Clinical trial NCT02303990
Conditions: Metastatic Cancers
Sponsor: Abramson Cancer Center at Penn Medicine
Start date: 2015-01-08; Completion date: 2019-12-31
Enrollment: 59 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Phase I clinical trial of hypofractionated radiotherapy to an isolated index lesion in combination with the PD-1 inhibitor, Pembrolizumab in patients with metastatic cancers who have failed anti-PD-1 therapy (melanoma and NSCLC) and patients with metastatic cancers who have have progressed after at least one regimen of systemic therapy (breast, pancreas, and other).

Detailed description:

Arms: arm 1: Hypofractionated RT and Pembro
Interventions: intervention 1: Pembrolizumab intervention 2: Radiotherapy
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
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RADVAX™: A STRATIFIED PHASE I TRIAL OF PEMBROLIZUMAB 
WITH HYPOFRACTIONATED RADIOTHERAPY IN PATIENTS WITH 
ADVANCED AND METASTATIC CANCERS 
 
Principle Investigator:  Amit Maity, MD, PhD 
                                      Radiation Oncology 
 
 
 
  3400 Civic Center Boulevard, TRC 2 West 
 
 
 
  Perelman Center for Advanced Medicine 
 
 
 
  Philadelphia, PA 19104 
 
 
 
  215-662-2428 
 
 
 
  Amit.maity@uphs.upenn.edu 
 
Sub Investigators:  Lynn Schuchter, MD 
 
 
       Ravi Amaravadi, MD 
 
 
       Tara Gangadhar, MD 
 
                    Robert Vonderheide, MD, D.Phil 
 
 
       Corey J. Langer, MD 
 
 
       Tracey L. Evans, MD 
 
 
       Charu Aggarwal, MD, MPH 
 
 
       Peter O’Dwyer, MD 
 
  
       Ursina Teitelbaum, MD 
 
 
       Arturo Loaiza-Bonilla, MD 
 
 
       David J. Vaughn, MD 
 
                   Angela M. DeMichele, MD, MSCE 
                                Kevin R. Fox, MD 
                               Susan M. Domchek, MD 
 
 
 
                                Roger B. Cohen, MD 
 
 
      Amy S. Clark, MD, MSCE 
 
 
      Charles B. Simone, II, MD 
                               Abigail T. Berman, MD 
                               Alexander Lin, MD 
                               Lilie Lin, MD 
                               Gary M. Freedman, MD 
 
 
      J. Nicolas Lukens, MD 
                               Edgar Ben-Josef, MD 
                               John Christodouleas, MD, MPH 
                               Samuel Swisher-McClure, MD 
                               E. John Wherry, PhD 
 
 
     Daniel A. Pryma, MD 
 
 
     Naomi B. Haas, MD 
 
 
     John P. Christodouleas, MD 
 
 
     Rosemarie Mick, MS 
 
  
     Fiona Simpkins, MD 
 
                   Mark A. Morgan, MD 
 
 
      Kim Reiss-Binder, MD 


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      Michael Farwell, MD 


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1.0                     TRIAL SUMMARY 
Abbreviated Title 
RadVax™: 
 
Pembrolizumab 
& 
Hypofractionated 
Radiotherapy 
Phase 
Phase I 
Clinical Indication 
Metastatic cancers 
Trial Type 
Phase I cohort with randomized expansion phase 
Type of control 
N/A 
Route of administration 
i.v. 
Trial Blinding 
N/A 
Treatment Groups  
2 radiotherapy cohorts; 5 disease cohorts 
Number of trial subjects 
70 
Estimated duration of trial 2 years 
Duration of Participation 
3 months 
 
 
 
IRB #: 821403 
UPCC#: 40914 
 
Original Version: February 3, 2015 
 
 
 
 
This document is a protocol for a human research study. This study is to be conducted 
according to US and international standards of Good Clinical Practice (FDA Title 21 part 312 
and International Conference on Harmonization guidelines), applicable government 
regulations and Institutional research policies and procedures.  
 


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2.0 TRIAL DESIGN 
2.1 
Trial Design 
This is a Phase I cohort study of a fixed dose of Pembrolizumab in combination with two 
distinct regimens of hypofractionated radiotherapy.  There will be five groups of patient 
diagnoses: 
• Metastatic melanoma patients who have progressed while on PD-1 or PDL-1therapy 
• Metastatic NSCLC patients who have progressed while on PD-1 or PDL-1 therapy 
• Metastatic & locally advanced pancreatic cancer patients 
• Metastatic Breast cancer patients 
• Other metastatic cancer patients 
 
Pembrolizumab will be administered at a dose of 200 mg every 3 weeks beginning 7 days 
(+/- 3 days) prior to the first fraction of hypofractionated radiation and will continue for a 
total of 6 cycles.  In the initial Safety Phase, there will be two cohorts of patients based upon 
the radiotherapy dose delivered to the index metastatic lesion in the lung, liver, bone or soft 
tissue: 
Cohort 1:  8 Gy x 3 to the index lesion  
Cohort 2: 17 Gy x 1 to the index lesion* 
*Subjects with locally advanced pancreatic cancer will be enrolled only in the 8 Gy x 3 
cohort. 
Patients are stratified by prior PD-1 therapy. 24 patients will be enrolled, 12 per stratum and 
6 per fractionation cohort.  Standard safety decision-making will be used.  The regimen is 
safe if 0-1 dose-limiting toxicities (DLT) in 6 patients (3 from each strata). Enrollment in a 
cohort will stop if 2+ DLT are observed within a cohort at any time during the safety phase.  
If 2+ DLT are observed in Cohort 1, then Cohort 2 will still be tested. Cohort 1  Cohort 2 
is not an escalation of dose.  DLT is defined as any Grade 3 or higher non-hematological 
toxicity and any Grade 4 hematological toxicity that is probably, possibly or definitely 
related to the combination of Pembrolizumab and hypofractionated radiotherapy. The 
window in which DLTs will be recorded is from the first Pembrolizumab infusion to 35 days 
after the last radiation fraction. 
In the Expansion Phase, patients will be stratified by disease site. If both fractionation 
regimens are safe, then we randomize patients. Otherwise, all patients will be enrolled on the 
single regimen determined to be safe.  46 patients will be enrolled. Randomization will aid in 
the preliminary assessment of clinical response by avoiding selection bias. Accrual is 
expected to occur over 24 months or 3-4 subjects per month. 


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2.2 
Trial Diagram 
 
3.0 OBJECTIVE(S & HYPOTHESIS(ES) 
3.1 
Primary Objective(s) & Hypothesis(es) 
(1) Objective:  To determine the safety of combining Pembrolizumab with hypofractionated 
radiotherapy in patients with advanced and metastatic cancers. 
Hypothesis:  Pembrolizumab will be safe and well tolerated in patients with advanced 
and metastatic cancers when combined with hypofractionated radiotherapy. 
3.2 
Secondary Objectives 
Objective:  To estimate the immune-related response rate in non-index metastatic lesions of 
the combination of Pembrolizumab and hypofractionated radiotherapy 
 
 
3.3 
Exploratory Objective 
(1) Objective:  To explore the immune pharmacodynamic changes after treatment with 
the combination of Pembrolizumab and hypofrationated radiotherapy 
(2) Objective:  To explore the relationship between PD-1 expression and response to 
Pembrolizumab and hypofractionated radiotherapy 
 
 
4.0 BACKGROUND & RATIONALE 
4.1 
Background 
              Historically patients with metastatic disease from epithelial cancers have rarely been 
cured. The 5-year survival rates for patients diagnosed between 2004 and 2010 with 


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metastatic NSCLC, melanoma, and breast cancer are respectively 4%, 16%, and 25% 
(http://seer.cancer.gov/statfacts/).  Pancreatic cancer, regardless of stage has a poor 
prognosis, with an overall survival rate of 6.7%. For patients with localized pancreatic 
cancer, survival is 25.8%, with regional disease 9.9% and with distant metastases 2.3%.   
Hypofractionated radiotherapy for oligometastatic disease 
 
Hypofractionated radiotherapy for metastatic disease is commonly delivered with 
stereotactic body radiotherapy (SBRT) in which several non-coplanar photon beams are used 
to treat a tumor with a high degree of conformality resulting in little dose to surrounding 
normal tissues.   SBRT has proven to be an effective local treatment for small, localized 
tumors. Initially, it was integrated as an ablative approach with a goal of tumor sterilization 
in oligometastatic disease with minimal morbidity and good long-term clinical outcome in 
these highly selected patients (1-4). Our goal in this protocol is different; we propose to use 
is hypofractionated radiotherapy, either with or without an SBRT technique, to irradiate a 
single lesion in the setting of immune checkpoint blockade with the hope of augmenting a 
systemic response.   
Immunologic approaches to treating patients with advanced stage cancer 
Due to these poor survival rates, many different approaches have been tried for 
patients with advanced stage cancers.  In particular, recent studies have shown benefit from 
immunotherapy. T lymphocytes are prime mediators of tumor immunosurveillance. Several 
immune checkpoint receptors are expressed on T cells that downregulate the activity of these 
cells after they have been activated.  Hence, inhibition of these regulatory molecules is a 
means of augmenting anti-tumor response. Cytotoxic T-lymphocyte antigen-4 (CTLA-4; 
CD152) is a cell-surface receptor that is expressed (within approximately 72 hours in vitro) 
on T-lymphocytes in response to the activation by interaction with APCs or pharmacologic 
stimulation of the T-cell receptor (5). CTLA-4 activation downregulates T-cell proliferation 
and cytokine secretion, effectively limiting the immune reactivity directed against a given 
antigen stimulus. Therefore, inhibition of CTLA4 using an antibody is a potential strategy to 
prevent downregulation of the immune response. In 2010 Hodi et al. published the first phase 
III randomized trial demonstrating a survival benefit in patients with metastatic melanoma 
treated with ipilimumab, a fully human monoclonal antibody (IgG1) that blocks CTLA-4 (6).  
Based on this trial the drug was approved for use by the FDA in March 2011 for patients with 
metastatic melanoma.   
Another immunomodulatory receptor that has garnered a great deal of attention is 
Programmed Death-1 (PD-1).  PD-1 signaling involves binding to several discrete ligands, 
including PD-L1 and PD-L2. PD-L1 is often expressed within the tumor microenvironment 
by cancer cells and macrophages whereas PD-L2 is expressed primarily on professional 
antigen presenting cells (5).  PD-1 negatively regulates the effector phase of the T cell 
response after ligation of PD-L1 to the receptor.  Antibodies that block the PD-L1/PD-1 
interaction prevent the downregulation of the anti-tumor immune response, hence 
augmenting the cytotoxic function of tumor-specific T cells.  


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Several PD-1 inhibitors have been used in large clinical trials.  PEMBROLIZUMAB 
is a highly selective, humanized monoclonal antibody (IgG4) that blocks PD-1.  Its safety 
and efficacy (response rate of 38% by RECIST criteria) have been demonstrated in 
melanoma (7) . Another PD-1 inhibitor, BMS-936558, was found to be safe and to yield 
response rates (by RECIST) of 18%, 28%, 27% respectively in patients with advanced stage 
non-small lung cancer, melanoma and renal cell carcinoma (8).   
Hypofractionated radiotherapy and immune activation 
 
The effectiveness of the immunologic strategy outlined above is contingent upon T-
lymphocyte activation through interaction with the APC having already occurred.  Therefore, 
the development of novel strategies that successfully “vaccinate” patients to their cancer near 
the time of the delivery of the immunomodulatory antibody is an important area of clinical 
research.  One means of potentially increasing exposure of T cells to tumor antigen is to 
expose the tumors to a few large fractions of radiation (hypofractionated radiotherapy).   
There is emerging evidence that radiotherapy (RT) can stimulate the immune 
response, by a variety of mechanisms such as increasing TLR4 expression on dendritic cells, 
increasing priming of T cells in draining lymph nodes, and increasing tumor cell antigen 
presentation by dendritic cells (reviewed in (9)). Recently Verbrugge et al. showed that 
radiotherapy can enrich tumors of functionally active, tumor-specific effector cells (10). Lee 
et al. demonstrated that the therapeutic effect with ablative hypofractionated radiotherapy on 
local tumor control required activation of CD8+ T- lymphocytes  (11).   
Hypofractionated radiation has also been shown to potentiate systemic response to 
immunomodulatory therapy.  A single large dose of RT increased the effects of Flt-3 ligand 
administration on distant pulmonary metastases, an effect that was only seen in 
immunocompetent C57Bl/6 mice, not immunodeficient nude mice (12).  Hypofractionated 
radiation has also been shown to amplify immune response to traditional vaccines (13).  
Additionally, there are pre-clinical data to suggest that CTLA-4 blockade along with ablative 
radiotherapy to an index lesion can prevent the growth of a tumor outside the irradiated field 
(abscopal effect) through an immune-mediated effect (14).  
In addition to these pre-clinical data, Postow et al. reported a patient with metastatic 
melanoma having progressive disease while on ipilimumab therapy who then underwent a 
course of hypofractionated RT to a painful paraspinal mass.  The patient received a dose of 
ipilimumab two months after RT, and then had radiologic imaging two months after this, 
which showed radiologic regression of disease in the irradiated site as well as in regions 
outside the radiation fields (15).  
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; 3; 4; 5; 6].  In particular, the presence of CD8+ T-cells and the ratio 


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of CD8+ effector T-cells / FoxP3+ regulatory T-cells seems to correlate with improved 
prognosis and long-term survival in many solid tumors. 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control.  The normal function of PD-1, expressed on the cell surface of activated T-
cells under healthy conditions, is to down-modulate unwanted or excessive immune 
responses, including autoimmune reactions.  PD-1 (encoded by the gene Pdcd1) is an Ig 
superfamily member related to CD28 and CTLA-4 which has been shown to negatively 
regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2) [7; 
8].  The structure of murine PD-1 has been resolved [9].  PD-1 and family members are type 
I transmembrane glycoproteins containing an Ig Variable-type (V-type) domain responsible 
for ligand binding and a cytoplasmic tail which is responsible for the binding of signaling 
molecules.  The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an 
immunoreceptor tyrosine-based inhibition motif (ITIM) and an immunoreceptor tyrosine-
based switch motif (ITSM).  Following T-cell stimulation, PD-1 recruits the tyrosine 
phosphatases SHP-1 and SHP-2 to the ITSM motif within its cytoplasmic tail, leading to the 
dephosphorylation of effector molecules such as CD3ζ, PKCθ and ZAP70 which are 
involved in the CD3 T-cell signaling cascade [7; 10; 11; 12].  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 [13; 14].  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 [15; 16].  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 [18; 19; 20; 13].  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 [13].  Although healthy organs express little (if any) PD-L1, a variety of 
cancers were demonstrated to express abundant levels of this T-cell inhibitor.  PD-1 has been 
suggested to regulate tumor-specific T-cell expansion in subjects with melanoma (MEL) 
[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 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.   
4.1.2 Preclinical and Clinical Trial Data 
Refer to the Investigator’s Brochure for Preclinical and Clinical data. 


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4.2 
Rationale 
Current RADVAX™ trial at Penn using hypofractionated RT and ipilumumab  
 
Simulated by our own anecdotal report of a patient having progressive disease on 
immunomodulatory therapy who had a dramatic abscopal response to radiotherapy, we 
initiated a phase I/II trial at Penn to determine whether it would be safe to deliver ipilimumab 
following hypofractionated radiotherapy. Patients received either 2 or 3 fractions of 
radiotherapy, followed by 4 cycles of the anti-CTLA4 agent ipilimumab.  By trial design 
patients were required to have at least two discrete metastatic lesions from melanoma, only 
one of which was irradiated.   
 
The primary goal of the trial was to assess safety.  To date 21 patients have been 
enrolled. Overall treatment was well tolerated with no deaths attributable to therapy and no 
grade 4 toxicities.  The most common grade 3 toxicity was anemia. There were no dose-
limiting toxicities (DLTs), which for this study was defined as any grade 4 or higher immune 
treatment-related toxicity or grade 3 or higher non-immune treatment (RT-related) toxicity.  
Fourteen patients completed the entire 4 cycles of ipilimumab (2 patients completed only 2 
cycles and 2 patients only 3 cycles due to progressive disease; 2 patients received only 3 
cycles due to the development of colitis). 
 
The impact of the therapy on the irradiated lesion and the non-irradiated lesion(s) was 
evaluated using two standard modalities: (i) 18F-2-deoxyfluoro-2-deoxyglucose (FDG) 
activity on positron emission tomography-computer tomography (PET-CT) as a measure of 
biological effects of therapy and (ii) CT imaging for Response Evaluation Criteria in Solid 
Tumors (RECIST 1.1) assessment. 19 patients have been followed long enough to evaluate 
radiologic response.  Metabolic responses were observed by FDG-PET-CT in the irradiated 
(“index”) lesion in 9 out of 19 patients (47%) with 4 of these 9 patient showing a complete 
metabolic response (CMR) and 5 of the 9 showing a partial metabolic response (PMR).  Of 
the remaining 10 patients, 7 did not have repeat PET imaging, and 3 had stable metabolic 
disease (SMD).  For the lesions that were not irradiated, metabolic responses were seen in 4 
patients (21%), of which 2 were CMR and 2 were PMR.  Of the remaining 15 patients, 7 did 
not have repeat PET imaging, and 8 had progressive metabolic disease (PMD).  Using 
RECIST criteria on non-irradiated lesions, 4 out of 19 patients (21%) had a partial response 
(PR), 2 patients had stable disease (SD), and 12 patients had progressive disease (PD).  One 
patient did not have CT scanning performed to assess tumor response.  
 
The median progression-free survival (PFS) is 4.9 months and the median overall 
survival (OS) 10.7 months. Ipilimumab alone resulted in a response rate of 10.9% in the 
study by Hodi et al. (6).  In summary, the combination of ipilumumab with hypofractionated 
radiotherapy was safe without DLTs.  However, ipilumumab-related side effects were 
significant and the combination of ipilimumab and RT showed modest improvement over 
what is reported in the literature.  Although our study was not designed to assess response, 
the results do not show that the majority of the patients have significant shrinkage of their 
unirradiated lesions in response to radiation.   The results of our Phase I study support the 
investigation of the anti-PD1 agent, Pembrolizumab, with radiation given its probable 


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superior toxicity profile compared to ipilumimab. 
Preclinical Studies of RT and anti-PD1/PD-L1 therapy   
 
RT has also been combined with inhibition of the PD1/PD-L1 pathway.  Deng et al. 
found that PD-L1 was upregulated in the tumor microenvironment after radiation (16). 
Administration of anti-PD-L1 antibody enhanced the efficacy of RT through a cytotoxic T 
cell-dependent mechanism. Concomitant with tumor regression, RT and anti-PD-L1 
synergistically reduced the local accumulation of tumor-infiltrating myeloid-derived 
suppressor cells (MDSCs), which suppress T cells and alter the tumor immune 
microenvironment.  
 
Our own group at Penn has generated data using anti-PD1 therapy with RT.  As noted 
above, emerging data indicate that optimal results will require combination therapies, of 
which radiation (RT) may hold promise. The effectiveness and mechanisms of action for this 
combination have not been well characterized, which potentially hinders efficient clinical 
translation. To address these issues, we have developed several pre-clinical mouse models for 
melanoma, breast cancer, and other cancer types to mechanistically dissect the combination 
of RT and immune checkpoint blockade. Using these models, we have determined that RT 
and immune checkpoint inhibitors such as anti-PD-1/PD-L1 cooperate to promote tumor 
response in both irradiated and unirradiated tumors (Minn, A personal communication). 
Survival and complete responses are significantly improved, and long-term anti-tumor 
immunity ensues. Using a series treatment resistant sublines that we derived combined with 
unbiased genome-wide and immune approaches, we have discovered mechanisms of 
resistance and druggable targets to inhibit resistance. Studies on immune mechanisms and 
biological effects of RT are providing insight into how combination therapy can work in non-
redundant ways to improve response. Insight into immune mechanisms has also driven the 
discovery of potential blood-based biomarkers for response. In summary, by using pre-
clinical models, our preclinical studies demonstrate that anti-PD1 therapy in combination 
with hypofractionated radiotherapy leads to significant responses in non-index (non-
irradiated) lesions and therefore supports the proposed trial of Pembrolizumab with radiation. 
We plan to continue to address critical questions on which combinations are effective, what 
mechanisms of resistance might emerge, how resistance can be rationally targeted, and 
whether mechanistic insight can guide the development of biomarkers to predict response 
4.2.1 Rationale for the Trial and Selected Subject Population 
Anti-PD1 therapies have shown activity in melanoma and NSCLC (XX-ref).  It is not clear if 
these agents will have activity in other diseases nor is it clear whether the immunostimulatory 
effect of hypofractionated radiotherapy in combination with these agents is cancer-specific or 
dependent upon single agent activity of the immunotherapeutic agent.  Our preclinical data 
suggest that activity is observed in a broader range of tumor types.  Therefore, we propose to 
study the safety and preliminary efficacy of the combination of Pembrolizumab and 
radiotherapy in five groups of patient diagnoses:  melanoma, NSCLC, pancreatic cancer, 
breast cancer, and other.  Our hypothesis is that safety will be established and that an 
exploratory analysis will demonstrate robust responses in all disease groups. 


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4.2.2 Rationale for Dose Selection/Regimen/Modification  
An open-label Phase I trial (Protocol 001) is being conducted to evaluate the safety and 
clinical activity of single agent PEMBROLIZUMAB.  The dose escalation portion of this 
trial evaluated three dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 
weeks (Q2W) in subjects with advanced solid tumors.  All three dose levels were well 
tolerated and no dose-limiting toxicities were observed.  This first in human study of 
PEMBROLIZUMAB showed evidence of target engagement and objective evidence of 
tumor size reduction at all dose levels (1 mg/kg, 3 mg/kg and 10 mg/kg Q2W).  No MTD has 
been identified to date.  10.0 mg/kg Q2W, the highest dose tested in PN001, will be the dose 
and schedule utilized in combination with hypofractionated radiotherapy.  Recent data from 
other clinical studies within the PEMBROLIZUMAB program has shown that a lower dose 
of PEMBROLIZUMAB and a less frequent schedule may be sufficient for target engagement 
and clinical activity. 
 
PK data analysis of PEMBROLIZUMAB administered Q2W and Q3W showed slow 
systemic clearance, limited volume of distribution, and a long half-life (refer to IB).  
Pharmacodynamic data (IL-2 release assay) suggested that peripheral target engagement is 
durable (>21 days).  This early PK and pharmacodynamic data provides scientific rationale 
for testing a Q2W and Q3W dosing schedule.   
 
A population pharmacokinetic analysis has been performed using serum concentration time 
data from 476 patients. Within the resulting population PK model, clearance and volume 
parameters of PEMBROLIZUMAB were found to be dependent on body weight. The 
relationship between clearance and body weight, with an allometric exponent of 0.59, is 
within the range observed for other antibodies and would support both body weight 
normalized dosing or a fixed dose across all body weights.  PEMBROLIZUMAB has been 
found to have a wide therapeutic range based on the melanoma indication.  The differences in 
exposure for a 200 mg fixed dose regimen relative to a 2 mg/kg Q3W body weight based 
regimen are anticipated to remain well within the established 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. 
 
4.2.3 Rationale for Primary Endpoint 
This is a Phase I study that will determine the safety of combining Pembrolizumab with 
hypofractionated radiotherapy.  The absence of clinical data regarding the safety of this 
combination mandates the performance of a Phase I trial.  The primary endpoint, therefore, 
will be the safe dose or doses of hypofractionated radiotherapy in combination with 
Pembrolizumab as defined by 0 or 1 DLTs observed in 6 patients within each radiation dose 
cohort. 


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4.2.3.1 Efficacy Endpoints 
This is a Phase I study and therefore, efficacy will not be the primary endpoint.  Nonetheless, 
we have designed the study to obtain an estimate of the immune-related response rate in non-
index metastatic lesions of the combination of Pembrolizumab and hypofractionated 
radiotherapy (please see statistical section for greater detail. 
4.2.3.2 Biomarker Research 
While this is a Phase I study and not necessarily powered for extensive statistical 
evaluation of biomarkers, we will begin to directly test whether promising biomarkers exist 
for more in depth analysis.  The focus on immune-related response rate in non-index 
metastatic lesions will be the basis for examining circulating immune responses for correlates 
of tumor response. 
The main goals of these studies are to perform in-depth immune phenotyping and 
analysis of samples from humans treated with hypofractionated radiotherapy in combination 
with Pembrolizumab.  Biosamples (blood and, where available, tumor) obtained from 
patients before and at serial time points during treatment will be analyzed.  The primary goals 
for the basic studies with these human samples will be: 
• High dimensional (15-17 color) flow cytometry to analyze T cell subsets (including 
naïve, effector, memory (effector memory and central memory), effector memory 
RA, exhausted, Th1, Treg and Tfh), co-expression of sets of multiple inhibitory 
receptors by relevant T cell subsets, transcription factor expression, and T 
comprehensive functional analysis (expression of cytokines, chemokines, cytotoxic 
molecules, and degranulation).  These studies will focus on sophisticated immune 
phenotyping and defining correlates of response to hypofractionated radiotherapy in 
combination with Pembrolizumab.  These studies will be performed on PBMC and, 
where available, TIL. 
• Deep sequencing of the TCR will also be performed from blood and tumor as a novel 
way to interrogate tumor-specific T-cell responses induced by treatment. This method 
does not require a priori understanding of a particular tumor antigen or MHC. Of 
particular interest will be evidence of TCR clones increasing in the circulation after 
therapy that are also found in the patient’s tumor. Such observations would be 
consistent with a “vaccine effect” of therapy and the persistence of these T cell clones 
over time may be a predictor of a durable response. 
• Whole genome transcriptional profiling will be performed using PBMC and/or tumor 
to develop predictors of responses and to reveal underlying pathways.  These studies 
will be integrated with findings from pre-clinical models to help define novel 
signatures of clinical responses. 
 


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Summary 
Based on our own clinical data with RT and ipilumumab, and pre-clinical data from our 
group and in the literature, we propose a stratified phase I clinical trial of hypofractionated 
radiotherapy to an isolated index lesion in combination with the PD-1 inhibitor, 
Pembrolizumab in patients with metastatic cancers who have failed anti-PD-1 therapy 
(melanoma and NSCLC) and patients with metastatic cancers who have have progressed 
after at least one regimen of systemic therapy (breast, pancreas, and other).  In our protocol, 
the primary goal is to demonstrate that Pembrolizumab can be safely administered with 
hypofractionated radiotherapy.  We will also estimate the immune-related response rate of 
non-index metastatic lesions.  
5.0 METHODOLOGY 
5.1 
Entry Criteria 
5.1.1 Diagnosis/Condition for Entry into the Trial 
This is a cohort study of a fixed dose of Pembrolizumab in combination with two distinct 
regimens of hypofractionated radiotherapy.  There will be five groups of patient diagnoses: 
• Metastatic melanoma patients who have progressed while on PD-1 or PDL-1therapy 
or have been on such therapy for at least 6 months with recent scan showing stable 
disease 
• Metastatic NSCLC patients who have progressed while on PD-1 or PDL-1 therapy or 
have been on such therapy for at least 6 months with recent scan showing stable 
disease 
• Metastatic & locally advanced pancreatic cancer patients 
• Metastatic Breast cancer patients 
• Other metastatic cancer patients 
 
5.1.2 Subject Inclusion Criteria 
In order to be eligible for participation in this trial, the subject must: 
1. Be willing and able to provide written informed consent/assent for the trial. 
2. Be ≥ 18 years of age on day of signing informed consent. 
3. Histologically confirmed diagnosis of cancer as per the cohort specifications 
 
4. Stage IV cancer by AJCC staging criteria (except for pancreatic cancer cohort) 
 
5. Locally advanced or metastatic pancreatic cancer for the pancreatic cancer cohort  
 


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6. Progression of disease while on anti-PD-1 or anti-PD-L1 therapy for melanoma and 
NSCLC patients.  For this group, patients must met the following criteria: 
 
a.  Received at least 2 doses of an anti-PD1 or anti-PD-L1 therapy 
b.  Had progressive disease documented radiologically by RECIST v1.1 criteria.   
 
7. Patients with metastatic melanoma or NSCLC who have been on anti-PD1 or anti-
PD-L1 therapy for at least 6 months with a recent scan showing stable disease are 
also eligible.   
 
8. Progression or refractory disease to at least one regimen of therapy for metastatic 
disease in the breast and pancreatic cancer cohorts 
 
9. Presence of an index lesion > 1 cm amenable to hypofractionated radiotherapy 
 
10. Patients who have metastatic cancer must have at least one lesion that is outside the 
radiation field that measures greater than one cm that can be followed by RECIST 
1.1. This lesion, if it is close to the radiated lesion, must receive no more than 10% of 
the dose prescribed to the target lesion.  
11. Have provided tissue from an archival tissue sample or newly obtained core or 
excisional biopsy of a tumor lesion. 
12. Have a performance status of 0 or 1 on the ECOG Performance Scale. 
13. Ability to tolerate hypofractionated radiation therapy (e.g. lie flat and hold position) 
 
14. Demonstrate adequate organ function as defined in Table 1, all screening labs should 
be performed within 21  days of signing study consent.   
Table 1  Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematological
 
Absolute 
neutrophil 
count 
(ANC) 
≥1,500 /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
 
≥60 mL/min for subject with creatinine levels > 
1.5 X institutional ULN 
Hepatic 
 


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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. 
 
15. 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.   
16. Female subjects of childbearing potential should be willing to use 2 methods of birth 
control or be surgically sterile, or abstain from heterosexual activity for the course of 
the study through 120 days after the last dose of study medication (Reference Section 
5.7.2).  Subjects of childbearing potential are those who have not been surgically 
sterilized or have not been free from menses for > 1 year.  
16. Male subjects should agree to use an adequate method of contraception starting with 
the first dose of study therapy through 120 days after the last dose of study therapy. 
5.1.3 Subject Exclusion Criteria 
The subject must be excluded from participating in the trial if the subject: 
1. Is currently participating in or has participated in a study of an investigational agent 
or using an investigational device within 4 weeks of the first dose of treatment. 
2. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any 
other form of immunosuppressive therapy within 7 days prior to the first dose of trial 
treatment. Systemic steroids administered specifically as a premedication for 
chemotherapy infusion or radiotherapy are allowed.  
3. Has had a prior monoclonal antibody within 4 weeks prior to study Day 1 or who has 
not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents 
administered more than 4 weeks earlier.  
4. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy 
within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at 
baseline) from adverse events due to a previously administered agent. 
- 
Note:  Subjects with ≤ Grade 2 neuropathy are an exception to this criterion 
and may qualify for the study. 


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- 
Note:  If subject received major surgery, they must have recovered adequately 
from the toxicity and/or complications from the intervention prior to starting 
therapy.   
5. A history of prior radiotherapy that precludes delivery of hypofractionated 
radiotherapy 
6. Has a known additional malignancy that is progressing or requires active treatment.  
Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the 
skin, or in situ cervical cancer that has undergone potentially curative therapy.   
7. Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis.  Subjects with previously treated brain metastases may participate 
provided they are stable (without evidence of progression by imaging for at least four 
weeks prior to the first dose of trial treatment and any neurologic symptoms have 
returned to baseline), have no evidence of new or enlarging brain metastases, and are 
not using steroids for at least 7 days prior to trial treatment.   
8. Has an active automimmune disease requiring systemic treatment within the past 3 
months or a documented history of clinically severe autoimmune disease, or a 
syndrome that requires systemic steroids or immunosuppressive agents.  Subjects 
with vitiligo or resolved childhood asthma/atopy would be an exception to this rule.  
Subjects that require intermittent use of bronchodilators or local steroid injections 
would not be excluded from the study.  Subjects with hypothyroidism stable on 
hormone replacement or Sjogren’s syndrome will not be excluded from the study. 
9. Has evidence of interstitial lung disease or active, non-infectious pneumonitis. 
10. Has an active infection requiring systemic therapy. 
11. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the trial, interfere with the subject’s participation 
for the full duration of the trial, or is not in the best interest of the subject to 
participate, in the opinion of the treating investigator.   
12. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
13. Is pregnant or breastfeeding, or expecting to conceive or father 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. 
14. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
15. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected). 


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16. Has received a live vaccine within 30 days prior to the first dose of trial treatment.   
5.2 
Trial Treatments 
The treatment to be used in this trial is outlined below in Tables 2 and 3 
 
 
Table 2  Pembrolizumab Treatment 
Drug 
Dose/Pote
ncy 
Dose 
Frequency
Route of 
Administration 
Regimen/Treat
ment Period 
Use 
Pembrolizumab 
200 mg 
Every 3 
weeks 
IV infusion 
6 three week 
cycles* 
Experimental 
The PEMBROLIZUMAB dosing interval may be increased due to toxicity as described in 
Section 5.2.1.2. 
Pembrolizumab should be administered 7 days (+/- 3 days) prior to the first fraction of 
hypofractionated radiation.  
*NOTE:  Patients who have stable or responding disease and are felt to be clinically 
benefiting from the drug can continue receiving pembroluzimab for up to 2 years. For 
cancers not currently commercially approved for treatment with pembroluzimab, the drug 
will be provided by Merck.   
In the initial Safety Phase, there will be two cohorts of patients based upon the radiotherapy 
dose delivered to the index metastatic lesion in the lung, liver, bone or soft tissue: 
Cohort 1:  8 Gy x 3 to the index lesion  
Cohort 2: 17 Gy x 1 to the index lesion* 
*Subjects with locally advanced pancreatic cancer will be enrolled only in the 8 Gy x 3 
cohort. 
Patients are stratified by prior PD-1 therapy. 24 patients will be enrolled, 12 per stratum and 
6 per fractionation cohort within each stratum.  Standard safety decision-making will be 
used.  The regimen is safe if no more than 0-1 dose-limiting toxicities (DLT) are observed in 
6 patients within a cohort within a stratum. Enrollment in a cohort within a stratum will stop 
if 2+ DLT are observed within that cohort at any time during the safety phase.  If 2+ DLT are 
observed in Cohort 1 in a stratum, then Cohort 2 within that stratum will still be tested. 
Cohort 1  Cohort 2 is not an escalation of dose.  DLT is defined as any Grade 3 or higher 
non-hematological toxicity and any Grade 4 hematological toxicity that is probably, possibly 
or definitely related to the combination of Pembrolizumab and hypofractionated 
radiotherapy.  
 


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Table 3.  Hypofractionated Radiotherapy 
Safety Phase:  
 
 
Cohort 1: 8 Gy x 3 
Number of Patients 
Cohort 2: 17 Gy x 1
Number of Patients 
 
TOTAL 
 
Progressed on Prior 
PD-1 (Melanoma or 
NSCLC) 
 
6 
 
6 
 
12 
Stratify 
 
 
 
 
 
No 
Prior 
PD-1 
(Pancreas, Breast or 
Other) 
 
6 
 
6* 
 
12 
TOTAL
12 
12 
24 
 
* Breast or Other cancer patients only 
 
 
Expansion Phase  
 
Randomize 
 
 
Number of  
Randomized 
Patients 
Disease  
Cohort 1: 8 Gy x 3 
Number of Patients 
Cohort 2: 17 Gy x 1 
Number of Patients 
Melanoma 
7 
7 
14 
NSCLC 
7 
7 
14 
Pancreas 
6 
0 
6* 
Breast 
3 
3 
6 
Other 
3 
3 
6 


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TOTAL 
26 
20 
46 
 
* Pancreas patients are not randomized, they are assigned to 8 Gy x 3 
In the Expansion Phase, patients will be stratified by disease site. If both fractionation 
regimens are safe, then we randomize patients. Otherwise, all patients will be enrolled on the 
single regimen determined to be safe.  We will proceed to the Expansion phase once 12 
patients have been treated in a given stratum in the Safety phase and the requisite amount of 
time for observing DLTs has elapsed; i.e. once 12 patients have been treated in  “No Prior 
PD-1 (Pancreas, Breast, Other)” stratum, patients can be enrolled on the Pancreas, Breast and 
Other strata in the Expansion phase. Likewise, once 12 patients have been treated in  
“Progressed on the Prior PD-1 (Melanoma, NSCLC)” stratum in the Safety phase and the 
requisite amount of time for observing DLTs has elapsed, patients can be enrolled on the 
Pancreas, Breast and Other strata in the Expansion phase. 
 
46 patients will be enrolled. Randomization will aid in the preliminary assessment of clinical 
response by avoiding selection bias. Accrual is expected to occur over 24 months or 3-4 
subjects per month. 
Radiation Therapy 
All subjects will be immobilized in a custom designed device in the appropriate position to 
isolate the index lesion. Radiotherapy treatment planning using CT or PET/CT scans (with 
contrast, unless contraindicated) will be required to define the gross target volume (GTV) 
and planning target volume (CTV). The treatment planning PET/CT scan should be acquired 
with the subject in the same position and using the same immobilization device as for 
treatment. Treatment planning will be done using a 3D based CT treatment planning system.  
All tissues to be irradiated must be included in the CT scan. Planning CT scan will be done at 
< 5 mm intervals from encompassing the region of interest with sufficient margin for 
treatment planning.  
Target Contouring 
Gross Tumor Volume (GTV) is defined as all known gross disease encompassing the 
selected index lesion. The GTV will consist of the index lesion as visualized on CT and PET.   
Internal Gross Tumor Volume (IGTV) is defined for mobile index lesions at the discretion of 
the treating physician. A 4-D CT scan may be acquired in order to account for the motion of 
the lesion during respiration. The IGTV will be defined as the union of the visualized index 
lesion on all gated CT data sets. 
Planning Target Volume (PTV) will be defined as per the convention for photon beam 
radiotherapy. A 3-dimensional margin will be created on the GTV or IGTV (if available) to 
allow for daily set-up variance.  


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Normal Structures  
Organ at risk volume (OAR) is contoured as visualized on the planning CT or MR scan.  
Planning PAR is the OAR expanded for setup uncertainty or organ motion.  The physician 
will contour the OAR.  The dosimetrist will create the PAR by expanding the OAR by 2-3 
mm, depending on the situation. 
Dose Fractionation and Specification  
The prescription dose per fraction to the PTV will be 8 Gy x three fraction for Cohort 1 and 
17 Gy per fraction x one fractions in Cohort 2.  The total dose for Cohort 2 will be 24 Gy 
over 3 fractions. 
Treatment Planning  
Three-dimensional coplanar or non-coplanar beam arrangements will be custom designed for 
each case to deliver highly conformal prescription dose distributions. Non-opposing, 
noncoplanar beams are preferable.  
Many of the patients on this trial will undergo SBRT. For these patients, standard protocols 
and constraints that have been developed in the Department of Radiation Oncology will be 
followed.  For SBRT, typically, ≥ 10 beams of radiation will be used with roughly equal 
weighting. Generally, more beams are used for larger lesion sizes. When static beams are 
used, a minimum of 7 non-opposing beams should be used. For arc rotation techniques, a 
minimum of 340 degrees (cumulative for all beams) should be utilized. For arc rotation 
techniques, a minimum of 340 degrees (cumulative for all beams) should be utilized. In order 
to obtain acceptable coverage, field aperture size and shape should correspond nearly 
identically to the projection of the PTV along a beam’s eye view (i.e., no additional “margin” 
for dose buildup at the edges of the blocks or MLC jaws beyond the PTV). The only 
exception should be when observing the minimum field dimension of 3.5 cm when treating 
small lesions.  As such, prescription lines covering the PTV will typically be the 60-90% line 
(where the maximum dose is 100%); however, higher isodoses (hotspots) must be 
manipulated to occur within the target and not in adjacent normal tissue.  
Dose Selection/Modification 
5.2.1.1 Dose Selection 
The rationale for selection of pembrolizumab and radiotherapy doses to be used in this trial is 
provided in Section 4.0 – Background and Rationale.   
Details on the dose preparation and administration are provided in the Merck Protocol, 
reference. 


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5.2.1.2 Dose Modification  
PEMBROLIZUMAB will be withheld for drug-related Grade 3 or 4 hematologic toxicities 
(with the caveats as shown in Table 4 below) or Grade 3 or 4 non-hematological toxicity  
including laboratory abnormalities, and severe or life-threatening AEs. 
Table 4: Dose modification guidelines for drug-related adverse events. 
Toxicity 
Grade 
Hold 
Treatmen
t (Y/N) 
Timing 
for 
restartin
g 
treatmen
t 
Dose/Schedule 
for restarting 
treatment 
Discontinue 
Subject 
(after 
consultation 
with 
Sponsor) 
Hematologic
al Toxicity 
 
1, 2 
No 
N/A 
N/A 
N/A 
3* 
*Excluding 
Grade 3 
neutropenia, 
anemia, and 
thrombocytopen
ia 
Yes 
Toxicity 
resolves 
to Grade 
0-1 or 
baseline 
May increase 
the dosing 
interval by 1 
week  
Toxicity does 
not resolve 
within 12 
weeks of last 
infusion 
Permanent 
discontinuatio
n should be 
considered 
for any severe 
or life-
threatening 
event 
4 
Yes 
Toxicity 
resolves 
to Grade 
0-1 or 
baseline 
May increase 
the dosing 
interval by 1 
week  
Non-
hematologica
l toxicity 
 
Note:  
Exception to 
be 
treated 
similar 
to 
grade 
1 
toxicity  
• Grade 2 
alopecia 
• Grade 2 
fatigue 
 
1 
No 
N/A 
N/A 
N/A 
2 
Consider 
withholdin
g for 
persistent 
symptoms 
Toxicity 
resolves 
to Grade 
0-1 or 
baseline 
Clinical AE 
resolves within 
4 weeks:  Same 
dose and 
schedule 
(reference 
Section 5.6.1.2 
for 
recommendatio
ns regarding 
pneumonitis) 
Clinical AE 
does not resolve 
within 4 weeks:  
May increase 
Toxicity does 
not resolve 
within 12 
weeks of last 
infusion 


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Toxicity 
Grade 
Hold 
Treatmen
t (Y/N) 
Timing 
for 
restartin
g 
treatmen
t 
Dose/Schedule 
for restarting 
treatment 
Discontinue 
Subject 
(after 
consultation 
with 
Sponsor) 
For 
additional 
information 
regarding 
Adverse 
Events with a 
potential 
Immune-
Etiology 
reference 
Section 
5.6.1.1. 
the dosing 
interval by  1 
week for each 
occurrence 
3, 4 
 
Yes 
 
Toxicity 
resolves 
to Grade 
0-1 or 
baseline 
 
May increase 
the dosing 
interval by 1 
week for each 
occurrence 
 
Toxicity does 
not resolve 
within 12 
weeks of last 
infusion 
Permanent 
discontinuatio
n should be 
considered 
for any severe 
or life-
threatening 
event 
 
 
In case toxicity does not resolve to Grade 0-1 within 12 weeks after last infusion, trial 
treatment should be discontinued after consultation with the Sponsor.  With investigator and 
Sponsor agreement, subjects with a laboratory adverse event still at Grade 2 after 12 weeks 
may continue treatment in the trial only if asymptomatic and controlled.  For information on 
the management of adverse events, see Section 5.6.1.   
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 discontinued from trial 
treatment. 
There will be no modification of radiotherapy. 
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. 


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All trial treatments will be administered on an outpatient basis. 
PEMBROLIZUMAB will be administered as a 30 minute IV infusion (treatment cycle 
intervals may be increased due to toxicity as described in Section 5.2.1.2).  Sites should make 
every effort to target infusion timing to be as close to 30 minutes as possible.  However, 
given the variability of infusion pumps from site to site, a window of -5 minutes and +10 
minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min). 
The Procedures Manual contains specific instructions for PEMBROLIZUMAB dose 
calculation, reconstitution, preparation of the infusion fluid, and administration. 
5.2.3 Trial Blinding/Masking 
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered. 
5.3 
Stratification and Randomization 
During the Safety Phase of this study, patients will be stratified on the basis of having 
received prior immunotherapy (see Table 3).  During the Expansion Phase, patients will be 
stratified by disease site. If both fractionation regimens are safe, then we will randomize 
patients. Otherwise, all patients will be enrolled on the single regimen determined to be safe.  
Randomization will aid in the preliminary assessment of clinical response by avoiding 
selection bias.  The randomization procedure is described in the Statistical Section. 
5.4 
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.  
5.4.1 Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care.  All concomitant medication will be recorded on the case report form (CRF) 
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications 
and fluids.  If changes occur during the trial period, documentation of drug dosage, 
frequency, route, and date may also be included on the CRF. 
All concomitant medications received within 28 days before the first dose of trial treatment 
and 30 days after the last dose of trial treatment should be recorded.  Concomitant 


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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. 
5.4.2 Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase (including retreatment for post-complete response relapse) of this trial: 
• Anti-cancer systemic chemotherapy or biological therapy  
• Immunotherapy not specified in this protocol 
• Chemotherapy not specified in this protocol 
• Investigational agents other than PEMBROLIZUMAB 
• Additional Radiation therapy beyond that described in the radiotherapy section 
o Note:  Radiation therapy to a symptomatic solitary lesion or to the brain may 
be allowed after consultation with Sponsor.   
• 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.  
• Glucocorticoids for any purpose other than to modulate symptoms from an event of 
clinical interest of suspected immunologic etiology.  The use of physiologic doses of 
corticosteroids may be approved after consultation with the Sponsor.  
Subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial.  
Subjects may receive other medications that the investigator deems to be medically 
necessary. 
The Exclusion Criteria describes other medications that are prohibited in this trial. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
5.5 
Rescue Medications & Supportive Care 
5.5.1 Supportive Care Guidelines 
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  These supportive care measures will be instituted for both 
Pembrolizumab and hypofractionated radiotherapy and include but not limited to the items 
outlined below: 


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• Diarrhea: Subjects should be carefully monitored for signs and symptoms of 
enterocolitis (such as diarrhea, abdominal pain, blood or mucus in stool, with or 
without fever) and of bowel perforation (such as peritoneal signs and ileus).  In 
symptomatic subjects, infectious etiologies should be ruled out, and if symptoms are 
persistent and/or severe, endoscopic evaluation should be considered. 
o In subjects with severe enterocolitis (Grade 3), PEMBROLIZUMAB will be 
permanently discontinued and treatment with systemic corticosteroids should 
be initiated at a dose of 1 to 2 mg/kg/day of prednisone or equivalent.  When 
symptoms improve to Grade 1 or less, corticosteroid taper should be started 
and continued over at least 1 month. 
o In subjects with moderate enterocolitis (Grade 2), PEMBROLIZUMAB 
should be withheld and anti-diarrheal treatment should be started.  If 
symptoms are persistent for more than one week, systemic corticosteroids 
should be initiated (e.g., 0.5 mg/kg/day of prednisone or equivalent).  When 
symptoms improve to Grade 1 or less, corticosteroid taper should be started 
and continued over at least 1 month.  Regarding guidelines for continuing 
treatment with PEMBROLIZUMAB, see Section 5.2. 
o All subjects who experience diarrhea should be advised to drink liberal 
quantities of clear fluids.  If sufficient oral fluid intake is not feasible, fluid 
and electrolytes should be substituted via IV infusion. 
• Nausea/vomiting: Nausea and vomiting should be treated aggressively, and 
consideration should be given in subsequent cycles to the administration of 
prophylactic antiemetic therapy according to standard institutional practice.  Subjects 
should be strongly encouraged to maintain liberal oral fluid intake. 
• Anti-infectives: Subjects with a documented infectious complication should receive 
oral or IV antibiotics or other anti-infective agents as considered appropriate by the 
treating investigator for a given infectious condition, according to standard 
institutional practice. 
• Immune-related adverse events: Please see Section 5.6.1.1 below and the separate 
guidance document in the administrative binder regarding diagnosis and management 
of adverse experiences of a potential immunologic etiology.   
• Management of Infusion Reactions:  Acute infusion reactions (which can include 
cytokine release syndrome, angioedema, or anaphylaxis) are different from 
allergic/hypersensitive reactions, although some of the manifestations are common to 
both AEs.  Signs and symptoms usually develop during or shortly after drug infusion 
and generally resolve completely within 24 hours of completion of infusion. 
Signs/symptoms may include: Allergic reaction/hypersensitivity (including drug 
fever); Arthralgia (joint pain); Bronchospasm; Cough; Dizziness; Dyspnea (shortness 
of breath); Fatigue (asthenia, lethargy, malaise); Headache; Hypertension; 


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Hypotension; Myalgia (muscle pain); Nausea; Pruritis/itching; Rash/desquamation; 
Rigors/chills; Sweating (diaphoresis); Tachycardia; Tumor pain (onset or 
exacerbation of tumor pain due to treatment); Urticaria (hives, welts, wheals); 
Vomiting. 
Table 5 below shows treatment guidelines for subjects who experience an infusion reaction 
associated with administration of PEMBROLIZUMAB. 
 
 
Table 5 Infusion Reaction Treatment Guidelines 
 
NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
Grade 1 
Mild reaction; infusion 
interruption not 
indicated; intervention 
not indicated 
 
Increase monitoring of vital 
signs as medically indicated until 
the subject is deemed medically 
stable in the opinion of the 
investigator. 
 
None 
Grade 2 
Requires infusion 
interruption but responds 
promptly to symptomatic 
treatment (e.g., 
antihistamines, NSAIDS, 
narcotics, IV fluids); 
prophylactic medications 
indicated for < =24 hrs 
 
Stop Infusion and monitor 
symptoms. 
Additional appropriate medical 
therapy may include but is not 
limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital 
signs as medically indicated until 
the subject is deemed medically 
stable in the opinion of the 
investigator. 
If symptoms resolve within one 
hour of stopping drug infusion, 
the infusion may be restarted at 
50% of the original infusion rate 
(e.g. from 100 mL/hr to 50 
mL/hr).  Otherwise dosing will 
be held until symptoms resolve 
and the subject should be 
premedicated for the next 
scheduled dose. 
 
Subject may be 
premedicated 1.5h (± 
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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NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
Subjects who develop Grade 2 
toxicity despite adequate 
premedication should be 
permanently discontinued 
from further trial treatment 
administration.
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not 
rapidly responsive to 
symptomatic medication 
and/or brief interruption 
of infusion); recurrence 
of symptoms following 
initial improvement; 
hospitalization indicated 
for other clinical sequelae 
(e.g., renal impairment, 
pulmonary infiltrates) 
 
Grade 4: 
Life-threatening; pressor 
or ventilatory support 
indicated 
 
Stop Infusion. 
Additional appropriate medical 
therapy may include but is not 
limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
 
Increase monitoring of vital 
signs as medically indicated until 
the subject is deemed medically 
stable in the opinion of the 
investigator. 
Hospitalization may be 
indicated. 
Subject is permanently 
discontinued from further trial 
treatment administration.
 
No subsequent dosing 
Appropriate resuscitation equipment should be available in the room and a physician 
readily available during the period of drug administration. 
For Further information, please refer to the Common Terminology Criteria for Adverse 
Events v4.0 (CTCAE) at http://ctep.cancer.gov 
5.5.1.1 Supportive Care Guidelines for Events of Clinical Interest and Immune-related 
Adverse Events (irAEs) 
Events of clinical interest of a potential immunologic etiology (irECIs) may be defined as an 
adverse event of unknown etiology, associated with drug exposure and is consistent with an 
immune phenomenon.  irAEs may be predicted based on the nature of the 
PEMBROLIZUMAB compound, its mechanism of action, and reported experience with 


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immunotherapies that have a similar mechanism of action.  Special attention should be paid 
to AEs that may be suggestive of potential irAEs.  An irAE can occur shortly after the first 
dose or several months after the last dose of treatment.   
If an irAE is suspected, efforts should be made to rule out neoplastic, infectious, metabolic, 
toxin or other etiologic causes prior to labeling an adverse event as an irAE.  Information on 
how to identify and evaluate irAEs has been developed and is included in the Event of 
Clinical Interest and Immune-Related Adverse Event Guidance Document located in the 
Administrative Binder.  Subjects who develop a Grade 2 or higher irAE should be discussed 
immediately with the Sponsor.   
Recommendations to managing irAEs not detailed elsewhere in the protocol are detailed in 
Table 6. 
Table 6  General Approach to Handling irAEs 
irAE 
Withhold/Discontinue 
PEMBROLIZUMAB?
Supportive Care 
Grade 1 
No action 
Provide symptomatic treatment 
Grade 2 
May 
withhold 
PEMBROLIZUMAB 
Consider systemic corticosteroids in 
addition to appropriate symptomatic 
treatment 
Grade 3 and Grade 4 Withhold 
PEMBROLIZUMAB 
Discontinue if unable to 
reduce 
corticosteroid 
dose to < 10 mg per 
day 
prednisone 
equivalent within 12 
weeks of toxicity 
Systemic corticosteroids are indicated 
in addition to appropriate symptomatic 
treatment.  May utilize 1 to 2 mg/kg 
prednisone or equivalent per day. 
Steroid taper should be considered 
once symptoms improve to Grade 1 or 
less and tapered over at least 4 weeks. 
 
5.5.1.2 Supportive Care Guidelines for Pneumonitis 
Subjects 
with 
symptomatic 
pneumonitis 
should 
immediately 
stop 
receiving 
PEMBROLIZUMAB and have an evaluation.  The evaluation may include bronchoscopy 
and pulmonary function tests to rule out other causes such as infection.  If the subject is 
determined to have study drug associated pneumonitis, the suggested treatment plan is 
detailed in Table 7. 
Table 7  Recommended Approach to Handling Pneumonitis 
Study drug 
associated 
Withhold/Discontinue 
Supportive Care 


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pneumonitis 
PEMBROLIZUMAB?
Grade 1 
(asymptomatic) 
No action 
Intervention not indicated 
Grade 2 
Withhold 
PEMBROLIZUMAB, 
may return to treatment 
if improves to Grade 1 
or resolves within 12 
weeks 
Systemic corticosteroids are indicated.  
Taper if necessary. 
Grade 3 and Grade 4 Discontinue 
PEMBROLIZUMAB 
Systemic corticosteroids are indicated. 
The use of infliximab may be indicated 
as appropriate.  Refer to the Event of 
Clinical Interest and Immune-related 
Adverse Event Guidance Document for 
additional recommendations. 
 
For Grade 2 pneumonitis that improves to ≤ Grade 1 within 12 weeks, the following rules 
should apply: 
• First episode of pneumonitis 
o May increase dosing interval by one week in subsequent cycles 
• Second episode of pneumonitis – permanently discontinue PEMBROLIZUMAB if 
upon rechallenge subject develops pneumonitis ≥ Grade 2 
Acute toxicities related to hypofractionated radiotherapy are mild (Grade I) and no treatment 
interruptions of radiotherapy are anticipated. 
 
5.6 
Diet/Activity/Other Considerations 
5.6.1 Diet 
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea or vomiting. 
5.6.2 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 


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years of age and has not had menses for greater than 1 year will be considered 
postmenopausal), or 3) not heterosexually active for the duration of the study.  The two birth 
control methods can be either two barrier methods or a barrier method plus a hormonal 
method to prevent pregnancy. Subjects should start using birth control from study Visit 1 
throughout the study period up to 120 days after the last dose of study therapy.  
The following are considered adequate barrier methods of contraception: diaphragm, condom 
(by the partner), copper intrauterine device, sponge, or spermicide.  Appropriate hormonal 
contraceptives will include any registered and marketed contraceptive agent that contains an 
estrogen and/or a progestational agent (including oral, subcutaneous, intrauterine, or 
intramuscular agents). 
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 and to Merck 
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. 
5.6.3 Use in Pregnancy 
5.6.4 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 and to Merck 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 to Merck and followed as 
described above and in Section 7.2.2.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. 
5.7 
Subject Withdrawal/Discontinuation Criteria 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur.  In addition, a subject may be 
withdrawn by the investigator or the Sponsor if enrollment into the trial is inappropriate, the 


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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: 
• The subject or legal representative (such as a parent or legal guardian) withdraws 
consent. 
• Confirmed radiographic disease progression 
Note: For unconfirmed radiographic disease progression, please see Section 5.2.2 
Note: A subject may be granted an exception to continue on treatment with 
confirmed radiographic progression if clinically stable or clinically improved, 
please see Section 7.1.2.7.1 
• Unacceptable adverse experiences as described in Section 5.2.1.2 
• Intercurrent illness that prevents further administration of treatment 
• Investigator’s decision to withdraw the subject 
• The subject has a confirmed positive serum pregnancy test 
• Noncompliance with trial treatment or procedure requirements 
• The subject is lost to follow-up 
• Completed 24 months of treatment with PEMBROLIZUMAB 
Note: 24 months of study medication is calculated from the date of first dose. Subjects 
who stop PEMBROLIZUMAB after 24 months may be eligible for up to one year of 
additional study treatment if they progress after stopping study treatment provided 
they meet the requirements detailed in Section 7.1.5.2.1. 
• 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 7.2.3.1).  Subjects 
who discontinue for reasons other than progressive disease will have post-treatment follow-
up for disease status until disease progression, initiating a non-study cancer treatment, 
withdrawing consent or becoming lost to follow-up.  After documented disease progression 
each subject will be followed by telephone for overall survival until death, withdrawal of 
consent, or the end of the study, whichever occurs first. 


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5.8 
Subject Replacement Strategy 
Replacement of subjects will occur if the subject did not complete the course of therapy as 
defined as follows (unless they discontinue treatment because of a DLT). 
Cohort 1: all 3 RT fractions and 3 of 6 Pembrolizumab doses, 1 before RT and 2 after RT 
Cohort 2: 1 RT fraction and 3 of 6 Pembrolizumab doses, 1 before RT and 2 after RT 
No subject can be replaced if they discontinue therapy as a result of DLT. 
5.9 
Clinical Criteria for Early Trial Termination 
Early trial termination will be the result of the criteria specified below: 
1. Quality or quantity of data recording is inaccurate or incomplete 
2. Poor adherence to protocol and regulatory requirements 
3. Incidence or severity of adverse drug reaction in this or other studies indicates a potential 
health hazard to subjects 
4. Plans to modify or discontinue the development of the study drug 
In the event of Merck 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 
Table 8  
 
Main 
Study 
Screeni
ng Visit
Pembrolizumab 
Administration, Cycles 1-6 
Hypofractionated 
Radiotherapy 
Post-
radiation 
Safety visit 
Post-
Pembrolizu
mab 
Safety visit 
Post-
treatment  
Follow up 
visit 
Scheduling 
Window 
-28 to -
1 
Days 1, 22, 43, 64, 85, 106 
+3 
Treatment completion = Day 
106 
Cohort 1: Day 8 + 3 
Cohort 2:  Days 8, 10 & 12 
+3 
30 days + 7 
post 
completion 
of 
radiotherap
y  
30 days + 7 
post 
treatment 
completion 
(Day 136) 
Day 196 + 
14 
Informed consent  
X 
 
 
 
 
 
Eligibility 
checklist review 
X 
 
 
 
 
 
Tests 
and 
Observations 
 
 
 
 
 
 
History and PE 
X 
X – Days 1, 22, 43, 64, 85, 
106 +3  
X 
X 
X 
X 
ECOG score 
X 
X – Days 1, 22, 43, 64, 85, 
106 +3  
X 
X 
X 
X 
18F-FDG PET/CT 
and/or CT scan or 
X (also 
needed 
 
 
 
 
 


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MRI – baseline@ 
for 
treatment 
planning 
study 
priorto 
Day 8) 
 
18F-FDG PET/CT 
and/or CT scan or 
MRI – restaging 
** 
 
X – Day 64 
 
 
X 
X 
Biopsy or Archival 
Tissue*** 
X 
 
 
 
 
X 
CBC 
X* 
X – Days 1, 22, 43, 64, 85, 
106 +3  
 
 
X 
X 
Comp 
Metabolic 
Panel 
X* 
X – Days 1, 22, 43, 64, 85, 
106 +3  
 
 
X 
X 
Pregnancy Test* 
X 
 
 
 
 
 
Toxicity 
Assessment 
X 
X 
X 
X 
X 
X 
Correlative studies 
(Five 10 ml green 
top tubes and one 
Xa 
Xb – Days 1, 22, 43, 85 +3  
X – Day 8 
 
X 
X c 


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5 ml SST tube) 
X*- Measurements must be made within 21 days of signing study consent. 
X@ - Imaging studies must be performed within 30 days + 3 of treatment initiation 
** After radiological tumor assessment at screening, the first radiological assessment of tumor response status will be performed at 
day 64 (+/- 7 days), unless there is clinical indication warranting earlier radiologic imaging.  If imaging at 64 days shows PD, 
treatment with pembrolizumab may continue until a repeat assessment 4-6 weeks later confirms PD.   If this scan confirms progression 
of disease compared with previous scan that showed PD, then pembrolizumab should be discontinued. 
  Subsequent studies will be performed as per standard of care. 
 
*** There is a potential for a second biopsy if patient is willing and has a lesion that is amenable. 
 
a/b The pre-treatment correlative studies sample can be drawn at either the main study screening visit or at Pembrolizumab infusion #1 
(as long as the sample is drawn before the infusion takes place). 
c Additional blood samples may be obtained if  patient requires additional  radiation for palliation. This will at the discretion of the PI. 
This could take place even after patient has completed this trial.  At most there would be 4 blood draws that could include pre-
radiation samples, samples during the course of radiation, and samples 1-3 weeks after completion of radiation and then 5-7 weeks 
after completion of radiation.    


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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 and/or 
Merck for reasons related to subject safety. In some cases, such evaluation/testing may be 
potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations may 
require that additional informed consent be obtained from the subject.  In these cases, such 
evaluations/testing will be performed in accordance with those regulations. 
Study Visit Schedule 
Days -28 to -1:  Subject will be screened for enrollment in the study.  After the subject is 
deemed potentially eligible for the study and consents, the subject will be seen in the 
outpatient radiation therapy and/or medical oncology clinics for a history, physical exam, 
baseline laboratory studies, correlative studies, scheduling of imaging studies (if needed), and 
scheduling of radiotherapy treatment planning and Pembrolizumab infusion.  Radiotherapy 
treatment planning is a standard procedure and will consist of a simulation CT scan or 18F-
FDG PET/CT or MRI scan as per the Department of Radiation Therapy standards.  The 
simulation will be scheduled so that the subject may begin hypofractionated radiotherapy on 
Day 8 +3 
Day 1:  Pembrolizumab infusion in medical oncology offices. 
Day 8:  Hypofractionated radiotherapy   will be given in either three fractions of 8 Gy 
delivered on Days 8, 10 & 12 +/-3 or, one fraction of 17 Gy delivered on day 8  +/- 3.  
Days 1, 22, 43, 64, 85, 106+ 3:  Pembrolizumab infusion in medical oncology offices.  
History, PE, ECOG assessment, correlative studies, and laboratory studies on Days 1, 22, 43, 
64, 85, 106 + 3. 
Day 38 or Day 42:  Follow up safety visit with the radiation oncologist 30 days + 7 post 
completion of radiotherapy (Day 38 + 7 for Cohort 1 and Day 42 + 7 for Cohort 2).  History, 
PE, and ECOG assessment,. 
Day 106+7:  Follow up safety visit with the radiation oncologist or medical oncologist 30 
days + 7 post completion of the 6th cycle of Pembrolizumab.  History, PE, ECOG assessment, 
laboratory studies, correlative studies, and imaging restaging will be performed at this visit. 


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Day 196:  Follow up safety visit with the radiation oncologist or medical oncologist 90 days 
+ 14 post the Day 136 safety visit.  History, PE, ECOG assessment, laboratory studies, 
correlative studies, and imaging restaging will be performed at this visit. 
Additional blood samples may be obtained if  patient requires additional  radiation for 
palliation. This will at the discretion of the PI. This could take place even after patient has 
completed this trial.  At most there would be 4 blood draws that could include pre-radiation 
samples, samples during the course of radiation, and samples 1-3 weeks after completion of 
radiation and then 5-7 weeks after completion of radiation 
Subject is considered off study following the completion of the Day 191 + 14 visit.  Subjects 
will then be referred to the referring physician for subsequent follow up, according to 
standard of care. Every effort will be made to obtain records of subjects for post Day 191 
follow up visits, and permission will be sought for the investigators to recontact the patient 
directly with regard to health status and toxicity. 
*NOTE:  Patients who have stable or responding disease and are felt to be clinically 
benefiting from the drug can continue receiving pembroluzimab for up to 2 years. For 
cancers not currently commercially approved for treatment with pembroluzimab, the drug 
will be provided by Merck.   
7.1.1 Administrative Procedures 
7.1.1.1.  General Informed Consent 
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature 
of the person conducting the consent discussion.  
A copy of the signed and dated consent form should be given to the subject before 
participation in the trial. 
The initial informed consent form, any subsequent revised written informed consent form 
and any written information provided to the subject must receive the IRB/ERC’s 
approval/favorable opinion in advance of use.  The subject or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’s willingness to continue participation in the trial.  The 
communication of this information will be provided and documented via a revised consent 
form or addendum to the original consent form that captures the subject’s dated signature or 
by the subject’s legally acceptable representative’s dated signature. 
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level.   


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The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements. 
 
7.1.1.1 Inclusion/Exclusion Criteria 
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial.  
7.1.1.2 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.   
7.1.1.3 Prior and Concomitant Medications Review 
Prior and concomitant medication review will be performed as part of the medical history 
described in 7.1.1.4 
7.1.1.3.1 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.  
7.1.1.3.2 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. 
7.1.1.4 Disease Details and Treatments 
7.1.1.4.1 Disease Details 
The investigator or qualified designee will obtain prior and current details regarding disease 
status.  
7.1.1.4.2 Prior Treatment Details 
The investigator or qualified designee will review all prior cancer treatments including 
systemic treatments, radiation and surgeries. 


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7.1.1.4.3 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.  
7.1.1.5 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 (see Section 12.2).  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 hypofractionated radiotherapy and 
Pembrolizumab exposure or Pembrolizumab exposure alone should be evaluated to 
determine if it is possibly an event of clinical interest (ECI) of a potentially immunologic 
etiology (irAE).  See Section 5.6.1.1 and the separate guidance document in the 
administrative binder 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.   
7.1.1.6 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,  
7.1.1.7 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.   
7.1.1.8 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. 


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7.1.1.9 Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The investigator or qualified designee will assess ECOG status (see Section 12.4) 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. 
7.1.1.10 Tumor Imaging and Assessment of Disease 
Imaging studies, typically a CT scan or an 18F-FDG PET/CT scan will be performed as per 
institutional standards for the purposes of baseline tumor assessment, radiotherapy treatment 
planning, and restaging. 
7.1.1.11 Tumor Tissue Collection and Correlative Studies Blood Sampling 
Where available tumor tissue from tumor resections and/or biopsies will be analyzed 
by flow cytometry, TCR sequencing and/or transcriptional profiling as described in section 
4.2.3.2.  Sample availability including the number of cells obtained and the timing of tumor 
tissue availability relative to treatment will be considered in how the samples are analyzed.  
Our priorities will be: 1) flow cytometric analysis of TIL for T cell activation, exhaustion and 
reinvigoration as well as for PD-L1 expression; 2) TCR sequencing; 3) transcriptional 
profiling. 
7.1.2 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 can be found in the Procedures 
Manual.  
7.1.2.1 Laboratory Safety Evaluations (Hematology, Chemistry) 
Laboratory tests for hematology, chemistry, 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 and by 
sample type per subject can be found in the Procedures Manual.  
 


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Table 9  Laboratory Tests 
Hematology 
Chemistry 
 
 
Hematocrit 
Albumin 
 
 
Hemoglobin 
Alkaline phosphatase 
 
 
Platelet count 
Alanine aminotransferase 
(ALT) 
 
 
WBC (total and differential) Aspartate aminotransferase 
(AST) 
 
 
Red Blood Cell Count 
 
 
 
Absolute Neutrophil Count 
Carbon Dioxide ‡ 
 
 
 
  (CO2 or biocarbonate) 
 
 
 
 
 
 
 
Calcium 
 
 
 
Chloride 
 
 
 
Glucose 
 
 
 
 
 
 
 
Potassium   
 
 
 
Sodium 
 
 
 
 
 
 
 
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 


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Hematology 
Chemistry 
 
 
test will be required.   
‡ If considered standard of care in your region. 
 
Laboratory tests for screening or entry into the Second Course Phase should be performed within 10 days prior to the first dose of 
treatment.  After Cycle 1, pre-dose laboratory procedures can be conducted up to 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.  
 
 
 
 
 
 
 
 
 
7.1.3 Other Procedures 
7.1.3.1 Withdrawal/Discontinuation 
When a subject discontinues/withdraws prior to trial completion, all applicable activities scheduled for the 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 


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followed in accordance with the safety requirements outlined in Section 7.2 - Assessing and Recording Adverse Events.  Subjects who 
a) attain a CR or b) complete 24 months of treatment with PEMBROLIZUMAB may discontinue treatment with the option of 
restarting treatment if they meet the criteria specified in Section 7.1.5.2.1.  After discontinuing treatment following assessment of CR, 
these subjects should return to the site for a Safety Follow-up Visit (described in Section 7.1.5.3.1) and then proceed to the Follow-Up 
Period of the study (described in Section 7.1.5.4). 
7.1.4 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. 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.   
7.1.4.1 Follow-up Visits 
Subjects who discontinue trial treatment for a reason other than disease progression will move into the Follow-Up Phase and will be 
assessed by radiologic imaging as per clinical judgment of the Medical Oncologist to monitor disease status.  Every effort should be 
made to collect information regarding disease status until the start of new anti-neoplastic therapy, disease progression, death, end of 
the study or if the subject begins retreatment with PEMBROLIZUMAB as detailed in Section 7.1.5.2.1.  Information regarding post-
study anti-neoplastic treatment will be collected if new treatment is initiated. 
Subjects who are eligible to receive retreatment with PEMBROLIZUMAB according to the criteria in Section 7.1.5.2.1 will move 
from the follow-up phase to the Second Course Phase when they experience disease progression.  Details are provided in Section 6.2 – 
Trial Flow Chart for Retreatment.    


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7.1.4.1.1 Survival Follow-up 
Once a subject experiences confirmed disease progression or starts a new anti-cancer therapy, the subject moves into the survival 
follow-up phase and should be contacted by telephone every 12 weeks to assess for survival status until death, withdrawal of consent, 
or the end of the study, whichever occurs first.  
7.1.4.4.2 Tumor Response 
To systematically characterize additional patterns of response in patients with metastatic cancer, Response Evaluation Criteria in Solid 
Tumors (RECIST) version 1.1 will be used.  The details as to how RECIST criteria are applied are given below.  
A maximum of 5 target lesions in total (and up to 2 per organ) can be identified at baseline and measured throughout the course of 
therapy.  In order to be considered a measurable target lesion, a nodal lesion must be > 1.5 cm in short axis diameter (SAD), and an 
extranodal lesion must be > 1.0 cm in longest diameter (LD).  The irradiated lesion will not be included as a target lesion for 
measurement using RECIST.  The sum of diameters of the target lesions (SAD for nodal lesions and LD for extranodal lesions) is 
followed through the course of therapy.  
Disappearance of all known lesions will be counted as complete response (CR). A reduction of at least 30% in the sum of the 
diameters of target lesions is defined as partial response (PR).  Progressive disease (PD) is defined as >20% increase in the sum of 
diameters of target lesions from nadir (including baseline if it is smallest sum).  PD is also defined as unequivocal progression of 
existing non-target lesions that merits discontinuation of therapy.   
7.1.4.4.3 Tumor Progression  
If imaging at any time shows PD, treatment with pembrolizumab may continue until a repeat assessment 4-6 weeks later confirms PD.   
If this scan confirms progression of disease compared with previous scan that showed PD, then pembrolizumab should be 
discontinued.  However, the referring Medical Oncologist may remove the  patient from the protocol after the first imaging showing 
PD.  .  It will be up to the patient’s medical oncologist to determine the next course of therapy (if any).   Further radiologic imaging 
will be obtained as per the referring physician’s clinical judgment.   
 
 


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7.2 
Assessing and Recording Adverse Events 
An adverse event is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An adverse event can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease 
temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the 
medicinal product or protocol-specified procedure.  Any worsening (i.e., any clinically significant adverse change in frequency and/or 
intensity) of a preexisting condition that is temporally associated with the use of the Merck’s product, is also an adverse event. 
Changes resulting from normal growth and development that do not vary significantly in frequency or severity from expected levels 
are not to be considered adverse events.  Examples of this may include, but are not limited to, teething, typical crying in infants and 
children and onset of menses or menopause occurring at a physiologically appropriate time. 
Merck product includes any pharmaceutical product, biological product, device, diagnostic agent or protocol-specified procedure, 
whether investigational (including placebo or active comparator medication) or marketed, manufactured by, licensed by, provided by 
or distributed by Merck for human use. 
Adverse events may occur during the course of the use of Merck product in clinical trials or within the follow-up period specified by 
the protocol, or prescribed in clinical practice, from overdose (whether accidental or intentional), from abuse and from withdrawal. 
Adverse events may also occur in screened subjects during any pre-allocation baseline period as a result of a protocol-specified 
intervention, including washout or discontinuation of usual therapy, diet, placebo treatment or a procedure. 
All adverse events will be recorded from the time the consent form is signed through 30 days following cessation of treatment and at 
each examination on the Adverse Event case report forms/worksheets. The reporting timeframe for adverse events meeting any serious 
criteria is described in section 7.2.3.1. 
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. 


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7.2.1 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 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) 
7.2.2 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 completing the trial, or 30 days following cessation of treatment 
if the subject initiates new anticancer therapy, whichever is earlier.  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) 


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7.2.3 Immediate Reporting of Adverse Events to the Sponsor and to Merck 
7.2.3.1 Serious Adverse Events 
A serious adverse event is any adverse event occurring at any dose or during any use of Merck’s product that: 
• Results in death; 
• Is life threatening; 
• Results in persistent or significant disability/incapacity; 
• Results in or prolongs an existing inpatient hospitalization; 
• Is a congenital anomaly/birth defect; 
• Is a new cancer (that is not a condition of the study); 
• Is associated with an overdose; 
• Is an other important medical event  
Refer to Table 10 for additional details regarding each of the above criteria. 
Progression of the cancer under study is not considered an adverse event unless it results in hospitalization or death. 
Any serious adverse event, or follow up to a serious adverse event, including death due to any cause other than progression of the 
cancer under study that occurs to any subject from the time the consent is signed through 90 days following cessation of treatment, or 
the initiation of new anti-cancer therapy, whichever is earlier, whether or not related to Merck product, must be reported within 24 
hours to the Sponsor and within 2 working days to Merck Global Safety.  
Non-serious Events of Clinical Interest will be forwarded to Merck Global Safety and will be handled in the same manner as SAEs.  
Additionally, any serious adverse event, considered by an investigator who is a qualified physician to be related to Merck product that 
is brought to the attention of the investigator at any time outside of the time period specified in the previous paragraph also must be 
reported immediately to the Sponsor and to Merck. 
SAE reports and any other relevant safety information are to be forwarded to the Merck Global Safety facsimile number:  +1-
215-993-1220 


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A copy of all 15 Day Reports and Annual Progress Reports is submitted as required by FDA, European Union (EU), Pharmaceutical 
and Medical Devices agency (PMDA) or other local regulators. Investigators will cross reference this submission according to local 
regulations to the Merck Investigational Compound Number (IND, CSA, etc.) at the time of submission.  Additionally investigators 
will submit a copy of these reports to Merck & Co., Inc. (Attn: Worldwide Product Safety; FAX 215 993-1220) at the time of 
submission to FDA. 
All subjects with serious adverse events must be followed up for outcome. 
7.2.3.2 Events of Clinical Interest 
Selected non-serious and serious adverse events are also known as Events of Clinical Interest (ECI) and must be 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 7.2.1 - Definition of an Overdose for This Protocol and Reporting of Overdose 
to the Sponsor, that is not associated with clinical symptoms or abnormal laboratory results.  
2.  An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of normal and an elevated total bilirubin lab 
value that is greater than or equal to 2X the upper limit of normal and, at the same time, an alkaline phosphatase lab value that is less 
than 2X the upper limit of normal, as determined by way of protocol-specified laboratory testing or unscheduled laboratory testing.* 
*Note:  These criteria are based upon available regulatory guidance documents. The purpose of the criteria is to specify a threshold 
of abnormal hepatic tests that may require an additional evaluation for an underlying etiology.  The trial site guidance for 
assessment and follow up of these criteria can be found in the Investigator Trial File Binder (or equivalent). 
3.  In the event a subject develops any of the following AEs, a detailed narrative of the event should be reported as an ECI to the 
Sponsor within 24 hours and to Merck Global Safety within 2 working days of the event: 
a.  Grade ≥ 3 diarrhea 
b.  Grade ≥  3 colitis 
c.  Grade ≥ 2 pneumonitis 


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d.  Grade ≥ 3 hypo- or  hyperthyroidism 
 
A separate guidance document has been provided entitled “event of Clinical Interest and Immune-Related Adverse Event Guidance 
Document.”  This document provides guidance regarding identification, evaluation and management of ECIs and irAEs.  Additional 
ECIs are identified in this guidance document and also need to be reported to the Sponsor within 24 hours and to Merck Global Safety 
within 2 working days of the event.   
Subjects should be assessed for possible ECIs prior to each dose.  Lab results should be evaluated and subjects should be asked for 
signs and symptoms suggestive of an immune-related event.  Subjects who develop an ECI thought to be immune-related should have 
additional testing to rule out other etiologic causes.  If lab results or symptoms indicate a possible immune-related ECI, then additional 
testing should be performed to rule out other etiologic causes.  If no other cause is found, then it is assumed to be immune-related.  
ECIs that occur in any subject from the date of first dose through 90 days following cessation of treatment, or the initiation of a new 
anticancer therapy, whichever is earlier, whether or not related to the Merck’s product, must be reported within 24 hours to the 
Sponsor and to Merck Global Safety within 2 working days. 
7.2.4 Evaluating Adverse Events 
An investigator who is a qualified physician will evaluate all adverse events according to the NCI Common Terminology for Adverse 
Events (CTCAE), version 4.0. Any adverse event which 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. 


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Table 10 Evaluating Adverse Events 
An investigator who is a qualified physician, will evaluate all adverse events as to: 
V4.0 
CTCAE 
Grading 
Grade 1 
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention 
not indicated. 
 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental ADL.
 
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation or hospitalization indicated; disabling; limiting self-care ADL.
 
Grade 4 
Life threatening consequences; urgent intervention indicated.
 
Grade 5 
Death related to AE
Seriousness 
A serious adverse event is any adverse event occurring at any dose or during any use of Merck product that: 
 
†Results in death; or 
 
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event 
as it occurred (Note: This does not include an adverse event that, had it occurred in a more severe form, might have 
caused death.); or 
 
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct 
normal life functions); or 
 
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient 
admission, regardless of length of stay, even if the hospitalization is a precautionary measure for continued 
observation. (Note: Hospitalization [including hospitalization for an elective procedure] for a preexisting condition 
which has not worsened does not constitute a serious adverse event.); or 
 
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to 
diagnosis);or 
 
Is a new cancer; (that is not a condition of the study) or 
 
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a 
serious adverse event. An overdose that is not associated with an adverse event is considered a non-serious event of 
clinical interest and must be reported within 24 hours. 
 
Other important medical events that may not result in death, not be life threatening, or not require hospitalization 
may be considered a serious adverse event when, based upon appropriate medical judgment, the event may 


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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 test drug  
Did the Merck product cause the adverse event? The determination of the likelihood that the Merck product caused 
the adverse event will be provided by an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE form, ensures that a 
medically qualified assessment of causality was done. This initialed document must be retained for the required 
regulatory time frame. The criteria below are intended as reference guidelines to assist the investigator in assessing 
the likelihood of a relationship between the test drug and the adverse event based upon the available information.  
The following components are to be used to assess the relationship between the Merck product and the AE; 
the greater the correlation with the components and their respective elements (in number and/or intensity), the more 
likely the Merck product caused the adverse event (AE): 
 
Exposure 
Is there evidence that the subject was actually exposed to the Merck product such as: reliable history, 
acceptable compliance assessment (pill count, diary, etc.), expected pharmacologic effect, or 
measurement of drug/metabolite in bodily specimen? 
 
Time 
Course 
Did the AE follow in a reasonable temporal sequence from administration of the Merck product?  
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with 
investigational medicinal product)? 
 
Likely 
Cause 
Is the AE not reasonably explained by another etiology such as underlying disease, other 
drug(s)/vaccine(s), or other host or environmental factors 
 
 
Relationship
The following components are to be used to assess the relationship between the test drug and the AE: 
(continued)
to Merck 
product 
(continued)  
Dechallenge
Was the Merck product discontinued or dose/exposure/frequency reduced? 
If yes, did the AE resolve or improve? 
If yes, this is a positive dechallenge. If no, this is a negative dechallenge. 
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the 
AE resolved/improved despite continuation of the Merck product; or (3) the trial is a single-dose 


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


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7.2.5 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.  
7.2.6 Investigator reporting: notifying the Penn IRB 
This section describes the requirements for safety reporting by investigators who are Penn 
faculty, affiliated with a Penn research site, or otherwise responsible for safety reporting to 
the Penn IRB. The University of Pennsylvania IRB (Penn IRB) requires expedited reporting 
of those events related to study participation that are unforeseen and indicate that participants 
or others are at increased risk of harm.  The Penn IRB will not acknowledge safety reports or 
bulk adverse event submissions that do not meet the criteria outlined below.  The Penn IRB 
requires researchers to submit reports of the following problems within 10 working days 
from the time the investigator becomes aware of the event: 
• 
Any adverse event (regardless of whether the event is serious or non-serious, on-site 
or off-site) that occurs any time during or after the research study, which in the opinion of the 
principal investigator is: 
Unexpected (An event is “unexpected” when its specificity and severity are not accurately 
reflected in the protocol-related documents, such as the IRB-approved research protocol, any 
applicable investigator brochure, and the current IRB-approved informed consent document 
and other relevant sources of information, such as product labeling and package inserts.) 
AND 
Related to the research procedures (An event is “related to the research procedures” if in the 
opinion of the principal investigator or sponsor, the event was possibly, probably, or 
definitely caused by the research procedures.) 
Reporting Process 
Unanticipated problems posing risks to subjects or others as noted above will be reported to 
the Penn IRB using the form: “Unanticipated Problems Posing Risks to Subjects or Others 
Including Reportable Adverse Events” or as a written report of the event (including a 
description of the event with information regarding its fulfillment of the above criteria, 
follow-up/resolution and need for revision to consent form and/or other study 
documentation). 
Copies of each report and documentation of IRB notification and receipt will be kept in the 
Clinical Investigator’s study file. 
Data Safety Monitoring Committee (DSMC) Reporting to the Abramson Cancer 
Center: 
All related events regardless of expectedness will be submitted to the DSMC within 10 days. 
All grade 3 or higher events will be submitted to the DSMC within 5 days of knowledge. 


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All unexpected events regardless of attribution will be submitted to the DSMC within 10 
days. 
 
We will continue to send reports to the DSMC for 90 days following the last date the final 
subject received study treatment/therapy/intervention or was exposed to an investigational 
device. We will not send reports after the 90 day window. 
 
All unexpected deaths or deaths related to the study agent(s)/device(s) will be reported within 
24 hours. All other deaths will be reported within 30 days.  Deaths of subjects off study for 
greater than 30 days from the last study intervention/treatment are not reportable except if the 
death is in house gene or cellular-therapies, deaths on in-house studies utilizing on-campus 
manufacturing of the study agent(s) or components of study agent(s) and deaths on first-in-
human studies.  
 
A deviation is a one time, unintentional action or process that departs from the IRB and 
DSMC approved study protocol, involving one incident and identified retrospectively, after 
the event occurred. If the impact on the protocol disrupts the study design, may affect the 
outcome (endpoints) or compromises the safety and welfare of the subjects, the deviation 
must be reported to the DSMC within 5 business days and the IRB within 10 business days. 
Reporting Deaths:  more rapid reporting requirements 
Concerning deaths that occur during the course of a research study, the following describes 
the more rapid reporting requirement of the Penn IRB for specific situations: 
• 
Report the event within 24 hours when the death is unforeseen (unexpected) and 
indicates participants or others are at increased risk of harm. 
• 
Report the event within 72 hours, for all other deaths, regardless of whether the death 
is related to study participation. 
 
For reportable deaths, the initial submission to the Penn IRB may be made by contacting the 
IRB Director or Associate Director. The AE/Unanticipated Problem Form is required as a 
follow up to the initial submission. 
Other Reportable events: 
For clinical drug trials, the following events are also reportable to the Penn IRB: 
• 
Any adverse experience that, even without detailed analysis, represents a serious 
unexpected adverse event that is rare in the absence of drug exposure (such as 
agranulocytosis, hepatic necrosis, Stevens-Johnson syndrome). 
• 
Any adverse event that would cause the sponsor to modify the investigators brochure, 
protocol or informed consent form, or would prompt other action by the IRB to assure 
protection of human subjects. 


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• 
Information that indicates a change to the risks or potential benefits of the research, in 
terms of severity or frequency. For example:  
– 
An interim analysis indicates that participants have a lower rate of response to 
treatment than initially expected. 
– 
Safety monitoring indicates that a particular side effect is more severe, or more 
frequent than initially expected. 
– 
A paper is published from another study that shows that an arm of your research 
study is of no therapeutic value. 
• 
Change in FDA safety labeling or withdrawal from marketing of a drug, device, or 
biologic used in a research protocol. 
• 
Breach of confidentiality 
• 
Change to the protocol taken without prior IRB review to eliminate apparent 
immediate hazard to a research participant. 
• 
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. 
• 
Complaint of a participant when the complaint indicates unexpected risks or the 
complaint cannot be resolved by the research team. 
• 
Protocol violation (meaning an accidental or unintentional deviation from the IRB 
approved protocol) that in the opinion of the investigator placed one or more participants at 
increased risk, or affects the rights or welfare of subjects. 
7.3 
Medical Monitoring 
It is the responsibility of the Principal Investigator to oversee the safety of the study at his/her 
site.  This safety monitoring will include careful assessment and appropriate reporting of 
adverse events as noted above, as well as the construction and implementation of a site data 
and safety-monitoring plan (see section 9 Auditing, Monitoring and Inspecting).  Medical 
monitoring will include a regular assessment of the number and type of serious adverse 
events. 
8.0 STATISTICAL ANALYSIS PLAN 
This is a stratified phase I trial with 2 phases: a safety phase and an expansion phase. 
Safety Phase: Pembrolizumab is fixed. Two radiotherapy fractionation schedules are tested: 8 
Gy x 3 and 17 Gy x 1. Patients are stratified by prior PD-1 therapy. 24 patients will be 
enrolled, 12 per stratum and 6 per fractionation cohort.  
Table 11 
 
 
Cohort 1: 8 Gy x 3 
Number of Patients
Cohort 2: 17 Gy x 1 
Number of Patients 
 
TOTAL 
 
Progressed on Prior PD-1  
(Melanoma or NSCLC) 
 
6 
 
6 
 
12 


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Stratify 
 
 
 
 
 
No Prior PD-1 
(Pancreas, Breast or Other 
cancers) 
 
6 
 
6* 
 
12 
TOTAL
12 
12 
24 
 
* Breast or Other cancer patients only
 
Safety Phase Decision-making: Dose limiting toxicity (DLT) is defined in Sections 2.1 and 
5.2. The regimen is considered safe if 0-1 DLTs are observed in 6 patients within a stratum. 
Stop if 2+ DLT at any time. If 2+ DLT in Cohort 1, then Cohort 2 will still be tested. Cohort 
1  Cohort 2 is not an escalation of dose.  
Expansion Phase: Patients are now stratified by disease site.  
• If both fractionation regimens are considered safe for both prior PD-1 therapy strata, 
then we will randomize patients. Randomization will aid in our preliminary 
assessment of clinical response by avoiding selection bias. Although unlikely, if only 
one of the fractionation regimens is considered safe for both prior PD-1 therapy 
strata, then  all patients will be enrolled on the fractionation regimen which was 
determined to be safe.  
Table 12 
 
Randomize 
 
 
Number of  
Randomized 
Patients 
Disease  
Cohort 1: 8 Gy x 3 
Number of Patients 
Cohort 2: 17 Gy x 1 
Number of Patients 
Melanoma 
7 
7 
14 
NSCLC 
7 
7 
14 
Pancreas 
6 
0 
  6* 
Breast 
3 
3 
6 
Other cancers 
3 
3 
6 
TOTAL 
26 
20 
46 
 
* Pancreas patients are not randomized, they are assigned to 
8 Gy x 3 
 
Expansion Phase Decision-making:  We will first evaluate response rate by fractionation 
cohort.  We will pool all disease sites. This is a global assessment of RADVAX™ by 
fractionation cohort. Of 38 patients in cohort 1, 26 (68%) and of 32 patients in cohort 2, 20 
(63%) will have been randomized to treatment in the expansion phase, which strengthens any 
comparative conclusions, although preliminary. Immune PD markers will also be examined 
by fractionation cohort.  
 
 


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Table 13 
 
Cohort 1: 8 Gy x 3 
Number of Patients 
Cohort 2: 17 Gy x 1 
Number of Patients 
STUDY  
TOTAL
Safety phase 
12 
12 
24 
Expansion phase 
26 
20 
46 
TOTAL 
38 
32 
70 
 
The following are examples of response rates and exact 95% CIs based on 38 patients in 
Cohort 1 and 32 patients in Cohort 2.  
Table 14 
Cohort 1 
Cohort 2 
N= 38 patients 
N = 32 patients 
#  
Respond 
Response 
Rate 
95% exact CI 
#  
Respond 
Response 
Rate 
95% exact CI 
5 
13.2% 
4.4 – 28.1% 
4 
12.5% 
3.5 – 29.0 
10 
26.3% 
13.4 – 43.1% 
8 
25.0% 
11.5 – 43.4 
19 
50.0% 
33.4 – 66.6% 
16 
50.0% 
31.9 – 68.1 
30 
78.9% 
62.7 – 90.4% 
24 
75.0% 
56.6 – 88.5 
35 
92.1% 
78.6 – 98.3% 
28 
87.5% 
71.0 – 96.5 
 
Next we will evaluate response rate by disease site. Here we pool fractionation cohorts.  This 
is an assessment of RADVAX™ activity by disease, although preliminary.  
Table 15 
 
Disease 
Safety Phase 
(Number is expected  
not required**) 
Expansion Phase 
(Number is required) 
STUDY  
TOTAL  
Melanoma 
6 
14 
20 
NSCLC 
6 
14 
20 
Pancreas 
4 
6 
10 
Breast 
4 
6 
10 
Other cancers 
4 
6 
10 
** assumes equal numbers by disease strata in (12 prior PD-1 and 12 no prior PD-1
 
For Melanoma and NSCLC cohorts: If 0/14 in the expansion phase respond then we can rule 
out a 20% response rate with 95% confidence. If 0/20 (pooling both phases) respond, then we 
can rule out a 15% response rate with 95% confidence. 


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For Pancreas, breast cancer and other cancers: If 0/6 in the expansion phase respond then we 
can rule out a 40% response rate with 95% confidence. If 0/10 (pooling both phases) 
respond, then we can rule out a 27% response rate with 95% confidence. 
 
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 16. 
Table 16  Product Description 
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.   
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site. 
Clinical supplies may not be used for any purpose other than that stated in the protocol. 


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9.5 
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. 
10.0 ADMINISTRATIVE AND REGULATORY DETAILS 
10.1 Compliance with Trial Registration and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely 
responsible for determining whether the trial and its results are subject to the requirements 
for submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov.  Information 
posted will allow subjects to identify potentially appropriate trials for their disease conditions 
and pursue participation by calling a central contact number for further information on 
appropriate trial locations and trial site contact information.     
11.0  DATA HANDLING AND RECORD KEEPING 
11.1 
Confidentiality 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  
Those regulations require a signed subject authorization informing the subject of the 
following:  
• 
What protected health information (PHI) will be collected from subjects in this study 
• 
Who will have access to that information and why 
• 
Who will use or disclose that information 
• 
The rights of a research subject to revoke their authorization for use of their PHI.  
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of 
subject authorization.  For subjects that have revoked authorization to collect or use PHI, 
attempts should be made to obtain permission to collect at least vital status (i.e. that the 
subject is alive) at the end of their scheduled study period. 


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11.2 
Source Documents 
Source data is all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial.  Source 
data are contained in source documents.  Examples of these original documents, and data 
records include: hospital records, clinical and office charts, laboratory notes, memoranda, 
subjects’ diaries or evaluation checklists, pharmacy dispensing records, recorded data from 
automated instruments, copies or transcriptions certified after verification as being accurate 
and complete, microfiches, photographic negatives, microfilm or magnetic media, x-rays, 
subject files, and records kept at the pharmacy, at the laboratories, and at medico-technical 
departments involved in the clinical trial. 
11.3 
Case Report Forms 
The study case report form (CRF) is the primary data collection instrument for the study.  All 
data requested on the CRF must be recorded.  All missing data must be explained.  If a space 
on the CRF is left blank because the procedure was not done or the question was not asked, 
write “N/D”.  If the item is not applicable to the individual case, write “N/A”.  All entries 
should be printed legibly in black ink.  If any entry error has been made, to correct such an 
error, draw a single straight line through the incorrect entry and enter the correct data above 
it.  All such changes must be initialed and dated.  DO NOT ERASE OR WHITE OUT 
ERRORS.  For clarification of illegible or uncertain entries, print the clarification above the 
item, then initial and date it. 
11.4 
Records Retention 
It is the investigator’s responsibility to retain study essential documents for at least 2 years 
after the last approval of a marketing application in their country and until there are no 
pending or contemplated marketing applications in their country or at least 2 years have 
elapsed since the formal discontinuation of clinical development of the investigational 
product.  
12.0  ETHICAL CONSIDERATIONS 
This study is to be conducted according to US and international standards of Good Clinical 
Practice (FDA Title 21 part 312 and International Conference on Harmonization guidelines), 
applicable government regulations and Institutional research policies and procedures. 
This protocol and any amendments will be submitted to a properly constituted independent 
Ethics Committee (EC) or Institutional Review Board (IRB), in agreement with local legal 
prescriptions, for formal approval of the study conduct.  The decision of the EC/IRB 
concerning the conduct of the study will be made in writing to the investigator and a copy of 
this decision will be provided to the sponsor before commencement of this study.  The 
investigator should provide a list of EC/IRB members and their affiliate to the sponsor. 
All subjects for this study will be provided a consent form describing this study and 
providing sufficient information for subjects to make an informed decision about their 
participation in this study.  See attachment for a copy of the Subject Informed Consent Form.  
This consent form will be submitted with the protocol for review and approval by the 


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EC/IRB for the study.  The formal consent of a subject, using the EC/IRB-approved consent 
form, must be obtained before that subject undergoes any study procedure.  The consent form 
must be signed by the subject, and the investigator-designated research professional 
obtaining the consent.  
13.0 STUDY FINANCES 
13.1 
Funding Source 
This study will be supported with funds from Merck, Inc. and internal funds from the 
Department of Radiation Oncology. 
13.2 
Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or 
financial gain greater than the minimum allowable by their institution, etc.) must have the 
conflict reviewed by a properly constituted Conflict of Interest Committee with a Committee-
sanctioned conflict management plan that has been reviewed and approved by the study 
sponsor prior to participation in this study.  All University of Pennsylvania investigators will 
follow the University conflict of interest policy. 
14.0  PUBLICATION PLAN 
Neither the complete nor any part of the results of the study carried out under this protocol, 
nor any of the information provided by the sponsor for the purposes of performing the study, 
will be published or passed on to any third party without the consent of the study sponsor.  
Any investigator involved with this study is obligated to provide the sponsor with complete 
test results and all data derived from the study.  Rule regarding the publication of results 
from this study are covered in the sponsored research agreement between Merck and the 
University of Pennsylvania. 
15.0 LIST OF REFERENCES (IN PARENTHESES) 
1. 
Milano, M.T., Katz, A.W., Zhang, H., and Okunieff, P. 2012. Oligometastases treated 
with stereotactic body radiotherapy: long-term follow-up of prospective study. Int J 
Radiat Oncol Biol Phys 83:878-886. 
2. 
Rusthoven, K.E., Kavanagh, B.D., Cardenes, H., Stieber, V.W., Burri, S.H., 
Feigenberg, S.J., Chidel, M.A., Pugh, T.J., Franklin, W., Kane, M., et al. 2009. Multi-
institutional phase I/II trial of stereotactic body radiation therapy for liver metastases. 
J Clin Oncol 27:1572-1578. 
3. 
Salama, J.K., Hasselle, M.D., Chmura, S.J., Malik, R., Mehta, N., Yenice, K.M., 
Villaflor, V.M., Stadler, W.M., Hoffman, P.C., Cohen, E.E., et al. 2012. Stereotactic 
body radiotherapy for multisite extracranial oligometastases: final report of a dose 
escalation trial in patients with 1 to 5 sites of metastatic disease. Cancer 118:2962-
2970. 


Product:  PEMBROLIZUMAB
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4. 
Weichselbaum, R.R., and Hellman, S. 2011. Oligometastases revisited. Nat Rev Clin 
Oncol 8:378-382. 
5. 
Pardoll, D.M. 2012. The blockade of immune checkpoints in cancer immunotherapy. 
Nat Rev Cancer 12:252-264. 
6. 
Hodi, F.S., O'Day, S.J., McDermott, D.F., Weber, R.W., Sosman, J.A., Haanen, J.B., 
Gonzalez, R., Robert, C., Schadendorf, D., Hassel, J.C., et al. 2010. Improved 
survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 
363:711-723. 
7. 
Hamid, O., Robert, C., Daud, A., Hodi, F.S., Hwu, W.J., Kefford, R., Wolchok, J.D., 
Hersey, P., Joseph, R.W., Weber, J.S., et al. 2013. Safety and tumor responses with 
lambrolizumab (anti-PD-1) in melanoma. N Engl J Med 369:134-144. 
8. 
Topalian, S.L., Hodi, F.S., Brahmer, J.R., Gettinger, S.N., Smith, D.C., McDermott, 
D.F., Powderly, J.D., Carvajal, R.D., Sosman, J.A., Atkins, M.B., et al. 2012. Safety, 
activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 
366:2443-2454. 
9. 
Burnette, B., Fu, Y.X., and Weichselbaum, R.R. 2012. The confluence of 
radiotherapy and immunotherapy. Front Oncol 2:143. 
10. 
Verbrugge, I., Hagekyriakou, J., Sharp, L.L., Galli, M., West, A., McLaughlin, N.M., 
Duret, H., Yagita, H., Johnstone, R.W., Smyth, M.J., et al. 2012. Radiotherapy 
increases the permissiveness of established mammary tumors to rejection by 
immunomodulatory antibodies. Cancer Res 72:3163-3174. 
11. 
Lee, Y., Auh, S.L., Wang, Y., Burnette, B., Wang, Y., Meng, Y., Beckett, M., 
Sharma, R., Chin, R., Tu, T., et al. 2009. Therapeutic effects of ablative radiation on 
local tumor require CD8+ T cells: changing strategies for cancer treatment. Blood 
114:589-595. 
12. 
Chakravarty, P.K., Alfieri, A., Thomas, E.K., Beri, V., Tanaka, K.E., Vikram, B., and 
Guha, C. 1999. Flt3-ligand administration after radiation therapy prolongs survival in 
a murine model of metastatic lung cancer. Cancer Res 59:6028-6032. 
13. 
Chakraborty, M., Abrams, S.I., Coleman, C.N., Camphausen, K., Schlom, J., and 
Hodge, J.W. 2004. External beam radiation of tumors alters phenotype of tumor cells 
to render them susceptible to vaccine-mediated T-cell killing. Cancer Res 64:4328-
4337. 
14. 
Dewan, M.Z., Galloway, A.E., Kawashima, N., Dewyngaert, J.K., Babb, J.S., 
Formenti, S.C., and Demaria, S. 2009. Fractionated but not single-dose radiotherapy 
induces an immune-mediated abscopal effect when combined with anti-CTLA-4 
antibody. Clin Cancer Res 15:5379-5388. 


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15. 
Postow, M.A., Callahan, M.K., Barker, C.A., Yamada, Y., Yuan, J., Kitano, S., Mu, 
Z., Rasalan, T., Adamow, M., Ritter, E., et al. 2012. Immunologic correlates of the 
abscopal effect in a patient with melanoma. N Engl J Med 366:925-931. 
16. 
Deng, L., Liang, H., Burnette, B., Beckett, M., Darga, T., Weichselbaum, R.R., and 
Fu, Y.X. 2014. Irradiation and anti-PD-L1 treatment synergistically promote 
antitumor immunity in mice. J Clin Invest 124:687-695. 
17. 
Fieuws, S., Verbeke, G., and Molenberghs, G. 2007. Random-effects models for 
multivariate repeated measures. Stat Methods Med Res 16:387-397. 
 
16.0 LIST OF REFERENCES [IN BRACKETS] 
1. 
Disis ML.  Immune regulation of cancer. J Clin Oncol 2010; 28(29):4531-8. 
2. 
Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, et al. Tumor-
associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. 
Nat Med 2002;8(8):793-800.   
3. 
Sharpe AH, Freeman GJ. The B7-CD28 superfamily. Nature 2002;2:116-26. 
4. 
Brown JA, Dorfman DM, Ma F-R, Sullivan EL, Munoz O, Wood CR, et al. Blockade of 
programmed death-1 ligands on dendritic cells enhances T cell activation and cytokine 
production. J Immunol 2003;170:1257-66.   
5. 
Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and autoimmunity. 
Immunol Rev 2010;236:219-42. 
6. 
Thompson RH, Dong H, Lohse CM, Leibovich BC, Blute ML, Cheville JC, et al. PD-1 
expressed by tumor-infiltrating immune cells and is associated with poor outcome for 
patients with renal cell carcinoma. Clin Caner Res 2007;13(6):1757-61.   
7. 
Talmadge JE, Donkor M, Scholar E. Inflammatory cell infiltration of tumors: Jekyll or 
Hyde. Cancer Metastasis Rev 2007;26:373-400. 
8. 
Usubütün A, Ayhan A, Uygur MC, zen H, klu C, acan S. Prognostic factors in renal cell 
carcinoma. J Exp Clin Cancer Res 1998;17(1):77-81.   
9. 
Al-Shibli KI, Donnem T, Al-Saad S, Persson M, Bremnes RM, Busund L-T. Prognostic 
effect of epithelial and stromal symphocyte infiltration in non-small cell lung cancer. 
Clin Cancer Res 2008;14(16):5220-7. 
10. Deschoolmeester V, Baay M, Van Marck E, Weyler J, Vermeulen p, Lardon F, et al. 
Tumor infiltrating lymphocytes: an intriguing player in the survival of colorectal cancer 
patients. BMC Immunol 2010;11:19. 


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11. Diez M, Pollán M, Enriquez JM, Dominguez P, Santana A, Tobaruela E, et al. 
Histopathologic prognostic score in colorectal adenocarcinomas. Anticancer Res 
1998;18:689-94.   
12. Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pagès C, et al. 
Type, density, and location of immune cells within human colorectal tumors predict 
clinical outcome. Science 2006;313:1960-4.   
13. Hiraoka N. Tumor-infiltrating lymphocytes and hepatocellular carcinoma: molecular 
biology. Int J Clin Oncol 2010;15:544-51.   
14. Nobili C, Degrate L, Caprotti R, Franciosi C, Leone BE, Trezzi R, et al. Prolonged 
survival of a patient affected by pancreatic adenocarcinoma with massive lymphocyte 
and dendritic cell infiltration after interleukin-2 immunotherapy. Report of a case. 
Tumori 2008;94:426-30.   
15. Hodi FS, Dranoff G. The biologic importance of tumor-infiltrating lymphocytes. J Cutan 
Pathol 2010;37(Suppl 1):48-53.   
16. Kloor M. Lymphocyte infiltration and prognosis in colorectal cancer. Lancet 
2009;10(840):841.   
17. Hillen F, Baeten CIM, van de Winkel A, Creytens D, van der Schaft DWJ, 
Winnepenninckx V, et al. Leukocyte infiltration and tumor cell plasticity are parameters 
of aggressiveness in primary cutaneous melanoma. Cancer Immunol Immunother 
2008;57:97-106.   
18. Lee HE, Chae SW, Lee YJ, Kim MA, Lee HS, Lee BL, et al. Prognostic implications of 
type and density of tumour-infiltrating lymphocytes in gastric cancer. Br J Cancer 
2008;99(10):1704-11.   
19. Leffers N, Gooden MJM, de Jong RA, Hoogeboom B-N, ten Hoor KA, Hollema H, et 
al. Prognostic significance of tumor-infiltrating T-lymphocytes in primary and 
metastatic lesions of advanced stage ovarian cancer. Cancer Immunol Immunother 
2009;58:449-59.   
20. Nishimura H, Honjo T, Minato N. Facilitation of β selection and modification of 
positive selection in the thymus of PD-1-deficient mice. J Exp Med 2000;191(5):891-7.   
21. Liotta F, Gacci M, Frosali F, Querci V, Vittori G, Lapini A, et al. Frequency of 
regulatory T cells in peripheral blood and in tumour-infiltrating lymphocytes correlates 
with poor prognosis in renal cell carcinoma. BJU Intern 2010;107:1500-6.   
22. Ropponen KM, Eskelinen MJ, Lipponen PK, Alhava E, Kosma V-M. Prognostic value 
of tumour-infiltrating lynmphocytes (TILs) in colorectal cancer. J Pathol 1997;182:318-
24.   


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65
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23. Dudley ME, Wunderlich JR, Yang JC, Sherry RM, Topalian SL, Restifo NP, et al. 
Adoptive cell transfer therapy following non-myeloablative but lymphodepleting 
chemotherapy for the treatment of patients with refractory metastatic melanoma. J Clin 
Oncol 2005;23(10):2346-57.   
24. Hunder NN, Wallen H, Cao J, Hendricks DW, Reilly JZ, Rodmyre R, et al. Treatment of 
metastatic melanoma with autologous CD4+ T cells against NY-ESO-1. N Engl J Med 
2008;358(25):2698-703.   
25. Ölcher M, Braun M, Friedrichs N, Rudlowski C, Bercht E, Fimmers R, et al. Foxp3+ 
cell infiltration and granzyme B+/Foxp3+ cell ratio are associated with outcome in 
neoadjuvant chemotherapy-treated ovarian carcinoma. Cancer Immunol Immunother 
2010;59:909-19.   
26. Okazaki T, Maeda A, Nishimura H, Kurosaki T, Honjo T. PD-1 immunoreceptor 
inhibits B cell receptor-mediated signaling by recruiting src homology 2-domain-
containing tyrosine phosphatase 2 to phosphotyrosine. PNAS 2001;98(24):13866-71. 
27. Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisted. Annu Rev Immunol 
2005;23:515-48.   
28. Homsi J, Kashani-Sabet M, Messina JL, Daud A. Cutaneous melanoma:  prognostic 
factors. Cancer Control 2005;12(4):223-9.   
29. Iannone R, Gergich K, Cong C, Kang P, Daud A, Dronca R, et al.  Efficacy and safety 
of PEMBROLIZUMAB in patients with advanced melanoma.  Pigment Cell Melanoma 
Res 2012;25:836-903. 
30. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. 
Safety, activity, and immune correlates of Anti-PD-1 antibody in cancer. N Engl J Med 
2012:doi: 10.1056/NEJMoa1200690.   
31. Lyford-Pike S, Peng S, Young GD, et al.  Evidence for a role of the PD-1:PD-L1 
pathway in immune resistance of HPV-associated head and neck squamous cell 
carcinoma.  Cancer Res 2013;73(2): Published online January 3. 
32. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent R, Ford R, et al.  New 
response evaluation criteria in solid tumors: Revised RECIST guideline (version 1.1). 
Eur J Cancer 2009;45(2):228-47. 
33. Wolchok JD, Hoos A, O’Day S, Weber JS, Hamid O, Lebbe C, et al.  Guidelines for the 
evaluation of immune therapy activity in solid tumors: immune-related response criteria.  
Clin Cancer Res 2009;15(23):7412-20. 
34. Blum JL, Jones SE, Buzdar AU, LoRusso PM, et al. Multicenter Phase II Study of 
Capecitabine in Paclitaxel-Refractory Metastatic Breast Cancer. J Clin Oncol 17: 485-
493, 1999 


Product:  PEMBROLIZUMAB
66
Protocol/Amendment No.:  
 
 
 May 3, 2017 
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35. Martin M, Ruiz A, Munoz M, Balil A, Garcia-Mata J, Calvo L, et al. Gemcitabine plus 
vinorelbine monotherapy in patients with metastatic breast cancer previously treated 
with anthracyclines and taxanes: final results of the phase III Spanish Breast Cancer 
Research Group (GEICAM) trial. Lancet Oncol. 2007;8(3):219. 
36. Sledge GW, Neuberg D, Bernardo P, Ingle JN, Martino S, et al.  Phase III Trial of 
Doxorubicin, Paclitaxel, and the Combination of Doxorubicin and Paclitaxel as Front-
Line Chemotherapy for Metastatic Breast Cancer: An Intergroup Trial (E1193).   J Clin 
Oncol. 2003;21(4):588. 
37. Stewart JSW, Ezra E.W. Cohen EEW, Licitra L, Van Herpen CML, et al.  Phase III 
Study of Gefitinib Compared With Intravenous Methotrexate for Recurrent Squamous 
Cell Carcinoma of the Head and Neck.  J Clin Oncol. 2009;27(11):1864. 
38. Vermorken JB, Trigo J, Hitt R, Koralewski P, Diaz-Rubio E, et al.  Open-Label, 
Uncontrolled, Multicenter Phase II Study to Evaluate the Efficacy and Toxicity of 
Cetuximab As a Single Agent in Patients With Recurrent and/or Metastatic Squamous 
Cell Carcinoma of the Head and Neck Who Failed to Respond to Platinum-Based 
Therapy.   J Clin Oncol. 2007;25(16):2171. 
39. Bellmunt J, Théodore C, Demkov T, Komyakov B, Sengelov L, et al.  Phase III Trial of 
Vinflunine Plus Best Supportive Care Compared With Best Supportive Care Alone 
After a Platinum-Containing Regimen in Patients With Advanced Transitional Cell 
Carcinoma of the Urothelial Tract.  J Clin Oncol. 2009;27(27):4454 
40. Sweeney CJ, Roth BJ, Kabbinavar FF, Vaughn DJ, Arning M, et al.  Phase II Study of 
Pemetrexed for Second-Line Treatment of Transitional Cell Cancer of the Urothelium.  J 
Clin Oncol. 2006;24(21):3451 
41. Clopper C and Pearson ES. The use of confidence or fiducial limits illustrated in the 
case of the binomial. Biometrika 1934;26:404-413. 


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17.0 APPENDICES 
17.1 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. 
 
17.2 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) 


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17.3 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. 
 
17.4  Pembrolizumab Event of Clinical Interest Guidance Document