
Serum free light chains10 
X 
X 
 
X 
 
X 
 
X 
 
24-hour urine for UTP, UPEP, 
UIF3,10 
X 
X 
 
X 
 
X 
 
X 
 
B-2-M, CRP3,10 
X 
X 
 
X 
 
X 
 
X 
 
Bone marrow Aspirate and Biopsy4 
X 
 X13 
 
 
 
 
 
 
 
Skeletal Scan 
X 
 
 
 
 
 
 
 
 
PET/CT OR MRI7 
X 
X 
 
 
 
 Tumor Biopsies/Archival Tissue Collection/Correlative Studies Blood (Optional) 
Bone Marrow Aspirate 
X 
X14 
 
 
 
 
 
 
 
Correlative Studies Blood 
Collection8,9  
X 
X 
X 
 
 
 
 
 
 


Product:  MK-3475 & Pomalidomide in R/R Myeloma 
Amendment No. 3.1   page46 
 
 
 
 
14. To be collected on Cycle 3 Day 1 (+/- 3 days) only if standard of care bone marrow sample is done.   
15.  Day 1 of cycles 3 and 6 only.  
16. Run off phase patients have study visits only on Day 1 of every cycle. Day 15 study visit is applicable only if they have Correlative blood collections or for clinical care.  
17. During cycle 1 only, subjects will come in on week 2 and week 4 for safety lab checks.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Amendment No. 3.1   page46 
 
 
 
 
 
7.1 Maintenance Trial Flow Chart 
 
Trial Period 
Maintenance  
Maintenance Treatment Cycle 
Once Weekly  
Days 1-21 
Once Monthly  
Every 3 Months  
Once Yearly 
Administration Procedures 
 
 
IV MK-3475 Administration1 
 
 
X 
 
 
Oral POM Dosing 
 
X 
 
 
 
Oral Dexamethasone Dosing 
X 
 
 
 
 
Laboratory Procedures 
 
 
CBC with Differential 
 
 
X 
 
 
Comprehensive Serum Chemistry 
Panel (refer to footnote 2 on trial 
flow chart)  
 
 
X 
 
 
SPEP, IFE, 24-hour urine for UTP, 
UPEP, , UIFE 
 
 
X 
 
 
T3, FT4 and TSH 
 
 
 
X 
 
Bone marrow Aspirate and Biopsy 
 
 
 
 
X 
Free serum light chain 
 
 
X 
 
 
 Beta-2 microglobulin (B2M) 
 
 
X 
 
 
C-reactive protein-CRP 
 
 
X 
 
 


Product:  MK-3475 & Pomalidomide in R/R Myeloma 
Amendment No. 3.1   page46 
 
 
 
 
1. Day 1 of each month
Quantitative immunoglobulin (IgG, 
IgA, IgM) 
 
 
X 
 
 


Product:  MK-3475 & Pomalidomide in R/R Myeloma 
Amendment No. 3.1   page46 
 
 
 
 
 
8. TRIAL PROCEDURES 
8.1 Administrative Procedures  
8.1.1 Informed Consent 
The Investigator or designated personal must obtain documented consent from each potential 
subject prior to participating in a clinical trial. 
Consent must be documented by the subject’s dated signature on a consent form along with 
the dated signature of the person conducting the consent discussion.  
A copy of the signed and dated consent form should be given to the subject before 
participation in the trial. 
The initial informed consent form, any subsequent revised written informed consent form 
and any written information provided to the subject must receive the IRB/ERC’s 
approval/favorable opinion in advance of use.  The subject should be informed in a timely 
manner if new information becomes available that may be relevant to the subject’s 
willingness to continue participation in the trial.  The communication of this information will 
be provided and documented via a revised consent form or addendum to the original consent 
form that captures the subject’s dated signature.  
Specifics about the trial and the trial population will be added to the consent form template at 
the protocol level.   
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements. 
8.1.2 Inclusion/Exclusion Criteria 
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial.  
8.1.3 Subject Study Oral Study Drug Diary 
All subjects will be given a study diary to record the oral study drug administration.  The 
diary will be given at cycle 1 day 1.   
8.1.4 Medical History 
A medical history will be obtained by the investigator or qualified designee.  Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that 
are considered to be clinically significant by the Investigator.  Details regarding the disease 
for which the subject has enrolled in this study will be recorded separately and not listed as 
medical history.   
8.1.5 Prior and Concomitant Medications Review 
a. Prior Medications 
The investigator or qualified designee will review prior medication use, including 
any protocol-specified washout requirement, and record prior medication taken by 
the subject within 28 days before starting the trial.  Treatment for the disease for 


Product:  MK-3475 & Pomalidomide in R/R Myeloma 
Amendment No. 3.1   page46 
 
 
 
 
which the subject has enrolled in this study will be recorded separately and not 
listed as a prior medication.  
b. Concomitant Medications 
The investigator or qualified designee will record medication, if any, taken by the 
subject during the trial.  All medications related to reportable SAEs and ECIs 
should be recorded as defined in Section 8.12.1, and 8.12.2. 
8.1.6 Disease Details and Treatments 
 
      a. Disease Details 
The investigator or qualified designee will obtain prior and current details 
regarding disease status.  
b. Prior Treatment Details 
The investigator or qualified designee will review all prior cancer treatments 
including systemic treatments, radiation and surgeries. 
c. Subsequent Anti-Cancer Therapy Status 
The investigator or qualified designee will review all new anti-neoplastic therapy 
initiated after the last dose of trial treatment.  If a subject initiates a new anti-
cancer therapy within 30 days after the last dose of trial treatment, the 30 day 
Safety Follow-up visit must occur before the first dose of the new therapy.  Once 
new anti-cancer therapy has been initiated the subject will move into survival 
follow-up.  
8.2 Clinical Procedures/Assessments 
8.2.1 Adverse Event (AE) Monitoring 
The investigator or qualified designee will assess each subject to evaluate for potential new 
or worsening AEs as specified in the Trial Flow Chart and more frequently if clinically 
indicated.  Adverse experiences will be graded and recorded throughout the study and during 
the follow-up period according to NCI CTCAE Version 4.0.   Toxicities will be characterized 
in terms regarding seriousness, causality, toxicity grading, and action taken with regard to 
trial treatment.  
All AEs of unknown etiology associated with MK-3475 exposure should be evaluated to 
determine if it is possibly an event of clinical interest (ECI) of a potentially immunologic 
etiology (irAE).  See Appendix D for the separate guidance document regarding the 
identification, evaluation and management of AEs of a potential immunological etiology.   
Please refer to section 7.9 for detailed information regarding the assessment and recording of 
AEs.   
8.2.2 Full Physical Exam 
The investigator or qualified designee will perform a complete physical exam during the 
screening period and day 1 of all cycles.  Clinically significant abnormal findings should be 
recorded as medical history.  A full physical exam should be performed during screening,  


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8.2.3 Directed Physical Exam 
 
For cycles that do not require a full physical exam per the Trial Flow Chart, the investigator 
or qualified designee will perform a directed physical exam as clinically indicated prior to 
trial treatment administration.   
8.2.4 Vital Signs 
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of trial treatment and at treatment discontinuation as specified in 
the Trial Flow Chart (Section 7.0).  Vital signs should include temperature, pulse, respiratory 
rate, weight and blood pressure.  Height will be measured at screening only. 
8.2.5 Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The investigator or qualified designee will assess ECOG status (see Appendix A) at 
screening,  and prior to the administration of trial treatment on Day 1 of each cycle,and at 
discontinuation of trial treatment as specified in the Trial Flow Chart.  After Cycle 8 
assessment of ECOG status will be performed every other cycle in conjunction with the 
directed or full physical exam. 
8.2.6 Multiple Myeloma Response Assessment  
Myeloma objective response rate will be assessed using the International Myeloma Working 
Group Uniform Response Criteria (See Appendix C1 & C2). Response rate categories that 
will be evaluated include Stringent Complete Response, Complete Response, Very Good 
Partial Response, Partial Response, Stable Disease, Plateau Disease, Minimal Response and 
Disease Progression. 
Progression-Free Survival and Overall Survival PFS will be defined as the time from first 
treatment day until objective or symptomatic progression or death. OS will be defined as the 
time from first treatment day until death. 
8.2.7 Tumor Tissue Collection and Correlative Studies Blood Sampling 
All patients will be encouraged to consent for correlative studies. We will collect from 
consenting patients: peripheral blood (10 ml) at initial screening, Day 1 and 15 of cycle 1, 2 
and 3 and at time of relapse 
Bone marrow aspirate (5 ml) will be obtained at initial screening and confirmation of 
remission as well as at progression. The response or lack off for each patient will be 
correlated with the PD-1/PDL-1 expression in patients’ samples and possibly 
pharmacogenomics using gene expression profiling.  Staining for PD1, CD3 and T cell 
markers CD4, CD8, CD45RO, and FoxP3 
See lab manual for more information regarding collection and processing of samples. 
8.3 Laboratory Procedures/Assessments 
8.3.1 Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) 
Laboratory tests for hematology, chemistry, urinalysis, and others are specified in Table 10.  
The amount of blood/tissue to be drawn/collected over the course of the trial (from pre-trial 
to post-trial visits), are all standard of care. Less than 30 ml will be collected as research over 
the study period. 


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Table 10 Laboratory Tests 
 
Hematology 
Chemistry 
Urinalysis 
Other 
Hematocrit 
Albumin 
Blood 
SPEP = serum protein electrophoresis; IF = 
serum immunofixation,  
Hemoglobin 
Alkaline phosphatase 
Glucose 
Serum β-human chorionic gonadotropin† 
Platelet count 
Alanine aminotransferase (ALT) 
Protein 
  (β-hCG)† 
WBC (total and differential) 
Aspartate aminotransferase (AST) 
Specific gravity  
aPTT 
Red Blood Cell Count 
Lactate dehydrogenase (LDH) 
Microscopic exam (If abnormal)  
Total thriiodothyronine (T3) 
Absolute Neutrophil Count 
Carbon Dioxide ‡ 
results are noted 
Free tyroxine (T4) 
 
  (CO2 or biocarbonate) 
Urine pregnancy test † 
Thyroid stimulating hormone (TSH) 
 
Uric Acid 
UTP = urine total protein; UPEP = 
urine protein electrophoresis; UIF = 
urine immunofixation 
B2M = beta-2 microglobulin, CRP = C-
reactive protein 
 
Calcium 
 
Free serum light chains 
 
Chloride 
 
Blood for correlative studies 
 
Glucose 
 
  
 
Phosphorus 
 
  
 
Potassium   
 
  
 
Sodium 
 
  
 
Magnesium 
 
  
 
Total Bilirubin 
 
  
 
Direct Bilirubin (If total bilirubin is 
elevated above the upper limit of 
normal) 
 
 
 
Total protein 
 
 
 
Blood Urea Nitrogen 
 
 
 
Creatinine 
 
 
† Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed as negative, a serum pregnancy test will be required.   
‡ If considered standard of care in your region. 


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8.4 Withdrawal/Discontinuation 
When a subject discontinues/withdraws prior to trial completion, all applicable activities 
scheduled for the discontinuation trial visit should be performed at the time of 
discontinuation. 
 
Any 
adverse 
events 
which 
are 
present 
at 
the 
time 
of 
discontinuation/withdrawal should be followed in accordance with the safety requirements 
outlined in Section 8.9 - Assessing and Recording Adverse Events.  After discontinuing 
treatment following assessment of complete disease response (CR), these subjects should 
return to the site for a Safety Follow-up Visit (described in Section 8.6 and then proceed to 
the Follow-Up Period of the study (described in Section 8.7). 
8.5 Visit Requirements 
Visit requirements are outlined in Section 7.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 8.0, Trial Procedures. 
8.6 Safety Follow-Up Visit 
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days (+/- 7 
days) after the last dose of trial treatment or before the initiation of a new anti-cancer 
treatment, whichever comes first.  All AEs that occur prior to the Safety Follow-Up Visit 
should be recorded.  Subjects with an AE of Grade > 1 will be followed until the resolution 
of the AE to Grade 0-1 or until the beginning of a new anti-neoplastic therapy, whichever 
occurs first.  SAEs that occur within 30 days of the end of treatment or before initiation of a 
new anti-cancer treatment should also be followed and recorded.   
8.7 Follow-up Visits 
Subjects who discontinue trial treatment for a reason other than disease progression will 
move into the Follow-Up Phase and should be assessed every 8 weeks (56 ± 7 days) by 
restaging to monitor disease status.  Every effort should be made to collect information 
regarding disease status until the start of new anti-neoplastic therapy, disease progression, 
death, or end of the study as detailed in Section 6.2.2.  Information regarding post-study anti-
neoplastic treatment will be collected if new treatment is initiated. 
8.8 Survival Follow-up 
Once a subject experiences confirmed disease progression or starts a new anti-cancer 
therapy, the subject moves into the survival follow-up phase and should be contacted by 
telephone every 12-16 weeks or via the patient’s medical record review to assess for survival 
status until death, withdrawal of consent, or the end of the study, whichever occurs first.  
8.9 Assessing and Recording Adverse Events 
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.   
 


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Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) 
of a preexisting condition that is temporally associated with the protocol therapy is also an 
adverse event. 
 
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  
Examples of this may include, but are not limited to, teething, typical crying in infants and 
children and onset of menses or menopause occurring at a physiologically appropriate time. 
Investigational product includes any pharmaceutical product, biological product, device, 
diagnostic agent or protocol-specified procedure, whether investigational (including placebo 
or active comparator medication) or marketed, manufactured by, licensed by, provided by or 
distributed by Merck for human use. 
Adverse events may occur during the course of the trial or within the follow-up period 
specified by the protocol, or prescribed in clinical practice, from overdose (whether 
accidental or intentional), from abuse and from withdrawal. 
Adverse events may also occur in screened subjects during any pre-allocation baseline period 
as a result of a protocol-specified intervention, including washout or discontinuation of usual 
therapy, diet, placebo treatment or a procedure. 
All adverse events will be recorded from the time the consent form is signed through 30 days 
following cessation of treatment and at each examination on the Adverse Event case report 
forms/worksheets. The reporting timeframe for adverse events meeting any serious criteria is 
described in section 8.12. 
If the subject requires a blood draw, fresh tumor biopsy etc., the subject is first required to 
provide consent to the main study and AEs will be captured according to guidelines for 
standard AE reporting. 
8.10 Definition of an Overdose for This Protocol and Reporting of Overdose to  
Merck 
For purposes of this trial, an overdose will be defined as any dose exceeding 1000mg for 
MK-3475 by 20% over the prescribed dose or extra-doses of Pomalidomide. No specific 
information is available on the treatment of overdose of MK-3475 or pomalidomide. In the 
event of overdose, therapy should be discontinued and the subject should be observed closely 
for signs of toxicity.  Appropriate supportive treatment should be provided if clinically 
indicated. 
If an adverse event(s) is associated with (“results from”) the overdose of MK-3475 or 
pomalidomide, the adverse event(s) is reported as a serious adverse event, even if no other 
seriousness criteria are met. 
If a dose of MK-3475 meeting the protocol definition of overdose is taken without any 
associated clinical symptoms or abnormal laboratory results, the overdose is reported as a 
non-serious Event of Clinical Interest (ECI), using the terminology “accidental or intentional 
overdose without adverse effect.” 


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All reports of overdose with and without an adverse event must be reported within 24 hours 
to the Sponsor and within 2 working days hours to Merck Global Safety.  
8.11 Reporting of Pregnancy and Lactation to Merck 
All subjects and female partners of male subjects who become pregnant must be followed to 
the completion/termination of the pregnancy.  Pregnancy outcomes of spontaneous abortion, 
missed abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, 
miscarriage and stillbirth must be reported as serious events (Important Medical Events).  If 
the pregnancy continues to term, the pregnancy outcome  must also be reported. 
Such events must be reported within 24 hours to the Sponsor and within 2 working days to 
Merck Global Safety. (Attn: Worldwide Product Safety; FAX (215) 993-1220) 
8.12 Immediate Reporting of Adverse Events to Merck 
Serious adverse events (SAE) are defined below.  The investigator must inform Merck in 
writing of any SAE within 2 business days of being aware of the event.  The initial report 
must be as complete as possible, including an assessment of the causal relationship between 
the event and the investigational product(s), if available.  Information not available at the 
time of the initial report (e.g., an end date for the adverse event or laboratory values received 
after the report) must be documented on a follow-up report.  A final report to document 
resolution of the SAE is required.   
Reporting of Adverse Events 
Investigators are responsible for monitoring the safety of patients who have entered this 
study and for alerting the UMGCC DSM/QAC to any event that seems unusual, even if this 
event may be considered an unanticipated benefit to the patient.  Any adverse experiences 
which occur at any time during the clinical study or within 30 days of receiving the last dose 
of study medication, whether or not related to the study drug will be reported as per 
institutional policy. 
Adverse events will be tracked starting from Dose 1. The AE grading scale will be based on 
CTCAE version 4 to grade the severity of the events.  Expeditious reporting to the IRB, 
based according to the UM IRB Reportable New Information (RNI) criteria, will follow 
HRPO’s current guidelines.  All AEs whether or not related to the study drugs will be 
reported to the DSM/QAC according to the UMGCC DSM/QAC SOP.  
8.12.1 Serious Adverse Events 
A serious adverse event is any adverse event occurring at any dose or during any use of the 
investigational product that: 
• Results in death; 
• Is life threatening; 
• Results in persistent or significant disability/incapacity; 
• Results in or prolongs an existing inpatient hospitalization; 
• Is a congenital anomaly/birth defect; 


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• Is a new cancer (that is not a condition of the study); 
• Is associated with an overdose; 
• Is another important medical event  
Refer to Table 11 for additional details regarding each of the above criteria. 
Progression of the cancer under study is not considered an adverse event unless it results in 
hospitalization or death. 
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 from 
the time the consent is signed through 90 days following cessation of treatment, or the 
initiation of new anti-cancer therapy, whichever is earlier, whether or not related to the 
protocol therapy, must be reported locally to the site Institutional Review Board (IRB) per 
local policy  and within 2 working days to Merck Global Safety.  The sponsor will then 
report the event to Merck Global Safety (Attn: Worldwide Product Safety; FAX: 215 993-
1220) using FDA Form 3500A (MedWatch Form) within 2 working days of becoming aware 
of the event.  The event should also be reported locally to the site Institutional Review Board 
(IRB) per local policy.  The serious adverse event must also be reported to the FDA using 
FDA Form 3500A (MedWatch Form) within 7 days. If the serious event is unexpected fatal, 
or life threatening it must be reported to the FDA as soon as possible but no later than 7 
calendar days following the sponsor’s initial receipt of the information.  
Additionally, any serious adverse event considered by an investigator (who is a qualified 
physician) to be related to protocol therapy that is brought to the attention of the study team 
at any time outside of the time period specified in the previous paragraph also must be 
reported immediately to the Sponsor.  The sponsor will then report the event to Merck using 
FDA Form 3500A (MedWatch Form). 
Non-serious Events of Clinical Interest will be forwarded to Merck Global Safety and will be 
handled in the same manner as SAEs.  
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to protocol therapy that is brought to the attention of the investigator 
at any time outside of the time period specified in the previous paragraph also must be 
reported immediately to the Sponsor and to Merck. 
SAE reports and any other relevant safety information are to be forwarded to the Merck 
Global Safety facsimile number:  +1 (215) 993-1220 
A copy of all 15 Day Reports and Annual Progress Reports is submitted as required by FDA, 
European Union (EU), Pharmaceutical and Medical Devices agency (PMDA) or other local 
regulators. Investigators will cross reference this submission according to local regulations to 
the Merck Investigational Compound Number (IND, CSA, etc.) at the time of submission.  
Additionally investigators will submit a copy of these reports to Merck & Co., Inc. (Attn: 
Worldwide Product Safety; FAX (215) 993-1220) at the time of submission to FDA. 
All subjects with serious adverse events must be followed for the duration of the SAE to 
determine outcome. 


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8.12.2 Events of Clinical Interest 
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be recorded as such on the Adverse Event case report forms/worksheets and 
reported within 2 working days to Merck Global Safety. (Attn: Worldwide Product Safety; 
FAX (215) 993-1220) 
Events of clinical interest for this trial include: 
1.  an overdose of Merck product, as defined in Section 7.10 - Definition of an Overdose for 
This Protocol and Reporting of Overdose to the Sponsor, that is not associated with clinical 
symptoms or abnormal laboratory results.  
2.  an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal AND an elevated total bilirubin lab value that is greater than or equal to 2X the upper 
limit of normal AND, at the same time, an alkaline phosphatase lab value that is less than 2X 
the upper limit of normal, as determined by way of protocol-specified laboratory testing or 
unscheduled laboratory testing. 
3.  In the event a subject develops any of the following AEs, a detailed narrative of the event 
should be reported as an ECI to Merck Global Safety within 2 working days of the event: 
a.  Grade ≥ 3 diarrhea 
b.  Grade ≥  3 colitis 
c.  Grade ≥ 2 pneumonitis 
d.  Grade ≥ 3 hypo- or  hyperthyroidism 
 
Potential Skin Events of Clinical Interest: 
Every attempt should be made by the study team to take photographs of the actual ECI skin 
lesion or rash as soon as possible.  If affected, photographs should be taken of:  
o the head (to assess mucosal or eye involvement) 
o the trunk and extremities 
o a close-up of the skin lesion/rash.  
 
If possible, a ruler should be placed alongside the site of the skin occurrence as a fixed 
marker of distance.  
o The time/date stamp should be set in the 'ON' position for documentation 
purposes.  
o Photographs should be stored with the subject’s study records.  
o Merck may request copies of photographs.  
 
In addition to the photographs, the following documents from the Merck Pembrolizumab 
Program (MK-3475) Event of Clinical Interest Guidance Document (at the end of the 
protocol) need to be completed and faxed  to Merck Global Safety (Attn:  Worldwide 
Product Safety, FAX:  215-993-1220) within 2 business day of the subject’s presentation 
with the dermatologic event: 
o Appendix 2—Past Medical History Related to Dermatologic Event 
o Appendix 3—Presentation of the Dermatologic Event 


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o Appendix 4—Focused Skin Examination 
A separate guidance document has been provided entitled “event of Clinical Interest and 
Immune-Related Adverse Event Guidance Document.”  This document provides guidance 
regarding identification, evaluation and management of ECIs and irAEs.  Additional ECIs are 
identified in this guidance document and also need to be reported to Merck Global Safety 
within 2 working days of the event.   
Subjects should be assessed for possible ECIs prior to each dose.  Lab results should be 
evaluated and subjects should be asked for signs and symptoms suggestive of an immune-
related event.  Subjects who develop an ECI thought to be immune-related should have 
additional testing to rule out other etiologic causes.  If lab results or symptoms indicate a 
possible immune-related ECI, then additional testing should be performed to rule out other 
etiologic causes.  If no other cause is found, then it is assumed to be immune-related.  
ECIs that occur in any subject from the date of first dose through 90 days following cessation 
of treatment, or the initiation of a new anticancer therapy, whichever is earlier, whether or 
not related to the Merck’s product, must be reported to Merck Global Safety within 2 
working days. 
8.12.3 Evaluating Adverse Events 
An investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), version 4.0. Any adverse event 
which changes CTCAE grade over the course of a given episode will have each change of 
grade recorded on the adverse event case report forms/worksheets. 
All adverse events regardless of CTCAE grade must also be evaluated for seriousness. 
8.12.4 Sponsor Responsibility for Reporting Adverse Events 
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations.  
 
 


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Table 11 Evaluating Adverse Events 
V4.0 CTCAE 
Grading 
Grade 1 
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not indicated. 
 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL. 
 
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or 
hospitalization indicated; disabling; limiting self-care ADL. 
 
Grade 4 
Life threatening consequences; urgent intervention indicated. 
 
Grade 5 
Death related to AE 
Seriousness 
A serious adverse event is any adverse event occurring at any dose or during any use of Merck product that: 
 
†Results in death; or 
 
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: 
This does not include an adverse event that, had it occurred in a more severe form, might have caused death.); or 
 
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or 
 
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of 
stay, even if the hospitalization is a precautionary measure for continued observation. (Note: Hospitalization [including hospitalization for an 
elective procedure] for a preexisting condition which has not worsened does not constitute a serious adverse event.); or 
 
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or 
 
Is a new cancer; (that is not a condition of the study) or 
 
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event. An 
overdose that is not associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 
hours. 
 
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a 
serious adverse event when, based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or 
surgical intervention to prevent one of the outcomes listed previously (designated above by a †). 
Duration 
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units 
Action taken  
Did the adverse event cause the study treatment  to be discontinued? 
Relationship 
to test drug  
Did the Merck product cause the adverse event? The determination of the likelihood that the Merck product caused the adverse event will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated initials on the source document or worksheet that 
supports the causality noted on the AE form, ensures that a medically qualified assessment of causality was done. This initialed document 
must be retained for the required regulatory time frame. The criteria below are intended as reference guidelines to assist the investigator in 
assessing the likelihood of a relationship between the test drug and the adverse event based upon the available information.  
The following components are to be used to assess the relationship between the Merck product and the AE; the greater the correlation 
with the components and their respective elements (in number and/or intensity), the more likely the Merck product caused the adverse event 
(AE): 
 
Exposure 
Is there evidence that the subject was actually exposed to the Merck product such as: reliable history, acceptable 
compliance assessment (pill count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in 
bodily specimen? 
 
Time Course 
Did the AE follow in a reasonable temporal sequence from administration of the Merck product?  


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Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal 
product)? 
 
Likely Cause 
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host 
or environmental factors 
 
Relationship 
The following components are to be used to assess the relationship between the test drug and the AE: (continued) 
to Merck 
product 
(continued)  
Dechallenge 
Was the Merck product discontinued or dose/exposure/frequency reduced? 
If yes, did the AE resolve or improve? 
If yes, this is a positive dechallenge. If no, this is a negative dechallenge. 
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE 
resolved/improved despite continuation of the Merck product; or (3) the trial is a single-dose drug trial); or (4) Merck 
product(s) is/are only used one time.) 
 
Rechallenge 
Was the subject re-exposed to the Merck product in this study? 
If yes, did the AE recur or worsen? 
If yes, this is a positive rechallenge. If no, this is a negative rechallenge. 
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or (2) the trial is a 
single-dose drug trial); or (3) Merck product(s) is/are used only one time). 
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH 
MAY HAVE BEEN CAUSED BY THE MERCK PRODUCT, OR IF REEXPOSURE TO THE MERCK PRODUCT 
POSES ADDITIONAL POTENTIAL SIGNIFICANT RISK TO THE SUBJECT, THEN THE RECHALLENGE MUST 
BE APPROVED IN ADVANCE BY THE U.S. CLINICAL MONITOR AS PER DOSE MODIFICATION GUIDELINES 
IN THE PROTOCOL. 
 
Consistency 
with Trial 
Treatment 
Profile 
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the Merck product or 
drug class pharmacology or toxicology? 
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best 
clinical judgment, including consideration of the above elements. 
Record one of the following 
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of a Merck product 
relationship). 
Yes, there is a reasonable 
possibility of Merck product 
relationship. 
There is evidence of exposure to the Merck product.  The temporal sequence of the AE onset relative to the administration 
of the Merck product is reasonable.  The AE is more likely explained by the Merck product than by another cause. 
No, there is not a reasonable 
possibility Merck product 
relationship 
Subject did not receive the Merck product OR temporal sequence of the AE onset relative to administration of the Merck 
product is not reasonable OR there is another obvious cause of the AE.  (Also entered for a subject with overdose without 
an associated AE.) 


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9.0 STATISTICAL ANALYSIS PLAN 
The main objectives in this study of the study in patients with relapsed/refractory multiple 
myeloma are assessment of the efficacy and safety of the new combination immunotherapy. The 
primary endpoint used to evaluate the efficacy is the overall response (CR, VGPR, PR). A true 
overall response (OR) rate of at least 42.5% would be considered active in this particular patient 
population. The Simon’s two-stage design will be used for the study to ensure that the number of 
patients exposed to this new treatment is minimized. Twenty six patients will be initially entered. 
If there are at least six responses among the 20 patients, an additional 22 patients will be entered. 
If at least 15 patients among the forty two patients responded to the treatment, then the 
combination will be considered a promising treatment. The probability of stopping early if the 
true response rate is 25% is 0.62, and 0.09, if the true response rate is 42.5%. If the true overall 
response rate is 42.5%, the probability of concluding that the combination has sufficient activity 
is 0.82 (power of the study), and 0.07 if the true rate is 25%. 
Total accrual is 42 subjects plus 6 patients in the runoff phase, since we expect about 5% of 
patients to be not evaluable.   
The toxicity data will be monitored closely through the therapy. Addressing the safety of the 
combination, a maximum width 90% confidence interval for any grade 3 or higher toxicity will 
be about 26%. For 44 patients in the study, if the true unknown probability of a rare toxicity is 
10%, the probability of observing 1 or more toxicities is 99%, for 5% it is 90%, and, if the true 
toxicity rate is 3%, then the probability of observing one or more rare toxicities is 74%.We do 
not anticipate additional toxicity with the addition of MK-3475. 
Given current accrual rate for patients with relapsed/refractory MM in the GCC system, we 
would anticipate about 25 patients per year. If the study continues, about 2 year time period will 
be required to complete accrual.  
Secondary endpoints 
The most clinically relevant endpoint for this MM population is progression free survival (PFS) 
where failure is defined as death or the appearance of symptomatic myeloma. Progression-free 
survival (PFS) functions will be estimated using the Kaplan-Meier approach. PFS will be 
compared between patients’ subgroups by the log-rank test. PFS medians and the 95% CI will be 
reported. The Cox regression model will be used to assess plausible risk factors in patients PFS.  
All demographic and patients-on-study characteristics will be summarized and reported. The 
response rates will be estimated with the corresponding 95% confidence intervals (CI). Due to a 
rather small sample size all tests will be exact, 2-sided and done at type I error of 0.05.  
Statistical analysis will be done in R (x64, v.3.0.3), and conducted by the GCC BSS.  
However, the exploratory studies involving biomarkers and pharmacogenomics analyses will be 
done by Merck’s central scientific laboratory. Correlative samples will be used for microarray 
data analysis. These tasks can be accomplished using various software such as MAS 5.0 from 
Affy, or the R packages affy, affycomp, gcrma, and affyPLM.  


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 10.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES 
10.1 MK-3475 
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and regulations. 
Clinical Supplies will be provided by Merck as summarized in Table 11. 
Table 12 Product Descriptions 
Product Name & Potency 
Dosage Form 
 
 
MK-3475 100 mg/ 4mL 
Solution for Injection 
 
10.1.1 Packaging and Labeling Information 
Clinical supplies will be affixed with a clinical label in accordance with regulatory requirements. 
10.1.2 Clinical Supplies Disclosure 
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or 
designee are not blinded to treatment. Drug identity (name, strength) is included in the label text; 
random code/disclosure envelopes or lists are not provided. 
10.1.3 Storage and Handling Requirements 
Clinical supplies must be stored in a secure, limited-access location under the storage conditions 
specified on the label.   
Receipt and dispensing of trial medication must be recorded by an authorized person at the trial 
site. 
Clinical supplies may not be used for any purpose other than that stated in the protocol. 
10.1.4 Returns and Reconciliation 
The investigator is responsible for keeping accurate records of the clinical supplies received from 
Merck or designee, the amount dispensed to and returned by the subjects and the amount 
remaining at the conclusion of the trial.  
Upon completion or termination of the study, all unused and/or partially used investigational 
product will be destroyed at the site per institutional policy. It is the Investigator’s responsibility 
to arrange for disposal of all empty containers, provided that procedures for proper disposal 
have been established according to applicable federal, state, local and institutional guidelines and 
procedures, and provided that appropriate records of disposal are kept. 
10.2 Pomalidomide  
Pomalidomide, 4-amino-2-(2,6-dioxo-3-piperidyl)isoindoline-1’-one)-1,3-dione, belongs to the 
IMiDs class of compounds.  The Chemical Abstract Service (CAS) registry number for CC-4047 
is 19171-19-8.  The chemical structure of the active pharmaceutical ingredient (API) is as 
follows:  


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Pomalidomide has an asymmetric carbon atom and can therefore exist as the optically active 
forms S (-) and R (+).  Pomalidomide is being developed as a racemate.  
10.2.1 Clinical Pharmacology 
Mechanism of Action:  
Pomalidomide is a novel immunomodulatory drug under development for the treatment of MM. 
Pomalidomide is a member of a class of pharmaceutical compounds known as 
immunomodulatory drugs (IMiDs). It shares a number of the beneficial pharmacologic properties 
of thalidomide and lenalidomide, but it is a more potent anti-proliferative immunomodulating 
agent than either drug. The pharmacodynamic properties of pomalidomide are of potential 
therapeutic benefit in the treatment of MM.  
Dose and tolerability: 
Pomalidomide was safe at doses of up to 5 mg in a phase 1 single dose study in normal, healthy 
male volunteers and up to 5 mg QOD or 2 mg QD in a phase 1 multidose clinical study in 
subjects with relapsed or refractory multiple myeloma; DLTs seen in subjects receiving higher 
doses were predominantly hematopoietic (i.e., neutropenia), and lower grade, self-limited 
neutropenia was also seen in some of the 1 and 2 mg QD and 5 mg QOD recipients. In a 
multidose, phase 2 clinical study of subjects with prostate cancer, 2 mg QD dosing was well 
tolerated and, unlike the multiple myeloma subjects who received 1 and 2 mg QD doses, only an 
overall shift to lower neutrophil counts was noted. No clinically relevant neutropenic AEs were 
observed, and no grade 3 or 4 neutropenic events occurred. It is, therefore, likely that subjects 
with solid tumors that do not extensively involve the bone marrow will have a higher 
pomalidomide MTD than subjects with hematologic malignancies. 
Supplier(s) 
POMALYST® (pomalidomide) is available commercially, and the patient’s insurance will be 
charged for it.  
Dosage form 
Pomalidomide will be supplied as 1.0 mg, 2.0 mg, 3.0 mg and 4.0 mg capsules for oral 
administration.   


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Packaging 
Pomalidomide will be shipped directly to patients or to the clinic site for IND studies.   Bottles 
will contain a sufficient number of capsules for one cycle of dosing.    
Labeling 
Pomalidomide supplies are dispensed in individual bottles of capsules.  Each bottle will identify 
the contents as study medication. 
Pregnancy Testing    
Must follow pregnancy testing requirements outlined in the POMALYST REMS™ program.  
• All study participants must be registered into the mandatory POMALYST REMS™ 
program, and be willing and able to comply with the requirements of the POMALYST 
REMS™ program. 
• Females of reproductive potential must adhere to the scheduled pregnancy testing as 
required in the POMALYST REMS™ program. Able to take aspirin (81 or 325 mg) daily 
as prophylactic anticoagulation (patients intolerant to ASA may use warfarin or low 
molecular weight heparin). 
Dosing  
Pomalidomide capsules should be swallowed whole, and should not be broken, chewed or 
opened.  Pomalidomide should be taken without food, at least 2 hours before or 2 hours after a 
meal. 
If a dose of pomalidomide is missed, it should be taken as soon as possible on the same day.  If it 
is missed for the entire day, it should not be made up, rather it should be taken at the next 
scheduled time point.  
Patients who take more than the prescribed dose of pomalidomide should be instructed to seek 
emergency medical care if needed and contact study staff immediately.   
Special Handling Instructions 
Females of childbearing potential should not handle or administer pomalidomide unless they are 
wearing gloves. 
Record of administration 
Accurate records will be kept of all study drug administration (including dispensing and dosing)  
in the source documents.   
10.3 Dexamethasone 
Dexamethasone 
For further information on dexamethasone please refer to the approved package insert. 
10.3.1 Other Names 


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Decadron, Hexadrol, Dexameth, Dexone, DXM, others. 
10.3.2 Classification 
Adrenal corticosteroid. 
10.3.4 Mode of Action 
Dexamethasone is a potent synthetic glucocorticoid that affects almost every body system. It has 
anti-inflammatory, immunosuppressant, antineoplastic, and antiemetic properties and very little 
mineralocorticoid activity. As an antineoplastic agent, dexamethasone may bind to specific 
proteins (receptors) within the cell forming a steroid-receptor complex. Binding of the receptor 
steroid complex with nuclear chromatin alters mRNA and protein synthesis within the cell. 
10.3.5 Storage and Stability 
The drug is stored at room temperature in a dry place. 
10.3.6 Dose Specifics 
Patients will be given 40 mg of dexamethasone on days 1, 8, 15, & 22, as outlined in Section 
6.2.1. 
10.3.7 Route of Administration 
Oral. 
10.3.8 Availability 
Commercially available. 
10.3.9 Side Effects 
Gastrointestinal: Nausea, vomiting, anorexia, increased appetite, weight gain, aggravation of 
peptic ulcers. 
Dermatologic: Rash, skin atrophy, facial hair growth, acne, facial erythema, ecchymoses. 
Genitourinary: Menstrual changes (amenorrhea, menstrual irregularities). 
Neurological: Insomnia, euphoria, headache, vertigo, psychosis, depression, seizures, muscle 
weakness. 
Cardiovascular: Fluid retention and edema, hypertension; rarely, thrombophlebitis. 
Ocular: Cataracts, increased intraocular pressure, exophthalmos. 
Metabolic: Hyperglycemia, decreased glucose tolerance, aggravation or precipitation 
of diabetes mellitus, adrenal suppression (with Cushingoid features), hypokalemia. 
Hematologic: Leukocytosis. 
Other: Osteoporosis (and resulting back pain), appearance of serious infections including herpes 
zoster, varicella zoster, fungal infections, Pneumocystis carinii, tuberculosis, muscle wasting, 
delayed wound healing, suppression of reactions to skin tests. 
10.3.10 Nursing/Patient Implications 
( Monitor regularly for hypertension, CHF, and other evidence of fluid retention. 


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(Advise patient of possible mood or behavioral changes, i.e., depression, euphoria, insomnia, 
even psychosis. Instruct patient to report any suspected changes to healthcare team. 
(Assess for symptoms of gastric ulcer, heartburn, or gastritis. Suggest antacids. Instruct patient to 
report symptoms to healthcare team if unable to control. 
(Evaluate signs of infection, particularly local candidal infections and treat appropriately. 
(Monitor blood glucose frequently. 
(Instruct patient to report frequent, unrelenting headaches or visual changes to healthcare team. 
(Advise patient that easy bruising is a side effect. Dexamethasone may have an effect on liver 
microenzymes such as CYP, and hence patients on both arms should be monitored closely if on 
warfarin. 
11.0 COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in accordance with current U.S. Food and Drug Administration 
(FDA) Regulations, Good Clinical Practices (GCPs) and International Counsel on 
Harmonization (ICH) E6 Guidelines. 
 
ADMINISTRATIVE AND REGULATORY DETAILS 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the trial and its results will be 
submitted to the Clinical Trials Data Bank, http://www.clinicaltrials.gov.  
 Information posted will allow subjects to identify potentially appropriate trials for their disease 
conditions and pursue participation by calling a central contact number for further information 
on appropriate trial locations and trial site contact information.     
 
11.1.1 Institutional Review Board (IRB)  
This protocol will be submitted to the University of Maryland IRB.  Study procedures will begin 
once IRB approval is secured. All amendments, instances of reportable new information (i.e. 
unanticipated problems, data breaches, etc.) and continuing review reports will be submitted to 
the University of Maryland IRB. 
 
11.1.2 Clinical Trial Monitoring 
Data safety and verification monitoring will be conducted in accordance with the Greenebaum 
Cancer Center Sponsor-Investigator Monitoring Standard Operating Procedure (SOP), the Code 
of Federal Regulations (CFR), and FDA and International Counsel on Harmonization (ICH) E6 
Guidelines. 
 
11.1.3 Data Safety and Monitoring Board (DSMB) 
DSMB oversight will be conducted in accordance with the Greenebaum Cancer Center DSMB 
standard operating procedures. 
 
11.1.4 FDA Reporting 
The FDA Annual Report will be submitted to the Agency within +/- 60 days of the date on the 
IND approval letter.  Major amendments will be submitted to FDA at the time of IRB 


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submission.  Minor amendments will be reported to FDA at the time of the next major 
amendment or at the next FDA Annual Report (whichever comes first). 
 
11.1.5   Records Retention 
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or at least 2 years have elapsed since the formal discontinuation of 
clinical development of the investigational product. Records and documents pertaining to the 
conduct of this study and the distribution of investigational drug, including CRFs, consent forms, 
laboratory test results, and medication inventory records will be maintained in secure offsite 
storage after completion of study follow-up and data analysis. 
 
11.2 Compliance with Trial Registration and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely 
responsible for determining whether the trial and its results are subject to the requirements for 
submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov.  Information posted 
will allow subjects to identify potentially appropriate trials for their disease conditions and 
pursue participation by calling a central contact number for further information on appropriate 
trial locations and trial site contact information.     
 
11.3 Data Management 
Clinical data will be entered into the OnCore® database by the designated data manager at the 
University of Maryland Marlene and Stewart Greenebaum Cancer Center (UMGCC). Oncore® 
is 21CRF11.10 (electronic medical records) compliant and is equipped for HIPAA-compliant 
internet-based entry of protocol tracking and review information.   
 
All study data will be collected by the research team at each and every study visit and recorded 
in the research record. This data will then be entered in to the OnCore® study database. 
 
All source documents will be obtained and retained along with any study forms, and 
placed into the patient’s research folder. 
 
11.4 DATA QUALITY ASSURANCE 
Accurate, consistent, and reliable data will be ensured through the use of standard practices and 
procedures. This study will be conducted per Good Clinical Practice Guidelines (GCP) and 
policies and procedures defined by the University of Maryland HRPO. ONCORE will be used to 
develop study specific CRFs. 
 
The UMGCC Data Safety Monitoring/Quality Assurance Committee (DSM/QAC) will review 
research subject safety and the integrity of this study related to the patient safety and quality 
control by reviewing all internal and external serious adverse event (SAE) and protocol-
designated significant adverse event (AE) experiences per UMGCC DSM/QAC guidelines.  The 
DSM/QAC will also make recommendations on proceeding with the trial by reviewing 
successive levels of accrual.  DSM/QAC functions are in addition to, not in place of, the IRB or 
other sponsor reporting/ monitoring that may be required within certain timetables.  UMGCC 


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will be the auditing entity by serving to monitor activities at minimum to include verifying that 
research documents (e.g. informed consent, eligibility checklist, case report forms), and attesting 
that the regulatory binder are complete and current. 
12.0 LIST OF REFERENCES 
1. 
Palumbo, A. and K. Anderson, Multiple myeloma. N Engl J Med, 2011. 364(11): p. 1046-60. 
2. 
Zablotska, L.B., et al., Leukemia, lymphoma and multiple myeloma mortality (1950-1999) and 
incidence (1969-1999) in the Eldorado uranium workers cohort. Environ Res, 2014. 130: p. 43-
50. 
3. 
Kumar, S.K., et al., Risk of progression and survival in multiple myeloma relapsing after therapy 
with IMiDs and bortezomib: a multicenter international myeloma working group study. 
Leukemia, 2012. 26(1): p. 149-57. 
4. 
Disis, M.L., Immune regulation of cancer. J Clin Oncol, 2010. 28(29): p. 4531-8. 
5. 
Dong, H., et al., Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of 
immune evasion. Nat Med, 2002. 8(8): p. 793-800. 
6. 
Sharpe, A.H. and G.J. Freeman, The B7-CD28 superfamily. Nat Rev Immunol, 2002. 2(2): p. 
116-26. 
7. 
Talmadge, J.E., M. Donkor, and E. Scholar, Inflammatory cell infiltration of tumors: Jekyll or 
Hyde. Cancer Metastasis Rev, 2007. 26(3-4): p. 373-400. 
8. 
Galon, J., et al., Type, density, and location of immune cells within human colorectal tumors 
predict clinical outcome. Science, 2006. 313(5795): p. 1960-4. 
9. 
Kloor, M., Lymphocyte infiltration and prognosis in colorectal cancer. Lancet Oncol, 2009. 
10(9): p. 840-1. 
10. 
Hillen, F., et al., Leukocyte infiltration and tumor cell plasticity are parameters of aggressiveness 
in primary cutaneous melanoma. Cancer Immunol Immunother, 2008. 57(1): p. 97-106. 
11. 
Nishimura, H., T. Honjo, and N. Minato, Facilitation of beta selection and modification of 
positive selection in the thymus of PD-1-deficient mice. J Exp Med, 2000. 191(5): p. 891-8. 
12. 
Liotta, F., et al., Frequency of regulatory T cells in peripheral blood and in tumour-infiltrating 
lymphocytes correlates with poor prognosis in renal cell carcinoma. BJU Int, 2011. 107(9): p. 
1500-6. 
13. 
Gorgun, G., et al., Immunomodulatory effects of lenalidomide and pomalidomide on interaction 
of tumor and bone marrow accessory cells in multiple myeloma. Blood, 2010. 116(17): p. 3227-
37. 
14. 
Henry, J.Y., et al., Enhanced cross-priming of naive CD8+ T cells by dendritic cells treated by 
the IMiDs(R) immunomodulatory compounds lenalidomide and pomalidomide. Immunology, 
2013. 139(3): p. 377-85. 
15. 
Gandhi, A.K., et al., Immunomodulatory agents lenalidomide and pomalidomide co-stimulate T 
cells by inducing degradation of T cell repressors Ikaros and Aiolos via modulation of the E3 
ubiquitin ligase complex CRL4(CRBN.). Br J Haematol, 2014. 164(6): p. 811-21. 
16. 
Lacy, M.Q. and A.R. McCurdy, Pomalidomide. Blood, 2013. 122(14): p. 2305-9. 


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17. 
Richardson, P.G., et al., Phase 1 study of pomalidomide MTD, safety, and efficacy in patients 
with refractory multiple myeloma who have received lenalidomide and bortezomib. Blood, 2013. 
121(11): p. 1961-7. 
18. 
San Miguel, J., et al., Pomalidomide plus low-dose dexamethasone versus high-dose 
dexamethasone alone for patients with relapsed and refractory multiple myeloma (MM-003): a 
randomised, open-label, phase 3 trial. Lancet Oncol, 2013. 14(11): p. 1055-66. 
19. 
Dimopoulos, M.A., et al., Expert panel consensus statement on the optimal use of pomalidomide 
in relapsed and refractory multiple myeloma. Leukemia, 2014. 
20. 
Larocca, A., et al., Pomalidomide, cyclophosphamide, and prednisone for relapsed/refractory 
multiple myeloma: a multicenter phase 1/2 open-label study. Blood, 2013. 122(16): p. 2799-806. 
21. 
Scott, L.J., Pomalidomide: a review of its use in patients with recurrent multiple myeloma. Drugs, 
2014. 74(5): p. 549-62. 
22. 
Offidani, M., et al., Pomalidomide for the treatment of relapsed-refractory multiple myeloma: a 
review of biological and clinical data. Expert Rev Anticancer Ther, 2014. 14(5): p. 499-510. 
23. 
Kuranda, K., et al., A subpopulation of malignant CD34+CD138+B7-H1+ plasma cells is 
present in multiple myeloma patients. Exp Hematol, 2010. 38(2): p. 124-31. 
24. 
Liu, J., et al., Plasma cells from multiple myeloma patients express B7-H1 (PD-L1) and increase 
expression after stimulation with IFN-{gamma} and TLR ligands via a MyD88-, TRAF6-, and 
MEK-dependent pathway. Blood, 2007. 110(1): p. 296-304. 
25. 
Tamura, H., et al., Marrow stromal cells induce B7-H1 expression on myeloma cells, generating 
aggressive characteristics in multiple myeloma. Leukemia, 2013. 27(2): p. 464-72. 
26. 
Zhang, C., et al., B7-H1 protein vaccine induces protective and therapeutic antitumor responses 
in SP2/0 myeloma-bearing mice. Oncol Rep, 2013. 30(5): p. 2442-8. 
27. 
Rosenblatt, J., et al., PD-1 blockade by CT-011, anti-PD-1 antibody, enhances ex vivo T-cell 
responses to autologous dendritic cell/myeloma fusion vaccine. J Immunother, 2011. 34(5): p. 
409-18. 
28. 
Luptakova, K., et al., Lenalidomide enhances anti-myeloma cellular immunity. Cancer Immunol 
Immunother, 2013. 62(1): p. 39-49. 
29. 
Atanackovic, D., T. Luetkens, and N. Kroger, Coinhibitory molecule PD-1 as a potential target 
for the immunotherapy of multiple myeloma. Leukemia, 2013. 
 
APPENDICES 
A. ECOG Performance Status 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease performance without 
restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous activity, but 
ambulatory and able to carry out work of a light or sedentary nature (e.g., light 
housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, but unable to 
carry out any work activities. Up and about more than 50% of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined to bed or 
chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally 


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confined to bed or chair. 
5 
Dead. 
* As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative 
Oncology Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, 
Robert Comis M.D., Group Chair. 
 
B. Common Terminology Criteria for Adverse Events V4.0 (CTCAE) 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0 will be utilized for adverse event reporting. 
(http://ctep.cancer.gov/reporting/ctc.html) 
o Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for 
Evaluating Response in Solid Tumors 
RECIST version 1.1* will be used in this study for assessment of tumor response. While either 
CT or MRI may be utilized, as per RECIST 1.1, CT is the preferred imaging technique in this 
study. 
* As published in the European Journal of Cancer: 
 
E.A. Eisenhauer, P. Therasse, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J. Dancey, 
S. Arbuck, S. Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. Kaplan, D. 
Lacombe, J. Verweij. New response evaluation criteria in solid tumors: Revised RECIST 
guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. 
In addition, volumetric analysis will be explored by central review for response assessment. 
 
DEFINITION OF DOSE LIMITING TOXICITY: 
The occurrence of any of the following toxicities during Cycle 1 in the first 6 patients of the run 
off phase and the expansion phase respectively will be considered a DLT, if judged by the 
Investigator to be possibly, probably or definitely related to MK-3475 in combination with 
pomalidomide/dexamethasone. Please refer to Section 6.2 for dose level guidelines following 
DLT evaluation of Cycle 1.   
1. Grade 4 hematologic toxicity lasting ≥7 days.  
2. Grade 4 non-hematologic toxicity (not laboratory). 
3. Grade 3 non-hematologic toxicity (not laboratory) will be considered a DLT, except for 
inadequately treated nausea, hypersensitivity reactions, or fatigue lasting ≤3 days. 
4. Any Grade 3 non-hematologic laboratory value if:  
1. Renal or liver function abnormality 
2. Medical intervention is required to treat the subject, or 
3. The abnormality leads to hospitalization, or 
4. The abnormality persists for >1 week. 
5. Febrile neutropenia Grade 3 or Grade 4: 


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● Grade 3 is defined as ANC <1000/mm3 with a single temperature of >38.3 degrees C 
(101 degrees F) or a sustained temperature of ≥38 degrees C (100.4 degrees F) for more 
than one hour. 
• Grade 4 is defined as ANC <500/mm3 with a single temperature of >38.3 degrees C (101 
degrees F) or a sustained temperature of ≥38 degrees C (100.4 degrees F) for more than 
one hour, with life-threatening consequences and urgent intervention indicated. 
6. Thrombocytopenia <25,000/mm3 if associated with: 
● A bleeding event which does not result in hemodynamic instability but requires an 
elective platelet transfusion, or 
● A life-threatening bleeding event which results in urgent intervention and admission to an 
Intensive Care Unit. 
7. Grade 5 toxicity (i.e., death). 
8. A delay of > 1 week due to drug-related toxicity in initiating Cycle 2. 
 
9. Unable to complete at least 80% of any of the three treatments during the first course of 
therapy due to treatment-related toxicity (even if not meeting above DLT criteria).  
 
C 1. The International Myeloma Working Group Response Criteria 
Response 
IMWG criteria 
sCR 
CR as defined below plus normal FLC ratio and absence of clonal cells in bone 
marrow3 by immunohistochemistry or immunofluorescence4 
CR 
Negative immunofixation on the serum and urine and disappearance of any soft 
tissue plasmacytomas and < 5% plasma cells in bone marrow3 
VGPR 
Serum and urine M-protein detectable by immunofixation but not on electrophoresis 
or > 90% reduction in serum M-protein plus urine M-protein level < 100 mg/24 h 
PR 
> 50% reduction of serum M-protein and reduction in 24 hours urinary M-protein by 
>90% or to < 200 mg/24 h 
If the serum and urine M-protein are unmeasurable,5 a > 50% decrease in the 
difference between involved and uninvolved FLC levels is required in place of the 
M-protein criteria 
If serum and urine M-protein are not measurable, and serum free light assay is also 
not measureable, > 50% reduction in plasma cells is required in place of M-protein, 
provided baseline bone marrow plasma cell percentage was > 30% 
In addition to the above listed criteria, if present at baseline, a > 50% reduction in the 
size of soft tissue plasmacytomas is also required 
MR 
See Appendix C2 below.  
No change/Stable 
disease 
Not meeting criteria for CR, VGPR, PR, or progressive disease 
Plateau 
NA 


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Progressive disease5 Increase of > 25% from lowest response value in any one or more of the following: 
• Serum M-component and/or (the absolute increase must be > 0.5 g/dL)6 
• Urine M-component and/or (the absolute increase must be > 200 mg/24 h) 
• Only in patients without measurable serum and urine M-protein levels; the 
difference between involved and uninvolved FLC levels. The absolute 
increase must be > 10 mg/dL 
• Bone marrow plasma cell percentage; the absolute percentage must be > 10%7 
• Definite development of new bone lesions or soft tissue plasmacytomas or definite 
increase in the size of existing bone lesions or soft tissue plasmacytomas 
• Development of hypercalcaemia (corrected serum calcium > 11.5 mg/dL or 2.65 
mmol/L) that can be attributed solely to the plasma cell proliferative disorder 
Relapse 
Clinical relapse requires one or more of: Direct indicators of increasing disease 
and/or end organ dysfunction (CRAB features).6 It is not used in calculation of time 
to progression or progression-free survival but is listed here as something that can be 
reported optionally or for use in clinical practice 
• Development of new soft tissue plasmacytomas or bone lesions 
• Definite increase in the size of existing plasmacytomas or bone lesions. A definite 
increase is defined as a 50% (and at least 1 cm) increase as measured serially 
by the sum of the products of the cross-diameters of the measurable lesion 
• Hypercalcemia (> 11.5 mg/dL) [2.65 mmol/L] 
• Decrease in haemoglobin of > 2 g/dL [1.25 mmol/L] 
• Rise in serum creatinine by 2 mg/dL or more [177 mmol/L or more] 
Relapse from CR5 
(To be used only if 
the end point studied 
is DFS)8 
Any one or more of the following: 
• Reappearance of serum or urine M-protein by immunofixation or electrophoresis 
• Development of > 5% plasma cells in the bone marrow7 
• Appearance of any other sign of progression (i.e., new plasmacytoma, lytic bone 
lesion, or hypercalcaemia) 
BGM Durie et al. International uniform response criteria for multiple myeloma. Leukemia (2006) 1- 
Adapted from Durie BGM, et al. Leukemia 2006; 20: 1467-1473; and Kyle RA, Rajkumar SV. Leukemia 
2008; 23:3-9. Note: A clarification to IMWG criteria for coding CR and VGPR in patients in whom the only 
measurable disease is by serum FLC levels: CR in such patients is defined as a normal FLC ratio of 0.26–1.65 
in addition to CR criteria listed above. VGPR in such patients is defined as a >90% decrease in the difference 
between involved and uninvolved free light chain (FLC) levels.3 Confirmation with repeat bone marrow 
biopsy not needed.4 Presence/absence of clonal cells is based upon the kappa/lambda ratio. An abnormal 
kappa/lambda ratio by immunohistochemistry and/or immunofluorescence requires a minimum of 100 plasma 
cells for analysis. An abnormal ratio reflecting presence of an abnormal clone is kappa/lambda of > 4:1 or < 
1:2.5 All relapse categories require two consecutive assessments made at anytime before classification as 
relapse or disease progression and/or the institution of any new therapy. In the IMWG criteria, CR patients 
must also meet the criteria for progressive disease shown here to be classified as progressive disease for the 
purposes of calculating time to progression and progression-free survival. The definitions of relapse, clinical 
relapse and relapse from CR are not to be used in calculation of time to progression or progression-free 
survival.6 For progressive disease, serum M-component increases of >1 gm/dL are sufficient to define relapse 


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if starting M-component is >5 g/dL.7 Relapse from CR has the 5% cut-off versus 10% for other categories of 
relapse.8 For purposes of calculating time to progression and progression-free survival, CR patients should also 
be evaluated using criteria listed above for progressive disease. 
C 2.  Definition of Minimal Response per EBMT Criteria 
Criteria MRa - ≥ 25 but < 49% reduction in serum M-protein and a 50–89% reduction in 24-hour 
urinary M-protein, which still exceeds 200 mg per 24 h. For patients with non-secretory 
myeloma only, 25–49% reduction in plasma cells in a bone marrow aspirate and on trephine 
biopsy, if biopsy is performed 
If the serum and urine M-protein are not measurable, a decrease of 25%–49% in the difference 
between involved and uninvolved FLC levels is required in place of the M-protein criteria. 25–
49% reduction in the size of soft tissue plasmacytomas (by radiography or clinical examination) 
No increase in size or number of lytic bone lesions (development of compression fracture does 
not exclude response). Sources: Bladé 1998; Kyle 2009. 
EBMT = European Group for Blood and Marrow Transplantation; MR = minimal response. 
a The response category MR requires 2 consecutive assessments made at any time before the 
institution of any new therapy, as well as no known evidence of progressive or new bone lesions 
if radiographic studies were performed. Radiographic studies are not required to satisfy these 
response requirements. Bone marrow assessments are not required to be confirmed by repeat 
testing. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
D. Pembrolizumab Event of Clinical Interest Guidance Document 
 
PEMBROLIZUMAB PROGRAM 


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(MK-3475) 
EVENT OF CLINICAL INTEREST 
GUIDANCE DOCUMENT 
Version 5.0 
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1 
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Pembrolizumab Event of Clinical Interest Guidance Document 
REVISION HISTORY LOG 
Version 
Effective  
Date* 
Revision  
Author 
Action 
1 
08-Aug-2012 
Kevin Gergich 
Initial Release of guidance document for MK-3475 
2 
07-June-2013 
Marty Huber,  
Kevin Gergich,  
Holly Brown 
Revised title, formerly was “MK-3475 Immune-Related 
Adverse Event Identification, Evaluation and Management 
Guidance Document for Investigators” 
Revised the format of irAE Guidance document, including 
layout, font, sectioning, etc. for consistency with Sponsor 
Events of Clinical Interest guidance documents. 
Modified Categories for irAEs: 
– 
Replaced GI with Colitis category. 
– 
Removed Neurologic category. 
– 
Added Renal category. 
Removed detail in the irAE Guidance document that can 
be located in the Investigator’s Brochure for MK-3475. 
Removed details regarding non-MK-3475 compounds. 
Added ECI reporting guidelines. 
Included a Table Events of Clinical Interest: Immune-
Related Adverse Events that includes the key terms. 
– 
Also placed a pull-out quick-review sheet in the  
Appendix. 
Updated background, diagnosis and course of treatment 
details for irAEs. 


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3 
10-Sep-2014 
Marty Huber,  
Kevin Gergich,  
Holly Brown 
Renamed the document: “Pembrolizumab Program (MK-
3475) - Events of Clinical Interest Guidance Document”. 
Introduced generic name: pembrolizumab (MK-3475) and 
inserted throughout the document. 
Updated Overview – Section 1 
- Clarified the scope of the document and the reporting 
window for ECIs 
- Updated Table 1 with medDRA Preferred Terms for 
adverse events to correspond with reporting of terms to 
clinical database, rearranged the order, and updated the 
reporting criteria. 
- Updated the dose modification/discontinuation section to 
clarify discontinuation and hold terminology. 
Updated Section 2 – ECI Reporting Guidelines 
 
 
 
 
 
 
 
 
 
 
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– Clarified that ECIs must be reported to Merck within 24 
hours regardless of attribution to study treatment or 
etiology. 
Updated Section 3 
– For All Sections, removed the Course of Action for 
Grade 1 events. 
- Section 3.1 Pneumonitis 
– Moved Pneumonitis to beginning of ECI Section – 
Updated management guidelines for Grade 2 and Grade 3-4 
events 
- 
Section 3.2 Colitis: 
- Updated AE terms and ECI criteria, updated course 
of action language for clarity 
- Section 3.3 Endocrine: 
- Updated ECI criteria and updated course of action 
language for clarity. 
- Added subsections for hypophysitis, hyperthyroidism 
and hypothyroidism to clarify management guidelines. 
- Section 3.4 Hematologic: 
- New section added. 
- Section 3.5: Hepatic: 
- Updated terms and added additional guidance for reporting 
of DILI ECI; updated course of action for clarity 
- Section 3.6 Neurologic: 
- New section added. 
- Section 3.7 Ocular: 
- Changed the name of this section from Eye to Ocular 
- Added the term “iritis”, updated ECI guidance, and 
updated course of action language for clarity 
- Section 3.8 Renal: 
- Updated section for clarity. 
- Section 3.9 Skin: 
- Updated list of terms and added terms for reporting of 
other skin ECIs; added section 3.9.1: Immediate Evaluation 
for Potential Skin ECIs 
- Section 3.10 Other: 
- Updated list of terms for clarity; revised course of action 
for clarity. 


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- Section 3.11 Infusion Reactions: 
- 
New section added. 
- Section 3.12: Follow-up to Resolution: 
- 
New section added. 
- Section 4: 
- 
References updated. 
- Section 5: 
- 
ECI table updated for consistency with Table 1. 
- Section 6: Appendix 2 – Past Medical History Related to 
Dermatologic Event: New section added. 
- Section 7: Appendix 3 – Presentation of the 
Dermatologic Event: New section added. 
- Section 8: Appendix 4 – Focused Skin Examination: 
New section added. 
4 
04-Dec-2014 Scot Ebbinghaus, 
Oswaldo Bracco, 
Holly Brown, 
Kevin Gergich 
- Table 1 
- 
Updated Endocrine (reported as ECI if ≥ Grade 3  
or ≥ Grade 2 and resulting in dose modification or use of 
systemic steroids to treat the AE) Section to include: 
- 
Hyperglycemia, if ≥Grade 3 and associated  
with ketosis or metabolic acidosis (DKA) 
- 
Created new section in Table 1 – Endocrine  
(reported as ECI) and added: 
- 
Type 1 diabetes mellitus (if new onset) 
- 
Hepatic: Clarified Transaminase elevations as: 
- 
Transaminase elevations (ALT and/or AST)  
- Section 3.2 Colitis 
- Updated the duration of diarrhea requirments under the 
Course of Action for Grade 2 and Grade 3 
- Section 3.3 Endocrine 
- 
Clarified Course of Action for hyperthyroidism  
and hypothyroidism 
- 
Added Course of Action section for Type 1  
diabetes mellitus (if new onset) and ≥ Grade 3 
hyperglycemia 
- Section 5 
- 
Updated Reference Table in Appendix 1 
5 
18-Dec-2014 
Holly Brown  
Kevin Gergich 
- Section 3.3 Endocrine 
- 
Updated the Course of Action for Hypophysitis 
- 
Merged Grades 2-4 into one course of action 
 
*Ensure that you are using the most current version of this document. 
 
 
 
 
 
 
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Pembrolizumab Event of Clinical Interest Guidance Document 
TABLE OF CONTENTS 
1. OVERVIEW ................................................................................................................................ 6 
2. ECI REPORTING GUIDELINES ............................................................................................... 8 
3. ECI CATEGORIES AND TERMS ............................................................................................. 8 
3.1 Pneumonitis ................................................................................................................................. 9 
3.2 Colitis ........................................................................................................................................  10 
3.3 Endocrine ..................................................................................................................................  12 
3.4 Hematologic ..............................................................................................................................  15 
3.5 Hepatic ......................................................................................................................................  16 
3.6 Neurologic.................................................................................................................................  18 
3.7 Ocular ......................................................................................................................................... 19 
3.8 Renal .......................................................................................................................................... 20 
3.9 Skin ............................................................................................................................................ 21 
3.9.1. Immediate Evaluation for Potential Skin ECIs ...................................................................... 22 
3.10 Other ........................................................................................................................................ 23 
3.11 Infusion Reactions ................................................................................................................... 24 
3.12 Follow-up to Resolution .......................................................................................................... 26 
4. REFERENCES .......................................................................................................................... 27 
5. APPENDIX 1 –Events of Clinical Interest (ECI) – Reference Table ....................................... 28 
6. APPENDIX 2 – Past Medical History Related to Dermatologic Event .................................... 29 
7. APPENDIX 3 – Presentation of the Dermatologic Event ......................................................... 30 
8. APPENDIX 4 – Focused Skin Examination 
 
 
 
 
 
 
 
 
 
 
 
 
 
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1. OVERVIEW 
The purpose of this document is to provide study sites with guidance on the identification and 
management of Events of Clinical Interest for the MK-3475 (also known as pembrolizumab) 
program. 
Based on the literature review [1-11], and consideration of mechanism of action of 
pembrolizumab, potential immune-related adverse events (irAEs) are the primary Event of 
Clinical Interest (ECI). Immune-related AEs are adverse events associated with the treatment 
of patients with immunotherapy treatments that appear to be associated with the immune 
therapy’s mechanism of action. Based on these potential irAEs, the sponsor has defined a list 
of specific adverse event terms (ECIs) that are selected adverse experiences that must be 
reported to Merck within 24 hours from the time the Investigator/physician is aware of such 
an occurrence, regardless of whether or not the investigator/physician considers the event to 
be related to study drug(s). In addition, these ECIs require additional detailed information to 
be collected and entered in the study database. ECIs may be identified through spontaneous 
patient report and / or upon review of subject data. Table 1 provides the list of terms and 
reporting requirements for AEs that must be reported as ECIs for MK-3475 protocols. Of 
note, the requirement for reporting of ECIs applies to all arms, including comparators, of MK-
3475 clinical trials 
 
Given that our current list of events of clinical interest is not comprehensive for all potential 
immune-related events, it is possible that AEs other than those listed in this document may be 
observed in patients receiving pembrolizumab. Therefore any Grade 3 or higher event that the 
investigator/physician considers to be immune-related should be reported as an ECI regardless 
of whether the specific event term is in Table 1 and reported to Merck within 24 hours from 
the time the Investigator/physician is aware of such an occurrence. Adverse events that are 
both an SAE and an ECI should be reported one time as an SAE only, however the event must 
be appropriately identified as an ECI as well in in the database.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Pembrolizumab Event of Clinical Interest Guidance Document 
Table 1: Events of Clinical Interest 
Pneumonitis (reported as ECI if > Grade 2) 
Acute interstitial pneumonitis 
Interstitial lung disease 
Pneumonitis 
Colitis (reported as ECI if > Grade 2 or any grade resulting in dose modification or use of systemic steroids to treat the AE) 
Intestinal Obstruction 
Colitis 
Colitis microscopic 
Enterocolitis 
Enterocolitis hemorrhagic 
Gastrointestinal perforation 
Necrotizing colitis 
Diarrhea 
 
Endocrine (reported as ECI if > Grade 3 or ≥ Grade 2 and resulting in dose modification or use of systemic steroids to 
treat the AE) 
Adrenal Insufficiency 
Hyperthyroidism 
Hypophysitis 
Hypopituitarism 
Hypothyroidism 
Thyroid disorder 
Thyroiditis 
Hyperglycemia, if >Grade 3 and associated with ketosis or metabolic acidosis (DKA) 
Endocrine (reported as ECI) 
Type 1 diabetes mellitus (if new onset) 
 
Hematologic (reported as ECI if ≥ Grade 3 or any grade resulting in dose modification or use of systemic steroids to treat 
the AE) 
Autoimmune hemolytic anemia 
Aplastic anemia 
Thrombotic Thrombocytopenic 
Purpura (TTP) 
Idiopathic (or immune) 
Thrombocytopenia Purpura (ITP) 
Disseminated Intravascular 
Coagulation (DIC) 
Haemolytic Uraemic Syndrome (HUS) 
Any Grade 4 anemia regardless of underlying mechanism 
Hepatic (reported as ECI if ≥ Grade 2, or any grade resulting in dose modification or use of systemic steroids to treat the AE) 
Hepatitis 
Autoimmune hepatitis 
Transaminase elevations (ALT and/or 
AST)
Infusion Reactions (reported as ECI for any grade) 
Allergic reaction 
Anaphylaxis 
Cytokine release syndrome 
Serum sickness 
Infusion reactions 
Infusion-like reactions 
Neurologic (reported as ECI for any grade) 
Autoimmune neuropathy 
Guillain-Barre syndrome 
Demyelinating polyneuropathy 
Myasthenic syndrome 
 
 
Ocular (report as ECI if ≥ Grade 2 or any grade resulting in dose modification or use of systemic steroids to treat the AE) 
Uveitis 
Iritis 
 
Renal (reported as ECI if > Grade 2) 
Nephritis 
Nephritis autoimmune 
Renal Failure 
Renal failure acute 
Creatinine elevations (report as ECI if >Grade 3 or any grade resulting in 
dose modification or use of systemic steroids to treat the AE) 
Skin (reported as ECI for any grade) 
Dermatitis exfoliative 
Erythema multiforme 
Stevens-Johnson syndrome 
Toxic epidermal necrolysis 
 
 
Skin (reported as ECI if > Grade 3) 
Pruritus 
Rash 
Rash generalized 
Rash maculo-papular 
 
 
Any rash considered clinically significant in the physician’s judgment 
Other (reported as ECI for any grade) 
Myocarditis 
Pancreatitis 
Pericarditis 


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Any other Grade 3 event which is considered immune-related by the physician 
Pembrolizumab Event of Clinical Interest Guidance Document 
 
Each of the events above is described within this guidance document, along with site 
requirements for reporting these events to the Sponsor. The information collected should be 
entered into the narrative field(s) of the Adverse Event module in the database (please note, if 
narrative entry into the database is not available, please use the narrative text box on the 
1727/AER Form). If additional Medical History or Concomitant Medications are reported, the 
Medical History and Concomitant Medication modules in the database must be updated. 
 
In addition, the guidelines include recommendations on the management of these ECIs. These 
guidelines are intended to be applied when the physician determines the events to be related to 
pembrolizumab. Note: if after the evaluation the event is determined not to be related, the 
physician is instructed to follow the ECI reporting guidance but does not need to follow the 
treatment guidance (below). Therefore, these recommendations should be seen as guidelines 
and the treating physician should exercise individual clinical judgment based on the patient. 
For any question of dose modification or other treatment options, the specific language in the 
protocol should be followed. Any questions pertaining to the collection of this information or 
management of ECIs should be directed to your local Sponsor contact. 
 
Dose Modification/Discontinuation 
The treatment guidance provides specific direction when to hold and/or discontinue 
pembrolizumab for each immune related adverse event. Of note, when the guidance states to 
“discontinue” pembrolizumab this is the permanent discontinuation of treatment with 
pembrolizumab. “Hold” means to stop treating with pembrolizumab but resumption of 
treatment may be considered assuming the patient meets the criteria for resumption of 
treatment. 
 
2. ECI REPORTING GUIDELINES 
ECIs are selected non-serious and serious adverse experiences that must be reported to Merck 
within 24 hours regardless of attribution to study treatment. The AEs listed in this document 
and any event that meets the ECI criteria (as noted) in Table 1 or in the respective protocol 
(event term and Grade) must be reported regardless of physician-determined causality with 
study medication and whether or not considered immune-related by the physician (unless 
otherwise specified). Physicians/study coordinators/designated site personnel are required to 
record these experiences as ECIs on the Adverse Experience electronic Case Report Forms 
(eCRFs) (or on paper) and to provide supplemental information (such as medical history, 
concomitant medications, investigations, etc.) about the event. 
 
– Please refer to the Data Entry Guidelines (DEGs) for your protocol. 
– Please refer to protocol for details on reporting timelines and reporting of Overdose and Drug 
Induced Liver Injury (DILI). 
 
3. ECI CATEGORIES AND TERMS 
This section describes the ECI categories and outlines subject management guidelines when 
an ECI is reported. 
 
 
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3.1 Pneumonitis 
The following AE terms, if considered ≥ Grade 2, are considered ECIs and should be reported 
to the Sponsor within 24 hours of the event: 
 
– Pneumonitis 
– Interstitial lung disease 
– Acute interstitial pneumonitis 
 
If symptoms indicate possible new or worsening cardiac abnormalities additional testing and/or 
a cardiology consultation should be considered. 
 
All attempts should be made to rule out other causes such as metastatic disease, bacterial or 
viral infection. It is important that patients with a suspected diagnosis of pneumonitis be 
managed as per the guidance below until treatment-related pneumonitis is excluded. 
Treatment of both a potential infectious etiology and pneumonitis in parallel may be 
warranted. Management of the treatment of suspected pneumonitis with steroid treatment 
should not be delayed for a therapeutic trial of antibiotics. If an alternative diagnosis is 
established, the patient does not require management as below; however the AE should be 
reported regardless of etiology. 
 
Course of Action 
 
Grade 2 events: 
– Report as ECI 
– Hold pembrolizumab. 
– Consider pulmonary consultation with bronchoscopy and biopsy/BAL. 
– Consider ID consult 
– Conduct an in person evaluation approximately twice per week 
– Consider frequent Chest X-ray as part of monitoring 
– Treat with systemic corticosteroids at a dose of 1 to 2 mg/kg/day prednisone or 
equivalent. When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 
weeks. 
– Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or 
equivalent per day within 12 weeks. 
– Second episode of pneumonitis – discontinue pembrolizumab if upon re-challenge the patient 
develops 
a second episode of Grade 2 or higher pneumonitis. 
 
Grade 3 and 4 events: 
– Report as ECI 
– Discontinue pembrolizumab. 
– Hospitalize patient 
 
 
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– Bronchoscopy with biopsy and/or BAL is recommended. 
– Immediately treat with intravenous steroids (methylprednisolone 125 mg IV). When 
symptoms improve to Grade 1 or less, a high dose oral steroid (prednisone 1 to 2 mg/kg once 
per day or dexamethasone 4 mg every 4 hours) taper should be started and continued over no 
less than 4 weeks. 
– If IV steroids followed by high dose oral steroids does not reduce initial symptoms within 
48 to 72 hours, treat with additional anti-inflammatory measures. Discontinue additional anti-
inflammatory measures upon symptom relief and initiate a prolonged steroid taper over 45 to 
60 days. If symptoms worsen during steroid reduction, initiate a retapering of steroids starting 
at a higher dose of 80 or 100 mg followed by a more prolonged taper and administer 
additional anti-inflammatory measures, as needed 
– Add prophylactic antibiotics for opportunistic infections. 
3.2 Colitis 
The following AE terms, if considered ≥ Grade 2 or resulting in dose modification or use of 
systemic steroids to treat the AE, are considered ECIs and should be reported to the Sponsor 
within 24 hours of the event: 
– Colitis 
– Colitis microscopic 
– Enterocolitis 
– Enterocolitis hemorrhagic 
– Gastrointestinal perforation 
– Intestinal obstruction 
– Necrotizing colitis 
– Diarrhea 
All attempts should be made to rule out other causes such as metastatic disease, bacterial or 
parasitic infection, viral gastroenteritis, or the first manifestation of an inflammatory bowel 
disease by examination for stool leukocytes, stool cultures, a Clostridium difficile titer and 
endoscopy. However the AE should be reported regardless of etiology. 
Course of Action 
Grade 2 Diarrhea/Colitis (4-6 stools/day over baseline, dehydration requiring IV fluids < 24 
hours, abdominal 
pain, mucus or blood in stool): 
– Report as ECI 
– Hold pembrolizumab. 
– Symptomatic Treatment 
– For Grade 2 diarrhea that persists for greater than 3 days, and for diarrhea with blood and/or 
mucus, 
o Consider GI consultation and endoscopy to confirm or rule out colitis 
o Administer oral corticosteroids (prednisone 1-2 mg/kg QD or equivalent) 
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– When symptoms improve to Grade 1 or less, steroid taper should be started and continued 
over no less than 4 weeks. 
– Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
– If symptoms worsen or persist > 3 days treat as Grade 3 
Grade 3 Diarrhea/Colitis (or Grade 2 diarrhea that persists for > 1 week): 
– Report as ECI 
– Hold pembrolizumab. 
– Rule out bowel perforation. Imaging with plain films or CT can be useful. 
– Recommend consultation with Gastroenterologist and confirmation biopsy with endoscopy. 
– Treat with intravenous steroids (methylprednisolone 125 mg) followed by high dose oral 
steroids (prednisone 1 to 2 mg/kg once per day or dexamethasone 4 mg every 4 hours) When 
symptoms improve to Grade 1 or less, steroid taper should be started and continued over no 
less than 4 weeks. Taper over 6 to 8 weeks in patients with diffuse and severe ulceration and/or 
bleeding. 
– Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
– If IV steroids followed by high dose oral steroids does not reduce initial symptoms within 48 
to 72 hours, consider treatment with additional anti-inflammatory measures as described in the 
literature [5]. Discontinue additional anti-inflammatory measures upon symptom relief and 
initiate a prolonged steroid taper over 45 to 60 days. If symptoms worsen during steroid 
reduction, initiate a retapering of steroids starting at a higher dose of 80 or 100 mg followed by 
a more prolonged taper and administer additional anti-inflammatory measures as needed. 
Grade 4 events: 
– Report as ECI 
– Permanently discontinue pembrolizumab. –  
Manage as per Grade 3. 
 
3.3 Endocrine 
The following AE terms, if considered  Grade 3 or if Grade 2 and require 
holding/discontinuation/ modification of pembrolizumab dosing, are considered ECIs and 
should be reported to the Sponsor within 24 hours of the event: 
– Adrenal insufficiency 
– Hyperthyroidism 
– Hypophysitis 
– Hypopituitarism 
– Hypothyroidism 
– Thyroid disorder 
– Thyroiditis 
 
 
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All attempts should be made to rule out other causes such as brain metastases, sepsis and/or 
infection. However the AE should be reported regardless of etiology. 
Hypophysitis or other symptomatic endocrinopathy other than hypo- or hyperthyroidism 
Grade 2-4 events: 
– Report as ECI if appropriate 
– Hold pembrolizumab 
– Rule out infection and sepsis with appropriate cultures and imaging. 
– Monitor thyroid function or other hormonal level tests and serum chemistries more 
frequently until returned to baseline values. 
– Pituitary gland imaging should be considered (MRIs with gadolinium and selective 
cuts of the pituitary can show enlargement or heterogeneity and confirm the diagnosis). 
– Treat with prednisone 40 mg p.o. or equivalent per day. 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. 
– Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
– Hypophysitis with clinically significant adrenal insufficiency and hypotension, 
dehydration, and electrolyte abnormalities (such as hyponatremia and hyperkalemia) constitutes 
adrenal crisis. 
– Consultation with an endocrinologist may be considered. 
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Document Hyperthyroidism and Hypothyroidism 


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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. 
Grade 2 hyperthyroidism, Grade 2-4 hypothyroidism events: 
– Report as ECI if appropriate (see Table 1) 
– Monitor thyroid function or other hormonal level tests and serum chemistries more 
frequently until 
returned to baseline values. 
– Thyroid hormone and/or steroid replacement therapy to manage adrenal insufficiency. 
– Therapy with pembrolizumab can be continued while treatment for the thyroid disorder is 
instituted. 
– 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. 
– Consultation with an endocrinologist may be considered. 
Grade 3 hyperthyroidism events: 
– Report as ECI 
– Hold pembrolizumab. 
– Rule out infection and sepsis with appropriate cultures and imaging. 
– Treat with an initial dose of methylprednisolone 1 to 2 mg/kg intravenously followed by oral 
prednisone 1 to 2 mg/kg per day. 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. 
– Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
Grade 4 
hyperthyroidism 
events: – Report 
as ECI 
– Discontinue 
pembrolizumab. – 
Manage as per Grade 
3 
 
 
 
 
 
 
 
 
 
 
 
 


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Type 1 diabetes mellitus (if new onset) and ≥ Grade 3 Hyperglycemia 
The following AE terms are considered ECIs and should be reported to the Sponsor within 24 
hours of the event: 
– Type I diabetes mellitus (T1DM), if new onset, including diabetic ketoacidosis (DKA) 
– Grade 3 or higher hyperglycemia, if associated with ketosis (ketonuria) or metabolic acidosis 
(DKA). 
Immune-mediated diabetes may present as new onset of Type 1 diabetes or an abrupt 
worsening of preexisting diabetes associated with laboratorial evidence of beta cell failure. All 
attempts should be made to rule out other causes such as type 2 diabetes mellitus (T2DM), 
T2DM decompensation, steroid-induced diabetes, physiologic stress-induced diabetes, or 
poorly controlled pre-existing diabetes (either T1DM or T2DM), but events meeting the above 
criteria should be reported as ECIs regardless of etiology. The patients may present with 
hyperglycemia (abrupt onset or abrupt decompensation) with clinical evidence of diabetic 
ketoacidosis or laboratory evidence of insulin deficiency, such as ketonuria, laboratory 
evidence of metabolic acidosis, or low or undetected c-peptide. 
Course of Action 
T1DM should be immediately treated with insulin. 
T1DM or Grade 3-4 Hyperglycemia events: 
- Report as ECI if appropriate (see Table 1) 
- Hold pembrolizumab for new onset Type 1 diabetes mellitus or Grade 3-4 hyperglycemia 
associated with evidence of beta cell failure, and resume pembrolizumab when patients are 
clinically and metabolically stable. 
- Insulin replacement therapy is recommended for Type I diabetes mellitus and for Grade 3-4 
hyperglycemia associated with metabolic acidosis or ketonuria. 
- Evaluate patients with serum glucose and a metabolic panel, urine ketones, glycosylated 
hemoglobin, and C-peptide. 
- Consultation with an Endocrinologist is recommended. 
- Consider local testing for islet cell antibodies and antibodies to GAD, IA-2, ZnT8, and insulin 
may be obtained. 
 
 
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3.4 Hematologic 
The following AE term, if considered Grade ≥3 or requiring dose modification or use of systemic steroids to treat 
the AE, are considered an ECI and should be reported to the Sponsor within 24 hours of the event: 
– Autoimmune hemolytic anemia 
– Aplastic anemia 
– Disseminated Intravascular Coagulation (DIC) 
– Haemolytic Uraemic Syndrome (HUS) 
– Idiopathic (or immune) Thrombocytopenia Purpura (ITP) 
– Thrombotic Thrombocytopenic Purpura (TTP) 
– Any Grade 4 anemia regardless of underlying mechanism 
 
All attempts should be made to rule out other causes such as metastases, sepsis and/or infection. Relevant 
diagnostic studies such as peripheral blood smear, reticulocyte count, LDH, haptoglobin, bone marrow biopsy or 
Coomb’s test, etc., should be considered to confirm the diagnosis. However the AE should be reported regardless 
of etiology. 
 
Course of Action 
Grade 2 events: 
– Report as ECI 
– Hold pembrolizumab 
– Prednisone 1-2 mg/kg daily may be indicated 
– Consider Hematology consultation. 
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of prednisone or 
equivalent per day within 12 weeks. 
Grade 3 events: 
– Report as ECI 
– Hematology consultation. 
– Hold pembrolizumab Discontinuation should be considered as per specific protocol guidance. 
– Treat with methylprednisolone 125 mg iv or prednisone 1-2 mg/kg p.o. (or equivalent) as appropriate 
– Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of prednisone or 
equivalent per day within 12 weeks. 
Grade 4 events: 
– Report as ECI 
– Hematology consultation 
– Discontinue pembrolizumab for all solid tumor indications; refer to protocol for hematologic 
malignancies. 
– Treat with methylprednisolone 125 mg iv or prednisone 1-2 mg/kg p.o. (or equivalent) as appropriate 
 
 
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3.5 Hepatic 
The following AE terms, if considered 2 Grade 2 or greater (or any grade with dose modification or use of 
systemic steroids to treat the AE), are considered ECIs and should be reported to the Sponsor within 24 hours of 
the event: 
– Autoimmune hepatitis – 
Hepatitis 
– Transaminase elevations 
 
All attempts should be made to rule out other causes such as metastatic disease, infection or other hepatic 
diseases. However the AE should be reported regardless of etiology. 
 
Drug Induced Liver Injury (DILI) 
In addition, the event must be reported as a Drug Induced Liver Injury (DILI) ECI, if the patient meets the 
laboratory criteria for potential DILI defined as: 
 
 An elevated alanine transaminase (ALT) or aspartate transaminase (AST) lab value that is greater than or 
equal to three times (3X) the upper limit of normal (ULN) and 
 An elevated total bilirubin lab value that is greater than or equal to two times (2X) ULN and 
 At the same time, an alkaline phosphatase (ALP) lab value that is less than 2X ULN, 
 As a result of within-protocol-specific testing or unscheduled testing. 
 
Note that any hepatic immune ECI meeting DILI criteria should only be reported once as a DILI event.  
 
Course of Action 
Grade 2 events: 
– Report as ECI 
– Hold pembrolizumab when AST or ALT >3.0 to 5.0 times ULN and/or total bilirubin >1.5 to 3.0 times ULN. 
– Monitor liver function tests more frequently until returned to baseline values (consider weekly). 
o Treat with 0.5-1 mg/kg/day methylprednisolone or oral equivalent and when LFT returns to grade 1 
or baseline, taper steroids over at least 1 month, consider prophylactic antibiotics for opportunistic infections, 
and resume pembrolizumab per protocol 
– Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent 
per day within 12 weeks. 
– Permanently discontinue pembrolizumab for patients with liver metastasis who begin treatment with Grade 2 
elevation of AST or ALT, and AST or ALT increases 250% relative to baseline and lasts 21 week. 
 
Grade 3 events: 
– Report as ECI 
– Discontinue pembrolizumab when AST or ALT >5.0 times ULN and/or total bilirubin >3.0 times ULN. 
– Consider appropriate consultation and liver biopsy to establish etiology of hepatic injury, if necessary – Treat 
with high-dose intravenous glucocorticosteroids for 24 to 48 hours. When symptoms improve to Grade 1 or less, 
a steroid taper with dexamethasone 4 mg every 4 hours or prednisone at 1 to 2 mg/kg should be started and 
continued over no less than 4 weeks. 
– If serum transaminase levels do not decrease 48 hours after initiation of systemic steroids, oral mycophenolate 
mofetil 500 mg every 12 hours may be given. Infliximab is not recommended due to its potential for 
hepatotoxicity. 
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– Several courses of steroid tapering may be necessary as symptoms may worsen when the steroid dose is 
decreased. 
– Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of prednisone or 
equivalent per day within 12 weeks. 
Grade 4 events: 
– Report as ECI 
– Permanently discontinue pembrolizumab – 
Manage patient as per Grade 3 above 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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3.6 Neurologic 
The following AE terms, regardless of grade, are considered ECIs and should be reported 
to the Sponsor within 24 hours of the event: 
– Autoimmune 
neuropathy – 
Demyelinating 
polyneuropathy – 
Guillain-Barre syndrome 
– Myasthenic syndrome 
All attempts should be made to rule out other causes such as metastatic disease, other 
medications or infectious causes. However the AE should be reported regardless of etiology. 
Course of Action 
Grade 2 events: 
– Report as ECI 
– Moderate (Grade 2) – consider withholding pembrolizumab. 
– Consider treatment with prednisone 1-2 mg/kg p.o. daily as appropriate 
– Consider Neurology consultation. Consider biopsy for confirmation of diagnosis. 
– Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or 
equivalent per day within 12 weeks. 
Grade 3 and 4 events: 
– Report as ECI 
– Discontinue pembrolizumab 
– Obtain neurology consultation. Consider biopsy for confirmation of diagnosis 
– Treat with systemic corticosteroids at a dose of 1 to 2 mg/kg prednisone or equivalent once per 
day. If 
condition worsens consider IVIG or other immunosuppressive therapies as per local guidelines 
 
When symptoms improve to Grade 1 or less, steroid taper should be started and continued over 
no less than 4 weeks. 
 
 
 
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3.7 Ocular 
The following AE terms, if considered Grade ≥2 or requiring dose modification or use of systemic steroids to 
treat the AE, is considered an ECI and should be reported to the Sponsor within 24 hours of the event: 
– 
Uveitis 
– 
Iritis 
All attempts should be made to rule out other causes such as metastatic disease, infection or other ocular disease 
(e.g. glaucoma or cataracts). However the AE should be reported regardless of etiology. 
Course of Action 
Grade 2 events: 
– Evaluation by an ophthalmologist is strongly recommended. 
– Treat with topical steroids such as 1% prednisolone acetate suspension and iridocyclitics. 
– Discontinue pembrolizumab as per protocol if symptoms persist despite treatment with topical 
immunosuppressive therapy. 
Grade 3 events: 
– Evaluation by an ophthalmologist is strongly recommended 
– Hold pembrolizumab and consider permanent discontinuation as per specific protocol guidance. – Treat with 
systemic corticosteroids such as prednisone at a dose of 1 to 2 mg/kg per day. When 
symptoms improve to Grade 1 or less, steroid taper should be started and continued over no less than 4 
weeks. 
– Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent 
per day within 12 weeks. 
Grade 4 events: 
– Evaluation by an ophthalmologist is strongly recommended – 
Permanently discontinue pembrolizumab. 
– Treat with corticosteroids as per Grade 3 above 
 
 
 
 
 
 
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Pembrolizumab Event of Clinical Interest Guidance Document 
3.8 Renal 
The following AEs if ? Grade 2 are considered ECIs and should be reported to the Sponsor 
within 24 hours of the event: 
– Nephritis 
– Nephritis 
autoimmune – 
Renal failure 
– Renal failure acute 
Creatinine elevations ? Grade 3 or any grade with dose modification or use of systemic steroids 
to treat the AE. 
All attempts should be made to rule out other causes such as obstructive uropathy, progression of 
disease, or injury due to other chemotherapy agents. A renal consultation is recommended. 
However the AE should be reported regardless of etiology. 
Course of Action 
Grade 2 events: 
– Hold pembrolizumab 
– Treatment with prednisone 1-2 mg/kg p.o. daily. 
– Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or 
equivalent per day within 12 weeks. 
Grade 3-4 events: 
– Discontinue pembrolizumab 
– Renal consultation with consideration of ultrasound and/or biopsy as appropriate 
– Treat with systemic corticosteroids at a dose of 1 to 2 mg/kg prednisone IV or equivalent 
once per 
day. 
 
When symptoms improve to Grade 1 or less, steroid taper should be started and continued over 
no less than 4 weeks. 
 
 
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3.9 Skin 
Rash and Pruritus 
The following AEs should be considered as ECIs, if ≥ Grade 3 and should be reported to the Sponsor within 24 
hours of the event: 
– Pruritus 
– Rash 
– Rash generalized 
– Rash maculo-papular 
– In addition to CTCAE Grade 3 rash, any rash that is considered clinically significant, in the physician's 
judgment, should be treated as an ECI. Clinical significance is left to the physician to determine, and could 
possibly include rashes such as the following: 
o rash with a duration >2 weeks; OR 
o rash that is >10% body surface area; OR 
o rash that causes significant discomfort not relieved by topical medication or temporary cessation of 
study drug. 
Other Skin ECIs 
The following AEs should always be reported as ECIs, regardless of grade, and should be reported to the Sponsor 
within 24 hours of the event: 
– Dermatitis exfoliative 
– Erythema multiforme 
– Steven’s Johnson syndrome – 
Toxic epidermal necrolysis 
Please note, the AE should be reported regardless of etiology. 
Course of Action 
Grade 2 events: 
– Symptomatic treatment should be given such as topical glucocorticosteroids (e.g., betamethasone 0.1% cream 
or hydrocortisone 1%) or urea-containing creams in combination with oral anti-pruritics (e.g., diphenhydramine 
HCl or hydroxyzine HCl). 
– Treatment with oral steroids is at physician’s discretion for Grade 2 events. 
 
 
 
 
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Grade 3 events: 
– Hold pembrolizumab. 
– Consider Dermatology Consultation and biopsy for confirmation of diagnosis. 
– Treatment with oral steroids is recommended, starting with 1 mg/kg prednisone or equivalent once per day or 
dexamethasone 4 mg four times orally daily. When symptoms improve to Grade 1 or less, steroid taper should be 
started and continued over no less than 4 weeks. 
– Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent 
per day within 12 weeks. 
Grade 4 events: 
– Permanently discontinue pembrolizumab. 
– Dermatology consultation and consideration of biopsy and clinical dermatology photograph. 
– Initiate steroids at 1 to 2 mg/kg prednisone or equivalent. When symptoms improve to Grade 1 or 
less, steroid taper should be started and continued over no less than 4 weeks. 
Pembrolizumab Event of Clinical Interest Guidance Document 3.9.1.  
 
3.9.1 Immediate Evaluation for Potential Skin ECIs 
A. Photographs: 
Every attempt should be made to get a photograph of the actual ECI skin lesion or rash as soon as possible. 
Obtain appropriate consent for subject photographs if a consent form addendum is required by your 
IRB/ERC. 
 
– Take digital photographs of: 
o the head (to assess mucosal or eye involvement), 
o the trunk and extremities, and 
o a close-up of the skin lesion/rash. 
– If possible, a ruler should be placed alongside the site of a skin occurrence as a fixed marker of distance. 
– The time/date stamp should be set in the 'ON' position for documentation purposes. – 
Photographs should be stored with the subject’s study records. 
– The Sponsor may request copies of photographs. The local study contact (e.g., CRA) will provide guidance to 
the site, if needed. 
B. Past Medical History: 
Collect past medical history relevant to the event, using the questions in Appendix 2 (Past Medical History 
Related to Dermatologic Event) as a guide. Any preexisting conditions not previously reported (e.g., drug 
allergy) should be entered into the Medical History eCRF. 
 
 
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C. Presentation of the Event: 
Collect information on clinical presentation and potential contributing factors using the questions in Appendix 3 
(Presentation of the Dermatologic Event) as a guide. This information should be summarized and entered in 
narrative format in the AE eCRF. Please use the available free-text fields, such as Signs and Symptoms. Note 
pertinent negatives where applicable to reflect that the information was collected. Any treatments administered 
should be entered on the Concomitant Medication eCRF. 
D. Vitals Signs and Standard Laboratory Tests: 
Measure vital signs (pulse, sitting BP, oral temperature, and respiratory rate) and record on the Vital Signs 
eCRF. Perform standard laboratory tests (CBC with manual differential and serum chemistry panel, including 
LFTs). 
E. Focused Skin Examination: 
Perform a focused skin examination using the questions in Appendix 4 (Focused Skin Examination) as a 
guide. Information should be summarized and entered on the Adverse Experience eCRF as part of the 
narrative. 
F. Dermatology Consult  
Refer the subject to a dermatologist as soon as possible. 
– For a “severe rash”, the subject must be seen within 1-2 days of reporting the event. – For 
clinically significant rash, the subject should be seen within 3-5 days. 
The dermatologist should submit a biopsy sample to a certified dermatopathology laboratory or to a pathologist 
experienced in reviewing skin specimens. 
The site should provide the dermatologist with all relevant case history, including copies of clinical photographs 
and laboratory test results. 
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3.10 Other 
The following AEs, regardless of grade, are considered ECIs and should be reported to the Sponsor within 24 
hours of the event: 
Myocarditis – Pericarditis 
Pancreatitis – Any additional Grade 3 or higher event which the physician considers to be immune related. 
All attempts should be made to rule out other causes. Therapeutic specialists should be consulted as appropriate. 
However the AE should be reported regardless of etiology. 
Course of Action 
Grade 2 events or Grade 1 events that do not improve with symptomatic treatment: 
– Withhold pembrolizumab. 
– Systemic corticosteroids may be indicated. 
– Consider biopsy for confirmation of diagnosis. 
– If pembrolizumab held and corticosteroid required, manage as per grade 3 below. 
Grade 3 events: 
– Hold pembrolizumab 
– Treat with systemic corticosteroids at a dose of 1 to 2 mg/kg prednisone or equivalent once per day. 
– When symptoms improve to Grade 1 or less, steroid taper should be started and continued over no less than 4 
weeks. 
– Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent 
per day within 12 weeks. Otherwise, pembrolizumab treatment may be restarted and the dose modified as 
specified in the protocol 
Grade 4 events: 
– Treat with systemic corticosteroids at a dose of 1 to 2 mg/kg prednisone or equivalent once per day. – 
Discontinue pembrolizumab 
 
 
 
 
 
 
 
 
 
 
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3.11 Infusion Reactions 
The following AE terms, regardless of grade, are considered ECIs and should be reported to the Sponsor 
within 24 hours of the event: 
– Allergic reaction 
– Anaphylaxis 
– Cytokine release syndrome 
– Serum sickness 
– Infusion reactions 
– Infusion-like reactions 
Please note, the AE should be reported regardless of etiology. 
Course of Action 
Refer to infusion reaction table in the protocol and below. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Infusion Reactions 
NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
Grade 1 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the investigator. 
None 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
Grade 2 
Stop Infusion. 
Additional appropriate medical therapy 
may include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the investigator. 
If symptoms resolve within one hour of 
stopping drug infusion, the infusion may be 
restarted at 50% of the original infusion 
rate (e.g. from 100 mL/hr to 50 mL/hr). 
Otherwise dosing will be held until 
symptoms resolve and the subject should 
be premedicated for the next scheduled 
dose. 
Subjects who develop Grade 2 toxicity 
despite adequate premedication should 
be permanently discontinued from 
further trial treatment administration. 
Subject may be premedicated 
1.5h (± 30 minutes) prior to 
infusion of pembrolizumab with: 
Diphenhydramine 50 mg p.o. 
(or equivalent dose of 
antihistamine). 
Acetaminophen 500-1000 mg 
p.o. (or equivalent dose of 
antipyretic). 
Requires infusion interruption 
but responds promptly to 
symptomatic treatment (e.g., 
antihistamines, NSAIDS, 
narcotics, IV fluids); 
prophylactic medications 
indicated for < =24 hrs 
Grades 3 or 4 
Stop Infusion. 
Additional appropriate medical therapy 
may include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the investigator. 
Hospitalization may be indicated. 
Subject is permanently discontinued 
from further trial treatment 
administration. 
No subsequent dosing 
Grade 3: 
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial improvement; 
hospitalization indicated for 
other clinical sequelae (e.g., 
renal impairment, pulmonary 
infiltrates) 
Grade 4: 
Life-threatening; pressor or 
ventilatory support indicated 
Appropriate resuscitation equipment should be available in the room and a physician readily available during the 
period of drug administration. 
For Further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE) at 
http://ctep.cancer.gov 
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3.12 Follow-up to Resolution 
Subjects should be followed to resolution. The Adverse Experience eCRF should be updated with information 
regarding duration and clinical course of the event. Information obtained from the consulting specialist, including 
diagnosis, should be recorded in the appropriate AE fields. Free-text fields should be used to record narrative 
information: 
– Clinical course of the event – 
Course of treatment 
– Evidence supporting recovery – 
Follow-up to the clinical course 
 
Any treatments administered for the event should also be entered in the Concomitant Medication eCRF. 
 
 
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Pembrolizumab Event of Clinical Interest Guidance Document 
4. REFERENCES 
1. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nature Reviews Cancer 2012; 
12:252-264. 
2. Weber JS Practical Management of Immune-Related Adverse Events from Immune Checkpoint Protein 
Antibodies for the Oncologist. American Society of Clinical Oncology 2012; 1092-9118/10/1-10. 
3. Weber JS, Ka¨hler KC, and Hauschild A. Management of Immune-Related Adverse Events and Kinetics 
of Response With  Ipilimumab.  J Clin Oncol 30. 2012.  
http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2012.41.6750. 
4. Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, et al. Improved Survival with Ipilimumab in 
Patients with Metastatic Melanoma. N Engl J Med 363:711-723, 2010. 
5. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, Activity, and 
Immune Correlates of Anti-PD-1 Antibody in Cancer. N Engl J Med 2012; 366:2443-2454. 
6. Brahmer JR, Tykodi SS, Chow LQM, Hwu WJ, et al. Safety and Activity of Anti–PD-L1 Antibody in 
Patients with Advanced Cancer. N Engl J Med 2012; 366:2455-2465. 
7. Weber J, Thompson JA, Hamid O, et al: A randomized, double-blind, placebo-controlled, phase II study 
comparing the tolerability and efficacy of ipilimumab administered with or without prophylactic 
budesonide in patients with unresectable stage III or IV melanoma. Clin Cancer Res 15:5591-5598, 2009. 
8. Lemech C and Arkenau HT. Novel Treatments for Metastatic Cutaneous Melanoma and the Management of 
Emergent Toxicities. Clinical Medicine Insights: Oncology 2012:6 53–66. 
9. Phan GQ, Weber JS, and Sondak VK. CTLA-4 Blockade with Monoclonal Antibodies in Patients with 
Metastatic Cancer: Surgical Issues. Annals of Surgical Oncology 15(11):3014–3021. 
10. Bristol-Myers Squibb: YERVOY (ipilimumab): Serious and fatal immune-mediated adverse reactions— 
YERVOY Risk Evaluation and Mitigation Strategy (REMS). http://www.yervoy.com/hcp/rems.aspx 
11. Bristol-Myers Squibb: YERVOY (ipilimumab) prescribing information revised March 2011. 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/125377s0000lbl.pdf 
 
 
 
 
 
 
 
 
 
 
 
 
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5. APPENDIX 1 –Events of Clinical Interest (ECI) – Reference Table 
Pneumonitis (reported as ECI if > Grade 2) 
Acute interstitial pneumonitis 
Interstitial lung disease 
Pneumonitis 
Colitis (reported as ECI if > Grade 2 or any grade resulting in dose modification or use of systemic steroids to treat the AE) 
Intestinal Obstruction 
Colitis 
Colitis microscopic 
Enterocolitis 
Enterocolitis hemorrhagic 
Gastrointestinal perforation 
Necrotizing colitis 
Diarrhea 
 
Endocrine (reported as ECI if > Grade 3 or ≥ Grade 2 and resulting in dose modification or use of systemic steroids to treat 
the AE) 
Adrenal Insufficiency 
Hyperthyroidism 
Hypophysitis 
Hypopituitarism 
Hypothyroidism 
Thyroid disorder 
Thyroiditis 
Hyperglycemia, if >Grade 3 and associated with ketosis or metabolic acidosis (DKA) 
Endocrine (reported as ECI) 
Type 1 diabetes mellitus (if new onset) 
 
Hematologic (reported as ECI if ≥ Grade 3 or any grade resulting in dose modification or use of systemic steroids to treat the 
AE) 
Autoimmune hemolytic anemia 
Aplastic anemia 
Thrombotic Thrombocytopenic 
Purpura (TTP) 
Idiopathic 
(or 
immune) 
Thrombocytopenia Purpura (ITP) 
Disseminated 
Intravascular 
Coagulation (DIC) 
Haemolytic Uraemic Syndrome (HUS) 
Any Grade 4 anemia regardless of underlying mechanism 
Hepatic (reported as ECI if ≥ Grade 2, or any grade resulting in dose modification or use of systemic steroids to treat the AE) 
Hepatitis 
Autoimmune hepatitis 
Transaminase elevations (ALT and/or AST) 
Infusion Reactions (reported as ECI for any grade) 
Allergic reaction 
Anaphylaxis 
Cytokine release syndrome 
Serum sickness 
Infusion reactions 
Infusion-like reactions 
Neurologic (reported as ECI for any grade) 
Autoimmune neuropathy 
Guillain-Barre syndrome 
Demyelinating polyneuropathy 
Myasthenic syndrome 
 
 
Ocular (report as ECI if ≥ Grade 2 or any grade resulting in dose modification or use of systemic steroids to treat the AE) 
Uveitis 
Iritis 
 
Renal (reported as ECI if > Grade 2) 
Nephritis 
Nephritis autoimmune 
Renal Failure 
Renal failure acute 
Creatinine elevations (report as ECI if >Grade 3 or any grade resulting in 
dose modification or use of systemic steroids to treat the AE) 
Skin (reported as ECI for any grade) 
Dermatitis exfoliative 
Erythema multiforme 
Stevens-Johnson syndrome 
Toxic epidermal necrolysis 
 
 
Skin (reported as ECI if > Grade 3) 
Pruritus 
Rash 
Rash generalized 
Rash maculo-papular 
 
 
Any rash considered clinically significant in the physician’s judgment 
Other (reported as ECI for any grade) 
Myocarditis 
Pancreatitis 
Pericarditis 
Any other Grade 3 event which is considered immune-related by the physician 
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6. APPENDIX 2 – Past Medical History Related to Dermatologic Event 
Past Medical History: 
Any preexisting conditions not previously reported (e.g., drug allergy) should be entered into the 
Medical History eCRF. 
1. Does the subject have any allergies? □ Yes □ No 
If yes, please obtain the following information: 
a. Any allergy to drugs (including topical or ophthalmic drugs)? □ Yes □ No List the drug 
name(s) and describe the type of allergic response (e.g. rash, anaphylaxis, etc): 
b. Any allergy to external agents, such as laundry detergents, soaps, poison ivy, nickel, etc.? □ Yes 
□ No 
Describe the agent and type of allergic response: 
 
c. Any allergy to food? □ Yes □ No 
Describe the food and type of allergic response: 
d. Any allergy to animals, insects? □ Yes □ No 
Describe the allergen and type of allergic response: 
 
e. Any other allergy? □ Yes □ No 
Describe the allergen and type of allergic response: 
 
2. Does the subject have any other history of skin reactions, skin eruptions, or rashes? □ Yes □ No 
If so what kind? ___________________________________________________  
3. Has the subject ever been treated for a skin condition? □ Yes □ No 
If so what kind? ___________________________________________________  
4. Is the current finding similar to a past experience? □ Yes □ No 
Pembrolizumab Event of Clinical Interest Guidance Document 
 


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7. APPENDIX 3 – Presentation of the Dermatologic Event 
Presentation of the event: 
Collect information on clinical presentation and potential contributing factors. Key information 
should be summarized and entered on the Adverse Experience eCRF. Any treatments 
administered should be entered on the Concomitant Medication eCRF. 
1. What is the onset time of the skin reaction, skin eruption, or rash relative to dose of study drug? 
________________________________________________ 
2. Has the subject contacted any known allergens? □ Yes □ No 
If so what kind? ___________________________________________________  
3. Has the subject contacted new, special, or unusual substances (e.g., new laundry detergents, 
soap, personal care product, poison ivy, etc.)? □ Yes □ No 
If so what kind? _______________________________________________________  
4. Has the subject taken any other medication (over the counter, prescription, vitamins, and 
supplement)? □ Yes □ No 
If so what kind? _______________________________________________________  
5. Has the subject consumed unaccustomed, special or unusual foods? □ Yes □ No 
If so what kind? _______________________________________________________  
6. Does the subject have or had in the last few days any illness? □ Yes □ No 
If so what kind? ________________________________________________________  
7. Has the subject come into contact with any family or house members who are ill? □ Yes □ No 
If so who and what? __________________________________________________  
 
8. Has the subject recently been near children who have a skin reaction, skin eruption, or rash 
(e.g. Molluscum Contagiosum)? □ Yes □ No 
 
 
 
 
 
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Pembrolizumab Event of Clinical Interest Guidance Document 
9. Has the subject had recent sun exposure? □ Yes □ No 
10. For the current rash, have there been any systemic clinical signs? □ Yes □ No 
If so what kind? 
i. Anaphylaxis? □ Yes □ No 
ii. Signs of hypotension? □ Yes □ No 
iii. Signs of dyspnea? □ Yes □ No 
iv. Fever, night sweats, chills? □ Yes □ No 
11. For the current rash, has the subject needed subcutaneous epinephrine or other systemic catecholamine 
therapy? □ Yes □ No 
If so what kind? 
12. For the current rash, has the subject used any other medication, such as inhaled bronchodilators, 
antihistaminic medication, topical corticosteroid, and/or systemic corticosteroid? □ Yes □ No 
List medication(s) and dose(s): 
 
 
 
13. Is the rash pruritic (itchy)? □ Yes □ No 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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8. APPENDIX 4 – Focused Skin Examination 
Focused Skin Examination: 
Key information should be summarized and entered on the Adverse Experience eCRF. 
 
Primary Skin Lesions Description  
Color: 
General description: 
 
 
Describe the distribution of skin reaction, skin eruption, or rash on the body: 
 
 
Is skin reaction, skin eruption, or rash resolving or continuing to spread? 
 
 
Any associated signs on physical examination? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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