Clinical trial NCT02316002
Conditions: Oligometastatic Non-small Cell Lung Cancer (NSCLC)
Sponsor: Abramson Cancer Center at Penn Medicine
Start date: 2015-01-21; Completion date: 2022-12-01
Enrollment: 51 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The main purpose of this study is to see how well the experimental drug pembrolizumab (MK-3475) works in people with oligometastatic NSCLC who have already had treatment for their disease. All patients will receive 200 mg of pembrolizumab intravenously on Day 1 of each 21-day cycle. Patients will receive the study drug for up to 8 cycles, and then if their disease is doing well and the study doctor thinks they will benefit patients may receive pembrolizumab for up to 8 more cycles.

Detailed description:

Arms: arm 1: Pembrolizumab 200 mg every 3 weeks
Interventions: intervention 1: Pembrolizumab
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_SAP_000.pdf: 
Protocol/Amendment No 7: 03/06/2019 
1 
 
  
 
 
 
CLINICAL RESEARCH PROTOCOL 
 
 
 
Phase II Study of Pembrolizumab after Curative Intent 
Treatment for Oligometastatic Non-Small Cell Lung Cancer 
 
 
Regulatory Sponsor: 
Joshua Bauml, MD 
Hospital of the University of Pennsylvania 
19 Penn Tower 
Philadelphia, Pennsylvania 19104 
Phone: 215-614-1858 
Fax: 215-615-5888 
Email: Joshua.bauml@uphs.upenn.edu 
 
Funding Sponsor: 
 
 
 
  
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., 
Inc. 
One Merck Drive 
P.O. Box 100 
Whitehouse Station, NJ 08889-0100 
 
Statistician:  
Biostatistics Core Facility of the Abramson Cancer Center. 
 
Study Product: 
Pembrolizumab (MK-3475) 
 
Protocol Number: 
 
UPCC 25514 
 
 
Medical Monitor: 
Dr. Dan Vogl 
 
Initial version:  
08/26/2014 
Amendment 1: 
09/19/2014 
Amendment 2:  
10/30/2015 
Amendment 3: 
10/28/2016 
Amendment 4: 
04/27/2017 
Amendment 5: 
06/14/2017 
Amendment 6: 
01/08/2018 
Amendment 7:                   03/06/2019 
 


Product:  Pembrolizumab 
UPCC 25514 (IRB #820987) 
Pembrolizumab in Oligometastatic NSCLC 
 
 
Protocol/Amendment No 7: 03/06/2019 
2 
 
1.0 TRIAL SUMMARY 
Abbreviated Title 
Pembrolizumab in Oligometastatic NSCLC 
Trial Phase 
Phase II 
Clinical Indication 
The treatment of patients with oligometastatic non-small cell 
lung cancer (NSCLC), after treatment with definitive intent to 
all identifiable sites of disease. 
Trial Type 
Interventional 
Type of control 
Single arm – no control  
Route of administration 
Intravenous 
Trial Blinding 
Open-label 
Treatment Groups  
Pembrolizumab 200 mg every 3 weeks 
Number of trial subjects 
47 patients will be enrolled 
Estimated duration of trial The trial will require up to 60 months from the time the first 
subject signs informed consent until the last subject’s last 
visit. 
Duration of Participation 
Each subject will participate in the trial from the time the 
subject signs the Informed Consent Form (ICF) through the 
final protocol-specified contact.  Within 4-12 weeks of 
completing treatment with definitive intent, eligible subjects 
will receive assigned treatment on Day 1 of each 3-week 
(Q3W) dosing cycle.  Treatment with Pembrolizumab will 
continue for up to 6 months or 8 cycles (24 weeks) in the 
absence of documented disease progression, unacceptable 
adverse event(s), intercurrent illness precluding further 
administration of treatment, investigator’s decision to 
withdraw the subject, subject withdrawal of consent, 
pregnancy of the subject, noncompliance with trial treatment 
or procedure requirements, or administrative reasons. 
Patients with no evidence of disease progression at 6 
months may receive an additional 6 months of therapy with 
Pembrolizumab, at the discretion of the treating oncologist.  
After the end of treatment, each subject will be followed for 
a minimum of 30 days for adverse event monitoring (serious 
adverse events will be collected for up to 90 days after the 
end of treatment). Subjects will have post-treatment follow-
up for disease status for 5 years or until one of the following 
events: (1) disease progression; (2) initiation of non-study 
cancer treatment; (3) withdrawal of study consent; (4) loss 
to follow-up or (5) death.  In addition, survival status beyond 
PD or subsequent therapies will be documented. 
 


Product:  Pembrolizumab 
UPCC 25514 (IRB #820987) 
Pembrolizumab in Oligometastatic NSCLC 
 
 
Protocol/Amendment No 7: 03/06/2019 
3 
 
2.0 TRIAL DESIGN 
2.1 
Trial Design 
This is a single-arm Phase II trial of intravenous (IV) Pembrolizumab (MK-3475) in subjects 
with oligometastatic non-small cell lung cancer (NSCLC) who have completed treatment with 
definitive intent to all identifiable sites of tumor. Forty-two subjects will be enrolled in this trial 
to examine the efficacy of adding Pembrolizumab to the treatment regimen for patients with 
oligometastatic NSCLC being treated with definitive intent. Within 4-12 weeks after 
completion of treatment with definitive intent, subjects will receive Pembrolizumab at a fixed 
dose of 200 mg every 3 weeks (q3W). 
Subjects will be evaluated every 12 weeks (84 ± 7 days) with radiographic imaging to 
assess disease status.  If new signs or symptoms of progression occur between scheduled 
scans, directed imaging will be obtained at the clinically appropriate time point to document 
disease status.  Investigators will make all treatment-based decisions using RECIST 1.1. 
Adverse events will be monitored throughout the trial and graded in severity according to the 
NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. 
Treatment with Pembrolizumab will continue for a minimum of six months in the absence of 
(1) documented disease progression, (2) unacceptable adverse event(s), (3) intercurrent 
illness that prevents further administration of treatment, (4) investigator’s decision to withdraw 
the subject, (5) subject withdrawal of consent, (6) pregnancy of the subject, (7) noncompliance 
with trial treatment or procedure requirements, (8) institution of alternative systemic treatment, 
or (9) other administrative reasons. In the absence of disease progression, patients who have 
received 6 months of treatment may go on to receive an additional 6 months of therapy with 
Pembrolizumab, at the discretion of the treating oncologist. 
After the end of treatment, each subject will be followed for a minimum of 30 days for 
adverse event monitoring (serious adverse events will be collected for up to 90 days after 
the end of treatment). Subjects will have post-treatment follow-up for disease status until 
one of the following events: (1) disease progression; (2) initiation of non-study cancer 
treatment; (3) withdrawal of study consent; (4) loss to follow-up or (5) death.  In addition, 
survival status beyond the establishment of PD or initiation of subsequent therapies will be 
documented, as will all documented post-progression therapy.  The primary objectives of the 
trial include determination of PFS per RECIST 1.1 and safety as assessed by a variety of 
parameters of adverse events (AEs), including incidence and time to first Grade 3-5 AE. 
Pre-specified adverse events of clinical interest include the following events: 1) Grade ≥ 3 
diarrhea 2) Grade ≥ 2 colitis, 3) Grade ≥ 2 pneumonitis, 4) Grade ≥ 3 hypo- or 
hyperthyroidism, 5) Grade ≥ 2 hypophysitis, 6) Grade ≥ 2 uveitis, and 7) Grade ≥ 2 nephritis. 
Secondary objectives include Overall Survival and health-related quality-of-life. 
Participation in this trial will require supplying tumor tissue from either a newly obtained 
formalin-fixed specimen (preferred) or an older formalin-fixed, paraffin-embedded specimen, 
from locations not radiated prior to biopsy. The specimen will be evaluated at a central 
laboratory facility for expression status of PD-L1 in a retrospective manner. Eligibility for the 
trial will not be dependent upon PD-L1 expression status, but the sponsor may amend the 
trial in the future if new data arise regarding the predictive value of PD-L1 expression.  Any 
patient enrolled on the study prior to such an amendment, however, will remain on study. 
 


Product:  Pembrolizumab 
UPCC 25514 (IRB #820987) 
Pembrolizumab in Oligometastatic NSCLC 
 
 
Protocol/Amendment No 7: 03/06/2019 
4 
 
3.0 OBJECTIVE(S) & HYPOTHESIS(ES) 
3.1 
Primary Objectives & Hypotheses 
1) Objective: To evaluate the progression free survival of patients with oligometastatic 
NSCLC who are treated with Pembrolizumab after therapy with definitive intent 
Hypothesis 1: Patients treated with Pembrolizumab after definitive treatment for 
oligometastatic NSCLC will have an increased median progression free survival, as 
measured by RECIST 1.1. 
Exploratory Hypothesis: Patients treated with Pembrolizumab after definitive 
treatment for oligometastatic NSCLC will have an increased median progression free 
survival, as measured by immune related response criteria (irRC). 
Note:  The inclusion of both RECIST and irRC measures in this objective indicates 
the equipoise in the research community regarding the most appropriate measure of 
PFS in patients receiving immunotherapy.  Primary analysis is planned based upon 
RECIST criteria, but we will also monitor irRC closely. 
2) Objective: To evaluate toxicities (CTCAE v4.0 scoring) of Pembrolizumab in patients 
with oligometastatic NSCLC after therapy with definitive intent 
Hypothesis: Pembrolizumab will be well tolerated in patients with oligometastatic 
NSCLC after therapy with definitive intent 
3.2 
Secondary Objective(s) & Hypothesis(es) 
1) Objective: To assess the longitudinal effect of Pembrolizumab on quality of life when 
used after definitive treatment for oligometastatic NSCLC. 
Hypothesis: Patients treated with Pembrolizumab after definitive treatment for 
oligometastatic NSCLC will not have a significant decrement in quality of life 
compared to baseline, as measured by the FACT-L instrument. 
2) Objective: To evaluate overall survival of patients with oligometastatic NSCLC who 
are treated with Pembrolizumab after therapy with definitive intent. 
Hypothesis: Overall survival will be determined from the time Pembrolizumab is first 
initiated, which will be pivotal in the design of future phase II and III trials. 
3.3 
Exploratory Objectives 
Objective: To evaluate the PFS and OS as a function of PD-L1 expression, as well as other 
emerging indices of benefit. 
 


Product:  Pembrolizumab 
UPCC 25514 (IRB #820987) 
Pembrolizumab in Oligometastatic NSCLC 
 
 
Protocol/Amendment No 7: 03/06/2019 
5 
 
4.0 BACKGROUND & RATIONALE 
4.1 
Background 
4.1.1 
Pharmaceutical and Therapeutic Background 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades [1].  Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies [2-6].  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 between tumor cells and the immune system is a major 
pathway hijacked by tumors to suppress immune control.  The normal function of PD-1, 
expressed on the cell surface of activated T-cells under healthy conditions, is to down-modulate 
unwanted or excessive immune responses, including autoimmune reactions.  PD-1 (encoded by 
the gene Pdcd1) is an Ig superfamily member related to CD28 and CTLA-4 which has been 
shown to negatively regulate antigen receptor signaling upon engagement of its ligands (PD-L1 
and/or PD-L2) [7, 8].  The structure of murine PD-1 has been resolved.[9]  PD-1 and family 
members are type I transmembrane glycoproteins containing an Ig Variable-type (V-type) 
domain responsible for ligand binding and a cytoplasmic tail which is responsible for the binding 
of signaling molecules.  The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, 
an immunoreceptor tyrosine-based inhibition motif (ITIM) and an immunoreceptor tyrosine-based 
switch motif (ITSM).  Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases SHP-
1 and SHP-2 to the ITSM motif within its cytoplasmic tail, leading to the dephosphorylation of 
effector molecules such as CD3ζ, PKCθ and ZAP70 which are involved in the CD3 T-cell 
signaling cascade [10-13].  The mechanism by which PD-1 down modulates T-cell responses is 
similar to, but distinct from that of CTLA-4 as both molecules regulate an overlapping set of 
signaling proteins [14, 15].  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 [16, 17].  Expression 
has also been shown during thymic development on CD4-CD8- (double negative) T-cells as well 
as subsets of macrophages and dendritic cells [17].  The ligands for PD-1 (PD-L1 and PD-L2) 
are constitutively expressed or can be induced in a variety of cell types, including non-
hematopoietic tissues as well as in various tumors [14, 18-20].  Both ligands are type I 
transmembrane receptors containing both IgV- and IgC-like domains in the extracellular region 
and contain short cytoplasmic regions with no known signaling motifs.  Binding of either PD-1 
ligand to PD-1 inhibits T-cell activation triggered through the T-cell receptor.  PD-L1 is expressed 
at low levels on various non-hematopoietic tissues, most notably on vascular endothelium, 
whereas PD-L2 protein is only detectably expressed on antigen-presenting cells found in 
lymphoid tissue or chronic inflammatory environments.  PD-L2 is thought to control immune T-
cell activation in lymphoid organs, whereas PD-L1 serves to dampen unwarranted T-cell function 
in peripheral tissues.[14] Although healthy organs express little (if any) PD-L1, a variety of 
cancers have been demonstrated to express abundant levels of this T-cell inhibitor.  PD-1 has 
been suggested to regulate tumor-specific T-cell expansion in subjects with melanoma 
(MEL).[21] 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 and 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. 


Product:  Pembrolizumab 
UPCC 25514 (IRB #820987) 
Pembrolizumab in Oligometastatic NSCLC 
 
 
Protocol/Amendment No 7: 03/06/2019 
6 
 
4.1.2 
Preclinical and Clinical Trial Data 
Refer to the Investigator’s Brochure for Preclinical and Clinical data. 
4.2 
Rationale 
4.2.1 
Rationale for the Trial and Selected Subject Population 
NSCLC is the most common cause of cancer death in the United States. Almost half of 
patients present with metastatic disease at diagnosis, and are considered incurable with a 
historical median overall survival of 6 to 12 months.[22] Recent research, however, has 
revealed significant heterogeneity among patients with metastatic NSCLC.  Patients with a 
targetable mutation detected by advanced molecular techniques can enjoy a much longer 
disease free interval compared to the overall population, if treated with appropriate therapy.  
In addition, approximately 7% of patients with NSCLC present with a solitary site of 
metastatic disease or later develop solitary sites of progression.  In the past, such patents 
were generally considered incurable and treated with palliative chemotherapy and radiation 
therapy.[23] This conventional approach was based, in part, upon the Halstead theory of 
cancer progression, which holds that cancer spreads in an orderly fashion through the 
lymphatic system.  Based upon this theory, which was first published in 1894, once a cancer 
metastasized, it became a systemic disease and cure was impossible.[24] Exposing patients 
with metastatic disease to the toxicities of definitive intent surgical and radiation treatments, 
with this rationale, could not be justified. 
More recently, Hellman and Weichselbaum put forth a theory that the timing of cancer 
metastasis falls on a continuum.  While some malignancies spread contiguously and others 
are systemic from diagnosis, most malignancies fall on a spectrum between these two 
extremes.  This concept appears valid on the surface given our clinical observations in 
which we see some patients with a localized tumor fare poorly while others with 
disseminated metastases live for a prolonged time.  Recent molecular analyses revealing 
heterogeneity between primary and metastatic lesions support this contemporary theory.  
One hypothesis that links this theory to our clinical observation is that a “second hit” must 
happen to the malignant cells to allow metastasis.  An accumulation of additional “hits” can 
then allow a cancer cell to go from localized to oligometastatic to uncontrolled metastatic 
behavior.  With this newer paradigm, the concept of treating some metastatic lesions 
aggressively is increasingly justified, as their mere presence no longer de facto rules out 
therapy with curative intent.  The advent of minimally invasive surgery and stereotactic body 
radiotherapy (SBRT) has made such treatments feasible with less toxicity.  This approach 
has already become standard of care for some patients with metastatic colorectal cancer 
with isolated or limited hepatic metastases, and has been extended to other malignancies 
such as breast cancer. Multiple retrospective studies now show that this approach in 
selected patients with lung cancer is associated with a significant improvement in overall 
and progression free survival when compared to historical controls.[23, 25, 26]. 
With limited formal data [27], this approach has been used for many years in NSCLC 
patients with isolated adrenal or CNS metastases, where long-term survival has been 
observed. Indeed, in some series the number of metastatic sites was more strongly 
prognostic than the presence of extrathoracic disease itself.[28] Based upon these and other 
data, patients with a small number of metastases are often treated definitively to their 
primary tumor and metastatic site, rendering them radiographically free of disease.  This 
approach has recently been endorsed by the ESMO clinical practice guidelines. 


Product:  Pembrolizumab 
UPCC 25514 (IRB #820987) 
Pembrolizumab in Oligometastatic NSCLC 
 
 
Protocol/Amendment No 7: 03/06/2019 
7 
 
It is unclear, however, whether these patients should receive systemic therapy after completion 
of definitive treatment to metastatic lesions. There are no data to guide the use of cytotoxic 
chemotherapy in this setting.  In colorectal cancer, where the treatment of oligometastatic 
disease with curative intent is more established, there is no overall survival benefit for the use of 
perioperative chemotherapy in the oligometastatic setting.[29] The current standard of care for 
metastatic lung cancer involves the use of platinum doublet chemotherapy followed by 
consideration of maintenance chemotherapy.  This approach has been validated for patients 
with clinically evaluable metastatic disease in whom cure is not possible, but has questionable 
validity in patients where all evident disease has been definitively removed or ablated. In 
retrospective analyses of patients with oligometastatic NSCLC treated with definitive intent, very 
few received subsequent chemotherapy and its use has never been documented to improve 
overall survival or progression free survival.  Median overall survival in this group is 
approximately 20 months, with a progression free survival of approximately 6.6 months.[23] 
NSCLC has historically been considered non-responsive to immunotherapy, but recent 
advances using monoclonal antibodies targeting the Programmed Death 1 (PD-1) pathway has 
yielded some impressive clinical responses using agents that are reasonably well tolerated.  
Single agent response rates in heavily pre-treated patients approach 20 to 25%, and those 
figures appear to be even higher in patients whose tumors express PDL1 or in patients without 
pretreatment. (Garon, et al, ASCO 2014 Abstracts 8007 and 8020).  Many of the responses 
seen with targeting of the PD-1 pathway are quite durable. The use of such  agents might be 
ideal in patients with oligometastatic disease, since the overall burden of disease is low, patients 
have recently completed a definitive treatment modality that may be associated with antigen 
release, and patients will generally be fit and able to tolerate therapy. This study aims to assess 
the feasibility of administering Pembrolizumab, a humanized monoclonal antibody binding PD-1, 
in patients with solitary and oligometastatic NSCLC who have undergone treatment with 
definitive intent and are technically cancer-free or at least free from “active disease.” 
4.2.2 
Rationale for Dose Selection/Regimen/Modification 
An open-label Phase I trial (Protocol 001) evaluating Pembrolizumab at 1 mg/kg, 3 mg/kg, and 
10 mg/kg, administered every 2 weeks (Q2W) revealed no dose-limiting toxicities and showed 
objective evidence of tumor size reduction at all dose levels. Recent data from other clinical 
studies in the Pembrolizumab program have shown that a lower dose of Pembrolizumab and a 
less frequent schedule may be sufficient for target engagement and clinical activity. 
A population pharmacokinetic analysis has been performed using serum concentration time 
data from 476 patients. Within the resulting population PK model, clearance and volume 
parameters of Pembrolizumab were found to be dependent on body weight. The relationship 
between clearance and body weight, with an allometric exponent of 0.59, is within the range 
observed for other antibodies and would support both body weight normalized dosing or a 
fixed dose across all body weights. Pembrolizumab has been found to have a wide 
therapeutic range based on the melanoma indication. The differences in exposure for a 200 
mg fixed dose regimen relative to a 2 mg/kg Q3W body weight based regimen are 
anticipated to remain well within the established exposure margins of 0.5 – 5.0 for 
Pembrolizumab in the melanoma indication. The exposure margins are based on the notion 
of similar efficacy and safety in melanoma at 10 mg/kg Q3W vs. the proposed dose regimen 
of 2 mg/kg Q3W (i.e. 5-fold higher dose and exposure). The population PK evaluation 
revealed that there was no significant impact of tumor burden on exposure. In addition, 
exposure was similar between the NSCLC and melanoma indications. Therefore, there are 
no anticipated changes in exposure between different indication settings. 


Product:  Pembrolizumab 
UPCC 25514 (IRB #820987) 
Pembrolizumab in Oligometastatic NSCLC 
 
 
Protocol/Amendment No 7: 03/06/2019 
8 
 
4.2.3 
Rationale for Endpoints 
4.2.3.1 Efficacy Endpoints 
4.2.3.1.1 Primary 
Progression free survival (PFS), defined as the time from initiation of Pembrolizumab to 
documented disease progression, death due to any cause or last patient follow-up that 
documented lack of disease progression, is an acceptable scientific endpoint in the single-arm 
evaluation of novel treatment in a population that is expected to have a longer overall survival 
than would be expected from the general population of patients with metastatic NSCLC.  In 
this case, patients with oligometastatic NSCLC are known to have significantly longer overall 
survival than patients with widely metastatic NSCLC.  The choice of PFS is appropriate 
because a recurrence would indicate failure of the therapeutic approach to the patient. 
4.2.3.1.2 Secondary 
When adding systemic therapy in the definitive setting for oligometastatic disease, we are 
adding therapy with potential side effects to a time period often not associated with active 
therapy.  As such, it is essential for us to monitor quality of life throughout the course of 
therapy.  This will help determine if this treatment regimen is feasible when implemented 
widely.  To do this, we will utilize prospective FACT-L scores.  This extensively validated 
instrument incorporates the general FACT quality of life measure and also includes a 
subscale to identifying issues unique to patients with lung cancer.[30] 
5.0 METHODOLOGY 
5.1 
Entry Criteria 
5.1.1 
Diagnosis/Condition for Entry into the Trial 
Male/female patients with oligometastatic NSCLC (defined as ≤4 metastatic sites of 
disease), all treated with definitive intent using radiation, surgery, RFA, chemoradiation 
therapy, other definitive modalities or combinations of these. 
5.1.2 
Subject Inclusion Criteria 
In order to be eligible for participation in this trial, the subject must fulfill the following criteria: 
1. Provide written informed consent for the trial. 
2.   18 years of age on day of signing informed consent. 
3. Completion of definitive therapy 4-12 weeks prior to enrollment.  There are no 
specific limitations on which treatment modalities can be used in the definitive setting 
(e.g. the use of adjuvant chemotherapy is acceptable), but all other treatments must 
be complete at least 4 weeks prior to enrollment. 
4. Provision of tissue from an archival tissue sample or newly obtained core or 
excisional biopsy of a tumor lesion. 
a. Tumor tissue may be from a diagnostic biopsy or a portion of a surgical 
specimen, if surgery is a component of definitive intent therapy. 


Product:  Pembrolizumab 
UPCC 25514 (IRB #820987) 
Pembrolizumab in Oligometastatic NSCLC 
 
 
Protocol/Amendment No 7: 03/06/2019 
9 
 
b. Formalin fixed paraffin embedded (FFPE) tissue samples are acceptable; a fine 
needle aspirate, frozen sample, plastic embedded sample, cell block, clot, bone, 
bone marrow or cytologic specimen will not be acceptable for IHC analysis. 
c. It is recommended that FFPE blocks be sectioned fresh (within 7 days of 
sectioning and sending for PD-L1 analysis) onto positively charged slides. 
d. Recommended fixation time for samples is 24 hours to 48 hours in 10% neutral 
buffered formalin. 
5. Performance status of 0 or 1 on the ECOG Performance Scale. 
6. Adequate organ function as defined in Table 1, all screening labs should be 
performed within 10 days of treatment initiation. 
Table 1  Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
 
Hematological 
 
Absolute neutrophil count (ANC) ≥ 1,250 / mcL 
Platelets 
≥ 100,000 / mcL 
Hemoglobin 
≥ 9 g / dL or ≥ 5.6 mmol / L  
 
Renal 
 
Serum creatinine OR 
Measured or calculateda 
creatinine clearance 
(GFR can also be used in place 
of creatinine or CrCl) 
≤ 1.5 X upper limit of normal (ULN) OR 
 
≥ 50 mL / min for subject with creatinine levels  
> 1.5 X institutional ULN 
 
Hepatic 
 
Serum total bilirubin 
≤ 1.5 X ULN OR 
 
Direct bilirubin ≤ ULN for subjects with total 
bilirubin levels > 1.5 ULN 
AST (SGOT) and ALT (SGPT) 
≤ 2.5 X ULN OR 
≤ 5 X ULN for subjects with liver metastases 
aCreatinine clearance should be calculated per institutional standard. 
 
7. Female subject of childbearing potential should have a negative urine or serum 
pregnancy within 72 hours prior to receiving the first dose of study medication.  If the 
urine test is positive or cannot be confirmed as negative, a serum pregnancy test will 
be required. 
8. 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 duration of 


Product:  Pembrolizumab 
UPCC 25514 (IRB #820987) 
Pembrolizumab in Oligometastatic NSCLC 
 
 
Protocol/Amendment No 7: 03/06/2019 
10 
 
the study through 120 days after the last dose of study medication. Subjects of 
childbearing potential are those who have not been surgically sterilized or have not 
been free from menses for > 1 year. 
9. Male subjects who are partnered with women of childbearing potential should be 
willing to use 2 methods of birth control, be surgically sterile or abstain from 
heterosexual activity for the duration of the study through 120 days after the last 
dose of study medication. 
 
5.1.3 
Subject Exclusion Criteria 
The subject will be excluded from participating in the trial if any of the following criteria are met: 
1. Currently participating in or has participated in a study of an investigational agent or 
using an investigational device within 4 weeks of the first dose of treatment. 
2. Diagnosis of immunodeficiency or exposure to systemic steroid therapy or any other 
form of immunosuppressive therapy within 7 days prior to the first dose of trial 
treatment (Nasal or oral inhalers are permissible). 
3. Prior monoclonal antibody within 4 weeks prior to study Day 1 or individuals who 
have not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to 
agents administered more than 4 weeks earlier. 
4. Prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 
weeks prior to Day 1 drug administration on study or inability to recover (i.e., ≤ Grade 
1 or at baseline) from adverse events due to a previously administered agent. 
- 
Note:  Subjects with ≤ Grade 2 neuropathy or alopecia are exceptions to this 
criterion and may qualify for the study. 
- 
Note:  If subject had major surgery, they must have recovered adequately from 
the toxicity and/or complications from the intervention prior to starting therapy. 
5. Known additional malignancy that is progressing or requires active treatment.  
Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the 
skin, non-invasive bladder tumors, or in situ cervical cancer 
6. Known untreated central nervous system (CNS) metastases and/or carcinomatous 
meningitis. 
7. 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 are an exception to this rule.  Subjects that require 
intermittent use of bronchodilators or local steroid injections are not excluded from 
the study.  Subjects with hypothyroidism stable on hormone replacement or 
Sjorgen’s syndrome are not excluded from the study. 
8. Evidence of pre-existing interstitial lung disease, has a history of non-infectious 
pneumonitis which required steroids, or has current pneumonitis. 
9. Active infection requiring systemic therapy with IV antibiotics 
10. 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 


Product:  Pembrolizumab 
UPCC 25514 (IRB #820987) 
Pembrolizumab in Oligometastatic NSCLC 
 
 
Protocol/Amendment No 7: 03/06/2019 
11 
 
full duration of the trial, or is not in the best interest of the subject to participate, in the 
opinion of the treating investigator. 
11. Known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
12. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting with the pre-screening or screening visit 
through 120 days after the last dose of trial treatment. 
13. 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). 
14. Known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
15. Known active Hepatitis B (e.g., HBsAg positive or HBV DNA detectable) or Hepatitis 
C (e.g., HCV RNA [qualitative] is detected). 
16. Receipt of live vaccine within 30 days prior to the first dose of trial treatment. 
17. Progressive disease or sites of new metastasis after definitive therapy for 
oligometastatic disease. 
18. Completion of definitive therapy for oligometastatic disease greater than 12 weeks 
prior to enrollment. 
5.2 
Trial Treatments 
The treatment to be used in this trial is outlined below in Table 2 
Table 2  Trial Treatment 
Drug 
Dose/Potenc
y 
Dose 
Frequenc
y 
Route of 
Administratio
n 
Regimen/Treatmen
t Period 
Use 
Pembrolizuma
b 
200 mg 
Q3W 
IV infusion 
Day 1 of each cycle 
Experimenta
l 
 
5.2.1 
Dose Selection/Modification 
5.2.1.1 Dose Selection 
The rationale for selection of doses to be used in this trial is provided in Section 4.0 – 
Background and Rationale. 
5.2.1.2 Dose Modification 
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. See 
Section 5.4.1 for supportive care guidelines, including use of corticosteroids. 


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Table 3: Dose modification guidelines for drug-related adverse events. 
Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting Treatment 
Treatment Discontinuation 
Diarrhea/Colitis 
2-3 
 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks 
4 
Permanently discontinue 
Permanently discontinue 
AST, ALT, or 
Increased 
Bilirubin 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose 
3-4 
Permanently discontinue 
(see exception below)a 
Permanently discontinue 
Type 1 diabetes 
mellitus (if new 
onset) or 
Hyperglycemia 
T1DM or  
3-4 
Hold pembrolizumab for new onset 
Type 1 diabetes mellitus or Grade 3-4 
hyperglycemia associated with 
evidence of beta cell failure 
Resume pembrolizumab when patients are clinically and 
metabolically stable 
Hypophysitis 
2-4 
Toxicity resolves to Grade 0-1. 
Therapy with pembrolizumab can be 
continued while endocrine 
replacement therapy is instituted 
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks 
Hyperthyroidism  
3 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks 
4 
Permanently discontinue 
Permanently discontinue 
Hypothyroidism 
 
Therapy with pembrolizumab can be 
continued while thyroid replacement 
therapy is instituted 
Therapy with pembrolizumab can be continued while thyroid 
replacement therapy is instituted 
 
Infusion Reaction 
2b 
Toxicity resolves to Grade 0-1  
Permanently discontinue if toxicity develops despite adequate 
premedication  
3-4 
Permanently discontinue 
Permanently discontinue 
Pneumonitis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks 
3-4 or 
Recurrent 
Grade 2 
Permanently discontinue 
Permanently discontinue 
Renal Failure or 
Nephritis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks 
3-4 
Permanently discontinue 
Permanently discontinue 
 
Myocarditis 
 
1-2 
Toxicity resolves to Grade 0 
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks 
3-4 
Permanently Discontinue 
Permanently Discontinue 
All Other Drug-
Related Toxicityc 
3 or Severe 
 
 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks 
4 
Permanently discontinue 
Permanently discontinue 


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Table 3: Dose modification guidelines for drug-related adverse events. 
Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting Treatment 
Treatment Discontinuation 
Note: Permanently discontinue for any severe or Grade 3 (Grade 2 for pneumonitis) drug-related AE that recurs or any life-threatening 
event. 
a For patients with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT increases by greater than or equal to 50% relative 
to baseline and lasts for at least 1 week then patients should be discontinued. 
b If symptoms resolve within one hour of stopping drug infusion, the infusion may be restarted at 50% of the original infusion rate (e.g., from 100 
mL/hr to 50 mL/hr).  Otherwise dosing will be held until symptoms resolve and the subject should be premedicated for the next scheduled dose; 
Refer to Table 4– Infusion Treatment Guidelines for further management details. 
c Patients with intolerable or persistent Grade 2 drug-related AE may hold study medication at physician discretion.  Permanently discontinue study 
drug for persistent Grade 2 adverse reactions for which treatment with study drug has been held, that do not recover to Grade 0-1 within 12 weeks 
of the last dose. 
 
 
 
With investigator and medical monitor agreement, subjects with a laboratory adverse event 
still at Grade 2 after 12 weeks may continue treatment in the trial only if asymptomatic. 
Subjects who experience a recurrence of the same severe or life-threatening event at the 
same grade or greater with re-challenge of Pembrolizumab should be permanently 
discontinued from trial treatment. 
5.2.2 
Timing of Dose Administration 
Trial treatment should be administered on Day 1 of each cycle after all 
procedures/assessments have been completed as detailed on the Trial Flow Chart (Section 
6.0).  Trial treatment may be administered up to 3 days before or after the scheduled Day 1 
of each cycle due to administrative reasons. 
All trial treatments will be administered on an outpatient basis. 
Pembrolizumab will be administered as a 30 minute IV infusion every 3 weeks.  Sites should 
make every effort to target infusion timing to be as close to 30 minutes as possible.  
However, given the variability of infusion pumps from site to site, a window of -5 minutes and 
+10 minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min). 
5.3 
Concomitant Medications/Vaccinations (allowed & prohibited) 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for one of these or other medications 
or vaccinations specifically prohibited during the trial, discontinuation from trial therapy or 
vaccination may be required.  The investigator should discuss any questions regarding this 
with the Sponsor.  The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the subject's primary physician.  However, the decision to continue the 
subject on trial therapy or vaccination schedule requires the mutual agreement of the 
Investigator, the Sponsor, and the subject. 


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5.3.1 
Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care.  All concomitant medications will be recorded on the case report form (CRF) 
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications 
and fluids.  If changes occur during the trial period, documentation of drug dosage, 
frequency, route, and date may also be included on the CRF.  Examples of acceptable 
concomitant medications include zoledronic acid, denosumab, megestrol acetate, and 
cannabinoids. 
All concomitant medications received within 28 days before the first dose of trial treatment 
and 30 days after the last dose of trial treatment should be recorded.  Concomitant 
medications administered after 30 days after the last dose of trial treatment should be 
recorded for SAEs and ECIs as defined in Section 7.2. 
 
5.3.2 
Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase of this trial: 
 
Anti-cancer systemic chemotherapy or biological therapy 
 
Immunotherapy 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 after consultation with Sponsor, but would be regarded as a 
disease progression event for the primary outcome. 
 
Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial.  Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, chicken pox, yellow fever, rabies, BCG, and 
typhoid (oral) vaccine. Seasonal influenza vaccines for injection are generally killed 
virus vaccines and are allowed; however intranasal influenza vaccines (e.g. Flu-
Mist®) are live attenuated vaccines and are not allowed. 
 
Oral glucocorticoids for any purpose other than an abbreviated course to modulate 
symptoms from an event of clinical interest of suspected immunologic etiology.  The 
use of physiologic replacement doses of corticosteroids may be approved after 
consultation with the Sponsor-Investigator and Medical Monitor. Inhaled and topical 
steroids are permitted. 
Subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial.  
Subjects may receive other medications that the investigator or qualified designee deems to 
be medically necessary. 
The Exclusion Criteria describe other medications which are prohibited in this trial. 


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There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
5.4 
Rescue Medications & Supportive Care 
5.4.1 
Supportive Care Guidelines 
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator or qualified designee.  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 5.2.1.2 for 
dose modification. 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, 
or skin photography as part of evaluation of the event. 
 
Pneumonitis: 
o For Grade 2 events, treat with systemic corticosteroids. When symptoms 
improve to Grade 1 or less, steroid taper should be started and continued 
over no less than 4 weeks. 
o For Grade 3-4 events, immediately treat with intravenous steroids.  
Administer additional anti-inflammatory measures, as needed. 
o Add prophylactic antibiotics for opportunistic infections in the case of 
prolonged steroid administration. 
 
Diarrhea/Colitis: Subjects should be carefully monitored for signs and symptoms of 
enterocolitis (such as diarrhea, abdominal pain, blood or mucus in stool, with or 
without fever) and of bowel perforation (such as peritoneal signs and ileus). 
o All subjects who experience diarrhea/colitis should be advised to drink liberal 
quantities of clear fluids.  If sufficient oral fluid intake is not feasible, fluid and 
electrolytes should be replaced via IV infusion.  For Grade 2 or higher 
diarrhea, consider GI consultation and endoscopy to confirm or rule out colitis. 
o For Grade 2 diarrhea/colitis, administer oral corticosteroids. 
o For Grade 3 or 4 diarrhea/colitis, treat with intravenous steroids followed by 
high dose oral steroids. 
o When symptoms improve to Grade 1 or less, steroid taper should be started 
and continued over no less than 4 weeks. 
 
Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or      
≥ Grade 3 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic 
acidosis (DKA) 


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o For T1DM or Grade 3-4 Hyperglycemia 
 
Insulin replacement therapy is recommended for Type I diabetes mellitus and 
for Grade 3-4 hyperglycemia associated with metabolic acidosis or ketonuria. 
 
Evaluate patients with serum glucose and a metabolic panel, urine ketones, 
glycosylated hemoglobin, and C-peptide. 
 
Hypophysitis: 
o For Grade 2 events, treat with corticosteroids. When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less 
than 4 weeks. Replacement of appropriate hormones may be required as the 
steroid dose is tapered. 
o For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed 
by oral corticosteroids. When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the steroid dose is 
tapered. 
 
Hyperthyroidism or Hypothyroidism: 
Thyroid disorders can occur at any time during treatment. Monitor patients for 
changes in thyroid function (at the start of treatment, periodically during treatment, 
and as indicated based on clinical evaluation) and for clinical signs and symptoms of 
thyroid disorders. 
o Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism): 
 
In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are 
suggested as initial therapy. 
 
In hypothyroidism, thyroid hormone replacement therapy, with 
levothyroxine or liothyroinine, is indicated per standard of care. 
o Grade 3-4 hyperthyroidism 
 
Treat with an initial dose of IV corticosteroid followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the steroid 
dose is tapered. 
 
Hepatic: 
o For Grade 2 events, monitor liver function tests more frequently until returned 
to baseline values (consider weekly). 
 
Treat with IV or oral corticosteroids 
o For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 
hours. 
o When symptoms improve to Grade 1 or less, a steroid taper should be 
started and continued over no less than 4 weeks. 
 
Renal Failure or Nephritis: 
o For Grade 2 events, treat with corticosteroids. 


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o For Grade 3-4 events, treat with systemic corticosteroids. 
o When symptoms improve to Grade 1 or less, steroid taper should be started 
and continued over no less than 4 weeks. 
 
Management of Infusion Reactions:  Signs and symptoms usually develop during or 
shortly after drug infusion and generally resolve completely within 24 hours of 
completion of infusion. 
 
 
 
 
 
 
Table 4 below provides treatment guidelines for subjects who experience an infusion 
reaction associated with administration of Pembrolizumab. 
Table 4  Infusion Reaction Treatment Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
Grade 1 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
 
Increase monitoring of vital signs as 
medically indicated until the subject 
is deemed medically stable in the 
opinion of the investigator. 
 
None 


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Table 4  Infusion Reaction Treatment Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
Grade 2 
Requires infusion 
interruption but responds 
promptly to symptomatic 
treatment (e.g., 
antihistamines, NSAIDS, 
IV fluids); prophylactic 
medications indicated for 
< =24 hrs 
 
Stop Infusion and monitor 
symptoms. 
Additional appropriate medical 
therapy may include but is not 
limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Increase monitoring of vital signs as 
medically indicated until the subject 
is deemed medically stable in the 
opinion of the investigator. 
If symptoms resolve within one 
hour of stopping drug infusion, the 
infusion may be restarted at 50% of 
the original infusion rate (e.g. from 
100 mL/hr to 50 mL/hr).  Otherwise 
dosing will be held until symptoms 
resolve and the subject should be 
premedicated for the next 
scheduled dose. 
Subjects who develop Grade 2 
toxicity despite adequate 
premedication should be 
permanently discontinued from 
further trial treatment 
administration. 
 
Subject may be 
premedicated 1.5 h (± 
30 minutes) prior to 
infusion of 
Pembrolizumab with: 
 
Diphenhydramine 50 
mg po (or equivalent 
dose of antihistamine). 
 
Acetaminophen 500-
1000 mg po (or 
equivalent dose of 
antipyretic). 


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Table 4  Infusion Reaction Treatment Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
Grades 3 or 4 
 
Grade 3: 
Prolonged (i.e., not 
rapidly responsive to 
symptomatic medication 
and/or brief interruption 
of infusion); recurrence of 
symptoms following initial 
improvement; 
hospitalization indicated 
for other clinical sequelae 
(e.g., renal impairment, 
pulmonary infiltrates) 
 
Grade 4: 
Life-threatening; pressor 
or ventilatory support 
indicated 
 
 
Stop Infusion. 
Additional appropriate medical 
therapy may include but is not 
limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
 
Increase monitoring of vital signs as 
medically indicated until the subject 
is deemed medically stable in the 
opinion of the investigator. 
Hospitalization may be indicated. 
Subject is permanently 
discontinued from further trial 
treatment administration. 
 
No subsequent dosing 
Appropriate resuscitation equipment should be available in the room and a physician 
readily available during the period of drug administration. 
 
5.5 
Diet/Activity/Other Considerations 
5.5.1 
Diet 
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea or vomiting. 
5.5.2 
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.  Non-pregnant, 
non-breast-feeding women may be enrolled if they are willing to use 2 methods of birth 
control or are considered highly unlikely to conceive.  Highly unlikely to conceive is defined 
as 1) surgically sterilized, or 2) postmenopausal (a woman who is ≥45 years of age and has 
not had menses for greater than 1 year will be considered postmenopausal), or 3) not 
heterosexually active for the duration of the study.  Male subjects of reproductive potential 
must agree to avoid impregnating a partner while receiving study drug and for 120 days 
after the last dose of study drug either by practicing total abstinence from heterosexual 
activity or with a female partner using 2 methods of birth control.  The two birth control 


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methods can be either two barrier methods or a barrier method plus a hormonal method to 
prevent pregnancy. Subjects should start using birth control from study Visit 1 throughout 
the study period up to 120 days after the last dose of study therapy. 
The following are considered adequate barrier methods of contraception: diaphragm, condom, 
copper intrauterine device, sponge, or spermicide.  Appropriate hormonal contraceptives will 
include any registered and marketed contraceptive agent that contains an estrogen and/or a 
progestational agent (including oral, subcutaneous, intrauterine, or intramuscular agents). 
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 they must adhere to the contraception requirement (described above) for the 
duration of the study and during the follow-up period defined in section 7.2.2-Reporting of 
Pregnancy and Lactation to the Sponsor.  If there is any question that a subject will not 
reliably comply with the requirements for contraception, that subject should not be entered 
into the study. 
5.5.3 
Use in Pregnancy 
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.  The 
outcome of the pregnancy will be reported to the Sponsor without delay and within 24 hours if 
the outcome is a serious adverse experience (e.g., death, abortion, congenital anomaly, or other 
disabling or life-threatening complication to the mother or newborn).  The study investigator will 
make every effort to obtain permission to follow the outcome of the pregnancy and report the 
condition of the fetus or newborn to the Sponsor.  If a male subject impregnates his female 
partner the study personnel at the site must be informed immediately and the pregnancy 
reported to the Sponsor and followed as described above and in Section 7.2.2. 
5.5.4 
Use in Nursing Women 
It is unknown whether Pembrolizumab is excreted in human milk.  Since many drugs are 
excreted in human milk, and because of the potential for serious adverse reactions in the 
nursing infant, subjects who are breast-feeding are not eligible for enrollment. 
5.6 
Subject Withdrawal/Discontinuation Criteria 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur.  In addition, a subject may be 
withdrawn by the investigator or the Sponsor if enrollment into the trial is inappropriate, the trial 
plan is violated, or for administrative and/or other safety reasons.  Specific details regarding 
discontinuation or withdrawal are provided in Section 7.1.4 – Other Procedures. 
A subject must be discontinued from the trial for any of the following reasons: 
 
Withdrawal of 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, as 
consistent with irRC. 


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 
Unacceptable adverse experiences or toxicities 
 
Intercurrent illness that prevents further administration of treatment 
 
Investigator’s decision to withdraw the subject 
 
Confirmed positive serum pregnancy test and unwillingness to abort pregnancy 
 
Noncompliance with trial treatment or procedure requirements 
 
Loss to follow-up 
 
Completion of 12 months of treatment with Pembrolizumab 
Note: 12 months of study medication is calculated from the date of first dose. 
 
Other Administrative reasons 
The End of Treatment and Follow-up visit procedures are listed in Section 6 (Protocol Flow 
Chart) and Section 7.1.5 (Visit Requirements).  After the end of treatment, each subject will 
be followed for 30 days for adverse event monitoring (serious adverse events will be 
collected for 90 days after the end of treatment as described in Section 7.1.5.3.1).  Subjects 
who discontinue for reasons other than progressive disease will have post-treatment follow-
up for disease status until disease progression, initiation of non-study cancer treatment, 
withdrawal of consent or loss  to follow-up.  After documented disease progression each, 
subject will be followed by telephone or chart review for overall survival until death, 
withdrawal of consent, or the end of the study, whichever occurs first.  All subsequent 
therapies will be recorded, if feasible. 
5.7 
Subject Replacement Strategy 
Subjects who receive at least 1 dose of Pembrolizumab will be considered evaluable and 
will not be replaced. 
5.8 
Clinical Criteria for Early Trial Termination 
Early trial termination will be the result of the criteria specified below: 
1. Quality or quantity of data recording is inaccurate or incomplete 
2. Poor adherence to protocol and regulatory requirements 
3. Incidence or severity of adverse drug reaction in this or other studies indicates a 
potential health hazard to subjects 
4. Plans to modify or discontinue the development of the study drug 
In the event of Merck decision to no longer supply study drug, ample notification will be 
provided so that appropriate adjustments to subject treatment can be made. 
 


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6.0 TRIAL FLOW CHART 
 
6.1  Study Flow Chart 
Trial Period: 
Screening Phase 
Treatment Cycles 
End of 
Treatment 
Post-Treatment 
Treatment Cycle/Title: 
Pre-
screening 
(Visit 1) 
Main 
Study 
Screening 
(Visit 2) 
1 
2  
3 
4 
To be repeated 
beyond 8 cycles 
Discon 
Safety 
Follow-
up 
Follow 
Up 
Visits 
Survival 
Follow-
Up 
5 
6 
7 
8 
Scheduling Window (Days): 
 
-28 to -1 
 
± 3 ± 3 ± 3 ± 3 ± 3 ± 3 ± 3 
At time of 
Discon 
30 
days 
post 
discon 
Every 
8-12 
weeks 
post 
discon* 
Every 
12 
weeks ª  
Administrative Procedures 
Pre-screening Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Subject Identification Card 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and Medical 
History 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Prior and Concomitant 
Medication Review 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Trial Treatment Administration 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Post-study anticancer therapy 
status 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
Survival Status 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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6.1  Study Flow Chart 
Trial Period: 
Screening Phase 
Treatment Cycles 
End of 
Treatment 
Post-Treatment 
Treatment Cycle/Title: 
Pre-
screening 
(Visit 1) 
Main 
Study 
Screening 
(Visit 2) 
1 
2  
3 
4 
To be repeated 
beyond 8 cycles 
Discon 
Safety 
Follow-
up 
Follow 
Up 
Visits 
Survival 
Follow-
Up 
5 
6 
7 
8 
Scheduling Window (Days): 
 
-28 to -1 
 
± 3 ± 3 ± 3 ± 3 ± 3 ± 3 ± 3 
At time of 
Discon 
30 
days 
post 
discon 
Every 
8-12 
weeks 
post 
discon* 
Every 
12 
weeks ª  
Clinical Procedures/Assessments 
Review Adverse Events 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xᶜ  
 
Full Physical Examination 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
X 
 
Directed Physical Examination 
 
 
X 
X 
X 
 
X 
X 
X 
 
 
 
 
 
Vital Signs and Weight 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECOG Performance Status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Laboratory Procedures/Assessments: analysis performed by LOCAL laboratory 
Pregnancy Test – Urine or 
Serum β-HCG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
PT/INR and aPTT 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with Differential 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Comprehensive Serum 
Chemistry Panel 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Urinalysis 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
 


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6.1  Study Flow Chart 
Trial Period: 
Screening Phase 
Treatment Cycles 
End of 
Treatment 
Post-Treatment 
Treatment Cycle/Title: 
Pre-
screening 
(Visit 1) 
Main 
Study 
Screening 
(Visit 2) 
1 
2  
3 
4 
To be repeated 
beyond 8 cycles 
Discon 
Safety 
Follow-
up 
Follow 
Up 
Visits 
Survival 
Follow-
Up 
5 
6 
7 
8 
Scheduling Window (Days): 
 
-28 to -1 
 
± 3 ± 3 ± 3 ± 3 ± 3 ± 3 ± 3 
At time of 
Discon 
30 
days 
post 
discon 
Every 
8-12 
weeks 
post 
discon* 
Every 
12 
weeks ª  
TSH 
 
X 
 
X 
 
 
X 
 
 
 
X 
X 
X 
(First 6 
months of 
follow-up; 
then per 
physician 
discretion) 
 
T3 and FT4 
 
X 
 
X 
 
 
X 
 
 
 
X 
X 
 
 
Basic Metabolic Panel 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Efficacy Measurements 
Tumor Imaging  
 
Xᵇ 
 
 
 
X 
 
 
 
X 
X 
 
X 
 
Tumor Biopsies/Archival Tissue Collection/Correlative Studies Blood 
Archival or Newly Obtained 
Tissue Collection 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient Reported Outcomes 
FACT-L 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xᵈ  
 
 


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Protocol/Amendment No 7: 03/06/2019 
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* Follow-up scans for the first year can be 8-12 weeks.  Follow-up beyond the first year should be every 12 weeks (3 months) until 3 
years, at which time scan frequency can be at the oncologists’ discretion. 
ª  Patients in survival follow up (who are no longer on treatment and have moved on to further therapies) require only 6 month follow 
up of survival status and subsequent cancer therapy treatment only 
ᵇ  Tumor imaging may be up to 30 days prior to the start of treatment per section 7.1.5.1 
ᶜ  After the end of treatment, each subject will be followed for 30 days for adverse event monitoring (serious adverse events will be 
collected for 90 days after the end of treatment as described in Section 7.1.5.3.1). 
ᵈ  The FACT L is only required to be completed for the first 3 months post treatment (in patients who have not progressed and 
entered into survival only follow up) 
 
 


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7.0 TRIAL PROCEDURES 
7.1 
Trial Procedures 
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to 
perform these procedures at unscheduled time points if deemed clinically necessary by the 
investigator. 
Furthermore, additional evaluations/testing may be deemed necessary by the Sponsor for 
reasons related to subject safety. In these cases, such evaluations/testing will be performed 
in accordance with those regulations. 
7.1.1 
Administrative Procedures 
7.1.1.1 Informed Consent 
The Investigator or qualified designee must obtain documented consent from each potential 
subject prior to participating in a clinical trial.  Copies of the informed consent form must be 
placed in the electronic medical record as well as study folder. 
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated 
signature of the person conducting the consent discussion. 
A copy of the signed and dated consent form should be given to the subject before 
participation in the trial. 
The initial informed consent form, any subsequent revised written informed consent form 
and any written information provided to the subject must receive the IRB/ERC’s 
approval/favorable opinion in advance of use.  The subject or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’s willingness to continue participation in the trial.  The 
communication of this information will be provided and documented via a revised consent 
form or addendum to the original consent form that captures the subject’s dated signature or 
by the subject’s legally acceptable representative’s dated signature. 
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level. 
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements. 
7.1.1.2 Inclusion/Exclusion Criteria 
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial.  Waivers will not be granted without the 
explicit approval of the study monitor 


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7.1.1.3 Medical History 
A medical history will be obtained by the investigator or qualified designee.  Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that 
are considered to be clinically significant by the Investigator.  Details regarding the disease 
for which the subject has enrolled in this study will be recorded separately and not listed as 
medical history. 
7.1.1.4 Prior and Concomitant Medications Review 
7.1.1.4.1 Prior Medications 
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the subject 
within 28 days before starting the trial.  Treatment for the disease for which the subject has 
enrolled in this study will be recorded separately and not listed as a prior medication. 
7.1.1.4.2 Concomitant Medications 
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial.  All medications related to reportable SAEs and ECIs should be recorded as 
defined in Section 7.2. 
7.1.1.5 Disease Details and Treatments 
7.1.1.5.1 Disease Details 
The investigator or qualified designee will obtain prior and current details regarding disease 
status. 
7.1.1.5.2 Prior Treatment Details 
The investigator or qualified designee will review all prior cancer treatments including 
systemic treatments, radiation and surgeries. 
7.1.1.5.3 Subsequent Anti-Cancer Therapy Status 
The investigator or qualified designee will review all new anti-neoplastic therapy initiated 
after the last dose of trial treatment.  If a subject initiates a new anti-cancer therapy within 30 
days after the last dose of trial treatment, the 30 day Safety Follow-up visit must occur 
before the first dose of the new therapy.  Once new anti-cancer therapy has been initiated 
the subject will move into survival follow-up. 
7.1.1.6 Trial Compliance (Medication/Diet/Activity/Other) 
Interruptions from the protocol specified treatment plan for greater than 12 weeks between 
Pembrolizumab doses due to toxicity will require consultation between the investigator and 
the medical monitor and written documentation of the collaborative decision on subject 
management. 


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Protocol/Amendment No 7: 03/06/2019 
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7.1.2 
Clinical Procedures/Assessments 
7.1.2.1 Adverse Event (AE) Monitoring 
The investigator or qualified designee will assess each subject to evaluate for potential new or 
worsening AEs as specified in the Trial Flow Chart and more frequently if clinically indicated.  
Adverse experiences will be graded and recorded throughout the study and during the follow-up 
period according to NCI CTCAE Version 4.0.  Toxicities will be characterized in terms regarding 
seriousness, causality, toxicity grading, and action taken with regard to trial treatment. 
All AEs of unknown etiology associated with Pembrolizumab exposure should be evaluated to 
determine if it is possibly an event of clinical interest (ECI) of a potentially immunologic etiology 
(irAE).  See Section 7.5.3.2 regarding the identification, evaluation and management of AEs of a 
potential immunological etiology. 
Please refer to section 7.2 for detailed information regarding the assessment and recording 
of AEs. 
7.1.2.2 Full Physical Exam 
The investigator or qualified designee will perform a complete physical exam during the 
screening period.  Clinically significant abnormal findings should be recorded as medical 
history.  A full physical exam should be performed during screening. 
7.1.2.3 Directed Physical Exam 
For cycles that do not require a full physical exam per the Trial Flow Chart, the investigator 
or qualified designee will perform a directed physical exam as clinically indicated prior to trial 
treatment administration. 
7.1.2.4 Vital Signs 
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of trial treatment and at treatment discontinuation as specified in 
the Trial Flow Chart (Section 6.0).  Vital signs should include temperature, pulse, respiratory 
rate, weight and blood pressure.  Height will be measured at screening only. 
7.1.2.5 Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The investigator or qualified designee will assess ECOG status (see Section 11.0) at 
screening, prior to the administration of each dose of trial treatment and discontinuation of 
trial treatment as specified in the Trial Flow Chart.  After Cycle 8 assessment of ECOG 
status will be performed every other cycle in conjunction with the directed or full physical 
exam. 
7.1.2.6 Tumor Imaging and Assessment of Disease 
The initial tumor imaging will be performed within 30 days prior to the first dose of trial 
treatment. Scans performed as part of routine clinical management are acceptable for use 
as the screening scan if they are of diagnostic quality and performed within 30 days prior to 
the first dose of trial treatment. On-study imaging will be performed every 12 weeks (84 ± 7 


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Protocol/Amendment No 7: 03/06/2019 
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days) after the first dose of trial treatment or more frequently if clinically indicated. Tumor 
imaging timing should follow calendar days and should not be adjusted for delays in cycle 
starts or extension of Pembrolizumab cycle frequencies. 
After the first documentation of progression (if the subject is clinically stable) confirmatory 
scans may be performed as early as 28 days later; alternately, the scan performed at the 
next scheduled timepoint (e.g. every 63 ±7 days) may be used as confirmation. 
After the first documentation of progression, it is at the discretion of the investigator either to 
verify true PD, to keep a clinically stable subject on trial treatment or to stop trial treatment 
until repeat imaging performed at least 28 days later confirms progression. Clinical Stability 
is defined as: 
1) Absence of symptoms and signs indicating clinical significant progression of disease 
(including worsening of laboratory values) indicating disease progression. 
2) No decline in ECOG performance status. 
3) Absence of rapid progression of disease or progressive tumor at critical anatomical sites 
(e.g., cord compression) requiring urgent alternative medical intervention. 
Subjects who are deemed clinically unstable are not required to have repeat imaging for 
confirmation. If progression is confirmed, then the subject will be discontinued from trial 
treatment. If progression is not confirmed, then the subjects should resume/continue trial 
treatment and have their next scan after two more cycles of treatment which would be 
approximately 6 weeks from the date of the scan that first showed progression. When 
feasible, subjects should not be discontinued until progression is confirmed. 
Imaging during the follow-up period is to be repeated a minimum of every 12 weeks (84 ± 7 
days) for subjects who discontinue trial treatment for reasons other than disease 
progression until the subject experiences confirmed disease progression or starts a new 
antineoplastic therapy. 
The same imaging techniques should be used in a subject throughout the trial.  For patients 
with brain metastases, MRI brain should be included in the imaging follow up prior to 
treatment and at any time when a patient develops new neurologic symptoms. Ideally, CT 
scans should be used in lieu of PET imaging as the means of determining tumor status.  But 
PET imaging may be used to confirm PD, if suspected, but not yet clear. 
7.1.3 
Laboratory Procedures/Assessments 
Details regarding specific laboratory procedures/assessments to be performed in this trial 
are provided below.  The total amount of blood/tissue to be drawn/collected over the course 
of the trial (from pre-trial to post-trial visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per subject may vary depending upon clinical 
course of the subject and length of time on trial. 
7.1.3.1 Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) 
Laboratory tests for hematology, chemistry, urinalysis, and others are specified in Table 9.  
The total amount of blood/tissue to be drawn/collected over the course of the trial (from pre-
trial to post-trial visits), including approximate blood/tissue volumes drawn/collected by visit 


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Protocol/Amendment No 7: 03/06/2019 
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and by sample type per subject may vary depending upon clinical course of the subject and 
length of time on trial. 
Table 9  Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Other 
Hematocrit 
Albumin 
Blood 
Serum β-human 
chorionic gonadotropin† 
Hemoglobin 
Alkaline phosphatase 
Glucose 
  (β-hCG)† 
Platelet count 
Alanine aminotransferase 
(ALT) 
Protein 
PT (INR) 
WBC (total and differential) Aspartate aminotransferase 
(AST) 
Specific gravity  
aPTT 
Red Blood Cell Count 
Lactate dehydrogenase 
(LDH) 
Microscopic exam (If 
abnormal)  
Total thriiodothyronine 
(T3) 
Absolute Neutrophil Count Carbon Dioxide  
results are noted 
Free tyroxine (T4) 
 
(CO2 or biocarbonate) 
Urine pregnancy test † Thyroid stimulating 
hormone (TSH) 
 
Uric Acid 
 
 
 
Calcium 
 
 
 
Chloride 
 
 
 
Glucose 
 
  
 
Phosphorus 
 
  
 
Potassium   
 
  
 
Sodium 
 
  
 
Magnesium 
 
  
 
Total Bilirubin 
 
  
 
Direct Bilirubin (If total 
bilirubin is elevated above 
the upper limit of normal) 
 
 
 
Total protein 
 
 
 
Blood Urea Nitrogen 
 
 
† Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed as 
negative, a serum pregnancy test will be required.   
 
After Cycle 1, pre-dose laboratory procedures can be conducted up to 72 hours prior to 
dosing.  Results must be reviewed by the investigator or qualified designee and found to be 
acceptable prior to each dose of trial treatment. 
 


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7.1.4 
Other Procedures 
7.1.4.1 Withdrawal/Discontinuation 
When a subject discontinues/withdraws prior to trial completion, all applicable activities scheduled for 
the final trial visit should be performed at the time of discontinuation.  Any adverse events which are 
present at the time of discontinuation/withdrawal should be followed in accordance with the safety 
requirements outlined in Section 7.2 - Assessing and Recording Adverse Events. After discontinuing 
treatment, these subjects should return to the site for a Safety Follow-up Visit (described in Section 
7.1.5.3.1) and then proceed to the Follow-Up Period of the study (described in Section 7.1.5.4). 
7.1.4.2 Blinding/Unblinding 
Study treatment is open label for this study. 
7.1.5 
Visit Requirements 
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.  Specific procedure-related details are 
provided above in Section 7.1 - Trial Procedures. 
7.1.5.1 Screening 
Visit requirements are outlined in Section 6.0 - Trial Flow Chart. Specific procedure-related details are 
provided above in Section 7.1 - Trial Procedures. 
Approximately 28 days prior to treatment initiation, potential subjects will be evaluated to determine 
that they fulfill the entry requirements as set forth in Section 5.1. Screening procedures may be 
repeated. 
Written informed consent must be obtained prior to performing any protocol specific procedure. 
Results of a test performed prior to the subject signing consent as part of routine clinical management 
are acceptable in lieu of a screening test if performed within the specified time frame. Screening 
procedures are to be completed within 42 days prior to the first dose of trial treatment except for the 
following: 
 
Laboratory tests are to be performed within 10 days prior to the first dose of trial treatment. 
 
For women of reproductive potential, a urine pregnancy test will be performed within 72 hours 
prior to first dose of trial treatment. If urine pregnancy results cannot be confirmed as negative, 
a serum pregnancy test, performed by the local study site laboratory, will be required. 
 
Tumor imaging must be performed within 30 days prior to the first dose of trial treatment. 
Subjects may be rescreened after initially failing to meet the inclusion/exclusion criteria. Results from 
assessments performed during the initial screening period are acceptable in lieu of a repeating a 
screening test if performed within the specified time frame and the results meet the inclusion/exclusion 
criteria. 
7.1.5.2 Treatment Period 
Visit requirements are outlined in Section 6.0 - Trial Flow Chart. Specific procedure-related details are 
provided above in Section 7.1 - Trial Procedures. 


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7.1.5.3 Post-Treatment Visits 
Visit requirements are outlined in Section 6.0 - Trial Flow Chart. Specific procedure-related details are 
provided above in Section 7.1 - Trial Procedures. Patients will be followed for up to 5 years for both 
PFS and OS status. If the subject experiences tolerable toxicity in the absence of progression while on 
Pembrolizumab after 6 months of therapy, he/she will be eligible to receive up to 6 additional months 
of therapy with Pembrolizumab. After the completion of all therapy, subjects should be followed for up 
to 5 years, with no option for retreatment with Pembrolizumab on study. 
 
7.1.5.3.1  Safety Follow-Up Visit 
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the last dose 
of trial treatment or before the initiation of a new anti-cancer treatment, whichever comes first.  All AEs 
that occur prior to the Safety Follow-Up Visit should be recorded.  Subjects with an AE of Grade > 1 
will be followed until the resolution of the AE to Grade 0-1 or until the beginning of a new anti-
neoplastic therapy, whichever occurs first.  SAEs that occur within 90 days of the end of treatment or 
before initiation of a new anti-cancer treatment should also be followed and recorded. 
7.1.5.4 Follow-up Visits 
Subjects who discontinue trial treatment for a reason other than disease progression will move into the 
Follow-Up Phase and should be assessed every 8-12 weeks (56-84 ± 7 days) by radiologic imaging to 
monitor disease status.  After a year of follow up without progression, the patient can be assessed 
every 12 weeks (3 months) at the discretion of the treating physician.  A patient who has not 
experienced disease progression 3 years after enrollment may have his/her follow up visits and scans 
spaced out to every 6 months (24 weeks), at the discretion of the treating oncologist. 
Every effort should be made to collect information regarding disease status until the start of new anti-
neoplastic therapy, disease progression, death, or end of the study.  Information regarding post-study 
anti-neoplastic treatment will be collected if new treatment is initiated. 
7.1.5.5 Survival Follow-up 
Once a subject experiences confirmed disease progression or starts a new anti-cancer therapy, the 
subject moves into the survival follow-up phase and should be contacted by telephone every 12 weeks 
to assess for survival status until death, withdrawal of consent, or the end of the study, whichever 
occurs first. 
7.2 
Assessing and Recording Adverse Events 
An adverse event is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have to have a causal 
relationship with this treatment. An adverse event can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding, for example), symptom, or disease temporally 
associated with the use of a medicinal product or protocol-specified procedure, whether or not 
considered related to the medicinal product or protocol-specified procedure.  Any worsening (i.e., any 
clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is 
temporally associated with the use of the Merck’s product, is also an adverse event. 
Non-clinically significant labs as deemed by the investigator will not be captured as adverse events. 
Merck product includes any pharmaceutical product, biological product, device, diagnostic agent or 
protocol-specified procedure, whether investigational (including placebo or active comparator 


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medication) or marketed, manufactured by, licensed by, provided by or distributed by Merck for human 
use. 
Adverse events may occur during the course of the use of Merck product in clinical trials or within the 
follow-up period specified by the protocol, or prescribed in clinical practice, from overdose (whether 
accidental or intentional), from abuse and from withdrawal. 
Adverse events may also occur in screened subjects during any pre-allocation baseline period as a 
result of a protocol-specified intervention, including washout or discontinuation of usual therapy, diet, 
placebo treatment or a procedure. 
All adverse events will be recorded from the time the consent form is signed through 30 days following 
cessation of treatment and at each examination on the Adverse Event case report forms/worksheets. 
The reporting timeframe for adverse events meeting any serious criteria is described below. 
Adverse events will not be collected for subjects during the pre-screening period (for determination of 
archival tissue status) as long as that subject has not undergone any protocol-specified procedure or 
intervention.  If the subject requires a blood draw, fresh tumor biopsy etc., the subject is first required 
to provide consent to the main study and AEs will be captured according to guidelines for standard AE 
reporting. 
Applicable reporting to Abramson Cancer Center Data and Safety Monitoring Committee 
(DSMC) will occur as follows: 
On-Site subjects (this includes any subjects enrolled at other sites on an in-house study) 
Every effort should be made to report an event as a diagnosis, not as a list of symptoms. Symptoms that 
led to the diagnosis should be included in the event description, but should not be the actual event. 
1.  Unless covered by exclusions below all Grade 3 or higher events must be reported within     
10 days of knowledge. 
2. All unexpected deaths within one business day of knowledge. 
3. All other deaths within 30 days of knowledge. Deaths of subjects off-study for greater than    
30 days from the last study treatment/intervention are not reportable unless a longer time 
frame is specified in the protocol. 
EXCEPTIONS to AE/SAE Reporting: 
a. Grade 3 or 4 events that are judged by a study investigator to be clearly unrelated to 
protocol therapy.  The reason for determining that the event is unrelated must be clearly 
documented in the EMR. 
b. Grade 3 or 4 events that are probably or definitely related to progression of disease as 
judged by a study investigator. The fact that this event is related to disease progression 
must be clearly documented in the EMR. 


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Protocol/Amendment No 7: 03/06/2019 
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c. Grade 3 or 4 events that are probably or definitely related to an FDA approved agent. The 
fact that this event is related to the FDA approved agent must be clearly documented in the 
EMR. 
 
7.3 
Exceptions 
A one time, intentional action (planned prospectively) or process that departs from the IRB and 
CTSRMC approved study protocol, intended for one occurrence.  Advance documented IRB and 
DSMC approval is required. 
For in-house studies with a Medical Monitor or Safety Monitoring Committee (not DSMB), approval 
must be obtained from the Medical Monitor or Safety Monitoring Committee prior to submitting the 
exception request to the DSMC.  The following information must be contained in your exception 
request: 
 
When it is needed and why it is needed in that timeframe 
 
Has the Medical Monitor or Sponsor approved and provide the documentation of approval 
 
Is this an exception from eligibility, treatment, disease progression, study calendar windows, 
etc. 
 
Why the exception is needed (cite the section(s) of the protocol) along with the full clinical 
details of the subject. This must be determined by the sub-Investigator or PI. 
 
The reason why the protocol currently doesn't allow the situation for which an exception is 
being requested. This must be determined by the sub-Investigator or PI. 
 
If there are plans to amend the protocol and if not, why not. 
 
If additional follow-up or interventions will be required in order to protect the subject as a result 
of this exception. 
Study Exceptions the DSMC may Reject: 
Exceptions to eligibility, treatment/dosing, contraindicated treatment/therapies/interventions or safety 
tests for the following types of studies may be rejected by the DSMC: 
1. Any investigator-initiated treatment study. 
2. Any treatment study involving on-campus manufacturing of any component, regardless of sponsor. 
To seek approval, you must provide the DSMC with strong and compelling scientific and clinical 
information to support your request. You should also include a statement explaining whether or not the 
protocol will be amended. If the protocol will not be amended your reasoning must be provided. If this 
situation is likely to happen again, the DSMC will require a protocol amendment. 
7.4 
Deviation 
Any unintentional action or process that departs from the IRB and DSMC approval and is identified 
retrospectively. The deviation is reportable to the DSMC and the IRB within 10 days from the time the 
event becomes known to the study team only when: one or more participants were placed at increased 
risk of harm, or, the event has the potential to occur again, or the event has the potential to qualify as 
serious or continuing noncompliance. 


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If the PI determines that a deviation has any potential to impact participant safety (harm and/or risk), or 
the integrity of data produced from the participant, or some other overall impact on the study, the PI 
must report the deviation to the IRB and DSMC as described above. The IRB will make the final 
assessment of the impact. The DSMC will assess for additional safety and scientific integrity concerns. 
The following information must be contained in your deviation report: 
 
When it happened? When the study team (any member) became aware 
 
The full description of the deviation including important dates, test results, actions taken 
towards the subject, etc. Also, why it happened and how it was identified. 
 
Was the Medical Monitor or Sponsor notified. If so, their response? 
 
The PIs assessment of the impact on risk, safety and/or outcome. If no impact, why. If impact, 
what and what will happen next. 
 
The corrective actions that have been implemented to date and the impact of those corrective 
action plans. 
 
Future corrective action plans (if applicable) and the impact of those plans. 
 
If there are plans to amend the protocol (if applicable to prevent future deviations) and if not, 
why not. 
If the PI determines that the event had no potential to impact participant safety (harm and/or risk) or 
the integrity of data produced from the participant, the PI must fully document his/her rationale for each 
category (risk, harm, and participant data). 
7.5 
Events Requiring Prompt Reporting to the IRB including Unanticipated Problem Involving 
Risks to Subjects or Others Reporting Requirements 
Federal Regulation 21CFR §56.108(b)(1) and 45 CFR 46.103(b)(5) require the IRB to "follow written 
procedures for ensuring prompt reporting to the IRB…any unanticipated problems involving risk to 
human subjects or others." 
In alignment with 21 CFR 312, investigators are required to promptly report to the IRB: 
 (1) Unanticipated problems including suspected adverse reactions and adverse reactions. 
 
An event is considered a “suspected adverse reaction” when there is reasonable possibility that 
the drug/investigational product caused the adverse event.  For these reporting 
purposes, reasonable possibility means there is evidence to suggest a causal relationship 
between the drug/investigational product and the event. 
 
For University of Pennsylvania IRB reporting, this means an event should be considered 
probably or definitely related to the research procedures. 
 
An event is “unexpected” if it is not listed in the investigator’s brochure/package insert, or, is not 
listed at the specificity or severity that has previously been observed with the specific 
drug/investigational product; if an investigator’s brochure/package insert is not available, is not 
consistent with the risk information described in the general investigational plan.) 


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 
“Unexpected” also refers to events that are mentioned in the investigator’s brochure/package 
insert as occurring with a class of drugs or as anticipated, but, are not mentioned as to have 
been occurring (have been seen) with the particular drug/investigational product under study. 
 
(2) Unanticipated adverse device reaction. Any serious adverse effect on health or safety or any life-
threatening problem or death caused by, or associated with, a device, if that effect, problem, or death 
was not previously identified in nature, severity, or degree of incidence in the investigational plan or 
application (including a supplementary plan or application, or any other unanticipated serious problem 
associated with a device that relates to the rights, safety, or welfare of subjects. 
 
For drug/investigational product and device events, “serious” is defined as any death, life-
threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, a 
persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions, or a congenital anomaly/birth defect.  Other events that may be considered “serious” 
but not meet the prior criteria include: those events that may jeopardize the patient or subject 
and may require medical or surgical intervention to prevent one of the outcomes noted above. 
(3) In addition to unanticipated problems, the IRB also requires prompt reporting of the following events: 
 
Complaint of a participant when the complaint indicates unexpected risks or the complaint 
cannot be resolved by the research team. 
 
Violation or deviation (meaning an accidental or unintentional change to the IRB approved 
protocol) only when: one or more participants were placed at increased risk of harm, or, the 
event has the potential to occur again, the event represents serious or continuing 
noncompliance. 
(4)  Breach of confidentiality. 
(5) Incarceration of a participant when the research was not previously approved under Subpart C and 
the investigator believes it is in the best interest of the subject to remain on the study. 
This study will be monitored in accordance with the DSMC monitoring plan.  Dr. Dan Vogl will serve as 
medical monitor and will consult on decisions made as a part of this trial as noted above. 
7.5.1 
Definition of an Overdose for This Protocol and Reporting of Overdose to the Sponsor 
and to Merck 
For purposes of this trial, an overdose will be defined as any dose exceeding the prescribed dose for 
Pembrolizumab by 20% over the prescribed dose. No specific information is available on the treatment 
of overdose of Pembrolizumab. In the event of overdose, Pembrolizumab should be discontinued and 
the subject should be observed closely for signs of toxicity.  Appropriate supportive treatment should 
be provided if clinically indicated. 
If an adverse event(s) is associated with (“results from”) the overdose of 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 


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UPCC 25514 (IRB #820987) 
Pembrolizumab in Oligometastatic NSCLC 
 
 
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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) 
7.5.2 
Reporting of Pregnancy and Lactation to the Sponsor and to Merck 
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject (spontaneously 
reported to them), including the pregnancy of a male subject's female partner that occurs during the 
trial or within 120 days of completing the trial.  All subjects and female partners of male subjects who 
become pregnant must be followed to the completion/termination of the pregnancy.  Pregnancy 
outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, blighted ovum, fetal 
death, intrauterine death, miscarriage and stillbirth must be reported as serious events (Important 
Medical Events).  If the pregnancy continues to term, the 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) 
7.5.3 
Immediate Reporting of Adverse Events to the Sponsor and to Merck 
7.5.3.1 Serious Adverse Events 
A serious adverse event is any adverse event occurring at any dose or during any use of Merck’s 
product that: 
 
Results in death; 
 
Is life threatening; 
 
Results in persistent or significant disability/incapacity; 
 
Results in or prolongs an existing inpatient hospitalization; 
 
Is a congenital anomaly/birth defect; 
 
Is a new cancer (that is not a condition of the study); 
 
Is associated with an overdose; 
 
Is an other important medical event 
SAE reports and any other relevant safety information are to be forwarded to the Merck Global 
Safety facsimile number:  +1-215-993-1220 within two (2) business days of learning of the 
information. 
A copy of all 15 Day Reports and Annual Progress Reports is submitted as required by FDA, European 
Union (EU), Pharmaceutical and Medical Devices agency (PMDA) or other local regulators. 
Investigators will cross reference this submission according to local regulations to the Merck 
Investigational Compound Number (IND, CSA, etc.) at the time of submission.  Additionally 


Product:  Pembrolizumab 
UPCC 25514 (IRB #820987) 
Pembrolizumab in Oligometastatic NSCLC 
 
 
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investigators will submit a copy of these reports to Merck & Co., Inc. (Attn: Worldwide Product Safety; 
FAX 215 993-1220) at the time of submission to FDA. 
All subjects with serious adverse events must be followed up for outcome. 
7.5.3.2 Events of Clinical Interest 
Selected non-serious and serious adverse events are also known as Events of Clinical Interest (ECI) 
and must be recorded as such on the Adverse Event case report forms/worksheets and reported within 
24 hours to the Sponsor and within 2 working days to Merck Global Safety. (Attn: Worldwide Product 
Safety; FAX 215 993-1220) 
Events of clinical interest for this trial include: 
1.  an overdose of Merck product, as defined in Section 7.5.1 - Definition of an Overdose for This 
Protocol and Reporting of Overdose to the Sponsor, and to Merck 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.  The trial site guidance for assessment and follow up of these 
criteria can be found in the Investigator Trial File Binder (or equivalent). 
Subjects should be assessed for possible ECIs prior to each dose.  Lab results should be evaluated 
and subjects should be asked for signs and symptoms suggestive of an immune-related event.  
Subjects who develop an ECI thought to be immune-related should have additional testing to rule out 
other etiologic causes.  If lab results or symptoms indicate a possible immune-related ECI, then 
additional testing should be performed to rule out other etiologic causes.  If no other cause is found, 
then it is assumed to be immune-related. 
ECIs that occur in any subject from the date of first dose through 90 days following cessation of 
treatment, or the initiation of a new anticancer therapy, whichever is earlier, whether or not related to 
the Merck’s product, must be reported within 24 hours to the Sponsor and to Merck Global Safety 
within 2 working days. 
7.5.4 
Evaluating Adverse Events 
An investigator who is a physician or qualified designee will evaluate all adverse events according to 
the NCI Common Terminology for Adverse Events (CTCAE), version 4.0. Any adverse event which 
changes CTCAE grade over the course of a given episode will have each change of grade recorded 
on the adverse event case report forms/worksheets. 
All adverse events regardless of CTCAE grade must also be evaluated for seriousness. 
 


Product:  Pembrolizumab 
UPCC 25514 (IRB #820987) 
Pembrolizumab in Oligometastatic NSCLC 
 
 
Protocol/Amendment No 7: 03/06/2019 
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Table 10  Evaluating Adverse Events 
 
An investigator who is a physician or qualified designee, will evaluate all adverse events as to: 
V4.0 CTCAE 
Grading 
Grade 1 
Mild; asymptomatic or mid symptoms; clinical or 
diagnostic observations only; intervention not indicated. 
 
Grade 2 
Moderate; minimal, local or noninvasive intervention 
indicated; limiting age-appropriate instrumental ADL. 
 
Grade 3 
Severe or medically significant but not immediately life-
threatening; hospitalization or prolongation or 
hospitalization indicated; disabling; limiting self-care 
ADL. 
 
Grade 4 
Life threatening consequences; urgent intervention 
indicated. 
 
Grade 5 
Death related to AE 
 
Seriousness A serious adverse event is any adverse event occurring at any dose or 
during any use of Merck product that: 
 
†Results in death; or 
 
†Is life threatening; or places the subject, in the view of the investigator, 
at immediate risk of death from the event as it occurred (Note: This does 
not include an adverse event that, had it occurred in a more severe form, 
might have caused death.); or 
 
†Results in a persistent or significant disability/incapacity (substantial 
disruption of one’s ability to conduct normal life functions); or 
 
†Results in or prolongs an existing inpatient hospitalization 
(hospitalization is defined as an inpatient admission, regardless of length of 
stay, even if the hospitalization is a precautionary measure for continued 
observation. (Note: Hospitalization [including hospitalization for an elective 
procedure] for a preexisting condition which has not worsened does not 
constitute a serious adverse event.); or 
 
†Is a congenital anomaly/birth defect (in offspring of subject taking the 
product regardless of time to diagnosis);or 
 
Is a new cancer; (that is not a condition of the study) or 
 
Is an overdose (whether accidental or intentional).  Any adverse event 
associated with an overdose is considered a serious adverse event. An 
overdose that is not associated with an adverse event is considered a non-
serious event of clinical interest and must be reported within 24 hours. 


Product:  Pembrolizumab 
UPCC 25514 (IRB #820987) 
Pembrolizumab in Oligometastatic NSCLC 
 
 
Protocol/Amendment No 7: 03/06/2019 
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Table 10  Evaluating Adverse Events 
 
 
Other important medical events that may not result in death, not be life 
threatening, or not require hospitalization may be considered a serious 
adverse event when, based upon appropriate medical judgment, the event 
may jeopardize the subject and may require medical or surgical intervention 
to prevent one of the outcomes listed previously (designated above by a †). 
Duration 
Record the start and stop dates of the adverse event. If less than 1 day, 
indicate the appropriate length of time and units 
Action taken  Did the adverse event cause the Merck product to be discontinued? 
Relationship 
to Merck 
product 
Did the Merck product cause the adverse event? The determination of 
the likelihood that the Merck product caused the adverse event will be 
provided by an investigator who is a qualified physician. The 
investigator’s signed/dated initials on the source document or 
worksheet that supports the causality noted on the AE form, ensures 
that a medically qualified assessment of causality was done. This 
initialed document must be retained for the required regulatory time 
frame. The criteria below are intended as reference guidelines to assist 
the investigator in assessing the likelihood of a relationship between the 
test drug and the adverse event based upon the available information. 
The following components are to be used to assess the 
relationship between the Merck product and the AE; the greater the 
correlation with the components and their respective elements (in 
number and/or intensity), the more likely the Merck product caused the 
adverse event (AE): 
 
Exposure 
Is there evidence that the subject was actually exposed 
to the Merck product such as: reliable history, acceptable 
compliance assessment (pill count, diary, etc.), expected 
pharmacologic effect, or measurement of 
drug/metabolite in bodily specimen? 
 
Time 
Course 
Did the AE follow in a reasonable temporal sequence 
from administration of the Merck product? 
Is the time of onset of the AE compatible with a drug-
induced effect (applies to trials with investigational 
medicinal product)? 
 
Likely 
Cause 
Is the AE not reasonably explained by another etiology 
such as underlying disease, other drug(s)/vaccine(s), or 
other host or environmental factors 


Product:  Pembrolizumab 
UPCC 25514 (IRB #820987) 
Pembrolizumab in Oligometastatic NSCLC 
 
 
Protocol/Amendment No 7: 03/06/2019 
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Table 10  Evaluating Adverse Events 
 
Relationship 
to Merck 
product 
The following components are to be used to assess the relationship 
between the test drug and the AE: 
 
Dechallenge Was the Merck product discontinued or 
dose/exposure/frequency reduced? 
If yes, did the AE resolve or improve? 
If yes, this is a positive dechallenge. If no, this is a 
negative dechallenge. 
(Note: This criterion is not applicable if: (1) the AE resulted 
in death or permanent disability; (2) the AE 
resolved/improved despite continuation of the Merck 
product; or (3) the trial is a single-dose drug trial); or         
(4) Merck product(s) is/are only used one time.) 
 
Rechallenge Was the subject re-exposed to the Merck product in this 
study? 
If yes, did the AE recur or worsen? 
If yes, this is a positive rechallenge. If no, this is a 
negative rechallenge. 
(Note: This criterion is not applicable if: (1) the initial AE 
resulted in death or permanent disability, or (2) the trial is a 
single-dose drug trial); or (3) Merck product(s) is/are used 
only one time). 
NOTE: IF A RECHALLENGE IS PLANNED FOR AN 
ADVERSE EVENT WHICH WAS SERIOUS AND WHICH 
MAY HAVE BEEN CAUSED BY THE MERCK PRODUCT, 
OR IF REEXPOSURE TO THE MERCK PRODUCT 
POSES ADDITIONAL POTENTIAL SIGNIFICANT RISK TO 
THE SUBJECT, THEN THE RECHALLENGE MUST BE 
APPROVED IN ADVANCE BY THE U.S. CLINICAL 
MONITOR AS PER DOSE MODIFICATION GUIDELINES 
IN THE PROTOCOL. 
 
Consistency 
with Trial 
Treatment 
Profile 
Is the clinical/pathological presentation of the AE consistent 
with previous knowledge regarding the Merck product or 
drug class pharmacology or toxicology? 


Product:  Pembrolizumab 
UPCC 25514 (IRB #820987) 
Pembrolizumab in Oligometastatic NSCLC 
 
 
Protocol/Amendment No 7: 03/06/2019 
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Table 10  Evaluating Adverse Events 
 
The assessment of relationship will be reported on the case report forms /worksheets by an 
investigator who is a qualified physician according to his/her best clinical judgment, 
including consideration of the above elements. 
Record one 
of the 
following 
Use the following scale of criteria as guidance (not all criteria must be 
present to be indicative of a Merck product relationship). 
Yes, there is a reasonable 
possibility of Merck 
product relationship. 
There is evidence of exposure to the Merck product.  The 
temporal sequence of the AE onset relative to the 
administration of the Merck product is reasonable.  The AE 
is more likely explained by the Merck product than by 
another cause. 
No, there is not a 
reasonable possibility 
Merck product relationship 
Subject did not receive the Merck product OR temporal 
sequence of the AE onset relative to administration of the 
Merck product is not reasonable OR there is another 
obvious cause of the AE.  (Also entered for a subject with 
overdose without an associated AE.) 
 
7.5.5 
Sponsor Responsibility for Reporting Adverse Events 
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in accordance 
with all applicable global laws and regulations. 
8.0 STATISTICAL ANALYSIS PLAN 
8.1 
Statistical Analysis Plan Summary 
The statistical analysis of the data obtained from this study will be the responsibility of the Biostatistics 
Core Facility of the Abramson Cancer Center. 
8.2 
Statistical Analysis Plan 
8.2.1 
Hypothesis/Evaluation 
Objectives and hypotheses of the study are stated in Section 3.  The primary intent-to-treat analysis 
will estimate PFS from start of Pembrolizumab. A secondary proof of principle analysis will evaluate 
the benefit of adding Pembrolizumab after definitive therapy, determined by testing whether PFS is 
improved as compared an historical control population who received definitive therapy only. For this 
analysis, PFS is defined from the start of definitive therapy, which precedes enrollment on this trial. 
Since all patients signed informed consent agreeing that treatment history may be collected and 
analyzed, as part of this study, PFS from initiation of definitive therapy may be analyzed in a 
secondary analysis. For this proof of principle analysis, the null hypothesis is that the median PFS from 
start of definitive therapy is 6.6 months as compared to the alternative hypothesis that the median PFS 
is increased to 10 months. The study is considered to have met this objective if we reject the null 
hypothesis. 


Product:  Pembrolizumab 
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Pembrolizumab in Oligometastatic NSCLC 
 
 
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8.2.2 
Analysis Endpoints 
Primary 
There are two primary endpoints of this study: progression free survival (PFS) and tolerability of 
therapy. 
Progression Free Survival (PFS) from initiation of Pembrolizumab per RECIST 1.1 
For the primary analysis, Progression Free Survival is defined as the time from initiation of 
Pembrolizumab to the first documented disease progression per RECIST 1.1 based on radiologists’ 
review or death due to any cause, whichever occurs first or last patient follow-up that documented lack 
of disease progression. Since by definition all patients will have NED at time of enrollment, all 
instances of progressive disease will refer to new sites of disease.  Patients who have not had disease 
progression or who have died, will be censored on most recent clinical evaluation date that 
documented that they were progression-free. 
Tolerability of Therapy 
Tolerability of therapy will be determined on the basis of CTCAE adverse event reporting. 
Secondary 
Progression Free Survival (PFS) from start of definitive therapy 
For the secondary analysis, Progression Free Survival is defined as the time from initiation of definitive 
therapy to the first documented disease progression, whichever occurs first or last patient follow-up 
that documented lack of disease progression. Patients who have not had disease progression or who 
have died, will be censored on most recent clinical evaluation date that documented that they were 
progression-free. 
Overall Survival 
Overall Survival (OS) is defined as the time from initiation of Pembrolizumab to death due to any cause 
or last patient contact alive.  Subjects without documented death at the time of the final analysis will be 
censored at the date of the last follow-up. 
Progression Free Survival (PFS) per irRC 
Progression free survival is defined as the time from initiation of Pembrolizumab to the first 
documented disease progression per irRC based on investigators’ review or death due to any cause, 
whichever occurs first or last patient follow-up that documented lack of disease progression. 
Patient Reported Quality of Life 
FACT-L will be assessed in an exploratory analysis.  FACT-L is not a pure efficacy or safety endpoint, 
because it is affected by both disease progression and treatment tolerability. 
8.2.3 
Analysis Populations 
8.2.3.1 Efficacy Analysis Populations 
The analysis of primary efficacy endpoints is based on the intention -to-treat (ITT) population. A 
supportive analysis will be conducted in the full analysis set (FAS) that excludes those who did not 
meet the eligibility criteria or discontinued before receiving any dose of assigned treatment. 


Product:  Pembrolizumab 
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Pembrolizumab in Oligometastatic NSCLC 
 
 
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8.2.3.2 Safety Analysis Populations 
The All Patients as Treated (APaT) population will be used for the analysis of safety data in this study. 
The APaT population consists of all enrolled subjects who received at least one dose of study 
treatment. At least one laboratory or vital sign measurement obtained subsequent to at least one dose 
of trial treatment is required for inclusion in the analysis of each specific parameter. To assess change 
from baseline, a baseline measurement is also required. 
8.2.4 
Statistical Methods 
Primary Objectives 
1. The primary intent-to-treat analysis will estimate progression free survival from initiation of 
study therapy (Pembrolizumab) by the Kaplan-Meier method. Median PFS and 95% CI will be 
determined. 
2. A secondary proof of principle analysis will determine the clinical benefit of adding 
consolidation Pembrolizumab after definitive therapy. In this proof of principle analysis, we will 
compare progression free survival from initiation of definitive therapy to that of a historical 
control population who only received definitive therapy. This is the optimal comparator for our 
study population. We assume the median PFS for the historical control population treated with 
definitive therapy only is 6.6 months and the median PFS for the patients treated with definitive 
therapy and consolidation Pembrolizumab is 10 months. Assuming 47 patients are enrolled 
over 2 years and followed for an additional 12 months, the final analysis will have 80% power to 
detect an improvement in median PFS assuming exponential survival and 1-sided 5% 
significance level.  This trial design was deliberately structured to be slightly underpowered, 
given concerns that the patient population would be difficult to identify and accrual would be 
difficult.  In the case of robust accrual, however, we will plan to accrue up to 5 additional 
patients for a maximum sample size of 47 patients. 
3. Toxicities will be graded, categorized and tabled. 
 
Secondary Objectives 
1. Trends over time in QOL scores will first be visualized with boxplots and then will be analyzed 
with descriptive statistics (i.e., mean+SE). An exploratory analysis will compare baseline and 
end of treatment (at 6 months) QOL scores within patients using the Student’s t test for paired 
data (or by the nonparametric Wilcoxon signed ranks test, if necessary). Longitudinal methods, 
such as linear mixed effects models, will be used to examine trends over time in QOL scores. 
2. Overall survival will be estimated by the Kaplan-Meier method. Median OS and 95% CI will be 
determined. 


Product:  Pembrolizumab 
UPCC 25514 (IRB #820987) 
Pembrolizumab in Oligometastatic NSCLC 
 
 
Protocol/Amendment No 7: 03/06/2019 
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9.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES 
9.1 
Investigational Product 
The investigator shall take responsibility for and shall take all steps to maintain appropriate records 
and ensure appropriate supply, storage, handling, distribution and usage of investigational product in 
accordance with the protocol and any applicable laws and regulations. 
Clinical Supplies will be provided by Merck as summarized in Table 11. 
Table 11  Product Descriptions 
Product Name & Potency 
Dosage Form 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
 
9.2 
Packaging and Labeling Information 
Clinical supplies will be affixed with a clinical label in accordance with regulatory requirements. 
9.3 
Clinical Supplies Disclosure 
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or designee are 
not blinded to treatment. Drug identity (name, strength) is included in the label text; random 
code/disclosure envelopes or lists are not provided. 
9.4 
Storage and Handling Requirements 
Clinical supplies must be stored in a secure, limited-access location under the storage conditions 
specified on the label.  They will be stored in the Investigational Drug Pharmacy as part of the 
Abramson Cancer Center. 
Receipt and dispensing of trial medication must be recorded by an authorized person at the trial site. 
Clinical supplies may not be used for any purpose other than that stated in the protocol. 
9.5 
Returns and Reconciliation 
The investigator is responsible for keeping accurate records of the clinical supplies received from 
Merck or designee, the amount dispensed to and returned by the subjects and the amount remaining 
at the conclusion of the trial. 
Upon completion or termination of the study, all unused and/or partially used investigational product 
will be destroyed at the site per institutional policy. It is the Investigator’s responsibility to arrange for 
disposal of all empty containers, provided that procedures for proper disposal have been established 
according to applicable federal, state, local and institutional guidelines and procedures, and provided 
that appropriate records of disposal are kept. 


Product:  Pembrolizumab 
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10.0 ADMINISTRATIVE AND REGULATORY DETAILS 
10.1 Confidentiality 
10.1.1 Confidentiality of Data 
By signing this protocol, the investigator affirms to the Sponsor that information furnished to the 
investigator by the Sponsor will be maintained in confidence, and such information will be divulged to 
the institutional review board, ethics review committee (IRB/ERC) or similar or expert committee; 
affiliated institution and employees, only under an appropriate understanding of confidentiality with 
such board or committee, affiliated institution and employees. Data generated by this trial will be 
considered confidential by the investigator, except to the extent that it is included in a publication as 
provided in the Publications section of this protocol. 
10.1.2 Confidentiality of Subject Records 
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/ERC, or regulatory authority representatives may consult and/or copy trial documents in order to 
verify worksheet/case report form data. By signing the consent form, the subject agrees to this 
process. If trial documents will be photocopied during the process of verifying worksheet/case report 
form information, the subject will be identified by unique code only; full names/initials will be masked 
prior to transmission to the Sponsor. 
By signing this protocol, the investigator agrees to treat all subject data used and disclosed in 
connection with this trial in accordance with all applicable privacy laws, rules and regulations. 
10.1.3 Confidentiality of Investigator Information 
By signing this protocol, the investigator recognizes that certain personal identifying information with 
respect to the investigator, and all subinvestigators and trial site personnel, may be used and disclosed 
for trial management purposes, as part of a regulatory submissions, and as required by law. This 
information may include: 
1. Name, address, telephone number and e-mail address; 
2. Hospital or clinic address and telephone number; 
3. Curriculum vitae or other summary of qualifications and credentials; and 
4. Other professional documentation. 
Consistent with the purposes described above, this information may be transmitted to the Sponsor, 
and subsidiaries, affiliates and agents of the Sponsor, in this and other countries, including countries 
that do not have laws protecting such information. 
Additionally, the investigator’s name and business contact information may be included when reporting 
certain serious adverse events to regulatory authorities or to other investigators. By signing this 
protocol, the investigator expressly consents to these uses and disclosures. 
10.2 Compliance with Financial Disclosure Requirements 
Financial Disclosure requirements are outlined in the US Food and Drug Administration Regulations, 
Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the Sponsor's responsibility to 
determine, based on these regulations, whether a request for Financial Disclosure information is 
required. It is the investigator's/ subinvestigator's responsibility to comply with any such request. 


Product:  Pembrolizumab 
UPCC 25514 (IRB #820987) 
Pembrolizumab in Oligometastatic NSCLC 
 
 
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The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 CFR Part 54, 
to provide his/her financial interests in and/or arrangements with the Sponsor to allow for the submission 
of complete and accurate certification and disclosure statements. The investigator/subinvestigator(s) 
further agree to provide this information on a Certification/Disclosure Form, commonly known as a 
financial disclosure form, provided by the Sponsor or through a secure password-protected electronic 
portal provided by the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes. This may involve the transmission of 
information to countries that do not have laws protecting personal data. 
 
10.3 Compliance with Law, Audit and Debarment 
By signing this protocol, the investigator agrees to conduct the trial in an efficient and diligent manner 
and in conformance with this protocol; generally accepted standards of Good Clinical Practice (e.g., 
International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use Good Clinical Practice: Consolidated Guideline and other generally 
accepted standards of good clinical practice); and all applicable federal, state and local laws, rules and 
regulations relating to the conduct of the clinical trial. 
The investigator also agrees to allow monitoring, audits, IRB/ERC review and regulatory authority 
inspection of trial-related documents and procedures and provide for direct access to all trial-related 
source data and documents. 
The investigator agrees not to seek reimbursement from subjects, their insurance providers or from 
government programs for procedures included as part of the trial reimbursed to the investigator by the 
Sponsor. 
The investigator shall prepare and maintain complete and accurate trial documentation in compliance 
with Good Clinical Practice standards and applicable federal, state and local laws, rules and 
regulations; and, for each subject participating in the trial, provide all data, and, upon completion or 
termination of the clinical trial, submit any other reports to the Sponsor as required by this protocol or 
as otherwise required pursuant to any agreement with the Sponsor. 
Trial documentation will be promptly and fully disclosed to the Sponsor by the investigator upon 
request and also shall be made available at the trial site upon request for inspection, copying, review 
and audit at reasonable times by representatives of the Sponsor or any regulatory authorities. The 
investigator agrees to promptly take any reasonable steps that are requested by the Sponsor as a 
result of an audit to cure deficiencies in the trial documentation and worksheets/case report forms. 
The investigator must maintain copies of all documentation and records relating to the conduct of the 
trial in compliance with all applicable legal and regulatory requirements. This documentation includes, 
but is not limited to, the protocol, worksheets/case report forms, advertising for subject participation, 
adverse event reports, subject source data, correspondence with regulatory authorities and 
IRBs/ERCs, consent forms, investigator’s curricula vitae, monitor visit logs, laboratory reference 
ranges, laboratory certification or quality control procedures and laboratory director curriculum vitae. 
By signing this protocol, the investigator agrees that documentation shall be retained until at least 2 
years after the last approval of a marketing application in an ICH region or until there are no pending or 
contemplated marketing applications in an ICH region or until at least 2 years have elapsed since the 
formal discontinuation of clinical development of the investigational product. Because the clinical 
development and marketing application process is variable, it is anticipated that the retention period 
can be up to 15 years or longer after protocol database lock. The Sponsor will determine the minimum 


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Pembrolizumab in Oligometastatic NSCLC 
 
 
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retention period and notify the investigator when documents may be destroyed. The sponsor also 
recognizes that documents may need to be retained for a longer period if required by local regulatory 
requirements. All trial documents shall be made available if required by relevant regulatory authorities. 
The investigator must consult with and obtain written approval by the Sponsor prior to discarding trial 
and/or subject files. 
ICH Good Clinical Practice guidelines recommend that the investigator inform the subject’s primary 
physician about the subject’s participation in the trial if the subject has a primary physician and if the 
subject agrees to the primary physician being informed. 
The investigator will promptly inform the Sponsor of any regulatory authority inspection conducted for 
this trial. 
Persons debarred from conducting or working on clinical trials by any court or regulatory authority will 
not be allowed to conduct or work on this Sponsor’s trials. The investigator will immediately disclose in 
writing to the Sponsor if any person who is involved in conducting the trial is debarred or if any 
proceeding for debarment is pending or, to the best of the investigator’s knowledge, threatened. 
In the event the Sponsor prematurely terminates a particular trial site, the Sponsor will promptly notify 
that trial site’s IRB/IEC. 
10.4 Compliance with Trial Registration and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the Food and 
Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely responsible for 
determining whether the trial and its results are subject to the requirements for submission to the 
Clinical Trials Data Bank, http://www.clinicaltrials.gov.  Information posted will allow subjects to identify 
potentially appropriate trials for their disease conditions and pursue participation by calling a central 
contact number for further information on appropriate trial locations and trial site contact information. 
10.5 Quality Management System 
By signing this protocol, the Sponsor agrees to be responsible for implementing and maintaining a 
quality management system with written development procedures and functional area standard 
operating procedures (SOPs) to ensure that trials are conducted and data are generated, documented, 
and reported in compliance with the protocol, accepted standards of Good Clinical Practice, and all 
applicable federal, state, and local laws, rules and regulations relating to the conduct of the clinical 
trial. 
10.6 Data Management 
The investigator or qualified designee is responsible for recording and verifying the accuracy of subject 
data. By signing this protocol, the investigator acknowledges that his/her electronic signature is the 
legally binding equivalent of a written signature. By entering his/her electronic signature, the 
investigator confirms that all recorded data have been verified as accurate. 
Detailed information regarding Data Management procedures for this protocol will be provided by the 
Sponsor. 
10.7 Publications 
This trial is intended for publication, even if terminated prematurely. Publication may include any or all 
of the following: posting of a synopsis online, abstract and/or presentation at a scientific conference, or 


Product:  Pembrolizumab 
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Pembrolizumab in Oligometastatic NSCLC 
 
 
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publication of a full manuscript. The Sponsor will work with the authors to submit a manuscript 
describing trial results within 12 months after the last data become available, which may take up to 
several months after the last subject visit in some cases such as vaccine trials. However, manuscript 
submission timelines may be extended on OTC trials. 
These timelines may be extended for products that are not yet marketed, if additional time is needed 
for analysis, to protect intellectual property, or to comply with confidentiality agreements with other 
parties. Authors of the primary results manuscript will be provided the complete results from the 
Clinical Study Report, subject to the confidentiality agreement. When a manuscript is submitted to a 
biomedical journal, the Sponsor's policy is to also include the protocol and statistical analysis plan to 
facilitate the peer and editorial review of the manuscript. If the manuscript is subsequently accepted for 
publication, the Sponsor will allow the journal, if it so desires, to post on its website the key sections of 
the protocol that are relevant to evaluating the trial, specifically those sections describing the trial 
objectives and hypotheses, the subject inclusion and exclusion criteria, the trial design and 
procedures, the efficacy and safety measures, the statistical analysis plan, and any amendments 
relating to those sections. The Sponsor reserves the right to redact proprietary information. 
Authorship credit should be based on 1) substantial contributions to conception and design, or 
acquisition of data, or analysis and interpretation of data; 2) drafting the article or revising it critically for 
important intellectual content; and 3) final approval of the version to be published. Authors must meet 
conditions 1, 2 and 3. Significant contributions to trial execution may also be taken into account to 
determine authorship, provided that contributions have also been made to all three of the preceding 
authorship criteria. Although publication planning may begin before conducting the trial, final decisions 
on authorship and the order of authors’ names will be made based on participation and actual 
contributions to the trial and writing, as discussed above. The first author is responsible for defending 
the integrity of the data, method(s) of data analysis and the scientific content of the manuscript. 
The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or presentations 
regarding this trial 45 days prior to submission for publication/presentation. Any information identified 
by the Sponsor as confidential must be deleted prior to submission; this confidentiality does not include 
efficacy and safety results. Sponsor review can be expedited to meet publication timelines. 


Product:  Pembrolizumab 
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Pembrolizumab in Oligometastatic NSCLC 
 
 
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11.0 APPENDICES 
11.1 ECOG Performance Status 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, 
but unable to carry out any work activities. Up and about more than 
50% of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-
care. Totally confined to bed or chair. 
5 
Dead. 
* As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., 
Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: Toxicity And Response 
Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 
1982. The Eastern Cooperative Oncology Group, Robert Comis M.D., Group Chair. 
 
11.2 Common Terminology Criteria for Adverse Events V4.0 (CTCAE) 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0 will be utilized for adverse event reporting. 
(http://ctep.cancer.gov/reporting/ctc.html) 
 
11.3 Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for Evaluating 
Response in Solid Tumors 
RECIST version 1.1* will be used in this study for assessment of tumor response. While either CT or 
MRI may be utilized, as per RECIST 1.1, CT is the preferred imaging technique in this study. 
* As published in the European Journal of Cancer: 
 
E.A. Eisenhauer, P. Therasse, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J. Dancey, S. 
Arbuck, S. Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. Kaplan, D. Lacombe, J. 
Verweij. New response evaluation criteria in solid tumors: Revised RECIST guideline (version 1.1). Eur 
J Cancer. 2009 Jan;45(2):228-47. 
 


Product:  Pembrolizumab 
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enhances T cell activation and cytokine production. J Immunol 2003;170(3):1257-66. 
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2009;58(3):449-59. 


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Pembrolizumab in Oligometastatic NSCLC 
 
 
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