Phase I Trial of Adjuvant Pembrolizumab After Radiation Therapy for Lung-Intact Malignant Pleural Mesothelioma
Phase: PHASE1
Conditions: Pleural Malignant Mesothelioma
Sponsor: M.D. Anderson Cancer Center

 
 
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MD Anderson IND Sponsor Cover Sheet 
Protocol ID 
2015-0856 
Protocol Title 
Phase I Trial of Adjuvant Pembrolizumab After Radiation Therapy for 
Lung-Intact Malignant Pleural Mesothelioma 
Protocol Phase 
I 
Protocol Version 
23 
Version Date 
6/7/2022 
Protocol PI 
Matthew Ning 
Department 
Radiation Oncology 
IND Sponsor 
MD Anderson Cancer Center 
IND # 
132194 
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1.0 TRIAL SUMMARY 
Abbreviated Title 
Pembrolizumab after hemithoracic radiation therapy for lung intact 
mesothelioma 
Trial Phase 
I 
Clinical Indication 
Curative intent 
Trial Type 
 
Type of control 
None 
Route of administration 
IV 
Trial Blinding 
None 
Treatment Groups  
Single arm 
Number of trial subjects 
24 
Estimated enrollment period 
12-16 months 
Estimated duration of trial 
18-24 months 
Duration of Participation 
18-24 months 
 
 
 
 
2.0 TRIAL DESIGN 
2.1 
Trial Design 
This trial is a single-arm study assessing the role of Pembrolizumab after induction 
chemotherapy +/- lung-sparing surgery for malignant pleural mesothelioma (MPM).  Twelve 
patients will receive induction chemotherapy with a standard regimen (cisplatin/pemetrexed), 
followed by surgical resection if feasible with a lung-sparing approach (extrapleural 
pneumonectomy excluded), followed by hemithoracic radiation therapy with intensity 
modulated radiation therapy (IMRT) or proton beam therapy (PBT) to a total dose of 45 Gy in 
25 fractions to the entire hemithorax, with an optional simultaneous integrated boost of 60 Gy 
in 25 fractions.  Patients then will receive Pembrolizumab, 200 mg every 3 weeks until one of 
three timepoints (whatever comes first):  1) progression, 2) unacceptable toxicity, 3) 2 years.    
In addition, we will enroll 12 additional patients with MPM who receive radiation for palliative 
reasons to a limited field (non-hemithoracic).  This latter group of patients will be enrolled so 
that the abscopal/systemic effect can be evaluated in the context of very limited treatment 
options, to include patients that are not candidates for extensive radiation therapy.    
These two independent cohorts of 12 patients will be accrued simultaneously but monitored 
separately, as outlined in the Statistical Methods section below. 
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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 and tolerability of pembrolizumab administered after 
radiation therapy in patients with MPM who have not undergone extrapleural 
pneumonectomy. Two cohorts will be included, one receiving extensive hemithoracic 
radiation and the other receiving more limited, palliative treatment. These cohorts will be 
accrued simultaneously but monitored separately for toxicity. 
Hypothesis:  Pembrolizumab will be well tolerated when given after radiation therapy for 
MPM.    
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3.2 
Secondary Objective(s) & Hypothesis(es) 
(1) Objective:  To assess progression-free and overall survival (PFS and OS, respectively) in 
patients receiving Pembrolizumab after radiation therapy for MPM. 
Hypothesis:  Adding Pembrolizumab to radiation therapy for MPM will improve PFS and 
OS compared to historical controls. 
3.3 
Exploratory Objective 
(1) 
Objective: To evaluate biomarkers of interest, including cytokines, measurements of T-
cell activation, and serum exosome microRNAs  with the delivery of Pembrolizumab 
after radiation therapy for MPM. 
4.0 BACKGROUND & RATIONALE 
4.1 
Background 
 
Malignant pleural mesothelioma (MPM) occurs in approximately 2000-3000 new 
individuals each year in the United States.[1] MPM remains a difficult disease to treat with 
median overall survival rates remaining between 9–17 months, regardless of stage.[2-4]  In 
patients that present with locoregionally confined disease (e.g. non-metastatic), the standard of 
care for definitive intent has historically involved induction chemotherapy followed by an 
extrapleural pneumonectomy (EPP=removal of the ipsilateral lung, pleura, diaphragm, and 
pericardium) and consideration of postoperative radiation therapy.  However, many patients 
cannot tolerate an EPP, and as a result this resection is not a viable option for a large percentage 
of patients. In addition, several recent clinical studies have concluded that an EPP does not 
provide 
a 
survival 
advantage 
over 
lung 
sparing 
approaches, 
including 
a 
pleurectomy/decortication (e.g. “stripping” of the pleura without removing the lungs) or no 
surgery.   
Specifically, The Mesothelioma and Radical Surgery trial (MARs)[5, 6] which 
compared 50 randomized MPM patients to EPP (n=24) versus “no EPP” (n=26) reported that 
receipt of EPP led to a worse survival (hazard ratio (HR) 1.90, 95% CI 0.92 – 3.93, p=0.082).  
In this study, only 16 of the 24 patients in the EPP arm actually received the EPP and 19% 
(n=3) had post-operative deaths.   After accounting for prognostic factors (stage, histology, 
gender, age), the HR for EPP was reported as 2.75 (p=0.016).  The median overall survival 
was 14.4 months for patients in the EPP arm compared to 19.5 months for the patients in the 
“no EPP” arm.  This trial, although limited in numbers of patients, suggested that at worst, EPP 
can harm patients and at best, there was no clinical benefit for MPM patients.  In addition, 
Lang-Lazdunski et al.[7] conducted a nonrandomized study of consecutive MPM patients and 
compared 25 who received neoadjuvant chemotherapy followed by EPP and radiation to 54 
patients with P/D, hyperthermic lavage, adjuvant radiation and chemotherapy.  The study 
reported that the P/D arm was superior to the EPP arm for compliance, toxicity and survival.  
Patients in the P/D arm had 100% compliance to complete trimodality treatment versus 68% 
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in the EPP arm.  The P/D arm also had a higher median overall survival of 23 months versus 
12.8 months.[7]   
Studies such as these have suggested that patients are optimally treated with lung 
sparing approaches.  However, radiation therapy when the ipsilateral lung is intact, with or 
without surgery, presents unique issues.  First, the presence of functional lung tissue on the 
same side as the target volume exposes the patient to the risk of radiation pneumonitis in this 
lung.  Second, presuming that the ipsilateral lung is functional, patients can theoretically 
experience significant functional decline due to the difficulty in sparing this structure.  Finally, 
if much of the ipsilateral lung is nonfunctional after RT, a “shunting” effect can occur whereby 
patients continue to perfuse to the ipsilateral lung, yet air exchange does not occur.  For these 
reasons, hemithoracic radiation treatment with two functional lungs can paradoxically be more 
challenging than with only one lung intact.   
However, a limited number of institutions, including ours, have utilized advanced 
techniques to treat patients that do not undergo EPP with hemithoracic radiation therapy in the 
definitive setting.  The first of these approaches is IMRT, and Figure 1 depicts a representative 
IMRT plan in this setting.  We have recently published our results of 22 patients who 
underwent P/D followed by adjuvant IMRT to the involved hemithorax. Patients were treated 
to 45 Gy in 25 fractions with 9 patients receiving a simultaneous boost to 60 Gy to high risk 
areas.   Twenty patients received chemotherapy (15=induction, 2=adjuvant, 3=both). Median 
follow up was 14.7 months after surgery (range 4.1-37.1 months). The therapy was well 
tolerated. No grade 4-5 pulmonary toxicity was noted.  One case of grade 4 thrombocytopenia 
was observed.  Progressive decreases in pulmonary function were noted after surgery and 
IMRT.  Median baseline % predicted FVC, FEV1, and DLCO were 90%, 84%, and 87%. The 
change in % predicted FVC, FEV1 and DLCO was -18%, -11% and-17% after surgery and -
25% (p=0.02), -18% (p=0.01), and -27% (p=0.01) after IMRT. Rates of overall survival and 
progression free survival were 73% and 60% at 1 year, respectively, and 52% and 32% at 2 
years, respectively. Outcomes for IMRT after P/D were compared to 22 matched patients who 
underwent IMRT after EPP.  The patients who underwent P/D had less grade 4-5 toxicity (0/22 
vs 3/22, p=0.23) and a trend towards improved median overall survival (28.4 vs 14.2 months, 
p=0.14), median disease free survival (15.4 vs 10.2 months, p=0.18), and median time to 
distant metastasis (not reached vs 11.8 months, p=0.15). [8]  Thus, these results suggested that 
hemithoracic radiation after P/D provides comparable toxicity and efficacy as after EPP.   
 
Figure 1.  IMRT treatment plan with the lung intact. 
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Indeed, other reports have also been consistent with these findings.  Between 2005 and 
2010, 36 patients from Memorial Sloan-Kettering Cancer Center (MSKCC) with malignant 
pleural mesothelioma who were unable to undergo pneumonectomy underwent induction 
chemotherapy (89% of patients) and then P/D with adjuvant IMRT (56%) or IMRT with biopsy 
only (44%).  All patients were treated to the pleural surface of the involved hemithorax to a 
median dose of 46.8 Gy. Seven (20%) patients developed high grade pneumonitis (including 
1 death). For patients who underwent PL/D prior to IMRT, the 1- and 2-year survival rate was 
75% and 53%, and the median survival was 26 months. For patients who did not undergo 
surgical resection, the 1- and 2-year survival rate and median survival trended lower at 69% 
and 28%, and 17 months respectively.[9]  These investigators also recently examined patterns 
of failure when treating the external pleural hemithorax in 67 patients to a similar volume as 
Figure 2.  The rate of in-field local failure was 64%, with 1- and 2-year total failure rates of 
56% and 74%, respectively.  Interestingly, the authors also found that failure within the fissures 
was 16%, and only 1 patient had an incisional failure despite the practice of not routinely 
boosting the incisional sites [10].  Based on these two trials, we have recently completed a 
prospective study in conjunction with MSKCC examining the efficacy of patients treated with 
induction chemotherapy, then P/D or no surgery, followed by hemithoracic radiation therapy 
with IMRT.   Thirty nine patients enrolled, and in an interim report 21 patients completed 
IMRT.  Only one patient experienced Grade 3 pneumonitis, a rate below that which is often 
reported for locally advanced non-small cell lung cancer (NSCLC).[11] 
A second radiation technique that can be used to further increase normal tissue sparing 
is PBT, specifically intensity modulated proton therapy (IMPT).  Proton particles provide a 
dose distribution advantage by delivering less dose proximal and distal to the target region, 
with a sharper dose falloff (known as the “Bragg Peak”).  IMPT has been studied in multiple 
malignancies, including NSCLC [12-14].  In addition, we have recently reported our early 
experience with IMPT for lung-intact malignant pleural mesothelioma, in which we found 
lower does to multiple structures, including the contralateral lung, heart, and esophagus.  As a 
result, we continue to treat select patients with this technique [15]. Figure 2 shows an IMPT 
plan in a patient with the ipsilateral lung intact. 
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Figure 1.  Proton beam therapy (IMPT) treatment plan with the lung intact. 
 
 
In this study, we assess the role of conformal radiation techniques as part of a lung-sparing 
regimen with immunotherapy in patients with malignant pleural mesothelioma.  Specifically, 
we are combining radiation therapy with Pembrolizumab, and we hypothesize that through 
the utilization of inhibitors of the PD1/PDL1 axis after radiation therapy in MPM, we will 
improve rates of both local and distant disease control by taking advantage of the 
complementary biologic effects of the two modalities.   
Note that in addition to enrolling 12 patients with MPM who will receive induction 
chemotherapy and hemithoracic radiation therapy, we will also enroll 12 additional patients 
who will receive palliative radiation therapy to a limited field (non-hemithoracic), to assess the 
safety/efficacy of this approach.  In particular, this cohort of patients will allow us to assess 
the abscopal/systemic effect that has been observed in patients receiving radiation therapy and 
immunotherapy outside of the radiation field.  We will also be able to assess outcomes in the 
context of delivering less aggressive radiation fields.  Indeed, it may be the case that when 
immunotherapeutic agents are delivered, more limited fields can be used to provide analogous 
rates of disease control as in a hemithoracic field, but with more limited toxicity. We will be 
able to accrue to these two arms concurrently, which will also increase accrual rates and with 
one trial break for toxicity assessment halfway through each arm. 
 
There is evidence for the immune checkpoint process playing an active role in MPM.  
Both the T-cell inflamed phenotype and PD-L1 expression have been observed in this 
malignancey, particularly in non-epithelioid tumors.  In addition, PD-L1 expression is 
associated with a poorer prognosis [16].  And recently, results from the KEYNOTE-028 trial 
were presented at the American Association for Cancer Research annual meeting.  
Investigators enrolled 25 patients with MPM and PD-L1 positive disease who were then treated 
with Pembrolizumab for 24 months or until progression/intolerable toxicity.  They observed a 
28% objective response rate and a 76% disease control rate that was better than the historical 
response for second-line chemotherapy.  As a result, these findings were encouraging for 
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further evaluation of this agent in MPM.  The current study would be the first of its kind to 
combine Pembrolizumab with radiation therapy.[17]   
 
4.1.1 Pharmaceutical and Therapeutic Background 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades.  Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies.  In particular, the presence of CD8+ T-cells and the ratio of CD8+ 
effector T-cells / FoxP3+ regulatory T-cells seems to correlate with improved prognosis and 
long-term survival in many solid tumors. 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control.  The normal function of PD-1, expressed on the cell surface of activated T-
cells under healthy conditions, is to down-modulate unwanted or excessive immune responses, 
including autoimmune reactions.  PD-1 (encoded by the gene Pdcd1) is an Ig superfamily 
member related to CD28 and CTLA-4 which has been shown to negatively regulate antigen 
receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2).  The structure of 
murine PD-1 has been resolved.  PD-1 and family members are type I transmembrane 
glycoproteins containing an Ig Variable-type (V-type) domain responsible for ligand binding 
and a cytoplasmic tail which is responsible for the binding of signaling molecules.  The 
cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an immunoreceptor 
tyrosine-based inhibition motif (ITIM) and an immunoreceptor tyrosine-based switch motif 
(ITSM).  Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases SHP-1 and 
SHP-2 to the ITSM motif within its cytoplasmic tail, leading to the dephosphorylation of 
effector molecules such as CD3ζ, PKCθ and ZAP70 which are involved in the CD3 T-cell 
signaling cascade.  The mechanism by which PD-1 down modulates T-cell responses is similar 
to, but distinct from that of CTLA-4 as both molecules regulate an overlapping set of signaling 
proteins.  PD-1 was shown to be expressed on activated lymphocytes including peripheral 
CD4+ and CD8+ T-cells, B-cells, T regs and Natural Killer cells.  Expression has also been 
shown during thymic development on CD4-CD8- (double negative) T-cells as well as subsets 
of macrophages and dendritic cells.  The ligands for PD-1 (PD-L1 and PD-L2) are 
constitutively expressed or can be induced in a variety of cell types, including non-
hematopoietic tissues as well as in various tumors.  Both ligands are type I transmembrane 
receptors containing both IgV- and IgC-like domains in the extracellular region and contain 
short cytoplasmic regions with no known signaling motifs.  Binding of either PD-1 ligand to 
PD-1 inhibits T-cell activation triggered through the T-cell receptor.  PD-L1 is expressed at 
low levels on various non-hematopoietic tissues, most notably on vascular endothelium, 
whereas PD-L2 protein is only detectably expressed on antigen-presenting cells found in 
lymphoid tissue or chronic inflammatory environments.  PD-L2 is thought to control immune 
T-cell activation in lymphoid organs, whereas PD-L1 serves to dampen unwarranted T-cell 
function in peripheral tissues.  Although healthy organs express little (if any) PD-L1, a variety 
of cancers were demonstrated to express abundant levels of this T-cell inhibitor.  PD-1 has 
been suggested to regulate tumor-specific T-cell expansion in subjects with melanoma (MEL).  
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This suggests that the PD-1/PD-L1 pathway plays a critical role in tumor immune evasion and 
should be considered as an attractive target for therapeutic intervention. 
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of the 
IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, 
PD-L1 and PD-L2.  KeytrudaTM (pembrolizumab) has recently been approved in the United 
Stated for the treatment of patients with unresectable or metastatic melanoma and disease 
progression following ipilumumab and, if BRAF V600 mutation positive, a BRAF inhibitor. 
4.1.2 Preclinical and Clinical Trial Data 
Refer to the Investigator’s Brochure for Preclinical and Clinical data. 
4.2 
Rationale 
4.2.1 Rationale for the Trial and Selected Subject Population 
Please see section 4.1 for a detailed description of the rationale for this this trial.  We will enroll 
patients with malignant pleural mesothelioma who do not undergo an EPP, the rationale being 
that these patients often have a worse prognosis, with limited treatment options.  Therefore, 
we are aiming to benefit these patients using our highly conformal radiation techniques in 
combination with Pembrolizumab.  
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 
Cohorts A, B, C and D of this protocol to test for initial tumor activity.  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. 
 
 
A population pharmacokinetic analysis has been performed using serum concentration time 
data from 476 patients.  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. 
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5-fold higher dose and exposure). In addition, exposure was similar between the NSCLC and 
melanoma indications. Therefore, there are no anticipated changes in exposure between 
different indication settings. 
 
The rationale for further exploration of 2 mg/kg and comparable doses of pembrolizumab in 
solid tumors is based on: 1) similar efficacy and safety of pembrolizumab when dosed at either 
2 mg/kg or 10 mg/kg Q3W in melanoma patients, 2) the flat exposure-response relationships 
of pembrolizumab for both efficacy and safety in the dose ranges of 2 mg/kg Q3W to 10 mg/kg 
Q3W, 3) the lack of effect of tumor burden or indication on distribution behavior of 
pembrolizumab and 4) the assumption that the dynamics of pembrolizumab target engagement 
will not vary meaningfully with tumor type. 
The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed dosing is based 
on simulations showing that the fixed dose of 200 mg every 3 weeks will provide exposures 
that 1) are optimally consistent with those obtained with the 2 mg/kg dose every 3 weeks, 2) 
will maintain individual patient exposures in the exposure range established in melanoma as 
associated with maximal efficacy response and 3) will maintain individual patients exposure 
in the exposure range established in melanoma that are well tolerated and safe.  
A fixed dose regimen will simplify the dosing regimen to be more convenient for physicians 
and to reduce potential for dosing errors.  A fixed dosing scheme will also reduce complexity 
in the logistical chain at treatment facilities and reduce wastage. 
4.2.3 Rationale for Endpoints 
Given the lack of experience combining radiation therapy for MPM and immunotherapy, the 
primary endpoint will be high-grade toxicity, defined specifically in Table 3 below.   
Specifically, the Off-Study Criteria defined in Table 3 are the “Unacceptable” high-grade 
toxicities in the trial.  That is, patients that meet these criteria will be considered as having met 
the study endpoint and will be taken off study.  Patients will be monitored for 4 months after 
the start of RT. Since RT is approximately 1 month in duration, this monitoring period will 
include 3 months after the end of RT. 
4.2.3.1 Efficacy Endpoints 
Our secondary endpoints will be to estimate progression free survival (PFS) and overall 
survival (OS).   
4.2.3.2 Biomarker Research 
We will assess multiple biomarkers of interest through the collection of blood and tissue 
specimens through the following optional studies: 
A)  Tissue specimen collection for biomarker analysis:  Diagnostic and surgically resected 
tumor tissue will be acquired from the source used to establish the diagnosis of 
malignancy, including archival specimens stored in the Pathology Department and 
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residual fresh or fixed tissues banked in institutional tissue banks.  Cytologic samples 
may also be included, though cell blocks are strongly preferred.  The cell and tissue 
samples will be catalogued, then reviewed by a pathologist for malignant cell content 
and pathological analyses, and for correlative marker studies.  The molecular marker 
analysis will include, among others, the analysis of protein expression, gene expression, 
copy number, mutations, and translocations, and micro-RNA expression abnormalities.  
The methodology to be used to examine molecular changes will be selected based on 
the characteristics of the sample collected (e.g. cells or tissue, archival or frozen).  
Immune markers of interest include but are not limited to the following: 
Inhibitory Markers (blocking T-cell activation):  PD-1, PD-L1, CTLA-4, BTLA, 
TIM3, LAG3 
Costimulatory Markers (promoting T-cell activation):  CD28, CD80, CD86, HLA-1, 
ICOS, ICOSL, 41BBL, 41BB 
 B)  Serologies/Blood-Based Biomarkers – For evaluation of circulating immune biomarkers 
of interest including cytokines, measurements of T-cell activation, circulating tumor DNA 
(ctDNA) and exosome microRNAs.  Three categories of specimens will be collected: 
A)     EDTA Vaccutainer (CAFs): 10 mL = 1 x 10 mL 
B)     Streck CF-DNA BCT (ctDNA): 10 ml = 1 x 10 mL 
C)     Sodium Heparin (immunoprofiling=immuno): 60 ml = 6 x 10 mL 
All blood will be collected and processed by Thoracic Research Team according the 
institutional and laboratory standard operating procedures (SOPs). 
Optional blood samples will be collected at the following timepoints: 
1)  Prior to RT (baseline):  ctDNA, cytokine angiogenic factors (CAFs), 
immunoprofiling 
2)  After RT (+/- 3 days):  CAF, immunoprofiling 
3)  After 2 cycles of immunotherapy (+/- 3 days):  CAF, immunoprofiling  
4)  Progression/off study within 30 days of discontinuation or prior to starting next 
treatment:  ctDNA, CAF, immunoprofiling methodology 
4.3 
Entry Criteria 
4.3.1 Diagnosis/Condition for Entry into the Trial 
Patients will have a diagnosis of malignant pleural mesothelioma and will not have undergone 
EPP as a component of their treatment. 
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4.3.2 Subject Inclusion Criteria 
In order to be eligible for participation in this trial, the subject must: 
1. Patients must have a histologic diagnosis of malignant pleural mesothelioma, with 
histologic diagnosis from the pleura or relevant lymph node stations, including 
mediastinal, hilar, or supraclavicular lymph nodes. 
2. Be willing and able to provide written informed consent/assent for the trial. 
3. Be ≥ 18 years of age on day of signing informed consent. 
4. Have measurable or non-measurable disease per RECIST 1.1.  However, note that 
patients in Cohort 1 that have undergone an R0 resection will be eligible for the trial. 
5. Have a performance status of 0 or 1 on the ECOG Performance Scale. 
6. Demonstrate adequate organ function as defined in Table 1, all screening labs should 
be performed within 10-15 days of treatment initiation.   
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 without transfusion or EPO dependency 
(within 7 days of assessment) 
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 
 
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 
Albumin 
>2.5 mg/dL 
Coagulation 
International Normalized Ratio (INR) or 
Prothrombin Time (PT) 
 
Activated Partial Thromboplastin Time 
(aPTT) 
≤1.5 X ULN unless subject is receiving anticoagulant therapy 
as long as PT or PTT is within therapeutic range of intended use 
of anticoagulants 
≤1.5 X ULN unless subject is receiving anticoagulant therapy 
as long as PT or PTT is within therapeutic range of intended use 
of anticoagulants 
aCreatinine clearance should be calculated per institutional standard. 
 
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7. Female subject of childbearing potential should have a negative urine or serum 
pregnancy within 72 hours prior to receiving the first dose of study medication.  If the 
urine test is positive or cannot be confirmed as negative, a serum pregnancy test will 
be required.   
8. Female subjects of childbearing potential should be willing to use 2 methods of birth 
control or be surgically sterile, or abstain from heterosexual activity for the 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.  
9. Male subjects should agree to use an adequate method of contraception starting with 
the first dose of study therapy through 120 days after the last dose of study therapy. 
Additional Inclusion Criteria – Cohort 1 (Patients Receiving Hemithoracic Radiation 
Therapy) 
1. Patients must not have evidence of metastatic disease per PET/CT scan.  Mediastinal 
lymph node involvement is acceptable. 
2. Patients will have received at least 2 cycles of induction chemotherapy with 
pemetrexed/cisplatin or pemetrexed/carboplatin. 
3. The following pulmonary function tests are required: 
a. FEV1≥30% of predicted postoperative (ppoFEV1, as if the patient underwent a 
pneumonectomy) based on the following formula using a quantitative perfusion 
scan:  Predicted post-resection FEV1=FEV1 x % perfusion to the uninvolved 
lung from the quantitative perfusion report. 
b. DLCO>35% predicted. 
4.  Patients must be assessed to be a suitable candidate for hemithoracic radiation therapy 
per 
the 
treating 
radiation 
oncologist. 
 
If 
the 
patient 
undergoes 
pleurectomy/decortication, they must initiate hemithoracic radiation therapy within 4 
months of the surgery date.  Patients that do not meet the dose constraints outlined 
below will be removed from the study prior to radiation therapy. 
Additional Inclusion Criteria – Cohort 2 
1.  Patients must be assessed to be a suitable candidate for radiation therapy by the treating 
radiation oncologist.  Patients that do not meet the dose constraints outlined below will be 
removed from the study prior to radiation therapy. 
2.  Any prior number of prior therapies, including prior immunotherapy, is allowed.   
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3.  Patient has received prior treatment with a platinum-pemetrexed regimen. 
4.3.3 Subject Exclusion Criteria 
The subject must be excluded from participating in the trial if the subject: 
1. Is currently participating and receiving study therapy or has participated in a study of 
an investigational agent and received study therapy or used an investigational device 
within 4 weeks of the first dose of treatment. 
2. Has a diagnosis of immunodeficiency.  Note that patients should not receive steroids 
during Pembrolizumab administration. 
 
3. 3.Has a known history of active TB   (Bacillus Tuberculosis) 
 
4. Hypersensitivity to pembrolizumab or any of its excipients. 
5. Has had a prior anti-cancer monoclonal antibody (mAb) 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. 
6. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy 
within 2 weeks prior to study Day 1 and who have not recovered adequately from this 
treatment (≤Grade 2 toxicity at the time of enrollment). 
7. Has a known additional malignancy that is progressing or requires active treatment.  
Patients with a stage I-III cancer that has been cured over two years ago are not 
excluded in the study. 
8. 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.  This exception does not include 
carcinomatous meningitis which is excluded regardless of clinical stability.   
9. Has active autoimmune disease that has required systemic treatment in the past 2 years 
(i.e. with use of disease modifying agents, corticosteroids or immunosuppressive 
drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form 
of systemic treatment.  
10. Has a history of (non-infectious) pneumonitis that required steroids or current 
pneumonitis. 
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11. Has an active infection requiring systemic therapy. 
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). 
16. Has received a live vaccine within 30 days of planned start of study therapy. 
17. Evidence of interstitial lung disease. 
Note:  Seasonal influenza vaccines for injection are generally inactivated flu vaccines 
and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live 
attenuated vaccines, and are not allowed. 
Additional Exclusion Criteria – Cohorts 1  
1. 
Patients 
undergoing 
an 
EPP. 
Lung 
sparing 
surgeries, 
such 
as 
pleurectomy/decortication, are acceptable. 
Additional Exclusion Criteria – Cohort 1 
1. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. 
 
Additional Exclusion Criteria – Cohort 2 
1.    Patients in which hemithoracic radiation therapy is planned.  
2.  Patients who have received EPP for mesothelioma. 
Additional Exclusion Criteria – Cohorts 1 and 2 
1. Patients with inherited syndromes associated with hypersensitivity to ionizing radiation, 
specifically patients with known history of Ataxia-Telengiectasia, Nijmegen breakage 
syndrome.  
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4.4 
Trial Treatments 
The treatment to be used in this trial is outlined below in Table 2 
Table 2  Trial Treatment 
Drug 
Dose/Poten
cy 
Dose 
Frequenc
y 
Route of 
Administratio
n 
Regimen/Treatme
nt Period 
Use 
Pembrolizumab 
200 mg X 
mg/kg 
Q3W 
IV infusion 
Day 1 of each 3 
week cycle 
Experimenta
l 
Note: Patients must initiate treatment with Pembrolizumab within 1 month of the last day of 
radiation therapy.  
 
4.4.1 Dose Selection/Modification 
4.4.1.1 Dose Selection 
The rationale for selection of doses to be used in this trial is provided in Section 4.0 – 
Background and Rationale.   
Details on preparation and administration of pembrolizumab are provided in the Pharmacy 
Manual.   
4.4.1.2 Dose Modification  
Adverse events (both non-serious and serious) associated with pembrolizumab exposure may 
represent an immunologic etiology.  These adverse events may occur shortly after the first dose 
or several months after the last dose of treatment. Pembrolizumab must be withheld for drug-
related toxicities and severe or life-threatening AEs as per Table 3 below. See Section 5.6.1 
and Events of Clinical Interest Guidance Document for supportive care guidelines, including 
use of corticosteroids. 
Table 3 
Dose Modification Guidelines for Drug-Related Adverse Events (Note that discontinuation 
of subjects for all toxicities in Table 3 are contingent on the conclusion that they are 
treatment related.) 
 
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Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting Treatment 
Discontinue Subject/Off-Study Criteria (“Unacceptable” 
Toxicities) 
Diarrhea/Colitis 
2-3 
 
Toxicity resolves to Grade 0-1. 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks. 
4 
Permanently discontinue 
Permanently discontinue/Off-Study 
AST, ALT, or 
Increased Bilirubin 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose. 
3-4 
Permanently discontinue 
(see exceptions below)1,2 
Permanently discontinue/Off-Study 
Type 1 diabetes 
mellitus (if new 
onset) or 
Hyperglycemia 
T1DM or  
3-4 
Hold pembrolizumab for new onset Type 1 
diabetes 
mellitus 
or 
Grade 
3-4 
hyperglycemia associated with evidence of 
beta cell failure.  
 
Resume pembrolizumab when patients are clinically and 
metabolically stable. 
Hypophysitis 
2-3 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks. 
4 
Permanently discontinue 
Permanently discontinue/Off-Study 
Hyperthyroidism  
3 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks. 
4 
Permanently discontinue 
Permanently discontinue/Off-Study 
Hypothyroidism 
2-4 
Therapy with pembrolizumab can be 
continued while treatment for the thyroid 
disorder is instituted 
Therapy with pembrolizumab can be continued while treatment for 
the thyroid disorder is instituted. 
Infusion Reaction 
3-4 
Permanently discontinue 
Permanently discontinue/Off-Study 
Pneumonitis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks.  Recurrent grade 2 pneumonitis requires 
discontinuation of pembrolizumab. 
3-4 
Permanently discontinue 
Permanently discontinue/Off-Study 
Renal Failure or 
Nephritis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks. 
3-4 
Permanently discontinue 
Permanently discontinue/Off-Study 
All Other Drug-
Related Toxicity3 
3 or Severe 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks. 
4 
Permanently discontinue 
Permanently discontinue/Off-Study 
All other 
Radiation-Related 
Toxicity by 
CTCAE v4.0 
criteria (cardiac, 
esophageal, 
pericarditis, bowel, 
etc) 
3 or greater 
Off Study 
Off Study 
 
 
 
 
Note: Permanently discontinue for any severe or Grade 3 drug-related AE that recurs or any life-threatening event. 
1 For patients with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT increases by greater than or equal to 50% relative to baseline 
and lasts for at least 1 week then patients should be discontinued. 
2For patients with Grade 3 transaminitis, will recheck liver enzymes in 1-2 weeks and if the toxicity changes to Grade ≤2, patients can remain on study.  
3 Patients with intolerable or persistent Grade 2 drug-related AE may hold study medication at physician discretion.  Permanently discontinue study drug for 
persistent Grade 2 adverse reactions for which treatment with study drug has been held, that do not recover to Grade 0-1 within 12 weeks of the last dose.   
 
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Dosing interruptions are permitted in the case of medical / surgical events or logistical reasons  
not related to study therapy (e.g., elective surgery, unrelated medical events, patient vacation, 
and/or holidays). Subjects should be placed back on study therapy within 3 weeks of the 
scheduled interruption, unless otherwise discussed with Merck. The reason for interruption 
should be documented in the patient's study record. 
Management of Radiation Pneumonitis 
Patients who develop Grade ≥2 pneumonitis will be managed according to standard clinical 
guidelines.  If supportive measures are unsuccessful, and/or if the symptoms persist despite 
this approach, steroids and a referral to pulmonary medicine will be considered.  A standard 
regimen of prednisone includes 40-60 mg daily x 2 weeks, then tapering over the next 3-6 
weeks based on symptom status. Interventions such as hospitalization, intravenous steroids, 
and oxygen administration will be performed at the treating physician’s discretion. 
As noted in the Statistical Considerations section below (Section 8.0), the study will be stopped 
if 3/6 or 6/12 patients develop Grade 3 or higher radiation pneumonitis.  If 0/6, 1/6, or 2/6 
patients develop this toxicity, the study will continue.  No dose de-escalation will be performed 
because all patients are already receiving the minimal therapeutic microscopic dose of 
radiation, and therefore any further reductions in treatment intensity are not likely to control 
the disease (and still carry the risk of toxicity).  Furthermore, our institution does not have 
experience escalating the radiation dose in mesothelioma higher than that described in this 
study, and thus it is not appropriate to do so in conjunction with Pembrolizumab without first 
assessing the effect of higher doses of radiation therapy alone (without immunotherapy).  The 
study is thus addressing the question of whether our institution’s current radiation regimen for 
malignant pleural mesothelioma, in both the unresectable and pleurectomy/decortication 
settings, is safe with Pembrolizumab.  In essence, the two regimens that we are testing are 
those in the two cohorts that we have included, the first being the most aggressive and including 
the entire hemithorax (Cohort 1), and the second being a much more limited field and including 
only the region of palliation (Cohort 2).  This trial will provide data as to whether the 
immunotherapy-radiation combination should be further explored in neither context, only the 
less aggressive scenario, or in both patient populations. 
 
4.4.2 Timing of Dose Administration 
Trial treatment should be administered on Day 1 of each cycle after all procedures/assessments 
have been completed as detailed on the Trial Flow Chart (Section 6.0).  Trial treatment may 
be administered up to 3 days before or after the scheduled Day 1 of each cycle due to 
administrative reasons. 
All trial treatments will be administered on an outpatient basis at MDACC. 
Pembrolizumab 200 mg will be administered as a 30 minute IV infusion every 3 weeks for up 
to 2 years   
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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 Pharmacy Manual contains specific instructions for the preparation of the pembrolizumab 
infusion fluid and administration of infusion solution. 
4.4.3 Trial Blinding/Masking 
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered. 
4.4.4 Radiation Therapy 
4.4.4.1 Suggested Simulation Procedure 
Prior to radiation, we suggest that patients undergo a renal scan and baseline creatinine, to 
assess potential toxicity to the ipsilateral kidney.  Patients will undergo CT simulation in the 
Department of Radiation oncology.  Immobilization will occur with a vac-loc cradle and the 
arms above the head.  4D CT images will be obtained to assess for respiratory motion, and will 
scan from the lung apex to approximately L2 inferiorly.  Wiring the scars and drain sites with 
bolus is optional.  If bolus is used, we suggest 0.5 cm thickness and 3.5 cm in diameter.  
Treatment will be planned using IMRT or IMPT and delivered with image-guided radiation 
therapy (IGRT). 
4.4.4.2 Suggested Target Delineation 
Cohort 1 – Hemithoracic Radiation Therapy 
For patients with no gross residual disease, above the level of the diaphragm the planning target 
volume (PTV) will encompass the ipsilateral external pleura using a “rind” volume, including 
an 8 mm inner margin (PTV_inner) and 1-1.5 cm outer margin (PTV_outer).  The outer margin 
will should be extended lateral to the ribs, with approximately a 0.5 cm margin.  Non-
enhancing nodal beds will not be contoured or treated.   Below the level of the diaphragm, the 
PTV will encompass only a single crescent-shaped contour with will be named the PTV_outer.  
If bolus is placed, the target volume should extend towards the surface and encompass the 
region of the bolus. 
Cohort 2 – Non-Hemithoracic Radiation Therapy 
The gross disease, as delineated on the PET/CT scan and/or the CT scan with contrast, will be 
contoured as the GTV.  A 0.5-1 cm margin will be defined as the CTV, and another 0.5 cm 
margin will be placed as the PTV if daily kV imaging is performed.   
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4.4.4.3 Treatment Planning and Prescription Dose 
Cohort 1 – Hemithoracic Radiation Therapy 
Patients will be prescribed a prescription dose of 45 Gy in 25 fractions to the PTV, and 2.4 Gy 
x 25 fractions to the GTV (if applicable) using a simultaneous integrated boost.  Either IMRT 
or IMPT will be utilized, using techniques described in prior publications from our institutions 
[15, 18]. 
Cohort 2 – Non-Hemithoracic Radiation Therapy 
Patients will be treated to one of the following prescribed doses:  a)  3 Gy x 10 fractions = 30 
Gy, b)  4 Gy x 5 fractions = 20 Gy, c)  5 Gy x 5 fractions = 25 Gy, or d)  45-52.5 Gy in 15 
fractions.  Patients will be treated using either IMRT or 3D conformal therapy.   
4.4.4.4 – Radiation Dose Constraints – Both Cohorts 
Required Dose Constraints – Patients are required to meet the following dose constraints:  1) 
Normal Tissue Complication Probability (NTCP) of the lung <25%, calculated with the 
Lyman-Kutcher-Berman model [19]. 2)  At least 93% of the contralateral lung must receive 
less than 20 Gy (V20<7%). 3) Maximum spinal cord dose of <50 Gy. 
Suggested Dose Constraints – We suggest the following dose constraints:  1) At least 50% of 
heart receive less than 30 Gy, 2)  At least 50% of the liver receive less than 30 Gy. 3)  Mean 
dose to stomach (not PTV) <30 Gy, 4)  Maximum bowel dose<55 Gy, 5)  Kidney V18≤50%. 
4.5 
Randomization or Treatment Allocation 
No randomization will be performed. 
4.6 
Stratification 
 No stratification will be done. 
4.7 
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 Merck Clinical team.  The final decision on any supportive therapy or vaccination 
rests with the investigator and/or the subject's primary physician.  
4.7.1 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 
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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 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. 
4.7.2 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: 
• Antineoplastic systemic chemotherapy or biological therapy  
• Immunotherapy not specified in this protocol 
• Chemotherapy not specified in this protocol 
• Investigational agents other than pembrolizumab 
• Radiation therapy  
o Note:  Radiation therapy to a symptomatic solitary lesion or to the brain may 
be allowed at the investigator’s discretion.   
• Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial.  Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and 
typhoid vaccine.  
• Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
event of clinical interest of suspected immunologic etiology.  The use of physiologic 
doses of corticosteroids may be approved after consultation with Merck. 
Subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial.  Subjects 
may receive other medications that the investigator deems to be medically necessary. 
The Exclusion Criteria describes other medications which are prohibited in this trial. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
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4.8 
Rescue Medications & Supportive Care 
4.8.1 Supportive Care Guidelines 
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of adverse 
events with potential immunologic etiology are outlined below and in greater detail in the ECI 
guidance document. Where appropriate, these guidelines include the use of oral or intravenous 
treatment with corticosteroids as well as additional anti-inflammatory agents if symptoms do 
not improve with administration of corticosteroids.   Note that several courses of steroid 
tapering may be necessary as symptoms may worsen when the steroid dose is decreased. For 
each disorder, attempts should be made to rule out other causes such as metastatic disease or 
bacterial or viral infection, which might require additional supportive care. The treatment 
guidelines are intended to be applied when the investigator determines the events to be related 
to pembrolizumab.  
Note: if after the evaluation the event is determined not to be related, the investigator is 
instructed to follow the ECI reporting guidance but does not need to follow the treatment 
guidance (as outlined in the ECI guidance document). Refer to Section 5.2.1 for dose 
modification.  
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event. Suggested conditional procedures, as 
appropriate, can be found in the ECI guidance document. 
• Pneumonitis:  
o For Grade 2 events, treat with systemic corticosteroids. When symptoms 
improve to Grade 1 or less, steroid taper should be started and continued over 
no less than 4 weeks. 
o For Grade 3-4 events, immediately treat with intravenous steroids.  
Administer additional anti-inflammatory measures, as needed. 
o Add prophylactic antibiotics for opportunistic infections in the case of 
prolonged steroid administration. 
 
 
• Diarrhea/Colitis:  
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such 
as diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of 
bowel perforation (such as peritoneal signs and ileus).   
 
o All subjects who experience diarrhea/colitis should be advised to drink liberal 
quantities of clear fluids.  If sufficient oral fluid intake is not feasible, fluid and 
electrolytes should be substituted via IV infusion.  For Grade 2 or higher 
diarrhea, consider GI consultation and endoscopy to confirm or rule out colitis. 
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o For Grade 2 diarrhea/colitis that persists greater than 3 days, administer oral 
corticosteroids.  
o For Grade 3 or 4 diarrhea/colitis that persists > 1 week, treat with intravenous 
steroids followed by high dose oral steroids.   
o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
 
 
• Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or 
≥ Grade 3 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic 
acidosis (DKA) 
 
o For T1DM or Grade 3-4 Hyperglycemia 
 Insulin replacement therapy is recommended for Type I diabetes 
mellitus and for Grade 3-4 hyperglycemia associated with metabolic 
acidosis or ketonuria.  
 Evaluate patients with serum glucose and a metabolic panel, urine 
ketones, glycosylated hemoglobin, and C-peptide.  
 
• Hypophysitis: 
 
o For Grade 2 events, treat with corticosteroids. When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 
4 weeks. Replacement of appropriate hormones may be required as the steroid 
dose is tapered. 
o For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed 
by oral corticosteroids. When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 4 weeks. Replacement 
of appropriate hormones may be required as the steroid dose is tapered. 
 
 
• Hyperthyroidism or Hypothyroidism:  
Thyroid disorders can occur at any time during treatment. Monitor patients for changes 
in thyroid function (at the start of treatment, periodically during treatment, and as 
indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid 
disorders. 
 
o Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism): 
 In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are 
suggested as initial therapy. 
 In hypothyroidism, thyroid hormone replacement therapy, with 
levothyroxine or liothyroinine, is indicated per standard of care. 
o Grade 3-4 hyperthyroidism  
 Treat with an initial dose of IV corticosteroid followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid 
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taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the steroid 
dose is tapered. 
 
 
• Hepatic: 
o For Grade 2 events, monitor liver function tests more frequently until returned 
to baseline values (consider weekly). 
 Treat with IV or oral corticosteroids 
o For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 hours.  
o When symptoms improve to Grade 1 or less, a steroid taper should be started 
and continued over no less than 4 weeks. 
 
• Renal Failure or Nephritis: 
o For Grade 2 events, treat with corticosteroids. 
o For Grade 3-4 events, treat with systemic corticosteroids. 
o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks.  
 
• Management of Infusion Reactions: Signs and symptoms usually develop during or 
shortly after drug infusion and generally resolve completely within 24 hours of 
completion of infusion.  
 
 
Table 4 below shows treatment guidelines for subjects who experience an infusion 
reaction associated with administration of pembrolizumab. 
 
Table 4 Infusion Reaction Treatment Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
Grade 1 
Mild reaction; infusion interruption 
not indicated; intervention not 
indicated 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
None 
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 
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 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
If symptoms resolve within one hour of stopping 
drug infusion, the infusion may be restarted at 
50% of the original infusion rate (e.g., from 100 
mL/hr to 50 mL/hr).  Otherwise dosing will be 
held until symptoms resolve and the subject 
should be premedicated for the next scheduled 
dose. 
Subjects who develop Grade 2 toxicity despite 
adequate premedication should be 
permanently discontinued from further trial 
treatment administration. 
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. 
 
 
 
4.9 
Diet/Activity/Other Considerations 
4.9.1 Diet 
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea or vomiting. 
4.9.2 Contraception 
Pembrolizumab may have adverse effects on a fetus in utero.  Furthermore, it is not known if 
pembrolizumab has transient adverse effects on the composition of sperm.  Non-pregnant, non-
breast-feeding women may be enrolled if they are willing to use 2 methods of birth control or 
are considered highly unlikely to conceive.  Highly unlikely to conceive is defined as 1) 
surgically sterilized, or 2) postmenopausal (a woman who is ≥45 years of age and has not had 
menses for greater than 1 year will be considered postmenopausal), or 3) not heterosexually 
active for the duration of the study.  The two birth control methods can be either two barrier 
methods or a barrier method plus a hormonal method to prevent pregnancy. Subjects should 
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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. 
4.9.3 Use in Pregnancy 
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab, the 
subject will immediately be removed from the study.  The site will contact the subject at least 
monthly and document the subject’s status until the pregnancy has been completed or 
terminated.  The outcome of the pregnancy will be reported to the Sponsor and to Merck 
without delay and within 24 hours to the Sponsor and within 2 working days to Merck if the 
outcome is a serious adverse experience (e.g., death, abortion, congenital anomaly, or other 
disabling or life-threatening complication to the mother or newborn).   
The study investigator will make every effort to obtain permission to follow the outcome of 
the pregnancy and report the condition of the fetus or newborn 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. 
4.9.4 Use in Nursing Women 
It is unknown whether pembrolizumab is excreted in human milk.  Since many drugs are 
excreted in human milk, and because of the potential for serious adverse reactions in the 
nursing infant, subjects who are breast-feeding are not eligible for enrollment. 
4.10 Subject Withdrawal/Discontinuation Criteria 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur.  In addition, a subject may be 
withdrawn by the investigator or the Sponsor if enrollment into the trial is inappropriate, the 
trial plan is violated, or for administrative and/or other safety reasons.  Specific details 
regarding discontinuation or withdrawal are provided in Section 7.1.4 – Other Procedures. 
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A subject must be discontinued from the trial for any of the following reasons: 
• The subject or legal representative (such as a parent or legal guardian) withdraws 
consent. 
• Confirmed radiographic disease progression 
Note: A subject may be granted an exception to continue on treatment with 
confirmed radiographic progression if meeting the following criteria:  1) clinically 
stable, or 2) clinically improved, at the physician’s discretion. 
• 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 uninterrupted treatment with pembrolizumab or 35 
administrations of study medication, whichever is later. 
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 7.1.5.5 
• 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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4.10.1 Discontinuation of Study Therapy after CR  
Discontinuation of treatment may be considered for subjects who have attained a confirmed 
CR that have been treated for at least 24 weeks with pembrolizumab and had at least two 
treatments with pembrolizumab beyond the date when the initial CR was declared.  Subjects 
who then experience radiographic disease progression may be eligible for up to one year of 
additional treatment with pembrolizumab via the Second Course Phase at the discretion of the 
investigator if no cancer treatment was administered since the last dose of pembrolizumab, the 
subject meets the safety parameters listed in the Inclusion/Exclusion criteria, and the trial is 
open.  Subjects will resume therapy at the same dose and schedule at the time of initial 
discontinuation.  Additional details are provided in Section 7.1.5.5. 
4.11 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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5.0 TRIAL FLOW CHART 
5.1 
Study Flow Chart 
Trial Period: 
Screening Phase 
Treatment Cycles 
End of  
Study 
Treatment 
Post-Study Treatment  
Treatment Cycle/Title: 
Pre-
screen
ing 
(Visit 
1) 
Main 
Study 
Screening 
(Visit 2, 
Pre-RT) 
Last 
Week 
of RT 
1 
2 
3 
To be repeated beyond 7 
cycles 
Discon 
Safety 
Follow-up 
Follow Up 
Visits 
Every 6 weeks 
(42 +/- 7 days) 
until to 48 
weeks, then 
every 12 weeks 
(+/- 7 days) to 5 
years 
4 
5 
6 
7 
Scheduling Window (Days): 
 
-45 to -1 
± 7 
± 3 
± 
3 
± 3 
± 3 
± 3 
± 3 
± 3 
At time of 
Discon 
Approxima-
tely 30 days 
post discon 
Administrative Procedures 
Pre-screening Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics, 
Medical 
History, 
and 
Disease History 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Prior and Concomitant Medication Review 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pembrolizumab Administration 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Post-study anticancer therapy status 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Survival Status 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Clinical Procedures/Assessments 
Review Adverse Events 
 
 
X (start 
of RT:  
Grade 
3 or 
higher) 
X 
(begin
-ning 
Pemb-
ro:  all 
toxici-
ties) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Full Physical Examination 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Directed Physical Examination 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs and Weight 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 

 
 
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Trial Period: 
Screening Phase 
Treatment Cycles 
End of  
Study 
Treatment 
Post-Study Treatment  
Treatment Cycle/Title: 
Pre-
screen
ing 
(Visit 
1) 
Main 
Study 
Screening 
(Visit 2, 
Pre-RT) 
Last 
Week 
of RT 
1 
2 
3 
To be repeated beyond 7 
cycles 
Discon 
Safety 
Follow-up 
Follow Up 
Visits 
Every 6 weeks 
(42 +/- 7 days) 
until to 48 
weeks, then 
every 12 weeks 
(+/- 7 days) to 5 
years 
4 
5 
6 
7 
Scheduling Window (Days): 
 
-45 to -1 
± 7 
± 3 
± 
3 
± 3 
± 3 
± 3 
± 3 
± 3 
At time of 
Discon 
Approxima-
tely 30 days 
post discon 
ECOG Performance Status 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory Procedures/Assessments: analysis performed by LOCAL laboratory 
Pregnancy Test – Urine or Serum β-HCG 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Use of Birth Control 
 
X 
 
 
 
 
 
 
 
 
 
 
 
PT/INR and aPTT 
 
X 
 
 
 
 
 
 
 
 
 
 
 
CBC with Differential 
  
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Comprehensive Serum Chemistry Panel 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Urinalysis 
 
X 
 
 
 
 
 
 
 
 
 
 
 
T3, FT4 and TSH 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Pulmonary Function Tests 
 
X 
 
 
 
 
 
 
 
X (q6 
cycles) 
X 
 
X  
Quantitative Perfusion Scan (Cohort 1) 
 
X1 
 
 
 
 
 
 
 
 
 
 
 
Renal Perfusion Scan (Cohort 1) 
 
X1 
 
 
 
 
 
 
 
 
 
 
 
Efficacy Measurements 
Tumor Imaging 
 
X 
 
 
 
 
X 
 
 
X – 
repeat 
every 3 
cycles 
 
 
X 
Tumor Biopsies/Archival Tissue Collection/Correlative Studies Blood (Optional) 
Archival 
or 
Newly 
Obtained 
Tissue 
Collection 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Correlative Studies Blood Collection (as 
described in section 4.2.3.2) 
 
X 
(ctDNA, 
X 
(CAF, 
 
 
X 
(CAF, 
 
 
 
 
X (ctDNA, 
CAF, 
immuno) 
 
 

 
 
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Trial Period: 
Screening Phase 
Treatment Cycles 
End of  
Study 
Treatment 
Post-Study Treatment  
Treatment Cycle/Title: 
Pre-
screen
ing 
(Visit 
1) 
Main 
Study 
Screening 
(Visit 2, 
Pre-RT) 
Last 
Week 
of RT 
1 
2 
3 
To be repeated beyond 7 
cycles 
Discon 
Safety 
Follow-up 
Follow Up 
Visits 
Every 6 weeks 
(42 +/- 7 days) 
until to 48 
weeks, then 
every 12 weeks 
(+/- 7 days) to 5 
years 
4 
5 
6 
7 
Scheduling Window (Days): 
 
-45 to -1 
± 7 
± 3 
± 
3 
± 3 
± 3 
± 3 
± 3 
± 3 
At time of 
Discon 
Approxima-
tely 30 days 
post discon 
CAF, 
immuno) 
immun
o) 
immuno
)  
NOTE:  All screening studies should be done within 45 days of radiation therapy.  The exception to this guideline is laboratory 
tests, which should be done within 15 days of radiation therapy. 
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6.0 TRIAL PROCEDURES 
6.1 
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. 
6.1.1 Administrative Procedures 
6.1.1.1 Informed Consent 
The Investigator must obtain documented consent from each potential subject prior to 
participating in a clinical trial. 
7.1.1.1.1 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.   
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements. 
 
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6.1.1.2 Inclusion/Exclusion Criteria 
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial.  
6.1.1.3 Medical History 
A medical history will be obtained by the investigator or qualified designee.  Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that 
are considered to be clinically significant by the Investigator.  Details regarding the disease for 
which the subject has enrolled in this study will be recorded separately and not listed as medical 
history.   
6.1.1.4 Prior and Concomitant Medications Review 
6.1.1.4.1 Prior Medications 
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the subject 
within 28 days before starting the trial.  Treatment for the disease for which the subject has 
enrolled in this study will be recorded separately and not listed as a prior medication.  
6.1.1.4.2 Concomitant Medications 
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial.  All medications related to reportable SAEs and ECIs should be recorded as 
defined in Section 7.2. 
6.1.1.5 Disease Details and Treatments 
6.1.1.5.1 Disease Details 
The investigator or qualified designee will obtain prior and current details regarding disease 
status.  
6.1.1.5.2 Prior Treatment Details 
The investigator or qualified designee will review all prior cancer treatments including 
systemic treatments, radiation and surgeries. 
6.1.1.5.3 Subsequent Anti-Cancer Therapy Status 
The investigator or qualified designee will review all new anti-neoplastic therapy initiated after 
the last dose of trial treatment.  If a subject initiates a new anti-cancer therapy within 30 days 
after the last dose of trial treatment, the 30 day Safety Follow-up visit must occur before the 
first dose of the new therapy.  Once new anti-cancer therapy has been initiated the subject will 
move into survival follow-up.  
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6.1.2 Clinical Procedures/Assessments 
6.1.2.1 Adverse Event (AE) Monitoring 
The investigator or qualified designee will assess each subject to evaluate for potential new or 
worsening AEs as specified in the Trial Flow Chart and more frequently if clinically indicated.  
Adverse experiences will be graded and recorded throughout the study and during the follow-
up period according to NCI CTCAE Version 4.0 (see Section 11.2).  Toxicities will be 
characterized in terms regarding seriousness, causality, toxicity grading, and action taken with 
regard to trial treatment.  
For subjects receiving treatment with pembrolizumab all AEs of unknown etiology associated 
with pembrolizumab exposure should be evaluated to determine if it is possibly an event of 
clinical interest (ECI) of a potentially immunologic etiology (termed immune-related adverse 
events, or irAEs); see the separate ECI guidance document in Appendix 4 regarding the 
identification, evaluation and management of potential irAEs.   
Please refer to section 7.2 for detailed information regarding the assessment and recording of 
AEs.  Adverse events will be recorded in the Prometheus database.  We will capture all  adverse 
events (related to radiation therapy, pembrolizumab, or a combination of the two).  AE’s will 
be collected weekly during radiation therapy and grade 3 or higher toxicities will be 
documented.  The PI or designee will be responsible for determining attribution for all events, 
which will also be documented in the Prometheus database. 
6.1.2.2 Full Physical Exam 
The investigator or qualified designee will perform a complete physical exam during the 
screening period.  Clinically significant abnormal findings should be recorded as medical 
history.  A full physical exam should be performed during screening,  
6.1.2.3 Directed Physical Exam 
For cycles that do not require a full physical exam per the Trial Flow Chart, the investigator or 
qualified designee will perform a directed physical exam as clinically indicated prior to trial 
treatment administration.   
6.1.2.4 Vital Signs 
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of trial treatment and at treatment discontinuation as specified in 
the Trial Flow Chart (Section 6.0).  Vital signs should include temperature, pulse, respiratory 
rate, weight and blood pressure.  Height will be measured at screening only. 
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6.1.2.5 Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The investigator or qualified designee will assess ECOG status (see Section 11.1) at screening, 
prior to the administration of each dose of trial treatment and discontinuation of trial treatment 
as specified in the Trial Flow Chart.   
6.1.2.6 Tumor Imaging and Assessment of Disease 
Patients will have their history collected at screening, and a physical exam will be performed 
at screening, post-RT (+/- 7 days), on day 1 of each pembrolizumab cycle, at the end of 
treatment visit, and post-treatment.  Patients will be imaged with either:  1) CT scan of the 
chest with contrast, or 2)  PET/CT scan. This imaging will be done with the following 
frequency:  prior to radiation therapy, after cycle 3 of pembrolizumab, and every 3 cycles 
thereafter.  Pulmonary function tests will be done at the following timepoints:  1)  At 
enrollment, 2)  after every 6 cycles of pembrolizumab, and 3)  at the discontinuation of 
treatment. 
6.1.2.7 Tumor Tissue Collection and Correlative Studies Blood Sampling 
Tissue and tumor collection will be performed at diagnosis and at surgical resection or 
rebiopsy, as described in Section 4.2.3 above.   
  
6.1.3 Laboratory Procedures/Assessments 
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below. 
Laboratory tests for hematology, chemistry, urinalysis, and others are specified in Table 5.   
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Table 5  Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Other 
Hematocrit 
Albumin 
Blood 
Serum β-human chorionic gonadotropin† 
Hemoglobin 
Alkaline phosphatase 
Glucose 
  (β-hCG)† 
Platelet count 
Alanine aminotransferase (ALT) 
Protein 
PT (INR) 
WBC (total and differential) 
Aspartate aminotransferase (AST) 
Specific gravity  
aPTT 
Red Blood Cell Count 
Lactate dehydrogenase (LDH) 
Microscopic exam (If abnormal)  
Total thriiodothyronine (T3) 
Absolute Neutrophil Count 
Carbon Dioxide ‡ 
results are noted 
Free thyroxine (T4) 
Absolute Lymphocyte Count 
  (CO2 or biocarbonate) 
Urine pregnancy test † 
Thyroid stimulating hormone (TSH) 
 
Uric Acid 
 
 
 
Calcium 
 
 
 
Chloride 
 
Blood for correlative studies 
 
Glucose 
 
  
 
Phosphorus 
 
  
 
Potassium   
 
  
 
Sodium 
 
  
 
Magnesium 
 
  
 
Total Bilirubin 
 
  
 
Direct Bilirubin (If total bilirubin is 
elevated above the upper limit of 
normal) 
 
 
 
Total protein 
 
 
 
Blood Urea Nitrogen 
 
 
† Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed as negative, a serum pregnancy test will be required.   
‡ If considered standard of care in your region. 
 
 
 

 
 
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Laboratory tests for screening or entry into the Second Course Phase should be performed 
within 45 days prior to the first dose of treatment.  All screening studies should be done within 
45 days of radiation therapy.  The exception to this guideline is laboratory tests, which should 
be done within 15 days of radiation therapy.  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.  
6.1.3.1 Pharmacokinetic/Pharmacodynamic Evaluations 
6.1.3.1.1 Blood Collection for Serum Pembrolizumab 
Sample collection, storage and shipment instructions for serum samples will be provided in the 
Laboratory Manual. 
6.1.3.1.2 Blood Collection for Anti-Pembrolizumab Antibodies  
Sample collection, storage and shipment instructions for blood samples will be provided in the 
Laboratory Manual. 
6.1.4 Other Procedures 
6.1.4.1 Withdrawal/Discontinuation 
Off-Study Criteria.  Patients will remain on study until completion until they:  1)  experience 
a Grade 3 or higher toxicity during radiation therapy (in which case they will be deemed to be 
non-evaluable), 2)  meet the criteria of Permanent Discontinuation/Off-Study Criteria outlined 
in Table 3 above (evaluable patient), in which case subjects will be followed until resolution 
of symptoms, 3)  are lost-to follow-up, 4)  elect to come off study, or 5) die.  
When a subject discontinues/withdraws prior to trial completion, all applicable activities 
scheduled for the final trial visit should be performed at the time of discontinuation.  Any 
adverse events which are present at the time of discontinuation/withdrawal should be followed 
in accordance with the safety requirements outlined in Section 7.2 - Assessing and Recording 
Adverse Events.  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 7.1.5.5.  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). 
If a patient comes off study for toxicity, follow-up will still occur through the research team 
+/- clinical staff for survival purposes, either through clinic visits as clinically warranted or 
direct patient calls if the patient no longer follows up at our institution. 
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6.1.4.2 Blinding/Unblinding 
6.1.5 Visit Requirements 
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures. 
6.1.5.1 Screening 
 
6.1.5.1.1 Screening Period 
Patients will be screened with the appropriate tests prior to entering the study. 
6.1.5.2 Treatment Period 
The treatment period will encompass both the radiation therapy and the Pembrolizumab, 
administered as described above. Patients will undergo assessment of disease status  
6.1.5.3 Post-Treatment Visits 
7.1.5.3.1 Safety Follow-Up Visit 
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the 
last dose of trial treatment or before the initiation of a new anti-cancer treatment, whichever 
comes first.  All AEs that occur prior to the Safety Follow-Up Visit should be recorded.  
Subjects with an AE of Grade > 1 will be followed until the resolution of the AE to Grade 0-1 
or until the beginning of a new anti-neoplastic therapy, whichever occurs first.  SAEs that occur 
within 90 days of the end of treatment or before initiation of a new anti-cancer treatment should 
also be followed and recorded.  Subjects who are eligible for retreatment with pembrolizumab 
(as described in Section 7.1.5.5) may have up to two safety follow-up visits, one after the 
Treatment Period and one after the Second Course Phase. 
 
6.1.5.4 Follow-up Visits 
Subjects who discontinue trial treatment for a reason other than disease progression will move 
into the Follow-Up Phase and should be assessed every 6 weeks (42 ± 7 days) by radiologic 
imaging to monitor disease status.  After 48 weeks the imaging time point will occur every 12 
weeks (± 7 days), up to 5 years. 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 
7.1.5.5.  Information regarding post-study anti-neoplastic treatment will be collected if new 
treatment is initiated. 
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Subjects who are eligible to receive retreatment with pembrolizumab according to the criteria 
in Section 7.1.5.5 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.    
6.1.5.4.1 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.  
6.1.5.5 Second Course Phase (Retreatment Period) 
Subjects who stop pembrolizumab with SD or better may be eligible for up to one year of 
additional pembrolizumab therapy if they progress within one year after stopping study 
treatment.  This retreatment is termed the Second Course Phase of this study and is only 
available if the study remains open and the subject meets the following conditions: 
• Either  
o Stopped initial treatment with pembrolizumab after attaining an investigator-
determined confirmed CR according to RECIST 1.1, and 
 Was treated for at least 24 weeks with pembrolizumab before discontinuing 
therapy 
 Received at least two treatments with pembrolizumab beyond the date when 
the initial CR was declared 
 
 
OR 
o Had SD, PR or CR and stopped pembrolizumab treatment after 24 months of study 
therapy for reasons other than disease progression or intolerability 
AND 
• Experienced an investigator-determined confirmed radiographic disease progression 
after stopping their initial treatment with pembrolizumab 
• Did not receive any anti-cancer treatment since the last dose of pembrolizumab 
• Has a performance status of 0 or 1 on the ECOG Performance Scale 
• Demonstrates adequate organ function as detailed in Section 5.1.2 
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• Female subject of childbearing potential should have a negative serum or urine 
pregnancy test within 72 hours prior to receiving retreatment with study medication.   
• Female subject 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 child bearing potential are those who have not been surgically 
sterilized or have been free from menses for > 1 year.  
• Male subject 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.   
• Does not have a history or current evidence of any condition, therapy, or laboratory 
abnormality that might interfere with the subject’s participation for the full duration of 
the trial or is not in the best interest of the subject to participate, in the opinion of the 
treating investigator. 
• Absence of rapid progression of disease 
• Absence of progressive tumor at critical anatomical sites (e.g. cord compression) 
requiring urgent alternative medical intervention. 
Subjects who restart treatment will be retreated at the same dose and dose interval as when 
they last received pembrolizumab.  Treatment will be administered for up to one additional 
year. 
Visit requirements are outlined in Section 6.0 – Trial Flow Chart. 
 
6.2 
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. 
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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. 
Progression of the cancer under study is not considered an adverse event unless it is considered 
to be drug related by the investigator. 
In addition to documenting all Grade 3 or higher toxicities during radiation therapy, all adverse 
events will be recorded from the time of study invervention (pembrolizumab) 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. 
6.2.1 Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor and to Merck 
For purposes of this trial, an overdose of pembrolizumab will be defined as any dose of 1,000 
mg or greater (≥5 times the indicated dose).  No specific information is available on the 
treatment of overdose of pembrolizumab. Appropriate supportive treatment should be provided 
if clinically indicated. In the event of overdose, the subject should be observed closely for signs 
of toxicity.  Appropriate supportive treatment should be provided if clinically indicated. 
 
If an adverse event(s) is associated with (“results from”) the overdose of a Merck product, the 
adverse event(s) is reported as a serious adverse event, even if no other seriousness criteria are 
met. 
If a dose of Merck’s product meeting the protocol definition of overdose is taken without any 
associated clinical symptoms or abnormal laboratory results, the overdose is reported as a non-
serious Event of Clinical Interest (ECI), using the terminology “accidental or intentional 
overdose without adverse effect.” 
All reports of overdose with and without an adverse event must be reported within 24 hours to 
the Sponsor and within 2 working days to Merck Global Safety. (Attn: Worldwide Product 
Safety; FAX 215 993-1220). 
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6. 2. 2  Re p orti n g of Pre g n a nc y a n d L act ati o n t o t he S p o ns or a n d t o Merc k 
Alt h o u g h pre g na nc y a n d lactati o n are n ot c o nsi dere d a d verse e ve nts, it is t he res p o nsi bilit y of 
i n vesti gat ors or t heir desi g nees t o re p ort a n y pre g na nc y or lactati o n i n a s u bject (s p o nta ne o usl y 
re p orte d t o t he m), i ncl u di n g t he pre g na nc y of a male s u bject's fe male part ner t hat occ urs d uri n g 
t he trial or wit hi n 1 2 0 da ys of c o m pleti n g t he trial c o m pleti n g t he trial, or 3 0 da ys f oll o wi n g 
cessati o n of treat me nt if t he s u bject i nitiates ne w a ntica ncer t hera p y, w hic he ver is earlier .  All 
s u bjects a n d fe male part ners of male s u bjects w h o bec o me pre g na nt m ust be f oll o we d t o t he 
c o m pleti o n/ter mi nati o n  of  t he  pre g na nc y.   Pre g na nc y  o utc o mes  of  s p o nta ne o us  a b orti o n,  
misse d a b orti o n, be ni g n h y dati dif or m m ole, bli g hte d o v u m, fetal deat h, i ntra uteri ne deat h, 
miscarria ge a n d  still birt h m ust be re p orte d as seri o us e ve nts (I m p orta nt Me dical E ve nts).  If 
t he pre g na nc y c o nti n ues t o ter m, t he o utc o me ( healt h of i nfa nt) m ust als o be re p orte d. 
S uc h e ve nts m ust be re p orte d wit hi n 2 4 h o urs t o t he S p o ns or a n d wit hi n 2 w or ki n g da ys t o 
Merc k Gl o bal Safet y.  ( Att n: W orl d wi de Pr o d uct Safet y; F A X 2 1 5 9 9 3- 1 2 2 0) 
6. 2. 3  I m me di ate Re p orti n g of A d verse E ve nts t o t he S p o ns or a n d t o Merc k 
6. 2. 3. 1  Seri o us A d verse E ve nts  
S eri o u s A d v er s e E v e nt R e p orti n g ( S A E)    
A n a d v er s e e v e nt or s u s p e ct e d a d v er s e r e a cti o n i s c o n si d er e d “ s eri o u s” if, i n t h e vi e w of eit h er t h e 
i n v e sti g at or or t h e s p o n s or, it r e s ult s i n a n y of t h e f oll o wi n g o ut c o m e s: 
 D e at h  
 A lif e -t hr e at e ni n g a d v er s e dr u g e x p eri e n c e – a n y a d v er s e e x p eri e n c e t h at pl a c e s t h e p ati e nt, i n t h e 
vi e w of t h e i niti al r e p ort er, at i m m e di at e ri s k of d e at h fr o m t h e a d v er s e e x p eri e n c e a s it o c c urr e d. It 
d o e s n ot i n cl u d e a n a d v er s e e x p eri e n c e t h at, h a d it  o c c urr e d i n a m or e s e v er e f or m, mi g ht h a v e 
c a u s e d d e at h.  
 I n p ati e nt h o s pit ali z ati o n or pr ol o n g ati o n of e xi sti n g h o s pit ali z ati o n 
 A p er si st e nt or si g nifi c a nt i n c a p a cit y or s u b st a nti al di sr u pti o n of t h e a bilit y t o c o n d u ct n or m al lif e 
f u n cti o n s. 
 A c o n g e nit al a n o m al y/ birt h d ef e ct.  
I m p ort a nt m e di c al e v e nt s t h at m a y n ot r e s ult i n d e at h, b e lif e t hr e at e ni n g, or r e q uir e h o s pit ali z ati o n m a y 
b e c o n si d er e d a s eri o u s a d v er s e dr u g e x p eri e n c e w h e n, b a s e d u p o n a p pr o pri at e m e di c al j u d g m e nt, 
t h e y m a y j e o p ar di z e t h e p ati e nt or s u bj e ct a n d m a y r e q uir e m e di c al or s ur gi c al i nt er v e nti o n t o pr e v e nt 
o n e  of  t h e  o ut c o m e s  li st e d  i n  t hi s  d efi niti o n.  E x a m pl e s  of  s u c h  m e di c al  e v e nt s  i n cl u d e  all er gi c  
br o n c h o s p a s m r e q uiri n g i nt e n si v e tr e at m e nt i n a n e m er g e n c y r o o m or at h o m e, bl o o d d y s cr a si a s or 
c o n v ul si o n s t h at d o n ot r e s ult i n i n p ati e nt h o s pit ali z ati o n, or t h e d e v el o p m e nt of dr u g d e p e n d e n c y or 
dr u g a b u s e ( 2 1 C F R 3 1 2. 3 2).  
 I m p ort a nt m e di c al e v e nt s a s d efi n e d a b o v e, m a y al s o b e c o n si d er e d s eri o u s a d v er s e e v e nt s. 
A n y i m p ort a nt m e di c al e v e nt c a n a n d s h o ul d b e r e p ort e d a s a n S A E if d e e m e d a p pr o pri at e 
b y t h e Pri n ci p al I n v e sti g at or or t h e I N D S p o n s or, I N D Offi c e.  
Pr o pri et ar y I nf or m ati o n of M D A n d er s o n

 
 
2 0 1 5 -0 8 5 6  
 
 
Versi o n 2 0  
 
 
Pa ge 4 3  
 
 
 All e v e nt s o c c urri n g d uri n g t h e c o n d u ct of a pr ot o c ol a n d m e eti n g t h e d efi niti o n of a S A E m u st b e 
r e p ort e d t o t h e I R B i n a c c or d a n c e wit h t h e ti m efr a m e s a n d pr o c e d ur e s o utli n e d i n “ T h e U ni v er sit y 
of T e x a s M. D. A n d er s o n C a n c er C e nt er I n stit uti o n al R e vi e w B o ar d P oli c y f or I n v e sti g at or s o n 
R e p orti n g U n a nti ci p at e d A d v er s e E v e nt s f or Dr u g s a n d D e vi c e s”.  U nl e s s st at e d ot h er wi s e i n t h e 
pr ot o c ol, all S A E s, e x p e ct e d or u n e x p e ct e d, m u st b e r e p ort e d t o t h e I N D Offi c e, r e g ar dl e s s of 
attri b uti o n ( wit hi n 5 w or ki n g d a y s of k n o wl e d g e of t h e e v e nt).  
 
 All lif e -t hr e at e ni n g or f at al e v e nt s, t h at ar e u n e x p e ct e d, a n d r el at e d t o t h e st u d y dr u g, m u st h a v e 
a writt e n r e p ort s u b mitt e d wit hi n 2 4  h o ur s  ( n e xt w or ki n g d a y) of k n o wl e d g e of t h e e v e nt t o t h e 
S af et y Pr oj e ct M a n a g er i n t h e I N D Offi c e.  
 U nl e s s ot h er wi s e n ot e d, t h e el e ctr o ni c S A E a p pli c ati o n ( e S A E) will b e utili z e d f or s af et y 
r e p orti n g t o t h e I N D Offi c e a n d M D A C C I R B.  
 S eri o u s  a d v er s e  e v e nt s  will  b e  c a pt ur e d  fr o m  t h e  ti m e  of  t h e  fir st  pr ot o c ol -s p e cifi c 
i nt er v e nti o n, u ntil 9 0  d a y s aft er t h e l a st st u d y tr e at m e nt/i nt er v e nti o n, u nl e s s t h e p arti ci p a nt 
wit h dr a w s  c o n s e nt.  S eri o u s  a d v er s e  e v e nt s  m u st  b e  f oll o w e d  u ntil  cli ni c al  r e c o v er y  i s  
c o m pl et e  a n d  l a b or at or y  t e st s  h a v e  r et ur n e d  t o  b a s eli n e,  pr o gr e s si o n  of  t h e  e v e nt  h a s  
st a bili z e d, or t h er e h a s b e e n a c c e pt a bl e r e s ol uti o n of t h e e v e nt.  
 A d diti o n all y, a n y s eri o u s a d v er s e e v e nt s t h at o c c ur aft er t h e 3 0 d a y ti m e p eri o d t h at ar e 
r el at e d t o t h e st u d y tr e at m e nt m u st b e r e p ort e d t o t h e I N D Offi c e. T hi s m a y i n cl u d e t h e 
d e v el o p m e nt of a s e c o n d ar y m ali g n a n c y.  
R e p orti n g t o F D A:  
 S eri o u s a d v er s e e v e nt s will b e f or w ar d e d t o F D A b y t h e I N D S p o n s or ( S af et y Pr oj e ct M a n a g er I N D 
Offi c e) a c c or di n g t o 2 1 C F R 3 1 2. 3 2.  
It i s t h e r e s p o n si bilit y of t h e PI a n d t h e r e s e ar c h t e a m t o e n s ur e t h at s eri o u s a d v er s e e v e nt s ar e 
r e p ort e d a c c or di n g t o t h e C o d e of F e d er al R e g ul ati o n s, G o o d Cli ni c al Pr a cti c e s, t h e pr ot o c ol 
g ui d eli n e s, t h e s p o n s or’ s g ui d eli n e s, a n d I n s tit uti o n al R e vi e w B o ar d p oli c y. 
I n v e sti g at or C o m m u ni c ati o n wit h S u p p orti n g C o m p a ni e s: 
A n y seri o us a d verse e ve nt, or f oll o w u p t o a seri o us a d verse e ve nt, i ncl u di n g deat h d ue t o a n y 
ca use ot her t ha n pr o gressi o n of t he ca ncer u n der st u d y  t hat occ urs t o a n y s u bject fr o m t he ti me 
of first pr ot oc ol i nter ve nti o n  t hr o u g h 9 0 da ys f oll o wi n g cessati o n of treat ment, or t he i nitiati o n 
of ne w a nti -ca ncer t hera p y, w hic he ver is earlier, w het her or n ot relate d t o Merc k pr o d uct, m ust 
be re p orte d wit hi n 2 4 h o urs t o t he S p o ns or a n d wit hi n 2 w or ki n g  da ys t o Merc k G l o bal S afet y.  
T he M D A n ders o n I nter nal S A E Re p ort F or m f or Pr o m pt Re p orti n g will be use d, wit h t he 
Merc k pr ot oc ol n u m ber refere nce d ( 3 4 7 5- 3 6 0). 
N o n -seri o us E ve nts of Cli nical I nterest will be f or war de d t o Merc k Gl o bal S afet y a n d will be 
ha n dle d i n t he sa me ma n ner as S A Es.  
A d diti o nall y, a n y seri o us a d verse e ve nt, c o nsi dere d b y a n i n vesti gat or w h o is a q ualifie d 
p h ysicia n t o be relate d t o Merc k pr o d uct t hat is br o u g ht t o t he atte nti o n of t he i n vesti gat or at 
a n y ti me o utsi de of t he ti me peri o d s pecifie d i n t he pre vi o us para gra p h als o m ust be re p orte d 
i m me diatel y t o t he S p o ns or a n d t o Merc k. 
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SAE reports and any other relevant safety information are to be forwarded to the Merck 
Global Safety facsimile number:  +1-215-993-1220 
A copy of all 15 Day Reports and Annual Progress Reports is submitted as required by FDA, 
European Union (EU), Pharmaceutical and Medical Devices agency (PMDA) or other local 
regulators. Investigators will cross reference this submission according to local regulations to 
the Merck Investigational Compound Number (IND, CSA, etc.) at the time of submission.  
Additionally investigators will submit a copy of these reports to Merck & Co., Inc. (Attn: 
Worldwide Product Safety; FAX 215 993-1220) at the time of submission to FDA. 
All subjects with serious adverse events must be followed up for outcome. 
6.2.3.2 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). 
1. Additional adverse events: 
 
A separate guidance document has been provided entitled “Event of Clinical Interest 
Guidance Document” (previously entitled, “Event of Clinical Interest and Immune-Related 
Adverse Event Guidance Document”).  This document can be found in Appendix 4 and 
provides guidance regarding identification, evaluation and management of ECIs and irAEs.   
 
ECIs (both non-serious and serious adverse events) identified in this guidance document 
from the date of first dose through 90 days following cessation of treatment, or 30 days 
after the initiation of a new anticancer therapy, whichever is earlier, need to be reported 
within 24 hours to the Sponsor and within 2 working days to Merck Global Safety. (Attn: 
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Worldwide Product Safety; FAX 215 993-1220), regardless of attribution to study 
treatment, consistent with standard SAE reporting guidelines. 
 
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. 
 
 
6.2.4 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 6  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 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 
 

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

 
 
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6.2.5 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.  
7.0 STATISTICAL ANALYSIS PLAN 
7.1 
Statistical Analysis Plan Summary 
Our Phase I study, consisting of two distinct cohorts of patient, will assess toxicity of two 
radiation treatment plans.  Patients will be assigned to one of two study cohorts based on 
eligibility characteristics.  Randomization is not possible due to the distinct criteria required 
for the administration of the radiation treatment plan.  Each study cohort will be monitored for 
toxicity independently using a single treatment plan.   
7.2 
Statistical Analysis Plan 
We will enroll a total of 24 patients, twelve patients to each  cohort consisting of distinct 
radiation and immunotherapy treatment plans.  For each study cohort, treatment-related 
toxicity is defined in Table 3 above (in the column “Discontinue Treatment/Off-Study 
Criteria”.  Therefore, any patient meeting this criteria will be deemed to have experienced an 
“unacceptable” toxicity for the purposes of the trial.  For each study condition, we plan to 
enroll 12 patients  in cohorts of size 6.  All patients will be monitored for at least 4 months 
from the beginning of RT, before declaring the treatment acceptable for enrolling the next 
cohort of 6 patients.   
Continuous monitoring using the method of Thall [20] will be employed for each study cohort 
of 12 patients in cohorts of size 6 where each patient is monitored for at least 4 months from 
the start of RT.  We will stop the trail if we have reason to believe that the treatment-related 
toxicity rate is more than 30%.  Using the following probability rule 
Pr(rate of treatment-related toxicity 4 months from the start of RT > 30% | data) > 0.80. 
If we determine there is more than a 80% chance that the treatment-related toxicity rate is more 
than 30%, we will stop the trial.  We will assume a beta(0.6, 1.4) distribution for treatment-
related toxicity as this prior provides a mean of 30% and a standard deviation of 26.5%.  Thus 
the trial will be stopped if  
 
[# of patients with treatment-related toxicity 4 months from day 1 of the start of RT  / # of 
patients evaluated] 
 
 ≥ 3/6, 6/12  
 
Therefore, we will stop either study cohort if we observe 3 or more treatment-related toxicities 
in the first 6 patients, or if we observe 6 treatment related toxicities at any time while evaluating 
all 12 patients.  We will suspend accrual while evaluating the first 6 patients to ensure none of 
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the stopping boundaries have been reached prior to enrolling the final 6 patients of each study 
cohort.    The operating characteristics from this decision rule are shown in Table X and are 
based on 1000 simulations for each scenario.   
Table X. Operating characteristics for toxicity monitoring rule 
Treatment-related 
Toxicity 4 months after 
start of RX 
Probability of Stopping Early 
Sample Size 
 
Avg 
 
0.10 
0.017 
 
11.9 
 
0.20 
0.099 
 
11.4 
 
0.30 
0.254 
 
10.5 
 
0.40 
0.462 
 
9.2 
 
0.50 
0.650 
 
8.1 
 
• Operating Characteristics acquired using the Stata command stopbound 
If the true toxicity rate is 0.50, there is a 65.0% probability of stopping the trial early.   
Descriptive statistics will be used to summarize the study data.  For each study cohort, we will 
tabulate toxicities by dose, severity, and relationship to the treatment plan.  The method of 
Kaplan and Meier will be used to estimate median PFS and OS.   
A Toxicity/Efficacy Summary will be submitted to the IND Medical Monitor after the first 6 
evaluable subjects per cohort, complete 4 months from the initiation of Radiation Therapy and 
prior to the enrollment of the next cohort, and following the treatment of the next 6 evaluable 
subjects to each cohort. 
 
8.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES 
8.1 
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 7. 
Table 7  Product Descriptions 
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Product Name & Potency 
Dosage Form 
Pembrolizumab 50 mg 
Lyophilized Powder for Injection 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
 
8.2 
Packaging and Labeling Information 
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements. 
8.3 
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. 
8.4 
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. 
8.5 
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.  
 
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9.0 APPENDICES 
9.1 
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. 
 
9.2 
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) 
9.3 
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, 
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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. 
9.4 
Events of Clinical Interest Guidance Document 
Document attached as Appendix G in PDOL system. 
10.0   REFERENCES 
[1] Centers for Disease C, Prevention. Malignant mesothelioma mortality--United States, 
1999-2005. MMWR Morbidity and mortality weekly report. 2009;58:393-6. 
[2] Ahamad A, Stevens CW, Smythe WR, Liao Z, Vaporciyan AA, Rice D, et al. Promising 
early local control of malignant pleural mesothelioma following postoperative intensity 
modulated radiotherapy (IMRT) to the chest. Cancer journal. 2003;9:476-84. 
[3] Vogelzang NJ, Rusthoven JJ, Symanowski J, Denham C, Kaukel E, Ruffie P, et al. Phase 
III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with 
malignant pleural mesothelioma. J Clin Oncol. 2003;21:2636-44. 
[4] Krug LM, Pass HI, Rusch VW, Kindler HL, Sugarbaker DJ, Rosenzweig KE, et al. 
Multicenter phase II trial of neoadjuvant pemetrexed plus cisplatin followed by extrapleural 
pneumonectomy and radiation for malignant pleural mesothelioma. J Clin Oncol. 
2009;27:3007-13. 
[5] Treasure T, Lang-Lazdunski L, Waller D, Bliss JM, Tan C, Entwisle J, et al. Extra-pleural 
pneumonectomy versus no extra-pleural pneumonectomy for patients with malignant pleural 
mesothelioma: clinical outcomes of the Mesothelioma and Radical Surgery (MARS) 
randomised feasibility study. Lancet Oncol. 2011;12:763-72. 
[6] Treasure T, Sedrakyan A. Pleural mesothelioma: little evidence, still time to do trials. 
Lancet. 2004;364:1183-5. 
[7] Lang-Lazdunski L, Bille A, Lal R, Cane P, McLean E, Landau D, et al. 
Pleurectomy/decortication is superior to extrapleural pneumonectomy in the multimodality 
management of patients with malignant pleural mesothelioma. J Thorac Oncol. 2012;7:737-
43. 
[8] Chance WW, Rice DC, Allen P, Tsao A, Fontanilla H, Zhongxing L, et al. Postoperative 
hemithoracic intensity-modulated radiation therapy (IMRT) with an optional integrated boost 
for malignant pleural mesothelioma:  toxicity, patterns of failure, and a matched survival 
analysis. ASTRO abstract. 2014. 
[9] Rosenzweig KE, Zauderer MG, Laser B, Krug LM, Yorke E, Sima CS, et al. Pleural 
intensity-modulated radiotherapy for malignant pleural mesothelioma. International journal of 
radiation oncology, biology, physics. 2012;83:1278-83. 
[10] Rimner A, Spratt DE, Zauderer MG, Rosenzweig KE, Wu AJ, Foster A, et al. Failure 
Patterns After Hemithoracic Pleural Intensity Modulated Radiation Therapy for Malignant 
Pleural Mesothelioma. International journal of radiation oncology, biology, physics. 2014. 
[11] Liao ZX, Komaki RR, Thames HD, Jr., Liu HH, Tucker SL, Mohan R, et al. Influence of 
technologic advances on outcomes in patients with unresectable, locally advanced non-small-
cell lung cancer receiving concomitant chemoradiotherapy. International journal of radiation 
oncology, biology, physics. 2010;76:775-81. 
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[12] Li H, Zhang X, Park P, Liu W, Chang J, Liao Z, et al. Robust optimization in intensity-
modulated proton therapy to account for anatomy changes in lung cancer patients. 
Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and 
Oncology. 2015;114:367-72. 
[13] Kesarwala AH, Ko CJ, Ning H, Xanthopoulos E, Haglund KE, O'Meara WP, et al. 
Intensity-modulated proton therapy for elective nodal irradiation and involved-field radiation 
in the definitive treatment of locally advanced non-small-cell lung cancer: a dosimetric study. 
Clin Lung Cancer. 2015;16:237-44. 
[14] Kardar L, Li Y, Li X, Li H, Cao W, Chang JY, et al. Evaluation and mitigation of the 
interplay effects of intensity modulated proton therapy for lung cancer in a clinical setting. 
Practical radiation oncology. 2014;4:e259-68. 
[15] Pan HY, Jiang S, Sutton J, Liao Z, Chance WW, Frank SJ, et al. Early experience with 
intensity modulated proton therapy for lung-intact mesothelioma: A case series. Practical 
radiation oncology. 2015. 
[16] Cedres S, Ponce-Aix S, Zugazagoitia J, Sansano I, Enguita A, Navarro-Mendivil A, et al. 
Analysis of expression of programmed cell death 1 ligand 1 (PD-L1) in malignant pleural 
mesothelioma (MPM). PloS one. 2015;10:e0121071. 
[17] Alley EM, R.; Santoro, A.; Beckey, K.; Yuan, S.S.; Cheng, J.; Piperdi, B.; Schellens, 
J.H.M. Clinical safety and efficacy of Pembrolizumab (MK-3475) in patients iwth malignant 
pleural mesothelioma (MPM):  preliminary results from KEYNOTE-028. Proceedings of the 
American Association of Cancer Research, Philadelphia, PA, 2015. 2015. 
[18] Chance WWR, D.C.; Allen, P.K.; Tsao, A.S.; Fontanilla, H.P.; Liao, Z.; Chang, J.Y.; 
Tang, C.; Welsh, J.S.; Mehran, R.J.; Gomez, D.R. Hemithoracic intensity modulated radiation 
therapy after pleurectomy/decortication for malignant pleural mesothelioma:  toxicity, patterns 
of failure, and a matched survival analysis. International journal of radiation oncology, 
biology, physics. 2014;In press. 
[19] Tucker SL, Jin H, Wei X, Wang S, Martel MK, Komaki R, et al. Impact of Toxicity Grade 
and Scoring System on the Relationship Between Mean Lung Dose and Risk of Radiation 
Pneumonitis in a Large Cohort of Patients With Non-Small Cell Lung Cancer. International 
journal of radiation oncology, biology, physics. 2009. 
[20] Thall PF, Simon RM, Estey EH. Bayesian sequential monitoring designs for single-arm 
clinical trials with multiple outcomes. Stat Med. 1995;14:357-79. 
 
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