A Phase II Clinical Trial of Single Agent Pembrolizumab in Subjects With Advanced Adrenocortical Carcinoma
Phase: PHASE2
Conditions: Adrenocortical Carcinoma
Sponsor: Memorial Sloan Kettering Cancer Center

Memorial Sloan Kettering Cancer Center
IRB Number: 15-286 A(11) 
Approval date: 08-Feb-2019 
Page 1 of 45
 
 
 
 
 
 
A Phase II Cli nical Trial of Single Agent Pembrolizumab in Subjects with Advanced 
Adrenocortical Carcinoma 
 
PROTOCOL FACE PAGE FOR 
MS K THE RA P E UT IC /D IA GN OS T IC P RO T OC OL 
 
 
Principal Investigator/Department: 
Diane Reidy-Lagunes, MD 
Medicine 
Co-Principal 
Investigator(s)/Department: 
Leonard Saltz, MD 
Nitya Raj, MD 
Medicine 
Medicine 
Investigator(s)/Department: 
Ghassan Abou-Alfa, MD 
Andrea Cercek, MD 
Andrew Epstein, MD 
James Harding, MD 
David Ilson, MD, PhD 
Yelena Janjigian, MD 
David Kelsen, MD 
Nancy Kemeny, MD 
Geoffrey Ku, MD 
Eileen O‟Reilly, MD 
Armin Shahrokni, MD 
Neil Segal, MD, PhD 
Zsofia Stadler, MD 
Anna Varghese, MD 
Rona Yaeger, MD 
Kenneth Yu, MD 
Elizabeth Won, MD 
Jaclyn Norris, NP 
Claudia Calderon, NP 
Michal Segal, RN 
Danny Khalil, MD 
Karuna Ganesh, MD 
Wungki Park, MD 
Juan Schvartzman, MD 
Imane El Dika, MD 
Louise Connell, MD 
Marinela Capanu, PhD 
Anuradha Gopalan, MD 
Seth Katz, MD, PhD 
Jeremy Durack, MD, MS 
Ellen Hollywood, NP 
Erica Kaufmann, NP 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Nursing 
Nursing 
Nursing 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Biostatistics 
Pathology 
Radiology 
Interventional 
Nursing 
Nursing 
Consenting Professional(s)/Department: 
Ghassan Abou-Alfa, MD 
Andrea Cercek, MD 
Andrew Epstein, MD 
James Harding, MD 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 

Memorial Sloan Kettering Cancer Center
IRB Number: 15-286 A(11) 
Approval date: 08-Feb-2019 
Page 2 of 45
 
 
 
 
 
David Ilson, MD, PhD 
Yelena Janjigian, MD 
David Kelsen, MD 
Nancy Kemeny, MD 
Geoffrey Ku, MD 
Eileen O‟Reilly, MD 
Armin Shahrokni, MD 
Diane Reidy-Lagunes, MD 
Nitya Raj, MD 
Leonard Saltz, MD 
Neil Segal, MD, PhD 
Zsofia Stadler, MD 
Anna Varghese, MD 
Rona Yaeger, MD 
Kenneth Yu, MD 
Elizabeth Won, MD 
Wungki Park, MD 
Juan Schvartzman, MD 
Imane El Dika, MD 
Louise Connell, MD 
Karuna Ganesh, MD 
Jaclyn Norris, NP 
Claudia Calderon, NP 
Danny Khalil, MD 
Ellen Hollywood, NP 
Erica Kaufmann, NP 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
 
 
 
Nursing 
Nursing 
Medicine 
Nursing 
Nursing 
 
 
Ple ase Note: A Consenting Professional must have completed the mandatory Human 
Subje cts Education and Ce rtification Program. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 

Memorial Sloan Kettering Cancer Center
IRB Number: 15-286 A(11) 
Approval date: 08-Feb-2019 
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Table of Contents 
 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ....................................................................... 4 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS ................................................................................. 5 
 
3.0 
BACKGROUND AND RATIONALE ...................................................................................... 5 
 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION............................................................ 10 
 
4.1 
Design ............................................................................................................................... 10 
 
4.2 
Intervention........................................................................................................................ 11 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS ............................................................................ 12 
 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY ............................................................................ 12 
 
6.1 
Subject Inclusion Criteria .................................................................................................. 12 
 
6.2 
Subject Exclusion Criteria ................................................................................................. 13 
 
7.0 
RECRUITMENT PLAN ......................................................................................................... 15 
 
8.0 
PRETREATMENT EVALU ATION........................................................................................ 15 
 
9.0 
TREATMENT/INTERVENTION  PLAN................................................................................. 16 
 
10.0 EVALU ATION DURING TREATMENT/INTERVENTION ................................................... 27 
 
11.0 TOXICITIES/SIDE EFFECTS............................................................................................... 28 
 
12.0 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ...................... 32 
 
13.0 CRITERIA FOR REMOVAL FROM STUDY........................................................................ 35 
 
14.0 BIOSTATISTICS................................................................................................................... 36 
 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
37 
 
15.1 Research Participant Registration .................................................................................... 37 
 
15.2 Randomization .................................................................................................................. 38 
 
16.0 DAT A M AN AGEMENT ISSUES .......................................................................................... 38 
 
16.1 Quality Assurance............................................................................................................. 38 
 
16.2 Data and Safety Monitoring .............................................................................................. 38 
 
17.0 PROTECTION OF HUMAN SUBJECTS ............................................................................. 40 
 
17.1 Privacy............................................................................................................................... 40 
 
17.2 Serious Adverse Event (SAE) Reporting .......................................................................... 40 
 
17.2.1 ........................................................................................................................................ 42 
 
18.0 INFORMED CONSENT PROCEDURES ............................................................................. 43 
 
19.0 REFERENCES...................................................................................................................... 44 
 
20.0 APPENDICES....................................................................................................................... 45 

Memorial Sloan Kettering Cancer Center
IRB Number: 15-286 A(11) 
Approval date: 08-Feb-2019 
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1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
 
Title  of  Study:  A  phase  II  clinical  trial  of  single  agent  pem brolizumab  in  subjects  with  advanced 
adrenocortical carcinoma (A CC) 
Study Center s: Mem orial Sloan Kettering Cancer Center (MSK CC) 
Trial Phase: II 
Clinical Indication: Adrenocortical carcinom a (ACC) 
Trial Type: Interventional 
Type of contr ol: No treatment control 
Route of administration: Intravenous (IV ) 
Trial blinding: Unbli nded open -label 
Group s: Pembrolizum ab 200 mg every 3 weeks (Q3W) 
Number of trial subjects: 21-39 (21 fi rst stage; up to 39 if promising) 
Estimated  duration  of trial: Approximately  36 m onths  from the time the fi rst subject signs the informed 
consent until the last subject‟s last visit. 
Study De sign: This will be a single center, non -randomized, single arm phase II clinical trial using a Sim o n 
two stage minim ax design. It will be conducted to determine the efficacy and safety of pembrolizum ab i n 
subjects  with advanced ACC (whic h is defined as  either unresectable  or stage IV metastatic  diseas e).All 
s ubjects will receive pembrolizum ab vi a IV infusion at 200 mg Q3W, and continue treatment Q3W for up to 
24 months, or until documented  disease progression, unacceptabl e side effects or intercurrent illness that 
prevents   further  administrati on  of  treatment,  investigators‟   decision  to  withdraw  the  subject,  subject 
withdraws consent, pregnancy of the patient, noncompliance of the patient, or for admi nistrati ve reas ons . 
For subj ects who do recei ve treatment for 24 months in t he absence of disease progression, there will b e 
the option to resum e treatm ent for an additi onal 12 months in the fut ure upon diseas e progression. 
Patients will be evaluat ed by physical exam and routine blood tests every  3 weeks duri ng the study period. 
CT or MRI will be performed during screening, and t hen at 9 week intervals. E valuati on of tum or resp ons es 
will be performed accordi ng to RE CIS T v1.1, however subjects  may continue to recei ve pembrolizum a b 
beyond radiographic progression in the absence of clinical deterioration  gi ven the potential for tum or flar e 
with  immune  modulating  therapies ,  after  discussion  with  the  P rincipal  Investigator.   After  the  en d  o f 
treatment, each subject will be followed for 30 days for adverse event monitoring (serious adverse e vents  
and events of clinical interest will be collected for 90 days after the end of t reatm ent or 30 days a fter th e 
end of treatment i f the subj ect initiates new cancer therapy, whichever is earli er). S ubjects who discontinu e 
treatment for reasons other than disease progression  will have posttreatment foll ow -up for disease s tatus  
until disease progression, initiating a non -study canc er treatment, withdrawing consent, or becoming los t to 
follow-up. All s ubjects will be foll owed by telephone contact for overall survi val until death or withdra wal o f 
consent. 
The  prim ary  endpoi nt  of this  trial  is to determine  the  anti -tum or acti vity  of pem brolizumab  by  objecti ve 
response rate (ORR) using RE CIS T v1. 1 in subjects with unresectable or stage IV ACC. A Simon two s tag e 
minimax design will be em ployed to carry out this obj ecti ve. In the fi rst stage, 2 1 patients will be enrolled. If 
at least 3 out of 21 patients respond (partial response - PR or compl ete response  - CR), we will enroll a n 
additional 18 patients for a tot al of 39 patients. At the end of the study, 8 of 39 patients will need to res  pon d 
to consider the therapy promising.  The study will be complete when all subjects have either compl eted 2 4 
months of drug therapy, progressed, or discontinued from the study for other reasons. The accrual tim e is  
estimated to be 2 years . 
Although subjects will be enrolled regardless of PD -L1 status, subjects will be required to provi de tissue o f a 
tumor lesion (either arc hi ved tissue or a fresh bi opsy before initiating therapy) to be evaluated at a centr al 
laboratory for expression status of PD -L1 by immunohistochemistry. 
We anticipate that 10-20% of subjects will have disease that respon ds to treatm ent and will be amenabl e to 
surgical resection. In patients who have a PR or CR and who have dis ease amenabl e to surgical resection, 

Memorial Sloan Kettering Cancer Center
IRB Number: 15-286 A(11) 
Approval date: 08-Feb-2019 
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surgically resected tissue will be collected when avail abl e. In patients with tumor response who do not h a ve 
disease  amenabl e to surgical  resection,  an  optional  core  biopsy  will  be  requested  and  performed  afte r 
obtaini ng  patient  consent.  All  specimens   (biopsies  and  surgical  s pecimens)  will  undergo  com pl ete 
characterization   of  the  immune   milieu;   tumor  immunohistochemistry   may   be  performed   for  P D-L 1  
expression and quantification of tumor infiltrating lymphocyte (TIL) subtypes, including CD8+ T-cells , CD4+ 
T-cells,  Regulatory  T-cells  (Treg),  and  Myeloi d  Deri ved  Suppressor  Cells  (M DSCs).  Peri pheral  bloo d 
samples  will be obtained in all patients  at baseline then weeks  3, 6 and 9. Plasma ma y be analyzed fo r 
change in antibody res ponses to a broad panel of anti gens (seromics). Flow cytometry  may be perfo rm e d 
for peri pheral bl ood immune cell phenotype and their acti vation status,  including CD8+  T-cells,  C D4+ T- 
cells,  Tregs,  and  MDS Cs.  The  amount  of  PD-L1  expression,  changes  in  immune  cell  repertoi re  an d 
activation status within the tum or and peripheral bl ood as well as imm une responses agai nst specific tum o r 
antigens  will be correlat ed  with clinical outcom e in an expl oratory  manner in order t o identify  predicti ve 
makers for response, and to further our understanding of pem brolizum ab in A CC. 
 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
 
• 
The primary objective is to determine the anti-tumor activity of pembrolizumab by objective 
response rate (ORR) (CR and PR) using RECIST v1.1 in subjects with advanced ACC 
(either unresectable or stage IV ACC). 
• 
The secondary objectives are to: 
o Determine the safety and tolerability of pembrolizumab in subjects with advanced 
ACC. 
o Evaluate the expression of PD-L1 (B7H1) using immunohistochemical staining on 
ACC tumor cells. 
o Identify and characterize the populations and activation status of tumor infiltrating 
lymphocytes. 
o Characterize   the   expression   of   immune   co-receptors on   tumor   infiltrating 
lymphocytes using immunohistochemical staining. 
o Estimate the event free survival (EFS) and overall survival (OS) using RECIST 
v1.1 in subjects with advanced ACC. 
• 
The exploratory objectives are to investigate both blood and tumor biomarkers for their 
association with efficacy. In patients where the tumor responds, we will ask them for a 
post-treatment tissue biopsy to see if we can evaluate a marker to help predict response. 
 
3.0 
BACKGROUND AND RATIONALE 
 
3.1 
Adrenocortical carcinoma (ACC) 
 
ACCs are rare and aggressive tumors, with an incidence of 0.5-2 per million in the United States 
with 5-year survival less than 35%.[1] Nearly 60% of patients present with metastatic disease at 
the time of diagnosis and even after complete surgical resection, recurrences are common. In a 
single center report of 202 cases of ACC, 40% of patients with stage I to III disease had 
developed distant metastases two years after diagnosis [2, 3]. 
 
Unfortunately treatment options for ACC are limited. Mitotane, an adrenocorticolytic drug, is the 
only FDA approved drug for ACC and is marked by low efficacy and high treatment toxicity. 
Currently mitotane, either alone or in combination with other cytotoxic agents, is used in any line 
of therapy, including the adjuvant setting, for primary therapy of unresectable disease, and for the 
treatment of disease recurrence.[4] 

Memorial Sloan Kettering Cancer Center
IRB Number: 15-286 A(11) 
Approval date: 08-Feb-2019 
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In the setting of metastatic disease, few studies have been conducted of primary, single agent, 
mitotane therapy. In the small reports that are available, which date back to the 1960-70s, the 
median survival was about 6.5 months, similar to the survival expected in untreated patients.[5-9] 
 
In addition, even when mitotane is used in combination with cytotoxic chemotherapy, results are 
overall poor. The FIR M-ACT trial, the only phase III trial ever done for ACC, compared treatment 
with mitotane with etoposide, doxorubicin and cisplatin (EDP) or with streptozocin.[10] Median 
progression free survival was 5 months for the EDP treated group and 2.1 months for the 
streptozocin treated arm, with median OS of 14.8 versus 12 months, respectively. ≥ Grade 3 
toxicity was seen in 58.1% of EDP treated patients and 41.6% of streptozocin treated patients. In 
an attempt to identify targeted therapy options, despite promising pre-clinical work, targeted 
therapies for ACC with VEGF inhibitors and IGF-1R monoclonal antibody treatment are marked 
by early progression and poor overall survival.[11-13] 
 
Given the limited treatment options, there is an urgent need for more effective regimens with less 
drug toxicity for ACC in order to improve outcomes for these patients. MSKCC has one of the 
largest ACC programs in the country and we also are building a powerful immunotherapy program 
under the leadership of Dr. Jedd Wolchok, which will enable us to complete an immunotherapy 
trial for such a rare disease. 
 
3.2 
Rationale for immunotherapy in adrenocortical carcinoma 
 
Immunotherapy represents a promising treatment strategy for ACC despite limited pre-clinical and 
human data detailing the immune microenvironment. There was initial interest in investigating 
immunotherapy in ACC after observing a high incidence of endocrine related adverse events 
leading to adrenal insufficiency as a result of hypophysitis or primary adrenalitis with treatment 
with ipilimumab.[14] We then looked at publicly available RNA Seq data and noted increased 
expression of CTLA-4 compared to normal adrenal tissue. RNA Seq data also showed expression 
of PD-L1, PD-1, B7DC and T cell co-receptors in both normal and cancerous tissue, although this 
is difficult to interpret and of unknown significance (unpublished data). 
 
Until recently, only one published study by Yamamoto et al., investigated the presence of tumor 
infiltrating lymphocytes (TILs) in adrenocortical carcinoma.[15] Three patients were studied and 
TILs were harvested, expanded and stimulated in co-culture and then cytotoxic activity was 
measured against autologous tumor. In two of the three patients, small but significant cytotoxic 
activity was present. Unstimulated TILs were unable to mount any type of response, however, in 
this study staining for immune exhaustion markers such as PD-1 or CTLA-4 were not performed. 
T cells did express CD45RO, indicative of a memory T cell population. Also of importance, when 
the researchers examined the T cell receptor repertoire amongst the TILs and compared this to 
circulating lymphocytes within the blood, they saw a more limited repertoire, which is indicative 
that these T cells were clonally expanded against a specific tumor antigen. 
 
Characterization of PD-L1 expression on both tumor infiltrating monocytes as well as ACC cell 
membrane expression was reported earlier this year.[16] Nearly all samples (27/28) from patients 
with ACC had expression of PD-L1 on tumor infiltrating monocytes and nearly 11% had surface 
membrane expression on the tumor cells. While the presence of PD-L1 staining described above 

Memorial Sloan Kettering Cancer Center
IRB Number: 15-286 A(11) 
Approval date: 08-Feb-2019 
Page 7 of 45 
 
 
 
 
 
is promising, more work in the field of melanoma as well as solid organ tumors have shown that 
responses to treatment with anti-PD-1 therapy are also seen in patients without staining for PD-L1 
either due to tumor heterogeneity or mechanisms yet to be described. 
 
Historically, immunotherapy has focused on treating cancers such as melanoma with a high 
mutational burden. Adrenocortical carcinoma has marked chromosomal instability but high 
volume somatic hypermutations are only found in 5% of cases.[17] However, in unpublished data 
from our institution, metastatic lesions carry a higher mutational rate than those found in their 
paired primary tumor indicating a rationale for immunotherapy. 
 
Furthermore, recent work, even in melanoma, has found that high mutational burden in itself is not 
completely predictive of immune response.[18] Work with whole exome sequencing performed in 
combination with bioinformatics has been able to predict the presence of tumor neoantigens in 
epithelial based tumors and their likelihood to generate cytotoxic T cell responses.[19] Our 
institution is currently performing whole exome sequencing of adrenocortical tumors giving us a 
unique opportunity for secondary endpoint analyses. In addition, steroidogenic proteins expressed 
by the adrenal gland and adrenocortical carcinomas are known antigenic targets in autoimmune 
disease in both human and pre-clinical models.[20, 21] 
 
Finally, immunohistochemical diagnosis of ACC is actually made by expression of Melan-A 
(MART-1), a known antigenic target in melanoma.[22] This has not been studied as a potential 
antigenic target in ACC, nor has this been investigated in cases of immune mediated endocrine 
adverse events. 
 
Pembrolizumab is an excellent choice for investigation in ACC, as this agent has already 
demonstrated activity in solid organ tumors. ACC is an appropriate target for pembrolizumab 
given the above rationale and the unmet need for novel therapies in this disease, given the lack of 
currently available treatments. 
 
3.3 
Pembrolizumab 
 
3.3.1  Pharmaceutical and Therapeutic Background 
 
The importance of intact immune surveillance in controlling outgrowth of neoplastic transformation 
has been known for decade. Accumulating evidence shows a correlation between TILs in cancer 
tissue and favorable prognosis in various malignancies [23-26]. In particular, the presence of 
CD8+ T-cells and the ratio of CD8+ effector T-cells / FoxP3+ regulatory T-cells seems to correlate 
with improved prognosis and long-term survival in many solid tumors. 
 
The PD-1 receptor-ligand interaction is a major pathway exploited 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-regulate immune responses as an adaptive mechanism to prevent 
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). 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. 

Memorial Sloan Kettering Cancer Center
IRB Number: 15-286 A(11) 
Approval date: 08-Feb-2019 
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The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an immunoreceptor 
tyrosine-based inhibition motif (ITIM) and an immunoreceptor tyros ine-based switch motif (ITSM). 
Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases SHP-1 and SHP-2 to the 
ITSM motif within its cytoplasmic tail, leading to the dephosphorylation of effector molecules such 
as CD3ζ, PKCθ and ZAP70 which are involved in the CD3 T-cell signaling cascade. The 
mechanism by which PD-1 down regulates T-cell responses is similar to, but distinct from that of 
CTLA-4 as both molecules regulate an overla pping set of signaling proteins. PD-1 was shown to 
be expressed on activated lymphocytes including peripheral CD4+ and CD8+ T-cells, B-cells, T 
regs and Natural Killer cells. Expression has also been shown during thymic development on 
CD4-CD8- (double negative) T-cells as well as subsets of macrophages and dendritic cells. The 
ligands for PD-1 (PD-L1 and PD-L2) are constitutively expressed or can be induced in a variety of 
cell types, including non-hematopoietic tissues, lymphocytes, monocytes as well as in various 
tumors. Both ligands are type I transmembrane receptors containing both IgV- and IgC-like 
domains in the extracellular region and contain s hort 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.[27]  Although healthy organs express little (if any) PD-L1, a 
variety of cancers were demonstrated to express abundant le vels of this T-cell inhibitor. PD-1 has 
been suggested to regulate tumor-specific T-cell expansion in subjects with melanoma. This 
suggests that the PD-1/PD-L1 pathway plays a critical role in tumor immune evasion and should 
be considered as an attractive target for therapeutic intervention. 
 
Pembrolizumab (previously known as MK-3475 or SCH 900475) 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. 
 
3.3.2  Preclinical and Clinical Trial Data 
 
3.3.2.1 Non-Clin ical Toxicology Summary of Results 
 
In the 1-month and 6-month toxic ology study in cynomolgus monkeys, pembrolizumab 
administered once a week and once every other week respectively, intravenously up to 200 
mg/kg resulted in no adverse treatment related effects. The exposure multiple based on a 
predicted AUC 0-tau of 4464 µg/day/mL at the maximum anticipated human clinical dose of 
10 mg/kg Q2W or Q3W is 15-fold at 200 mg/kg, the NOAEL for the 6-month monkey study. 
Additionally, in the tissue cross-reactivity study of pembrolizumab with human and monkey 
tissues demonstrated the expected on-target staining of the membranes  of mononuclear 
leukocytes  in both species. Off-target cross-reactivity  staining was also noted in both 
species but was limited to cytoplasm of various cell types/tissues and the stroma 
(extracellular  connective  tissue  matrix), and  was  considered  related  to  the experimental 
method artifacts, i.e. tissue processing  for IHC, that are well recognized limitations  of 
tissue  cross-reactivity  studies  and,  thus  not  considered  toxicologically relevant. 

Memorial Sloan Kettering Cancer Center
IRB Number: 15-286 A(11) 
Approval date: 08-Feb-2019 
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No reproductive or developmental toxicity studies are planned with pembrolizumab. Therefore, 
inclusion of women of childbearing potential in clinical trials should be in accordance with 
the  study  protocol  and  applicable  regulatory   guidance  (e.g.,   ICH   M3(R2): Nonclinical 
Safety Studies  for the Conduct  of Human  Clinical  Trials  and  Marketing Authorization for 
Pharmaceuticals). 
 
3.3.2.2 Clinical Summary of Results 
 
As of 18-Oct-2013,  1,000  patients  have  been treated with  pembrolizumab  at several  dose- 
schedules, including 10 mg/kg every 2 w eeks . Pembrolizumab has been generally well 
tolerated, as  expected  based  on preclinical  findings  and  other anti-PD-1  monoclonal 
antibodies. As  of 18-Oct-2013  no serious  infusions  reactions  have been  reported  in 
PN001,   however,   since  the  potential exists, investigators  should be vigilant to this 
possibility. Less  than 1% of patients  thus far assayed had confirmed positive AD A samples 
and among these, no or no clear impact on exposure has been observed. There is no 
contraindication to further clinical investigation with pembrolizumab. Pharmacokinetics  were 
as  expected, based on pembrolizumab being an IgG mAb  and based on preclinical data, 
which support dosing once every 2 or 3 weeks. Pembrolizumab  monotherapy  induced  an 
ORR  of  25% and 27%  in patients  with  ipilimumab- exposed melanoma by central 
independent  RECIST and oncology review/investigator assessed  irRC, respectively. 
Pembrolizumab monotherapy induced an ORR of 39% and 43% in patients with ipilimumab- 
naive melanoma by central independent RECIST and oncology review/investigator assessed 
irRC, respectively. These responses are remarkably durable. The  preliminary  1-year  survival 
rate  for  patients,  many of whom  have  had  multiple therapies, including ipilimumab, who 
receive pembrolizumab is 81%. Pembrolizumab monotherapy induces  an ORR  of 21% and 
24%  in patients  with  previously-treated  NSCLC  by central independent RECIST/investigator 
assessed irRC, respectively, with these responses also remarkably  durable. Preliminary  data 
suggest  higher  levels  of PD-L1  expression  in tumors  of NSCLC  are associated  with 
increased  activity (ORR  67%  by investigator assessed  irRC/57%  by central  independent 
RECIST);  additional  data  are required  to define the optimal PD-L1 cut point. 
 
The most commonly reported treatment emergent AEs experienced are fatigue (43.8%), 
nausea (26.7%), cough (25.3%), pruritus (24.6%), diarrhea (22.3%) and rash (21.5%). 
Immune-related adverse events were reported in 21.4% of melanoma patients; most of these 
events (15.8%) were considered drug-related by the investigator. The most commonly reported, 
immune-related adverse events across the dose-schedules  are  rash  (3.2%),  pruritus  (2.9%), 
vitiligo  (2.9%),  hypothyroidism (2.7%), arthralgia (2.2%),  diarrhea (2.2%),  and pneumonitis 
(1.9%). Review  of the overall benefit: risk ratio of pembrolizumab favors enrollment of 
eligible patients into clinical trials of pembrolizumab. 
 
3.3.2.3 Rationale for Dose Se lection/Regimen/Modification 
 
An open-label Phase I trial (Protocol 001) was conducted to evaluate the safety and clinical 
activity of single agent pembrolizumab. The dose escalation portion of that 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 

Memorial Sloan Kettering Cancer Center
IRB Number: 15-286 A(11) 
Approval date: 08-Feb-2019 
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were observed. This first in human study of pembrolizumab showed evidence of target 
engagement and objective evidence of tumor size reduction at all dose levels (1 mg/kg, 3 mg/kg 
and 10 mg/kg Q2W). No MTD was identified. Recent data from other clinical studies within the 
pembrolizumab program has shown that a lower dose of pembrolizumab and a less frequent 
schedule may be sufficient for target engagement and clinical activity. 
 
PK data analysis of pembrolizumab administered Q2W and Q3W showed slow systemic 
clearance, limited volume of distribution, and a long half-life (refer to IB). Pharmacodynamic data 
(IL-2 release assay) suggested that peripheral target engagement is durable (>21 days). This 
early PK and pharmacodynamic data provides scientific rationale for testing a Q3W dosing 
schedule. 
 
A population pharmacokinetic analysis has been performed using serum concentration time data 
from 476 patients. Within the resulting population PK model, clearance and volume parameters of 
pembrolizumab were found to be dependent on body weight. The relationship between clearance 
and body weight, with an allometric exponent of 0.59, is within the range observed for other 
antibodies and would support both body weight normalized dosing or a fixed dose across all body 
weights. Pembrolizumab has been found to have a wide therapeutic range based on its use in 
melanoma. 
 
The rationale for further exploration of 2 mg/kg and comparable doses of pembrolizumab in solid 
tumors is based on: 1) similar efficacy and safety of pembrolizumab when dosed at either 2 mg/kg 
or 10 mg/kg Q3W in melanoma patients, 2) the flat exposure-response relationships of 
pembrolizumab for both efficacy and safety in the dose ranges of 2 mg/kg Q3W to 10 mg/kg Q3W, 
3) the lack of effect of tumor burden or indication on distribution behavior of pembrolizumab (as 
assessed by the population PK model) and 4) the assumption that the dynamics of 
pembrolizumab target engagement will not vary meaningfully with tumor type. 
 
The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed dosing is based on 
simulations performed using the population PK model of pembrolizumab showing that the fixed 
dose of 200 mg every 3 weeks will provide exposures that 1) are optimally consistent with those 
obtained with the 2 mg/kg dose every 3 weeks, 2) will maintain individual patient exposures in the 
exposure range established in melanoma as associated with maximal efficacy response and 3) 
will maintain individual patients exposure in the exposure range established in melanoma that are 
well tolerated and safe. 
 
A fixed dose regimen will simplify the dosing regimen to be more convenient for physicians and to 
reduce potential for dosing errors.  A fixed dosing scheme will also reduce complexity in the 
logistical chain at treatment facilities and reduce wastage. 
 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.1 
Design 
 
This is a single center, non-randomized, single arm, phase II clinical trial.  The primary endpoint of 
this trial is to assess best overall response rate of pembrolizumab using RECIST v1.1 in subjects 
with unresectable or stage IV ACC. A Simon minimax 2 stage design will be employed to carry 
out this objective. In the first stage, 21 patients will be enrolled. If at least 3 out of 21 patients 

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Page 11 of 45
 
 
 
 
 
respond (PR or CR) then we will enroll an additional 18 patients for a total of 39 patients and at 
the end, at least 8 of 39 patients will need to respond to consider the therapy promising. With 39 
patients, we anticipate an improvement from 12% to 29%.  The design assumes a type 1 error 
(falsely accepting a nonpromising drug) and type 2 error (falsely rejecting a promising drug) of 
10% each. The probability of early termination is 50%. 
 
4.2 
Intervention 
 
All subjects will receive 200 mg of pembrolizumab administered Q3W. Subjects will 
continue treatment Q3W for up to 24 months, or until documented disease progression, 
unacceptable side effects or intercurrent illness that prevents further administration of 
treatment, investigators decision to withdraw the subject, subject withdraws consent, 
pregnancy of the patient, noncompliance of the patient, or for administrative reasons . For 
subjects who do receive treatment for 24 months in the absence of disease progression, 
there will be the option to resume treatment for an additional 12 months upon disease 
progression in the future.  During the study period, patients will be clinically evaluated by 
physical exam and with routine blood work Q3W . Subjects will be evaluated every 9 
weeks with radiographic imaging (CT or MR I) to assess response to treatment by a 
radiologist using RECIST v1.1. RECIST will be adapted to accommodate for the tumor 
response patterns seen with pembrolizumab treatment (e.g., tumor flare), and this adapted 
RECIST will be used as determined by site assessment for treatment decisions. Given the 
possibility of tumor flare, subjects may continue to receive pembrolizumab beyond 
radiographic disease progression in the absence of clinical deterioration, and after 
discussion with the Principle Investigator. 
 
Adverse events will be monitored throughout the trial and graded in severity according to 
the guidelines outlined in the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0. 
 
At the end of treatment, each subject will be followed for 30 days for adverse event 
monitoring (serious adverse events and events of clinical interest will be collected for 90 
days after the end of treatment or 30 days after the end of treatment if the subject initiates 
new anticancer therapy, whichever is earlier). Subjects who discontinue treatment for 
reasons other than disease progression will have posttreatment follow-up for disease 
status until disease progression, initiating a non-study cancer treatment, withdrawing 
consent, or becoming lost to follow-up. All subjects will be followed by telephone contact 
for overall survival until death or withdrawal of consent. 
 
Although subjects will be enrolled regardless of PD-L1 status, subjects will be required to 
provide tissue of a tumor lesion (either archived tissue or a fresh biopsy before initiating 
therapy) to be evaluated at a central laboratory for expression status of PD-L1 by 
immunohistochemistry. Exploratory research studies to evaluate the effect of 
pembrolizumab will be performed in subjects using research blood draws, as well as an 
optional tumor biopsy in subjects who demonstrate a PR or CR to therapy, in an effort to 
identify predictive markers for response. 

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4.3 
Estimated Duration of Subject Participation 
 
Subjects may be treated for up to 24 months, and in the absence of disease progression 
during this time, will have the option in the future to resume treatment for an additional 12 
months upon disease progression. All subjects will be followed by telephone contact for 
OS until death or withdrawal of consent. 
 
 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
 
5.1 
Pembrolizumab 
 
Pembrolizumab will be provided by Merck. Pembrolizumab 200 mg will be administered as 
a 30 minute IV infusion Q3W. Please refer to the Investigator‟s Brochure, which contains 
specific instructions for the preparation of pembrolizumab infusion fluid and administration 
of the infusion solution. 
 
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 affixed with a clinical label in accordance with 
regulatory requirements. 
 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY 
 
6.1 
Subject Inclusion Criteria 
 
In order to be eligible for participation in this trial, the subject must: 
 
1.  Be willing and able to provide written informed consent for the trial. 
 
2.  Be ≥ 18 years of age on day of signing informed consent. 
 
3.  Have histologically- or cytologically- confirmed unresectable or metastatic ACC that is 
considered incurable by local therapies. 
 
4.  Have an ECOG performance status of 0 or 1. 
 
5.  Have measurable disease based on RECIST v1.1.. 
 
6.  Have provided tissue for PD-L1 biomarker analysis from either archived tissue or a 
newly obtained core or excisional biopsy. 
 
7.  Consent for use of archived tissue for research purposes. 
 
8.  Demonstrate adequate organ function as defined in Table 1, all screening labs should 
be performed within 28 days of treatment initiation. 

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Table 1:  Ade quate Organ Function Laboratory Values 
 
Sys tem 
Laboratory Value 
Hematological 
Abs olute neutrophil count (ANC) 
≥1,500 /m cL 
Platelets 
≥100,000 / m cL 
Renal 
Serum creatinine 
OR 
Meas ured or calculateda creatinine 
clearance (GFR can als o be us ed in 
place of creatinine or CrCl) 
≤1.5 X upper lim it of norm al (ULN) 
OR 
≥60 m L/m in for s ubject w ith creatinine levels > 1.5 X 
ins titutional ULN 
Hepatic 
Serum total bilirubin 
≤ 1.5 X ULN  OR 
Direct bilirubin ≤ ULN for s ubjects w ith total bilirubin levels > 
1.5 ULN 
AST (SGOT) and ALT (SGPT) 
≤ 2.5 X ULN  OR 
≤ 5 X ULN for s ubjects w ith liver m etas tas es 
Coagulation 
International Normalized Ratio (INR) or 
Prothrom bin Time (PT) 
Acti vated Partial Thromboplas tin Tim e 
(aPTT) 
≤1.5 X ULN unless s ubject is receiving anticoagulant therapy 
as long as PT or PTT is w ithin therapeutic range of intended 
use of anticoagulants 
≤1.5 X ULN unless s ubject is receiving anticoagulant the rapy 
as long as PT or PTT is w ithin therapeutic range of intended 
use of anticoagulants 
aCreatinine clearance s hould be calculated per ins titutional s tandard. 
 
 
9.  Female subjects of childbearing potential should have a negative serum pregnancy 
test within 72 hours prior to receiving first dose of study medication. If the urine test is 
positive or cannot be confirmed as negative, a serum pregnancy test will be required. 
 
10. Female subjects of childbearing potential should be willing to use 2 methods of birth 
control or be surgically sterile, or abstain from heterosexual activity for the course of 
the study through 120 days after the last dose of study medication (Reference Section 
9.5.2). Subjects of childbearing potential are those who have not been surgically 
sterilized or have not been free of menses for >1 year. 
 
11. 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. 
 
6.2 
Subject Exclusion Criteria 
 
The subject must be excluded from participating in the trial if the subject: 
 
1.  Is currently participating in or has participated in a study of an investigational agent or 
using an investigational device within 4 weeks prior to the first dose of trial treatment. 
 
2.  Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any 
other form of immunosuppressive therapy within 7 days prior to the first dose of tria l 
treatment. The use of physiologic doses of corticosteroids for adrenal and pituitary 

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Page 14 of 45
 
 
 
 
 
insufficiency is not considered a form of systemic steroid therapy and would not 
exclude a subject from the study. 
 
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 within 2 weeks prior to 
study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse 
events due to a previously administered agent. 
 
• 
Note: Subjects with ≤ Grade 2 neuropathy or ≤ Grade 2 alopecia are an 
exception to this criterion and may qualify for the study. 
 
5.  If subject underwent major surgery, they must have recovered adequately from the 
toxicity and/or complications from the intervention prior to starting therapy. 
 
6.  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. 
 
7.  Has known active central nervous system metastases and/or carcinomatous 
meningitis. Subjects with previously treated brain metastases may participate provided 
they are stable (without evidence of progression by imaging for at least four weeks 
prior to the first dose of trial treatment and any neurologic symptoms have returned to 
baseline), have no evidence of new or enlarging brain metastases, and are not using 
steroids for brain metastases for at least 7 days prior to trial treatment. This exception 
does not include carcinomatous meningitis which is excluded regardless of clinical 
stability. 
 
8.  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. Subjects that have adrenal 
or pituitary insufficiency that require physiologic corticosteroid replacement therapy 
would not be excluded from the study. 
 
9.  Has evidence of interstitial lung disease or history of (non-infectious) pneumonitis that 
required steroids or current pneumonitis. 
 
10. Has an active infection requiring systemic therapy. 
 
11. 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 subjec t to participate, in 
the opinion of the treating investigator. 

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12. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
 
13. Is pregnant or breastfeeding, or expecting to conceive or father c hildren 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. 
 
14. 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 any other antibody or drug specifically targeting T-cell co-stimulation or 
checkpoint pathways). 
 
15. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
 
16. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected). 
 
17. Has received a live vaccine within 30 days prior to the first dose of trial treatment. 
 
• 
Note: Seasonal influenza vaccines for injection are generally inactivated flu 
vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu- 
Mist) are live attenuated vaccines, and are not allowed. 
 
7.0 
RECRUITMENT PLAN 
 
This study will be available to all patients seen at MSKCC, who meet the eligibility criteria 
outlined in section 6.0. 
 
Potential research subjects will be identified by doctors from the medical oncology and 
surgical clinics at MSKCC. The principal investigator, member of the treatment team, or a 
research study assistant will discuss the study with the patient. They will use the 
information provided by the patient and/or medical record to confirm that the patient is 
eligible and to contact the patient regarding study enrollment. All eligible patients, 
regardless of sex and race, will be approached for participation. The investigators are 
aware of the NIH policy concerning inclusion of women and minorities in clinical research 
populations. 
 
Participation in the study is completely voluntary. Patients will be required to read, agree 
to, and sign an IRB-approved informed consent form prior to registration on this trial; 
registration is described in section 15.0. Patients will not receive payment for  their 
participation on this study. Patients are free to withdraw from the study without 
consequence at any time. 
 
8.0 
PRETREATMENT EVALUATION 
 
To be completed within 28 days of starting pembrolizumab: 
 
1.  CT scan of the chest, abdomen, and pelvis with contrast. If patient is unable to receive 
CT contrast, or the abdominal/pelvic target lesion is indeterminate on CT scan then 
MR I abdomen and pelvis with contrast plus CT chest without contrast may be 

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perfromed. Non-contrast CT chest, abdomen, and pelvis may be used if the target 
lesion(s) do not require contrast for accurate measurements. 
 
2.  12-lead Electrocardiogram (EKG). 
 
3.  Signed informed consent for study participation. 
 
4.  History and physical examination, including height, weight, vital signs (temperature, 
pulse rate, respiration rate, blood pressure), and ECOG performance status. 
 
5.  Serum pregnancy test for all women of childbearing potential (within 72 hours prior to 
receiving first dose of study medication). If the test result is positive related to 
pregnancy, the patient will not be allowed to participate in this study. 
 
6.  CBC with differential and platelet count, serum chemistries (Na, K, Cl, CO2, BUN, 
creatinine, glucose, calcium, albumin, and total protein), liver function tests (AST, ALT, 
alkaline phosphatase, total bilirubin), coagulation studies (PT, INR, and aPTT), and 
baseline TSH, fT3, and fT4 levels. 
 
7.  Serology for HepBsAg, HepBcAb and hepatitis C antibody (negative test acceptable 
prior to screening period). 
 
8.  Blood test for research purposes. 
 
9.  Perform baseline tumor biopsy or obtain archived tissue for research purposes. 
 
9.0 
TREATMENT/INTERVENTION PLAN 
 
9.1 
Dosing Instructions and Schedule 
 
The treatment to be used in this trial is outlined below in Table 2. 
 
Table 2: Trial Tre atment 
 
Drug 
Dose/ 
Potency 
Dose 
Frequency 
Route of 
Administration 
Regimen/ 
Treatment 
Period 
Use 
Pembrolizumab 
200 mg 
Q3W 
IV infusion 
Day 1 of each 3 
week cycle 
Experimental 
 
 
Day 1 is considered the first day of dosing. Each cycle is 3 weeks. Treatment with pembrolizumab 
should be administered on Day 1 of each 3 week cycle. Trial treatment may be administered up to 
3 days before or after the scheduled Day 1 of each cycle due to administrative reasons. All trial 
treatments will be administered on an outpatient basis. 
 
Pembrolizumab 200 mg will be administered as a 30 minute IV infusion Q3W. Every effort should 
be made to target the 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 

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permitted (i.e., infusion time is 30 minutes: -5 min/+10 min). The reason for any delay in infusion 
outside of the protocol specified window should be documented in the patient‟s chart and 
recorded in the case report form. Treatment will be administered through central venous catheters 
or vascular access devices. 
 
Details on the preparation and administration of pembrolizumab infusion fluid are provided in the 
Investigator‟s Brochure. 
 
9.2 
Concomitant Medications 
 
9.2.1 Acce ptable Concomitant Medication 
 
Investigators may prescribe concomitant medications or treatments (e.g., acetaminophen, 
diphenhydramine) deemed necessary to provide adequate prophylactic or supportive care and 
are necessary for a subject‟s welfare within the standards of medical care, with the exception for 
those medications listed as “prohibited” in section 9.2.2. 
 
9.2.2 Prohibited Concomitant Medications 
 
Subjects are prohibited from receiving the following therapies during the Screening and Treatment 
Phase of this trial: 
 
• 
Antineoplastic systemic chemotherapy or biological therapy 
 
• 
Immunotherapy not specified in this protocol 
 
• 
Chemotherapy not specified in this protocol 
 
• 
Investigational agents other than pembrolizumab 
 
• 
Radiation therapy 
 
o Note: Radiation therapy to a symptomatic solitary lesion or to the brain may be 
allowed at the investigator‟s discretion. 
 
• 
Live vaccines within 30 days prior to the first dose of trial treatment and while participating 
in  the  trial. Examples  of  live  vaccines  include,  but  are  not  limited  to,  the  following: 
measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and typhoid vaccine. 
 
• 
Systemic glucocorticoids for any purpose other than to modulate symptoms from an event 
of clinical interest of suspected immunologic etiology. The use of physiologic doses of 
corticosteroids may be approved after consultation with the Sponsor. 
 
Subjects who, in the assessment by the investigator, require the use of any of the aforementio ned 
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. 
9.3 
Dose Selection/Modification 
 
9.3.1 Dose Se lection (Pre paration) 

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Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting Treatment 
Treatment Discontinuation 
Diarrhea / Co lit is 
2-3 
Toxic ity resolves to Gra de 0-1 
Toxic ity does not reso lve w ithin 1 2 w eeks of last dose or 
inab ility to reduce cort icostero id to 10 mg or less of 
predn isone or equ ivalent per day w ithin 12 w eeks 
4 
Per ma nent ly d isconti nue 
Per ma nent ly d isconti nue 
AST, AL T, or 
Incre ased 
Bi liru bin 
2 
Toxic ity resolves to Gra de 0-1 
Toxic ity does not reso lve w ithin 1 2 w eeks of last dose 
3 
Toxic ity resolves to Base li ne 
(see bel ow ) 
Toxic ity does not reso lve w ith therapy 
4 
Per ma nent ly d isconti nue 
(see exceptio n b elow )
a 
Per ma nent ly d isconti nue 
Type 1 d iab etes 
mel lit us (if new 
onset) or 
Hyper glyce mia 
T1 DM or 
3-4 
Ho ld pe mbrolizu mab f or new onset 
Type 1 d iab etes mel lit us or Gr ade 3- 
4 hyperg lyce mi a associat ed w ith 
evidence of beta ce ll f ailure 
Resu me pe mbrol izu mab w hen pat ients ar e cli nica lly a nd 
meta bolically stab le 
Hypo physit is 
2-4 
Toxic ity resolves to Gra de 0-1. 
Th erapy w ith pe mbr olizu ma b can b e 
contin ued w hile end ocrine 
replace ment thera py is i nstitu ted 
Toxic ity does not reso lve w ithin 1 2 w eeks of last dose or 
inab ility to reduce cort icostero id to 10 mg or less of predn 
isone or equ ivalent per day w ithin 12 w eeks 
Hypert hyroid is m 
3 
Toxic ity resolves to Gra de 0-1 
(see bel ow ) d 
Toxic ity does not reso lve w ithin 1 2 w eeks of last dose or 
inab ility to reduce cort icostero id to 10 mg or less of 
predn isone or equ ivalent per day w ithin 12 w eeks 
4 
Per ma nent ly d isconti nue 
Per ma nent ly d isconti nue 
Hypo thyroi dis m 
Th erapy w ith pe mbr olizu ma b can b e 
contin ued w hile t hyroid r eplace me nt 
therapy is insti tute d 
Th erapy w ith pe mbr olizu ma b can b e cont inu ed w hile t hyroid 
replace ment thera py is i nstitu ted 
Inf usio n Re actio n 
2
b 
Toxic ity resolves to Gra de 0-1 
Per ma nent ly d iscontinue if toxicity d evelo ps desp ite adeq uate 
pre med icat ion 
3 
Toxic ity resolves to Gra de 0 
(see bel ow ) d 
Toxic ity does not reso lve w ith therapy 
4 
Per ma nent ly d isconti nue 
Per ma nent ly d isconti nue 
Pneu mo nit is 
2 
Toxic ity resolves to Gra de 0-1 
Toxic ity does not reso lve w ithin 1 2 w eeks of last dose or 
inab ility to reduce cort icostero id to 10 mg or less of 
predn isone or equ ivalent per day w ithin 12 w eeks 
3 
Toxic ity resolves to Gra de 0 
(see bel ow ) d 
Toxic ity does not reso lve w ith therapy 
4 
Per ma nent ly d isconti nue 
Per ma nent ly d isconti nue 
Re na l Fa ilure or 
Ne phri tis 
2 
Toxic ity resolves to Gra de 0-1 
Toxic ity does not reso lve w ithin 1 2 w eeks of last dose or 
inab ility to reduce cort icostero id to 10 mg or less of 
predn isone or equ ivalent per day w ithin 12 w eeks 
3 
Toxic ity resolves to Gra de 0 
Toxic ity does not reso lve w ith therapy 
 
 
 
The rationale for selection of dose of pembrolizumab to be used in this trial is provided in section 
3.3.2.3. Details on preparation and administration of pembrolizumab are provided in the 
Investigator‟s Brochure. 
 
9.3.2 Dose Modification (Escalation/Titration/Other) 
 
Adverse events (both non-serious and serious) associated with pembrolizumab exposure may 
represent an immunologic etiology. These adverse events may occur shortly after the first dose or 
several months after the last dose of treatment. Pembrolizumab must be withheld for drug-related 
toxicities and severe or life-threatening AEs as per Table 3 below. See Section 9.4 for supportive 
care guidelines, including use of corticosteroids. 
 
Table 3: Dose Modification Guidelines for Drug-Related Adv erse Events 
 
 
 
 
 
 
 
 
 
 
 
 
d 

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Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting Treatment 
Treatment Discontinuation 
(see bel ow ) d 
4 
Per ma nent ly d isconti nue 
Per ma nent ly d isconti nue 
All Other Dr ug- 
Re lat ed Tox icity c 
3 or Sever e 
Toxic ity resolves to Gra de 0-1 
d 
(see bel ow ) 
Toxic ity does not reso lve w ithin 1 2 w eeks of last dose or 
inab ility to reduce cort icostero id to 10 mg or less of 
predn isone or equ ivalent per day w ithin 12 w eeks 
4 
Per ma nent ly d isconti nue 
Per ma nent ly d isconti nue 
Myocard it is 
Grad e 1 or 2 
Toxic ity resolves to Gra de 0 
Based on severity of AE a d min ister corticostero ids 
Grad e 3 or 4 
Per ma nent ly d isconti nue 
Per ma nent ly d isconti nue 
Note : Perm ane ntly dis continue for any seve re or Grade 3 drug -re lated AE that re curs or any life -thre atening e vent. 
a For patients w ith liver metastasis w ho begin treatment w ith Grade 2 AST or ALT, if AST or ALT increases by greater than or equal to 50% relative 
to baseline and lasts f or at least 1 w eek then patients should be discontinued. 
b If symptoms resolve w ithin one hour of stopping drug inf usion, the inf usion may be restarted at 50% of the original inf usion rate  (e.g., f rom 100 
mL/hr to 50 mL/hr).  Otherw ise dosing w ill be held until symptoms resolve and the subject should be premedicated  for the nex t scheduled dose; 
Ref er to Error! Reference source not found. – Inf usion Treatment Guidelines f or f urther management details. 
c Patients w ith intolerable or persistent Grade 2 drug-related AE may hold study medication at physician discretion.  Permanently discontinue study 
drug f or persistent Grade 2 adverse reactions f or w hich treatment w ith study drug has been held, that do not recover to Grade 0-1 w ithin 12 
w eeks of the last dose. 
d Patients w ith grade 3 toxicity w ill stop therapy and be treated per section 9.4. If toxicity returns back to grade 0 af ter the appropriate supportive 
care measures, patients w ho have previously clinically or radiographically responded to pembrolizumab can be eligible f or re-treatment w ith drug 
in the f uture af ter review and discussion of the case w ith the Principal Investigator. 
 
 
Dosing interruptions are permitted in the case of medical/surgical events or logistical reasons not 
related to study therapy (e.g., elective surgery, unrelated medical events, patient vacation, and/or 
holidays). Subjects should be placed back on study therapy within 3 weeks of the scheduled 
interruption, unless otherwise discussed with the Sponsor. The reason for interruption should be 
documented in the patient's study record. 
 
9.4 
Rescue Medications/Supportive Care Guidelines 
 
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator. Suggested supportive care measures for the management of adverse events 
with potential immunologic etiology are outlined below. Where appropriate, these guidelines 
include the use of oral or intravenous treatment with corticosteroids as well as additional anti- 
inflammatory agents if symptoms do not improve with administration of corticosteroids. Note that 
several courses of steroid tapering may be necessary as symptoms may worsen when the steroid 
dose is decreased. For each disorder, attempts should be made to rule out other causes such as 
metastatic disease or bacterial or viral infection, which might require additional supportive care. 
The treatment guidelines are intended to be applied when the investigator determines the events 
to be related to pembrolizumab. 
 
Note: if after the evaluation the event is determined not to be related, the investigator does not 
need to follow the treatment guidance (as outlined below). Refer to Section 9.3 for dose 
modification. 
 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or skin 
photography as part of evaluation of the event. 
 
• 
Pne umonitis: 

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o For Grade 2 events, treat with systemic corticosteroids. When symptoms improve 
to Grade 1 or less, steroid taper should be started and continued over no less than 
4 weeks. 
 
o For Grade 3-4 events, immediately treat with intravenous steroids.  Administer 
additional anti-inflammatory measures, as needed. 
 
o Add prophylactic  antibiotics  for opportunistic  infections  in the case of prolonged 
steroid administration. 
 
• 
Diarrhe a/Colitis: 
 
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such as 
diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of bowel 
perforation (such as peritoneal signs and ileus). 
 
o All  subjects  who  experience  diarrhea/colitis  should  be advised  to  drink  liber al 
quantities of clear fluids.   If sufficient oral fluid intake is not feasible, fluid and 
electrolytes should be substituted via IV infusion.  For Grade 2 or higher diarrhea, 
consider GI consultation and endoscopy to confirm or rule out colitis. 
 
o For Grade 2 diarrhea/colitis,  administer oral corticosteroids. 
o For Grade 3 or 4 diarrhea/colitis, treat with intravenous steroids followed by high 
dose oral steroids. 
 
o When symptoms improve to Grade 1 or less, steroid taper should be started a nd 
continued over no less than 4 weeks. 
 
• 
Type 1 diabetes mellitus (if ne w onset, including diabetic ketoacidosis [DKA]) or ≥ 
Grade 3 Hype rglycemia, if associated with ke tosis (ketonuria) or me tabolic acidosis 
(DKA) 
 
o For T1DM or Grade 3-4 Hyperglycemia 
 
▪
 
Insulin replacement therapy is recommended for Type I diabetes mellitus 
and for Grade 3-4 hyperglycemia associated with metabolic acidosis or 
ketonuria. 
 
▪
 
Evaluate patients with serum glucose and a metabolic panel, urine ketones, 
glycosylated hemoglobin, and C-peptide. 
 
• 
Hypophysitis: 
 
o For Grade 2 events, treat with corticosteroids. When symptoms improve to Grade 
1 or less, steroid taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the steroid dose is 
tapered. 
 
o For Grade 3-4 events, treat with an initial dose of IV corticosteroids  followed by 
oral corticosteroids. When symptoms improve to Grade 1 or less, steroid taper 
should be started and continued over no less than 4 weeks. Replacement of 
appropriate hormones may be required as the steroid dose is tapered. 
 
• 
Hype rthyroidism or 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. 
 
o Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism): 
 
▪
 
In  hyperthyroidism,   non-selective   beta-blockers   (e.g.  propranolol)   are 
suggested as initial therapy. 
 
▪
 
In    hypothyroidism,     thyroid    hormone    replacement     therapy,    with 
levothyroxine or liothyroinine, is indicated per standard of care. 
 
o Grade 3-4 hyperthyroidism 
 
▪
 
Treat   with   an   initial   dose   of   IV   corticosteroid   followed   by   or al 
corticosteroids. When symptoms improve to Grade 1 or less, steroid taper 
should be started and continued over no less than 4 weeks. Replacement 
of appropriate hormones may be required as the steroid dose is tapered. 
 
• 
He patic: 
 
o For Grade 2 events, monitor liver function tests more frequently until returned to 
baseline values (consider weekly). 
 
▪
 
Treat with IV or oral corticosteroids 
 
o For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 hours. 
 
o When symptoms improve to Grade 1 or less, a steroid taper should be started and 
continued over no less than 4 weeks. 
 
• 
Re nal Failure or Ne phritis: 
 
o For Grade 2 events, treat with corticosteroids. 
 
o For Grade 3-4 events, treat with systemic corticosteroids. 
 
o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
 
• 
Management  of  Infusion  Re actions:  Signs  and symptoms  usually develop  during or 
shortly after drug infusion and generally resolve completely within 24 hours of completion 
of infusion. 
 
Table 4 below shows treatment guidelines for subjects who experience an infusion 
reaction associated with administration of pembrolizumab. 
 
 
 
Table 4: Infusion Re action Tre atment Guidelines 
 
NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
Grade 1 
Mild reaction; infus ion 
interruption not indicated; 
intervention not indicated 
Increas e m onitoring of vital s igns as 
m edically indicated until the s ubject is 
deem ed medically s table in the opinion 
of the inves tigator. 
None 
Grade 2 
Stop Infusion and monit or 
Subject m ay be 

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NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
Requires infusion interruption 
but responds prom ptly to 
s ym ptomatic treatment (e.g., 
antihis tamines , NSAIDS, 
narcotics , IV fluids ); 
prophylactic m edications 
indicated for < =24 hrs 
symptoms. 
Additional appropriate m edical therapy 
m ay include but is not limited to: 
IV fluids 
Antihis tam ines 
NSAIDS 
Acetam inophen 
Narcotics 
Increas e m onitoring of vital s igns as 
m edically indicated until the s ubject is 
deem ed medically s table in the opinion 
of the inves tigator. 
If s ym ptoms resolve w ithin one hour of 
s topping drug infus ion, the infusion m ay 
be res tarted at 50% of the original 
infus ion rate (e.g., from 100 m L/hr to 50 
m L/hr). Otherw is e dos ing w il be held 
until s ym ptoms res olve and the s ubject 
s hould be premedicated for the next 
s cheduled dos e. 
Subjects w ho develop Grade 2 
toxicity despite adequate 
premedication should be 
permanently discont inued from 
further trial treatment administration. 
prem edicated 1.5h (± 30 
m inutes ) prior to infus ion of 
pem brolizumab (MK-3475) 
w ith: 
Diphenhydram ine 50 m g po 
(or equivalent dos e of 
antihis tamine). 
Acetam inophen 500-1000 
m g po (or equivalent dos e of 
antipyretic). 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly 
responsive to s ym ptom atic 
m edication and/or brief 
interruption of infus ion); 
recurrence of s ym ptoms 
following initial im provem ent; 
hos pitalization indicated for 
other clinical s equelae (e.g., 
renal impairment, pulm onary 
infiltrates ) 
Grade 4: 
Life-threatening; press or or 
ventilatory s upport indicated 
Stop Infusion. 
Additional appropriate m edical therapy 
m ay include but is not limited to: 
IV fluids 
Antihis tam ines 
NSAIDS 
Acetam inophen 
Narcotics 
Oxygen 
Pressors 
Corticos teroids 
Epinephrine 
Increas e m onitoring of vital s igns as 
m edically indicated until the s ubject is 
deem ed medically s table in the opinion 
of the inves tigator. 
Hos pitalization m ay be indicated. 
Subject is permanently discont inued 
from further trial treatment 
administration. 
No subs equent dos ing 
Appropriate res us citation equipment should be available in the room and a physician readily available 
during the period of drug adminis tration. 

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9.5   Diet/ Activity/ Other Considerat ions 
 
9.5.1    Die t 
 
Subjects should maintain a normal diet unless modifications are required to manage an AE such 
as diarrhea, nausea or vomiting. 
 
9.5.2    Contraception 
 
Pembrolizumab may have adverse effects on a fetus in utero.  Furthermore, it is not known if 
pembrolizumab has transient adverse effects on the composition of sperm. 
 
For this trial, male subjects will be considered to be of non-reproductive potential if they have 
azoospermia (whether due to having had a vasectomy or due to an underlying medical condition). 
 
Female subjects will be considered of non-reproductive potential if they are either: 
 
(1) postmenopausal (defined as at least 12 months with no menses without an alternative medical 
cause; in women < 45 years of age a high follicle stimulating hormone (FSH) level in the 
postmenopausal range may be used to confirm a post-menopausal state in women not using 
hormonal contraception or hormonal replacement therapy. In the absence of 12 months of 
amenorrhea, a single FSH measurement is insufficient.); 
 
OR 
 
(2) have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or bilateral 
tubal ligation/occlusion, at least 6 weeks prior to screening; 
 
OR 
 
(3) has a congenital or acquired condition that prevents childbearing. 
 
Female and male subjects of reproductive potential must agree to avoid becoming pregnant or 
impregnating a partner, respectively, while receiving study drug and for 120 days after the last 
dose of study drug by complying with one of the following: 
 
(1) practice abstinence†  from heterosexual activity; 
OR 
(2) use (or have their partner use) acceptable contraception during heterosexual activity. 
Acceptable methods of contraception are
‡: 
Single method (one of the following is acceptable): 
 
•          intrauterine device (IUD) 
 
•          vasectomy of a female subject‟s male partner 

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• 
contraceptive rod implanted into the skin 
 
Combination method (requires use of two of the following): 
 
• 
diaphragm with spermicide (cannot be used in conjunction with cervical cap/spermicide) 
 
• 
cervical cap with spermicide (nulliparous women only) 
 
• 
contraceptive sponge (nulliparous women only) 
 
• 
male condom or female condom (cannot be us ed together) 
 
• 
hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or progestin-only 
pill), contraceptive skin patch, vaginal contraceptive ring, or subcutaneous contraceptive 
injection 
 
†Abstinence (relative to heterosexual activity) c an be used as the sole method of 
contraception if it is consistently employed as the subject‟s preferred and usual lifestyle 
and if considered acceptable by local regulatory agencies and ERCs/IRBs. Periodic 
abstinence (e.g., calendar, ovulation, sympto-thermal, post-ovulation methods, etc.) and 
withdrawal are not acceptable methods of contraception. 
 
‡If a contraceptive method listed above is restricted by local regulations/guidelines, then 
it does not qualify as an acceptable method of contraception for subjects participating at 
sites in this country/region. 
 
Subjects should be informed that taking the study medication may involve unknown risks to the 
fetus (unborn baby) if pregnancy were to occur during the study. In order to participate in the 
study subjects of childbearing potential must adhere to the contraception requirement (described 
above) from the day of study medication initiation (or 14 days prior to the initiation of study 
medication for oral contraception) throughout the study period up to 120 da ys after the last dose 
of trial therapy. If there is any question that a subject of childbearing potential will not reliably 
comply with the requirements for contraception, that subject should not be entered into the study. 
 
9.5.3 Use in Pre gnancy 
 
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab, the subject 
will immediately be removed from the study. The site will contact the subject at least monthly and 
document the subject‟s status until the pregnancy has been completed or terminated. 
 
If a male subject impregnates his female partner the study personnel at the site must be informed 
immediately. 
 
9.5.4 Use in Nursing Wome n 
 
It is unknown whether pembrolizumab is excreted in human milk. Since many drugs are excreted 
in human milk, and because of the potential for serious adverse reactions in the nursing infant, 
subjects who are breast-feeding are not eligible for enrollment. 

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9.6 Subject Withdrawal/Discontinuat ion Cr iter ia 
 
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. 
 
A subject must be discontinued from the trial for any of the following reasons: 
 
• 
The  subject  or  legal  representative  (such  as  a  parent  or  legal  guardian)  withdraws 
consent. 
 
• 
Confirmed radiographic disease progression 
 
Note: A subject may be granted an exception to continue on treatment with confirmed 
radiographic progression if clinically stable or clinically improved given the potential for 
tumor flare on pembrolizumab. 
 
• 
Unacceptable adverse experiences as described in section 9.3.2. 
 
• 
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 
 
• 
Administrative reasons 
 
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). 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. 
 
9.7 Subject Replacement Strategy 
 
A subject who discontinues from the trial will not be replaced. 
 
9.8 Beginning and End of the Trial 
 
The trial begins when the first subject signs the informed consent form. The trial ends when the 
last subject completes the last study related phone call or visit, discontinues from the trial, or is 
lost to follow-up. 

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9.9 
Clinical Criteria for Early Trial Termination 
 
There are no pre-specified criteria for terminating the trial early. 
 
9.10 
Research blood and biopsy specimens 
 
9.10.1 Re search blood 
 
For the first 21 patients, blood specimens will be obtained for research purposes during screening 
or on day 1, then at weeks 3, 6 and 9 (± 3 days).  An additional blood draw beyond week 9 is 
permitted based upon interesting clinical/immunological findings. 
 
Specimens should be collected prior to drug administration. Four (4) tubes of blood are to be 
collected in BD Vacutainer® CPT™ Cell Preparation Tubes with Sodium Heparin. Each tube 
should contain approximately 10 cc of blood. Peripheral blood mononuclear cells and plasma will 
then be isolated per institutional practice in the Immune Monitoring Facility (IMF). 
 
9.10.2 Re search biopsy 
 
For all patients, either a pre-treatment tumor biopsy of an index lesion will be obtained or archived 
tissue will be provided. Patients will be permitted to continue enrollment and treatment on protocol 
in the event that insufficient material was obtained from the biopsy. 
 
In patients who exhibit a PR or a CR and who proceed to surgical resection, surgically resected 
tissue will be collected after obtaining patient consent. In patients with tumor response who do not 
have disease amenable to surgical resection, an optional core biopsy will be requested and 
performed after obtaining patient consent. Next-generation sequencing of the tumor tissue may 
be considered for these responder patients, however if next-generation sequencing is pursued, 
patients will be separately consented to protocol #12-245 to have MSK-IMPACT testing 
performed through our institutional protocol. 
 
9.10.3  Correlative studies 
 
Pharmacodynamic changes may be evaluated for associations with clinical activity, and safety 
(adverse event) data. Core biopsies may be used for correlative studies such as IHC, tumor 
mutation analysis, proteomic analysis, and immunodiversity. PDL-1 immunohistochemistry will be 
done by a Merck designated laboratory. Other assessment will be done at MSKCC. 
 
9.10.3.1  Whole Blood 
 
Flow cytometry will be performed at baseline and during treatment to assess baseline and 
changes in composition/activation status of lymphocyte subsets present in peripheral blood 
mononuclear cell preparations (PBMCs). Lymphocyte subsets to be assayed may include, but are 
not limited to CD8+ and CD4+ T-cell subsets (activated; effector/memory; regulatory) and 
populations of those cells as defined by the expression of activation, exhaustion, or signaling 
markers such as ICOS, HLA-DR, PD-1, CTLA-4, and/or intracellular IFNγ. NK cell populations 
may be monitored in a similar fashion with a focus on characterizing subsets defined by the 
expression of activation markers (e.g. NKG2D; IL-21R) and/or by markers that are associated 
with the potential of NK cells to lyse target cells (e.g., CD107a, granzyme, perforin). Additional 
flow cytometry-based assays will focus on defining and monitoring the abundance of myeloid- 
derived suppressor cells (MDSCs), a cell type which appears to negatively impact  anti-tumor 

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activity and which has been shown to promote immune escape by limiting activated CD8 T-cell 
infiltration into the tumor microenvironment [27]. 
 
Immune cells may be evaluated using HLA-A2-restricted tetramer assays to detect and quantify 
the presence of T cells directed against specific antigens which are anticipated to be presented to 
the immune system due to study treatment. Detecting on-treatment increases in these T cell 
populations may be considered evidence of adaptive immune responses in ACC. 
 
9.10.3.2  Plasma 
 
To understand the prevalence of circulating proteins and the impact they may have on the clinical 
activity and/or safety of pembrolizumab treatment, the protein concentrations of a panel of 
cytokines, chemokines, and other relevant immunomodulatory, soluble factors may be 
investigated by ELISA and/or other relevant multiplex-based protein assay methods. Examples of 
analytes to be assessed may include but are not limited to factors induced by IFNγ signaling (e.g., 
T cell chemoattractants CXCL9; CXCL10) and other factors generally involved in inflammatory 
processes. Plasma may be used also to assess the presence and/or concentration of anti-tumor 
antibodies using a mulitplex platform such as Invitrogen‟s Protoarray platform(c). Levels of sPD- 
L1 in peripheral blood may also be assessed. 
 
9.10.3.4  Tissue Biopsies and/or archived tissue 
 
The presence of TILs within tumors in response to pembrolizumab treatment will be evaluated at 
baseline and on biopsies or surgical specimens from responder patients . Archived tissue (up to 
20 x 5 m slides) and biopsy tissue may be analyzed using immunohistochemistry for PD-L1 
expression and other immune-related genes, and gene expression (microarray and/or RT- QPCR) 
research platforms. Laser Capture Microdissection may be utilized to enrich specific regions of 
tumor material for use in similar or additional downstream applications, which may include in-situ 
hybridization, flow cytometry, ELISA, and/or assessment of miRNA. In all cases, the goal may be 
to determine the abundance of a battery of immunoregulatory genes or proteins associated with 
cancer cells and/or cancer-interacting lymphocytes derived from biopsied material. Other 
biomarkers may be evaluated as determined by additional data. Remaining specimens may be 
stored for future studies related to ACC immunity. 
 
10.0 
EVALUATION DURING TREATMENT/INTER VENTION 
 
Study Cale ndar 
 
Period 
Screening 
Treatment 
End of 
study 
visit 
Cycle1 
2 
<28 days 
113 
2 
3 
4 
5 
6 
7+ 
Week 
0 
3 
6 
9 
12 
15 
18+ 
Inform ed cons ent 
x 
Medical his tory 
x 
EKG 
x 
CT/MRI3 
x 
x 
x 
x 
Height4 
x 
Phys ical exam ination 
x 
x 
x 
x 
x 
x 
x 
x 
x 

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Vital s igns /Performance s tatus 4 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Report m edications 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Report s ide effects 
x 
x 
x 
x 
x 
x 
x 
CBC5,6 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Com p5,7 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Coagulation s tudies (PT, INR, 
aPTT) 
x 
Thyroid function (TSH, fT3,f T4) 
x 
x 
x 
odd 
cycles 
Hepatitis B and C8 
x 
Pregnancy tes t if fem ale (Serum )9 
x 
Res earch blood tes ts 10 
x 
x 
x 
x 
Obtain archived tiss ue11 
x 
Res earch tumor biops y12 
x 
On therapy if partial or complete res pons e 
Pembrolizum ab 
x 
x 
x 
x 
x 
x 
x 
 
1. 
Each cycle is approximately 3 w eeks in duration, corres ponds to 1 com pleted treatm ent. 
2. 
Procedures mus t be perform ed w ithin 28 days prior to dos e 1 of Pem brolizumab on Day 1. 
3. 
CT or MRI w ill be performed during s creening, then at 9 w eek (±1 w k) intervals and at final visit if m ore than 4 
w eeks from prior imaging. If patient is unable to receive CT contras t or the abdom inal/pelvic target lesion is 
indeterminate on CT then MRI w ith contras t (abdomen and pelvis ) plus CT w ithout contras t (ches t) ma y be 
perform ed. 
4. 
Vital s igns to include heart rate, respiratory rate, blood press ure, and w eight. 
5. 
Blood to be collected prior to dos ing any s tudy m edications . 
6. 
Hem atology to include s tandard com plete blood cell (CBC) panel. 
7. 
Com prehensive m etabolic panel included s odium , potass ium , chloride, bicarbonate, BUN, creatinine, glucose, 
total protein, album in, bilirubin, alkaline phos phatas e, AST, ALT, calcium . 
8. 
Serology for HepBs Ag, HepBcAb and hepatitis C antibody (unless previous ly tes ted negative). 
9. 
Serum pregnancy tes t is required w ithin 72 hours prior to s tarting Pem brolizumab. 
10.  Blood draws for res earch purposes perform ed during s creening or day 1, then w eeks 3, 6 and 9 for the firs t 21 
patients enrolled. 
11.  Up to 20 x 5 m s lides (uns tained) w il be reques ted on all patients for research purposes . 
12.  Res earch tumor biops y w ill be perform ed as bas eline (if archived tissue is not available) and w hile on treatm ent for 
responder patients . 
13.  CBC & Com p m us t be performed on day of firs t treatm ent or w ithin 3 days of Cycle 1 Week 0. 
 
 
11.0 
TOXICITIES/SIDE EFFECTS 
 
The most commonly reported treatment emergent AEs related to pembrolizumab are fatigue 
(43.8%), nausea (26.7%), cough (25.3%), pruritus (24.6%), diarrhea (22.3%) and rash (21.5%). 
Immune-related adverse events were reported in 21.4% of melanoma patients; most of these 
events (15.8%) were considered drug-related by the investigator. The most commonly reported, 
immune-related adverse events across the dose-schedules  are  rash  (3.2%),  pruritus  (2.9%), 
vitiligo  (2.9%),  hypothyroidism (2.7%), arthralgia (2.2%),  diarrhea (2.2%),  and pneumonitis 
(1.9%). 
 
11.1 
SAFETY MONITORING 
Subjects will be evaluated for occurrence of AEs at each visit. Events will be characterized and 
reported as described below. Safety will also be monitored by performing physical exams and 
routine laboratory procedures. 

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11.1.1 Adv erse Events and Se rious Adv erse Events 
Definitions of AEs, non-serious AEs, and serious adverse events (SAEs) are provided in this 
section.  Additionally, provided in the sections below are reporting guidelines for any AE or SAE 
occurring during this study. 
 
De finition of Adverse Event and Non-Serious Adv erse Event 
 
The following definition of AE will be used for the study: “Any untoward medical occurrence in a 
subject 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), symptom, or 
disease temporally associated with the use of a medicinal (investigational) product, whether or not 
related to medicinal (investigational) product.” 
 
This definition includes any abnormalities or anomalies that were not seen at baseline or which 
worsened during the course of the study, if present at baseline. 
 
A “non-serious” adverse event is any event that does not meet the definition of “serious adverse 
event” as presented, below. 
 
Re porting and Treating Non-Serious Events 
 
It is the responsibility of the investigator to perform regular assessments for AEs. Subjects will be 
regularly queried about the occurrence of any AEs and will be monitored throughout the study for 
reactions to study drug and/or study procedures. The investigator and clinical staff will record all 
AEs, whether volunteered by or elicited from the subject, at any time during a subject‟s 
participation in the study. All events occurring prior to the first dosing will be recorded on the 
Medical History page of the CRDB. All AEs occurring at any time after the initiation of the first 
dose of study drug will be recorded on the Adverse Event page of the CRDB. AEs will be 
recorded according to “Common Terminology Criteria for Adverse Events” v4.0 (CTCAE). AEs 
meeting the definition of SAE require additional reporting as described below. 
 
All subjects experiencing an AE will be evaluated by the investigator and monitored until resolution 
of the events or until the investigator deems the event clinically stable and/or at an acceptable 
level. Unless the event requires hospitalization (SAE), medical treatment will be provided to the 
subjects at the unit and treatment medication and/or m edical procedures will be provided per the 
treating-investigator‟s clinical discretion. All clinically significant AEs, including clinically significant 
laboratory abnormalities, will be followed until resolution. SAEs require special reporting in 
addition to documentation in the CRDB as described below. 
 
All AEs, including SAEs, must be recorded in the CRDB. Events occurring prior to initiation of first 
dose should be recorded on the Medical History page of the CRDB. Any AE occurring at initiation 
of first dose and or during any point throughout the study should be recorded on the Adverse 
Event page of the CRDB. AEs should be recorded in the CRDB using the medical terminology 
found in the source documentation. Whenever possible, diagnoses should be given when signs 
and symptoms are due to a common etiology. It is the investigator‟s responsibility to provide 

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his/her assessment of the relationship of the event to the study drug and the severity of the event 
using the following scales: 
 
• 
Relationship 
 
➢   Unrelated: The AE is clearly attributable to a concurrent illness, concurrent medication, clinical 
state, or environmental factor other than the investigative agent. 
 
➢   Unlikely: The occurrence of the AE does not follow the study in a temporal sequence and/or 
based upon available subject information, e.g., medical history, disease process, known 
pharmacology of drug, a relationship between the drug and AE is unlikely. 
 
➢   Possible: The AE follows a reasonable temporal sequence from the time of study drug 
administration, but it is possible that other factors; e.g., subject‟s clinical state or concomitant 
mediations, environmental factors, or the drug‟s pharmacology may have caused the AE. 
 
➢   Probable: The AE follows a reasonable temporal sequence from the time of study drug 
administration, follows a known response pattern of the medication class, and cannot be 
reasonably explained by other factors. 
 
• 
Severity 
 
The severity of all adverse events should be graded according to the Common Terminology 
Criteria for Adverse Events (CTCAE) v4.0. For those adverse events not listed in the CTCAE, the 
following grading system should be employed: 
 
➢   Mild (CTCAE Grade 1): Transient symptoms, awareness of sign/symptom, but easily tolerated 
and no interference with subject‟s daily activities 
 
➢   Moderate (CTCAE Grade 2): Marked signs/symptoms that interfere with subject‟s usual 
activities, but still acceptable 
 
➢   Severe (CTCAE Grade 3): Incapacitating signs/symptoms which cause considerable 
interference with the subject‟s daily activities, unacceptable 
 
➢   Life-threatening (CTCAE Grade 4):  Life-threatening of disabling AE 
 
➢   Death (CTCAE Grade 5):  Death-related AE. See CTCAE Guidelines for assigning Grade 5. 
 
De finition of Serious Adv erse Ev ent 
 
The following definition of SAE applies for the study: “A serious AE means any AE occurring at 
any dose that results in any of the following outcomes: death, a life-threatening AE, inpatient 
hospitalization or prolongation of existing hospitalization, a persistent or significant 
disability/incapacity, a congenital anomaly/birth defect, or overdose of study drug. Important 
medical events that may not result in death, be life threatening, or require hospitalization may be 
considered a serious AE when, based upon appropriate medical judgment, they may jeopardize 
the subject or subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. A life-threatening AE is any AE that places the subject or 

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Approval date: 08-Feb-2019 
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subject, in the view of the investigator, at immediate risk of death from the reaction as it occurred 
(e.g., it does not include a reaction that, had it occurred in a more severe form, might have 
caused death).” Reporting and Treating Serious Adverse Events as per section 17.2. 
 
Pre gnancies 
 
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject (spontaneously 
reported to them) that occurs during the trial. 
 
Pregnancies and lactations that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but not 
limited to washout or discontinuation of usual therapy, diet, placebo treatment or a procedure. 
 
Pregnancies and lactations that occur from the time of treatment allocation/randomization through 
120 days following cessation of Sponsor‟s product, or 30 days following cessation of treatment if 
the subject initiates new anticancer therapy, whichever is earlier, must be reported by the 
investigator.  All reported pregnancies must be followed to the completion/termination of the 
pregnancy. Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform 
mole, blighted ovum, fetal death, intrauterine death, miscarriage and stillbirth must be reported 
as serious events (Important Medical Events). If the pregnancy continues to term, the outcome 
(health of infant) must also be reported. 
 
Such events must be reported within 24 hours to the Sponsor and within 2 working days to Merck 
Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220) 
 
11.1.3 
Othe r Events of Special Interest 
 
He patic Function Abnormality 
 
Hepatic function abnormality is defined as any increase in ALT or AST to greater than 3 × ULN 
and concurrent increase in bilirubin to greater than 2 × ULN. Concurrent findings are those that 
derive from a single blood draw or from separate blood draws taken within 8 days of each other. 
Follow-up investigations and inquiries will be initiated promptly by the investigational site to 
determine whether the findings are reproducible and/or whether there is objective evidence that 
clearly supports causation by a disease (e.g., cholelithiasis and bile duct obstruction with 
distended gallbladder) or an agent other than the investigational product. 
 
Events of hepatic function abnormality (as defined above) should be recorded according to the 
definitions of AE and SAE: 
 
• 
If an event of hepatic function abnormality is considered to be related to a pre-existing 
condition and does not represent a worsening of this condition and/or is considered to be 
within the range of normal physiological fluctuation for the subject, the event does not meet 
the definition of an AE and does not need to be recorded as such. 

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• 
If a definitive diagnosis for an underlying condition unrelated to the investigational product is 
established for an event of hepatic function abnormality, the diagnosis should be recorded as 
an AE/SAE. 
 
• 
If no definitive diagnosis is determined for an event of hepatic function abnormality, the term 
“hepatic function abnormal” should be used to report the AE/SAE. 
 
De finition of an Overdose for This Protocol and Reporting of Ove rdose to Merck 
For purposes of this trial, an overdose of pembrolizumab will be defined as any dose of 1,000 mg 
or greater (≥5 times the indicated dose). No specific information is available on the treatment of 
overdose of pembrolizumab. Appropriate supportive treatment should be provided if clinically 
indicated. In the event of overdose, the subject should be observed closely for signs of toxicity. 
Appropriate supportive treatment should be provided if clinically indicated. 
 
If an adverse event(s) is associated with (“results from”) the overdose of a Merck product, the 
adverse event(s) is reported as a serious adverse event, even if no other seriousness criteria are 
met. 
 
If a dose of Merck‟s product meeting the protocol definition of overdose is taken without any 
associated clinical symptoms or abnormal laboratory results, the overdose is reported as a non- 
serious Event of Clinical Interest (ECI), using the terminology “accidental or intentional overdose 
without adverse effect.” 
 
All reports of overdose with and without an adverse event must be reported within 24 hours to the 
Sponsor and within 2 working days hours to Merck Global Safety. (Attn: Worldwide Product 
Safety; FAX 215 993-1220) 
 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
 
For the purposes of this study, patients will be evaluated for response every 3 cycles 
(approximately 9 weeks), or as clincially indicated if interim toxicity occurs mandating cancer 
staging re-assessment. RECIST v1.1 criteria will be used. 
 
CT scan with contrast of the chest, abdomen, and pelvis 
 
• 
CT scans should be performed with contiguous cuts in slice thickness of 5 mm or less. 
Spiral CT should be performed using a 5-mm contiguous reconstruction algorithm. 
 
MR I scans 
 
• 
MR I of the abdomen and pelvis is acceptable for measurement of lesions provided that the 
same anatomical plane is used for serial assessments. If possible, the same imaging 
device should be used for serial evaluations. In case of MRI, measurements will be 
preferably performed in the axial (transverse) plane on contrast-enhanced T1-weighted 
images. However, there are no specific sequence recommendations. 
 
Measurability of Tumor Le sions 
 
Tumor lesions will be categorized as follows: 

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• 
Measurable Le sions - Must be accurately measured in at least one dimension (longest 
diameter in the plane of measurement is to be recorded) with a minimum size of: 
 
• 
10 mm by CT scan (irrespective of scanner type) and MR I (no less than double the 
slice thickness and a minimum of 10 mm) 
 
• 
10 mm caliper measurement by clinical exam (when superficial) 
 
• 
Malignant lymph nodes are considered pathologically enlarged and measurable, a 
lymph node must be ≥ 15 mm in short axis when assessed by CT scan (CT scan 
slice thickness recommended to be no greater than 5 mm). 
 
• 
Nonme asurable Le sions - Nonmeasurable lesions are defined as all other lesions (or 
sites of disease), including small lesions (longest diameter < 10 mm or pathological lymph 
nodes with ≥ 10 to < 15 mm short axis). Lesions considered truly nonmeasurable include 
the following: leptomeningeal disease, ascites, pleural/pericardial effusion, inflammatory 
breast disease, lymphangitic involvement of skin or lung, abdominal masses/abdominal 
organomegaly identified by physical exam that is not measurable by reproducible imaging 
techniques. 
 
• 
Targe t Le sions - All lesions up to a maximum of 5 lesions total (and a maximum of 2 
lesions per organ) representative of all involved organs should be identified as target 
lesions. It may be the case that, on occasion, the largest lesion does not lend itself to 
reproducible measurement in which circumstance the next largest lesion which can be 
measured reproducibly should be selected. 
 
• 
Non-target Le sions - It is possible to record multiple nontarget lesions involving the same 
organ as a single item on the case record form (e.g., “multiple enlarged pelvic lymph 
nodes” or “multiple liver metastases”) 
 
Re sponse Criteria 
 
Ev aluation of Target Le sions 
 
• 
Comple te Re sponse - Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to < 10 mm (the sum may 
not be “0” if there are target nodes). 
 
• 
Partial Re sponse - At least a 30% decrease in the sum of the diameters of target lesions, 
taking as reference the baseline sum diameters. 
 
• 
Progressive Dise ase - At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more 
new lesions is also considered progression.) 
 
• 
Stable Disease - Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum of diameters while on study. 

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Target Lesion s 
Non-target Lesion s 
New Lesion s 
Overall Respon se 
Com plete response 
Com plete response 
No 
Com plete response 
Com plete response 
Not evaluabl e 
No 
Partial response 
Com plete response 
Non-com plete response / 
non-progressi ve disease 
No 
Partial response 
Partial response 
Non-progressi ve diseas e and 
a 
not evaluable 
No 
Partial response 
Stable diseas e 
Non-progressi ve diseas e and 
a 
not evaluable 
No 
Stable diseas e 
Not all evaluated 
Non-progressi ve diseas e 
No 
Not evaluabl e 
Progressi ve disease 
Any 
Yes/No 
Progressi ve disease 
Any 
Progressi ve disease 
Yes/No 
Progressi ve disease 
Any 
Any 
Yes 
Progressi ve disease 
 
 
 
Ev aluation of Non-target Le sions 
 
• 
Comple te Re sponse - Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (< 10 mm short axis). 
 
• 
Non-complete re sponse/Non-progressive  disease - Persistence of 1 or more non- 
target lesion(s) and/or maintenance of tumor marker level above the normal limits. 
 
• 
Progressive Dise ase - Unequivocal progression of existing non-target lesions will be 
defined as the overall level of substantial worsening in non-target disease such that, even 
in presence of SD or PR in target disease, the overall tumor burden has increased 
sufficiently to merit discontinuation of therapy. In the absence of measurable disease, 
change in non-measurable disease comparable in magnitude to the increase that would 
be required to declare PD for measurable disease. Examples include an increase in a 
pleural effusion from „trace‟ to „large,‟ an increase in lymphangitic disease from localized to 
widespread. 
 
Appe arance of Ne w Le sions 
 
The appearance of new lesions is considered PD according to RECIST v1.1 guidelines. 
Considering the unique response kinetics that have been observed with immunotherapy, new 
lesions may not represent true disease progression. In the absence of rapid clinical deterioration, 
subjects may continue to receive treatment with pembrolizumab. 
 
Ev aluation of Overall Re sponse 
 
Table 12 provides overall responses for all possible combinations of tumor responses in target 
and non-target lesions with or without the appearance of new lesions. 
 
Table 5: Ev aluation of Overall Re sponse 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a Not evaluable is def ined as either w hen no or only a subset of lesion measurements are made at an assessment. 

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13.0 
CRITERIA FOR REMOVAL FROM STUDY 
 
In the absence of serious toxicity or complications, all patients will continue treatment until 
evidence of disease progression, or for up to 24 months, whichever is first. In the absence of 
treatment delays due to adverse event(s), treatment may continue until one of the following 
criteria applies: 
 
• 
Progression of disease. Patients will be allowed to stay on study in the setting of 
progression of disease, if they appear to be deriving clinical benefit, per the PI‟s discretion, 
given the potential for tumor flare. 
• 
24 months of treatment with pembrolizumab. These patients will be eligible to receive an 
additional 12 months of treatment in the future, should they experience disease 
progression at a later date. 
• 
Development of an intercurrent medical condition or need for concomitant treatment that 
precludes further participation in the trial. 
• 
Unacceptable toxicity or any adverse event that precludes further participation in the trial. 
• 
The investigator removes the patient from the trial in the best interests of the patient. 
• 
Patient death. 
• 
Study completion or discontinuation for any reason. 
• 
Patient withdraws consent to continued participation in the trial or is lost to follow up. 
 
Subjects who are permanently discontinued from receiving investigational product will return for 
end of study visit, unless consent is withdrawn, the subject is lost to follow-up or begins another 
treatment. All subjects will be followed for survival by phone every 3 months until death or 
withdrawal of consent. 
 
If consent is withdrawn, the subject will not receive any further investigational product or further 
study observation. 

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14.0    BIOSTATISTICS 
 
Re sponse: The null and alternative overall response rates used to determine the sample size 
calculation as follows: 
 
The primary endpoint of this trial is to assess best overall response rate of pembrolizumab using 
RECIST v1.1 in subjects with unresectable or stage IV ACC. A Simon minimax 2 stage design will 
be employed to test the null hypothesis that the true response rate is ≤ 12% versus the alternative 
hypothesis that the true response rate is at least 29% with type I and II error rates of 10% each. 
In the first stage, 21 patients will be enrolled. If at least 3 out of 21 patients respond (PR or CR) , 
then the study will be expanded to enroll an additional 18 patients for a total of 39 patients . At the 
end of the study, ≥ 8 of 39 tumor responses by RECIST 1.1 are observed, further investigation of 
pembrolizumab will be considered worthwhile. With 39 patients, we anticipate an improvement 
from 12% to 29%.  The probability of early termination is 53%. 
 
ORR of 12% comes from the FIR MACT which is the only randomized study in ACC. In that study, 
ORR in the control arm was 9% versus approximately 20% in the experimental arm, however, the 
rate of serious adverse events on the experimental arm was 58%.  Our patient population in this 
current study includes patients that are untreated and treated with platinum based therapy. For 
that reason, we said that an ORR ≤ 12% would be unworthy of further investigation. [10] 
 
Secondary outcomes, including safety, the additional measures of immune system activation, and 
exploratory objectives will also be summarized. 
 
The study will be complete when all subjects have either completed 24 months of drug therap y, 
progressed, or discontinued from the study for other reasons. The accrual time is estimated to be 
2 years. This study requires accrual of a minimum of 21 subjects and up to a maximum of 39 
subjects if the study is expanded to the second stage. Patients that have been enrolled and then 
deemed ineligible prior to starting treatment may be replaced. 
 
 
 
Antitumor Activ ity 
 
Assessments  of antitumor  activity will be based on ORR. RECIST v1.1   with modifications  to 
account for the unique response patterns observed with immunotherapy will be used to determine 
tumor response.[28] 
 
The ORR is defined as the proportion of subjects with CR or PR based on RECIST criteria. The 
exact 95% CI of ORR will be estimated using the binomial distribution. EFS will be measured from 
the start of treatment with  pembrolizumab  until  the documentation  of disease  recurrence (for 
those patients who proceed to surgical resection after treatment), progression, or death due to 
any cause, whichever occurs first. EFS will be censored on the date of last tumor assessment 
documenting absence of tumor progression for subjects who are still alive prior to data cutoff, 
dropout, or the initiation of alternate anticancer treatment. Subjects having no tumor assessments 

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after  the start  of treatment with  pembrolizumab  will have  EFS censored  on the first date  of 
treatment with pembrolizumab. EFS will be evaluated using the Kaplan-Meier method. OS will be 
determined as the time from the start of treatment with pembrolizumab until death. For subjects 
who are alive at the end of study or lost to follow-up, OS will be censored on the last date when 
subjects are known to be alive. The OS will be evaluated using the Kaplan-Meier method. 
 
Safe ty and Tolerability Analyse s 
 
All recorded adverse events will be listed and tabulated by system organ class, preferred term 
and treatment. Any significant vital signs and clinical laboratory test results will be listed and 
summarized. Any significant physical examination findings, and clinical laboratory results will be 
listed. 
 
Biomarker Analysis 
 
Exploratory research studies that will be done to evaluate the effect of pembrolizumab will be 
performed using research blood draws and tumor biopsies. Research bloods are collected at 
baseline and weeks 3, 6, and 9.  Tumor biopsy is performed at baseline (if archival tissue is not 
available) and in patients where the tumor responds (and at the time of response). 
 
Endpoints from blood tissue -The pharmacodynamic  effect of pembrolizumab on TILs, such as 
CD4+ and CD8+ T-cells, will be assessed by summary statistics, and investigated graphically to 
explore  patterns  of  change.  The  pharmacodynamic  effect  of  pembrolizumab  on markers  in 
peripheral blood, such as   ICOS, HLA-DR, PD-1, CTLA-4; and, serum proteins, such as CXCL9; 
CXCL10, will be assessed by summary statistics, and investigated graphically to explore patter ns 
of change over time, i.e.: pretreatment, then week 3, week 6 and week 9. 
 
In addition,  the relationship  of TIL changes  and tumor  marker  expression  with measures  of 
peripheral blood markers will be summarized descriptively. 
 
Endpoints from biopsy tissue - Expression of tumor markers PD-L1, from pre-treatment to post- 
treatment biopsy specimens will also be assessed by summary statistics in those patients that 
achieve a response to therapy and either ha ve a resection or consent to a biopsy 
 
Associations between the markers and response by RECIST will be explored. 
 
Fisher‟s exact test will be employed to assess associations between categorical variables while 
Spearman's rank correlation will be used for continuous variables. Wilcoxon signed rank test will 
be used to test for differences in continuous expression tumor markers between pre- and post- 
treatment specimens while McNemar‟s test will be used to assess these relationships for bin ary 
markers. 
 
 
15.0     RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
 
15.1 
Re search Participant Re gistration 
 
Confirm eligibility as defined in the section entitled Criteria for Patient/Subject Eligibility. 

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Obtain informed consent, by following procedures defined in section entitled Informed 
Consent Procedures. 
 
During the registration process registering individuals will be required to complete a 
protocol specific Eligibility Checklist. 
 
All participants must be registered through the Protocol Participant Registration (PPR) 
Office at Memorial Sloan Kettering Cancer Center. PPR is available Monday through 
Friday from 8:30am – 5:30pm at 646-735-8000. Registrations must be submitted via the 
PPR Electronic Registration System (http://ppr/).  The completed signature page of the 
written consent/RA or verbal script/RA, a completed Eligibility Checklist and other relevant 
documents must be uploaded via the PPR Electronic Registration System. 
 
15.2    Randomization 
 
Not applicable. 
 
16.0 
DAT A M AN AGEMENT ISSUES 
 
A Research Study Assistant (RSA) will be assigned to the study. The responsibilities  of 
the RSA include project compliance, data collection, abstraction and entry, data reporting, 
regulatory monitoring, problem resolution and prioritization, and coordinate the activities of 
the protocol study team. 
 
The data collected for this study will be entered into a secure database (Clinical Research 
Database, CRDB). Source documentation will be available to support the computerized 
patient record. 
 
16.1    Quality Assurance 
 
Weekly registration  reports  will be generated  to monitor  patient accruals  and 
completeness of registration data. Routine data quality reports will be generated to assess 
missing data and inconsistencies. Accrual rates and extent, and accuracy of evaluations 
and follow-up will be monitored periodically throughout the study period and potential 
problems will be brought to the attention of the study team for discussion and action. 
 
Random-sample  data quality and protocol compliance audits  will be conducted by t he 
study team, at a minimum of two times per year, more frequently if indicated. 
 
16.2    Data and Safety Monitoring 
 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan Kettering Cancer Center 
were approved by the National Cancer Institute in September 2001. The plans address the 
new policies set forth by the NC I in the document entitled “Policy of the National Cancer 
Institute for Data and Safety Monitoring of Clinical Trials” which can be found at: 
http://cancertrials.nci.nih.gov/researchers/dsm/index.html.  The  DSM  Plans  at  MSKCC 
were established and are monitored by the Office of Clinical Research. The MSKCC Data 
and    Safety    Monitoring    Plans    can    be    found    on    the    MSKCC    Intranet    at: 

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http://mskweb5.mskcc.org/intranet/_assets/_tables/content/359689/Data_safety%20Monit 
oring07.pdf 
 
There are several different mechanisms  by which clinical trials are monitored for data, 
safety and quality. There are institutional processes in place for quality assurance (e.g., 
protocol monitoring,  compliance and data verification audits, therapeutic  response, and 
staff education on clinical research QA) and departmental procedures for quality control, 
and there are two institutional committees that are responsible for monitoring the activities 
of our clinical trials programs. The committees:  Data and Safety Monitoring Committee 
(DSMC)  for  Phase  I and  II clinical  trials,  and the  Data  and Safety  Monitoring  Board 
(DSMB)  for  Phase  III  clinical  trials,  report  to  the  Center‟s  Research  Council  and 
Institutional Review Board. 
 
During the protocol development and review process, each protocol will be assessed for 
its level of risk and degree of monitoring required. Every type of protocol (e.g., NIH 
sponsored, in-house sponsored, industrial sponsored, NCI cooperative group, etc.) will be 
addressed and the monitoring procedures will be established at the time of protocol 
activation. 

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17.0 
PROTECTION OF HUMAN SUBJECTS 
 
All the patients will be required to sign an IRB-approved informed consent and will have all 
their questions fully addressed before enrolling in the study. During informed consent, it will 
be made clear to the patient that participation is voluntary. All the data will be confidential, 
maintained in a password protected electronic database and will comply with all HIPAA 
guidelines. 
 
Benefits: It is possible that this treatment will result in shrinkage of ACC or in a stabilization of 
an otherwise progressing disease. It is not known, of course, whether these or any other 
favorable events will occur. 
 
Costs: The patient will be responsible for the costs of standard medical care, including, CT or 
MR I scans, all drug administration  fees and all hospitalizations,  even for complications  of 
treatment. Pembrolizumab will be supplied to patients by Merck at no cost. Patients will not 
be responsible for the costs of blood procurement obtained for research purposes or the cost 
for obtaining the tumor biopsy for research purposes. 
Incentives: No incentives will be offered to patients/subjects for participation in the study. 
Alternatives/options  for treatment: Patients may be eligible for other investigational studies, 
standard treatment options, or focus on palliative care options. 
 
Confidentiality: Every effort will be made to maintain patient confidentiality. Research and 
hospital  records   are  confidential.   Patient‟s   name  or  any  other  personally  identifying 
information will not be used in reports or publications resulting from this study. The Food and 
Drug  Administration  or  other  authorized  agencies  (e.g.,  qualified  monitors ) may  review 
patients‟ records and pathology slides, as required. 
 
17.1    Priv acy 
 
MSK‟s Privacy Office may allow the use and disclosure of protected health information 
pursuant to a completed and signed Research Authorization form. The use and disclosure of 
protected health information will be limited to the individuals described in the Research 
Authorization form. A Research Authorization form must be completed by the Principal 
Investigator and approved by the IRB and Privacy Board (IRB/PB). 
 
17.2    Se rious Adverse Event (SAE) Re porting 
 
An adverse event is considered serious if it results in ANY of the following outcomes: 
•    Death 
•    A life-threatening adverse event 
• 
An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization 

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• 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• 
A congenital anomaly/birth defect 
• 
Important Medical Events (IME) that may not result in death, be life threatening, or 
require hospitalization may be considered serious when, based upon medical judgment, 
they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition 
Note: Hospital admission for a planned procedure/disease treatment is not considered an 
SAE. 
 
 
SAE reporting is required as soon as the participant signs consent.  SAE reporting is 
required for 30-days after the participant‟s last investigational treatment or intervention. Any 
events that occur after the 30-day period and that are at least possibly related to protocol 
treatment must be reported. 
 
If an SAE requires submission to the IRB office per IRB SOP RR-408 „Reporting of Serious 
Adverse Events‟, the SAE report must be sent to the IRB within 5 calendar days of the event. 
The IRB requires a Clinical Research Database (CRDB) SAE report be submitted 
electronically to the SAE Office as follows: 
 
For IND/IDE trials: Reports that include a Grade 5 SAE should be sent to 
saegrade5@mskcc.org.  All other reports should be sent to saemskind@mskcc.org. 
  
For all other trials: Reports that include a Grade 5 SAE should be sent to 
saegrade5@mskcc.org.  All other reports should be sent to sae@mskcc.org. 
 
The report should contain the following information: 
Fields populated from CRDB: 
• 
Subject‟s initials 
• 
Medical record number 
• 
Disease/histology (if applicable) 
• 
Protocol number and title 
 
Data needing to be entered: 
 
• 
The date the adverse event occurred 
• 
The adverse event 
• 
The grade of the event 
• 
Relationship of the adverse event to the treatment (drug, device, or intervention) 
• 
If the AE was expected 
• 
The severity of the AE 
• 
The intervention 
• 
Detailed text that includes the following 

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o A explanation of how the AE was handled 
o A description of the subject‟s condition 
o Indication if the subject remains on the study 
• 
If an amendment will need to be made to the protocol and/or consent form 
• 
If the SAE is an Unanticipated Problem 
 
The PI‟s signature and the date it was signed are required on the completed report. 
  
 
 
17.2.1  For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any serious adverse event, or follow up to a serious adverse event, 
including death due to any cause other than progression of the cancer under study that occurs to 
any subject must be reported within 24 hours to the Sponsor and within 2 working days to Merck 
Global Safety if it causes the subject to be excluded from the trial, or is the result of a protocol- 
specified intervention, including but not limited to washout or discontinuation of usual therapy, diet, 
placebo treatment or a procedure. 
 
For the time period beginning at treatment allocation/randomization through 90 days following 
cessation of treatment, or 30 days following cessation of treatment if the subject initiates new 
anticancer therapy, whichever is earlier, any serious adverse event, or follow up to a serious 
adverse event, including death due to any cause other than progression of the cancer under study 
whether or not related to the Merck product, must be reported within 24 hours to the Sponsor and 
within 2 working days to Merck Global Safety. 
 
Additionally, any serious adverse event, considered by an investigator who is a qualified physician to 
be related to Merck product that is brought to the attention of the investigator at any time following 
consent through the end of the specified safety follow-up period specified in the paragraph above, or 
at any time outside of the time period specified in the previous paragraph also must be reported 
immediately to the Sponsor and to Merck Global Safety. 
 
All subjects with serious adverse events must be followed up for outcome. 
  
SAE re ports and any other relevant safety information are to be forwarded to the Merck Global 
Safe ty 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 (PMD A) 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. 
 
Eve nts of Clinical Interest 
 
Selected non-serious and serious adverse events are also known as Events of Clinical Interest (ECI) 
and must be reported within 24 hours to the Sponsor and within 2 working days to Merck Global 
Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220). 

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For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any EC I, or follow up to an ECI, that occurs to any subject must be 
reported within 24 hours to the Sponsor and within 2 working days to Merck Global Safety if it 
causes the subject to be excluded from the trial, or is the result of a protocol-specified intervention, 
including but not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure. 
 
For the time period beginning at treatment allocation/randomization through 90 days following 
cessation of treatment, or 30 days following cessation of treatment if the subject initiates new 
anticancer therapy, whichever is earlier, any EC I, or follow up to an ECI, whether or not related to 
Merck product, must be reported within 24 hours to the Sponsor and within 24 hours to Merck Global 
Safety. 
 
Events of clinical interest for this trial include: 
 
1. an overdose of Merck product, as defined in Section 11.1.3 - 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.* 
 
*Note:  These criteria are based upon available regulatory guidance documents. The purpose of the 
criteria is to specify a threshold of abnormal hepatic tests that may require an additional evaluation 
for an underlying etiology. 
 
 
 
18.0 
INFORMED CONSENT PROCEDURES 
 
Before protocol-specified procedures are carried out, consenting professionals will explain full 
details of the protocol and study procedures as well as the risks involved to participants prior 
to their inclusion in the study. Participants will also be informed that they are free to withdraw 
from the study at any time. All p articipants must sign an IRB/PB-approved consent form 
indicating their consent to participate. This consent form meets the requirements of the Code 
of Federal Regulations and the Institutional Review Board/Privacy Board of this Center. The 
consent form will include the following: 
 
1.  The nature and objectives, potential risks and benefits of the intended study. 
2.  The length of study and the likely follow-up required. 
3.  Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of supportive 
care for therapeutic studies.) 
4.  The name of the investigator(s) responsible for the protocol. 
5.  The right of the participant to accept or refuse study interventions/interactions and to 
withdraw from participation at any time. 

Memorial Sloan Kettering Cancer Center
IRB Number: 15-286 A(11) 
Approval date: 08-Feb-2019 
Page 44 of 45
 
 
 
 
 
Before any protocol-specific procedures can be carried out, the consenting professional will 
fully explain the aspects of patient privacy concerning research specific information.  In 
addition to signing the IRB Informed Consent, all patients must agree to the Research 
Authorization component of the informed consent form. 
 
Each participant and consenting professional will sign the consent form. The participant must 
receive a copy of the signed informed consent form. 
 
 
19.0 
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Memorial Sloan Kettering Cancer Center
IRB Number: 15-286 A(11) 
Approval date: 08-Feb-2019 
Page 45 of 45
 
 
 
 
 
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20.0 
APPENDICES 
 
Appendix A: Investigator‟s Brochure