Conditions: Non-small Cell Lung Cancer, NSCLC
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 25
Healthy volunteers: no

Brief summary:
The goal of this study is to explore if, for locally advanced non-small cell lung cancer patients whose tumors have high levels of PD-L1 (a marker associated with benefits from immunotherapy), a combination of immunotherapy and a personalized 4-week radiotherapy course could be more effective than standard treatment, which is a combination of chemotherapy and radiotherapy.

Detailed description:
This is a Phase II trial evaluating the efficacy and safety of sequential pembrolizumab (200 mg every three weeks) and accelerated, dose-painted radiotherapy for patients with locally advanced NSCLC with PD-L1 expression ≥ 50%. Patients with PD-L1 expression \< 50% will be treated with concurrent chemoradiotherapy as part of standard of care.

Arms:
arm 1: Subjects with PD-L1 expression ≥ 50%:

Combination of sequential pembrolizumab (200mg every 3 weeks) and accelerated, dose-painted radiotherapy for locally advanced NSCLC patients with high (≥ 50%) PD-L1 expression.

Subjects with PD-L1 expression \< 50%:

Patients with PD-L1 expression \< 50% will also be enrolled and treated with standard concurrent chemoradiotherapy

Interventions: intervention 1: PembroRT
Intervention descriptions: intervention 1: Patients whose tumors are found to have high (≥ 50%) PD-L1 expression will automatically be placed in the PembroRT group. These patients will receive three intravenous treatments with pembrolizumab, followed by four weeks of daily radiotherapy, followed by up to 12 more treatments with pembrolizumab. Pembrolizumab is given as an intravenous infusion once every three weeks. This treatment course will last, in total, up to one year.

Patients whose tumors are found to have low (\< 50%) PD-L1 will be treated with a standard-o-care regimen and not be a part of this clinical trial.

Protocol document:
Prot_SAP_000.pdf: 
Title: The Selective Personalized Radio-Immunotherapy for 
Locally Advanced NSCLC (SPRINT)
IRB No: 2018-8945
NCT03523702
Approval Date: 09/09/2020


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SPONSOR: Montefiore Medical Center 
 
TITLE: The Selective Personalized Radio-Immunotherapy for locally advanced NSCLC 
Trial (SPRINT) 
 
 
IND Number: IND Exempt 
 
Principal Investigator 
Nitin Ohri, MD 
111 East 210th Street 
Bronx, NY 10467 
Tel: (718)920-7750 
Email: NOHRI@montefiore.org 
 
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1.0 TRIAL SUMMARY 
Abbreviated Title 
Radioimmunotherapy for LA-NSCLC 
Trial Phase 
II 
Clinical Indication 
Locally advanced non-small cell lung cancer 
Trial Type 
Single Arm, Open Label, with 2 cohorts 
Type of control 
None 
Route of administration 
Intravenous 
Trial Blinding 
None 
Treatment Groups  
PembroRT Cohort – Subjects with PD-L1 expression ≥ 50% 
ChemoRT Cohort - Subjects with PD-L1 expression < 50% 
Number of trial participants 
PembroRT Cohort – 25 
ChemoRT Cohort – Approximately 38 
Estimated enrollment period 
3/1/2018 to 9/1/2019 
Estimated duration of trial 
18 months 
Duration of Participation 
28 months 
Estimated average length of 
treatment per patient 
PembroRT Cohort - One year 
 
 
 
 
2.0 TRIAL DESIGN 
2.1 
Trial Design 
This is a Phase II trial evaluating the efficacy and safety of sequential pembrolizumab (200 mg 
every three weeks) and accelerated, dose-painted radiotherapy for patients with locally advanced 
NSCLC with PD-L1 expression ≥ 50%. Patients with PD-L1 expression < 50% will also be 
enrolled and treated with standard concurrent chemoradiotherapy to serve as a non-randomized 
comparison group. 
2.2 
Trial Diagram 
 
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3.0 OBJECTIVE(S) & HYPOTHESIS(ES) 
3.1 
Primary Objective(s) & Hypothesis 
(1) Objective: To characterize progression-free survival rates following treatment with 
sequential pembrolizumab and radiotherapy for locally advanced NSCLC with PD-L1 
expression ≥ 50%. 
Hypothesis: We hypothesize that sequential pembrolizumab and radiotherapy for locally 
advanced NSCLC with PD-L1 expression ≥ 50% prolongs progression-free survival 
compared to historical outcomes. 
3.2 
Secondary Objective(s) & Hypotheses 
(1) Objective: To characterize freedom from distant metastasis rates following treatment with 
sequential pembrolizumab and radiotherapy for locally advanced NSCLC with PD-L1 
expression ≥ 50%.  
Hypothesis: We hypothesize that sequential pembrolizumab and radiotherapy for locally 
advanced NSCLC with PD-L1 expression ≥ 50% prolongs freedom from distant metastasis 
compared to historical outcomes. 
(2) Objective: To characterize freedom from intrathoracic disease progression rates following 
treatment with sequential pembrolizumab and radiotherapy for locally advanced NSCLC 
with PD-L1 expression ≥ 50%.  
Hypothesis: We hypothesize that sequential pembrolizumab and radiotherapy for locally 
advanced NSCLC with PD-L1 expression ≥ 50% prolongs freedom from intrathoracic 
disease progression compared to historical outcomes. 
(3) Objective: To characterize overall survival rates following treatment with sequential 
pembrolizumab and radiotherapy for locally advanced NSCLC with PD-L1 expression ≥ 
50%.  
Hypothesis: We hypothesize that sequential pembrolizumab and radiotherapy for locally 
advanced NSCLC with PD-L1 expression ≥ 50% prolongs overall survival compared to 
historical outcomes. 
(4) Objective: To estimate the rate of disease progression during 3 cycles of induction 
pembrolizumab prior to radiotherapy for locally advanced NSCLC with PD-L1 expression ≥ 
50%.  
Hypothesis: We hypothesize that the rate of disease progression during 3 cycles of induction 
pembrolizumab prior to radiotherapy for locally advanced NSCLC with PD-L1 expression ≥ 
50% is less than 10%. 
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(5) Objective: To demonstrate, within the limitations of a nonrandomized study, that sequential 
pembrolizumab and radiotherapy for locally advanced NSCLC reduces severe adverse event 
rates compared to standard concurrent chemoradiotherapy.  
Hypothesis: We hypothesize that sequential pembrolizumab and radiotherapy for locally 
advanced NSCLC reduces severe adverse event rates compared to standard concurrent 
chemoradiotherapy. 
(6) Objective: To demonstrate, within the limitations of a nonrandomized study, that sequential 
pembrolizumab and radiotherapy for locally advanced NSCLC does not significantly 
increase rates of pneumonitis compared to standard concurrent chemoradiotherapy.  
Hypothesis: We hypothesize that that sequential pembrolizumab and radiotherapy for locally 
advanced NSCLC not significantly increase rates of pneumonitis compared to standard 
concurrent chemoradiotherapy. 
(7) Objective: To demonstrate, within the limitations of a nonrandomized study, that sequential 
pembrolizumab and radiotherapy for locally advanced NSCLC reduces patient-reported 
treatment-related toxicities compared to standard concurrent chemoradiotherapy.  
Hypothesis: We hypothesize that sequential pembrolizumab and radiotherapy for locally 
advanced NSCLC reduces patient-reported treatment-related toxicities compared to standard 
concurrent chemoradiotherapy. 
(8) Objective: To demonstrate, within the limitations of a nonrandomized study, that sequential 
pembrolizumab and radiotherapy for locally advanced NSCLC preserves physical function 
compared to standard concurrent chemoradiotherapy.  
Hypothesis: We hypothesize that sequential pembrolizumab and radiotherapy for locally 
advanced NSCLC preserves physical function, as measured by daily step counts, compared 
to standard concurrent chemoradiotherapy. 
(9) Objective: To demonstrate, within the limitations of a nonrandomized study, that sequential 
pembrolizumab and radiotherapy for locally advanced NSCLC reduces hospitalization rates 
compared to standard concurrent chemoradiotherapy.  
Hypothesis: We hypothesize that sequential pembrolizumab and radiotherapy for locally 
advanced NSCLC reduces hospitalization rates compared to standard concurrent 
chemoradiotherapy. 
 
 
3.3 
Translational Objectives 
(1) 
Objective: To demonstrate, within the limitations of a nonrandomized study, that 
sequential pembrolizumab and radiotherapy for locally advanced NSCLC with PD-L1 
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expression ≥ 50% increases the rate of circulating tumor DNA clearance compared to 
standard concurrent chemoradiotherapy. 
(2) 
Objective:  To correlate PD-L1 TPS score and expression of alternative immune 
checkpoint molecules (e.g.: HHLA2, B7x, and B7-H3) with clinical outcomes. 
(3) 
Objective:  To correlate baseline tumor mutational burden with clinical outcomes. 
(4) 
Objective:  To correlate markers of immune activation and expansion of immune cell 
subsets with clinical outcomes. 
4.0 BACKGROUND & RATIONALE 
4.1 
Locally Advanced Non-small Cell Lung Cancer 
Lung cancer is the leading cause of cancer-related death worldwide, with more than 1.5 million 
deaths per year [1, 2]. More than 220,000 new cases of lung cancer are diagnosed each year in 
the United States. Non–small-cell lung cancer represents more than 80% of lung cancers, and 
about 35% of NSCLC patients present with stage III disease [3]. Standard treatment for patients 
with locally advanced NSCLC, which may be defined as stage III disease or unresectable stage II 
disease, typically consists of conventionally-fractionated (1.8-2.0 Gy/day) radiotherapy to a total 
dose of approximately 60 Gy with concurrent chemotherapy. This treatment approach yields 
median survival times of only 16-30 months and can cause significant acute and late toxicities 
[4-9]. The five-year survival rate following concurrent chemoradiotherapy for stage III NSCLC 
is approximately 20%. Outcomes for patients who are deemed unfit for concurrent 
chemoradiotherapy are even poorer.  
In the recently published PACIFIC study [10], the anti-programmed death ligand 1 (PD-L1) 
antibody durvalumab was compared to placebo as consolidation therapy lasting up to 12 months 
in patients with stage III NSCLC without disease progression after concurrent 
chemoradiotherapy. Adjuvant durvalumab significantly prolonged progression-free survival. 
Overall survival data from that trial are not yet available.  
4.2 
Pembrolizumab 
The introduction of immune checkpoint inhibitors has revolutionized the management of 
advanced NSCLC. Most lung cancers, in particular those associated with smoking, harbor many 
missense mutations and are some of the most immunogenic tumors through the presentation of 
neo-antigens. In many lung tumors, a T-cell response is established but is negatively regulated 
via the tumoral expression of checkpoint molecules. In the majority of cases of advanced 
NSCLC, the molecular makeup of the tumor measured by tumor mutation burden, the inflamed 
status of the tumor measured by markers of immune activation such as expansion of T4/T8 
subsets, regulatory T-cell numbers and myeloid derived suppressor cells, and tumoral “defense” 
response, assessed by PD-L1 expression, provide promising biomarkers to assess candidacy for 
checkpoint inhibitor therapy [11]. 
In the pivotal Keynote-010 study, pembrolizumab was proven to prolong progression-free and 
overall survival compared to docetaxel in patients with PD-L1 positive (defined as PD-L1 
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expression on at least 1% of tumor cells) NSCLC that was previously treated with at least one 
line of , with a striking improvement in the subset of patients with PD-L1 expression of at least 
50% [12]. This study led to FDA approval of pembrolizumab in the second line setting for PD-
L1 positive (expression>1%) tumors and provided impetus for biomarker selected first-line 
studies such as the Keynote-024 study. In Keynote-024, single-agent pembrolizumab was 
compared to standard doublet chemotherapy for patients with treatment-naïve advanced NSCLC 
with PD-L1 tumor proportion score (TPS) of 50% or higher. Treatment with pembrolizumab 
rather than chemotherapy led to a significant overall survival benefit and fewer adverse event, 
leading to the approval of pembrolizumab as first-line treatment for advanced PD-L1 positive (≥ 
50%) NSCLC [13].  
 
4.3 
Radiotherapy 
Locally-advanced NSCLC is typically treated with thoracic radiotherapy, often in combination 
with concurrent chemotherapy.  Despite advances in the evaluation, treatment techniques, and 
supportive care measures provided to locally advanced NSCLC patients, local disease 
progression and distant metastases frequently develop following definitive therapy. Randomized 
trials have tested changes or additions to systemic therapy[14-18], radiotherapy dose escalation, 
and the addition of surgical resection[19] but have failed to improve overall survival for this 
patient population. A recent landmark randomized trial demonstrated that radiotherapy dose 
escalation, applied to the primary tumor and all involved regional lymph nodes, may reduce 
survival rates, highlighting gaps in our understanding of the effects of thoracic radiotherapy for 
LA-NSCLC. 
A growing body of literature indicates that minimizing cardiac irradiation should be a goal in 
planning thoracic radiotherapy. Recent publications have demonstrated a strong association 
between cardiac irradiation and both cardiac events [20-23] and all-cause mortality[17]. The 
risks of cardiac irradiation may be highest in subjects with comorbid conditions such as existing 
heart disease[20, 21] or a smoking history [23], which are common in NSCLC patients. 
Somewhat surprisingly, these effects have been seen within a few years of radiotherapy delivery 
[17, 20-22] and in populations with high risk of cancer-specific mortality [17, 20, 21]. In 
retrospect, this is consistent with previous analyses demonstrating that excessive [24] or 
unnecessary [25] mediastinal irradiation for lung cancer can meaningfully reduce survival rates. 
Thoracic irradiation may directly lead to coronary artery stenosis[26] and may also impair 
patients’ immune systems [27]. 
Based on accumulating evidence demonstrating the prognostic and predictive value of FDG-PET 
metrics [28-32], we recently performed a single-institution phase II study testing dose-painted 
intensity-modulated radiotherapy (IMRT) as a strategy to improve the efficacy and safety of 
chemoradiotherapy for locally advanced NSCLC[33]. In that trial, tumors and lymph nodes 
deemed to be at low risk for local progression following chemoradiotherapy were treated with a 
relatively low radiotherapy dose of 52.5 Gy. Our results indicate that this novel strategy yields 
high rates of metabolic response, local disease control, and overall survival. The aforementioned 
high-profile studies highlighting the importance of minimizing cardiac irradiation in NSCLC 
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patients will draw additional attention to our dose-painting approach for locally advanced 
NSCLC. 
 
Kaplan-Meier curves for overall survival and progression-free survival from the 
Montefiore/Einstein phase II study of dose-painted IMRT for LA-NSCLC. 
 
 
Cumulative incidence curves for disease progression in individual tumors or lymph nodes from 
the Montefiore/Einstein phase II study of dose-painted IMRT for LA-NSCLC. Progression at 
other sites or death from any cause were treated as competing risks. Of note, lesions with 
metabolic tumor volumes (MTV) below 25 cc were treated with relatively low radiotherapy 
doses of 57 Gy (n=20) or 52.5 Gy (n=72). 
 
0
5
10
15
20
Time (Months)
0
10
20
30
40
50
60
70
80
90
100
Survival (%)
33
26
18
13
# at Risk:
22
11
8
6
# at Risk:
Overall Survival
Progression-Free Survival
0
5
10
15
20
Time after Chemoradiotherapy (months)
0
5
10
15
20
25
30
35
40
45
50
Cumulative Incidence Rate (%)
15
8
7
5
# at Risk:
74
33
24
21
# at Risk:
MTV > 25 cc, 24 lesions
MTV < 25 cc, 92 lesions
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4.4 
Activity Monitoring 
In addition to pioneering a novel way to deliver thoracic radiotherapy, we at the 
Montefiore/Einstein Cancer Center have established a novel program to monitor patients for 
acute complications during radiotherapy. We performed a pilot trial in which patients undergoing 
concurrent chemoradiotherapy for a variety of malignancies were equipped with commercial 
fitness trackers, and activity levels were monitored throughout the treatment course[34]. We 
found that daily step counts can serve as powerful and dynamic predictors of unplanned 
hospitalization during chemoradiotherapy. Specifically, we found a 38% reduction in the risk of 
hospitalization for every 1,000 steps taken each day. In a follow-up study, we are utilizing 
activity data to provide customized supportive care for patients based on changes in activity 
levels, with the aim of reducing the rate of hospitalization during treatment. A third trial at our 
institution is testing a simple pedometer-based walking program as an intervention to reduce 
systemic inflammation and reduce treatment interruptions during chemoradiotherapy. A fourth 
study will explore activity data as a predictor of adverse events for patients with advanced 
malignancies receiving systemic therapy. Activity data is now collected automatically by 
wireless access clients every time a patient enters our cancer center. 
 
4.5 
Patient-Reported Outcomes 
Patient-reported outcomes are becoming a standard tool for evaluating health-related quality of 
life, treatment preferences, and treatment quality in cancer care[35]. They may be particularly 
important in studies involving radiotherapy for NSCLC. This is exemplified by the results of 
RTOG 0617, which was a multi-institutional randomized trial testing uniform radiotherapy dose 
escalation (including all tumors and regional lymph nodes) with concurrent chemotherapy for 
LA-NSCLC. Dose escalation from 60 Gy to 74 Gy was unexpectedly found to increase the risk 
of mortality, with median overall survival durations of 29 months with the standard dose of 60 
Gy and only 20 months for subjects treated with 74 Gy[17]. Investigators found no statistically 
significant differences in serious (grade ≥ 3) adverse events between radiotherapy dose groups, 
demonstrating the disconnect between physician-scored toxicity and important clinical outcomes. 
Impairments in patient-reported quality of life, on the other hand, occurred more frequently in 
the high dose radiotherapy arm[36]. Additionally, baseline quality of life score was found to be a 
powerful predictor of overall survival. 
 
The National Cancer Institute recently developed the Patient-Reported Outcomes Version of the 
Common Terminology Criteria for Adverse Events (PRO-CTCAE)[37]. The PRO-CTCAE item 
library is comprised of 78 symptomatic adverse events, each of which is elicited using between 
one and three questions (representing frequency, severity, and/or interference), for a total of 124 
individual questions. For any given clinical trial, relevant PRO-CTCAE items can be selected 
from the online library to create a concise patient questionnaire that has been validated in several 
languages. This promising tool has not yet been utilized extensively in chemoradiotherapy trials 
for NSCLC. One recent study demonstrated the extent to which CTCAE and PRO-CTCAE 
findings may differ in this setting[38].  As an example, clinicians using CTCAE reported that 
high-level anxiety occurred in 0/130 subjects.  PRO-CTCAE demonstrated that 28/120 subjects 
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had high-level anxiety. Large differences between CTCAE and PRO-CTCAE were observed for 
several other adverse events, including anorexia, cough, dysphagia, fatigue, and pain. 
 
We have developed a concise PRO-CTCAE tool that includes the elements that are likely most 
relevant to LA-NSCLC patients who are treated with thoracic radiotherapy (Appendix). We 
expect that patient-reported outcomes for these elements will be improved with the use of 
radiotherapy and pembrolizumab compared to standard chemoradiotherapy in this setting. 
 
4.6 
Study Rationale 
We hypothesize that a combination of pembrolizumab and dose-painted radiotherapy will yield 
improved efficacy and tolerability compared to standard chemoradiotherapy for locally advanced 
NSCLC patients with high (≥ 50%) PD-L1 expression. We will explore this hypothesis in the 
“pembroRT” arm of this prospective non-randomized trial. Subjects with PD-L1 expression 
below 50% will also be enrolled to a “chemoRT arm” and treated with standard concurrent 
chemoradiotherapy, to allow exploratory comparisons of toxicities and clinical outcomes 
following pembrolizumab and radiotherapy versus chemotherapy and radiotherapy. Subjects on 
both arms will use wearable fitness trackers, which will allow us to monitor closely for adverse 
events and demonstrate that our novel treatment approach preserves functional status compared 
to standard chemoradiotherapy. We will also follow patient-reported outcomes for subjects in 
both cohorts. 
While study subjects allocated to the “chemoRT” arm of this trial based on low PD-L1 
expression, will not be receiving novel therapy, we believe that the inclusion of the “chemoRT” 
arm in this trial is critical for several reasons: 
• To characterize outcomes following chemoradiotherapy and modern adjuvant therapy. 
Since RTOG 0617 was conducted (2007-2011)[17], and even after our in-house PAINT 
trial (2013-2016)[33], early results from the PACIFIC trial have changed the standard of 
care for many patients with locally advanced NSCLC[10]. Clinicians caring for this 
patient population are currently in an unusual situation, where we consider treatment with 
one year of adjuvant durvalumab following chemoradiotherapy without published data 
demonstrating how this treatment affects overall survival. It is therefore important that 
we characterize survival rates in a contemporary patient cohort receiving 
chemoradiotherapy for locally advanced NSCLC.  Of note, the PACIFIC trial 
demonstrated that the prolongation of PFS and distant metastasis-free survival with 
durvalumab was not influenced by PD-L1 expression. Additionally, we have not found 
that PD-L1 expression is a prognostic factor for patients treated with chemoradiotherapy 
at our institution (see figures below). While comparisons of outcomes in our two study 
cohorts will be limited by the non-randomized treatment allocation, outcomes in the 
“chemoRT” cohort will provide some frame of reference for outcomes seen in the 
“pembroRT” group. 
 
 
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Kaplan-Meier curves depicting progression-free survival and overall survival in patients who 
have been treated with concurrent chemoradiotherapy for locally advanced NSCLC at our 
institution and underwent tumor PD-L1 testing. 
• To allow comparison of the safety profiles of “pembroRT” and “chemoRT”. 
We expect that, compared to standard chemoradiotherapy, sequential pembrolizumab and 
dose-painted accelerated radiotherapy will reduce clinician and patient-reported serious 
adverse event rates, reduce hospitalization rates, and preserve physical function. Of note, 
we have not found that PD-L1 expression is associated with hospitalization rates or step 
counts in patients we have treated with chemoradiotherapy for locally advanced NSCLC 
(see figures below). While comparisons of outcomes in our two study cohorts will be 
limited by the non-randomized treatment allocation, adverse event rates in the 
“chemoRT” cohort will provide some frame of reference for those seen in the 
“pembroRT” group. 
 
4.6.1 Justification for Pembrolizumab Dose  
The planned dose of pembrolizumab for this study is 200 mg every 3 weeks (Q3W).  Based on 
the totality of data generated in the Keytruda development program, 200 mg Q3W is the 
appropriate dose of pembrolizumab for adults across all indications and regardless of tumor type.  
As outlined below, this dose is justified by: 
• Clinical data from 8 randomized studies demonstrating flat dose- and exposure-efficacy 
relationships from 2 mg/kg Q3W to 10 mg/kg every 2 weeks (Q2W),  
• Clinical data showing meaningful improvement in benefit-risk including overall survival 
at 200 mg Q3W across multiple indications, and 
• Pharmacology data showing full target saturation in both systemic circulation (inferred 
from pharmacokinetic [PK] data) and tumor (inferred from physiologically-based PK 
[PBPK] analysis) at 200 mg Q3W 
0
5
10
15
20
Time (Months)
0
10
20
30
40
50
60
70
80
90
100
Progression-Free Survival (%)
Logrank p = 0.964
PD-L1 Low (n=15)
PD-L1 High (n=6)
0
5
10
15
20
Time (Months)
0
10
20
30
40
50
60
70
80
90
100
Overall Survival (%)
Logrank p = 0.779
PD-L1 Low (n=15)
PD-L1 High (n=6)
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Among the 8 randomized dose-comparison studies, a total of 2262 participants were enrolled 
with melanoma and non-small cell lung cancer (NSCLC), covering different disease settings 
(treatment naïve, previously treated, PD-L1 enriched, and all-comers) and different treatment 
settings (monotherapy and in combination with chemotherapy).  Five studies compared 2 mg/kg 
Q3W versus 10 mg/kg Q2W (KN001 Cohort B2, KN001 Cohort D, KN002, KN010, and 
KN021), and 3 studies compared 10 mg/kg Q3W versus 10 mg/kg Q2W (KN001 Cohort B3, 
KN001 Cohort F2 and KN006).  These studies demonstrated flat dose- and exposure-response 
relationships across the doses studied representing an approximate 5- to 7.5-fold difference in 
exposure.  The 2 mg/kg (or 200 mg fixed-dose) Q3W provided similar responses to the highest 
doses studied.  Subsequently, flat dose-exposure-response relationships were also observed in 
other tumor types including head and neck cancer, bladder cancer, gastric cancer and classical 
Hodgkin Lymphoma, confirming 200 mg Q3W as the appropriate dose independent of the tumor 
type.  These findings are consistent with the mechanism of action of pembrolizumab, which acts 
by interaction with immune cells, and not via direct binding to cancer cells. 
Additionally, pharmacology data clearly show target saturation at 200 mg Q3W.  First, PK data 
in KN001 evaluating target-mediated drug disposition (TMDD) conclusively demonstrated 
saturation of PD-1 in systemic circulation at doses much lower than 200 mg Q3W.  Second, a 
PBPK analysis was conducted to predict tumor PD-1 saturation over a wide range of tumor 
penetration and PD-1 expression.  This evaluation concluded that pembrolizumab at 200 mg 
Q3W achieves full PD-1 saturation in both blood and tumor. 
Finally, population PK analysis of pembrolizumab, which characterized the influence of body 
weight and other participant covariates on exposure, has shown that the fixed-dosing provides 
similar control of PK variability as weight-based dosing, with considerable overlap in the 
distribution of exposures from the 200 mg Q3W fixed dose and 2 mg/kg Q3W dose.  Supported 
by these PK characteristics and given that fixed-dose has advantages of reduced dosing 
complexity and reduced potential of dosing errors, the 200 mg Q3W fixed-dose was selected for 
evaluation across all pembrolizumab protocols. 
 
4.6.2 Rationale for Endpoints 
4.6.2.1 Efficacy Endpoints 
• Progression-free survival duration following study enrollment (primary endpoint). 
o Progression-free survival is a standard assessment of clinical benefit of treatments 
for locally advanced NSCLC. 
• Duration of freedom from distant metastasis following study enrollment. 
o Freedom from distant metastasis is a standard assessment for patients with locally 
advanced NSCLC, who are at high risk of developing metastatic disease. 
• Duration of freedom from intrathoracic disease progression following study enrollment. 
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o Freedom from intrathoracic disease progression is a standard assessment for 
patients with locally advanced NSCLC, who are at high risk of developing 
local/regional disease progression. 
• Survival duration following study enrollment. 
o Overall survival is a standard assessment of clinical benefit of treatments for 
NSCLC. 
• Disease progression during induction pembrolizumab for patients with PD-L1 expression 
≥ 50%. 
o As induction pembrolizumab prior to radiotherapy for locally advanced NSCLC is 
a novel treatment approach, it will be important to characterize the rate of disease 
progression during induction therapy. 
4.6.2.2 Safety Endpoints 
• Severe (grade ≥ 3) adverse events, scored using CTCAE v 4.03. 
o It will be important to characterize the toxicity profile of sequential 
pembrolizumab and radiotherapy for locally advanced NSCLC, as this is a novel 
treatment approach. 
• Pneumonitis (grade ≥ 2). 
o It will be important to characterize the rate of pneumonitis, which may occur 
because of radiotherapy or immunotherapy, for study subjects. 
• Patient-reported treatment-related toxicity, scored using PRO-CTCAE. 
o See Section 4.5 
• Unplanned hospitalization. 
o Many patients treated with radiotherapy or chemoradiotherapy for locally 
advanced NSCLC are hospitalized due to treatment toxicity. It will be important 
to characterize the hospitalization rate for patients treated with pembrolizumab 
and radiotherapy for locally advanced NSCLC. 
• Daily step counts, measured using wearable fitness trackers. 
o See Section 4.4 
4.6.2.3 Translational Endpoints 
• Clearance of circulating tumor DNA following radiotherapy. 
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o Subjects in the PembroRT and ChemoRT cohorts will undergo circulating tumor 
DNA testing at study entry and several weeks after the completion of thoracic 
radiotherapy. Circulating tumor DNA clearance may be a powerful predictor of 
disease control following conventional treatment for locally advanced 
NSCLC[39]. We will test the prognostic utility of circulating tumor DNA testing 
for patients treated with pembrolizumab and radiotherapy and compare rates of 
circulating tumor DNA clearance in the two study cohorts. 
• PD-L1 TPS score and expression of alternate immune checkpoint molecules. 
o Tumor PD-L1 expression as determined by immunohistochemistry (IHC) has 
been implicated as a predictive biomarker for benefit from treatment with PD-
1/PD-L1 inhibitors[40, 41]. We will assess baseline PD-L1 expression for each 
study subject using our in-house and FDA-approved immunohistochemical assay 
on archival FFPE tumor tissue. Sections cut from FFPE blocks will be 
deparaffinized and subjected to heat-induced epitope retrieval. Slides will be 
incubated with the primary antibody (monoclonal mouse anti-PD-L1, clone 22C3) 
and visualized using the EnVision FLEX system on the Dako Autostainer Link 
48. Protein expression will be quantified as tumor proportion score (TPS), which 
is the percentage of tumor cells demonstrating PD-L1 membrane staining. 
Subjects will be assigned to the PembroRT or ChemoRT cohort based on PD-L1 
expression, using a cutoff of 50%. Within each cohort, we will explore if PD-L1 
expression level is associated with clinical outcomes, including progression-free 
survival and overall survival.  
o We will also quantify baseline tumor expression of alternate immune checkpoint 
molecules in peripheral blood as well as from fresh tumor material (if available). 
From blood samples, peripheral blood mononuclear cells will be isolated using 
Ficoll Paque density gradient centrifugation, followed by antibody labeling and 
analysis. From biopsy specimens, tumor will be dissociated without enzymatic 
digestion, followed by antibody labeling for multi-color flow cytometric analysis 
that will focus on expression of HHLA2, PD-L1, PD-L2, B7-H3, and B7x (B7-
H4/B7S1) in CD8-positive T cells and regulatory cells.  We will explore if 
expression of immune checkpoint molecules is associated with clinical outcomes. 
• Tumor mutational burden. 
o Tumor mutational burden has been identified as a predictive factor for response to 
immune checkpoint blockade in several settings[42-44]. We will utilize a 
validated commercial platform to explore tumor mutational burden as a 
prognostic factor for study subjects. 
• Markers of immune activation. 
o The PD-1 receptor and its ligands define a novel regulatory pathway with 
potential inhibitory effects on T, B, and monocyte responses[41, 45]. We will 
characterize how study therapy affects several markers of immune activation 
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throughout the treatment course. Blood collected from study subjects will be 
centrifuged to isolate peripheral blood mononuclear cells, and flow cytometry will 
be performed for immunophenotyping of mononuclear cells using several panels 
to quantify populations of B cells, CD4 and CD8 cells, natural killer cells, 
monocytes, and myeloid and plasmacytoid dendritic cells. CD4, CD8, and 
regulatory T cell populations will be tested for markers of activation, including 
expression of PD-1, ICOS, and CTLA-4. We may identify predictors of long-term 
clinical outcomes. Additionally, we may identify bottlenecks where treatment 
resistance may be overcome by the addition of additional immunomodulatory 
agents in the future. 
 
5.0 METHODOLOGY 
5.1 
Study Population 
5.1.1 Participant Inclusion Criteria 
Participants are eligible to be included in the study only if all the following criteria apply: 
1. Male/female participants who are at least 18 years of age on the day of signing informed 
consent with histologically confirmed diagnosis of non-small cell lung cancer will be 
enrolled in this study. 
2. Previously untreated, pathologically proven NSCLC with measurable disease (at least 1 
unidimensional, radiographically measurable lesion based on RECIST v1.1) and one of 
the following stages: (prior resection for early stage disease is allowed) 
a. AJCC version 8 Stage II disease, medically or technically unresectable  
b. AJCC version 8 Stage III disease 
3. Whole body PET/CT within 42 days prior to study entry demonstrating hypermetabolic 
pulmonary lesion(s) and/or thoracic lymph node(s). If PET/CT was obtained more than 
42 days prior to study entry and is not repeated, CT within 28 days prior to study entry 
demonstrating no evidence of metastatic disease is required. 
4. MRI of the brain or head CT with contrast within 42 days prior to study entry. 
5. PFTs within 42 days of study entry 
6. ECOG performance status 0-1 
7. Adequate end-organ function, based on routine clinical and laboratory workup: 
a. ANC >1,500 cells/µl, Platelets ≥ 100,000 cells/µl, Hemoglobin ≥ 9.0 g/dl 
b. Serum creatinine ≤ 1.5 x ULN or calculated creatinine clearance ≥ 50 ml/min 
c. Total bilirubin ≤ 1.5 x ULN (or direct bilirubin below the ULN), AST and ALT ≤ 
2.5 x ULN 
d. International normalized ratio (INR) (or prothrombin time (PT)) and activated 
partial thromboplastin time (aPTT) ≤ 1.5 x ULN unless participant is receiving 
anticoagulant therapy, as long as values are within the intended therapeutic range 
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e. Thyroid stimulating hormone (TSH) within normal limits. If TSH is not within 
normal limits, the participant may be eligible if T3 and free T4 are within normal 
limits. 
8. A female participant is eligible to participate if she is not pregnant (see Exclusion 
Criteria), not breastfeeding, and at least one of the following conditions applies: 
a. Not a woman of childbearing potential (WOCBP) as defined in the Appendix 
b. A WOCBP who agrees to follow the contraceptive guidance in the Appendix 
during the treatment period and for at least 120 days after the last dose of study 
treatment with pembrolizumab (pembroRT cohort) or at least 180 days after the 
last dose of chemotherapy (chemoRT cohort). 
9. A male participant must agree to use contraception during the treatment period and for at 
least 28 days after the last dose of study treatment and refrain from donating sperm 
during this period. 
10. The participant (or legally acceptable representative if applicable) provides written 
informed consent for the trial.   
 
 
5.1.2 Participant Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
1. Malignant pleural or pericardial effusion, based on clinical, imaging, or pathologic 
evaluation. 
2. Systemic therapy for lung cancer within the past year. 
3. Prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent 
directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX-40, 
CD137). 
4. Contraindication to protocol-specified radiotherapy, such as prior thoracic radiotherapy 
or active serious collagen vascular disease (e.g. scleroderma). 
5. Is currently participating in or has participated in a study of an investigational agent or 
has used an investigational device within 4 weeks prior to the first dose of study 
treatment. 
6. Active malignancy other than lung cancer that requires active treatment other than 
hormonal therapy or is deemed by the treating physicians to be likely to affect the 
subject’s survival duration.  
7. A history of (non-infectious) pneumonitis that required steroids or current pneumonitis.  
8. Active infection requiring antimicrobial therapy.  
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9. Has a known history of active TB (Bacillus Tuberculosis).  
10. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the study, interfere with the subject’s participation for 
the full duration of the study, or is not in the best interest of the subject to participate, in 
the opinion of the treating investigator.  
11. Has known psychiatric or substance abuse disorders that would interfere with cooperation 
with the requirements of the trial. 
12. Pregnancy, assessed in WOCBP (defined in Appendix) with urine pregnancy test within 
72 hours prior to study treatment allocation. If urine pregnancy test is positive or cannot 
be confirmed as negative, a serum pregnancy test is required. If more than 72 hours 
elapse between screening pregnancy test and the first dose of study treatment, another 
pregnancy test (urine or serum) must be performed and must be negative. 
13. For patients receiving pembrolizumab/radiotherapy 
a. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its 
excipients. 
b. Active autoimmune disease other than vitiligo, thyroid disorders, Sjogren’s 
disease, and well-controlled rheumatoid arthritis not requiring disease-modifying 
therapy. 
c. Has received a live vaccine within 30 days prior to the first dose of study drug.  
Examples of live vaccines include, but are not limited to, the following:  measles, 
mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus 
Calmette–Guérin (BCG), and typhoid vaccine.  Seasonal influenza vaccines for 
injection are generally killed virus vaccines and are allowed; however, intranasal 
influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not 
allowed. 
d. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid 
therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other 
form of immunosuppressive therapy within 7 days prior to the first dose of study 
drug. 
 
5.1.3 Lifestyle Restrictions 
5.1.3.1 Meals and Dietary Restrictions 
Participants should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea or vomiting. 
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5.1.3.2 Contraception 
Pembrolizumab may have adverse effects on a fetus in utero.  Refer to Appendix for approved 
methods of contraception. 
For this study, male participants will be considered to be of non-reproductive potential if they 
have azoospermia (whether due to having had a vasectomy or due to an underlying medical 
condition).   
5.1.4 Pregnancy 
If a participant inadvertently becomes pregnant while on treatment with pembrolizumab, the 
participant will be immediately discontinued from study treatment.  The site will contact the 
participant at least monthly and document the participant’s status until the pregnancy has been 
completed or terminated.  The outcome of the pregnancy will be reported to Merck within 2 
working days 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 Merck.  If a male participant 
impregnates his female partner, the study personnel at the site must be informed immediately and 
the pregnancy must be reported to Merck and followed as described in Section 7.2.2. 
5.1.5 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, participants who are breast-feeding are not eligible for enrollment. 
5.2 
Study Treatments and Activity Monitoring 
5.2.1 Pembrolizumab (PembroRT Cohort Only) 
5.2.1.1 Pembrolizumab Timing 
The timing of pembrolizumab infusions is summarized in the Study Flow Chart. Trial treatment 
may be administered up to 3 days before or after the scheduled treatment due to administrative 
reasons. Trial treatments should be administered on an outpatient basis. 
Pembrolizumab 200 mg will be administered as a 30-minute IV infusion every 3 weeks.  Sites 
should make every effort to target infusion timing to be as close to 30 minutes as possible.  
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. 
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5.2.1.2 Pembrolizumab Dose Modification and Management of Immune-Related Adverse 
Events 
AEs associated with pembrolizumab exposure may represent an immunologic etiology. These 
immune-related AEs (irAEs) may occur shortly after the first dose or several months after the 
last dose of pembrolizumab treatment and may affect more than on body system simultaneously. 
Therefore, early recognition and initiation of treatment is critical to reduce complications.  Based 
on existing clinical study data, most irAEs were reversible and could be managed with 
interruptions of pembrolizumab, administration of corticosteroids and/or other supportive care. 
For suspected irAEs, ensure adequate evaluation to confirm etiology or exclude other causes. 
Additional procedures or tests such as bronchoscopy, endoscopy, skin biopsy may be included as 
part of the evaluation. Based on the severity of irAEs, withhold or permanently discontinue 
pembrolizumab and administer corticosteroids. Dose modification and toxicity management 
guidelines for irAEs associated with pembrolizumab are provided in Table 3. 
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Table 3 Dose modification and toxicity management guidelines for immune-related AEs associated with pembrolizumab  
General instructions: 
1. Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks. 
2. For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 or 0 and 
corticosteroid has been tapered. Pembrolizumab should be permanently discontinued if AE does not resolve within 12 weeks of last dose or 
corticosteroids cannot be reduced to ≤10 mg prednisone or equivalent per day within 12 weeks.  
3. For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive treatment 
should be initiated if irAEs cannot be controlled by corticosteroids. 
 
Immune-related 
AEs 
Toxicity grade or 
conditions 
(CTCAEv4.0) 
Action taken to 
pembrolizumab 
irAE management with 
corticosteroid and/or other 
therapies  
Monitor and follow-up  
Pneumonitis  
Grade 2 
Withhold  
• Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper 
 
• 
Monitor participants for signs and 
symptoms of pneumonitis 
• 
Evaluate participants with suspected 
pneumonitis with radiographic imaging and 
initiate corticosteroid treatment 
• 
Add prophylactic antibiotics for 
opportunistic infections 
Grade 3 or 4, or 
recurrent Grade 2 
Permanently 
discontinue 
Diarrhea / Colitis  Grade 2 or 3 
Withhold 
• Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper 
 
• 
Monitor participants for signs and symptoms 
of enterocolitis (ie, diarrhea, abdominal 
pain, blood or mucus in stool with or 
without fever) and of bowel perforation 
(ie, peritoneal signs and ileus). 
• 
Participants with ≥ Grade 2 diarrhea 
suspecting colitis should consider GI 
consultation and performing endoscopy to 
rule out colitis.  
• 
Participants with 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. 
Grade 4 
Permanently 
discontinue 
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AST / ALT 
elevation or 
Increased 
bilirubin 
Grade 2 
Withhold 
• Administer corticosteroids (initial 
dose of 0.5- 1 mg/kg prednisone or 
equivalent) followed by taper 
• 
Monitor with liver function tests (consider 
weekly or more frequently until liver 
enzyme value returned to baseline or is 
stable 
Grade 3 or 4  
Permanently 
discontinue 
• Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper 
Type 1 diabetes 
mellitus (T1DM) 
or 
Hyperglycemia 
 
Newly onset 
T1DM or  
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of β-cell 
failure 
Withhold 
• Initiate insulin replacement 
therapy for participants with 
T1DM  
• Administer anti-hyperglycemic in 
participants with hyperglycemia  
 
• 
Monitor participants for hyperglycemia or 
other signs and symptoms of diabetes. 
Hypophysitis 
Grade 2 
Withhold 
• Administer corticosteroids and 
initiate hormonal replacements as 
clinically indicated.   
 
• 
Monitor for signs and symptoms of 
hypophysitis (including hypopituitarism and 
adrenal insufficiency)  
Grade 3 or 4  
Withhold or 
permanently 
discontinue1  
Hyperthyroidism  
Grade 2 
Continue  
• Treat with non-selective beta-
blockers (eg, propranolol) or 
thionamides as appropriate  
• 
Monitor for signs and symptoms of thyroid 
disorders.  
 
Grade 3 or 4  
Withhold or  
permanently 
discontinue1 
Hypothyroidism 
Grade 2-4 
Continue  
• Initiate thyroid replacement 
hormones (eg, levothyroxine or 
liothyroinine) per standard of care 
• 
Monitor for signs and symptoms of thyroid 
disorders.  
 
Nephritis and 
Renal 
dysfunction 
Grade 2 
Withhold  
• Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by taper. 
• 
Monitor changes of renal function 
 
Grade 3 or 4  
Permanently 
discontinue 
Myocarditis 
Grade 1 or 2 
Withhold 
• Based on severity of AE 
administer corticosteroids 
• 
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes 
 
Grade 3 or 4 
Permanently 
discontinue 
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All other 
immune-related 
AEs 
Intolerable/ 
persistent Grade 2 
Withhold 
• Based on type and severity of AE 
administer corticosteroids  
• 
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes 
 
Grade 3 
Withhold or 
discontinue based 
on the type of 
event.  Events that 
require 
discontinuation 
include and not 
limited to:  
Gullain-Barre 
Syndrome, 
encephalitis 
Grade 4 or 
recurrent Grade 3  
Permanently 
discontinue 
1. Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.   
NOTE:  
For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, pembrolizumab may be resumed 
when AE resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or achieved metabolic control (in case of T1DM).   
 
 
 
 
 
 
 
 
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Dose modification and toxicity management of infusion-reactions related to pembrolizumab 
Pembrolizumab may cause severe or life-threatening infusion-reactions including severe hypersensitivity or anaphylaxis. Signs and 
symptoms usually develop during or shortly after drug infusion and generally resolve completely within 24 hours of completion of 
infusion. Dose modification and toxicity management guidelines on pembrolizumab associated infusion reaction are provided in Table 
4.  
 
Table 4. Pembrolizumab Infusion Reaction Dose modification and 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 
participant is deemed medically stable in the opinion of the investigator. 
None 
Grade 2 
Requires therapy or infusion 
interruption but responds 
promptly to symptomatic 
treatment (e.g., antihistamines, 
NSAIDs, narcotics, IV fluids); 
prophylactic medications 
indicated for ≤24 hours 
Stop Infusion. 
Additional appropriate medical therapy may include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDs 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as medically indicated until the 
participant is deemed medically stable in the opinion of the investigator. 
If symptoms resolve within 1 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 participant should be premedicated for the next scheduled dose. 
Participants who develop Grade 2 toxicity despite adequate 
premedication should be permanently discontinued from further 
study drug treatment 
Participant may be premedicated 1.5h 
(± 30 minutes) prior to infusion of 
_____ with: 
Diphenhydramine 50 mg po (or 
equivalent dose of antihistamine). 
Acetaminophen 500-1000 mg po (or 
equivalent dose of analgesic). 
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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: 
Epinephrine** 
IV fluids 
Antihistamines 
NSAIDs 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Increase monitoring of vital signs as medically indicated until the 
participant is deemed medically stable in the opinion of the investigator. 
Hospitalization may be indicated. 
**In cases of anaphylaxis, epinephrine should be used immediately. 
Participant is permanently discontinued from further study drug 
treatment. 
No subsequent dosing 
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period of drug administration. 
For further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE) at http://ctep.cancer.gov 
 
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Other allowed dose interruption for pembrolizumab  
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as 
medical / surgical events or logistical reasons not related to study therapy. Participants should 
be placed back on study therapy within 3 weeks of the scheduled interruption, unless 
otherwise discussed with the Sponsor. The reason for interruption should be documented in 
the patient's study record. 
 
5.2.2 Chemotherapy (ChemoRT Cohort Only) 
Chemotherapy will be administered weekly during radiotherapy. This concurrent 
chemotherapy will consist of carboplatin (AUC 2, IV) and paclitaxel (50 mg/m2, IV). 
Standard institutional procedures will be used for chemotherapy formulation, calculation of 
AUC, and chemotherapy administration. Treating physicians may implement dose reductions 
or withhold chemotherapy in the event of adverse events or laboratory abnormalities, per 
usual care. 
Adjuvant systemic therapy may be administered for patients on the ChemoRT cohort, at the 
discretion of the treating physicians. In some cases, this may consist of adjuvant systemic 
doses of chemotherapy (e.g.: carboplatin AUC 6 and paclitaxel 200 mg/m2). Based on 
emerging data[10], patients on the ChemoRT cohort may be treated with adjuvant 
immunotherapy. 
 
5.2.3 Radiotherapy 
The timing of radiotherapy with respect to systemic therapy in the two study cohorts is 
summarized in the Study Flow Chart. 
Immobilization, Simulation, and Localization 
Patients will be immobilized in a stable position capable of allowing accurate daily 
reproducibility of the target position. A variety of immobilization systems may be used, 
including stereotactic frames that surround the patient on three sides and large rigid pillows 
(conforming to patients’ external contours) with reference to the stereotactic coordinate 
system.  Patient immobilization must be reliable enough to ensure that the gross tumor 
volume (GTV) does not deviate beyond the confines of the planning treatment volume (PTV) 
with any significant probability (i.e., < 5%). 
Special considerations will be made to account for the effect of internal organ motion (e.g., 
breathing) on target positioning and reproducibility. Acceptable maneuvers include reliable 
abdominal compression, accelerator beam gating with the respiratory cycle, active breath-
holding techniques, and use of 4D simulation CT to generate internal target volumes (ITVs).  
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Internal organ inhibition maneuvers must be reliable enough to ensure that the GTV does not 
deviate beyond the confines of the PTV with any significant probability (i.e., < 5%). 
Computed tomography will be the primary image platform for targeting and treatment 
planning. Axial acquisitions with gantry 0 degrees and spacing ≤ 3.0 mm between scans in 
the region of the tumor are required. Images will be transferred to the treatment planning 
system for radiotherapy planning. 
Isocenter or reference point port localization images (anterior/posterior and lateral) should be 
obtained immediately before each treatment to ensure proper alignment of the geometric 
center (isocenter) of the simulated fields.  Verification CT scans and portal films following 
each treatment may be taken at the discretion of the treating physician but are not required. 
Target Volumes and Treatment Planning 
Target lesions will be drawn on simulation CT imaging, using lung or mediastinal window 
levels as appropriate.  PET imaging should be registered to simulation CT scans to aid with 
localization of hypermetabolic lesions. If 4D CT simulation is used, gross tumor volumes 
(GTVs) should be generated on each CT phase that will be used for treatment (typically 4/10 
phases if respiratory gating is employed or 10/10 phases if the patient will be treated while 
breathing freely).  GTVs will be combined to form internal target volumes (ITVs). 
For patients treated with pembrolizumab and radiotherapy, the low-risk GTV (GTV_4800) 
shall include the pulmonary tumor(s) as well as any suspicious lymph nodes (based on 
appearance, PET findings, size ≥ 1cm in short axis, or pathologic data).  A high-risk gross 
tumor volume (GTV_5500), will also be defined and will include only lesions with MTV > 
20 cc on PET obtained after induction pembrolizumab and before radiotherapy.  MTV 
calculations will be performed on PET imaging using a semiautomatic gradient-based 
contouring algorithm (“PET Edge”, MIMvista Corp, Cleveland, OH) or using a thresholding 
tool to encompass all voxels with SUV > 40% of the maximum SUV[46].  GTV_5500 will 
be contained within GTV_4800. Each GTV (or ITV) will be expanded by 7-10 mm to form a 
CTV (CTV_4800 and CTV_5500).  CTVs may be trimmed to exclude anatomic boundaries 
to microscopic tumor spread.  CTV_5500 will contained within CTV_4800. Each CTV will 
be expanded to form a PTV. PTV expansions will be 5 mm in all directions if respiratory 
motion has been accounted for (e.g.: with beam gating, breath hold, or use of 4D-CT to form 
internal target volumes).  Otherwise, PTV expansions will be 5 mm radially and 
approximately 10 mm in the superior and inferior directions.  PTV_5500 will be contained 
within PTV_4800. Adaptive radiotherapy (adjustment of target volumes during the course of 
radiotherapy) is not allowed in this protocol, unless difficulties with daily patient setup 
require repeating the CT simulation procedure. 
Subjects receiving standard concurrent chemoradiotherapy may be treated with a standard 
treatment planning approach, where the entire target volume is treated with a uniform 
prescription dose, or with a dose-painting technique. The prescription dose must be between 
48 Gy and 66.6 Gy, delivered over a course of 20-37 fractions. 
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Megavoltage equipment is required with effective photon energies of 6-18 MV. Use of IMRT 
or volumetric modulated arc therapy (VMAT) should be used for dose-painting in this 
protocol. If these treatment techniques are not available for some reason (e.g.: a subject’s 
insurance company refuses to authorize IMRT), treatment may be delivered using a 
sequential boost technique (2.75 Gy x 17 to the low-risk PTV followed by 2.75 Gy x 3 to the 
high-risk PTV). All treatment planning will be performed using tissue heterogeneity 
corrections. 
Target Coverage 
The goal is to deliver conformal treatment that minimizes normal tissue irradiation.  As a 
guideline, a conformity index (ratio of the volume of the highest prescription isodose surface 
to the corresponding PTV) of < 1.5 is desirable.  The prescription isodose surface should 
encompass at least 95% of each PTV.  The minimum PTV dose (to 0.3 cm3) must not fall 
below 90% of the prescription dose.  The maximum dose must not exceed a value that is 
115% of the highest prescribed dose, and the hot spot must be located within the PTV.  
Critical Structures 
Lung, spinal cord, esophagus, brachial plexus, and heart/pericardium should be contoured 
based on atlases published on the RTOG web site. Dosimetric constraints for organs at risk 
are listed below.  These have been adapted from recent cooperative group chemoradiotherapy 
protocols. 
Structure 
Metric 
No Deviation 
Deviation 
Acceptable 
Deviation 
Unacceptable 
Lungs-CTV 
Max Dose 
Mean Dose 
Volume>20 Gy 
Volume>5 Gy 
≤110% Rx 
Dose 
≤20 Gy 
≤35% 
≤50% 
≤113% Rx 
Dose 
≤21 Gy 
≤36% 
≤55% 
>113% Rx 
Dose 
>21 Gy 
>36% 
>55% 
Heart & 
Pericardium 
Max Dose 
Mean Dose 
Volume>40 Gy 
Volume>60 Gy 
≤65 Gy 
≤30 Gy 
≤80% 
≤30% 
≤67 Gy 
≤31 Gy 
≤85% 
≤33% 
>67 Gy 
>31 Gy 
>85% 
>33% 
Esophagus 
Mean Dose 
≤34 Gy 
≤35 Gy 
>35 Gy 
Spinal Cord 
Max Dose (>25 fractions) 
Max Dose (20-25 fractions) 
≤50 Gy 
≤44 Gy 
≤52 Gy 
≤46 Gy 
>52 Gy 
>46 Gy 
Brachial Plexus 
Max Dose (>25 fractions) 
Max Dose (20-25 fractions) 
≤63 Gy 
≤55 Gy 
≤65 Gy 
≤58 Gy 
>65 Gy 
>58 Gy 
 
Radiotherapy Adverse Events 
Reversible or permanent alopecia, bone marrow toxicity, skin pigmentation, and esophagitis 
are expected side effects of radiation therapy.  Radiation induced myocarditis or transverse 
myelitis rarely when the pericardium and spinal cord receive doses lower than 50 Gy. 
Radiographic evidence of radiation change and subsequent fibrosis of the lung may occur, 
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typically within lung volumes receiving≥ 20 Gy and within the first six months after 
treatment. It is important to spare as much normal lung as possible to avoid symptomatic 
lung injury.   Esophageal complaints are common with combined modality therapy. 
Esophagitis does not constitute a reason to interrupt or delay radiotherapy or systemic 
therapy, provided oral intake is sufficient to maintain hydration.  Patients should be advised 
to avoid alcoholic, acidic, or spicy foods or beverages.  Viscous Xylocaine, Carafate, or other 
medications should be used for symptomatic relief.  Occasionally, narcotics may be required.  
It is not necessary to biopsy acute esophagitis in the first 2 weeks of combined therapy since 
it is rarely due to underlying viral or fungal disease. Acute esophagitis may persist for 4-6 
weeks.  Esophagitis should be graded using CTCAE v.4.0.  If high grade esophagitis occurs, 
and a treatment interruption is being considered, every effort should be made to minimize the 
treatment break duration. Acute esophageal toxicity, which typically manifests as dysphagia, 
odynophagia, and reflux symptoms, should be pharmacologically managed with the 
following approach: 
 
5.2.4 Physical Activity Monitoring 
Some study sites may elect not to offer activity monitoring to study subjects. Additionally, 
some subjects may choose not to participate in the optional activity monitoring component of 
the protocol. The remainder of this section applies to subjects who consent to participate in 
physical activity monitoring. 
A commercially-available fitness tracker (e.g., Garmin Vivofit) will be placed on the 
patient’s wrist at the time of study registration.  The device will be activated and synced with 
a computer or mobile device, and the device will be set to show the time.  Patients will be 
shown how to remove the device (similar to removing a wristwatch) in case they wish to 
remove it temporarily or permanently.  However, patients will be asked to keep the device on 
continuously throughout the first six months of the study. Patients may continue to wear the 
device for an additional six months if they wish to do so. The device is waterproof, so 
patients will not need to remove it when bathing. The device has a battery life of over one 
year, so patients will not need to charge it.  Data will be synced every time the patient enters 
one of the Medical Oncology or Radiation Oncology clinics using a wireless access client or 
by a member of the study team. 
 
   
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5.3 
Treatment Allocation 
Subjects will be stratified based on baseline PD-L1 TPS score. Subjects whose score is less 
than 50% will be treated with chemotherapy and radiotherapy (ChemoRT Cohort). Subjects 
whose score is 50% or higher will be treated with pembrolizumab and radiotherapy 
(PembroRT Cohort). 
5.4 
Concomitant Medications/Vaccinations (allowed & prohibited) 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for one of these or other medications 
or vaccinations specifically prohibited during the trial, discontinuation from trial therapy or 
vaccination may be required.  The final decision on any supportive therapy or vaccination 
rests with the investigator and/or the participant’s primary physician.  
5.4.1 Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a participant’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care.  All concomitant medication will be recorded on the case report form (CRF) 
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications 
and fluids.  If changes occur during the trial period, documentation of drug dosage, 
frequency, route, and date may also be included on the CRF. 
All concomitant medications received within 28 days before the first dose of trial treatment 
and 30 days after the last dose of trial treatment should be recorded.  Concomitant 
medications administered after 30 days after the last dose of trial treatment should be 
recorded for SAEs and ECIs as defined in Section 7.2. 
5.4.2 Prohibited Concomitant Medications 
Participants are prohibited from receiving the following therapies during the Screening and 
Treatment Phase (including retreatment for post-complete response relapse) of this trial: 
• Immunotherapy not specified in this protocol 
• Chemotherapy not specified in this protocol 
• Investigational agents other than pembrolizumab 
 
• (PembroRT Cohort only) Live vaccines within 30 days prior to the first dose of study 
treatment and while participating in the study.  Examples of live vaccines include, but 
are not limited to, the following: measles, mumps, rubella, varicella/zoster, yellow 
fever, rabies, BCG, and typhoid vaccine. Seasonal influenza vaccines for injection are 
generally killed virus vaccines and are allowed; however, intranasal influenza 
vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed.  
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• Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
event of clinical interest of suspected immunologic etiology.  The use of physiologic 
doses of corticosteroids may be approved after consultation with the Sponsor. 
Participants who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the study.  All 
treatments that the Investigator considers necessary for a participant’s welfare may be 
administered at the discretion of the Investigator in keeping with the community standards of 
medical care.   
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing study.  If there is a clinical indication for any medication or vaccination 
specifically prohibited during the study, discontinuation from study therapy or vaccination 
may be required.  The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the participant's primary physician.  However, the decision to continue 
the participant on study treatment requires the agreement of the investigator, the Sponsor and 
the participant. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
5.4.3 Rescue Medications & Supportive Care 
Participants should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of AEs with 
potential immunologic etiology are outlined along with the dose modification guidelines in 
Section 5.2.2, [Table 3].  Where appropriate, these guidelines include the use of oral or IV 
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 of the event, it is determined not to be related to pembrolizumab, 
the Investigator does not need to follow the treatment guidance.  Refer to [Table 3] in Section 
5.2.2 for guidelines regarding dose modification and supportive care.  
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event.  
5.5 
Participant Withdrawal/Discontinuation Criteria 
Participants may discontinue study treatment at any time for any reason or be dropped from 
the study treatment at the discretion of the investigator should any untoward effect occur.  In 
addition, a participant may be discontinued from study treatment by the investigator or the 
Sponsor if study treatment is inappropriate, the trial plan is violated, or for administrative 
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and/or other safety reasons.  Specific details regarding procedures to be performed at study 
treatment discontinuation are provided in Section 7.1.4 – Other Procedures. 
A participant must be discontinued from study treatment but continue to be monitored in the 
study for any of the following reasons: 
• The participant or participant’s legally acceptable representative requests to 
discontinue study treatment 
• Confirmed radiographic disease progression outlined in Section 7.1.2.6 
• Unacceptable adverse experiences as described in Section 5.2.2. 
• The participant has a medical condition or personal circumstance which, in the 
opinion of the investigator and/or sponsor, placed the participant at unnecessary risk 
from continued administration of study treatment. 
• The participant has a confirmed positive serum pregnancy test 
• Recurrent Grade 2 pneumonitis 
• The participant is lost to follow-up 
• Completion of 15 treatments (approximately 1 year) with pembrolizumab 
Note: The number of treatments is calculated starting with the first dose.  Participants 
who stop the combination or pembrolizumab after receiving 15 doses may be eligible for 
retreatment if they progress after stopping study treatment. Participants may be retreated 
in the Second Course Phase (Retreatment) for up to an additional 17 cycles 
(approximately 1 year). 
• Administrative reasons 
5.6 
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 participants 
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 participant treatment can be made. 
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5.7 
Study Registration and Data Management 
Most study subjects will be enrolled by the study sponsors at Montefiore Medical Center. 
This study will also be activated at three additional subsites (Rogel Cancer Center- 
University of Michigan, New York University Langone Health and Henry Ford Cancer 
Institution). The following procedures will be performed for registration of each study 
subject: 
• (subsites only) Notify sponsor when a patient is in screening. If an ICF is signed, a 
copy of the ICF will be sent to the sponsor. 
• (all sites) Complete screening procedures and generate a signed eligibility checklist 
• (subsites only) Send a copy of the signed eligibility checklist to the sponsor. 
• (sponsor only) Enroll study subject with CPDMU and in Velos. All subjects will be 
registered through the Clinical Trials Office at Montefiore Medical Center 
(Telephone: 718-379-6861, Monday through Friday 9:00am – 5:00pm Eastern 
Standard Time). The “On Study Form” and the completed Informed Consent Form 
will be emailed to the clinical trials office at Montefiore Medical Center, 
(cpdmuregistration@montefiore.org) at the time of registration and prior to patient 
treatment initiation. At the time of registration, all eligibility criteria must be checked. 
A signed eligibility checklist will be stored for each subject. 
• (all sites) Complete local study subject registration processes. 
 
Study data will be warehoused by the lead investigators at Montefiore Medical Center and 
the Albert Einstein College of Medicine. Data for study subjects who are treated at other 
institutions will be recorded on electronic case report forms (CRF) in a deidentified manner 
and transmitted to the Montefiore/Einstein investigators. Data for subjects from institutions 
other than Montefiore will be recorded in Velos in a de-identified manner following our 
institutional standard operating procedure, where subjects are given a de-identified medical 
record number (eg: “NYU-01-001”) and an approximate date of birth is entered. Local 
investigators will be responsible for maintaining a log linking study subject identification 
numbers to patient identities. Local investigators must complete local subject registration 
processes and maintain accurate documentation (source data) that supports the information 
entered in the CRF. 
For the purpose of data collection, all untoward events that occur after informed consent 
through 90 days after the last dose of study drug must be recorded on the subject’s CRF by 
the investigational site. This requirement includes AEs from unscheduled as well as 
scheduled visits. The investigator is responsible for ensuring that all AEs and SAEs that are 
observed or reported during the study are recorded on appropriate CRFs and reported in 
accordance with protocol instructions. The study period during which all AEs must be 
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reported begins after informed consent is obtained and study treatment is initiated and ends 
90 days after last administration of study treatment, or at the time of initiation of another 
anti-cancer therapy, whichever occurs first. AEs and SAEs that are observed or reported prior 
to initiation of study treatment should be recorded on appropriate CRFs if they are associated 
with protocol-mandated interventions (e.g., invasive procedures such as biopsies). 
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6.0 TRIAL FLOW CHART 
 
 
() - Optional 
^ - May be replaced by PET/CT 
* - Every 3 weeks, starting 4-6 weeks after completion of radiotherapy 
+ - May be performed one week before or after the protocol-specified timepoint 
 
 
 
 
 
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7.0 TRIAL PROCEDURES 
7.1 
Trial Procedures 
The Trial Flow Chart summarizes selected 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 participant 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 participant.  In these cases, 
such evaluations/testing will be performed in accordance with those regulations. 
7.1.1 Administrative Procedures 
7.1.1.1 Informed Consent 
The Investigator must obtain documented consent from each potential participant prior to 
participating in a clinical trial. 
Consent must be documented by the participant’s dated signature or by the participant’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 participant before 
participation in the trial. 
The initial informed consent form, any subsequent revised written informed consent form 
and any written information provided to the participant must receive the IRB/ERC’s 
approval/favorable opinion in advance of use.  The participant or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the participant’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 participant’s dated signature 
or by the participant’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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7.1.1.2 Inclusion/Exclusion Criteria 
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the participant qualifies for the trial.  
7.1.1.3 Medical History 
A medical history will be obtained by the investigator or qualified designee.  Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that 
are considered to be clinically significant by the Investigator.  Details regarding the disease 
for which the participant has enrolled in this study will be recorded separately and not listed 
as medical history.   
7.1.1.4 Prior and Concomitant Medications Review 
7.1.1.4.1 Prior Medications 
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the participant 
within 28 days before starting the trial.  Treatment for the disease for which the participant 
has enrolled in this study will be recorded separately and not listed as a prior medication.  
7.1.1.4.2 Concomitant Medications 
The investigator or qualified designee will record medication, if any, taken by the participant 
during the trial.  All medications related to reportable SAEs and ECIs should be recorded as 
defined in Section 7.2. 
7.1.1.5 Disease Details and Treatments 
7.1.1.5.1 Disease Details 
The investigator or qualified designee will obtain prior and current details regarding disease 
status.  
7.1.1.5.2 Prior Treatment Details 
The investigator or qualified designee will review all prior cancer treatments including 
systemic treatments, radiation and surgeries. 
7.1.1.5.3 Subsequent Anti-Cancer Therapy Status 
The investigator or qualified designee will review all new anti-neoplastic therapy initiated 
after the last dose of trial treatment.  If a participant 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 
participant will move into survival follow-up.  
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7.1.2 Clinical Procedures/Assessments 
7.1.2.1 Adverse Event (AE) Monitoring 
The investigator or qualified designee will assess each participant 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 Appendix).  Toxicities will 
be characterized in terms regarding seriousness, causality, toxicity grading, and action taken 
with regard to trial treatment.  
Please refer to section 7.2 for detailed information regarding the assessment and recording of 
AEs.   
7.1.2.2 Full Physical Exam 
The investigator or qualified designee will perform a complete physical exam during the 
screening period.  Clinically significant abnormal findings should be recorded as medical 
history.  A full physical exam should be performed during screening,  
7.1.2.3 Directed Physical Exam 
For cycles that do not require a full physical exam per the Trial Flow Chart, the investigator 
or qualified designee will perform a directed physical exam as clinically indicated prior to 
trial treatment administration.   
7.1.2.4 Vital Signs 
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of trial treatment and at treatment discontinuation as specified in 
the Trial Flow Chart.  Vital signs should include temperature, pulse, respiratory rate, weight 
and blood pressure.  Height will be measured at screening only. 
7.1.2.5 Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The investigator or qualified designee will assess ECOG status (see Appendix) at each clinic 
visit, as specified in the Trial Flow Chart.   
7.1.2.6 Tumor Imaging and Assessment of Disease 
Except where PET/CT is indicated based on the Study Flow Chart, computed tomography 
(CT) is the preferred tumor imaging.  For the abdomen and pelvis, contrast-enhanced 
magnetic resonance imaging (MRI) may be used when CT with iodinated contrast is 
contraindicated, or when local practice mandates it.  MRI is the strongly preferred modality 
for imaging the brain.  The same imaging technique regarding modality, ideally the same 
scanner, and the use of contrast should be used in a participant throughout the study to 
optimize the reproducibility of the assessment of existing and new tumor burden and improve 
the accuracy of the assessment of response or progression based on imaging. 
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Brain imaging is required for all participants at screening.  MRI is preferred; however, CT 
imaging will be acceptable, if MRI is medically contraindicated. 
Participant eligibility will be determined using local assessment (Investigator assessment) 
based on RECIST 1.1.  In addition, images (including via other modalities) that are obtained 
at an unscheduled time point to determine disease progression, as well as imaging obtained 
for other reasons, but which demonstrate radiologic progression, should also be used to 
determine progression. 
When the Investigator identifies radiographic progression per RECIST 1.1, efforts should be 
made to verify radiologic PD. Treatment should continue until PD has been verified.  
Regardless of whether PD is verified, if the Investigator considers the participant has 
progressed, but elects to implement iRECIST, the Investigator will assess for confirmation of 
progression by iRECIST at subsequent time points.   
7.1.2.6.1 Initial Tumor Imaging 
Initial tumor imaging at Screening must be performed within 42 days prior to the date of 
allocation.  The site study team must review screening images to confirm the participant has 
measurable disease per RECIST 1.1.  
The screening images must be submitted to the central imaging vendor for retrospective 
review. 
Tumor imaging performed as part of routine clinical management is acceptable for use as 
screening tumor imaging if they are of diagnostic quality and performed within 42 days prior 
to the date of allocation and can be assessed by the central imaging vendor.  
Brain imaging is required to rule out radiographically detectable untreated brain metastases.  
Magnetic resonance imaging is preferred; however, CT imaging will be acceptable, if MRI is 
medically contraindicated or CT is mandated by local practice. 
7.1.2.6.1 Tumor Imaging During the Study 
On-study imaging assessments should be performed at the timepoints (±7 days) detailed in 
the Trial Flow Chart for each study cohort. Imaging timing should follow calendar days and 
should not be adjusted for delays in cycle starts. Imaging should continue to be performed 
until disease progression is identified by the Investigator. Once disease progression is 
confirmed, imaging should be performed as needed for routine clinical care and does not 
need to adhere to the Trial Flow Chart. 
Per iRECIST (Section 9.2.1.6), disease progression should be confirmed by the site 4 to 
8 weeks after first radiologic evidence of PD in clinically stable participants.  Participants 
who have unconfirmed disease progression may continue on treatment at the discretion of the 
Investigator until progression is confirmed by the site provided they have met the conditions 
detailed in Section 9.2.1.6.  Participants who receive confirmatory imaging do not need to 
undergo the next scheduled tumor imaging if it is less than 4 weeks later; tumor imaging may 
resume at the subsequent scheduled imaging time point, if clinically stable.  Participants who 
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have confirmed disease progression by iRECIST, as assessed by the site, will discontinue 
study treatment.  Exceptions are detailed in Section 9.2.1.6. 
7.1.2.6.2 End of Treatment and Follow-up Tumor Imaging 
In participants who discontinue study treatment, tumor imaging should be performed at the 
time of treatment discontinuation (±4-week window).  If previous imaging was obtained 
within 4 weeks prior to the date of discontinuation, then imaging at treatment discontinuation 
is not mandatory.  In participants who discontinue study treatment due to documented disease 
progression and the Investigator elects not to implement iRECIST, this is the final required 
tumor imaging. 
In participants who discontinue study treatment without documented disease progression, 
every effort should be made to continue monitoring their disease status by tumor imaging 
using the same imaging schedule used while on treatment. 
7.1.2.6.3 RECIST 1.1 Assessment of Disease 
RECIST 1.1 will be used as the primary measure for assessment of tumor response, date of 
disease progression, and as a basis for all protocol guidelines related to disease status (e.g., 
discontinuation of study treatment).  Although RECIST 1.1 references a maximum of 5 target 
lesions in total and 2 per organ, the Sponsor allows a maximum of 10 target lesions in total 
and 5 per organ, if clinically relevant to enable a broader sampling of tumor burden.  
7.1.2.6.4 iRECIST Assessment of Disease 
iRECIST is based on RECIST 1.1, but adapted to account for the unique tumor response seen 
with immunotherapeutic drugs.  When clinically stable, participants should not be 
discontinued until progression is confirmed by the Investigator, working with local 
radiology, according to the rules below.  This allowance to continue treatment despite initial 
radiologic PD takes into account the observation that some participants can have a transient 
tumor flare in the first few months after the start of immunotherapy, and then experience 
subsequent disease response. 
A description of the adaptations and iRECIST process is provided in the Appendix, with 
additional detail in the iRECIST publication[47].  iRECIST will be used by the Investigator 
to assess tumor response and progression, and make treatment decisions.   
 
 
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Imaging and Treatment after First Radiologic Evidence of Progressive Disease 
 
Clinically Stable 
Clinically Unstable 
Imaging 
Treatment 
Imaging 
Treatment 
First radiologic evidence of PD 
by RECIST 1.1  
Repeat imaging at 4 to 
8 weeks to confirm PD. 
May continue study treatment at the 
Investigator’s discretion while 
awaiting confirmatory tumor 
imaging by site by iRECIST. 
Repeat imaging at 4 to 
8 weeks to confirm PD per 
Investigator’s discretion only. 
Discontinue treatment 
Repeat tumor imaging 
confirms PD (iCPD) by 
iRECIST per Investigator 
assessment 
No additional imaging 
required. 
Discontinue treatment (exception is 
possible upon consultation with 
Sponsor). 
No additional imaging 
required. 
Not applicable 
Repeat tumor imaging shows 
iUPD by iRECIST per 
Investigator assessment 
Repeat imaging at 4 to 
8 weeks to confirm PD.  May 
occur at next regularly 
scheduled imaging visit. 
Continue study treatment at the 
Investigator’s discretion. 
Repeat imaging at 4 to 
8 weeks to confirm PD per 
Investigator’s discretion only. 
Discontinue treatment 
Repeat tumor imaging shows 
iSD, iPR, or iCR by iRECIST 
per Investigator assessment. 
Continue regularly scheduled 
imaging assessments. 
Continue study treatment at the 
Investigator’s discretion. 
Continue regularly scheduled 
imaging assessments. 
May restart study treatment if 
condition has improved and/or 
clinically stable per Investigator’s 
discretion.  Next tumor image should 
occur according to the regular imaging 
schedule. 
iCPD = iRECIST confirmed progressive disease; iCR = iRECIST complete response; iRECIST = modified Response Evaluation Criteria in Solid Tumors 1.1 for immune-based 
therapeutics; iSD = iRECIST stable disease; iUPD = iRECIST unconfirmed progressive disease; PD = progressive disease; RECIST 1.1 = Response Evaluation Criteria in Solid 
Tumors 1.1. 
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Imaging and Treatment for Clinically Stable Participants after First Radiologic Evidence of 
PD Assessed by the Investigator 
 
 
7.1.3 Other Procedures 
7.1.3.1 Withdrawal/Discontinuation 
When a participant 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. 
7.1.4 Visit Requirements 
Visit requirements are outlined in the Trial Flow Chart.   Specific procedure-related details 
are provided above in Section 7.1 - Trial Procedures. 
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7.1.5 Post-treatment Visits 
7.1.5.1 Safety Follow-Up Visit 
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the 
last dose of study 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.  
Participants 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-cancer therapy, whichever occurs first.  SAEs that 
occur within 90 days of the end of treatment or before initiation of a new anti-cancer 
treatment should also be followed and recorded. 
7.1.5.2 Follow-up Visits 
Participants who discontinue study treatment for a reason other than disease progression will 
move into the Follow-Up Phase and should be assessed every 12 weeks (84 ± 7 days) by 
radiologic imaging to monitor disease status.  Every effort should be made to collect 
information regarding disease status. Information regarding post-study anti-cancer treatment 
will be collected if new treatment is initiated. 
7.1.5.3 Survival Follow-up 
Participants who experience confirmed disease progression or start a new anticancer therapy, 
will move 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 
trial, whichever occurs first.  
7.2 
Assessing and Recording Adverse Events 
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation participant 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. 
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 
as prescribed in clinical practice, from overdose (whether accidental or intentional), from 
abuse and from withdrawal. 
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All AEs, SAEs and other reportable safety events that occur after the consent form is signed 
but before treatment allocation/randomization must be reported by the investigator if the 
participant is receiving placebo run-in or other run-in treatment, if the event causes the 
participant to be excluded from the study, or is the result of a protocol-specified intervention, 
including but not limited to washout or discontinuation of usual therapy, diet, or a procedure.  
● All AEs from the time of treatment allocation/randomization through 30 days following 
cessation of study treatment must be reported by the investigator.  
● All AEs meeting serious criteria, from the time of treatment allocation/randomization 
through 90 days following cessation of study treatment, or 30 days following cessation of 
study treatment if the participant initiates new anticancer therapy, whichever is earlier must 
be reported by the investigator.  
● All pregnancies and exposure during breastfeeding, from the time of treatment 
allocation/randomization through 120 days (pembroRT cohort) or 180 days (chemoRT 
cohort) following cessation of study treatment, or 30 days following cessation of study 
treatment if the participant initiates new anticancer therapy must be reported by the 
investigator.  
● Additionally, any SAE brought to the attention of an investigator at any time outside of the 
time period specified above must be reported immediately by the investigator if the event is 
considered to be drug-related. 
Investigators are not obligated to actively seek AE or SAE or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study treatment or study participation, the 
investigator must promptly notify Merck. 
7.2.1 Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor and to Merck 
For purposes of this study, 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. In the event of overdose, the participant 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 
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non-serious Event of Clinical Interest (ECI), using the terminology “accidental or intentional 
overdose without adverse effect.” 
All reports of overdose with and without an adverse event must be reported within 24 hours 
to the Sponsor and within 2 working days hours to Merck Global Safety. (Attn: Worldwide 
Product Safety; FAX 215-661-6229) 
7.2.2 Reporting of Pregnancy and Lactation to the Sponsor and to Merck 
Although pregnancy and infant exposure during breast feeding are not considered adverse 
events, it is the responsibility of investigators or their designees to report any pregnancy or 
lactation in a participant (spontaneously reported to them) that occurs during the study. 
Pregnancies and infant exposures during breastfeeding that occur after the consent form is 
signed but before treatment allocation/randomization must be reported by the investigator if 
they cause the participant to be excluded from the trial, or are the result of a protocol-
specified intervention, including but not limited to washout or discontinuation of usual 
therapy, diet, placebo treatment or a procedure.   
Pregnancies and infant exposures during breastfeeding that occur from the time of treatment 
allocation/randomization through 120 days following cessation of pembrolizumab 
(pembroRT cohort) or 180 days following cessation of chemotherapy (chemoRT cohort) or 
30 days following cessation of treatment if the participant initiates new anticancer therapy, 
whichever is earlier, must be reported by the investigator.  All reported pregnancies must be 
followed to the completion/termination of the pregnancy. Pregnancy outcomes of 
spontaneous abortion, missed abortion, benign hydatidiform mole, blighted ovum, fetal 
death, intrauterine death, miscarriage and stillbirth must be reported as serious events 
(Important Medical Events). If the pregnancy continues to term, the outcome (health of 
infant) must also be reported. 
Such events must be reported within 24 hours to the Sponsor and within 2 working days to 
Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215-661-6229) 
7.2.3 Immediate Reporting of Adverse Events to the Sponsor and to Merck 
7.2.3.1 Serious Adverse Events 
A serious adverse event is any adverse event occurring at any dose or during any use of 
Merck’s product that: 
• Results in death; 
• Is life threatening; 
• Results in persistent or significant disability/incapacity; 
• Results in or prolongs an existing inpatient hospitalization; 
• Is a congenital anomaly/birth defect; 
• Is another important medical event  
• Note: In addition to the above criteria, adverse events meeting either of the below 
criteria, although not serious per ICH definition, are reportable to the Merck in the 
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same timeframe as SAEs to meet certain local requirements. Therefore, these events 
are considered serious by Merck for collection purposes. 
• Is a new cancer (that is not a condition of the study); 
• Is associated with an overdose. 
 
Refer to Table 7 for additional details regarding each of the above criteria. 
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any serious adverse event, or follow up to a serious adverse event, 
including death due to any cause that occurs to any participant must be reported within 24 
hours to the Sponsor and within 2 working days to Merck Global Safety if it causes the 
participant to be excluded from the trial, or is the result of a protocol-specified intervention, 
including but not limited to washout or discontinuation of usual therapy, diet, placebo 
treatment or a procedure. 
For the time period beginning at treatment allocation through 90 days following cessation of 
treatment, or 30 days following cessation of treatment if the participant initiates new 
anticancer therapy, whichever is earlier, any serious adverse event, or follow up to a serious 
adverse event, including death due to any cause whether or not related to the Merck product, 
must be reported within 24 hours to the Sponsor and within 2 working days to Merck Global 
Safety. 
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to Merck product that is brought to the attention of the investigator at 
any time following consent through the end of the specified safety follow-up period specified 
in the paragraph above, or at any time outside of the time period specified in the previous 
paragraph also must be reported immediately to Merck Global Safety. 
All participants with serious adverse events must be followed up for outcome. 
SAE reports and any other relevant safety information are to be forwarded to the Merck 
Global Safety facsimile number:  +1-215-661-6229 
SAE reports and any other relevant safety information are to be forwarded to Principal 
Investigator (Nitin Ohri, M.D., nohri@montefiore.org) as well as the study sponsor's Data 
Safety Monitoring Committee (rupatel@montefiore.org). 
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 215-661-6229) at the time of submission to FDA. 
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7.2.3.2 Events of Clinical Interest 
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported within 2 working days to Merck Global Safety. (Attn: Worldwide 
Product Safety; FAX 215-661-6229). 
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any participant 
must be reported within 2 working days to Merck Global Safety if it causes the participant to 
be excluded from the trial, or is the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure. 
For the time period beginning at treatment allocation through 90 days following cessation of 
treatment, or 30 days following cessation of treatment if the participant initiates new 
anticancer therapy, whichever is earlier, any ECI, or follow up to an ECI, whether or not 
related to Merck product, must be reported within 2 working days to Merck Global Safety. 
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.  
 
7.2.4 Evaluating Adverse Events 
An investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), version 4.0. Any adverse event 
which changes CTCAE grade over the course of a given episode will have each change of 
grade recorded on the adverse event case report forms/worksheets. 
All adverse events regardless of CTCAE grade must also be evaluated for seriousness. 
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Table 7 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 participant, 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 for an elective procedure to treat a pre-existing condition that has not 
worsened is not a serious adverse event.  A pre-existing condition is a clinical condition that is diagnosed prior to the use of a Merck product and is documented in 
the patient’s medical history.); or 
 
†Is a congenital anomaly/birth defect (in offspring of participant taking the product regardless of time to diagnosis); or 
 
Is a new cancer (that is not a condition of the study) (although not serious per ICH definition, is reportable to the Sponsor within 24 hours and to Merck within 2 
working days to meet certain local requirements); or 
 
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event for collection purposes. 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 to the Sponsor and to 
Merck within 2 working days. 
 
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 participant and may require medical or surgical intervention to prevent one of the outcomes 
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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 Merck product to be discontinued? 
Relationship to 
Merck Product  
Did Merck product cause the adverse event? The determination of the likelihood that 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 Merck product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely Merck product caused the adverse event (AE): 
 
Exposure 
Is there evidence that the participant was actually exposed to 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 
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 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 Sponsor’s product; or (3) the trial is a single-dose drug trial); or (4) Sponsor’s product(s) is/are only used one time.) 
 
Rechallenge 
Was the participant re-exposed to 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) Sponsor’s 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 MERCK PRODUCT, OR IF REEXPOSURE TO MERCK PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT RISK 
TO THE PARTICIPANT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR 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 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 Merck product relationship). 
Yes, there is a reasonable 
possibility of Merck product 
relationship. 
There is evidence of exposure to Merck product.  The temporal sequence of the AE onset relative to the administration of Merck product is 
reasonable.  The AE is more likely explained by Merck product than by another cause. 
No, there is not a reasonable 
possibility of Merck product 
relationship 
Participant did not receive the Merck product OR temporal sequence of the AE onset relative to administration of Merck product is not reasonable 
OR the AE is more likely explained by another cause than the Merck product.  (Also entered for a participant with overdose without an associated 
AE.) 
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7.2.5 Sponsor Responsibility for Reporting Adverse Events 
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations.  
8.0 STATISTICAL ANALYSIS PLAN 
8.1 
Statistical Analysis Plan – Primary Endpoint and Sample Size Calculation 
The primary endpoint is progression-free survival (PFS) in the PembroRT cohort one year 
following study enrollment.  PFS duration will be defined as the time from study registration 
to the date of disease progression or death from any cause. In cases where a scan is 
concerning for progressive disease based on RECIST 1.1 criteria, and progression is 
confirmed on a subsequent scan 4-8 weeks later (satisfying iRECIST criteria for 
progression), the date of disease progression would be the date of the first scan 
demonstrating progression. PFS rates will be estimated using the Kaplan-Meier Survival 
method, from which the probability of PFS at various time points and corresponding 95% 
confidence intervals will be estimated. If a patient is lost to follow-up without having disease 
progression, progression-free survival will be censored at the date of the patient’s last clinic 
visit. Based on published multi-institutional trials and data from our institution, we expect the 
one-year progression-free survival rate (H0) to be to 40% with standard chemoradiotherapy.  
We hypothesize that this rate will be at least 65% (H1) for subjects in the PembroRT cohort.  
A one sample two-sided log-rank test will be used to compare the one-year PFS rate in the 
PembroRT cohort against the expected rate with ChemoRT. We plan to accrue 25 subjects 
to the PembroRT cohort. Assuming that the accrual period will last 18 months and that 
event rates will follow an exponential distribution, this sample size will provide 81% power 
to detect an improvement in PFS at 1 year at a 5% level of significance using a one sample 
two-sided log-rank test [48, 49]. 
The ChemoRT cohort will be open to accrual while accrual to the PembroRT cohort is 
ongoing. We expect that approximately 40% of patients with locally advanced NSCLC have 
PD-L1 expression of at least 50%.  We therefore expect that approximately 38 subjects will 
be enrolled and treated with standard concurrent chemoradiotherapy as part of this trial, 
which will yield a total sample size of approximately 63 subjects.  
 
8.2 
Statistical Analysis Plan – Secondary Endpoints 
Time-to-event outcomes (overall survival, freedom from distant metastasis, freedom from 
intrathoracic progression, freedom from hospitalization) will be analyzed using the Kaplan-
Meier method, from which rates at various time points and corresponding 95% confidence 
intervals will be estimated.  Exploratory comparisons for time-to-event outcomes between 
the PembroRT and ChemoRT cohorts will be performed using log-rank tests. Univariate and 
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multivariable Cox regression models will be used to evaluate associations between time-to-
event outcomes and clinical covariates, including study cohort. 
Rates of radiographic responses and disease progression during induction pembrolizumab for 
subjects in the PembroRT cohort will be described using counts and percentages.  Logistic 
regression models will be used to evaluate potential predictors of response or progression 
(e.g.: PD-L1 TPS). 
Hospitalization rates and adverse event rates, scored using CTCAE as well as PRO-CTCAE, 
will be presented as counts and percentages. Exploratory comparisons between the 
PembroRT cohort and the ChemoRT cohort will be performed using chi-square or Fisher 
Exact testing, as appropriate.  
Daily step counts throughout the study period will be presented using descriptive statistics 
and will be analyzed using a generalized linear mixed-model for repeated measures.  
Rates of circulating tumor DNA clearance will be presented as counts and percentages, and 
predictors of circulating tumor DNA clearance will be explored using chi-square or Fisher 
exact testing, as appropriate.  Exploratory analyses will be performed to evaluate PD-L1 
expression, expression of alternative immune checkpoint molecules (e.g., HHLA2, B7x, and 
B7-H3), baseline tumor mutational burden, and markers of immune activation (e.g., 
expansion of T4/T8 subsets, myeloid derived suppressor cell levels, expansion of T-cell 
repertoire) as predictors of PFS and overall survival. 
 
9.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES 
9.1 
Investigational Product  
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and 
regulations. 
Pembrolizumab will be provided by Merck as summarized in Table 8. 
Table 8 Product Descriptions 
Product Name & Potency 
Dosage Form 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
 
9.2 
Packaging and Labeling Information 
Supplies will be labeled in accordance with regulatory requirements. 
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9.3 
Clinical Supplies Disclosure 
This trial is open-label; therefore, the participant, the trial site personnel, the Sponsor and/or 
designee are not blinded to treatment. Drug identity (name, strength) is included in the label 
text; random code/disclosure envelopes or lists are not provided. 
9.4 
Storage and Handling Requirements 
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.   
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site. 
Clinical supplies may not be used for any purpose other than that stated in the protocol. 
9.5 
Returns and Reconciliation 
The investigator is responsible for keeping accurate records of the clinical supplies received 
from Merck or designee, the amount dispensed to and returned by the participants and the 
amount remaining at the conclusion of the trial.  
Upon completion or termination of the study, all unused and/or partially used 
investigational product will be destroyed at the site per institutional policy. It is the 
Investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, 
local and institutional guidelines and procedures, and provided that appropriate records of 
disposal are kept. 
10.0 ADMINISTRATIVE AND REGULATORY DETAILS 
 
 
 
 
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11.0 APPENDICES 
Appendix 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. 
 
 
 
 
 
 
 
 
 
 
 
 
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Appendix 2: Common Terminology Criteria for Adverse Events V4.0 (CTCAE) 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0 will be utilized for adverse event reporting. 
(http://ctep.cancer.gov/reporting/ctc.html) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Appendix 3: Contraceptive Guidance and Pregnancy Testing 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below)  
Women in the following categories are not considered WOCBP: 
● 
Premenarchal 
● 
Premenopausal female with 1 of the following: 
○ Documented hysterectomy 
○ Documented bilateral salpingectomy 
○ Documented bilateral oophorectomy 
Note:  Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview. 
● 
Postmenopausal female 
○ A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.  
▪ 
A high follicle stimulating hormone (FSH) level in the postmenopausal range may 
be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence 
of 12 months of amenorrhea, confirmation with two FSH measurements in the 
postmenopausal range is required.  
○ Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-hormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment. 
Contraception Requirements 
Female Participants: 
Female participants of childbearing potential are eligible to participate if they agree to use a 
highly effective method of contraception consistently and correctly as described in Table 10 
while receiving study therapy.  
 
Table 10 Highly Effective Contraception Methods 
 
Highly Effective Contraceptive Methods That Are User Dependent a  
Failure rate of <1% per year when used consistently and correctly. 
● Combined (estrogen- and progestogen- containing ) hormonal contraception b 
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○ Oral  
○ Intravaginal  
○ Transdermal  
○ Injectable 
● Progestogen-only hormonal contraception b 
○ Oral  
○ Injectable  
Highly Effective Methods That Have Low User Dependency  
Failure rate of <1% per year when used consistently and correctly. 
● Progestogen- only contraceptive implant b  
● Intrauterine hormone-releasing system (IUS) 
● Intrauterine device (IUD) 
● Bilateral tubal occlusion 
● Vasectomized partner  
A vasectomized partner is a highly effective contraception method provided that the partner is the sole 
male sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional 
highly effective method of contraception should be used.  
● Sexual abstinence  
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatment. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the 
preferred and usual lifestyle of the participant.)  
Notes:  
Use should be consistent with local regulations regarding the use of contraceptive methods for 
participants of clinical studies.  
 
a) Typical use failure rates are lower than perfect-use failure rates (i.e. when used consistently and 
correctly).  
b) If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, 
acceptable hormonal contraceptives are limited to those which inhibit ovulation.  
 
Pregnancy Testing 
WOCBP should only be included after a negative highly sensitive urine or serum pregnancy 
test.  
Following initiation of treatment, pregnancy testing will be performed whenever an expected 
menstrual cycle is missed or when pregnancy is otherwise suspected 
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Appendix 4:  Description of the iRECIST Process for Assessment of Disease 
Progression 
Assessment at Screening and Prior to RECIST 1.1 Progression 
Until radiographic progression based on RECIST 1.1, there is no distinct iRECIST 
assessment. 
Assessment and Decision at RECIST 1.1 Progression 
In participants who show evidence of radiological PD by RECIST 1.1 the Investigator will 
decide whether to continue a participant on study treatment until repeat imaging is obtained 
(using iRECIST for participant management (see Table 5 and Figures 1 and 3).  This decision 
by the Investigator should be based on the participant’s overall clinical condition. 
Clinical stability is defined as the following:  
• Absence of symptoms and signs indicating clinically significant progression of 
disease 
• No decline in ECOG performance status  
• No requirements for intensified management, including increased analgesia, 
radiation, or other palliative care 
Any participant deemed clinically unstable should be discontinued from study treatment at 
site-assessed first radiologic evidence of PD, and is not required to have repeat tumor 
imaging for confirmation of PD by iRECIST. 
If the Investigator decides to continue treatment, the participant may continue to receive 
study treatment and the tumor assessment should be repeated 4 to 8 weeks later to confirm 
PD by iRECIST, per Investigator assessment.  I 
Tumor flare may manifest as any factor causing radiographic progression per RECIST 1.1, 
including: 
• Increase in the sum of diameters of target lesion(s) identified at baseline to ≥ 20% and 
≥ 5 mm from nadir 
o Please note: the iRECIST publication uses the terminology “sum of 
measurements”, but “sum of diameters” will be used in this protocol, consistent 
with the original RECIST 1.1 terminology. 
• Unequivocal progression of non-target lesion(s) identified at baseline 
• Development of new lesion(s) 
iRECIST defines new response categories, including iUPD (unconfirmed progressive 
disease) and iCPD (confirmed progressive disease).  For purposes of iRECIST assessment, 
the first visit showing progression according to RECIST 1.1 will be assigned a visit (overall) 
response of iUPD, regardless of which factors caused the progression. 
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At this visit, target and non-target lesions identified at baseline by RECIST 1.1 will be 
assessed as usual. 
New lesions will be classified as measurable or non-measurable, using the same size 
thresholds and rules as for baseline lesion assessment in RECIST 1.1.  From measurable new 
lesions, up to 5 lesions total (up to 2 per organ), may be selected as New Lesions – Target.  
The sum of diameters of these lesions will be calculated, and kept distinct from the sum of 
diameters for target lesions at baseline.  All other new lesions will be followed qualitatively 
as New Lesions – Non-target. 
Assessment at the Confirmatory Imaging 
On the confirmatory imaging, the participant will be classified as progression confirmed 
(with an overall response of iCPD), or as showing persistent unconfirmed progression (with 
an overall response of iUPD), or as showing disease stability or response (iSD/iPR/iCR). 
Confirmation of Progression 
Progression is considered confirmed, and the overall response will be iCPD, if ANY of the 
following occurs: 
• Any of the factors that were the basis for the initial iUPD show worsening 
o For target lesions, worsening is a further increase in the sum of diameters of 
≥ 5 mm, compared to any prior iUPD time point 
o For non-target lesions, worsening is any significant growth in lesions overall, 
compared to a prior iUPD time point; this does not have to meet the 
“unequivocal” standard of RECIST 1.1 
o For new lesions, worsening is any of these: 
 An increase in the new lesion sum of diameters by ≥ 5 mm from a prior iUPD 
time point  
 Visible growth of new non-target lesions  
 The appearance of additional new lesions 
• Any new factor appears that would have triggered PD by RECIST 1.1 
Persistent iUPD 
Progression is considered not confirmed, and the overall response remains iUPD, if: 
• None of the progression-confirming factors identified above occurs AND 
• The target lesion sum of diameters (initial target lesions) remains above the initial PD 
threshold (by RECIST 1.1) 
Additional imaging for confirmation should be scheduled 4 to 8 weeks from the scan on 
which iUPD is seen.  This may correspond to the next visit in the original visit schedule.  The 
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assessment of the subsequent confirmation scan proceeds in an identical manner, with 
possible outcomes of iCPD, iUPD, and iSD/iPR/iCR. 
Resolution of iUPD 
Progression is considered not confirmed, and the overall response becomes iSD/iPR/iCR, if: 
• None of the progression-confirming factors identified above occurs, AND 
• The target lesion sum of diameters (initial target lesions) is not above the initial PD 
threshold.  
The response is classified as iSD or iPR (depending on the sum of diameters of the target 
lesions), or iCR if all lesions resolve. 
In this case, the initial iUPD is considered to be pseudo-progression, and the level of 
suspicion for progression is “reset”.  This means that the next visit that shows radiographic 
progression, whenever it occurs, is again classified as iUPD by iRECIST, and the 
confirmation process is repeated before a response of iCPD can be assigned. 
Management Following the Confirmatory Imaging 
If repeat imaging does not confirm PD per iRECIST, as assessed by the Investigator, and the 
participant continues to be clinically stable, study treatment may continue and follow the 
regular imaging schedule.  If PD is confirmed, participants will be discontinued from study 
treatment. 
NOTE: If a participant has confirmed radiographic progression (iCPD) as defined above, but 
the participant is achieving a clinically meaningful benefit, an exception to continue study 
treatment may be considered.  In this case, if study treatment is continued, tumor imaging 
should continue to be performed following the intervals as outlined in the Trial Flow Chart. 
Detection of Progression at Visits After Pseudo-progression Resolves 
After resolution of pseudo-progression (i.e., achievement of iSD/iPR/iCR), iUPD is indicated 
by any of the following events: 
• Target lesions 
o Sum of diameters reaches the PD threshold (≥ 20% and ≥ 5 mm increase from 
nadir) either for the first time, or after resolution of previous pseudo-progression.  
The nadir is always the smallest sum of diameters seen during the entire trial, 
either before or after an instance of pseudo-progression. 
• Non-target lesions 
o If non-target lesions have never shown unequivocal progression, their doing so for 
the first-time results in iUPD. 
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o If non-target lesions had shown previous unequivocal progression, and this 
progression has not resolved, iUPD results from any significant further growth of 
non-target lesions, taken as a whole. 
• New lesions 
o New lesions appear for the first time 
o Additional new lesions appear 
o Previously identified new target lesions show an increase of ≥ 5 mm in the new 
lesion sum of diameters, from the nadir value of that sum 
o Previously identified non-target lesions show any significant growth 
If any of the events above occur, the overall response for that visit is iUPD, and the iUPD 
evaluation process (see Assessment at the Confirmatory Imaging above) is repeated.  
Progression must be confirmed before iCPD can occur. 
The decision process is identical to the iUPD confirmation process for the initial PD, except 
in one respect. If new lesions occurred at a prior instance of iUPD, and at the confirmatory 
scan the burden of new lesions has increased from its smallest value (for new target lesions, 
their sum of diameters is ≥5 mm increased from its nadir), then iUPD cannot resolve to iSD 
or iPR. It will remain iUPD until either a decrease in the new lesion burden allows resolution 
to iSD or iPR, or until a confirmatory factor causes iCPD. 
Additional details about iRECIST are provided in the iRECIST publication[47]. 
 
 
 
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Appendix 5:  PRO-CTCAE Assessment Tool 
 
 
 
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Fournel, P., et al., Randomized phase III trial of sequential chemoradiotherapy 
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Blank, C., T.F. Gajewski, and A. Mackensen, Interaction of PD-L1 on tumor cells 
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Senan, S., et al., PROCLAIM: Randomized phase III Trial of pemetrexed-cisplatin or 
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Albain, K.S., et al., Radiotherapy plus chemotherapy with or without surgical 
resection for stage III non-small-cell lung cancer: a phase III randomised controlled 
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Wang, K., et al., Cardiac Toxicity After Radiotherapy for Stage III Non–Small-Cell 
Lung Cancer: Pooled Analysis of Dose-Escalation Trials Delivering 70 to 90 Gy. 
Journal of Clinical Oncology, 2017: p. JCO. 2016.70. 0229. 
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Dess, R.T., et al., Cardiac Events After Radiation Therapy: Combined Analysis of 
Prospective Multicenter Trials for Locally Advanced Non–Small-Cell Lung Cancer. 
Journal of Clinical Oncology, 2017: p. JCO. 2016.71. 6142. 
22. 
Darby, S.C., et al., Risk of ischemic heart disease in women after radiotherapy for 
breast cancer. New England Journal of Medicine, 2013. 368(11): p. 987-998. 
23. 
Taylor, C., et al., Estimating the risks of breast cancer radiotherapy: evidence from 
modern radiation doses to the lungs and heart and from previous randomized trials. 
Journal of Clinical Oncology, 2017. 35(15): p. 1641-1649. 
24. 
Machtay, M., et al., Risk of death from intercurrent disease is not excessively 
increased by modern postoperative radiotherapy for high-risk resected non–small-
cell lung carcinoma. Journal of clinical oncology, 2001. 19(19): p. 3912-3917. 
25. 
Group, P.M.-a.T., Postoperative radiotherapy in non-small-cell lung cancer: 
systematic review and meta-analysis of individual patient data from nine randomised 
controlled trials. The Lancet, 1998. 352(9124): p. 257-263. 
26. 
Nilsson, G., et al., Distribution of coronary artery stenosis after radiation for breast 
cancer. Journal of Clinical Oncology, 2011. 30(4): p. 380-386. 
27. 
Tang, C., et al., Lymphopenia association with gross tumor volume and lung V5 and 
its effects on non-small cell lung cancer patient outcomes. International Journal of 
Radiation Oncology* Biology* Physics, 2014. 89(5): p. 1084-1091. 
28. 
Machtay, M., et al., Prediction of Survival by [18F]Fluorodeoxyglucose Positron 
Emission Tomography in Patients With Locally Advanced Non-Small-Cell Lung 
Cancer Undergoing Definitive Chemoradiation Therapy: Results of the ACRIN 
6668/RTOG 0235 Trial. J Clin Oncol, 2013. 31(30): p. 3823-30. 
29. 
Ohri, N., et al., Pretreatment FDG-PET Metrics in Stage III Non–Small Cell Lung 
Cancer: ACRIN 6668/RTOG 0235. Journal of the National Cancer Institute, 2015. 
107(4): p. djv004. 
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30. 
Ohri, N., et al., Pre-treatment FDG-PET predicts the site of in-field progression 
following concurrent chemoradiotherapy for stage III non-small cell lung cancer. 
Lung Cancer, 2015. 87(1): p. 23-27. 
31. 
Ohri, N., et al., Pretreatment 18F-FDG PET Textural Features in Locally Advanced 
Non–Small Cell Lung Cancer: Secondary Analysis of ACRIN 6668/RTOG 0235. 
Journal of Nuclear Medicine, 2016. 57(6): p. 842-848. 
32. 
Ohri, N., et al., 18 F-Fluorodeoxyglucose/Positron Emission Tomography Predicts 
Patterns of Failure After Definitive Chemoradiation Therapy for Locally Advanced 
Non-Small Cell Lung Cancer. International Journal of Radiation Oncology* Biology* 
Physics, 2017. 97(2): p. 372-380. 
33. 
Ohri, N., et al., Positron Emission Tomography–Adjusted Intensity Modulated 
Radiation Therapy for Locally Advanced Non-Small Cell Lung Cancer. International 
Journal of Radiation Oncology* Biology* Physics, 2017. 
34. 
Ohri, 
N., 
et 
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Continuous 
Activity 
Monitoring 
during 
Concurrent 
Chemoradiotherapy. International Journal of Radiation Oncology* Biology* Physics, 
2016. 
35. 
Gotay, C.C., et al., The Prognostic Significance of Patient-Reported Outcomes in 
Cancer Clinical Trials. J Clin Oncol, 2008. 26: p. 1355-1363. 
36. 
Movsas, B., et al., Quality of life (QOL) analysis of the randomized radiation (RT) 
dose-escalation NSCLC trial (RTOG 0617): the rest of the story. Int J Radiat Oncol 
Biol Phys, 2013. 87(2 Supplement): p. S1-S2. 
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Basch, E., et al., Development of the National Cancer Institute’s patient-reported 
outcomes version of the common terminology criteria for adverse events (PRO-
CTCAE). Journal of the National Cancer Institute, 2014. 106(9): p. dju244. 
38. 
Fogh, S., et al., A Randomized Phase II Trial of Prophylactic Manuka Honey for the 
Reduction of Chemoradiation Therapy Induced Esophagitis During the Treatment of 
Lung Cancer: Results of Trial. International Journal of Radiation Oncology* 
Biology* Physics, 2016. 
39. 
Newman, A.M., et al., An ultrasensitive method for quantitating circulating tumor 
DNA with broad patient coverage. Nature medicine, 2014. 20(5): p. 548-554. 
40. 
Sacher, A.G. and L. Gandhi, Biomarkers for the Clinical Use of PD-1/PD-L1 
Inhibitors in Non–Small-Cell Lung Cancer: A Review. JAMA oncology, 2016. 2(9): 
p. 1217-1222. 
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Woo, S.-R., L. Corrales, and T.F. Gajewski, Innate immune recognition of cancer. 
Annual review of immunology, 2015. 33: p. 445-474. 
42. 
Snyder, A., et al., Genetic basis for clinical response to CTLA-4 blockade in 
melanoma. New England Journal of Medicine, 2014. 371(23): p. 2189-2199. 
43. 
Rizvi, N.A., et al., Mutational landscape determines sensitivity to PD-1 blockade in 
non–small cell lung cancer. Science, 2015. 348(6230): p. 124-128. 
44. 
Le, D.T., et al., PD-1 blockade in tumors with mismatch-repair deficiency. New 
England Journal of Medicine, 2015. 372(26): p. 2509-2520. 
45. 
Bennett, F., et al., Program death-1 engagement upon TCR activation has distinct 
effects on costimulation and cytokine-driven proliferation: attenuation of ICOS, IL-4, 
and IL-21, but not CD28, IL-7, and IL-15 responses. The Journal of Immunology, 
2003. 170(2): p. 711-718. 
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Werner-Wasik, M., et al., What is the best way to contour lung tumors on PET scans? 
Multiobserver validation of a gradient-based method using a NSCLC digital PET 
phantom. International Journal of Radiation Oncology* Biology* Physics, 2012. 
82(3): p. 1164-1171. 
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Seymour, L., et al., iRECIST: guidelines for response criteria for use in trials testing 
immunotherapeutics. The Lancet Oncology, 2017. 18(3): p. e143-e152. 
48. 
Wu, J., A new one-sample log-rank test. Journal of Biometrics & Biostatistics, 2014. 
5(4): p. 1. 
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Finkelstein, D.M., A. Muzikansky, and D.A. Schoenfeld, Comparing survival of a 
sample to that of a standard population. Journal of the National Cancer Institute, 
2003. 95(19): p. 1434-1439. 
 
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ICF_001.pdf: 
Version 1.1, dated 08/6/2018
Page 1 of 11
ALBERT EINSTEIN COLLEGE OF MEDICINE 
MONTEFIORE MEDICAL CENTER
DOCUMENTATION OF INFORMED CONSENT AND HIPAA AUTHORIZATION
Introduction
You are being asked to participate in a clinical trial called The Selective Personalized Radio-
Immunotherapy for Locally Advanced NSCLC Trial (SPRINT). Your participation is 
voluntary - it is up to you whether you would like to participate. It is fine to say “no” now or at any 
time after you have started the study. If you say “no,” your decision will not affect any of your 
rights or benefits or your access to care.
The researcher in charge of this project is called the 
“Principal Investigator.” His name is Nitin Ohri, MD. 
You can reach Dr. Ohri at: 
Office Address: 111 E 210th Street
Bronx, NY 10467
Telephone #: (718)920-7750
For questions about the research study, or if you 
believe you have an injury, contact the Principal 
Investigator or the IRB.
Support for this research study is provided by 
MERCK Pharmaceuticals
The Institutional Review Board (IRB) of the 
Albert Einstein College of Medicine and 
Montefiore Medical Center has approved 
this research study. The IRB # is in the 
stamp in the upper right-hand corner of this 
page. If you have questions regarding your 
rights as a research subject you may contact 
the IRB office at 718-430-2253, by e-mail at 
irb@einstein.yu.edu, or by mail:
Einstein IRB 
Albert Einstein College of Medicine
1300 Morris Park Ave., Belfer Bldg #1002
Bronx, New York 10461
Why is this study being done? 
The goal of this study is to determine if, for locally advanced non-small cell lung cancer patients 
whose tumors have high levels of PD-L1 (a marker associated with benefits from 
immunotherapy), a combination of immunotherapy and a personalized 4-week radiotherapy 
course is safe and effective. Standard treatment for these patients is a combination of 
chemotherapy and radiotherapy. Immunotherapy is a form of medication intended to stimulate a 
person’s immune system to fight cancer. The immunotherapy that will be used in this study is 
called Keytruda, or pembrolizumab. Pembrolizumab is already approved as an initial treatment 
for patients with metastatic non-small cell lung cancer with high PD-L1 expression, but it has not 
been tested in combination with radiotherapy for patients without metastatic disease. Patients in 
this study who are found to have low tumor levels of PD-L1 will be treated with standard 
chemotherapy and radiotherapy.
Why am I being asked to participate? 
You are being asked to participate in this study because you have recently been diagnosed with 
locally advanced non-small cell lung cancer. Your cancer has not spread outside the chest, but 
your physicians do not believe that you will benefit from surgery.
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How many people will take part in the research study?
You will be one of about 63 people who will be participating in this study. 
How long will I take part in this research?
This study will take place over a period of up to one year. As standard clinical care for a patient 
with lung cancer, your physicians will continue to follow you indefinitely after that. Outcomes 
beyond one year, such as how long you live, may be included in study results. 
What will happen if I participate in the study? 
There are two treatment groups in this study. If you decide to participate, you will be placed in 
one of these groups based on tests performed on the same biopsy sample that was used to 
diagnose your lung cancer. Enrollment on this trial will not require an extra biopsy. 
Patients whose tumors are found to have high PD-L1 levels will receive three intravenous 
treatments with pembrolizumab, followed by four weeks of daily radiotherapy, followed by up to 
12 more treatments with pembrolizumab. Pembrolizumab is given as an intravenous infusion 
once every three weeks. This treatment course will last up to one year. 
Patients whose tumors are found to have low PD-L1 levels will receive radiotherapy over a 
course of four to seven weeks. During radiotherapy, patients will also receive two standard 
chemotherapy agents (carboplatin and paclitaxel) once each week. Following completion of 
chemotherapy and radiotherapy, patients may receive additional treatments with chemotherapy 
or immunotherapy as part of routine care. These treatments are optional. 
All Subjects:
Before you take part in this study, you will have some tests and procedures to be sure you 
qualify for the study. This may take place in a screening visit, which can take about an hour and 
includes many procedures that are performed as part of standard care for patients with your 
disease. The study doctor will review the results of these tests and procedures. If you are not 
eligible for this study, the study doctor will explain why. At this visit we will: 

Ask you about your medical history

Perform a physical exam, including height, weight, and “vital signs” (blood pressure,
temperature, heart rate, breathing rate, and pain score)

Draw a blood sample. We will be looking for circulating tumor DNA or other tumor
markers of immune system activation found in the blood. 

Test your blood for pregnancy, if you are a female able to become pregnant.  Pregnant
women cannot take part in this research study.

Order whole body PET/CT and brain MRI if these have not already been done.
Once we have the results of these tests, if we have determined that you are eligible to 
participate in the study, you will also have a number of visits with your doctor while on 
treatment, which is standard practice for all patients. The schedule for treatments will depend on 
your treatment group:
Pembrolizumab plus radiotherapy:
Immunotherapy (before radiation)
Three infusions, every 3 weeks
Radiation Therapy
Daily (Monday-Friday) for 4 weeks
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Immunotherapy (after radiation)
12 infusions, every 3 weeks
Chemotherapy plus radiotherapy:
Radiotherapy
Daily (Monday-Friday) for 4-7 weeks
Chemotherapy
Weekly during radiotherapy
OPTIONAL Chemotherapy or 
Immunotherapy after Radiotherapy
Variable
At these treatment visits, we will: 

Check your vital signs

Ask you about side effects or health problems since your last visit

Draw a blood sample. In addition to routine blood tests, we will draw a small quantity of
extra blood at several time points to test for markers of immune activation and the 
presence of cancer cells’ DNA in your blood. 

Give you some questionnaires to fill out

Review your medication diaries
When you are done, or taken off treatment, we will continue to see you for follow-up as standard 
care. You will undergo CT scans approximately every three months after completing 
radiotherapy, which is standard.
A description of this clinical trial will be available on www.ClinicalTrials.gov, as required by U.S. 
law. This Web site will not include information that can identify you. At most, the Web site will 
include a summary of the results. You can search this Web site at any time.
Optional Activity Monitoring
You may be asked to participate in an optional activity monitoring component of this trial. If you 
choose to participate in this portion of the study, we will give you a wearable activity monitor, 
which will be placed on your wrist. When you are given the device, it will be activated, synced 
with a computer or mobile device, and set to show the time. We will show you how to remove 
the device (similar to removing a watch) if needed, but we will ask you to keep the device on 
continuously throughout the course of treatment.  With this device, we will be able to track your 
daily step counts, which may provide information about side effects from treatment and your 
general health. The device will be yours to keep. There is no additional cost to participate in this 
portion of the study. 
INITIAL ONE (1) OF THE FOLLOWING OPTIONS
_______ I consent to participate in the optional activity monitoring portion of the study and 
agree to wear the fitness tracker throughout the course of my treatment.
_______ I do NOT consent to the optional activity monitoring portion of the study.
Genetic Testing 
This study will not involve genetic research or genetic testing. 
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Specimen Banking (Future Use and Storage)
We will store your specimens and information about you in a “biobank”, which is a library of 
information and specimens (tissue and blood) from many studies. These specimens and 
information cannot be linked to you. In the future, researchers can apply for permission to use 
the specimens and information for new studies to prevent, diagnose, or treat disease, including 
genetic research. Your specimens and information may be kept for a long time, perhaps longer 
than 50 years. If you agree to the future use, some of your de-identified genetic and health 
information (not linked to you) may be placed into one or more scientific databases. These may 
include databases maintained by the federal government.
INITIAL ONE (1) OF THE FOLLOWING OPTIONS
_______ I consent to have my specimens and information about me used for future research 
studies.
_______ I do NOT consent to have my specimens and information about me used for future 
research studies. Information about me will be kept as long as required by regulations and 
institutional policy, but will not be used for future studies.
Will I be paid for being in this research study? 
You will not receive any payment or other compensation for taking part in this study.
Some researchers may develop tests, treatments or products that are worth money. You will not 
receive payment of any kind for your specimens and information or for any tests, treatments, 
products or other things of value that may result from the research.
Will it cost me anything to participate in this study? 
Taking part in this study will not involve added costs to you. If you are in the group receiving 
pembrolizumab plus radiotherapy, the pembrolizumab will be provided free of charge by the 
study sponsor (Merck Pharmaceuticals). Other treatments in this study are considered standard 
care and will be billed to your insurance company.
What will happen if I am injured because I took part in this study?
If you are injured as a result of this research, only immediate, essential, short-term medical 
treatment, as determined by the participating hospital or sponsoring company, will be available 
for the injury without charge to you personally.  

No monetary compensation will be offered.

You are not waiving any of your legal rights by signing this informed consent document.

In addition, the sponsor will provide reimbursement for the reasonable costs of medical
treatment.  
Immediately report any discomforts, problems or injuries you experience during the course of 
your participation in the study to Dr. Nitin Ohri at 718-920-7750. 
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What else do I have to do?

You must tell the research study doctor about any past and present diseases or allergies
you are aware of and about all medications you are taking including “over-the-counter”
remedies and nutritional supplements or herbs.

Drugs may cause a reaction that, if not treated promptly, could be life-threatening.
It is important that you report all symptoms, reactions and other complaints to the
research study doctor. 

If you think you have become pregnant, contact your research study doctor immediately.

If any other doctor recommends that you take any medicine, please inform him/her that
you are taking part in a research study. You should give the other doctor the research 
study doctor’s name and phone number.

You may carry out all your normal daily activities.
Confidentiality
We will keep your information confidential. Your research records will be kept confidential and 
your name will not be used in any written or verbal reports. Your information will be given a code 
number and separated from your name or any other information that could identify you. The 
form that links your name to the code number will be kept in a secure manner and only the 
investigator and study staff will have access to the file. All information will be kept in a secure 
manner and computer records will be password protected. Your study information and 
specimens will be kept as long as they are useful for this research.
Medical information collected during the research, such as test results, may be entered into your 
Montefiore electronic medical record and will be available to clinicians and other staff at 
Montefiore who provide care to you.
The only people who can see your research records are:

the research team and staff who work with them

the organization that funded the research, Merck Pharmaceuticals

groups that review research (the Einstein IRB, and the Office for Human Research
Protections, and the US Food and Drug Administration)
These people, who receive your health information, may not be required by privacy laws to 
protect it and may share your information with others without your permission, if permitted by 
laws governing them.  All of these groups have been asked to keep your information 
confidential.
Are there any risks to me? 
Radiation Risks
You will be receiving radiation as part of study treatment. You may have side effects while on 
study that are common with all radiation therapy treatment for lung cancer. If you are in the 
PembroRT cohort, you will receive a relatively short course of radiotherapy (4 weeks). If you are 
in the ChemoRT cohort, you will receive a standard radiotherapy course that may span 4-7 
weeks, at the discretion of your treating physicians. We are using a 4-week radiotherapy course 
in the PembroRT cohort because we believe that for patients receiving immunotherapy it will be 
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at least as safe and effective as the standard course (approximately 6 weeks). However, it is 
possible that the 4-week treatment may be less effective than a standard longer course.
Some of the side effects of radiation include:
Common side effects:

Difficulty, pain, or burning sensation when swallowing, which often is temporary

Tiredness, which is temporary

Tanning, redness of skin, and hair loss within the treatment area, which is temporary

Skin in treatment area may remain permanently dry, and chest hair may not grow back

Scarring in the lung, which sometimes causes collapse of the lung

Fluid collection in the lung sac
Less common side effects:

Cough and some difficulty in breathing (or shortness of breath) due to lung inflammation
or scarring, which may be severe at times

Irritation of the heart sac

Irritation of the heart muscle

Injury to the tube that carries food to your stomach

Injury to the tube that carries oxygen to your lungs

Bleeding from injury to the large blood vessels
Uncommon and Rare side effects:

Inflammation of the spinal cord

A second cancer caused by the radiation you receive
Risks to Women Who Are or May Become Pregnant
The effects of radiation and chemotherapy on an embryo or fetus (developing baby still in the 
womb), or on a breastfeeding infant, may be harmful. Because of these unknown risks, women 
cannot take part in this study if they are:

Pregnant

Trying to become pregnant

Breastfeeding or sharing breast milk
If you are a menopausal woman and have not had a menstrual period for the past 12 months or 
more, you will not need to have a pregnancy test. Also, you will not need to have a pregnancy 
test if you have had a hysterectomy (surgical removal of your uterus and/or ovaries). All other 
female subjects must have a negative pregnancy test before starting the study drug.
If you are sexually active and able to become pregnant, you must agree to use one of the birth 
control methods listed below. You must use birth control for the duration of the study.
Acceptable birth control methods for use in this study are:

Hormonal methods, such as birth control pills, patches, injections, vaginal ring, or
implants

Barrier methods (such as a condom or diaphragm) used with a spermicide (a foam,
cream, or gel that kills sperm)

Intrauterine device (IUD)

Abstinence (no sex)
IRB NUMBER: 2018-8945
IRB APPROVAL DATE: 6/9/2021
IRB EXPIRATION DATE: 6/8/2022


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Pembrolizumab Side Effects
The immunotherapy you will receive, pembrolizumab, is a standard treatment for metastatic 
lung cancer whose side effects have been studied carefully.  The strategy of giving 
pembrolizumab before and after radiotherapy is considered experimental, so the side effects of 
this combination cannot fully be predicted. Pembrolizumab treats cancer by working with your 
immune system. It can sometimes cause your immune system to attack normal organs and 
tissues in any area of your body and can affect the way they work. These problems can 
sometimes become serious or life-threatening.
Very common side effects seen in at least 20% of patients include:

Itching of the skin


Loose or watery stools
Common side effects seen in at least 10% and less than 20 % of patients include:

Joint pain

Fever

Back pain

Rash
Side effects seen in at least 1% and less than 10 % of patients include:

Low level of salt in the blood that may cause you to feel tired, confused, headache,
muscle cramps or sick to your stomach

Pain in your belly

Inflammation of the lungs so you may feel short of breath and cough. Rarely this might
lead to death

Inflammation of the bowels/gut that may cause pain in your belly with loose or watery
stools

Not enough thyroid hormone so you may feel tired, gain weight, feel cold, have
infrequent or hard stools

Too much thyroid hormone so you may feel anxious, angry, can’t sleep, weak, tremble,
sweat, tired, have loose and watery stools

Inflammation of the skin so you may have peeling of the skin, itching, skin redness

Loss of skin color

Dizziness or fainting (low blood pressure), flushing, rash, fever, shortness of breath or
sick to your stomach at the time of receiving your infusion or just after or pain at the site 
of infusion
Serious side effects seen in between 1% and 4% of patients include:

Inflammation of the lungs so you may feel short of breath and cough.  Rarely this might
lead to death

Inflammation of the bowels/gut that can cause pain in your belly with loose or watery 
stools

Fever
Serious side effects seen in 1% or less of patients include:

Inflammation of the skin so you may have widespread peeling of the skin, itching, skin
redness. More sever skin reactions may involve the inside of your mouth, the surface of 
your eyes, and genital areas, and/or may cause the top layer of your skin to peel from 
IRB NUMBER: 2018-8945
IRB APPROVAL DATE: 6/9/2021
IRB EXPIRATION DATE: 6/8/2022


Version 1.1, dated 08/6/2018
Page 8 of 11
all over your body which can cause severe infection.  Rarely these reactions lead to 
death.

Inflammation of the liver that may cause a poor appetite, feeling tired, mild fever, muscle
or joint aches, sick to your stomach and vomiting, pain in your belly, yellow eyes and
skin, and dark urine

Inflammation of the pituitary gland (a gland in the head) which may cause headaches,
sick to your stomach, changes in behavior, double vision, few to no menstrual cycles,
weakness, vomiting and dizziness or fainting.

Too much thyroid hormone so you may feel anxious, angry, can’t sleep, weak, tremble,
increased sweating, weight loss, hair loss, tired, have loose and watery stools

Not enough thyroid hormone so you may feel tired, gain weight, feel cold, have
infrequent or hard bowel movements

Inflammation of the kidney so you may pass less urine or have cloudy or bloody urine,
swelling and low back pain

Inflammation of the muscles so you may feel weak or pain in the muscles

Inflammation of the pancreas (a gland in your abdomen that controls sugar levels) so
you may have severe pain in the top part of your belly that may move to the back, sick 
to your stomach, and vomiting that gets worse when you eat

Inflammation of the eye so you may have redness of the eye, blurred vision, sensitive to
light, have eye pain, see floaters or have headaches

Adrenal glands (glands on top of the kidneys) not making enough hormone causing
tiredness, weight loss, muscle weakness, feeling faint, joint, muscle and abdominal 
aches, nausea, vomiting, loose or watery stools, fever, salt craving, and sometimes 
darkening of the skin like a suntan

Inflammation of the nerves that may cause pain, weakness, or tingling in the hands and
feet, and may spread to the legs, arms and upper body leading to severe muscle 
weakness and possible temporary paralysis

Too much sugar in your blood (diabetes), so you may feel thirsty, and are likely to need
regular insulin shots

Inflammation of the middle layer of your heart wall (myocarditis) that may cause your
heart to have difficulty pumping blood throughout your body, which can cause chest 
pain, shortness of breath and swelling of the legs. You may experience a fast or 
irregular heartbeat that may cause you dizziness or fainting. Sometimes this condition 
can lead to death.

Dizziness or fainting (low blood pressure), flushing, rash, fever, shortness of breath or
sick to your stomach at the time of receiving your infusion (IV) or just after, or pain at the 
site of infusion
Chemotherapy Side Effects
Common side effects could include:

Low white blood cell counts, which may result in serious or even fatal infections

Low red blood cell counts, which may result in tiredness or weakness

Low platelet counts, which may result in bruising or bleeding

Nausea

Vomiting

Loss of appetite

Diarrhea
IRB NUMBER: 2018-8945
IRB APPROVAL DATE: 6/9/2021
IRB EXPIRATION DATE: 6/8/2022
O


Version 1.1, dated 08/6/2018
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
Fatigue

Hair loss

Muscle weakness

Joint and muscle aches

Lightheadedness

Headaches

Numbness in the hands and feet

Changes in blood pressure

Skin irritation at site of drug injection
Less likely side effects could include:

Sores in mouth and/or throat

Alterations in taste

Allergic reaction (including flushing, skin rash, changes in blood pressure and/or
difficulty breathing)

Stomach cramps

Loss of blood supply to the intestines, which may require surgery

Inflammation of the pancreas (an organ in the abdomen), which may result in abdominal
pain and/or weight loss

Dizziness and shooting back pain when bending your neck forward

Confusion

Blurred vision or a sensation of flashing light

Mood change

Kidney damage

Liver damage and/or failure

Seizures

Fainting

Irregular heartbeat

Heart attack
Questionnaire
You may feel uncomfortable answering questions about your current health or overall quality of 
life. You can choose not to answer questions that make you feel uncomfortable.
Blood Draw
Rarely, the vein where we insert the needle will become sore or red. Sometimes, a bruise may 
develop. Very rarely, fainting may occur. 
New Findings
If we learn any significant new findings during the study that might influence your decision to 
participate, we will contact you and explain them.
Unknown Risks
We have described all the risks we know. However, because this is research, there a possibility 
that you will have a reaction that we do not know about yet and is not expected.
IRB NUMBER: 2018-8945
IRB APPROVAL DATE: 6/9/2021
IRB EXPIRATION DATE: 6/8/2022


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Are there possible benefits to me? 
There is no guarantee that you will benefit from being a subject in this study. While doctors hope 
that the schedule of immunotherapy and radiotherapy will be more useful against cancer 
compared to the usual treatment, there is no proof of this yet. The information from this study 
may help doctors learn more about the effectiveness of this approach as a treatment for cancer. 
This information could help future cancer patients. 
What choices do I have other than participating in this study?
You can refuse to participate in the study. If you decide not to participate, the medical care 
providers at this facility will still give you all of the standard care and treatment that is 
appropriate for you.
Are there any consequences to me if I decide to stop participating in this study?
No. If you decide to take part, you are free to stop participating at any time without giving a 
reason. This will not affect your care and you will continue to be treated at this facility. However, 
some of the information may have already been entered into the study and that will not be 
removed. The researchers and the sponsor may continue to use and share the information they 
have already collected.
To revoke (take back) your consent and authorization, you must contact the Principal 
Investigator in writing at the address on page 1 of this form. However, you may first call or 
speak to the Principal Investigator and he will stop collecting new information about you.  If you 
take back your consent and authorization, you will not be allowed to continue to participate in 
this research study. 
Can the study end my participation early?
Your participation could end if the investigator, the study sponsor, the U.S. Food and Drug 
Administration, or the committee that oversees this study to safeguard subjects’ rights stops the 
study earlier than expected. 
IRB NUMBER: 2018-8945
IRB APPROVAL DATE: 6/9/2021
IRB EXPIRATION DATE: 6/8/2022


Version 1.1, dated 08/6/2018
Page 11 of 11
CONSENT TO PARTICIPATE
I have read the consent form and I understand that it is up to me whether or not I participate. I 
know enough about the purpose, methods, risks and benefits of the research study to decide 
that I want to take part in it. I understand that I am not waiving any of my legal rights by signing 
this informed consent document. I will be given a signed copy of this consent form.
Printed name of participant
Signature of participant
Date
Time
Printed name of the person 
conducting the consent 
process
Signature
Date
Time
IRB NUMBER: 2018-8945
IRB APPROVAL DATE: 6/9/2021
IRB EXPIRATION DATE: 6/8/2022